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Reliable predictors for electroconvulsive therapy (ECT) effectiveness would allow a more precise and personalized approach for the treatment of major depressive disorder (MDD). Prediction models were created using a priori selected clinical variables based on previous meta-analyses. Multivariable linear regression analysis was used, applying backwards selection to determine predictor variables while allowing non-linear relations, to develop a prediction model for depression outcome post-ECT (and logistic regression for remission and response as secondary outcome measures). Internal validation and internal-external cross-validation were used to examine overfitting and generalizability of the model's predictive performance. In total, 1892 adult patients with MDD were included from 22 clinical and research cohorts of the twelve sites within the Dutch ECT Consortium. The final primary prediction model showed several factors that significantly predicted a lower depression score post-ECT: higher age, shorter duration of the current depressive episode, severe MDD with psychotic features, lower level of previous antidepressant resistance in the current episode, higher pre-ECT global cognitive functioning, absence of a comorbid personality disorder, and a lower level of failed psychotherapy in the current episode. The optimism-adjusted R² of the final model was 19%. This prediction model based on readily available clinical information can reduce uncertainty of ECT outcomes and hereby inform clinical decision-making, as prompt referral for ECT may be particularly beneficial for individuals with the above-mentioned characteristics. However, despite including a large number of pretreatment factors, a large proportion of the variance in depression outcome post-ECT remained unpredictable., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The dexamethasone suppression test (DST), which measures HPA-axis functioning, is a potential biomarker for suicidal behavior. The current study aimed (a) to synthesize available knowledge on the association between DST non-suppression and suicidal behavior, and (b) to study potential moderators., Methods: A total of 4236 studies were screened, 43 were included. Suicide attempts and suicide completion were studied separately. The meta-analysis included 37 effect sizes for suicide attempts (n = 3733) and 11 effect sizes for suicide completion (n = 1626)., Results: DST non-suppression was associated with completed suicide (odds ratio (OR) = 2.10, (95 % CI [1.37, 3.23]). For suicide attempts, we found no evidence that DST status was associated in the overall meta-analysis including all patient samples. However, moderator analysis indicated that the DST status was associated with suicide attempts in patient samples that included psychopathology other than just mood disorders, such as psychotic, substance use and personality disorders (OR = 2.34, 95 % CI [1.39-3.93], k = 11)., Limitations: The potential influence of publication bias and exclusion of some relevant published studies (since effect sizes could not be calculated, authors could not supply data or authors could not be reached) are limitations. Furthermore, missing moderator data decreased our ability to explain heterogeneity between studies., Conclusions: The results of this meta-analysis support the hypothesis that DST non-suppression is predictive of suicidal behavior. More research is needed to investigate optimal cut-off values, confounding factors and the potential usefulness of the DST in clinical practice in terms of personalized medicine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Abstract: Postictal agitation (PIA) is an adverse effect of electroconvulsive therapy (ECT) and is known to predict other side effects of ECT, but inconsistencies in the literature remain regarding PIA prognostic factors and incidence. Therefore, a systematic review and meta-analysis were conducted (1) to identify prognostic factors for PIA following ECT and (2) to elucidate the diverse incidences of PIA following ECT based on demographic and clinical characteristics. Specifically, electronic databases were searched for