Frontiers in Psychiatry
July 22, 2022
Lai Fong Chan, Luke Sy-Cherng Woon, Nuur Asyikin Mohd Shukor et al.
2 citations
For patients with treatment-resistant depression who do not achieve functional recovery after multiple pharmacotherapies, combining brexpiprazole with esketamine or ketamine may offer a more rapid and effective augmentation strategy. This case series describes five complex cases of unipolar and bipolar treatment-resistant depression where conventional treatments failed to manage high-risk suicidal behavior or restore function. The authors discuss potential synergistic mechanisms of this novel combination, patient and clinical factors affecting response, challenges encountered, and implications for future practice and research.
Frontiers in Psychiatry
January 22, 2026
Jae Sevelius, Rachel Lynn Golden, B. Stott et al.
1 citation
A novel group-based ketamine-assisted psychotherapy program called Kindred, which integrates cognitive processing therapy, was tested with eight transgender and gender-expansive adults. The nine-week intervention alternated ketamine dosing sessions with cognitive skills-building and integration sessions. All participants completed the program and reported high satisfaction. Significant reductions in depression, anxiety, and cognitive fusion scores were observed, alongside qualitative reports of decreased shame, suicidality, and internalized transphobia. Participants identified group belonging, peer validation, and shared identity as important therapeutic factors. The findings suggest Kindred is a feasible and promising intervention for addressing mental health symptoms related to identity-based trauma in this population.
Frontiers in Psychiatry
December 17, 2025
Veronika Savica, Liene Sīle, Māris Taube
1 citation
Dissociation—a disruption in the normal integration of psychological functions—is a common adverse effect of esketamine nasal sprays. Individuals with high trait dissociation face greater risk of severe induced dissociation. However, intense dissociation may also predict better therapeutic response. This case report describes a patient with histrionic personality disorder (HPD) who experienced an unusually intense and persistent dissociative reaction during esketamine therapy. The case suggests that certain HPD personality traits may heighten vulnerability to esketamine-induced dissociation, underscoring the need to identify patient-level factors that amplify dissociative responses for improved risk stratification and clinical care.
Frontiers in Psychiatry
September 2, 2025
Mina Kheirkhah, Nastasia McDonald, Julia Aepfelbacher et al.
1 citation
Adding mindfulness, music, and a light-occluding eye mask during ketamine infusion for depression did not improve antidepressant effects compared to ketamine alone, but it enriched the subjective experience. Participants in the combined sensory intervention group reported deeper engagement, a stronger sense of connection to reality, increased focus, moments of relief from sadness, and feelings of awe and spiritual insight. However, four individuals in that group reported discomfort. The findings suggest that while the sensory interventions make the experience more meaningful for many, they may cause discomfort for a few, and making them optional could avoid this.
Frontiers in Psychiatry
August 4, 2025
Wierzbicka Małgorzata, Renata Kopczyk, Alexander L. Gerlach et al.
1 citation
Depression is especially common in head and neck cancer (HNC) patients, who have twice the rate of major depressive disorder as other cancer patients, and this depression independently worsens clinical outcomes. Standard antidepressants and psychological therapies take weeks to work, a serious problem when surgery is imminent. Psilocybin, metabolized to psilocin, acts on serotonin and dopamine receptors and can lift mood within hours, outperforming escitalopram in trials for depression and also showing efficacy in PTSD and treatment-resistant depression. However, no studies have tested psilocybin for perioperative use in HNC patients. Legal status varies by country; in Poland it is restricted to research under the 1971 Psychotropic Convention, creating barriers despite its therapeutic promise. Overcoming these barriers will require collaboration among oncologists, psychiatrists, and policymakers.
Frontiers in Psychiatry
March 19, 2024
1 citation
Medical training often overlooks culturally adapted tools that respect patients' beliefs and realities. In Ethiopia, transformative learning theory helped bridge biomedical and traditional healing for psychosis; only 58% of rural patients access biomedical care, with most relying on Orthodox Christian traditional healers who are less stigmatized. Collaborative partnerships between spiritual healers and researchers reduced stigma and increased referrals to psychiatric clinics. Low parental mental health literacy and stigma are fundamental treatment barriers across Ethiopia, Kenya, and Democratic Republic of Congo. One paper from an LMIC cohort uses psilocybin in psychotherapy. Creative arts modalities, including Zentangle, offer accessible, transportable treatment for serious mental illness. In Qatar, 75% of the population are migrant workers, yet community mental health services remain underdeveloped, especially for children, women, and migrants.
