Assessment of visuo-spatial memory in patients with schizophrenia using the Location Learning Test

Recent studies give good evidence that memory impairment is one of the most profound cognitive deficits in schizophrenia. Multiple meta-analytic studies have demonstrated impairments especially in working and episodic memory including both its verbal and visual aspects. The scope of the present study was to examine the short and long term visuo-spatial memory in free immediate and delay recall conditions in patients with schizophrenia. We used Learning Location Test (LLT), a brief test designed initially to measure visuo-spatial recall and learning in older adults with possible dementia, as a new approach to the assessment of visuo-spatial memory and learning impairment in schizophrenia. We studied 30 pa­tients with schizophrenia in comparison with 30 normal subjects matched with socio-demographic parameters. Patients with schizophrenia performed significantly lower in all tasks of LLT compared to the healthy subjects. The comparison between the two diagnostic groups of patients (paranoid and non paranoid patients) did not show any statistically significant difference regarding the three main index of LLT. Furthermore, the results indicate that patients have a tendency to form two separate groups: one achieving “good scores” and one achieving “very bad scores”. In order to enhance the validity of the test and to reveal the characteristics of the two subgroups, further study in this population is needed

Ethnic Minority Status, Age-at-Immigration and Psychosis Risk in Rural Environments:Evidence From the SEPEA Study

Objective: Several ethnic minority groups experience elevated rates of first-episode psychosis (FEP), but most studies have been conducted in urban settings. We investigated whether incidence varied by ethnicity, generation status, and age-at-immigration in a diverse, mixed rural, and urban setting. Method: We identified 687 people, 16–35 years, with an ICD-10 diagnosis of FEP, presenting to Early Intervention Psychosis services in the East of England over 2 million person-years. We used multilevel Poisson regression to examine incidence variation by ethnicity, rural–urban setting, generation status, and age-at-immigration, adjusting for several confounders including age, sex, socioeconomic status, population density, and deprivation. Results: People of black African (incidence rate ratio: 4.06; 95% confidence interval [CI]: 2.63–6.25), black Caribbean (4.63; 95% CI: 2.38–8.98) and Pakistani (2.31; 95% CI: 1.35–3.94) origins were at greatest FEP risk relative to the white British population, after multivariable adjustment. Non-British white migrants were not at increased FEP risk (1.00; 95% CI: 0.77–1.32). These patterns were independently present in rural and urban settings. For first-generation migrants, migration during childhood conferred greatest risk of psychotic disorders (2.20; 95% CI: 1.33–3.62). Conclusions: Elevated psychosis risk in several visible minority groups could not be explained by differences in postmigratory socioeconomic disadvantage. These patterns were observed across rural and urban areas of our catchment, suggesting that elevated psychosis risk for some ethnic minority groups is not a result of selection processes influencing rural–urban living. Timing of exposure to migration during childhood, an important social and neurodevelopmental window, may also elevate risk

The Epidemiology of First-Episode Psychosis in Early Intervention in Psychosis Services: Findings From the Social Epidemiology of Psychoses in East Anglia [SEPEA] Study.

OBJECTIVE: Few studies have characterized the epidemiology of first-episode psychoses in rural or urban settings since the introduction of early intervention psychosis services. To address this, the authors conducted a naturalistic cohort study in England, where such services are well established. METHOD: All new first-episode psychosis cases, 16-35 years old, presenting to early intervention psychosis services in the East of England were identified during 2 million person-years follow-up. Presence of ICD-10 F10-33 psychotic disorder was confirmed using OPCRIT [operational criteria for psychotic illness]. Incidence rate ratios were estimated following multivariable Poisson regression, adjusting for age, sex, ethnicity, socioeconomic status, neighborhood-level deprivation, and population density. RESULTS: Of 1,005 referrals, 687 participants (68.4%) fulfilled epidemiological and diagnostic criteria for first-episode psychosis (34.0 new cases per 100,000 person-years; 95% CI=31.5-36.6). Median age at referral was similar for men (22.5 years; interquartile range: 19.5-26.7) and women (23.4 years; interquartile range: 19.5-29.1); incidence rates were highest for men and women before 20 years of age. Rates increased for ethnic minority groups (incidence rate ratio: 1.4; 95% CI=1.1-1.6), as well as with lower socioeconomic status (incidence rate ratio: 1.3; 95% CI=1.2-1.4) and in more urban (incidence rate ratio: 1.4;95%CI=1.0-1.8) and deprived (incidence rate ratio: 2.1; 95% CI=1.3-3.3) neighborhoods, after adjustment for confounders. CONCLUSIONS: Pronounced variation in psychosis incidence, peaking before 20 years old, exists in populations served by early intervention psychosis services. Excess rates were restricted to urban and deprived communities, suggesting that a threshold of socioenvironmental adversity may be necessary to increase incidence. This robust epidemiology can inform service development in various settings about likely population-level need.Wellcome Trust (Sir Henry Wellcome Research Fellowship; Grant ID: WT085540)This is the author accepted manuscript. The final version is available from the American Psychiatric Association via http://dx.doi.org/10.1176/appi.ajp.2016.1601010

