During my residency training years, I had many rosy and bold dreams about the future of psychiatry, hoping for many breakthroughs.

Early on, I decided to pursue an academic career, and specifically to focus on the neurobiology of schizophrenia, bipolar disorder, and other psychoses. I secured a neuroscience mentor, conducted a research project, and presented my findings at the American Psychiatric Association Annual Meeting. Although at the time everyone used the term “functional” to describe mental illnesses, I was convinced that they were all neurologic conditions, with prominent psychiatric manifestations. And I have been proven right.

After my residency, I eagerly pursued a neuroscience fellowship at the National Institutes of Health. My fantasy was that during my career as a psychiatric neuroscientist, brain exploration would uncover the many mysteries of psychiatric disorders. I was insightful enough to recognize that what I envisioned for the future of psychiatry qualified as science fiction, but I never stopped dreaming.

Today, the advances in psychiatric neuroscience that were unimaginable during my residency have become dazzling discoveries. My journey as a psychiatric neuroscientist has been more thrilling than I ever imagined. I recall doing postmortem research on the brains of hundreds of deceased psychiatric patients, noticing sulci widening and ventricular dilatation, and wondering whether one day we would be able to detect those atrophic changes while the patients were alive. Although I measured those changes in postmortem brains, I was cognizant that due to preservation artifacts, such measurements were less reliable than measurements of living brains.

And then the advent of neuroimaging fulfilled my fantasies. This began towards the end of my fellowship, and has exploded with neurobiologic findings throughout my academic career. Then came dramatic methodologies to probe brain molecular and cellular pathologies, followed by breakthrough clinical advances. Entirely new vistas of research into psychiatric brain disorders are opening every day. The exhilaration will never end!

From science fiction to clinical reality

Here is a quick outline of some of the “science fiction” of psychiatry that has come true since my training days. Back then, these discoveries were completely absent from the radar screen of psychiatry, when it was still a fledgling medical specialty struggling to emerge from the dominant yet nonempirical era of psychoanalysis.

Brain exploration methods. Unpre­cedented breakthroughs in computer technology have allowed psychiatric neuroscientists to create a new field of neuroimaging research that includes:

• cerebral blood flow (CBF)
• position emission tomography (PET)
• single photon emission computed tomography (SPECT).

Continue to: These functional neuroimaging...

These functional neuroimaging methods (using ionizing radiation) have enabled clinicians to see abnormal blood flow patterns in the brains of living patients. One of the earliest findings was hypofrontality in patients with schizophrenia, implicating frontal pathology in this severe brain disorder. PET was also used for dopamine and serotonin receptor imaging.

Computerized axia tomography. Compared with skull X-rays, CT (“CAT”) scans provided a more detailed view of brain tissue, and began a structural neuroimaging revolution that enriched psychiatric research, but also was applied to organs other than the brain.

Magnetic resonance imaging (MRI) became the “big kahuna” of neuroimaging when arrived in the early 1980s and quickly supplanted CT research because it is safer (no ionizing radiation, and it can be repeated multiple times with or without tasks). It also provided exquisite neuroanatomical details of brain tissue with stunning fidelity. Subsequently, several MRI techniques/software programs were developed that advanced research in psychiatry to multiple new frontiers, including:

• Morphological neuroimaging with MRI
• Magnetic resonance spectroscopy (MRS), which acts like a living, noninvasive biopsy of several chemicals (such as choline, lactate, glutamine, adenosine triphosphate, and the neuronal marker N-acetylcysteine) in a small volume (≤1 cc) of neural tissue in various regions
• Functional MRI (fMRI), which measures blood flow changes during actual or imagined tasks in the brains of patients vs healthy controls
• Diffusion tensor imaging (DTI), which evaluates the integrity of white matter (60% of brain volume, including 137,000 miles of myelinated fibers) by measuring the flow of water inside myelinated fibers (anisotropy and diffusivity). DTI of the corpus callosum, the largest brain commissure that is comprised of 200 million interhemispheric fibers, has revealed many abnormalities. This was one of the structures I investigated during my fellowship, including a histopathological study.¹

All 4 of these neuroimaging techniques continue to generate a wealth of data about brain structure and function in psychosis, mood disorders, anxiety disorders, borderline personality disorder, obsessive-compulsive disorder, eating disorders, and substance use disorders. All these discoveries were utterly impossible to predict during my residency. I am proud to have published the first reports in the literature of ventricular enlargement in patients with bipolar disorder,² cortical atrophy in schizophrenia and mania,³ reductions of hippocampal volume in patients with schizophrenia using MRS,⁴ and progressive brain atrophy in patients with schizophrenia.⁵ It is especially gratifying that I played a small role in translating my science fiction fantasies into clinical reality!

Other breakthrough methodologies that are advancing psychiatric neuroscience today but were science fiction during my residency days include:

• Pluripotent stem cells, which enable the de-differentiation of adult skin cells and then re-differentiating them into any type of cell, including neurons. This allows researchers to conduct studies on any patient’s brain cells without needing to do an invasive, high-risk brain biopsy. As a young resident, I would never have predicted that this virtual brain biopsy would be possible!
• Optogenetics, which enables controlling cell behavior using light and genetically encoded light-sensitive proteins. This triggered a cornucopia of neuroscience discoveries by using optogenetics to modulate cell-signaling cascades to understand cellular biology. Halorhodopsin and bacteriorhodopsin are used as tools to turn neurons off or on rapidly and safely.
• Genome-wide association studies (GWAS) have revolutionized the field of molecular neurogenetics and are enabling clinicians to detect risk genes by comparing the DNA samples of thousands of psychiatric patients with thousands of healthy controls. This is how several hundred risk genes have been identified for schizophrenia, bipolar disorder, autism spectrum disorder, and more to come.
• Clustered regularly interspaced short palindromic repeats (CRISPR) is a remarkable genetic “scissors” (that earned its inventors the 2020 Nobel Prize) that allows splicing out a disease gene and splicing in a normal gene. This will have an enormous future application in preventing an adulthood illness at its roots during fetal life. The future medical implications for psychiatric disorders are prodigious!

Continue to: Clinical advances

Clinical advances. Many therapies or approaches that did not exist during my residency (and how I dreamed about them back then!) are available to today’s clinicians. These include:

• Rapid-acting antidepressants that reverse severe and chronic depression and suicidal urges within a few hours or a couple of days. As a resident, I waited for weeks or months to see patients with depression reach the full remission that is now achieved practically the same day with IV ketamine, intranasal esketamine, IV scopolamine, and inhalable nitrous oxide. During my residency, the closest thing we had to a rapid-acting treatment for depression was electroconvulsive therapy (ECT), but that usually took 2 to 3 weeks. Psychiatric clinicians should never cease to appreciate how an intractable, treatment-refractory depression can rapidly be turned off like a light switch, restoring normal mood to desperately ill persons.
• Neuromodulation techniques are flourishing. Beyond ECT, transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), transcranial direct current stimulation (tDCS), deep brain stimulation (DBS), low field magnetic stimulation (LFMS), magnetic seizure therapy (MST), near-infrared radiation (NIR), and focused ultrasound (FUS) are approved or under development, offering millions of patients with various neuropsychiatric disorders potential recovery not with pharmacotherapy, but via a brain-targeted approach.
• Telepsychiatry. Now taken for granted during the COVID-19 pandemic, telepsychiatry was completely unimaginable during my residency. Yes, we had phones, but not smartphones! The only “zoom” we knew was the furious sound of a sports car engine! To be able to see and evaluate a patient literally anywhere in the world was science fiction personified! Increased remote access to psychiatric care by patients everywhere is a truly remarkable advance that helped avoid a disastrous lack of psychiatric treatment during the current pandemic that brought in-person interactions between psychiatric physicians and their patients to a screeching halt.
• Neurobiologic effects of psychotherapy. Viewing psychotherapy as a neurobiologic treatment was totally unknown and unimaginable during my residency. I was heavily trained in various types of psychotherapies, but not once did any of my supervisors mention experiential neuroplasticity as a brain-altering process, or that psychotherapy changes brain structure, induces experimental neuroplasticity, and induces billions of dendritic spines in patients’ cortex and limbic structures, helping them connect the dots and develop new insights. No one knew that psychotherapy can mimic the neural effects of pharmacotherapy.
• Immunomodulatory effects of psychotherapy. It was completely unknown that psychotherapies such as cognitive-behavioral therapy can lower levels of inflammatory biomarkers in patients’ CSF and serum. Back then, no one imagined that psychotherapy had immunomodulatory effects. These discoveries are revolutionary for us psychiatrists and confirm the neurobiologic mechanisms of psychotherapy for every patient we treat.
• Epigenetics. This was rarely, if ever, mentioned when I was a resident. We knew from clinical studies that children who were abused or neglected often develop severe mood or psychotic disorders in adulthood. But we did not know that trauma modifies some genes via under- or overexpression, and that such epigenetic changes alter brain development towards psychopathology. The mysteries of psychiatric brain disorders generated by childhood trauma have been clarified by advances in epigenetics.

Aspirational, futuristic therapies. Even now, as a seasoned psychiatric neuroscientist, I continue to dream. Research is providing many clues for potentially radical psychiatric treatments that go beyond standard antipsychotics, antidepressants, mood stabilizers, or anxiolytics. But today, I fully expect that scientific dreams eventually come true through research. For example, the following neuroscientific therapeutics strategies may someday become routine in clinical practice:

• microglia inhibition
• mitochondria repair
• anti-apoptotic therapy
• white matter connectivity restoration
• neuroprotection (enhancing neurogenesis, increasing neurotropic factors, and enhancing synaptogenesis)
• reverse glutamate N-methyl-d-aspartate hypofunction
• prevent amyloid formation.

Data analysis breakthroughs. Side-by-side with the explosion of new findings and amassing mountains of data in psychiatric neuroscience, unprecedented and revolutionary data-management techniques have emerged to facilitate the herculean task of data analysis to extract the mythical needle in a haystack and derive the overall impact of masses of data. These techniques, whose names were not in our vocabulary during my residency days, include:

• machine learning
• artificial intelligence
• deep learning
• big data.

With the help of powerful computers and ingenious software, discovering critical nuggets of knowledge about the brain and predicting the best approaches to healing dysfunctional brains are now possible. Those powerful methods of analyzing massive data are the vehicles for transforming science fiction to reality by assembling the jigsaw puzzle(s) of the human brain, arguably the last frontier in medical science.

My life experiences as a psychiatric neuroscientist have convinced me that nothing is beyond the reach of scientific research. Unraveling the divine brain’s complexities will eventually become reality. So, let us never stop dreaming and fantasizing!

During my residency training years, I had many rosy and bold dreams about the future of psychiatry, hoping for many breakthroughs.

Early on, I decided to pursue an academic career, and specifically to focus on the neurobiology of schizophrenia, bipolar disorder, and other psychoses. I secured a neuroscience mentor, conducted a research project, and presented my findings at the American Psychiatric Association Annual Meeting. Although at the time everyone used the term “functional” to describe mental illnesses, I was convinced that they were all neurologic conditions, with prominent psychiatric manifestations. And I have been proven right.

After my residency, I eagerly pursued a neuroscience fellowship at the National Institutes of Health. My fantasy was that during my career as a psychiatric neuroscientist, brain exploration would uncover the many mysteries of psychiatric disorders. I was insightful enough to recognize that what I envisioned for the future of psychiatry qualified as science fiction, but I never stopped dreaming.

Today, the advances in psychiatric neuroscience that were unimaginable during my residency have become dazzling discoveries. My journey as a psychiatric neuroscientist has been more thrilling than I ever imagined. I recall doing postmortem research on the brains of hundreds of deceased psychiatric patients, noticing sulci widening and ventricular dilatation, and wondering whether one day we would be able to detect those atrophic changes while the patients were alive. Although I measured those changes in postmortem brains, I was cognizant that due to preservation artifacts, such measurements were less reliable than measurements of living brains.

And then the advent of neuroimaging fulfilled my fantasies. This began towards the end of my fellowship, and has exploded with neurobiologic findings throughout my academic career. Then came dramatic methodologies to probe brain molecular and cellular pathologies, followed by breakthrough clinical advances. Entirely new vistas of research into psychiatric brain disorders are opening every day. The exhilaration will never end!

From science fiction to clinical reality

Here is a quick outline of some of the “science fiction” of psychiatry that has come true since my training days. Back then, these discoveries were completely absent from the radar screen of psychiatry, when it was still a fledgling medical specialty struggling to emerge from the dominant yet nonempirical era of psychoanalysis.

Brain exploration methods. Unpre­cedented breakthroughs in computer technology have allowed psychiatric neuroscientists to create a new field of neuroimaging research that includes:

• cerebral blood flow (CBF)
• position emission tomography (PET)
• single photon emission computed tomography (SPECT).

Continue to: These functional neuroimaging...

These functional neuroimaging methods (using ionizing radiation) have enabled clinicians to see abnormal blood flow patterns in the brains of living patients. One of the earliest findings was hypofrontality in patients with schizophrenia, implicating frontal pathology in this severe brain disorder. PET was also used for dopamine and serotonin receptor imaging.

Computerized axia tomography. Compared with skull X-rays, CT (“CAT”) scans provided a more detailed view of brain tissue, and began a structural neuroimaging revolution that enriched psychiatric research, but also was applied to organs other than the brain.

Magnetic resonance imaging (MRI) became the “big kahuna” of neuroimaging when arrived in the early 1980s and quickly supplanted CT research because it is safer (no ionizing radiation, and it can be repeated multiple times with or without tasks). It also provided exquisite neuroanatomical details of brain tissue with stunning fidelity. Subsequently, several MRI techniques/software programs were developed that advanced research in psychiatry to multiple new frontiers, including:

• Morphological neuroimaging with MRI
• Magnetic resonance spectroscopy (MRS), which acts like a living, noninvasive biopsy of several chemicals (such as choline, lactate, glutamine, adenosine triphosphate, and the neuronal marker N-acetylcysteine) in a small volume (≤1 cc) of neural tissue in various regions
• Functional MRI (fMRI), which measures blood flow changes during actual or imagined tasks in the brains of patients vs healthy controls
• Diffusion tensor imaging (DTI), which evaluates the integrity of white matter (60% of brain volume, including 137,000 miles of myelinated fibers) by measuring the flow of water inside myelinated fibers (anisotropy and diffusivity). DTI of the corpus callosum, the largest brain commissure that is comprised of 200 million interhemispheric fibers, has revealed many abnormalities. This was one of the structures I investigated during my fellowship, including a histopathological study.¹

All 4 of these neuroimaging techniques continue to generate a wealth of data about brain structure and function in psychosis, mood disorders, anxiety disorders, borderline personality disorder, obsessive-compulsive disorder, eating disorders, and substance use disorders. All these discoveries were utterly impossible to predict during my residency. I am proud to have published the first reports in the literature of ventricular enlargement in patients with bipolar disorder,² cortical atrophy in schizophrenia and mania,³ reductions of hippocampal volume in patients with schizophrenia using MRS,⁴ and progressive brain atrophy in patients with schizophrenia.⁵ It is especially gratifying that I played a small role in translating my science fiction fantasies into clinical reality!

Other breakthrough methodologies that are advancing psychiatric neuroscience today but were science fiction during my residency days include:

• Pluripotent stem cells, which enable the de-differentiation of adult skin cells and then re-differentiating them into any type of cell, including neurons. This allows researchers to conduct studies on any patient’s brain cells without needing to do an invasive, high-risk brain biopsy. As a young resident, I would never have predicted that this virtual brain biopsy would be possible!
• Optogenetics, which enables controlling cell behavior using light and genetically encoded light-sensitive proteins. This triggered a cornucopia of neuroscience discoveries by using optogenetics to modulate cell-signaling cascades to understand cellular biology. Halorhodopsin and bacteriorhodopsin are used as tools to turn neurons off or on rapidly and safely.
• Genome-wide association studies (GWAS) have revolutionized the field of molecular neurogenetics and are enabling clinicians to detect risk genes by comparing the DNA samples of thousands of psychiatric patients with thousands of healthy controls. This is how several hundred risk genes have been identified for schizophrenia, bipolar disorder, autism spectrum disorder, and more to come.
• Clustered regularly interspaced short palindromic repeats (CRISPR) is a remarkable genetic “scissors” (that earned its inventors the 2020 Nobel Prize) that allows splicing out a disease gene and splicing in a normal gene. This will have an enormous future application in preventing an adulthood illness at its roots during fetal life. The future medical implications for psychiatric disorders are prodigious!

Continue to: Clinical advances

Clinical advances. Many therapies or approaches that did not exist during my residency (and how I dreamed about them back then!) are available to today’s clinicians. These include:

• Rapid-acting antidepressants that reverse severe and chronic depression and suicidal urges within a few hours or a couple of days. As a resident, I waited for weeks or months to see patients with depression reach the full remission that is now achieved practically the same day with IV ketamine, intranasal esketamine, IV scopolamine, and inhalable nitrous oxide. During my residency, the closest thing we had to a rapid-acting treatment for depression was electroconvulsive therapy (ECT), but that usually took 2 to 3 weeks. Psychiatric clinicians should never cease to appreciate how an intractable, treatment-refractory depression can rapidly be turned off like a light switch, restoring normal mood to desperately ill persons.
• Neuromodulation techniques are flourishing. Beyond ECT, transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), transcranial direct current stimulation (tDCS), deep brain stimulation (DBS), low field magnetic stimulation (LFMS), magnetic seizure therapy (MST), near-infrared radiation (NIR), and focused ultrasound (FUS) are approved or under development, offering millions of patients with various neuropsychiatric disorders potential recovery not with pharmacotherapy, but via a brain-targeted approach.
• Telepsychiatry. Now taken for granted during the COVID-19 pandemic, telepsychiatry was completely unimaginable during my residency. Yes, we had phones, but not smartphones! The only “zoom” we knew was the furious sound of a sports car engine! To be able to see and evaluate a patient literally anywhere in the world was science fiction personified! Increased remote access to psychiatric care by patients everywhere is a truly remarkable advance that helped avoid a disastrous lack of psychiatric treatment during the current pandemic that brought in-person interactions between psychiatric physicians and their patients to a screeching halt.
• Neurobiologic effects of psychotherapy. Viewing psychotherapy as a neurobiologic treatment was totally unknown and unimaginable during my residency. I was heavily trained in various types of psychotherapies, but not once did any of my supervisors mention experiential neuroplasticity as a brain-altering process, or that psychotherapy changes brain structure, induces experimental neuroplasticity, and induces billions of dendritic spines in patients’ cortex and limbic structures, helping them connect the dots and develop new insights. No one knew that psychotherapy can mimic the neural effects of pharmacotherapy.
• Immunomodulatory effects of psychotherapy. It was completely unknown that psychotherapies such as cognitive-behavioral therapy can lower levels of inflammatory biomarkers in patients’ CSF and serum. Back then, no one imagined that psychotherapy had immunomodulatory effects. These discoveries are revolutionary for us psychiatrists and confirm the neurobiologic mechanisms of psychotherapy for every patient we treat.
• Epigenetics. This was rarely, if ever, mentioned when I was a resident. We knew from clinical studies that children who were abused or neglected often develop severe mood or psychotic disorders in adulthood. But we did not know that trauma modifies some genes via under- or overexpression, and that such epigenetic changes alter brain development towards psychopathology. The mysteries of psychiatric brain disorders generated by childhood trauma have been clarified by advances in epigenetics.

Aspirational, futuristic therapies. Even now, as a seasoned psychiatric neuroscientist, I continue to dream. Research is providing many clues for potentially radical psychiatric treatments that go beyond standard antipsychotics, antidepressants, mood stabilizers, or anxiolytics. But today, I fully expect that scientific dreams eventually come true through research. For example, the following neuroscientific therapeutics strategies may someday become routine in clinical practice:

• microglia inhibition
• mitochondria repair
• anti-apoptotic therapy
• white matter connectivity restoration
• neuroprotection (enhancing neurogenesis, increasing neurotropic factors, and enhancing synaptogenesis)
• reverse glutamate N-methyl-d-aspartate hypofunction
• prevent amyloid formation.

Data analysis breakthroughs. Side-by-side with the explosion of new findings and amassing mountains of data in psychiatric neuroscience, unprecedented and revolutionary data-management techniques have emerged to facilitate the herculean task of data analysis to extract the mythical needle in a haystack and derive the overall impact of masses of data. These techniques, whose names were not in our vocabulary during my residency days, include:

• machine learning
• artificial intelligence
• deep learning
• big data.

With the help of powerful computers and ingenious software, discovering critical nuggets of knowledge about the brain and predicting the best approaches to healing dysfunctional brains are now possible. Those powerful methods of analyzing massive data are the vehicles for transforming science fiction to reality by assembling the jigsaw puzzle(s) of the human brain, arguably the last frontier in medical science.

My life experiences as a psychiatric neuroscientist have convinced me that nothing is beyond the reach of scientific research. Unraveling the divine brain’s complexities will eventually become reality. So, let us never stop dreaming and fantasizing!

During my residency training years, I had many rosy and bold dreams about the future of psychiatry, hoping for many breakthroughs.

Early on, I decided to pursue an academic career, and specifically to focus on the neurobiology of schizophrenia, bipolar disorder, and other psychoses. I secured a neuroscience mentor, conducted a research project, and presented my findings at the American Psychiatric Association Annual Meeting. Although at the time everyone used the term “functional” to describe mental illnesses, I was convinced that they were all neurologic conditions, with prominent psychiatric manifestations. And I have been proven right.

