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Moving forward: how depression heterogeneity hinders progress in treatment and research
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Few would argue that depression research in the last two decades has led to major improvements of clinical care for patients. The tools and insights we have at our disposal today have not changed m...
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“At the extreme, two individuals can meet criteria for a diagnosis of major depressive disorder without sharing any single symptom. 7”
From Time for united action on depression: a Lancet–World Psychiatric Association Commission (2022) · cites this paper as [7]
In the citing paper
“Revisiting the hypothesis of Taylor and colleagues (46), one potential reason why model personalisation may provide benefits over “traditional” machine learning methods is because this allows to deal with heterogeneity, a feature that is characteristic both of depression and the way patients respond to treatment (83, 84).”
From Personalised depression forecasting using mobile sensor data and ecological momentary assessment (2022) · cites this paper as [83]
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“Despite its medical importance MDD is poorly defined and diagnosed since its diagnosis is mostly based on data subjectively reported by the patients themselves (13–15) and lack of objective, clinically relevant outcome measure.”
From A narrative review of digital biomarkers in the management of major depressive disorder and treatment-resistant forms (2023) · cites this paper as [13]
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Time for united action on depression: a Lancet–World Psychiatric Association Commission
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“The definition of MDD stems from the 1970s and has not essentially changed since then, although it is increasingly clear that the validity of the construct is problematic (De Jonge et al., 2015; Fried, 2017).”
BackgroundRevisiting the theoretical and methodological foundations of depression measurement
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“Individual symptoms on depression scales, such as insomnia or suicidal ideation, might represent more valid and reliable phenotypes than symptom sum scores or categorical diagnoses 52,127,129 .”
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“This heterogeneity of depression hinders both research and treatment of this highly prevalent disorder (Fried, 2017).”
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“Since depression is a complex and heterogeneous disorder (Fried, 2017; Wray et al., 2018), multiple features will likely have to be considered in a multivariate model to allow accurate prediction of treatment outcomes (Gillan & Whelan, 2017; Kautzky et al., 2017; Kessler, 2018).”
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“Depressive and anxiety disorders as they are currently classified (DSM diagnosis) are heterogeneous in terms of symptomatology (Fried, 2017), underlying pathophysiological mechanisms, and clinical course (Jentsch et al., 2015; Verduijn et al., 2017).”
BackgroundThe genetic basis of major depressive disorder
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“…genetic roots, with a complex and poorly understood set of interactions between the two; the disorder is highly comorbid with other psychiatric disorders and with chronic disease; differences in personality, sex and age all contribute differentially to the risk of developing the illness [44, 45].”
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The gut microbiota and depressive symptoms across ethnic groups
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On Dimensionality, Measurement Invariance, and Suitability of Sum Scores for the PHQ-9 and the GAD-7
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“However, this limitation is not specific to the measures scrutinized here, and applies across mental health measures (Fried, 2017).”
BackgroundInfluentialSelf-citationAllostasis, action and affect in depression: Insights from the theory of constructed emotion
Shaffer, C., Westlin, C., Quigley, K. S., Whitfield-Gabrieli, S., & Barrett, L. F. (2022) · Annual Review of Clinical Psychology · doi:10.1146/annurev-clinpsy-081219-115627 · Cited by 94
“MDD and other psychiatric disorders can present as a population of highly variable features that are both mental and physical, rather than as consistent set of disordered categories, neatly dividing into subtypes based on domains of symptoms (Fried 2017, Goldberg 2011).”
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“Furthermore, MDD is a highly heterogeneous disorder [27].”
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“2018), lack of reliability and validity of MDD DSM-5 criteria diagnosis (Fried 2017).”
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“This is particularly relevant for a heterogenous condition such as MDD or bipolar depression [125], where effect sizes of potential biomarkers are likely to be modest.”
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“Several reasons could account for this disparity including patient sample sizes [1], disease heterogeneity [2,3], or that disease phenotypes cut across diagnostic criteria for different diseases [4,5].”
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“One approach to address these questions is the symptomics framework (Fried, 2017), which focuses on individual symptoms and their (potentially causal) relationships among each other.”
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“They also are of interest in supporting the need for more multimodal imaging studies [72 – 76] that use diverse MRI data in an integrated way to perhaps improve prediction as well as understanding of treatment response in MDD.”
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“However, MDD is clinically heterogeneous, significantly challenging individualized diagnosis and treatment (Fried, 2017).”
