Journal of Psychopharmacology

Ketamine and esketamine (“es/ketamine”) treatment protocols have been investigated in patients’ samples with treatment-refractory anxiety disorders. We systematically reviewed publications in which es/ketamine was used to treat anxiety symptoms in the context of either Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) anxiety disorders or treatment-resistant depression (TRD).

The literature search of English-language studies combining each of the keywords “ketamine” or “esketamine” with various psychopathological terms produced 4086 results. Through the use of specific inclusion/exclusion criteria, a total of 78 studies were eligible for inclusion.

Eleven studies investigated ketamine pharmacotherapy (no esketamine study was found) of patients suffering primarily from a DSM-5 anxiety disorder. Additionally, we found 67 studies which: (a) reported es/ketamine pharmacotherapy for treating primarily unipolar/bipolar depression and secondarily assessed changes in anxiety symptoms (N = 55); or (b) compared the outcome (depression/suicidality severity) of es/ketamine between “anxious” versus “non-anxious” TRD (N = 12). These studies were notably heterogeneous, and included randomized controlled trials, crossover trials, open-label studies, and case reports. Methods of administration of ketamine varied, including subcutaneous, intravenous, intramuscular, and oral; outcome measures also varied. Study findings suggest that es/ketamine is associated with a reduction of anxiety in the context either of anxiety disorders or of unipolar/bipolar TRD. These effects are sustained, especially with repeated doses and maintenance treatment: however, after terminating maintenance treatment anxiety symptoms may soon re-emerge. The tablet formulation reduces anxiety more slowly, but with fewer side effects.

There are indications that es/ketamine pharmacotherapy may reduce pathological anxiety, although relapse may follow its termination. More studies are needed to confirm these preliminary findings.

Previous systematic reviews and meta-analyses have reported impressive antidepressant effects of ketamine in treatment-resistant depression (TRD). While ketamine has been compared with electroconvulsive therapy (ECT), the gold standard treatment, the extent and durability of its antidepressant effects over longer periods remain unclear. To our knowledge, this is the first systematic review comparing average time-to-relapse between ECT and ketamine in TRD.

To compare the average time-to-relapse between ECT and ketamine for TRD.

We conducted this systematic review using PubMed, Medline, ScienceDirect, Cochrane Library, Ovid, PsycNET, Embase and Google Scholar, against predetermined criteria. PROSPERO ID: CRD42025643824.

Thirteen studies met inclusion criteria: 10 examined ketamine/(s)ketamine, and 3 focused on ECT. Twelve were randomised controlled trials (RCTs), and one was retrospective. Heterogeneity was observed in dosing regimens and administration schedules, with some studies having limited follow-up and small sample sizes. Findings are synthesised narratively. In summary, there is evidence for sustained therapeutic potential of both ECT and ketamine, ECT possibly being associated with longer remission. Increased dose, frequency and use of maintenance ECT/ketamine appear to prolong remission, and continuing oral antidepressants may prolong this further. It should also be noted that this review excluded studies involving psychotic depression, leading to the exclusion of some head-to-head studies, thus limiting the generalisability of the findings in these populations.

There is currently a lack of studies within our inclusion criteria that directly compare time-to-relapse after ECT and ketamine, preventing formal statistical analysis. More high-quality, large-scale RCTs directly comparing these treatment modalities with longer follow-up times are needed.

The trajectory and predictors of response under routine clinical care of esketamine nasal spray (ESK NS) over treatment-resistant depression (TRD) require elucidation.

This retrospective, longitudinal cohort study was conducted across three Spanish centers. Adults diagnosed with TRD who initiated ESK NS and completed at least the induction phase were included. Assessments occurred at baseline, weeks 2, 4, 8, 12, 16, and at discharge. Primary outcomes included depressive severity assessed with the Montgomery–Åsberg Depression Rating Scale (MADRS), functioning assessed with the Sheehan Disability Scale (SDS), and suicidal risk assessed with the Columbia–Suicide Severity Rating Scale (C-SSRS). Multivariable logistic regression examined several response predictors.

The study included 50 patients (52% women). Significant improvements were observed in MADRS and SDS scores at every time point (all p < 0.001), with notable increases during weeks 8–16, coinciding with optimization phase. The median time to response was 8 weeks, and to remission was 16 weeks. The last observation across the entire cohort indicated response and remission rates of 70% and 68%, respectively. C-SSRS risk categories shifted early toward lower risk with no suicide attempts during monitored treatment. Higher Maudsley Staging Model scores, indicating greater refractoriness, independently predicted lower odds of response (OR: 0.50, 95% CI: 0.29–0.86) and remission (OR: 0.59, 95% CI: 0.36–0.97). Among those discharged, 86% remained clinically stable over approximately 10 months.

In real-world clinical setting, ESK NS produces progressive improvements in depressive symptoms and functioning that often consolidating beyond the induction phase, especially during optimization phase.