Frontiers in Psychiatry
October 19, 2023
1 citation
Psychedelics may offer new treatments for substance use disorders (SUDs), which cause high rates of illness and death. Current treatments often fail: in one trial, 57% of patients on buprenorphine and 65% on naltrexone relapsed by 24 weeks, and 40% leave 12-step groups within a year. This special issue presents seven articles exploring psychedelics' potential for SUDs, including psilocybin for methamphetamine use disorder and ketamine's effects on brain plasticity. One review found mixed evidence for ketamine's impact on synaptic markers in the hippocampus and prefrontal cortex. A perspective piece argues for equitable access to psychedelic therapies, including training diverse clinicians and serving higher-risk patients.
Frontiers in Psychiatry
February 23, 2023
Rammohan Shukla, Mohamed Sherif, Mostafa Z. Khalil et al.
1 citation
Destroying synapses in a machine-learning model of the neocortex reduces the confidence of its predictions before reducing their number. The model, based on the temporal memory algorithm, was trained on random letter sequences representing affective states. Removing 50% of synapses only slightly lowered the number of predictions, but a 25% reduction distinctly dropped prediction confidence. This suggests that in major depressive disorder, synaptic loss in interoceptive cortices could trap the brain in limited affective states with high prediction error. The growth of new synapses, as proposed for ketamine and psilocybin, would allow more confident and futuristic predictions.
Frontiers in Psychiatry
January 4, 2023
Felix P. Mayer, Dino Luethi, Lorena B. Areal et al.
1 citation
Psychoactive substances have been consumed throughout human history, first from plants and fungi, then isolated compounds like cocaine, and later synthetic drugs such as LSD. Many recreational drugs also have clinical uses, e.g., amphetamines for ADHD. New psychoactive substances (NPS) have expanded the drug market and improved understanding of structure-activity relationships. Recent clinical trials are reevaluating psychedelics like psilocybin and MDMA for conditions such as depression and PTSD. This special issue includes studies on synthetic opioids, NBOMe derivatives, psilocybin's anxiolytic effects in healthy volunteers, psilocybin reducing body weight in obese rats, and reviews linking mystical experiences to symptom reduction. The collection highlights both risks and therapeutic potential of psychoactive compounds.
Frontiers in Psychiatry
July 15, 2026
Rafał Marecki, Wiktoria Zaniewska, Adam Hamed et al.
Classic psychedelics such as psilocybin, LSD, DMT, 5-MeO-DMT, mescaline, and DOI work primarily by activating 5-HT2A receptors, causing widespread brain and behavior changes relevant to psychiatric research. Evidence from rodent studies shows that these effects differ by sex across pharmacokinetics, physiology, neuroplasticity, behavior, and disease models. Females often show stronger or qualitatively distinct behavioral responses, including head twitch, locomotor activity, prepulse inhibition, stress reactivity, and social behavior, with ovarian cycle phase further modulating some effects. Disease model studies also find sex-dependent outcomes, such as psilocybin's effects on alcohol consumption and DMT microdosing on mood and neuroplasticity. The review concludes that sex is a critical biological variable shaping psychedelic effects in rodents, and integrating sex-specific analyses is essential for improving translational validity and guiding clinical applications.
Frontiers in Psychiatry
July 13, 2026
Scott Shannon, Andrew Weil
Psychiatric models that focus on isolated biological dysfunction fail to capture the complexity and context dependence of mental disorders. Drawing on neuroscience, complexity science, and psychedelic research, this paper proposes a systems-based framework where therapeutic change involves a phased process of perturbation, reorganization, and consolidation. Interventions modulate system stability and plasticity, with outcomes shaped by biological, psychological, relational, and environmental factors. Psychedelic-assisted therapies exemplify this by transiently destabilizing entrenched patterns, increasing flexibility, and enabling reorganization under supportive conditions. Recovery is reframed as increased coherence, flexibility, and adaptive capacity rather than mere symptom reduction. This perspective calls for longitudinal, context-sensitive outcome measures and hybrid methodologies.
Frontiers in Psychiatry
July 9, 2026
Alqassem Y. Hakami
Ketamine, a drug that rapidly alters brain connections, shows promise for treating both treatment-resistant depression and substance use disorders, particularly alcohol and cocaine addiction. When combined with psychotherapy, small-to-moderate Phase 2 trials found it reduced cravings and increased days of abstinence. However, results vary widely due to differences in dosing, comparison treatments, and follow-up lengths, and effects on preventing relapse have been inconsistent. Ketamine works by blocking NMDA receptors and boosting synaptic plasticity, which may help disrupt harmful reward memories. While supervised use causes only temporary side effects, the drug carries a clear risk of misuse, especially without supervision. Larger, longer studies are needed before it becomes standard care.
