Drug dependence and prescribing ketamine for treatment-resistant depression in Australia and New Zealand.

Ketamine is a restricted and regulated medication in Australia and New Zealand, which has implications when considering treatment for patients with treatment-resistant depression and a history of illicit drug use, abuse or dependence. Regulations governing prescription of ketamine for treatment-resistant depression vary between jurisdictions in Australia and New Zealand, though most restrict use in those with drug dependence. There is substantial variation in definitions of drug dependence used in each jurisdiction, and between the legal and clinical definitions, with the latter specified in the current International Classification of Diseases, Eleventh Revision and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. This paper reviews the literature assessing the risk of ketamine misuse and dependence in patients with a history of illicit drug use, abuse or dependence and presents recommendations for psychiatrists who prescribe ketamine in such patients with treatment-resistant depression.

Individualised Transcranial Magnetic Stimulation Targeting of the Left Dorsolateral Prefrontal Cortex for Enhancing Cognition: A Randomised Controlled Trial.

Repetitive transcranial magnetic stimulation (rTMS) has been demonstrated to produce cognitive enhancing effects across different neuropsychiatric disorders; however, so far, these effects have been limited. This trial investigated the efficacy of using a novel individualised approach to target the left dorsolateral prefrontal cortex (L-DLPFC) for enhancing cognitive flexibility based on performance on a cognitive task. First, forty healthy participants had their single target site at the L-DLPFC determined based on each individual's performance on a random letter generation task. Participants then received, in a cross-over single-blinded experimental design, a single session of intermittent theta burst stimulation (iTBS) to their individualised DLPFC target site, an active control site and sham iTBS. Following each treatment condition, participants completed the Task Switching task and Colour-Word Stroop test. There was no significant main effect of treatment condition on the primary outcome measure of switch reaction times from the Task Switching task [F = 1.16 (2, 21.6), p = 0.33] or for any of the secondary cognitive outcome measures. The current results do not support the use of our novel individualised targeting methodology for enhancing cognitive flexibility in healthy participants. Research into alternative methodological targeting approaches is required to further improve rTMS's cognitive enhancing effects.

Cognitive outcomes from the randomised, active-controlled Ketamine for Adult Depression Study (KADS).

BACKGROUND: Due to its rapid antidepressant effect, ketamine has recently been clinically translated for people with treatment-resistant depression. However, its cognitive profile remains unclear, particularly with repeated and higher doses. In the present study, we report the cognitive results from a recent large multicentre randomised controlled trial, the Ketamine for Adult Depression Study (KADS). METHODS: In this randomised, double-blind, active-controlled, parallel group, multicentre phase 3 trial study we investigated potential cognitive changes following repeated treatment of subcutaneous racemic ketamine compared to an active comparator, midazolam, over 4 weeks, which involved two cohorts; Cohort 1 involved a fixed dose treatment protocol (0.5 mg/kg ketamine), Cohort 2 involved a dose escalation protocol (0.5-0.9 mg/kg) based on mood outcomes. Participants with treatment-resistant Major Depressive Disorder (MDD) were recruited from 7 mood disorder centres and were randomly assigned to receive ketamine (Cohort 1 n = 33; Cohort 2 n = 53) or midazolam (Cohort 1 n = 35; Cohort 2 n = 53) in a 1:1 ratio. Cognitive measurements were assessed at baseline and at the end of randomised treatment. RESULTS: Results showed that in Cohort 1, there were no differences between ketamine and midazolam in cognitive outcomes. For Cohort 2, there was similarly no difference between conditions for cognitive outcomes. LIMITATIONS: The study included two Cohorts with different dosing regimes. CONCLUSIONS: The findings support the cognitive safety of repeated fixed and escalating doses at least in the short-term in people with treatment resistant MDD.

Who are you after psychedelics? A systematic review and a meta-analysis of the magnitude of long-term effects of serotonergic psychedelics on cognition/creativity, emotional processing and personality.

