Methods/Principal Findings Cochrane systematic review methodology, with meta-analyses and trial . Mol. Neuropsychopharmacol. Toward this end, the development of staging methods provides promising solutions. Coll. Jha, M. K. et al. Psychotherapy, also known as talk therapy, involves working with a qualified mental healthcare professional to explore and address the emotional issues that are causing depression. Regarded as the gold standard, ECT has been successfully used for many years to treat severe TRD and exhibits both relatively rapid and sustained onset of efficacy; approximately 50% of all patients reach response criteria at the third treatment, typically within 1 week. The search was conducted in PubMed, Scopus, and Google Scholar with no restrictions on time period and concluded in October 2018. Br. Am. It should be noted that counter-regulatory mechanisms or resilience factors, such as social support, may exist that counter SLEs. Clinical Trial, Phase III Research Support, Non-U.S. Gov't Akathisia, Drug-Induced / drug therapy Antipsychotic Agents / adverse effects* Antipsychotic Agents / therapeutic use* Combined Modality Therapy J. How effective is algorithm-guided treatment for depressed inpatients? Affect. Kadriu, B. et al. -D., Lisanby, S. H. & Peterchev, A. V. Electric field strength and focality in electroconvulsive therapy and magnetic seizure therapy: a finite element simulation study. J. Geriatr. Heritable risk for MDD is between 30 and 40%, with higher rates in women. Horowitz, L. M. et al. Algorithm-guided treatment of depression reduces treatment costsresults from the randomized controlled German Algorithm Project (GAPII). Article Genetic findings suggest that testing for CYP450 isoenzyme activity may improve treatment outcomes. For a graphical summary of these findings see Fig. 42, 11371144 (2008). Trivedi, M. H. et al. Balestri, M. et al. Nelson, J., Klumparendt, A., Doebler, P. & Ehring, T. Childhood maltreatment and characteristics of adult depression: meta-analysis. CAS J. Coll. Major depression includes symptoms of depressed mood or loss of interest, most of the time for at least 2 weeks, that interfere with daily activities. Bergfeld, I. O. et al. Cusin, C. & Dougherty, D. D. Somatic therapies for treatment-resistant depression: ECT, TMS, VNS, DBS. Science 329, 959964 (2010). In contrast to pharmaceutical treatments that exert their efficacy at the molecular level, electrical stimulation techniques target entire neuronal circuits. J. Desseilles, M. et al. Ther. Prim Care Companion CNS Disord. Brunoni, A. R., Baeken, C., Machado-Vieira, R., Gattaz, W. F. & Vanderhasselt, M. A. BDNF blood levels after electroconvulsive therapy in patients with mood disorders: a systematic review and meta-analysis. After being hospitalized numerous times, I was diagnosed with three mental illnesses. Psychiatry 71, 939946 (2012). 3, which also illustrates the need for more third- and fourth-stage treatment options). Neuropsychopharmacol. J. ECT 26, 6267 (2010). The authors suggested that alternative splicing could lead to shifts in the proportion of isoforms and altered biological functions of these proteins94. 189, 224232 (2016). Taken together, this review outlines important clinical, psychosocial, and biological factors associated with response and remission to antidepressant treatment (see Table 3). Psychiatry 14, 334385 (2013). Psychiatry 74, 250256 (2013). The purpose of this guidance is to assist sponsors in the clinical development of drugs for the monotherapeutic, combination, and adjunctive treatment of . Dev. 139). Sci. Interestingly, one study found that individuals with atypical depression had significantly higher body-mass index, waist circumference, levels of inflammatory markers, and triglyceride levels, and lower levels of high-density lipid cholesterol than those with melancholic depression or controls126. This review, though comprehensive, was not able to consider several lines of evidence on outcome prediction and treatment improvement. Neuropsychopharmacol. Article Kraus, C., Kadriu, B., Lanzenberger, R. et al. Med. Neuropsychopharmacol. 8, 57 (2018). Pract. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. 12, 175 (2018). Funding for this work was supported in part by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIA MH002927). Gen. Psychiatry 61, 378386 (2004). Neuropsychopharmacology 36, 23752394 (2011). 