Having witnessed the devastating impact of stigma on patients with mental illness throughout my psychiatric career, I am fed up and disgusted with this malevolent scourge.

I regard the stigma that engulfs neuropsychiatric disorders as a malignancy that mutilates patients’ souls and hastens their mortality.

Stigma is hate speech

How would you feel if you had a serious medical illness, a disabling brain disorder such as schizophrenia, depression, or anxiety, and people refer to you with pejorative and insulting terms such as crazy, deranged, lunatic, unhinged, nutty, insane, wacky, berserk, cuckoo, bonkers, flaky, screwball, or unglued? This is hate speech generated by stigma against people with mental illness. Individuals with heart disease, cancer, or diabetes never get called such disgraceful and stigmatizing terms that shame, stain, besmirch, and scar them, which happens daily to persons with psychiatric brain disorders.

The damage and harm of the discriminatory stigma on our patients is multifaceted. It is painful, detrimental, pernicious, and deleterious. It is corrosive to their spirits, crippling to their self-image, and subversive to their self-confidence. Hate speech is not simply words, but a menacing weapon that assaults the core humanity of medically ill psychiatric patients.

Although hate speech is punishable by law, there are rarely any legal actions against those who hurl hate speech at psychiatric patients every day. Society has institutionalized the stigma of mental illness and takes it in stride instead of recognizing it as an illegal, harmful act.

Long before the stresses of the COVID-19 pandemic, 43% of the population had been shown to experience a diagnosable psychiatric disorder over the course of their life.¹ Thus, tens of millions of people are burdened by stigma and the hate speech associated with it. This is directly related to massive ignorance about mental illness being the result of a neurobiological condition due to either genetic or intrauterine adverse events that disrupt brain development. Delusions and hallucinations are symptoms of a malfunctioning brain, depression is not a sign of personal weakness, anxiety is the most prevalent mental disorder in the world, and obsessive-compulsive disorder (OCD) is not odd behavior but the result of dysfunction of neural circuits. Correcting public misperceptions about psychiatric brain disorders can mitigate stigma, but it has yet to happen.

Stigma is a hate crime

Stigma can accelerate physical death and premature mortality. Many studies have confirmed that persons with schizophrenia do not receive basic primary care treatments for the life-shortening medical conditions that often afflict them, such as diabetes, dyslipidemia, and hypertension.² Stigma is responsible for a significant disparity of medical^3-5 and intensive care⁶ among individuals with mental illness compared to the general population. It’s no wonder most psychiatric disorders are associated with accelerated mortality.⁷ A recent study during the pandemic by Balasuriya et al⁸ reported that patients with depression had poor access to care. Stigma interferes with or delays necessary medical care, leading to clinical deterioration and unnecessary, preventable death. Stigma shortens life and is a hate crime.

Continue to: The extremely high suicide rates...

The extremely high suicide rates among individuals with serious mental illness, who live under the oppressiveness of stigma, is another example of how stigma is a hate crime that can cause patients with psychiatric disorders to give up and end their lives. Zaheer et al⁹ found that young patients with schizophrenia had an astronomical suicide rate compared to the general population (1 in 52 in individuals with schizophrenia, compared to 12 in 100,000 in the general population, roughly a 200-fold increase!). This is clearly a consequence of stigma and discrimination,¹⁰ which leads to demoralization, shame, loneliness, distress, and hopelessness. Stigma can be fatal, and that makes it a hate crime.

Stigma also limits vocational opportunities for individuals with mental illness. They are either not hired, or quickly fired. Even highly educated professionals such as physicians, nurses, lawyers, or teachers can lose their jobs if they divulge a history of a psychiatric disorder or alcohol or substance abuse, regardless of whether they are receiving treatment and are medically in remission. Even highly qualified politicians have been deemed “ineligible” for higher office if they disclose a history of psychiatric treatment. Stigma is loaded with outrageous discrimination that deprives our patients of “the pursuit of happiness,” a fundamental constitutional right.

Stigma surrounding the mental health professions

Stigma also engulfs mental health professionals, simply because they deal with psychiatric patients every day. In a classic article titled “The Enigma of Stigma,”¹¹ Dr. Paul Fink, past president of the American Psychiatric Association (1988-1989), described how psychiatrists are perceived as “different” from other physicians by the public and by the media. He said psychiatrists are tarred by the same brush as their patients as “undesirables” in society. And movies such as Psycho and One Flew Over the Cuckoo’s Nest reinforce the stigma against both psychiatric patients and the psychiatrists and nurses who treat them. The health care system that carves out “behavioral health” from the umbrella of “medical care” further accentuates the stigma by portraying the “separateness” of psychiatry, a genuine medical specialty, from its fellow medical disciplines. This becomes fodder for the antipsychiatry movement at every turn and can even lead to questioning the existence of mental illness, as Thomas Szasz¹² did by declaring that mental illness is a myth and describing psychiatry as “the science of lies.” No other medical specialty endures abuse and insults like psychiatry, and that’s a direct result of stigma.

Extinguishing stigma is a societal imperative

So what can be done to squelch stigma and defeat it once and for all, so that psychiatric patients can be treated with dignity and compassion, like people with cancer, heart attacks, diabetes, or brain tumors? The pandemic, terrible as it has been for the entire world, did have the silver lining of raising awareness about the ubiquity of psychiatric symptoms, such as anxiety and depression, across all ages, genders, educational and religious backgrounds, and socioeconomic classes. But there should also be a robust legal battle against the damaging effects of stigma. There are laws to sanction and penalize hate speech and hate crimes that must be implemented when stigma is documented. There are also parity laws, but they have no teeth and have not ameliorated the insurance discrepancies and economic burden of psychiatric disorders. A bold step would be to reclassify serious psychiatric brain disorders (schizophrenia, bipolar disorder, major depressive disorder, OCD, attention-deficit/hyperactivity disorder, generalized anxiety disorder/panic attacks, and borderline personality disorder) as neurologic disorders, which would automatically give patients with these disorders broad access to medical care, which happened when autism was reclassified as a neurologic disorder. Finally, a much more intensive public education must be disseminated about the neurobiological etiologies, brain structure, and function in psychiatric disorders, and the psychiatric symptoms associated with all neurologic disorders. Regrettably, empathy can be difficult to teach.

Stigma is hate speech and a hate crime. It must be permanently eliminated by effective laws and by erasing the widespread ignorance about the medical and neurologic roots of mental disorders, and by emphasizing the fact that they are as treatable as other general medical conditions.

Having witnessed the devastating impact of stigma on patients with mental illness throughout my psychiatric career, I am fed up and disgusted with this malevolent scourge.

I regard the stigma that engulfs neuropsychiatric disorders as a malignancy that mutilates patients’ souls and hastens their mortality.

Stigma is hate speech

How would you feel if you had a serious medical illness, a disabling brain disorder such as schizophrenia, depression, or anxiety, and people refer to you with pejorative and insulting terms such as crazy, deranged, lunatic, unhinged, nutty, insane, wacky, berserk, cuckoo, bonkers, flaky, screwball, or unglued? This is hate speech generated by stigma against people with mental illness. Individuals with heart disease, cancer, or diabetes never get called such disgraceful and stigmatizing terms that shame, stain, besmirch, and scar them, which happens daily to persons with psychiatric brain disorders.

The damage and harm of the discriminatory stigma on our patients is multifaceted. It is painful, detrimental, pernicious, and deleterious. It is corrosive to their spirits, crippling to their self-image, and subversive to their self-confidence. Hate speech is not simply words, but a menacing weapon that assaults the core humanity of medically ill psychiatric patients.

Although hate speech is punishable by law, there are rarely any legal actions against those who hurl hate speech at psychiatric patients every day. Society has institutionalized the stigma of mental illness and takes it in stride instead of recognizing it as an illegal, harmful act.

Long before the stresses of the COVID-19 pandemic, 43% of the population had been shown to experience a diagnosable psychiatric disorder over the course of their life.¹ Thus, tens of millions of people are burdened by stigma and the hate speech associated with it. This is directly related to massive ignorance about mental illness being the result of a neurobiological condition due to either genetic or intrauterine adverse events that disrupt brain development. Delusions and hallucinations are symptoms of a malfunctioning brain, depression is not a sign of personal weakness, anxiety is the most prevalent mental disorder in the world, and obsessive-compulsive disorder (OCD) is not odd behavior but the result of dysfunction of neural circuits. Correcting public misperceptions about psychiatric brain disorders can mitigate stigma, but it has yet to happen.

Stigma is a hate crime

Stigma can accelerate physical death and premature mortality. Many studies have confirmed that persons with schizophrenia do not receive basic primary care treatments for the life-shortening medical conditions that often afflict them, such as diabetes, dyslipidemia, and hypertension.² Stigma is responsible for a significant disparity of medical^3-5 and intensive care⁶ among individuals with mental illness compared to the general population. It’s no wonder most psychiatric disorders are associated with accelerated mortality.⁷ A recent study during the pandemic by Balasuriya et al⁸ reported that patients with depression had poor access to care. Stigma interferes with or delays necessary medical care, leading to clinical deterioration and unnecessary, preventable death. Stigma shortens life and is a hate crime.

Continue to: The extremely high suicide rates...

The extremely high suicide rates among individuals with serious mental illness, who live under the oppressiveness of stigma, is another example of how stigma is a hate crime that can cause patients with psychiatric disorders to give up and end their lives. Zaheer et al⁹ found that young patients with schizophrenia had an astronomical suicide rate compared to the general population (1 in 52 in individuals with schizophrenia, compared to 12 in 100,000 in the general population, roughly a 200-fold increase!). This is clearly a consequence of stigma and discrimination,¹⁰ which leads to demoralization, shame, loneliness, distress, and hopelessness. Stigma can be fatal, and that makes it a hate crime.

Stigma also limits vocational opportunities for individuals with mental illness. They are either not hired, or quickly fired. Even highly educated professionals such as physicians, nurses, lawyers, or teachers can lose their jobs if they divulge a history of a psychiatric disorder or alcohol or substance abuse, regardless of whether they are receiving treatment and are medically in remission. Even highly qualified politicians have been deemed “ineligible” for higher office if they disclose a history of psychiatric treatment. Stigma is loaded with outrageous discrimination that deprives our patients of “the pursuit of happiness,” a fundamental constitutional right.

Stigma surrounding the mental health professions

Stigma also engulfs mental health professionals, simply because they deal with psychiatric patients every day. In a classic article titled “The Enigma of Stigma,”¹¹ Dr. Paul Fink, past president of the American Psychiatric Association (1988-1989), described how psychiatrists are perceived as “different” from other physicians by the public and by the media. He said psychiatrists are tarred by the same brush as their patients as “undesirables” in society. And movies such as Psycho and One Flew Over the Cuckoo’s Nest reinforce the stigma against both psychiatric patients and the psychiatrists and nurses who treat them. The health care system that carves out “behavioral health” from the umbrella of “medical care” further accentuates the stigma by portraying the “separateness” of psychiatry, a genuine medical specialty, from its fellow medical disciplines. This becomes fodder for the antipsychiatry movement at every turn and can even lead to questioning the existence of mental illness, as Thomas Szasz¹² did by declaring that mental illness is a myth and describing psychiatry as “the science of lies.” No other medical specialty endures abuse and insults like psychiatry, and that’s a direct result of stigma.

Extinguishing stigma is a societal imperative

So what can be done to squelch stigma and defeat it once and for all, so that psychiatric patients can be treated with dignity and compassion, like people with cancer, heart attacks, diabetes, or brain tumors? The pandemic, terrible as it has been for the entire world, did have the silver lining of raising awareness about the ubiquity of psychiatric symptoms, such as anxiety and depression, across all ages, genders, educational and religious backgrounds, and socioeconomic classes. But there should also be a robust legal battle against the damaging effects of stigma. There are laws to sanction and penalize hate speech and hate crimes that must be implemented when stigma is documented. There are also parity laws, but they have no teeth and have not ameliorated the insurance discrepancies and economic burden of psychiatric disorders. A bold step would be to reclassify serious psychiatric brain disorders (schizophrenia, bipolar disorder, major depressive disorder, OCD, attention-deficit/hyperactivity disorder, generalized anxiety disorder/panic attacks, and borderline personality disorder) as neurologic disorders, which would automatically give patients with these disorders broad access to medical care, which happened when autism was reclassified as a neurologic disorder. Finally, a much more intensive public education must be disseminated about the neurobiological etiologies, brain structure, and function in psychiatric disorders, and the psychiatric symptoms associated with all neurologic disorders. Regrettably, empathy can be difficult to teach.

Stigma is hate speech and a hate crime. It must be permanently eliminated by effective laws and by erasing the widespread ignorance about the medical and neurologic roots of mental disorders, and by emphasizing the fact that they are as treatable as other general medical conditions.

Having witnessed the devastating impact of stigma on patients with mental illness throughout my psychiatric career, I am fed up and disgusted with this malevolent scourge.

I regard the stigma that engulfs neuropsychiatric disorders as a malignancy that mutilates patients’ souls and hastens their mortality.

Stigma is hate speech

How would you feel if you had a serious medical illness, a disabling brain disorder such as schizophrenia, depression, or anxiety, and people refer to you with pejorative and insulting terms such as crazy, deranged, lunatic, unhinged, nutty, insane, wacky, berserk, cuckoo, bonkers, flaky, screwball, or unglued? This is hate speech generated by stigma against people with mental illness. Individuals with heart disease, cancer, or diabetes never get called such disgraceful and stigmatizing terms that shame, stain, besmirch, and scar them, which happens daily to persons with psychiatric brain disorders.

The damage and harm of the discriminatory stigma on our patients is multifaceted. It is painful, detrimental, pernicious, and deleterious. It is corrosive to their spirits, crippling to their self-image, and subversive to their self-confidence. Hate speech is not simply words, but a menacing weapon that assaults the core humanity of medically ill psychiatric patients.

Although hate speech is punishable by law, there are rarely any legal actions against those who hurl hate speech at psychiatric patients every day. Society has institutionalized the stigma of mental illness and takes it in stride instead of recognizing it as an illegal, harmful act.

Long before the stresses of the COVID-19 pandemic, 43% of the population had been shown to experience a diagnosable psychiatric disorder over the course of their life.¹ Thus, tens of millions of people are burdened by stigma and the hate speech associated with it. This is directly related to massive ignorance about mental illness being the result of a neurobiological condition due to either genetic or intrauterine adverse events that disrupt brain development. Delusions and hallucinations are symptoms of a malfunctioning brain, depression is not a sign of personal weakness, anxiety is the most prevalent mental disorder in the world, and obsessive-compulsive disorder (OCD) is not odd behavior but the result of dysfunction of neural circuits. Correcting public misperceptions about psychiatric brain disorders can mitigate stigma, but it has yet to happen.

Stigma is a hate crime

Stigma can accelerate physical death and premature mortality. Many studies have confirmed that persons with schizophrenia do not receive basic primary care treatments for the life-shortening medical conditions that often afflict them, such as diabetes, dyslipidemia, and hypertension.² Stigma is responsible for a significant disparity of medical^3-5 and intensive care⁶ among individuals with mental illness compared to the general population. It’s no wonder most psychiatric disorders are associated with accelerated mortality.⁷ A recent study during the pandemic by Balasuriya et al⁸ reported that patients with depression had poor access to care. Stigma interferes with or delays necessary medical care, leading to clinical deterioration and unnecessary, preventable death. Stigma shortens life and is a hate crime.

Continue to: The extremely high suicide rates...

The extremely high suicide rates among individuals with serious mental illness, who live under the oppressiveness of stigma, is another example of how stigma is a hate crime that can cause patients with psychiatric disorders to give up and end their lives. Zaheer et al⁹ found that young patients with schizophrenia had an astronomical suicide rate compared to the general population (1 in 52 in individuals with schizophrenia, compared to 12 in 100,000 in the general population, roughly a 200-fold increase!). This is clearly a consequence of stigma and discrimination,¹⁰ which leads to demoralization, shame, loneliness, distress, and hopelessness. Stigma can be fatal, and that makes it a hate crime.

Stigma also limits vocational opportunities for individuals with mental illness. They are either not hired, or quickly fired. Even highly educated professionals such as physicians, nurses, lawyers, or teachers can lose their jobs if they divulge a history of a psychiatric disorder or alcohol or substance abuse, regardless of whether they are receiving treatment and are medically in remission. Even highly qualified politicians have been deemed “ineligible” for higher office if they disclose a history of psychiatric treatment. Stigma is loaded with outrageous discrimination that deprives our patients of “the pursuit of happiness,” a fundamental constitutional right.

Stigma surrounding the mental health professions

Stigma also engulfs mental health professionals, simply because they deal with psychiatric patients every day. In a classic article titled “The Enigma of Stigma,”¹¹ Dr. Paul Fink, past president of the American Psychiatric Association (1988-1989), described how psychiatrists are perceived as “different” from other physicians by the public and by the media. He said psychiatrists are tarred by the same brush as their patients as “undesirables” in society. And movies such as Psycho and One Flew Over the Cuckoo’s Nest reinforce the stigma against both psychiatric patients and the psychiatrists and nurses who treat them. The health care system that carves out “behavioral health” from the umbrella of “medical care” further accentuates the stigma by portraying the “separateness” of psychiatry, a genuine medical specialty, from its fellow medical disciplines. This becomes fodder for the antipsychiatry movement at every turn and can even lead to questioning the existence of mental illness, as Thomas Szasz¹² did by declaring that mental illness is a myth and describing psychiatry as “the science of lies.” No other medical specialty endures abuse and insults like psychiatry, and that’s a direct result of stigma.

Extinguishing stigma is a societal imperative

So what can be done to squelch stigma and defeat it once and for all, so that psychiatric patients can be treated with dignity and compassion, like people with cancer, heart attacks, diabetes, or brain tumors? The pandemic, terrible as it has been for the entire world, did have the silver lining of raising awareness about the ubiquity of psychiatric symptoms, such as anxiety and depression, across all ages, genders, educational and religious backgrounds, and socioeconomic classes. But there should also be a robust legal battle against the damaging effects of stigma. There are laws to sanction and penalize hate speech and hate crimes that must be implemented when stigma is documented. There are also parity laws, but they have no teeth and have not ameliorated the insurance discrepancies and economic burden of psychiatric disorders. A bold step would be to reclassify serious psychiatric brain disorders (schizophrenia, bipolar disorder, major depressive disorder, OCD, attention-deficit/hyperactivity disorder, generalized anxiety disorder/panic attacks, and borderline personality disorder) as neurologic disorders, which would automatically give patients with these disorders broad access to medical care, which happened when autism was reclassified as a neurologic disorder. Finally, a much more intensive public education must be disseminated about the neurobiological etiologies, brain structure, and function in psychiatric disorders, and the psychiatric symptoms associated with all neurologic disorders. Regrettably, empathy can be difficult to teach.

Stigma is hate speech and a hate crime. It must be permanently eliminated by effective laws and by erasing the widespread ignorance about the medical and neurologic roots of mental disorders, and by emphasizing the fact that they are as treatable as other general medical conditions.

Twitter, a microblogging and social networking service, has become a “go-to’” for conversations, updates, breaking news, and sharing the more mundane aspects of our lives. Tweets, which were lengthened from 140 to 280 characters in 2017, rapidly communicate and disseminate information to a wide audience. Generally, tweets are visible to everyone, though users can mute and block other users from viewing their tweets. Spikes in tweets and tweeting frequency reflect hyper-current events: the last minutes of the Super Bowl, certification of an election, or a new movie release. In fact, social scientists have analyzed tweet frequencies to examine the impact of local and national events. However, few are aware that like celebrities, politicians, influencers, and ordinary citizens, the human brain also tweets.

In this article, we describe the components of the brain’s “Twitter” system, how it works, and how it might someday be used to improve the diagnosis and treatment of psychiatric disorders.

Brain tweets

The brain’s Twitter system involves extracellular vesicles (EVs), tiny (<1 µm) membrane-bound vesicles that are released from neurons, glia, and other neuronal cells (Table). These EVs cross the blood-brain barrier and facilitate cell-to-cell communication within and among tissues (Figure 1).

First described in the 1980s,¹ EVs are secreted by a diverse array of cells: mast cells reticulocytes, epithelial cells, immune cells, neurons, glia, and oligodendrocytes. Like tweets, EVs rapidly disseminate packets of information throughout the brain and body and direct the molecular activity of recipient cells in both health and disease. These “brain tweets” contain short, circumscribed messages, and the characters are the EV cargos: RNAs, proteins, lipids, and metabolites. Like a Twitter feed, EVs cast a wide communication net across the body, much of which finds its way to the blood. As neuroscientists, we can follow these tweets by isolating tissue-derived EVs in plasma and examining their surface molecules and cargo. By following this Twitter feed, we can tap into important molecular communications and identify “trending” (evolving) pathological processes, and perhaps use the brain Twitter feed to improve diagnosis and treatments. We can pinpoint, in the blood, signals from CNS processes, down to the level of identifying EV cargos from specific brain cell types.

Within the CNS, EVs are secreted by neurons, where they may modulate synaptic plasticity and transfer molecular cargo among neurons. EVs also facilitate communication between neurons and glia, maintain homeostasis, trigger neuroprotective processes, and even regulate synaptic transmission.²

What’s in a brain tweet?