While ketamine is widely used in anesthesia and pain management, its non-medical use is increasing worldwide. In France, surveillance data indicate a sharp rise in ketamine-related disorders, but comprehensive characterization of affected patients and associated complications remains limited.

To examine trends on ketamine in France from 2019 to 2023, and describe severe associated complications, with a focus on urinary, biliary, and ketamine use-related disorders, using data from the French Addictovigilance Network.

Two authors reviewed all ketamine-related cases reported to the French Addictovigilance Network between 2019 and 2023 and recorded in the French National Pharmacovigilance Database. In this retrospective descriptive analysis of national surveillance data, we included cases involving clinical complications related to ketamine use or abuse. Data were extracted on patient sociodemographic, use patterns, co-substance, and clinical features related to ketamine use (complications, seriousness, medical care).

We included 411 cases with 497 clinical manifestations, representing a 16-fold increase over 5 years. The median age was 23 years, and 59.1% of cases were classified as serious, with emergency or intensive care admissions frequently required. The main complications included ketamine use disorders (137 cases), psychiatric symptoms (124 cases), and neurological disorders (93 cases). Urinary tract toxicity was reported in 36 cases, with several requiring cystectomy and bladder reconstruction, and 8 cases involved cholangitis or cholestasis. Daily or regular use, often via the intranasal route, and polydrug use were common.

These findings demonstrate a marked increase in ketamine-related complications in France, particularly among young users. Severe urinary and biliary complications, alongside rising reports of ketamine use disorder, highlight an urgent need for awareness among clinicians, systematic screening, and targeted harm reduction and clinical screening strategies.

While research on novel therapeutic applications of ketamine is expanding, particularly in controlled settings, there is limited exploration of its consumption related to self-treatment of psychiatric conditions. This study investigated the characteristics of people who use ketamine and psychedelics for self-treatment of psychiatric conditions, providing insight into patterns of use within this population.

Utilising the 2020 Global Drug Survey, the analysis incorporates data from 5831 respondents who reported self-treating with unregulated drugs to treat diagnosed psychiatric conditions. We compare three groups: those self-treating with only ketamine (n = 242), ketamine and other psychedelics (n = 1072), and non-ketamine psychedelic only substances (n = 4517). Negative binomial regression was conducted to assess the impact of self-treating psychiatric conditions with ketamine and other psychedelics on the volume of recreational ketamine use.

A high proportion (>60%) had prior psychiatric diagnoses, with depression and anxiety being the most common. People who used both ketamine and other substances reported higher festival and clubbing attendance than the other two groups. People who used ketamine and combined it with other psychedelics used it more frequently (incidence rate ratio (IRR): 0.729, 95% confidence interval (CI): 0.336–1.581), while those using non-ketamine psychedelics only showed a significant reduction in ketamine usage volume (IRR: 0.160, 95% CI: 0.079–0.322) compared to other groups. Almost half of the respondents sought online advice before starting ketamine self-treatment.

This study extends knowledge about various populations using ketamine for self-treatment purposes, proposes areas for future research and suggests online platforms as the most effective place for harm reduction resources relating to ketamine use.

Lithium monotherapy has been recommended as first-line maintenance or long-term pharmacological therapy for bipolar disorder (BD). Previous research has linked early lithium use with better outcomes for people with BD. Despite extensive evidence as an effective treatment for BD, lithium prescribing continues to decline.

Our primary aim was to determine the time between initial assessment by mental health services and lithium initiation in people with BD who were prescribed and concordant with lithium. Secondary objectives included determining the time between the first assessment and recorded BD diagnosis, number of prior mood episodes, polarity when lithium was prescribed and number of antipsychotics before lithium initiation.

Free-text clinical notes were extracted from a de-identified electronic health record database. Eligible records comprised adults with a BD diagnosis who were concordant with lithium treatment.

Eighty-eight people were identified, based on inclusion and exclusion criteria. Median time between first assessment and lithium initiation was 659 days. Median time between first assessment and BD diagnosis was 220 days, with a median of 2.5 mood episodes and 2 antipsychotics prescribed prior to lithium. Around 30% of people presented with manic symptoms at the time of lithium prescription. There is a significant delay between first contact with services and initiation of lithium in people with BD.

This highlights the potential for earlier intervention with lithium, which could improve outcomes for people with BD.

Lithium is the gold-standard mood stabilizer in bipolar disorder (BD) showing putative neuroprotective effects, but its association with cognition in older adults with BD (OABD) remains unclear.

To examine the association of long-term lithium treatment with cognitive performance in euthymic OABD.

Forty outpatients aged 50–70 years with BD-I, without dementia or lifetime substance use disorder, completed a comprehensive neuropsychological battery. Participants were classified as lithium- (n = 19) or non-lithium-treated (n = 21). Test scores were converted to age- and education-adjusted Z-scores. We used t-tests/Mann–Whitney U tests, and Person’s correlations were Bonferroni-corrected. A principal component analysis-generated general cognitive factor was entered into logistic regression models predicting lithium status, with sequential adjustment for various covariates.

