depression research and treatment impact factor

Depression Research and Treatment

Subject Area and Category

• Psychiatry and Mental Health
• Clinical Psychology

Hindawi Limited

Publication type

20901321, 2090133X

Information

How to publish in this journal

The set of journals have been ranked according to their SJR and divided into four equal groups, four quartiles. Q1 (green) comprises the quarter of the journals with the highest values, Q2 (yellow) the second highest values, Q3 (orange) the third highest values and Q4 (red) the lowest values.

The SJR is a size-independent prestige indicator that ranks journals by their 'average prestige per article'. It is based on the idea that 'all citations are not created equal'. SJR is a measure of scientific influence of journals that accounts for both the number of citations received by a journal and the importance or prestige of the journals where such citations come from It measures the scientific influence of the average article in a journal, it expresses how central to the global scientific discussion an average article of the journal is.

Evolution of the number of published documents. All types of documents are considered, including citable and non citable documents.

This indicator counts the number of citations received by documents from a journal and divides them by the total number of documents published in that journal. The chart shows the evolution of the average number of times documents published in a journal in the past two, three and four years have been cited in the current year. The two years line is equivalent to journal impact factor ™ (Thomson Reuters) metric.

Evolution of the total number of citations and journal's self-citations received by a journal's published documents during the three previous years. Journal Self-citation is defined as the number of citation from a journal citing article to articles published by the same journal.

Evolution of the number of total citation per document and external citation per document (i.e. journal self-citations removed) received by a journal's published documents during the three previous years. External citations are calculated by subtracting the number of self-citations from the total number of citations received by the journal’s documents.

International Collaboration accounts for the articles that have been produced by researchers from several countries. The chart shows the ratio of a journal's documents signed by researchers from more than one country; that is including more than one country address.

Not every article in a journal is considered primary research and therefore "citable", this chart shows the ratio of a journal's articles including substantial research (research articles, conference papers and reviews) in three year windows vs. those documents other than research articles, reviews and conference papers.

Ratio of a journal's items, grouped in three years windows, that have been cited at least once vs. those not cited during the following year.

Evolution of the percentage of female authors.

Evolution of the number of documents cited by public policy documents according to Overton database.

Evoution of the number of documents related to Sustainable Development Goals defined by United Nations. Available from 2018 onwards.

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Depression Research and Treatment - Impact Score, Ranking, SJR, h-index, Citescore, Rating, Publisher, ISSN, and Other Important Details

Published By: Hindawi Limited

Abbreviation: Depress. Res. Treat.

Impact Score The impact Score or journal impact score (JIS) is equivalent to Impact Factor. The impact factor (IF) or journal impact factor (JIF) of an academic journal is a scientometric index calculated by Clarivate that reflects the yearly mean number of citations of articles published in the last two years in a given journal, as indexed by Clarivate's Web of Science. On the other hand, Impact Score is based on Scopus data.

Important details.

About Depression Research and Treatment

Depression Research and Treatment is a journal published by Hindawi Limited . This journal covers the area[s] related to Clinical Psychology, Psychiatry and Mental Health, etc . The coverage history of this journal is as follows: 2010-2022. The rank of this journal is 3401 . This journal's impact score, h-index, and SJR are 5.00, 33, and 1.134, respectively. The ISSN of this journal is/are as follows: 20901321, 2090133X . The best quartile of Depression Research and Treatment is Q1 . This journal has received a total of 201 citations during the last three years (Preceding 2022).

Depression Research and Treatment Impact Score 2022-2023

The impact score (IS), also denoted as the Journal impact score (JIS), of an academic journal is a measure of the yearly average number of citations to recent articles published in that journal. It is based on Scopus data.

Prediction of Depression Research and Treatment Impact Score 2023

Impact Score 2022 of Depression Research and Treatment is 5.00 . If a similar upward trend continues, IS may increase in 2023 as well.