retrospective observational studies and randomized controlled trials (RCTs) that objectively reported PIA incidence. Additional inclusion criteria encompassed studies involving patients 18 years or older and allowed for the extraction of PIA prognostic factors. This resulted in the inclusion of 21 articles with 66,047 patients in total. A total of 35 prognostic factors were identified for PIA after ECT, consisting of 8 anesthesia-related, 19 patient-related, and 8 ECT-related prognostic factors. A meta-analysis was conducted for 7 prognostic factors. None of the prognostic factors demonstrated a significant effect on reducing or increasing PIA incidence. Mean PIA was 13.9% (18.0% adjusted) at the patient level and 12.4% (16.5% adjusted) at the session level. Overall risk of bias was generally moderate to low, except in the outcome measurement domain, where 43% of the studies had a high risk of bias. Although none of the prognostic factors in meta-analysis were significant, several other prognostic factors consistently indicated increased or decreased risk, providing direction for future research. A scarcity of (high-quality) data emphasizes the need for additional research on this topic to be conducted., Competing Interests: The authors have no conflicts of interest or financial disclosures to report., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Psychotic depression is a severe and difficult-to-treat subtype of major depressive disorder for which higher rates of treatment-resistant depression were found. Studies have been performed aiming to predict treatment-resistant depression or treatment nonresponse. However, most of these studies excluded patients with psychotic depression. We created a genetic risk score (GRS) based on a large treatment-resistant depression genome-wide association study. We tested whether this GRS was associated with nonresponse, nonremission and the number of prior adequate antidepressant trials in patients with a psychotic depression. Using data from a randomized clinical trial with patients with a psychotic depression (n = 122), we created GRS deciles and calculated positive prediction values (PPV), negative predictive values (NPV) and odds ratios (OR). Nonresponse and nonremission were assessed after 7 weeks of treatment with venlafaxine, imipramine or venlafaxine plus quetiapine. The GRS was negatively correlated with treatment response (r = -0.32, p = 0.0023, n = 88) and remission (r = -0.31, p = 0.0037, n = 88), but was not correlated with the number of prior adequate antidepressant trials. For patients with a GRS in the top 10%, we observed a PPV of 100%, a NPV of 73.7% and an OR of 52.4 (p = 0.00072, n = 88) for nonresponse. For nonremission, a PPV of 100%, a NPV of 51.9% and an OR of 21.3 (p = 0.036, n = 88) was observed for patients with a GRS in the top 10%. Overall, an increased risk for nonresponse and nonremission was seen in patients with GRSs in the top 40%. Our results suggest that a treatment-resistant depression GRS is predictive of treatment nonresponse and nonremission in psychotic depression., (© 2024. The Author(s).)

Selegiline is an irreversible, selective type-B monoamine oxidase inhibitor (MAOI) approved for Parkison's disease-oral and major depressive disorder-transdermal formulation) resulting in non-selective MAOI activity at oral doses≥20 mg/day. The present systematic review and meta-analysis appraises the evidence of different formulations/dosages of selegiline across different psychiatric conditions. We inquired PubMed/MEDLINE/Cochrane-Central/WHO-ICTRP/Clarivate-WebOfScience and the Chinese-Electronic-Journal Database from inception to 10/26/2022 for selegiline trials involving psychiatric patients. Random-effects meta-analyses assessed heterogeneity, publication/risk biases, and confidence in the evidence, followed by sensitivity, subgroup, and meta-regression analyses. Co-primary outcomes were: changes in symptom score (standardized mean difference=SMD) and author-defined response (risk ratios=RRs). RRs of adverse events and all-cause discontinuation were secondary and acceptability outcomes, respectively. Systematic-review included 42 studies; meta-analysis, 23. Selegiline outperformed placebo in depressive symptom reduction (SMD=-0.96, 95%C.I.