PARP1 and OGG1 in Medicated Patients With Depression and the Response to ECT.

BACKGROUND: Oxidative stress and oxidation-induced DNA damage may contribute to the pathophysiology of depression. Two key mediators of base excision repair (BER) in response to oxidative damage of DNA are OGG1 and PARP1. Few studies have examined changes in OGG1 or PARP1 mRNA in patients with depression or following antidepressant treatment. We examined PARP1 and OGG1 mRNA levels in patients with depression at baseline/pre-electroconvulsive therapy (baseline/pre-ECT) vs in healthy controls and in patients following a course of ECT. METHODS: PARP1 and OGG1 were examined in whole blood samples from medicated patients with depression and controls using quantitative real-time polymerase chain reaction. Exploratory subgroup correlational analyses were performed to determine associations between PARP1 and OGG1 and mood (Hamilton Depression Rating Scale 24-item version) scores as well as with vitamin B3, SIRT1, PGC1α, and tumor necrosis factor alpha levels, as previously reported on in this cohort. RESULTS: PARP1 levels were reduced in samples from patients with depression vs controls (P = .03), though no difference was noted in OGG1. ECT had no effect on PARP1 or OGG1. Higher baseline PARP1 weakly correlated with greater mood improvement post ECT (P = .008). Moreover, PARP1 positively correlated with SIRT1 at baseline and post ECT, and positive correlations were noted between change in PARP1 and change in OGG1 with change in tumor necrosis factor alpha post ECT. CONCLUSIONS: To our knowledge, this is the first study to examine the effect of ECT on BER enzymes. A better understanding of BER enzymes and DNA repair in depression could unearth new mechanisms relevant to the pathophysiology of this condition and novel antidepressant treatments.

Microglia and their LAG3 checkpoint underlie the antidepressant and neurogenesis-enhancing effects of electroconvulsive stimulation.

Despite evidence implicating microglia in the etiology and pathophysiology of major depression, there is paucity of information regarding the contribution of microglia-dependent molecular pathways to antidepressant procedures. In this study, we investigated the role of microglia in a mouse model of depression (chronic unpredictable stress-CUS) and its reversal by electroconvulsive stimulation (ECS), by examining the effects of microglia depletion with the colony stimulating factor-1 antagonist PLX5622. Microglia depletion did not change basal behavioral measures or the responsiveness to CUS, but it completely abrogated the therapeutic effects of ECS on depressive-like behavior and neurogenesis impairment. Treatment with the microglia inhibitor minocycline concurrently with ECS also diminished the antidepressant and pro-neurogenesis effects of ECS. Hippocampal RNA-Seq analysis revealed that ECS significantly increased the expression of genes related to neurogenesis and dopamine signaling, while reducing the expression of several immune checkpoint genes, particularly lymphocyte-activating gene-3 (Lag3), which was the only microglial transcript significantly altered by ECS. None of these molecular changes occurred in microglia-depleted mice. Immunohistochemical analyses showed that ECS reversed the CUS-induced changes in microglial morphology and elevation in microglial LAG3 receptor expression. Consistently, either acute or chronic systemic administration of a LAG3 monoclonal antibody, which readily penetrated into the brain parenchyma and was found to serve as a direct checkpoint blocker in BV2 microglia cultures, rapidly rescued the CUS-induced microglial alterations, depressive-like symptoms, and neurogenesis impairment. These findings suggest that brain microglial LAG3 represents a promising target for novel antidepressant therapeutics.

International pooled patient-level meta-analysis of ketamine infusion for depression: In search of clinical moderators.

