Gestational exposure to benzodiazepines or z-hypnotics and neurodevelopmental disorders in offspring: Systematic review and meta-analysis.

INTRODUCTION: Benzodiazepine (BDZP) and/or z-hypnotic dispensing during pregnancy has increased globally, as have rates of autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). This systematic review and meta-analysis aimed to estimate the association between gestational exposure to BDZP and/or z-hypnotics and diagnosis of ASD or ADHD in offspring. METHODS: We searched MEDLINE, EMBASE, and SCOPUS from inception till December 2023 for relevant English-language articles. Outcomes of interest were risk of ASD and ADHD, two independent primary outcomes, in children exposed anytime during pregnancy to BDZP and/or z-hypnotics versus those unexposed. Secondary outcomes were trimester-wise analyses. Using a random effects model, we pooled the overall and trimester-wise hazard ratios (HRs), with 95% confidence intervals (CIs), separately for risk of ASD and ADHD. RESULTS: We found six eligible retrospective cohort studies and no case-control studies. There was no increased risk of ASD associated with anytime gestational BDZP and/or z-hypnotic exposure (primary outcome, HR, 1.10; 95% CI, 0.81-1.50; 4 studies; n = 3,783,417; 80,270 exposed, 3,703,147 unexposed) nor after first trimester exposure (HR, 1.15; 95% CI, 0.83-1.58; 3 studies; n = 1,539,335; 70,737 exposed, 1,468,598 unexposed) or later trimester exposures. A very small but significantly increased risk of ADHD was noted with anytime gestational exposure to these drugs (primary outcome, HR, 1.07; 95% CI, 1.03-1.12; 4 studies; n = 2,000,777; 78,912 exposed, 1,921,865 unexposed) and also with (only) second trimester exposure (HR, 1.07; 95% CI, 1.03-1.12; 3 studies; n = 1,539,281; 33,355 exposed, 1,505,926 unexposed). Findings were consistent in sensitivity analyses. CONCLUSION: Gestational exposure to benzodiazepines or z-hypnotics was not associated with an increased risk of ASD and with only a marginally increased risk of ADHD in offspring. Given the likelihood of confounding by indication and by unmeasured variables in the original studies, our findings should reassure women who need these medications for severe anxiety or insomnia during pregnancy.

The prescriber's guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression.

This article is a clinical guide which discusses the "state-of-the-art" usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion-this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy-while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward "bridging" methods that may be used to transition simply and safely from other antidepressants to MAOIs.

Efficacy of adjunctive D-Cycloserine for the treatment of schizophrenia: a systematic review and meta-analysis of randomized controlled trials.

D-Cycloserine is a partial agonist at the glycine site of the N-methyl-D-aspartate (NMDA) receptor. Results have been inconsistent in trials on the efficacy of D-Cycloserine in patients with schizophrenia. We examined the efficacy of D-Cycloserine against negative and cognitive symptoms (primary and co-primary outcomes). Secondary outcomes were efficacy of D-Cycloserine against positive symptoms and the examination of early treatment outcomes. A systematic literature search was carried out using following selection criteria: Population = Patients with Schizophrenia; Intervention = Trials using D-Cycloserine either as monotherapy or adjuvant therapy; Comparison = Placebo or active comparator; Outcome = Change in negative symptoms, cognitive symptoms and positive symptoms; Study design = Randomized controlled trials with parallel design. We used the Cochrane Collaboration tool for risk of bias for study quality appraisal. Effect sizes for trials were calculated separately for negative, positive and cognitive symptom dimensions using the DerSimonian-Laird random effects model. Seven studies (pooled N = 413) provided data for meta-analysis. The pooled Standardized Mean Difference (SMD) for negative, cognitive, and positive symptom change scores were - 0.32 (95% CI, - 0.75 to 0.11), - 0.05 (95% CI, - 0.91 to 0.81), and - 0.08 (95% CI, - 0.37 to 0.20), respectively. No significant improvement was noted with regard to early outcome. I2 values for heterogeneity were 61%, 67%, and 0% for studies assessing negative, cognitive, and positive symptom ratings, respectively. D-Cycloserine did not exhibit significant efficacy in treating negative, cognitive, or positive symptoms of schizophrenia at either study-defined endpoint (4-36 weeks) or at four weeks (early outcome).

