Clinical predictive factors and trajectories of suicidal remission over 6 weeks following intravenous ketamine for suicidal ideation.

BACKGROUND: Ketamine is efficient for short-term reduction of suicidal ideas. Predictive factors and outcome trajectories are poorly characterized. METHODS: Secondary analyses were conducted on the KETIS study (Abbar et al. BMJ 2022): 156 suicidal patients were randomized to two intravenous infusions of racemic ketamine (0.5 mg/kg) or placebo. Response or remission was assessed over six weeks based on the Beck Scale for Suicidal Ideation (SSI). We calculated i) predictive values of 12 baseline variables on remission ii) outcome courses, and iii) positive (PPV) and negative predictive values. RESULTS: In multivariate analyses, bipolar disorder, lower patient-rated suicidal ideas, and higher physical pain were predictive of suicidal remission at day 3. No clinical factor predicted remission at week 6. Twenty and 24 different clinical courses were identified in early (day 3) and later (week 6) follow-up, respectively, including around 40 % sustained remission, 50 % fluctuating course and 10 % no response. Suicidal remissions at day 1 and day 3 were highly predictive of remissions at day 3 and week 6 (PPV = 96.8 and 92.6 %). LIMITATIONS: SSI may not be adapted for rapid variations and repeated measures. CONCLUSIONS: Clinical factors were poorly predictive of remission. Fluctuations in suicidal ideas were frequent, even after ketamine (although less than placebo), necessitating vigilance and multimodal care. Remission at day 1 after one infusion was highly predictive of future remission. The benefits of a second infusion will have to be tested.

Development of the PREMIUM computerized adaptive testing for measuring the access and care coordination for patients with severe mental illness.

Severe mental illness (SMI) patients often have complex health needs, which makes it difficult to access and coordinate their care. This study aimed to develop a computerized adaptive testing (CAT) tool, PREMIUM CAT-ACC, to measure SMI patients' experience with access and care coordination. This multicenter and cross-sectional study included 496 adult in- and out-patients with SMI (i.e., schizophrenia, bipolar disorder, or major depressive disorder). Psychometric analysis of the 13-item bank showed adequate properties, with preliminary evidence of external validity and no substantial differential item functioning for sex, age, care setting, and diagnosis, making it suitable for CAT administration. A post-hoc CAT simulation demonstrated that the tool was efficient and accurate, with an average of seven items, compared to the full item bank administration. Its use by clinicians can contribute to optimizing patient care pathways and transitioning towards more person-centered healthcare.

Ketamine and esketamine in suicidal thoughts and behaviors: a systematic review.

Background: More than 2% of the general population experience suicidal ideas each year and a large number of them will attempt suicide. Evidence-based therapeutic options to manage suicidal crisis are currently limited. Objectives: The aim of this study was to overview the findings on the use of ketamine and esketamine for the treatment of suicidal ideas and acts. Design: Systematic review. Data Sources and methods: PubMed, article references, and Clinicaltrials.gov up to June 30, 2022. Meta-analyses published within the last 2 years were also reviewed. Results: We identified 12 randomized controlled trials with reduction of suicidal ideation as the primary objective and 14 trials as secondary objectives. Intravenous racemic ketamine was superior to control drugs (placebo or midazolam) within the first 72 h, in spite of large placebo effects. Adverse events were minor and transient. In contrast, intranasal esketamine did not differ from placebo in large-scale studies. Limitations, clinical considerations, and opportunities for future research include the following points: large placebo effects when studying suicidal ideation reduction; small concerns about blinding quality due to dissociative effects; no studies on the risk/prevention of suicidal acts and mortality; lack of studies beyond affective disorders; no studies in adolescents and older people; lack of knowledge of long-term side effects, notably liability for abuse; no robust predictive markers; limited understanding of the mechanisms of ketamine on suicidal ideas; need for improved assessment of suicidal ideation in clinical trials; need for studies in outpatient settings, emergency room, and liaison consultation; need for research on ketamine administration; limited knowledge on the positive and negative effects of concomitant treatments. Conclusion: Overall, there is compelling evidence for a favorable short-term benefit-risk balance with intravenous racemic ketamine but not intranasal esketamine. The place of ketamine will have to be defined within a multimodal care strategy for suicidal patients. Caution remains necessary for clinical use, and pharmacovigilance will be essential.