Depression is disabling and highly prevalent. Intravenous (IV) ketamine displays rapid-onset antidepressant properties, but little is known regarding which patients are most likely to benefit, limiting personalized prescriptions. We identified randomized controlled trials of IV ketamine that recruited individuals with a relevant psychiatric diagnosis (e.g., unipolar or bipolar depression; post-traumatic stress disorder), included one or more control arms, did not provide any other study-administered treatment in conjunction with ketamine (although clinically prescribed concurrent treatments were allowable), and assessed outcome using either the Montgomery-Åsberg Depression Rating Scale or the Hamilton Rating Scale for Depression (HRSD-17). Individual patient-level data for at least one outcome was obtained from 17 of 25 eligible trials [pooled n = 809]. Rates of participant-level data availability across 33 moderators that were solicited from these 17 studies ranged from 10.8% to 100% (median = 55.6%). After data harmonization, moderators available in at least 40% of the dataset were tested sequentially, as well as with a data-driven, combined moderator approach. Robust main effects of ketamine on acute [~24-hours; ß*(95% CI) = 0.58 (0.44, 0.72); p < 0.0001] and post-acute [~7 days; ß*(95% CI) = 0.38 (0.23, 0.54); p < 0.0001] depression severity were observed. Two study-level moderators emerged as significant: ketamine effects (relative to placebo) were larger in studies that required a higher degree of previous treatment resistance to federal regulatory agency-approved antidepressant medications (≥2 failed trials) for study entry; and in studies that used a crossover design. A comprehensive data-driven search for combined moderators identified statistically significant, but modest and clinically uninformative, effects (effect size r ≤ 0.29, a small-medium effect). Ketamine robustly reduces depressive symptoms in a heterogeneous range of patients, with benefit relative to placebo even greater in patients more resistant to prior medications. In this largest effort to date to apply precision medicine approaches to ketamine treatment, no clinical or demographic patient-level features were detected that could be used to guide ketamine treatment decisions.Review Registration: PROSPERO Identifier: CRD42021235630.

Study protocol for Ketamine as an adjunctive therapy for major depression (2): a randomised controlled trial (KARMA-Dep [2]).

BACKGROUND: Depression is a common psychiatric disorder and a leading cause of disability worldwide. Conventional monoaminergic antidepressants have limited efficacy and take weeks to exert a therapeutic effect. Single infusions of subanaesthetic doses of ketamine exhibit rapid antidepressant action but effects are transient and relapse is common. One potential strategy for increasing ketamine's antidepressant efficacy and/or prolonging its therapeutic benefit may be serial infusions. There is limited evidence on the efficacy and safety of repeated ketamine infusions against an active comparator. METHODS: This protocol describes an ongoing pragmatic, randomised, controlled, parallel-group, patient- and rater-blind, superiority trial. Eligible adult inpatients with a confirmed DSM-5 diagnosis of a major depressive episode (unipolar or bipolar) are randomly allocated in a 1:1 ratio to a course of up to eight infusions of ketamine or midazolam twice-weekly over four weeks. The primary objective is to assess the efficacy of serial adjunctive ketamine infusions versus active comparator midazolam by measuring Montgomery-Åsberg Depression Rating Scale score difference between arms from before the first infusion to 24 h after the final infusion, supplemented by a 95% confidence interval. To facilitate generalisability of results, the trial takes place under "real world" conditions with both groups continuing to receive regular inpatient care including treatment-as-usual pharmacotherapy, nursing care, and psychological and other therapies during the randomised treatment phase and regular outpatient care thereafter. Participants are monitored for relapse during a 24-week follow-up after the end of the randomised phase. Secondary objectives of the trial are to assess: response and remission rates at the end of randomised phase; relapse status during the 24-week follow-up after the end of the randomised phase; the safety and tolerability of repeated ketamine infusions regarding psychotomimetic and other psychiatric side effects, cognitive side effects, as well as withdrawal symptoms, haemodynamic stability, neurological, urological, and other physical side effects; and quality of life and cost-effectiveness. DISCUSSION: There is an unmet clinical need for rapidly-acting novel antidepressants. This trial will provide efficacy, safety and health economic data on serial ketamine infusions and thus help inform clinical practice on the potential role of this treatment in the management of depression. TRIAL REGISTRATION: EudraCT 2019-003109-92. Registered 2 October 2019. CLINICALTRIALS: gov NCT04939649. Registered 25 June 2021.

Decision-making Capacity for Treatment After Electroconvulsive Therapy for Depression.

OBJECTIVES: Depression can impair decision-making capacity (DMC) for health care decisions. However, it is unclear whether DMC improves after treatments for depression such as electroconvulsive therapy (ECT). There is limited evidence available on DMC for treatment in patients with depression referred for ECT, and it is unknown whether ECT has any impact on DMC. We hypothesized that ECT will improve DMC in severely depressed patients and that this change will be associated with reduced depressive symptom severity. METHODS: Using the MacArthur Competence Assessment Tool-Treatment, 4 abilities related to DMC were evaluated: Understanding, Appreciation, Reasoning, and Expressing a choice. This prospective study compared DMC abilities, depression severity, and cognition scores in 24 patients hospitalized with a major depressive episode before and 3 to 5 days after a course of ECT. RESULTS: Although Understanding scores significantly improved after ECT (P = 0.004, r = 0.41), there was no change in other abilities related to DMC or cognition scores. As expected, there was a large improvement in mood ratings after ECT, but the change in DMC abilities was not associated with change in depressive symptoms. CONCLUSIONS: To our knowledge, this is the first study to provide data on the effects of ECT on DMC in patients with depression. Abilities related to DMC that may be affected in this group before treatment include Understanding and Reasoning. Findings indicate that DMC to consent to treatment mostly does not change after a course of ECT and some aspects can improve in patients with depression.