To discuss what’s in a brain tweet, we must first understand how a brain tweet is composed. EVs are pinched off from membranes of intercellular structures (eg, golgi or endoplasmic reticulum) or pinched off directly from cell membranes, where upon release they become EVs. There is a complex cellular machinery that transports what ultimately becomes an EV to the cell membrane.³ EVs contain unique mixtures of lipids, proteins, and nucleic acids (eg, microRNA [miRNA], mRNA, and noncoding RNA).⁴ To date, nearly 10,000 proteins, 11,000 lipids, 3,500 mRNAs, and 3,000 miRNAs have been identified as cargos in extracellular vesicles (Figure 1). Similar to how the release of EVs is dependent on complex intracellular machinery, the packing of these contents into what will become the EV involves a parallel set of complex machinery that is largely directed by endosomal sorting complexes required for transport (ESCRT) proteins.⁵ Of interest, when viruses attack cells, they hijack this EV packaging system to package and release new viruses. EVs vary in size, shape, and density; this variation is related to the cell origin, among other things. EVs also differ in their membrane lipid composition and in terms of transmembrane proteins as well as the proteins that facilitate EV binding to target cells (Figure 2).⁶ Ultimately, these exosomes are taken up by the recipient cells.

EV-facilitated neuron-to-neuron tweets have been implicated in neuronal growth and differentiation.⁷ EV-driven communication between cells also can decrease dendrite growth and can trigger microglia to prune synapses.⁸ EVs from glial cells may promote neuronal integrity, directly boost presynaptic glutamate release,⁹ or even, through miRNAs, change the expression of glutamate receptors.¹⁰ EVs from astrocytes transport proteins that enable neuronal repair, while EVs from microglia regulate neuronal homeostasis. EV cargos—lipids, proteins, and miRNAs—from neurons modify signal transduction and protein expression in recipient cells. Taken together, data suggest that EVs facilitate anterograde and retrograde transfer of signals across synapses,^7,11 a putative mechanism for driving synaptic plasticity,¹² which is a process implicated in the therapeutic efficacy of psychotropic medications and psychotherapies.

Continue to: #Targets and #neuron

 

 

#Targets and #neuron

Adding a hashtag to a tweet links it to other tweets, just as membrane features of EVs direct how EVs link to target cells. When these EVs bind to target cells, they fuse and release their cargo into the target cell (Figure 2). These directed cargo—whether mRNA, proteins, or other molecules—can direct the recipient cell to modify its firing rate (in the case of neurons), alter transmitter release, and increase or decrease expression of various genes. The targeting process is complex, and our understanding of this process is evolving. Briefly, integrin, lipid composition, glycans (eg, polysaccharides), and tetraspanin components of EVs influence their affinity for specific target cells.¹³ Recently, we have been able to read these hashtags and isolate cell-specific, neuron-derived EVs. Immunoadsorption techniques that leverage antibodies against L1 cell adhesion molecule protein (L1CAM(+)), primarily expressed in neurons, can identify neuronally-derived EVs (Figure 3). The specific EVs contain cargos of neuronal origin and provide a “window” into molecular processes in the brain by way of the blood (or other peripheral fluids). In following the neuronal tweets, we can follow molecular measures of important brain molecules in biofluids outside the CNS, including saliva and potentially urine (Figure 1B and 1C). In following these specific neuronal Twitter feeds, we can gain critical insights into specific brain processes.

EVs in psychiatric disorders

EVs are implicated in neuroinflammation,¹⁴ neurogenesis, synaptic plasticity, and epigenetic regulation—all processes that are involved in the pathophysiology of psychiatric disorders. Postmortem research suggests that EVs in the brain carry pro­inflammatory molecules from microglia, as well as secretions of regulatory miRNA that are responsible for synaptic plasticity and dendritic growth in depression, bipolar disorder, schizophrenia, and addiction. In addition, second-generation antipsychotics change the composition of EV cargos in the brain, altering their RNA, protein, and lipid content, often reflecting profound changes in gene expression in various cells in the CNS. In our lab, we have identified several molecules in plasma EVs, both lipids and miRNA, that can potentially predict the response to treatment of pediatric anxiety with selective serotonin reuptake inhibitors as well as opiate addiction.¹⁵

Further, given our increasing understanding of the way in which EV cargo reflects neuronal physiology as well as the potential pathophysiologic states of cells (including neurons), studying EVs’ molecular content can identify molecular messages—in blood—that are derived from the neurons in the brain. Having the tools to examine molecular brain regulators or other markers of disease progression (eg, beta amyloid) or brain health (eg, brain-derived neurotrophic factor) may advance our understanding and treatment of psychiatric disorders and create opportunities for precision medicine driven by biological rather than ethnologic and phenomenological markers. Whereas in the not-too-distant past molecular processes in the brain were only accessible through invasive measures—such as brain biopsy or through a lumbar puncture—studying CNS-derived EVs in blood offers us an opportunity to gain access to brain molecular signatures with relative ease. Often, these molecular signatures predate clinical changes by years or months, allowing us the prospects of potentially identifying and treating CNS disorders early on, possibly even before the onset of symptoms.

Therapeutic use of the Twitter feed

EV may be used to alter brain receptor structures in a targeted way to facilitate treatment of various psychiatric disorders. One example is a proof-of-concept study in mice in which administration of artificially manufactured EVs led to a decrease of opioid receptor mu.¹⁶ This was done by constructing EVs that carry neuron-specific rabies viral glycoprotein (RVG) peptide on the membrane surface to deliver mu opioid receptor small interfering RNA into the brain. This resulted in downregulation of mu opioid receptor and a decrease in morphine relapse.¹⁶

Additional ways in which EVs can be used therapeutically is via targeted drug delivery CNS methods. EVs may represent the next generation of treatment by allowing not only medication transport into the CNS,¹⁷ but also by facilitating directed CNS transport. What if we could use a molecular hashtag to send a dopaminergic agent to the substantia nigra of a patient with Parkinson disease but avoid sending that same treatment to the limbic cortex, where it might produce perceptual disturbances or hallucinations? In the future, EVs may help clinicians access the CNS, which is traditionally restricted by the blood brain barrier, and make it easier to achieve CNS concentrations of medications¹³ while decreasing medication exposure in other parts of the body. The therapeutic potential of EVs for medication delivery and regenerative medicine is awe-inspiring. Several studies have modified EVs to improve their therapeutic properties and to target delivery to specific cells¹³ by leveraging EV surface markers.¹⁸

Future directions for EVs

A better understanding of neuron-derived EVs may eventually help us abandon nosology-based diagnostic criteria and adopt molecular-based diagnostic approaches in psychiatry. It may allow us to consider a molecular synaptic etiology of psychiatric disorders, and diagnose patients based on synaptic pathology utilizing “neuron-derived EV liquid biopsies.” Such a shift would align psychiatry with other medical fields in which diagnosis and treatment are often based on biopsies and blood tests. Because proteins in EVs often exist in their native states, intact with their posttranslational modifications, they provide a window into testing their actual in vivo functioning. EVs have an immense potential to revolutionize psychiatric diagnosis, facilitate precision treatment, predict response, and discover much-needed novel therapeutics.

Bottom Line

Much like a tweet, extracellular vesicles (EVs) encode short messages that are transmit ted efficiently throughout the CNS and body. They may represent a reservoir for CNS-specific biomarkers that can be is olated from plasma to guide psychiatric diagnosis and treatment. EVs represent a new frontier in the molecular study of psychiatric illness.

Related Resources

Vesiclepedia. www.microvesicles.org/

Twitter, a microblogging and social networking service, has become a “go-to’” for conversations, updates, breaking news, and sharing the more mundane aspects of our lives. Tweets, which were lengthened from 140 to 280 characters in 2017, rapidly communicate and disseminate information to a wide audience. Generally, tweets are visible to everyone, though users can mute and block other users from viewing their tweets. Spikes in tweets and tweeting frequency reflect hyper-current events: the last minutes of the Super Bowl, certification of an election, or a new movie release. In fact, social scientists have analyzed tweet frequencies to examine the impact of local and national events. However, few are aware that like celebrities, politicians, influencers, and ordinary citizens, the human brain also tweets.

In this article, we describe the components of the brain’s “Twitter” system, how it works, and how it might someday be used to improve the diagnosis and treatment of psychiatric disorders.

Brain tweets

The brain’s Twitter system involves extracellular vesicles (EVs), tiny (<1 µm) membrane-bound vesicles that are released from neurons, glia, and other neuronal cells (Table). These EVs cross the blood-brain barrier and facilitate cell-to-cell communication within and among tissues (Figure 1).

First described in the 1980s,¹ EVs are secreted by a diverse array of cells: mast cells reticulocytes, epithelial cells, immune cells, neurons, glia, and oligodendrocytes. Like tweets, EVs rapidly disseminate packets of information throughout the brain and body and direct the molecular activity of recipient cells in both health and disease. These “brain tweets” contain short, circumscribed messages, and the characters are the EV cargos: RNAs, proteins, lipids, and metabolites. Like a Twitter feed, EVs cast a wide communication net across the body, much of which finds its way to the blood. As neuroscientists, we can follow these tweets by isolating tissue-derived EVs in plasma and examining their surface molecules and cargo. By following this Twitter feed, we can tap into important molecular communications and identify “trending” (evolving) pathological processes, and perhaps use the brain Twitter feed to improve diagnosis and treatments. We can pinpoint, in the blood, signals from CNS processes, down to the level of identifying EV cargos from specific brain cell types.

Within the CNS, EVs are secreted by neurons, where they may modulate synaptic plasticity and transfer molecular cargo among neurons. EVs also facilitate communication between neurons and glia, maintain homeostasis, trigger neuroprotective processes, and even regulate synaptic transmission.²

What’s in a brain tweet?

To discuss what’s in a brain tweet, we must first understand how a brain tweet is composed. EVs are pinched off from membranes of intercellular structures (eg, golgi or endoplasmic reticulum) or pinched off directly from cell membranes, where upon release they become EVs. There is a complex cellular machinery that transports what ultimately becomes an EV to the cell membrane.³ EVs contain unique mixtures of lipids, proteins, and nucleic acids (eg, microRNA [miRNA], mRNA, and noncoding RNA).⁴ To date, nearly 10,000 proteins, 11,000 lipids, 3,500 mRNAs, and 3,000 miRNAs have been identified as cargos in extracellular vesicles (Figure 1). Similar to how the release of EVs is dependent on complex intracellular machinery, the packing of these contents into what will become the EV involves a parallel set of complex machinery that is largely directed by endosomal sorting complexes required for transport (ESCRT) proteins.⁵ Of interest, when viruses attack cells, they hijack this EV packaging system to package and release new viruses. EVs vary in size, shape, and density; this variation is related to the cell origin, among other things. EVs also differ in their membrane lipid composition and in terms of transmembrane proteins as well as the proteins that facilitate EV binding to target cells (Figure 2).⁶ Ultimately, these exosomes are taken up by the recipient cells.

EV-facilitated neuron-to-neuron tweets have been implicated in neuronal growth and differentiation.⁷ EV-driven communication between cells also can decrease dendrite growth and can trigger microglia to prune synapses.⁸ EVs from glial cells may promote neuronal integrity, directly boost presynaptic glutamate release,⁹ or even, through miRNAs, change the expression of glutamate receptors.¹⁰ EVs from astrocytes transport proteins that enable neuronal repair, while EVs from microglia regulate neuronal homeostasis. EV cargos—lipids, proteins, and miRNAs—from neurons modify signal transduction and protein expression in recipient cells. Taken together, data suggest that EVs facilitate anterograde and retrograde transfer of signals across synapses,^7,11 a putative mechanism for driving synaptic plasticity,¹² which is a process implicated in the therapeutic efficacy of psychotropic medications and psychotherapies.

Continue to: #Targets and #neuron

 

 

#Targets and #neuron

Adding a hashtag to a tweet links it to other tweets, just as membrane features of EVs direct how EVs link to target cells. When these EVs bind to target cells, they fuse and release their cargo into the target cell (Figure 2). These directed cargo—whether mRNA, proteins, or other molecules—can direct the recipient cell to modify its firing rate (in the case of neurons), alter transmitter release, and increase or decrease expression of various genes. The targeting process is complex, and our understanding of this process is evolving. Briefly, integrin, lipid composition, glycans (eg, polysaccharides), and tetraspanin components of EVs influence their affinity for specific target cells.¹³ Recently, we have been able to read these hashtags and isolate cell-specific, neuron-derived EVs. Immunoadsorption techniques that leverage antibodies against L1 cell adhesion molecule protein (L1CAM(+)), primarily expressed in neurons, can identify neuronally-derived EVs (Figure 3). The specific EVs contain cargos of neuronal origin and provide a “window” into molecular processes in the brain by way of the blood (or other peripheral fluids). In following the neuronal tweets, we can follow molecular measures of important brain molecules in biofluids outside the CNS, including saliva and potentially urine (Figure 1B and 1C). In following these specific neuronal Twitter feeds, we can gain critical insights into specific brain processes.

EVs in psychiatric disorders

EVs are implicated in neuroinflammation,¹⁴ neurogenesis, synaptic plasticity, and epigenetic regulation—all processes that are involved in the pathophysiology of psychiatric disorders. Postmortem research suggests that EVs in the brain carry pro­inflammatory molecules from microglia, as well as secretions of regulatory miRNA that are responsible for synaptic plasticity and dendritic growth in depression, bipolar disorder, schizophrenia, and addiction. In addition, second-generation antipsychotics change the composition of EV cargos in the brain, altering their RNA, protein, and lipid content, often reflecting profound changes in gene expression in various cells in the CNS. In our lab, we have identified several molecules in plasma EVs, both lipids and miRNA, that can potentially predict the response to treatment of pediatric anxiety with selective serotonin reuptake inhibitors as well as opiate addiction.¹⁵

Further, given our increasing understanding of the way in which EV cargo reflects neuronal physiology as well as the potential pathophysiologic states of cells (including neurons), studying EVs’ molecular content can identify molecular messages—in blood—that are derived from the neurons in the brain. Having the tools to examine molecular brain regulators or other markers of disease progression (eg, beta amyloid) or brain health (eg, brain-derived neurotrophic factor) may advance our understanding and treatment of psychiatric disorders and create opportunities for precision medicine driven by biological rather than ethnologic and phenomenological markers. Whereas in the not-too-distant past molecular processes in the brain were only accessible through invasive measures—such as brain biopsy or through a lumbar puncture—studying CNS-derived EVs in blood offers us an opportunity to gain access to brain molecular signatures with relative ease. Often, these molecular signatures predate clinical changes by years or months, allowing us the prospects of potentially identifying and treating CNS disorders early on, possibly even before the onset of symptoms.

Therapeutic use of the Twitter feed

EV may be used to alter brain receptor structures in a targeted way to facilitate treatment of various psychiatric disorders. One example is a proof-of-concept study in mice in which administration of artificially manufactured EVs led to a decrease of opioid receptor mu.¹⁶ This was done by constructing EVs that carry neuron-specific rabies viral glycoprotein (RVG) peptide on the membrane surface to deliver mu opioid receptor small interfering RNA into the brain. This resulted in downregulation of mu opioid receptor and a decrease in morphine relapse.¹⁶

Additional ways in which EVs can be used therapeutically is via targeted drug delivery CNS methods. EVs may represent the next generation of treatment by allowing not only medication transport into the CNS,¹⁷ but also by facilitating directed CNS transport. What if we could use a molecular hashtag to send a dopaminergic agent to the substantia nigra of a patient with Parkinson disease but avoid sending that same treatment to the limbic cortex, where it might produce perceptual disturbances or hallucinations? In the future, EVs may help clinicians access the CNS, which is traditionally restricted by the blood brain barrier, and make it easier to achieve CNS concentrations of medications¹³ while decreasing medication exposure in other parts of the body. The therapeutic potential of EVs for medication delivery and regenerative medicine is awe-inspiring. Several studies have modified EVs to improve their therapeutic properties and to target delivery to specific cells¹³ by leveraging EV surface markers.¹⁸

Future directions for EVs

A better understanding of neuron-derived EVs may eventually help us abandon nosology-based diagnostic criteria and adopt molecular-based diagnostic approaches in psychiatry. It may allow us to consider a molecular synaptic etiology of psychiatric disorders, and diagnose patients based on synaptic pathology utilizing “neuron-derived EV liquid biopsies.” Such a shift would align psychiatry with other medical fields in which diagnosis and treatment are often based on biopsies and blood tests. Because proteins in EVs often exist in their native states, intact with their posttranslational modifications, they provide a window into testing their actual in vivo functioning. EVs have an immense potential to revolutionize psychiatric diagnosis, facilitate precision treatment, predict response, and discover much-needed novel therapeutics.

Bottom Line

Much like a tweet, extracellular vesicles (EVs) encode short messages that are transmit ted efficiently throughout the CNS and body. They may represent a reservoir for CNS-specific biomarkers that can be is olated from plasma to guide psychiatric diagnosis and treatment. EVs represent a new frontier in the molecular study of psychiatric illness.

Related Resources

Vesiclepedia. www.microvesicles.org/

Twitter, a microblogging and social networking service, has become a “go-to’” for conversations, updates, breaking news, and sharing the more mundane aspects of our lives. Tweets, which were lengthened from 140 to 280 characters in 2017, rapidly communicate and disseminate information to a wide audience. Generally, tweets are visible to everyone, though users can mute and block other users from viewing their tweets. Spikes in tweets and tweeting frequency reflect hyper-current events: the last minutes of the Super Bowl, certification of an election, or a new movie release. In fact, social scientists have analyzed tweet frequencies to examine the impact of local and national events. However, few are aware that like celebrities, politicians, influencers, and ordinary citizens, the human brain also tweets.

In this article, we describe the components of the brain’s “Twitter” system, how it works, and how it might someday be used to improve the diagnosis and treatment of psychiatric disorders.

Brain tweets

The brain’s Twitter system involves extracellular vesicles (EVs), tiny (<1 µm) membrane-bound vesicles that are released from neurons, glia, and other neuronal cells (Table). These EVs cross the blood-brain barrier and facilitate cell-to-cell communication within and among tissues (Figure 1).

First described in the 1980s,¹ EVs are secreted by a diverse array of cells: mast cells reticulocytes, epithelial cells, immune cells, neurons, glia, and oligodendrocytes. Like tweets, EVs rapidly disseminate packets of information throughout the brain and body and direct the molecular activity of recipient cells in both health and disease. These “brain tweets” contain short, circumscribed messages, and the characters are the EV cargos: RNAs, proteins, lipids, and metabolites. Like a Twitter feed, EVs cast a wide communication net across the body, much of which finds its way to the blood. As neuroscientists, we can follow these tweets by isolating tissue-derived EVs in plasma and examining their surface molecules and cargo. By following this Twitter feed, we can tap into important molecular communications and identify “trending” (evolving) pathological processes, and perhaps use the brain Twitter feed to improve diagnosis and treatments. We can pinpoint, in the blood, signals from CNS processes, down to the level of identifying EV cargos from specific brain cell types.

Within the CNS, EVs are secreted by neurons, where they may modulate synaptic plasticity and transfer molecular cargo among neurons. EVs also facilitate communication between neurons and glia, maintain homeostasis, trigger neuroprotective processes, and even regulate synaptic transmission.²

What’s in a brain tweet?

To discuss what’s in a brain tweet, we must first understand how a brain tweet is composed. EVs are pinched off from membranes of intercellular structures (eg, golgi or endoplasmic reticulum) or pinched off directly from cell membranes, where upon release they become EVs. There is a complex cellular machinery that transports what ultimately becomes an EV to the cell membrane.³ EVs contain unique mixtures of lipids, proteins, and nucleic acids (eg, microRNA [miRNA], mRNA, and noncoding RNA).⁴ To date, nearly 10,000 proteins, 11,000 lipids, 3,500 mRNAs, and 3,000 miRNAs have been identified as cargos in extracellular vesicles (Figure 1). Similar to how the release of EVs is dependent on complex intracellular machinery, the packing of these contents into what will become the EV involves a parallel set of complex machinery that is largely directed by endosomal sorting complexes required for transport (ESCRT) proteins.⁵ Of interest, when viruses attack cells, they hijack this EV packaging system to package and release new viruses. EVs vary in size, shape, and density; this variation is related to the cell origin, among other things. EVs also differ in their membrane lipid composition and in terms of transmembrane proteins as well as the proteins that facilitate EV binding to target cells (Figure 2).⁶ Ultimately, these exosomes are taken up by the recipient cells.

EV-facilitated neuron-to-neuron tweets have been implicated in neuronal growth and differentiation.⁷ EV-driven communication between cells also can decrease dendrite growth and can trigger microglia to prune synapses.⁸ EVs from glial cells may promote neuronal integrity, directly boost presynaptic glutamate release,⁹ or even, through miRNAs, change the expression of glutamate receptors.¹⁰ EVs from astrocytes transport proteins that enable neuronal repair, while EVs from microglia regulate neuronal homeostasis. EV cargos—lipids, proteins, and miRNAs—from neurons modify signal transduction and protein expression in recipient cells. Taken together, data suggest that EVs facilitate anterograde and retrograde transfer of signals across synapses,^7,11 a putative mechanism for driving synaptic plasticity,¹² which is a process implicated in the therapeutic efficacy of psychotropic medications and psychotherapies.

