European archives of psychiatry and clinical neuroscience
December 1, 2021
Josef Parnas, Annick Urfer-Parnas, Helene Stephensen
59 citations
People with schizophrenia can live in two separate worlds at once: the shared social world and a private delusional world. Eugen Bleuler called this "double bookkeeping" but never explained it. This article shows that double bookkeeping appears across many psychotic symptoms and can be observed before psychosis starts and in schizotypal disorder. The authors propose that double bookkeeping arises from instability in how the self feels itself from within, a process called auto-affection. They discuss four implications for diagnosis, understanding, treatment, and research into causes.
European archives of psychiatry and clinical neuroscience
June 1, 2022
Lucas Silva Rodrigues, Giordano Novak Rossi, Juliana Mendes Rocha et al.
48 citations
Ayahuasca and its alkaloids show therapeutic potential for substance use disorders, according to an updated systematic review of nine studies (four preclinical, five observational) published between 2016 and 2020. Preclinical rodent studies found reductions in amphetamine self-administration, anxiety, and conditioned place preference for alcohol and methylphenidate. Observational studies in healthy ritual ayahuasca users and patients with substance use disorders reported decreased drug use, anxiety, and depression, along with improved quality of life and well-being. The review replicates earlier findings but notes limited translation from animal studies, inability to infer causality from observational designs, and lack of dose standardization. Randomized controlled trials are needed.
European archives of psychiatry and clinical neuroscience
September 1, 2024
Helene Stephensen, Annick Urfer-Parnas, Josef Parnas
28 citations
In schizophrenia, many patients experience a second, private reality alongside everyday shared reality, a phenomenon called double bookkeeping. In a qualitative study of 25 patients, most felt in contact with another dimension of reality that they considered more profound and real than the shared world. Hallucinations and delusions belonged to this separate reality, which patients usually kept distinct from ordinary life. This double reality persisted even during remission, and patients did not view their condition as an illness like a physical disease. Many described a vague sense of duality that began in childhood or early adolescence, tied to a fundamental alienation from self, world, and others.
European archives of psychiatry and clinical neuroscience
October 1, 2023
Juliana Mendes Rocha, José A S Reis, José Carlos Bouso et al.
21 citations
Ibogaine, a psychoactive alkaloid from the west-African shrub Tabernanthe iboga, is increasingly sought in Western cultures for its claimed anti-addictive properties, though evidence remains preliminary. Its use often occurs without medical supervision in uncontrolled settings and has been linked to severe adverse events. This systematic review evaluated clinical studies of ibogaine, focusing on administration settings to identify criteria promoting safer use. Following PRISMA guidelines, searches in PubMed, Scielo, ClinicalTrials.gov, and Core.ac.uk retrieved clinical studies published through November 17, 2022; 12 sources were synthesized. The review concludes that controlled settings with trained professionals and equipment for rigorous medical, psychiatric, and cardiac monitoring are essential for patient safety.
European archives of psychiatry and clinical neuroscience
July 13, 2024
Jenessa N Johnston, Carlos A Zarate, Mark D Kvarta
18 citations
Esketamine, the (S)-enantiomer of racemic ketamine, is an FDA-approved rapid-acting antidepressant for treatment-resistant depression (TRD) that outperforms traditional oral antidepressants. Research on biomarkers predicting response to esketamine remains limited and mostly extrapolated from racemic ketamine studies. Genetic, proteomic, and metabolomic profiles suggest inflammation and mitochondrial function may contribute to its effects, but these findings require verification. Neuroimaging consistently implicates the prefrontal cortex, striatum, and anterior cingulate cortex. In perioperative settings, esketamine reduces depression and anxiety, correlating with increased brain-derived neurotrophic factor and serotonin. Better-designed biomarker-focused clinical trials are needed to clarify mechanisms and identify patients most likely to benefit.
European archives of psychiatry and clinical neuroscience
February 1, 2025
Johanna Schwarz, Marcus Gertzen, Andrea Rabenstein et al.
14 citations
Chemsex users—men who have sex with men who use substances like methamphetamine, GHB, mephedrone, or ketamine to enhance sex—show more depression, hypersexuality, and sexual risk behavior than non-users. Their brain activity during a decision-making task revealed reduced N2 responses in fronto-central regions, indicating impaired executive function and inhibitory control. P3 amplitudes did not differ between groups. These deficits may contribute to greater risk of drug abuse and hypersexuality, and understanding them could inform interventions to reduce harm and improve well-being.
European archives of psychiatry and clinical neuroscience
February 1, 2023
Giordano Novak Rossi, Jaime E C Hallak, Glen Baker et al.
14 citations
A systematic review of clinical trials examined whether the antidepressant effects of ketamine and classical hallucinogens (ayahuasca) in treatment-resistant depression are linked to changes in inflammatory and neurotrophic biomarkers. Twelve studies involving 587 participants were analyzed, including two with oral ayahuasca and ten with ketamine. Results across all measured biomarkers were contradictory and inconclusive. The authors conclude that larger randomized controlled trials are needed to determine whether peripheral biomarkers can reliably indicate or measure the antidepressant effects of these substances.