Electroconvulsive therapy for depression: 80 years of progress.

Electroconvulsive therapy is the most effective treatment for severe, psychotic or treatment-resistant depression. However, its effectiveness continues to be questioned, both in mainstream media and narratives within the scientific literature. In this analysis, we use an evidence-based approach to demonstrate the efficacy and safety of modern electroconvulsive therapy.

Relapse following bitemporal and high-dose right unilateral electroconvulsive therapy for major depression.

OBJECTIVE: Electroconvulsive therapy (ECT) is an effective acute treatment for severe and/or medication-resistant depression but maintaining remission following completion of a course remains a clinical challenge. METHODS: EFFECT-Dep Trial (ISRCTN23577151) participants with a DSM-IV major depressive episode who met remission criteria after a randomly assigned course of twice-weekly brief-pulse bitemporal (1.5 × seizure threshold) or high-dose (6 × seizure threshold) right unilateral ECT were monitored for relapse for 12 months. In line with the pragmatic trial design, all patients received treatment-as-usual individualised pharmacotherapy during and after ECT; no remitter received continuation ECT. RESULTS: Of 61 remitters, 24 (39.3%) relapsed, one (1.6%) withdrew from the study while in remission and the remaining 36 (59.0%) stayed well for a year. Most relapses occurred within the first six months, resulting in a cumulative six-month relapse rate of 31.1%. In a multivariable Cox proportional hazards regression model, older age (p = 0.039) and psychotic features at pre-ECT baseline (p = 0.037) were associated with a more favourable long-term prognosis while a greater number of previous depressive episodes (p = 0.028) and bipolar II (but not bipolar I) diagnosis (p = 0.030) were associated with a worse long-term outcome. Electrode placement and medication resistance prior to ECT had no effect on relapse. Adjusting for covariates, fewer patients treated with lithium relapsed in the overall group (p = 0.008) and in the unipolar depression subgroup (p = 0.027). CONCLUSION: Long-term outcome following high-dose right unilateral ECT does not differ from bitemporal ECT. Prognosis is particularly favourable in older adults, psychotic depression and patients maintained on lithium.

Speed of electroconvulsive therapy for depression: Effects of electrode placement.

OBJECTIVE: Electroconvulsive therapy (ECT) is a rapidly effective treatment for severe depression. Treatment with right unilateral (RUL) or bitemporal (BT) ECT may explain individual differences in speed of ECT effectiveness. There is limited evidence for demographic and clinical factors that predict speed of response and remission with ECT. We aimed to investigate differences in speed of improvement as well as achieving response and remission between twice-weekly brief-pulse high-dose (6 × seizure threshold) RUL ECT and moderate-dose (1.5 × seizure threshold) BT ECT. We also explored demographic and clinical characteristics that predict speed of response and remission. METHODS: Weekly 24-item Hamilton Depression Rating Scale scores were assessed among patients with severe depression who participated in the EFFECT-Dep trial (ISRCTN23577151). Speed of improvement in patients randomised to RUL ECT (n = 69) or BT ECT (n = 69) was compared using independent sample t tests. Pearson's chi-square and Fisher's exact tests compared proportions of responders and remitters at each weekly assessment. Predictors of speed of response and remission were explored using Cox regression analyses. RESULTS: There were no significant differences between RUL and BT ECT in speed of improvement, response or remission. Exploratory analyses indicated that speed of response and remission were not predicted by a wide variety of demographic and clinical characteristics. CONCLUSION: ECT electrode placement did not have predictive value when determining speed of improvement, response and remission with ECT. Other clinical factors, such as cognitive side-effects, may be more relevant when making the clinical choice between RUL and BT ECT.

Nursing home staff mental health during the Covid-19 pandemic in the Republic of Ireland.