Psilocybin Efficacy and Mechanisms of Action in Major Depressive Disorder: a Review.

PURPOSE OF THE REVIEW: We aim to provide an overview of the current state of knowledge about the efficacy of psilocybin in the treatment of depression, as well as its mechanisms of action. RECENT FINDINGS: Psilocybin has a large, rapid, and persistent clinical effect in the treatment of resistant or end-of-life depression. Tolerance is good, with mild side effects limited to a few hours after dosing. The studies conducted to date have had small sample sizes. One clinical trial has been conducted against a reference treatment (escitalopram) without showing a significant superiority of psilocybin in the main outcome. The neurobiological mechanisms, mostly unknown, differ from those of SSRI antidepressants. Psilocybin represents a promising alternative in the treatment of depression. Further research with larger sample sizes, particularly against reference treatments, is needed to better understand the neurobiological factors of its effects and to investigate its potential for use in everyday practice.

Association between brain metabolism and clinical course of motor functional neurological disorders.

Features of resting brain metabolism in motor functional neurological disorder are poorly characterized. This study aimed to investigate the alterations of resting brain metabolism in a cohort of patients experiencing a first episode of motor functional neurological disorder with recent symptom onset and their association with persistent disability after 3 months. Patients eligible for inclusion were diagnosed with first episode of motor functional neurological disorder, were free from bipolar disorder, substance use disorder, schizophrenia, psychogenic non-epileptic seizure or any chronic or acute organic neurological disorder. Exclusion criteria included current suicidal ideation, antipsychotic intake and previous history of functional neurological disorder. Nineteen patients were recruited in Psychiatry and Neurology departments from two hospitals. Resting brain metabolism measured with 18F-fluorodeoxyglucose positron emission computed tomography at baseline and 3 months was compared to 23 controls without neurological impairment. Disability was scored using Expanded Disability Status Scale and National Institutes of Health Stroke Scale score at baseline and 3 months. Correlations were calculated with Spearman correlation coefficient. Hypometabolism was found at baseline in bilateral frontal regions in patients versus controls, disappearing by 3 months. The patients with Expanded Disability Status Scale score improvement showed greater resting state activity of prefrontal dorsolateral cortex, right orbito-frontal cortex and bilateral frontopolar metabolism at 3 months versus other patients. The resting state metabolism of the right subgenual anterior cingular cortex at baseline was negatively correlated with improvement of motor disability (measured with Expanded Disability Status Scale) between inclusion and 3 months (r = -0.75, P = 0.0018) and with change in motor symptoms assessed with the National Institutes of Health Stroke Scale (r = -0.81, P = 0.0005). The resting state metabolism of the left subgenual anterior cingular cortex at baseline was negatively correlated with improvement in Expanded Disability Status Scale and National Institutes of Health Stroke Scale scores between inclusion and 3 months (r = -0.65, P = 0.01 and r = -0.75, P = 0.0021, respectively). The negative association between the brain metabolism of the right subgenual anterior cingular cortex at baseline and change in National Institutes of Health Stroke Scale score remained significant (r = -0.81, P = 0.0414) after correction for multiple comparisons. Our findings suggest the existence of metabolic 'state markers' associated with motor disability and that brain markers are associated with motor recovery in functional neurological disorder patients.

Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial.