Continue to: #Targets and #neuron

 

 

#Targets and #neuron

Adding a hashtag to a tweet links it to other tweets, just as membrane features of EVs direct how EVs link to target cells. When these EVs bind to target cells, they fuse and release their cargo into the target cell (Figure 2). These directed cargo—whether mRNA, proteins, or other molecules—can direct the recipient cell to modify its firing rate (in the case of neurons), alter transmitter release, and increase or decrease expression of various genes. The targeting process is complex, and our understanding of this process is evolving. Briefly, integrin, lipid composition, glycans (eg, polysaccharides), and tetraspanin components of EVs influence their affinity for specific target cells.¹³ Recently, we have been able to read these hashtags and isolate cell-specific, neuron-derived EVs. Immunoadsorption techniques that leverage antibodies against L1 cell adhesion molecule protein (L1CAM(+)), primarily expressed in neurons, can identify neuronally-derived EVs (Figure 3). The specific EVs contain cargos of neuronal origin and provide a “window” into molecular processes in the brain by way of the blood (or other peripheral fluids). In following the neuronal tweets, we can follow molecular measures of important brain molecules in biofluids outside the CNS, including saliva and potentially urine (Figure 1B and 1C). In following these specific neuronal Twitter feeds, we can gain critical insights into specific brain processes.

EVs in psychiatric disorders

EVs are implicated in neuroinflammation,¹⁴ neurogenesis, synaptic plasticity, and epigenetic regulation—all processes that are involved in the pathophysiology of psychiatric disorders. Postmortem research suggests that EVs in the brain carry pro­inflammatory molecules from microglia, as well as secretions of regulatory miRNA that are responsible for synaptic plasticity and dendritic growth in depression, bipolar disorder, schizophrenia, and addiction. In addition, second-generation antipsychotics change the composition of EV cargos in the brain, altering their RNA, protein, and lipid content, often reflecting profound changes in gene expression in various cells in the CNS. In our lab, we have identified several molecules in plasma EVs, both lipids and miRNA, that can potentially predict the response to treatment of pediatric anxiety with selective serotonin reuptake inhibitors as well as opiate addiction.¹⁵

Further, given our increasing understanding of the way in which EV cargo reflects neuronal physiology as well as the potential pathophysiologic states of cells (including neurons), studying EVs’ molecular content can identify molecular messages—in blood—that are derived from the neurons in the brain. Having the tools to examine molecular brain regulators or other markers of disease progression (eg, beta amyloid) or brain health (eg, brain-derived neurotrophic factor) may advance our understanding and treatment of psychiatric disorders and create opportunities for precision medicine driven by biological rather than ethnologic and phenomenological markers. Whereas in the not-too-distant past molecular processes in the brain were only accessible through invasive measures—such as brain biopsy or through a lumbar puncture—studying CNS-derived EVs in blood offers us an opportunity to gain access to brain molecular signatures with relative ease. Often, these molecular signatures predate clinical changes by years or months, allowing us the prospects of potentially identifying and treating CNS disorders early on, possibly even before the onset of symptoms.

Therapeutic use of the Twitter feed

EV may be used to alter brain receptor structures in a targeted way to facilitate treatment of various psychiatric disorders. One example is a proof-of-concept study in mice in which administration of artificially manufactured EVs led to a decrease of opioid receptor mu.¹⁶ This was done by constructing EVs that carry neuron-specific rabies viral glycoprotein (RVG) peptide on the membrane surface to deliver mu opioid receptor small interfering RNA into the brain. This resulted in downregulation of mu opioid receptor and a decrease in morphine relapse.¹⁶

Additional ways in which EVs can be used therapeutically is via targeted drug delivery CNS methods. EVs may represent the next generation of treatment by allowing not only medication transport into the CNS,¹⁷ but also by facilitating directed CNS transport. What if we could use a molecular hashtag to send a dopaminergic agent to the substantia nigra of a patient with Parkinson disease but avoid sending that same treatment to the limbic cortex, where it might produce perceptual disturbances or hallucinations? In the future, EVs may help clinicians access the CNS, which is traditionally restricted by the blood brain barrier, and make it easier to achieve CNS concentrations of medications¹³ while decreasing medication exposure in other parts of the body. The therapeutic potential of EVs for medication delivery and regenerative medicine is awe-inspiring. Several studies have modified EVs to improve their therapeutic properties and to target delivery to specific cells¹³ by leveraging EV surface markers.¹⁸

Future directions for EVs

A better understanding of neuron-derived EVs may eventually help us abandon nosology-based diagnostic criteria and adopt molecular-based diagnostic approaches in psychiatry. It may allow us to consider a molecular synaptic etiology of psychiatric disorders, and diagnose patients based on synaptic pathology utilizing “neuron-derived EV liquid biopsies.” Such a shift would align psychiatry with other medical fields in which diagnosis and treatment are often based on biopsies and blood tests. Because proteins in EVs often exist in their native states, intact with their posttranslational modifications, they provide a window into testing their actual in vivo functioning. EVs have an immense potential to revolutionize psychiatric diagnosis, facilitate precision treatment, predict response, and discover much-needed novel therapeutics.

Bottom Line

Much like a tweet, extracellular vesicles (EVs) encode short messages that are transmit ted efficiently throughout the CNS and body. They may represent a reservoir for CNS-specific biomarkers that can be is olated from plasma to guide psychiatric diagnosis and treatment. EVs represent a new frontier in the molecular study of psychiatric illness.

Related Resources

Vesiclepedia. www.microvesicles.org/

Approved by the FDA on April 5, 2022, dexmedetomidine sublingual film (Igalmi, manufactured and distributed by BioXcel Therapeutics, Inc., New Haven, CT USA) is indicated in adults for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder (Table).^1,2 It is administered sublingually or buccally under the supervision of a health care provider. After administration, patients should have their vital signs and alertness assessed but there is no FDA Risk Evaluation and Mitigation Strategy (REMS) required for use. A limitation of use is that the safety and effectiveness of dexmedetomidine sublingual film has not been established beyond 24 hours from the first dose.² There are no contraindications for use.²

Dexmedetomidine is a well-known efficacious alpha-2 adrenergic receptor agonist available since 1999 in an IV formulation indicated for sedation of initially intubated and mechanically ventilated patients in an ICU setting, and sedation of nonintubated patients prior to and/or during surgical and other procedures.^3,4 The reformulation of dexmedetomidine as a sublingual film allows the broader use of this agent in psychiatric settings when managing agitation in patients with schizophrenia or bipolar disorder, and thus potentially avoiding the use of IM administration of antipsychotics and/or benzodiazepines. Noninvasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and health care professionals.⁵

Dosing

Dexmedetomidine sublingual film is distributed commercially in the following strengths: 180 mcg and 120 mcg. It consists of a lightly mint-flavored, rectangular film containing 2 microdeposits of dexmedetomidine hydrochloride. Dosage strengths of 90 mcg and 60 mcg are available by cutting the 180 mcg or 120 mcg film in half between the 2 visible darker blue dots. The recommended dose depends on the severity of agitation, age, and the presence of hepatic impairment.² For severe agitation, the recommended dose is 180 mcg. For mild or moderate agitation, the recommended dose is 120 mcg. Dosage is reduced in patients with mild/moderate hepatic impairment (120 mcg for severe agitation and 90 mcg for mild or moderate agitation) or severe hepatic impairment (90 mcg and 60 mcg, for severe and mild/moderate agitation, respectively). The dose recommended for geriatric patients (defined as age ≥65 years) is 120 mcg for either mild, moderate, or severe agitation. Patients are advised not to eat or drink for at least 15 minutes after sublingual administration, or at least 1 hour after buccal administration (defined as placement in the mouth directly behind the lower lip).

If agitation persists after the initial dose, up to 2 additional doses (90 mcg if the initial dose was 180 mcg, otherwise 60 mcg if the initial dose was 120, 90, or 60 mcg) may be given at least 2 hours apart. Assessment of vital signs, including orthostatic measurements, is required prior to the administration of any subsequent doses. Due to risk of hypotension, additional doses are not recommended in patients with systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, heart rate <60 beats per minute, or postural decrease in systolic blood pressure ≥20 mm Hg or in diastolic blood pressure ≥10 mm Hg.

Mechanism of action and pharmacodynamics

Dexmedetomidine is an alpha-2 adrenergic receptor agonist and the mechanism of action in the acute treatment of agitation is thought to be due to activation of presynaptic alpha-2 adrenergic receptors.² Binding affinities (Ki values) are 4 to 6 nM at the alpha-2 adrenergic receptor subtypes.²

Dexmedetomidine exhibits concentration-dependent QT prolongation, with mean QTc increases from baseline from 6 msec (120 mcg single dose) to 11 msec (180 mcg plus 2 additional doses of 90 mcg 2 hours apart for a total of 3 doses).² Placing the observation about QTc prolongation into clinical context, studies of IM administration of ziprasidone 20 mg and 30 mg and haloperidol 7.5 mg and 10 mg resulted in changes of the QTc interval of 4.6 msec and 6.0 msec, respectively, after 1 dose.⁶ After a second injection, these values were 12.8 msec and 14.7 msec, respectively.⁶

Clinical pharmacokinetics

The sublingual film formulation is absorbed orally, bypassing first-pass metabolism, and achieving higher dexmedetomidine bioavailability than ingested formulations.⁷ Exposure is dose-dependent, with dexmedetomidine being quantifiable in plasma after 5 to 20 minutes post dosing, and with a plasma half-life of 2 to 3 hours.^2,8 Mean time for the film to dissolve in the mouth was approximately 6 to 8 minutes following sublingual administration, and 18 minutes following buccal administration.² Absolute bioavailability was approximately 72% and 82% following sublingual and buccal administration, respectively.² Mean maximal plasma concentrations of dexmedetomidine were reached approximately 2 hours after sublingual or buccal administration.² Compared to drinking water at 2 hours post administration, early water intake (as early as 15 minutes post-dose) had minimal effects on the rate or extent of sublingual absorption but was not assessed after buccal administration.² The average protein binding was 94% and was constant across the different plasma concentrations evaluated and similar in males and females, but significantly decreased in participants with hepatic impairment compared to healthy individuals.² In contrast, the pharmacokinetic profile of dexmedetomidine is not significantly different in patients with creatinine clearance <30 mL/minute compared to those with normal renal function.² Dexmedetomidine undergoes almost complete biotransformation to inactive metabolites via direct glucuronidation as well as cytochrome P450 (CYP) (primarily CYP2A6)–mediated metabolism.² There is no evidence of any CYP–mediated drug interactions that are likely to be of clinical relevance.²

Continue to: Efficacy

 

 

Efficacy

The efficacy and tolerability of 120 mcg and 180 mcg doses of dexmedetomidine sublingual film was evaluated in 2 similarly designed, randomized, double-blind, placebo-controlled, Phase 3 trials in the treatment of acute agitation associated with schizophrenia, schizoaffective, or schizophreniform disorder⁹ and bipolar I or II disorder.¹⁰ These studies included a total of 758 adult patients age range 18 to 71 (mean age approximately 46.5), with about 59% male participants.² In contrast to other agents approved by the FDA for treatment of agitation associated with bipolar disorder, dexmedetomidine sublingual film was assessed in patients regardless of polarity (manic, mixed features, or depressed).⁵ The primary efficacy measure for the dexmedetomidine sublingual film studies was the investigator-administered Positive and Negative Syndrome Scale-Excited Component (PANSS-EC), consisting of the following 5 items: excitement, tension, hostility, uncooperativeness, and poor impulse control.¹¹ The items from the PANSS-EC are rated from 1 (not present) to 7 (extremely severe) and thus the total scores range from 5 to 35. For enrollment in the studies, patients had to be judged to be clinically agitated with a total PANSS-EC score ≥14, with at least 1 individual item score ≥4.²

After study medication administration, the PANSS-EC was assessed from 10 minutes through 24 hours, with the primary endpoint being at 2 hours post-dose. Patients with schizophrenia or bipolar disorder who were treated with dexmedetomidine sublingual film 120 mcg or 180 mcg had superior symptomatic improvements from baseline to 2 hours post-dose compared to placebo, with treatment effects beginning as early as 20 to 30 minutes post-dose (for patients with schizophrenia, dexmedetomidine was statistically significantly superior to placebo beginning at 20 minutes following dosing with the 180 mcg dose and 30 minutes after the 120 mcg dose; for patients with bipolar disorder, differences from placebo were statistically significant beginning at 20 minutes after treatment with both the 120 mcg and 180 mcg doses).² Evaluation of effect size for dexmedetomidine vs placebo for PANSS-EC response at 2 hours (defined as ≥40% improvement from baseline) resulted in a number needed to treat (NNT) of 3 when combining both studies and both doses,¹² comparing favorably with the NNT values observed for IM formulations of aripiprazole, haloperidol, lorazepam, olanzapine, and ziprasidone,¹³ and inhaled loxapine.¹⁴

Overall tolerability and safety

The highlights of the prescribing information contain warnings and precautions regarding hypotension/orthostatic hypotension/bradycardia, QT interval prolongation, and somnolence.² Advice is provided to ensure that patients are alert and not experiencing orthostatic or symptomatic hypotension prior to resuming ambulation, a concern commonly raised when assessing potential treatments for agitation.¹⁵ Dexmedetomidine sublingual film should be avoided in patients with risk factors for prolonged QT interval, a precaution that was evident for the use of ziprasidone¹⁶ and where an effect is also noted with haloperidol.⁶ As per the prescribing information, the most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) are somnolence, oral paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension. Rates of adverse reactions of somnolence (including fatigue and sluggishness) with dexmedetomidine 120 mcg or 180 mcg are almost the same (22% and 23%, respectively), and higher than the 6% observed with placebo.² Other adverse reactions are substantially lower in frequency. These include oral paresthesia or oral hypoesthesia (6%, 7%, and 1%, for dexmedetomidine 120 mcg, 180 mcg, or placebo, respectively), dizziness (4%, 6%, 1%), hypotension (5%, 5%, 0%), orthostatic hypotension (3%, 5%, <1%), dry mouth (7%, 4%, 1%), nausea (2%, 3%, 2%), bradycardia (2%, 2%, 0%), and abdominal discomfort (0%, 2%, 1%).²

Regarding dose-dependent changes in blood pressure during the studies, 16%, 18%, and 9% of patients treated with 120 mcg, 180 mcg, and placebo, respectively, experienced orthostatic hypotension at 2 hours post dose. However, at 24 hours, none of the patients in the 180-mcg group experienced a systolic blood pressure ≤90 mm Hg with a decrease ≥20 mm Hg, compared with one patient (<1%) in the 120-mcg group and none in the placebo group.²

The prescribing information advises that concomitant use of dexmedetomidine sublingual film with anesthetics, sedatives, hypnotics, or opioids is likely to lead to enhanced CNS depressant effects, and that the prescriber should consider a reduction in dosage of dexmedetomidine or the concomitant anesthetic, sedative, hypnotic, or opioid.²

Summary

Dexmedetomidine sublingual film is an oral medication indicated in adults for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder. The recommended dose depends on severity of agitation, age, and the presence of hepatic impairment. A dose of 180 mcg is recommended for severe agitation and a dose of 120 mcg is recommended for mild or moderate agitation, with doses adjusted lower in the presence of hepatic impairment. There are no contraindications but there are warnings and precautions regarding hypotension/orthostatic hypotension/bradycardia, QT interval prolongation, and somnolence. Clinicians should monitor vital signs and alertness after administration to prevent falls and syncope; however, there is no FDA REMS required for use. The clinical trial evidence supporting the use of dexmedetomidine is robust, with evidence of a treatment effect as early as 20 minutes after administration. Noninvasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and health care professionals.

Bottom Line

Dexmedetomidine sublingual film provides an opportunity to rethink the approach to the management of agitation and avoid the potentially unnecessary use of IM injections. Dexmedetomidine sublingual film acts rapidly and is simple to use.

Related Resources

• Dexmedetomidine sublingual film (Iglami) prescribing information. https://www.igalmihcp.com/igalmi-pi.pdf

Drug Brand Names

Aripiprazole • Abilify
Dexmedetomidine • Igalmi, Precedex
Haloperidol • Haldol
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Olanzapine • Zyprexa
Ziprasidone • Geodon

Approved by the FDA on April 5, 2022, dexmedetomidine sublingual film (Igalmi, manufactured and distributed by BioXcel Therapeutics, Inc., New Haven, CT USA) is indicated in adults for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder (Table).^1,2 It is administered sublingually or buccally under the supervision of a health care provider. After administration, patients should have their vital signs and alertness assessed but there is no FDA Risk Evaluation and Mitigation Strategy (REMS) required for use. A limitation of use is that the safety and effectiveness of dexmedetomidine sublingual film has not been established beyond 24 hours from the first dose.² There are no contraindications for use.²

Dexmedetomidine is a well-known efficacious alpha-2 adrenergic receptor agonist available since 1999 in an IV formulation indicated for sedation of initially intubated and mechanically ventilated patients in an ICU setting, and sedation of nonintubated patients prior to and/or during surgical and other procedures.^3,4 The reformulation of dexmedetomidine as a sublingual film allows the broader use of this agent in psychiatric settings when managing agitation in patients with schizophrenia or bipolar disorder, and thus potentially avoiding the use of IM administration of antipsychotics and/or benzodiazepines. Noninvasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and health care professionals.⁵

Dosing

Dexmedetomidine sublingual film is distributed commercially in the following strengths: 180 mcg and 120 mcg. It consists of a lightly mint-flavored, rectangular film containing 2 microdeposits of dexmedetomidine hydrochloride. Dosage strengths of 90 mcg and 60 mcg are available by cutting the 180 mcg or 120 mcg film in half between the 2 visible darker blue dots. The recommended dose depends on the severity of agitation, age, and the presence of hepatic impairment.² For severe agitation, the recommended dose is 180 mcg. For mild or moderate agitation, the recommended dose is 120 mcg. Dosage is reduced in patients with mild/moderate hepatic impairment (120 mcg for severe agitation and 90 mcg for mild or moderate agitation) or severe hepatic impairment (90 mcg and 60 mcg, for severe and mild/moderate agitation, respectively). The dose recommended for geriatric patients (defined as age ≥65 years) is 120 mcg for either mild, moderate, or severe agitation. Patients are advised not to eat or drink for at least 15 minutes after sublingual administration, or at least 1 hour after buccal administration (defined as placement in the mouth directly behind the lower lip).

If agitation persists after the initial dose, up to 2 additional doses (90 mcg if the initial dose was 180 mcg, otherwise 60 mcg if the initial dose was 120, 90, or 60 mcg) may be given at least 2 hours apart. Assessment of vital signs, including orthostatic measurements, is required prior to the administration of any subsequent doses. Due to risk of hypotension, additional doses are not recommended in patients with systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, heart rate <60 beats per minute, or postural decrease in systolic blood pressure ≥20 mm Hg or in diastolic blood pressure ≥10 mm Hg.