=-1.78, -0.14, k = 10, n = 1,308), depression (RR=1.61, 95%C.I.=1.20, 2.15, k = 9, n = 1,238) and atypical-depression response (RR=2.23, 95%C.I.=1.35, 3.68, k = 3, n = 136). Selegiline failed to outperform the placebo in negative (k = 4) or positive symptoms of schizophrenia (k = 4), attention-deficit-hyperactivity disorder (ADHD) symptoms reduction (k = 2), and smoking abstinence rate (k = 4). Selegiline did not differ from methylphenidate and ADHD scores (k = 2). No significant difference emerged in acceptability, incident diarrhea, headache, dizziness, and nausea RRs, in contrast to xerostomia (RR=1.58, 95%C.I. =1.03, 2.43, k = 6, n = 1,134), insomnia (RR=1.61, 95%C.I.=1.19, 2.17, k = 10, n = 1,768), and application-site reaction for transdermal formulation (RR=1.81, 95%C.I.=1.40, 2.33, k = 6, n = 1,662). Confidence in findings was low/very-low for most outcomes; moderate for depressive symptoms reduction (transdermal). Selegiline proved effective, safe, and well-tolerated for depressive disorders, yet further evidence is warranted about specific psychiatric disorders., Competing Interests: Conflict of interest SS has served as a consultant to Acadia, AbbVie/Allergan, Alkermes, Altus, Cerevel, Clearview, Clexio, Done, Enveric Biosciences, Faber Kramer, Gedeon Richter, Genetica, Intra-Cellular Therapies, Janssen, Karuna Therapeutics, Libbs, Lipidio, Longboard, Lundbeck, Merck, Neurocrine Biosciences, Neurawell, Otsuka, Recordati, Relmada Therapeutics, Sage Therapeutics, Saniona, Sunovion, Supernus, Teva, Tonix, and Tris Pharma; he holds options in Genomind, Lipidio, Neurawell and Delix; he has served on speakers bureaus for Abbvie/Allergan, Acadia, Lundbeck, Neurocrine, Otsuka, Servier, Sunovion, and Teva; he has received research and/or grant support from Acadia, Allergan/AbbVie, Avanir, Boehringer Ingelheim Braeburn Pharmaceuticals, Daiichi Sankyo- Brazil Eisai, Eli Lilly, Harmony Biosciences, Indivior, Intra-Cellular Therapies, Ironshore, Neurocrine, Otsuka, Pear Therapeutics, Sage, Shire Sunovion, Supernus, and Torrent. VVdE receives or has received consulting fees from: PsychoTropical Research, NeuraWell Therapeutics, and Aristo Pharma GmbH; he has stock options in NeuraWell Therapeutics. HGR receives or has received: grants from ZonMW (#016.126.059 and #10140021910006), the Hersenstichting (HA2015.01.07), and the Dutch Ministry of Health; and speaking fees from Lundbeck NV and Janssen BV; he is a member of the Scientific Advisory Board of hersenonderzoek.nl; he is a member of the Executive Board of the International Society for Affective Disorders. TKB is a member of the Dutch guideline committee on the use of ECT, and the Dutch guideline committee on pharmacogenetics. KG has equity interests in, and is on the advisory board of NeuraWell Therapeutics. AdB has received research support from Janssen, Lundbeck, and Otsuka and lecture fees for educational meeting from Chiesi, Lundbeck, Roche, Sunovion, Vitria, Recordati, Angelini and Takeda; he has served on advisory boards for Eli Lilly, Jansen, Lundbeck, Otsuka, Roche, and Takeda, Chiesi, Recordati, Angelini, Vitria. MF served as a rater for Massachusetts General Hospital Clinical Trials Network and Institute, Boston, MA, USA, and its subsidiaries for the following entities: i) Biohaven Pharmaceuticals, Inc. (“Sponsor”) to provide services for Sponsor trial entitled “A Randomized, Double-Blind, Placebo-Controlled Trial of Adjunctive Troriluzole in Obsessive Compulsive Disorder,” protocol BHV4157–302; and “A Randomized, Double-Blind, Placebo-Controlled Trial of Adjunctive Troriluzole in Obsessive Compulsive Disorder,” protocol BHV4157–303 (“Study”), ii) ACADIA Pharmaceuticals Inc. (“Sponsor”) to provide services for Sponsor protocol ACP-103–064 entitled “A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Pimavanserin as Adjunctive Treatment for the Negative Symptoms of Schizophrenia (ADVANCE-2)” (“Study”). MF also received honoraria from the American Society of Clinical Psychopharmacology (ASCP). All other authors declare that they have no conflicts of interest., (Copyright © 2023 Elsevier B.V. and ECNP. All rights reserved.)