Correlation between cognitive deficiency and psychopathological parameters in schizophrenia

The cognitive impairment in schizophrenia has been recognized as a nuclear feature of the disease and has been recently studied in relation to the clinical manifestations of schizophrenia , aiming to illustrate the links between them as an indication of a common anatomic or pathophysiologic substrate . The purpose of this study was to investigate the relationships between the five clinical factors of PANSS (as derived from factor analysis of the PANSS) and the cognitive function in a group of patients with Schizophrenia . It has also been examined if the above correlations alter when are studied separately in patients with positive or negative syndrome and whether neuropsychological deficits or clinical and demographic characteristics can predict the level of functioning in these patients.69 patients with schizophrenia according to DSM-IV criteria were clinically evaluated with the PANSS, the ESRS for extrapyramidal symptoms and the GAF scale for estimating the level of functionality. Their demographic data were also collected. They were divided in patients with positive (n1 = 30) and negative (n2 = 39) syndrome. A battery of neuropsychological tests was used to assess attention, memory, visuospatial perception, psychomotor speed and executive function. It was a cross-sectional study that investigated partial correlations between clinical and neuropsychological factors controlling for age and education level. Predictors of GAF were explored by implementing multiple stepwise regression.The duration of the disease was not associated with any of the neuropsychological tests . The negative PANSS factor was correlated most with the tests and was associated with the visual memory , attention, psychomotor speed and executive functions . The positive , the cognitive and the depression factor were associated with fewer tests involving mainly executive functions , while the anxiety-excitement factor showed no significant correlation with the examined cognitive functions. Groups of positive and negative syndrome showed no particular differences between them as to neuropsychological performance, but their partial correlations differed from those of the total sample. Although statistically significant, the correlations found were not strong enough to suggest that cognitive impairment and psychopathology in schizophrenia have common structural or functional substrate .The level of functionality (GAF) was predicted mainly by clinical characteristics such as the subscale of General Psychopathology of PANSS, the total score of ESRS for assessing extrapyramidal symptoms and the depression PANSS factor explaining 54.4 % of the variance of GAF. Amongst the neuropsychological tests, the performance of the Trail Making Test A was recognized as the only predictor of the GAF, explaining no more than 13% of the variance.Our study could not reveal specific brain regions or functional networks connected through neurocognitive deficits with clinical manifestations of schizophrenia. In contrast, the wide range of non-specific cognitive dysfunctions are indicative of a more general cognitive impairment . Moreover, clinical manifestations and cognitive impairment in schizophrenia appear to be distinct pathophysiological processes, without this meaning that cognitive function cannot mediate between clinical symptoms and neurobiology of schizophrenia.