Mechanism of action and pharmacodynamics

Dexmedetomidine is an alpha-2 adrenergic receptor agonist and the mechanism of action in the acute treatment of agitation is thought to be due to activation of presynaptic alpha-2 adrenergic receptors.² Binding affinities (Ki values) are 4 to 6 nM at the alpha-2 adrenergic receptor subtypes.²

Dexmedetomidine exhibits concentration-dependent QT prolongation, with mean QTc increases from baseline from 6 msec (120 mcg single dose) to 11 msec (180 mcg plus 2 additional doses of 90 mcg 2 hours apart for a total of 3 doses).² Placing the observation about QTc prolongation into clinical context, studies of IM administration of ziprasidone 20 mg and 30 mg and haloperidol 7.5 mg and 10 mg resulted in changes of the QTc interval of 4.6 msec and 6.0 msec, respectively, after 1 dose.⁶ After a second injection, these values were 12.8 msec and 14.7 msec, respectively.⁶

Clinical pharmacokinetics

The sublingual film formulation is absorbed orally, bypassing first-pass metabolism, and achieving higher dexmedetomidine bioavailability than ingested formulations.⁷ Exposure is dose-dependent, with dexmedetomidine being quantifiable in plasma after 5 to 20 minutes post dosing, and with a plasma half-life of 2 to 3 hours.^2,8 Mean time for the film to dissolve in the mouth was approximately 6 to 8 minutes following sublingual administration, and 18 minutes following buccal administration.² Absolute bioavailability was approximately 72% and 82% following sublingual and buccal administration, respectively.² Mean maximal plasma concentrations of dexmedetomidine were reached approximately 2 hours after sublingual or buccal administration.² Compared to drinking water at 2 hours post administration, early water intake (as early as 15 minutes post-dose) had minimal effects on the rate or extent of sublingual absorption but was not assessed after buccal administration.² The average protein binding was 94% and was constant across the different plasma concentrations evaluated and similar in males and females, but significantly decreased in participants with hepatic impairment compared to healthy individuals.² In contrast, the pharmacokinetic profile of dexmedetomidine is not significantly different in patients with creatinine clearance <30 mL/minute compared to those with normal renal function.² Dexmedetomidine undergoes almost complete biotransformation to inactive metabolites via direct glucuronidation as well as cytochrome P450 (CYP) (primarily CYP2A6)–mediated metabolism.² There is no evidence of any CYP–mediated drug interactions that are likely to be of clinical relevance.²

Continue to: Efficacy

 

 

Efficacy

The efficacy and tolerability of 120 mcg and 180 mcg doses of dexmedetomidine sublingual film was evaluated in 2 similarly designed, randomized, double-blind, placebo-controlled, Phase 3 trials in the treatment of acute agitation associated with schizophrenia, schizoaffective, or schizophreniform disorder⁹ and bipolar I or II disorder.¹⁰ These studies included a total of 758 adult patients age range 18 to 71 (mean age approximately 46.5), with about 59% male participants.² In contrast to other agents approved by the FDA for treatment of agitation associated with bipolar disorder, dexmedetomidine sublingual film was assessed in patients regardless of polarity (manic, mixed features, or depressed).⁵ The primary efficacy measure for the dexmedetomidine sublingual film studies was the investigator-administered Positive and Negative Syndrome Scale-Excited Component (PANSS-EC), consisting of the following 5 items: excitement, tension, hostility, uncooperativeness, and poor impulse control.¹¹ The items from the PANSS-EC are rated from 1 (not present) to 7 (extremely severe) and thus the total scores range from 5 to 35. For enrollment in the studies, patients had to be judged to be clinically agitated with a total PANSS-EC score ≥14, with at least 1 individual item score ≥4.²

After study medication administration, the PANSS-EC was assessed from 10 minutes through 24 hours, with the primary endpoint being at 2 hours post-dose. Patients with schizophrenia or bipolar disorder who were treated with dexmedetomidine sublingual film 120 mcg or 180 mcg had superior symptomatic improvements from baseline to 2 hours post-dose compared to placebo, with treatment effects beginning as early as 20 to 30 minutes post-dose (for patients with schizophrenia, dexmedetomidine was statistically significantly superior to placebo beginning at 20 minutes following dosing with the 180 mcg dose and 30 minutes after the 120 mcg dose; for patients with bipolar disorder, differences from placebo were statistically significant beginning at 20 minutes after treatment with both the 120 mcg and 180 mcg doses).² Evaluation of effect size for dexmedetomidine vs placebo for PANSS-EC response at 2 hours (defined as ≥40% improvement from baseline) resulted in a number needed to treat (NNT) of 3 when combining both studies and both doses,¹² comparing favorably with the NNT values observed for IM formulations of aripiprazole, haloperidol, lorazepam, olanzapine, and ziprasidone,¹³ and inhaled loxapine.¹⁴

Overall tolerability and safety

The highlights of the prescribing information contain warnings and precautions regarding hypotension/orthostatic hypotension/bradycardia, QT interval prolongation, and somnolence.² Advice is provided to ensure that patients are alert and not experiencing orthostatic or symptomatic hypotension prior to resuming ambulation, a concern commonly raised when assessing potential treatments for agitation.¹⁵ Dexmedetomidine sublingual film should be avoided in patients with risk factors for prolonged QT interval, a precaution that was evident for the use of ziprasidone¹⁶ and where an effect is also noted with haloperidol.⁶ As per the prescribing information, the most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) are somnolence, oral paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension. Rates of adverse reactions of somnolence (including fatigue and sluggishness) with dexmedetomidine 120 mcg or 180 mcg are almost the same (22% and 23%, respectively), and higher than the 6% observed with placebo.² Other adverse reactions are substantially lower in frequency. These include oral paresthesia or oral hypoesthesia (6%, 7%, and 1%, for dexmedetomidine 120 mcg, 180 mcg, or placebo, respectively), dizziness (4%, 6%, 1%), hypotension (5%, 5%, 0%), orthostatic hypotension (3%, 5%, <1%), dry mouth (7%, 4%, 1%), nausea (2%, 3%, 2%), bradycardia (2%, 2%, 0%), and abdominal discomfort (0%, 2%, 1%).²

Regarding dose-dependent changes in blood pressure during the studies, 16%, 18%, and 9% of patients treated with 120 mcg, 180 mcg, and placebo, respectively, experienced orthostatic hypotension at 2 hours post dose. However, at 24 hours, none of the patients in the 180-mcg group experienced a systolic blood pressure ≤90 mm Hg with a decrease ≥20 mm Hg, compared with one patient (<1%) in the 120-mcg group and none in the placebo group.²

The prescribing information advises that concomitant use of dexmedetomidine sublingual film with anesthetics, sedatives, hypnotics, or opioids is likely to lead to enhanced CNS depressant effects, and that the prescriber should consider a reduction in dosage of dexmedetomidine or the concomitant anesthetic, sedative, hypnotic, or opioid.²

Summary

Dexmedetomidine sublingual film is an oral medication indicated in adults for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder. The recommended dose depends on severity of agitation, age, and the presence of hepatic impairment. A dose of 180 mcg is recommended for severe agitation and a dose of 120 mcg is recommended for mild or moderate agitation, with doses adjusted lower in the presence of hepatic impairment. There are no contraindications but there are warnings and precautions regarding hypotension/orthostatic hypotension/bradycardia, QT interval prolongation, and somnolence. Clinicians should monitor vital signs and alertness after administration to prevent falls and syncope; however, there is no FDA REMS required for use. The clinical trial evidence supporting the use of dexmedetomidine is robust, with evidence of a treatment effect as early as 20 minutes after administration. Noninvasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and health care professionals.

Bottom Line

Dexmedetomidine sublingual film provides an opportunity to rethink the approach to the management of agitation and avoid the potentially unnecessary use of IM injections. Dexmedetomidine sublingual film acts rapidly and is simple to use.

Related Resources

• Dexmedetomidine sublingual film (Iglami) prescribing information. https://www.igalmihcp.com/igalmi-pi.pdf

Drug Brand Names

Aripiprazole • Abilify
Dexmedetomidine • Igalmi, Precedex
Haloperidol • Haldol
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Olanzapine • Zyprexa
Ziprasidone • Geodon

Approved by the FDA on April 5, 2022, dexmedetomidine sublingual film (Igalmi, manufactured and distributed by BioXcel Therapeutics, Inc., New Haven, CT USA) is indicated in adults for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder (Table).^1,2 It is administered sublingually or buccally under the supervision of a health care provider. After administration, patients should have their vital signs and alertness assessed but there is no FDA Risk Evaluation and Mitigation Strategy (REMS) required for use. A limitation of use is that the safety and effectiveness of dexmedetomidine sublingual film has not been established beyond 24 hours from the first dose.² There are no contraindications for use.²

Dexmedetomidine is a well-known efficacious alpha-2 adrenergic receptor agonist available since 1999 in an IV formulation indicated for sedation of initially intubated and mechanically ventilated patients in an ICU setting, and sedation of nonintubated patients prior to and/or during surgical and other procedures.^3,4 The reformulation of dexmedetomidine as a sublingual film allows the broader use of this agent in psychiatric settings when managing agitation in patients with schizophrenia or bipolar disorder, and thus potentially avoiding the use of IM administration of antipsychotics and/or benzodiazepines. Noninvasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and health care professionals.⁵

Dosing

Dexmedetomidine sublingual film is distributed commercially in the following strengths: 180 mcg and 120 mcg. It consists of a lightly mint-flavored, rectangular film containing 2 microdeposits of dexmedetomidine hydrochloride. Dosage strengths of 90 mcg and 60 mcg are available by cutting the 180 mcg or 120 mcg film in half between the 2 visible darker blue dots. The recommended dose depends on the severity of agitation, age, and the presence of hepatic impairment.² For severe agitation, the recommended dose is 180 mcg. For mild or moderate agitation, the recommended dose is 120 mcg. Dosage is reduced in patients with mild/moderate hepatic impairment (120 mcg for severe agitation and 90 mcg for mild or moderate agitation) or severe hepatic impairment (90 mcg and 60 mcg, for severe and mild/moderate agitation, respectively). The dose recommended for geriatric patients (defined as age ≥65 years) is 120 mcg for either mild, moderate, or severe agitation. Patients are advised not to eat or drink for at least 15 minutes after sublingual administration, or at least 1 hour after buccal administration (defined as placement in the mouth directly behind the lower lip).

If agitation persists after the initial dose, up to 2 additional doses (90 mcg if the initial dose was 180 mcg, otherwise 60 mcg if the initial dose was 120, 90, or 60 mcg) may be given at least 2 hours apart. Assessment of vital signs, including orthostatic measurements, is required prior to the administration of any subsequent doses. Due to risk of hypotension, additional doses are not recommended in patients with systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, heart rate <60 beats per minute, or postural decrease in systolic blood pressure ≥20 mm Hg or in diastolic blood pressure ≥10 mm Hg.

Mechanism of action and pharmacodynamics

Dexmedetomidine is an alpha-2 adrenergic receptor agonist and the mechanism of action in the acute treatment of agitation is thought to be due to activation of presynaptic alpha-2 adrenergic receptors.² Binding affinities (Ki values) are 4 to 6 nM at the alpha-2 adrenergic receptor subtypes.²

Dexmedetomidine exhibits concentration-dependent QT prolongation, with mean QTc increases from baseline from 6 msec (120 mcg single dose) to 11 msec (180 mcg plus 2 additional doses of 90 mcg 2 hours apart for a total of 3 doses).² Placing the observation about QTc prolongation into clinical context, studies of IM administration of ziprasidone 20 mg and 30 mg and haloperidol 7.5 mg and 10 mg resulted in changes of the QTc interval of 4.6 msec and 6.0 msec, respectively, after 1 dose.⁶ After a second injection, these values were 12.8 msec and 14.7 msec, respectively.⁶

Clinical pharmacokinetics

The sublingual film formulation is absorbed orally, bypassing first-pass metabolism, and achieving higher dexmedetomidine bioavailability than ingested formulations.⁷ Exposure is dose-dependent, with dexmedetomidine being quantifiable in plasma after 5 to 20 minutes post dosing, and with a plasma half-life of 2 to 3 hours.^2,8 Mean time for the film to dissolve in the mouth was approximately 6 to 8 minutes following sublingual administration, and 18 minutes following buccal administration.² Absolute bioavailability was approximately 72% and 82% following sublingual and buccal administration, respectively.² Mean maximal plasma concentrations of dexmedetomidine were reached approximately 2 hours after sublingual or buccal administration.² Compared to drinking water at 2 hours post administration, early water intake (as early as 15 minutes post-dose) had minimal effects on the rate or extent of sublingual absorption but was not assessed after buccal administration.² The average protein binding was 94% and was constant across the different plasma concentrations evaluated and similar in males and females, but significantly decreased in participants with hepatic impairment compared to healthy individuals.² In contrast, the pharmacokinetic profile of dexmedetomidine is not significantly different in patients with creatinine clearance <30 mL/minute compared to those with normal renal function.² Dexmedetomidine undergoes almost complete biotransformation to inactive metabolites via direct glucuronidation as well as cytochrome P450 (CYP) (primarily CYP2A6)–mediated metabolism.² There is no evidence of any CYP–mediated drug interactions that are likely to be of clinical relevance.²

Continue to: Efficacy

 

 

Efficacy

The efficacy and tolerability of 120 mcg and 180 mcg doses of dexmedetomidine sublingual film was evaluated in 2 similarly designed, randomized, double-blind, placebo-controlled, Phase 3 trials in the treatment of acute agitation associated with schizophrenia, schizoaffective, or schizophreniform disorder⁹ and bipolar I or II disorder.¹⁰ These studies included a total of 758 adult patients age range 18 to 71 (mean age approximately 46.5), with about 59% male participants.² In contrast to other agents approved by the FDA for treatment of agitation associated with bipolar disorder, dexmedetomidine sublingual film was assessed in patients regardless of polarity (manic, mixed features, or depressed).⁵ The primary efficacy measure for the dexmedetomidine sublingual film studies was the investigator-administered Positive and Negative Syndrome Scale-Excited Component (PANSS-EC), consisting of the following 5 items: excitement, tension, hostility, uncooperativeness, and poor impulse control.¹¹ The items from the PANSS-EC are rated from 1 (not present) to 7 (extremely severe) and thus the total scores range from 5 to 35. For enrollment in the studies, patients had to be judged to be clinically agitated with a total PANSS-EC score ≥14, with at least 1 individual item score ≥4.²

After study medication administration, the PANSS-EC was assessed from 10 minutes through 24 hours, with the primary endpoint being at 2 hours post-dose. Patients with schizophrenia or bipolar disorder who were treated with dexmedetomidine sublingual film 120 mcg or 180 mcg had superior symptomatic improvements from baseline to 2 hours post-dose compared to placebo, with treatment effects beginning as early as 20 to 30 minutes post-dose (for patients with schizophrenia, dexmedetomidine was statistically significantly superior to placebo beginning at 20 minutes following dosing with the 180 mcg dose and 30 minutes after the 120 mcg dose; for patients with bipolar disorder, differences from placebo were statistically significant beginning at 20 minutes after treatment with both the 120 mcg and 180 mcg doses).² Evaluation of effect size for dexmedetomidine vs placebo for PANSS-EC response at 2 hours (defined as ≥40% improvement from baseline) resulted in a number needed to treat (NNT) of 3 when combining both studies and both doses,¹² comparing favorably with the NNT values observed for IM formulations of aripiprazole, haloperidol, lorazepam, olanzapine, and ziprasidone,¹³ and inhaled loxapine.¹⁴

Overall tolerability and safety

The highlights of the prescribing information contain warnings and precautions regarding hypotension/orthostatic hypotension/bradycardia, QT interval prolongation, and somnolence.² Advice is provided to ensure that patients are alert and not experiencing orthostatic or symptomatic hypotension prior to resuming ambulation, a concern commonly raised when assessing potential treatments for agitation.¹⁵ Dexmedetomidine sublingual film should be avoided in patients with risk factors for prolonged QT interval, a precaution that was evident for the use of ziprasidone¹⁶ and where an effect is also noted with haloperidol.⁶ As per the prescribing information, the most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) are somnolence, oral paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension. Rates of adverse reactions of somnolence (including fatigue and sluggishness) with dexmedetomidine 120 mcg or 180 mcg are almost the same (22% and 23%, respectively), and higher than the 6% observed with placebo.² Other adverse reactions are substantially lower in frequency. These include oral paresthesia or oral hypoesthesia (6%, 7%, and 1%, for dexmedetomidine 120 mcg, 180 mcg, or placebo, respectively), dizziness (4%, 6%, 1%), hypotension (5%, 5%, 0%), orthostatic hypotension (3%, 5%, <1%), dry mouth (7%, 4%, 1%), nausea (2%, 3%, 2%), bradycardia (2%, 2%, 0%), and abdominal discomfort (0%, 2%, 1%).²

Regarding dose-dependent changes in blood pressure during the studies, 16%, 18%, and 9% of patients treated with 120 mcg, 180 mcg, and placebo, respectively, experienced orthostatic hypotension at 2 hours post dose. However, at 24 hours, none of the patients in the 180-mcg group experienced a systolic blood pressure ≤90 mm Hg with a decrease ≥20 mm Hg, compared with one patient (<1%) in the 120-mcg group and none in the placebo group.²

The prescribing information advises that concomitant use of dexmedetomidine sublingual film with anesthetics, sedatives, hypnotics, or opioids is likely to lead to enhanced CNS depressant effects, and that the prescriber should consider a reduction in dosage of dexmedetomidine or the concomitant anesthetic, sedative, hypnotic, or opioid.²

Summary

Dexmedetomidine sublingual film is an oral medication indicated in adults for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder. The recommended dose depends on severity of agitation, age, and the presence of hepatic impairment. A dose of 180 mcg is recommended for severe agitation and a dose of 120 mcg is recommended for mild or moderate agitation, with doses adjusted lower in the presence of hepatic impairment. There are no contraindications but there are warnings and precautions regarding hypotension/orthostatic hypotension/bradycardia, QT interval prolongation, and somnolence. Clinicians should monitor vital signs and alertness after administration to prevent falls and syncope; however, there is no FDA REMS required for use. The clinical trial evidence supporting the use of dexmedetomidine is robust, with evidence of a treatment effect as early as 20 minutes after administration. Noninvasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and health care professionals.

Bottom Line

Dexmedetomidine sublingual film provides an opportunity to rethink the approach to the management of agitation and avoid the potentially unnecessary use of IM injections. Dexmedetomidine sublingual film acts rapidly and is simple to use.

Related Resources

• Dexmedetomidine sublingual film (Iglami) prescribing information. https://www.igalmihcp.com/igalmi-pi.pdf

Drug Brand Names

Aripiprazole • Abilify
Dexmedetomidine • Igalmi, Precedex
Haloperidol • Haldol
Lorazepam • Ativan
Loxapine inhaled • Adasuve
Olanzapine • Zyprexa
Ziprasidone • Geodon

Mr. L, age 31, presents to the emergency department (ED) with somnolence after sustaining an arm laceration at work. While in the ED, Mr. L explains he has opioid use disorder (OUD) and last week received an initial 300 mg injection of extended-release buprenorphine (BUP-XR). Due to ongoing opioid cravings, he took nonprescribed fentanyl and alprazolam before work.

The ED clinicians address Mr. L’s arm injury and transfer him to the hospital’s low-threshold outpatient addiction clinic for further assessment and management. There, he is prescribed sublingual buprenorphine/naloxone (SL-BUP) 8 mg/2 mg daily as needed for 1 week to address ongoing opioid cravings, and is encouraged to return for another visit the following week.

The United States continues to struggle with the overdose crisis, largely fueled by illicitly manufactured opioids such as fentanyl.¹ Opioid agonist and partial agonist treatments such as methadone and buprenorphine decrease the risk of death in individuals with OUD by up to 50%.² While methadone has a history of proven effectiveness for OUD, accessibility is fraught with barriers (eg, patients must attend an opioid treatment program daily to receive a dose, pharmacies are unable to dispense methadone for OUD).

Buprenorphine has been shown to decrease opioid cravings while limiting euphoria due to its partial—as opposed to full—agonist activity.³ Several buprenorphine formulations are available (Table). Buprenorphine presents an opportunity to treat OUD like other chronic illnesses. In accordance with the US Department of Health and Human Services Practice Guideline (2021), any clinician can obtain a waiver to prescribe buprenorphine in any treatment setting, and patients can receive the medication at a pharmacy.⁴

However, many patients have barriers to consistent daily dosing of buprenorphine due to strict clinic/prescriber requirements, transportation difficulties, continued cravings, and other factors. BUP-XR, a buprenorphine injection administered once a month, may address several of these concerns, most notably the potential for better suppression of cravings by delivering a consistent level of buprenorphine over the course of 28 days.⁵ Since BUP-XR was FDA-approved in 2017, questions remain whether it can adequately quell opioid cravings in early treatment months prior to steady-state concentration.

This article addresses whether clinicians should consider supplemental SL-BUP in addition to BUP-XR during early treatment months and/or prior to steady-state.

Pharmacokinetics of BUP-XR

BUP-XR is administered by subcutaneous injection via an ATRIGEL delivery system (BUP-XR; Albany Molecular Research, Burlington, Massachusetts).⁶ Upon injection, approximately 7% of the buprenorphine dose dissipates with the solvent, leading to maximum concentration approximately 24 hours post-dose. The remaining dose hardens to create a depot that elutes buprenorphine gradually over 28 days.⁷

Continue to: Buprenorphine requires...

Buprenorphine requires ≥70% mu-opioid receptor (MOR) occupancy to effectively suppress symptoms of craving and withdrawal in patients with OUD. Buprenorphine serum concentration correlates significantly with MOR occupancy, such that concentrations of 2 to 3 ng/mL are acknowledged as baseline minimums for clinical efficacy.⁸

BUP-XR is administered in 1 of 2 dosing regimens. In both, 2 separate 300 mg doses are administered 28 days apart during Month 1 and Month 2, followed by maintenance doses of either 300 mg (300/300 mg dosing regimen) or 100 mg (300/100 mg dosing regimen) every 28 days thereafter. Combined Phase II and Phase III data analyzing serum concentrations of BUP-XR across both dosing regimens revealed that, for most patients, there is a noticeable period during Month 1 and Month 2 when serum concentrations fall below 2 ng/mL.⁷ Steady-state concentrations of both regimens develop after 4 to 6 appropriately timed injections, providing average steady-state serum concentrations in Phase II and Phase III trials of 6.54 ng/mL for the 300/300 mg dosing regimen and 3.00 ng/mL for 300/100 mg dosing regimen.⁷

Real-world experiences with BUP-XR

The theoretical need for supplementation has been voiced in practice. A case series by Peckham et al⁹ noted that 55% (n = 22) of patients required SL-BUP supplementation for up to 120 days after the first BUP-XR injection to quell cravings and reduce nonprescribed opioid use.

The RECOVER trial by Ling et al¹⁰ demonstrated the importance of the first 2 months of BUP-XR therapy in the overall treatment success for patients with OUD. In this analysis, patients maintained on BUP-XR for 12 months reported a 75% likelihood of abstinence, compared to 24% for patients receiving 0 to 2 months of BUP-XR treatment. Other benefits included improved employment status and reduced depression rates. This trial did not specifically discuss supplemental SL-BUP or subthreshold concentrations of buprenorphine during early months.¹⁰

Individualized treatment should be based on OUD symptoms

While BUP-XR was designed to continuously deliver at least 2 ng/mL of buprenorphine, serum concentrations are labile during the first 2 months of treatment. This may result in breakthrough OUD symptoms, particularly withdrawal or opioid cravings. Additionally, due to individual variability, some patients may still experience serum concentrations below 2 ng/mL after Month 2 and until steady-state is achieved between Month 4 and Month 6.⁷

Continue to: Beyond a theoretical...