BACKGROUND: Nursing homes for older adults have been disproportionately affected by the Covid-19 pandemic with increased mortality of residents and staff distress. OBJECTIVE: To quantify the mental health of nursing home staff during the Covid-19 pandemic in the Republic of Ireland. DESIGN/METHODS: Cross-sectional anonymous study of Republic of Ireland nursing home staff (n = 390) during the third wave of the Covid-19 pandemic. Online survey collecting demographic information, Covid-19 exposure history and mental health measures. RESULTS: There were significant differences between nurses, healthcare assistants (HCA) and non-clinical staff history in age, ethnicity, years' experience, history of Covid-19 infection and contact with Covid-19 positive acquaintances. Moderate-severe post-traumatic stress disorder symptoms were found in 45.1% (95% confidence interval [CI] 40.2%-50.1%) of all staff. A World Health Organisation-5 (WHO-5) wellbeing index score ≤32, indicating low mood, was reported by 38.7% (95% CI, 33.9%-43.5%) of staff; significantly more nurses reported low mood. Suicidal ideation and suicide planning were reported, respectively, by 13.8% (95% CI, 10.4%-17.3%) and 9.2% (95% CI, 6.4%-12.1%) of participants with no between-group differences. HCAs reported a significantly higher degree of moral injury than non-clinical staff. Nurses were more likely to use approach coping styles than non-clinical staff. Work ability was insufficient in 24.6% (95% CI 20.3%-28.9%) of staff. CONCLUSION: Nursing home staff report high levels of post-traumatic stress, mood disturbance and moral injury during the Covid-19 pandemic. Differences in degree of moral injury, wellbeing and coping styles were found between staff groups, which need to be incorporated into planning supports for this neglected workforce.

PBMC telomerase activity in depression and the response to electroconvulsive therapy.

Telomerase, the DNA polymerase responsible for maintaining telomere length, has previously been implicated in depression and the response to antidepressant drugs. In this study, we aimed to compare telomerase activity in peripheral blood mononuclear cells between patients with severe depression recruited as part of the KEEP-WELL Trial (Ketamine for Depression Relapse Prevention Following ECT; NCT02414932) and age- and sex-matched healthy volunteers both at baseline/pre-ECT and at follow-up 1 month later for controls or in patients after a course of ECT. We found no differences in telomerase activity between patients with depression (n = 20) compared to healthy controls (n = 33) at baseline/pre-ECT, or between patients treated with ECT compared to controls at follow-up. In patients, telomerase activity was not associated with mood, as assessed by the 24-item Hamilton Rating Scale for Depression, or the duration of the current depressive episode. Additionally, we found no significant relationship between telomerase activity and exposure to recent or childhood adversity in either the patient or control groups. Overall, our results suggest that telomerase activity is not associated with depression, the therapeutic response to ECT, or exposure to adversity.

Telomere length in depression and association with therapeutic response to electroconvulsive therapy and cognitive side-effects.

BACKGROUND: Electroconvulsive therapy (ECT) is the most acutely effective treatment for severe treatment-resistant depression. However, there are concerns about its cognitive side-effects and we cannot yet confidently predict who will experience these. Telomeres are DNA-protein complexes that maintain genomic integrity. In somatic cells, telomeres shorten with each cell division. Telomere length (TL) can thus provide a measure of 'biological' aging. TL appears to be reduced in depression, though results are mixed. We sought to test the following hypotheses: (1) that TL would be shorter in patients with depression compared to controls; (2) that TL would be a predictor of response to ECT; and (3) that shorter TL would predict cognitive side-effects following ECT. METHOD: We assessed TL in whole blood DNA collected from severely depressed patients (n = 100) recruited as part of the EFFECT-Dep Trial and healthy controls (n = 80) using quantitative real-time polymerase chain reaction. Mood and selected cognitive measures, including global cognition, re-orientation time, and autobiographical memory, were obtained pre-/post-ECT and from controls. RESULTS: Our results indicate that TL does not differ between patients with depression compared to controls. TL itself was not associated with mood ratings and did not predict the therapeutic response to ECT. Furthermore, shorter baseline TL is not a predictor of cognitive side-effects post-ECT. CONCLUSIONS: Overall, TL assessed by PCR does not represent a useful biomarker for predicting the therapeutic outcomes or risk for selected cognitive deficits following ECT.

Tryptophan metabolite concentrations in depressed patients before and after electroconvulsive therapy.