This systematic review and a meta-analysis synthesised the results from contemporary, randomized and non-randomized controlled studies to assess lasting (one week minimum) changes on cognition/creativity, emotional processing and personality from serotonergic psychedelics. PubMed, Embase and PsycInfo were searched in July 2022. Risk of bias was assessed using Rob 2.0 and ROBINS-I. Ten studies met the eligibility criteria which involved 304 participants. No statistically significant effects were found for the majority outcome measures across the three constructs. A meta-analysis of emotional recognition outcomes found an overall significant effect for faster reaction times in the active treatment groups for disgust (SMD=-0.63, 95% CI=[-1.01 to -0.25], I2 = 65%) and sadness (SMD=-0.45, 95% CI=[-0.85 to -0.06], I2 = 60%). Future research should include larger samples, better control conditions, standardized doses and longer follow-up periods to confirm these preliminary findings.

Cognitive Effects Following Offline High-Frequency Repetitive Transcranial Magnetic Stimulation (HF-rTMS) in Healthy Populations: A Systematic Review and Meta-Analysis.

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) is a commonly used form of rTMS to treat neuropsychiatric disorders. Emerging evidence suggests that 'offline' HF-rTMS may have cognitive enhancing effects, although the magnitude and moderators of these effects remain unclear. We conducted a systematic review and meta-analysis to clarify the cognitive effects of offline HF-rTMS in healthy individuals. A literature search for randomised controlled trials with cognitive outcomes for pre and post offline HF-rTMS was performed across five databases up until March 2022. This study was registered on the PROSPERO international prospective protocol for systematic reviews (PROSPERO 2020 CRD 42,020,191,269). The Risk of Bias 2 tool was used to assess the risk of bias in randomised trials. Separate analyses examined the cognitive effects of excitatory and inhibitory forms of offline HF-rTMS on accuracy and reaction times across six cognitive domains. Fifty-three studies (N = 1507) met inclusion criteria. Excitatory offline HF-rTMS showed significant small sized effects for improving accuracy (k = 46, g = 0.12) and reaction time (k = 44, g = -0.13) across all cognitive domains collapsed. Excitatory offline HF-rTMS demonstrated a relatively greater effect for executive functioning in accuracy (k = 24, g = 0.14). Reaction times were also improved for the executive function (k = 21, g = -0.11) and motor (k = 3, g = -0.22) domains following excitatory offline HF-rTMS. The current review was restricted to healthy individuals and future research is required to examine cognitive enhancement from offline HF-rTMS in clinical cohorts.

Electroconvulsive Therapy Credentialing for Psychiatrists-Review of Required Standards Across States and Territories in Australia.

ABSTRACT: Electroconvulsive therapy (ECT) is a complex medical procedure, the delivery of which requires specialist knowledge and skills. We reviewed the standards required for ECT credentialing in different jurisdictions in Australia. We reviewed the Chief Psychiatrist guidelines and statewide policy standards on ECT and focused on standards required for initial credentialing and ongoing privileging in ECT. We compared the credentialing requirements within these documents with the standards specified in the Royal Australian and New Zealand College of Psychiatrists professional practice guideline for ECT. Most of the jurisdictions had specific standards for initial credentialing and maintenance of this credentialing; however, there was significant variance in the credentialing process and standards required. It would be useful to have a minimum standard for credentialing for ECT psychiatrists and prescribers. This standard would be relevant for practice of ECT internationally. States and territories would have the responsibility for implementation of these standards. Appropriate training and establishing good clinical governance processes are essential to the provision of high quality ECT.

Randomised controlled trial of neurostimulation for symptoms of anorexia nervosa (TRENA study): study protocol.

