Background: Obsessive-compulsive disorder (OCD) is a common psychiatric disorder, with two-thirds of affected individuals reporting severe impairment. Despite its substantial burden and moderate heritability, the etiology of OCD remains poorly understood, and treatments are often suboptimal. Although recent genome-wide association studies (GWAS) have identified some risk loci, much of the genetic architecture of OCD remains undiscovered, underscoring the need for scalable approaches to identify large, well-defined patient cohorts. Objective: This study aimed to develop and validate a scalable electronic health record (EHR)–based phenotyping algorithm for identifying OCD cases to support large-scale genetic and translational research. Methods: We leveraged EHR-linked biobank data from 2 large hospital systems, namely Vanderbilt University Medical Center (VUMC) and Mass General Brigham (MGB), to develop a high-throughput phenotyping algorithm integrating diagnostic codes, medication records, and natural language processing (NLP) of clinical notes. Algorithm performance was evaluated through expert chart review, and genetic analyses were performed in individuals of European genetic ancestry using the polygenic scores (PGS) of OCD, major depressive disorder (MDD), and height derived from the most recent GWAS. Results: Expert chart reviews demonstrated our algorithm combining both () codes and NLP achieved the highest positive predictive values (PPV) for OCD case identification (0.84 at VUMC; 0.91 at MGB) compared to using either codes or NLP alone, albeit with reduced case yield. At both sites, algorithm-defined OCD cases of European genetic ancestry showed significantly higher OCD PGS than controls. In sensitivity analyses adjusting for MDD status, OCD PGS associations were more robust than MDD PGS associations, while height PGS showed no association, supporting the genetic plausibility and relative specificity of the phenotype. Conclusions: This study presents a scalable and cost-efficient EHR-based approach for identifying OCD cases across health systems. The algorithm achieves high PPV, and among individuals of European genetic ancestry, algorithm-defined cases show significant OCD PGS enrichment, supporting its utility for large-scale genetic studies and advancing understanding of the disorder’s complex etiology.
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Neurons Involved in Generating Anxiety After Cannabinoid Drug Exposure Identified in Mice
Working with mice, Northwestern scientists have for the first time identified a set of neurons in the brain that play a role in generating anxiety after exposure to cannabinoid drugs, especially under stressful conditions. Cannabinoids are a class of substances that includes tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis and synthetic analogs.
Scientists exposed mice to a predator odor after giving them a placebo or a cannabinoid drug. Animals given the cannabinoid froze more and spent less time investigating the odor. Using small microscopes, scientists identified neurons activated by the drug that helped drive anxious behaviors. When those neurons were silenced the cannabinoid no longer triggered the same level of anxious behaviors.
The findings could help scientists better understand how cannabis exerts its psychoactive effects, and potentially point to strategies for holding back anxiety in affected individuals. The results could provide insights into strategies for reducing anxiety symptoms in other contexts, outside of cannabis use.
“The results of this study could explain why a good trip can turn bad pretty quickly if people consume too much cannabis or the situation they are in turns stressful or scary,” said Sachin Patel, MD, PhD, chair of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine.
Patel is senior and corresponding author of the team’s published paper in Nature Communications, titled “Cannabinoid modulation of central amygdala population dynamics during threat investigation.” In their paper the team concluded that their results “… could ultimately provide important insights into how cannabinoids augment threat reactivity and the interactions between cannabis use and anxiety disorders.”
Plant-derived cannabinoids are widely used for medicinal and recreational purposes, and exert broad-ranging behavioral and physiological effects on mood, anxiety, memory, appetite, and sleep, the authors noted. But they can also precipitate anxiety and panic reactions in people, and increase threat-related defensive responses in rodents. “Specifically, while tension and anxiety relief represent major reasons for cannabis use, paradoxical dose- and context-dependent increases in anxiety and panic are also well-documented, and some studies have suggested associations between cannabis use and the development and worsening of anxiety disorders, especially in heavy cannabis users.” However, they continued, Despite well-established research findings, “… how cannabinoids affect in vivo neural dynamics associated with threat-related behavior has not been examined.”