19, 519527 (2014). If material is not included in the articles Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. CNS Drugs 32, 197227 (2018). World J. Biol. Dunlop, B. W. et al. In particular, replicable prospective and retrospective studies indicate that shorter duration of untreated diseaseboth in terms of first and recurrent episodesis a prognostic factor indicating better treatment response and better long-term outcomes5,6,7,8,9,10, although not all studies have found such an association11. Am. To obtain 16, 701711 (2013). Ghio, L., Gotelli, S., Marcenaro, M., Amore, M. & Natta, W. Duration of untreated illness and outcomes in unipolar depression: a systematic review and meta-analysis. Berman, R. M. et al. Kohler-Forsberg, O. et al. Kautzky, A. et al. Standardization, validation, and clinical utility. 18 (2016). Genet. It is developed based on subtype-selective NMDA receptor (SNRMs) technology. Higher prevalence estimates with questionnaire- or criterion-based interviews (such as the SCID) administered either in person or by phone (especially in recent years) Drug Discov. Repetitive transcranial magnetic stimulation (rTMS) is a widely used treatment for major depressive disorder (MDD), and its effectiveness in preventing relapse/recurrence of MDD has been explored. Zarate, C. A. et al. Lamers, F. et al. Olgiati, P. et al. We argue that disease-inherent heterogeneity, in concert with inaccurate group stratification tools, might have contributed to the lack of clinically applicable stratification and response prediction markers. Cognitive Behavioral Therapy (CBT) 24, 277288 (2009). Scand. https://doi.org/10.1038/s41398-019-0460-3, DOI: https://doi.org/10.1038/s41398-019-0460-3. Enck, P., Bingel, U., Schedlowski, M. & Rief, W. The placebo response in medicine: minimize, maximize or personalize? Ketamine safety and tolerability in clinical trials for treatment-resistant depression. Thank you for visiting nature.com. Dr. Zarate is a full-time U.S government employee. At least one symptom is either depressed mood or loss of interest or pleasure. Screening tools for early identification of depressed patients can be helpful111, and such instruments can start with as few as two itemsfor instance, the Patient Health Questionnaire-2112 or Ask Suicide-Screening Questions (asQem)113and proceed to more detailed instruments if initial screens are positive. Henter, I. D., de Sousa, R. T. & Zarate, C. A. Jr. Glutamatergic modulators in depression. Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review. Interestingly, two recent meta-analyses found that initial improvement was linked to response and outcome but failed to be associated with treatment resistance19,20. Paksarian, D. et al. 88, 105112 (2017). : J. Ment. J. Psychiatry 173, 499508 (2016). Bifrontal, bitemporal and right unilateral electrode placement in ECT: randomised trial. The technique is safe, removable, and does not cause lasting neuronal lesions. Neuropsychopharmacol. In the past two decades, large, collaborative studies using treatment-based algorithms have introduced standardized, sequential treatments; these include the Texas Medication Algorithm Project133, the STAR*D trial21, and the German algorithm project134. PubMed PubMed Central Publ. In combination with neuroimaging techniques such as fMRI, genes or blood-based markers have a high potential of future implementation in stratification of MDD or serve as prognostic marker on treatment outcome. Initial positive trials of add-on agentssuch as buprenorphine168,169, rapastinel170, or scopolamine145have also been conducted. The impact of medical comorbidity on acute treatment in major depressive disorder. Major depressive disorder (MDD) is a debilitating disease that is characterized by depressed mood, diminished interests, impaired cognitive function and vegetative symptoms, such as disturbed. Speed of response and remission in major depressive disorder with acute electroconvulsive therapy (ECT): a Consortium for Research in ECT (CORE) report. Wilkinson, S. T. & Sanacora, G. A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems. Biol. JAMA Psychiatry 73, 456464 (2016). Presently, however, the relative lack of biologically defined MDD subgroups and their stratification are key obstacles to finding and establishing treament outcome predictors appropriate for broader clinical applications. McClintock, S. M. et al. : J. Eur. Glutamatergic neurotransmission: pathway to developing novel rapid-acting antidepressant treatments. Clinical implementation of pharmacogenetic decision support tools for antidepressant drug prescribing. Studies also found gender-specific effects; in particular, at lower stress levels females were at higher risk of MDD than males34. The underlying principle behind LIFU therapy is based on the concept of neuromodulation, which involves the selective alteration of neural activity in targeted brain regions. Bewernick, B. H. et al. Pretreatment and early-treatment cortical thickness is associated with SSRI treatment response in major depressive disorder. Nevertheless, preliminary research suggests that the impact of SLEs on MDD may depend on measurable factors such as gender and the timing of exposure119. 