Impact Score Graph

Check below the impact score trends of depression research and treatment. this is based on scopus data..

Depression Research and Treatment h-index

The h-index of Depression Research and Treatment is 33 . By definition of the h-index, this journal has at least 33 published articles with more than 33 citations.

What is h-index?

The h-index (also known as the Hirsch index or Hirsh index) is a scientometric parameter used to evaluate the scientific impact of the publications and journals. It is defined as the maximum value of h such that the given Journal has published at least h papers and each has at least h citations.

Depression Research and Treatment ISSN

The International Standard Serial Number (ISSN) of Depression Research and Treatment is/are as follows: 20901321, 2090133X .

The ISSN is a unique 8-digit identifier for a specific publication like Magazine or Journal. The ISSN is used in the postal system and in the publishing world to identify the articles that are published in journals, magazines, newsletters, etc. This is the number assigned to your article by the publisher, and it is the one you will use to reference your article within the library catalogues.

ISSN code (also called as "ISSN structure" or "ISSN syntax") can be expressed as follows: NNNN-NNNC Here, N is in the set {0,1,2,3...,9}, a digit character, and C is in {0,1,2,3,...,9,X}

Depression Research and Treatment Ranking and SCImago Journal Rank (SJR)

SCImago Journal Rank is an indicator, which measures the scientific influence of journals. It considers the number of citations received by a journal and the importance of the journals from where these citations come.

Depression Research and Treatment Publisher

The publisher of Depression Research and Treatment is Hindawi Limited . The publishing house of this journal is located in the Egypt . Its coverage history is as follows: 2010-2022 .

Call For Papers (CFPs)

Please check the official website of this journal to find out the complete details and Call For Papers (CFPs).

Abbreviation

The International Organization for Standardization 4 (ISO 4) abbreviation of Depression Research and Treatment is Depress. Res. Treat. . ISO 4 is an international standard which defines a uniform and consistent system for the abbreviation of serial publication titles, which are published regularly. The primary use of ISO 4 is to abbreviate or shorten the names of scientific journals using the technique of List of Title Word Abbreviations (LTWA).

As ISO 4 is an international standard, the abbreviation ('Depress. Res. Treat.') can be used for citing, indexing, abstraction, and referencing purposes.

How to publish in Depression Research and Treatment

If your area of research or discipline is related to Clinical Psychology, Psychiatry and Mental Health, etc. , please check the journal's official website to understand the complete publication process.

Acceptance Rate

• Interest/demand of researchers/scientists for publishing in a specific journal/conference.
• The complexity of the peer review process and timeline.
• Time taken from draft submission to final publication.
• Number of submissions received and acceptance slots
• And Many More.

The simplest way to find out the acceptance rate or rejection rate of a Journal/Conference is to check with the journal's/conference's editorial team through emails or through the official website.

Frequently Asked Questions (FAQ)

What is the impact score of depression research and treatment.

The latest impact score of Depression Research and Treatment is 5.00. It is computed in the year 2023.

What is the h-index of Depression Research and Treatment?

The latest h-index of Depression Research and Treatment is 33. It is evaluated in the year 2023.

What is the SCImago Journal Rank (SJR) of Depression Research and Treatment?

The latest SCImago Journal Rank (SJR) of Depression Research and Treatment is 1.134. It is calculated in the year 2023.

What is the ranking of Depression Research and Treatment?

The latest ranking of Depression Research and Treatment is 3401. This ranking is among 27955 Journals, Conferences, and Book Series. It is computed in the year 2023.

Who is the publisher of Depression Research and Treatment?

Depression Research and Treatment is published by Hindawi Limited. The publication country of this journal is Egypt.

What is the abbreviation of Depression Research and Treatment?

This standard abbreviation of Depression Research and Treatment is Depress. Res. Treat..

Is "Depression Research and Treatment" a Journal, Conference or Book Series?

Depression Research and Treatment is a journal published by Hindawi Limited.

