MDedge Psychiatry

While laboratory studies move forward at full speed, the clinical use of stem cells—undifferentiated cells that can develop into many different types of specialized cells—remains controversial. Presently, only unadulterated stem cells are allowed to be used in patients, and only on an experimental and investigational basis. Stem cells that have been expanded, modified, or enhanced outside of the body are not allowed to be used for clinical application in the United States at this time. In June 2021, the FDA strengthened the language of stem cell regulation, further limiting their clinical application (see https://www.fda.gov/vaccines-blood-biologics/consumers-biologics/important-patient-and-consumer-information-about-regenerative-medicine-therapies). Yet some applications, such as treatment of lymphoma or restorative knee injections, are covered by some health insurance plans, and the acceptance of stem cell treatment is growing.

In this article, I describe the basics of stem cells, and explore the potential therapeutic use of stem cells for treating various mental illnesses.

Stem cells: A primer

Human embryonic stem cells were initially investigated for their healing properties. However, the need to harvest these cells from embryos drew much criticism, and many found the process to be ethically and religiously unacceptable. This was resolved by the Nobel prize–winning discovery that adult somatic cells can be reprogrammed into cells with embryonic stem cell properties by introducing specific transcription factors. These cells have been termed “induced pluripotent stem cells” (iPSCs).¹ The use of adult stem cells and stem cells from the umbilical cords of healthy newborns has allowed for wider acceptance of stem cell research and treatment.

Stem cells may be collected from the patient himself or herself; these are autologous stem cells. They may also be harvested from healthy newborn waste, such as the umbilical cord blood and wall; these are allogenic stem cells. Autologous stem cells are present in almost any tissue but are usually collected from the patient’s adipose tissue or from bone marrow. Understandably, younger stem cells possess higher healing properties. Stem cells may be mesenchymal, producing primarily connective and nervous tissue, or hematopoietic, influencing the immune system and blood cell production, though there is a considerable overlap in the function of these types of cells.

Adult somatic stem cells may be turned into stem cells (iPSCs) and then become any tissue, including neurons. This ability of stem cells to physically regenerate the CNS is directly relevant to psychiatry.

In addition to neurogenesis, stem cell transplants can assist in immune and vascular restoration as well as in suppressing inflammation. The ability of stem cells to replace mutated genes may be useful for addressing inheritable neuropsychiatric conditions.

Both autoimmune and inflammatory mechanisms play an important role in most psychiatric illnesses. The more we learn, the more it is clear that brain function is profoundly dependent on more than just its structure, and that structure depends on more than blood supply. Stem cells influence the vascular, nutritional, functional, inflammatory, and immune environment of the brain, potentially assisting in cognitive and emotional rehabilitation.

Stem cells operate in 2 fundamental ways: via direct cell-to-cell interaction, and via the production and release of growth, immune-regulating, and anti-inflammatory factors. Such factors are produced within the cells and then released in the extracellular environment as a content of exosomes. The route of administration is important in the delivery of the stem cells to the target tissue. Unlike their direct introduction into a joint, muscle, or intervertebral disk, injection of stem cells into the brain is more complicated and not routinely feasible. Intrathecal injections may bring stem cells into the CNS, but cerebrospinal fluid does not easily carry stem cells into the brain, and certainly cannot deliver them to an identified target within the brain. Existing technology can allow stem cells to be packaged in such a way that they can penetrate the blood-brain barrier, but this requires stem cell modification, which presently is not permitted in clinical practice in the United States. Alternatively, there is a way to weaken the blood-brain barrier to allow stem cells to travel through the “opened doors,” so to speak, but this allows everything to have access to the CNS, which may be unsafe. IV administration is technologically easy, and it grants stem cells the environment to multiply and produce extracellular factors that can cross the blood-brain barrier, while large cells cannot.

Continue to: Stem cells as a treatment for mental illness...

Stem cells as a treatment for mental illness

Based on our understanding of the function of stem cells, many neurodegenerative-, vascular-, immune-, and inflammation-based psychiatric conditions can be influenced by stem cell treatment. Here I review the potential therapeutic role of stem cells in the treatment of several psychiatric disorders.

Alzheimer’s dementia

Alzheimer’s dementia (AD) is a progressive neurodegenerative pathology based on neuronal and synaptic loss. Repopulation and regeneration of depleted neuronal circuitry by exogenous stem cells may be a rational therapeutic strategy.² The regeneration of lost neurons has the potential to restore cognitive function. Multiple growth factors that regulate neurogenesis are abundant during child development but dramatically decline with age. The introduction of stem cells—especially those derived from newborn waste—seem to promote recovery from neuro­degenerative disease or injury.³

There currently is no cure for AD. Cellular therapy promises new advances in treatment.⁴ Neurogenesis occurs not only during fetal development but in the adult brain. Neural stem cells reside in the adult CNS of all mammals.⁵ They are intimately involved in continuous restoration, but age just like the rest of the animal tissue, providing ever-decreasing restorative potential.

The number of studies of stem cells in AD has increased since the early 2000 s,^6,7 and research continues to demonstrate robust CNS neurogenesis. In a 2020 study, Zappa Villar et al⁸ evaluated stem cells as a treatment for rats in which an AD model was induced by the intracerebroventricular injection of streptozotocin (STZ). The STZ-treated rats displayed poor performance in all behavioral tests. Stem cell therapy increased exploratory behavior, decreased anxiety, and improved spatial memory and marble-burying behavior; the latter was representative of daily life activities. Importantly, stem cell therapy ameliorated and restored hippocampal atrophy and some presynaptic protein levels in the rats with AD.⁸ Animal models cannot be automatically applied to humans, but they shine a light on the areas that need further exploration.

In humans, elevated cortisol levels during aging predict hippocampal atrophy and memory deficits,⁹ and this deficiency may be positively influenced by stem cell treatment.

Schizophrenia

Recent research indicates that schizophrenia may begin with abnormal neurogenesis from neural stem cells inside the embryo, and that this process may be particularly vulnerable to numerous genetic and/or environmental disturbances of early brain development.¹⁰ Because neurogenesis is not confined to the womb but is a protracted process that continues into postnatal life, adolescence and beyond, influencing this process may be a way to add to the schizophrenia treatment armamentarium.¹⁰ Sacco et al¹¹ described links between the alteration of intrauterine and adult neurogenesis and the causes of neuropsychiatric disorders, including schizophrenia. Immune and inflammatory mechanisms are important in the etiology of schizophrenia. By their core function, stem cells address both mechanisms, and may directly modulate this devastating disease.

In addition to clinical hopes, advances in research tools hold the promise of new discoveries. With the advent of iPSC technology, it is possible to generate live neurons in vitro from somatic tissue of patients with schizophrenia. Despite its many limitations, this revolutionary technology has already helped to advance our understanding of schizophrenia.¹¹

Bipolar disorder

Many of the fundamental neurobiological mechanisms of schizophrenia are mirrored in bipolar disorder.¹² Though we are not ready to bring stem cells into the day-to-day treatment of this condition, several groups are starting to apply iPSC technology to the study of bipolar disorder.¹³

Neurodevelopmental factors—particularly pathways related to nervous system development, cell migration, extracellular matrix, methylation, and calcium signaling—have been identified in large gene expression studies as altered in bipolar disorder.¹⁴ Stem cell technology opens doorways to reverse engineering of human neuro­degenerative disease.¹⁵

Continue to: Autism spectrum disorders...

The exact mechanisms of action of MSCs to restore function in patients with ASDs are largely unknown, but proposed mechanisms include:

• synthesizing and releasing anti-inflammatory cytokines and survival-promoting growth factors
• integrating into the existing neural and synaptic network
• restoring plasticity.¹⁸

In a study of transplantation of human cord blood cells and umbilical cord–derived MSCs for patients with ASDs, Bradstreet et al¹⁹ found a statistically significant difference on scores for domains of speech, sociability, sensory, and overall health, as well as reductions in the total scores, in those who received transplants compared to their pretreatment values.

In another study of stem cell therapy for ASDs, Lv et al²⁰ demonstrated the safety and efficacy of combined transplantation of human cord blood cells and umbilical cord–derived MSCs in treating children with ASDs. The transplantations included 4 stem cell IV infusions and intrathecal injections once a week. Statistically significant differences were shown at 24 weeks post-treatment. Although this nonrandomized, open-label, single-center Phase I/II trial cannot be relied on for any definitive conclusions, it suggests an important area of investigation.²⁰

The vascular aspects of ASDs’ pathogenesis should not be overlooked. For example, specific temporal lobe areas associated with facial recognition, social interaction, and language comprehension have been demonstrated to be hypoperfused in children with ASDs, but not in controls. The degree of hypoperfusion and resulting hypoxia correlates with the severity of ASD symptoms. The damage causing hypoperfusion of temporal areas was associated with the onset of autism-like disorders. Damage of the amygdala, hippocampus, or other temporal structures induces permanent or transient autistic-like characteristics, such as unexpressive faces, little eye contact, and motor stereotypes. Clinically, temporal lobe damage by viral and other means has been implicated in the development of ASD in children and adults. Hypoperfusion may contribute to defects, not only by inducing hypoxia, but also by allowing for abnormal metabolite or neurotransmitter accumulation. This is one of the reasons glutamate toxicity has been implicated in ASD. The augmentation of perfusion through stimulation of angiogenesis by stem cells should allow for metabolite clearance and restoration of functionality. Vargas et al²¹ compared brain autopsy samples from 11 children with ASDs to those of 7 age-matched controls. They demonstrated an active neuroinflammatory process in the cerebral cortex, white matter, and cerebellum of patients with ASDs, both by immunohistochemistry and morphology.²¹

Multiple studies have confirmed that the systemic administration of cord blood cells is sufficient to induce neuroregeneration.^22,23 Angiogenesis has been experimentally demonstrated in peripheral artery disease, myocardial ischemia, and stroke, and has direct implications on brain repair.²⁴ Immune dysregulation^25,26 and immune modulation²⁷ also are addressed by stem cell treatment, which provides a promising avenue for battling ASDs.

Like attention-deficit/hyperactivity disorder and obsessive-compulsive disorder, ASDs are neurodevelopmental conditions. Advances based on the use of stem cells hold great promise for understanding, diagnosing and, possibly, treating these psychiatric disorders.^28,29

Depression

Neuropsychiatric disorders arise from deviations from the regular differentiation process of the CNS, leading to altered neuronal connectivity. Relatively subtle abnormalities in the size and number of cells in the prefrontal cortex and basal ganglia have been observed in patients with depressive disorder and Tourette syndrome.³⁰ Fibroblast-derived iPSCs generate serotonergic neurons through the exposure of the cells to growth factors and modulators of signaling pathways. If these serotonergic neurons are made from the patients’ own cells, they can be used to screen for new therapeutics and elucidate the unknown mechanisms through which current medications may function.³¹ This development could lead to the discovery of new medication targets and new insights into the molecular biology of depression.³²

Deficiencies of brain-derived neurotrophic factor (BDNF) have a role in depression, anxiety, and other neuropsychiatric illnesses. The acute behavioral effects of selective serotonin reuptake inhibitors and tricyclic antidepressants seem to require BDNF signaling, which suggests that BDNF holds great potential as a therapeutic agent. Cell therapies focused on correcting BDNF deficiencies in mice have had some success.³³

Dysregulation of GABAergic neurons has also been implicated in depression and anxiety. Patients with major depressive disorder have reduced gamma aminobutyric acid (GABA) receptors in the parahippocampal and lateral temporal lobes.³⁴

Ultimately, the development of differentiation protocols for serotonergic and GABAergic neuronal populations will pave the way for examining the role of these populations in the pathogenesis of depression and anxiety, and may eventually open the door for cell-based therapies in humans.³⁵

Studies have demonstrated a reduction in the density of pyramidal and nonpyramidal neurons in the anterior cingulate cortex of patients with schizophrenia and bipolar disorder,³⁶ glial reduction in the subgenual prefrontal cortex in mood disorders,³⁷ and morphometric evidence for neuronal and glial prefrontal cell pathology in major depressive disorder.³⁸ The potential for stem cells to repair such pathology may be of clinical benefit to many patients.

Aside from their other suggested clinical uses, iPSCs may be utilized in new pathways for research on the biology and pharmacology of major depressive disorder.³⁹

Continue to: Obsessive-compulsive disorder...

Obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is often characterized by excessive behaviors related to cleanliness, including grooming, which is represented across most animal species. In mice, behaviors such as compulsive grooming and hair removal—similar to behaviors in humans with OCD or trichotillomania—are associated with a specific mutation. Chen et al⁴⁰ reported that the transplantation of bone marrow stem cells into mice with this mutation (bone marrow–derived microglia specifically home to the brain) rescues their pathological phenotype by repairing native neurons.

The autoimmune, inflammatory, and neurodegenerative changes that are prevalent in OCD may be remedied by stem cell treatment in a fashion described throughout this article.

Other conditions

The Box^41-50 describes a possible role for stem cells in the treatment or prevention of several types of substance use disorders.

Box

Chronic pain is a neuropsychiatric condition that involves the immune system, inflammation, vascularization, trophic changes, and other aspects of the CNS function in addition to peripheral factors and somatic pain generators. Treatment of painful conditions with the aid of stem cells represents a large and ever-developing field that lies outside of the scope of this article.⁵¹

Experimental, but promising

It is not easy to accept revolutionary new approaches in medicine. Endless research and due diligence are needed to prove a concept and then to work out specific applications, safeguards, and limitations for any novel treatments. The stem cell terrain is poorly explored, and one needs to be careful when venturing there. Presently, the FDA appropriately sees treatment with stem cells as experimental and investigational, particularly in the mental health arena. Stem cells are not approved for treatment of any specific condition. At the same time, research and clinical practice suggest stem cell treatment may someday play a more prominent role in health care. Undoubtedly, psychiatry will eventually benefit from the knowledge and application of stem cell research and practice.

Related Resources

• De Los Angeles A, Fernando MB, Hall NAL, et al. Induced pluripotent stem cells in psychiatry: an overview and critical perspective. Biol Psychiatry. 2021;90(6):362-372.
• Heider J, Vogel S, Volkmer H, et al. Human iPSC-derived glia as a tool for neuropsychiatric research and drug development. Int J Mol Sci. 2021;22(19):10254.

Drug Brand Name

Streptozotocin • Zanosar

Bottom Line

Treatment with stem cell transplantation is experimental and not approved for any medical or psychiatric illness. However, based on our growing understanding of the function of stem cells, and preliminary research conducted mainly in animals, many neurodegenerative-, vascular-, immune-, and inflammation-based psychiatric conditions might be beneficially influenced by stem cell treatment.

While laboratory studies move forward at full speed, the clinical use of stem cells—undifferentiated cells that can develop into many different types of specialized cells—remains controversial. Presently, only unadulterated stem cells are allowed to be used in patients, and only on an experimental and investigational basis. Stem cells that have been expanded, modified, or enhanced outside of the body are not allowed to be used for clinical application in the United States at this time. In June 2021, the FDA strengthened the language of stem cell regulation, further limiting their clinical application (see https://www.fda.gov/vaccines-blood-biologics/consumers-biologics/important-patient-and-consumer-information-about-regenerative-medicine-therapies). Yet some applications, such as treatment of lymphoma or restorative knee injections, are covered by some health insurance plans, and the acceptance of stem cell treatment is growing.

In this article, I describe the basics of stem cells, and explore the potential therapeutic use of stem cells for treating various mental illnesses.

Stem cells: A primer

Human embryonic stem cells were initially investigated for their healing properties. However, the need to harvest these cells from embryos drew much criticism, and many found the process to be ethically and religiously unacceptable. This was resolved by the Nobel prize–winning discovery that adult somatic cells can be reprogrammed into cells with embryonic stem cell properties by introducing specific transcription factors. These cells have been termed “induced pluripotent stem cells” (iPSCs).¹ The use of adult stem cells and stem cells from the umbilical cords of healthy newborns has allowed for wider acceptance of stem cell research and treatment.

Stem cells may be collected from the patient himself or herself; these are autologous stem cells. They may also be harvested from healthy newborn waste, such as the umbilical cord blood and wall; these are allogenic stem cells. Autologous stem cells are present in almost any tissue but are usually collected from the patient’s adipose tissue or from bone marrow. Understandably, younger stem cells possess higher healing properties. Stem cells may be mesenchymal, producing primarily connective and nervous tissue, or hematopoietic, influencing the immune system and blood cell production, though there is a considerable overlap in the function of these types of cells.

Adult somatic stem cells may be turned into stem cells (iPSCs) and then become any tissue, including neurons. This ability of stem cells to physically regenerate the CNS is directly relevant to psychiatry.

In addition to neurogenesis, stem cell transplants can assist in immune and vascular restoration as well as in suppressing inflammation. The ability of stem cells to replace mutated genes may be useful for addressing inheritable neuropsychiatric conditions.

Both autoimmune and inflammatory mechanisms play an important role in most psychiatric illnesses. The more we learn, the more it is clear that brain function is profoundly dependent on more than just its structure, and that structure depends on more than blood supply. Stem cells influence the vascular, nutritional, functional, inflammatory, and immune environment of the brain, potentially assisting in cognitive and emotional rehabilitation.

Stem cells operate in 2 fundamental ways: via direct cell-to-cell interaction, and via the production and release of growth, immune-regulating, and anti-inflammatory factors. Such factors are produced within the cells and then released in the extracellular environment as a content of exosomes. The route of administration is important in the delivery of the stem cells to the target tissue. Unlike their direct introduction into a joint, muscle, or intervertebral disk, injection of stem cells into the brain is more complicated and not routinely feasible. Intrathecal injections may bring stem cells into the CNS, but cerebrospinal fluid does not easily carry stem cells into the brain, and certainly cannot deliver them to an identified target within the brain. Existing technology can allow stem cells to be packaged in such a way that they can penetrate the blood-brain barrier, but this requires stem cell modification, which presently is not permitted in clinical practice in the United States. Alternatively, there is a way to weaken the blood-brain barrier to allow stem cells to travel through the “opened doors,” so to speak, but this allows everything to have access to the CNS, which may be unsafe. IV administration is technologically easy, and it grants stem cells the environment to multiply and produce extracellular factors that can cross the blood-brain barrier, while large cells cannot.

Continue to: Stem cells as a treatment for mental illness...

Stem cells as a treatment for mental illness

Based on our understanding of the function of stem cells, many neurodegenerative-, vascular-, immune-, and inflammation-based psychiatric conditions can be influenced by stem cell treatment. Here I review the potential therapeutic role of stem cells in the treatment of several psychiatric disorders.

Alzheimer’s dementia

Alzheimer’s dementia (AD) is a progressive neurodegenerative pathology based on neuronal and synaptic loss. Repopulation and regeneration of depleted neuronal circuitry by exogenous stem cells may be a rational therapeutic strategy.² The regeneration of lost neurons has the potential to restore cognitive function. Multiple growth factors that regulate neurogenesis are abundant during child development but dramatically decline with age. The introduction of stem cells—especially those derived from newborn waste—seem to promote recovery from neuro­degenerative disease or injury.³

There currently is no cure for AD. Cellular therapy promises new advances in treatment.⁴ Neurogenesis occurs not only during fetal development but in the adult brain. Neural stem cells reside in the adult CNS of all mammals.⁵ They are intimately involved in continuous restoration, but age just like the rest of the animal tissue, providing ever-decreasing restorative potential.

The number of studies of stem cells in AD has increased since the early 2000 s,^6,7 and research continues to demonstrate robust CNS neurogenesis. In a 2020 study, Zappa Villar et al⁸ evaluated stem cells as a treatment for rats in which an AD model was induced by the intracerebroventricular injection of streptozotocin (STZ). The STZ-treated rats displayed poor performance in all behavioral tests. Stem cell therapy increased exploratory behavior, decreased anxiety, and improved spatial memory and marble-burying behavior; the latter was representative of daily life activities. Importantly, stem cell therapy ameliorated and restored hippocampal atrophy and some presynaptic protein levels in the rats with AD.⁸ Animal models cannot be automatically applied to humans, but they shine a light on the areas that need further exploration.