BACKGROUND: Anorexia nervosa (AN) has amongst the highest mortality rates and the highest treatment costs of any psychiatric disorder. Recently, interest in non-invasive brain stimulation as a novel treatment for AN has grown. These include repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). METHODS: This double-blind, randomised sham-controlled trial will compare the relative acceptability and efficacy of tDCS and rTMS in people with AN. 70 participants will be randomised to active or sham tDCS, or active or sham rTMS treatment (2:1:2:1 ratio) over an 8-week treatment period. Participants will receive treatment as usual across the study duration. The primary outcomes are change on the Eating Disorder Examination Questionnaire and treatment acceptability. Secondary outcomes will include change in weight, cognition, mood, interpersonal functioning, and quality of life. Following the 8-week assessment, all participants will have the option of receiving an additional 12 weeks of at-home tDCS. A follow-up assessment will be conducted at 20 weeks post treatment. DISCUSSION: Research into non-invasive brain stimulation as treatments for AN has potential to improve clinical outcomes for patients by comparing the relative efficacy and acceptability of both treatment modalities in the inpatient and at-home setting (i.e., for at-home tDCS) results from this study will provide important information for informing future larger clinical trials of these treatments for AN. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05788042.

A systematic review of the print media representation of ketamine treatments for psychiatric disorders.

BACKGROUND: Public and patient expectations of treatment influence health behaviours and decision-making. AIMS: We aimed to understand how the media has portrayed the therapeutic use of ketamine in psychiatry. METHOD: We systematically searched electronic databases for print and online news articles about ketamine for psychiatric disorders. The top ten UK, USA, Canadian and Australian newspapers by circulation and any trade and consumer magazines indexed in the databases were searched from 2015 to 2020. Article content was quantitatively coded with a framework encompassing treatment indication, descriptions of prior use, references to research, benefits and harms, treatment access and process, patient and professional testimony, tone and factual basis. RESULTS: We found 119 articles, peaking in March 2019 when the United States Food and Drug Administration approved esketamine. Ketamine treatment was portrayed in an extremely positive light (n = 82, 68.9%), with significant contributions of positive testimony from key opinion leaders (e.g. clinicians). Positive research results and ketamine's rapid antidepressant effect (n = 87, 73.1%) were frequently emphasised, with little reference to longer-term safety and efficacy. Side-effects were frequently reported (n = 96, 80.7%), predominantly ketamine's acute psychotomimetic effects and the potential for addiction and misuse, and rarely cardiovascular and bladder effects. Not infrequently, key opinion leaders were quoted as being overly optimistic compared with the existing evidence base. CONCLUSIONS: Information pertinent to patient help-seeking and treatment expectations is being communicated through the media and supported by key opinion leaders, although some quotes go well beyond the evidence base. Clinicians should be aware of this and may need to address their patients' beliefs directly.

The association between outpatient continuation/maintenance electroconvulsive therapy, readmission risk and total direct cost in patients with depressive, bipolar and psychotic disorders: A naturalistic retrospective cohort study.

BACKGROUND: The transdiagnostic effect of continuation/maintenance ECT (CM-ECT) across mood and psychotic disorders on hospital psychiatric readmission risk and total direct cost remains unclear. METHODS: A naturalistic retrospective analysis of 540 patients who received inpatient acute ECT treatment from May 2017 to Mar 2021 in a tertiary psychiatric institution. Patients were assessed with validated clinical rating scales pre-ECT and after the first 6 treatments of a course of inpatient acute ECT. After discharge, patients who continued with CM-ECT were compared with those not receiving CM-ECT using survival analysis of hospital readmission. Total direct cost (hospitalisation and ECT treatment cost) was also analysed. All patients were subjected to a standard post-discharge monitoring program with case managers checking in on the patients regularly after discharge and ensuring they were given an outpatient appointment within a month of discharge. RESULTS: Both cohorts had significant improvement in their rating scales scores after their first six 6 sessions of inpatient acute ECT. Patients who continued with CM-ECT after completing their inpatient acute ECT (mean number of acute ECT: N = 9.9, SD 5.3), had a significantly lower risk of readmission [adjusted hazard ratio of 0.68 (95 % CI: 0.49-0.94, p = 0.020)]. Patients who received CM-ECT also had a significantly lower average total direct cost compared to those who did not (SGD$35,259 vs SGD$61,337). For patients with mood disorders, the CM-ECT group had a significantly lower inpatient ECT cost, hospitalisation cost and total direct costs compared to those without CM-ECT. LIMITATIONS: The naturalistic study cannot prove a causal relationship between CM-ECT and reduced readmission and lower healthcare costs. CONCLUSION: CM-ECT is associated with lower readmission risks and lower total direct healthcare costs for the treatment of mood and psychotic disorders, especially for mood disorders.