Tryptophan and kynurenine pathway (KP) metabolites are implicated in the pathophysiology of depression. We aimed to investigate their plasma concentrations in medicated patients with depression (n = 94) compared to age- and sex-matched healthy controls (n = 57), and in patients with depression after electroconvulsive therapy (ECT) in a real-world clinical setting, taking account of co-variables including ECT modality and heterogenous psychopathology. Depression severity was assessed using the Hamilton Depression Rating Scale (HAM-D24). Tryptophan (TRP) and kynurenine (KYN) metabolite concentrations [anthranilic acid (AA), 3-hydroxyanthranilic acid (3HAA), picolinic acid (PA), kynurenic acid (KYNA), and xanthurenic acid (XA)] and KYNA/KYN and KYNA/quinolinic acid (QUIN) ratios were lower in patients compared to controls. For the total group there was no significant change in KP metabolites post-ECT or correlations with mood ratings. However, improvements in mood score were correlated with increased KYN, 3-hydroxykynurenine (3HK), 3HAA, QUIN, and KYN/TRP in a subgroup of unipolar depressed patients. Additionally, in remitters baseline KYN, 3HK, and QUIN were associated with baseline HAM-D24 scores, and changes in 3HK and 3HAA concentrations post-ECT correlated with improvement in mood. KYN, KYNA, AA, 3HK, XA, PA, and QUIN were increased in a smaller 3-month follow-up group (n = 19) compared to pre-ECT concentrations. Overall, the results indicate that ECT mobilizes the KP, where a moderate association between selected metabolites and treatment response in unipolar depressed patients is evident.

International Consortium on the Genetics of Electroconvulsive Therapy and Severe Depressive Disorders (Gen-ECT-ic).

Recent genome-wide association studies have demonstrated that the genetic burden associated with depression correlates with depression severity. Therefore, conducting genetic studies of patients at the most severe end of the depressive disorder spectrum, those with treatment-resistant depression and who are prescribed electroconvulsive therapy (ECT), could lead to a better understanding of the genetic underpinnings of depression. Despite ECT being one of the most effective forms of treatment for severe depressive disorders, it is usually placed at the end of treatment algorithms of current guidelines. This is perhaps because ECT has controlled risk and logistical demands including use of general anaesthesia and muscle relaxants and side-effects such as short-term memory impairment. Better understanding of the genetics and biology of ECT response and of cognitive side-effects could lead to more personalized treatment decisions. To enhance the understanding of the genomics of severe depression and ECT response, researchers and ECT providers from around the world and from various depression or ECT networks, but not limited to, such as the Psychiatric Genomics Consortium, the Clinical Alliance and Research in ECT, and the National Network of Depression Centers have formed the Genetics of ECT International Consortium (Gen-ECT-ic). Gen-ECT-ic will organize the largest clinical and genetic collection to date to study the genomics of severe depressive disorders and response to ECT, aiming for 30,000 patients worldwide using a GWAS approach. At this stage it will be the largest genomic study on treatment response in depression. Retrospective data abstraction and prospective data collection will be facilitated by a uniform data collection approach that is flexible and will incorporate data from many clinical practices. Gen-ECT-ic invites all ECT providers and researchers to join its efforts.

Physician, heal thyself: a cross-sectional survey of doctors' personal prescribing habits.

BACKGROUND: Self-prescribing and prescribing to personal contacts is explicitly discouraged by General Medical Council guidelines. AIMS: This study examines how widespread the practice of self-prescribing and prescribing to personal contacts is. METHODS: A 16-item questionnaire was distributed via an online forum comprising 4445 young medical doctors (representing 20% of all Irish registered doctors), which asked respondents about previous prescribing to themselves, their families, friends and colleagues, including the class of medication prescribed. Demographic details were collected including medical grade and specialty. RESULTS: A total of 729 responses were obtained, the majority of which were from young non-consultant hospital doctors from a range of specialties. Two-thirds of respondents had self-prescribed, over 70% had prescribed to family, and nearly 60% had prescribed to a friend or colleague. Older doctors were more likely to self-prescribe (χ2=17.51, p<0.001). Interns being less likely to self-prescribe was not unexpected (χ2=69.55, p<0.001), while general practitioners (GPs) and paediatricians were more likely to self-prescribe (χ2=13.33, p<0.001; χ2=11.35, p<0.001). GPs, paediatricians and hospital medicine specialties were more likely to prescribe to family (χ2=5.19, p<0.05; χ2=8.38, p<0.05; χ2=6.17, p<0.05) and surgeons were more likely to prescribe to friends (χ2=15.87, p<0.001). Some 3% to 7% who had self-prescribed had prescribed an opiate, benzodiazepine or psychotropic medication. Male doctors, anaesthetists and surgeons were more likely to self-prescribe opioids (χ2=7.82, p<0.01; χ2=7.31, p<0.01; χ2=4.91, p<0.05), while those in hospital medicine were more likely to self-prescribe psychotropic medications (χ2=5.47, p<0.05). CONCLUSION: Prescribing outside the traditional doctor-patient relationship is widespread despite clear professional guidance advising against it.