What is the scope of Depression Research and Treatment?

• Clinical Psychology
• Psychiatry and Mental Health

For detailed scope of Depression Research and Treatment, check the official website of this journal.

What is the ISSN of Depression Research and Treatment?

The International Standard Serial Number (ISSN) of Depression Research and Treatment is/are as follows: 20901321, 2090133X.

What is the best quartile for Depression Research and Treatment?

The best quartile for Depression Research and Treatment is Q1.

What is the coverage history of Depression Research and Treatment?

The coverage history of Depression Research and Treatment is as follows 2010-2022.

Credits and Sources

• Scimago Journal & Country Rank (SJR), https://www.scimagojr.com/
• Journal Impact Factor, https://clarivate.com/
• Issn.org, https://www.issn.org/
• Scopus, https://www.scopus.com/

Note: The impact score shown here is equivalent to the average number of times documents published in a journal/conference in the past two years have been cited in the current year (i.e., Cites / Doc. (2 years)). It is based on Scopus data and can be a little higher or different compared to the impact factor (IF) produced by Journal Citation Report. Please refer to the Web of Science data source to check the exact journal impact factor ™ (Thomson Reuters) metric.

Impact Score, SJR, h-Index, and Other Important metrics of These Journals, Conferences, and Book Series

Check complete list

Depression Research and Treatment Impact Score (IS) Trend

Top Journals/Conferences in Clinical Psychology

Top journals/conferences in psychiatry and mental health.

Depression Research And Treatment impact factor, indexing, ranking (2024)

Aim and Scope

The Depression Research And Treatment is a research journal that publishes research related to Medicine; Psychology . This journal is published by the Hindawi Limited. The ISSN of this journal is 20901321, 2090133X . Based on the Scopus data, the SCImago Journal Rank (SJR) of depression research and treatment is 1.134 .

Depression Research And Treatment Ranking

The SJR (SCImago Journal Rank) measures citations weighted by prestige. It is useful for comparing journals within the same field, and forms the basis of the subject category ranking. A journal SJR indicator is a numeric value representing the average number of weighted citations received during a selected year per document published in that journal during the previous three years, as indexed by Scopus. Higher SJR indicator values are meant to indicate greater journal prestige. SJR is developed by the Scimago Lab, originated from a research group at University of Granada. Q1 journals are cited more often and by more prestigious journals than those in the other quartiles.

Each subject category of journals is divided into four quartiles: Q1, Q2, Q3, Q4. Q1 is occupied by the top 25% of journals in the list; Q2 is occupied by journals in the 25 to 50% group; Q3 is occupied by journals in the 50 to 75% group and Q4 is occupied by journals in the 75 to 100% group.

CiteScore of an academic journal is a measure reflecting the yearly average number of citations to recent articles published in that journal. This journal evaluation metric was launched in December 2016 by Elsevier as an alternative to the generally used JCR impact factors (calculated by Clarivate). CiteScore is based on the citations recorded in the Scopus database rather than in JCR, and those citations are collected for articles published in the preceding four years instead of two or five.

Source Normalized Impact per Paper (SNIP) is calculated annually from Scopus data. It is a sophisticated metric that intrinsically accounts for field-specific differences in citation practices.

Important Metrics

depression research and treatment Indexing

The depression research and treatment is indexed in:

An indexed journal means that the journal has gone through and passed a review process of certain requirements done by a journal indexer.

The Web of Science Core Collection includes the Science Citation Index Expanded (SCIE), Social Sciences Citation Index (SSCI), Arts & Humanities Citation Index (AHCI), and Emerging Sources Citation Index (ESCI).

Depression Research And Treatment Quartile

The latest Quartile of depression research and treatment is Q1 .

Publication fee

According to journal website, the publication fee of depression research and treatment is around 800 USD .

The depression research and treatment has also Journal waiver policy (for developing countries, authors etc).