In humans, elevated cortisol levels during aging predict hippocampal atrophy and memory deficits,⁹ and this deficiency may be positively influenced by stem cell treatment.

Schizophrenia

Recent research indicates that schizophrenia may begin with abnormal neurogenesis from neural stem cells inside the embryo, and that this process may be particularly vulnerable to numerous genetic and/or environmental disturbances of early brain development.¹⁰ Because neurogenesis is not confined to the womb but is a protracted process that continues into postnatal life, adolescence and beyond, influencing this process may be a way to add to the schizophrenia treatment armamentarium.¹⁰ Sacco et al¹¹ described links between the alteration of intrauterine and adult neurogenesis and the causes of neuropsychiatric disorders, including schizophrenia. Immune and inflammatory mechanisms are important in the etiology of schizophrenia. By their core function, stem cells address both mechanisms, and may directly modulate this devastating disease.

In addition to clinical hopes, advances in research tools hold the promise of new discoveries. With the advent of iPSC technology, it is possible to generate live neurons in vitro from somatic tissue of patients with schizophrenia. Despite its many limitations, this revolutionary technology has already helped to advance our understanding of schizophrenia.¹¹

Bipolar disorder

Many of the fundamental neurobiological mechanisms of schizophrenia are mirrored in bipolar disorder.¹² Though we are not ready to bring stem cells into the day-to-day treatment of this condition, several groups are starting to apply iPSC technology to the study of bipolar disorder.¹³

Neurodevelopmental factors—particularly pathways related to nervous system development, cell migration, extracellular matrix, methylation, and calcium signaling—have been identified in large gene expression studies as altered in bipolar disorder.¹⁴ Stem cell technology opens doorways to reverse engineering of human neuro­degenerative disease.¹⁵

Continue to: Autism spectrum disorders...

The exact mechanisms of action of MSCs to restore function in patients with ASDs are largely unknown, but proposed mechanisms include:

• synthesizing and releasing anti-inflammatory cytokines and survival-promoting growth factors
• integrating into the existing neural and synaptic network
• restoring plasticity.¹⁸

In a study of transplantation of human cord blood cells and umbilical cord–derived MSCs for patients with ASDs, Bradstreet et al¹⁹ found a statistically significant difference on scores for domains of speech, sociability, sensory, and overall health, as well as reductions in the total scores, in those who received transplants compared to their pretreatment values.

In another study of stem cell therapy for ASDs, Lv et al²⁰ demonstrated the safety and efficacy of combined transplantation of human cord blood cells and umbilical cord–derived MSCs in treating children with ASDs. The transplantations included 4 stem cell IV infusions and intrathecal injections once a week. Statistically significant differences were shown at 24 weeks post-treatment. Although this nonrandomized, open-label, single-center Phase I/II trial cannot be relied on for any definitive conclusions, it suggests an important area of investigation.²⁰

The vascular aspects of ASDs’ pathogenesis should not be overlooked. For example, specific temporal lobe areas associated with facial recognition, social interaction, and language comprehension have been demonstrated to be hypoperfused in children with ASDs, but not in controls. The degree of hypoperfusion and resulting hypoxia correlates with the severity of ASD symptoms. The damage causing hypoperfusion of temporal areas was associated with the onset of autism-like disorders. Damage of the amygdala, hippocampus, or other temporal structures induces permanent or transient autistic-like characteristics, such as unexpressive faces, little eye contact, and motor stereotypes. Clinically, temporal lobe damage by viral and other means has been implicated in the development of ASD in children and adults. Hypoperfusion may contribute to defects, not only by inducing hypoxia, but also by allowing for abnormal metabolite or neurotransmitter accumulation. This is one of the reasons glutamate toxicity has been implicated in ASD. The augmentation of perfusion through stimulation of angiogenesis by stem cells should allow for metabolite clearance and restoration of functionality. Vargas et al²¹ compared brain autopsy samples from 11 children with ASDs to those of 7 age-matched controls. They demonstrated an active neuroinflammatory process in the cerebral cortex, white matter, and cerebellum of patients with ASDs, both by immunohistochemistry and morphology.²¹

Multiple studies have confirmed that the systemic administration of cord blood cells is sufficient to induce neuroregeneration.^22,23 Angiogenesis has been experimentally demonstrated in peripheral artery disease, myocardial ischemia, and stroke, and has direct implications on brain repair.²⁴ Immune dysregulation^25,26 and immune modulation²⁷ also are addressed by stem cell treatment, which provides a promising avenue for battling ASDs.

Like attention-deficit/hyperactivity disorder and obsessive-compulsive disorder, ASDs are neurodevelopmental conditions. Advances based on the use of stem cells hold great promise for understanding, diagnosing and, possibly, treating these psychiatric disorders.^28,29

Depression

Neuropsychiatric disorders arise from deviations from the regular differentiation process of the CNS, leading to altered neuronal connectivity. Relatively subtle abnormalities in the size and number of cells in the prefrontal cortex and basal ganglia have been observed in patients with depressive disorder and Tourette syndrome.³⁰ Fibroblast-derived iPSCs generate serotonergic neurons through the exposure of the cells to growth factors and modulators of signaling pathways. If these serotonergic neurons are made from the patients’ own cells, they can be used to screen for new therapeutics and elucidate the unknown mechanisms through which current medications may function.³¹ This development could lead to the discovery of new medication targets and new insights into the molecular biology of depression.³²

Deficiencies of brain-derived neurotrophic factor (BDNF) have a role in depression, anxiety, and other neuropsychiatric illnesses. The acute behavioral effects of selective serotonin reuptake inhibitors and tricyclic antidepressants seem to require BDNF signaling, which suggests that BDNF holds great potential as a therapeutic agent. Cell therapies focused on correcting BDNF deficiencies in mice have had some success.³³

Dysregulation of GABAergic neurons has also been implicated in depression and anxiety. Patients with major depressive disorder have reduced gamma aminobutyric acid (GABA) receptors in the parahippocampal and lateral temporal lobes.³⁴

Ultimately, the development of differentiation protocols for serotonergic and GABAergic neuronal populations will pave the way for examining the role of these populations in the pathogenesis of depression and anxiety, and may eventually open the door for cell-based therapies in humans.³⁵

Studies have demonstrated a reduction in the density of pyramidal and nonpyramidal neurons in the anterior cingulate cortex of patients with schizophrenia and bipolar disorder,³⁶ glial reduction in the subgenual prefrontal cortex in mood disorders,³⁷ and morphometric evidence for neuronal and glial prefrontal cell pathology in major depressive disorder.³⁸ The potential for stem cells to repair such pathology may be of clinical benefit to many patients.

Aside from their other suggested clinical uses, iPSCs may be utilized in new pathways for research on the biology and pharmacology of major depressive disorder.³⁹

Continue to: Obsessive-compulsive disorder...

Obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is often characterized by excessive behaviors related to cleanliness, including grooming, which is represented across most animal species. In mice, behaviors such as compulsive grooming and hair removal—similar to behaviors in humans with OCD or trichotillomania—are associated with a specific mutation. Chen et al⁴⁰ reported that the transplantation of bone marrow stem cells into mice with this mutation (bone marrow–derived microglia specifically home to the brain) rescues their pathological phenotype by repairing native neurons.

The autoimmune, inflammatory, and neurodegenerative changes that are prevalent in OCD may be remedied by stem cell treatment in a fashion described throughout this article.

Other conditions

The Box^41-50 describes a possible role for stem cells in the treatment or prevention of several types of substance use disorders.

Box

Chronic pain is a neuropsychiatric condition that involves the immune system, inflammation, vascularization, trophic changes, and other aspects of the CNS function in addition to peripheral factors and somatic pain generators. Treatment of painful conditions with the aid of stem cells represents a large and ever-developing field that lies outside of the scope of this article.⁵¹

Experimental, but promising

It is not easy to accept revolutionary new approaches in medicine. Endless research and due diligence are needed to prove a concept and then to work out specific applications, safeguards, and limitations for any novel treatments. The stem cell terrain is poorly explored, and one needs to be careful when venturing there. Presently, the FDA appropriately sees treatment with stem cells as experimental and investigational, particularly in the mental health arena. Stem cells are not approved for treatment of any specific condition. At the same time, research and clinical practice suggest stem cell treatment may someday play a more prominent role in health care. Undoubtedly, psychiatry will eventually benefit from the knowledge and application of stem cell research and practice.

Related Resources

• De Los Angeles A, Fernando MB, Hall NAL, et al. Induced pluripotent stem cells in psychiatry: an overview and critical perspective. Biol Psychiatry. 2021;90(6):362-372.
• Heider J, Vogel S, Volkmer H, et al. Human iPSC-derived glia as a tool for neuropsychiatric research and drug development. Int J Mol Sci. 2021;22(19):10254.

Drug Brand Name

Streptozotocin • Zanosar

Bottom Line

Treatment with stem cell transplantation is experimental and not approved for any medical or psychiatric illness. However, based on our growing understanding of the function of stem cells, and preliminary research conducted mainly in animals, many neurodegenerative-, vascular-, immune-, and inflammation-based psychiatric conditions might be beneficially influenced by stem cell treatment.

While laboratory studies move forward at full speed, the clinical use of stem cells—undifferentiated cells that can develop into many different types of specialized cells—remains controversial. Presently, only unadulterated stem cells are allowed to be used in patients, and only on an experimental and investigational basis. Stem cells that have been expanded, modified, or enhanced outside of the body are not allowed to be used for clinical application in the United States at this time. In June 2021, the FDA strengthened the language of stem cell regulation, further limiting their clinical application (see https://www.fda.gov/vaccines-blood-biologics/consumers-biologics/important-patient-and-consumer-information-about-regenerative-medicine-therapies). Yet some applications, such as treatment of lymphoma or restorative knee injections, are covered by some health insurance plans, and the acceptance of stem cell treatment is growing.

In this article, I describe the basics of stem cells, and explore the potential therapeutic use of stem cells for treating various mental illnesses.

Stem cells: A primer

Human embryonic stem cells were initially investigated for their healing properties. However, the need to harvest these cells from embryos drew much criticism, and many found the process to be ethically and religiously unacceptable. This was resolved by the Nobel prize–winning discovery that adult somatic cells can be reprogrammed into cells with embryonic stem cell properties by introducing specific transcription factors. These cells have been termed “induced pluripotent stem cells” (iPSCs).¹ The use of adult stem cells and stem cells from the umbilical cords of healthy newborns has allowed for wider acceptance of stem cell research and treatment.

Stem cells may be collected from the patient himself or herself; these are autologous stem cells. They may also be harvested from healthy newborn waste, such as the umbilical cord blood and wall; these are allogenic stem cells. Autologous stem cells are present in almost any tissue but are usually collected from the patient’s adipose tissue or from bone marrow. Understandably, younger stem cells possess higher healing properties. Stem cells may be mesenchymal, producing primarily connective and nervous tissue, or hematopoietic, influencing the immune system and blood cell production, though there is a considerable overlap in the function of these types of cells.

Adult somatic stem cells may be turned into stem cells (iPSCs) and then become any tissue, including neurons. This ability of stem cells to physically regenerate the CNS is directly relevant to psychiatry.

In addition to neurogenesis, stem cell transplants can assist in immune and vascular restoration as well as in suppressing inflammation. The ability of stem cells to replace mutated genes may be useful for addressing inheritable neuropsychiatric conditions.

Both autoimmune and inflammatory mechanisms play an important role in most psychiatric illnesses. The more we learn, the more it is clear that brain function is profoundly dependent on more than just its structure, and that structure depends on more than blood supply. Stem cells influence the vascular, nutritional, functional, inflammatory, and immune environment of the brain, potentially assisting in cognitive and emotional rehabilitation.

Stem cells operate in 2 fundamental ways: via direct cell-to-cell interaction, and via the production and release of growth, immune-regulating, and anti-inflammatory factors. Such factors are produced within the cells and then released in the extracellular environment as a content of exosomes. The route of administration is important in the delivery of the stem cells to the target tissue. Unlike their direct introduction into a joint, muscle, or intervertebral disk, injection of stem cells into the brain is more complicated and not routinely feasible. Intrathecal injections may bring stem cells into the CNS, but cerebrospinal fluid does not easily carry stem cells into the brain, and certainly cannot deliver them to an identified target within the brain. Existing technology can allow stem cells to be packaged in such a way that they can penetrate the blood-brain barrier, but this requires stem cell modification, which presently is not permitted in clinical practice in the United States. Alternatively, there is a way to weaken the blood-brain barrier to allow stem cells to travel through the “opened doors,” so to speak, but this allows everything to have access to the CNS, which may be unsafe. IV administration is technologically easy, and it grants stem cells the environment to multiply and produce extracellular factors that can cross the blood-brain barrier, while large cells cannot.

Continue to: Stem cells as a treatment for mental illness...

Stem cells as a treatment for mental illness

Based on our understanding of the function of stem cells, many neurodegenerative-, vascular-, immune-, and inflammation-based psychiatric conditions can be influenced by stem cell treatment. Here I review the potential therapeutic role of stem cells in the treatment of several psychiatric disorders.

Alzheimer’s dementia

Alzheimer’s dementia (AD) is a progressive neurodegenerative pathology based on neuronal and synaptic loss. Repopulation and regeneration of depleted neuronal circuitry by exogenous stem cells may be a rational therapeutic strategy.² The regeneration of lost neurons has the potential to restore cognitive function. Multiple growth factors that regulate neurogenesis are abundant during child development but dramatically decline with age. The introduction of stem cells—especially those derived from newborn waste—seem to promote recovery from neuro­degenerative disease or injury.³

There currently is no cure for AD. Cellular therapy promises new advances in treatment.⁴ Neurogenesis occurs not only during fetal development but in the adult brain. Neural stem cells reside in the adult CNS of all mammals.⁵ They are intimately involved in continuous restoration, but age just like the rest of the animal tissue, providing ever-decreasing restorative potential.

The number of studies of stem cells in AD has increased since the early 2000 s,^6,7 and research continues to demonstrate robust CNS neurogenesis. In a 2020 study, Zappa Villar et al⁸ evaluated stem cells as a treatment for rats in which an AD model was induced by the intracerebroventricular injection of streptozotocin (STZ). The STZ-treated rats displayed poor performance in all behavioral tests. Stem cell therapy increased exploratory behavior, decreased anxiety, and improved spatial memory and marble-burying behavior; the latter was representative of daily life activities. Importantly, stem cell therapy ameliorated and restored hippocampal atrophy and some presynaptic protein levels in the rats with AD.⁸ Animal models cannot be automatically applied to humans, but they shine a light on the areas that need further exploration.

In humans, elevated cortisol levels during aging predict hippocampal atrophy and memory deficits,⁹ and this deficiency may be positively influenced by stem cell treatment.

Schizophrenia

Recent research indicates that schizophrenia may begin with abnormal neurogenesis from neural stem cells inside the embryo, and that this process may be particularly vulnerable to numerous genetic and/or environmental disturbances of early brain development.¹⁰ Because neurogenesis is not confined to the womb but is a protracted process that continues into postnatal life, adolescence and beyond, influencing this process may be a way to add to the schizophrenia treatment armamentarium.¹⁰ Sacco et al¹¹ described links between the alteration of intrauterine and adult neurogenesis and the causes of neuropsychiatric disorders, including schizophrenia. Immune and inflammatory mechanisms are important in the etiology of schizophrenia. By their core function, stem cells address both mechanisms, and may directly modulate this devastating disease.

In addition to clinical hopes, advances in research tools hold the promise of new discoveries. With the advent of iPSC technology, it is possible to generate live neurons in vitro from somatic tissue of patients with schizophrenia. Despite its many limitations, this revolutionary technology has already helped to advance our understanding of schizophrenia.¹¹

Bipolar disorder

Many of the fundamental neurobiological mechanisms of schizophrenia are mirrored in bipolar disorder.¹² Though we are not ready to bring stem cells into the day-to-day treatment of this condition, several groups are starting to apply iPSC technology to the study of bipolar disorder.¹³

Neurodevelopmental factors—particularly pathways related to nervous system development, cell migration, extracellular matrix, methylation, and calcium signaling—have been identified in large gene expression studies as altered in bipolar disorder.¹⁴ Stem cell technology opens doorways to reverse engineering of human neuro­degenerative disease.¹⁵

Continue to: Autism spectrum disorders...

The exact mechanisms of action of MSCs to restore function in patients with ASDs are largely unknown, but proposed mechanisms include:

• synthesizing and releasing anti-inflammatory cytokines and survival-promoting growth factors
• integrating into the existing neural and synaptic network
• restoring plasticity.¹⁸

In a study of transplantation of human cord blood cells and umbilical cord–derived MSCs for patients with ASDs, Bradstreet et al¹⁹ found a statistically significant difference on scores for domains of speech, sociability, sensory, and overall health, as well as reductions in the total scores, in those who received transplants compared to their pretreatment values.

In another study of stem cell therapy for ASDs, Lv et al²⁰ demonstrated the safety and efficacy of combined transplantation of human cord blood cells and umbilical cord–derived MSCs in treating children with ASDs. The transplantations included 4 stem cell IV infusions and intrathecal injections once a week. Statistically significant differences were shown at 24 weeks post-treatment. Although this nonrandomized, open-label, single-center Phase I/II trial cannot be relied on for any definitive conclusions, it suggests an important area of investigation.²⁰

The vascular aspects of ASDs’ pathogenesis should not be overlooked. For example, specific temporal lobe areas associated with facial recognition, social interaction, and language comprehension have been demonstrated to be hypoperfused in children with ASDs, but not in controls. The degree of hypoperfusion and resulting hypoxia correlates with the severity of ASD symptoms. The damage causing hypoperfusion of temporal areas was associated with the onset of autism-like disorders. Damage of the amygdala, hippocampus, or other temporal structures induces permanent or transient autistic-like characteristics, such as unexpressive faces, little eye contact, and motor stereotypes. Clinically, temporal lobe damage by viral and other means has been implicated in the development of ASD in children and adults. Hypoperfusion may contribute to defects, not only by inducing hypoxia, but also by allowing for abnormal metabolite or neurotransmitter accumulation. This is one of the reasons glutamate toxicity has been implicated in ASD. The augmentation of perfusion through stimulation of angiogenesis by stem cells should allow for metabolite clearance and restoration of functionality. Vargas et al²¹ compared brain autopsy samples from 11 children with ASDs to those of 7 age-matched controls. They demonstrated an active neuroinflammatory process in the cerebral cortex, white matter, and cerebellum of patients with ASDs, both by immunohistochemistry and morphology.²¹

Multiple studies have confirmed that the systemic administration of cord blood cells is sufficient to induce neuroregeneration.^22,23 Angiogenesis has been experimentally demonstrated in peripheral artery disease, myocardial ischemia, and stroke, and has direct implications on brain repair.²⁴ Immune dysregulation^25,26 and immune modulation²⁷ also are addressed by stem cell treatment, which provides a promising avenue for battling ASDs.