Prescribing electroconvulsive therapy for depression: Not as simple as it used to be.

In the last century, prescribing electroconvulsive therapy usually involved considering the relative merits of unilateral versus bilateral electroconvulsive therapy, with most other parameters fixed. However, research over the last 30 years has discovered that several parameters of the electroconvulsive therapy stimulus can have a significant impact on efficacy and cognitive side effects. The stimulus dose relative to seizure threshold was shown to significantly affect efficacy, especially for right unilateral electroconvulsive therapy, where suprathreshold doses in the vicinity of 5-6 times seizure threshold were far more efficacious than doses closer to threshold. However, this did not hold for bitemporal electroconvulsive therapy, where near-threshold stimuli were equally effective as suprathreshold stimuli. Then, changes in stimulus pulse width were found to also have a significant impact on both efficacy and side effects, with ultrabrief pulse widths of 0.3 ms having significantly fewer cognitive side effects in unilateral electroconvulsive therapy than standard brief pulse widths of 1.0 ms, with only slightly reduced efficacy. Therefore, choosing the optimum electroconvulsive therapy prescription for an individual patient now requires consideration of placement, pulse width and stimulus dose relative to seizure threshold, and how these three interact with each other. This viewpoint aims to raise awareness of these issues for psychiatrists involved in electroconvulsive therapy practice.

Time-course of the tDCS antidepressant effect: An individual participant data meta-analysis.

INTRODUCTION: Prefrontal transcranial direct current stimulation (tDCS) shows promise as an effective treatment for depression. However, factors influencing treatment and the time-course of symptom improvements remain to be elucidated. METHODS: Individual participant data was collected from ten randomised controlled trials of tDCS in depression. Depressive symptom scores were converted to a common scale, and a linear mixed effects individual growth curve model was fit to the data using k-fold cross-validation to prevent overfitting. RESULTS: Data from 576 participants were analysed (tDCS: n = 311; sham: n = 265), of which 468 were unipolar and 108 had bipolar disorder. tDCS effect sizes reached a peak at approximately 6 weeks, and continued to diverge from sham up to 10 weeks. Significant predictors associated with worse response included higher baseline depression severity, treatment resistance, and those associated with better response included bipolar disorder and anxiety disorder. CONCLUSIONS: Our findings suggest that longer treatment courses, lasting at least 6 weeks in duration, may be indicated. Further, our results show that tDCS is effective for depressive symptoms in bipolar disorder. Compared to unipolar depression, participants with bipolar disorder may require additional maintenance sessions to prevent rapid relapse.

Transcranial Direct Current Stimulation Modulates Working Memory Maintenance Processes in Healthy Individuals.

The effects of transcranial direct current stimulation (tDCS) at the pFC are often investigated using cognitive paradigms, particularly working memory tasks. However, the neural basis for the neuromodulatory cognitive effects of tDCS, including which subprocesses are affected by stimulation, is not completely understood. We investigated the effects of tDCS on working memory task-related spectral activity during and after tDCS to gain better insights into the neurophysiological changes associated with stimulation. We reanalyzed data from 100 healthy participants grouped by allocation to receive either sham (0 mA, 0.016 mA, and 0.034 mA) or active (1 mA or 2 mA) stimulation during a 3-back task. EEG data were used to analyze event-related spectral power in frequency bands associated with working memory performance. Frontal theta event-related synchronization (ERS) was significantly reduced post-tDCS in the active group. Participants receiving active tDCS had slower RTs following tDCS compared with sham, suggesting interference with practice effects associated with task repetition. Theta ERS was not significantly correlated with RTs or accuracy. tDCS reduced frontal theta ERS poststimulation, suggesting a selective disruption to working memory cognitive control and maintenance processes. These findings suggest that tDCS selectively affects specific subprocesses during working memory, which may explain heterogenous behavioral effects.