Frontiers in Psychiatry
July 9, 2026
Patrice A. Bellanti, Jordan Lewis, Brian Seifferth et al.
In a community psychiatric clinic, adults with treatment-resistant depression who received either intranasal esketamine or intravenous ketamine showed large reductions in depression severity, as measured by the PHQ-9 questionnaire. Both groups had similar average decreases of about 10 points, with response rates around 65–69% and remission rates of 23–32%. Most patients completed the induction phase, and no serious adverse events occurred. The study was not large enough to detect meaningful differences between the two treatments, and the different dosing schedules further limit direct comparison. The findings suggest both treatments are effective in real-world settings, consistent with prior controlled trials.
Frontiers in Psychiatry
July 8, 2026
Lotem Zvi, Jonathan E. Handelzalts, Danny Horesh et al.
Women with histories of childhood sexual abuse (CSA) and co-occurring psychiatric disorders admitted to a specialized integrative inpatient unit in Israel showed that dissociative symptoms, particularly maladaptive absorption, were strongly linked to PTSD severity. In a cross-sectional phase with 108 women, all facets of dissociation correlated positively with PTSD symptoms. In a smaller treatment phase with 28 women, PTSD symptoms decreased after the program, and reductions in absorption were tied to improvements in overall PTSD and hyperarousal. The findings suggest dissociation should be a key therapeutic target, though larger controlled trials are needed.
Frontiers in Psychiatry
July 6, 2026
Qinglin Bao, Dezhi Yang, Zhiheng Dong et al.
Disruptions in self-referential processing (SRP), the mental activity of linking experiences to the self, are a transdiagnostic feature across psychiatric disorders such as schizophrenia, major depressive disorder, and anxiety disorders. These disruptions involve distorted self-perception, negative cognitive-affective biases, and altered connectivity in the default mode network and medial prefrontal cortex. SRP and empathy have a bidirectional relationship: impaired self-processing can hinder understanding others' states, while poor empathic attunement may worsen maladaptive self-focus. This interplay contributes to social withdrawal and emotional dysregulation. Interventions like metacognitive therapy, mindfulness, and psychedelic-assisted psychotherapy show preliminary promise for modulating shared neurocognitive mechanisms and improving social functioning.
Frontiers in Psychiatry
July 3, 2026
Jingqiang Xie, Chunying Pu, Mingyue Sun
For people with treatment-resistant depression, adding intranasal esketamine to an oral antidepressant produces a modest but rapid reduction in depressive symptoms within two days, with greater symptom reduction at four weeks compared to placebo nasal spray plus an oral antidepressant. The combination therapy also increases the likelihood of response and remission, and improves daily functioning. Among those who initially respond, continued esketamine treatment halves the risk of relapse. However, acute treatment increases side effects, including dissociation and elevated blood pressure, and more patients discontinue due to adverse events. These findings support the use of esketamine under medical supervision with careful individual benefit-risk assessment.
Frontiers in Psychiatry
July 1, 2026
Chun-Hung Chang, Yu-Der Hsia, W Liu et al.
A 29-year-old woman hospitalized for severe depression with high-risk suicidal ideation, who had not responded to multiple antidepressants, psychotherapy, and standard transcranial magnetic stimulation, received a combination of intranasal esketamine (84 mg) and an accelerated schedule of intermittent theta-burst stimulation (iTBS) over four days. Her depressive symptoms improved, with scores on the Patient Health Questionnaire-9 dropping from 15 to 11, the Hamilton Depression Rating Scale from 27 to 20, and the Beck Depression Inventory from 41 to 28. Suicidal ideation also improved, and gains were maintained at a two-week follow-up. The case suggests the combined treatment is feasible for inpatient settings, though controlled studies are needed.
Frontiers in Psychiatry
June 24, 2026
Kathryn Fletcher, Nadine Ezard, Krista J. Siefried et al.
People with methamphetamine use disorder who underwent ketamine-assisted psychotherapy described the treatment as a multi-stage process rather than a simple drug effect. Participants reported that ketamine created a temporary state of reduced emotional and cognitive reactivity, which they called 'psychological space,' making them more receptive to psychotherapy. However, behavioral changes—including reduced methamphetamine use—were variable and depended on ongoing therapeutic engagement, personal motivation, and life context. Participants were uncertain whether improvements came from the ketamine, the therapy, or the supportive environment. Acceptability was generally high when treatment occurred in a structured clinical setting.