Like attention-deficit/hyperactivity disorder and obsessive-compulsive disorder, ASDs are neurodevelopmental conditions. Advances based on the use of stem cells hold great promise for understanding, diagnosing and, possibly, treating these psychiatric disorders.^28,29

Depression

Neuropsychiatric disorders arise from deviations from the regular differentiation process of the CNS, leading to altered neuronal connectivity. Relatively subtle abnormalities in the size and number of cells in the prefrontal cortex and basal ganglia have been observed in patients with depressive disorder and Tourette syndrome.³⁰ Fibroblast-derived iPSCs generate serotonergic neurons through the exposure of the cells to growth factors and modulators of signaling pathways. If these serotonergic neurons are made from the patients’ own cells, they can be used to screen for new therapeutics and elucidate the unknown mechanisms through which current medications may function.³¹ This development could lead to the discovery of new medication targets and new insights into the molecular biology of depression.³²

Deficiencies of brain-derived neurotrophic factor (BDNF) have a role in depression, anxiety, and other neuropsychiatric illnesses. The acute behavioral effects of selective serotonin reuptake inhibitors and tricyclic antidepressants seem to require BDNF signaling, which suggests that BDNF holds great potential as a therapeutic agent. Cell therapies focused on correcting BDNF deficiencies in mice have had some success.³³

Dysregulation of GABAergic neurons has also been implicated in depression and anxiety. Patients with major depressive disorder have reduced gamma aminobutyric acid (GABA) receptors in the parahippocampal and lateral temporal lobes.³⁴

Ultimately, the development of differentiation protocols for serotonergic and GABAergic neuronal populations will pave the way for examining the role of these populations in the pathogenesis of depression and anxiety, and may eventually open the door for cell-based therapies in humans.³⁵

Studies have demonstrated a reduction in the density of pyramidal and nonpyramidal neurons in the anterior cingulate cortex of patients with schizophrenia and bipolar disorder,³⁶ glial reduction in the subgenual prefrontal cortex in mood disorders,³⁷ and morphometric evidence for neuronal and glial prefrontal cell pathology in major depressive disorder.³⁸ The potential for stem cells to repair such pathology may be of clinical benefit to many patients.

Aside from their other suggested clinical uses, iPSCs may be utilized in new pathways for research on the biology and pharmacology of major depressive disorder.³⁹

Continue to: Obsessive-compulsive disorder...

Obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is often characterized by excessive behaviors related to cleanliness, including grooming, which is represented across most animal species. In mice, behaviors such as compulsive grooming and hair removal—similar to behaviors in humans with OCD or trichotillomania—are associated with a specific mutation. Chen et al⁴⁰ reported that the transplantation of bone marrow stem cells into mice with this mutation (bone marrow–derived microglia specifically home to the brain) rescues their pathological phenotype by repairing native neurons.

The autoimmune, inflammatory, and neurodegenerative changes that are prevalent in OCD may be remedied by stem cell treatment in a fashion described throughout this article.

Other conditions

The Box^41-50 describes a possible role for stem cells in the treatment or prevention of several types of substance use disorders.

Box

Chronic pain is a neuropsychiatric condition that involves the immune system, inflammation, vascularization, trophic changes, and other aspects of the CNS function in addition to peripheral factors and somatic pain generators. Treatment of painful conditions with the aid of stem cells represents a large and ever-developing field that lies outside of the scope of this article.⁵¹

Experimental, but promising

It is not easy to accept revolutionary new approaches in medicine. Endless research and due diligence are needed to prove a concept and then to work out specific applications, safeguards, and limitations for any novel treatments. The stem cell terrain is poorly explored, and one needs to be careful when venturing there. Presently, the FDA appropriately sees treatment with stem cells as experimental and investigational, particularly in the mental health arena. Stem cells are not approved for treatment of any specific condition. At the same time, research and clinical practice suggest stem cell treatment may someday play a more prominent role in health care. Undoubtedly, psychiatry will eventually benefit from the knowledge and application of stem cell research and practice.

Related Resources

• De Los Angeles A, Fernando MB, Hall NAL, et al. Induced pluripotent stem cells in psychiatry: an overview and critical perspective. Biol Psychiatry. 2021;90(6):362-372.
• Heider J, Vogel S, Volkmer H, et al. Human iPSC-derived glia as a tool for neuropsychiatric research and drug development. Int J Mol Sci. 2021;22(19):10254.

Drug Brand Name

Streptozotocin • Zanosar

Bottom Line

Treatment with stem cell transplantation is experimental and not approved for any medical or psychiatric illness. However, based on our growing understanding of the function of stem cells, and preliminary research conducted mainly in animals, many neurodegenerative-, vascular-, immune-, and inflammation-based psychiatric conditions might be beneficially influenced by stem cell treatment.

The COVID-19 pandemic is a biosocial phenomenon. Patients and doctors alike find themselves assigned to groups designated as responsible and wise, or selfish and irrational, based strictly upon their personal assessments of medical risk. This trend in our culture is represented by threats of disciplinary action issued by medical regulators against physicians who are perceived to be undermining the public health message by spreading “misinformation.”

Our review of the literature reveals many references to “misinformation” but no definition narrow and precise enough to be interpreted consistently in a disciplinary environment. More pressing, this ambiguous word’s use is correlated with negative meaning and innuendo, often discrediting valuable information a priori without actual data points.

The most basic definition available is Merriam Webster’s: “incorrect or misleading information.” This definition includes no point of reference against which competing scientific claims can be measured.

Claudia E. Haupt, PhD, a political scientist and law professor, articulates a useful framework for understanding the relationship between medicine and state regulators. In the Yale Law Journal, Dr. Haupt wrote: “Knowledge communities have specialized expertise and are closest to those affected; they must have the freedom to work things out for themselves. The professions as knowledge communities have a fundamental interest in not having the state (or anyone else, for that matter) corrupt or distort what amounts to the state of the art in their respective fields.”

Injecting the artificial term “misinformation” into the science information ecosystem obfuscates and impedes the very ability of this vital knowledge community to perform its raison d’être. Use of the term misinformation with no clear scientific parameters ultimately makes it into a word that discredits, restrains, and incites, rather than attending to healing or promoting progress.

Time has certainly shown us that science is anything but settled on all things COVID. If the scientific community accepts disrespect as the response of choice to difference of opinion and practice, we lose the trust in one another as colleagues; we need to keep scientific inquiry and exploration alive. Curiosity, equanimity, and tolerance are key components of the professional attitude as we deftly maneuver against the virus together.

In the face of deadly disease, it is especially imperative that intelligent, thoughtful, highly respected scientists, researchers, and physicians have room to safely share their knowledge and clinical experience. The Association of American Physicians and Surgeons has published a statement on scientific integrity that can be used as a measuring stick for claims about misinformation in medicine. We call on physicians to pull together as a knowledge community. Kindness and respect for patients starts with kindness and respect for one another as colleagues.
 

Dr. Kohanski is in private practice in Somerset, N.J., and is a diplomate of the American Board of Psychiatry & Neurology. She disclosed no relevant financial relationships. Dr. Emmons is part-time clinical associate professor in the department of psychiatry at the University of Vermont, Burlington, and is a past chair of the Ethics Committee for the Vermont District Branch of the American Psychiatric Association. He is in private practice in Moretown, Vt., and disclosed no relevant financial relationships.

The COVID-19 pandemic is a biosocial phenomenon. Patients and doctors alike find themselves assigned to groups designated as responsible and wise, or selfish and irrational, based strictly upon their personal assessments of medical risk. This trend in our culture is represented by threats of disciplinary action issued by medical regulators against physicians who are perceived to be undermining the public health message by spreading “misinformation.”

Our review of the literature reveals many references to “misinformation” but no definition narrow and precise enough to be interpreted consistently in a disciplinary environment. More pressing, this ambiguous word’s use is correlated with negative meaning and innuendo, often discrediting valuable information a priori without actual data points.

The most basic definition available is Merriam Webster’s: “incorrect or misleading information.” This definition includes no point of reference against which competing scientific claims can be measured.

Claudia E. Haupt, PhD, a political scientist and law professor, articulates a useful framework for understanding the relationship between medicine and state regulators. In the Yale Law Journal, Dr. Haupt wrote: “Knowledge communities have specialized expertise and are closest to those affected; they must have the freedom to work things out for themselves. The professions as knowledge communities have a fundamental interest in not having the state (or anyone else, for that matter) corrupt or distort what amounts to the state of the art in their respective fields.”

Injecting the artificial term “misinformation” into the science information ecosystem obfuscates and impedes the very ability of this vital knowledge community to perform its raison d’être. Use of the term misinformation with no clear scientific parameters ultimately makes it into a word that discredits, restrains, and incites, rather than attending to healing or promoting progress.

Time has certainly shown us that science is anything but settled on all things COVID. If the scientific community accepts disrespect as the response of choice to difference of opinion and practice, we lose the trust in one another as colleagues; we need to keep scientific inquiry and exploration alive. Curiosity, equanimity, and tolerance are key components of the professional attitude as we deftly maneuver against the virus together.

In the face of deadly disease, it is especially imperative that intelligent, thoughtful, highly respected scientists, researchers, and physicians have room to safely share their knowledge and clinical experience. The Association of American Physicians and Surgeons has published a statement on scientific integrity that can be used as a measuring stick for claims about misinformation in medicine. We call on physicians to pull together as a knowledge community. Kindness and respect for patients starts with kindness and respect for one another as colleagues.
 

Dr. Kohanski is in private practice in Somerset, N.J., and is a diplomate of the American Board of Psychiatry & Neurology. She disclosed no relevant financial relationships. Dr. Emmons is part-time clinical associate professor in the department of psychiatry at the University of Vermont, Burlington, and is a past chair of the Ethics Committee for the Vermont District Branch of the American Psychiatric Association. He is in private practice in Moretown, Vt., and disclosed no relevant financial relationships.

The COVID-19 pandemic is a biosocial phenomenon. Patients and doctors alike find themselves assigned to groups designated as responsible and wise, or selfish and irrational, based strictly upon their personal assessments of medical risk. This trend in our culture is represented by threats of disciplinary action issued by medical regulators against physicians who are perceived to be undermining the public health message by spreading “misinformation.”

Our review of the literature reveals many references to “misinformation” but no definition narrow and precise enough to be interpreted consistently in a disciplinary environment. More pressing, this ambiguous word’s use is correlated with negative meaning and innuendo, often discrediting valuable information a priori without actual data points.

The most basic definition available is Merriam Webster’s: “incorrect or misleading information.” This definition includes no point of reference against which competing scientific claims can be measured.

Claudia E. Haupt, PhD, a political scientist and law professor, articulates a useful framework for understanding the relationship between medicine and state regulators. In the Yale Law Journal, Dr. Haupt wrote: “Knowledge communities have specialized expertise and are closest to those affected; they must have the freedom to work things out for themselves. The professions as knowledge communities have a fundamental interest in not having the state (or anyone else, for that matter) corrupt or distort what amounts to the state of the art in their respective fields.”

Injecting the artificial term “misinformation” into the science information ecosystem obfuscates and impedes the very ability of this vital knowledge community to perform its raison d’être. Use of the term misinformation with no clear scientific parameters ultimately makes it into a word that discredits, restrains, and incites, rather than attending to healing or promoting progress.

Time has certainly shown us that science is anything but settled on all things COVID. If the scientific community accepts disrespect as the response of choice to difference of opinion and practice, we lose the trust in one another as colleagues; we need to keep scientific inquiry and exploration alive. Curiosity, equanimity, and tolerance are key components of the professional attitude as we deftly maneuver against the virus together.

In the face of deadly disease, it is especially imperative that intelligent, thoughtful, highly respected scientists, researchers, and physicians have room to safely share their knowledge and clinical experience. The Association of American Physicians and Surgeons has published a statement on scientific integrity that can be used as a measuring stick for claims about misinformation in medicine. We call on physicians to pull together as a knowledge community. Kindness and respect for patients starts with kindness and respect for one another as colleagues.
 

Dr. Kohanski is in private practice in Somerset, N.J., and is a diplomate of the American Board of Psychiatry & Neurology. She disclosed no relevant financial relationships. Dr. Emmons is part-time clinical associate professor in the department of psychiatry at the University of Vermont, Burlington, and is a past chair of the Ethics Committee for the Vermont District Branch of the American Psychiatric Association. He is in private practice in Moretown, Vt., and disclosed no relevant financial relationships.

The field of psychiatric therapeutics is now experiencing its third generation of progress. No sooner had the pace of innovation in psychiatry and psychopharmacology hit the doldrums a few years ago, following the dwindling of the second generation of progress, than the current third generation of new drug development in psychopharmacology was born.

That is, the first generation of discovery of psychiatric medications in the 1960s and 1970s ushered in the first known psychotropic drugs, such as the tricyclic antidepressants, as well as major and minor tranquilizers, such as chlorpromazine and benzodiazepines, only to fizzle out in the 1980s. By the 1990s, the second generation of innovation in psychopharmacology was in full swing, with the “new” serotonin selective reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors for depression, and the “atypical” antipsychotics for schizophrenia. However, soon after the turn of the century, pessimism for psychiatric therapeutics crept in again, and “big Pharma” abandoned their psychopharmacology programs in favor of other therapeutic areas. Surprisingly, the current “green shoots” of new ideas sprouting in our field today have not come from traditional big Pharma returning to psychiatry, but largely from small, innovative companies. These new entrepreneurial small pharmas and biotechs have found several new therapeutic targets. Furthermore, current innovation in psychopharmacology is increasingly following a paradigm shift away from DSM-5 disorders and instead to domains or symptoms of psychopathology that cut across numerous psychiatric conditions (transdiagnostic model).

So, what are the new therapeutic mechanisms of this current third generation of innovation in psychopharmacology? Not all of these can be discussed here, but 2 examples of new approaches to psychosis deserve special mention because, for the first time in 70 years, they turn away from blocking postsynaptic dopamine D2 receptors to treat psychosis and instead stimulate receptors in other neurotransmitter systems that are linked to dopamine neurons in a network “upstream.” That is, trace amine-associated receptor 1 (TAAR1) agonists target the pre-synaptic dopamine neuron, where dopamine synthesis and release are too high in psychosis, and cause dopamine synthesis to be reduced so that blockade of postsynaptic dopamine receptors is no longer necessary (Table 1 and Figure 1).¹ Similarly, muscarinic cholinergic 1 and 4 receptor agonists target excitatory cholinergic neurons upstream, and turn down their stimulation of dopamine neurons, thereby reducing dopamine release so that postsynaptic blockade of dopamine receptors is also not necessary to treat psychosis with this mechanism (Table 1 and Figure 2).¹ A similar mechanism of reducing upstream stimulation of dopamine release by serotonin has led to demonstration of antipsychotic actions of blocking this stimulation at serotonin 2A receptors (Table 2), and multiple approaches to enhancing deficient glutamate actions upstream are also under investigation for the treatment of psychosis. ¹

Another major area of innovation in psychopharmacology worthy of emphasis is the rapid induction of neurogenesis that is associated with rapid reduction in the symptoms of depression, even when many conventional treatments have failed. Blockade of N-methyl-D-aspartate (NMDA) glutamate receptors is associated with rapid neurogenesis

that may hypothetically drive rapid recovery from depression.¹ Proof of this concept was first shown with intravenous ketamine, and then intranasal esketamine, and now the oral NMDA antagonists dextromethorphan (combined with either bupropion or quinidine) and esmethadone (Table 1).¹ Interestingly, this same mechanism may lead to a novel treatment of agitation in Alzheimer’s dementia as well.¹

Continue to: Yet another mechanism...

Yet another mechanism of potentially rapid onset antidepressant action is that of the novel agents known as neuroactive steroids that have a novel action at gamma aminobutyric acid A (GABA-A) receptors that are not sensitive to benzodiazepines (as well as those that are) (Table 1 and Figure 3).¹ Finally, psychedelic drugs that target serotonin receptors such as psilocybin and 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) seem to also have rapid onset of both neurogenesis and antidepressant action.¹ The list of innovations goes on and on, and also includes many novel potential indications for already approved agents (Table 2). Hopefully, these tables listing new therapeutic targets for psychiatric disorders as well as the discussion here provide the reader with a glimpse into the excitement and innovations afoot in this third generation of drug development in psychiatry.

The field of psychiatric therapeutics is now experiencing its third generation of progress. No sooner had the pace of innovation in psychiatry and psychopharmacology hit the doldrums a few years ago, following the dwindling of the second generation of progress, than the current third generation of new drug development in psychopharmacology was born.

That is, the first generation of discovery of psychiatric medications in the 1960s and 1970s ushered in the first known psychotropic drugs, such as the tricyclic antidepressants, as well as major and minor tranquilizers, such as chlorpromazine and benzodiazepines, only to fizzle out in the 1980s. By the 1990s, the second generation of innovation in psychopharmacology was in full swing, with the “new” serotonin selective reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors for depression, and the “atypical” antipsychotics for schizophrenia. However, soon after the turn of the century, pessimism for psychiatric therapeutics crept in again, and “big Pharma” abandoned their psychopharmacology programs in favor of other therapeutic areas. Surprisingly, the current “green shoots” of new ideas sprouting in our field today have not come from traditional big Pharma returning to psychiatry, but largely from small, innovative companies. These new entrepreneurial small pharmas and biotechs have found several new therapeutic targets. Furthermore, current innovation in psychopharmacology is increasingly following a paradigm shift away from DSM-5 disorders and instead to domains or symptoms of psychopathology that cut across numerous psychiatric conditions (transdiagnostic model).

So, what are the new therapeutic mechanisms of this current third generation of innovation in psychopharmacology? Not all of these can be discussed here, but 2 examples of new approaches to psychosis deserve special mention because, for the first time in 70 years, they turn away from blocking postsynaptic dopamine D2 receptors to treat psychosis and instead stimulate receptors in other neurotransmitter systems that are linked to dopamine neurons in a network “upstream.” That is, trace amine-associated receptor 1 (TAAR1) agonists target the pre-synaptic dopamine neuron, where dopamine synthesis and release are too high in psychosis, and cause dopamine synthesis to be reduced so that blockade of postsynaptic dopamine receptors is no longer necessary (Table 1 and Figure 1).¹ Similarly, muscarinic cholinergic 1 and 4 receptor agonists target excitatory cholinergic neurons upstream, and turn down their stimulation of dopamine neurons, thereby reducing dopamine release so that postsynaptic blockade of dopamine receptors is also not necessary to treat psychosis with this mechanism (Table 1 and Figure 2).¹ A similar mechanism of reducing upstream stimulation of dopamine release by serotonin has led to demonstration of antipsychotic actions of blocking this stimulation at serotonin 2A receptors (Table 2), and multiple approaches to enhancing deficient glutamate actions upstream are also under investigation for the treatment of psychosis. ¹

Another major area of innovation in psychopharmacology worthy of emphasis is the rapid induction of neurogenesis that is associated with rapid reduction in the symptoms of depression, even when many conventional treatments have failed. Blockade of N-methyl-D-aspartate (NMDA) glutamate receptors is associated with rapid neurogenesis

that may hypothetically drive rapid recovery from depression.¹ Proof of this concept was first shown with intravenous ketamine, and then intranasal esketamine, and now the oral NMDA antagonists dextromethorphan (combined with either bupropion or quinidine) and esmethadone (Table 1).¹ Interestingly, this same mechanism may lead to a novel treatment of agitation in Alzheimer’s dementia as well.¹

Continue to: Yet another mechanism...

Yet another mechanism of potentially rapid onset antidepressant action is that of the novel agents known as neuroactive steroids that have a novel action at gamma aminobutyric acid A (GABA-A) receptors that are not sensitive to benzodiazepines (as well as those that are) (Table 1 and Figure 3).¹ Finally, psychedelic drugs that target serotonin receptors such as psilocybin and 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) seem to also have rapid onset of both neurogenesis and antidepressant action.¹ The list of innovations goes on and on, and also includes many novel potential indications for already approved agents (Table 2). Hopefully, these tables listing new therapeutic targets for psychiatric disorders as well as the discussion here provide the reader with a glimpse into the excitement and innovations afoot in this third generation of drug development in psychiatry.

The field of psychiatric therapeutics is now experiencing its third generation of progress. No sooner had the pace of innovation in psychiatry and psychopharmacology hit the doldrums a few years ago, following the dwindling of the second generation of progress, than the current third generation of new drug development in psychopharmacology was born.