Population Pharmacokinetics and Pharmacodynamics of the Therapeutic and Adverse Effects of Ketamine in Patients With Treatment-Refractory Depression.

We aimed to develop population pharmacokinetic/pharmacodynamic (PK/PD) models that can effectively describe ketamine and norketamine PK/PD relationships for Montgomery-Åsberg Depression Rating Scale (MADRS) scores, blood pressure (BP), and heart rate (HR) following i.v., s.c., and i.m. ketamine administration in patients with treatment-refractory depression. Ketamine PK/PD data were collected from 21 treatment-refractory depressed participants who received ketamine (dose titration 0.1-0.5 mg/kg as single doses) by i.v., s.c., or i.m. administration. Model development used nonlinear mixed effect modeling. Ketamine and norketamine PK were best described using two-compartment models with first-order absorption after s.c. and i.m. administration. Estimated ketamine bioavailability after i.m. and s.c. was ~ 64% with indistinguishable first-order absorption rate constants. Allometric scaling of body weight on all clearance and volumes of distribution improved the model fit. The delay in the concentration-response relationship for MADRS scores was best described using a turnover model (turnover time ~ 42 hours), whereas for the BP and HR rates this was an immediate effect model. For all PD effects, ketamine alone was superior to models with norketamine concentration linked to an effect. No covariates were identified for PD effects. The estimated half-maximal effective concentration from the MADRS score, BP, and HR were 0.44, 468, and 7,580 ng/mL, respectively. The integrated population models were able to effectively describe the PK/PD relationships for MADRS scores, BP, and HR after i.v., s.c., and i.m. ketamine administration. These findings allow for a deeper understanding of the complex relationships between route of ketamine administration and clinical response and safety.

The Ketamine Side Effect Tool (KSET): A comprehensive measurement-based safety tool for ketamine treatment in psychiatry.

OBJECTIVES: On a background of the rapidly expanding clinical use of ketamine and esketamine for treatment of depression and other conditions, we examined safety monitoring, seeking to identify knowledge gaps relevant to clinical practice. METHODS: An international group of psychiatrists discussed the issue of safety of ketamine and esketamine and came to a consensus on key safety gaps. RESULTS: There is no standard safety monitoring for off-label generic ketamine. For intranasal esketamine, each jurisdiction providing regulatory approval may specify monitoring. Treatment is often provided beyond the period for which safety has been demonstrated, with no agreed framework for monitoring of longer term side effects for either generic ketamine or intranasal esketamine. LIMITATIONS: The KSET has established face and content validity, however it has not been validated against other measures of safety. CONCLUSIONS: We recommend the Ketamine Side Effect Tool (KSET) as a comprehensive safety monitoring tool for acute and longer term side effects.

A novel approach for targeting the left dorsolateral prefrontal cortex for transcranial magnetic stimulation using a cognitive task.

Repetitive transcranial magnetic stimulation (rTMS) has the potential to be developed as a novel treatment for cognitive dysfunction. However, current methods of targeting rTMS for cognition fail to consider inter-individual functional variability. This study explored the use of a cognitive task to individualise the target site for rTMS administered to the left dorsolateral prefrontal cortex (L-DLPFC). Twenty-five healthy participants were enrolled in a sham-controlled, crossover study. Participants performed a random letter generation task under the following conditions: no stimulation, sham and active 'online' rTMS applied to F3 (International 10-20 System) and four standardised surrounding sites. Across all sites combined, active 'online' rTMS was associated with significantly reduced performance compared to sham rTMS for unique trigrams (p = 0.012), but not for unique digrams (p > 0.05). Using a novel localisation methodology based on performance outcomes from both measures, a single optimal individualised site was identified for 92% [n = 23] of participants. At the individualised site, performance was significantly poorer compared to a common standard site (F3) and both control conditions (ps < 0.01). The current results suggest that this localisation methodology using a cognitive task could be used to individualise the rTMS target site at the L-DLPFC for modulating and potentially enhancing cognitive functioning.