Background: Electroconvulsive therapy (ECT) is the most effective treatment for severe major depressive episodes (MDEs). Nonetheless, firmly established associations between ECT outcomes and biological variables are currently lacking. Polygenic risk scores (PRSs) carry clinical potential, but associations with treatment response in psychiatry are seldom reported. Here, we examined whether PRSs for major depressive disorder, schizophrenia (SCZ), cross-disorder, and pharmacological antidepressant response are associated with ECT effectiveness., Methods: A total of 288 patients with MDE from 3 countries were included. The main outcome was a change in the 17-item Hamilton Depression Rating Scale scores from before to after ECT treatment. Secondary outcomes were response and remission. Regression analyses with PRSs as independent variables and several covariates were performed. Explained variance (R 2 ) at the optimal p-value threshold is reported., Results: In the 266 subjects passing quality control, the PRS-SCZ was positively associated with a larger Hamilton Depression Rating Scale decrease in linear regression (optimal p-value threshold = .05, R 2  = 6.94%, p < .0001), which was consistent across countries: Ireland (R 2  = 8.18%, p = .0013), Belgium (R 2  = 6.83%, p = .016), and the Netherlands (R 2  = 7.92%, p = .0077). The PRS-SCZ was also positively associated with remission (R 2  = 4.63%, p = .0018). Sensitivity and subgroup analyses, including in MDE without psychotic features (R 2  = 4.42%, p = .0024) and unipolar MDE only (R 2  = 9.08%, p < .0001), confirmed the results. The other PRSs were not associated with a change in the Hamilton Depression Rating Scale score at the predefined Bonferroni-corrected significance threshold., Conclusions: A linear association between PRS-SCZ and ECT outcome was uncovered. Although it is too early to adopt PRSs in ECT clinical decision making, these findings strengthen the positioning of PRS-SCZ as relevant to treatment response in psychiatry., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Major depressive disorder (MDD) is a severe psychiatric disorder that is associated with various cognitive impairments, including learning and memory deficits. As synaptic plasticity is considered an important mechanism underlying learning and memory, deficits in cortical plasticity might play a role in the pathophysiology of patients with MDD. We used Transcranial Magnetic Stimulation (TMS) to assess inhibitory neurotransmission and cortical plasticity in the motor cortex of MDD patients and controls., Methods: We measured the cortical silent period (CSP) and short interval cortical inhibition (SICI), as well as intermittent theta-burst stimulation (iTBS), in 9 drug-free MDD inpatients and 18 controls., Results: The overall response to the CSP, SICI, and iTBS paradigms was not significantly different between the patient and control groups. iTBS induction resulted in significant potentiation after 20 mins in the control group ( t (17) = -2.8, p = 0.01), whereas no potentiation was observed in patients., Conclusions: Potentiation of MEP amplitudes was not observed within the MDD group. No evidence was found for medium-to-large effect size differences in CSP and SICI measures in severely depressed drug-free patients, suggesting that reduced cortical inhibition is unlikely to be a robust correlate of the pathophysiological mechanism in MDD. However, these findings should be interpreted with caution due to the high inter-subject variability and the small sample size., Significance: These findings advance our understanding of neurophysiological functioning in drug-free severely depressed inpatients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Castricum, Birkenhager, Kushner, Elgersma and Tulen.)

