A genetic risk score to predict treatment nonresponse in psychotic depression.

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.

The Relationship of Early Sleep Improvement With Response to Pharmacotherapy in Unipolar Psychotic Depression.

BACKGROUND: Since insomnia and depression are interrelated, improved sleep early in antidepressant pharmacotherapy may predict a positive treatment outcome. We investigated whether early insomnia improvement (EII) predicted treatment outcome in psychotic depression (PD) and examined if there was an interaction effect between EII and treatment type to assess if findings were treatment-specific. METHODS: This study is a secondary analysis of a randomized trial comparing 7 weeks treatment with the antidepressants venlafaxine, imipramine and venlafaxine plus the antipsychotic quetiapine in PD ( n = 114). Early insomnia improvement, defined as ≥20% reduced insomnia after 2 weeks, was assessed by the Hamilton Rating Scale for Depression (HAM-D-17). Associations between EII and treatment outcome were examined using logistic regressions. Subsequently, we added interaction terms between EII and treatment type to assess interaction effects. The predictive value of EII was compared with early response on overall depression (≥20% reduced HAM-D-17 score after 2 weeks). RESULTS: EII was associated with response (odds ratio [OR], 7.9; 95% confidence interval [CI], 2.7-23.4; P = <0.001), remission of depression (OR, 6.1; 95% CI, 1.6-22.3; P = 0.009), and remission of psychosis (OR, 4.1; 95% CI, 1.6-10.9; P = 0.004). We found no interaction effects between EII and treatment type on depression outcome. Early insomnia improvement and early response on overall depression had a comparable predictive ability for treatment outcome. CONCLUSIONS: Early insomnia improvement was associated with a positive outcome in pharmacotherapy of PD, regardless of the medication type. Future studies are needed to confirm our findings and to examine the generalizability of EII as predictor in treatment of depression.

On the Origins of MAOI Misconceptions: Reaffirming their Role in Melancholic Depression.

The first monoamine oxidase inhibitors (MAOIs) used for the treatment of depression in the 1950-60s were credited with treating severe melancholic depression (MeD) successfully and greatly reducing the need for electroconvulsive therapy (ECT). Following the hiatus caused by the then ill-understood cheese reaction, MAOI use was relegated to atypical and treatment-resistant depressions only, based on data from insufficiently probing research studies suggesting their comparatively lesser effectiveness in MeD. The siren attraction of new 'better' drugs with different mechanisms amplified this trend. Following a re-evaluation of the data, we suggest that MAOIs are effective in MeD. Additionally, the broad unitary conceptualisation of major depressive disorder (MDD) in the DSM model diminished the chance of demonstrating distinctive responses to different antidepressant drugs (ADs) such as SSRIs, TCAs, and MAOIs, thereby further reducing the interest in MAOIs. More reliable categorical distinction of MeD, disentangling it from MDD, may be possible if more sensitive measuring instruments (CORE, SMPI) are used. We suggest these issues will benefit from re-appraisement via an inductive reasoning process within a binary (rather than a unitary) model for defining the different depressive disorders, allowing for the use of more reliable diagnostic criteria for MeD in particular. We conclude that MAOIs remain essential for, inter alia, TCA-resistant MeD, and should typically be used prior to ECT; additionally, they have a role in maintaining remission in cases treated with ECT (and ketamine/esketamine). We suggest that MAOIs should be utilized earlier in treatment algorithms and with greater regularity than is presently the case.

Efficacy and safety of selegiline across different psychiatric disorders: A systematic review and meta-analysis of oral and transdermal formulations.

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.

Clinical characteristics associated with relapse 2 years after electroconvulsive therapy for major depression.