That is, the first generation of discovery of psychiatric medications in the 1960s and 1970s ushered in the first known psychotropic drugs, such as the tricyclic antidepressants, as well as major and minor tranquilizers, such as chlorpromazine and benzodiazepines, only to fizzle out in the 1980s. By the 1990s, the second generation of innovation in psychopharmacology was in full swing, with the “new” serotonin selective reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors for depression, and the “atypical” antipsychotics for schizophrenia. However, soon after the turn of the century, pessimism for psychiatric therapeutics crept in again, and “big Pharma” abandoned their psychopharmacology programs in favor of other therapeutic areas. Surprisingly, the current “green shoots” of new ideas sprouting in our field today have not come from traditional big Pharma returning to psychiatry, but largely from small, innovative companies. These new entrepreneurial small pharmas and biotechs have found several new therapeutic targets. Furthermore, current innovation in psychopharmacology is increasingly following a paradigm shift away from DSM-5 disorders and instead to domains or symptoms of psychopathology that cut across numerous psychiatric conditions (transdiagnostic model).

So, what are the new therapeutic mechanisms of this current third generation of innovation in psychopharmacology? Not all of these can be discussed here, but 2 examples of new approaches to psychosis deserve special mention because, for the first time in 70 years, they turn away from blocking postsynaptic dopamine D2 receptors to treat psychosis and instead stimulate receptors in other neurotransmitter systems that are linked to dopamine neurons in a network “upstream.” That is, trace amine-associated receptor 1 (TAAR1) agonists target the pre-synaptic dopamine neuron, where dopamine synthesis and release are too high in psychosis, and cause dopamine synthesis to be reduced so that blockade of postsynaptic dopamine receptors is no longer necessary (Table 1 and Figure 1).¹ Similarly, muscarinic cholinergic 1 and 4 receptor agonists target excitatory cholinergic neurons upstream, and turn down their stimulation of dopamine neurons, thereby reducing dopamine release so that postsynaptic blockade of dopamine receptors is also not necessary to treat psychosis with this mechanism (Table 1 and Figure 2).¹ A similar mechanism of reducing upstream stimulation of dopamine release by serotonin has led to demonstration of antipsychotic actions of blocking this stimulation at serotonin 2A receptors (Table 2), and multiple approaches to enhancing deficient glutamate actions upstream are also under investigation for the treatment of psychosis. ¹

Another major area of innovation in psychopharmacology worthy of emphasis is the rapid induction of neurogenesis that is associated with rapid reduction in the symptoms of depression, even when many conventional treatments have failed. Blockade of N-methyl-D-aspartate (NMDA) glutamate receptors is associated with rapid neurogenesis

that may hypothetically drive rapid recovery from depression.¹ Proof of this concept was first shown with intravenous ketamine, and then intranasal esketamine, and now the oral NMDA antagonists dextromethorphan (combined with either bupropion or quinidine) and esmethadone (Table 1).¹ Interestingly, this same mechanism may lead to a novel treatment of agitation in Alzheimer’s dementia as well.¹

Continue to: Yet another mechanism...

Yet another mechanism of potentially rapid onset antidepressant action is that of the novel agents known as neuroactive steroids that have a novel action at gamma aminobutyric acid A (GABA-A) receptors that are not sensitive to benzodiazepines (as well as those that are) (Table 1 and Figure 3).¹ Finally, psychedelic drugs that target serotonin receptors such as psilocybin and 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) seem to also have rapid onset of both neurogenesis and antidepressant action.¹ The list of innovations goes on and on, and also includes many novel potential indications for already approved agents (Table 2). Hopefully, these tables listing new therapeutic targets for psychiatric disorders as well as the discussion here provide the reader with a glimpse into the excitement and innovations afoot in this third generation of drug development in psychiatry.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].
 

Since the recent legalization and decriminalization of cannabis (marijuana) use throughout the United States, adolescents’ access to, and use of, cannabis has increased.¹ Cannabis products have been marketed in ways that attract adolescents, such as edible gummies, cookies, and hard candies, as well as by vaping.¹ The adolescent years are a delicate period of development during which individuals are prone to psychiatric illness, including depression, anxiety, and psychosis.^2,3 Here we discuss the relationship between adolescent cannabis use and the development of psychosis.

How cannabis can affect the adolescent brain

The 2 main psychotropic substances found within the cannabis plant are tetrahydrocannabinol (THC) and cannabidiol (CBD).^1,4 Endocannabinoids are fatty acid derivatives produced in the brain that bind to cannabinoid (CB) receptors found in the brain and the peripheral nervous system.^1,4

During adolescence, neurodevelopment and neurochemical balances are evolving, and it’s during this period that the bulk of prefrontal pruning occurs, especially in the glutamatergic and gamma aminobutyric acidergic (GABAergic) neural pathways.⁵ THC affects the CB1 receptors by downregulating the neuron receptors, which then alters the maturation of the prefrontal cortical GABAergic neurons. Also, THC affects the upregulation of the microglia located on the CB2 receptors, thereby altering synaptic pruning even further.^2,5

All of these changes can cause brain insults that can contribute to the precipitation of psychotic decompensation in adolescents who ingest products that contain THC. In addition, consuming THC might hasten the progression of disorder in adolescents who are genetically predisposed to psychotic disorders. However, existing studies must be interpreted with caution because there are other contributing risk factors for psychosis, such as social isolation, that can alter dopamine signaling as well as oligodendrocyte maturation, which can affect myelination in the prefrontal area of the evolving brain. Factors such as increased academic demand can alter the release of cortisol, which in turn affects the dopamine response as well as the structure of the hippocampus as it responds to cortisol. With all of these contributing factors, it is difficult to attribute psychosis in adolescents solely to the use of THC.⁵

How to discuss cannabis usewith adolescents

Clinicians should engage in open-ended therapeutic conversations about cannabis use with their adolescent patients, including the various types of cannabis and methods of use (ingestion vs inhalation, etc). Educate patients about the acute and long-term effects of THC use, including an increased risk of depression, schizophrenia, and substance abuse in adulthood.

For a patient who has experienced a psychotic episode, early intervention has proven to result in greater treatment response and functional improvement because it reduces brain exposure to neurotoxic effects in adolescents.³ Access to community resources such as school counselors can help to create coping strategies and enhance family support, which can optimize treatment outcomes and medication adherence, all of which will minimize the likelihood of another psychotic episode. Kelleher et al⁶ found an increased risk of suicidal behavior after a psychotic experience from any cause in adolescents and young adults, and thereby recommended that clinicians conduct continuous assessment of suicidal ideation in such patients.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].
 

Since the recent legalization and decriminalization of cannabis (marijuana) use throughout the United States, adolescents’ access to, and use of, cannabis has increased.¹ Cannabis products have been marketed in ways that attract adolescents, such as edible gummies, cookies, and hard candies, as well as by vaping.¹ The adolescent years are a delicate period of development during which individuals are prone to psychiatric illness, including depression, anxiety, and psychosis.^2,3 Here we discuss the relationship between adolescent cannabis use and the development of psychosis.

How cannabis can affect the adolescent brain

The 2 main psychotropic substances found within the cannabis plant are tetrahydrocannabinol (THC) and cannabidiol (CBD).^1,4 Endocannabinoids are fatty acid derivatives produced in the brain that bind to cannabinoid (CB) receptors found in the brain and the peripheral nervous system.^1,4

During adolescence, neurodevelopment and neurochemical balances are evolving, and it’s during this period that the bulk of prefrontal pruning occurs, especially in the glutamatergic and gamma aminobutyric acidergic (GABAergic) neural pathways.⁵ THC affects the CB1 receptors by downregulating the neuron receptors, which then alters the maturation of the prefrontal cortical GABAergic neurons. Also, THC affects the upregulation of the microglia located on the CB2 receptors, thereby altering synaptic pruning even further.^2,5

All of these changes can cause brain insults that can contribute to the precipitation of psychotic decompensation in adolescents who ingest products that contain THC. In addition, consuming THC might hasten the progression of disorder in adolescents who are genetically predisposed to psychotic disorders. However, existing studies must be interpreted with caution because there are other contributing risk factors for psychosis, such as social isolation, that can alter dopamine signaling as well as oligodendrocyte maturation, which can affect myelination in the prefrontal area of the evolving brain. Factors such as increased academic demand can alter the release of cortisol, which in turn affects the dopamine response as well as the structure of the hippocampus as it responds to cortisol. With all of these contributing factors, it is difficult to attribute psychosis in adolescents solely to the use of THC.⁵

How to discuss cannabis usewith adolescents

Clinicians should engage in open-ended therapeutic conversations about cannabis use with their adolescent patients, including the various types of cannabis and methods of use (ingestion vs inhalation, etc). Educate patients about the acute and long-term effects of THC use, including an increased risk of depression, schizophrenia, and substance abuse in adulthood.

For a patient who has experienced a psychotic episode, early intervention has proven to result in greater treatment response and functional improvement because it reduces brain exposure to neurotoxic effects in adolescents.³ Access to community resources such as school counselors can help to create coping strategies and enhance family support, which can optimize treatment outcomes and medication adherence, all of which will minimize the likelihood of another psychotic episode. Kelleher et al⁶ found an increased risk of suicidal behavior after a psychotic experience from any cause in adolescents and young adults, and thereby recommended that clinicians conduct continuous assessment of suicidal ideation in such patients.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].
 

Since the recent legalization and decriminalization of cannabis (marijuana) use throughout the United States, adolescents’ access to, and use of, cannabis has increased.¹ Cannabis products have been marketed in ways that attract adolescents, such as edible gummies, cookies, and hard candies, as well as by vaping.¹ The adolescent years are a delicate period of development during which individuals are prone to psychiatric illness, including depression, anxiety, and psychosis.^2,3 Here we discuss the relationship between adolescent cannabis use and the development of psychosis.

How cannabis can affect the adolescent brain

The 2 main psychotropic substances found within the cannabis plant are tetrahydrocannabinol (THC) and cannabidiol (CBD).^1,4 Endocannabinoids are fatty acid derivatives produced in the brain that bind to cannabinoid (CB) receptors found in the brain and the peripheral nervous system.^1,4

During adolescence, neurodevelopment and neurochemical balances are evolving, and it’s during this period that the bulk of prefrontal pruning occurs, especially in the glutamatergic and gamma aminobutyric acidergic (GABAergic) neural pathways.⁵ THC affects the CB1 receptors by downregulating the neuron receptors, which then alters the maturation of the prefrontal cortical GABAergic neurons. Also, THC affects the upregulation of the microglia located on the CB2 receptors, thereby altering synaptic pruning even further.^2,5

All of these changes can cause brain insults that can contribute to the precipitation of psychotic decompensation in adolescents who ingest products that contain THC. In addition, consuming THC might hasten the progression of disorder in adolescents who are genetically predisposed to psychotic disorders. However, existing studies must be interpreted with caution because there are other contributing risk factors for psychosis, such as social isolation, that can alter dopamine signaling as well as oligodendrocyte maturation, which can affect myelination in the prefrontal area of the evolving brain. Factors such as increased academic demand can alter the release of cortisol, which in turn affects the dopamine response as well as the structure of the hippocampus as it responds to cortisol. With all of these contributing factors, it is difficult to attribute psychosis in adolescents solely to the use of THC.⁵

How to discuss cannabis usewith adolescents

Clinicians should engage in open-ended therapeutic conversations about cannabis use with their adolescent patients, including the various types of cannabis and methods of use (ingestion vs inhalation, etc). Educate patients about the acute and long-term effects of THC use, including an increased risk of depression, schizophrenia, and substance abuse in adulthood.

For a patient who has experienced a psychotic episode, early intervention has proven to result in greater treatment response and functional improvement because it reduces brain exposure to neurotoxic effects in adolescents.³ Access to community resources such as school counselors can help to create coping strategies and enhance family support, which can optimize treatment outcomes and medication adherence, all of which will minimize the likelihood of another psychotic episode. Kelleher et al⁶ found an increased risk of suicidal behavior after a psychotic experience from any cause in adolescents and young adults, and thereby recommended that clinicians conduct continuous assessment of suicidal ideation in such patients.

From 2017 to 2018, the 30-day prevalence of “vaping” nicotine rose dramatically among 8th graders, 10th graders, 12th graders, college students, and young adults; the increase was the greatest among college students.¹ As vaping has become a common phenomenon in our society, it is prudent to have a basic understanding of what vaping is, and its potential health risks.

How it works

Vaping is the inhaling and exhaling of aerosol that is produced by a device.² Users can vape nicotine, tetrahydrocannabinol (THC), or synthetic drugs. The aerosol, often mistaken for water vapor, consists of fine particles that contain varying amounts of toxic chemicals and heavy metals that enter the lungs and bloodstream when vaping.² In general, vaping devices consist of a mouthpiece, a battery, a cartridge for containing the e-juice/e-liquid, and a heating component that turns the e-juice/e-liquid into vapor.² The e-juice/e-liquid usually contains a propylene glycol or vegetable glycerin-based liquid with nicotine, THC, or synthetic drugs.² The e-juice/e-liquid also contains flavorings, additives, and other chemicals and metals (but not tobacco).²

There are 4 types of vaping devices³:

E-cigarettes. This first generation of vaping devices was introduced to US markets in 2007. E-cigarettes look similar to cigarettes and come in disposable or rechargeable forms.³ They may emit a light when the user puffs. E-cigarettes have shorter battery lives and are less expensive than other vaping devices.

Vape pens. These second-generation vaping devices resemble fountain pens. Vape pens also come in disposable and rechargeable forms.³ They can be refilled with e-juice/e-liquid.³

Vaping mods. These third-generation vaping devices were created when users modified items such as flashlights to create a more powerful vaping experience; however, these self-modifications often are unsafe. Vaping mods are larger than vape pens and e-cigarettes and include modification options. They also have large-capacity batteries that are replaceable. Vaping mods are typically rechargeable and deliver more nicotine than earlier-generation vaping devices.

Pod systems. Pod systems, such as Juul, are the latest generation of vaping devices. These small, sleek devices resemble a USB drive.³ They can be recharged on a laptop or any USB charger.³ Pods combine the portability of e-cigarettes or vape pens with the power of a mod system. There are 2 types of pod systems: open and closed. Open pod systems consist of removable pods that are filled with the user’s choice of e-juice/e-liquid and then replaced after being refilled several times. Closed pod systems are purchased pre-filled with e-juice/e-liquid and are disposable, similar to single-use coffee pods. Juul is the most popular vape brand in the United States.⁴ For a visual guide of the different vaping devices, see https://www.cdc.gov/tobacco/basic_information/e-cigarettes/pdfs/ecigarette-or-vaping-products-visual-dictionary-508.pdf
 

What are the risks?

Vaping is relatively new, so the long-term health effects are not well studied. Although less harmful than smoking cigarettes, vaping is still not safe because users are exposed to chemicals in the aerosol, such as nicotine, heavy metals such as lead, volatile organic compounds, and cancer-causing agents.³ Vaping nicotine can result in the same cardiac and pulmonary complications as smoking cigarettes. Vaping nicotine can also be more addictive than smoking cigarettes because users can buy cartridges with higher concentrations of nicotine or increase the vaping device’s voltage to get a greater “hit” of nicotine (or whatever substance the user is vaping.) Vaping devices can also cause unintentional injuries due to fires and explosions from defective batteries.³

Vaping—particularly vaping THC—has been linked to a condition called e-cigarette, or vaping, product use-associated lung injury (EVALI).⁵ As of February 18, 2020, the CDC had received reports of approximately 2,800 patients with EVALI who were hospitalized or had died.⁵ Most EVALI cases have been linked to e-cigarette or vaping products that contained THC, particularly products obtained from informal sources such as friends, family, or in-person or online dealers.⁵ Vitamin E acetate, an additive in some THC-containing vaping products, has been strongly linked to EVALI.⁵ When ingested as a vitamin supplement or applied to the skin, vitamin E usually is harmless, but when inhaled, it may interfere with normal lung functioning.⁵ The CDC recommends that individuals who vape do not use products that contain THC; avoid getting vaping products from informal sources, such as friends, family, or online dealers; and not modify or add any substances to a vaping device other than as intended by the manufacturer.⁵

From 2017 to 2018, the 30-day prevalence of “vaping” nicotine rose dramatically among 8th graders, 10th graders, 12th graders, college students, and young adults; the increase was the greatest among college students.¹ As vaping has become a common phenomenon in our society, it is prudent to have a basic understanding of what vaping is, and its potential health risks.

How it works

Vaping is the inhaling and exhaling of aerosol that is produced by a device.² Users can vape nicotine, tetrahydrocannabinol (THC), or synthetic drugs. The aerosol, often mistaken for water vapor, consists of fine particles that contain varying amounts of toxic chemicals and heavy metals that enter the lungs and bloodstream when vaping.² In general, vaping devices consist of a mouthpiece, a battery, a cartridge for containing the e-juice/e-liquid, and a heating component that turns the e-juice/e-liquid into vapor.² The e-juice/e-liquid usually contains a propylene glycol or vegetable glycerin-based liquid with nicotine, THC, or synthetic drugs.² The e-juice/e-liquid also contains flavorings, additives, and other chemicals and metals (but not tobacco).²

There are 4 types of vaping devices³:

E-cigarettes. This first generation of vaping devices was introduced to US markets in 2007. E-cigarettes look similar to cigarettes and come in disposable or rechargeable forms.³ They may emit a light when the user puffs. E-cigarettes have shorter battery lives and are less expensive than other vaping devices.

Vape pens. These second-generation vaping devices resemble fountain pens. Vape pens also come in disposable and rechargeable forms.³ They can be refilled with e-juice/e-liquid.³

Vaping mods. These third-generation vaping devices were created when users modified items such as flashlights to create a more powerful vaping experience; however, these self-modifications often are unsafe. Vaping mods are larger than vape pens and e-cigarettes and include modification options. They also have large-capacity batteries that are replaceable. Vaping mods are typically rechargeable and deliver more nicotine than earlier-generation vaping devices.

Pod systems. Pod systems, such as Juul, are the latest generation of vaping devices. These small, sleek devices resemble a USB drive.³ They can be recharged on a laptop or any USB charger.³ Pods combine the portability of e-cigarettes or vape pens with the power of a mod system. There are 2 types of pod systems: open and closed. Open pod systems consist of removable pods that are filled with the user’s choice of e-juice/e-liquid and then replaced after being refilled several times. Closed pod systems are purchased pre-filled with e-juice/e-liquid and are disposable, similar to single-use coffee pods. Juul is the most popular vape brand in the United States.⁴ For a visual guide of the different vaping devices, see https://www.cdc.gov/tobacco/basic_information/e-cigarettes/pdfs/ecigarette-or-vaping-products-visual-dictionary-508.pdf
 

What are the risks?

Vaping is relatively new, so the long-term health effects are not well studied. Although less harmful than smoking cigarettes, vaping is still not safe because users are exposed to chemicals in the aerosol, such as nicotine, heavy metals such as lead, volatile organic compounds, and cancer-causing agents.³ Vaping nicotine can result in the same cardiac and pulmonary complications as smoking cigarettes. Vaping nicotine can also be more addictive than smoking cigarettes because users can buy cartridges with higher concentrations of nicotine or increase the vaping device’s voltage to get a greater “hit” of nicotine (or whatever substance the user is vaping.) Vaping devices can also cause unintentional injuries due to fires and explosions from defective batteries.³

Vaping—particularly vaping THC—has been linked to a condition called e-cigarette, or vaping, product use-associated lung injury (EVALI).⁵ As of February 18, 2020, the CDC had received reports of approximately 2,800 patients with EVALI who were hospitalized or had died.⁵ Most EVALI cases have been linked to e-cigarette or vaping products that contained THC, particularly products obtained from informal sources such as friends, family, or in-person or online dealers.⁵ Vitamin E acetate, an additive in some THC-containing vaping products, has been strongly linked to EVALI.⁵ When ingested as a vitamin supplement or applied to the skin, vitamin E usually is harmless, but when inhaled, it may interfere with normal lung functioning.⁵ The CDC recommends that individuals who vape do not use products that contain THC; avoid getting vaping products from informal sources, such as friends, family, or online dealers; and not modify or add any substances to a vaping device other than as intended by the manufacturer.⁵

From 2017 to 2018, the 30-day prevalence of “vaping” nicotine rose dramatically among 8th graders, 10th graders, 12th graders, college students, and young adults; the increase was the greatest among college students.¹ As vaping has become a common phenomenon in our society, it is prudent to have a basic understanding of what vaping is, and its potential health risks.