Η γνωσιακή έκπτωση στη Σχιζοφρένεια έχει αναγνωρισθεί σαν πυρηνικό χαρακτηριστικό της νόσου και έχει μελετηθεί τα τελευταία χρόνια σε σχέση με τις κλινικές εκδηλώσεις της Σχιζοφρένειας, αποσκοπώντας στην αποκάλυψη μεταξύ τους σχέσεων ενδεικτικών κοινού ανατομικού ή παθοφυσιολογικού υποστρώματος. Σκοπός αυτής της διατριβής ήταν η διερεύνηση σχέσεων μεταξύ των πέντε κλινικών παραγόντων της PANSS (όπως προκύπτουν από την ανάλυση παραγόντων της PANSS) και της γνωσιακής λειτουργίας σε μία ομάδα ασθενών με Σχιζοφρένεια. Εξετάσθηκε, επίσης, εάν οι συσχετίσεις που προκύπτουν μεταβάλλονται όταν μελετηθούν ξεχωριστά σε ασθενείς με θετικό ή αρνητικό σύνδρομο και κατά πόσο τα νευροψυχολογικά ελλείμματα ή κλινικοδημογραφικοί παράγοντες μπορούν να προβλέψουν το επίπεδο λειτουργικότητας σε αυτούς τους ασθενείς.69 ασθενείς με Σχιζοφρένεια κατά DSM-IV εκτιμήθηκαν κλινικά με την κλίμακα PANSS, την ESRS για την εξωπυραμιδική συμπτωματολογία και την κλίμακα GAF για την αξιολόγηση του επιπέδου λειτουργικότητας και συλλέχθηκαν τα δημογραφικά τους στοιχεία. Διακρίθηκαν σε ασθενείς με θετικό (n1=30) και αρνητικό (n2=39) σύνδρομο. Για τη νευροψυχολογική διερεύνηση χρησιμοποιήθηκε μία σειρά δοκιμασιών για την εκτίμηση της προσοχής, της μνήμης, της οπτικοχωρικής αντίληψης, της ψυχοκινητικής ταχύτητας και των εκτελεστικών λειτουργιών. Επιχειρήθηκαν διπαραγοντικές μερικές συσχετίσεις στα πλαίσια μελέτης χρονικής στιγμής, ελέγχοντας για ηλικία και επίπεδο εκπαίδευσης. Για την πρόβλεψη της GAF χρησιμοποιήθηκε πολλαπλή βηματική παλινδρόμηση.Η διάρκεια της νόσου δε συσχετίστηκε με τις επιδόσεις στις νευροψυχολογικές δοκιμασίες. Ο αρνητικός παράγοντας της PANSS συσχετίστηκε με τις περισσότερες δοκιμασίες και συνδέθηκε με την οπτική μνήμη, την προσοχή, την ψυχοκινητική ταχύτητα και τις εκτελεστικές λειτουργίες. Ο θετικός, ο γνωσιακός και ο παράγοντας της κατάθλιψης συσχετίστηκαν με ελάχιστες δοκιμασίες στις οποίες εμπλέκονται κυρίως εκτελεστικές λειτουργίες, ενώ ο παράγοντας ανησυχίας-διέγερσης δεν παρουσίασε καμία σημαντική συσχέτιση. Οι ομάδες θετικού και αρνητικού συνδρόμου δεν παρουσίασαν ιδιαίτερες διαφορές μεταξύ τους ως προς τις νευροψυχολογικές επιδόσεις, αλλά οι επιμέρους συσχετίσεις διαφοροποιήθηκαν από αυτές του συνολικού δείγματος. Όλες οι συσχετίσεις που βρέθηκαν αν και στατιστικά σημαντικές, δεν ήταν ισχυρές αρκετά ώστε να μπορεί να υποστηριχθεί ότι η γνωσιακή έκπτωση και η ψυχοπαθολογία στη Σχιζοφρένεια έχουν κοινό παθοφυσιολογικό μηχανισμό ή κοινό δομικό-λειτουργικό εγκεφαλικό υπόστρωμα. Ως παράγοντες πρόβλεψης του επιπέδου λειτουργικότητας των ασθενών που μελετήθηκαν θεωρήθηκαν κυρίως οι εξής κλινικοί παράγοντες: η κλίμακα Γενικής Ψυχοπαθολογίας της PANSS, το συνολικό σκορ της ESRS για την εκτίμηση της εξωπυραμιδικής συμπτωματολογίας και ο παράγοντας κατάθλιψης της PANSS που ερμηνεύουν το 54,4% της διακύμανσης της GAF. Η γνωσιακή λειτουργία δεν μπόρεσε να ερμηνεύσει παρά το 13% της διακύμανσης της GAF και ως μοναδικός παράγοντας πρόβλεψης θεωρήθηκε η δοκιμασία Trail Making Test A.Από τα ευρήματά μας δεν μπόρεσαν να αποκαλυφθούν συγκεκριμένες εγκεφαλικές περιοχές ή λειτουργικά δίκτυα που να συνδέονται μέσω των νευρογνωσιακών ελλειμμάτων με τις κλινικές εκδηλώσεις της Σχιζοφρένειας. Αντιθέτως το ευρύ φάσμα των μη ειδικών γνωσιακών δυσλειτουργιών είναι ενδεικτικό μιας γενικότερης γνωσιακής έκπτωσης. Επίσης, οι κλινικές εκδηλώσεις και η γνωσιακή έκπτωση στη Σχιζοφρένεια φαίνεται να αποτελούν διακριτές μεταξύ τους παθολογίες, χωρίς αυτό όμως να σημαίνει ότι η γνωσιακή λειτουργία δεν μπορεί να διαμεσολαβεί ανάμεσα στα κλινικά συμπτώματα και τη νευροβιολογία της Σχιζοφρένειας