An article processing charge (APC), also known as a publication fee, is a fee which is sometimes charged to authors. Most commonly, it is involved in making a work available as open access (OA), in either a full OA journal or in a hybrid journal.

Journal Publication Time

The Journal Publication Time means the average number of weeks between article submission and publication. According to the journal website, the depression research and treatment publishes research articles in 10 weeks on an average.

Call for Papers

Visit to the official website of the journal/ conference to check the details about call for papers.

How to publish in Depression Research And Treatment?

If your research is related to Medicine; Psychology, then visit the official website of depression research and treatment and send your manuscript.

Tips for publishing in Depression Research And Treatment:

• Selection of research problem.
• Presenting a solution.
• Designing the paper.
• Make your manuscript publication worthy.
• Write an effective results section.
• Mind your references.

Acceptance Rate

Final summary.

• It is published by Hindawi Limited .
• The journal is indexed in UGC CARE, Scopus, DOAJ, PubMed .
• It is an open access journal .
• The (SJR) SCImago Journal Rank is 1.134 .
• The publication time (Average number of weeks between article submission and publication) of the journal is 10 weeks .
• The Publication fee (APC) of depression research and treatment 800 USD .

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2090-1321 (Print)  / 2090-133X (Online)

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Publishing with this journal

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→ This journal checks for plagiarism .

Expect on average 10 weeks from submission to publication.

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This journal began publishing in open access in 2010 . What does DOAJ define as Open Accesss?

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Attribution

→ Look up their open access statement and their license terms .

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Journal metadata

Publisher Hindawi Limited , United Kingdom Manuscripts accepted in English

LCC subjects Look up the Library of Congress Classification Outline Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry: Neurology. Diseases of the nervous system: Psychiatry Philosophy. Psychology. Religion: Psychology Keywords depressive disorders depression

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Topics covered on depression research and treatment, depression research and treatment journal specifications.

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Recently Published Papers in Depression Research and Treatment

• 15 Apr 2024
• Depression research and treatment
• 21 Mar 2024
• 12 Jan 2024
• 12 Oct 2023
• 12 Aug 2023

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Check if your research matches the topics covered in Depression Research and Treatment?

Depression research and treatment scite analysis.

289 articles received 5.8K citations see all

• 451 Supporting
• 5,044 Mentioning
• 93 Contrasting

Depression Research and Treatment Editorial notices

• 0 Retractions
• 0 Withdrawals
• 1 Corrections
• 1 Expression of Concern

FAQs on Depression Research and Treatment

How many articles did depression research and treatment publish last year.

In 2023, Depression Research and Treatment publsihed 10 articles.

What is the eISSN & pISSN for Depression Research and Treatment?

For Depression Research and Treatment, eISSN is 2090-133X and pISSN is 2090-1321.

What is Citescore for Depression Research and Treatment?

Citescore for Depression Research and Treatment is 4.8.

What is the H Index for Depression Research and Treatment ?

H Index for Depression Research and Treatment is 33.

What is SNIP score for Depression Research and Treatment?

SNIP score for Depression Research and Treatment is 1.23.

What is the SJR for Depression Research and Treatment?

SJR for Depression Research and Treatment is Q1.

Who is the publisher of Depression Research and Treatment?

Hindawi is the publisher of Depression Research and Treatment.

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©  BMJ Publishing Group Ltd. 2023

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Editor-in-Chief: Professor Andrea Cipriani, University of Oxford 

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Depression Research and Treatment Impact Factor & Key Scientometrics

Depression research and treatment overview, impact factor, i. basic journal info, journal issn: 20901321, 2090133x, publisher: hindawi limited, history: 2010-2021, journal hompage: link, how to get published:, research categories, scope/description:, ii. science citation report (scr), depression research and treatment scr impact factor, depression research and treatment scr journal ranking, depression research and treatment scimago sjr rank, depression research and treatment scopus 2-year impact factor trend, depression research and treatment scopus 3-year impact factor trend, depression research and treatment scopus 4-year impact factor trend, depression research and treatment impact factor history, iii. other science influence indicators, depression research and treatment h-index, depression research and treatment h-index history.