How it works

Vaping is the inhaling and exhaling of aerosol that is produced by a device.² Users can vape nicotine, tetrahydrocannabinol (THC), or synthetic drugs. The aerosol, often mistaken for water vapor, consists of fine particles that contain varying amounts of toxic chemicals and heavy metals that enter the lungs and bloodstream when vaping.² In general, vaping devices consist of a mouthpiece, a battery, a cartridge for containing the e-juice/e-liquid, and a heating component that turns the e-juice/e-liquid into vapor.² The e-juice/e-liquid usually contains a propylene glycol or vegetable glycerin-based liquid with nicotine, THC, or synthetic drugs.² The e-juice/e-liquid also contains flavorings, additives, and other chemicals and metals (but not tobacco).²

There are 4 types of vaping devices³:

E-cigarettes. This first generation of vaping devices was introduced to US markets in 2007. E-cigarettes look similar to cigarettes and come in disposable or rechargeable forms.³ They may emit a light when the user puffs. E-cigarettes have shorter battery lives and are less expensive than other vaping devices.

Vape pens. These second-generation vaping devices resemble fountain pens. Vape pens also come in disposable and rechargeable forms.³ They can be refilled with e-juice/e-liquid.³

Vaping mods. These third-generation vaping devices were created when users modified items such as flashlights to create a more powerful vaping experience; however, these self-modifications often are unsafe. Vaping mods are larger than vape pens and e-cigarettes and include modification options. They also have large-capacity batteries that are replaceable. Vaping mods are typically rechargeable and deliver more nicotine than earlier-generation vaping devices.

Pod systems. Pod systems, such as Juul, are the latest generation of vaping devices. These small, sleek devices resemble a USB drive.³ They can be recharged on a laptop or any USB charger.³ Pods combine the portability of e-cigarettes or vape pens with the power of a mod system. There are 2 types of pod systems: open and closed. Open pod systems consist of removable pods that are filled with the user’s choice of e-juice/e-liquid and then replaced after being refilled several times. Closed pod systems are purchased pre-filled with e-juice/e-liquid and are disposable, similar to single-use coffee pods. Juul is the most popular vape brand in the United States.⁴ For a visual guide of the different vaping devices, see https://www.cdc.gov/tobacco/basic_information/e-cigarettes/pdfs/ecigarette-or-vaping-products-visual-dictionary-508.pdf
 

What are the risks?

Vaping is relatively new, so the long-term health effects are not well studied. Although less harmful than smoking cigarettes, vaping is still not safe because users are exposed to chemicals in the aerosol, such as nicotine, heavy metals such as lead, volatile organic compounds, and cancer-causing agents.³ Vaping nicotine can result in the same cardiac and pulmonary complications as smoking cigarettes. Vaping nicotine can also be more addictive than smoking cigarettes because users can buy cartridges with higher concentrations of nicotine or increase the vaping device’s voltage to get a greater “hit” of nicotine (or whatever substance the user is vaping.) Vaping devices can also cause unintentional injuries due to fires and explosions from defective batteries.³

Vaping—particularly vaping THC—has been linked to a condition called e-cigarette, or vaping, product use-associated lung injury (EVALI).⁵ As of February 18, 2020, the CDC had received reports of approximately 2,800 patients with EVALI who were hospitalized or had died.⁵ Most EVALI cases have been linked to e-cigarette or vaping products that contained THC, particularly products obtained from informal sources such as friends, family, or in-person or online dealers.⁵ Vitamin E acetate, an additive in some THC-containing vaping products, has been strongly linked to EVALI.⁵ When ingested as a vitamin supplement or applied to the skin, vitamin E usually is harmless, but when inhaled, it may interfere with normal lung functioning.⁵ The CDC recommends that individuals who vape do not use products that contain THC; avoid getting vaping products from informal sources, such as friends, family, or online dealers; and not modify or add any substances to a vaping device other than as intended by the manufacturer.⁵

‘Grainy’ or ‘pixelated’ vision can be an alarming symptom for patients. The phenomenon is called visual snow, and although it was first described only recently, it is fairly common.

“This is a symptom of vision where patients describe numerous flickering dots throughout their vision. Sometimes they’ll use the term grainy or pixelated vision. Many times there’s a dynamic moving component to this. Many patients will describe this as like a TV static overlay on their vision,” Carrie Robertson, MD, said during a presentation on the topic at the 2021 Scottsdale Headache Symposium. Dr. Robertson is a neurologist at the Mayo Clinic in Rochester, Minn.

“It turns out that a little over 3% of us probably see this in our vision. So even if you haven’t seen this in the clinic yet, it’s likely that you will in the future,” said Dr. Robertson.

The first report describing visual snow appeared in 1995, among migraine patients. As of 2014 there were only 10 cases described in the literature. Although the condition was initially thought of as an unusual feature of migraine, a 2014 combined chart review and survey found that 15 of 22 patients had additional visual symptoms, such as photophobia or difficulty with night vision. Twenty of the 22 patients had comorbid migraine. Other symptoms include visual ghosts that persist after looking away from an object, as well as a higher frequency of experiencing floaters.

Symptoms aren’t restricted to the visual domain. Migraine, tinnitus, dizziness, and impaired concentration also occur.

The condition is more common than many suspect. “We used to think it was very rare. Now we assume that this was just under recognized,” said Dr. Robertson. One survey in the United Kingdom found that 3.7% of respondents reported visual snow, and 2.2% met the criteria for the syndrome.
 

A common and typically benign problem

It is a common clinical problem, according to Andrew Charles, MD, professor of neurology at the University of California, Los Angeles, and director of the UCLA Goldberg Migraine Program. “Almost every week I personally see somebody and then in our group, we have a whole host of them,” he said.

“When you see these patients in clinic, it’s important to remember that this is a heterogeneous disorder,” said Dr. Robertson. “Some patients will say, ‘Oh yeah, I’ve seen visual snow for as long as I can remember, I didn’t even know it was abnormal.’ Some will describe a family history of visual snow. Others will show up in clinic panicked because their visual snow just started or sometimes it’ll start after a triggering events like a head injury or hallucinogen use, and they’re worried that they’re going to go blind.”

It’s important to rule out other potential causes. Dr. Robertson’s group examined 248 cases of visual snow and found that 89 had a comorbidity that explained the condition. Issues within the retina, cornea, and the optical nerve can cause visual snow, which makes it critical that patients be seen by an ophthalmologist.

Some patients reported improvement when they stopped a new medication. “I always ask if there was a specific medicine that they started at the onset of their symptoms,” said Dr. Robertson. Other rare conditions associated with visual snow include idiopathic intracranial hypertension, posterior cortical atrophy, and even the Heidenhain variant of Creutzfeldt-Jakob disease.

In the absence of a secondary cause, and the if condition doesn’t worsen, physicians should reassure patients that the condition is typically benign. “Many of these patients are panicked that they’re going to lose their vision, and that’s what brings them to your office. It’s important to stress that visual snow is real, that you believe them, that they’re seeing what they say that they’re seeing. It’s not a migraine aura, but it’s typically benign. I like to give the analogy that it’s similar to tinnitus because I think that that’s helpful for patients to put it in that category of benign but very annoying,” said Dr. Robertson.
 

Limited treatment options

Unfortunately, there is little evidence on medications to treat the problem. According to Dr. Robertson, the best available evidence – from case reports – is for lamotrigine. Nearly 20% of patients achieve a partial response, and complete responses are rare.

Clinical trials are a possibility, but patients should be made aware that medications have the potential to worsen visual snow.

Nonpharmaceutical approaches include visual and mental distraction, along with manipulation of lighting at work and at home. Stress reduction may help, and Dr. Robertson may send patients with dizziness for visual vestibular therapy to work on visual motion desensitization exercises.

There are visual snow relief videos available on YouTube, which may provide temporary relief. “It’s probably similar to white noise therapy for tinnitus,” said Dr. Robertson.

Colored glass lenses may be helpful. “I’m having the best success at this point with FL-41 lenses. Some prefer amber, and others prefer the rose-tinted, just like migraine. I usually start with that,” said Dr. Robertson. Yellow lenses may help with nyctalopia.

She recommends that patients avoid consuming too much caffeine, and that they avoid stimulants, especially attention-deficit disorder (ADD) medications. “I’ve had a lot of patients worsen with ADD medication,” said Dr. Robertson. She also warns patients away from marijuana and hallucinogens.

There is a large community available for patients with visual snow, including more than 60 Facebook groups, and many YouTube videos of patients describing their experiences. There is even a visual snow simulator that neurologists can show patients to confirm what they are seeing. “It’s very validating for the patient,” said Dr. Robertson.

Dr. Charles noted the relatively few treatment options and poor understanding of the mechanisms behind the condition. “It’s incredibly frustrating that we have to tell them that we have so little understanding of basic mechanisms, and no really clear therapeutic strategy that we can apply across all patients and expect results,” said Dr. Charles.

The heightened interest in the condition does represent some hope. “It’s very much reassuring to people that, number one, we’re starting to understand it – but number two, that they’re not crazy. It’s very much validating to hear that it’s now a topic of much more rigorous investigation,” said Dr. Charles.

Dr. Robertson and Dr. Charles have no relevant financial disclosures.

‘Grainy’ or ‘pixelated’ vision can be an alarming symptom for patients. The phenomenon is called visual snow, and although it was first described only recently, it is fairly common.

“This is a symptom of vision where patients describe numerous flickering dots throughout their vision. Sometimes they’ll use the term grainy or pixelated vision. Many times there’s a dynamic moving component to this. Many patients will describe this as like a TV static overlay on their vision,” Carrie Robertson, MD, said during a presentation on the topic at the 2021 Scottsdale Headache Symposium. Dr. Robertson is a neurologist at the Mayo Clinic in Rochester, Minn.

“It turns out that a little over 3% of us probably see this in our vision. So even if you haven’t seen this in the clinic yet, it’s likely that you will in the future,” said Dr. Robertson.

The first report describing visual snow appeared in 1995, among migraine patients. As of 2014 there were only 10 cases described in the literature. Although the condition was initially thought of as an unusual feature of migraine, a 2014 combined chart review and survey found that 15 of 22 patients had additional visual symptoms, such as photophobia or difficulty with night vision. Twenty of the 22 patients had comorbid migraine. Other symptoms include visual ghosts that persist after looking away from an object, as well as a higher frequency of experiencing floaters.

Symptoms aren’t restricted to the visual domain. Migraine, tinnitus, dizziness, and impaired concentration also occur.

The condition is more common than many suspect. “We used to think it was very rare. Now we assume that this was just under recognized,” said Dr. Robertson. One survey in the United Kingdom found that 3.7% of respondents reported visual snow, and 2.2% met the criteria for the syndrome.
 

A common and typically benign problem

It is a common clinical problem, according to Andrew Charles, MD, professor of neurology at the University of California, Los Angeles, and director of the UCLA Goldberg Migraine Program. “Almost every week I personally see somebody and then in our group, we have a whole host of them,” he said.

“When you see these patients in clinic, it’s important to remember that this is a heterogeneous disorder,” said Dr. Robertson. “Some patients will say, ‘Oh yeah, I’ve seen visual snow for as long as I can remember, I didn’t even know it was abnormal.’ Some will describe a family history of visual snow. Others will show up in clinic panicked because their visual snow just started or sometimes it’ll start after a triggering events like a head injury or hallucinogen use, and they’re worried that they’re going to go blind.”

It’s important to rule out other potential causes. Dr. Robertson’s group examined 248 cases of visual snow and found that 89 had a comorbidity that explained the condition. Issues within the retina, cornea, and the optical nerve can cause visual snow, which makes it critical that patients be seen by an ophthalmologist.

Some patients reported improvement when they stopped a new medication. “I always ask if there was a specific medicine that they started at the onset of their symptoms,” said Dr. Robertson. Other rare conditions associated with visual snow include idiopathic intracranial hypertension, posterior cortical atrophy, and even the Heidenhain variant of Creutzfeldt-Jakob disease.

In the absence of a secondary cause, and the if condition doesn’t worsen, physicians should reassure patients that the condition is typically benign. “Many of these patients are panicked that they’re going to lose their vision, and that’s what brings them to your office. It’s important to stress that visual snow is real, that you believe them, that they’re seeing what they say that they’re seeing. It’s not a migraine aura, but it’s typically benign. I like to give the analogy that it’s similar to tinnitus because I think that that’s helpful for patients to put it in that category of benign but very annoying,” said Dr. Robertson.
 

Limited treatment options

Unfortunately, there is little evidence on medications to treat the problem. According to Dr. Robertson, the best available evidence – from case reports – is for lamotrigine. Nearly 20% of patients achieve a partial response, and complete responses are rare.

Clinical trials are a possibility, but patients should be made aware that medications have the potential to worsen visual snow.

Nonpharmaceutical approaches include visual and mental distraction, along with manipulation of lighting at work and at home. Stress reduction may help, and Dr. Robertson may send patients with dizziness for visual vestibular therapy to work on visual motion desensitization exercises.

There are visual snow relief videos available on YouTube, which may provide temporary relief. “It’s probably similar to white noise therapy for tinnitus,” said Dr. Robertson.

Colored glass lenses may be helpful. “I’m having the best success at this point with FL-41 lenses. Some prefer amber, and others prefer the rose-tinted, just like migraine. I usually start with that,” said Dr. Robertson. Yellow lenses may help with nyctalopia.

She recommends that patients avoid consuming too much caffeine, and that they avoid stimulants, especially attention-deficit disorder (ADD) medications. “I’ve had a lot of patients worsen with ADD medication,” said Dr. Robertson. She also warns patients away from marijuana and hallucinogens.

There is a large community available for patients with visual snow, including more than 60 Facebook groups, and many YouTube videos of patients describing their experiences. There is even a visual snow simulator that neurologists can show patients to confirm what they are seeing. “It’s very validating for the patient,” said Dr. Robertson.

Dr. Charles noted the relatively few treatment options and poor understanding of the mechanisms behind the condition. “It’s incredibly frustrating that we have to tell them that we have so little understanding of basic mechanisms, and no really clear therapeutic strategy that we can apply across all patients and expect results,” said Dr. Charles.

The heightened interest in the condition does represent some hope. “It’s very much reassuring to people that, number one, we’re starting to understand it – but number two, that they’re not crazy. It’s very much validating to hear that it’s now a topic of much more rigorous investigation,” said Dr. Charles.

Dr. Robertson and Dr. Charles have no relevant financial disclosures.

‘Grainy’ or ‘pixelated’ vision can be an alarming symptom for patients. The phenomenon is called visual snow, and although it was first described only recently, it is fairly common.

“This is a symptom of vision where patients describe numerous flickering dots throughout their vision. Sometimes they’ll use the term grainy or pixelated vision. Many times there’s a dynamic moving component to this. Many patients will describe this as like a TV static overlay on their vision,” Carrie Robertson, MD, said during a presentation on the topic at the 2021 Scottsdale Headache Symposium. Dr. Robertson is a neurologist at the Mayo Clinic in Rochester, Minn.

“It turns out that a little over 3% of us probably see this in our vision. So even if you haven’t seen this in the clinic yet, it’s likely that you will in the future,” said Dr. Robertson.

The first report describing visual snow appeared in 1995, among migraine patients. As of 2014 there were only 10 cases described in the literature. Although the condition was initially thought of as an unusual feature of migraine, a 2014 combined chart review and survey found that 15 of 22 patients had additional visual symptoms, such as photophobia or difficulty with night vision. Twenty of the 22 patients had comorbid migraine. Other symptoms include visual ghosts that persist after looking away from an object, as well as a higher frequency of experiencing floaters.

Symptoms aren’t restricted to the visual domain. Migraine, tinnitus, dizziness, and impaired concentration also occur.

The condition is more common than many suspect. “We used to think it was very rare. Now we assume that this was just under recognized,” said Dr. Robertson. One survey in the United Kingdom found that 3.7% of respondents reported visual snow, and 2.2% met the criteria for the syndrome.
 

A common and typically benign problem

It is a common clinical problem, according to Andrew Charles, MD, professor of neurology at the University of California, Los Angeles, and director of the UCLA Goldberg Migraine Program. “Almost every week I personally see somebody and then in our group, we have a whole host of them,” he said.

“When you see these patients in clinic, it’s important to remember that this is a heterogeneous disorder,” said Dr. Robertson. “Some patients will say, ‘Oh yeah, I’ve seen visual snow for as long as I can remember, I didn’t even know it was abnormal.’ Some will describe a family history of visual snow. Others will show up in clinic panicked because their visual snow just started or sometimes it’ll start after a triggering events like a head injury or hallucinogen use, and they’re worried that they’re going to go blind.”

It’s important to rule out other potential causes. Dr. Robertson’s group examined 248 cases of visual snow and found that 89 had a comorbidity that explained the condition. Issues within the retina, cornea, and the optical nerve can cause visual snow, which makes it critical that patients be seen by an ophthalmologist.

Some patients reported improvement when they stopped a new medication. “I always ask if there was a specific medicine that they started at the onset of their symptoms,” said Dr. Robertson. Other rare conditions associated with visual snow include idiopathic intracranial hypertension, posterior cortical atrophy, and even the Heidenhain variant of Creutzfeldt-Jakob disease.

In the absence of a secondary cause, and the if condition doesn’t worsen, physicians should reassure patients that the condition is typically benign. “Many of these patients are panicked that they’re going to lose their vision, and that’s what brings them to your office. It’s important to stress that visual snow is real, that you believe them, that they’re seeing what they say that they’re seeing. It’s not a migraine aura, but it’s typically benign. I like to give the analogy that it’s similar to tinnitus because I think that that’s helpful for patients to put it in that category of benign but very annoying,” said Dr. Robertson.
 

Limited treatment options

Unfortunately, there is little evidence on medications to treat the problem. According to Dr. Robertson, the best available evidence – from case reports – is for lamotrigine. Nearly 20% of patients achieve a partial response, and complete responses are rare.

Clinical trials are a possibility, but patients should be made aware that medications have the potential to worsen visual snow.

Nonpharmaceutical approaches include visual and mental distraction, along with manipulation of lighting at work and at home. Stress reduction may help, and Dr. Robertson may send patients with dizziness for visual vestibular therapy to work on visual motion desensitization exercises.

There are visual snow relief videos available on YouTube, which may provide temporary relief. “It’s probably similar to white noise therapy for tinnitus,” said Dr. Robertson.

Colored glass lenses may be helpful. “I’m having the best success at this point with FL-41 lenses. Some prefer amber, and others prefer the rose-tinted, just like migraine. I usually start with that,” said Dr. Robertson. Yellow lenses may help with nyctalopia.

She recommends that patients avoid consuming too much caffeine, and that they avoid stimulants, especially attention-deficit disorder (ADD) medications. “I’ve had a lot of patients worsen with ADD medication,” said Dr. Robertson. She also warns patients away from marijuana and hallucinogens.

There is a large community available for patients with visual snow, including more than 60 Facebook groups, and many YouTube videos of patients describing their experiences. There is even a visual snow simulator that neurologists can show patients to confirm what they are seeing. “It’s very validating for the patient,” said Dr. Robertson.

Dr. Charles noted the relatively few treatment options and poor understanding of the mechanisms behind the condition. “It’s incredibly frustrating that we have to tell them that we have so little understanding of basic mechanisms, and no really clear therapeutic strategy that we can apply across all patients and expect results,” said Dr. Charles.

The heightened interest in the condition does represent some hope. “It’s very much reassuring to people that, number one, we’re starting to understand it – but number two, that they’re not crazy. It’s very much validating to hear that it’s now a topic of much more rigorous investigation,” said Dr. Charles.

Dr. Robertson and Dr. Charles have no relevant financial disclosures.

Cognitive-behavioral therapy (CBT) is linked to a significantly reduced risk of depression in patients with insomnia, new research shows.

Insomnia affects over 50% of older adults, and insomnia contributes to a twofold greater risk for major depression, investigators noted.