Low-grade inflammation plays a role not only in the pathogenesis of major depressive disorder (MDD) but probably also in the poor responsiveness to regular antidepressants. There are also indications that anti-inflammatory agents improve the outcomes of antidepressants. Aim: To study whether the presence of low-grade inflammation predicts the outcome of antidepressants, anti-inflammatory agents, or combinations thereof. Methods: We carried out a systematic review of the literature on the prediction capability of the serum levels of inflammatory compounds and/or the inflammatory state of circulating leukocytes for the outcome of antidepressant/anti-inflammatory treatment in MDD. We compared outcomes of the review with original data (collected in two limited trials carried out in the EU project MOODINFLAME) on the prediction capability of the inflammatory state of monocytes (as measured by inflammatory gene expression) for the outcome of venlafaxine, imipramine, or sertraline treatment, the latter with and without celecoxib added. Results: Collectively, the literature and original data showed that: 1) raised serum levels of pro-inflammatory compounds (in particular of CRP/IL-6) characterize an inflammatory form of MDD with poor responsiveness to predominately serotonergic agents, but a better responsiveness to antidepressant regimens with a) (add-on) noradrenergic, dopaminergic, or glutamatergic action or b) (add-on) anti-inflammatory agents such as infliximab, minocycline, or eicosapentaenoic acid, showing-next to anti-inflammatory-dopaminergic or lipid corrective action; 2) these successful anti-inflammatory (add-on) agents, when used in patients with low serum levels of CRP/IL-6, decreased response rates in comparison to placebo. Add-on aspirin, in contrast, improved responsiveness in such "non-inflammatory" patients; 3) patients with increased inflammatory gene expression in circulating leukocytes had a poor responsiveness to serotonergic/noradrenergic agents. Conclusions: The presence of inflammation in patients with MDD heralds a poor outcome of first-line antidepressant therapies. Immediate step-ups to dopaminergic or glutamatergic regimens or to (add-on) anti-inflammatory agents are most likely indicated. However, at present, insufficient data exist to design protocols with reliable inflammation parameter cutoff points to guide such therapies, the more since detrimental outcomes are possible of anti-inflammatory agents in "non-inflamed" patients.

Objective: To investigate whether older age predicts a higher efficacy of electroconvulsive therapy (ECT) in severely depressed patients. Also, to analyze whether psychomotor disturbance and/or psychotic features might explain the potential higher efficacy of ECT in older age., Method: A total of 96 patients with major depressive disorder treated with bilateral ECT were evaluated. The 17-item HAM-D and the MADRS were used to evaluate the efficacy of ECT and time to remission, respectively. Psychomotor disturbance was defined according the HAM-D., Results: Middle-aged (MA; 50-70 years) and older-aged (OA; ≥70 years) patients had a non-significant larger symptom reduction compared with young-aged (YA; <50 years) patients. Medium effect size was found in favor of MA (d = 0.44) and small effect size in favor of OA (d = 0.30), when compared to YA. Patients with psychotic features and patients with psychomotor retardation had a significantly larger symptom reduction (p < 0.001 and p = 0.005, respectively; d = 0.88 and d = 0.66, respectively). The association between age and ECT efficacy is mediated by psychomotor retardation (p = 0.049) and in lesser extent by psychotic features (p = 0.071)., Conclusion: The results show that psychomotor retardation and psychotic features are strong predictors of ECT efficacy and explain the association between age and ECT efficacy. Instead of focusing on the age of a patient, clinicians should focus on the presence of psychomotor disturbances and psychotic features of depression, when considering ECT treatment., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Antidepressant treatment for major depressive disorder remains suboptimal with response rates of just over 50%. Although treatment guidelines, algorithms and clinical keys are available to assist the clinician, the process of finding an effective pharmacotherapy to maximise benefit for the individual patient is largely by "trial and error" and remains challenging. This highlights a clear need to identify biomarkers of treatment response to help guide personalised treatment strategies. We have carried out the largest multiplex immunoassay based longitudinal study to date, examining up to 258 serum markers involved in immune, endocrine and metabolic processes as potential biomarkers associated with treatment response in 332 depression patients recruited from four independent clinical centres. We demonstrated for the first time that circulating Apolipoprotein A-IV, Endoglin, Intercellular Adhesion Molecule 1, Tissue Inhibitor of Metalloproteinases 1, Plasminogen Activator Inhibitor 1, Thrombopoietin, Complement C3, Hepatocyte Growth Factor and Insulin-like Growth Factor-Binding Protein 2 were associated with response to different