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• Published: 18 June 2020

Advances in depression research: second special issue, 2020, with highlights on biological mechanisms, clinical features, co-morbidity, genetics, imaging, and treatment

• Julio Licinio 1 &
• Ma-Li Wong 1  

Molecular Psychiatry volume  25 ,  pages 1356–1360 ( 2020 ) Cite this article

10k Accesses

11 Citations

4 Altmetric

Metrics details

The current speed of progress in depression research is simply remarkable. We have therefore been able to create a second special issue of Molecular Psychiatry , 2020, focused on depression, with highlights on mechanisms, genetics, clinical features, co-morbidity, imaging, and treatment. We are also very proud to present in this issue a seminal paper by Chottekalapanda et al., which represents some of the last work conducted by the late Nobel Laureate Paul Greengard [ 1 ]. This brings to four the number of papers co-authored by Paul Greengard and published in our two 2020 depression special issues [ 1 , 2 , 3 , 4 ].

The research content of this special depression issue starts with Chottekalapanda et al.’s outstanding contribution aimed at determining whether neuroadaptive processes induced by antidepressants are modulated by the regulation of specific gene expression programs [ 1 ]. That team identified a transcriptional program regulated by activator protein-1 (AP-1) complex, formed by c-Fos and c-Jun that is selectively activated prior to the onset of the chronic SSRI response. The AP-1 transcriptional program modulated the expression of key neuronal remodeling genes, including S100a10 (p11), linking neuronal plasticity to the antidepressant response. Moreover, they found that AP-1 function is required for the antidepressant effect in vivo. Furthermore, they demonstrated how neurochemical pathways of BDNF and FGF2, through the MAPK, PI3K, and JNK cascades, regulate AP-1 function to mediate the beneficial effects of the antidepressant response. This newly identified molecular network provides “a new avenue that could be used to accelerate or potentiate antidepressant responses by triggering neuroplasticity.”

A superb paper by Schouten et al. showed that oscillations of glucocorticoid hormones (GC) preserve a population of adult hippocampal neural stem cells in the aging brain [ 5 ]. Moreover, major depressive disorder (MDD) is characterized by alterations in GC-related rhythms [ 6 , 7 ]. GC regulate neural stem/precursor cells (NSPC) proliferation [ 8 , 9 ]. The adrenals secrete GC in ultradian pulses that result in a circadian rhythm. GC oscillations control cell cycle progression and induce specific genome-wide DNA methylation profiles. Schouten et al. studied primary hippocampal NSPC cultures and showed that GC oscillations induced lasting changes in the methylation state of a group of gene promoters associated with cell cycle regulation and the canonical Wnt signaling pathway. Furthermore, in a mouse model of accelerated aging, they showed that disruption of GC oscillations induced lasting changes in dendritic complexity, spine numbers and morphology of newborn granule neurons. Their results indicate that GC oscillations preserve a population of GR-expressing NSPC during aging, preventing their activation possibly by epigenetic programming through methylation of specific gene promoters. These important observations suggest a novel mechanism mediated by GC that controls NSPC proliferation and preserves a dormant NSPC pool, possibly contributing to neuroplasticity reserve in the aging brain.

MDD has a critical interface with addiction and suicide, which is of immense clinical and research importance [ 10 ]. Peciña et al. have reviewed a growing body of research indicating that the endogenous opioid system is directly involved in the regulation of mood and is dysregulated in MDD [ 11 ]. Halikere et al. provide evidence that addiction associated N40D mu-opioid receptor variant modulates synaptic function in human neurons [ 12 ].

Two papers by Amare et al. and Coleman et al. examine different genetic substrates for MDD, identifying novel depression-related loci as well as studying the interface with trauma [ 13 , 14 ].