After my residency, I eagerly pursued a neuroscience fellowship at the National Institutes of Health. My fantasy was that during my career as a psychiatric neuroscientist, brain exploration would uncover the many mysteries of psychiatric disorders. I was insightful enough to recognize that what I envisioned for the future of psychiatry qualified as science fiction, but I never stopped dreaming.

Today, the advances in psychiatric neuroscience that were unimaginable during my residency have become dazzling discoveries. My journey as a psychiatric neuroscientist has been more thrilling than I ever imagined. I recall doing postmortem research on the brains of hundreds of deceased psychiatric patients, noticing sulci widening and ventricular dilatation, and wondering whether one day we would be able to detect those atrophic changes while the patients were alive. Although I measured those changes in postmortem brains, I was cognizant that due to preservation artifacts, such measurements were less reliable than measurements of living brains.

And then the advent of neuroimaging fulfilled my fantasies. This began towards the end of my fellowship, and has exploded with neurobiologic findings throughout my academic career. Then came dramatic methodologies to probe brain molecular and cellular pathologies, followed by breakthrough clinical advances. Entirely new vistas of research into psychiatric brain disorders are opening every day. The exhilaration will never end!

From science fiction to clinical reality

Here is a quick outline of some of the “science fiction” of psychiatry that has come true since my training days. Back then, these discoveries were completely absent from the radar screen of psychiatry, when it was still a fledgling medical specialty struggling to emerge from the dominant yet nonempirical era of psychoanalysis.

Brain exploration methods. Unpre­cedented breakthroughs in computer technology have allowed psychiatric neuroscientists to create a new field of neuroimaging research that includes:

• cerebral blood flow (CBF)
• position emission tomography (PET)
• single photon emission computed tomography (SPECT).

Continue to: These functional neuroimaging...

These functional neuroimaging methods (using ionizing radiation) have enabled clinicians to see abnormal blood flow patterns in the brains of living patients. One of the earliest findings was hypofrontality in patients with schizophrenia, implicating frontal pathology in this severe brain disorder. PET was also used for dopamine and serotonin receptor imaging.

Computerized axia tomography. Compared with skull X-rays, CT (“CAT”) scans provided a more detailed view of brain tissue, and began a structural neuroimaging revolution that enriched psychiatric research, but also was applied to organs other than the brain.

Magnetic resonance imaging (MRI) became the “big kahuna” of neuroimaging when arrived in the early 1980s and quickly supplanted CT research because it is safer (no ionizing radiation, and it can be repeated multiple times with or without tasks). It also provided exquisite neuroanatomical details of brain tissue with stunning fidelity. Subsequently, several MRI techniques/software programs were developed that advanced research in psychiatry to multiple new frontiers, including:

• Morphological neuroimaging with MRI
• Magnetic resonance spectroscopy (MRS), which acts like a living, noninvasive biopsy of several chemicals (such as choline, lactate, glutamine, adenosine triphosphate, and the neuronal marker N-acetylcysteine) in a small volume (≤1 cc) of neural tissue in various regions
• Functional MRI (fMRI), which measures blood flow changes during actual or imagined tasks in the brains of patients vs healthy controls
• Diffusion tensor imaging (DTI), which evaluates the integrity of white matter (60% of brain volume, including 137,000 miles of myelinated fibers) by measuring the flow of water inside myelinated fibers (anisotropy and diffusivity). DTI of the corpus callosum, the largest brain commissure that is comprised of 200 million interhemispheric fibers, has revealed many abnormalities. This was one of the structures I investigated during my fellowship, including a histopathological study.¹

All 4 of these neuroimaging techniques continue to generate a wealth of data about brain structure and function in psychosis, mood disorders, anxiety disorders, borderline personality disorder, obsessive-compulsive disorder, eating disorders, and substance use disorders. All these discoveries were utterly impossible to predict during my residency. I am proud to have published the first reports in the literature of ventricular enlargement in patients with bipolar disorder,² cortical atrophy in schizophrenia and mania,³ reductions of hippocampal volume in patients with schizophrenia using MRS,⁴ and progressive brain atrophy in patients with schizophrenia.⁵ It is especially gratifying that I played a small role in translating my science fiction fantasies into clinical reality!

Other breakthrough methodologies that are advancing psychiatric neuroscience today but were science fiction during my residency days include:

• Pluripotent stem cells, which enable the de-differentiation of adult skin cells and then re-differentiating them into any type of cell, including neurons. This allows researchers to conduct studies on any patient’s brain cells without needing to do an invasive, high-risk brain biopsy. As a young resident, I would never have predicted that this virtual brain biopsy would be possible!
• Optogenetics, which enables controlling cell behavior using light and genetically encoded light-sensitive proteins. This triggered a cornucopia of neuroscience discoveries by using optogenetics to modulate cell-signaling cascades to understand cellular biology. Halorhodopsin and bacteriorhodopsin are used as tools to turn neurons off or on rapidly and safely.
• Genome-wide association studies (GWAS) have revolutionized the field of molecular neurogenetics and are enabling clinicians to detect risk genes by comparing the DNA samples of thousands of psychiatric patients with thousands of healthy controls. This is how several hundred risk genes have been identified for schizophrenia, bipolar disorder, autism spectrum disorder, and more to come.
• Clustered regularly interspaced short palindromic repeats (CRISPR) is a remarkable genetic “scissors” (that earned its inventors the 2020 Nobel Prize) that allows splicing out a disease gene and splicing in a normal gene. This will have an enormous future application in preventing an adulthood illness at its roots during fetal life. The future medical implications for psychiatric disorders are prodigious!

Continue to: Clinical advances

Clinical advances. Many therapies or approaches that did not exist during my residency (and how I dreamed about them back then!) are available to today’s clinicians. These include:

• Rapid-acting antidepressants that reverse severe and chronic depression and suicidal urges within a few hours or a couple of days. As a resident, I waited for weeks or months to see patients with depression reach the full remission that is now achieved practically the same day with IV ketamine, intranasal esketamine, IV scopolamine, and inhalable nitrous oxide. During my residency, the closest thing we had to a rapid-acting treatment for depression was electroconvulsive therapy (ECT), but that usually took 2 to 3 weeks. Psychiatric clinicians should never cease to appreciate how an intractable, treatment-refractory depression can rapidly be turned off like a light switch, restoring normal mood to desperately ill persons.
• Neuromodulation techniques are flourishing. Beyond ECT, transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), transcranial direct current stimulation (tDCS), deep brain stimulation (DBS), low field magnetic stimulation (LFMS), magnetic seizure therapy (MST), near-infrared radiation (NIR), and focused ultrasound (FUS) are approved or under development, offering millions of patients with various neuropsychiatric disorders potential recovery not with pharmacotherapy, but via a brain-targeted approach.
• Telepsychiatry. Now taken for granted during the COVID-19 pandemic, telepsychiatry was completely unimaginable during my residency. Yes, we had phones, but not smartphones! The only “zoom” we knew was the furious sound of a sports car engine! To be able to see and evaluate a patient literally anywhere in the world was science fiction personified! Increased remote access to psychiatric care by patients everywhere is a truly remarkable advance that helped avoid a disastrous lack of psychiatric treatment during the current pandemic that brought in-person interactions between psychiatric physicians and their patients to a screeching halt.
• Neurobiologic effects of psychotherapy. Viewing psychotherapy as a neurobiologic treatment was totally unknown and unimaginable during my residency. I was heavily trained in various types of psychotherapies, but not once did any of my supervisors mention experiential neuroplasticity as a brain-altering process, or that psychotherapy changes brain structure, induces experimental neuroplasticity, and induces billions of dendritic spines in patients’ cortex and limbic structures, helping them connect the dots and develop new insights. No one knew that psychotherapy can mimic the neural effects of pharmacotherapy.
• Immunomodulatory effects of psychotherapy. It was completely unknown that psychotherapies such as cognitive-behavioral therapy can lower levels of inflammatory biomarkers in patients’ CSF and serum. Back then, no one imagined that psychotherapy had immunomodulatory effects. These discoveries are revolutionary for us psychiatrists and confirm the neurobiologic mechanisms of psychotherapy for every patient we treat.
• Epigenetics. This was rarely, if ever, mentioned when I was a resident. We knew from clinical studies that children who were abused or neglected often develop severe mood or psychotic disorders in adulthood. But we did not know that trauma modifies some genes via under- or overexpression, and that such epigenetic changes alter brain development towards psychopathology. The mysteries of psychiatric brain disorders generated by childhood trauma have been clarified by advances in epigenetics.

Aspirational, futuristic therapies. Even now, as a seasoned psychiatric neuroscientist, I continue to dream. Research is providing many clues for potentially radical psychiatric treatments that go beyond standard antipsychotics, antidepressants, mood stabilizers, or anxiolytics. But today, I fully expect that scientific dreams eventually come true through research. For example, the following neuroscientific therapeutics strategies may someday become routine in clinical practice:

• microglia inhibition
• mitochondria repair
• anti-apoptotic therapy
• white matter connectivity restoration
• neuroprotection (enhancing neurogenesis, increasing neurotropic factors, and enhancing synaptogenesis)
• reverse glutamate N-methyl-d-aspartate hypofunction
• prevent amyloid formation.

Data analysis breakthroughs. Side-by-side with the explosion of new findings and amassing mountains of data in psychiatric neuroscience, unprecedented and revolutionary data-management techniques have emerged to facilitate the herculean task of data analysis to extract the mythical needle in a haystack and derive the overall impact of masses of data. These techniques, whose names were not in our vocabulary during my residency days, include:

• machine learning
• artificial intelligence
• deep learning
• big data.

With the help of powerful computers and ingenious software, discovering critical nuggets of knowledge about the brain and predicting the best approaches to healing dysfunctional brains are now possible. Those powerful methods of analyzing massive data are the vehicles for transforming science fiction to reality by assembling the jigsaw puzzle(s) of the human brain, arguably the last frontier in medical science.

My life experiences as a psychiatric neuroscientist have convinced me that nothing is beyond the reach of scientific research. Unraveling the divine brain’s complexities will eventually become reality. So, let us never stop dreaming and fantasizing!

CASE Sudden-onset low mood

Mr. G, age 64, is obese (body mass index [BMI] 37 kg/m²) and has a history of schizoaffective disorder. He is recovering from a sleeve gastrectomy, a surgical weight-loss procedure in which a large portion of the stomach is removed. Seven weeks after his surgery, he experiences a sudden onset of “low mood” and fears that he will become suicidal; he has a history of suicide attempts. Mr. G calls his long-term outpatient clinic and is advised to go to the emergency department (ED).

For years, Mr. G had been stable in a group home setting, and had always been adherent to treatment and forthcoming about his medications with both his bariatric surgeon and psychiatrist. Within the last month, he had been seen at the clinic, had no psychiatric symptoms, and was recovering well from the sleeve gastrectomy.

HISTORY A stable regimen

Mr. G’s psychiatric symptoms initially developed when he was in his 20s, during a time in which he reported using “a lot of drugs.” He had multiple suicide attempts, and multiple inpatient and outpatient treatments. He was diagnosed with schizoaffective disorder.

Mr. G has been stable on medications for the last 2 years. His outpatient psychotropic regimen is divalproex sodium extended-release (ER), 2,500 mg every night at bedtime; iloperidone, 8 mg twice a day; escitalopram, 10 mg/d; and mirtazapine, 30 mg every night at bedtime.

In the group home, Mr. G spends his days socializing, studying philosophy, and writing essays. He hopes to find a job in the craftsman industry.

Mr. G’s medical history includes obesity (BMI: 37 kg/m²). Since the surgery, he has been receiving omeprazole, 40 mg/d, a proton pump inhibitor (PPI), to decrease the amount of acid in his stomach. Three weeks after surgery, he had an unremarkable postoperative outpatient psychiatry visit. Divalproex sodium ER was maintained at the pre-surgical dose of 2,500 mg/d.

EVALUATION Depressed and frightened

In the ED, Mr. G’s vitals are normal, but his serum valproic acid (VPA) level is 33.68 µg/mL (therapeutic range: 50 to 125 µg/mL), despite being compliant with treatment. Mr. G is discharged from the ED and told to follow up with his outpatient psychiatrist the next day.

Continue to: At his outpatient psychiatry appointment...

At his outpatient psychiatry appointment, Mr. G’s vital signs are normal, but he reports increasing depression and worsened mood. On mental status examination, Mr. G’s appearance is well groomed, and no agitation nor fidgeting are observed. His behavior is cooperative but somewhat disorganized. He is perseverative on “feeling so low.” He has poor eye contact, which is unusual for him. Mr. G’s speech is loud compared with his baseline. Affect is congruent to mood, which he describes as “depressed and frightened.” He is also noted to be irritable. His thought process is abstract and tangential, which is within his baseline. Mr. G’s thought content is fearful and negativistic, despite his usual positivity and optimism. He denies hallucinations and is oriented to time, place, and person. His judgment, attention, and memory are all within normal limits.

[polldaddy:10790537]

The authors’ observations

The psychiatrist rules out malingering/nonadherence due to Mr. G’s long history of treatment compliance, as evidenced by his past symptom control and therapeutic serum VPA levels. Mr. G was compliant with his postoperative appointments and has been healing well. Therefore, the treatment team believed that Mr. G’s intense and acute decompensation had to be related to a recent change. The notable changes in Mr. G’s case included his sleeve gastrectomy, and the addition of omeprazole to his medication regimen.

The treatment team observed that Mr. G had a long history of compliance with his medications and his symptoms were consistent with a low serum VPA level, which led to the conclusion that the low serum VPA level measured while he was in the ED was likely accurate. This prompted the team to consider Mr. G’s recent surgery. It is well documented that some bariatric surgeries can cause poor absorption of certain vitamins, minerals, and medications. However, Mr. G had a sleeve gastrectomy, which preserves absorption. At this point, the team considered if the patient’s recent medication change was the source of his low VPA level.

The psychiatrist concluded that the issue must have been with the addition of omeprazole because Mr. G’s sleeve gastrectomy was noneventful, he was healing well and being closely monitored by his bariatric surgeon, and this type of surgery preserves absorption. Fortunately, Mr. G was a good historian and had informed his psychiatrist about the addition of omeprazole after his sleeve gastrectomy. The psychiatrist knew acidity was important for the absorption of some medications. Although she was unsure as to whether the problem was a lack of absorption or lack of delivery, the psychiatrist knew a medication change was necessary to raise Mr. G’s serum VPA levels.

TREATMENT A change in divalproex formulation

The psychiatrist switches Mr. G’s formulation of divalproex sodium ER, 2,500 mg/d, to valproic acid immediate-release (IR) liquid capsules. He receives a total daily dose of 2,500 mg, but the dosage is split into 3 times a day. The omeprazole is continued to maintain the postoperative healing process, and he receives his other medications as well (iloperidone, 8 mg twice a day; escitalopram, 10 mg/d; and mirtazapine, 30 mg every night at bedtime).

[polldaddy:10790540]

Continue to: The authors' observations

The authors’ observations

The key component to creating a treatment plan for Mr. G centered on understanding drug metabolism and delivery. Acidity plays a role in dissolution of many medications, which led the team to surmise that the PPI, omeprazole, was the culprit. Through research, they understood that the divalproex sodium ER formulation needed a more acidic environment to dissolve, and therefore, an IR formulation was needed.

Different formulations, different characteristics

Medications can be produced in different formulations such as IR, delayed-release (DR), and ER formulations. Different formulations may contain the same medication at identical strengths; however, they may not be bioequivalent and should be titrated based on both the properties of the medication and the release type.¹

Immediate-release formulations are developed to dissolve without delaying or prolonging absorption of the medication. These formulations typically include “superdisintegrants” containing croscarmellose sodium² so that they disintegrate, de-aggregate, and/or dissolve when they come into contact with water or the gastrointestinal tract.^3-7

Delayed-release formulations rely on the gastrointestinal pH to release the medication after a certain amount of time has elapsed due to the enteric coating surrounding the tablet. This enteric coating prevents gastric mucosa/gastric juices from inactivating an acid-labile medication.⁸

Extended-release formulations, such as the divalproex sodium ER that was originally prescribed to Mr. G, are designed to release the medication in a controlled manner over an extended period of time, and at a predetermined rate and location following administration.^8-9 The advantage of this type of formulation is that it can be used to reduce dose frequency and improve adherence.¹⁰ Extended-release formulations are designed to minimize fluctuations in serum drug concentration between doses,¹¹ thereby reducing the risk of adverse effects.^12,13 A list of some common extended-release psychiatric medications is shown in the Table.

Continue to: The 5 oral formulations...

The 5 oral formulations of medications that contain valproic acid include:

• syrup
• capsule
• sprinkle
• enteric-coated delayed-release and extended-release

A parenteral form via IV is available for patients who are unable to swallow.

Absorption vs delivery

Any gastric bypass surgery can have postoperative complications, one of which can include absorption deficiencies of vitamins and minerals. Sleeve gastrectomy has the least amount of absorption-related nutritional deficiencies.¹⁴ Additionally, this procedure preserves the stomach’s ability to produce gastric acid. Therefore, regardless of formulation, there should be no initial postsurgical need to change psychotropic medication formulations. However, because VPA is related to B-vitamin deficiency, supplementation can be considered.

Omeprazole is a PPI that increases pH in the stomach and is often prescribed to promote healing of gastric surgery. However, in Mr. G’s case, omeprazole created a non-acidic environment in his stomach, which prevented the divalproex sodium ER formulation from being dissolved and the medication from being delivered. Mr. G’s absorption ability was preserved, which was confirmed by his rapid recovery and increased serum VPA levels once he was switched to the IR formulation. There is no literature supporting a recommended length of time a patient can receive omeprazole therapy for sleeve gastrectomy; this is at the surgeon’s discretion. Mr. G’s prescription for omeprazole was for 3 months.

Proper valproate dosing

In Mr. G’s case, it could be hypothesized that the VPA dosing was incorrect. For mood disorders, oral VPA dosing is 25 mg/kg/d. Mr. G lost 40 pounds, which would translate to a 450-mg reduction in dose. Despite maintaining his original dose, his serum VPA levels decreased by almost 50% and could not be attributed to trough measurement. In this case, Mr. G was prescribed a higher dose than needed given his weight loss.

Continue to: Divalproex sodium ER...

Divalproex sodium ER is a hydrophilic matrix tablet that requires a low pH to dissolve. Switching to an IR formulation bypassed the need for a low pH and the VPA was delivered and absorbed. Mr. G was always able to absorb the medication, but only when delivered. The Table lists other psychiatric medications that clinicians should be aware of that utilize similar hydrophilic matrix technology to slowly release medications through the gastrointestinal tract and also require low pH to release the medication from the tablet.

OUTCOME Stable once again

Two and a half weeks after his medication formulation is changed from divalproex sodium ER to IR, Mr. G shows improvement in his symptoms. His serum VPA level is 52 µg/mL, which is within therapeutic limits. He continues receiving his previous medications as well. He reports “feeling much better” and denies having any depressive symptoms nor anxiety. Mr. G is able to maintain eye contact, and has positive thought content, improved organization of thinking, and retained abstraction.

Bottom Line

All medication changes should be identified at each visit. Many extended-release psychiatric medications require lower pH to release the medication from the tablet. When evaluating nonresponse to psychotropic medications, anything that affects pH in the stomach should be considered.

Related Resources

• Monte SV, Russo KM, Mustafa E. Impact of sleeve gastrectomy on psychiatric medication use and symptoms. J Obes. 2018; 2018:8532602. doi: 10.1155/2018/8532602
• Qiu Y, Zhou D. Understanding design and development of modified release solid oral dosage forms. J Validation Technol. 2011;17(2):23-32.
• ObesityHelp, Inc. https://www.obesityhelp.com/medications-after-bariatric-surgery-wls/

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Clonidine ER • Kapvay
Divalproex sodium extended- release tablets • Depakote ER
Escitalopram • Lexapro
Iloperidone • Fanapt
Methylphenidate ER tablet • Concerta
Methylphenidate ER capsule • Metadate, Jornay
Methylphenidate LA capsule • Ritalin LA
Mirtazapine • Remeron
Omeprazole • Prilosec, Zegerid
Paroxetine • Paxil
Valproic acid immediate- release capsules and solution • Depakene
Valproate sodium IV • Depacon
Venlafaxine • Effexor

CASE Sudden-onset low mood

Mr. G, age 64, is obese (body mass index [BMI] 37 kg/m²) and has a history of schizoaffective disorder. He is recovering from a sleeve gastrectomy, a surgical weight-loss procedure in which a large portion of the stomach is removed. Seven weeks after his surgery, he experiences a sudden onset of “low mood” and fears that he will become suicidal; he has a history of suicide attempts. Mr. G calls his long-term outpatient clinic and is advised to go to the emergency department (ED).

For years, Mr. G had been stable in a group home setting, and had always been adherent to treatment and forthcoming about his medications with both his bariatric surgeon and psychiatrist. Within the last month, he had been seen at the clinic, had no psychiatric symptoms, and was recovering well from the sleeve gastrectomy.

HISTORY A stable regimen

Mr. G’s psychiatric symptoms initially developed when he was in his 20s, during a time in which he reported using “a lot of drugs.” He had multiple suicide attempts, and multiple inpatient and outpatient treatments. He was diagnosed with schizoaffective disorder.