Low Circulating Levels of GR, FKBP5, and SGK1 in Medicated Patients With Depression Are Not Altered by Electroconvulsive Therapy.

OBJECTIVES: Hypothalamic-pituitary-adrenal axis dysregulation is frequently observed in patients with depression, with increased levels of the glucocorticoid (GC) cortisol commonly reported. Hypothalamic-pituitary-adrenal axis dysregulation may be a consequence of impaired feedback inhibition due to GC receptor (GR) impairments or dysfunction, termed "glucocorticoid resistance." Here, our objective was to assess mRNA levels of GC-related markers (GR, FKBP5, serum glucocorticoid kinase 1 [SGK1]) in patients with depression versus controls and in patient samples after electroconvulsive therapy (ECT). We also examined the relationship between these GC-related markers and 24-item Hamilton Depression Rating Scale (HAM-D24) scores to assess the utility of using them as biological markers for depression or the therapeutic response to ECT. METHODS: GR, FKBP5, and SGK1 mRNA levels were examined in whole blood samples from 88 medicated patients with depression pre-/post-ECT and 63 controls using quantitative real-time polymerase chain reaction. Exploratory subgroup correlational analyses were performed to determine the relationship between GR, FKBP5, and SGK1 and 24-item Hamilton Depression Rating Scale scores. RESULTS: GR, FKBP5, and SGK1 mRNA levels were significantly lower in medicated patients with depression compared with controls (P < 0.001, P = 0.03, P < 0.001, respectively), but ECT did not alter their levels (all P > 0.05). There was no relationship between GR, FKBP5, or SGK1 and 24-item Hamilton Depression Rating Scale scores. CONCLUSIONS: GR, FKBP5, and SGK1 do not seem to be involved in the peripheral molecular response to ECT and do not represent useful biomarkers for predicting the therapeutic response to ECT in a real-world clinical setting.

Peroxisome proliferator-activated receptor gamma co-activator-1 alpha in depression and the response to electroconvulsive therapy.

BACKGROUND: The transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator (PGC-1α), termed the 'master regulator of mitochondrial biogenesis', has been implicated in stress and resilience to stress-induced depressive-like behaviours in animal models. However, there has been no study conducted to date to examine PGC-1α levels in patients with depression or in response to antidepressant treatment. Our aim was to assess PGC-1α mRNA levels in blood from healthy controls and patients with depression pre-/post-electroconvulsive therapy (ECT), and to examine the relationship between blood PGC-1α mRNA levels and clinical symptoms and outcomes with ECT. METHODS: Whole blood PGC-1α mRNA levels were analysed in samples from 67 patients with a major depressive episode and 70 healthy controls, and in patient samples following a course of ECT using quantitative real-time polymerase chain reaction (qRT-PCR). Exploratory subgroup correlational analyses were carried out to determine the relationship between PGC-1α and mood scores. RESULTS: PGC-1α levels were lower in patients with depression compared with healthy controls (p = 0.03). This lower level was predominantly accounted for by patients with psychotic unipolar depression (p = 0.004). ECT did not alter PGC-1α levels in the depressed group as a whole, though exploratory analyses revealed a significant increase in PGC-1α in patients with psychotic unipolar depression post-ECT (p = 0.045). We found no relationship between PGC-1α mRNA levels and depression severity or the clinical response to ECT. CONCLUSIONS: PGC-1α may represent a novel therapeutic target for the treatment of depression, and be a common link between various pathophysiological processes implicated in depression.

Alcohol Use Disorder and Comorbid Depression: A Randomized Controlled Trial Investigating the Effectiveness of Supportive Text Messages in Aiding Recovery.