“We show that by treating insomnia with a simple behavioral approach called Cognitive Behavioral Therapy for Insomnia, or CBT-I, you can reduce the likelihood of developing depression by over 50%,” lead author Michael R. Irwin, MD, Cousins Distinguished Professor of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, said in an interview.

The study is unique in that the treatment “is not just reducing depression, it’s preventing depression,” Dr. Irwin added.

The findings were published online Nov. 24 in JAMA Psychiatry.
 

Primary outcome met

The study included 291 patients aged 60 years and older (mean age, 70 years; 58% women) with confirmed insomnia disorder and no major depression within the previous 12 months.

All were randomly assigned to receive either CBT-I or Sleep Education Therapy (SET).

CBT-I is a first-line treatment for insomnia that includes five components: cognitive therapy targeting dysfunctional thoughts about sleep, stimulus control, sleep restriction, sleep hygiene, and relaxation.

SET provides information on behavioral and environmental factors contributing to poor sleep. While sleep education provides tips on improving sleep, CBT-I helps patients implement those changes and behaviors, Dr. Irwin noted.

Both interventions were delivered by trained personnel in weekly 120-minute group sessions for 2 months, consistent with the format and duration of most CBT-I trials.

The primary outcome was time to incident or recurrent major depressive disorder as diagnosed by the Structured Clinical Interview of the DSM-5 every 6 months during 36 months of follow-up. A monthly Patient Health Questionnaire 9 (PHQ-9) was used to screen for depressive symptoms.

Results showed depression occurred in 12.2% of the CBT-I group versus 25.9% of the SET group. The hazard ratio (HR) for depression in the CBT-I group compared with the SET group was 0.51 (95% confidence interval, 0.29-0.88; P = .02). The number needed to treat to prevent incident or recurrent depression was 7.3.

After adjustment for factors affecting depression risk such as sex, educational level, income, comorbidity, and history of depression, the HR for depression in the CBT-I group versus the SET group was 0.45 (95% CI, 0.23-0.86; P = .02).

Treatment with CBT-I yielded an annual 4.1% incidence of depression, which is similar to the population rate and half the rate in SET, which was 8.6%.
 

‘Remission is key’

The secondary outcome was sustained remission of insomnia disorder. The investigators found a greater proportion of the CBT-I group than the SET group achieved remission after treatment (50.7% vs. 37.7%; 95% CI, 0.10-0.93; P = .02).

“Remission is really key to the benefits that we’re seeing,” said Dr. Irwin.

Inflammation may explain why insomnia raises the risk for depression, he noted. “We know sleep disturbance can lead to inflammation and we also know inflammation can produce depression,” Dr. Irwin said.

It is also possible insomnia leads to an impaired pleasure or reward system, which is linked to depression, he added.

The authors noted that because insomnia is associated with suicidal ideation and dementia, CBT-I may reduce risk for suicide or cognitive decline.

While 8-week CBT-I treatments are readily available, “unfortunately, most clinicians will prescribe medications,” said Dr. Irwin. He noted that in older adults, drugs are linked to adverse events such as falls and cognitive problems.

These new results “really argue that psychology and psychiatry need to be fully integrated into what we call collaborative care models,” Dr. Irwin said.

There were no adverse events during treatment, and none of the serious events that occurred during follow-up were attributed to the trial.
 

Convincing argument?

Commenting on the findings for this news organization, Philip R. Muskin, MD, professor of psychiatry at Columbia University Irving Medical Center, New York, said the study was “nicely written” and the authors put forward “a very convincing argument” for CBT-I to prevent depression.

“It’s eye opening in that it’s a robust study; it’s carefully done; subjects were followed for a long period of time, and it’s an accessible treatment,” said Dr. Muskin, who was not involved with the research.

The study also shows “it’s possible to intervene in something we know is a risk factor in elderly people,” he added. “We think of older people as being less malleable to these kinds of things, but they’re not. They clearly participated, and there wasn’t a huge dropout rate.”

Dr. Muskin noted that less than half of the older participants were married or had a partner. He would have liked more information on this status because being widowed or divorced, as well as when this life change occurred, could affect vulnerability to depression.

The authors of an accompanying editorial called the study “seminal,” and noted that insomnia treatment possibly preventing depressive disorders is a “major finding.”

Proving this preventive strategy is effective in older adults will be important because “insomnia and depression are highly prevalent in this population and the uptake of both preventive and treatment services is low,” wrote Pim Cuijpers, PhD, department of clinical, neuro, and developmental psychology, Amsterdam Public Health Research Institute, and Charles F. Reynolds III, MD, department of psychiatry, University of Pittsburgh.

If the reduced rates of depression observed in the study could be generalized to the total population with insomnia, “the incidence of major depression could be reduced considerably,” they wrote.

“Can we prevent depression through interventions aimed at procrastination in college students, interventions aimed at perfectionism in perinatal women, stress management training for employees, social skills training in adolescents?” they asked.

This approach to preventing depressive disorders “offers all kinds of new opportunities to develop and test indirect interventions” for problems that are significantly associated with the onset of depression, the editorialists wrote.

The study was funded by a grant from the National Institute on Aging to the University of California, which partially supported the authors’ salaries. Dr. Irwin, Dr. Muskin, and Dr. Cuijpers have reported no relevant financial relationships. Dr. Reynolds reported being coinventor of the Pittsburgh Sleep Quality Index, for which he receives royalties.

A version of this article first appeared on Medscape.com.

Cognitive-behavioral therapy (CBT) is linked to a significantly reduced risk of depression in patients with insomnia, new research shows.

Insomnia affects over 50% of older adults, and insomnia contributes to a twofold greater risk for major depression, investigators noted.

“We show that by treating insomnia with a simple behavioral approach called Cognitive Behavioral Therapy for Insomnia, or CBT-I, you can reduce the likelihood of developing depression by over 50%,” lead author Michael R. Irwin, MD, Cousins Distinguished Professor of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, said in an interview.

The study is unique in that the treatment “is not just reducing depression, it’s preventing depression,” Dr. Irwin added.

The findings were published online Nov. 24 in JAMA Psychiatry.
 

Primary outcome met

The study included 291 patients aged 60 years and older (mean age, 70 years; 58% women) with confirmed insomnia disorder and no major depression within the previous 12 months.

All were randomly assigned to receive either CBT-I or Sleep Education Therapy (SET).

CBT-I is a first-line treatment for insomnia that includes five components: cognitive therapy targeting dysfunctional thoughts about sleep, stimulus control, sleep restriction, sleep hygiene, and relaxation.

SET provides information on behavioral and environmental factors contributing to poor sleep. While sleep education provides tips on improving sleep, CBT-I helps patients implement those changes and behaviors, Dr. Irwin noted.

Both interventions were delivered by trained personnel in weekly 120-minute group sessions for 2 months, consistent with the format and duration of most CBT-I trials.

The primary outcome was time to incident or recurrent major depressive disorder as diagnosed by the Structured Clinical Interview of the DSM-5 every 6 months during 36 months of follow-up. A monthly Patient Health Questionnaire 9 (PHQ-9) was used to screen for depressive symptoms.

Results showed depression occurred in 12.2% of the CBT-I group versus 25.9% of the SET group. The hazard ratio (HR) for depression in the CBT-I group compared with the SET group was 0.51 (95% confidence interval, 0.29-0.88; P = .02). The number needed to treat to prevent incident or recurrent depression was 7.3.

After adjustment for factors affecting depression risk such as sex, educational level, income, comorbidity, and history of depression, the HR for depression in the CBT-I group versus the SET group was 0.45 (95% CI, 0.23-0.86; P = .02).

Treatment with CBT-I yielded an annual 4.1% incidence of depression, which is similar to the population rate and half the rate in SET, which was 8.6%.
 

‘Remission is key’

The secondary outcome was sustained remission of insomnia disorder. The investigators found a greater proportion of the CBT-I group than the SET group achieved remission after treatment (50.7% vs. 37.7%; 95% CI, 0.10-0.93; P = .02).

“Remission is really key to the benefits that we’re seeing,” said Dr. Irwin.

Inflammation may explain why insomnia raises the risk for depression, he noted. “We know sleep disturbance can lead to inflammation and we also know inflammation can produce depression,” Dr. Irwin said.

It is also possible insomnia leads to an impaired pleasure or reward system, which is linked to depression, he added.

The authors noted that because insomnia is associated with suicidal ideation and dementia, CBT-I may reduce risk for suicide or cognitive decline.

While 8-week CBT-I treatments are readily available, “unfortunately, most clinicians will prescribe medications,” said Dr. Irwin. He noted that in older adults, drugs are linked to adverse events such as falls and cognitive problems.

These new results “really argue that psychology and psychiatry need to be fully integrated into what we call collaborative care models,” Dr. Irwin said.

There were no adverse events during treatment, and none of the serious events that occurred during follow-up were attributed to the trial.
 

Convincing argument?

Commenting on the findings for this news organization, Philip R. Muskin, MD, professor of psychiatry at Columbia University Irving Medical Center, New York, said the study was “nicely written” and the authors put forward “a very convincing argument” for CBT-I to prevent depression.

“It’s eye opening in that it’s a robust study; it’s carefully done; subjects were followed for a long period of time, and it’s an accessible treatment,” said Dr. Muskin, who was not involved with the research.

The study also shows “it’s possible to intervene in something we know is a risk factor in elderly people,” he added. “We think of older people as being less malleable to these kinds of things, but they’re not. They clearly participated, and there wasn’t a huge dropout rate.”

Dr. Muskin noted that less than half of the older participants were married or had a partner. He would have liked more information on this status because being widowed or divorced, as well as when this life change occurred, could affect vulnerability to depression.

The authors of an accompanying editorial called the study “seminal,” and noted that insomnia treatment possibly preventing depressive disorders is a “major finding.”

Proving this preventive strategy is effective in older adults will be important because “insomnia and depression are highly prevalent in this population and the uptake of both preventive and treatment services is low,” wrote Pim Cuijpers, PhD, department of clinical, neuro, and developmental psychology, Amsterdam Public Health Research Institute, and Charles F. Reynolds III, MD, department of psychiatry, University of Pittsburgh.

If the reduced rates of depression observed in the study could be generalized to the total population with insomnia, “the incidence of major depression could be reduced considerably,” they wrote.

“Can we prevent depression through interventions aimed at procrastination in college students, interventions aimed at perfectionism in perinatal women, stress management training for employees, social skills training in adolescents?” they asked.

This approach to preventing depressive disorders “offers all kinds of new opportunities to develop and test indirect interventions” for problems that are significantly associated with the onset of depression, the editorialists wrote.

The study was funded by a grant from the National Institute on Aging to the University of California, which partially supported the authors’ salaries. Dr. Irwin, Dr. Muskin, and Dr. Cuijpers have reported no relevant financial relationships. Dr. Reynolds reported being coinventor of the Pittsburgh Sleep Quality Index, for which he receives royalties.

A version of this article first appeared on Medscape.com.

Cognitive-behavioral therapy (CBT) is linked to a significantly reduced risk of depression in patients with insomnia, new research shows.

Insomnia affects over 50% of older adults, and insomnia contributes to a twofold greater risk for major depression, investigators noted.

“We show that by treating insomnia with a simple behavioral approach called Cognitive Behavioral Therapy for Insomnia, or CBT-I, you can reduce the likelihood of developing depression by over 50%,” lead author Michael R. Irwin, MD, Cousins Distinguished Professor of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, said in an interview.

The study is unique in that the treatment “is not just reducing depression, it’s preventing depression,” Dr. Irwin added.

The findings were published online Nov. 24 in JAMA Psychiatry.
 

Primary outcome met

The study included 291 patients aged 60 years and older (mean age, 70 years; 58% women) with confirmed insomnia disorder and no major depression within the previous 12 months.

All were randomly assigned to receive either CBT-I or Sleep Education Therapy (SET).

CBT-I is a first-line treatment for insomnia that includes five components: cognitive therapy targeting dysfunctional thoughts about sleep, stimulus control, sleep restriction, sleep hygiene, and relaxation.

SET provides information on behavioral and environmental factors contributing to poor sleep. While sleep education provides tips on improving sleep, CBT-I helps patients implement those changes and behaviors, Dr. Irwin noted.

Both interventions were delivered by trained personnel in weekly 120-minute group sessions for 2 months, consistent with the format and duration of most CBT-I trials.

The primary outcome was time to incident or recurrent major depressive disorder as diagnosed by the Structured Clinical Interview of the DSM-5 every 6 months during 36 months of follow-up. A monthly Patient Health Questionnaire 9 (PHQ-9) was used to screen for depressive symptoms.

Results showed depression occurred in 12.2% of the CBT-I group versus 25.9% of the SET group. The hazard ratio (HR) for depression in the CBT-I group compared with the SET group was 0.51 (95% confidence interval, 0.29-0.88; P = .02). The number needed to treat to prevent incident or recurrent depression was 7.3.

After adjustment for factors affecting depression risk such as sex, educational level, income, comorbidity, and history of depression, the HR for depression in the CBT-I group versus the SET group was 0.45 (95% CI, 0.23-0.86; P = .02).

Treatment with CBT-I yielded an annual 4.1% incidence of depression, which is similar to the population rate and half the rate in SET, which was 8.6%.
 

‘Remission is key’

The secondary outcome was sustained remission of insomnia disorder. The investigators found a greater proportion of the CBT-I group than the SET group achieved remission after treatment (50.7% vs. 37.7%; 95% CI, 0.10-0.93; P = .02).

“Remission is really key to the benefits that we’re seeing,” said Dr. Irwin.

Inflammation may explain why insomnia raises the risk for depression, he noted. “We know sleep disturbance can lead to inflammation and we also know inflammation can produce depression,” Dr. Irwin said.

It is also possible insomnia leads to an impaired pleasure or reward system, which is linked to depression, he added.

The authors noted that because insomnia is associated with suicidal ideation and dementia, CBT-I may reduce risk for suicide or cognitive decline.

While 8-week CBT-I treatments are readily available, “unfortunately, most clinicians will prescribe medications,” said Dr. Irwin. He noted that in older adults, drugs are linked to adverse events such as falls and cognitive problems.

These new results “really argue that psychology and psychiatry need to be fully integrated into what we call collaborative care models,” Dr. Irwin said.

There were no adverse events during treatment, and none of the serious events that occurred during follow-up were attributed to the trial.
 

Convincing argument?

Commenting on the findings for this news organization, Philip R. Muskin, MD, professor of psychiatry at Columbia University Irving Medical Center, New York, said the study was “nicely written” and the authors put forward “a very convincing argument” for CBT-I to prevent depression.

“It’s eye opening in that it’s a robust study; it’s carefully done; subjects were followed for a long period of time, and it’s an accessible treatment,” said Dr. Muskin, who was not involved with the research.

The study also shows “it’s possible to intervene in something we know is a risk factor in elderly people,” he added. “We think of older people as being less malleable to these kinds of things, but they’re not. They clearly participated, and there wasn’t a huge dropout rate.”

Dr. Muskin noted that less than half of the older participants were married or had a partner. He would have liked more information on this status because being widowed or divorced, as well as when this life change occurred, could affect vulnerability to depression.

The authors of an accompanying editorial called the study “seminal,” and noted that insomnia treatment possibly preventing depressive disorders is a “major finding.”

Proving this preventive strategy is effective in older adults will be important because “insomnia and depression are highly prevalent in this population and the uptake of both preventive and treatment services is low,” wrote Pim Cuijpers, PhD, department of clinical, neuro, and developmental psychology, Amsterdam Public Health Research Institute, and Charles F. Reynolds III, MD, department of psychiatry, University of Pittsburgh.

If the reduced rates of depression observed in the study could be generalized to the total population with insomnia, “the incidence of major depression could be reduced considerably,” they wrote.

“Can we prevent depression through interventions aimed at procrastination in college students, interventions aimed at perfectionism in perinatal women, stress management training for employees, social skills training in adolescents?” they asked.

This approach to preventing depressive disorders “offers all kinds of new opportunities to develop and test indirect interventions” for problems that are significantly associated with the onset of depression, the editorialists wrote.

The study was funded by a grant from the National Institute on Aging to the University of California, which partially supported the authors’ salaries. Dr. Irwin, Dr. Muskin, and Dr. Cuijpers have reported no relevant financial relationships. Dr. Reynolds reported being coinventor of the Pittsburgh Sleep Quality Index, for which he receives royalties.

A version of this article first appeared on Medscape.com.

A new tool designed by psychiatrists to help guide nutritional counseling in patients with schizophrenia spectrum disorders (SSD) has been released.

Lisovskaya/ThinkStock

The worksheet and clinician guide were developed using results from a recent scoping review on the relationship between diet and mental health in patients with SSD, and a feedback process involving a focus group with psychiatrists and individuals who had lived experience with psychosis.

“Mental health clinicians already have the training to help our patients make behavioral changes,” lead author Laura LaChance, MD, lecturer, department of psychiatry, and a psychiatrist at St. Mary’s Hospital Centre, McGill University, Montreal, said in an interview.

“We work every day with patients to help them to reduce their substance use, improve their sleep, take medications, etc., and nutrition should be added to the radar [since] eating well for mental health is part of self-care and can be included in mental health treatment plans,” she said.

The paper was published online Nov. 10 in BMC Psychiatry.
 

Nutrition frequently ignored

Dr. LaChance noted that “nutrition is largely absent from mental health training programs and often ignored in clinical practice.”

The investigators “wanted to create a tool to help incorporate basic nutritional counseling into the care of individuals with severe mental illness.” They wanted the tool “to be simple enough to understand for patients and simple enough to use for mental health care professionals who don’t have any official nutrition training.”

The team developed a worksheet that includes dietary recommendations, the majority of which are supported by the scoping review and consistent with Canada’s Food Guide. The review “identified all of the published literature related to the relationship between diet and psychiatric symptoms of SSD,” synthesizing the results of 822 prior articles.

It promotes the addition of nutritious food rather than the restriction of calories or individual foods and does not contradict generally accepted recommendations for weight management. It is suitable for all patients including those with low or normal body mass index and provides psychoeducation about the importance of quality nutrition as a determinant of mental health.
 

Positive tone

The worksheet was informed by social cognitive theory, which “highlights the important role of goal setting and behavior contracting, reinforcement, self-control, social norms, attitudes, and self-efficacy.”

It provides “basic education about important nutrition principles” as well as “very simple recommendations to increase knowledge about healthy eating” and “actionable tips for individuals to incorporate.” The researchers used a “positive” tone and included motivational interviewing questions.

“Delivery of the intervention by the patient’s mental health care provider is by design, in an attempt to address the widely held misbelief that nutrition intervention is of limited importance to mental health care and begin to change norms,” Dr. LaChance said.

The worksheet addresses monetary barriers to healthy eating; offers practical tips to “increase perceived control and self-efficacy”; is written in simple, accessible, nontechnical language; and includes foods from a range of cultural backgrounds.

To ensure that the worksheet and clinical guide met the needs of the target population, the researchers conducted a focus group with five psychiatrists and individual phone interviews with people who live with psychosis (n = 6).

Participants with psychosis were evenly divided between male and female and six age groups were represented: younger than 20 years; 21-30 years; 31-40 years; 41-50 years; 51-50 years; and older than 60 years. Of these participants, half scored in the “limited literacy” range, based on a nutritional literacy assessment tool (the Newest Vital Sign [NVS]).

A revised version of the worksheet, taking participants’ feedback into account, was mailed to all participants, who then provided further feedback on the revised version.


 

‘Unspoken area’

The clinician guide contains not only an overview and a suggested agenda to steer discussion, but also a sample visual representation of the recommended relative proportions of different food categories in an ideal meal as well as sample meals, a budgeting discussion, and a list of goals.

A closing statement encourages the clinician to “keep the messaging positive, celebrate small victories, and provide encouragement.”

Specific dietary recommendations include choosing complex carbohydrates and healthy fats, reducing highly processed foods and sugar, adding vegetables and fruits to meals and snacks, and eating protein-rich foods throughout the day.