The dissection of MDD clinical phenotypes, including their interface with other illnesses is a topic of several articles in this special issue. Belvederi Murri et al. examined the symptom network structure of depressive symptoms in late-life in a large European population in the 19 country Survey of Health, Ageing, and Retirement in Europe (SHARE) (mean age 74 years, 59% females, n  = 8557) [ 15 ]. They showed that the highest values of centrality were in the symptoms of death wishes, depressed mood, loss of interest, and pessimism. Another article focused on a specific feature of MDD, namely changes in appetite. Simmons et al. aimed at explaining why some individuals lose their appetite when they become depressed, while others eat more, and brought together data on neuroimaging, salivary cortisol, and blood markers of inflammation and metabolism [ 16 ]. Depressed participants experiencing decreased appetite had higher cortisol levels than other subjects, and their cortisol values correlated inversely with the ventral striatal response to food cues. In contrast, depressed participants experiencing increased appetite exhibited marked immunometabolic dysregulation, with higher insulin, insulin resistance, leptin, c-reactive protein (CRP), interleukin 1 receptor antagonist (IL-1RA), and IL-6, and lower ghrelin than subjects in other groups, and the magnitude of their insulin resistance correlated positively with the insula response to food cues. Their findings support the existence of pathophysiologically distinct depression subtypes for which the direction of appetite change may be an easily measured behavioral marker.

Mulugeta et al. studied the association between major depressive disorder and multiple disease outcomes in the UK Biobank ( n  = 337,536) [ 17 ]. They performed hypothesis-free phenome-wide association analyses between MDD genetic risk score (GRS) and 925 disease outcomes. MDD was associated with several inflammatory and hemorrhagic gastrointestinal diseases, and intestinal E. coli infections. MDD was also associated with disorders of lipid metabolism and ischemic heart disease. Their results indicated a causal link between MDD and a broad range of diseases, suggesting a notable burden of co-morbidity. The authors concluded that “early detection and management of MDD is important, and treatment strategies should be selected to also minimize the risk of related co-morbidities.” Further information on the shared mechanisms between coronary heart disease and depression in the UK Biobank ( n  = 367,703) was explored by Khandaker et al. [ 18 ]. They showed that family history of heart disease was associated with a 20% increase in depression risk; however, a genetic risk score that is strongly associated with CHD risk was not associated with depression. Their data indicate that comorbidity between depression and CHD arises largely from shared environmental factors.

In a systematic review and meta-analysis of cohort studies, Wang et al. examined the interface of depression and anxiety in relation to cancer incidence and mortality [ 19 ]. Their analyses suggest that depression and anxiety may have an etiologic role and prognostic impact on cancer, although there is potential reverse causality.

Several papers in this issue examine imaging in MDD, either to unravel the underlying disease processes or to identify imaging biomarkers of treatment response. Let us first look at the studies focused on elucidating brain circuitry alterations in MDD. Arterial spin labeling (ASL) was used by Cooper et al. to measure cerebral blood flow (CBF; perfusion) in order to discover and replicate alterations in CBF in MDD [ 20 ]. Their analyses revealed reduced relative CBF (rCBF) in the right parahippocampus, thalamus, fusiform, and middle temporal gyri, as well as the left and right insula, for those with MDD. They also revealed increased rCBF in MDD in both the left and the right inferior parietal lobule, including the supramarginal and angular gyri. According to the authors, “these results (1) provide reliable evidence for ASL in detecting differences in perfusion for multiple brain regions thought to be important in MDD, and (2) highlight the potential role of using perfusion as a biosignature of MDD.” Further data on imaging in MDD was provided by a coordinated analysis across 20 international cohorts in the ENIGMA MDD working group. In that paper, van Velzen et al. showed that in a coordinated and harmonized multisite diffusion tensor imaging study there were subtle, but widespread differences in white matter microstructure in adult MDD, which may suggest structural disconnectivity [ 21 ].

