The SARS-CoV-2 pandemic has resulted in 762 million infections worldwide from 2020 to date, of which approximately ten percent are suffering from the effects after infection in 2019 (COVID-19) [1, 40]. In Germany, it is now assumed that at least one million people suffer from post-COVID condition with long-term consequences. These have been previously reported in diseases like Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS). Symptoms show a changing variability and recent surveys in the COVID context indicate that 10-30 % of outpatients, 50 to 70% of hospitalised patients suffer from sequelae. Recent data suggest that only 13% of all ill people were completely free of symptoms after recovery [3, 9]. Current hypotheses consider chronic inflammation, mitochondrial dysfunction, latent viral persistence, autoimmunity, changes of the human microbiome or multilocular sequelae in various organ system after infection. Hyperbaric oxygen therapy (HBOT) is applied since 1957 for heart surgery, scuba dive accidents, CO intoxication, air embolisms and infections with anaerobic pathogens. Under hyperbaric pressure, oxygen is physically dissolved in the blood in higher concentrations and reaches levels four times higher than under normobaric oxygen application. Moreover, the alternation of hyperoxia and normoxia induces a variety of processes at the cellular level, which improves oxygen supply in areas of locoregional hypoxia. Numerous target gene effects on new vessel formation, anti-inflammatory and anti-oedematous effects have been demonstrated [74]. The provision of intermittently high, local oxygen concentrations increases repair and regeneration processes and normalises the predominance of hyperinflammation. At present time only one prospective, randomized and placebo-controlled study exists with positive effects on global cognitive function, attention and executive function, psychiatric symptoms and pain interference. In conclusion, up to this date HBO is the only scientifically proven treatment in a prospective randomized controlled trial to be effective for cognitive improvement, regeneration of brain network and improvement of cardiac function. HBOT may have not only theoretical but also potential impact on targets of current pathophysiology of Post COVID condition, which warrants further scientific studies in patients.

Individuals with persistent depressive disorder (PDD) are at increased risk for suicidality. Suicidality may be precipitated by loneliness. However, their temporal interplay in PDD has not been studied. We conducted a feasibility study using ecological momentary assessment (EMA) to measure short-term courses of suicidality and loneliness in 20 inpatients with PDD and current suicidality. EMA adherence of 13 completers was 81.3%. Suicidal ideations and loneliness varied with one standard deviation over three to six hours. This pilot study confirmed the feasibility of EMA in PDD and provided new insights in dynamics of suicidality and loneliness informing future study designs.

Recent empirical findings suggest that negative symptoms are not limited to schizophrenia (SCZ) but also present in major depressive disorder (MDD) and bipolar disorder (BD) patients. Although SCZ patients generally showed a latent structure comprising the motivation and pleasure (MAP) and expression (EXP) factors, it remains unclear whether the same latent structure exists in MDD and BD patients. We administered the Clinical Assessment Interview for Negative Symptoms (CAINS) and the Brief Negative Symptom Scale (BNSS) to 179 MDD patients and 152 BD patients. Confirmatory Factor Analysis (CFA) was conducted to examine the one-factor model, the two-factor model of the MAP and the EXP domain, the five-factor model of anhedonia, avolition, asociality, alogia, and blunted affect, and the hierarchical model comprising the first-order five-factor, and the second-order two-factor (MAP and EXP factors). We further examined the correlations between demographics and the negative symptom dimensions found in the best factor model. The CFA showed that, when the CAINS and the BNSS were combined together, the two-factor model of MAP and EXP provided the best model fit than other competing models, in the MDD alone sample, BD alone sample, and the combined clinical sample. The two-factor model of the MAP and EXP appears to be a stable, transdiagnostic latent structure of negative symptoms across BD and MDD. Clarifying negative symptoms in MDD and BD can facilitate future research on the underlying neural mechanisms of the MAP and EXP dimensions.