AIM: The aim of this randomized controlled trial was to examine the impact of daily supportive text messages over a 6-month treatment period on mood and alcohol consumption in individuals with a dual diagnosis of alcohol use disorder (AUD) and depression following completion of an inpatient treatment programme. METHOD: Ninety-five adult participants with AUD and comorbid depression were recruited into this randomized control trial, which took place after completing a 30-day rehabilitation programme. The intervention group (n = 47) received twice-daily supportive text messages over 6-months while control participants (n = 48) had treatment as usual for a 6-month period, with an added 6-month post-treatment follow-up for both groups. Drinking history in the previous 90 days as well as symptoms of depression, anxiety and stress were measured at baseline, 3- and 6-month treatment points and 6-month post treatment follow up. RESULTS: Depression scores (P = 0.02) and perceived stress scores (P < 0.01) were significantly reduced at 3-month treatment point in the intervention group relative to control participants with small to medium effect. The intervention group also showed a significantly greater reduction in units per drinking day from baseline to 6-month treatment point compared to the control group with a medium effect size (P = 0.03). There were no differences in drinking or mood measures at 6-month post treatment follow-up. CONCLUSIONS: Supportive text messages provide an early initial benefit in decreasing symptoms of depression and stress, with a further positive impact on alcohol consumption following a longer treatment period. Benefits did not persist six months after the intervention ended.

Ketamine Versus Midazolam for Depression Relapse Prevention Following Successful Electroconvulsive Therapy: A Randomized Controlled Pilot Trial.

OBJECTIVE: Depression relapse after electroconvulsive therapy (ECT) is common (40% at 6 months). Ketamine has a robust antidepressant effect, but there are no reported studies of ketamine for depression relapse prevention. This pilot trial (NCT02414932) was designed to assess feasibility of the proposed trial protocol, including examining reasons for nonrecruitment, nonrandomization, and dropout. METHODS: Patients with unipolar depression referred for ECT were monitored weekly for therapeutic response, using the 24-item Hamilton Rating Scale for Depression (monitoring phase). Those who met standard response criteria were invited to be randomized to a course of 4 once-weekly infusions of ketamine (0.5 mg/kg) or the active comparator, midazolam (0.045 mg/kg), over 40 minutes to examine trial processes (treatment phase). Participants were followed up for 6 months after ECT to assess for relapse. RESULTS: One hundred seventy-five referrals were screened over 18 months, and 68% of eligible participants (n = 43) were recruited to the monitoring phase; 60.5% of participants met ECT response criteria (n = 26), but only 26% (6) of these consented to take part in the treatment phase. These were randomized (3 to ketamine and 3 to midazolam), and no participant completed the 4-week treatment protocol. Information was gathered on reasons for nonrecruitment, nonrandomization, and dropout, which included practical aspects of infusions and lack of interest in further treatment after response to ECT. CONCLUSIONS: The proposed treatment protocol is not suitable for a definitive trial in our center. Information collected on reasons for dropout may inform future clinical trials of intravenous ketamine. TRIAL REGISTRATION: www.clinicaltrials.gov NCT02414932.

Vascular endothelial growth factor plasma levels in depression and following electroconvulsive therapy.

Both animal and human studies have implicated the neurotrophic and angiogenic mediator vascular endothelial growth factor (VEGF) in depression, with meta-analyses, indicating that protein levels are raised in patients with depression. In line with this, we have previously shown that VEGFA mRNA levels are higher in whole blood from patients with depression compared to controls, in particular in patients with psychotic unipolar depression, and that treatment with electroconvulsive therapy (ECT) alters VEGFA mRNA levels. The aim of the present study was, therefore, to extend this previous work by assessing plasma VEGF protein levels in patients with depression compared to healthy controls, and in patients following treatment with ECT. We found that there was no difference between controls and patients with depression with regard to plasma VEGF (p = 0.59), and that VEGF levels were unaltered by ECT (p = 0.09) after correction for potential covariates. We found no correlation between VEGF protein and mRNA levels. Within the subgroup of patients receiving treatment with bitemporal ECT (n = 34), we identified a moderate negative correlation (ρ = - 0.54, p = 0.001) between the change in VEGF and the change in depression severity following treatment; however, no other association between VEGF and mood, responder/remitter status, polarity of depression, or presence of psychosis were found. Overall, our results indicate that the measurement of VEGF protein is not a useful marker for depression or response to treatment, and suggest that the measurement of VEGFA mRNA may prove more useful.