Beyond a theoretical need for supplementation with SL-BUP, there is limited information regarding optimal dosing, dosage intervals, or length of supplementation. Therefore, clear guidance is not available at this time, and treatment should be individualized based on subjective and objective OUD symptoms.

What also remains unknown are potential barriers patients may face in receiving 2 concurrent buprenorphine prescriptions. BUP-XR, administered in a health care setting, can be obtained 2 ways. A clinician can directly order the medication from the distributor to be administered via buy-and-bill. An alternate option requires the clinician to send a prescription to an appropriately credentialed pharmacy that will ship patient-specific orders directly to the clinic. Despite this, most SL-BUP prescriptions are billed and dispensed from community pharmacies. At the insurance level, there is risk the prescription claim will be rejected for duplication of therapy, which may require additional collaboration between the prescribing clinician, pharmacist, and insurance representative to ensure patients have access to the medication.

Pending studies and approvals may also provide greater guidance and flexibility in decision-making for patients with OUD. The CoLAB study currently underway in Australia is examining the efficacy and outcomes of an intermediate dose (200 mg) of BUP-XR and will also allow for supplemental SL-BUP doses.¹¹ Additionally, an alternative BUP-XR formulation, Brixadi, currently in use in the European Union as Buvidal, has submitted an application for FDA approval in the United States. The application indicates that Brixadi will be available with a wider range of doses and at both weekly and monthly intervals. Approval has been delayed due to deficiencies in the United States–based third-party production facilities. It is unclear how the FDA and manufacturer plan to proceed.¹²

Short-term supplementation with SL-BUP during early the months of treatment with BUP-XR should be considered to control OUD symptoms and assist with patient retention. Once steady-state is achieved, trough concentrations of buprenorphine are not expected to drop below 2 ng/mL with continued on-time maintenance doses and thus, supplementation can likely cease.

CASE CONTINUED

Mr. L is seen in the low-threshold outpatient clinic 1 week after his ED visit. His arm laceration is healing well, and he is noticeably more alert and engaged. Each morning this week, he awakes with cravings, sweating, and anxiety. These symptoms alleviate after he takes SL-BUP. Mr. L’s clinician gives him a copy of the Subjective Opioid Withdrawal Scale so he can assess his withdrawal symptoms each morning and provide this data at follow-up appointments. Mr. L and his clinician decide to meet weekly until his next injection to continue assessing his current supplemental dose, symptoms, and whether there should be additional adjustments to his treatment plan.

Related Resources

• Cho J, Bhimani J, Patel M, et al. Substance abuse among older adults: a growing problem. Current Psychiatry. 2018;17(3):14-20.
• Verma S. Opioid use disorder in adolescents: an overview. Current Psychiatry. 2020;19(2):12-14,16-21.

Drug Brand Names

Alprazolam • Xanax
Buprenorphine • Sublocade, Subutex
Buprenorphine/naloxone • Suboxone, Zubsolv
Methadone • Methadose

Mr. L, age 31, presents to the emergency department (ED) with somnolence after sustaining an arm laceration at work. While in the ED, Mr. L explains he has opioid use disorder (OUD) and last week received an initial 300 mg injection of extended-release buprenorphine (BUP-XR). Due to ongoing opioid cravings, he took nonprescribed fentanyl and alprazolam before work.

The ED clinicians address Mr. L’s arm injury and transfer him to the hospital’s low-threshold outpatient addiction clinic for further assessment and management. There, he is prescribed sublingual buprenorphine/naloxone (SL-BUP) 8 mg/2 mg daily as needed for 1 week to address ongoing opioid cravings, and is encouraged to return for another visit the following week.

The United States continues to struggle with the overdose crisis, largely fueled by illicitly manufactured opioids such as fentanyl.¹ Opioid agonist and partial agonist treatments such as methadone and buprenorphine decrease the risk of death in individuals with OUD by up to 50%.² While methadone has a history of proven effectiveness for OUD, accessibility is fraught with barriers (eg, patients must attend an opioid treatment program daily to receive a dose, pharmacies are unable to dispense methadone for OUD).

Buprenorphine has been shown to decrease opioid cravings while limiting euphoria due to its partial—as opposed to full—agonist activity.³ Several buprenorphine formulations are available (Table). Buprenorphine presents an opportunity to treat OUD like other chronic illnesses. In accordance with the US Department of Health and Human Services Practice Guideline (2021), any clinician can obtain a waiver to prescribe buprenorphine in any treatment setting, and patients can receive the medication at a pharmacy.⁴

However, many patients have barriers to consistent daily dosing of buprenorphine due to strict clinic/prescriber requirements, transportation difficulties, continued cravings, and other factors. BUP-XR, a buprenorphine injection administered once a month, may address several of these concerns, most notably the potential for better suppression of cravings by delivering a consistent level of buprenorphine over the course of 28 days.⁵ Since BUP-XR was FDA-approved in 2017, questions remain whether it can adequately quell opioid cravings in early treatment months prior to steady-state concentration.

This article addresses whether clinicians should consider supplemental SL-BUP in addition to BUP-XR during early treatment months and/or prior to steady-state.

Pharmacokinetics of BUP-XR

BUP-XR is administered by subcutaneous injection via an ATRIGEL delivery system (BUP-XR; Albany Molecular Research, Burlington, Massachusetts).⁶ Upon injection, approximately 7% of the buprenorphine dose dissipates with the solvent, leading to maximum concentration approximately 24 hours post-dose. The remaining dose hardens to create a depot that elutes buprenorphine gradually over 28 days.⁷

Continue to: Buprenorphine requires...

Buprenorphine requires ≥70% mu-opioid receptor (MOR) occupancy to effectively suppress symptoms of craving and withdrawal in patients with OUD. Buprenorphine serum concentration correlates significantly with MOR occupancy, such that concentrations of 2 to 3 ng/mL are acknowledged as baseline minimums for clinical efficacy.⁸

BUP-XR is administered in 1 of 2 dosing regimens. In both, 2 separate 300 mg doses are administered 28 days apart during Month 1 and Month 2, followed by maintenance doses of either 300 mg (300/300 mg dosing regimen) or 100 mg (300/100 mg dosing regimen) every 28 days thereafter. Combined Phase II and Phase III data analyzing serum concentrations of BUP-XR across both dosing regimens revealed that, for most patients, there is a noticeable period during Month 1 and Month 2 when serum concentrations fall below 2 ng/mL.⁷ Steady-state concentrations of both regimens develop after 4 to 6 appropriately timed injections, providing average steady-state serum concentrations in Phase II and Phase III trials of 6.54 ng/mL for the 300/300 mg dosing regimen and 3.00 ng/mL for 300/100 mg dosing regimen.⁷

Real-world experiences with BUP-XR

The theoretical need for supplementation has been voiced in practice. A case series by Peckham et al⁹ noted that 55% (n = 22) of patients required SL-BUP supplementation for up to 120 days after the first BUP-XR injection to quell cravings and reduce nonprescribed opioid use.

The RECOVER trial by Ling et al¹⁰ demonstrated the importance of the first 2 months of BUP-XR therapy in the overall treatment success for patients with OUD. In this analysis, patients maintained on BUP-XR for 12 months reported a 75% likelihood of abstinence, compared to 24% for patients receiving 0 to 2 months of BUP-XR treatment. Other benefits included improved employment status and reduced depression rates. This trial did not specifically discuss supplemental SL-BUP or subthreshold concentrations of buprenorphine during early months.¹⁰

Individualized treatment should be based on OUD symptoms

While BUP-XR was designed to continuously deliver at least 2 ng/mL of buprenorphine, serum concentrations are labile during the first 2 months of treatment. This may result in breakthrough OUD symptoms, particularly withdrawal or opioid cravings. Additionally, due to individual variability, some patients may still experience serum concentrations below 2 ng/mL after Month 2 and until steady-state is achieved between Month 4 and Month 6.⁷

Continue to: Beyond a theoretical...

Beyond a theoretical need for supplementation with SL-BUP, there is limited information regarding optimal dosing, dosage intervals, or length of supplementation. Therefore, clear guidance is not available at this time, and treatment should be individualized based on subjective and objective OUD symptoms.

What also remains unknown are potential barriers patients may face in receiving 2 concurrent buprenorphine prescriptions. BUP-XR, administered in a health care setting, can be obtained 2 ways. A clinician can directly order the medication from the distributor to be administered via buy-and-bill. An alternate option requires the clinician to send a prescription to an appropriately credentialed pharmacy that will ship patient-specific orders directly to the clinic. Despite this, most SL-BUP prescriptions are billed and dispensed from community pharmacies. At the insurance level, there is risk the prescription claim will be rejected for duplication of therapy, which may require additional collaboration between the prescribing clinician, pharmacist, and insurance representative to ensure patients have access to the medication.

Pending studies and approvals may also provide greater guidance and flexibility in decision-making for patients with OUD. The CoLAB study currently underway in Australia is examining the efficacy and outcomes of an intermediate dose (200 mg) of BUP-XR and will also allow for supplemental SL-BUP doses.¹¹ Additionally, an alternative BUP-XR formulation, Brixadi, currently in use in the European Union as Buvidal, has submitted an application for FDA approval in the United States. The application indicates that Brixadi will be available with a wider range of doses and at both weekly and monthly intervals. Approval has been delayed due to deficiencies in the United States–based third-party production facilities. It is unclear how the FDA and manufacturer plan to proceed.¹²

Short-term supplementation with SL-BUP during early the months of treatment with BUP-XR should be considered to control OUD symptoms and assist with patient retention. Once steady-state is achieved, trough concentrations of buprenorphine are not expected to drop below 2 ng/mL with continued on-time maintenance doses and thus, supplementation can likely cease.

CASE CONTINUED

Mr. L is seen in the low-threshold outpatient clinic 1 week after his ED visit. His arm laceration is healing well, and he is noticeably more alert and engaged. Each morning this week, he awakes with cravings, sweating, and anxiety. These symptoms alleviate after he takes SL-BUP. Mr. L’s clinician gives him a copy of the Subjective Opioid Withdrawal Scale so he can assess his withdrawal symptoms each morning and provide this data at follow-up appointments. Mr. L and his clinician decide to meet weekly until his next injection to continue assessing his current supplemental dose, symptoms, and whether there should be additional adjustments to his treatment plan.

Related Resources

• Cho J, Bhimani J, Patel M, et al. Substance abuse among older adults: a growing problem. Current Psychiatry. 2018;17(3):14-20.
• Verma S. Opioid use disorder in adolescents: an overview. Current Psychiatry. 2020;19(2):12-14,16-21.

Drug Brand Names

Alprazolam • Xanax
Buprenorphine • Sublocade, Subutex
Buprenorphine/naloxone • Suboxone, Zubsolv
Methadone • Methadose

Mr. L, age 31, presents to the emergency department (ED) with somnolence after sustaining an arm laceration at work. While in the ED, Mr. L explains he has opioid use disorder (OUD) and last week received an initial 300 mg injection of extended-release buprenorphine (BUP-XR). Due to ongoing opioid cravings, he took nonprescribed fentanyl and alprazolam before work.

The ED clinicians address Mr. L’s arm injury and transfer him to the hospital’s low-threshold outpatient addiction clinic for further assessment and management. There, he is prescribed sublingual buprenorphine/naloxone (SL-BUP) 8 mg/2 mg daily as needed for 1 week to address ongoing opioid cravings, and is encouraged to return for another visit the following week.

The United States continues to struggle with the overdose crisis, largely fueled by illicitly manufactured opioids such as fentanyl.¹ Opioid agonist and partial agonist treatments such as methadone and buprenorphine decrease the risk of death in individuals with OUD by up to 50%.² While methadone has a history of proven effectiveness for OUD, accessibility is fraught with barriers (eg, patients must attend an opioid treatment program daily to receive a dose, pharmacies are unable to dispense methadone for OUD).

Buprenorphine has been shown to decrease opioid cravings while limiting euphoria due to its partial—as opposed to full—agonist activity.³ Several buprenorphine formulations are available (Table). Buprenorphine presents an opportunity to treat OUD like other chronic illnesses. In accordance with the US Department of Health and Human Services Practice Guideline (2021), any clinician can obtain a waiver to prescribe buprenorphine in any treatment setting, and patients can receive the medication at a pharmacy.⁴

However, many patients have barriers to consistent daily dosing of buprenorphine due to strict clinic/prescriber requirements, transportation difficulties, continued cravings, and other factors. BUP-XR, a buprenorphine injection administered once a month, may address several of these concerns, most notably the potential for better suppression of cravings by delivering a consistent level of buprenorphine over the course of 28 days.⁵ Since BUP-XR was FDA-approved in 2017, questions remain whether it can adequately quell opioid cravings in early treatment months prior to steady-state concentration.

This article addresses whether clinicians should consider supplemental SL-BUP in addition to BUP-XR during early treatment months and/or prior to steady-state.

Pharmacokinetics of BUP-XR

BUP-XR is administered by subcutaneous injection via an ATRIGEL delivery system (BUP-XR; Albany Molecular Research, Burlington, Massachusetts).⁶ Upon injection, approximately 7% of the buprenorphine dose dissipates with the solvent, leading to maximum concentration approximately 24 hours post-dose. The remaining dose hardens to create a depot that elutes buprenorphine gradually over 28 days.⁷

Continue to: Buprenorphine requires...

Buprenorphine requires ≥70% mu-opioid receptor (MOR) occupancy to effectively suppress symptoms of craving and withdrawal in patients with OUD. Buprenorphine serum concentration correlates significantly with MOR occupancy, such that concentrations of 2 to 3 ng/mL are acknowledged as baseline minimums for clinical efficacy.⁸

BUP-XR is administered in 1 of 2 dosing regimens. In both, 2 separate 300 mg doses are administered 28 days apart during Month 1 and Month 2, followed by maintenance doses of either 300 mg (300/300 mg dosing regimen) or 100 mg (300/100 mg dosing regimen) every 28 days thereafter. Combined Phase II and Phase III data analyzing serum concentrations of BUP-XR across both dosing regimens revealed that, for most patients, there is a noticeable period during Month 1 and Month 2 when serum concentrations fall below 2 ng/mL.⁷ Steady-state concentrations of both regimens develop after 4 to 6 appropriately timed injections, providing average steady-state serum concentrations in Phase II and Phase III trials of 6.54 ng/mL for the 300/300 mg dosing regimen and 3.00 ng/mL for 300/100 mg dosing regimen.⁷

Real-world experiences with BUP-XR

The theoretical need for supplementation has been voiced in practice. A case series by Peckham et al⁹ noted that 55% (n = 22) of patients required SL-BUP supplementation for up to 120 days after the first BUP-XR injection to quell cravings and reduce nonprescribed opioid use.

The RECOVER trial by Ling et al¹⁰ demonstrated the importance of the first 2 months of BUP-XR therapy in the overall treatment success for patients with OUD. In this analysis, patients maintained on BUP-XR for 12 months reported a 75% likelihood of abstinence, compared to 24% for patients receiving 0 to 2 months of BUP-XR treatment. Other benefits included improved employment status and reduced depression rates. This trial did not specifically discuss supplemental SL-BUP or subthreshold concentrations of buprenorphine during early months.¹⁰

Individualized treatment should be based on OUD symptoms

While BUP-XR was designed to continuously deliver at least 2 ng/mL of buprenorphine, serum concentrations are labile during the first 2 months of treatment. This may result in breakthrough OUD symptoms, particularly withdrawal or opioid cravings. Additionally, due to individual variability, some patients may still experience serum concentrations below 2 ng/mL after Month 2 and until steady-state is achieved between Month 4 and Month 6.⁷

Continue to: Beyond a theoretical...

Beyond a theoretical need for supplementation with SL-BUP, there is limited information regarding optimal dosing, dosage intervals, or length of supplementation. Therefore, clear guidance is not available at this time, and treatment should be individualized based on subjective and objective OUD symptoms.

What also remains unknown are potential barriers patients may face in receiving 2 concurrent buprenorphine prescriptions. BUP-XR, administered in a health care setting, can be obtained 2 ways. A clinician can directly order the medication from the distributor to be administered via buy-and-bill. An alternate option requires the clinician to send a prescription to an appropriately credentialed pharmacy that will ship patient-specific orders directly to the clinic. Despite this, most SL-BUP prescriptions are billed and dispensed from community pharmacies. At the insurance level, there is risk the prescription claim will be rejected for duplication of therapy, which may require additional collaboration between the prescribing clinician, pharmacist, and insurance representative to ensure patients have access to the medication.

Pending studies and approvals may also provide greater guidance and flexibility in decision-making for patients with OUD. The CoLAB study currently underway in Australia is examining the efficacy and outcomes of an intermediate dose (200 mg) of BUP-XR and will also allow for supplemental SL-BUP doses.¹¹ Additionally, an alternative BUP-XR formulation, Brixadi, currently in use in the European Union as Buvidal, has submitted an application for FDA approval in the United States. The application indicates that Brixadi will be available with a wider range of doses and at both weekly and monthly intervals. Approval has been delayed due to deficiencies in the United States–based third-party production facilities. It is unclear how the FDA and manufacturer plan to proceed.¹²

Short-term supplementation with SL-BUP during early the months of treatment with BUP-XR should be considered to control OUD symptoms and assist with patient retention. Once steady-state is achieved, trough concentrations of buprenorphine are not expected to drop below 2 ng/mL with continued on-time maintenance doses and thus, supplementation can likely cease.

CASE CONTINUED

Mr. L is seen in the low-threshold outpatient clinic 1 week after his ED visit. His arm laceration is healing well, and he is noticeably more alert and engaged. Each morning this week, he awakes with cravings, sweating, and anxiety. These symptoms alleviate after he takes SL-BUP. Mr. L’s clinician gives him a copy of the Subjective Opioid Withdrawal Scale so he can assess his withdrawal symptoms each morning and provide this data at follow-up appointments. Mr. L and his clinician decide to meet weekly until his next injection to continue assessing his current supplemental dose, symptoms, and whether there should be additional adjustments to his treatment plan.

Related Resources

• Cho J, Bhimani J, Patel M, et al. Substance abuse among older adults: a growing problem. Current Psychiatry. 2018;17(3):14-20.
• Verma S. Opioid use disorder in adolescents: an overview. Current Psychiatry. 2020;19(2):12-14,16-21.

Drug Brand Names

Alprazolam • Xanax
Buprenorphine • Sublocade, Subutex
Buprenorphine/naloxone • Suboxone, Zubsolv
Methadone • Methadose

CASE Schizophrenia, leukemia, and chemotherapy

Mr. A, age 30, has schizophrenia but has been stable on clozapine 600 mg/d. He presents to the emergency department with generalized pain that started in his right scapula, arm, elbow, and back. Laboratory tests and a diagnostic examination reveal severe leukocytosis, thrombocytopenia, and anemia, and clinicians diagnose Mr. A with B-cell acute lymphocytic leukemia (B-ALL). Upon admission, Mr. A is neutropenic with an absolute neutrophil count (ANC) of 1,420 µL (reference range 2,500 to 6,000 µL). The hematology team recommends chemotherapy. The treating clinicians also consult the psychiatry team for recommendations on how to best manage Mr. A’s schizophrenia during chemotherapy, including whether clozapine should be discontinued.

HISTORY Stable on clozapine for >10 years

Mr. A was diagnosed with schizophrenia at age 15 after developing paranoia and auditory hallucinations of people talking to him and to each other. He had been hospitalized multiple times for worsened auditory hallucinations and paranoia that led to significant agitation and violence. Previous treatment with multiple antipsychotics, including haloperidol, quetiapine, aripiprazole, olanzapine, risperidone, and ziprasidone, was not successful. Mr. A began clozapine >10 years ago, and his symptoms have been stable since, without any further psychiatric hospitalizations. Mr. A takes clozapine 600 mg/d and divalproex sodium 1,500 mg/d, which he tolerates well and without significant adverse effects. Though he continues to have intermittent auditory hallucinations, they are mild and manageable. Mr. A lives with his mother, who reports he occasionally talks to himself but when he does not take clozapine, the auditory hallucinations worsen and cause him to become paranoid and aggressive. His ANC is monitored monthly and had been normal for several years until he was diagnosed with B-ALL.

[polldaddy:11125941]

The authors’ observations

The decision to continue clozapine during chemotherapy is challenging and should weigh the risk of agranulocytosis against that of psychiatric destabilization. Because clozapine and chemotherapy are both associated with agranulocytosis, there is concern that concurrent treatment could increase this risk in an additive or synergistic manner. To the best of our knowledge, there are currently no controlled studies investigating the interactions between clozapine and chemotherapeutic agents. Evidence on the hematopoietic consequences of concurrent clozapine and chemotherapy treatment has been limited to case reports because the topic does not lend itself well to randomized controlled trials.