The Impact of COVID-19 on Electroconvulsive Therapy: A Multisite, Retrospective Study From the Clinical Alliance and Research in Electroconvulsive Therapy and Related Treatments Network.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has led to reported change in electroconvulsive therapy (ECT) services worldwide. However, minimal data have been published demonstrating tangible changes across multiple ECT centers. This article aimed to examine changes in ECT patients and ECT service delivery during the pandemic. METHODS: We retrospectively assessed data collected on ECT patients within the Clinical Alliance and Research in Electroconvulsive Therapy and Related Treatments (CARE) Network during a 3-month period starting at the first COVID-19 restrictions in 2020 and compared data with predicted values based on the corresponding 3-month period in 2019. Mixed-effects repeated-measures analyses examined differences in the predicted and actual number of acute ECT courses started and the total number of acute ECT treatments given in 2020. Sociodemographic, clinical, treatment factors, and ECT service delivery factors were compared for 2020 and 2019. RESULTS: Four Australian and 1 Singaporean site participated in the study. There were no significant differences between the predicted and actual number of acute ECT courses and total number of acute ECT treatments administered in 2020. During 2020, there were statistically significant increases in the proportion of patients requiring ECT under substitute consent and receiving ECT for urgent reasons compared with 2019. CONCLUSIONS: This multisite empirical study is among the first that supports anecdotal reports of changes in the triaging and delivery of ECT during COVID-19. Results suggest that ECT was prioritized for the most severely ill patients. Further data assessing the impacts of COVID-19 on ECT are needed.

Effects of modifying the electrode placement and pulse width on cognitive side effects with unilateral ECT: A pilot randomised controlled study with computational modelling.

BACKGROUND: The electrode placement and pulse width for electroconvulsive therapy (ECT) are important treatment parameters associated with ECT related retrograde memory side-effects. Modification of these parameters with right unilateral (RUL) ECT may have utility for further reducing these side-effects. OBJECTIVE: This study explored use of the frontoparietal (FP) placement for reducing retrograde memory side effects with ECT. We hypothesised that superior retrograde memory outcomes would occur with FP compared to temporoparietal (TP) placement and with ultrabrief (UB: 0.3 ms) compared to brief pulse (BP: 1.0 ms) width ECT. METHODS: In this randomised cross-over, double-blinded study, participants received a single treatment of BP TP, BP FP, UB TP and UB FP ECT. Neuropsychological testing was conducted prior to and immediately following each treatment. Computational modelling was conducted to explore associations between E-fields in regions-of-interest associated with memory. RESULTS: Nine participants completed the study. The FP placement was not superior to TP for retrograde memory outcomes. For both electrode placements UB pulse width was associated with significantly better visual retrograde memory compared to BP (p < .05). With TP ECT, higher E-fields in regions-of-interest were significantly associated with greater visual retrograde memory side-effects (hippocampi: r = -0.77, p = .04; inferior frontal gyri: r = -0.92, p < .01; middle frontal gyri: r = -0.84, p = .02). CONCLUSIONS: Modification of pulse-width had greater effects than electrode placement for reducing retrograde memory side-effects with RUL ECT. Preliminary findings suggested that higher E-fields may be associated with greater cognitive side-effects with ECT.

Behavioural and neurophysiological differences in working memory function of depressed patients and healthy controls.

OBJECTIVE: Major depressive disorder (MDD) is associated with deficits in working memory. Several cognitive subprocesses interact to produce working memory, including attention, encoding, maintenance and manipulation. We sought to clarify the contribution of functional deficits in these subprocesses in MDD by varying cognitive load during a working memory task. METHODS: 41 depressed participants and 41 age and gender-matched healthy controls performed the n-back working memory task at three levels of difficulty (0-, 1-, and 2-back) in a pregistered study. We assessed response times, accuracy, and event-related electroencephalography (EEG), including P2 and P3 amplitudes, and frontal theta power (4-8 Hz). RESULTS: MDD participants had prolonged response times and more positive frontal P3 amplitudes (i.e., Fz) relative to controls, mainly in the most difficult 2-back condition. Working memory accuracy, P2 amplitudes and frontal theta event-related synchronisation did not differ between groups at any level of task difficulty. CONCLUSIONS: Depression is associated with generalized psychomotor slowing of working memory processes, and may involve compensatory hyperactivity in frontal and parietal regions. SIGNIFICANCE: These findings provide insights into MDD working memory deficits, indicating that depressed individuals dedicate greater levels of cortical processing and cognitive resources to achieve comparable working memory performance to controls.