Aripiprazole (intramuscular) for psychosis-induced aggression or agitation (rapid tranquillisation)

Background: People experiencing psychosis may become aggressive. Antipsychotics, such as aripiprazole in intramuscular form, can be used in such situations. Objectives: To evaluate the effects of intramuscular aripiprazole in the treatment of psychosis-induced aggression or agitation (rapid tranquillisation). Search methods: On 11 December 2014 and 11 April 2017, we searched the Cochrane Schizophrenia Group’s Study-based Register of Trials which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. Selection criteria: All randomised controlled trials (RCTs) that randomised people with psychosis-induced aggression or agitation to receive either intramuscular aripiprazole or another intramuscular intervention. Data collection and analysis: We independently inspected citations and, where possible, abstracts, ordered papers and re-inspected and quality assessed these. We included studies that met our selection criteria. At least two review authors independently extracted data from the included studies. We chose a fixed-effect model. We analysed dichotomous data using risk ratio (RR) and the 95% confidence intervals (CI). We analysed continuous data using mean differences (MD) and their CIs. We assessed risk of bias for included studies and used GRADE to create 'Summary of findings' tables. Main results: Searching found 63 records referring to 21 possible trials. We could only include three studies, all completed over the last decade, with 885 participants, of which 707 were included for quantitative analyses in this systematic review. Due to limited comparisons, small size of trials and a paucity of investigated and reported 'pragmatic' outcomes, evidence was mostly graded as low or very low quality. No trials reported useful data for one of our primary outcomes of tranquil or asleep by 30 minutes. Economic outcomes were also not reported in the trials. When compared with placebo, fewer people in the aripiprazole group needed additional injections compared to the placebo group (2 RCTs, n = 382, RR 0.69, 95% CI 0.56 to 0.85, very low-quality evidence). Clinically important improvement in agitation at two hours favoured the aripiprazole group (2 RCTs, n = 382, RR 1.50, 95% CI 1.17 to 1.92, very low-quality evidence). The numbers of non-responders after the first injection also favoured aripiprazole (1 RCT, n = 263, RR 0.49, 95% CI 0.34 to 0.71, low-quality evidence). Although no effect was found, more people in the aripiprazole compared to the placebo group experienced adverse effects (1 RCT, n = 117, RR 1.51, 95% CI 0.93 to 2.46, very low-quality evidence). Aripiprazole required more injections compared to haloperidol (2 RCTs, n = 477, RR 1.28, 95% CI 1.00 to 1.63, very low-quality evidence), with no significant difference in agitation (2 RCTs, n = 477, RR 0.94, 95% CI 0.80 to 1.11, very low-quality evidence), and similar non-responders after first injection (1 RCT, n = 360, RR 1.18, 95% CI 0.78 to 1.79, low-quality evidence). Aripiprazole and haloperidol did not differ when taking into account the overall number of people that experienced at least one adverse effect (1 RCT, n = 113, RR 0.91, 95% CI 0.61 to 1.35, very low-quality evidence). Compared to aripiprazole, olanzapine was better at reducing agitation (1 RCT, n = 80, RR 0.77, 95% CI 0.60 to 0.99, low-quality evidence) and had a more favourable effect on global state change scores (1 RCT, n = 80, MD 0.58, 95% CI 0.01 to 1.15, low-quality evidence), both at two hours. No differences were found in terms of experiencing at least one adverse effect during the 24 hours after treatment (1 RCT, n = 80, RR 0.75, 95% CI 0.45 to 1.24, very low-quality evidence). However, participants allocated to aripiprazole experienced less somnolence (1 RCT, n = 80, RR 0.25, 95% CI 0.08 to 0.82, low-quality evidence). Authors' conclusions: The available evidence is of poor quality but there is some evidence aripiprazole is effective compared to placebo and haloperidol, but not when compared to olanzapine. However, considering that evidence comes from only three studies, caution is required in generalising these results to real-world practice. This review firmly highlights the need for more high-quality trials on intramuscular aripiprazole in the management of people with acute aggression or agitation

Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder

Background: Many studies have recently been conducted to assess the antidepressant efficacy of glutamate modification in mood disorders. This is an update of a review first published in 2015 focusing on the use of glutamate receptor modulators in unipolar depression. Objectives: To assess the effects - and review the acceptability and tolerability - of ketamine and other glutamate receptor modulators in alleviating the acute symptoms of depression in people with unipolar major depressive disorder. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Embase and PsycINFO all years to July 2020. We did not apply any restrictions to date, language or publication status. Selection criteria: Double- or single-blinded randomised controlled trials (RCTs) comparing ketamine, memantine, esketamine or other glutamate receptor modulators with placebo (pill or saline infusion), other active psychotropic drugs, or electroconvulsive therapy (ECT) in adults with unipolar major depression. Data collection and analysis: Three review authors independently identified studies, assessed trial quality and extracted data. The primary outcomes were response rate (50% reduction on a standardised rating scale) and adverse events. We decided a priori to measure the efficacy outcomes at different time points and run sensitivity/subgroup analyses. Risk of bias was assessed using the Cochrane tool, and certainty of the evidence was assessed using GRADE. Main results: Thirty-one new studies were identified for inclusion in this updated review. Overall, we included 64 studies (5299 participants) on ketamine (31 trials), esketamine (9), memantine (5), lanicemine (4), D-cycloserine (2), Org26576 (2), riluzole (2), atomoxetine (1), basimglurant (1), citicoline (1), CP-101,606 (1), decoglurant (1), MK-0657 (1), N-acetylcysteine (1), rapastinel (1), and sarcosine (1). Forty-eight studies were placebo-controlled, and 48 were two-arm studies. The majority of trials defined an inclusion criterion for the severity of depressive symptoms at baseline: 29 at least moderate depression; 17 severe depression; and five mild-to-moderate depression. Nineteen studies recruited only patients with treatment-resistant depression, defined as inadequate response to at least two antidepressants. The majority of studies investigating ketamine administered as a single dose, whilst all of the included esketamine studies used a multiple dose regimen (most frequently twice a week for four weeks). Most studies looking at ketamine used intravenous administration, whilst the majority of esketamine trials used intranasal routes. The evidence suggests that ketamine may result in an increase in response and remission compared with placebo at 24 hours odds ratio (OR) 3.94, 95% confidence interval (CI) 1.54 to 10.10; n = 185, studies = 7, very low-certainty evidence). Ketamine may reduce depression rating scale scores over placebo at 24 hours, but the evidence is very uncertain (standardised mean difference (SMD) -0.87, 95% CI -1.26 to -0.48; n = 231, studies = 8, very low-certainty evidence). There was no difference in the number of participants assigned to ketamine or placebo who dropped out for any reason (OR 1.25, 95% CI 0.19 to 8.28; n = 201, studies = 6, very low-certainty evidence). When compared with midazolam, the evidence showed that ketamine increases remission rates at 24 hours (OR 2.21, 95% CI 0.67 to 7.32; n = 122,studies = 2, low-certainty evidence). The evidence is very uncertain about the response efficacy of ketamine at 24 hours in comparison with midazolam, and its ability to reduce depression rating scale scores at the same time point (OR 2.48, 95% CI 1.00 to 6.18; n = 296, studies = 4,very low-certainty evidence). There was no difference in the number of participants who dropped out of studies for any reason between ketamine and placebo (OR 0.33, 95% CI 0.05 to 2.09; n = 72, studies = 1, low-certainty evidence). Esketamine treatment likely results in a large increase in participants achieving remission at 24 hours compared with placebo (OR 2.74, 95% CI 1.71 to 4.40; n = 894, studies = 5, moderate-certainty evidence). Esketamine probably results in decreases in depression rating scale scores at 24 hours compared with placebo (SMD -0.31, 95% CI -0.45 to -0.17; n = 824, studies = 4, moderate-certainty evidence). Our findings show that esketamine increased response rates, although this evidence is uncertain (OR 2.11, 95% CI 1.20 to 3.68; n = 1071, studies = 5, low-certainty evidence). There was no evidence that participants assigned to esketamine treatment dropped out of trials more frequently than those assigned to placebo for any reason (OR 1.58, 95% CI 0.92 to 2.73; n = 773, studies = 4,moderate-certainty evidence). We found very little evidence for the remaining glutamate receptor modulators. We rated the risk of bias as low or unclear for most domains, though lack of detail regarding masking of treatment in the studies reduced our certainty in the effect for all outcomes. Authors' conclusions: Our findings show that ketamine and esketamine may be more efficacious than placebo at 24 hours. How these findings translate into clinical practice, however, is not entirely clear. The evidence for use of the remaining glutamate receptor modulators is limited as very few trials were included in the meta-analyses for each comparison and the majority of comparisons included only one study. Long term non-inferiority RCTs comparing repeated ketamine and esketamine, and rigorous real-world monitoring are needed to establish comprehensive data on safety and efficacy

Ketamine and other glutamate receptor modulators for depression in adults with bipolar disorder