Mr. G has been stable on medications for the last 2 years. His outpatient psychotropic regimen is divalproex sodium extended-release (ER), 2,500 mg every night at bedtime; iloperidone, 8 mg twice a day; escitalopram, 10 mg/d; and mirtazapine, 30 mg every night at bedtime.

In the group home, Mr. G spends his days socializing, studying philosophy, and writing essays. He hopes to find a job in the craftsman industry.

Mr. G’s medical history includes obesity (BMI: 37 kg/m²). Since the surgery, he has been receiving omeprazole, 40 mg/d, a proton pump inhibitor (PPI), to decrease the amount of acid in his stomach. Three weeks after surgery, he had an unremarkable postoperative outpatient psychiatry visit. Divalproex sodium ER was maintained at the pre-surgical dose of 2,500 mg/d.

EVALUATION Depressed and frightened

In the ED, Mr. G’s vitals are normal, but his serum valproic acid (VPA) level is 33.68 µg/mL (therapeutic range: 50 to 125 µg/mL), despite being compliant with treatment. Mr. G is discharged from the ED and told to follow up with his outpatient psychiatrist the next day.

Continue to: At his outpatient psychiatry appointment...

At his outpatient psychiatry appointment, Mr. G’s vital signs are normal, but he reports increasing depression and worsened mood. On mental status examination, Mr. G’s appearance is well groomed, and no agitation nor fidgeting are observed. His behavior is cooperative but somewhat disorganized. He is perseverative on “feeling so low.” He has poor eye contact, which is unusual for him. Mr. G’s speech is loud compared with his baseline. Affect is congruent to mood, which he describes as “depressed and frightened.” He is also noted to be irritable. His thought process is abstract and tangential, which is within his baseline. Mr. G’s thought content is fearful and negativistic, despite his usual positivity and optimism. He denies hallucinations and is oriented to time, place, and person. His judgment, attention, and memory are all within normal limits.

[polldaddy:10790537]

The authors’ observations

The psychiatrist rules out malingering/nonadherence due to Mr. G’s long history of treatment compliance, as evidenced by his past symptom control and therapeutic serum VPA levels. Mr. G was compliant with his postoperative appointments and has been healing well. Therefore, the treatment team believed that Mr. G’s intense and acute decompensation had to be related to a recent change. The notable changes in Mr. G’s case included his sleeve gastrectomy, and the addition of omeprazole to his medication regimen.

The treatment team observed that Mr. G had a long history of compliance with his medications and his symptoms were consistent with a low serum VPA level, which led to the conclusion that the low serum VPA level measured while he was in the ED was likely accurate. This prompted the team to consider Mr. G’s recent surgery. It is well documented that some bariatric surgeries can cause poor absorption of certain vitamins, minerals, and medications. However, Mr. G had a sleeve gastrectomy, which preserves absorption. At this point, the team considered if the patient’s recent medication change was the source of his low VPA level.

The psychiatrist concluded that the issue must have been with the addition of omeprazole because Mr. G’s sleeve gastrectomy was noneventful, he was healing well and being closely monitored by his bariatric surgeon, and this type of surgery preserves absorption. Fortunately, Mr. G was a good historian and had informed his psychiatrist about the addition of omeprazole after his sleeve gastrectomy. The psychiatrist knew acidity was important for the absorption of some medications. Although she was unsure as to whether the problem was a lack of absorption or lack of delivery, the psychiatrist knew a medication change was necessary to raise Mr. G’s serum VPA levels.

TREATMENT A change in divalproex formulation

The psychiatrist switches Mr. G’s formulation of divalproex sodium ER, 2,500 mg/d, to valproic acid immediate-release (IR) liquid capsules. He receives a total daily dose of 2,500 mg, but the dosage is split into 3 times a day. The omeprazole is continued to maintain the postoperative healing process, and he receives his other medications as well (iloperidone, 8 mg twice a day; escitalopram, 10 mg/d; and mirtazapine, 30 mg every night at bedtime).

[polldaddy:10790540]

Continue to: The authors' observations

The authors’ observations

The key component to creating a treatment plan for Mr. G centered on understanding drug metabolism and delivery. Acidity plays a role in dissolution of many medications, which led the team to surmise that the PPI, omeprazole, was the culprit. Through research, they understood that the divalproex sodium ER formulation needed a more acidic environment to dissolve, and therefore, an IR formulation was needed.

Different formulations, different characteristics

Medications can be produced in different formulations such as IR, delayed-release (DR), and ER formulations. Different formulations may contain the same medication at identical strengths; however, they may not be bioequivalent and should be titrated based on both the properties of the medication and the release type.¹

Immediate-release formulations are developed to dissolve without delaying or prolonging absorption of the medication. These formulations typically include “superdisintegrants” containing croscarmellose sodium² so that they disintegrate, de-aggregate, and/or dissolve when they come into contact with water or the gastrointestinal tract.^3-7

Delayed-release formulations rely on the gastrointestinal pH to release the medication after a certain amount of time has elapsed due to the enteric coating surrounding the tablet. This enteric coating prevents gastric mucosa/gastric juices from inactivating an acid-labile medication.⁸

Extended-release formulations, such as the divalproex sodium ER that was originally prescribed to Mr. G, are designed to release the medication in a controlled manner over an extended period of time, and at a predetermined rate and location following administration.^8-9 The advantage of this type of formulation is that it can be used to reduce dose frequency and improve adherence.¹⁰ Extended-release formulations are designed to minimize fluctuations in serum drug concentration between doses,¹¹ thereby reducing the risk of adverse effects.^12,13 A list of some common extended-release psychiatric medications is shown in the Table.

Continue to: The 5 oral formulations...

The 5 oral formulations of medications that contain valproic acid include:

• syrup
• capsule
• sprinkle
• enteric-coated delayed-release and extended-release

A parenteral form via IV is available for patients who are unable to swallow.

Absorption vs delivery

Any gastric bypass surgery can have postoperative complications, one of which can include absorption deficiencies of vitamins and minerals. Sleeve gastrectomy has the least amount of absorption-related nutritional deficiencies.¹⁴ Additionally, this procedure preserves the stomach’s ability to produce gastric acid. Therefore, regardless of formulation, there should be no initial postsurgical need to change psychotropic medication formulations. However, because VPA is related to B-vitamin deficiency, supplementation can be considered.

Omeprazole is a PPI that increases pH in the stomach and is often prescribed to promote healing of gastric surgery. However, in Mr. G’s case, omeprazole created a non-acidic environment in his stomach, which prevented the divalproex sodium ER formulation from being dissolved and the medication from being delivered. Mr. G’s absorption ability was preserved, which was confirmed by his rapid recovery and increased serum VPA levels once he was switched to the IR formulation. There is no literature supporting a recommended length of time a patient can receive omeprazole therapy for sleeve gastrectomy; this is at the surgeon’s discretion. Mr. G’s prescription for omeprazole was for 3 months.

Proper valproate dosing

In Mr. G’s case, it could be hypothesized that the VPA dosing was incorrect. For mood disorders, oral VPA dosing is 25 mg/kg/d. Mr. G lost 40 pounds, which would translate to a 450-mg reduction in dose. Despite maintaining his original dose, his serum VPA levels decreased by almost 50% and could not be attributed to trough measurement. In this case, Mr. G was prescribed a higher dose than needed given his weight loss.

Continue to: Divalproex sodium ER...

Divalproex sodium ER is a hydrophilic matrix tablet that requires a low pH to dissolve. Switching to an IR formulation bypassed the need for a low pH and the VPA was delivered and absorbed. Mr. G was always able to absorb the medication, but only when delivered. The Table lists other psychiatric medications that clinicians should be aware of that utilize similar hydrophilic matrix technology to slowly release medications through the gastrointestinal tract and also require low pH to release the medication from the tablet.

OUTCOME Stable once again

Two and a half weeks after his medication formulation is changed from divalproex sodium ER to IR, Mr. G shows improvement in his symptoms. His serum VPA level is 52 µg/mL, which is within therapeutic limits. He continues receiving his previous medications as well. He reports “feeling much better” and denies having any depressive symptoms nor anxiety. Mr. G is able to maintain eye contact, and has positive thought content, improved organization of thinking, and retained abstraction.

Bottom Line

All medication changes should be identified at each visit. Many extended-release psychiatric medications require lower pH to release the medication from the tablet. When evaluating nonresponse to psychotropic medications, anything that affects pH in the stomach should be considered.

Related Resources

• Monte SV, Russo KM, Mustafa E. Impact of sleeve gastrectomy on psychiatric medication use and symptoms. J Obes. 2018; 2018:8532602. doi: 10.1155/2018/8532602
• Qiu Y, Zhou D. Understanding design and development of modified release solid oral dosage forms. J Validation Technol. 2011;17(2):23-32.
• ObesityHelp, Inc. https://www.obesityhelp.com/medications-after-bariatric-surgery-wls/

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Clonidine ER • Kapvay
Divalproex sodium extended- release tablets • Depakote ER
Escitalopram • Lexapro
Iloperidone • Fanapt
Methylphenidate ER tablet • Concerta
Methylphenidate ER capsule • Metadate, Jornay
Methylphenidate LA capsule • Ritalin LA
Mirtazapine • Remeron
Omeprazole • Prilosec, Zegerid
Paroxetine • Paxil
Valproic acid immediate- release capsules and solution • Depakene
Valproate sodium IV • Depacon
Venlafaxine • Effexor

CASE Sudden-onset low mood

Mr. G, age 64, is obese (body mass index [BMI] 37 kg/m²) and has a history of schizoaffective disorder. He is recovering from a sleeve gastrectomy, a surgical weight-loss procedure in which a large portion of the stomach is removed. Seven weeks after his surgery, he experiences a sudden onset of “low mood” and fears that he will become suicidal; he has a history of suicide attempts. Mr. G calls his long-term outpatient clinic and is advised to go to the emergency department (ED).

For years, Mr. G had been stable in a group home setting, and had always been adherent to treatment and forthcoming about his medications with both his bariatric surgeon and psychiatrist. Within the last month, he had been seen at the clinic, had no psychiatric symptoms, and was recovering well from the sleeve gastrectomy.

HISTORY A stable regimen

Mr. G’s psychiatric symptoms initially developed when he was in his 20s, during a time in which he reported using “a lot of drugs.” He had multiple suicide attempts, and multiple inpatient and outpatient treatments. He was diagnosed with schizoaffective disorder.

Mr. G has been stable on medications for the last 2 years. His outpatient psychotropic regimen is divalproex sodium extended-release (ER), 2,500 mg every night at bedtime; iloperidone, 8 mg twice a day; escitalopram, 10 mg/d; and mirtazapine, 30 mg every night at bedtime.

In the group home, Mr. G spends his days socializing, studying philosophy, and writing essays. He hopes to find a job in the craftsman industry.

Mr. G’s medical history includes obesity (BMI: 37 kg/m²). Since the surgery, he has been receiving omeprazole, 40 mg/d, a proton pump inhibitor (PPI), to decrease the amount of acid in his stomach. Three weeks after surgery, he had an unremarkable postoperative outpatient psychiatry visit. Divalproex sodium ER was maintained at the pre-surgical dose of 2,500 mg/d.

EVALUATION Depressed and frightened

In the ED, Mr. G’s vitals are normal, but his serum valproic acid (VPA) level is 33.68 µg/mL (therapeutic range: 50 to 125 µg/mL), despite being compliant with treatment. Mr. G is discharged from the ED and told to follow up with his outpatient psychiatrist the next day.

Continue to: At his outpatient psychiatry appointment...

At his outpatient psychiatry appointment, Mr. G’s vital signs are normal, but he reports increasing depression and worsened mood. On mental status examination, Mr. G’s appearance is well groomed, and no agitation nor fidgeting are observed. His behavior is cooperative but somewhat disorganized. He is perseverative on “feeling so low.” He has poor eye contact, which is unusual for him. Mr. G’s speech is loud compared with his baseline. Affect is congruent to mood, which he describes as “depressed and frightened.” He is also noted to be irritable. His thought process is abstract and tangential, which is within his baseline. Mr. G’s thought content is fearful and negativistic, despite his usual positivity and optimism. He denies hallucinations and is oriented to time, place, and person. His judgment, attention, and memory are all within normal limits.

[polldaddy:10790537]

The authors’ observations

The psychiatrist rules out malingering/nonadherence due to Mr. G’s long history of treatment compliance, as evidenced by his past symptom control and therapeutic serum VPA levels. Mr. G was compliant with his postoperative appointments and has been healing well. Therefore, the treatment team believed that Mr. G’s intense and acute decompensation had to be related to a recent change. The notable changes in Mr. G’s case included his sleeve gastrectomy, and the addition of omeprazole to his medication regimen.

The treatment team observed that Mr. G had a long history of compliance with his medications and his symptoms were consistent with a low serum VPA level, which led to the conclusion that the low serum VPA level measured while he was in the ED was likely accurate. This prompted the team to consider Mr. G’s recent surgery. It is well documented that some bariatric surgeries can cause poor absorption of certain vitamins, minerals, and medications. However, Mr. G had a sleeve gastrectomy, which preserves absorption. At this point, the team considered if the patient’s recent medication change was the source of his low VPA level.

The psychiatrist concluded that the issue must have been with the addition of omeprazole because Mr. G’s sleeve gastrectomy was noneventful, he was healing well and being closely monitored by his bariatric surgeon, and this type of surgery preserves absorption. Fortunately, Mr. G was a good historian and had informed his psychiatrist about the addition of omeprazole after his sleeve gastrectomy. The psychiatrist knew acidity was important for the absorption of some medications. Although she was unsure as to whether the problem was a lack of absorption or lack of delivery, the psychiatrist knew a medication change was necessary to raise Mr. G’s serum VPA levels.

TREATMENT A change in divalproex formulation

The psychiatrist switches Mr. G’s formulation of divalproex sodium ER, 2,500 mg/d, to valproic acid immediate-release (IR) liquid capsules. He receives a total daily dose of 2,500 mg, but the dosage is split into 3 times a day. The omeprazole is continued to maintain the postoperative healing process, and he receives his other medications as well (iloperidone, 8 mg twice a day; escitalopram, 10 mg/d; and mirtazapine, 30 mg every night at bedtime).

[polldaddy:10790540]

Continue to: The authors' observations

The authors’ observations

The key component to creating a treatment plan for Mr. G centered on understanding drug metabolism and delivery. Acidity plays a role in dissolution of many medications, which led the team to surmise that the PPI, omeprazole, was the culprit. Through research, they understood that the divalproex sodium ER formulation needed a more acidic environment to dissolve, and therefore, an IR formulation was needed.

Different formulations, different characteristics

Medications can be produced in different formulations such as IR, delayed-release (DR), and ER formulations. Different formulations may contain the same medication at identical strengths; however, they may not be bioequivalent and should be titrated based on both the properties of the medication and the release type.¹

Immediate-release formulations are developed to dissolve without delaying or prolonging absorption of the medication. These formulations typically include “superdisintegrants” containing croscarmellose sodium² so that they disintegrate, de-aggregate, and/or dissolve when they come into contact with water or the gastrointestinal tract.^3-7

Delayed-release formulations rely on the gastrointestinal pH to release the medication after a certain amount of time has elapsed due to the enteric coating surrounding the tablet. This enteric coating prevents gastric mucosa/gastric juices from inactivating an acid-labile medication.⁸

Extended-release formulations, such as the divalproex sodium ER that was originally prescribed to Mr. G, are designed to release the medication in a controlled manner over an extended period of time, and at a predetermined rate and location following administration.^8-9 The advantage of this type of formulation is that it can be used to reduce dose frequency and improve adherence.¹⁰ Extended-release formulations are designed to minimize fluctuations in serum drug concentration between doses,¹¹ thereby reducing the risk of adverse effects.^12,13 A list of some common extended-release psychiatric medications is shown in the Table.

Continue to: The 5 oral formulations...

The 5 oral formulations of medications that contain valproic acid include:

• syrup
• capsule
• sprinkle
• enteric-coated delayed-release and extended-release

A parenteral form via IV is available for patients who are unable to swallow.

Absorption vs delivery

Any gastric bypass surgery can have postoperative complications, one of which can include absorption deficiencies of vitamins and minerals. Sleeve gastrectomy has the least amount of absorption-related nutritional deficiencies.¹⁴ Additionally, this procedure preserves the stomach’s ability to produce gastric acid. Therefore, regardless of formulation, there should be no initial postsurgical need to change psychotropic medication formulations. However, because VPA is related to B-vitamin deficiency, supplementation can be considered.

Omeprazole is a PPI that increases pH in the stomach and is often prescribed to promote healing of gastric surgery. However, in Mr. G’s case, omeprazole created a non-acidic environment in his stomach, which prevented the divalproex sodium ER formulation from being dissolved and the medication from being delivered. Mr. G’s absorption ability was preserved, which was confirmed by his rapid recovery and increased serum VPA levels once he was switched to the IR formulation. There is no literature supporting a recommended length of time a patient can receive omeprazole therapy for sleeve gastrectomy; this is at the surgeon’s discretion. Mr. G’s prescription for omeprazole was for 3 months.

Proper valproate dosing

In Mr. G’s case, it could be hypothesized that the VPA dosing was incorrect. For mood disorders, oral VPA dosing is 25 mg/kg/d. Mr. G lost 40 pounds, which would translate to a 450-mg reduction in dose. Despite maintaining his original dose, his serum VPA levels decreased by almost 50% and could not be attributed to trough measurement. In this case, Mr. G was prescribed a higher dose than needed given his weight loss.

Continue to: Divalproex sodium ER...

Divalproex sodium ER is a hydrophilic matrix tablet that requires a low pH to dissolve. Switching to an IR formulation bypassed the need for a low pH and the VPA was delivered and absorbed. Mr. G was always able to absorb the medication, but only when delivered. The Table lists other psychiatric medications that clinicians should be aware of that utilize similar hydrophilic matrix technology to slowly release medications through the gastrointestinal tract and also require low pH to release the medication from the tablet.

OUTCOME Stable once again

Two and a half weeks after his medication formulation is changed from divalproex sodium ER to IR, Mr. G shows improvement in his symptoms. His serum VPA level is 52 µg/mL, which is within therapeutic limits. He continues receiving his previous medications as well. He reports “feeling much better” and denies having any depressive symptoms nor anxiety. Mr. G is able to maintain eye contact, and has positive thought content, improved organization of thinking, and retained abstraction.

Bottom Line

All medication changes should be identified at each visit. Many extended-release psychiatric medications require lower pH to release the medication from the tablet. When evaluating nonresponse to psychotropic medications, anything that affects pH in the stomach should be considered.

Related Resources

• Monte SV, Russo KM, Mustafa E. Impact of sleeve gastrectomy on psychiatric medication use and symptoms. J Obes. 2018; 2018:8532602. doi: 10.1155/2018/8532602
• Qiu Y, Zhou D. Understanding design and development of modified release solid oral dosage forms. J Validation Technol. 2011;17(2):23-32.
• ObesityHelp, Inc. https://www.obesityhelp.com/medications-after-bariatric-surgery-wls/

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Clonidine ER • Kapvay
Divalproex sodium extended- release tablets • Depakote ER
Escitalopram • Lexapro
Iloperidone • Fanapt
Methylphenidate ER tablet • Concerta
Methylphenidate ER capsule • Metadate, Jornay
Methylphenidate LA capsule • Ritalin LA
Mirtazapine • Remeron
Omeprazole • Prilosec, Zegerid
Paroxetine • Paxil
Valproic acid immediate- release capsules and solution • Depakene
Valproate sodium IV • Depacon
Venlafaxine • Effexor

Ms. N, age 30, presents to the emergency department for altered mental status, insomnia, and behavioral changes, which she has experienced for 1 week. On evaluation, she grabs a clinician’s hand and details her business ideas and life story with no prompting. Ms. N’s mental status examination is significant for hyperverbal speech with increased rate and volume; tangential thought process; and bright, expanded affect.

One week earlier, Ms. N was hospitalized for sudden-onset chest pain, weakness, and dizziness. She received 45 minutes of cardiopulmonary resuscitation prior to presentation and was found to have a ST-segment elevation myocardial infarction that required emergent left anterior descending coronary artery and right coronary artery percutaneous coronary intervention to place drug-eluting stents. Her recovery was complicated by acute cardiogenic shock, pulmonary edema, and hypoxic respiratory failure. Subsequently, she was intubated, admitted to the ICU, and received high-dose corticosteroids, including IV methylprednisolone, 40 mg every 12 hours, which was tapered prior to discharge. Her husband reports that since Ms. N came home, she has been more talkative and irritable, ruminating about past events, unable to sleep (<1 hour/night), and crying frequently. She has also been endorsing visual and auditory hallucinations, with increased praying and listening to religious music.

The frequent clinical use of steroids necessitates an understanding of these medications’ various adverse effects. The manifestations of steroid-induced psychiatric symptoms are broad and can involve affective, behavioral, and cognitive domains. While the current mechanism is unknown, this phenomenon may be related to decreased levels of corticotropin, norepinephrine, and beta-endorphin immunoreactivity, as well as effects on brain regions such as the hippocampus and amygdala. The best interventions for steroid-induced psychiatric symptoms are awareness and early diagnosis. There are no FDA-approved treatments for steroid-induced psychiatric symptoms; initial measures should include tapering or discontinuing corticosteroids.

In this article, we review the literature on the incidence, characteristics, differential diagnoses, proposed mechanism, risk factors, and proposed treatments of steroid-induced psychiatric symptoms.