A recent systematic review found no adverse outcomes among the 27 published cases in which clozapine was continued during myelosuppressive chemotherapy.¹ The most notable finding was an association between clozapine discontinuation and psychiatric decompensation, which was reported in 12 of 13 cases in which clozapine was prophylactically discontinued to minimize the risk of agranulocytosis.

Patient-specific factors must also be considered, such as the likelihood that psychotic symptoms will recur or worsen if clozapine is discontinued, as well as the extent to which symptom recurrence would interfere with cancer treatment. Clinicians should evaluate the feasibility of switching to another antipsychotic by obtaining a thorough history of the patient’s previous antipsychotics, doses, treatment duration, and response. However, many patients are treated with clozapine because their psychotic symptoms did not improve with other treatments. The character and severity of the patient’s psychotic symptoms when untreated or prior to clozapine treatment can provide a clearer understanding of how a recurrence of symptoms may interfere with cancer treatment. To formulate an accurate assessment of risks and benefits, it is necessary to consider both available evidence and patient-specific factors. The significant agitation and paranoia that Mr. A experienced when not taking clozapine was likely to disrupt chemotherapy. Thus, the adverse consequences of discontinuing clozapine were both severe and likely.

TREATMENT Continuing clozapine

After an extensive discussion of risks, benefits, and alternative treatments with the hematology and psychiatry teams, Mr. A and his family decide to continue clozapine with increased ANC monitoring during chemotherapy. Concurrent treatment was pursued with close collaboration among the patient, the patient’s family, and the hematology and pharmacy teams, and in careful consideration of the clozapine risk evaluation and mitigation strategy. Mr. A’s ANC was monitored daily during chemotherapy treatments and weekly in the intervals between treatments.

As expected, chemotherapy resulted in bone marrow suppression and pancytopenia. Mr. A’s ANC steadily decreased during the next 10 days until it reached 0 µL. This was consistent with the predicted ANC nadir between Day 10 and Day 14, after which recovery was expected. However, Mr. A’s ANC remained at 0 µL on Day 15.

[polldaddy:11125947]

Continue to: The authors' observations

 

 

The authors’ observations

Temporary decreases in ANC are expected during chemotherapy, and the timing of onset and recovery is often well characterized. Prior to Day 15, the observed progressive marrow suppression was solely due to chemotherapy. However, because Mr. A’s ANC remained 0 µL longer than anticipated, reevaluation of clozapine’s effects was warranted.

Timing, clinical course, and comprehensive hematologic monitoring can provide important clues as to whether clozapine may be responsible for prolonged neutropenia. Though a prolonged ANC of 0 µL raised concern for clozapine-induced agranulocytosis (CIAG), comprehensive monitoring of hematologic cell lines was reassuring because CIAG selectively targets granulocytic cells (neutrophils).² In contrast, chemo­therapy can affect other cell lineages, including lymphocytes, red blood cells, and platelets, which causes pancytopenia.³ For Mr. A, though the clinical presentation of pancytopenia was significant and concerning, it was inconsistent with CIAG.

Additionally, the patient’s baseline risk of CIAG should be considered. After 18 weeks of clozapine treatment, the risk of CIAG decreases to a level similar to that associated with other antipsychotics.^4,5 Therefore, CIAG would be unlikely in a patient treated with clozapine for more than 1 year and who did not have a history of neutropenia, as was the case with Mr. A.

While bone marrow biopsy can help differentiate between the causes of agranulocytosis,⁶ it is highly invasive and may not be necessary if laboratory evidence is sufficient. However, if a treatment team is strongly considering discontinuing clozapine and there are no suitable alternatives, a biopsy may provide additional clarification.

TREATMENT CAR T-cell therapy and cancer remission

Clozapine is continued with daily monitoring. On Day 19, Mr. A’s ANC increases, reaching 2,600 µL by discharge on Day 40. Mr. A remains psychiatrically stable throughout his hospitalization and does not experience any complications associated with neutropenia, despite its prolonged duration.

Continue to: Unfortunately, multiple cycles of...

Unfortunately, multiple cycles of chemo­therapy fail to induce remission. Mr. A is referred for CD19/CD22 chimeric antigen receptor (CAR) T-cell therapy, which helps achieve remission. Allogeneic hematopoietic stem cell transplant (HSCT) is recommended to maximize the likelihood of sustained remission.⁷ As with chemotherapy, Mr. A and his family agree with the multidisciplinary treatment recommendation to continue clozapine during both CAR T-cell therapy and HSCT, because the risks associated with psychiatric decompensation were greater than a potential increased risk of agranulocytosis. Clozapine treatment is continued throughout both therapies without issue.

Four months after HSCT, Mr. A is admitted for neutropenic fever and left face cellulitis. Upon admission, his ANC is 30 µL and subsequently decreases to 0 µL. In addition to neutropenia, Mr. A is also anemic and thrombocytopenic. He undergoes a bone marrow biopsy.

[polldaddy:11125950]

The authors’ observations

While no published cases have examined the bone marrow of patients experiencing CIAG, 2 retrospective studies have characterized 2 classes of bone marrow findings associated with drug-induced agranulocytosis resulting from nonchemotherapeutic agents (Table).^8,9 Type I marrow appears hypercellular with adequate neutrophil precursors but an arrested neutrophil maturation, with few or no mature forms of neutrophils beyond myelocytes.^8,9 Type II demonstrates a severe reduction or complete absence of granulocytic precursors with normal or increased erythropoiesis and megakaryocytes.^8,9 These findings have been used to accurately differentiate between chemotherapy and nonchemotherapy drug-induced agranulocytosis,⁶ resulting in successful identification and discontinuation of the responsible agent.

Mr. A’s bone marrow biopsy showed severe pancytopenia with profound neutropenia and normocytic anemia, without evidence of residual leukemia, inconsistent with Type I or Type II. Findings were suggestive of a myelodysplastic syndrome, consistent with secondary graft failure. Symptoms resolved after treatment with antibiotics, granulocyte colony-stimulating factor, epoetin alfa, and thrombopoietin. Mr. A’s ANC remained 0 µL for 22 days before returning to normal (>1,500 µL) by Day 29. He had no secondary complications resulting from neutropenia. As the clinical evidence suggested, Mr. A’s neutropenia was unlikely to be due to clozapine. Clozapine was continued throughout his cancer treatment, and he remained psychiatrically stable.

Clozapine, cancer treatments, and agranulocytosis

This case demonstrates that clozapine can be safely continued during a variety of cancer treatments (ie, chemotherapy, CAR T-cell therapy, HSCT), even with the development of agranulocytosis and prolonged neutropenia. Evidence to guide psychiatric clinicians to evaluate the likelihood that agranulocytosis is clozapine-induced is limited.

Continue to: We offer an algorithm...

We offer an algorithm to assist clinicians faced with this challenging clinical dilemma (Figure). Based on our experience and limited current evidence, we recommend continuing clozapine during cancer treatment unless there is clear evidence to suggest otherwise. Presently, no evidence in published literature suggests worsened outcomes in patients treated concurrently with clozapine and cancer therapies.

OUTCOME Cancer-free and psychiatrically stable

Mr. A continues clozapine therapy throughout all phases of treatment, without interruption. No adverse effects are determined to be secondary to clozapine. He remains psychiatrically stable throughout treatment, and able to participate and engage in his oncologic therapy. Mr. A is now more than 1 year in remission with no recurrence of graft failure, and his psychiatric symptoms continue to be well controlled with clozapine.

Bottom Line

Clozapine can be safely continued during a variety of cancer treatments (ie, chemotherapy, CAR T-cell therapy, HSCT), even in patients who develop agranulocytosis and prolonged neutropenia. Based on our experience and limited evidence, we offer an algorithm to assist clinicians faced with this challenging clinical dilemma.

Related Resources

• Grainger BT, Arcasoy MO, Kenedi CA. Feasibility of myelosuppressive chemotherapy in psychiatric patients on clozapine: a systematic review of the literature. Eur J Haematol. 2019;103(4):277-286. doi:10.1111/ejh.13285
• Daniel JS, Gross T. Managing clozapine-induced neutropenia and agranulocytosis. Current Psychiatry. 2016;15(12):51-53.

Drug Brand Names

Aripiprazole • Abilify
Clozapine • Clozaril
Divalproex sodium • Depakote
Epoetin alfa • Epogen
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Ziprasidone • Geodon

CASE Schizophrenia, leukemia, and chemotherapy

Mr. A, age 30, has schizophrenia but has been stable on clozapine 600 mg/d. He presents to the emergency department with generalized pain that started in his right scapula, arm, elbow, and back. Laboratory tests and a diagnostic examination reveal severe leukocytosis, thrombocytopenia, and anemia, and clinicians diagnose Mr. A with B-cell acute lymphocytic leukemia (B-ALL). Upon admission, Mr. A is neutropenic with an absolute neutrophil count (ANC) of 1,420 µL (reference range 2,500 to 6,000 µL). The hematology team recommends chemotherapy. The treating clinicians also consult the psychiatry team for recommendations on how to best manage Mr. A’s schizophrenia during chemotherapy, including whether clozapine should be discontinued.

HISTORY Stable on clozapine for >10 years

Mr. A was diagnosed with schizophrenia at age 15 after developing paranoia and auditory hallucinations of people talking to him and to each other. He had been hospitalized multiple times for worsened auditory hallucinations and paranoia that led to significant agitation and violence. Previous treatment with multiple antipsychotics, including haloperidol, quetiapine, aripiprazole, olanzapine, risperidone, and ziprasidone, was not successful. Mr. A began clozapine >10 years ago, and his symptoms have been stable since, without any further psychiatric hospitalizations. Mr. A takes clozapine 600 mg/d and divalproex sodium 1,500 mg/d, which he tolerates well and without significant adverse effects. Though he continues to have intermittent auditory hallucinations, they are mild and manageable. Mr. A lives with his mother, who reports he occasionally talks to himself but when he does not take clozapine, the auditory hallucinations worsen and cause him to become paranoid and aggressive. His ANC is monitored monthly and had been normal for several years until he was diagnosed with B-ALL.

[polldaddy:11125941]

The authors’ observations

The decision to continue clozapine during chemotherapy is challenging and should weigh the risk of agranulocytosis against that of psychiatric destabilization. Because clozapine and chemotherapy are both associated with agranulocytosis, there is concern that concurrent treatment could increase this risk in an additive or synergistic manner. To the best of our knowledge, there are currently no controlled studies investigating the interactions between clozapine and chemotherapeutic agents. Evidence on the hematopoietic consequences of concurrent clozapine and chemotherapy treatment has been limited to case reports because the topic does not lend itself well to randomized controlled trials.

A recent systematic review found no adverse outcomes among the 27 published cases in which clozapine was continued during myelosuppressive chemotherapy.¹ The most notable finding was an association between clozapine discontinuation and psychiatric decompensation, which was reported in 12 of 13 cases in which clozapine was prophylactically discontinued to minimize the risk of agranulocytosis.

Patient-specific factors must also be considered, such as the likelihood that psychotic symptoms will recur or worsen if clozapine is discontinued, as well as the extent to which symptom recurrence would interfere with cancer treatment. Clinicians should evaluate the feasibility of switching to another antipsychotic by obtaining a thorough history of the patient’s previous antipsychotics, doses, treatment duration, and response. However, many patients are treated with clozapine because their psychotic symptoms did not improve with other treatments. The character and severity of the patient’s psychotic symptoms when untreated or prior to clozapine treatment can provide a clearer understanding of how a recurrence of symptoms may interfere with cancer treatment. To formulate an accurate assessment of risks and benefits, it is necessary to consider both available evidence and patient-specific factors. The significant agitation and paranoia that Mr. A experienced when not taking clozapine was likely to disrupt chemotherapy. Thus, the adverse consequences of discontinuing clozapine were both severe and likely.

TREATMENT Continuing clozapine

After an extensive discussion of risks, benefits, and alternative treatments with the hematology and psychiatry teams, Mr. A and his family decide to continue clozapine with increased ANC monitoring during chemotherapy. Concurrent treatment was pursued with close collaboration among the patient, the patient’s family, and the hematology and pharmacy teams, and in careful consideration of the clozapine risk evaluation and mitigation strategy. Mr. A’s ANC was monitored daily during chemotherapy treatments and weekly in the intervals between treatments.

As expected, chemotherapy resulted in bone marrow suppression and pancytopenia. Mr. A’s ANC steadily decreased during the next 10 days until it reached 0 µL. This was consistent with the predicted ANC nadir between Day 10 and Day 14, after which recovery was expected. However, Mr. A’s ANC remained at 0 µL on Day 15.

[polldaddy:11125947]

Continue to: The authors' observations

 

 

The authors’ observations

Temporary decreases in ANC are expected during chemotherapy, and the timing of onset and recovery is often well characterized. Prior to Day 15, the observed progressive marrow suppression was solely due to chemotherapy. However, because Mr. A’s ANC remained 0 µL longer than anticipated, reevaluation of clozapine’s effects was warranted.

Timing, clinical course, and comprehensive hematologic monitoring can provide important clues as to whether clozapine may be responsible for prolonged neutropenia. Though a prolonged ANC of 0 µL raised concern for clozapine-induced agranulocytosis (CIAG), comprehensive monitoring of hematologic cell lines was reassuring because CIAG selectively targets granulocytic cells (neutrophils).² In contrast, chemo­therapy can affect other cell lineages, including lymphocytes, red blood cells, and platelets, which causes pancytopenia.³ For Mr. A, though the clinical presentation of pancytopenia was significant and concerning, it was inconsistent with CIAG.

Additionally, the patient’s baseline risk of CIAG should be considered. After 18 weeks of clozapine treatment, the risk of CIAG decreases to a level similar to that associated with other antipsychotics.^4,5 Therefore, CIAG would be unlikely in a patient treated with clozapine for more than 1 year and who did not have a history of neutropenia, as was the case with Mr. A.

While bone marrow biopsy can help differentiate between the causes of agranulocytosis,⁶ it is highly invasive and may not be necessary if laboratory evidence is sufficient. However, if a treatment team is strongly considering discontinuing clozapine and there are no suitable alternatives, a biopsy may provide additional clarification.

TREATMENT CAR T-cell therapy and cancer remission

Clozapine is continued with daily monitoring. On Day 19, Mr. A’s ANC increases, reaching 2,600 µL by discharge on Day 40. Mr. A remains psychiatrically stable throughout his hospitalization and does not experience any complications associated with neutropenia, despite its prolonged duration.

Continue to: Unfortunately, multiple cycles of...

Unfortunately, multiple cycles of chemo­therapy fail to induce remission. Mr. A is referred for CD19/CD22 chimeric antigen receptor (CAR) T-cell therapy, which helps achieve remission. Allogeneic hematopoietic stem cell transplant (HSCT) is recommended to maximize the likelihood of sustained remission.⁷ As with chemotherapy, Mr. A and his family agree with the multidisciplinary treatment recommendation to continue clozapine during both CAR T-cell therapy and HSCT, because the risks associated with psychiatric decompensation were greater than a potential increased risk of agranulocytosis. Clozapine treatment is continued throughout both therapies without issue.

Four months after HSCT, Mr. A is admitted for neutropenic fever and left face cellulitis. Upon admission, his ANC is 30 µL and subsequently decreases to 0 µL. In addition to neutropenia, Mr. A is also anemic and thrombocytopenic. He undergoes a bone marrow biopsy.

[polldaddy:11125950]

The authors’ observations

While no published cases have examined the bone marrow of patients experiencing CIAG, 2 retrospective studies have characterized 2 classes of bone marrow findings associated with drug-induced agranulocytosis resulting from nonchemotherapeutic agents (Table).^8,9 Type I marrow appears hypercellular with adequate neutrophil precursors but an arrested neutrophil maturation, with few or no mature forms of neutrophils beyond myelocytes.^8,9 Type II demonstrates a severe reduction or complete absence of granulocytic precursors with normal or increased erythropoiesis and megakaryocytes.^8,9 These findings have been used to accurately differentiate between chemotherapy and nonchemotherapy drug-induced agranulocytosis,⁶ resulting in successful identification and discontinuation of the responsible agent.

Mr. A’s bone marrow biopsy showed severe pancytopenia with profound neutropenia and normocytic anemia, without evidence of residual leukemia, inconsistent with Type I or Type II. Findings were suggestive of a myelodysplastic syndrome, consistent with secondary graft failure. Symptoms resolved after treatment with antibiotics, granulocyte colony-stimulating factor, epoetin alfa, and thrombopoietin. Mr. A’s ANC remained 0 µL for 22 days before returning to normal (>1,500 µL) by Day 29. He had no secondary complications resulting from neutropenia. As the clinical evidence suggested, Mr. A’s neutropenia was unlikely to be due to clozapine. Clozapine was continued throughout his cancer treatment, and he remained psychiatrically stable.

Clozapine, cancer treatments, and agranulocytosis

This case demonstrates that clozapine can be safely continued during a variety of cancer treatments (ie, chemotherapy, CAR T-cell therapy, HSCT), even with the development of agranulocytosis and prolonged neutropenia. Evidence to guide psychiatric clinicians to evaluate the likelihood that agranulocytosis is clozapine-induced is limited.

Continue to: We offer an algorithm...

We offer an algorithm to assist clinicians faced with this challenging clinical dilemma (Figure). Based on our experience and limited current evidence, we recommend continuing clozapine during cancer treatment unless there is clear evidence to suggest otherwise. Presently, no evidence in published literature suggests worsened outcomes in patients treated concurrently with clozapine and cancer therapies.

OUTCOME Cancer-free and psychiatrically stable

Mr. A continues clozapine therapy throughout all phases of treatment, without interruption. No adverse effects are determined to be secondary to clozapine. He remains psychiatrically stable throughout treatment, and able to participate and engage in his oncologic therapy. Mr. A is now more than 1 year in remission with no recurrence of graft failure, and his psychiatric symptoms continue to be well controlled with clozapine.

Bottom Line

Clozapine can be safely continued during a variety of cancer treatments (ie, chemotherapy, CAR T-cell therapy, HSCT), even in patients who develop agranulocytosis and prolonged neutropenia. Based on our experience and limited evidence, we offer an algorithm to assist clinicians faced with this challenging clinical dilemma.

Related Resources

• Grainger BT, Arcasoy MO, Kenedi CA. Feasibility of myelosuppressive chemotherapy in psychiatric patients on clozapine: a systematic review of the literature. Eur J Haematol. 2019;103(4):277-286. doi:10.1111/ejh.13285
• Daniel JS, Gross T. Managing clozapine-induced neutropenia and agranulocytosis. Current Psychiatry. 2016;15(12):51-53.

Drug Brand Names

Aripiprazole • Abilify
Clozapine • Clozaril
Divalproex sodium • Depakote
Epoetin alfa • Epogen
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Ziprasidone • Geodon

CASE Schizophrenia, leukemia, and chemotherapy

Mr. A, age 30, has schizophrenia but has been stable on clozapine 600 mg/d. He presents to the emergency department with generalized pain that started in his right scapula, arm, elbow, and back. Laboratory tests and a diagnostic examination reveal severe leukocytosis, thrombocytopenia, and anemia, and clinicians diagnose Mr. A with B-cell acute lymphocytic leukemia (B-ALL). Upon admission, Mr. A is neutropenic with an absolute neutrophil count (ANC) of 1,420 µL (reference range 2,500 to 6,000 µL). The hematology team recommends chemotherapy. The treating clinicians also consult the psychiatry team for recommendations on how to best manage Mr. A’s schizophrenia during chemotherapy, including whether clozapine should be discontinued.

HISTORY Stable on clozapine for >10 years

Mr. A was diagnosed with schizophrenia at age 15 after developing paranoia and auditory hallucinations of people talking to him and to each other. He had been hospitalized multiple times for worsened auditory hallucinations and paranoia that led to significant agitation and violence. Previous treatment with multiple antipsychotics, including haloperidol, quetiapine, aripiprazole, olanzapine, risperidone, and ziprasidone, was not successful. Mr. A began clozapine >10 years ago, and his symptoms have been stable since, without any further psychiatric hospitalizations. Mr. A takes clozapine 600 mg/d and divalproex sodium 1,500 mg/d, which he tolerates well and without significant adverse effects. Though he continues to have intermittent auditory hallucinations, they are mild and manageable. Mr. A lives with his mother, who reports he occasionally talks to himself but when he does not take clozapine, the auditory hallucinations worsen and cause him to become paranoid and aggressive. His ANC is monitored monthly and had been normal for several years until he was diagnosed with B-ALL.

[polldaddy:11125941]

The authors’ observations

The decision to continue clozapine during chemotherapy is challenging and should weigh the risk of agranulocytosis against that of psychiatric destabilization. Because clozapine and chemotherapy are both associated with agranulocytosis, there is concern that concurrent treatment could increase this risk in an additive or synergistic manner. To the best of our knowledge, there are currently no controlled studies investigating the interactions between clozapine and chemotherapeutic agents. Evidence on the hematopoietic consequences of concurrent clozapine and chemotherapy treatment has been limited to case reports because the topic does not lend itself well to randomized controlled trials.

A recent systematic review found no adverse outcomes among the 27 published cases in which clozapine was continued during myelosuppressive chemotherapy.¹ The most notable finding was an association between clozapine discontinuation and psychiatric decompensation, which was reported in 12 of 13 cases in which clozapine was prophylactically discontinued to minimize the risk of agranulocytosis.