Background: Glutamergic system dysfunction has been implicated in the pathophysiology of bipolar depression. This is an update of the 2015 Cochrane Review for the use of glutamate receptor modulators for depression in bipolar disorder. Objectives: 1. To assess the effects of ketamine and other glutamate receptor modulators in alleviating the acute symptoms of depression in people with bipolar disorder. 2. To review the acceptability of ketamine and other glutamate receptor modulators in people with bipolar disorder who are experiencing depressive symptoms. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Embase and PsycINFO all years to July 2020. We did not apply any restrictions to date, language or publication status. Selection criteria: RCTs comparing ketamine or other glutamate receptor modulators with other active psychotropic drugs or saline placebo in adults with bipolar depression. Data collection and analysis: Two review authors independently selected studies for inclusion, assessed trial quality and extracted data. Primary outcomes were response rate and adverse events. Secondary outcomes included remission rate, depression severity change scores, suicidality, cognition, quality of life, and dropout rate. The GRADE framework was used to assess the certainty of the evidence. Main results: Ten studies (647 participants) were included in this review (an additional five studies compared to the 2015 review). There were no additional studies added to the comparisons identified in the 2015 Cochrane review on ketamine, memantine and cytidine versus placebo. However, three new comparisons were found: ketamine versus midazolam, N-acetylcysteine versus placebo, and riluzole versus placebo. The glutamate receptor modulators studied were ketamine (three trials), memantine (two), cytidine (one), N-acetylcysteine (three), and riluzole (one). Eight of these studies were placebo-controlled and two-armed. In seven trials the glutamate receptor modulators had been used as add-on drugs to mood stabilisers. Only one trial compared ketamine with an active comparator, midazolam. The treatment period ranged from a single intravenous administration (all ketamine studies), to repeated administration for riluzole, memantine, cytidine, and N-acetylcysteine (with a follow-up of eight weeks, 8 to 12 weeks, 12 weeks, and 16 to 20 weeks, respectively). Six of the studies included sites in the USA, one in Taiwan, one in Denmark, one in Australia, and in one study the location was unclear. All participants had a primary diagnosis of bipolar disorder and were experiencing an acute bipolar depressive episode, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders fourth edition (IV) or fourth edition text revision (IV-TR). Among all glutamate receptor modulators included in this review, only ketamine appeared to be more efficacious than placebo 24 hours after infusion for response rate (odds ratio (OR) 11.61, 95% confidence interval (CI) 1.25 to 107.74; P = 0.03; participants = 33; studies = 2; I² = 0%, low-certainty evidence). Ketamine seemed to be more effective in reducing depression rating scale scores (MD -11.81, 95% CI -20.01 to -3.61; P = 0.005; participants = 32; studies = 2; I2 = 0%, very low-certainty evidence). There was no evidence of ketamine's efficacy in producing remission over placebo at 24 hours (OR 5.16, 95% CI 0.51 to 52.30; P = 0.72; participants = 33; studies = 2; I2 = 0%, very low-certainty evidence). Evidence on response, remission or depression rating scale scores between ketamine and midazolam was uncertain at 24 hours due to very low-certainty evidence (OR 3.20, 95% CI 0.23 to 45.19). In the one trial assessing ketamine and midazolam, there were no dropouts due to adverse effects or for any reason (very low-certainty evidence). Placebo may have been more effective than N-acetylcysteine in reducing depression rating scale scores at three months, although this was based on very low-certainty evidence (MD 1.28, 95% CI 0.24 to 2.31; participants = 58; studies = 2). Very uncertain evidence found no difference in response at three months (OR 0.82, 95% CI 0.32 to 2.14; participants = 69; studies = 2; very low-certainty evidence). No data were available for remission or acceptability. Extremely limited data were available for riluzole vs placebo, finding only very-low certainty evidence of no difference in dropout rates (OR 2.00, 95% CI 0.31 to 12.84; P = 0.46; participants = 19; studies = 1; I2 = 0%). Authors' conclusions: It is difficult to draw reliable conclusions from this review due to the certainty of the evidence being low to very low, and the relatively small amount of data usable for analysis in bipolar disorder, which is considerably less than the information available for unipolar depression. Nevertheless, we found uncertain evidence in favour of a single intravenous dose of ketamine (as add-on therapy to mood stabilisers) over placebo in terms of response rate up to 24 hours, however ketamine did not show any better efficacy for remission in bipolar depression. Even though ketamine has the potential to have a rapid and transient antidepressant effect, the efficacy of a single intravenous dose may be limited. We did not find conclusive evidence on adverse events with ketamine, and there was insufficient evidence to draw meaningful conclusions for the remaining glutamate receptor modulators. However, ketamine's psychotomimetic effects (such as delusions or delirium) may have compromised study blinding in some studies, and so we cannot rule out the potential bias introduced by inadequate blinding procedures. To draw more robust conclusions, further methodologically sound RCTs (with adequate blinding) are needed to explore different modes of administration of ketamine, and to study different methods of sustaining antidepressant response, such as repeated administrations

Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder

Background: Many studies have recently been conducted to assess the antidepressant efficacy of glutamate modification in mood disorders. This is an update of a review first published in 2015 focusing on the use of glutamate receptor modulators in unipolar depression. Objectives: To assess the effects - and review the acceptability and tolerability - of ketamine and other glutamate receptor modulators in alleviating the acute symptoms of depression in people with unipolar major depressive disorder. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Embase and PsycINFO all years to July 2020. We did not apply any restrictions to date, language or publication status. Selection criteria: Double- or single-blinded randomised controlled trials (RCTs) comparing ketamine, memantine, esketamine or other glutamate receptor modulators with placebo (pill or saline infusion), other active psychotropic drugs, or electroconvulsive therapy (ECT) in adults with unipolar major depression. Data collection and analysis: Three review authors independently identified studies, assessed trial quality and extracted data. The primary outcomes were response rate (50% reduction on a standardised rating scale) and adverse events. We decided a priori to measure the efficacy outcomes at different time points and run sensitivity/subgroup analyses. Risk of bias was assessed using the Cochrane tool, and certainty of the evidence was assessed using GRADE. Main results: Thirty-one new studies were identified for inclusion in this updated review. Overall, we included 64 studies (5299 participants) on ketamine (31 trials), esketamine (9), memantine (5), lanicemine (4), D-cycloserine (2), Org26576 (2), riluzole (2), atomoxetine (1), basimglurant (1), citicoline (1), CP-101,606 (1), decoglurant (1), MK-0657 (1), N-acetylcysteine (1), rapastinel (1), and sarcosine (1). Forty-eight studies were placebo-controlled, and 48 were two-arm studies. The majority of trials defined an inclusion criterion for the severity of depressive symptoms at baseline: 29 at least moderate depression; 17 severe depression; and five mild-to-moderate depression. Nineteen studies recruited only patients with treatment-resistant depression, defined as inadequate response to at least two antidepressants. The majority of studies investigating ketamine administered as a single dose, whilst all of the included esketamine studies used a multiple dose regimen (most frequently twice a week for four weeks). Most studies looking at ketamine used intravenous administration, whilst the majority of esketamine trials used intranasal routes. The evidence suggests that ketamine may result in an increase in response and remission compared with placebo at 24 hours odds ratio (OR) 3.94, 95% confidence interval (CI) 1.54 to 10.10; n = 185, studies = 7, very low-certainty evidence). Ketamine may reduce depression rating scale scores over placebo at 24 hours, but the evidence is very uncertain (standardised mean difference (SMD) -0.87, 95% CI -1.26 to -0.48; n = 231, studies = 8, very low-certainty evidence). There was no difference in the number of participants assigned to ketamine or placebo who dropped out for any reason (OR 1.25, 95% CI 0.19 to 8.28; n = 201, studies = 6, very low-certainty evidence). When compared with midazolam, the evidence showed that ketamine increases remission rates at 24 hours (OR 2.21, 95% CI 0.67 to 7.32; n = 122,studies = 2, low-certainty evidence). The evidence is very uncertain about the response efficacy of ketamine at 24 hours in comparison with midazolam, and its ability to reduce depression rating scale scores at the same time point (OR 2.48, 95% CI 1.00 to 6.18; n = 296, studies = 4,very low-certainty evidence). There was no difference in the number of participants who dropped out of studies for any reason between ketamine and placebo (OR 0.33, 95% CI 0.05 to 2.09; n = 72, studies = 1, low-certainty evidence). Esketamine treatment likely results in a large increase in participants achieving remission at 24 hours compared with placebo (OR 2.74, 95% CI 1.71 to 4.40; n = 894, studies = 5, moderate-certainty evidence). Esketamine probably results in decreases in depression rating scale scores at 24 hours compared with placebo (SMD -0.31, 95% CI -0.45 to -0.17; n = 824, studies = 4, moderate-certainty evidence). Our findings show that esketamine increased response rates, although this evidence is uncertain (OR 2.11, 95% CI 1.20 to 3.68; n = 1071, studies = 5, low-certainty evidence). There was no evidence that participants assigned to esketamine treatment dropped out of trials more frequently than those assigned to placebo for any reason (OR 1.58, 95% CI 0.92 to 2.73; n = 773, studies = 4,moderate-certainty evidence). We found very little evidence for the remaining glutamate receptor modulators. We rated the risk of bias as low or unclear for most domains, though lack of detail regarding masking of treatment in the studies reduced our certainty in the effect for all outcomes. Authors' conclusions: Our findings show that ketamine and esketamine may be more efficacious than placebo at 24 hours. How these findings translate into clinical practice, however, is not entirely clear. The evidence for use of the remaining glutamate receptor modulators is limited as very few trials were included in the meta-analyses for each comparison and the majority of comparisons included only one study. Long term non-inferiority RCTs comparing repeated ketamine and esketamine, and rigorous real-world monitoring are needed to establish comprehensive data on safety and efficacy

Ketamine and other glutamate receptor modulators for depression in adults with bipolar disorder