A wide range of presentations

Steroid use has increased over the past 2 decades, with 10% of medical and surgical inpatients and 1% to 3% of the general population taking long-term glucocorticoids.¹ Even with topical application, steroid therapy is often systemically absorbed, and thus may lead to steroid-induced psychiatric symptoms. The incidence of steroid-induced psychiatric symptoms is difficult to assess because there can be a wide range of reactions that are dose- and time-related. Three reviews of a total of 122 cases reports found that an estimated 5% of patients treated with steroids experience severe psychiatric reactions.^1-3

Steroid-induced psychopathology can include mood, behavioral, and/or cognitive impairments. Mania/hypomania is the most common overall psychiatric symptom; the most common mood manifestations are anxiety and depression.^4,5 Other possible steroid-induced symptoms include psychosis, dementia, panic disorder, delirium, suicidal thinking and behavior, aggressive behavior, insomnia, agitation, depersonalization, and euphoria.⁵ The most common cognitive impairment is verbal or declarative memory deficit; others include distractibility and deficits in attention and psychomotor speed.⁵ These psychiatric symptoms can have a rapid onset, possibly within hours of starting steroids.¹ However, studies have reported a median time to onset of 11.5 days; 39% of cases had onset during the first week and 62% within 2 weeks.^3,6 After reducing or stopping the steroid, it may take days to weeks before symptoms start to subside.²

What to consider in the differential Dx

Psychiatric symptoms that are induced by steroids can mimic metabolic, neurologic, or toxic disorders. Other factors to consider include drug withdrawal/intoxication, infections, and paraneoplastic syndromes.^4,5 Although there is no reported correlation between the location of neurologic lesions and the development of specific psychiatric symptoms, manic symptoms appear most commonly with lesions in the right frontal lobe. ⁴ Other factors to note include the presence of new-onset psychiatric illnesses such as bipolar, mood, or thought disorders,⁴ as well as psychosocial stressors that might be contributing to the patient’s presentation.⁵

Continue to: Proposed mechanisms

Although the exact mechanism by which steroids induce psychiatric symptoms is unknown, several mechanisms have been proposed. One hypothesis is that steroid-induced psychopathology is related to decreased levels of corticotropin, norepinephrine, and beta-endorphin immunoreactivity.^4,5,7 This may explain why many patients with major depressive disorder have elevated cortisol production and/or lack of suppression of cortisol secretion during a dexamethasone stimulation test, and why approximately one-half of patients with Cushing’s disease experience depressive symptoms.⁸ This is also likely why antipsychotics, which typically reduce cortisol, are efficacious treatments for some steroid-induced psychiatric symptoms.⁹ 

Cognitive impairments from steroid use may be related to these agents’ effects on certain brain regions. One such area is the hippocampus, an important mediator in the creation and maintenance of episodic and declarative memories.^5,8,9 Acute glucocorticoid use is associated with decreased activity in the left hippocampus, reduced hippocampal glucose metabolism, and reduced cerebral blood flow in the posterior medial temporal lobe.¹⁰ Long-term glucocorticoid exposure is associated with smaller hippocampal volume and lower levels of temporal lobe N-acetylaspartate, a marker of neuronal viability.¹⁰ Because working memory depends on the prefrontal cortex and declarative memory relies on the hippocampus, deficits in these functions can be attributed to the effect of prolonged glucocorticoid exposure on glucocorticoid or mineralocorticoid receptors in the hippocampus, reduction of hippocampal volume, or elevated glutamate accumulation in that area.¹¹ In addition, high cortisol levels inhibit brain-derived neurotrophic factor, which plays a crucial role in maintaining neural architecture in key brain regions such as the hippocampus and prefrontal cortex.¹¹ There is also a correlation between the duration of prednisone treatment and atrophy of the right amygdala, which is an important regulator of mood and anxiety.¹¹ Both the hippocampus and amygdala have dense collections of glucocorticoid receptors. This may explain why patients who receive high-dose corticosteroids can have reversible atrophy in the hypothalamus and amygdala, leading to deficits in emotional learning and the stress response.

Factors that increase risk

Several factors can increase the risk of steroid-induced psychopathology. The most significant is the dose; higher doses are more likely to produce psychiatric symptoms.^1,5 Concurrent use of drugs that increase circulating levels of corticosteroids, such as inhibitors of the cytochrome P450 (CYP) enzyme (eg, clarithromycin), also increases the likelihood of developing psychiatric symptoms.^1,5 Risk is also increased in patients with liver or renal dysfunction.¹ Cerebral spinal fluid/serum albumin ratio, a marker of blood-brain barrier damage, and low serum complement levels were also reported to be independent risk factors,¹² with the thought that increased permeability of the blood-brain barrier may allow hydrophobic steroid molecules to more easily penetrate the CNS, leading to increased neuropsychiatric effects. Hypoalbuminemia is another reported risk factor, perhaps because lower levels of serum albumin are related to higher levels of free and active glucocorticoids, which are normally inactive when bound to albumin.¹³ There also appears to be an increased prevalence of steroid-induced psychopathology in women, perhaps due to greater propensity in women to seek medical care or a higher prevalence of women with medical disorders that are treated with steroids.⁵ A previous history of psychiatric disorders may not increase risk.⁵

Several methods for reducing risk have been proposed, including using a divided-dosing regimens that may lower peak steroid plasma concentrations.^13,14 However, the best prevention of steroid-induced psychiatric symptoms are awareness, early diagnosis, and intervention. Studies have suggested that N-methyl-d-aspartate (NMDA) antagonists¹⁵ and other agents that decrease glutamate release (such as phenytoin and lamotrigine¹⁶) may help prevent corticosteroid-induced hippocampal volume loss. Lamotrigine has been shown to reduce the amount of atrophy in the amygdala in patients taking corticosteroids.¹⁷ Phenytoin has also been reported to reduce the incidence of hypomania associated with corticosteroids, perhaps due to its induction of CYP450 activity and acceleration of steroid clearance.¹⁶

Treatment options

There are no FDA-approved medications for managing steroid-induced psychiatric symptoms.^1,16 Treatment is based on evidence from case reports and a few small case series (Table^2-5,17,18).

Continue to: When possible, initial treatment...

When possible, initial treatment should include discontinuing or tapering corticosteroids to <40 mg/d of prednisone-equivalent.^1,4,10,18 Most studies have reported rapid reversal of deficits in declarative memory and of hippocampal volume loss once corticosteroids were tapered and discontinued.^1,18 One study reported that >90% of patients recovered within 6 weeks, with patients with delirium recovering more quickly (mean: 5.4 days) than those with depression, mania, or psychosis (mean: 19.3 days).³ Another found that the vast majority (92%) of patients treated only with a steroid taper achieved clinical recovery, and 84% recovered with administration of antipsychotics without a steroid taper.³ In this study, all patients who received electroconvulsive therapy (ECT) recovered, as did those who received a steroid taper plus lithium or antipsychotics. Steroid tapering regimens are especially important for patients who have received long-term glucocorticoid treatment. Patients need to be closely monitored for signs of new or increased depression, delirium, or confusion during the taper. If these symptoms occur, the patient should be checked for adrenocortical insufficiency, which can be resolved by re-administering or increasing the dosage of the glucocorticoid.¹⁰

Mania. The treatment of mania/hypomania includes mood stabilizers (valproate, lithium, lamotrigine) and antipsychotics (quetiapine, olanzapine, haloperidol).^{2,4,5,10,14,18} Valproate has been reported to be an effective prophylactic of corticosteroid-induced mania,² perhaps because it dampens neuronal hyperexcitability by attenuating NMDA receptors, blocking voltage-dependent sodium channels, and inhibiting the synthesis of cortical GABAergic steroids. Starting valproate while continuing corticosteroids (if necessary) may help lessen mania.² Benzodiazepines also may be useful on a short-term basis. 

Depression. Steroid-induced depression may be treated with sertraline or other first-line antidepressants.^5,14 Consider ECT for patients with severe depression. Support for the use of antipsychotic medications stems from studies that reported steroids’ role in disrupting dopamine and 5HT2 activity. Lithium also has been used successfully to manage and prevent glucocorticoid-associated affective disorder.^10,18 It can be used alone or in combination with selective serotonin reuptake inhibitors to alleviate depressive symptoms.¹⁰ Tricyclic antidepressants are generally avoided because their anticholinergic effects can exacerbate or worsen delirium.¹⁸ In general, ECT is an effective treatment for persistent and/or unresponsive steroid-induced depression,^2,10 but may be difficult to use in patients with serious medical illnesses.

Agitation. Medications that have been proposed for treating steroid-induced agitation include benzodiazepines, haloperidol, and second-generation antipsychotics.^5,17

Other considerations. Clinicians, patients, and families should discuss in detail the risks of steroid-induced psychiatric symptoms so an early diagnosis and appropriate intervention can be implemented. Before starting steroids, it is important to review the patient’s current medication list to ensure that steroid treatment is indicated, and to check for potential drug–drug interactions. In addition, the medical condition that is being treated with steroids also needs to be carefully reviewed, because certain illnesses are associated with the development of psychiatric symptoms. ^5,10

Continue to: Young children...

Young children (age <6) and older adults appear to be at greater risk for cognitive and memory disturbances from steroid use.¹⁰ In addition, patients have individual levels of susceptibility to steroid-induced psychiatric symptoms that can vary over time. The risk for adverse effects may be elevated based on response to previous courses of glucocorticoid treatment.¹⁰ While gender, age, dosage, and duration of treatment influence risk, it is not possible to predict which patients will experience psychiatric effects during a given course of glucocorticoid therapy. Therefore, all patients should be considered to have the potential of developing such effects, and should be monitored during glucocorticoid treatment and withdrawal.

Goals for future research

To help reduce the severity of and cost associated with steroid-induced psychiatric symptoms,^5,14 future studies should focus on controlled trials of preventative strategies. In particular, recent advances in genetic mapping may help identify involvement of certain genes or polymorphisms.⁵ Because current guidelines for the prevention and treatment of steroid-induced psychiatric symptoms are not evidence-based, controlled clinical trials are needed to elucidate the optimal management of such symptoms. There is much interplay between many of the proposed mechanisms of steroid-induced psychiatric symptoms, and future studies can help uncover a deeper understanding of the intricacies of this phenomenon.

CASE CONTINUED

Mrs. N is admitted for altered mental status. Medical workup includes MRI of the brain, MRI of the neck, cardiac echocardiogram, and EEG. There is no evidence of acute structural pathology. She is started on olanzapine, 10 mg/d at bedtime for manic and psychotic symptoms, and is discharged after 5 days. After 1 month, the outpatient psychiatrist gradually decreases and discontinues olanzapine as Mrs. N steadily returns to baseline. One year after discharge, Mrs. N continues to report resolution of her manic and psychotic symptoms.

Bottom Line

Steroids can induce a wide range of psychiatric symptoms, including mania/ hypomania, anxiety, and depression. Initial treatment typically includes tapering or discontinuing the steroid when possible. Other proposed treatments include certain antipsychotics, antidepressants, and other psychotropics, but the supporting evidence is largely anecdotal or based on case studies. Additional research is needed to elucidate the mechanism and treatment recommendations.

Related Resources

• Janes M, Kuster S, Goldson TM, et al. Steroid-induced psychosis. Proc (Bayl Univ Med Cent). 2019;32(4):614-615.
• Mayo Clinic. Prednisone and other corticosteroids. https://www.mayoclinic.org/steroids/art-20045692

Drug Brand Names

Haloperidol • Haldol
Lamotrigine • Lamictal
Lithium • Eskalith, Lithobid
Methylprednisolone injection • Solu-Medrol
Olanzapine • Zyprexa
Paroxetine • Paxil
Phenytoin • Dilantin
Quetiapine • Seroquel
Risperidone • Risperdal
Sertraline • Zoloft
Valproate • Depakote

Ms. N, age 30, presents to the emergency department for altered mental status, insomnia, and behavioral changes, which she has experienced for 1 week. On evaluation, she grabs a clinician’s hand and details her business ideas and life story with no prompting. Ms. N’s mental status examination is significant for hyperverbal speech with increased rate and volume; tangential thought process; and bright, expanded affect.

One week earlier, Ms. N was hospitalized for sudden-onset chest pain, weakness, and dizziness. She received 45 minutes of cardiopulmonary resuscitation prior to presentation and was found to have a ST-segment elevation myocardial infarction that required emergent left anterior descending coronary artery and right coronary artery percutaneous coronary intervention to place drug-eluting stents. Her recovery was complicated by acute cardiogenic shock, pulmonary edema, and hypoxic respiratory failure. Subsequently, she was intubated, admitted to the ICU, and received high-dose corticosteroids, including IV methylprednisolone, 40 mg every 12 hours, which was tapered prior to discharge. Her husband reports that since Ms. N came home, she has been more talkative and irritable, ruminating about past events, unable to sleep (<1 hour/night), and crying frequently. She has also been endorsing visual and auditory hallucinations, with increased praying and listening to religious music.

The frequent clinical use of steroids necessitates an understanding of these medications’ various adverse effects. The manifestations of steroid-induced psychiatric symptoms are broad and can involve affective, behavioral, and cognitive domains. While the current mechanism is unknown, this phenomenon may be related to decreased levels of corticotropin, norepinephrine, and beta-endorphin immunoreactivity, as well as effects on brain regions such as the hippocampus and amygdala. The best interventions for steroid-induced psychiatric symptoms are awareness and early diagnosis. There are no FDA-approved treatments for steroid-induced psychiatric symptoms; initial measures should include tapering or discontinuing corticosteroids.

In this article, we review the literature on the incidence, characteristics, differential diagnoses, proposed mechanism, risk factors, and proposed treatments of steroid-induced psychiatric symptoms.

A wide range of presentations

Steroid use has increased over the past 2 decades, with 10% of medical and surgical inpatients and 1% to 3% of the general population taking long-term glucocorticoids.¹ Even with topical application, steroid therapy is often systemically absorbed, and thus may lead to steroid-induced psychiatric symptoms. The incidence of steroid-induced psychiatric symptoms is difficult to assess because there can be a wide range of reactions that are dose- and time-related. Three reviews of a total of 122 cases reports found that an estimated 5% of patients treated with steroids experience severe psychiatric reactions.^1-3

Steroid-induced psychopathology can include mood, behavioral, and/or cognitive impairments. Mania/hypomania is the most common overall psychiatric symptom; the most common mood manifestations are anxiety and depression.^4,5 Other possible steroid-induced symptoms include psychosis, dementia, panic disorder, delirium, suicidal thinking and behavior, aggressive behavior, insomnia, agitation, depersonalization, and euphoria.⁵ The most common cognitive impairment is verbal or declarative memory deficit; others include distractibility and deficits in attention and psychomotor speed.⁵ These psychiatric symptoms can have a rapid onset, possibly within hours of starting steroids.¹ However, studies have reported a median time to onset of 11.5 days; 39% of cases had onset during the first week and 62% within 2 weeks.^3,6 After reducing or stopping the steroid, it may take days to weeks before symptoms start to subside.²

What to consider in the differential Dx

Psychiatric symptoms that are induced by steroids can mimic metabolic, neurologic, or toxic disorders. Other factors to consider include drug withdrawal/intoxication, infections, and paraneoplastic syndromes.^4,5 Although there is no reported correlation between the location of neurologic lesions and the development of specific psychiatric symptoms, manic symptoms appear most commonly with lesions in the right frontal lobe. ⁴ Other factors to note include the presence of new-onset psychiatric illnesses such as bipolar, mood, or thought disorders,⁴ as well as psychosocial stressors that might be contributing to the patient’s presentation.⁵

Continue to: Proposed mechanisms

Although the exact mechanism by which steroids induce psychiatric symptoms is unknown, several mechanisms have been proposed. One hypothesis is that steroid-induced psychopathology is related to decreased levels of corticotropin, norepinephrine, and beta-endorphin immunoreactivity.^4,5,7 This may explain why many patients with major depressive disorder have elevated cortisol production and/or lack of suppression of cortisol secretion during a dexamethasone stimulation test, and why approximately one-half of patients with Cushing’s disease experience depressive symptoms.⁸ This is also likely why antipsychotics, which typically reduce cortisol, are efficacious treatments for some steroid-induced psychiatric symptoms.⁹ 

Cognitive impairments from steroid use may be related to these agents’ effects on certain brain regions. One such area is the hippocampus, an important mediator in the creation and maintenance of episodic and declarative memories.^5,8,9 Acute glucocorticoid use is associated with decreased activity in the left hippocampus, reduced hippocampal glucose metabolism, and reduced cerebral blood flow in the posterior medial temporal lobe.¹⁰ Long-term glucocorticoid exposure is associated with smaller hippocampal volume and lower levels of temporal lobe N-acetylaspartate, a marker of neuronal viability.¹⁰ Because working memory depends on the prefrontal cortex and declarative memory relies on the hippocampus, deficits in these functions can be attributed to the effect of prolonged glucocorticoid exposure on glucocorticoid or mineralocorticoid receptors in the hippocampus, reduction of hippocampal volume, or elevated glutamate accumulation in that area.¹¹ In addition, high cortisol levels inhibit brain-derived neurotrophic factor, which plays a crucial role in maintaining neural architecture in key brain regions such as the hippocampus and prefrontal cortex.¹¹ There is also a correlation between the duration of prednisone treatment and atrophy of the right amygdala, which is an important regulator of mood and anxiety.¹¹ Both the hippocampus and amygdala have dense collections of glucocorticoid receptors. This may explain why patients who receive high-dose corticosteroids can have reversible atrophy in the hypothalamus and amygdala, leading to deficits in emotional learning and the stress response.

Factors that increase risk

Several factors can increase the risk of steroid-induced psychopathology. The most significant is the dose; higher doses are more likely to produce psychiatric symptoms.^1,5 Concurrent use of drugs that increase circulating levels of corticosteroids, such as inhibitors of the cytochrome P450 (CYP) enzyme (eg, clarithromycin), also increases the likelihood of developing psychiatric symptoms.^1,5 Risk is also increased in patients with liver or renal dysfunction.¹ Cerebral spinal fluid/serum albumin ratio, a marker of blood-brain barrier damage, and low serum complement levels were also reported to be independent risk factors,¹² with the thought that increased permeability of the blood-brain barrier may allow hydrophobic steroid molecules to more easily penetrate the CNS, leading to increased neuropsychiatric effects. Hypoalbuminemia is another reported risk factor, perhaps because lower levels of serum albumin are related to higher levels of free and active glucocorticoids, which are normally inactive when bound to albumin.¹³ There also appears to be an increased prevalence of steroid-induced psychopathology in women, perhaps due to greater propensity in women to seek medical care or a higher prevalence of women with medical disorders that are treated with steroids.⁵ A previous history of psychiatric disorders may not increase risk.⁵

Several methods for reducing risk have been proposed, including using a divided-dosing regimens that may lower peak steroid plasma concentrations.^13,14 However, the best prevention of steroid-induced psychiatric symptoms are awareness, early diagnosis, and intervention. Studies have suggested that N-methyl-d-aspartate (NMDA) antagonists¹⁵ and other agents that decrease glutamate release (such as phenytoin and lamotrigine¹⁶) may help prevent corticosteroid-induced hippocampal volume loss. Lamotrigine has been shown to reduce the amount of atrophy in the amygdala in patients taking corticosteroids.¹⁷ Phenytoin has also been reported to reduce the incidence of hypomania associated with corticosteroids, perhaps due to its induction of CYP450 activity and acceleration of steroid clearance.¹⁶

Treatment options

There are no FDA-approved medications for managing steroid-induced psychiatric symptoms.^1,16 Treatment is based on evidence from case reports and a few small case series (Table^2-5,17,18).

Continue to: When possible, initial treatment...

When possible, initial treatment should include discontinuing or tapering corticosteroids to <40 mg/d of prednisone-equivalent.^1,4,10,18 Most studies have reported rapid reversal of deficits in declarative memory and of hippocampal volume loss once corticosteroids were tapered and discontinued.^1,18 One study reported that >90% of patients recovered within 6 weeks, with patients with delirium recovering more quickly (mean: 5.4 days) than those with depression, mania, or psychosis (mean: 19.3 days).³ Another found that the vast majority (92%) of patients treated only with a steroid taper achieved clinical recovery, and 84% recovered with administration of antipsychotics without a steroid taper.³ In this study, all patients who received electroconvulsive therapy (ECT) recovered, as did those who received a steroid taper plus lithium or antipsychotics. Steroid tapering regimens are especially important for patients who have received long-term glucocorticoid treatment. Patients need to be closely monitored for signs of new or increased depression, delirium, or confusion during the taper. If these symptoms occur, the patient should be checked for adrenocortical insufficiency, which can be resolved by re-administering or increasing the dosage of the glucocorticoid.¹⁰

Mania. The treatment of mania/hypomania includes mood stabilizers (valproate, lithium, lamotrigine) and antipsychotics (quetiapine, olanzapine, haloperidol).^{2,4,5,10,14,18} Valproate has been reported to be an effective prophylactic of corticosteroid-induced mania,² perhaps because it dampens neuronal hyperexcitability by attenuating NMDA receptors, blocking voltage-dependent sodium channels, and inhibiting the synthesis of cortical GABAergic steroids. Starting valproate while continuing corticosteroids (if necessary) may help lessen mania.² Benzodiazepines also may be useful on a short-term basis. 