4, 612 (2015). Neuroimaging 2, 327335 (2017). Fava, M. et al. Volume of the human hippocampus and clinical response following electroconvulsive therapy. Presently, no clinically relevant tools have been established for stratifying subgroups or predicting outcomes. First, the concept of treatment-resistant depression does not have reliable criteria for research and is conceptually empty. Int Clin. 18, 252260 (2013). Int. Substantial evidence also supports additional NMDAR-independent mechanisms, including the stabilization of glutamate release/excitatory transmission, active metabolites such as hydroxynorketamine, regulation of the dopaminergic system, G-alpha subunit translocation, and activation of cyclic adenosine monophosphate, as well as potential sigma-1 and mu-opioid receptor activation145. B. Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria, Christoph Kraus,Rupert Lanzenberger&Siegfried Kasper, Section on Neurobiology and Treatment of Mood Disorders, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA. Cross-sectional data from the GSRD108 identified a number of risk factors linked to TRD, including comorbidity (particularly anxiety and personality disorders), suicide risk, episode severity, number of hospitalizations, episode recurrence, early-onset, melancholic features, and non-response at first treatment28. This study aims to compare rs-fMRI of depressive disorder (DEP) patients with healthy participants, investigate whether pre-ECT dynamic . Publishers note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Defining anxious depression: a review of the literature. Oslin, D. W. et al. Stress exposure across the life span cumulatively increases depression risk and is moderated by neuroticism. Biol. Coll. Serum proteomic profiles of depressive subtypes. Care 41, 12841292 (2003). Kellner, C. H. et al. J. Coll. 50, 668681 (2018). Investigational drugs in recent clinical trials for treatment-resistant depression. With appropriate treatment, 70-80% of individuals with major depressive disorder can achi. Provided by the Springer Nature SharedIt content-sharing initiative, Translational Psychiatry (Transl Psychiatry) The images or other third party material in this article are included in the articles Creative Commons license, unless indicated otherwise in a credit line to the material. Res. Most importantly, TRD is life-threatening, and associated with a two- to threefold increased risk of suicide attempts compared to responding patients, and a 15-fold increased risk compared to the general population109. Psychol. J. Neural Eng. When treating TRD patients, physicians should consider illness severity, the chronicity of past and recent depressive episodes, the side effect profile of available treatment options, as well as previous refractoriness to particular treatment approaches. Dennehy, E. B., Marangell, L. B., Martinez, J., Balasubramani, G. K. & Wisniewski, S. R. Clinical and functional outcomes of patients who experience partial response to citalopram: secondary analysis of STAR*D. J. Psychiatr. J. Psychopharmacol. One meta-analysis found that all three were significantly elevated at baseline in MDD patients, but their treatment trajectories differed86; IL-6 levels decreased with antidepressant treatment, but outcomes were indistinguishable. Increased TSPO binding in MDD patients has been observed in the ACC, insula, and prefrontal cortex80. 267, 711721 (2017). J. 127, 337342 (2010). Studies have found that elevated baseline anxiety symptoms or comorbid anxiety disorder are associated with worse antidepressant response to first-line selective serotonin reuptake inhibitors (SSRIs) or second-line treatment strategies42,43. 36, 13191325 (2004). Psychiatry 66, 591597 (2005). Angstman, K. B. et al. This inhibition of serotonin reuptake results in an accumulation of serotonin. Parsing the heterogeneity of depression: An exploratory factor analysis across commonly used depression rating scales. 