A “noteworthy theme” that emerged in discussions with psychiatrists as well as participants with SSD was “the lack of nutrition training in medical education and psychiatric residency and the general absence of nutritional counseling in this field of medicine.”

One participant described nutrition as “definitely an unspoken area” in schizophrenia – especially in institutional settings, where “you are overloaded with sugars, not healthy grain, not complex grain. You get white bread sandwiches, shitty juice.”
 

Powerful tool

Commenting on the paper for this news organization, Uma Naidoo, MD, director of nutritional and lifestyle psychiatry, Massachusetts General Hospital, and a nutrition educator at Harvard Medical School, both in Boston, said she appreciates that this paper “is seeking methods to expand treatment options for those with SSD and improve provider understanding/knowledge of therapeutic foods.”

She called the pilot evaluation “notably small,” but added that it “provides results to suggest that scaling this worksheet/guide may hold promise to better provide nutritional counseling to those with psychiatric illness.”

Dr. Naidoo, also a chef and the author of “This Is Your Brain on Food,” who was not involved in the study said, “I’ve seen the power of food as medicine in my own hospital practice and do believe that food is one of the most powerful tools we have in supporting mental fitness and emotional well-being.”

The project was funded by the Canadian CAM Research Fund. Dr. LaChance and Dr. Naidoo have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new tool designed by psychiatrists to help guide nutritional counseling in patients with schizophrenia spectrum disorders (SSD) has been released.

Lisovskaya/ThinkStock

The worksheet and clinician guide were developed using results from a recent scoping review on the relationship between diet and mental health in patients with SSD, and a feedback process involving a focus group with psychiatrists and individuals who had lived experience with psychosis.

“Mental health clinicians already have the training to help our patients make behavioral changes,” lead author Laura LaChance, MD, lecturer, department of psychiatry, and a psychiatrist at St. Mary’s Hospital Centre, McGill University, Montreal, said in an interview.

“We work every day with patients to help them to reduce their substance use, improve their sleep, take medications, etc., and nutrition should be added to the radar [since] eating well for mental health is part of self-care and can be included in mental health treatment plans,” she said.

The paper was published online Nov. 10 in BMC Psychiatry.
 

Nutrition frequently ignored

Dr. LaChance noted that “nutrition is largely absent from mental health training programs and often ignored in clinical practice.”

The investigators “wanted to create a tool to help incorporate basic nutritional counseling into the care of individuals with severe mental illness.” They wanted the tool “to be simple enough to understand for patients and simple enough to use for mental health care professionals who don’t have any official nutrition training.”

The team developed a worksheet that includes dietary recommendations, the majority of which are supported by the scoping review and consistent with Canada’s Food Guide. The review “identified all of the published literature related to the relationship between diet and psychiatric symptoms of SSD,” synthesizing the results of 822 prior articles.

It promotes the addition of nutritious food rather than the restriction of calories or individual foods and does not contradict generally accepted recommendations for weight management. It is suitable for all patients including those with low or normal body mass index and provides psychoeducation about the importance of quality nutrition as a determinant of mental health.
 

Positive tone

The worksheet was informed by social cognitive theory, which “highlights the important role of goal setting and behavior contracting, reinforcement, self-control, social norms, attitudes, and self-efficacy.”

It provides “basic education about important nutrition principles” as well as “very simple recommendations to increase knowledge about healthy eating” and “actionable tips for individuals to incorporate.” The researchers used a “positive” tone and included motivational interviewing questions.

“Delivery of the intervention by the patient’s mental health care provider is by design, in an attempt to address the widely held misbelief that nutrition intervention is of limited importance to mental health care and begin to change norms,” Dr. LaChance said.

The worksheet addresses monetary barriers to healthy eating; offers practical tips to “increase perceived control and self-efficacy”; is written in simple, accessible, nontechnical language; and includes foods from a range of cultural backgrounds.

To ensure that the worksheet and clinical guide met the needs of the target population, the researchers conducted a focus group with five psychiatrists and individual phone interviews with people who live with psychosis (n = 6).

Participants with psychosis were evenly divided between male and female and six age groups were represented: younger than 20 years; 21-30 years; 31-40 years; 41-50 years; 51-50 years; and older than 60 years. Of these participants, half scored in the “limited literacy” range, based on a nutritional literacy assessment tool (the Newest Vital Sign [NVS]).

A revised version of the worksheet, taking participants’ feedback into account, was mailed to all participants, who then provided further feedback on the revised version.


 

‘Unspoken area’

The clinician guide contains not only an overview and a suggested agenda to steer discussion, but also a sample visual representation of the recommended relative proportions of different food categories in an ideal meal as well as sample meals, a budgeting discussion, and a list of goals.

A closing statement encourages the clinician to “keep the messaging positive, celebrate small victories, and provide encouragement.”

Specific dietary recommendations include choosing complex carbohydrates and healthy fats, reducing highly processed foods and sugar, adding vegetables and fruits to meals and snacks, and eating protein-rich foods throughout the day.

A “noteworthy theme” that emerged in discussions with psychiatrists as well as participants with SSD was “the lack of nutrition training in medical education and psychiatric residency and the general absence of nutritional counseling in this field of medicine.”

One participant described nutrition as “definitely an unspoken area” in schizophrenia – especially in institutional settings, where “you are overloaded with sugars, not healthy grain, not complex grain. You get white bread sandwiches, shitty juice.”
 

Powerful tool

Commenting on the paper for this news organization, Uma Naidoo, MD, director of nutritional and lifestyle psychiatry, Massachusetts General Hospital, and a nutrition educator at Harvard Medical School, both in Boston, said she appreciates that this paper “is seeking methods to expand treatment options for those with SSD and improve provider understanding/knowledge of therapeutic foods.”

She called the pilot evaluation “notably small,” but added that it “provides results to suggest that scaling this worksheet/guide may hold promise to better provide nutritional counseling to those with psychiatric illness.”

Dr. Naidoo, also a chef and the author of “This Is Your Brain on Food,” who was not involved in the study said, “I’ve seen the power of food as medicine in my own hospital practice and do believe that food is one of the most powerful tools we have in supporting mental fitness and emotional well-being.”

The project was funded by the Canadian CAM Research Fund. Dr. LaChance and Dr. Naidoo have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A new tool designed by psychiatrists to help guide nutritional counseling in patients with schizophrenia spectrum disorders (SSD) has been released.

Lisovskaya/ThinkStock

The worksheet and clinician guide were developed using results from a recent scoping review on the relationship between diet and mental health in patients with SSD, and a feedback process involving a focus group with psychiatrists and individuals who had lived experience with psychosis.

“Mental health clinicians already have the training to help our patients make behavioral changes,” lead author Laura LaChance, MD, lecturer, department of psychiatry, and a psychiatrist at St. Mary’s Hospital Centre, McGill University, Montreal, said in an interview.

“We work every day with patients to help them to reduce their substance use, improve their sleep, take medications, etc., and nutrition should be added to the radar [since] eating well for mental health is part of self-care and can be included in mental health treatment plans,” she said.

The paper was published online Nov. 10 in BMC Psychiatry.
 

Nutrition frequently ignored

Dr. LaChance noted that “nutrition is largely absent from mental health training programs and often ignored in clinical practice.”

The investigators “wanted to create a tool to help incorporate basic nutritional counseling into the care of individuals with severe mental illness.” They wanted the tool “to be simple enough to understand for patients and simple enough to use for mental health care professionals who don’t have any official nutrition training.”

The team developed a worksheet that includes dietary recommendations, the majority of which are supported by the scoping review and consistent with Canada’s Food Guide. The review “identified all of the published literature related to the relationship between diet and psychiatric symptoms of SSD,” synthesizing the results of 822 prior articles.

It promotes the addition of nutritious food rather than the restriction of calories or individual foods and does not contradict generally accepted recommendations for weight management. It is suitable for all patients including those with low or normal body mass index and provides psychoeducation about the importance of quality nutrition as a determinant of mental health.
 

Positive tone

The worksheet was informed by social cognitive theory, which “highlights the important role of goal setting and behavior contracting, reinforcement, self-control, social norms, attitudes, and self-efficacy.”

It provides “basic education about important nutrition principles” as well as “very simple recommendations to increase knowledge about healthy eating” and “actionable tips for individuals to incorporate.” The researchers used a “positive” tone and included motivational interviewing questions.

“Delivery of the intervention by the patient’s mental health care provider is by design, in an attempt to address the widely held misbelief that nutrition intervention is of limited importance to mental health care and begin to change norms,” Dr. LaChance said.

The worksheet addresses monetary barriers to healthy eating; offers practical tips to “increase perceived control and self-efficacy”; is written in simple, accessible, nontechnical language; and includes foods from a range of cultural backgrounds.

To ensure that the worksheet and clinical guide met the needs of the target population, the researchers conducted a focus group with five psychiatrists and individual phone interviews with people who live with psychosis (n = 6).

Participants with psychosis were evenly divided between male and female and six age groups were represented: younger than 20 years; 21-30 years; 31-40 years; 41-50 years; 51-50 years; and older than 60 years. Of these participants, half scored in the “limited literacy” range, based on a nutritional literacy assessment tool (the Newest Vital Sign [NVS]).

A revised version of the worksheet, taking participants’ feedback into account, was mailed to all participants, who then provided further feedback on the revised version.


 

‘Unspoken area’

The clinician guide contains not only an overview and a suggested agenda to steer discussion, but also a sample visual representation of the recommended relative proportions of different food categories in an ideal meal as well as sample meals, a budgeting discussion, and a list of goals.

A closing statement encourages the clinician to “keep the messaging positive, celebrate small victories, and provide encouragement.”

Specific dietary recommendations include choosing complex carbohydrates and healthy fats, reducing highly processed foods and sugar, adding vegetables and fruits to meals and snacks, and eating protein-rich foods throughout the day.

A “noteworthy theme” that emerged in discussions with psychiatrists as well as participants with SSD was “the lack of nutrition training in medical education and psychiatric residency and the general absence of nutritional counseling in this field of medicine.”

One participant described nutrition as “definitely an unspoken area” in schizophrenia – especially in institutional settings, where “you are overloaded with sugars, not healthy grain, not complex grain. You get white bread sandwiches, shitty juice.”
 

Powerful tool

Commenting on the paper for this news organization, Uma Naidoo, MD, director of nutritional and lifestyle psychiatry, Massachusetts General Hospital, and a nutrition educator at Harvard Medical School, both in Boston, said she appreciates that this paper “is seeking methods to expand treatment options for those with SSD and improve provider understanding/knowledge of therapeutic foods.”

She called the pilot evaluation “notably small,” but added that it “provides results to suggest that scaling this worksheet/guide may hold promise to better provide nutritional counseling to those with psychiatric illness.”

Dr. Naidoo, also a chef and the author of “This Is Your Brain on Food,” who was not involved in the study said, “I’ve seen the power of food as medicine in my own hospital practice and do believe that food is one of the most powerful tools we have in supporting mental fitness and emotional well-being.”

The project was funded by the Canadian CAM Research Fund. Dr. LaChance and Dr. Naidoo have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

COVID-19 cases are rising across 40 states and territories, setting the United States up for a rough fifth surge of the pandemic.

“A significant rise in cases just before Thanksgiving is not what we want to be seeing,” said Stephen Kissler, PhD, a postdoctoral researcher and data modeler at the Harvard TH Chan School of Public Health in Boston.

Dr. Kissler said he’d rather see increases in daily cases coming 2 weeks after busy travel periods, as that would mean they could come back down as people returned to their routines.

Seeing big increases in cases ahead of the holidays, he said, “is sort of like adding fuel to an already raging fire.”

Last winter, vaccines hadn’t been rolled out as the nation prepared for Thanksgiving. COVID-19 was burning through family gatherings.

But now that two-thirds of Americans over age 5 are fully vaccinated and booster doses are approved for all adults, will a rise in cases translate, once again, into a strain on our still thinly stretched healthcare system?

Experts say the vaccines are keeping people out of the hospital, which will help. And new antiviral pills are coming that seem to be able to cut a COVID-19 infection off at the knees, at least according to early data. A U.S. Food and Drug Administration panel meets next week to discuss the first application for a pill by Merck.

But experts caution that the coming surge will almost certainly tax hospitals again, especially in areas with lower vaccination rates.

And even states where blood testing shows that significant numbers of people have antibodies after a COVID-19 infection aren’t out of the woods, in part because we still don’t know how long the immunity generated by infection may last.
 

“Erosion of immunity”

“It’s hard to know how much risk is out there,” said Jeffrey Shaman, PhD, professor of environmental health sciences at Columbia University’s Mailman School of Public Health in New York City, who has been modeling the trajectory of the pandemic.

“We’re estimating, unfortunately, and we have for many weeks now, that there is an erosion of immunity,” Dr. Shaman said. “I think it could get bad. How bad? I’m not sure.”

Ali Mokdad, PhD, a professor of health metrics sciences at the University of Washington’s Institute for Health Metrics and Evaluation in Seattle, agrees.

Because there are so few studies on how long immunity from natural infection lasts, Dr. Mokdad and his colleagues are assuming that waning immunity after infection happens at least as quickly as it does after vaccination.

Their model is predicting that the average number of daily cases will peak at around 100,000, with another 100,000 going undetected, and will stay at that level until the end of January, as some states recover from their surges and others pick up steam.

While the number of daily deaths won’t climb to the heights seen during the summer surge, Dr. Mokdad said their model is predicting that daily deaths will climb again to about 1,200 a day.

“We are almost there right now, and it will be with us for a while,” he said. “We are predicting 881,000 deaths by March 1.”

The United States has currently recorded 773,000 COVID-19 deaths, so Dr. Mokdad is predicting about 120,000 more deaths between now and then.

He said his model shows that more than half of those deaths could be prevented if 95% of Americans wore their masks while in close proximity to strangers.

Currently, only about 36% of Americans are consistently wearing masks, according to surveys. While people are moving around more now, mobility is at prepandemic levels in some states.

“The rise that you are seeing right now is high mobility and low mask wearing in the United States,” Dr. Mokdad said.

The solution, he said, is for all adults to get another dose of vaccine — he doesn’t like calling it a booster.

“Because they’re vaccinated and they have two doses they have a false sense of security that they are protected. We needed to come ahead of it immediately and say you need a third dose, and we were late to do so,” Dr. Mokdad said.

A version of this article first appeared on Medscape.com.

COVID-19 cases are rising across 40 states and territories, setting the United States up for a rough fifth surge of the pandemic.

“A significant rise in cases just before Thanksgiving is not what we want to be seeing,” said Stephen Kissler, PhD, a postdoctoral researcher and data modeler at the Harvard TH Chan School of Public Health in Boston.

Dr. Kissler said he’d rather see increases in daily cases coming 2 weeks after busy travel periods, as that would mean they could come back down as people returned to their routines.

Seeing big increases in cases ahead of the holidays, he said, “is sort of like adding fuel to an already raging fire.”

Last winter, vaccines hadn’t been rolled out as the nation prepared for Thanksgiving. COVID-19 was burning through family gatherings.

But now that two-thirds of Americans over age 5 are fully vaccinated and booster doses are approved for all adults, will a rise in cases translate, once again, into a strain on our still thinly stretched healthcare system?

Experts say the vaccines are keeping people out of the hospital, which will help. And new antiviral pills are coming that seem to be able to cut a COVID-19 infection off at the knees, at least according to early data. A U.S. Food and Drug Administration panel meets next week to discuss the first application for a pill by Merck.

But experts caution that the coming surge will almost certainly tax hospitals again, especially in areas with lower vaccination rates.

And even states where blood testing shows that significant numbers of people have antibodies after a COVID-19 infection aren’t out of the woods, in part because we still don’t know how long the immunity generated by infection may last.
 

“Erosion of immunity”

“It’s hard to know how much risk is out there,” said Jeffrey Shaman, PhD, professor of environmental health sciences at Columbia University’s Mailman School of Public Health in New York City, who has been modeling the trajectory of the pandemic.

“We’re estimating, unfortunately, and we have for many weeks now, that there is an erosion of immunity,” Dr. Shaman said. “I think it could get bad. How bad? I’m not sure.”

Ali Mokdad, PhD, a professor of health metrics sciences at the University of Washington’s Institute for Health Metrics and Evaluation in Seattle, agrees.

Because there are so few studies on how long immunity from natural infection lasts, Dr. Mokdad and his colleagues are assuming that waning immunity after infection happens at least as quickly as it does after vaccination.

Their model is predicting that the average number of daily cases will peak at around 100,000, with another 100,000 going undetected, and will stay at that level until the end of January, as some states recover from their surges and others pick up steam.

While the number of daily deaths won’t climb to the heights seen during the summer surge, Dr. Mokdad said their model is predicting that daily deaths will climb again to about 1,200 a day.

“We are almost there right now, and it will be with us for a while,” he said. “We are predicting 881,000 deaths by March 1.”

The United States has currently recorded 773,000 COVID-19 deaths, so Dr. Mokdad is predicting about 120,000 more deaths between now and then.

He said his model shows that more than half of those deaths could be prevented if 95% of Americans wore their masks while in close proximity to strangers.

Currently, only about 36% of Americans are consistently wearing masks, according to surveys. While people are moving around more now, mobility is at prepandemic levels in some states.

“The rise that you are seeing right now is high mobility and low mask wearing in the United States,” Dr. Mokdad said.

The solution, he said, is for all adults to get another dose of vaccine — he doesn’t like calling it a booster.

“Because they’re vaccinated and they have two doses they have a false sense of security that they are protected. We needed to come ahead of it immediately and say you need a third dose, and we were late to do so,” Dr. Mokdad said.

A version of this article first appeared on Medscape.com.

COVID-19 cases are rising across 40 states and territories, setting the United States up for a rough fifth surge of the pandemic.

“A significant rise in cases just before Thanksgiving is not what we want to be seeing,” said Stephen Kissler, PhD, a postdoctoral researcher and data modeler at the Harvard TH Chan School of Public Health in Boston.

Dr. Kissler said he’d rather see increases in daily cases coming 2 weeks after busy travel periods, as that would mean they could come back down as people returned to their routines.

Seeing big increases in cases ahead of the holidays, he said, “is sort of like adding fuel to an already raging fire.”

Last winter, vaccines hadn’t been rolled out as the nation prepared for Thanksgiving. COVID-19 was burning through family gatherings.

But now that two-thirds of Americans over age 5 are fully vaccinated and booster doses are approved for all adults, will a rise in cases translate, once again, into a strain on our still thinly stretched healthcare system?

Experts say the vaccines are keeping people out of the hospital, which will help. And new antiviral pills are coming that seem to be able to cut a COVID-19 infection off at the knees, at least according to early data. A U.S. Food and Drug Administration panel meets next week to discuss the first application for a pill by Merck.

But experts caution that the coming surge will almost certainly tax hospitals again, especially in areas with lower vaccination rates.

And even states where blood testing shows that significant numbers of people have antibodies after a COVID-19 infection aren’t out of the woods, in part because we still don’t know how long the immunity generated by infection may last.
 

“Erosion of immunity”

“It’s hard to know how much risk is out there,” said Jeffrey Shaman, PhD, professor of environmental health sciences at Columbia University’s Mailman School of Public Health in New York City, who has been modeling the trajectory of the pandemic.

“We’re estimating, unfortunately, and we have for many weeks now, that there is an erosion of immunity,” Dr. Shaman said. “I think it could get bad. How bad? I’m not sure.”

Ali Mokdad, PhD, a professor of health metrics sciences at the University of Washington’s Institute for Health Metrics and Evaluation in Seattle, agrees.

Because there are so few studies on how long immunity from natural infection lasts, Dr. Mokdad and his colleagues are assuming that waning immunity after infection happens at least as quickly as it does after vaccination.

Their model is predicting that the average number of daily cases will peak at around 100,000, with another 100,000 going undetected, and will stay at that level until the end of January, as some states recover from their surges and others pick up steam.