For their newly reported study the scientists exposed mice to a threatening odor. Before being exposed to the scent, derived from fox urine, the mice either received a placebo or a synthetic cannabinoid drug. Patel and colleagues tested several doses of the synthetic cannabinoid on mice and tracked how much time they spent near the predator odor, and whether they froze or fled from the scent.
To simultaneously record brain activity, the team implanted a small microscope into the mice’s brain. The results showed that mice receiving the cannabinoid drug froze more often and spent less time investigating the predator odor. These anxious behaviors were linked to the drug’s activation of a small group of somatostatin neurons (SOM) in the brain’s central amygdala (CeA), a region that processes fear and stress.
Importantly, when the scientists genetically silenced the somatostatin neurons, mice given the cannabinoid drug did not avoid the predator scent as much. The researchers also conducted brain tissue experiments to analyze how the cannabinoids affected interactions between neurons. They found that the drug weakened the brain’s natural “brake” on the somatostatin neurons, allowing them to become more active. “Our data suggest suppression of GABA release from local afferents onto CeA SOM neurons underlies cannabinoid effects on CeA SOM neurons,” they wrote.
![Study authors Drs. Sachin Patel (left) and Farhana Yasmin looking at brain recordings from central amygdala neurons [Gr8y Productions]](https://www.genengnews.com/wp-content/uploads/2026/10/Low-Res_Dr.Patel_50-300x200.jpg)
“Higher doses of cannabinoids and environmental stress worked together to synergistically release the ‘brake’ on the central amygdala, which in turn drove excessive anxiety,” Patel noted. “Understanding how cannabis affects brain function to generate its psychoactive effects could ultimately reveal new ways to counteract negative consequences should they arise in some people,” Patel said, also noting that the findings could have implications beyond cannabis. “Suppressing the activity of somatostatin neurons in the central amygdala could represent a final pathway for reducing anxiety symptoms, not just in the context of cannabis side effects,” he explained.
Cannabis use in the U.S. has steadily increased in recent years and so have emergency department visits related to adverse effects from the drug. Previous studies have also found an association between cannabis use and increased risk of anxiety in the long term. What’s more, anxiety and mood disorders are also on the rise globally.
Commenting that their newly reported data begin to shed light on neural mechanisms subserving the “dark-side” adverse effects of cannabinoids, the authors concluded, “… we suggest cannabinoids could trigger context-dependent adverse anxiety and panic reactions, in part, via activation of CeA-related circuits and that cannabis-induced long-term adaptations in these circuits could contribute to observed associations between cannabis use and anxiety disorders.”
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Access to addiction meds for young people has improved — but retention hasn’t
In 2016, the American Academy of Pediatrics issued a policy statement urging doctors to offer medications for opioid use disorder to adolescent and young adult patients who needed them.
New national data show that more young people with an opioid use disorder diagnosis did start receiving addiction medications like buprenorphine and methadone, but the increase was small. And the number of young people who stayed on medication for six months — already quite low — may have actually decreased.