152154, 4551 (2014). : J. Ment. 69, 542548 (2018). CNS Spectr. JAMA Psychiatry 75, 547554 (2018). It was noted earlier that studies that defined remission as percent change of baseline values might be biased in favor of higher baseline scores, while absolute endpoints (e.g., remission defined below a cutoff score) favor less sick patients4. Figure 4, illustrates potential reasons for pseudoresistance42 that should be ruled out during this time-frame. Abstract. Res. Disord. Pioneering research on biological differencesfor instance, between patients with atypical versus melancholic depressionsuggests differential HPA axis or autonomous nervous system reactivity121,122, though the subtype results have been only moderately consistent across time and are prone to low group specificity123,124,125. Psychiatry 26, 307319 (2018). Prog. Ionescu, D. F., Niciu, M. J., Henter, I. D. & Zarate, C. A. & Prescott, C. A. Biol. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Psychiatry 48, 813829 (2000). Biol. ISSN 2158-3188 (online), Prognosis and improved outcomes in major depression: a review, https://doi.org/10.1038/s41398-019-0460-3, https://doi.org/10.1038/s41380-018-0093-6, http://creativecommons.org/licenses/by/4.0/, Anti-inflammatory effects of -FNA are sex-dependent in a pre-clinical model of LPS-induced inflammation, Reply to: The serotonin theory of depression: a systematic umbrella review of the evidence published by Moncrieff J, Cooper RE, Stockmann T, Amendola S, Hengartner MP, Horowitz MA in Molecular Psychiatry (2022 Jul 20. doi: 10.1038/s41380-022-01661-0), Effects of bilateral sequential theta-burst stimulation on 5-HT1A receptors in the dorsolateral prefrontal cortex in treatment-resistant depression: a proof-of-concept trial, Introducing a depression-like syndrome for translational neuropsychiatry: a plea for taxonomical validity and improved comparability between humans and mice, Basal Forebrain Cholinergic Innervation Induces Depression-Like Behaviors Through Ventral Subiculum Hyperactivation. Compelling evidence suggests that BDNF levels are decreased at baseline in MDD patients and elevated in response to pharmacological90,91 treatments as well as ECT92. Persistent depressive disorder (also called dysthymia or dysthymic disorder) consists of less severe symptoms of depression that last much longer, usually for at least 2 years. Remission is achieved by about 30% of patients within six ECT sessions179. : Off. Neurosci. Psychopharmacol. J. Clin. Ketamine has also been shown to be superior to any blinding counterpart158. J. Psychiatry 175, 463470 (2018). Biol. As noted above, severe SLEs constitute an important risk factor. In particular, we focused on clinical outcomes in humans and were, thus, unable to fully explore the highly valuable advances made in translational science. Biol. Nat. Diazgranados, N. et al. Psychopharmacol. Translational Psychiatry Google Scholar. J. Psychiatry 173, 11961204 (2016). Pharmacogenomics 16, 9971013 (2015). To date, no study has evaluated its efficacy and acceptability in a randomized controlled trial for . A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Reduced global 5-HT1A receptor binding has also been observed after ECT77. Klengel, T. & Binder, E. B. Gene x environment interactions in the prediction of response to antidepressant treatment. In this group, adjunctive VNS led to significantly better clinical outcomes and higher remission rates than treatment as usual (67.6% vs. 40.9%, respectively). JAMA Psychiatry 75, 139148 (2018). Herbison, C. E., Allen, K., Robinson, M., Newnham, J. Psychiatry 74, 760767 (2013). Psychiatry 79, 16m11385 (2018). This difference was absent in the intervention group, in which depression care managers helped physicians with guideline-concordant recommendations and helped patients adhere to treatment56. Safety of research into severe and treatment-resistant mood disorders: analysis of outcome data from 12 years of clinical trials at the US National Institute of Mental Health. Multifactorial determinants of the neurocognitive effects of electroconvulsive therapy. J. & Sackeim, H. A. Adjusting the dose of electrical stimuli (e.g., through refined electrode placement or individually adjusted pulse amplitudes) may improve ECTs side effect profile. World J. Biol. The mental health comorbidities of diabetes. The outline follows the classification of markers as suggested by others200 (modified and reprinted with permission from Springer). Biol. In contrast, one large and one smaller sham-controlled clinical study both failed to achieve their primary endpoints of symptom reduction197,198. Clinical depression, also known as major depressive disorder (MDD), is a mental health condition that causes a persistently low or depressed mood and a loss of interest in activities that once brought joy. 126 (Springer New York, New