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Personalised depression forecasting using mobile sensor data and ecological momentary assessment
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“…Taylor and colleagues (46), one potential reason why model personalisation may provide bene fi ts over “ traditional ” machine learning methods is because this allows to deal with heterogeneity , a feature that is characteristic both of depression and the way patients respond to treatment (83, 84).”
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“A new research framework entitled ‘Symptomics’ was proposed recently that aims to describe such studies under one framework, and complement diagnosis-level research with more detailed research on symptoms (Fried, 2017).”
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“35 Previous studies have highlighted the active role of symptom dynamics in worsening mental health conditions, where it has been found that not all symptoms of depression should be considered equal with respect to their reach and strength of impact on the aggravation of additional depressive…”
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“Given the well-documented variability in speech production 47 , the limitations of existing instruments for detecting depression 40 , and the heterogeneity in the manifestation of depression symptoms 48 , it is unlikely that stand-alone speech-based models will yield high-accuracy diagnostic models.”
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A meta-analysis on the uncinate fasciculus in depression
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“…work should investigate the relationship between UNC FA and sleep in individuals with MDD, as understanding this association could have implications for the treatment of MDD. Finally, we like to point out that depression as a diagnostic category might encompass multiple subtypes (Fried, 2017).”
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“One argument to explain the dif fi culties in correctly diagnosing and treating depression is the heterogeneity of the disorder (9).”
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“This presents a major challenge for research and treatment development in depression (Fried, 2015, 2017; Olbert, Gala, & Tupler, 2014).”
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“However, MDD heterogeneity (Athira et al., 2020; Fried, 2017) implies the likelihood of distinct subsets, with different risk factors resulting in similar depressive symptoms (Jermy et al., 2021).”
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“Thus, as the ‘depression’ label provides limited information about the particular problems experienced by a patient, some researchers have moved away from traditional methods of diagnosis such as the DSM-5 and have focused on symptom dimensions (Fried, 2017).”
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“Much research in this area has focused on treatment of depres sion, probably because this is such a heterogeneous condition 133 .”
Speech-Based Depression Assessment: A Comprehensive Survey
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“Finally, investmentinpersonalisedmedicinemayalsobeanapproachto overcomethelimitationsofthehighlyheterogeneousdepression phenotype[159].”
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“Clinical depression is a heterogenous condition, which often runs a relapsing and remitting course across the lifespan and where no single treatment has been shown to be effective for all patients (Fried, 2017; Fried & Nesse, 2015).”
Depression subtypes and their response to cognitive behavioral therapy: A latent transition analysis
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“However, an alternative argument is that depression is a highly heterogeneous condition (Goldberg, 2011)— potentially characterized by various subtypes—and clinical outcomes could be improved if treatment was based on more precise assessments of each individual's symptom profile (Fried, 2017).”
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Depression Subtypes in Individuals With or at Risk for Symptomatic Knee Osteoarthritis
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“Official classifications and corresponding treatments for major depressive disorder have traditionally used a “one size fits all” approach, yet it is becoming more accepted that such definitions and management strategies do not accurately reflect the immense heterogeneity of depressive symptomology (12,18).”
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“A systematic approach, such as “stepped-care” pharmacotherapy, has been proposed to improve the treatment of depression in older adults.34 Depending on the response to first-line antidepressants, providers were encouraged to follow the treatment algorithm to continue the prescription or switch to the next line of medi…”
BackgroundInfluentialMarcu, G. M., Szekely‐Copîndean, R. D., Radu, A. M., Bucuță, M. D., Fleacă, R. S., Tanasescu, C. A. H., Roman, M. D., Boicean, A., & Bacila, C. I. (2023) · Frontiers in Psychology · doi:10.3389/fpsyg.2023.1087081 · Cited by 22
“Given the known heterogeneity of depression and the issues raised in differential diagnosis (Ghaemi and Vöhringer, 2011; Fried, 2017; Lorenzo-Luaces et al., 2021), reliable objective criteria such as electroencephalography (EEG) indices would have been helpful in detecting and differentiating depressive states.”
BackgroundModeling Heterogeneous Brain Dynamics of Depression and Melancholia Using Energy Landscape Analysis
Regonia, P. R., Takamura, M., Nakano, T., Ichikawa, N., Fermin, A. S. R., Okada, G., Okamoto, Y., Yamawaki, S., Ikeda, K., & Yoshimoto, J. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.780997 · Cited by 21
“Considerable efforts has been made toward drawing boundaries within the currently accepted definition of major depressive disorder (47, 48), suggesting that investigations on individual depressive symptoms and their interactions may lead to new discoveries (49).”