Differences in autism features and adaptive functioning between adolescents with autism spectrum disorder and social communication disorder
IntroductionThis study aimed to characterize adolescents with social communication disorder (SCD) in comparison with those with autism spectrum disorder (ASD) across two dimensions: autism features and adaptive functioning. SCD shares social communication difficulties with ASD, resulting in unclear diagnostic boundaries and raising concerns about its clinical utility given that existing research and resources remain largely ASD-oriented.MethodsData from 76 adolescents with ASD and 44 with SCD (ages 10–18 years) were analyzed. Lifetime and current autism features were assessed using the Autism Diagnostic Interview–Revised (ADI-R) and Social Responsiveness Scale, Second Edition (SRS-2), respectively, and adaptive functioning using the Vineland Adaptive Behavior Scales, Second Edition. Propensity score matching was performed using age and Full-Scale Intelligence Quotient, and group differences were compared before and after matching. Exploratory interaction analyses additionally examined potential moderators of group differences.ResultsAfter matching, adolescents with SCD showed less severe lifetime autism features across the core ADI-R domains, with large effect sizes (ds = .98–1.34, all p <.001). Current autism features showed smaller group differences, which remained significant across all SRS-2 subscales except Social Motivation (ds = .46–.68, p = .004–.046). Adolescents with SCD showed better adaptive functioning than those with ASD, although group differences in Communication (p = .085) and Socialization (p = .144) were no longer statistically significant after matching. Psychiatric comorbidity moderated group differences in Communication, Socialization, and overall adaptive functioning, while attention-deficit/hyperactivity disorder showed a similar but less robust pattern for Communication, which did not remain significant after correction.DiscussionOverall, accounting for age and intellectual ability, the distinction between ASD and SCD remained evident at the symptom level, whereas functional differences were partly influenced by these factors. These findings suggest that diagnostic classification alone may not fully capture the functional needs of adolescents with ASD and SCD, highlighting the importance of a multidimensional approach that considers symptom profiles, adaptive functioning, developmental and intellectual factors, and psychiatric comorbidity.
Short-term BMI-SDS change during child and adolescent psychiatric hospitalization: associations with antipsychotic treatment and length of stay
Children and adolescents receiving inpatient psychiatric treatment may be at increased risk of short-term weight gain-related changes, particularly during antipsychotic exposure. In this retrospective cohort study we analyzed a patient-level cohort of 776 unique patients younger than 18 years treated between 2022 and 2024, after exclusion of eating disorder diagnoses and repeated hospitalizations. Clinical data were extracted from electronic medical records and included demographic and clinical characteristics, antipsychotic treatment, and anthropometric measurements. The median hospitalization duration was 3.0 days (IQR 2.0-7.0). Repeated BMI-SDS measurements permitting calculation of BMI-SDS change were available for 228 patients. Mean BMI-SDS change was +0.071 (SD = 0.242). BMI-SDS increased significantly among patients exposed to antipsychotics (n = 152; mean change +0.107, p < 0.001), whereas no significant change was observed among patients without antipsychotic exposure (n = 76). BMI-SDS change differed across antipsychotic treatment groups (Kruskal-Wallis p = 0.0006; ϵ² = 0.081). However, olanzapine monotherapy was not significantly different from no antipsychotic treatment after correction for multiple comparisons, although exploratory analysis showed a higher risk of BMI-SDS increase ≥0.5 with olanzapine exposure (NNH = 3.7, 95% CI 2.2–10.2). In multivariable linear regression analysis, longer hospitalization (B = 0.0035 per day, 95% CI 0.002-0.005, p < 0.001) and any antipsychotic exposure (B = 0.0668, 95% CI 0.003-0.131, p = 0.042) were associated with higher follow-up BMI-SDS after adjustment for baseline BMI-SDS. Sex, age and F20-F29 diagnosis were not significantly associated with follow-up BMI-SDS. These findings suggest that short-term BMI-SDS change during child and adolescent psychiatric hospitalization is associated with antipsychotic treatment and length of hospitalization. The results do not support a significant olanzapine dose-response relationship and should be interpreted as anthropometric associations rather than evidence of metabolic dysfunction or causality.