A Randomized, Double-Blind, Sham-Controlled Study of Transcranial Direct Current Stimulation as an Augmentation Intervention for the Attenuation of Motor Deficits in Patients With Stroke.

INTRODUCTION: Most studies of transcranial direct current stimulation (tDCS) for motor deficits in patients with stroke administered few sessions of tDCS and with low current amplitude. METHODS: During 2015 to 2019, we randomized 60 inpatients with ischemic/hemorrhagic stroke and motor deficits to true or sham tDCS. Transcranial direct current stimulation was administered at 2- to 3-mA current strength, twice daily, 6 days a week, for 2 weeks; anode and cathode were placed over ipsilesional and contralesional motor cortices, respectively. All patients received individualized motor and cognitive rehabilitation. Motor outcomes were assessed 1 day before and 1 day after the tDCS course using the Fugl-Meyer Assessment, the Jebson-Taylor Hand Function Test, and the Barthel index (all coprimary outcomes). Mood and cognition were also assessed. Motor outcomes were compared between groups using age, baseline scores, and latency to treatment as covariates. The study was prospectively registered (CTRI/2017/01/007733). RESULTS: The mean age of the patients was 46.9 years. The sample was 73.3% male. Six patients did not complete the study. The covariates were significantly related to motor outcomes. Although all patients showed motor improvements, after adjusting for covariates, tDCS was not superior to sham treatment on any motor, mood, or cognitive outcome. Laterality of hemispheric lesion influenced spatial but not motor outcomes with tDCS. One true tDCS patient developed blistering under the anode and was withdrawn from the study; 3 more reported transient itching during sessions. CONCLUSIONS: An intensive course of tDCS, as delivered in this study, does not improve motor, mood, and cognitive outcomes in ischemic/hemorrhagic stroke in patients undergoing individualized rehabilitation. The study provides important leads for directions for future research.

Ketamine as anaesthesia for ECT: is there room to improve a gold standard treatment?

One meta-analysis of ketamine anaesthesia for electroconvulsive therapy found no improvement of end-point antidepressant outcomes; another meta-analysis with a broader range of included trials found that ketamine improved both early and late outcomes. If ketamine anaesthesia is useful, researchers may need to look for benefits earlier during the treatment course. Declaration of interest None.

ECT and Pronounced Impairment in Spatial Cognition: The Fallacy of Drawing Conclusions From a Single Case.

INTRODUCTION: Electroconvulsive therapy (ECT) is associated with memory deficits on neuropsychological assessment. The association of ECT with nonmemory cognitive deficits has been poorly studied. METHODS: We present a 40-year-old woman who showed a bizarre form of spatial cognition impairment on a subtest of the Tactual Performance Test (TPT) after recovering from depression with 6 alternate day, thrice-weekly, inpatient ECT treatments. This woman was part of a naturalistic, nonblind study that examined nonmemory cognitive deficits in antidepressant-treated depressed patients who did and did not receive ECT. RESULTS: The impairment was in the form of bizarrely drawn reproductions of differently shaped wooden blocks that had been presented to the patient when she was blindfolded. The impairment was still evident when she was retested (3 hours later) under substantially simplified conditions but was much attenuated approximately 2.5 weeks later. CONCLUSIONS: On the surface, it seems that ECT had induced severe impairment in spatial cognition and that the impairment showed the familiar pattern of attenuation with the passage of time. However, another recovered patient in the study, who did not receive ECT, also showed substantial spatial deficits on the same subtest of the TPT, and the attenuation of the deficits across time in the ECT-treated patient was probably a result of repeated exposure to the task. We suggest that not all patients who seem to experience spectacular cognitive impairment after ECT have deficits that are attributable to ECT.

A Randomized, Nonblind, Naturalistic Comparison of Efficacy and Cognitive Outcomes With Right Unilateral, Bifrontal, and Bitemporal Electroconvulsive Therapy in Schizophrenia.