Cardiac autonomic dysfunction (CADF), mainly characterized by increased heart rate, decreased heart rate variability, and loss of vagal modulation, has been extensively described in patients with schizophrenia (SCZ) and their healthy first-degree relatives. As such, it represents an apparent physiological link that contributes to the increased cardiovascular mortality in these patients. Common genetic variation is a putative underlying mechanism, along with lifestyle factors and antipsychotic medications. However, the extent to which CADF is associated with genetic factors for SCZ is unknown. A sample of 83 drug-naive SCZ patients and 96 healthy controls, all of European origin, underwent a 30-minute autonomic assessment under resting conditions. We incorporated parameters from several domains into our model, including time and frequency domains (mean heart rate, low/high frequency ratio) and compression entropy, each of which provides different insights into the dynamics of cardiac autonomic function. These parameters were used as outcome variables in linear regression models with polygenic risk scores (PRS) for SCZ as predictors and age, sex, BMI, smoking status, principal components of ancestry and diagnosis as covariates. Of the three CADF parameters, SCZ PRS was significantly associated with mean heart rate in the combined case/control sample. However, this association was was no longer significant after including diagnosis as a covariate (p = 0.29). In contrast, diagnostic status is statistically significant for all three CADF parameters, accounting for a significantly greater proportion of the variance in mean heart rate compared to SCZ PRS (approximately 16% vs. 4%). Despite evidence for a common genetic basis of CADF and SCZ, we were unable to provide further support for an association between the polygenic burden of SCZ and cardiac autonomic function beyond the diagnostic state. This suggests that there are other important characteristics associated with SCZ that lead to CADF that are not captured by SCZ PRS.

This study aimed to examine longitudinal changes in motor dexterity (MD) performance in first episode of psychosis (FEP), focusing on diagnosis-specific trajectories. Participants were recruited from the project PAFIP in Spain (134 FEP, 84 HC). MD was assessed using the Grooved Pegboard Test at baseline and at 10-year follow-up. Clinical and premorbid data were collected for the patients. FEP participants were classified as having schizophrenia (SCZ) or other psychosis (OP) and compared with a group of healthy controls (HC). MD correlated significantly with age and intelligence in all participants. MD in SCZ patients was additionally correlated with premorbid adjustment and negative symptoms, whereas in the OP group the association was with antipsychotic dose. SCZ patients showed a slight decline in MD at follow-up, whereas the OP and HC groups remained stable. There may be different long-term trajectories of MD across diagnoses in FEP patients. Early developmental factors such as premorbid adaptation and cognitive function, together with age-related changes, may influence a mild decline in MD specifically in schizophrenia.

The modulation of gut microbiota through probiotics holds promise as a novel avenue for schizophrenia treatment. This study aims to analyze probiotic complementary therapy on individuals with schizophrenia systematically, to investigate probiotic efficacy, potential mechanisms, and implications for clinical practice. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched in Medline, Web of Science, Embase, ClinicalTrials.gov, CNKI, VIP, and WanFang databases using keywords ("probiotics" OR "prebiotics" OR "synbiotics" OR "Lactobacillus" OR "Bifidobacterium") AND ("schizophrenia"), focused on randomized controlled trials published before July 1, 2023. Among the identified studies, 8 randomized controlled trials met the inclusion criteria, encompassing a total of 342 participants in the intervention group and 306 participants in the control group. Our analysis revealed a statistically significant reduction (p = 0.03) in the total Positive and Negative Syndrome Scale (PANSS) scores following probiotic treatment in individuals with schizophrenia. While no statistical significance was observed in individual subscales (P > 0.05), significant improvements were noted in insulin levels, Insulin Resistance Index (IRI), and glucose levels. Additionally, the Quantitative Insulin Sensitivity Check Index (QUICKI) demonstrated a significant increase (all P < 0.05). The probiotic intervention significantly reduced gastrointestinal discomfort among schizophrenia patients (P = 0.003). This study suggests that probiotics could hold therapeutic potential for addressing clinical symptoms, abnormal glucose metabolism, and gastrointestinal discomfort in individuals with schizophrenia. Future research should encompass comparative trials employing robust experimental designs to explore the differential effects of various probiotic strains on schizophrenia treatment to provide evidence-based therapeutic approaches. TRIAL REGISTRATION: This review protocol was pre-registered on PROSPERO (No. CRD42023455273).

Prior research shows that locked doors and coercive measures are not only applied due to safety concerns, but also due to the specific local tradition of an institution. We examined the association of the use of coercive measures and the admission to a locked ward with person-related characteristics compared to the admission to a specific clinic. In this 15-year, naturalistic observational study, we examined 230,684 admissions to 14 German psychiatric inpatient clinics from Jan 1, 1998, to Dec 31, 2012. To analyze the degree to which admission to a locked ward and coercive measures (received vs. not received) were connected with person- and clinic-specific factors, two-step logistic regression analyses were applied. 27% of the variance of the admission to a locked ward were explained by person-related characteristics (Nagelkerke r = 0.269). By adding the clinic the person was admitted to, the explained variance increased by 15% (Nagelkerke r = 0.418). 36% of the variance of the use of coercive measures were explained by person-related characteristics (Nagelkerke r = 0.364). By adding the clinic the person was admitted to, the explained variance increased by 4% (Nagelkerke r = 0.400). The local tradition of a psychiatric clinic seems to play a more prominent role for the decision to admit a person to a locked ward than for the decision to use coercive measures. Clinicians should be made aware of the connection of local traditions with clinical pathways in acute psychiatry to avoid unnecessary admissions to locked wards.