Circulating miR-1260a as a potential biomarker for First-Episode of Psychosis: a replication study in a treatment-Naïve Romanian cohort
The diagnosis of first-episode psychosis (FEP) in adolescents and young adults remains primarily clinical, often complicated by symptom overlap and the heterogeneity of psychiatric presentations. There is a critical need for non-invasive, objective biomarkers to support early diagnosis and patient stratification. This study aimed to replicate a panel of 10 candidate microRNAs (miRNAs) identified in a previous exploratory study within a larger, independent cohort of treatment-naïve Romanian adolescents and young adults. This cross-sectional study included 50 participants (22 drug-naïve FEP patients and 28 age- and sex-matched controls). Total RNA was isolated from plasma, and the levels of miRNAs were measured using qRT-PCR. Clinical symptoms were assessed using standardized psychiatric scales (PANSS, HDRS, YMRS). We successfully replicated miR-1260a as significantly modified in the plasma of treatment-naïve FEP patients compared to controls (FDR Adj. p = 0.04). ROC analysis for miR-1260a yielded an AUC of 0.741 (p = 0.004). Furthermore, exploratory correlation analyses conducted exclusively within the FEP patient group indicated a negative correlation between miR-1260a levels and the positive PANSS score (p = 0.017, rho = -0.503), which did not retain statistical significance after FDR correction (FDR Adj. p = 0.102). Our results corroborate and enhance our prior exploratory research, highlighting miR-1260a as a prominent candidate among circulating biomarkers for early psychosis. Future longitudinal studies are necessary to evaluate the diagnostic, prognostic, and clinical monitoring efficacy of this miRNA.
You Are More Than Your OCD — Living with OCD
By Stuti Pemmaraju
I cannot pinpoint the exact moment that I first began experiencing symptoms of OCD, but my earliest recollection of a compulsion was during my fifth-grade distance learning class. The pandemic altered life for many people, and for me the biggest change was my obsessive thoughts. As a kid, I was easily scared—I would avoid watching horror movies and had a terrible fear of clowns and ghosts. During that time, those fears became intertwined with my OCD; as my compulsions got more frequent and terrifying, so did my obsessions. I found myself looking at the four corners of my room, turning the lights on and off, counting even or odd numbers more progressively, and looking behind my shoulder whenever I was alone, just to check if someone was watching me.
A few years later, middle school began, and my OCD was the worst it had ever been. Compulsions became more constant, and arbitrary thoughts quickly turned into obsessions that dictated my every move, making simple tasks seem like life-or-death situations. My OCD was controlling me, and I didn’t know that I had OCD—it never occurred to me that my thoughts were not normal. Looking back now, I recognize many themes my obsessions had taken over the years, including morality, harm, and identity fears. Every day, I somehow pushed through, mentally exhausted. From the outside, I looked like anyone else, but internally I was fighting a battle I thought everyone was expected to endure.
The conversation I had with my parents about my OCD after silently battling it for years was one of the most difficult things I’ve had to do. Mental health isn’t something that is generally acknowledged in South Asian communities, so I didn’t know how my parents would react. Thankfully, they were very understanding and helped me begin ERP therapy, which I have been doing for the past two years.
Even after coming to terms with this condition and learning techniques to fight it, I still struggled a lot this past year with frequent panic attacks and depressive episodes. It was then that my psychologist and I decided to move forward with medication.
Having OCD taught me that mental health is not linear and that there will always be bad moments. The most important thing is to keep pushing through, because not trying only makes the struggle worse. Something that helped me come to terms with my OCD was using writing as an outlet for my experiences, and finding interest in mental health advocacy and policy research.
OCD is something I navigate every day, but it is no longer something I face alone. I learned that while I cannot always control the thoughts my mind brings me, I can control how I respond to them. My message to other teenagers who are struggling is this: OCD is definitely a big part of your story, but it is not the entirety of who you are. You are so much more than your OCD, and remember that it does not define you.
While every experience with OCD is different, far too many kids and families face the same barriers to getting answers and effective treatment. See what new IOCDF findings reveal about pediatric OCD care—and what we can do to change it—in Losing Childhood to America’s OCD Care Crisis.
The post You Are More Than Your OCD — Living with OCD appeared first on International OCD Foundation.