antidepressants. In addition, we showed that specific sets of immune-endocrine proteins were associated with response to Venlafaxine (serotonin-norepinephrine reuptake inhibitor), Imipramine (tricyclic antidepressant) and other antidepressant drugs. However, we were not able to reproduce the literature findings on BDNF and TNF-α, two of the most commonly reported candidate treatment response markers. Despite the need for extensive validation studies, our preliminary findings suggest that a pre-treatment immune-endocrine profile may help to determine a patient's likelihood to respond to specific antidepressant and/or alternative treatments such as anti-inflammatory drugs, providing hope for future personalised treatment approaches., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Rationale: There is a substantial unmet need for biomarkers to predict treatment response in major depressive disorder (MDD). Evidence has converged on activation of the inflammatory response system as a fundamental mechanism underlying MDD., Objectives: By investigating circulating leukocyte subsets quantified by fluorescence-activated cell sorting (FACS) analysis before treatment, we aim to predict antidepressant response., Methods: Forty medication-free inpatients with melancholic, non-psychotic depression before treatment with either venlafaxine or imipramine and 40 age- and gender-matched healthy controls were included. Leukocyte subsets were quantified by FACS analysis using frozen peripheral blood mononuclear cells (PBMC) collected prior to and after 7 weeks of treatment with either venlafaxine (375 mg/day) or imipramine (blood level 200-300 ng/ml). Response was defined as at least 50 % reduction of the baseline Hamilton Rating Scale for Depression (HAM-D) score., Results: Prior to treatment, MDD patients showed reduced percentages of CD4(+)CD25(high)Foxp3(+) T regulatory (Treg) cells when compared with controls (1.5 ± 0.6 vs. 1.8 ± 0.6, p = .037). After treatment, robust rises in Treg cells were observed in patients (1.8 ± 0.7, p < .001), yet Treg cells were not predictors of the clinical outcome of treatment. Antidepressant non-responders showed increased CD8(+) cytotoxic T cell percentages (24.0 ± 8.6 vs. 15.9 ± 5.9, p = .004) and decreased natural killer (NK) cell percentages (14.0 ± 6.9 vs. 21.4 ± 11.9, p = .020) compared with responders before treatment. Both lymphocyte levels were not significantly modulated by treatment., Conclusion: In melancholic MDD, FACS analysis of circulating leukocyte subpopulations might help to discriminate between patients with high or low responsiveness to antidepressant treatment.

This report describes a 55-year-old woman who had 1 previous episode of major depression that responded favorably to treatment with tricyclic antidepressants. After the development of Addison disease, she experienced a new episode of major depression that failed to respond to adequate treatment with imipramine and was subsequently successfully treated with electroconvulsive therapy (ECT) with steroid cover. The patient did not experience adrenal crisis or adverse effects. After 9 ECT sessions, she attained full remission. These findings support the suggestion that ECT treatment is safe in patients with Addison disease when using 100 mg intravenous hydrocortisone as prophylaxis.

The purpose of the present study is to compare the efficacy of imipramine in the treatment of psychotic versus nonpsychotic depression. Previous studies report varying results of monotherapy with antidepressants in psychotic depression. Because psychotic depression is seriously underinvestigated, performing a post hoc analysis of randomized clinical trials consisting of both psychotic and nonpsychotic depressed patients may contribute to the discussion on the optimal treatment of depressed patients with mood-congruent psychotic features. A total of 112 patients diagnosed with major depression (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) (40 with psychotic depression and 82 without psychotic features) received treatment with imipramine for 6 weeks after a washout period of 7 days. Imipramine doses were adjusted to attain a predefined fixed plasma level. Treatment response was assessed with the Hamilton Rating Scale for Depression (HAM-D). A logistic regression analysis showed a significantly larger reduction in HAM-D score in the sample with psychotic features compared with the nonpsychotic sample (regression coefficient, -3.47; SE, 1.7; P = 0.04). According to the primary outcome criterion, that is, the change in HAM-D score, imipramine was significantly more effective in the sample with psychotic depression compared with the nonpsychotic depressed patients. The contradiction between our results and those of several previous studies may be due to the fixed plasma level dosing of imipramine refraining from concurrent psychotropic medication or limiting our patient sample to patients with mood-congruent psychotic features.

This case report describes a patient on tranylcypromine who erroneously received a single dose of imipramine and subsequently developed a fatal serotonin syndrome. Both the clinical features and the pathophysiology of the serotonin syndrome are discussed.