BackgroundToenders, Y. J., Schmaal, L., Nawijn, L., Han, L. K. M., Binnewies, J., van der Wee, N. J. A., van Tol, M., Veltman, D. J., Milaneschi, Y., Lamers, F., et al. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.06.056 · Cited by 20
“The heterogeneity in symptom expression in depression may result from heterogeneity in etiological pathways and may hamper treatment efficiency (Fried, 2017; Goldberg, 2011).”
BackgroundHicks, E. M., Seah, C., Cote, A. C., Marchese, S., Brennand, K., Nestler, E. J., Girgenti, M. J., & Huckins, L. M. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02412-7 · Cited by 21
Park, S., & Kim, Y. (2019) · Psychiatry Investigation · doi:10.30773/pi.2019.09.07 · Cited by 21
Verhagen, S. J. W., van Os, J., & Delespaul, P. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-822201-0.00017-4 · Cited by 20
Sun, Y., Li, X., Liu, H., Li, Y., Gui, J., Zhang, X., Li, X., Sun, L., Wang, C., Li, J., et al. (2024) · BMC Public Health · doi:10.1186/s12889-024-19627-y · Cited by 21
“This combines varied symptomatology and reduces clinically meaningful information that is critical to diagnosis and treatment [5].”
BackgroundKarvelis, P., Charlton, C. E., Allohverdi, S. G., Bedford, P., Hauke, D. J., & Diaconescu, A. O. (2022) · Network Neuroscience · doi:10.1162/netn_a_00233 · Cited by 20
“…such as HAMD (Hamilton, 1967), MADRS (Montgomery & Åsberg, 1979), BDI (Schwab, Bialow, Clemmons, Martin, & Holzer, 1967), and QIDS (Rush et al., 2003); these instruments differ considerably in their item content because they place different emphasis on different MDD symptoms (E. I. Fried, 2017).”
BackgroundAdvancing digital sensing in mental health research
Akre, S., Seok, D., Douglas, C., Aguilera, A., Carini, S., Dunn, J., Hotopf, M. H., Mohr, D. C., Bui, A. A. T., & Freimer, N. B. (2024) · npj Digital Medicine · doi:10.1038/s41746-024-01343-x · Cited by 21
Smit, A. C., Helmich, M. A., Bringmann, L. F., Oldehinkel, A. J., Wichers, M., & Snippe, E. (2025) · Clinical Psychological Science · doi:10.1177/21677026241305136 · Cited by 18
“Because it has become apparent that depression is a highly heterogeneous concept (Fried, 2017; Fried & Nesse, 2015; Monroe & Anderson, 2015), such broadly applicable EWSs may provide a consistent and reliable warning for upcoming transitions toward recurrence of depression even if the precise…”
Kim, I. B., & Park, S. (2021) · Diagnostics · doi:10.3390/diagnostics11091631 · Cited by 16
“This low remission rate is partly because diagnosing depression does not guarantee heterogeneous symptom subtypes [4].”
BackgroundIndividual-Specific Animated Profiles of Mental Health
Zilcha‐Mano, S. (2024) · Perspectives on Psychological Science · doi:10.1177/17456916231226308 · Cited by 18
“Two individuals sharing the same diagnosis may differ greatly in many of their traits (Borsboom, 2008; E. I. Fried, 2017; Kotov et al., 2021).”
Evaluation of major depression symptom networks using clinician-rated and patient-rated data
Feiten, J. G., Mosqueiro, B. P., Uequed, M., Passos, I. C., Fleck, M. P. D. A., & Caldieraro, M. A. (2021) · Journal of Affective Disorders · doi:10.1016/j.jad.2021.05.102 · Cited by 18
Núñez, C., Delgadillo, J., Barkham, M., & Behn, A. J. (2024) · European Psychiatry · doi:10.1192/j.eurpsy.2024.1756 · Cited by 16
“However, such a strategy has paid less attention to the interaction and mutual reinforcement between symptoms [28].”
Allison, G. O., Freeman, C. R., Renault, H., Banica, I., Ethridge, P., Sandre, A., & Weinberg, A. (2023) · Cognitive Affective & Behavioral Neuroscience · doi:10.3758/s13415-023-01063-x · Cited by 15
“However, depression is both etiologically and clinically heterogeneous (Buch & Liston, 2021; Cai et al., 2020; Fried, 2017; Lynch et al., 2020), and not all daughters of depressed mothers will develop depression themselves, complicating investigations into mechanisms of intergenerational transmission (Goodman & Gotlib…”
BackgroundImproving Depression Severity Prediction from Passive Sensing: Symptom-Profiling Approach
Akbarova, S., Im, M., Kim, S. H., Toshnazarov, K. E., Chung, K., Chun, J., Noh, Y., & Kim, Y.-A. (2023) · Sensors · doi:10.3390/s23218866 · Cited by 19
“In some cases, individuals may be diagnosed with depression without experiencing any shared symptoms [14].”