Confessions of an Eight-Year-Old – Living with OCD
By Julia Hyman
Knots in my youth-sized stomach. My brain pounding and constantly racing. Guilt was consuming my eight-year-old body. Those were my very first signs of OCD. I remember coming home from elementary school every day, constantly feeling like I had committed the worst kind of crime. I would confess every thought and feeling I had that day to my mom, worrying that God would punish me if I did not. I would tell her if I accidentally looked at a kid in my class’s private parts, if I was mean to another student, and if I was chastised at all that day in class. The need to be a “moral” human being, to avoid going to Hell, was all-consuming during this time in my life. Preparing for my first Reconciliation at age eight felt like preparing to go to war. I had to gather every single “sin” I had ever committed within my eight years of life to confess them to a Priest and be saved from Hell. The relief after Reconciliation was momentary, and guilt continued to consume me the moment I believed I had thought, said, or done something immoral.
My parents could not fathom why I constantly felt the need to confess every menial thing that crossed my mind or that happened at school that day. I have one really vivid memory of a time when I tried to hold off on confessing something that had happened at school that day, and how I absolutely erupted into tears right before bedtime, which is when I decided to confess it to my parents. In second grade, we had a “disciplinary stoplight,” in which we would move our name tag to yellow, orange, or red depending on the severity of our incident. One day, I was talking a lot in class, to the point where my nametag was moved to the “orange light.” My stomach was on the floor all day long, and I tried to hold off on confessing until bedtime, when my parents would tuck me in. I went through homework, dance class, and dinner before unloading what had happened that day onto my parents. I remember my parents being very sympathetic and more worried about my reaction to what had happened than the incident itself.
At this point in my OCD progression, my parents were wary of my behavior, but not quite alarmed to the point of intervention just yet. Once I turned nine years old, a new OCD theme came to the forefront, and that was contamination OCD. When I would go to the bathroom, I would wipe until I was bleeding, because in my OCD-ridden brain, blood meant clean. I would only pull up my pants after using the toilet with the hand that did not wipe and would proceed to wash my hands and arms until they were bloody, cracked, and scaly. I remember my mother starting to knock on the bathroom door every time I went to the bathroom, concerned about why I always took so long. These rituals escalated to scrubbing the bathroom floor almost every time I used the toilet, because I felt my business was seeping through the floor and infecting it after I had flushed, and to splashing the faucet a certain number of times before I could touch it to turn it off. I believe the last straw for my parents was one instance in particular, when I was sitting on the bathroom floor with the rugs pushed aside, scrubbing it and crying from exhaustion. After this instance, my parents diligently searched for a child therapist.
My first therapist would have multiple sessions in one sitting with my family and I – one talking with just my parents, one talking with just me, and one talking with all of us together. After describing what I was going through- the incessant confessing and cleaning of the bathroom – I was promptly diagnosed with Obsessive Compulsive Disorder. Following this session, my parents diligently researched and found a bunch of informational books on handling a child with OCD, and read through them. After educating themselves on the mechanisms of OCD, they began to become proactive in pointing out to me when my OCD was taking over.
They would refer to my OCD as the “bully in my brain,” and would encourage me to stand up to it. When I would start to confess something “bad” that I did, thought, or said on a particular day, they would gently redirect me to the present moment and point out to me that this was “the bully in my brain” making me feel guilty and feel the urge to confess when I did not need to. They would also try to set limits on how long I could spend in the bathroom and would knock on the bathroom door to remind me when I had been in there too long. Although their methods would work for the specific themes that they were targeting, handling my OCD became like “Wack-a-Mole.” New themes of obsessions and compulsions would arise, and they would have to adjust their approach to target each one.