OBJECTIVE: To confirm the rapid onset anti-suicidal benefits of ketamine in the short term and at six weeks, overall and according to diagnostic group. DESIGN: Prospective, double blind, superiority, randomised placebo controlled trial. SETTING: Seven French teaching hospitals between 13 April 2015 and 12 March 2019. ELIGIBILITY CRITERIA FOR PARTICIPANTS: Aged 18 or older with current suicidal ideation, admitted to hospital voluntarily. Exclusion criteria included a history of schizophrenia or other psychotic disorders, substance dependence, and contraindications for ketamine. PARTICIPANTS: 156 participants were recruited and randomised to placebo (n=83) or ketamine (n=73), stratified by centre and diagnosis: bipolar, depressive, or other disorders. INTERVENTION: Two 40 minute intravenous infusions of ketamine (0.5 mg/kg) or placebo (saline) were administered at baseline and 24 hours, in addition to usual treatment. MAIN OUTCOME MEASURES: The primary outcome was the rate of patients in full suicidal remission at day 3, according to the scale for suicidal ideation total score ≤3. Analyses were conducted on an intention-to-treat basis. RESULTS: More participants receiving ketamine reached full remission of suicidal ideas at day 3 than those receiving placebo: 46 (63.0%) of 83 participants in the ketamine arm and 25 (31.6%) of 73 in the placebo arm (odds ratio 3.7 (95% confidence interval 1.9 to 7.3), P<0.001). This effect differed according to the diagnosis (treatment: P<0.001; interaction: P=0.02): bipolar (odds ratio 14.1 (95% confidence interval 3.0 to 92.2), P<0.001), depressive (1.3 (0.3 to 5.2), P=0.6), or other disorders (3.7 (0.9 to 17.3, P=0.07)). Side effects were limited. No manic or psychotic symptom was seen. Moreover, a mediating effect of mental pain was found. At week 6, remission in the ketamine arm remained high, although non-significantly versus placebo (69.5% v 56.3%; odds ratio 0.8 (95% confidence interval 0.3 to 2.5), P=0.7). CONCLUSIONS: The findings indicate that ketamine is rapid, safe in the short term, and has persistent benefits for acute care in suicidal patients. Comorbid mental disorders appear to be important moderators. An analgesic effect on mental pain might explain the anti-suicidal effects of ketamine. TRIAL REGISTRATION: ClinicalTrials.gov NCT02299440.

Third-generation cognitive behavioral therapy versus treatment-as-usual for attention deficit and hyperactivity disorder: a multicenter randomized controlled trial.

BACKGROUND: This study aims to compare improvements in attention deficit and hyperactivity disorder (ADHD) symptom severity between a group of ADHD children and parents undergoing a new therapeutic program based on third-generation cognitive behavioral therapy (Hyper-mCBT) and a similar group undergoing treatment-as-usual with the Barkley program. METHODS: Two hundred forty-eight children diagnosed with ADHD will be randomly assigned to either a Hyper-mCBT program or a Barkley program. This is a multicenter randomized (1:1), 2 parallel-group, superiority trial with evaluator blinding and stratification according to center and methylphenidate treatment. The Hyper-mCBT program consists in a series of 16 simultaneous-but-separate therapy sessions for parents and for children. DISCUSSION: More effective psychotherapeutic approaches are needed for ADHD children. Pharmacotherapy seems to be more effective in reducing ADHD symptoms but it is not always helpful, it carries side effects, and it is rejected by many parents/professionals. Results for psychotherapy programs for ADHD are inconsistent although several studies have shown clinical improvements. This trial will substantiate encouraging preliminary results of an innovative psychotherapy program for both parents and children. TRIAL REGISTRATION: ClinicalTrials.gov NCT03437772 . Registered on February 19, 2018. Sponsor number: PHRC-N/2016/JLC-01. RCB identification: 2017-A01349-44.

Stress response in dissociation and conversion disorders: A systematic review.