The quantity and quality of real-world data and real-world evidence in schizophrenia research are at a high level. However, these results are not included in the grading systems used to develop treatment guidelines for schizophrenia. A meta-analysis and a network meta-analysis have independently provided evidence that the results of randomized clinical trials in schizophrenia adequately translate to real-world settings. The authors propose the incorporation of a synthesis of evidence derived from analyses of randomized controlled trials and real-world data as a novel and highest level of evidence in grading instruments used to develop treatment guidelines for schizophrenia.

Childhood maltreatment may be linked to epigenetics and brain-derived neurotrophic factor (BDNF) changes, which are mechanisms altered in several psychiatric conditions, including bipolar disorder (BD). However, the specific mechanisms connecting childhood maltreatment to the pathophysiology of BD remain unclear. The present study aims to examine the effects of childhood maltreatment on epigenetic and neurotrophic outcomes in BD patients and health controls. History of childhood maltreatment was obtained using the Childhood Trauma Questionnaire (CTQ) from 36 BD outpatients and 46 healthy subjects. DNA methyltransferase (DNMT) activity, HMTH3K9 activity, histone 3 lysine 9 tri-methylation (H3K9me3) levels, histone deacetylase (HDAC)1 levels, HDAC2 levels, histone 3 lysine 14 acetylation (H3K14ac) levels, and mRNA of BDNF were evaluated in peripheral blood mononuclear cells. Plasma BDNF levels were also measured. Total scores of CTQ, as well as the subscale scores of emotional abuse, sexual abuse, and emotional neglect, were predictive of changes in DNMT and HMTh3k9 activity, H3K9m3 levels, BDNF mRNA expression, and BDNF levels. These findings were observed in all our samples and, in some cases, among BD patients. Emotional abuse was the main childhood maltreatment subtype associated with epigenetic alterations in BD. Our results elucidate some mechanisms by which childhood maltreatment can alter epigenetic and neurotrophic markers. Especially in BD subjects, our results suggest childhood maltreatment per se is not a direct cause for epigenetic alterations. In another way, we suppose that the effect of childhood maltreatment could be cumulative and interact with other factors associated with the pathophysiology of BD.

Sleep Disturbances (SD) have been linked to children and adolescents with ADHD, impacting its progression and outcomes. Methylphenidate (MPH), a commonly used stimulant medication for ADHD treatment, has been observed to potentially influence SD as a side effect, while SD can in turn potentially affect the response to MPH. This study aimed to explore the potential role of SD on MPH response in children and adolescents with ADHD. At this aim, 43 children and adolescents with ADHD received a single dose of MPH and were assessed for attention before and after medication administration. As expected, the administration of MPH resulted in improved attention levels. Our data indicate that patients with higher SD experienced greater benefits from the medication, stabilizing Reaction Times Variability (VRTs). This suggests that SD might influence the response to MPH, with individuals exhibiting higher SD deriving more advantages from the treatment. In addition, we found that other factors, such as externalizing problems and IQ, interact with each other and with SD, influencing the response to stimulant medication. Early detection of SD, along with the study of cognitive and emotional-behavioral characteristics, could assist clinicians in predicting the effectiveness of MPH therapy in children and adolescents with ADHD. However, further research is necessary to gain a deeper understanding of the role of SD and other factors in the long-term effects of MPH.

Intermittent theta burst stimulation (iTBS) has demonstrated potential in reducing suicidal ideation (SI) in patients with depression, however, stimulation protocols vary greatly across studies. For this secondary analysis, data from a three-site double-blind, randomized and sham-controlled clinical trial was analyzed to investigate the efficacy of a once-daily versus twice-daily iTBS protocol in the treatment of SI in patients with treatment resistant depression. Secondarily we aimed to explore the associations among SI, anhedonia and quality of life (QOL) measures. The primary outcome for this analysis was SI, which was assessed by computing an average score from four suicidality items on separate depression scales. 158 participants who experienced some degree of SI at baseline were included in the analysis. After 10 days of treatment, 15 (18.3%) participants from the once-daily group and 19 (25%) from the twice-daily group achieved remission from SI which was defined as a SI score of 0. After 30 days of treatment the remission rates were 27 (32.9%) and 30 (39.5%), respectively. There were no significant differences in remission rates between the groups. Moderate correlations between change in SI and change in depressive symptoms were observed. In addition, correlations between change in SI, anhedonia and QOL were observed that remained significant after controlling for change in depressive symptoms. Achieving remission from SI appears to be at least partially correlated to the anti-depressant effect of iTBS. Further studies investigating optimal treatment protocols for the treatment of suicidality with different iTBS schedules are urgently needed. Trial registration Clinicaltrials.gov ID: NCT02729792 ( https://clinicaltrials.gov/ct2/show/NCT02729792 ).