Patient-specific factors must also be considered, such as the likelihood that psychotic symptoms will recur or worsen if clozapine is discontinued, as well as the extent to which symptom recurrence would interfere with cancer treatment. Clinicians should evaluate the feasibility of switching to another antipsychotic by obtaining a thorough history of the patient’s previous antipsychotics, doses, treatment duration, and response. However, many patients are treated with clozapine because their psychotic symptoms did not improve with other treatments. The character and severity of the patient’s psychotic symptoms when untreated or prior to clozapine treatment can provide a clearer understanding of how a recurrence of symptoms may interfere with cancer treatment. To formulate an accurate assessment of risks and benefits, it is necessary to consider both available evidence and patient-specific factors. The significant agitation and paranoia that Mr. A experienced when not taking clozapine was likely to disrupt chemotherapy. Thus, the adverse consequences of discontinuing clozapine were both severe and likely.

TREATMENT Continuing clozapine

After an extensive discussion of risks, benefits, and alternative treatments with the hematology and psychiatry teams, Mr. A and his family decide to continue clozapine with increased ANC monitoring during chemotherapy. Concurrent treatment was pursued with close collaboration among the patient, the patient’s family, and the hematology and pharmacy teams, and in careful consideration of the clozapine risk evaluation and mitigation strategy. Mr. A’s ANC was monitored daily during chemotherapy treatments and weekly in the intervals between treatments.

As expected, chemotherapy resulted in bone marrow suppression and pancytopenia. Mr. A’s ANC steadily decreased during the next 10 days until it reached 0 µL. This was consistent with the predicted ANC nadir between Day 10 and Day 14, after which recovery was expected. However, Mr. A’s ANC remained at 0 µL on Day 15.

[polldaddy:11125947]

Continue to: The authors' observations

 

 

The authors’ observations

Temporary decreases in ANC are expected during chemotherapy, and the timing of onset and recovery is often well characterized. Prior to Day 15, the observed progressive marrow suppression was solely due to chemotherapy. However, because Mr. A’s ANC remained 0 µL longer than anticipated, reevaluation of clozapine’s effects was warranted.

Timing, clinical course, and comprehensive hematologic monitoring can provide important clues as to whether clozapine may be responsible for prolonged neutropenia. Though a prolonged ANC of 0 µL raised concern for clozapine-induced agranulocytosis (CIAG), comprehensive monitoring of hematologic cell lines was reassuring because CIAG selectively targets granulocytic cells (neutrophils).² In contrast, chemo­therapy can affect other cell lineages, including lymphocytes, red blood cells, and platelets, which causes pancytopenia.³ For Mr. A, though the clinical presentation of pancytopenia was significant and concerning, it was inconsistent with CIAG.

Additionally, the patient’s baseline risk of CIAG should be considered. After 18 weeks of clozapine treatment, the risk of CIAG decreases to a level similar to that associated with other antipsychotics.^4,5 Therefore, CIAG would be unlikely in a patient treated with clozapine for more than 1 year and who did not have a history of neutropenia, as was the case with Mr. A.

While bone marrow biopsy can help differentiate between the causes of agranulocytosis,⁶ it is highly invasive and may not be necessary if laboratory evidence is sufficient. However, if a treatment team is strongly considering discontinuing clozapine and there are no suitable alternatives, a biopsy may provide additional clarification.

TREATMENT CAR T-cell therapy and cancer remission

Clozapine is continued with daily monitoring. On Day 19, Mr. A’s ANC increases, reaching 2,600 µL by discharge on Day 40. Mr. A remains psychiatrically stable throughout his hospitalization and does not experience any complications associated with neutropenia, despite its prolonged duration.

Continue to: Unfortunately, multiple cycles of...

Unfortunately, multiple cycles of chemo­therapy fail to induce remission. Mr. A is referred for CD19/CD22 chimeric antigen receptor (CAR) T-cell therapy, which helps achieve remission. Allogeneic hematopoietic stem cell transplant (HSCT) is recommended to maximize the likelihood of sustained remission.⁷ As with chemotherapy, Mr. A and his family agree with the multidisciplinary treatment recommendation to continue clozapine during both CAR T-cell therapy and HSCT, because the risks associated with psychiatric decompensation were greater than a potential increased risk of agranulocytosis. Clozapine treatment is continued throughout both therapies without issue.

Four months after HSCT, Mr. A is admitted for neutropenic fever and left face cellulitis. Upon admission, his ANC is 30 µL and subsequently decreases to 0 µL. In addition to neutropenia, Mr. A is also anemic and thrombocytopenic. He undergoes a bone marrow biopsy.

[polldaddy:11125950]

The authors’ observations

While no published cases have examined the bone marrow of patients experiencing CIAG, 2 retrospective studies have characterized 2 classes of bone marrow findings associated with drug-induced agranulocytosis resulting from nonchemotherapeutic agents (Table).^8,9 Type I marrow appears hypercellular with adequate neutrophil precursors but an arrested neutrophil maturation, with few or no mature forms of neutrophils beyond myelocytes.^8,9 Type II demonstrates a severe reduction or complete absence of granulocytic precursors with normal or increased erythropoiesis and megakaryocytes.^8,9 These findings have been used to accurately differentiate between chemotherapy and nonchemotherapy drug-induced agranulocytosis,⁶ resulting in successful identification and discontinuation of the responsible agent.

Mr. A’s bone marrow biopsy showed severe pancytopenia with profound neutropenia and normocytic anemia, without evidence of residual leukemia, inconsistent with Type I or Type II. Findings were suggestive of a myelodysplastic syndrome, consistent with secondary graft failure. Symptoms resolved after treatment with antibiotics, granulocyte colony-stimulating factor, epoetin alfa, and thrombopoietin. Mr. A’s ANC remained 0 µL for 22 days before returning to normal (>1,500 µL) by Day 29. He had no secondary complications resulting from neutropenia. As the clinical evidence suggested, Mr. A’s neutropenia was unlikely to be due to clozapine. Clozapine was continued throughout his cancer treatment, and he remained psychiatrically stable.

Clozapine, cancer treatments, and agranulocytosis

This case demonstrates that clozapine can be safely continued during a variety of cancer treatments (ie, chemotherapy, CAR T-cell therapy, HSCT), even with the development of agranulocytosis and prolonged neutropenia. Evidence to guide psychiatric clinicians to evaluate the likelihood that agranulocytosis is clozapine-induced is limited.

Continue to: We offer an algorithm...

We offer an algorithm to assist clinicians faced with this challenging clinical dilemma (Figure). Based on our experience and limited current evidence, we recommend continuing clozapine during cancer treatment unless there is clear evidence to suggest otherwise. Presently, no evidence in published literature suggests worsened outcomes in patients treated concurrently with clozapine and cancer therapies.

OUTCOME Cancer-free and psychiatrically stable

Mr. A continues clozapine therapy throughout all phases of treatment, without interruption. No adverse effects are determined to be secondary to clozapine. He remains psychiatrically stable throughout treatment, and able to participate and engage in his oncologic therapy. Mr. A is now more than 1 year in remission with no recurrence of graft failure, and his psychiatric symptoms continue to be well controlled with clozapine.

Bottom Line

Clozapine can be safely continued during a variety of cancer treatments (ie, chemotherapy, CAR T-cell therapy, HSCT), even in patients who develop agranulocytosis and prolonged neutropenia. Based on our experience and limited evidence, we offer an algorithm to assist clinicians faced with this challenging clinical dilemma.

Related Resources

• Grainger BT, Arcasoy MO, Kenedi CA. Feasibility of myelosuppressive chemotherapy in psychiatric patients on clozapine: a systematic review of the literature. Eur J Haematol. 2019;103(4):277-286. doi:10.1111/ejh.13285
• Daniel JS, Gross T. Managing clozapine-induced neutropenia and agranulocytosis. Current Psychiatry. 2016;15(12):51-53.

Drug Brand Names

Aripiprazole • Abilify
Clozapine • Clozaril
Divalproex sodium • Depakote
Epoetin alfa • Epogen
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Ziprasidone • Geodon

Boarding of psychiatric patients in the emergency department (ED) has been well documented.¹ Numerous researchers have discussed ways to address this public health crisis. In this Pearl, I use the acronym BOARDING to provide key strategies for psychiatric clinicians managing psychiatric patients who are boarding in an ED.

Be vigilant. As a patient’s time waiting in the ED increases, watch for clinical blind spots. New medical problems,² psychiatric issues, or medication errors³ may unexpectedly arise since the patient was originally stabilized by emergency medicine clinicians.

Orders. Since the patient could be waiting in the ED for 24 hours or longer, consider starting orders (eg, precautions, medications, diet, vital sign checks, labs, etc) as you would for a patient in an inpatient psychiatric unit or a dedicated psychiatric ED.

AWOL. Unlike inpatient psychiatric units, EDs generally are not locked. Extra resources (eg, sitter, safety alarm bracelet) may be needed to help prevent patients from leaving this setting unnoticed, especially those on involuntary psychiatric holds.

Re-evaluate. Ideally, re-evaluate the patient every shift. Does the patient still need an inpatient psychiatric setting? Can the involuntary psychiatric hold be discontinued?

Disposition. Is there a family member or reliable caregiver to whom the patient can be discharged? Can the patient go to a shelter or be stabilized in a short-term residential program, instead of an inpatient psychiatric unit?

Inpatient. If the patient waits 24 hours or longer, begin thinking like an inpatient psychiatric clinician. Are there any interventions you can reasonably begin in the ED that you would otherwise begin on an inpatient psychiatric unit?

Nursing. Work with ED nursing staff to familiarize them with the patient’s specific needs.

Guidelines. With the input of clinical and administrative leadership, establish local hospital-based guidelines for managing psychiatric patients who are boarding in the ED.

Boarding of psychiatric patients in the emergency department (ED) has been well documented.¹ Numerous researchers have discussed ways to address this public health crisis. In this Pearl, I use the acronym BOARDING to provide key strategies for psychiatric clinicians managing psychiatric patients who are boarding in an ED.

Be vigilant. As a patient’s time waiting in the ED increases, watch for clinical blind spots. New medical problems,² psychiatric issues, or medication errors³ may unexpectedly arise since the patient was originally stabilized by emergency medicine clinicians.

Orders. Since the patient could be waiting in the ED for 24 hours or longer, consider starting orders (eg, precautions, medications, diet, vital sign checks, labs, etc) as you would for a patient in an inpatient psychiatric unit or a dedicated psychiatric ED.

AWOL. Unlike inpatient psychiatric units, EDs generally are not locked. Extra resources (eg, sitter, safety alarm bracelet) may be needed to help prevent patients from leaving this setting unnoticed, especially those on involuntary psychiatric holds.

Re-evaluate. Ideally, re-evaluate the patient every shift. Does the patient still need an inpatient psychiatric setting? Can the involuntary psychiatric hold be discontinued?

Disposition. Is there a family member or reliable caregiver to whom the patient can be discharged? Can the patient go to a shelter or be stabilized in a short-term residential program, instead of an inpatient psychiatric unit?

Inpatient. If the patient waits 24 hours or longer, begin thinking like an inpatient psychiatric clinician. Are there any interventions you can reasonably begin in the ED that you would otherwise begin on an inpatient psychiatric unit?

Nursing. Work with ED nursing staff to familiarize them with the patient’s specific needs.

Guidelines. With the input of clinical and administrative leadership, establish local hospital-based guidelines for managing psychiatric patients who are boarding in the ED.

Boarding of psychiatric patients in the emergency department (ED) has been well documented.¹ Numerous researchers have discussed ways to address this public health crisis. In this Pearl, I use the acronym BOARDING to provide key strategies for psychiatric clinicians managing psychiatric patients who are boarding in an ED.

Be vigilant. As a patient’s time waiting in the ED increases, watch for clinical blind spots. New medical problems,² psychiatric issues, or medication errors³ may unexpectedly arise since the patient was originally stabilized by emergency medicine clinicians.

Orders. Since the patient could be waiting in the ED for 24 hours or longer, consider starting orders (eg, precautions, medications, diet, vital sign checks, labs, etc) as you would for a patient in an inpatient psychiatric unit or a dedicated psychiatric ED.

AWOL. Unlike inpatient psychiatric units, EDs generally are not locked. Extra resources (eg, sitter, safety alarm bracelet) may be needed to help prevent patients from leaving this setting unnoticed, especially those on involuntary psychiatric holds.

Re-evaluate. Ideally, re-evaluate the patient every shift. Does the patient still need an inpatient psychiatric setting? Can the involuntary psychiatric hold be discontinued?

Disposition. Is there a family member or reliable caregiver to whom the patient can be discharged? Can the patient go to a shelter or be stabilized in a short-term residential program, instead of an inpatient psychiatric unit?

Inpatient. If the patient waits 24 hours or longer, begin thinking like an inpatient psychiatric clinician. Are there any interventions you can reasonably begin in the ED that you would otherwise begin on an inpatient psychiatric unit?

Nursing. Work with ED nursing staff to familiarize them with the patient’s specific needs.

Guidelines. With the input of clinical and administrative leadership, establish local hospital-based guidelines for managing psychiatric patients who are boarding in the ED.

Ramadan is one of the obligatory pillars in Islam during which healthy Muslims are required to fast from dawn until sunset every day for 1 month. There are an estimated 3.45 million Muslims in the United States, and this population will continue to grow by 100,000 per year.¹ With the increased growth of the Muslim population, it is important for clinicians to be aware of how patients of Muslim faith are affected during Ramadan. In this article, we explore the potential risks, as well as the benefits, the month of Ramadan brings to patients. We will also explain how being religiously aware is necessary to provide optimal care for these individuals.

For some patients, fasting may pose risks

Similar to other communities in the United States, individuals who are Muslim experience mood disorders, anxiety disorders, posttraumatic stress disorder, obsessive-compulsive disorder, schizophrenia, substance use disorders, and other psychiatric illnesses.² During the month of Ramadan, Muslims are to abstain completely from eating and drinking from dawn until sunset. This includes medications as well as food and drink.

Due to these circumstances, patients will often change the timing, frequency, and dosing of their medications to allow them to fast. One study found 60% of Muslims made medication adjustments during Ramadan without seeking medical advice.³ It is possible that such alterations may be detrimental. During Ramadan, some Muslims wake up early in the morning to eat a pre-dawn meal, and often go back to sleep. This has been reported to cause a delay in sleep-wake times and to reduce rapid eye movement sleep.⁴ These circadian rhythm changes can be detrimental to patients with bipolar disorder. One study found higher rates of relapse to depression and mania in patients with bipolar disorder who were fasting during Ramadan.⁵ Circadian rhythm disturbances also may worsen depression.⁶ Another point of concern is patients with eating disorders. One small case series (N = 6) found that fasting during Ramadan exacerbated symptoms in patients with eating disorders.⁷

Another concern is that dehydration while fasting can lead to lithium toxicity. However, one study found lithium levels remained stable while fasting for 10 to 12 hours.⁵ Another showed that changing lithium dosing from twice a day to once a day allowed for easier administration without causing a subtherapeutic change in blood lithium levels.⁸

The practice also may have benefits for mental health

For many Muslims, Ramadan is the best time of the year, where they reconnect with their religion and experience the utmost spiritual growth. Studies have shown that the incidence of suicide is lowest during Ramadan compared to other months.⁹ A study of older men found that intermittent fasting and calorie restriction (not during Ramadan) resulted in decreases in tension, confusion, anger, and mood disturbance.¹⁰ Another study found that fasting during Ramadan had a positive impact on depression, anxiety, stress, and cognitive function.¹¹

Clinical considerations

To provide the best care for Muslim patients during Ramadan, clinicians should take a holistic approach and take all factors into consideration. It is common for circadian rhythm disruptions to exacerbate mood disorders, so encourage patients to maintain healthy sleep hygiene to their best ability during this month. Another important consideration is medication timing and dosing.¹² For patients prescribed a medication that typically is taken twice a day, determine if this dosing can be changed to once a day, or if both doses can be taken when it is permissible to eat (sunset to dawn). For medications that are absorbed with food, consider how these medications might be adjusted and maintained while a patient is fasting. Some medications may be sedating or activating, so the timing of administration may need to be adjusted to meet the patient’s needs. Lastly, keep in mind that certain medications can have withdrawal effects, and the likelihood of this occurring while a patient is fasting.

One vital point is that if a patient is at high risk of clinically decompensating due to fasting or medication adjustments or discontinuation, advise them to not fast. Muslims with physical or mental illnesses are excused from fasting. Bear in mind that because Ramadan is meant to be a month of heightened spirituality, many Muslims will prefer to fast.

Ramadan is one of the obligatory pillars in Islam during which healthy Muslims are required to fast from dawn until sunset every day for 1 month. There are an estimated 3.45 million Muslims in the United States, and this population will continue to grow by 100,000 per year.¹ With the increased growth of the Muslim population, it is important for clinicians to be aware of how patients of Muslim faith are affected during Ramadan. In this article, we explore the potential risks, as well as the benefits, the month of Ramadan brings to patients. We will also explain how being religiously aware is necessary to provide optimal care for these individuals.

For some patients, fasting may pose risks

Similar to other communities in the United States, individuals who are Muslim experience mood disorders, anxiety disorders, posttraumatic stress disorder, obsessive-compulsive disorder, schizophrenia, substance use disorders, and other psychiatric illnesses.² During the month of Ramadan, Muslims are to abstain completely from eating and drinking from dawn until sunset. This includes medications as well as food and drink.

Due to these circumstances, patients will often change the timing, frequency, and dosing of their medications to allow them to fast. One study found 60% of Muslims made medication adjustments during Ramadan without seeking medical advice.³ It is possible that such alterations may be detrimental. During Ramadan, some Muslims wake up early in the morning to eat a pre-dawn meal, and often go back to sleep. This has been reported to cause a delay in sleep-wake times and to reduce rapid eye movement sleep.⁴ These circadian rhythm changes can be detrimental to patients with bipolar disorder. One study found higher rates of relapse to depression and mania in patients with bipolar disorder who were fasting during Ramadan.⁵ Circadian rhythm disturbances also may worsen depression.⁶ Another point of concern is patients with eating disorders. One small case series (N = 6) found that fasting during Ramadan exacerbated symptoms in patients with eating disorders.⁷

Another concern is that dehydration while fasting can lead to lithium toxicity. However, one study found lithium levels remained stable while fasting for 10 to 12 hours.⁵ Another showed that changing lithium dosing from twice a day to once a day allowed for easier administration without causing a subtherapeutic change in blood lithium levels.⁸

The practice also may have benefits for mental health

For many Muslims, Ramadan is the best time of the year, where they reconnect with their religion and experience the utmost spiritual growth. Studies have shown that the incidence of suicide is lowest during Ramadan compared to other months.⁹ A study of older men found that intermittent fasting and calorie restriction (not during Ramadan) resulted in decreases in tension, confusion, anger, and mood disturbance.¹⁰ Another study found that fasting during Ramadan had a positive impact on depression, anxiety, stress, and cognitive function.¹¹

Clinical considerations

To provide the best care for Muslim patients during Ramadan, clinicians should take a holistic approach and take all factors into consideration. It is common for circadian rhythm disruptions to exacerbate mood disorders, so encourage patients to maintain healthy sleep hygiene to their best ability during this month. Another important consideration is medication timing and dosing.¹² For patients prescribed a medication that typically is taken twice a day, determine if this dosing can be changed to once a day, or if both doses can be taken when it is permissible to eat (sunset to dawn). For medications that are absorbed with food, consider how these medications might be adjusted and maintained while a patient is fasting. Some medications may be sedating or activating, so the timing of administration may need to be adjusted to meet the patient’s needs. Lastly, keep in mind that certain medications can have withdrawal effects, and the likelihood of this occurring while a patient is fasting.

One vital point is that if a patient is at high risk of clinically decompensating due to fasting or medication adjustments or discontinuation, advise them to not fast. Muslims with physical or mental illnesses are excused from fasting. Bear in mind that because Ramadan is meant to be a month of heightened spirituality, many Muslims will prefer to fast.

Ramadan is one of the obligatory pillars in Islam during which healthy Muslims are required to fast from dawn until sunset every day for 1 month. There are an estimated 3.45 million Muslims in the United States, and this population will continue to grow by 100,000 per year.¹ With the increased growth of the Muslim population, it is important for clinicians to be aware of how patients of Muslim faith are affected during Ramadan. In this article, we explore the potential risks, as well as the benefits, the month of Ramadan brings to patients. We will also explain how being religiously aware is necessary to provide optimal care for these individuals.

For some patients, fasting may pose risks

Similar to other communities in the United States, individuals who are Muslim experience mood disorders, anxiety disorders, posttraumatic stress disorder, obsessive-compulsive disorder, schizophrenia, substance use disorders, and other psychiatric illnesses.² During the month of Ramadan, Muslims are to abstain completely from eating and drinking from dawn until sunset. This includes medications as well as food and drink.