BackgroundVignapiano, A., Monaco, F., Pagano, C., Piacente, M., Farina, F., Petrillo, G., Sica, R., Marenna, A., Shin, J. I., Solmi, M., et al. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1321345 · Cited by 14
Meta-Analysis: Prevalence of Youth Mental Disorders in Sub-Saharan Africa
Jakobsson, C., Johnson, N. E., Ochuku, B., Baseke, R., Wong, E., Musyimi, C. W., Ndetei, D. M., & Venturo‐Conerly, K. E. (2024) · Cambridge Prisms Global Mental Health · doi:10.1017/gmh.2024.82 · Cited by 24
Yuan, Y., Lapane, K. L., Rothschild, A. J., & Ulbricht, C. M. (2020) · Aging & Mental Health · doi:10.1080/13607863.2020.1849021 · Cited by 15
“The diagnosis and treatment of depression in older adults could be complicated by its heterogeneous symptom profile (Fried, 2017).”
BackgroundInfluentialLuo, S., Mei, Z., Fang, G., Mu, G., Zhang, X., & Luo, S. (2024) · Frontiers in Public Health · doi:10.3389/fpubh.2024.1431062 · Cited by 16
“…model, which conceptualizes depression as a continuously process starting from subthreshold depression (17), with all individuals falling somewhere on the depressive symptom spectrum, distress and impairment occurring at the extremes of the continuum where the individual lies (4, 18–20).”
BackgroundDepression in a youth population-based sample from Brazil: Prevalence and symptom structure
Manfro, P. H., da Silva, C. T. B., Anselmi, L., Barros, F. C., Eaton, W. W., Gonçalves, H., Murray, J., Oliveira, I. O., Tovo‐Rodrigues, L., Wehrmeister, F. C., et al. (2021) · Journal of Affective Disorders · doi:10.1016/j.jad.2021.05.073 · Cited by 16
Taliaz, D., & Souery, D. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10143109 · Cited by 14
“As MDD is of particular medical importance, it is unfortunate that experts from the psychiatric community claim that MDD is poorly defined and diagnosed [7,8].”
BackgroundSteen, O. D., van Borkulo, C. D., & van Loo, H. M. (2021) · Journal of Affective Disorders · doi:10.1016/j.jad.2021.07.002 · Cited by 14
Morris, J., Leung, S. S. Y., Bailey, M. E. S., Cullen, B., Ferguson, A., Graham, N., Johnston, K. J. A., Lyall, D. M., Lyall, L. M., Ward, J., et al. (2020) · Genes · doi:10.3390/genes11111326 · Cited by 14
Piccin, J., Viduani, A. C., Buchweitz, C., Pereira, R. B., Zimerman, A., Amando, G. R., Cosenza, V., Ferreira, L. Z., McMahon, N. A. G., de Melo, R. F., et al. (2023) · JAACAP Open · doi:10.1016/j.jaacop.2023.11.002 · Cited by 14
“22,23 At a global level, 1 in 3 Internet users is under 18 years of age, and smartphones are the most popular devices used to go online.”
Fan, Q., & Zhang, H. (2024) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2024.111939 · Cited by 12
Hankin, B. L. (2019) · Behaviour Research and Therapy · doi:10.1016/j.brat.2019.04.006 · Cited by 17
“Two individuals can have the same diagnosis and share no symptoms in common; there are up to 1030 combinations of DSM-based symptoms that can uniquely characterize a depression diagnosis (Fried, 2017).”
BackgroundA Computational Neural Model for Mapping Degenerate Neural Architectures
Khan, Z., Wang, Y.-Y., Sennesh, E., Dy, J., Ostadabbas, S., van de Meent, J., Hutchinson, J. B., & Satpute, A. (2020) · bioRxiv · doi:10.1007/s12021-022-09580-9 · Cited by 6
“Emerging work suggests that distinct neuropathologies may underlie a common clinical phenotype (Fried, 2017).”