Efficacy, acceptability, and safety of antidepressants for low back pain: a systematic review and meta-analysis.

BACKGROUND: Antidepressant medicines are used to manage symptoms of low back pain. The efficacy, acceptability, and safety of antidepressant medicines for low back pain (LBP) are not clear. We aimed to evaluate the efficacy, acceptability, and safety of antidepressant medicines for LBP. METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov , the EU Clinical Trials Register, and the WHO International Clinical Trial Registry Platform from inception to May 2020. We included published and trial registry reports of RCTs that allocated adult participants with LBP to receive an antidepressant medicine or a placebo medicine. Pairs of authors independently extracted data in duplicate. We extracted participant characteristics, study sample size, outcome values, and measures of variance for each outcome. We data using random-effects meta-analysis models and calculated estimates of effects and heterogeneity for each outcome. We formed judgments of confidence in the evidence in accordance with GRADE. We report our findings in accordance with the PRISMA statement. We prespecified all outcomes in a prospectively registered protocol. The primary outcomes were pain intensity and acceptability. We measured pain intensity at end-of-treatment on a 0-100 point scale and considered 10 points the minimal clinically important difference. We defined acceptability as the odds of stopping treatment for any reason. RESULTS: We included 23 RCTs in this review. Data were available for pain in 17 trials and acceptability in 14 trials. Treatment with antidepressants decreased pain intensity by 4.33  points (95% CI - 6.15 to - 2.50) on a 0-100 scale, compared to placebo. Treatment with antidepressants increased the odds of stopping treatment for any reason (OR 1.27 [95% CI 1.03 to 1.56]), compared to placebo. CONCLUSIONS: Treatment of LBP with antidepressants is associated with small reductions in pain intensity and increased odds of stopping treatment for any reason, compared to placebo. The effect on pain is not clinically important. The effect on acceptability warrants consideration. These findings provide Level I evidence to guide clinicians in their use of antidepressants to treat LBP. TRIAL REGISTRATION: We prospectively registered the protocol for this systematic review on PROSPERO ( CRD42020149275 ).

An investigation of working memory deficits in depression using the n-back task: A systematic review and meta-analysis.

BACKGROUND: Depression is associated with cognitive deficits across multiple domains, including working memory. The n-back task, a convenient psychometric tool capable of computerised delivery and concurrent use with neuroimaging, can provide enhanced insight into working memory dysfunction in depression. This meta-analysis sought to investigate the n-back task under varying cognitive load conditions (i.e. different levels of 'n') to clarify the pattern of working memory deficits in depression. METHODS: We conducted a systematic review and meta-analysis of studies involving unipolar depressed participants and matched controls utilising the n-back task. Meta-analyses were performed for accuracy and response times at four levels of cognitive load (0-, 1-, 2-, and 3-back). RESULTS: 31 studies (total 1,666 participants) met inclusion criteria and were included for quantitative analyses. Depressed individuals had significantly reduced accuracy compared to controls for 1-, 2-, and 3-back tasks, but not the attentional 0-back task. Likewise, response latencies were prolonged for all task levels (0-, 1-, 2-, and 3-back). Additional meta-regression analyses indicated that participant age and clinical status (i.e. inpatient/outpatient) may exacerbate working memory deficits associated with depression. LIMITATIONS: Our results indicate high levels of heterogeneity between studies, particularly for response times. CONCLUSIONS: Accuracy impairments were worse at higher levels of n, with the largest effect size obtained on the 2-back task, suggesting deficits to higher executive functions. Response times were consistently prolonged at all cognitive loads in agreement with a pattern of generalised psychomotor retardation.