European archives of psychiatry and clinical neuroscience
April 25, 2024
Li-Yuan Zhao, Guang-Fen Zhang, Xue-Jie Lou et al.
11 citations
Over the past two decades, research on the antidepressant effects of ketamine and its enantiomers has grown substantially, culminating in the approval of esketamine nasal spray for treatment-resistant depression. A bibliometric analysis of 4,274 publications from 2000 to 2023, using visualization tools, reveals two main research foci: the efficacy and safety of these compounds in treating depression, and the mechanisms underlying their rapid antidepressant effects. The rapid onset of ketamine's effects has spurred further investigation into its mechanisms and the search for new antidepressants with fewer side effects.
European archives of psychiatry and clinical neuroscience
March 1, 2025
Arilton Martins Fonseca, Rafael Guimarães Dos Santos, Lívia Soman de Medeiros et al.
10 citations
Long-term ritualistic ayahuasca use, spanning over 20 years, does not impair cognition and may be linked to better working memory compared to short-term use. In a study of 48 participants from a Santo Daime church in Brazil, experienced users (over 20 years) scored higher on tests of verbal and visuospatial working memory than beginners (under 3 years). No evidence of cognitive decline was found among ayahuasca users. The control group, matched by sex, age, and education, showed similar cognitive performance. The brew's botanical identities and alkaloid content were confirmed.
European archives of psychiatry and clinical neuroscience
September 28, 2024
Yue Wang, Qiongyao Yang, Chuanchuan Chen et al.
10 citations
After six low-dose esketamine infusions, patients with treatment-resistant depression showed improvement in anhedonia and depressive symptoms. Plasma levels of cortisol, interleukin-6, and tumor necrosis factor-alpha decreased, while the anti-inflammatory cytokine interleukin-4 increased. Baseline cortisol levels correlated with anhedonia, but inflammatory factors showed no significant correlation. Elevated plasma cortisol may serve as a potential biomarker for anhedonia in treatment-resistant depression.
European archives of psychiatry and clinical neuroscience
August 29, 2024
Florian Freudenberg, Christine Reif-Leonhard, Andreas Reif
10 citations
Changes in glutamate-related brain plasticity may underlie depression, leading researchers to explore components of the glutamate synapse as targets for faster-acting antidepressants. The NMDA receptor blocker ketamine and its S-enantiomer esketamine already show rapid antidepressant effects. This review examines other glutamatergic rapid-acting antidepressants beyond (es)ketamine that have meaningful clinical trial data, including arketamine, esmethadone, nitrous oxide, and other glutamate receptor modulators. Substances successful only in preclinical studies or case reports are discussed marginally. The authors aim to highlight glutamatergic modulation's critical role in advancing antidepressant therapy, potentially improving clinical outcomes and reducing depression's burden through faster therapeutic effects.
European archives of psychiatry and clinical neuroscience
December 16, 2024
Gustavo C Leal, Isabel Lima-Araújo, David G Roiter et al.
7 citations
Arketamine, an enantiomer of ketamine, has been less studied than esketamine or racemic ketamine, but recent preclinical work suggests it may have prolonged antidepressant effects and a better safety profile. This scoping review of 20 studies involving 410 subjects found arketamine was primarily investigated for pain management and depression. Early evidence indicates it may reduce pain, though most studies were small and in non-clinical settings. In psychiatry, trials show potential antidepressant effects, but results are inconsistent and some studies unpublished. A consistent finding is arketamine's favorable safety profile, with fewer dissociative and psychotomimetic effects than esketamine or racemic ketamine. Larger, well-designed studies are needed to determine its therapeutic potential.
European archives of psychiatry and clinical neuroscience
November 17, 2024
Anastasia Demina, Benjamin Petit, Vincent Meille et al.
6 citations
Combining non-invasive brain stimulation with mindfulness-based interventions shows a large effect on anxiety symptoms compared to control interventions, based on a systematic review and meta-analysis of twelve randomized controlled trials. The effect on depression symptoms was small-to-medium and not statistically significant. The combined treatment was feasible and well tolerated. The evidence for anxiety is of moderate certainty, while for depression it is low. Future research should explore which combinations work best by examining neural correlates and should familiarize patients with mindfulness before starting the combined treatment.
European archives of psychiatry and clinical neuroscience
April 1, 2026
Lars Siersbæk Nilsson, Julie Nordgaard, Mads Gram Henriksen et al.
5 citations
Poor insight in schizophrenia is linked to fundamental alterations in the structure of subjective experience, known as self-disorders, rather than to other symptoms or general intelligence. In a study of 67 patients with schizophrenia or non-affective psychosis in a non-acute phase, those with impaired insight had significantly higher levels of self-disorders than those with good insight, while positive, negative, and depressive symptoms did not differ between groups. Regression analyses showed that only self-disorders were significantly associated with impaired insight. These findings support the idea that self-disorders contribute to poor insight, which may inform early intervention and treatment.
European archives of psychiatry and clinical neuroscience
October 28, 2024
Kaike Thiê da Costa Gonçalves, Vagner Deuel O de Tavares, Maria Luiza de Morais Barros et al.