Depression. Steroid-induced depression may be treated with sertraline or other first-line antidepressants.^5,14 Consider ECT for patients with severe depression. Support for the use of antipsychotic medications stems from studies that reported steroids’ role in disrupting dopamine and 5HT2 activity. Lithium also has been used successfully to manage and prevent glucocorticoid-associated affective disorder.^10,18 It can be used alone or in combination with selective serotonin reuptake inhibitors to alleviate depressive symptoms.¹⁰ Tricyclic antidepressants are generally avoided because their anticholinergic effects can exacerbate or worsen delirium.¹⁸ In general, ECT is an effective treatment for persistent and/or unresponsive steroid-induced depression,^2,10 but may be difficult to use in patients with serious medical illnesses.

Agitation. Medications that have been proposed for treating steroid-induced agitation include benzodiazepines, haloperidol, and second-generation antipsychotics.^5,17

Other considerations. Clinicians, patients, and families should discuss in detail the risks of steroid-induced psychiatric symptoms so an early diagnosis and appropriate intervention can be implemented. Before starting steroids, it is important to review the patient’s current medication list to ensure that steroid treatment is indicated, and to check for potential drug–drug interactions. In addition, the medical condition that is being treated with steroids also needs to be carefully reviewed, because certain illnesses are associated with the development of psychiatric symptoms. ^5,10

Continue to: Young children...

Young children (age <6) and older adults appear to be at greater risk for cognitive and memory disturbances from steroid use.¹⁰ In addition, patients have individual levels of susceptibility to steroid-induced psychiatric symptoms that can vary over time. The risk for adverse effects may be elevated based on response to previous courses of glucocorticoid treatment.¹⁰ While gender, age, dosage, and duration of treatment influence risk, it is not possible to predict which patients will experience psychiatric effects during a given course of glucocorticoid therapy. Therefore, all patients should be considered to have the potential of developing such effects, and should be monitored during glucocorticoid treatment and withdrawal.

Goals for future research

To help reduce the severity of and cost associated with steroid-induced psychiatric symptoms,^5,14 future studies should focus on controlled trials of preventative strategies. In particular, recent advances in genetic mapping may help identify involvement of certain genes or polymorphisms.⁵ Because current guidelines for the prevention and treatment of steroid-induced psychiatric symptoms are not evidence-based, controlled clinical trials are needed to elucidate the optimal management of such symptoms. There is much interplay between many of the proposed mechanisms of steroid-induced psychiatric symptoms, and future studies can help uncover a deeper understanding of the intricacies of this phenomenon.

CASE CONTINUED

Mrs. N is admitted for altered mental status. Medical workup includes MRI of the brain, MRI of the neck, cardiac echocardiogram, and EEG. There is no evidence of acute structural pathology. She is started on olanzapine, 10 mg/d at bedtime for manic and psychotic symptoms, and is discharged after 5 days. After 1 month, the outpatient psychiatrist gradually decreases and discontinues olanzapine as Mrs. N steadily returns to baseline. One year after discharge, Mrs. N continues to report resolution of her manic and psychotic symptoms.

Bottom Line

Steroids can induce a wide range of psychiatric symptoms, including mania/ hypomania, anxiety, and depression. Initial treatment typically includes tapering or discontinuing the steroid when possible. Other proposed treatments include certain antipsychotics, antidepressants, and other psychotropics, but the supporting evidence is largely anecdotal or based on case studies. Additional research is needed to elucidate the mechanism and treatment recommendations.

Related Resources

• Janes M, Kuster S, Goldson TM, et al. Steroid-induced psychosis. Proc (Bayl Univ Med Cent). 2019;32(4):614-615.
• Mayo Clinic. Prednisone and other corticosteroids. https://www.mayoclinic.org/steroids/art-20045692

Drug Brand Names

Haloperidol • Haldol
Lamotrigine • Lamictal
Lithium • Eskalith, Lithobid
Methylprednisolone injection • Solu-Medrol
Olanzapine • Zyprexa
Paroxetine • Paxil
Phenytoin • Dilantin
Quetiapine • Seroquel
Risperidone • Risperdal
Sertraline • Zoloft
Valproate • Depakote

Ms. N, age 30, presents to the emergency department for altered mental status, insomnia, and behavioral changes, which she has experienced for 1 week. On evaluation, she grabs a clinician’s hand and details her business ideas and life story with no prompting. Ms. N’s mental status examination is significant for hyperverbal speech with increased rate and volume; tangential thought process; and bright, expanded affect.

One week earlier, Ms. N was hospitalized for sudden-onset chest pain, weakness, and dizziness. She received 45 minutes of cardiopulmonary resuscitation prior to presentation and was found to have a ST-segment elevation myocardial infarction that required emergent left anterior descending coronary artery and right coronary artery percutaneous coronary intervention to place drug-eluting stents. Her recovery was complicated by acute cardiogenic shock, pulmonary edema, and hypoxic respiratory failure. Subsequently, she was intubated, admitted to the ICU, and received high-dose corticosteroids, including IV methylprednisolone, 40 mg every 12 hours, which was tapered prior to discharge. Her husband reports that since Ms. N came home, she has been more talkative and irritable, ruminating about past events, unable to sleep (<1 hour/night), and crying frequently. She has also been endorsing visual and auditory hallucinations, with increased praying and listening to religious music.

The frequent clinical use of steroids necessitates an understanding of these medications’ various adverse effects. The manifestations of steroid-induced psychiatric symptoms are broad and can involve affective, behavioral, and cognitive domains. While the current mechanism is unknown, this phenomenon may be related to decreased levels of corticotropin, norepinephrine, and beta-endorphin immunoreactivity, as well as effects on brain regions such as the hippocampus and amygdala. The best interventions for steroid-induced psychiatric symptoms are awareness and early diagnosis. There are no FDA-approved treatments for steroid-induced psychiatric symptoms; initial measures should include tapering or discontinuing corticosteroids.

In this article, we review the literature on the incidence, characteristics, differential diagnoses, proposed mechanism, risk factors, and proposed treatments of steroid-induced psychiatric symptoms.

A wide range of presentations

Steroid use has increased over the past 2 decades, with 10% of medical and surgical inpatients and 1% to 3% of the general population taking long-term glucocorticoids.¹ Even with topical application, steroid therapy is often systemically absorbed, and thus may lead to steroid-induced psychiatric symptoms. The incidence of steroid-induced psychiatric symptoms is difficult to assess because there can be a wide range of reactions that are dose- and time-related. Three reviews of a total of 122 cases reports found that an estimated 5% of patients treated with steroids experience severe psychiatric reactions.^1-3

Steroid-induced psychopathology can include mood, behavioral, and/or cognitive impairments. Mania/hypomania is the most common overall psychiatric symptom; the most common mood manifestations are anxiety and depression.^4,5 Other possible steroid-induced symptoms include psychosis, dementia, panic disorder, delirium, suicidal thinking and behavior, aggressive behavior, insomnia, agitation, depersonalization, and euphoria.⁵ The most common cognitive impairment is verbal or declarative memory deficit; others include distractibility and deficits in attention and psychomotor speed.⁵ These psychiatric symptoms can have a rapid onset, possibly within hours of starting steroids.¹ However, studies have reported a median time to onset of 11.5 days; 39% of cases had onset during the first week and 62% within 2 weeks.^3,6 After reducing or stopping the steroid, it may take days to weeks before symptoms start to subside.²

What to consider in the differential Dx

Psychiatric symptoms that are induced by steroids can mimic metabolic, neurologic, or toxic disorders. Other factors to consider include drug withdrawal/intoxication, infections, and paraneoplastic syndromes.^4,5 Although there is no reported correlation between the location of neurologic lesions and the development of specific psychiatric symptoms, manic symptoms appear most commonly with lesions in the right frontal lobe. ⁴ Other factors to note include the presence of new-onset psychiatric illnesses such as bipolar, mood, or thought disorders,⁴ as well as psychosocial stressors that might be contributing to the patient’s presentation.⁵

Continue to: Proposed mechanisms

Although the exact mechanism by which steroids induce psychiatric symptoms is unknown, several mechanisms have been proposed. One hypothesis is that steroid-induced psychopathology is related to decreased levels of corticotropin, norepinephrine, and beta-endorphin immunoreactivity.^4,5,7 This may explain why many patients with major depressive disorder have elevated cortisol production and/or lack of suppression of cortisol secretion during a dexamethasone stimulation test, and why approximately one-half of patients with Cushing’s disease experience depressive symptoms.⁸ This is also likely why antipsychotics, which typically reduce cortisol, are efficacious treatments for some steroid-induced psychiatric symptoms.⁹ 

Cognitive impairments from steroid use may be related to these agents’ effects on certain brain regions. One such area is the hippocampus, an important mediator in the creation and maintenance of episodic and declarative memories.^5,8,9 Acute glucocorticoid use is associated with decreased activity in the left hippocampus, reduced hippocampal glucose metabolism, and reduced cerebral blood flow in the posterior medial temporal lobe.¹⁰ Long-term glucocorticoid exposure is associated with smaller hippocampal volume and lower levels of temporal lobe N-acetylaspartate, a marker of neuronal viability.¹⁰ Because working memory depends on the prefrontal cortex and declarative memory relies on the hippocampus, deficits in these functions can be attributed to the effect of prolonged glucocorticoid exposure on glucocorticoid or mineralocorticoid receptors in the hippocampus, reduction of hippocampal volume, or elevated glutamate accumulation in that area.¹¹ In addition, high cortisol levels inhibit brain-derived neurotrophic factor, which plays a crucial role in maintaining neural architecture in key brain regions such as the hippocampus and prefrontal cortex.¹¹ There is also a correlation between the duration of prednisone treatment and atrophy of the right amygdala, which is an important regulator of mood and anxiety.¹¹ Both the hippocampus and amygdala have dense collections of glucocorticoid receptors. This may explain why patients who receive high-dose corticosteroids can have reversible atrophy in the hypothalamus and amygdala, leading to deficits in emotional learning and the stress response.

Factors that increase risk

Several factors can increase the risk of steroid-induced psychopathology. The most significant is the dose; higher doses are more likely to produce psychiatric symptoms.^1,5 Concurrent use of drugs that increase circulating levels of corticosteroids, such as inhibitors of the cytochrome P450 (CYP) enzyme (eg, clarithromycin), also increases the likelihood of developing psychiatric symptoms.^1,5 Risk is also increased in patients with liver or renal dysfunction.¹ Cerebral spinal fluid/serum albumin ratio, a marker of blood-brain barrier damage, and low serum complement levels were also reported to be independent risk factors,¹² with the thought that increased permeability of the blood-brain barrier may allow hydrophobic steroid molecules to more easily penetrate the CNS, leading to increased neuropsychiatric effects. Hypoalbuminemia is another reported risk factor, perhaps because lower levels of serum albumin are related to higher levels of free and active glucocorticoids, which are normally inactive when bound to albumin.¹³ There also appears to be an increased prevalence of steroid-induced psychopathology in women, perhaps due to greater propensity in women to seek medical care or a higher prevalence of women with medical disorders that are treated with steroids.⁵ A previous history of psychiatric disorders may not increase risk.⁵

Several methods for reducing risk have been proposed, including using a divided-dosing regimens that may lower peak steroid plasma concentrations.^13,14 However, the best prevention of steroid-induced psychiatric symptoms are awareness, early diagnosis, and intervention. Studies have suggested that N-methyl-d-aspartate (NMDA) antagonists¹⁵ and other agents that decrease glutamate release (such as phenytoin and lamotrigine¹⁶) may help prevent corticosteroid-induced hippocampal volume loss. Lamotrigine has been shown to reduce the amount of atrophy in the amygdala in patients taking corticosteroids.¹⁷ Phenytoin has also been reported to reduce the incidence of hypomania associated with corticosteroids, perhaps due to its induction of CYP450 activity and acceleration of steroid clearance.¹⁶

Treatment options

There are no FDA-approved medications for managing steroid-induced psychiatric symptoms.^1,16 Treatment is based on evidence from case reports and a few small case series (Table^2-5,17,18).

Continue to: When possible, initial treatment...

When possible, initial treatment should include discontinuing or tapering corticosteroids to <40 mg/d of prednisone-equivalent.^1,4,10,18 Most studies have reported rapid reversal of deficits in declarative memory and of hippocampal volume loss once corticosteroids were tapered and discontinued.^1,18 One study reported that >90% of patients recovered within 6 weeks, with patients with delirium recovering more quickly (mean: 5.4 days) than those with depression, mania, or psychosis (mean: 19.3 days).³ Another found that the vast majority (92%) of patients treated only with a steroid taper achieved clinical recovery, and 84% recovered with administration of antipsychotics without a steroid taper.³ In this study, all patients who received electroconvulsive therapy (ECT) recovered, as did those who received a steroid taper plus lithium or antipsychotics. Steroid tapering regimens are especially important for patients who have received long-term glucocorticoid treatment. Patients need to be closely monitored for signs of new or increased depression, delirium, or confusion during the taper. If these symptoms occur, the patient should be checked for adrenocortical insufficiency, which can be resolved by re-administering or increasing the dosage of the glucocorticoid.¹⁰

Mania. The treatment of mania/hypomania includes mood stabilizers (valproate, lithium, lamotrigine) and antipsychotics (quetiapine, olanzapine, haloperidol).^{2,4,5,10,14,18} Valproate has been reported to be an effective prophylactic of corticosteroid-induced mania,² perhaps because it dampens neuronal hyperexcitability by attenuating NMDA receptors, blocking voltage-dependent sodium channels, and inhibiting the synthesis of cortical GABAergic steroids. Starting valproate while continuing corticosteroids (if necessary) may help lessen mania.² Benzodiazepines also may be useful on a short-term basis. 

Depression. Steroid-induced depression may be treated with sertraline or other first-line antidepressants.^5,14 Consider ECT for patients with severe depression. Support for the use of antipsychotic medications stems from studies that reported steroids’ role in disrupting dopamine and 5HT2 activity. Lithium also has been used successfully to manage and prevent glucocorticoid-associated affective disorder.^10,18 It can be used alone or in combination with selective serotonin reuptake inhibitors to alleviate depressive symptoms.¹⁰ Tricyclic antidepressants are generally avoided because their anticholinergic effects can exacerbate or worsen delirium.¹⁸ In general, ECT is an effective treatment for persistent and/or unresponsive steroid-induced depression,^2,10 but may be difficult to use in patients with serious medical illnesses.

Agitation. Medications that have been proposed for treating steroid-induced agitation include benzodiazepines, haloperidol, and second-generation antipsychotics.^5,17

Other considerations. Clinicians, patients, and families should discuss in detail the risks of steroid-induced psychiatric symptoms so an early diagnosis and appropriate intervention can be implemented. Before starting steroids, it is important to review the patient’s current medication list to ensure that steroid treatment is indicated, and to check for potential drug–drug interactions. In addition, the medical condition that is being treated with steroids also needs to be carefully reviewed, because certain illnesses are associated with the development of psychiatric symptoms. ^5,10

Continue to: Young children...

Young children (age <6) and older adults appear to be at greater risk for cognitive and memory disturbances from steroid use.¹⁰ In addition, patients have individual levels of susceptibility to steroid-induced psychiatric symptoms that can vary over time. The risk for adverse effects may be elevated based on response to previous courses of glucocorticoid treatment.¹⁰ While gender, age, dosage, and duration of treatment influence risk, it is not possible to predict which patients will experience psychiatric effects during a given course of glucocorticoid therapy. Therefore, all patients should be considered to have the potential of developing such effects, and should be monitored during glucocorticoid treatment and withdrawal.

Goals for future research

To help reduce the severity of and cost associated with steroid-induced psychiatric symptoms,^5,14 future studies should focus on controlled trials of preventative strategies. In particular, recent advances in genetic mapping may help identify involvement of certain genes or polymorphisms.⁵ Because current guidelines for the prevention and treatment of steroid-induced psychiatric symptoms are not evidence-based, controlled clinical trials are needed to elucidate the optimal management of such symptoms. There is much interplay between many of the proposed mechanisms of steroid-induced psychiatric symptoms, and future studies can help uncover a deeper understanding of the intricacies of this phenomenon.

CASE CONTINUED

Mrs. N is admitted for altered mental status. Medical workup includes MRI of the brain, MRI of the neck, cardiac echocardiogram, and EEG. There is no evidence of acute structural pathology. She is started on olanzapine, 10 mg/d at bedtime for manic and psychotic symptoms, and is discharged after 5 days. After 1 month, the outpatient psychiatrist gradually decreases and discontinues olanzapine as Mrs. N steadily returns to baseline. One year after discharge, Mrs. N continues to report resolution of her manic and psychotic symptoms.

Bottom Line

Steroids can induce a wide range of psychiatric symptoms, including mania/ hypomania, anxiety, and depression. Initial treatment typically includes tapering or discontinuing the steroid when possible. Other proposed treatments include certain antipsychotics, antidepressants, and other psychotropics, but the supporting evidence is largely anecdotal or based on case studies. Additional research is needed to elucidate the mechanism and treatment recommendations.

Related Resources

• Janes M, Kuster S, Goldson TM, et al. Steroid-induced psychosis. Proc (Bayl Univ Med Cent). 2019;32(4):614-615.
• Mayo Clinic. Prednisone and other corticosteroids. https://www.mayoclinic.org/steroids/art-20045692

Drug Brand Names

Haloperidol • Haldol
Lamotrigine • Lamictal
Lithium • Eskalith, Lithobid
Methylprednisolone injection • Solu-Medrol
Olanzapine • Zyprexa
Paroxetine • Paxil
Phenytoin • Dilantin
Quetiapine • Seroquel
Risperidone • Risperdal
Sertraline • Zoloft
Valproate • Depakote

Mr. H, age 43, presents to your clinic for management of posttraumatic stress disorder (PTSD). At his last appointment 8 weeks ago, he was continued on fluoxetine, 60 mg/d; he had been stable on this medication for 6 months. Today, Mr. H reports an increase in the frequency and severity of nightmares. He states that he wakes at least 3 times every week with “disturbing dreams” about his time in the military and does not feel rested even when he sleeps through the night. His Clinician-Administered PTSD Scale (CAPS) score is 95 on this visit, suggesting extreme PTSD symptomatology. Mr. H asks if anything can be done to reduce the frequency and intensity of his nightmares.

PTSD is the development of characteristic symptoms following exposure to ≥1 traumatic events. According to DSM-5, PTSD symptoms include the presence of ≥1 intrusion symptoms (recurrent, intrusive memories of the traumatic event; recurrent distressing dreams; dissociative reactions), persistent avoidance of stimuli, negative alterations in cognition and mood, and marked alterations in arousal and reactivity associated with the traumatic event(s).¹ The symptoms must be present for >1 month, cause clinically significant distress or impairment in functioning, and not be attributable to the psychologic effects of a substance or medical conditions.¹ This article focuses specifically on the hyperarousal symptoms, and the clinical controversies surrounding the use of prazosin for PTSD.

Prazosin for PTSD treatment

Sleep disorders are extremely common in patients with PTSD. Up to 90% of patients report sleep disturbances, and up to 70% report nightmares.² Prazosin has been widely used in the treatment of PTSD-related sleep disorders and nightmares.The American Psychiatric Association³ and the British Association of Psychopharmacology⁴ guidelines in-­clude prazosin as a first-line recommendation for treatment of PTSD. However, updated 2017 guidelines from the Veterans Affairs/Department of Defense (VA/DoD)⁵ and data from the 2018 Prazosin and Combat Trauma PTSD (PACT) trial⁶ contradict these original recommendations. Previously, the 2010 VA/DoD guideline said prazosin had insufficient evidence for monotherapy, but recommended it as adjunctive treatment for sleep and nightmares.⁷ The updated 2017 VA/DoD guideline recommends “weak against” prazosin use for global symptoms of PTSD, and says there is insufficient evidence for its use in nightmares.⁵ Below we summarize the findings of studies that contributed to those original recommendations, along with results of the PACT trial.

Raskind et al^8,9 conducted 2 studies of prazosin use in combat veterans with PTSD. In both studies, prazosin had significant positive effects on the Clinician-Administered PTSD Scale (CAPS) and Clinical Global Impression of Change (CGIC) scores.^8,9 The 2007 study also found significant effects of prazosin on Pittsburgh Sleep Quality Index (PSQI) scores.⁹

Raskind et al¹⁰ conducted another study in 2013 of prazosin use for active-duty soldiers who had combat trauma PTSD with nightmares. Prazosin had positive effects for nightmares, sleep quality, and CAPS scores.¹⁰

Germain et al¹¹ reviewed prazosin for treating sleep disturbances in US military veterans. Prazosin was associated with significant improvements in insomnia and daytime PTSD symptom severity as demonstrated by changes in PSQI and CAPS scores.¹¹

Taylor et al¹² examined the effects of prazosin on sleep measures and clinical symptoms in civilians with PTSD. Prazosin significantly increased total sleep time, rapid eye movement sleep time, and CGIC scores while significantly decreasing trauma-related nightmares.¹²

Continue to: Overall, these trials...

Overall, these trials found efficacy for the use of prazosin for patients diagnosed with PTSD; however, the population size in each of these studies was small.

Results of the PACT trial

The PACT trial was a 26-week, multicenter, double-blind, randomized, placebo-controlled trial conducted across 12 VA medical centers.⁶ During the first 5 weeks, participants were randomized to receive placebo or prazosin, which could be titrated up to 20 mg/d in men and 12 mg/d in women. Participants remained on that dose from the end of Week 5 through Week 10. At that time, other pharmacologic therapies and psychotherapy could be added, discontinued, or adjusted. The mean maintenance total daily dose of prazosin was 14.8 mg.