Dissociative disorders (DD) and conversion disorders (CD) are frequent in general and psychiatric populations. Some evidence suggest that the hypothalamic-pituitary axis (HPA) and autonomic nervous system (ANS) are dysregulated in both disorders. We carried out a systematic review of the literature to summarize the existing knowledge on the stress response, via HPA and/or ANS, in patients with DD, CD, or dissociative symptoms. We systematically searched Medline and Web of Science using the Medical Subject Headings related to stress axis, CD, DD, and dissociative symptoms following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results suggest that in participants without psychiatric history, high cortisol secretion is related to high dissociation scores. Conversely the stress system might be blunted in patients with post-traumatic stress disorder who develop dissociative symptoms. Stress response changes seem to be associated with the emergence and persistence of dissociative and conversion disorders. Hence, monitoring the stress response and examining closely the history of stress exposure in DD and CD should be encouraged in future larger studies.

Impact of cannabis use on outcomes of patients admitted to an involuntary psychiatric unit: A retrospective cohort study.

INTRODUCTION: Cannabis is associated with an increased risk of mental disorders, including the onset or adverse evolution of schizophrenia, bipolar disorder and depression. The aim of our study was to examine how cannabis use influences length of stay and readmissions in a unit of involuntary care. METHOD: All patients admitted to one secure adult psychiatry unit in France in 2016 were included (n = 370). Patients were assigned to one of two groups according to detection of urinary tetrahydrocannabinol (THC + or -). Clinical outcomes, such as length of stay and readmissions, were compared between the groups in multivariate analyses. RESULTS: We identified 130 THC + patients and 240 THC- patients. THC + patients were often young men. In adjusted analyses, THC + status was significantly associated with one-year readmissions (OR = 2.29, p = .0082) and more prescriptions of benzodiazepines (OR = 1.93, p = .02), but not antipsychotics, at discharge. CONCLUSIONS: Cannabis users seem to have a particular profile in secure units, and are associated with specific diagnoses and treatments, and a higher risk of readmissions. Adapted management strategies might be warranted for these patients.

The French Version of the Revised Ritvo Autism and Asperger Diagnostic Scale: A Psychometric Validation and Diagnostic Accuracy Study.

The early recognition of ASD in adults is challenging, in particular due to the lack of appropriate and robust diagnostic tools. We performed a psychometric validation and diagnostic accuracy study of the French version of the RAADS-R on a sample of 305 adults: 105 with ASD without ID, 99 with psychiatric disorders, and 103 non-psychiatric control groups. The French version of the RAADS-R demonstrates good reliability and diagnostic validity, suggesting that it can help clinicians during the diagnostic process in adults with ASD without ID. However, the finding that a two-factor structure better fits the results requires further validation. This study point out the need of further study of RAADS in psychiatric disorders group due to the relatively high false positive rate (55.6%) of ASD.

Group Post-Admission Cognitive Therapy for Suicidality vs Individual Supportive Therapy for the prevention of repeat suicide attempts: a randomized controlled trial.

BACKGROUND: Suicide is a serious public health problem. The development and use of effective treatments for people hospitalized for suicide attempts remain a priority. Regarding psychosocial treatment, the evidence for treatments that effectively prevent suicide repetition of suicide attempts is extremely thin. There is some evidence that cognitive behavioural therapy may be effective for reducing suicide behaviour. The primary aim of this study is to compare Group Post-Admission Cognitive Therapy for Suicidality (GPACTS) versus Individual Supportive Therapy (IST) for preventing suicide. METHODS: In total, 240 participants with a high suicide risk score according to a Mini International Neuropsychiatric Interview (MINI) will be randomized to either GPACTS or IST. This is a multicentre, parallel group, randomized (1:1 ratio), two-tailed-superiority trial with endpoint-assessor blinding. Patients meeting inclusion criteria during a screening visit will be enrolled in the study and randomized into two groups: one group will undergo 6 weeks of GPACTS, and the second group will undergo 6 weeks of IST. Following 6 weeks of interventional therapy, patients are followed up for 12 months. Follow-up for both groups is identical and includes the administration of questionnaires at baseline and then within 10 days after the end of therapy sessions and then at 3, 6 and 12 months following the end of GPACTS/IST sessions. DISCUSSION: To our knowledge, this is the first RCT of its kind to be conducted in France, and so far, there are no studies in the literature on group psychotherapy for the treatment of individuals who have attempted suicide. The outcomes will provide clear guidance for professionals to apply psychological intervention with suicide attempts. The protocol respects ethical principles, and ethical approval was obtained from the local ethics committee. The results will be disseminated through an original research published as original research in peer-reviewed manuscript, through a therapist manual for cognitive therapy, and presentations at research conferences. TRIAL REGISTRATION: ClinicalTrials.gov NCT02664701 . Registered on January 27, 2017.