In this article we aimed synthesize all available evidence regarding the effects of non-invasive brain stimulation (NIBS) techniques combined with mindfulness-based interventions (MBIs) on mental health indicators. We performed a systematic review of randomized controlled trials evaluating NIBS/MBIs combinations in clinical populations and a random effects pairwise meta-analysis of studies evaluating anxiety and depression symptoms. After independent trial selection by two authors based on titles/abstracts, and then on full texts, twelve trials were retrieved. There was a large effect size favoring the NIBS/MBIs over the control intervention for anxiety symptoms (Cohen's d = - 0.82 (- 1.35, - 0.30), I = 55%, moderate certainty of evidence). As for depression symptoms, there was a small-to-medium effect size that did not reach statistical significance (Cohen's d = - 0.24 (- 0.61, 0.13), I = 30%, low certainty of evidence). MBIs/NIBS combination is feasible and well tolerated. There is preliminary evidence for its therapeutic promise. Future studies should inform combination choices by neural correlates of respective interventions and offer patients mindfulness familiarization before implementation of the NIBS/MBIs treatment.Trial registration CRD42022353971.

Diffusion imaging studies in Attention-deficit/hyperactivity disorder (ADHD) have revealed alterations in anatomical brain connections, such as the fronto-parietal connection known as superior longitudinal fasciculus (SLF). Studies in neurotypical adults have shown that the three SLF branches (SLF I, II, III) support distinct brain functions, such as attention and inhibition; and that their pattern of lateralization is associated with attention performance. However, most studies in ADHD have investigated the SLF as a single bundle and in children; thus, the potential contribution of the lateralization of the SLF branches to adult ADHD pathophysiology remains to be elucidated. We used diffusion-weighted spherical deconvolution tractography to dissect the SLF branches in 60 adults with ADHD (including 26 responders and 34 non-responders to methylphenidate, MPH) and 20 controls. Volume and hindrance modulated orientational anisotropy (HMOA), which respectively reflect white matter macro- and microstructure, were extracted to calculate the corresponding lateralization indices. We tested whether neurotypical controls differed from adults with ADHD, and from treatment response groups in sensitivity analyses; and investigated associations with clinico-neuropsychological profiles. All the three SLF branches were lateralized in adults with ADHD, but not in controls. The lateralization of the SLF I HMOA was associated with performance at the line bisection, not that of the SLF II volume as previously reported in controls. Further, an increased left-lateralization of the SLF I HMOA was associated with higher hyperactivity levels in the ADHD group. Thus, an altered asymmetry of the SLF, perhaps especially of the dorsal branch, may contribute to adult ADHD pathophysiology.

As a wide group of medicines, the effectiveness and safety of 'medical cannabis' products is likely to vary in relation to product-specific dimensions such as potency, dosage, route of administration, and cannabinoid composition. Systematic reviews can perform a crucial role in analysing and synthesising the outcomes of medical cannabis interventions found in empirical research. We analysed 23 contemporary systematic reviews on the effectiveness and safety of medical cannabis to discern the extent to which this body of work aimed to capture, and ultimately captured, the differing outcomes of medical cannabis products by product-specific dimensions of treatment. We further highlighted the methodological reasons given by authors for an inability to describe this granular level of information. We found that a minority of systematic reviews explicitly aimed to perform a subgroup analysis to determine differences in treatment outcomes by product-specific dimensions of medical cannabis, with even fewer subsequently doing so. Authors' stated reasons for this concerned either overly large or overly small levels of variation in the characteristics, compositions, and administrations of medical cannabis products used, rendering subgroup analyses methodologically inappropriate or inapplicable. Furthering systematic reviews' abilities to capture granular information on medical cannabis treatment outcomes in relation to product-specific dimensions of treatments will require further standardisation of treatments in empirical studies.