OBJECTIVE: High relapse rates are observed after electroconvulsive therapy (ECT) for major depression. Identifying patients who are at increased risk for relapse to intensify their treatment regimen post-ECT might reduce relapse rates. We aimed to determine clinical characteristics that are associated with relapse within 2 years after successful ECT. METHODS: Patients who remitted to ECT in a randomised controlled trial comparing adjuvant nortriptyline and placebo during a course of bilateral ECT were followed-up prospectively for 1 year with open-label nortriptyline (Dutch Trial Register NTR5579). Second-year follow-up data were collected retrospectively. Thirty-four patients were included in this follow-up cohort. To examine the association between clinical characteristics and the risk of relapse, unadjusted hazard ratios (HRs) were calculated. RESULTS: At 2 years post-ECT, the overall relapse rate was 50%, and the HRs for relapse in patients with psychotic features, a higher severity of depression, and medication resistance prior to ECT were 0.33 (CI 0.12-0.89; p = 0.029), 0.88 (CI 0.80-0.98; p = 0.014), and 4.48 (CI 1.28-15.73, p = 0.019), respectively. No effect was found for age, sex or episode duration on the relapse rate. CONCLUSIONS: Depressed patients with psychotic features, with higher symptom severity and without medication resistance prior to ECT have a significantly decreased risk of relapse after successful ECT. A sustained remission rate of 50% over 2 years in patients with severe major depression who were treated with nortriptyline monotherapy after successful ECT is encouraging.

Cognitive trajectories during and after electroconvulsive therapy in patients with MDE: Taking different perspectives.

Cognitive function during an ECT care pathway is mainly investigated at the group level by analyzing mean cognitive test scores over time. However, there are important inter-individual differences, with some patients experiencing residual invalidating cognitive deficits. This study provides a nuanced examination of cognitive functioning during and after ECT by combining three approaches for data analysis. A cognitive test battery was assessed in seventy-three ECT-treated patients with a Major Depressive Episode (MDE) at up to five time points (baseline, immediately prior to the third session and 1 week, 3 months and 6 months after completion of the index course). Group-level changes in cognitive function were investigated using linear mixed models and individual-level changes were examined using Reliable Change Indices (RCI). The presence of patient subgroups with similar cognitive trajectories was explored using Latent Class Growth Analysis (LCGA). At the group level, there was a temporary deterioration in processing speed, verbal memory and retrograde amnesia during and after index course of ECT. Individual-level analyses revealed considerable variability in cognitive effects of ECT. Three patient classes with a similar cognitive trajectory could be identified, all with a rather parallel courses over time, thus mainly differing in terms of pre-ECT cognitive functioning.

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.

Influence of adjuvant nortriptyline on the efficacy of electroconvulsive therapy: A randomized controlled trial and 1-year follow-up.

OBJECTIVE: There is limited evidence that adding an antidepressant to electroconvulsive therapy (ECT), compared with ECT monotherapy, improves outcomes. We aimed to determine whether the addition of nortriptyline to ECT enhances its efficacy and prevents post-ECT relapse. METHODS: We conducted a randomized, double-blind, placebo-controlled trial (RCT). Patients with major depressive disorder and an indication for ECT received either nortriptyline or placebo during a bilateral ECT course. Outcome measures were mean decrease in Hamilton Rating Scale for Depression (HRSD) score, response, remission, and time to response and remission. Patients who attained remission participated in a 1-year follow-up study with open-label nortriptyline. Outcome measures were relapse and time to relapse. RESULTS: We included 47 patients in the RCT. In the nortriptyline group, 83% showed response, 74% attained remission, and the mean decrease in HRSD score was 21.6 points. In the placebo group these figures were, respectively, 81% (p = 0.945), 73% (p = 0.928) and 20.7 points (p = 0.748). Thirty-one patients participated in the follow-up study. In patients who had received nortriptyline during the RCT, 47% relapsed at a mean of 34.2 weeks. Patients who had received placebo showed similar treatment results. In both study phases, no statistically significant differences between the nortriptyline and the placebo group were found. CONCLUSION: In our sample of severely depressed patients who were often medication resistant and suffering from psychotic depression, the addition of nortriptyline to ECT did not enhance its efficacy or prevent post-ECT relapse. Encouragingly, even in these patients ECT was highly effective and relapse rates were relatively low.

Cortical Inhibition and Plasticity in Major Depressive Disorder.

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.

Interrogating Associations Between Polygenic Liabilities and Electroconvulsive Therapy Effectiveness.

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 (R2) 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, R2 = 6.94%, p < .0001), which was consistent across countries: Ireland (R2 = 8.18%, p = .0013), Belgium (R2 = 6.83%, p = .016), and the Netherlands (R2 = 7.92%, p = .0077). The PRS-SCZ was also positively associated with remission (R2 = 4.63%, p = .0018). Sensitivity and subgroup analyses, including in MDE without psychotic features (R2 = 4.42%, p = .0024) and unipolar MDE only (R2 = 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.