Shared Decision-Making: a Systematic Review Focusing on Mood Disorders.

PURPOSE OF REVIEW: This study aims to provide a review of the randomized controlled studies evaluating the effects of shared decision-making (SDM) intervention in comparison to care as usual in patients with mood disorders. RECENT FINDINGS: Of the 14 randomized controlled studies identified, only three 6-month studies evaluated the interest of SDM interventions using decision aids in depressed patients. All of them showed that the intervention effectively improved patient satisfaction and engagement in the decision-making process. Only one study in patients with bipolar disorder (BD) showed improvement of depressive symptoms, functioning, and quality of life. Other included studies were collaborative care interventions using a SDM approach in patients with depression in specific populations depending on age, gender, income, and physical comorbidities. All of them showed significant improvement in depression outcomes or medication adherence. SDM interventions using decision aids and collaborative care showed evidence of improvements in the management of depression. Stronger evidence of SDM interest in BD is needed.

Neuroanatomy of conversion disorder: towards a network approach.

The pathophysiology of conversion disorder is not well understood, although studies using functional brain imaging in patients with motor and sensory symptoms are progressively increasing. We conducted a systematic review of the literature with the aim of summarising the available data on the neuroanatomical features of this disorder. We also propose a general model of the neurobiological disturbance in motor conversion disorder. We systematically searched articles in Medline using the Medical Subject Headings terms '(conversion disorder or hysterical motor disorder) and (neuropsychology or cognition) or (functional magnetic resonance imaging or positron emission tomography or neuroimaging) or (genetics or polymorphisms or epigenetics) or (biomarkers or biology)', following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two authors independently reviewed the retrieved records and abstracts, assessed the exhaustiveness of data abstraction, and confirmed the quality rating. Analysis of the available literature data shows that multiple specialised brain networks (self-agency, action monitoring, salience system, and memory suppression) influence action selection and modulate supplementary motor area activation. Some findings suggest that conceptualisation of movement and motor intention is preserved in patients with limb weakness. More studies are needed to fully understand the brain alterations in conversion disorders and pave the way for the development of effective therapeutic strategies.

Serotonin transporter gene expression predicts the worsening of suicidal ideation and suicide attempts along a long-term follow-up of a Major Depressive Episode.

The quest for biomarkers in suicidal behaviors has been elusive so far, despite their potential utility in clinical practice. One of the most robust biological findings in suicidal behaviors is the alteration of the serotonin transporter function in suicidal individuals. Our main objective was to investigate the predictive value of the serotonin transporter gene expression (SLC6A4) for suicidal ideation and as secondary, for suicide attempts in individuals with a major depressive episode (MDE). A 30-week prospective study was conducted on 148 patients with a MDE and 100 healthy controls including 4 evaluation times (0, 2, 8 and 30 weeks). Blood samples and clinical data were collected and SLC6A4 mRNA levels were measured from peripheral blood mononuclear cells using RT-qPCR. We first demonstrated the stability and reproducibility of SLC6A4 mRNA expression measures over time in healthy controls (F=0.658; p=0.579; η2=0.008; ICC=0.91, 95% CI [0.87-0.94]). Baseline SLC6A4 expression level (OR=0.563 [0.340-0.932], p=0.026) as well as early changes in SLC6A4 expression between baseline and the 2nd week (ß=0.200, p=0.042) predicted the worsening of suicidal ideation (WSI) in the following 8 weeks. Moreover, changes in SLC6A4 expression between the 2nd and 8th weeks predicted the occurrence of a suicide attempt within 30 weeks (OR=10.976 [1.438-83.768], p=0.021). Altogether, the baseline level and the changes in SLC6A4 mRNA expression during a MDE might predict the WSI and the occurrence of suicidal attempts and could be a useful biomarker in clinical practice.