Alcohol consumption (AC) is a leading risk factor for death, morbidity, and disability worldwide. Gender-specific differences in AC and its moderators, which may serve as markers for preventing severe alcohol use disorders (AUD), showed inconsistent results. Additionally, the impact of COVID-19-related lockdowns on these differences remains unclear. We examined gender-specific differences in short- and long-term factors affecting AC in individuals at risk for alcohol dependence, focusing on mood, stress, and the influence of restriction-dependent lockdown phases. 358 subjects with AUD aged 16 to 65 were studied over one year. Daily electronic diaries and monthly questionnaires were conducted from 10/01/2020 to 09/30/2021, assessing real-world trajectories of AC, mood (MDMQ), and stress (PSS-10) during Germany's second COVID-19 wave. Multi-level models were used to assess associations between these measures and with several within- and between-subject variables. During lockdown, women experienced lower and even decreasing mood (valence: β = - 0.2, p < .039; calmness: β = - 0.3, p < .010), while men's mood increased from the most restrictive lockdown phase (valence: β = 0.2, p < .001; calmness: β = 0.3, p < .001) to post-lockdown (valence: β = 0.5, p < .001; calmness: β = 0.6, p < .001). Stress increased earlier (β = 0.8, p < .001) and more prolonged (β = 0.4, p = .021) in women than in men. For both genders, daily mood was positively associated with daily AC (valence: β = 0.6, p = .004; calmness: β = 0.4, p = .013), leading to stronger drinking on days with elevated mood. Conversely, average mood was negatively associated with average AC (valence: β = - 1.6, p = .011; calmness: β = - 1.2, p = .041), indicating higher overall consumption with worse overall mood. Our findings highlight the need for interventions targeting mental distress in women with AUD during pandemics, as this group faces increased mental burden during social isolation and increased risk of alcohol dependence during persistent distress.

There is a need to identify and to better understand key processes involved in voice hearing, which can inform the targeting and development of psychological interventions for distressing voices. The current study aimed to examine interrelations between the negative impact of voices, voice characteristics, emotional distress and recovery before and after cognitive behavioural interventions for voices (Coping Strategy Enhancement, guided self-help Cognitive Behavioural Therapy, Relating Therapy and Person-Based Cognitive Therapy).

Reward system dysfunction is implicated in the pathogenesis of major psychiatric disorders. We conducted a genome-wide association study (GWAS) to identify genes that influence activation strength of brain regions within the extended reward system in humans. A homogeneous sample of 214 participants was genotyped and underwent functional magnetic resonance imaging (fMRI). All subjects performed the 'desire-reason dilemma' (DRD) paradigm allowing systematic investigation of systems-level mechanisms of reward processing in humans. As a main finding, we identified the single nucleotide variant rs113408797 in the DnaJ Heat Shock Protein Family Member C13 gene [DNAJC13], alias Receptor-Mediated Endocytosis 8 [RME-8], that was associated with the activation strength of the ventral tegmental area (VTA; p = 2.50E-07) and the nucleus accumbens (NAcc; p = 5.31E-05) in response to conditioned reward stimuli. Moreover, haplotype analysis assessing the information across the entire DNAJC13 locus demonstrated an impact of a five-marker haplotype on VTA activation (p = 3.21E-07), which further corroborates a link between this gene and reward processing. The present findings provide first direct empirical evidence that genetic variation of DNAJC13 influences neural responses within the extended reward system to conditioned stimuli. Further studies are required to investigate the role of this gene in the pathogenesis and pathophysiology of neuropsychiatric disorders.