Association of the neutrophil to lymphocyte ratio and white blood cell count with response to pharmacotherapy in unipolar psychotic depression: An exploratory analysis.

Background: Low-grade inflammation occurs in a subgroup of patients with Major Depressive Disorder (MDD) and may be associated with response to antidepressant medications. The Neutrophil to Lymphocyte Ratio (NLR) and total White Blood cell Count (WBC) are markers of systemic inflammation which have not been investigated as predictors for outcome to pharmacotherapy in unipolar depression yet. Moreover, the association between inflammation and treatment response has not been studied in unipolar Psychotic Depression (PD). We conducted an exploratory analysis to examine the prognostic significance of NLR and WBC in pharmacotherapy of PD. Methods: Baseline NLR and WBC were examined in their association with response to seven weeks of treatment with antidepressants (venlafaxine or imipramine) and the combination of an antidepressant with an antipsychotic (venlafaxine plus quetiapine) in 87 patients with PD. Logistic regression models were adjusted for age, gender, Body Mass Index (BMI), depression severity, duration of the current episode and number of previous depressive episodes. Secondary outcomes were remission of depression and disappearance of psychotic symptoms. Results: Higher NLR was associated with increased response to pharmacotherapy (Exp(B) 1.66, 95 % CI 1.03-2.66, p = 0.036), but not with remission of depression or disappearance of psychotic symptoms. WBC was not associated with any of the outcome measures. Conclusion: NLR may be a novel, inexpensive and widely available biomarker associated with response to pharmacotherapy in PD. The association between white blood cell measures and treatment outcome should be further investigated for different types of antidepressants in PD and in non-psychotic MDD.

Influence of an adjuvant antidepressant on the efficacy of electroconvulsive therapy: A systematic review and meta-analysis.

OBJECTIVE: The primary indication for electroconvulsive therapy is medication-resistant major depression. There is some evidence that combining electroconvulsive therapy with an antidepressant, instead of electroconvulsive therapy monotherapy, might improve remission rates. However, data on this topic have not been systematically studied. We undertook a systematic review and meta-analysis to determine the effectiveness of an adjuvant antidepressant during electroconvulsive therapy for major depression. METHODS: Embase, Medline Ovid, Web of Science, Cochrane Central, PsychINFO Ovid and Google Scholar were searched up to January 2019. Randomized controlled trials and cohort studies reporting on the influence of an adjuvant antidepressant on the efficacy of electroconvulsive therapy for major depression were included. Authors independently screened records, extracted data and assessed study quality. We reported this systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Nine studies were included in the meta-analysis. The meta-analysis revealed a significant advantage of adjuvant antidepressants versus placebo. The overall effect size per category of antidepressant was as follows: tricyclic antidepressants: Hedges' g 0.32 (95% confidence interval: [0.14, 0.51]) (k = 6) with low heterogeneity (I2: 4%, p = 0.39); selective serotonin reuptake inhibitors/serotonin noradrenaline reuptake inhibitors: Hedges' g 0.27 (95% confidence interval: [0.03, 0.52]) (k = 2) with a lack of heterogeneity (I2: 0%, p = 0.89); and monoamine oxidase inhibitors: Hedges' g 0.35 (95% confidence interval: [-0.07, 0.77]) with moderate heterogeneity (I2: 43%, p = 0.17) (k = 3). CONCLUSION: An adjuvant antidepressant enhances the efficacy of electroconvulsive therapy for major depression. Tricyclic antidepressants, selective serotonin reuptake inhibitors/serotonin noradrenaline reuptake inhibitors and monoamine oxidase inhibitors showed the same effect size. However, the effect sizes of tricyclic antidepressants and monoamine oxidase inhibitors are most likely underestimated, due to insufficient doses in most of the included studies. We recommend the routine use of an adequately dosed antidepressant during electroconvulsive therapy for major depression.

Toward Targeted ECT: The Interdependence of Predictors of Treatment Response in Depression Further Explained.