While the number of daily deaths won’t climb to the heights seen during the summer surge, Dr. Mokdad said their model is predicting that daily deaths will climb again to about 1,200 a day.

“We are almost there right now, and it will be with us for a while,” he said. “We are predicting 881,000 deaths by March 1.”

The United States has currently recorded 773,000 COVID-19 deaths, so Dr. Mokdad is predicting about 120,000 more deaths between now and then.

He said his model shows that more than half of those deaths could be prevented if 95% of Americans wore their masks while in close proximity to strangers.

Currently, only about 36% of Americans are consistently wearing masks, according to surveys. While people are moving around more now, mobility is at prepandemic levels in some states.

“The rise that you are seeing right now is high mobility and low mask wearing in the United States,” Dr. Mokdad said.

The solution, he said, is for all adults to get another dose of vaccine — he doesn’t like calling it a booster.

“Because they’re vaccinated and they have two doses they have a false sense of security that they are protected. We needed to come ahead of it immediately and say you need a third dose, and we were late to do so,” Dr. Mokdad said.

A version of this article first appeared on Medscape.com.

A growing trend of off-label, low-dose antipsychotic prescribing to treat disorders such as anxiety and insomnia has been tied to an increased risk of cardiometabolic death, new research shows.

Investigators studied data from large Swedish registries on over 420,000 individuals without previous psychotic, bipolar, or cardiometabolic disorders and found that off-label treatment with olanzapine or quetiapine for 6 to 12 months – even at a low dose – was associated with an almost twofold higher risk of cardiometabolic mortality, compared to no treatment. The risk remained elevated after 12 months, but the finding was not deemed significant.

“Clinicians should be made aware that low-dose treatment with these drugs is probably not a harmless choice for insomnia and anxiety, and while they have the benefit of not being addictive and [are] seemingly effective, they might come at a cost of shortening patients’ life span,” study investigator Jonas Berge, MD, PhD, associate professor and resident psychiatrist, Lund University, Sweden, said in an interview.

“Clinicians should take this information into account when prescribing the drugs and also monitor the patients with regular physical examinations and blood tests in the same way as when treating patients with psychosis with higher doses of these drugs,” he said.

The study was published online Nov. 9 in the Journal of Psychiatric Research.
 

A growing trend

Use of low-dose antipsychotics to treat a variety of psychiatric and behavioral disturbances, including anxiety, insomnia, and agitation, has “surged in popularity,” the authors wrote.

Quetiapine and olanzapine “rank as two of the most frequently prescribed second-generation antipsychotics and, next to clozapine, are considered to exhort the highest risk for cardiometabolic sequelae, including components of metabolic syndrome,” they added.

Previous research examining the association between second-generation antipsychotics and placebo has either not focused on cardiometabolic-specific causes or has examined only cohorts with severe mental illness, so those findings “do not necessarily generalize to others treated off-label,” they noted.

“The motivation for the study came from my work as a psychiatrist, in which I’ve noticed that the off-label use of these medications [olanzapine and quetiapine] for anxiety and insomnia seems highly prevalent, and that many patients seem to gain a lot of weight, despite low doses,” Dr. Berge said.

There is “evidence to suggest that clinicians may underappreciate cardiometabolic risks owing to antipsychotic treatment, as routine screening is often incomplete or inconsistent,” the authors noted.

“To do a risk-benefit analysis of these drugs in low doses, the risks involved – as well as the effects, of course – need to be studied,” Dr. Berge stated.

To investigate the question, the researchers turned to three large cross-linked Swedish registers: the National Patient Register, containing demographic and medical data; the Prescribed Drug Register; and the Cause of Death Register.

They identified all individuals aged 18 years and older with at least one psychiatric visit (inpatient or outpatient) between July 1, 2006, and Dec. 31, 2016, to see how many were prescribed low-dose olanzapine or quetiapine (defined as ≤ 5 mg/day of olanzapine or olanzapine equivalent [OE]), which was used as a proxy marker for off-label treatment, since this dose is considered subtherapeutic for severe mental illness.

They calculated two time-dependent variables – cumulative dose and past annual average dose – and then used those to compute three different exposure valuables: those treated with low-dose OE; cumulative exposure (i.e., period treated with an average 5 mg/day); and a continuous variable “corresponding to each year exposed OE 5 mg/day.”

The primary outcome was set as mortality from cardiometabolic-related disorders, while secondary outcomes were disease-specific and all-cause mortality.
 

‘Weak’ association

The final cohort consisted of 428,525 individuals (mean [SD] age, 36.8 [15.4] years, 52.7% female) at baseline, with observation taking place over a mean of 4.8 years [range, 1 day to 10.5 years]) or a total of over 2 million (2,062,241) person-years.

Of the cohort, 4.3% (n = 18,317) had at least two prescriptions for either olanzapine or quetiapine (although subsequently, 86.5% were censored for exceeding the average OE dose of 5 mg/day).

By the end of the study, 3.1% of the cohort had died during the observation time, and of these, 69.5% were from disease-specific causes, while close to one-fifth (19.5%) were from cardiometabolic-specific causes.

On the whole, treatment status (i.e., treated vs. untreated) was not significantly associated with cardiometabolic mortality (adjusted hazard ratio [HR], .86 [95% confidence interval, 0.64-1.15]; P = .307).

Compared to no treatment, treatment with olanzapine or quetiapine for less than 6 months was significantly associated with a reduced risk of cardiovascular mortality (adjusted HR, .56 [.37 – .87]; P = .010). On the other hand, treatment for 6-12 months was significantly associated with an almost twofold increased risk (adjusted HR, 1.89 [1.22-2.92]; P = .004). The increased risk continued beyond 12 months, although the difference no longer remained significant.

“In the subgroup analysis consisting of individuals who had ever been treated with olanzapine/quetiapine, starting at the date of their first prescription, the hazard for cardiometabolic mortality increased significantly by 45% (6%-99%; P = .019) for every year exposed to an average 5 mg/day,” the authors reported.

The authors concluded that the association between low-dose olanzapine/quetiapine treatment and cardiometabolic mortality was present, but “weak.”

The hazard for disease-specific mortality also significantly increased with each year exposed to an average of 5 mg/day of OE (HR, 1.24 [1.03-1.50]; P = .026).

Treatment status similarly was associated with all-cause mortality (HR, 1.16 [1.03-1.30]; P = .012), although the increased hazard for all-cause mortality with each year of exposure was not considered significant.

“The findings of this study are consistent with the hypothesis that continuous low-dose treatment with these drugs is associated with increased cardiometabolic mortality, but the results are somewhat divergent and not conclusive, so more research is needed,” Dr. Berge said.
 

Seek alternatives

Commenting on the study for this news organization, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the Mood Disorders Psychopharmacology Unit, called it a “timely paper” and “an important concept [because] low-doses of these antipsychotics are frequently prescribed across America and there has been less data on the safety [of these antipsychotics at lower doses].”

Dr. McIntyre, chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, who was not involved with the study, said that this “important report reminds us that there are metabolic safety concerns, even at low doses, where these medications are often used off label.”

He advised clinicians to “seek alternatives, and alternatives that are on-label, for conditions like anxiety and sleep disturbances.”

This work was supported by the South Region Board ALF, Sweden. Dr. Berge and coauthors have disclosed no relevant financial relationships. Dr. McIntyre has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation; and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Eisai, Minerva, Intra-Cellular, and AbbVie. Dr. McIntyre is CEO of AltMed.

A version of this article first appeared on Medscape.com.

A growing trend of off-label, low-dose antipsychotic prescribing to treat disorders such as anxiety and insomnia has been tied to an increased risk of cardiometabolic death, new research shows.

Investigators studied data from large Swedish registries on over 420,000 individuals without previous psychotic, bipolar, or cardiometabolic disorders and found that off-label treatment with olanzapine or quetiapine for 6 to 12 months – even at a low dose – was associated with an almost twofold higher risk of cardiometabolic mortality, compared to no treatment. The risk remained elevated after 12 months, but the finding was not deemed significant.

“Clinicians should be made aware that low-dose treatment with these drugs is probably not a harmless choice for insomnia and anxiety, and while they have the benefit of not being addictive and [are] seemingly effective, they might come at a cost of shortening patients’ life span,” study investigator Jonas Berge, MD, PhD, associate professor and resident psychiatrist, Lund University, Sweden, said in an interview.

“Clinicians should take this information into account when prescribing the drugs and also monitor the patients with regular physical examinations and blood tests in the same way as when treating patients with psychosis with higher doses of these drugs,” he said.

The study was published online Nov. 9 in the Journal of Psychiatric Research.
 

A growing trend

Use of low-dose antipsychotics to treat a variety of psychiatric and behavioral disturbances, including anxiety, insomnia, and agitation, has “surged in popularity,” the authors wrote.

Quetiapine and olanzapine “rank as two of the most frequently prescribed second-generation antipsychotics and, next to clozapine, are considered to exhort the highest risk for cardiometabolic sequelae, including components of metabolic syndrome,” they added.

Previous research examining the association between second-generation antipsychotics and placebo has either not focused on cardiometabolic-specific causes or has examined only cohorts with severe mental illness, so those findings “do not necessarily generalize to others treated off-label,” they noted.

“The motivation for the study came from my work as a psychiatrist, in which I’ve noticed that the off-label use of these medications [olanzapine and quetiapine] for anxiety and insomnia seems highly prevalent, and that many patients seem to gain a lot of weight, despite low doses,” Dr. Berge said.

There is “evidence to suggest that clinicians may underappreciate cardiometabolic risks owing to antipsychotic treatment, as routine screening is often incomplete or inconsistent,” the authors noted.

“To do a risk-benefit analysis of these drugs in low doses, the risks involved – as well as the effects, of course – need to be studied,” Dr. Berge stated.

To investigate the question, the researchers turned to three large cross-linked Swedish registers: the National Patient Register, containing demographic and medical data; the Prescribed Drug Register; and the Cause of Death Register.

They identified all individuals aged 18 years and older with at least one psychiatric visit (inpatient or outpatient) between July 1, 2006, and Dec. 31, 2016, to see how many were prescribed low-dose olanzapine or quetiapine (defined as ≤ 5 mg/day of olanzapine or olanzapine equivalent [OE]), which was used as a proxy marker for off-label treatment, since this dose is considered subtherapeutic for severe mental illness.

They calculated two time-dependent variables – cumulative dose and past annual average dose – and then used those to compute three different exposure valuables: those treated with low-dose OE; cumulative exposure (i.e., period treated with an average 5 mg/day); and a continuous variable “corresponding to each year exposed OE 5 mg/day.”

The primary outcome was set as mortality from cardiometabolic-related disorders, while secondary outcomes were disease-specific and all-cause mortality.
 

‘Weak’ association

The final cohort consisted of 428,525 individuals (mean [SD] age, 36.8 [15.4] years, 52.7% female) at baseline, with observation taking place over a mean of 4.8 years [range, 1 day to 10.5 years]) or a total of over 2 million (2,062,241) person-years.

Of the cohort, 4.3% (n = 18,317) had at least two prescriptions for either olanzapine or quetiapine (although subsequently, 86.5% were censored for exceeding the average OE dose of 5 mg/day).

By the end of the study, 3.1% of the cohort had died during the observation time, and of these, 69.5% were from disease-specific causes, while close to one-fifth (19.5%) were from cardiometabolic-specific causes.

On the whole, treatment status (i.e., treated vs. untreated) was not significantly associated with cardiometabolic mortality (adjusted hazard ratio [HR], .86 [95% confidence interval, 0.64-1.15]; P = .307).

Compared to no treatment, treatment with olanzapine or quetiapine for less than 6 months was significantly associated with a reduced risk of cardiovascular mortality (adjusted HR, .56 [.37 – .87]; P = .010). On the other hand, treatment for 6-12 months was significantly associated with an almost twofold increased risk (adjusted HR, 1.89 [1.22-2.92]; P = .004). The increased risk continued beyond 12 months, although the difference no longer remained significant.

“In the subgroup analysis consisting of individuals who had ever been treated with olanzapine/quetiapine, starting at the date of their first prescription, the hazard for cardiometabolic mortality increased significantly by 45% (6%-99%; P = .019) for every year exposed to an average 5 mg/day,” the authors reported.

The authors concluded that the association between low-dose olanzapine/quetiapine treatment and cardiometabolic mortality was present, but “weak.”

The hazard for disease-specific mortality also significantly increased with each year exposed to an average of 5 mg/day of OE (HR, 1.24 [1.03-1.50]; P = .026).

Treatment status similarly was associated with all-cause mortality (HR, 1.16 [1.03-1.30]; P = .012), although the increased hazard for all-cause mortality with each year of exposure was not considered significant.

“The findings of this study are consistent with the hypothesis that continuous low-dose treatment with these drugs is associated with increased cardiometabolic mortality, but the results are somewhat divergent and not conclusive, so more research is needed,” Dr. Berge said.
 

Seek alternatives

Commenting on the study for this news organization, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the Mood Disorders Psychopharmacology Unit, called it a “timely paper” and “an important concept [because] low-doses of these antipsychotics are frequently prescribed across America and there has been less data on the safety [of these antipsychotics at lower doses].”

Dr. McIntyre, chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, who was not involved with the study, said that this “important report reminds us that there are metabolic safety concerns, even at low doses, where these medications are often used off label.”

He advised clinicians to “seek alternatives, and alternatives that are on-label, for conditions like anxiety and sleep disturbances.”

This work was supported by the South Region Board ALF, Sweden. Dr. Berge and coauthors have disclosed no relevant financial relationships. Dr. McIntyre has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation; and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Eisai, Minerva, Intra-Cellular, and AbbVie. Dr. McIntyre is CEO of AltMed.

A version of this article first appeared on Medscape.com.

A growing trend of off-label, low-dose antipsychotic prescribing to treat disorders such as anxiety and insomnia has been tied to an increased risk of cardiometabolic death, new research shows.

Investigators studied data from large Swedish registries on over 420,000 individuals without previous psychotic, bipolar, or cardiometabolic disorders and found that off-label treatment with olanzapine or quetiapine for 6 to 12 months – even at a low dose – was associated with an almost twofold higher risk of cardiometabolic mortality, compared to no treatment. The risk remained elevated after 12 months, but the finding was not deemed significant.

“Clinicians should be made aware that low-dose treatment with these drugs is probably not a harmless choice for insomnia and anxiety, and while they have the benefit of not being addictive and [are] seemingly effective, they might come at a cost of shortening patients’ life span,” study investigator Jonas Berge, MD, PhD, associate professor and resident psychiatrist, Lund University, Sweden, said in an interview.

“Clinicians should take this information into account when prescribing the drugs and also monitor the patients with regular physical examinations and blood tests in the same way as when treating patients with psychosis with higher doses of these drugs,” he said.

The study was published online Nov. 9 in the Journal of Psychiatric Research.
 

A growing trend

Use of low-dose antipsychotics to treat a variety of psychiatric and behavioral disturbances, including anxiety, insomnia, and agitation, has “surged in popularity,” the authors wrote.

Quetiapine and olanzapine “rank as two of the most frequently prescribed second-generation antipsychotics and, next to clozapine, are considered to exhort the highest risk for cardiometabolic sequelae, including components of metabolic syndrome,” they added.

Previous research examining the association between second-generation antipsychotics and placebo has either not focused on cardiometabolic-specific causes or has examined only cohorts with severe mental illness, so those findings “do not necessarily generalize to others treated off-label,” they noted.

“The motivation for the study came from my work as a psychiatrist, in which I’ve noticed that the off-label use of these medications [olanzapine and quetiapine] for anxiety and insomnia seems highly prevalent, and that many patients seem to gain a lot of weight, despite low doses,” Dr. Berge said.

There is “evidence to suggest that clinicians may underappreciate cardiometabolic risks owing to antipsychotic treatment, as routine screening is often incomplete or inconsistent,” the authors noted.

“To do a risk-benefit analysis of these drugs in low doses, the risks involved – as well as the effects, of course – need to be studied,” Dr. Berge stated.

To investigate the question, the researchers turned to three large cross-linked Swedish registers: the National Patient Register, containing demographic and medical data; the Prescribed Drug Register; and the Cause of Death Register.

They identified all individuals aged 18 years and older with at least one psychiatric visit (inpatient or outpatient) between July 1, 2006, and Dec. 31, 2016, to see how many were prescribed low-dose olanzapine or quetiapine (defined as ≤ 5 mg/day of olanzapine or olanzapine equivalent [OE]), which was used as a proxy marker for off-label treatment, since this dose is considered subtherapeutic for severe mental illness.

They calculated two time-dependent variables – cumulative dose and past annual average dose – and then used those to compute three different exposure valuables: those treated with low-dose OE; cumulative exposure (i.e., period treated with an average 5 mg/day); and a continuous variable “corresponding to each year exposed OE 5 mg/day.”

The primary outcome was set as mortality from cardiometabolic-related disorders, while secondary outcomes were disease-specific and all-cause mortality.
 

‘Weak’ association

The final cohort consisted of 428,525 individuals (mean [SD] age, 36.8 [15.4] years, 52.7% female) at baseline, with observation taking place over a mean of 4.8 years [range, 1 day to 10.5 years]) or a total of over 2 million (2,062,241) person-years.

Of the cohort, 4.3% (n = 18,317) had at least two prescriptions for either olanzapine or quetiapine (although subsequently, 86.5% were censored for exceeding the average OE dose of 5 mg/day).

By the end of the study, 3.1% of the cohort had died during the observation time, and of these, 69.5% were from disease-specific causes, while close to one-fifth (19.5%) were from cardiometabolic-specific causes.

On the whole, treatment status (i.e., treated vs. untreated) was not significantly associated with cardiometabolic mortality (adjusted hazard ratio [HR], .86 [95% confidence interval, 0.64-1.15]; P = .307).

Compared to no treatment, treatment with olanzapine or quetiapine for less than 6 months was significantly associated with a reduced risk of cardiovascular mortality (adjusted HR, .56 [.37 – .87]; P = .010). On the other hand, treatment for 6-12 months was significantly associated with an almost twofold increased risk (adjusted HR, 1.89 [1.22-2.92]; P = .004). The increased risk continued beyond 12 months, although the difference no longer remained significant.

“In the subgroup analysis consisting of individuals who had ever been treated with olanzapine/quetiapine, starting at the date of their first prescription, the hazard for cardiometabolic mortality increased significantly by 45% (6%-99%; P = .019) for every year exposed to an average 5 mg/day,” the authors reported.

The authors concluded that the association between low-dose olanzapine/quetiapine treatment and cardiometabolic mortality was present, but “weak.”

The hazard for disease-specific mortality also significantly increased with each year exposed to an average of 5 mg/day of OE (HR, 1.24 [1.03-1.50]; P = .026).

Treatment status similarly was associated with all-cause mortality (HR, 1.16 [1.03-1.30]; P = .012), although the increased hazard for all-cause mortality with each year of exposure was not considered significant.

“The findings of this study are consistent with the hypothesis that continuous low-dose treatment with these drugs is associated with increased cardiometabolic mortality, but the results are somewhat divergent and not conclusive, so more research is needed,” Dr. Berge said.
 

Seek alternatives

Commenting on the study for this news organization, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the Mood Disorders Psychopharmacology Unit, called it a “timely paper” and “an important concept [because] low-doses of these antipsychotics are frequently prescribed across America and there has been less data on the safety [of these antipsychotics at lower doses].”

Dr. McIntyre, chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, who was not involved with the study, said that this “important report reminds us that there are metabolic safety concerns, even at low doses, where these medications are often used off label.”

He advised clinicians to “seek alternatives, and alternatives that are on-label, for conditions like anxiety and sleep disturbances.”

This work was supported by the South Region Board ALF, Sweden. Dr. Berge and coauthors have disclosed no relevant financial relationships. Dr. McIntyre has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation; and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Eisai, Minerva, Intra-Cellular, and AbbVie. Dr. McIntyre is CEO of AltMed.

A version of this article first appeared on Medscape.com.