Due to these circumstances, patients will often change the timing, frequency, and dosing of their medications to allow them to fast. One study found 60% of Muslims made medication adjustments during Ramadan without seeking medical advice.³ It is possible that such alterations may be detrimental. During Ramadan, some Muslims wake up early in the morning to eat a pre-dawn meal, and often go back to sleep. This has been reported to cause a delay in sleep-wake times and to reduce rapid eye movement sleep.⁴ These circadian rhythm changes can be detrimental to patients with bipolar disorder. One study found higher rates of relapse to depression and mania in patients with bipolar disorder who were fasting during Ramadan.⁵ Circadian rhythm disturbances also may worsen depression.⁶ Another point of concern is patients with eating disorders. One small case series (N = 6) found that fasting during Ramadan exacerbated symptoms in patients with eating disorders.⁷

Another concern is that dehydration while fasting can lead to lithium toxicity. However, one study found lithium levels remained stable while fasting for 10 to 12 hours.⁵ Another showed that changing lithium dosing from twice a day to once a day allowed for easier administration without causing a subtherapeutic change in blood lithium levels.⁸

The practice also may have benefits for mental health

For many Muslims, Ramadan is the best time of the year, where they reconnect with their religion and experience the utmost spiritual growth. Studies have shown that the incidence of suicide is lowest during Ramadan compared to other months.⁹ A study of older men found that intermittent fasting and calorie restriction (not during Ramadan) resulted in decreases in tension, confusion, anger, and mood disturbance.¹⁰ Another study found that fasting during Ramadan had a positive impact on depression, anxiety, stress, and cognitive function.¹¹

Clinical considerations

To provide the best care for Muslim patients during Ramadan, clinicians should take a holistic approach and take all factors into consideration. It is common for circadian rhythm disruptions to exacerbate mood disorders, so encourage patients to maintain healthy sleep hygiene to their best ability during this month. Another important consideration is medication timing and dosing.¹² For patients prescribed a medication that typically is taken twice a day, determine if this dosing can be changed to once a day, or if both doses can be taken when it is permissible to eat (sunset to dawn). For medications that are absorbed with food, consider how these medications might be adjusted and maintained while a patient is fasting. Some medications may be sedating or activating, so the timing of administration may need to be adjusted to meet the patient’s needs. Lastly, keep in mind that certain medications can have withdrawal effects, and the likelihood of this occurring while a patient is fasting.

One vital point is that if a patient is at high risk of clinically decompensating due to fasting or medication adjustments or discontinuation, advise them to not fast. Muslims with physical or mental illnesses are excused from fasting. Bear in mind that because Ramadan is meant to be a month of heightened spirituality, many Muslims will prefer to fast.

On April 12, 2022, the US Preventive Services Task Force (USPSTF) published a draft recommendation on screening for anxiety in children and adolescents. The recommendation states that clinicians should screen for anxiety in those ages 8 to 18 years. This is a “B” recommendation, which means there is moderate certainty that screening for anxiety in these individuals has a moderate net benefit. The USPSTF felt that the evidence was insufficient to recommend for or against screening at ages 7 years and younger.¹

Anxiety is common among young people in America. A survey conducted in 2018-2019 found that 7.8% of children and adolescents (ages 3 to 17 years) had a current anxiety disorder.² The isolation created by the COVID-19 pandemic has been associated with increased rates of clinically significant psychiatric symptoms; one study suggested that in the first year of the pandemic, 20% of young people experienced elevated anxiety symptoms.^3,4 Anxiety disorders in childhood and adolescence also are associated with an increased likelihood of a future anxiety disorder, or depression, in adulthood.

Therapy may improve outcomes. There is evidence that treatment of anxiety disorders can result in improved clinical outcomes. Treatment options include psychotherapy, pharmacotherapy, or a combination of both.⁵

However, studies showing benefit were conducted in young people whose anxiety was identified via signs or symptoms. The USPSTF could find no direct evidence that identifying anxiety in asymptomatic youth leads to better outcomes. The current draft recommendation is based on indirect evidence on the accuracy of the screening tools and the results of therapy in those who are symptomatic.

Speaking of screening tools ... There were 3 listed in the USPSTF evidence review: the Screen for Child Anxiety Related Disorders (SCARED), which assesses for generalized anxiety disorder (GAD) and any anxiety disorder⁶; the Patient Health Questionnaire-Adolescent, which screens for GAD and panic disorder⁷; and the Social Phobia Inventory.⁸ The SCARED and Social Phobia Inventory are the most widely used clinically.

The accuracy of the screening tests differed. For detection of GAD, sensitivity ranged from 50% to 88% and specificity from 63% to 98%; for social anxiety disorder, sensitivity ranged from 67% to 93% and specificity from 69% to 94%. False-positive results ranged from 17 to 361 per 1000 for GAD and from 104 to 254 per 1000 for social anxiety disorder.¹

The USPSTF emphasized that anxiety should not be diagnosed based on a screening test alone. A positive screen should prompt further assessment and confirmation.

An unexpected rating. Given the opportunity costs to administer a screening tool, the high false-positive rates, and the lack of evidence that screening results in improved outcomes among asymptomatic youth, it is curious that this topic did not result in an “I” recommendation. Many screening interventions for children and adolescents with similar evidence profiles—including screening for suicide risk, drug abuse, eating disorders, and alcohol abuse—have previously received an “I.”⁹

Keep in mind that this is currently a draft recommendation that is open for public comment. The final recommendation will be published in 4 to 12 months.

On April 12, 2022, the US Preventive Services Task Force (USPSTF) published a draft recommendation on screening for anxiety in children and adolescents. The recommendation states that clinicians should screen for anxiety in those ages 8 to 18 years. This is a “B” recommendation, which means there is moderate certainty that screening for anxiety in these individuals has a moderate net benefit. The USPSTF felt that the evidence was insufficient to recommend for or against screening at ages 7 years and younger.¹

Anxiety is common among young people in America. A survey conducted in 2018-2019 found that 7.8% of children and adolescents (ages 3 to 17 years) had a current anxiety disorder.² The isolation created by the COVID-19 pandemic has been associated with increased rates of clinically significant psychiatric symptoms; one study suggested that in the first year of the pandemic, 20% of young people experienced elevated anxiety symptoms.^3,4 Anxiety disorders in childhood and adolescence also are associated with an increased likelihood of a future anxiety disorder, or depression, in adulthood.

Therapy may improve outcomes. There is evidence that treatment of anxiety disorders can result in improved clinical outcomes. Treatment options include psychotherapy, pharmacotherapy, or a combination of both.⁵

However, studies showing benefit were conducted in young people whose anxiety was identified via signs or symptoms. The USPSTF could find no direct evidence that identifying anxiety in asymptomatic youth leads to better outcomes. The current draft recommendation is based on indirect evidence on the accuracy of the screening tools and the results of therapy in those who are symptomatic.

Speaking of screening tools ... There were 3 listed in the USPSTF evidence review: the Screen for Child Anxiety Related Disorders (SCARED), which assesses for generalized anxiety disorder (GAD) and any anxiety disorder⁶; the Patient Health Questionnaire-Adolescent, which screens for GAD and panic disorder⁷; and the Social Phobia Inventory.⁸ The SCARED and Social Phobia Inventory are the most widely used clinically.

The accuracy of the screening tests differed. For detection of GAD, sensitivity ranged from 50% to 88% and specificity from 63% to 98%; for social anxiety disorder, sensitivity ranged from 67% to 93% and specificity from 69% to 94%. False-positive results ranged from 17 to 361 per 1000 for GAD and from 104 to 254 per 1000 for social anxiety disorder.¹

The USPSTF emphasized that anxiety should not be diagnosed based on a screening test alone. A positive screen should prompt further assessment and confirmation.

An unexpected rating. Given the opportunity costs to administer a screening tool, the high false-positive rates, and the lack of evidence that screening results in improved outcomes among asymptomatic youth, it is curious that this topic did not result in an “I” recommendation. Many screening interventions for children and adolescents with similar evidence profiles—including screening for suicide risk, drug abuse, eating disorders, and alcohol abuse—have previously received an “I.”⁹

Keep in mind that this is currently a draft recommendation that is open for public comment. The final recommendation will be published in 4 to 12 months.

On April 12, 2022, the US Preventive Services Task Force (USPSTF) published a draft recommendation on screening for anxiety in children and adolescents. The recommendation states that clinicians should screen for anxiety in those ages 8 to 18 years. This is a “B” recommendation, which means there is moderate certainty that screening for anxiety in these individuals has a moderate net benefit. The USPSTF felt that the evidence was insufficient to recommend for or against screening at ages 7 years and younger.¹

Anxiety is common among young people in America. A survey conducted in 2018-2019 found that 7.8% of children and adolescents (ages 3 to 17 years) had a current anxiety disorder.² The isolation created by the COVID-19 pandemic has been associated with increased rates of clinically significant psychiatric symptoms; one study suggested that in the first year of the pandemic, 20% of young people experienced elevated anxiety symptoms.^3,4 Anxiety disorders in childhood and adolescence also are associated with an increased likelihood of a future anxiety disorder, or depression, in adulthood.

Therapy may improve outcomes. There is evidence that treatment of anxiety disorders can result in improved clinical outcomes. Treatment options include psychotherapy, pharmacotherapy, or a combination of both.⁵

However, studies showing benefit were conducted in young people whose anxiety was identified via signs or symptoms. The USPSTF could find no direct evidence that identifying anxiety in asymptomatic youth leads to better outcomes. The current draft recommendation is based on indirect evidence on the accuracy of the screening tools and the results of therapy in those who are symptomatic.

Speaking of screening tools ... There were 3 listed in the USPSTF evidence review: the Screen for Child Anxiety Related Disorders (SCARED), which assesses for generalized anxiety disorder (GAD) and any anxiety disorder⁶; the Patient Health Questionnaire-Adolescent, which screens for GAD and panic disorder⁷; and the Social Phobia Inventory.⁸ The SCARED and Social Phobia Inventory are the most widely used clinically.

The accuracy of the screening tests differed. For detection of GAD, sensitivity ranged from 50% to 88% and specificity from 63% to 98%; for social anxiety disorder, sensitivity ranged from 67% to 93% and specificity from 69% to 94%. False-positive results ranged from 17 to 361 per 1000 for GAD and from 104 to 254 per 1000 for social anxiety disorder.¹

The USPSTF emphasized that anxiety should not be diagnosed based on a screening test alone. A positive screen should prompt further assessment and confirmation.

An unexpected rating. Given the opportunity costs to administer a screening tool, the high false-positive rates, and the lack of evidence that screening results in improved outcomes among asymptomatic youth, it is curious that this topic did not result in an “I” recommendation. Many screening interventions for children and adolescents with similar evidence profiles—including screening for suicide risk, drug abuse, eating disorders, and alcohol abuse—have previously received an “I.”⁹

Keep in mind that this is currently a draft recommendation that is open for public comment. The final recommendation will be published in 4 to 12 months.

The inaugural issue of GI & Hepatology News was published in January 2007, and the newspaper has gone on to become part of the fabric of the AGA. This year, we celebrate the newspaper’s 15th year with a special 15th Anniversary Series that will run from June through December 2022. We will feature reflections from GIHN’s three former editors-in-chief, Dr. Charles J. Lightdale, Dr. Colin Howden, and Dr. John Allen, on the evolution of the newspaper (and the field of GI) over the past 15 years. We also will present a series of Then and Now columns, highlighting high-impact areas of GI and hepatology covered in past GIHN issues, and reflecting on how the field has changed since that time.

In this month’s issue, we are pleased to kick off the 15th Anniversary Series with reflections by Dr. Lightdale, GIHN’s inaugural editor-in-chief, as well as a Then and Now column written by Dr. Kimberly M. Persley (GIHN associate editor and longstanding AGA member) reflecting on how the demographics of gastroenterology and of the AGA as an organization have changed over the past 15 years. I hope you will find these special contributions to be engaging and thought-provoking. Other issue highlights include a lead article describing impacts of social determinants of health in driving disparities in IBD care and offering recommendations for achieving IBD health equity, a new AGA Clinical Practice Update on dietary options for our many patients with irritable bowel syndrome, and new data on the safety of anti-TNF medications prior to surgery in patients with inflammatory bowel disease.

As summer vacation season commences, I hope you will join me in taking some well-deserved time away from work demands, spending some quality time with friends and family, and seizing the opportunity to rest and recharge.

Megan A. Adams, MD, JD, MSc
Editor-in-Chief

The inaugural issue of GI & Hepatology News was published in January 2007, and the newspaper has gone on to become part of the fabric of the AGA. This year, we celebrate the newspaper’s 15th year with a special 15th Anniversary Series that will run from June through December 2022. We will feature reflections from GIHN’s three former editors-in-chief, Dr. Charles J. Lightdale, Dr. Colin Howden, and Dr. John Allen, on the evolution of the newspaper (and the field of GI) over the past 15 years. We also will present a series of Then and Now columns, highlighting high-impact areas of GI and hepatology covered in past GIHN issues, and reflecting on how the field has changed since that time.

In this month’s issue, we are pleased to kick off the 15th Anniversary Series with reflections by Dr. Lightdale, GIHN’s inaugural editor-in-chief, as well as a Then and Now column written by Dr. Kimberly M. Persley (GIHN associate editor and longstanding AGA member) reflecting on how the demographics of gastroenterology and of the AGA as an organization have changed over the past 15 years. I hope you will find these special contributions to be engaging and thought-provoking. Other issue highlights include a lead article describing impacts of social determinants of health in driving disparities in IBD care and offering recommendations for achieving IBD health equity, a new AGA Clinical Practice Update on dietary options for our many patients with irritable bowel syndrome, and new data on the safety of anti-TNF medications prior to surgery in patients with inflammatory bowel disease.

As summer vacation season commences, I hope you will join me in taking some well-deserved time away from work demands, spending some quality time with friends and family, and seizing the opportunity to rest and recharge.

Megan A. Adams, MD, JD, MSc
Editor-in-Chief

The inaugural issue of GI & Hepatology News was published in January 2007, and the newspaper has gone on to become part of the fabric of the AGA. This year, we celebrate the newspaper’s 15th year with a special 15th Anniversary Series that will run from June through December 2022. We will feature reflections from GIHN’s three former editors-in-chief, Dr. Charles J. Lightdale, Dr. Colin Howden, and Dr. John Allen, on the evolution of the newspaper (and the field of GI) over the past 15 years. We also will present a series of Then and Now columns, highlighting high-impact areas of GI and hepatology covered in past GIHN issues, and reflecting on how the field has changed since that time.

In this month’s issue, we are pleased to kick off the 15th Anniversary Series with reflections by Dr. Lightdale, GIHN’s inaugural editor-in-chief, as well as a Then and Now column written by Dr. Kimberly M. Persley (GIHN associate editor and longstanding AGA member) reflecting on how the demographics of gastroenterology and of the AGA as an organization have changed over the past 15 years. I hope you will find these special contributions to be engaging and thought-provoking. Other issue highlights include a lead article describing impacts of social determinants of health in driving disparities in IBD care and offering recommendations for achieving IBD health equity, a new AGA Clinical Practice Update on dietary options for our many patients with irritable bowel syndrome, and new data on the safety of anti-TNF medications prior to surgery in patients with inflammatory bowel disease.

As summer vacation season commences, I hope you will join me in taking some well-deserved time away from work demands, spending some quality time with friends and family, and seizing the opportunity to rest and recharge.

Megan A. Adams, MD, JD, MSc
Editor-in-Chief

The expanding range of therapies and interventions available for treatment of non–small cell lung cancer (NSCLC) has brought medical oncologists and interventional pulmonologists into closer partnership.

Oncologist Dr. Joy Feliciano and interventional pulmonologist Dr. A. Christine Argento, both colleagues at Johns Hopkins University, comment on their evolving relationship as a team.

Pulmonologists now often serve as the "gatekeepers into thoracic oncology," says Dr. Argento. Recent advances in technology, including endobronchial ultrasound, navigational bronchoscopy, and robotic-assisted bronchoscopy, allow for diagnosis, staging, and collection of sufficient tissue for advanced studies into molecular markers and genetic studies necessary to guide treatment decisions for metastatic NSCLC.

In resectable disease, patients who might have gone straight to surgery in the past now can be considered for neoadjuvant treatments. Here again, says Dr. Feliciano, it is critical for oncologists to understand the biomarkers and molecular profile of the tumor before considering an intervention, and the role of bronchoscopy is key.

A multidisciplinary practice of NSCLC specialists, who have access to on-site or virtual tumor boards, sometimes on an international scale, helps ensure optimal treatment for patients in the increasingly complex NSCLC arena.

--

A. Christine Argento, MD, Associate Professor of Medicine, Department of Pulmonary and Critical Care Medicine, Johns Hopkins University; Director of Bronchoscopy, Department of Interventional Pulmonary Medicine, Johns Hopkins Hospital, Baltimore, Maryland

A. Christine Argento, MD, has disclosed the following relevant financial relationships:

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Biodesix; Olympus; Cook; Intuitive; Boston Scientific

Josephine L. Feliciano, MD, Associate Professor, Clinical Director, Sidney Kimmel Cancer Center, Johns Hopkins University Hospital, Baltimore, Maryland

Josephine L. Feliciano, MD, has disclosed the following relevant financial relationships:

Received research grant from: Bristol-Myers; Pfizer; AstraZeneca.

Received income in an amount equal to or greater than $250 from: Genentech; AstraZeneca; Eli Lilly; Merck; Regeneron; Coherus; Takeda; Bristol-Myers

The expanding range of therapies and interventions available for treatment of non–small cell lung cancer (NSCLC) has brought medical oncologists and interventional pulmonologists into closer partnership.

Oncologist Dr. Joy Feliciano and interventional pulmonologist Dr. A. Christine Argento, both colleagues at Johns Hopkins University, comment on their evolving relationship as a team.

Pulmonologists now often serve as the "gatekeepers into thoracic oncology," says Dr. Argento. Recent advances in technology, including endobronchial ultrasound, navigational bronchoscopy, and robotic-assisted bronchoscopy, allow for diagnosis, staging, and collection of sufficient tissue for advanced studies into molecular markers and genetic studies necessary to guide treatment decisions for metastatic NSCLC.

In resectable disease, patients who might have gone straight to surgery in the past now can be considered for neoadjuvant treatments. Here again, says Dr. Feliciano, it is critical for oncologists to understand the biomarkers and molecular profile of the tumor before considering an intervention, and the role of bronchoscopy is key.

A multidisciplinary practice of NSCLC specialists, who have access to on-site or virtual tumor boards, sometimes on an international scale, helps ensure optimal treatment for patients in the increasingly complex NSCLC arena.

--

A. Christine Argento, MD, Associate Professor of Medicine, Department of Pulmonary and Critical Care Medicine, Johns Hopkins University; Director of Bronchoscopy, Department of Interventional Pulmonary Medicine, Johns Hopkins Hospital, Baltimore, Maryland

A. Christine Argento, MD, has disclosed the following relevant financial relationships:

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Biodesix; Olympus; Cook; Intuitive; Boston Scientific

Josephine L. Feliciano, MD, Associate Professor, Clinical Director, Sidney Kimmel Cancer Center, Johns Hopkins University Hospital, Baltimore, Maryland

Josephine L. Feliciano, MD, has disclosed the following relevant financial relationships:

Received research grant from: Bristol-Myers; Pfizer; AstraZeneca.

Received income in an amount equal to or greater than $250 from: Genentech; AstraZeneca; Eli Lilly; Merck; Regeneron; Coherus; Takeda; Bristol-Myers

The expanding range of therapies and interventions available for treatment of non–small cell lung cancer (NSCLC) has brought medical oncologists and interventional pulmonologists into closer partnership.

Oncologist Dr. Joy Feliciano and interventional pulmonologist Dr. A. Christine Argento, both colleagues at Johns Hopkins University, comment on their evolving relationship as a team.

Pulmonologists now often serve as the "gatekeepers into thoracic oncology," says Dr. Argento. Recent advances in technology, including endobronchial ultrasound, navigational bronchoscopy, and robotic-assisted bronchoscopy, allow for diagnosis, staging, and collection of sufficient tissue for advanced studies into molecular markers and genetic studies necessary to guide treatment decisions for metastatic NSCLC.

In resectable disease, patients who might have gone straight to surgery in the past now can be considered for neoadjuvant treatments. Here again, says Dr. Feliciano, it is critical for oncologists to understand the biomarkers and molecular profile of the tumor before considering an intervention, and the role of bronchoscopy is key.

A multidisciplinary practice of NSCLC specialists, who have access to on-site or virtual tumor boards, sometimes on an international scale, helps ensure optimal treatment for patients in the increasingly complex NSCLC arena.

--

A. Christine Argento, MD, Associate Professor of Medicine, Department of Pulmonary and Critical Care Medicine, Johns Hopkins University; Director of Bronchoscopy, Department of Interventional Pulmonary Medicine, Johns Hopkins Hospital, Baltimore, Maryland

A. Christine Argento, MD, has disclosed the following relevant financial relationships:

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Biodesix; Olympus; Cook; Intuitive; Boston Scientific

Josephine L. Feliciano, MD, Associate Professor, Clinical Director, Sidney Kimmel Cancer Center, Johns Hopkins University Hospital, Baltimore, Maryland

Josephine L. Feliciano, MD, has disclosed the following relevant financial relationships:

Received research grant from: Bristol-Myers; Pfizer; AstraZeneca.

Received income in an amount equal to or greater than $250 from: Genentech; AstraZeneca; Eli Lilly; Merck; Regeneron; Coherus; Takeda; Bristol-Myers