BackgroundAzevedo, R. D. M., Roest, A. M., Carney, R. M., Freedland, K. E., Lane, D. A., Parakh, K., de Jonge, P., & Denollet, J. (2017) · Journal of Affective Disorders · doi:10.1016/j.jad.2017.11.025 · Cited by 12
Depression Symptoms are Linked to Music Use
Kanagala, S. C., Schäfer, T., Greenberg, D. M., & Gabińska, A. (2021) · Music & Science · doi:10.1177/20592043211057217 · Cited by 15
Cusack, C. E., Ralph‐Nearman, C., Christian, C., Fisher, A. J., & Levinson, C. A. (2024) · Journal of Affective Disorders · doi:10.1016/j.jad.2024.04.034 · Cited by 19
Cohen-Stavi, C. J., Giveon, S. M., Key, C., Molcho, T., Balicer, R. D., & Shadmi, E. (2021) · BMJ Open · doi:10.1136/bmjopen-2020-040961 · Cited by 11
Dang, K., Ritvo, P., Katz, J. D., Gratzer, D., Knyahnytska, Y., Ortiz, A., Walters, C., Attia, M., Gonzalez‐Torres, C., Lustig, A., et al. (2023) · Interactive Journal of Medical Research · doi:10.2196/46419 · Cited by 12
“It is well established that symptoms vary substantially between patients [99,100], with at least 1030 unique symptom profiles identified [101].”
BackgroundRamos, S. D., Vincent, W., Siconolfi, D. E., Pollack, L. M., Horvath, K. J., Campbell, C. K., Tebbetts, S., Kegeles, S. M., & Storholm, E. D. (2023) · AIDS and Behavior · doi:10.1007/s10461-023-04186-x · Cited by 12
“…the literature, it is also important to note that depression itself is highly heterogeneous in presentation (e.g., experiencing negative affect, somatic disturbances, interpersonal problems, low positive affect), which may pose issues when examining asso - ciations to HIV care engagement [ 36–39].”
Hempel, M., Barnhofer, T., Domke, A., Hartling, C., Stippl, A., Carstens, L., Gärtner, M., & Grimm, S. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02647-w · Cited by 11
“In conclusion, the integration of rest-and task data with parameters of their relationship offers an avenue to gain a more comprehensive understanding of the processes underlying cognitive de fi cits and network mechanisms altered in MDD.”
Zhang, J., Liu, D., Liu, B., & Xiang, J. (2025) · Analytical Chemistry · doi:10.1021/acs.analchem.4c05967 · Cited by 11
The mediation effect analysis of nurse’s mental health status and burnout under COVID-19 epidemic
Liu, F., Zhao, Y., Chen, Y., & Tu, Z. (2023) · Frontiers in Public Health · doi:10.3389/fpubh.2023.1221501 · Cited by 12
Charles, S. J., Farias, M., & Dunbar, R. (2019) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2019.100003 · Cited by 10
“It is also likely that different ‘subtypes’ require different treatments (Fried, 2017).”
BackgroundVreijling, S. R., Penninx, B. W. J. H., Bot, M., Watkins, E. R., Owens, M., Kohls, E., Hegerl, U., Roca, M., Gili, M., Brouwer, I. A., et al. (2021) · Psychological Medicine · doi:10.1017/s0033291721000337 · Cited by 13
“Although depression is considered as a distinct disorder, its symptoms are diverse (Fried & Nesse, 2015), which complicates the examination of intervention effects on combined symptom rating scores (Fried, 2017).”
Howard, D. M., Folkersen, L., Coleman, J. R. I., Adams, M. J., Glanville, K. P., Werge, T. M., Hagenaars, S. P., Han, B., Porteous, D. J., Campbell, A., et al. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/134601 · Cited by 9
Metadata
- Authors
- Fried, E.
- Affiliations
- Departmenf of Psychology, University of Amsterdam, Amsterdam, Netherlands
- Venue
- Expert Review of Neurotherapeutics
- Publisher
- Informa UK Limited
- Published
- 2017-03-22
- Volume
- 17
- Issue
- 5
- Pages
- 423-425
- ISSN
- 1473-7175 (ISSN-L)
- 1744-8360
- OpenAlex
- W2601225127
- Cited by
- 220
- References
- 23
- Citations by year
- 2026: 22 · 2025: 34 · 2024: 31 · 2023: 31 · 2022: 22 · 2021: 40 · 2020: 13 · 2019: 15 · 2018: 7 · 2017: 5
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Expert Review of Neurotherapeutics (publishedVersion)
- PubMed (publishedVersion)
- UvA-DARE (University of Amsterdam) (submittedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- European Research Council Consolidator (647209)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Social Sciences › Psychology › Clinical Psychology › Psychological Treatments and Disorders
- Keywords
- depression heterogeneity, depression treatment, depression research, clinical care, endophenotypes
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