BACKGROUND: There is little literature on the relative efficacy and cognitive safety of right unilateral (RUL), bifrontal (BF), and bitemporal (BT) electroconvulsive therapy (ECT) in schizophrenia. METHODS: We present a randomized, nonblind, naturalist comparison of a fixed course of 8 moderately high-dose RUL (n = 24), threshold BF (n = 27), and threshold BT (n = 31) ECT in patients with schizophrenia. Assessments included the Positive and Negative Syndrome Scale (PANSS), the Wechsler Memory Scale-Revised, and an autobiographical memory interview. A completer analysis was planned and conducted to capture the cognitive outcomes. RESULTS: The sample as a whole improved significantly on all efficacy outcomes and deteriorated significantly on all cognitive outcomes. The primary efficacy outcome, improvement in PANSS total scores, did not differ significantly across groups. The PANSS positive score (but no other subscale score) improved significantly less with RUL relative to BF and BT ECT. For autobiographical memory and for almost all Wechsler Memory Scale subtests, including memory quotient (the primary adverse effect outcome), BT ECT was associated with greater impairment than RUL or BF ECT. Importantly, all statistically significant differences between treatments were clinically small in magnitude. CONCLUSIONS: In patients with schizophrenia who receive a fixed course of 8 ECTs, threshold BT ECT is associated with greater cognitive impairment across a range of measures, and moderately high-dose RUL ECT is associated with poorer efficacy against positive symptoms. Threshold BF ECT exhibits the best efficacy-cum-neurocognitive safety profile. All differences between groups, however, are small and perhaps clinically insignificant.

The role of ECT in posttraumatic stress disorder: A systematic review.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with a high burden of disability and mortality and frequently is treatment resistant. There is little to offer patients who are not responding to standard interventions. Thus, the objective of this report is to systematically review human data on whether electroconvulsive therapy (ECT) is effective in PTSD. METHODS: We performed a systematic literature review from 1958 through August 2016 for clinical studies and case reports published in English examining the efficacy of ECT in improving PTSD symptoms. RESULTS: The literature search generated 3 retrospective studies, 1 prospective uncontrolled clinical trial, and 5 case reports. It is not clear, given the small sample size and lack of a large randomized trial, whether favorable outcomes were attributed to improvement in depression (as opposed to core PTSD symptoms). CONCLUSIONS: Current efficacy data do not separate conclusively the effects of ECT on PTSD symptoms from those on depression. Randomized controlled trials are necessary to examine the use of ECT in medication-refractory PTSD patients with and without comorbid depression. Subsequent studies may address response in PTSD subtypes, and the use of novel techniques, such as memory reactivation, before ECT.

A Meta-review of the Safety of Electroconvulsive Therapy in Pregnancy.

BACKGROUND: Four systematic reviews have examined the safety of electroconvulsive therapy (ECT) in pregnancy. These have varied widely in methods, findings, and conclusions. METHODS: We compared these reviews with regard to search strategy, study selection criteria, total number of studies identified, total number of patients included, findings related to safety and adverse events, and interpretation of results. RESULTS: The number of studies (number of cases) included in the reviews ranged from 16 (n = 300) to 67 (n = 169) with only one review stating reasons for exclusion of nonselected studies. We provide comparisons about how the reviews described patient characteristics, illness characteristics, ECT characteristics, confounder characteristics, and outcome characteristics; there was wide variation in these regards. We list adverse outcomes that were identified by some but not other reviews. We provide a detailed breakdown of the adverse maternal and fetal outcomes identified in each review. Finally, we examine how different reviews interpreted their findings; whereas some reviews provided reasons for ruling out ECT as an explanation for an adverse outcome, one review adopted the stance that all adverse outcomes were potentially ECT-related. CONCLUSIONS: Our meta-review provides readers with comparative information on the strengths and limitations of the 4 systematic reviews, their findings, and their conclusions. It can assist with clinical decision making on the use of ECT in pregnancy by providing a more complete description of the available literature.

Serum Oxytocin Concentration in Patients Receiving Electroconvulsive Therapy: An Exploratory Study and Review of Literature.