How to: Measuring blood cytokines in biological psychiatry using commercially available multiplex immunoassays.

Cytokines produced by both immune and non-immune cells are likely to play roles in the development and/or progression of psychiatric disorders. Indeed, many investigators have compared the blood cytokine levels in psychiatric patients with those of healthy controls or monitored their levels in patients during disease progression to identify biomarkers. Nevertheless, very few studies have confirmed that such cytokines remain stable in healthy individuals through periods of weeks and months. This is an important issue to consider before using blood cytokine levels as biomarkers of disease traits, disease state, or treatment response. Although multiplex assay technology represents an advance in identifying biomarkers because it allows simultaneous examination of large panels of analytes from a small volume of sample, it is necessary to verify whether these assays yield enough sensitivity and reproducibility when applied to the blood from neuropsychiatric patients. Therefore, we compared two multiplex immunoassays, the bead-based Luminex® (Bio-Rad) and the electro-chemiluminescence-based V-plex® (MesoScaleDiscovery), for the detection and quantification of 31 cytokines, chemokines and growth factors in both the sera and plasma of patients with major depressive episodes (MDE) and age- and sex-matched healthy control subjects during a 30-week period. Although both platforms exhibited low coefficients of variability (CV) between the duplicates in the calibration curves, the linearity was better in general for the V-PLEX® platform. However, neither platform was able to detect the absolute values for all of the tested analytes. Among the 16 analytes that were detected by both assays, the intra-assay reproducibility was in general better with the V-PLEX® platform. Although it is not a general rule that the results from sera and plasma will be correlated, consistent results were more frequent with the V-PLEX® platform. Furthermore, the V-PLEX® results were more consistent with the gold standard ELISA simplex assay for IL-6 in both sera and plasma. The intra-individual variability of the measurements, among the sera and plasma for the 4 samples harvested from each healthy individual, was low for Eotaxin, G-CSF, IL-4, IL-7, IL-9, IL-12p40, IL-12p70, IL-15, MIP-1ß, PDGF-BB, TNF, TNF-ß and VEGF, but intermediate or high for IFN-γ, IL-6, IL-8, IL-10, and IP10. Together, these data suggest that extreme caution is needed in translating the results of multiplex cytokine profiling into biomarker discovery in psychiatry.

Iowa Gambling Task Performance in Elderly Persons with a Lifetime History of Suicidal Acts.

OBJECTIVES: Suicide in the elderly is a major public health problem. In the present study, we aimed to further understand the mechanisms of suicidal vulnerability in the elderly, focusing on high-risk decision-making. This trait-like impairment has been extensively studied in adolescent and middle-aged suicide attempters, but less often in older persons. DESIGN: Case-control study. SETTING: Community and university hospital. PARTICIPANTS: All participants were aged 65 and older. Thirty-five persons with a lifetime history of suicide attempts and depressive disorder were compared with 52 individuals with a past history of depressive disorder but no history suicidal acts, and 43 healthy comparison subjects. MEASUREMENTS: The Iowa Gambling Task was used as a measure of value-based decision-making. RESULTS: Taking into account age, sex, and Beck depression scores, no difference in decision-making performance was found between the three groups. The group of suicide attempters exhibited a significant heterogeneity, however, with those using violent means performing worse than non-violent attempters. CONCLUSIONS: This study does not confirm the hypothesis of a significant role for poor Iowa Gambling Task performance as a general marker of suicidal behavior among the elderly but highlights its association with the specific subtype of violent suicidal attempters. Combined with previous findings among other age groups, it suggests that Iowa Gambling Task impairment may be a risk marker of vulnerability to violent suicidal acts. Future prospective studies should assess if this may represent a risk marker for suicide completion.