A total of 413 patients were screened, 304 were randomized (152 per group), and 271 completed the 10-week primary outcome assessment. The population was almost entirely male (96.1% in the prazosin group and 99.3% in the placebo group), and most participants were White (64.5% in the prazosin group and 69.1% in the placebo group), with an average age of approximately 50 years. Primary outcomes included change from baseline to Week 10 in both CAPS item B2 (“recurrent distressing dreams”) and PSQI scores. CGIC score was evaluated at Week 10.

At Week 10, none of the primary outcomes were found to be statistically significant. The mean difference in change from baseline to Week 10 in CAPS item B2 score and PSQI score were 0.2 (P = .38) and 0.1 (P = .80), respectively. There was no significant difference in mean CGIC scores (P = .96). Repeated measures of CAPS item B2, PSQI, and CGIC scores were conducted through Week 26 as secondary outcomes. No significant differences were found. This study concluded that prazosin did not alleviate distressing dreams, improve sleep quality, or improve overall clinical symptoms.⁶

The PACT trial: Strengths and weaknesses

The PACT trial is the largest placebo-controlled trial for prazosin use in PTSD to date. It failed to show efficacy of prazosin for PTSD-associated nightmares, which contradicts previous studies. Although the mean total daily dose of prazosin was adequate and primary outcomes were measured with appropriate scales, the study failed to enroll the desired number of patients, which increased the possibility of false-negative results. Furthermore, participant recruitment may have led to selection bias because all participants were clinically stable, which could explain the lack of efficacy. However, the average CAPS scores were 80.7 in the prazosin group and 81.9 in the placebo group, which indicates that these patients had significant symptomatology at baseline and before entering the study.

Continue to: A major theme...

A major theme of studies evaluating prazosin treatment for PTSD is a focus on a military population and military-related trauma. Other than Taylor et al¹² (N=13), none of these trials included patients who were diagnosed with PTSD due to other traumas, such as sexual trauma, which limits the generalizability of the results. Furthermore, apart from the PACT trial, none of these studies had >100 participants, which further reduces external validity. Current guidelines have not been updated to include the results of the PACT trial, and it is unclear if the results of this trial are strong enough to change clinical practice.

CASE CONTINUED

To ensure patient-centered care, the treating clinicians conduct a risk/benefit discussion with the patient regarding starting prazosin. Mr. H opts to try prazosin, so the clinicians initiate a low dose (1 mg/d) to mitigate adverse effects, and plan to titrate to clinical effect or intolerability. Per evidence from the trials discussed, it is likely Mr. H will need to be titrated to at least 5 to 6 mg/d to see a clinical effect.

Related Resource

North CS, Hong BA, Downs DL. PTSD: A systematic approach to diagnosis and treatment. Current Psychiatry 2018;17(4):35-43.

Drug Brand Names

Fluoxetine • Prozac
Prazosin • Minipress

Mr. H, age 43, presents to your clinic for management of posttraumatic stress disorder (PTSD). At his last appointment 8 weeks ago, he was continued on fluoxetine, 60 mg/d; he had been stable on this medication for 6 months. Today, Mr. H reports an increase in the frequency and severity of nightmares. He states that he wakes at least 3 times every week with “disturbing dreams” about his time in the military and does not feel rested even when he sleeps through the night. His Clinician-Administered PTSD Scale (CAPS) score is 95 on this visit, suggesting extreme PTSD symptomatology. Mr. H asks if anything can be done to reduce the frequency and intensity of his nightmares.

PTSD is the development of characteristic symptoms following exposure to ≥1 traumatic events. According to DSM-5, PTSD symptoms include the presence of ≥1 intrusion symptoms (recurrent, intrusive memories of the traumatic event; recurrent distressing dreams; dissociative reactions), persistent avoidance of stimuli, negative alterations in cognition and mood, and marked alterations in arousal and reactivity associated with the traumatic event(s).¹ The symptoms must be present for >1 month, cause clinically significant distress or impairment in functioning, and not be attributable to the psychologic effects of a substance or medical conditions.¹ This article focuses specifically on the hyperarousal symptoms, and the clinical controversies surrounding the use of prazosin for PTSD.

Prazosin for PTSD treatment

Sleep disorders are extremely common in patients with PTSD. Up to 90% of patients report sleep disturbances, and up to 70% report nightmares.² Prazosin has been widely used in the treatment of PTSD-related sleep disorders and nightmares.The American Psychiatric Association³ and the British Association of Psychopharmacology⁴ guidelines in-­clude prazosin as a first-line recommendation for treatment of PTSD. However, updated 2017 guidelines from the Veterans Affairs/Department of Defense (VA/DoD)⁵ and data from the 2018 Prazosin and Combat Trauma PTSD (PACT) trial⁶ contradict these original recommendations. Previously, the 2010 VA/DoD guideline said prazosin had insufficient evidence for monotherapy, but recommended it as adjunctive treatment for sleep and nightmares.⁷ The updated 2017 VA/DoD guideline recommends “weak against” prazosin use for global symptoms of PTSD, and says there is insufficient evidence for its use in nightmares.⁵ Below we summarize the findings of studies that contributed to those original recommendations, along with results of the PACT trial.

Raskind et al^8,9 conducted 2 studies of prazosin use in combat veterans with PTSD. In both studies, prazosin had significant positive effects on the Clinician-Administered PTSD Scale (CAPS) and Clinical Global Impression of Change (CGIC) scores.^8,9 The 2007 study also found significant effects of prazosin on Pittsburgh Sleep Quality Index (PSQI) scores.⁹

Raskind et al¹⁰ conducted another study in 2013 of prazosin use for active-duty soldiers who had combat trauma PTSD with nightmares. Prazosin had positive effects for nightmares, sleep quality, and CAPS scores.¹⁰

Germain et al¹¹ reviewed prazosin for treating sleep disturbances in US military veterans. Prazosin was associated with significant improvements in insomnia and daytime PTSD symptom severity as demonstrated by changes in PSQI and CAPS scores.¹¹

Taylor et al¹² examined the effects of prazosin on sleep measures and clinical symptoms in civilians with PTSD. Prazosin significantly increased total sleep time, rapid eye movement sleep time, and CGIC scores while significantly decreasing trauma-related nightmares.¹²

Continue to: Overall, these trials...

Overall, these trials found efficacy for the use of prazosin for patients diagnosed with PTSD; however, the population size in each of these studies was small.

Results of the PACT trial

The PACT trial was a 26-week, multicenter, double-blind, randomized, placebo-controlled trial conducted across 12 VA medical centers.⁶ During the first 5 weeks, participants were randomized to receive placebo or prazosin, which could be titrated up to 20 mg/d in men and 12 mg/d in women. Participants remained on that dose from the end of Week 5 through Week 10. At that time, other pharmacologic therapies and psychotherapy could be added, discontinued, or adjusted. The mean maintenance total daily dose of prazosin was 14.8 mg.

A total of 413 patients were screened, 304 were randomized (152 per group), and 271 completed the 10-week primary outcome assessment. The population was almost entirely male (96.1% in the prazosin group and 99.3% in the placebo group), and most participants were White (64.5% in the prazosin group and 69.1% in the placebo group), with an average age of approximately 50 years. Primary outcomes included change from baseline to Week 10 in both CAPS item B2 (“recurrent distressing dreams”) and PSQI scores. CGIC score was evaluated at Week 10.

At Week 10, none of the primary outcomes were found to be statistically significant. The mean difference in change from baseline to Week 10 in CAPS item B2 score and PSQI score were 0.2 (P = .38) and 0.1 (P = .80), respectively. There was no significant difference in mean CGIC scores (P = .96). Repeated measures of CAPS item B2, PSQI, and CGIC scores were conducted through Week 26 as secondary outcomes. No significant differences were found. This study concluded that prazosin did not alleviate distressing dreams, improve sleep quality, or improve overall clinical symptoms.⁶

The PACT trial: Strengths and weaknesses

The PACT trial is the largest placebo-controlled trial for prazosin use in PTSD to date. It failed to show efficacy of prazosin for PTSD-associated nightmares, which contradicts previous studies. Although the mean total daily dose of prazosin was adequate and primary outcomes were measured with appropriate scales, the study failed to enroll the desired number of patients, which increased the possibility of false-negative results. Furthermore, participant recruitment may have led to selection bias because all participants were clinically stable, which could explain the lack of efficacy. However, the average CAPS scores were 80.7 in the prazosin group and 81.9 in the placebo group, which indicates that these patients had significant symptomatology at baseline and before entering the study.

Continue to: A major theme...

A major theme of studies evaluating prazosin treatment for PTSD is a focus on a military population and military-related trauma. Other than Taylor et al¹² (N=13), none of these trials included patients who were diagnosed with PTSD due to other traumas, such as sexual trauma, which limits the generalizability of the results. Furthermore, apart from the PACT trial, none of these studies had >100 participants, which further reduces external validity. Current guidelines have not been updated to include the results of the PACT trial, and it is unclear if the results of this trial are strong enough to change clinical practice.

CASE CONTINUED

To ensure patient-centered care, the treating clinicians conduct a risk/benefit discussion with the patient regarding starting prazosin. Mr. H opts to try prazosin, so the clinicians initiate a low dose (1 mg/d) to mitigate adverse effects, and plan to titrate to clinical effect or intolerability. Per evidence from the trials discussed, it is likely Mr. H will need to be titrated to at least 5 to 6 mg/d to see a clinical effect.

Related Resource

North CS, Hong BA, Downs DL. PTSD: A systematic approach to diagnosis and treatment. Current Psychiatry 2018;17(4):35-43.

Drug Brand Names

Fluoxetine • Prozac
Prazosin • Minipress

Mr. H, age 43, presents to your clinic for management of posttraumatic stress disorder (PTSD). At his last appointment 8 weeks ago, he was continued on fluoxetine, 60 mg/d; he had been stable on this medication for 6 months. Today, Mr. H reports an increase in the frequency and severity of nightmares. He states that he wakes at least 3 times every week with “disturbing dreams” about his time in the military and does not feel rested even when he sleeps through the night. His Clinician-Administered PTSD Scale (CAPS) score is 95 on this visit, suggesting extreme PTSD symptomatology. Mr. H asks if anything can be done to reduce the frequency and intensity of his nightmares.

PTSD is the development of characteristic symptoms following exposure to ≥1 traumatic events. According to DSM-5, PTSD symptoms include the presence of ≥1 intrusion symptoms (recurrent, intrusive memories of the traumatic event; recurrent distressing dreams; dissociative reactions), persistent avoidance of stimuli, negative alterations in cognition and mood, and marked alterations in arousal and reactivity associated with the traumatic event(s).¹ The symptoms must be present for >1 month, cause clinically significant distress or impairment in functioning, and not be attributable to the psychologic effects of a substance or medical conditions.¹ This article focuses specifically on the hyperarousal symptoms, and the clinical controversies surrounding the use of prazosin for PTSD.

Prazosin for PTSD treatment

Sleep disorders are extremely common in patients with PTSD. Up to 90% of patients report sleep disturbances, and up to 70% report nightmares.² Prazosin has been widely used in the treatment of PTSD-related sleep disorders and nightmares.The American Psychiatric Association³ and the British Association of Psychopharmacology⁴ guidelines in-­clude prazosin as a first-line recommendation for treatment of PTSD. However, updated 2017 guidelines from the Veterans Affairs/Department of Defense (VA/DoD)⁵ and data from the 2018 Prazosin and Combat Trauma PTSD (PACT) trial⁶ contradict these original recommendations. Previously, the 2010 VA/DoD guideline said prazosin had insufficient evidence for monotherapy, but recommended it as adjunctive treatment for sleep and nightmares.⁷ The updated 2017 VA/DoD guideline recommends “weak against” prazosin use for global symptoms of PTSD, and says there is insufficient evidence for its use in nightmares.⁵ Below we summarize the findings of studies that contributed to those original recommendations, along with results of the PACT trial.

Raskind et al^8,9 conducted 2 studies of prazosin use in combat veterans with PTSD. In both studies, prazosin had significant positive effects on the Clinician-Administered PTSD Scale (CAPS) and Clinical Global Impression of Change (CGIC) scores.^8,9 The 2007 study also found significant effects of prazosin on Pittsburgh Sleep Quality Index (PSQI) scores.⁹

Raskind et al¹⁰ conducted another study in 2013 of prazosin use for active-duty soldiers who had combat trauma PTSD with nightmares. Prazosin had positive effects for nightmares, sleep quality, and CAPS scores.¹⁰

Germain et al¹¹ reviewed prazosin for treating sleep disturbances in US military veterans. Prazosin was associated with significant improvements in insomnia and daytime PTSD symptom severity as demonstrated by changes in PSQI and CAPS scores.¹¹

Taylor et al¹² examined the effects of prazosin on sleep measures and clinical symptoms in civilians with PTSD. Prazosin significantly increased total sleep time, rapid eye movement sleep time, and CGIC scores while significantly decreasing trauma-related nightmares.¹²

Continue to: Overall, these trials...

Overall, these trials found efficacy for the use of prazosin for patients diagnosed with PTSD; however, the population size in each of these studies was small.

Results of the PACT trial

The PACT trial was a 26-week, multicenter, double-blind, randomized, placebo-controlled trial conducted across 12 VA medical centers.⁶ During the first 5 weeks, participants were randomized to receive placebo or prazosin, which could be titrated up to 20 mg/d in men and 12 mg/d in women. Participants remained on that dose from the end of Week 5 through Week 10. At that time, other pharmacologic therapies and psychotherapy could be added, discontinued, or adjusted. The mean maintenance total daily dose of prazosin was 14.8 mg.

A total of 413 patients were screened, 304 were randomized (152 per group), and 271 completed the 10-week primary outcome assessment. The population was almost entirely male (96.1% in the prazosin group and 99.3% in the placebo group), and most participants were White (64.5% in the prazosin group and 69.1% in the placebo group), with an average age of approximately 50 years. Primary outcomes included change from baseline to Week 10 in both CAPS item B2 (“recurrent distressing dreams”) and PSQI scores. CGIC score was evaluated at Week 10.

At Week 10, none of the primary outcomes were found to be statistically significant. The mean difference in change from baseline to Week 10 in CAPS item B2 score and PSQI score were 0.2 (P = .38) and 0.1 (P = .80), respectively. There was no significant difference in mean CGIC scores (P = .96). Repeated measures of CAPS item B2, PSQI, and CGIC scores were conducted through Week 26 as secondary outcomes. No significant differences were found. This study concluded that prazosin did not alleviate distressing dreams, improve sleep quality, or improve overall clinical symptoms.⁶

The PACT trial: Strengths and weaknesses

The PACT trial is the largest placebo-controlled trial for prazosin use in PTSD to date. It failed to show efficacy of prazosin for PTSD-associated nightmares, which contradicts previous studies. Although the mean total daily dose of prazosin was adequate and primary outcomes were measured with appropriate scales, the study failed to enroll the desired number of patients, which increased the possibility of false-negative results. Furthermore, participant recruitment may have led to selection bias because all participants were clinically stable, which could explain the lack of efficacy. However, the average CAPS scores were 80.7 in the prazosin group and 81.9 in the placebo group, which indicates that these patients had significant symptomatology at baseline and before entering the study.

Continue to: A major theme...

A major theme of studies evaluating prazosin treatment for PTSD is a focus on a military population and military-related trauma. Other than Taylor et al¹² (N=13), none of these trials included patients who were diagnosed with PTSD due to other traumas, such as sexual trauma, which limits the generalizability of the results. Furthermore, apart from the PACT trial, none of these studies had >100 participants, which further reduces external validity. Current guidelines have not been updated to include the results of the PACT trial, and it is unclear if the results of this trial are strong enough to change clinical practice.

CASE CONTINUED

To ensure patient-centered care, the treating clinicians conduct a risk/benefit discussion with the patient regarding starting prazosin. Mr. H opts to try prazosin, so the clinicians initiate a low dose (1 mg/d) to mitigate adverse effects, and plan to titrate to clinical effect or intolerability. Per evidence from the trials discussed, it is likely Mr. H will need to be titrated to at least 5 to 6 mg/d to see a clinical effect.

Related Resource

North CS, Hong BA, Downs DL. PTSD: A systematic approach to diagnosis and treatment. Current Psychiatry 2018;17(4):35-43.

Drug Brand Names

Fluoxetine • Prozac
Prazosin • Minipress

Lumateperone is a novel antipsychotic that possesses a variety of unique receptor affinities. The recommended dose of lumateperone is 42 mg/d. In clinical trials, reductions in Positive and Negative Syndrome Scale scores observed with lumateperone, 28 mg/d and 84 mg/d, failed to separate from placebo.¹ However, in these trials, safety profiles were similar for all 3 doses.

Despite the popular understanding of lumateperone’s “unexplained narrow therapeutic window,”² we report the case of a patient with schizophrenia who responded well to lumateperone, 84 mg/d, without adverse effects or EKG changes.

Case report. Mr. W, age 26, has treatment-resistant schizophrenia (paranoid type). He failed to achieve remission on fluphenazine (10 to 25 mg/d), perphenazine (4 to 24 mg/d), risperidone (started at 4 mg/d and increased to 8 mg/d), and olanzapine (15, 20, and 25 mg/d). None of these medications eliminated his auditory or visual hallucinations. His response was most robust to perphenazine, as he reported a 50% reduction in the frequency of auditory hallucinations and a near-complete resolution of visual hallucinations (once or twice per week), but he never achieved full remission.

We started lumateperone, 42 mg/d, without a cross-taper. After 4 weeks of partial response, the patient escalated his dose to 84 mg/d on his own. At a follow-up visit 3.5 weeks after this self-directed dose increase, Mr. W reported a complete resolution of his auditory and visual hallucinations.  

Six months later, Mr. W continued to receive lumateperone, 84 mg/d, without extrapyramidal symptoms, tardive dyskinesia, or other adverse effects. His QTc showed no significant change (410 ms vs 412 ms).

Although some studies indicate a possible “therapeutic window” for lumateperone dosing, clinicians should not deprive patients who partially respond to the recommended 42 mg/d dose of the opportunity for additional benefit through dose escalation. Due to the vagaries of psychiatric pathology, and unique profiles of metabolism and receptor sensitivity, there will always be patients who may require higher-than-recommended doses of lumateperone, as with all other agents.

Lumateperone is a novel antipsychotic that possesses a variety of unique receptor affinities. The recommended dose of lumateperone is 42 mg/d. In clinical trials, reductions in Positive and Negative Syndrome Scale scores observed with lumateperone, 28 mg/d and 84 mg/d, failed to separate from placebo.¹ However, in these trials, safety profiles were similar for all 3 doses.

Despite the popular understanding of lumateperone’s “unexplained narrow therapeutic window,”² we report the case of a patient with schizophrenia who responded well to lumateperone, 84 mg/d, without adverse effects or EKG changes.

Case report. Mr. W, age 26, has treatment-resistant schizophrenia (paranoid type). He failed to achieve remission on fluphenazine (10 to 25 mg/d), perphenazine (4 to 24 mg/d), risperidone (started at 4 mg/d and increased to 8 mg/d), and olanzapine (15, 20, and 25 mg/d). None of these medications eliminated his auditory or visual hallucinations. His response was most robust to perphenazine, as he reported a 50% reduction in the frequency of auditory hallucinations and a near-complete resolution of visual hallucinations (once or twice per week), but he never achieved full remission.

We started lumateperone, 42 mg/d, without a cross-taper. After 4 weeks of partial response, the patient escalated his dose to 84 mg/d on his own. At a follow-up visit 3.5 weeks after this self-directed dose increase, Mr. W reported a complete resolution of his auditory and visual hallucinations.  

Six months later, Mr. W continued to receive lumateperone, 84 mg/d, without extrapyramidal symptoms, tardive dyskinesia, or other adverse effects. His QTc showed no significant change (410 ms vs 412 ms).

Although some studies indicate a possible “therapeutic window” for lumateperone dosing, clinicians should not deprive patients who partially respond to the recommended 42 mg/d dose of the opportunity for additional benefit through dose escalation. Due to the vagaries of psychiatric pathology, and unique profiles of metabolism and receptor sensitivity, there will always be patients who may require higher-than-recommended doses of lumateperone, as with all other agents.

Lumateperone is a novel antipsychotic that possesses a variety of unique receptor affinities. The recommended dose of lumateperone is 42 mg/d. In clinical trials, reductions in Positive and Negative Syndrome Scale scores observed with lumateperone, 28 mg/d and 84 mg/d, failed to separate from placebo.¹ However, in these trials, safety profiles were similar for all 3 doses.

Despite the popular understanding of lumateperone’s “unexplained narrow therapeutic window,”² we report the case of a patient with schizophrenia who responded well to lumateperone, 84 mg/d, without adverse effects or EKG changes.

Case report. Mr. W, age 26, has treatment-resistant schizophrenia (paranoid type). He failed to achieve remission on fluphenazine (10 to 25 mg/d), perphenazine (4 to 24 mg/d), risperidone (started at 4 mg/d and increased to 8 mg/d), and olanzapine (15, 20, and 25 mg/d). None of these medications eliminated his auditory or visual hallucinations. His response was most robust to perphenazine, as he reported a 50% reduction in the frequency of auditory hallucinations and a near-complete resolution of visual hallucinations (once or twice per week), but he never achieved full remission.