Beginning in the middle of my third-grade year, my obsessions and compulsions began to be geared towards my schoolwork. I would be sitting at the kitchen table working on assignments for four to six hours straight at nine years old. I was constantly adding more words and ideas to assignments, checking assignments, and re-reading words in books and study materials. School became downright exhausting, and I would cry and have a knot in my stomach going back to school everyday, knowing I would have to overwork myself repeatedly. My parents became increasingly concerned with how much time I was spending on elementary school assignments, that they met with my teacher and therapist to discuss it. It took around five years to find a therapeutic technique that worked to limit my school and homework-based obsessions, but I finally was able to find an effective therapist who gave me efficient tools and techniques to limit copious amounts of time spent on schoolwork. My therapist, with the cooperation and compliance of my parents and I, implemented a system that would allow me to break up my schoolwork into chunks, while setting an overall time limit on completion. The method was entitled “The Pomodoro Method,” and it allowed me to work for thirty minutes to an hour straight, take a break for thirty minutes, then go back to work for another thirty minutes to an hour. The overall time limit they set for homework completion each day was around three hours, and after three hours, they did not allow me to go back into my backpack and check and/or work on any assignments. When I would ask for reassurance about my homework, my parents would try to not give an answer, to not fuel the obsessive-compulsive cycle.
Throughout my childhood years combating OCD, I was truly fortunate enough to have parents that caught onto the signs early on and got me proper help. While growing up and becoming more mature and educated, OCD themes tend to change to latch onto what is most prominent in your life in a certain moment. Finding the right OCD therapist that can pivot when themes change and provide research-based and effective OCD treatment modalities, such as Exposure and Response Prevention (ERP) and Inference-Based Cognitive Behavioral Therapy (ICBT) is crucial to understanding and combating the intricacies of OCD. Because I received effective support from several therapists at an early age, I came to understand that OCD is ego-dystonic, meaning it causes intrusive thoughts and obsessions that conflict with a person’s true values, morals, and sense of self. My OCD often centered on fears of being an immoral or unacceptable person, such as fears of being a pedophile, not working hard enough in school, or not being a clean and moral individual, despite these fears being completely inconsistent with who I was.
Furthermore, my parents and I were able to thoroughly educate ourselves on how OCD operates within the brain, and how reassurance, checking, and other compulsions only work to teach the brain that these obsessions and doubts are “dangerous” and thus must be paid attention to, when that is not the case. “The bully” in my brain- which was what we referred to my OCD as- would demand one compulsion in one minute, and once that was completed, would demand even more of me the next time I had an intrusive thought. Having parents to remind me that an urge to compulse was just “the bully” demanding more nonsensical actions from me allowed me to eventually come off the high emotions fueled by urge and re-ground myself to the present.
I am not going to lie and say that OCD is an easy fix with the methods I have described above.
It takes time, resiliency, constant ongoing education, and patience to start to retrain an OCD-ridden brain, especially as a child with a more limited understanding. Today, I am twenty-four years old and am still battling OCD. In the heat of the moment, when an intrusive thought strikes and feels real, urgent, and life-threatening, it is extremely hard to remind yourself of the mechanisms of OCD and ground yourself back to the present moment. Especially for young kids who do not understand that they have a neurological condition that is making them feel these scary feelings, it is extremely hard to discern between a true worry versus an OCD intrusive thought. The Amygdala, which is the brain’s emotion center and alarm system, flags every intrusive thought, no matter how irrational it sounds, as a danger.
My final advice to any parent reading this article is this: please give your child patience, grace, and do not make them feel “crazy” for having these thoughts. For us with OCD brains, these thoughts truly feel probable, realistic, scary, and urgent to check and seek reassurance over. Working with your child each day, with the help of a licensed OCD professional, will help them eventually to tolerate the discomfort from intrusive thoughts without responding to them, or to see them from a more grounded and rational perspective.
While every experience with OCD is different, far too many kids and families face the same barriers to getting answers and effective treatment. See what new IOCDF findings reveal about pediatric OCD care—and what we can do to change it—in Losing Childhood to America’s OCD Care Crisis.
The post Confessions of an Eight-Year-Old – Living with OCD appeared first on International OCD Foundation.