York, NY, 2017). Med. Psychiatry 13, 861868 (2005). & Schoenfeld, D. A. Psychiatry 73, 12041212 (2013). Finniss, D. G., Kaptchuk, T. J., Miller, F. & Benedetti, F. Biological, clinical, and ethical advances of placebo effects. : J. Eur. Clear evidence of an inverse relationship between duration of episode and treatment outcome (either response or remission) underscores the importance of early intervention in MDD4 (Table 1). In contrast, several controlled clinical studies found that elevated baseline severity correlated with improved response and remission rates25. Genet. A specific laboratory test for the diagnosis of melancholia. Am. In the meantime, to ensure continued support, we are displaying the site without styles Clinicians should tailor treatment strategies based on patientsresponse, tolerability, and disease severity . Slade, E. P., Jahn, D. R., Regenold, W. T. & Case, B. G. Association of electroconvulsive therapy with psychiatric readmissions in US hospitals. J. Psychiatry 174, 533545 (2017). Br. Google Scholar. Martinez-Amoros, E. et al. Psychiatr. Lancet 375, 686695 (2010). Suppl. High stress levels significantly influence outcomes in MDD patients who are prone to vulnerable states, such as those with high levels of neuroticism33,34. Blood Flow. How to Start Treatment Treatment usually begins when you see a doctor concerning possible symptoms of depression that you may be experiencing. A large non-inferiority trial of 414 moderately resistant MDD patients found that TBS was at least as effective as rTMS in reducing depressive symptoms177. Another study found that early improvement in work productivity was a significant positive predictor of higher remission rates after three and seven months of treatment16. Given the importance of neuroplasticity in the pathophysiology and treatment of depression, interest has grown in studying brain-derived neurotrophic factor (BDNF), a neurotrophin involved in the structural adaptation of neuronal networks and a prerequisite for neuronal reactions to stressors. & Russo, J. Psychiatry 56, 101112 (2004). This led to the introduction of phenotype categoriespoor, intermediate, extensive (normal), and ultrarapid metabolizersbased on CYP450 isoenzyme status and their relationship to plasma levels at fixed doses102. Neuropsychopharmacol. Psychiatry 87, 269280 (2018). Rev. Clinical depression can also affect how you sleep, your appetite and your ability to think clearly. . This is in line with results from a previous study that found that baseline function predicted antidepressant response in TRD patients23. Potential biomarkers have been explored, including hippocampal volumes, neuronal activity of the anterior cingulate cortex, and levels of brain-derived neurotrophic factor (BDNF) and central and peripheral inflammatory markers (e.g., translocator protein (TSPO), interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor alpha (TNF)). However, this discrepancy might be explained by variations in outcome according to parameter. Psychiatric comorbidity has been shown to influence outcome in both treated and untreated patients40,41. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Coll. Kautzky, A. et al. However, given its easy implementation and the short time needed to acquire measurements, fMRI appears to be a promising tool for identifying imaging biomarkers. Habert, J. et al. PubMed Dr. Kraus has received travel grants from Roche Austria GmbH and AOP Orphan. 22, 239258 (2012). Psychiatry, https://doi.org/10.1038/s41380-018-0093-6 (2018). J. Med. Med. A 5-Year observational study of patients with treatment-resistant depression treated with vagus nerve stimulation or treatment as usual: comparison of response, remission, and suicidality. Jayashri Kulkarni. Adli, M. et al. Magnetic seizure therapy in treatment-resistant depression: clinical, neuropsychological and metabolic effects. J. Psychiatr. 145, 4248 (2013). Affect Disord. Predicting onset of major depression in general practice attendees in Europe: extending the application of the predictD risk algorithm from 12 to 24 months. I dealt with anorexia, major depressive disorder, and borderline personality disorder. Christoph Kraus,Bashkim Kadriu&Carlos A. Zarate Jr. You can also search for this author in Thompson, A. E. & Kaplan, C. A. Childhood emotional abuse. Affect Disord. Psychiatry 18, 528 (2017). Thus, based on currently available guidelines, we have outlined a sequential treatment optimization scheme that includes options for TRD; such work highlights the substantial need to develop and improve third-line-and-beyond