We started lumateperone, 42 mg/d, without a cross-taper. After 4 weeks of partial response, the patient escalated his dose to 84 mg/d on his own. At a follow-up visit 3.5 weeks after this self-directed dose increase, Mr. W reported a complete resolution of his auditory and visual hallucinations.  

Six months later, Mr. W continued to receive lumateperone, 84 mg/d, without extrapyramidal symptoms, tardive dyskinesia, or other adverse effects. His QTc showed no significant change (410 ms vs 412 ms).

Although some studies indicate a possible “therapeutic window” for lumateperone dosing, clinicians should not deprive patients who partially respond to the recommended 42 mg/d dose of the opportunity for additional benefit through dose escalation. Due to the vagaries of psychiatric pathology, and unique profiles of metabolism and receptor sensitivity, there will always be patients who may require higher-than-recommended doses of lumateperone, as with all other agents.

Chlorpromazine (CPZ), a low-potency first-generation antipsychotic (FGA), was the first medication approved for the management of schizophrenia. Since its approval, some psychiatrists have prescribed subsequent antipsychotics based on CPZ’s efficacy and dosing. Comparing dosages of newer antipsychotics using a CPZ equivalent as a baseline remains a relevant method of determining which agent to prescribe, and at what dose.^1,2

Psychiatrists frequently care for patients who are treatment-refractory or older adults with poor medication tolerance and age-related medical illness. Quick access to the comparative potency of different antipsychotics can help guide titration to the approximate equivalent dose of CPZ when initiating a medication, switching from 1 antipsychotic to another, or augmenting or combining antipsychotics. Fortunately, many authors, such as Woods²and Davis,³ have codified the dosing ratio equivalences of FGAs and second-generation antipsychotics (SGAs) using CPZ, 100 mg. To help psychiatrists use CPZ dosages as a point of comparison for prescribing other antipsychotics, the Table^1,2,4 (page 14) lists dose equivalents for oral FGAs and SGAs based on CPZ, 100 mg. (For information on dose equivalents for injectable antipsychotics, see “Second-generation long-acting injectable antipsychotics: A practical guide,” Current Psychiatry, March 2020, p. 24-32.)

While this information cannot replace a psychiatrist’s clinical judgment, it can serve as a clinically useful prescribing tool. In addition to providing this Table, we discuss what you should consider when using these equivalents to switch antipsychotics and estimate the ultimate dose target for effective management of psychotic disorders.

A few caveats

Bioactive equivalent dosages should be targeted as a rough guide when switching from one FGA or SGA to another. Common indications for switching antipsychotics include an inadequate therapeutic response after a medication trial of an adequate dose and duration; relapse of psychosis despite medication adherence; intolerable adverse effects; cost; a new-onset, contraindicating medical illness; and lapses in medication compliance that necessitate a change to IM formulations.⁵ Keep in mind that medication changes should be tailored to the patient’s specific clinical characteristics.

Several other clinical and pharmacologic variabilities should be kept in mind when switching antipsychotics using CPZ dosage equivalents^5,6:

• The therapeutic CPZ equivalent doses may be less precise for SGAs than for FGAs because the equivalents are largely based on dopaminergic blockade instead of cholinergic, serotonergic, or histaminergic systems
• For some antipsychotics, the relationship between dose and potency is nonlinear. For example, as the dosage of haloperidol increases, its relative antipsychotic potency decreases
• Differences in half-lives between 2 agents can add complexity to calculating the dosage equivalent
• Regardless of comparative dosing, before initiating a new antipsychotic, psychiatrists should read the dosing instructions in the FDA-approved package insert, and exercise caution before titrating a new medication to the maximum recommended dose.

Chlorpromazine (CPZ), a low-potency first-generation antipsychotic (FGA), was the first medication approved for the management of schizophrenia. Since its approval, some psychiatrists have prescribed subsequent antipsychotics based on CPZ’s efficacy and dosing. Comparing dosages of newer antipsychotics using a CPZ equivalent as a baseline remains a relevant method of determining which agent to prescribe, and at what dose.^1,2

Psychiatrists frequently care for patients who are treatment-refractory or older adults with poor medication tolerance and age-related medical illness. Quick access to the comparative potency of different antipsychotics can help guide titration to the approximate equivalent dose of CPZ when initiating a medication, switching from 1 antipsychotic to another, or augmenting or combining antipsychotics. Fortunately, many authors, such as Woods²and Davis,³ have codified the dosing ratio equivalences of FGAs and second-generation antipsychotics (SGAs) using CPZ, 100 mg. To help psychiatrists use CPZ dosages as a point of comparison for prescribing other antipsychotics, the Table^1,2,4 (page 14) lists dose equivalents for oral FGAs and SGAs based on CPZ, 100 mg. (For information on dose equivalents for injectable antipsychotics, see “Second-generation long-acting injectable antipsychotics: A practical guide,” Current Psychiatry, March 2020, p. 24-32.)

While this information cannot replace a psychiatrist’s clinical judgment, it can serve as a clinically useful prescribing tool. In addition to providing this Table, we discuss what you should consider when using these equivalents to switch antipsychotics and estimate the ultimate dose target for effective management of psychotic disorders.

A few caveats

Bioactive equivalent dosages should be targeted as a rough guide when switching from one FGA or SGA to another. Common indications for switching antipsychotics include an inadequate therapeutic response after a medication trial of an adequate dose and duration; relapse of psychosis despite medication adherence; intolerable adverse effects; cost; a new-onset, contraindicating medical illness; and lapses in medication compliance that necessitate a change to IM formulations.⁵ Keep in mind that medication changes should be tailored to the patient’s specific clinical characteristics.

Several other clinical and pharmacologic variabilities should be kept in mind when switching antipsychotics using CPZ dosage equivalents^5,6:

• The therapeutic CPZ equivalent doses may be less precise for SGAs than for FGAs because the equivalents are largely based on dopaminergic blockade instead of cholinergic, serotonergic, or histaminergic systems
• For some antipsychotics, the relationship between dose and potency is nonlinear. For example, as the dosage of haloperidol increases, its relative antipsychotic potency decreases
• Differences in half-lives between 2 agents can add complexity to calculating the dosage equivalent
• Regardless of comparative dosing, before initiating a new antipsychotic, psychiatrists should read the dosing instructions in the FDA-approved package insert, and exercise caution before titrating a new medication to the maximum recommended dose.

Chlorpromazine (CPZ), a low-potency first-generation antipsychotic (FGA), was the first medication approved for the management of schizophrenia. Since its approval, some psychiatrists have prescribed subsequent antipsychotics based on CPZ’s efficacy and dosing. Comparing dosages of newer antipsychotics using a CPZ equivalent as a baseline remains a relevant method of determining which agent to prescribe, and at what dose.^1,2

Psychiatrists frequently care for patients who are treatment-refractory or older adults with poor medication tolerance and age-related medical illness. Quick access to the comparative potency of different antipsychotics can help guide titration to the approximate equivalent dose of CPZ when initiating a medication, switching from 1 antipsychotic to another, or augmenting or combining antipsychotics. Fortunately, many authors, such as Woods²and Davis,³ have codified the dosing ratio equivalences of FGAs and second-generation antipsychotics (SGAs) using CPZ, 100 mg. To help psychiatrists use CPZ dosages as a point of comparison for prescribing other antipsychotics, the Table^1,2,4 (page 14) lists dose equivalents for oral FGAs and SGAs based on CPZ, 100 mg. (For information on dose equivalents for injectable antipsychotics, see “Second-generation long-acting injectable antipsychotics: A practical guide,” Current Psychiatry, March 2020, p. 24-32.)

While this information cannot replace a psychiatrist’s clinical judgment, it can serve as a clinically useful prescribing tool. In addition to providing this Table, we discuss what you should consider when using these equivalents to switch antipsychotics and estimate the ultimate dose target for effective management of psychotic disorders.

A few caveats

Bioactive equivalent dosages should be targeted as a rough guide when switching from one FGA or SGA to another. Common indications for switching antipsychotics include an inadequate therapeutic response after a medication trial of an adequate dose and duration; relapse of psychosis despite medication adherence; intolerable adverse effects; cost; a new-onset, contraindicating medical illness; and lapses in medication compliance that necessitate a change to IM formulations.⁵ Keep in mind that medication changes should be tailored to the patient’s specific clinical characteristics.

Several other clinical and pharmacologic variabilities should be kept in mind when switching antipsychotics using CPZ dosage equivalents^5,6:

• The therapeutic CPZ equivalent doses may be less precise for SGAs than for FGAs because the equivalents are largely based on dopaminergic blockade instead of cholinergic, serotonergic, or histaminergic systems
• For some antipsychotics, the relationship between dose and potency is nonlinear. For example, as the dosage of haloperidol increases, its relative antipsychotic potency decreases
• Differences in half-lives between 2 agents can add complexity to calculating the dosage equivalent
• Regardless of comparative dosing, before initiating a new antipsychotic, psychiatrists should read the dosing instructions in the FDA-approved package insert, and exercise caution before titrating a new medication to the maximum recommended dose.

On occasion, a patient may refuse to cooperate with a suicide risk assessment or is unable to participate due to the severity of a psychiatric or medical condition. In such situations, how can we conduct an assessment that meets our ethical, professional, and legal obligations?

First, skipping a suicide risk assessment is never an option. A patient’s refusal or inability to cooperate does not release us from our duty of care. We are obligated to gather information about suicide risk to anticipate the likelihood and severity of harm.¹ Furthermore, collecting information helps us evaluate what types of precautions are necessary to reduce or eliminate suicide risk.

Some clinicians may believe that a suicide risk assessment is only possible when they can ask patients about ideation, intent, plans, and past suicidal behavior. While the patient’s self-report is valuable, it is only one data point, and in some cases, it may not be reliable or credible.² So how should you handle such situations? Here I describe 3 steps to take to estimate a patient’s suicide risk without their participation.

1. Obtain information from other sources.

These can include:

• your recent contacts with the patient
• the patient’s responses to previous inquiries about suicidality
• collateral reports from staff
• the patient’s chart and past medical records
• past suicide attempts (including the precipitants, the patient’s reasons for the attempt, details of the actions taken and methods used, any medical outcome, and the patient’s reaction to surviving)³
• past nonsuicidal self-injury
• past episodes of suicidal thinking
• treatment progress to date
• mental status.

Documenting your sources of information will indicate that you made reasonable efforts to appreciate the risk despite imperfect circumstances. Furthermore, these sources of data can support your work to assess the severity of the patient’s current suicidality, to clinically formulate why the patient is susceptible to suicidal thoughts and behavior, and to anticipate circumstances that could constitute a high-risk period for your patient to attempt suicide.

2. Document the reasons you were unable to interview the patient. For patients who are competent to refuse services, document the efforts you made to gain the patient’s cooperation. If the patient’s psychiatric condition (eg, florid psychosis) was the main impediment, note this.

3. Explain the limitations of your assessment. This might include acknowledging that your estimation of the patient’s suicide risk is missing important information but is the best possible estimate at the time. Explain how you determined the level of risk with a statement such as, “Because the patient was unable to participate, I estimated risk based on….” If the patient’s lack of participation lowers your confidence in your risk estimate, this also should be documented. Reduced confidence may indicate the need for additional steps to assure the patient’s safety (eg, admission, delaying discharge, initiating continuous observation).

On occasion, a patient may refuse to cooperate with a suicide risk assessment or is unable to participate due to the severity of a psychiatric or medical condition. In such situations, how can we conduct an assessment that meets our ethical, professional, and legal obligations?

First, skipping a suicide risk assessment is never an option. A patient’s refusal or inability to cooperate does not release us from our duty of care. We are obligated to gather information about suicide risk to anticipate the likelihood and severity of harm.¹ Furthermore, collecting information helps us evaluate what types of precautions are necessary to reduce or eliminate suicide risk.

Some clinicians may believe that a suicide risk assessment is only possible when they can ask patients about ideation, intent, plans, and past suicidal behavior. While the patient’s self-report is valuable, it is only one data point, and in some cases, it may not be reliable or credible.² So how should you handle such situations? Here I describe 3 steps to take to estimate a patient’s suicide risk without their participation.

1. Obtain information from other sources.

These can include:

• your recent contacts with the patient
• the patient’s responses to previous inquiries about suicidality
• collateral reports from staff
• the patient’s chart and past medical records
• past suicide attempts (including the precipitants, the patient’s reasons for the attempt, details of the actions taken and methods used, any medical outcome, and the patient’s reaction to surviving)³
• past nonsuicidal self-injury
• past episodes of suicidal thinking
• treatment progress to date
• mental status.

Documenting your sources of information will indicate that you made reasonable efforts to appreciate the risk despite imperfect circumstances. Furthermore, these sources of data can support your work to assess the severity of the patient’s current suicidality, to clinically formulate why the patient is susceptible to suicidal thoughts and behavior, and to anticipate circumstances that could constitute a high-risk period for your patient to attempt suicide.

2. Document the reasons you were unable to interview the patient. For patients who are competent to refuse services, document the efforts you made to gain the patient’s cooperation. If the patient’s psychiatric condition (eg, florid psychosis) was the main impediment, note this.

3. Explain the limitations of your assessment. This might include acknowledging that your estimation of the patient’s suicide risk is missing important information but is the best possible estimate at the time. Explain how you determined the level of risk with a statement such as, “Because the patient was unable to participate, I estimated risk based on….” If the patient’s lack of participation lowers your confidence in your risk estimate, this also should be documented. Reduced confidence may indicate the need for additional steps to assure the patient’s safety (eg, admission, delaying discharge, initiating continuous observation).

On occasion, a patient may refuse to cooperate with a suicide risk assessment or is unable to participate due to the severity of a psychiatric or medical condition. In such situations, how can we conduct an assessment that meets our ethical, professional, and legal obligations?

First, skipping a suicide risk assessment is never an option. A patient’s refusal or inability to cooperate does not release us from our duty of care. We are obligated to gather information about suicide risk to anticipate the likelihood and severity of harm.¹ Furthermore, collecting information helps us evaluate what types of precautions are necessary to reduce or eliminate suicide risk.

Some clinicians may believe that a suicide risk assessment is only possible when they can ask patients about ideation, intent, plans, and past suicidal behavior. While the patient’s self-report is valuable, it is only one data point, and in some cases, it may not be reliable or credible.² So how should you handle such situations? Here I describe 3 steps to take to estimate a patient’s suicide risk without their participation.

1. Obtain information from other sources.

These can include:

• your recent contacts with the patient
• the patient’s responses to previous inquiries about suicidality
• collateral reports from staff
• the patient’s chart and past medical records
• past suicide attempts (including the precipitants, the patient’s reasons for the attempt, details of the actions taken and methods used, any medical outcome, and the patient’s reaction to surviving)³
• past nonsuicidal self-injury
• past episodes of suicidal thinking
• treatment progress to date
• mental status.

Documenting your sources of information will indicate that you made reasonable efforts to appreciate the risk despite imperfect circumstances. Furthermore, these sources of data can support your work to assess the severity of the patient’s current suicidality, to clinically formulate why the patient is susceptible to suicidal thoughts and behavior, and to anticipate circumstances that could constitute a high-risk period for your patient to attempt suicide.

2. Document the reasons you were unable to interview the patient. For patients who are competent to refuse services, document the efforts you made to gain the patient’s cooperation. If the patient’s psychiatric condition (eg, florid psychosis) was the main impediment, note this.

3. Explain the limitations of your assessment. This might include acknowledging that your estimation of the patient’s suicide risk is missing important information but is the best possible estimate at the time. Explain how you determined the level of risk with a statement such as, “Because the patient was unable to participate, I estimated risk based on….” If the patient’s lack of participation lowers your confidence in your risk estimate, this also should be documented. Reduced confidence may indicate the need for additional steps to assure the patient’s safety (eg, admission, delaying discharge, initiating continuous observation).

The Biden administration has passed and signed the $1.9 trillion American Rescue Plan, which contains a plethora of moneys targeted to people, businesses, and health systems impacted by the pandemic. According to the Economist, the bill would bring the amount of COVID-related spending since December 2020 to $3 trillion (14% of prepandemic GDP) and to $6 trillion since the start of the pandemic. This type of stimulus (regarded as income, not savings, by most people) will generate unprecedented consumer spending. The risk, of course, is inflation, rising interest rates, and long-term debt.

That said, there is substantial funding targeting scientific research, vaccine distribution, public health entities, global health initiatives, rural health care, and a variety of other health-related issues. By my rough estimation, the Centers for Disease Control and Prevention will see $12 billion in incremental funding, $10 billion for public health projects including $3 billion for community health centers and federally qualified health centers, and over $3 billion for mental and behavioral health. The Department of Health & Human Services will see substantial funding for a variety of projects. Teaching health centers will see $330 million additional funds (including a $10,000 per-resident increase and payments to establish new graduate residency training programs).

The impact on low-income families and childhood poverty will be substantial and reverses the philosophical underpinning of recent welfare reforms. U.S. welfare dates back to the early 1900s and the philosophical foundation has evolved over time. According to the Constitutional Rights Foundation (www.crf-usa.org), it began after food riots broke out during the Great Depression. The Great Depression affected children and the elderly most severely, so the nation’s willingness to implement federal welfare was high. Prior to the Depression, the only federal program providing money to low-income people was the “mothers pension” designed to support poor fatherless children, but it excluded divorced, deserted and minority mothers. President Roosevelt was able to pass the Social Security Act (1935), which supported the elderly and began Federal welfare. During the Clinton presidency, welfare “as we know it” changed to include work requirements. With the passage of the current Biden legislation, those requirements are rolled back and funds are targeted broadly to low income Americans and children.
 

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

The Biden administration has passed and signed the $1.9 trillion American Rescue Plan, which contains a plethora of moneys targeted to people, businesses, and health systems impacted by the pandemic. According to the Economist, the bill would bring the amount of COVID-related spending since December 2020 to $3 trillion (14% of prepandemic GDP) and to $6 trillion since the start of the pandemic. This type of stimulus (regarded as income, not savings, by most people) will generate unprecedented consumer spending. The risk, of course, is inflation, rising interest rates, and long-term debt.

That said, there is substantial funding targeting scientific research, vaccine distribution, public health entities, global health initiatives, rural health care, and a variety of other health-related issues. By my rough estimation, the Centers for Disease Control and Prevention will see $12 billion in incremental funding, $10 billion for public health projects including $3 billion for community health centers and federally qualified health centers, and over $3 billion for mental and behavioral health. The Department of Health & Human Services will see substantial funding for a variety of projects. Teaching health centers will see $330 million additional funds (including a $10,000 per-resident increase and payments to establish new graduate residency training programs).

The impact on low-income families and childhood poverty will be substantial and reverses the philosophical underpinning of recent welfare reforms. U.S. welfare dates back to the early 1900s and the philosophical foundation has evolved over time. According to the Constitutional Rights Foundation (www.crf-usa.org), it began after food riots broke out during the Great Depression. The Great Depression affected children and the elderly most severely, so the nation’s willingness to implement federal welfare was high. Prior to the Depression, the only federal program providing money to low-income people was the “mothers pension” designed to support poor fatherless children, but it excluded divorced, deserted and minority mothers. President Roosevelt was able to pass the Social Security Act (1935), which supported the elderly and began Federal welfare. During the Clinton presidency, welfare “as we know it” changed to include work requirements. With the passage of the current Biden legislation, those requirements are rolled back and funds are targeted broadly to low income Americans and children.
 

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

The Biden administration has passed and signed the $1.9 trillion American Rescue Plan, which contains a plethora of moneys targeted to people, businesses, and health systems impacted by the pandemic. According to the Economist, the bill would bring the amount of COVID-related spending since December 2020 to $3 trillion (14% of prepandemic GDP) and to $6 trillion since the start of the pandemic. This type of stimulus (regarded as income, not savings, by most people) will generate unprecedented consumer spending. The risk, of course, is inflation, rising interest rates, and long-term debt.

That said, there is substantial funding targeting scientific research, vaccine distribution, public health entities, global health initiatives, rural health care, and a variety of other health-related issues. By my rough estimation, the Centers for Disease Control and Prevention will see $12 billion in incremental funding, $10 billion for public health projects including $3 billion for community health centers and federally qualified health centers, and over $3 billion for mental and behavioral health. The Department of Health & Human Services will see substantial funding for a variety of projects. Teaching health centers will see $330 million additional funds (including a $10,000 per-resident increase and payments to establish new graduate residency training programs).

The impact on low-income families and childhood poverty will be substantial and reverses the philosophical underpinning of recent welfare reforms. U.S. welfare dates back to the early 1900s and the philosophical foundation has evolved over time. According to the Constitutional Rights Foundation (www.crf-usa.org), it began after food riots broke out during the Great Depression. The Great Depression affected children and the elderly most severely, so the nation’s willingness to implement federal welfare was high. Prior to the Depression, the only federal program providing money to low-income people was the “mothers pension” designed to support poor fatherless children, but it excluded divorced, deserted and minority mothers. President Roosevelt was able to pass the Social Security Act (1935), which supported the elderly and began Federal welfare. During the Clinton presidency, welfare “as we know it” changed to include work requirements. With the passage of the current Biden legislation, those requirements are rolled back and funds are targeted broadly to low income Americans and children.
 

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

What is the incidence of endometriosis in women, and does the condition affect certain patient populations more often than others?