Innovative mechanisms of action for pharmaceutical cognitive enhancement: A systematic review.

Pharmacological cognitive enhancement refers to improvement in cognitive functions after drug use in healthy individuals. This popular topic attracts attention both from the general public and the scientific community. The objective was to explore innovative mechanisms of psychostimulant's action, whose potential effectiveness was assessed in randomized placebo-controlled trials (RCTs). A systematic review was carried out, using the words "attention", "memory", "learning", "executive functions", and "vigilance/wakefulness" combined to "cognitive enhancer" or "smart drug". Methylphenidate, amphetamines, modafinil, nicotine, acetylcholine esterase inhibitors and antidepressants were extensively studied in previous meta-analyses and were not included in the present work. Drugs were classified according to their primary mode of action, namely catecholaminergic drugs (tolcapone, pramipexole, guanfacine), cholinergic drugs (anticholinergics), glutamatergic drugs (ampakines), histaminergic drugs, and non-specified (glucocorticoids). Overall, 50 RCTs were included in the present review. In conclusion, a number of new active drugs were found to improve some cognitive functions, in particular verbal episodic memory. However the number of RCTs was limited, and most of the studies found negative results. Future studies should assess both effectiveness and tolerance of repeated doses administration, and individual variability in dose response (including baseline characteristics and potential genetic polymorphisms). One explanation for the limited number of recent RCTs with new psychostimulants seems to be the ethical debate surrounding pharmaceutical cognitive enhancement in healthy subjects.

Ketamine administration in depressive disorders: a systematic review and meta-analysis.

INTRODUCTION: Ketamine's efficacy in depressive disorders has been established in several controlled trials. The aim of the present study was to determine whether or not ketamine administration significantly improves depressive symptomatology in depression and more specifically in major depressive disorder (MDD), bipolar depression, resistant depression (non-ECT studies), and as an anesthetic agent in electroconvulsive therapy (ECT) for resistant depression (ECT studies). Secondary outcomes were the duration of ketamine's effect, the efficacy on suicidal ideations, the existence of a dose effect, and the safety/tolerance of the treatment. METHODS: Studies were included if they met the following criteria (without any language or date restriction): design: randomized controlled trials, intervention: ketamine administration, participants: diagnosis of depression, and evaluation of severity based on a validated scale. We calculated standardized mean differences (SMDs) with 95 % confidence intervals (CIs) for each study. We used fixed and random effects models. Heterogeneity was assessed using the I2 statistic. RESULTS: We included nine non-ECT studies in our quantitative analysis (192 patients with major depressive disorder and 34 patients with bipolar depression). Overall, depression scores were significantly decreased in the ketamine groups compared to those in the control groups (SMD = -0.99; 95 % CI -1.23, -0.75; p < 0.01). Ketamine's efficacy was confirmed in MDD (resistant to previous pharmacological treatments or not) (SMD = -0.91; 95 % CI -1.19,-0.64; p < 0.01), in bipolar depression (SMD = -1.34; 95 % CI -1.94, -0.75), and in drug-free patients as well as patients under medication. Four ECT trials (118 patients) were included in our quantitative analysis. One hundred and three patients were diagnosed with major depressive disorder and 15 with bipolar depression. Overall, depression scores were significantly improved in the 58 patients receiving ketamine in ECT anesthesia induction compared to the 60 patients (SMD = -0.56; 95 % CI -1.10, -0.02; p = 0.04; I2 = 52.4 %). The duration of ketamine's effects was assessed in only two non-ECT studies and seemed to persist for 2-3 days; this result needs to be confirmed. Three of four studies found significant decrease of suicidal thoughts and one found no difference between groups, but suicidal ideations were only studied by the suicide item of the depressive scales. It was not possible to determine a dose effect; 0.5 mg/kg was used in the majority of the studies. Some cardiovascular events were described (mostly transient blood pressure elevation that may require treatment), and ketamine's use should remain cautious in patients with a cardiovascular history. CONCLUSION: The present meta-analysis confirms ketamine's efficacy in depressive disorders in non-ECT studies, as well as in ECT studies. The results of this first meta-analysis are encouraging, and further studies are warranted to detail efficacy in bipolar disorders and other specific depressed populations. Middle- and long-term efficacy and safety have yet to be explored. Extrapolation should be cautious: Patients included had no history of psychotic episodes and no history of alcohol or substance use disorders, which is not representative of all the depressed patients that may benefit from this therapy.