Lithium-treated patients showed large, widespread cognitive advantages in attention/working memory (Digit Symbol Forward Test (DSFT), d = 1.481; DSBT, d = 1.519), verbal learning and memory (Rey’s Auditory Verbal Learning Test (RAVLT) recognition, d = 1.803), processing speed (Symbol Digit Modalities Test (SDMT), d = 2.147), executive function (Trail Making Test – Part B, d = 1.330), and verbal fluency (Controlled Oral Word Association Test (COWAT), d = 1.423). Higher lithium levels correlated with better DSFT and SDMT performance after correction. Antipsychotic dose was strongly and negatively correlated with Mini-Mental State Examination, particularly in the non-lithium group. The general cognitive factor distinguished lithium from non-lithium patients (R² = 0.70), and its effect remained large and mostly significant across six adjusted models.

In euthymic OABD, chronic lithium treatment is associated with markedly better global cognition, independent of mood, illness severity, and polypharmacy. Our findings provide support for the role of lithium in cognitive preservation and are worthy of further investigation in larger longitudinal studies.

Lithium is an effective treatment for recurrent affective disorders, but it has a narrow therapeutic window and requires regular serum concentration monitoring, especially during periods of dose titration. Numerous attempts have been made to develop dose prediction methods to facilitate initiation and swift achievement of effective levels, but these typically lack sufficient accuracy and can be challenging to implement in practice.

Develop a pharmacokinetic model of lithium to enable accurate dose prediction which is adaptable for clinical practice.

The calculator was developed from a one-compartment model, which assumes that lithium distributes into total body water and requires only simple body measurements (age, sex, height and weight) as input variables. Its performance was compared to six commonly cited dose prediction methods in patients with bipolar disorder taking lithium, using two independent research samples from the United Kingdom (n = 40) and Germany (n = 18).

Our one-compartment model performed better than the previous models, accurately predicting the required lithium dose within one 200 mg lithium carbonate tablet. The mean prediction error was 10 mg (SD = 148 mg) in this sample of euthymic subjects taking stable doses of lithium sampled at steady state.

This model sets a new benchmark for lithium dose prediction accuracy and requires only simple body measurements. Further validation work in larger, diverse samples and future developments, such as the ability of the model to back-calculate levels from samples taken outside the recommended 12-hour window, may support its translation and use in practice.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has gained attention for its rapid antidepressant effects at subanesthetic doses. However, its potential for overdose and cognitive side effects, especially after misuse, remains a concern. The impact of ketamine on inhibitory control, a critical component of executive function, is not well understood. Oxytocin, a neuropeptide involved in emotional regulation and social cognition, may modulate cognitive functions, but its interaction with ketamine, particularly in relation to inhibitory control, remains unclear.

This study aimed to investigate the effects of ketamine on inhibitory control and explore whether oxytocin could mitigate these effects in a macaque monkey model.

In experiment 1, macaque monkeys (N = 4) received intramuscular ketamine (0.25, 0.5, or 1.0 mg/kg) or saline before performing the stop-signal task. In experiment 2, the 1.0 mg/kg ketamine dose was selected to assess whether intranasal oxytocin (50 IU) pretreatment could attenuate ketamine-induced cognitive impairments.

Ketamine significantly impaired response inhibition and execution in a dose-dependent manner, with the greatest deficits at 1.0 mg/kg. Oxytocin pretreatment significantly restored inhibitory control, normalizing stop-signal reaction time to levels comparable to the saline control condition.

These findings suggest that low-dose ketamine disrupts executive control in non-human primates, and that oxytocin may counteract these effects, particularly in inhibitory control. This interaction highlights a promising therapeutic pathway for executive dysfunction in neuropsychiatric disorders.

Interleukin-6 (IL-6) has been implicated as a potential predictor of ketamine response in treatment-resistant depression (TRD). Esketamine, the S-enantiomer of ketamine, produces rapid antidepressant effects and offers improved safety and intranasal administration.

To examine whether baseline IL-6 predicts treatment response to esketamine in individuals with TRD.

Fourteen adults with TRD received intranasal esketamine twice weekly for 4 weeks, followed by a tapering phase, in a 24-week open-label Phase 2 trial. Depression severity and functional disability were assessed using the Montgomery–Åsberg Depression Rating Scale (MADRS) and World Health Organization Disability Assessment Schedule at baseline, week 8, and week 24. Serum IL-6 levels were measured at the same time points. Linear mixed-effects models were used to evaluate the predictive value of IL-6.

MADRS scores improved significantly over time. Higher IL-6 levels were associated with more rapid symptom reduction, whereas lower IL-6 predicted greater symptom severity and higher disability. IL-6 levels did not change significantly over the course of treatment.

Baseline IL-6 may predict response to esketamine in TRD, highlighting the potential role of inflammation in treatment resistance and supporting biomarker-guided personalized interventions.