Dr. Taylor: Endometriosis occurs in about 5% to 10% of reproductive-aged women, and it is underdiagnosed. Many women have subtle endometriosis or asymptomatic endometriosis that may be missed or may take a long time to diagnose, and the incidence may be somewhat higher. It is much more common in women with pelvic pain, as these women have a greater than 50% incidence of endometriosis, and those with infertility similarly have roughly a 50% incidence of endometriosis. Endometriosis is a very common disease, most common in the reproductive age range, particularly more common in the most fertile years. The typical course of the disease is that it begins in teenagers or in the early 20s, progresses through the 20s and 30s, but starts to wane in the 40s, and goes away at the time of menopause in the early 50s. Those particularly susceptible to the disease are those with early menarche or frequent or heavy periods. Recurrent periods lead to more retrograde menstruation, which is menstrual flow through the fallopian tubes. It then starts to implant in the abdomen, specifically in the peritoneal cavity.

What are some of the reasons for missed or delayed diagnosis?

Dr. Taylor: There are many reasons why diagnosis may be missed or delayed. One of the most common reasons for delayed diagnosis is that the patient does not know that painful periods are not normal and may not report them to her clinician. Dysmenorrhea, or menstrual pain, is the only pain that we consider normal. It is the only experience we go through that is expected to hurt. It is also a very subjective issue. How do you know if your menstrual cramps are worse than someone else’s? Often, the first thing that happens when someone complains about severe dysmenorrhea is that their friends or family members will say to them, “We all get menstrual cramps. Just toughen up and bear with it.” But, of course, sometimes these menstrual cramps, or dysmenorrhea, get so bad that they become disabling. When people miss school or work, or they cannot participate in normal social or athletic activities, that is when they first get attention. Often, the disease has been bothering someone for a long time before it is diagnosed.

Another reason that diagnosis may be delayed is because of the social stigma surrounding discussing these types of issues. It is difficult sometimes, especially for a teenager, to talk about issues such as painful periods, pain with bowel movements or urination, or pain with intercourse. A generation ago, people did not talk about such topics so openly and publicly. Thankfully, it is becoming easier, and I think this generation is more open to talking about these issues, but it is still difficult for some who are hesitant to discuss it. Parents can also have a difficult time discussing these issues with their children, and they may dismiss it. Even physicians who are not familiar with this issue may not be comfortable discussing these matters.

Other times, it is truly asymptomatic. Someone can have significant endometriosis that does not show up until it is found on ultrasonography or until someone tries to get pregnant but experiences infertility, and then it is recognized. Typically, people with endometriosis do present with painful menses. If we are more attuned to listening for those symptoms and open to talking about these symptoms, I think we can catch this disease much earlier.

Another barrier to diagnosis is that for too long the gold standard has been surgery, a laparoscopy, to look for endometriosis. If that is a clinician’s method of determining if somebody has endometriosis, it creates quite a barrier to diagnosis. In the near future, I believe we will have noninvasive tests that will help us determine if somebody has endometriosis without surgery. Even now a clinical history can be very helpful in deciding who has endometriosis. I am also of the opinion that people are becoming much more confident about making a clinical diagnosis of endometriosis.

Diagnosing endometriosis relies on identifying flags in the patient’s history and through physical exams. How can clinicians better their chances for having the flags converge for successful diagnosis?

Dr. Taylor: I think it is important to keep the focus on some of the main symptoms of endometriosis. Most women with endometriosis start by having dysmenorrhea, which progresses over time. Some women with painful periods from menarche may not have endometriosis. Their primary dysmenorrhea may be due to other etiologies. If someone has relatively normal menses initially and then goes on to have progressively increasing dysmenorrhea, most often that is endometriosis. Eventually, the pain can spread to other times in the cycle, beyond just dysmenorrhea. Pain can start in the pelvis, but, as endometriosis causes side effects outside of the reproductive organs, it can start to affect other organs and start to cause pain outside of the pelvis. Endometriosis can also inflame the pelvis and affect the bowel, the bladder, and many other surrounding organs. If somebody has bowel symptoms or bladder symptoms that are cyclic and accompanied by dysmenorrhea or cyclic pelvic pain, endometriosis should be thought of first, rather than a primary bowel or bladder problem. Too often medical professionals can be misled by these other false clues. I have seen many patients who come to me after a very thorough workup for a gastrointestinal issue, including a colonoscopy, or a bladder issue, including a cystoscopy, when the underlying problem really was endometriosis. It is important not to be misled by these “red herrings,” and to focus on progressive cyclic pelvic pain.  Endometriosis is always at least initially cyclic in character.

We also know that endometriosis can have effects far beyond the pelvis. Conditions such as anxiety and depression are more common in patients with endometriosis. Women with endometriosis tend to be thinner. There are many other manifestations of this disease. Although it is complex, and can affect almost any organ system, we need to focus on the primary problem, which is cyclic pelvic pain that is progressive in nature. A woman who has dysmenorrhea that may progress to cyclic pain that gets worse over time, more than likely has endometriosis. We can rule out other etiologies, such as masses, fibroids, and cysts, with a simple physical exam and/or an ultrasound. In general, from a good history focusing on the cyclic progressive pelvic pain and a good physical exam to rule out other etiologies for that pain, we can rapidly narrow in on the diagnosis of endometriosis. We can make the diagnosis very straightforward. Cyclic progressive pelvic pain is essentially synonymous with endometriosis.

With a current medical lens focused on addressing racial disparities and inequities in medicine, do you feel that there are gaps in endometriosis study enrollment, diagnosis, and management that need to be addressed?

Dr. Taylor: Traditionally, there have been disparities in diagnosing endometriosis. There was a time when it was presumed that White women had endometriosis and Black women were more likely to have an infectious etiology for their pelvic pain—which is not true. The incidence is slightly higher in Asian and White women compared with Black women, but this is very likely because of bias and access to care. When examining women who have been diagnosed and are being evaluated and treated for infertility, those racial differences disappear. When access to care is available, when patients are seen by a physician, when they are under medical care for another reason, the racial disparities are not seen in endometriosis; it occurs equally. I think there clearly are disparities in access and bias in how we diagnose endometriosis; we should be cognizant of that and realize that endometriosis is very similar in its frequency in all ethnic groups.

What is the incidence of endometriosis in women, and does the condition affect certain patient populations more often than others?

Dr. Taylor: Endometriosis occurs in about 5% to 10% of reproductive-aged women, and it is underdiagnosed. Many women have subtle endometriosis or asymptomatic endometriosis that may be missed or may take a long time to diagnose, and the incidence may be somewhat higher. It is much more common in women with pelvic pain, as these women have a greater than 50% incidence of endometriosis, and those with infertility similarly have roughly a 50% incidence of endometriosis. Endometriosis is a very common disease, most common in the reproductive age range, particularly more common in the most fertile years. The typical course of the disease is that it begins in teenagers or in the early 20s, progresses through the 20s and 30s, but starts to wane in the 40s, and goes away at the time of menopause in the early 50s. Those particularly susceptible to the disease are those with early menarche or frequent or heavy periods. Recurrent periods lead to more retrograde menstruation, which is menstrual flow through the fallopian tubes. It then starts to implant in the abdomen, specifically in the peritoneal cavity.

What are some of the reasons for missed or delayed diagnosis?

Dr. Taylor: There are many reasons why diagnosis may be missed or delayed. One of the most common reasons for delayed diagnosis is that the patient does not know that painful periods are not normal and may not report them to her clinician. Dysmenorrhea, or menstrual pain, is the only pain that we consider normal. It is the only experience we go through that is expected to hurt. It is also a very subjective issue. How do you know if your menstrual cramps are worse than someone else’s? Often, the first thing that happens when someone complains about severe dysmenorrhea is that their friends or family members will say to them, “We all get menstrual cramps. Just toughen up and bear with it.” But, of course, sometimes these menstrual cramps, or dysmenorrhea, get so bad that they become disabling. When people miss school or work, or they cannot participate in normal social or athletic activities, that is when they first get attention. Often, the disease has been bothering someone for a long time before it is diagnosed.

Another reason that diagnosis may be delayed is because of the social stigma surrounding discussing these types of issues. It is difficult sometimes, especially for a teenager, to talk about issues such as painful periods, pain with bowel movements or urination, or pain with intercourse. A generation ago, people did not talk about such topics so openly and publicly. Thankfully, it is becoming easier, and I think this generation is more open to talking about these issues, but it is still difficult for some who are hesitant to discuss it. Parents can also have a difficult time discussing these issues with their children, and they may dismiss it. Even physicians who are not familiar with this issue may not be comfortable discussing these matters.

Other times, it is truly asymptomatic. Someone can have significant endometriosis that does not show up until it is found on ultrasonography or until someone tries to get pregnant but experiences infertility, and then it is recognized. Typically, people with endometriosis do present with painful menses. If we are more attuned to listening for those symptoms and open to talking about these symptoms, I think we can catch this disease much earlier.

Another barrier to diagnosis is that for too long the gold standard has been surgery, a laparoscopy, to look for endometriosis. If that is a clinician’s method of determining if somebody has endometriosis, it creates quite a barrier to diagnosis. In the near future, I believe we will have noninvasive tests that will help us determine if somebody has endometriosis without surgery. Even now a clinical history can be very helpful in deciding who has endometriosis. I am also of the opinion that people are becoming much more confident about making a clinical diagnosis of endometriosis.

Diagnosing endometriosis relies on identifying flags in the patient’s history and through physical exams. How can clinicians better their chances for having the flags converge for successful diagnosis?

Dr. Taylor: I think it is important to keep the focus on some of the main symptoms of endometriosis. Most women with endometriosis start by having dysmenorrhea, which progresses over time. Some women with painful periods from menarche may not have endometriosis. Their primary dysmenorrhea may be due to other etiologies. If someone has relatively normal menses initially and then goes on to have progressively increasing dysmenorrhea, most often that is endometriosis. Eventually, the pain can spread to other times in the cycle, beyond just dysmenorrhea. Pain can start in the pelvis, but, as endometriosis causes side effects outside of the reproductive organs, it can start to affect other organs and start to cause pain outside of the pelvis. Endometriosis can also inflame the pelvis and affect the bowel, the bladder, and many other surrounding organs. If somebody has bowel symptoms or bladder symptoms that are cyclic and accompanied by dysmenorrhea or cyclic pelvic pain, endometriosis should be thought of first, rather than a primary bowel or bladder problem. Too often medical professionals can be misled by these other false clues. I have seen many patients who come to me after a very thorough workup for a gastrointestinal issue, including a colonoscopy, or a bladder issue, including a cystoscopy, when the underlying problem really was endometriosis. It is important not to be misled by these “red herrings,” and to focus on progressive cyclic pelvic pain.  Endometriosis is always at least initially cyclic in character.

We also know that endometriosis can have effects far beyond the pelvis. Conditions such as anxiety and depression are more common in patients with endometriosis. Women with endometriosis tend to be thinner. There are many other manifestations of this disease. Although it is complex, and can affect almost any organ system, we need to focus on the primary problem, which is cyclic pelvic pain that is progressive in nature. A woman who has dysmenorrhea that may progress to cyclic pain that gets worse over time, more than likely has endometriosis. We can rule out other etiologies, such as masses, fibroids, and cysts, with a simple physical exam and/or an ultrasound. In general, from a good history focusing on the cyclic progressive pelvic pain and a good physical exam to rule out other etiologies for that pain, we can rapidly narrow in on the diagnosis of endometriosis. We can make the diagnosis very straightforward. Cyclic progressive pelvic pain is essentially synonymous with endometriosis.

With a current medical lens focused on addressing racial disparities and inequities in medicine, do you feel that there are gaps in endometriosis study enrollment, diagnosis, and management that need to be addressed?

Dr. Taylor: Traditionally, there have been disparities in diagnosing endometriosis. There was a time when it was presumed that White women had endometriosis and Black women were more likely to have an infectious etiology for their pelvic pain—which is not true. The incidence is slightly higher in Asian and White women compared with Black women, but this is very likely because of bias and access to care. When examining women who have been diagnosed and are being evaluated and treated for infertility, those racial differences disappear. When access to care is available, when patients are seen by a physician, when they are under medical care for another reason, the racial disparities are not seen in endometriosis; it occurs equally. I think there clearly are disparities in access and bias in how we diagnose endometriosis; we should be cognizant of that and realize that endometriosis is very similar in its frequency in all ethnic groups.

What is the incidence of endometriosis in women, and does the condition affect certain patient populations more often than others?

Dr. Taylor: Endometriosis occurs in about 5% to 10% of reproductive-aged women, and it is underdiagnosed. Many women have subtle endometriosis or asymptomatic endometriosis that may be missed or may take a long time to diagnose, and the incidence may be somewhat higher. It is much more common in women with pelvic pain, as these women have a greater than 50% incidence of endometriosis, and those with infertility similarly have roughly a 50% incidence of endometriosis. Endometriosis is a very common disease, most common in the reproductive age range, particularly more common in the most fertile years. The typical course of the disease is that it begins in teenagers or in the early 20s, progresses through the 20s and 30s, but starts to wane in the 40s, and goes away at the time of menopause in the early 50s. Those particularly susceptible to the disease are those with early menarche or frequent or heavy periods. Recurrent periods lead to more retrograde menstruation, which is menstrual flow through the fallopian tubes. It then starts to implant in the abdomen, specifically in the peritoneal cavity.

What are some of the reasons for missed or delayed diagnosis?

Dr. Taylor: There are many reasons why diagnosis may be missed or delayed. One of the most common reasons for delayed diagnosis is that the patient does not know that painful periods are not normal and may not report them to her clinician. Dysmenorrhea, or menstrual pain, is the only pain that we consider normal. It is the only experience we go through that is expected to hurt. It is also a very subjective issue. How do you know if your menstrual cramps are worse than someone else’s? Often, the first thing that happens when someone complains about severe dysmenorrhea is that their friends or family members will say to them, “We all get menstrual cramps. Just toughen up and bear with it.” But, of course, sometimes these menstrual cramps, or dysmenorrhea, get so bad that they become disabling. When people miss school or work, or they cannot participate in normal social or athletic activities, that is when they first get attention. Often, the disease has been bothering someone for a long time before it is diagnosed.

Another reason that diagnosis may be delayed is because of the social stigma surrounding discussing these types of issues. It is difficult sometimes, especially for a teenager, to talk about issues such as painful periods, pain with bowel movements or urination, or pain with intercourse. A generation ago, people did not talk about such topics so openly and publicly. Thankfully, it is becoming easier, and I think this generation is more open to talking about these issues, but it is still difficult for some who are hesitant to discuss it. Parents can also have a difficult time discussing these issues with their children, and they may dismiss it. Even physicians who are not familiar with this issue may not be comfortable discussing these matters.

Other times, it is truly asymptomatic. Someone can have significant endometriosis that does not show up until it is found on ultrasonography or until someone tries to get pregnant but experiences infertility, and then it is recognized. Typically, people with endometriosis do present with painful menses. If we are more attuned to listening for those symptoms and open to talking about these symptoms, I think we can catch this disease much earlier.

Another barrier to diagnosis is that for too long the gold standard has been surgery, a laparoscopy, to look for endometriosis. If that is a clinician’s method of determining if somebody has endometriosis, it creates quite a barrier to diagnosis. In the near future, I believe we will have noninvasive tests that will help us determine if somebody has endometriosis without surgery. Even now a clinical history can be very helpful in deciding who has endometriosis. I am also of the opinion that people are becoming much more confident about making a clinical diagnosis of endometriosis.

Diagnosing endometriosis relies on identifying flags in the patient’s history and through physical exams. How can clinicians better their chances for having the flags converge for successful diagnosis?

Dr. Taylor: I think it is important to keep the focus on some of the main symptoms of endometriosis. Most women with endometriosis start by having dysmenorrhea, which progresses over time. Some women with painful periods from menarche may not have endometriosis. Their primary dysmenorrhea may be due to other etiologies. If someone has relatively normal menses initially and then goes on to have progressively increasing dysmenorrhea, most often that is endometriosis. Eventually, the pain can spread to other times in the cycle, beyond just dysmenorrhea. Pain can start in the pelvis, but, as endometriosis causes side effects outside of the reproductive organs, it can start to affect other organs and start to cause pain outside of the pelvis. Endometriosis can also inflame the pelvis and affect the bowel, the bladder, and many other surrounding organs. If somebody has bowel symptoms or bladder symptoms that are cyclic and accompanied by dysmenorrhea or cyclic pelvic pain, endometriosis should be thought of first, rather than a primary bowel or bladder problem. Too often medical professionals can be misled by these other false clues. I have seen many patients who come to me after a very thorough workup for a gastrointestinal issue, including a colonoscopy, or a bladder issue, including a cystoscopy, when the underlying problem really was endometriosis. It is important not to be misled by these “red herrings,” and to focus on progressive cyclic pelvic pain.  Endometriosis is always at least initially cyclic in character.

We also know that endometriosis can have effects far beyond the pelvis. Conditions such as anxiety and depression are more common in patients with endometriosis. Women with endometriosis tend to be thinner. There are many other manifestations of this disease. Although it is complex, and can affect almost any organ system, we need to focus on the primary problem, which is cyclic pelvic pain that is progressive in nature. A woman who has dysmenorrhea that may progress to cyclic pain that gets worse over time, more than likely has endometriosis. We can rule out other etiologies, such as masses, fibroids, and cysts, with a simple physical exam and/or an ultrasound. In general, from a good history focusing on the cyclic progressive pelvic pain and a good physical exam to rule out other etiologies for that pain, we can rapidly narrow in on the diagnosis of endometriosis. We can make the diagnosis very straightforward. Cyclic progressive pelvic pain is essentially synonymous with endometriosis.

With a current medical lens focused on addressing racial disparities and inequities in medicine, do you feel that there are gaps in endometriosis study enrollment, diagnosis, and management that need to be addressed?

Dr. Taylor: Traditionally, there have been disparities in diagnosing endometriosis. There was a time when it was presumed that White women had endometriosis and Black women were more likely to have an infectious etiology for their pelvic pain—which is not true. The incidence is slightly higher in Asian and White women compared with Black women, but this is very likely because of bias and access to care. When examining women who have been diagnosed and are being evaluated and treated for infertility, those racial differences disappear. When access to care is available, when patients are seen by a physician, when they are under medical care for another reason, the racial disparities are not seen in endometriosis; it occurs equally. I think there clearly are disparities in access and bias in how we diagnose endometriosis; we should be cognizant of that and realize that endometriosis is very similar in its frequency in all ethnic groups.

Medical management of chronic rhinosinusitis with nasal polyposis (CRSwNP) typically has focused on controlling tissue inflammation. Approximately 85% of patients will exhibit a type 2 inflammatory pattern, and recent studies have examined the implications of this process for the treatment of CRSwNP.

As in other respiratory diseases, emerging CRSwNP endotypes are helping researchers identify actionable targets and develop targeted biologic treatments. In fact, therapies targeting cytokines IL-4 and IL-13, which contribute to type 2 inflammation in CRSwNP, recently have been approved by the FDA.

Dr Stella Lee from the University of Pittsburgh discusses the use of new biologic therapies in clinical practice as well as strategies to test for potential drivers of type 2 inflammation.

---

Stella Lee, MD, Chief, Sinonasal Disorder and Allergy; Assistant Professor, Otolaryngology, Department of Head & Neck Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania .

Stella Lee, MD, has disclosed the following relevant financial relationships:
Received research grant from: sanofi-aventis; Regeneron Pharmaceuticals Inc; GlaxoSmithKline; AstraZeneca Pharmaceuticals LP; Genentech.

Medical management of chronic rhinosinusitis with nasal polyposis (CRSwNP) typically has focused on controlling tissue inflammation. Approximately 85% of patients will exhibit a type 2 inflammatory pattern, and recent studies have examined the implications of this process for the treatment of CRSwNP.

As in other respiratory diseases, emerging CRSwNP endotypes are helping researchers identify actionable targets and develop targeted biologic treatments. In fact, therapies targeting cytokines IL-4 and IL-13, which contribute to type 2 inflammation in CRSwNP, recently have been approved by the FDA.

Dr Stella Lee from the University of Pittsburgh discusses the use of new biologic therapies in clinical practice as well as strategies to test for potential drivers of type 2 inflammation.

---

Stella Lee, MD, Chief, Sinonasal Disorder and Allergy; Assistant Professor, Otolaryngology, Department of Head & Neck Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania .

Stella Lee, MD, has disclosed the following relevant financial relationships:
Received research grant from: sanofi-aventis; Regeneron Pharmaceuticals Inc; GlaxoSmithKline; AstraZeneca Pharmaceuticals LP; Genentech.

Medical management of chronic rhinosinusitis with nasal polyposis (CRSwNP) typically has focused on controlling tissue inflammation. Approximately 85% of patients will exhibit a type 2 inflammatory pattern, and recent studies have examined the implications of this process for the treatment of CRSwNP.

As in other respiratory diseases, emerging CRSwNP endotypes are helping researchers identify actionable targets and develop targeted biologic treatments. In fact, therapies targeting cytokines IL-4 and IL-13, which contribute to type 2 inflammation in CRSwNP, recently have been approved by the FDA.

Dr Stella Lee from the University of Pittsburgh discusses the use of new biologic therapies in clinical practice as well as strategies to test for potential drivers of type 2 inflammation.

---

Stella Lee, MD, Chief, Sinonasal Disorder and Allergy; Assistant Professor, Otolaryngology, Department of Head & Neck Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania .

Stella Lee, MD, has disclosed the following relevant financial relationships:
Received research grant from: sanofi-aventis; Regeneron Pharmaceuticals Inc; GlaxoSmithKline; AstraZeneca Pharmaceuticals LP; Genentech.