Frontiers in Psychiatry
June 10, 2026
Wesley H. Fleming
Moral injury involves disruptions in self-referential processing, including rigid negative self-appraisals and impaired meaning-making after morally injurious events. This paper proposes self-transcendence—a metacognitive state of reduced self-focus, expanded awareness, and prosocial meaning—as a mechanism for recovery. Drawing on Mindfulness-to-Meaning Theory, mindfulness practice is theorized to cultivate self-transcendence via decentering and meta-awareness, which broaden attentional scope and modulate habitual self-processing. The integrative review suggests that fostering self-transcendence through mindfulness-based and contemplative practices may reduce rigid self-focus, expand interpretive frameworks of meaning, and support moral identity repair. Implications for designing interventions that cultivate self-transcendence are discussed, along with limitations in measurement and reliable induction of such states.
Frontiers in Psychiatry
April 13, 2026
Craig F. Ferris
Psychiatric drug development has stagnated for decades, with treatments for depression, schizophrenia, and PTSD offering only partial relief—remission rates of 30-40% for treatment-resistant depression and 60-70% of schizophrenia patients experiencing persistent symptoms. A paradigm shift proposes that mental illness stems from breakdowns in the brain's sensory filtering mechanisms, which gate irrelevant stimuli. The cerebellum is identified as a critical hub for bottom-up sensory gating, housing over half the brain's neurons and showing disrupted connectivity during PTSD symptom provocation. Psychedelic drugs may recalibrate these filters by disrupting entrenched filtering architectures and reopening plasticity windows. This framework extends predictive processing theory with a specific neural substrate and suggests novel therapeutic targets.
Frontiers in Psychiatry
April 7, 2026
Ravi Philip Rajkumar
Complex PTSD (C-PTSD) is a chronic condition that includes both the classic PTSD triad of reexperiencing, avoidance, and hypervigilance, plus a second triad of disturbances in self-organization: mood dysregulation, interpersonal difficulties, and negative self-image. About 2-8% of the world's population is affected, with higher rates in refugees and childhood abuse survivors. Current treatments for PTSD symptoms show limited benefit for the disturbances in self-organization. Animal research suggests that alterations in oxytocin and vasopressin, linked to evolved appeasement and submission behaviors, may underlie these social and emotional symptoms. This model requires further verification in human studies.
Frontiers in Psychiatry
April 1, 2026
Jonathan Stellmacher, Christopher Schmidt, Helena Aicher et al.
Therapists in Switzerland who provide psychedelic-assisted therapy (PAT) adapt psychotherapeutic techniques to the psychedelic context but retain similarities to non-psychedelic practices. The psychedelic and psychotherapeutic elements work synergistically, amplifying general therapeutic factors such as trust, a sense of profundity, and the emergence of therapeutic experiences. Therapists agreed that psychedelics act as unspecific catalysts for psychotherapeutic processes, while also acknowledging unique interactions between the drug and therapy. For specific indications, incorporating psychedelics into long-term psychotherapy may strengthen therapeutic processes.
Frontiers in Psychiatry
March 4, 2026
Robert Queissner, F. Fellendorf, E. Z. Reininghaus
Ketamine and its derivative esketamine provide rapid and effective relief from depressive symptoms in treatment-resistant bipolar depression, with a low risk of triggering mania or hypomania. Evidence from randomized controlled trials and real-world studies shows significant improvement in depressive symptoms within hours of administration. Intranasal esketamine demonstrates comparable efficacy and safety in bipolar and unipolar depression, with no reported cases of mania or hypomania. These treatments offer a mechanistically novel alternative to conventional antidepressants, which often work slowly or incompletely and may increase the risk of mood switching. Long-term data are still needed to confirm sustained safety and efficacy.
Frontiers in Psychiatry
January 22, 2026
Alka Christnacht, Therry Rose Eparwa, Emily Whinkin et al.
Ketamine assisted psychotherapy (KAP) may help treat postpartum mood and anxiety disorders (PMADs) when introduced within the first two years after childbirth. Existing medications often fail to work quickly enough, are hard to access, or provide only short-term relief. This retrospective case series describes three individuals who received KAP as part of a comprehensive treatment plan. The report highlights how psychedelic insights gained during sessions may contribute to symptom improvement, suggesting KAP could offer a more effective and sustained therapeutic option for postpartum mental health.
Frontiers in Psychiatry
December 4, 2025
Adam Włodarczyk, Jakub Słupski, Joanna Szarmach et al.
Ketamine may be a viable treatment option for patients with treatment-resistant post-stroke depression. Further research is needed to better understand its efficacy and safety in this specific patient population.