D2 and D3 dopamine receptor affinity predicts effectiveness of antipsychotic drugs in obsessive-compulsive disorders: a metaregression analysis.

RATIONALE AND OBJECTIVE: The relationship between clinically effective antipsychotic drugs in obsessive-compulsive disorders (OCD) and binding affinities to cloned dopamine and serotonin receptor subtypes was analyzed in an effort to clarify the contribution of individual receptor subtypes to medication response. METHODS: Meta-analysis was used to update previous meta-analyses of effectiveness data of add-on antipsychotic drugs to selective serotonin reuptake inhibitors (SSRIs) in OCD. Twelve previously analyzed randomized controlled trials (RCTs) and one new RCT were included. We performed a metaregression using a mixed-effect model to examine the association between antipsychotic's effectiveness and receptor affinity. RESULTS: A total of 5 treatment arms obtained from 13 RCTs (431 patients) were included in our study. The results of our metaregression showed a significant association between D2 and D3 dopamine receptor affinities and effectiveness in OCD (respectively, slope = -0.36, p = 0.01; and slope = -0.50, p = 0.01) whereas other dopamine receptors and serotonin receptors were not significantly associated. CONCLUSIONS: These observations suggest that increasing D2 and D3 dopamine receptor binding affinities enhances antipsychotics' effectiveness in obsessive-compulsive disorders.

Smoking behavior characteristics of non-selected smokers with childhood attention-deficit/hyperactivity disorder (AD/HD) history: a systematic review and meta-analysis.

It is unclear whether adult smokers with childhood attention-deficit/hyperactivity disorder history (CH) have more severe smoking behavior than non-CH smokers, while it is clearly suggested that CH adolescents have more severe smoking behavior than CH adolescents. The aim of the present comprehensive meta-analysis is to determine whether CH smokers have more severe smoking behavior characteristics than those without and the effect of age on the association between CH and smoking behavior. We included all case-control studies and first round data collection of observational studies addressing the difference in smoking behavior characteristics of CH smokers versus non-CH smokers, with validated scales or structured interviews, without any language or date restriction. Nine studies (including 365 smokers with CH and 1,708 smokers without) were included. Compared to non-CH smokers, CH smokers smoked significantly more cigarettes [standardized mean differences (SMD) = 0.15, 95 % CI 0.01-0.28, p = 0.04] and began to regularly smoke earlier (SMD = -0.28, 95 % CI -0.49; -0.07, p = 0.01) but were not significantly more nicotine dependent (SMD = 0.23, 95 % CI -0.04 to 0.48, p = 0.08). After removing the single adolescent study, the significant association between CH and number of daily smoked cigarettes disappeared, and subgroups analyses confirmed that the significant association between CH and number of daily smoked cigarettes disappeared as age increased. Our meta-analysis illustrates a clinically important link between CH and tobacco smoking in adolescence but not later in life. Further high-quality studies are needed to confirm this finding, as only two studies included participants with a mean age below 20 years.