Longitudinal white matter network reorganization after rTMS in first-episode schizophrenia: associations with sleep improvement
BackgroundSleep disturbances are highly prevalent in first-episode schizophrenia and are associated with poor clinical and functional outcomes. Although repetitive transcranial magnetic stimulation (rTMS) has shown therapeutic potential for insomnia and schizophrenia, its efficacy for sleep disturbances in first-episode schizophrenia remains insufficiently characterized, and the underlying white matter network mechanisms remain unclear. This study aimed to determine whether active rTMS improves sleep quality compared with sham stimulation and whether longitudinal white matter network reorganization is associated with treatment-related sleep improvement.MethodsOne hundred patients with first-episode schizophrenia were included in the final analysis and randomly assigned to receive active rTMS or sham stimulation over an 8-week intervention period. Subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI), and objective sleep parameters were measured using wrist actigraphy. Diffusion tensor imaging was acquired at baseline and after treatment to construct individual white matter structural networks. Graph-theoretical metrics, nodal efficiency, and rich-club organization were examined. Linear mixed-effects models were used to evaluate group-by-time interaction effects, and correlation analyses were performed to examine associations between network changes and sleep improvement.ResultsCompared with sham stimulation, active rTMS produced greater improvements in subjective and objective sleep outcomes, including reduced PSQI scores, increased sleep efficiency, and decreased wake after sleep onset and sleep latency. Active rTMS was also associated with greater longitudinal increases in global efficiency, local efficiency, clustering coefficient, and nodal efficiency in prefrontal, default-mode, temporal, and salience-related regions. Rich-club connectivity increased more strongly after active rTMS than after sham stimulation, whereas feeder connectivity, normalized rich-club coefficient, and local connectivity did not show significant group-by-time interaction effects after FDR correction. In the active rTMS group, increases in rich-club connectivity were positively associated with improvements in actigraphy-derived sleep efficiency (r = 0.43, P = 0.002).ConclusionsActive rTMS improved sleep quality more effectively than sham stimulation in patients with first-episode schizophrenia and was accompanied by longitudinal changes in DTI-derived white matter network organization. The association between increased rich-club connectivity and improved sleep efficiency suggests that hub-related network reorganization may represent a network-level correlate of rTMS-related sleep improvement.
Ketamine in psychiatry: a systematic review of clinical applications, safety considerations, and emerging challenges
Ketamine has progressed from solely being an anesthetic agent to a drug of rising clinical and research interest due to its distinctive pharmacological properties. Its dissociative properties and rapid-acting antidepressant effects have made it a prominent area of investigation across many medical and psychiatric applications. This systematic review examines ketamine’s history, mechanisms of action, clinical uses, and significant challenges. A systematic search of PubMed, SCOPUS, PsycINFO, and other sources, generated peer-reviewed publications that addressed the history of ketamine, its pharmacology, clinical applications, recreational use, safety considerations, and societal consequences. Overall, 106 articles were identified for inclusion in this study. At the receptor level, ketamine is an antagonist of NMDA receptors that triggers a number of downstream effects ranging from heightened glutamate transmission, AMPA receptor activation, increased BDNF expression, synaptogenesis, and mTOR pathway signaling. At the network level, it alters activity within large-scale brain circuits including the default mode network, affecting cognition, mood, and perception. Clinically, ketamine is used for anesthesia, treatment-resistant depression, and pain, with off-label uses for PTSD, anxiety disorders, and bipolar disorder. The review also examines current challenges related to ketamine’s recreational use, associated risks, sociocultural factors, and key clinical and ethical considerations, including safety, monitoring, and telehealth prescribing of oral and sublingual formulations. It integrates previously fragmented research from anesthesiology, neuroscience, pharmacology, psychiatry, and public health, consolidates clinical and ethical guidance, identifies critical gaps in current knowledge, and proposes directions for future research.