OBJECTIVE: Several clinical variables assumed to be predictive of electroconvulsive therapy (ECT) outcome in major depressive disorder show substantial interrelations. The current study tries to disentangle this interdependence to distill the most important predictors of treatment success to help improve patient-treatment matching. METHODS: We constructed a conceptual framework of interdependence capturing age, episode duration, and treatment resistance, all variables associated with ECT outcome, and the clinical symptoms of what we coin core depression, ie, depression with psychomotor agitation, retardation, psychotic features, or a combination of the three. The model was validated in a sample of 73 patients with a major depressive episode according to DSM-5 treated twice weekly with ECT (August 2015-January 2018) using path analyses, with the size and direction of all direct and indirect paths being estimated using structural equation modeling. Reduction in Montgomery-Asberg Depression Rating Scale (MADRS) scores during treatment was the ECT outcome measure. RESULTS: The baseline presence of psychomotor agitation, retardation, and/or psychotic symptoms strongly correlated with beneficial ECT outcome (z = 0.84 [SE = 0.17]; P < .001), and the association between age and the effect of ECT appears to be mediated by their presence (z = 0.53 [SE = 0.18]; P = .004). There was no direct correlation between age and ECT response (P = .479), but there was for episode duration and ECT outcome (z = -0.38 [SE = 0.08]; P < .001). CONCLUSIONS: ECT is a very effective treatment option for severe depressive disorder, especially for patients suffering from severe depression characterized by the presence of psychomotor agitation, psychomotor retardation, psychotic symptoms, or a combination of these 3 features, with the chance of a beneficial outcome being reduced in patients with a longer episode duration. Age may heretofore have been given too much weight in ECT decision making. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02562846.

Psychomotor Retardation and the prognosis of antidepressant treatment in patients with unipolar Psychotic Depression.

BACKGROUND: Psychomotor Retardation is a key symptom of Major Depressive Disorder. According to the literature its presence may affect the prognosis of treatment. Aim of the present study is to investigate the prognostic role of Psychomotor Retardation in patients with unipolar Psychotic Depression who are under antidepressant treatment. METHODS: The Salpetriere Retardation Rating Scale was administered at baseline and after 6 weeks to 122 patients with unipolar Psychotic Depression who were randomly allocated to treatment with imipramine, venlafaxine or venlafaxine plus quetiapine. We studied the effects of Psychomotor Retardation on both depression and psychosis related outcome measures. RESULTS: 73% of the patients had Psychomotor Retardation at baseline against 35% after six weeks of treatment. The presence of Psychomotor Retardation predicted lower depression remission rates in addition to a higher persistence of delusions. After six weeks of treatment, venlafaxine was associated with higher levels of Psychomotor Retardation compared to imipramine and venlafaxine plus quetiapine. CONCLUSIONS: Our data confirm that Psychomotor Retardation is a severity marker of unipolar Psychotic Depression. It is highly prevalent and predicts lower effectivity of antidepressant psychopharmacological treatment.

Symptom Profile and Clinical Course of Inpatients with Unipolar versus Bipolar Depression.

BACKGROUND: Although differences in symptom profiles and outcome between depressive patients with an underlying major depressive disorder (MDD) and bipolar depression (BD) have been reported, studies with sequential short-interval assessments in a real-life inpatient setting are scarce. OBJECTIVES: To examine potential differences in symptom profile and course of depressive symptomatology in depressive inpatients with underlying MDD and BD. METHODS: A cohort of 276 consecutive inpatients with MDD (n = 224) or BD (n = 52) was followed during their hospitalization using routine outcome monitoring (ROM), which included a structured diagnostic interview at baseline (Mini-International Neuropsychiatric Interview Plus [MINI-Plus]) and repeated 17-item Hamilton Depression Rating Scale every 2 weeks. MDD and BD were compared regarding their symptom profiles and time to response and remission. Furthermore, the concordance between the MINI-Plus and clinical diagnosis was analyzed. RESULTS: Patients were on average 52 and 47 years old in the MDD and BD group, respectively, and 66 versus 64% were female. Compared to patients with BD, patients with MDD scored higher on weight loss (p = 0.02), whereas the BD group showed a higher long-term likelihood of response (hazard ratio = 1.93, 95% confidence interval 1.16-3.20, p for interaction with time = 0.04). Although the same association was seen for remission, the interaction with time was not significant (p = 0.48). Efficiency between the MINI-Plus and clinical diagnosis of BD was high (0.90), suggesting that the MINI-Plus is an adequate ROM diagnostic tool. CONCLUSIONS: In routine clinical inpatient care, minor differences in the symptom profile and the course of depressive symptomatology may be helpful in distinguishing MDD and BD, particularly when using sequential ROM assessments.