therapeutics. Khan, A. NeuroImage 63, 874881 (2012). Treatment outcomes for major depressive disorder (MDD) need to be improved. Zarate, C. A. et al. Gen. Psychiatry 61, 669680 (2004). Dold, M. et al. In this manner, the presence of weak alleles in candidate genes such as BDNF, SERT, and others would be increasingly detrimental in the presence of SLEs116,117. Article J. Wang, L. et al. Ionescu, D. F. & Papakostas, G. I. Since 2005, the FDA has approved VNS use for the adjunctive long-term treatment of long-lasting recurrent depression in patients 18 years and older who are experiencing a major depressive episode and have failed to respond to four or more previous adequate standard antidepressant treatment trials. Garay, R. P. et al. 45, 10731092 (2015). Finding the right therapist helped me manage my mental health and open up about my feelings. Depress Anxiety 31, 737745 (2014). To date, the number of MDD patients treated with DBS has been very small compared to other treatment options, including ECT and TMS. Other research groups have tried to overcome conventional psychopathological subgroups and model biotypes using resting-state fMRI69. It should be noted that treatment success might have more discriminatory power for identifying subgroups than psychopathological subgroup stratification. The volume of other brain regions, including the anterior cingulate or orbitofrontal cortices, have also been shown to be decreased in MDD subjects63, but more longitudinal neuroimaging trials with antidepressants are needed to clarify this association. Care Community Health 8, 233238 (2017). Psychiatry 75, e785e793 (2014). Despite its clinical efficacy, ECT remains underutilized. Developing more-targeted drug treatment options for people with mood disorders, based on variations in brain imaging patterns, brain metabolism and genetic makeup; Publications. Strikingly, 65% of TRD patients met response criteria through Day 57. Increase in hippocampal volume after electroconvulsive therapy in patients with depression: a volumetric magnetic resonance imaging study. Can C-reactive protein inform antidepressant medication selection in depressed outpatients? Schosser, A. Papakostas, G. I. Psychiatry 22, 900909 (2017). Transl Psychiatry 9, 127 (2019). Inflammation and clinical response to treatment in depression: A meta-analysis. The issue of placebo response in antidepressant trials has become increasingly important137,138. We thank the 7SE research unit and staff for their support. Pretreatment rostral anterior cingulate cortex theta activity in relation to symptom improvement in depression: A randomized clinical trial. Background: Despite the high prevalence of major depressive disorder and the related societal burden, access to effective traditional face-to-face or video-based psychotherapy is a challenge. Oltedal, L. et al. A period of at least two weeks when a person experienced a depressed mood or loss of interest or pleasure in daily activities, and had a majority of specified symptoms, such as problems with sleep, eating, energy, concentration, or self-worth. The problem of the placebo response in clinical trials for psychiatric disorders: culprits, possible remedies, and a novel study design approach. Pract. Similar findings have been observed for IL-6 and TNF. Porcelli, S., Fabbri, C. & Serretti, A. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy. 91, 113 (2017). Musil, R. et al. The risk for major depression conferred by childhood maltreatment is multiplied by BDNF and SERT genetic vulnerability: a replication study. Spies, M. et al. Nevertheless, brain-electrode interfaces are evolving quickly and it is possible that next generation brain-responsive stimulation devices will be able to adjust stimulation on-demand only when abnormal biological marker impulses (e.g., pulse amplitude) are detected199. Specific analyses identified neuronal genes (but not microglia or astrocytes), gene-expression regulating genes (such as RBFOX1), genes involved in gene-splicing, as well as genes that are the targets of antidepressant treatment. Other task-based and resting-state fMRI studies found that ACC activity (including pregenual activity) predicted treatment response70, a finding corroborated by an expanded electroencephalography study71 as well as a meta-analysis60. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Psychiatry 6, e851 (2016). JAMA 312, 691692 (2014). For instance, a treatment study using escitalopram and nortriptyline investigated the association between number of SLEs (e.g., job loss, psychological trauma, loss of a loved one) and antidepressant treatment.