5 citations
A systematic review of 29 studies examined whether the psychoactive effects of ketamine are linked to its therapeutic benefits for psychiatric disorders. About half of the studies (51.72%) found a positive relationship between ketamine-induced altered states of consciousness and clinical outcomes, while 44.83% found no link, and one study found a negative association. For mood disorders like major depressive disorder and bipolar disorder, 48% of studies showed a positive relationship and 48% showed none. All three studies on substance use disorder reported a positive correlation. The authors conclude the relationship remains uncertain due to high variability across studies.
European archives of psychiatry and clinical neuroscience
October 9, 2024
Jiafeng Li, Ling Ma, Huan Sun et al.
5 citations
Racemic ketamine monotherapy rapidly reduces suicidal thoughts in people with unipolar or bipolar depression, but the effect is short-lived and esketamine shows inconsistent evidence. A meta-analysis of 13 randomized controlled trials involving 1,109 individuals found that those receiving racemic ketamine had a significantly higher rate of acute remission of suicidal ideation compared to placebo or midazolam (risk ratio 2.06). Racemic ketamine also lowered suicidal ideation scores. However, no significant long-term anti-suicidal effects were found for either racemic ketamine or esketamine, and evidence for esketamine was inconsistent.
European archives of psychiatry and clinical neuroscience
September 29, 2024
Ege T Kavalali, Lisa M Monteggia
4 citations
Ketamine's rapid antidepressant action works by driving synaptic plasticity mechanisms rather than altering neuronal circuitry or triggering neurogenesis. This discovery makes fast-acting treatments for mood disorders plausible. The review covers the authors' decade of research on the specific synaptic plasticity events that mediate these rapid effects, and discusses growing interest in alternative psychoactive compounds with similar properties.
European archives of psychiatry and clinical neuroscience
May 21, 2024
Zack Y Shan, Adem T Can, Abdalla Z Mohamed et al.
3 citations
Ketamine treatment for chronic suicidality alters how brain networks synchronize and transition over time. In a 6-week open-label trial with 29 patients, those who received ketamine showed significantly more transitions among whole-brain connectivity states after treatment. At a 10-week follow-up, patients spent more time in and more frequently visited a highly synchronized brain state, and these changes correlated with reduced suicidal ideation scores. Patients who persistently responded to ketamine had a higher baseline fraction of a cognitive control network state with strong connections, suggesting that pre-treatment brain connectivity patterns may help predict who will benefit from ketamine therapy. These findings point to a biological mechanism for ketamine's suicide-prevention effects.
European archives of psychiatry and clinical neuroscience
July 1, 2025
Erhan Kavakbasi, Kevin Rosemann, Mert Yilmaz et al.
2 citations
In patients with treatment-resistant depression, a history of not responding to electroconvulsive therapy does not significantly affect the outcome of subsequent treatment with intranasal esketamine. Among 96 inpatients, those who had previously not responded to ECT showed similar improvements in depression scores compared to those who had not received an adequate ECT course. Response and remission rates were numerically lower in the ECT non-response group, but the differences were not statistically significant. The findings support offering esketamine to ECT non-responders, given limited alternative treatments.
European archives of psychiatry and clinical neuroscience
June 1, 2025
Jan Sarlon, Else Schneider, Annette B Brühl et al.
2 citations
Adding a daily 30-day mindfulness mobile app (Headspace) to standard treatment helped reduce depression severity more than standard treatment alone in people with major depressive disorder. In a randomized trial with 83 patients, those using the app showed a significantly greater decrease in clinician-rated depression scores (HDRS) and lower systolic blood pressure after one month. Both groups improved from partial remission at hospital discharge, but the app group improved more. The total dropout rate was 29%. Short-term app-based mindfulness appears beneficial as a supplement to usual care.
European archives of psychiatry and clinical neuroscience
June 1, 2026
Ziping He, Yijie Wang, Jiemin Chen et al.
1 citation
A review of seven trials involving 464 adults with major depressive disorder found that psilocybin significantly reduces depression symptoms and is generally safe and tolerable. Higher doses (35–50 mg per 70 kg of body weight) and a double-dosing schedule were associated with better outcomes. The overall quality of the trials was moderate, and the authors note that the results are limited by small sample sizes and short follow-up periods, indicating a need for further research.
European archives of psychiatry and clinical neuroscience
June 30, 2026
C Hohoff, T Lange, L Steinbach et al.
Treatment resistance in major depressive disorder affects a substantial minority of patients and is hard to recognize early, delaying intensified care. The EMBER-MDD study is a non-interventional, in-vitro investigation that will analyze biospecimens from approximately 420 adults with major depressive disorder—about 210 who received esketamine nasal spray and 210 who received treatment as usual. Using genomics, epigenomics, transcriptomics, and proteomics/metabolomics, the study aims to discover individual-omic and integrated multi-omic biomarkers and signatures associated with treatment resistance risk and molecular correlates of clinical response. All outputs are research-only and will not support individual clinical decision-making. The study will deliver robust biosignatures and mechanistic hypotheses to guide future validation and inform stratified intervention strategies in subsequent trials.