BACKGROUND: Neuroendocrine biomarkers have long been studied in the context of electroconvulsive therapy (ECT). We prospectively assessed serum oxytocin change and moderators thereof in an exploratory study of patients receiving ECT. METHODS: Serum oxytocin concentrations were assessed immediately before and 1 to 3 minutes after the first ECT in 33 patients with schizophrenia (n = 14), other nonaffective psychosis (n = 6), mania (n = 10), and depression (n = 3) who received 6 to 7 bitemporal, brief-pulse ECTs. Change in serum oxytocin was assessed in the sample as a whole, and as a function of age, sex, diagnosis, and treatment response. The primary outcome was change in serum oxytocin in the overall sample. RESULTS: There was much variation across patients; oxytocin concentrations increased marginally by a mean (standard deviation) (M [SD]) of 6.4 (82.7) pg/mL (P = 0.43). The M (SD) change was -8.2 (85.0) pg/mL in patients with schizophrenia and other nonaffective psychoses (P = 0.84). There was no significant correlation between change in Brief Psychiatric Rating Scale scores and change in oxytocin concentrations in patients with schizophrenia, other nonaffective psychoses, and mania (ρ = 0.10, P = 0.61). Serum oxytocin rose in men, after ECT, and fell in women (P = 0.01). CONCLUSIONS: Change in serum oxytocin immediately after the first ECT in a course may not be a useful biomarker of ECT action. This is the first report on the subject in a sample comprising mostly patients with nonaffective psychosis and mania rather than depression. We discuss our findings in the light of previous research and offer general conclusions about the field.

Reversible abnormality of the splenium in a bipolar patient with neuroleptic malignant syndrome.

OBJECTIVE: To report reversible abnormality of the splenium in a bipolar patient with neuroleptic malignant syndrome (NMS). METHODS: We studied a 23-year-old male who received oral and parenteral neuroleptics, atypical antipsychotic agents, and mood stabilizers, as well as a course of six electroconvulsive therapy treatments, for an episode of mania. He improved. Five days after discharge on maintenance atypical antipsychotic agents and mood stabilizers, he returned with symptoms suggestive of NMS. Laboratory investigations revealed leucopenia, thrombocytopenia, and elevated creatine phosphokinase levels. Brain magnetic resonance imaging showed swelling of the splenium with centrally restricted diffusion; there was no other abnormality. He was defensively treated with antimicrobials, methylprednisolone, and bromocriptine. RESULTS: Clinical recovery was complete after nine days, and the splenium lesion resolved after four further days; there were no neuropsychiatric sequelae. Nine months later, the patient remains well on maintenance lithium therapy. CONCLUSIONS: This is the first report of an isolated splenial lesion reversing within days of resolution of NMS. The outcome supports the recent literature which suggests that an isolated splenial lesion does not need investigation, and that prognosis depends on the underlying disorder, and not on the presence or absence of the splenial lesion.

Electroconvulsive therapy, hypertensive surge, blood-brain barrier breach, and amnesia: exploring the evidence for a connection.

Preclinical and clinical evidence show that electroconvulsive therapy (ECT)-induced intraictal surge in blood pressure may result in a small, transient breach in the blood-brain barrier, leading to mild cerebral edema and a possible leach of noxious substances from blood into brain tissues. These changes may impair neuronal functioning and contribute to the mechanisms underlying ECT-induced cognitive deficits. Some but not all clinical data on the subject suggest that blood pressure changes during ECT correlate with indices of cognitive impairment. In animal models, pharmacological manipulations of blood pressure during electroconvulsive shocks attenuate electroconvulsive shock-induced amnestic changes; however, the evidence suggests that antihypertensive mechanisms may not necessarily be involved. Clinical studies involving pre-ECT administration of antihypertensive medications do not provide convincing evidence of benefits. It is concluded that there is insufficient support, at present, for the hypothesis that the hypertensive surge during ECT and the resultant blood-brain barrier breach contribute meaningfully to ECT-induced cognitive deficits. Future research should address the subset of patients who experience pronounced hypertensive changes during ECT, and clinically relevant outcome measures, such as autobiographical memory impairment, should be examined.