Background: Glutamergic system dysfunction has been implicated in the pathophysiology of bipolar depression. This is an update of the 2015 Cochrane Review for the use of glutamate receptor modulators for depression in bipolar disorder. Objectives: 1. To assess the effects of ketamine and other glutamate receptor modulators in alleviating the acute symptoms of depression in people with bipolar disorder. 2. To review the acceptability of ketamine and other glutamate receptor modulators in people with bipolar disorder who are experiencing depressive symptoms. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Embase and PsycINFO all years to July 2020. We did not apply any restrictions to date, language or publication status. Selection criteria: RCTs comparing ketamine or other glutamate receptor modulators with other active psychotropic drugs or saline placebo in adults with bipolar depression. Data collection and analysis: Two review authors independently selected studies for inclusion, assessed trial quality and extracted data. Primary outcomes were response rate and adverse events. Secondary outcomes included remission rate, depression severity change scores, suicidality, cognition, quality of life, and dropout rate. The GRADE framework was used to assess the certainty of the evidence. Main results: Ten studies (647 participants) were included in this review (an additional five studies compared to the 2015 review). There were no additional studies added to the comparisons identified in the 2015 Cochrane review on ketamine, memantine and cytidine versus placebo. However, three new comparisons were found: ketamine versus midazolam, N-acetylcysteine versus placebo, and riluzole versus placebo. The glutamate receptor modulators studied were ketamine (three trials), memantine (two), cytidine (one), N-acetylcysteine (three), and riluzole (one). Eight of these studies were placebo-controlled and two-armed. In seven trials the glutamate receptor modulators had been used as add-on drugs to mood stabilisers. Only one trial compared ketamine with an active comparator, midazolam. The treatment period ranged from a single intravenous administration (all ketamine studies), to repeated administration for riluzole, memantine, cytidine, and N-acetylcysteine (with a follow-up of eight weeks, 8 to 12 weeks, 12 weeks, and 16 to 20 weeks, respectively). Six of the studies included sites in the USA, one in Taiwan, one in Denmark, one in Australia, and in one study the location was unclear. All participants had a primary diagnosis of bipolar disorder and were experiencing an acute bipolar depressive episode, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders fourth edition (IV) or fourth edition text revision (IV-TR). Among all glutamate receptor modulators included in this review, only ketamine appeared to be more efficacious than placebo 24 hours after infusion for response rate (odds ratio (OR) 11.61, 95% confidence interval (CI) 1.25 to 107.74; P = 0.03; participants = 33; studies = 2; I² = 0%, low-certainty evidence). Ketamine seemed to be more effective in reducing depression rating scale scores (MD -11.81, 95% CI -20.01 to -3.61; P = 0.005; participants = 32; studies = 2; I2 = 0%, very low-certainty evidence). There was no evidence of ketamine's efficacy in producing remission over placebo at 24 hours (OR 5.16, 95% CI 0.51 to 52.30; P = 0.72; participants = 33; studies = 2; I2 = 0%, very low-certainty evidence). Evidence on response, remission or depression rating scale scores between ketamine and midazolam was uncertain at 24 hours due to very low-certainty evidence (OR 3.20, 95% CI 0.23 to 45.19). In the one trial assessing ketamine and midazolam, there were no dropouts due to adverse effects or for any reason (very low-certainty evidence). Placebo may have been more effective than N-acetylcysteine in reducing depression rating scale scores at three months, although this was based on very low-certainty evidence (MD 1.28, 95% CI 0.24 to 2.31; participants = 58; studies = 2). Very uncertain evidence found no difference in response at three months (OR 0.82, 95% CI 0.32 to 2.14; participants = 69; studies = 2; very low-certainty evidence). No data were available for remission or acceptability. Extremely limited data were available for riluzole vs placebo, finding only very-low certainty evidence of no difference in dropout rates (OR 2.00, 95% CI 0.31 to 12.84; P = 0.46; participants = 19; studies = 1; I2 = 0%). Authors' conclusions: It is difficult to draw reliable conclusions from this review due to the certainty of the evidence being low to very low, and the relatively small amount of data usable for analysis in bipolar disorder, which is considerably less than the information available for unipolar depression. Nevertheless, we found uncertain evidence in favour of a single intravenous dose of ketamine (as add-on therapy to mood stabilisers) over placebo in terms of response rate up to 24 hours, however ketamine did not show any better efficacy for remission in bipolar depression. Even though ketamine has the potential to have a rapid and transient antidepressant effect, the efficacy of a single intravenous dose may be limited. We did not find conclusive evidence on adverse events with ketamine, and there was insufficient evidence to draw meaningful conclusions for the remaining glutamate receptor modulators. However, ketamine's psychotomimetic effects (such as delusions or delirium) may have compromised study blinding in some studies, and so we cannot rule out the potential bias introduced by inadequate blinding procedures. To draw more robust conclusions, further methodologically sound RCTs (with adequate blinding) are needed to explore different modes of administration of ketamine, and to study different methods of sustaining antidepressant response, such as repeated administrations