The Ritvo Autism Asperger Diagnostic Scale-Revised (RAADS-R) demonstrated excellent results in its original study, with a sensitivity of 97% and a specificity of 100% (Ritvo et al. in J Autism Dev Disord 41:1076-1089, 2011). As a result, it was included in the National Institute for Health and Care Excellence (NICE) guidelines (Recommendations | Autism spectrum disorder in adults: diagnosis and management | Guidance | NICE, 2022). The questionnaire includes 80 questions across four subcategories (language, social relatedness, circumscribed interests, sensory motor). So far, the subcategory sensory motor has not been addressed in most available instruments, despite being part of the diagnostic criteria specified in DSM-5 (Falkai et al., in Diagnostisches Und Statistisches Manual Psychischer Störungen DSM-5. Hogrefe, 2015) and ICD-11 (ICD-11 for Mortality and Morbidity Statistics, 2022). In our validation study, we tested a translated German version of the questionnaire in 299 individuals (110 persons with ASD according to ICD-10 F84.0, F84.5, 64 persons with an primary mental disorders (PMD), 125 persons with no disorders). To enhance the practical use of the instrument in clinical everyday practice, the questionnaire was completed by the participants without the presence of a clinician-unlike the original study. Psychiatric diagnoses were established following the highest standards, and psychometric properties were calculated using established protocols. The German version of the RADS-R yielded very good results, with a high sensitivity of 92.5% and a high specificity of 93.6%. The area under the curve (AUC = 0.976), indicates a high quality and discriminatory power of RADS-R. Furthermore, the ROC curve analysis showed that the optimal threshold to distinguish between the ASD and non-ASD groups in the German version of the RAADS-R is a score of 81. In comparison to the RADS-R, the co-administered instruments Social Responsiveness Scale (SRS), Autism Spectrum Quotient (AQ), and Empathy Quotient (EQ) each showed slightly better specificity but worse sensitivity in this sample.The study included individuals already diagnosed with ASD according to ICD-10 (F84.0, F84.5), with or without an primary mental disorders, preventing us from identifying the influence of comorbidities on the RADS-R results. In addition, a self-report questionnaire has generally only limited objectivity and may allow for false representation of the symptoms. The RADS-R compares well with other questionnaires and can provide valuable additional information. It could turn out to be a helpful diagnostic tool for patients in Germany. We propose naming the German version RADS-R (Ritvo Autism Diagnostic Scale - rRevised) to reflect the change in terminology.

We present a narrative review of clinical trials investigating the anxiolytic and antidepressant effects of silexan, an active substance derived from lavender oil and summarize nonclinical findings from pharmacological studies supporting its therapeutic use. Six studies investigated the efficacy of the lavender oil in patients with subthreshold and generalized anxiety disorders as well as in mixed anxiety and depressive disorder (MADD). Furthermore, we present data indicating that silexan may influence sleep quality as well as anxiety or depressive disorders in individuals with post-COVID-19. Silexan taken orally at a daily dose of 80 mg for 10 weeks was significantly superior to placebo in reducing psychic and somatic symptoms of anxiety and was as effective as 0.5 mg/d lorazepam and 20 mg/d paroxetine. In patients with mild or moderate major depression, silexan was superior to placebo and comparably effective to 50 mg/d sertraline. Significant antidepressant effects were also observed in MADD and depression co-morbid with anxiety. The herbal product had a beneficial effect on activities of daily living and health-related quality of life. Adverse events associated with silexan in clinical trials were limited to eructation and mild, transient gastrointestinal complaints. The herbal product was not associated with drug interactions, sedation, sleep disturbance, dependence and abuse potential, sexual dysfunction, weight gain or withdrawal symptoms. Silexan was therefore safe and effective in subthreshold and syndromal anxiety disorders and in major depression.

This systematic review aims to elucidate the nexus between ketamine's psychoactive properties and its efficacy in treating a broad spectrum of psychiatric disorders. We searched three databases and used citation tracking to include 29 studies. Predominantly, mood disorders, including bipolar disorder (BD) and major depressive disorder (MDD) (MDD + BD: + n = 25 studies), a large part of them involve treatment-resistant patients (n = 14 studies), substance use disorder (SUD, n = 3 studies), and social anxiety disorder (SAD, n = 1 study). From all included studies (n = 29), 15 (51.72%) of them identified a positive relation between ketamine-induced altered states of consciousness and clinical outcomes, while 13 studies (44.83%) showed no linkage between them, and one study (3.45%) delineated a negative association. Focusing solely on intravenous (IV) ketamine infusions (n = 25), 14 studies (56%) reported a positive modulation of ketamine's psychoactive effects and therapeutic benefits, whereas 10 studies (40%) confirmed no relationship, and one study (4%) showed a negative association. The single study (33.34%) involving subcutaneous ketamine and all three studies (66.6%) intranasal administration did not demonstrate a significant interaction between ketamine's psychoactive effects and therapeutic response. All three SUD studies reported a positive correlation between ketamine's psychoactive effects and therapeutic response. In contrast, the single SAD study did not find a relationship between these parameters. For studies involving mood disorders (n = 25), 12 studies (48%) reported a positive relationship between psychoactive effects and therapeutic response. Others 12 studies (48%) identified a null relationship, and one study (4%) found a significant negative association. Although we have found a larger association than previous studies between ketamine's psychoactive properties and its efficacy in treating a broad spectrum of psychiatric disorders, its topic remains indeterminate, mainly due to the high heterogeneity.