Four articles in this special issue examine imaging biomarkers of treatment response. Greenberg et al. studied reward-related ventral striatal activity and differential response to sertraline versus placebo in depressed using functional magnetic resonance imaging while performing a reward task [ 22 ]. They found that ventral striatum (VS) dynamic response to reward expectancy (expected outcome value) and prediction error (difference between expected and actual outcome), likely reflecting serotonergic and dopaminergic deficits, was associated with better response to sertraline than placebo. Their conclusion was that treatment measures of reward-related VS activity may serve as objective neural markers to advance efforts to personalize interventions by guiding individual-level choice of antidepressant treatment. Utilizing whole-brain functional connectivity analysis to identify neural signatures of remission following antidepressant treatment, and to identify connectomic predictors of treatment response, Korgaonkar et al. showed that intrinsic connectomes are a predictive biomarker of remission in major depressive disorder [ 23 ]. Based on their results that team proposed that increased functional connectivity within and between large-scale intrinsic brain networks may characterize acute recovery with antidepressants in depression. Repple et al. created connectome matrices via a combination of T1-weighted magnetic resonance imaging (MRI) and tractography methods based on diffusion-weighted imaging severity of current depression and remission status in 464 MDD patients and 432 healthy controls [ 24 ]. Reduced global fractional anisotropy (FA) was observed specifically in acute depressed patients compared to fully remitted patients and healthy controls. Within the MDD patients, FA in a subnetwork including frontal, temporal, insular, and parietal nodes was negatively associated with symptom intensity, an effect remaining when correcting for lifetime disease severity. Their findings provide new evidence of MDD to be associated with structural, yet dynamic, state-dependent connectome alterations, which covary with current disease severity and remission status after a depressive episode. The effects of electroconvulsive therapy (ECT), the most effective treatment for depression, on the dentate gyrus (DG) were studied by Nuninga et al. through an optimized MRI scan at 7-tesla field strength, allowing sensitive investigation of hippocampal subfields [ 25 , 26 ]. They documented a large and significant increase in DG volume after ECT, while other hippocampal subfields were unaffected. Furthermore, an increase in DG volume was related to a decrease in depression scores, and baseline DG volume predicted clinical response. These findings suggest that the volume change of the DG is related to the antidepressant properties of ECT, possibly reflecting neurogenesis.

Three articles report new directions for antidepressant therapeutics. Papakostas et al. presented the results of a promising phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a novel neurogenic compound, in MDD patients [ 27 ]. As the endogenous opioid system is thought to play an important role in the regulation of mood, Fava et al. studied the buprenorphine/samidorphan combination as an investigational opioid system modulator for adjunctive treatment of MDD in two phase 3, randomized, double-blind, placebo-controlled studies that utilized the same sequential parallel-comparison design [ 28 ]. One of the studies achieved the primary endpoint, namely change from baseline in Montgomery–Åsberg Depression Rating Scale (MADRS)-10 at week 5 versus placebo) and the other study did not achieve the primary endpoint. However, the pooled analysis of the two studies demonstrated consistently greater reduction in the MADRS-10 scores from baseline versus placebo at multiple timepoints, including end of treatment. These data provide cautious optimism and support further controlled trials for this potential new treatment option for patients with MDD who have an inadequate response to currently available antidepressants. Fava et al. also report the results of a double-blind, placebo-controlled, dose-ranging trial of intravenous (IV) ketamine as adjunctive therapy in treatment-resistant depression, using four doses of ketamine and a control [ 29 , 30 ]. They show that there was evidence for the efficacy of the two higher doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of the two lower doses studied.

Overall, in this issue, immense progress in depression research is provided by outstanding studies that highlight advances in our understanding of MDD biology, clinical features, co-morbidity, genetics, brain imaging (including imaging biomarkers), and treatment. Building on the groundbreaking articles from our previous 2020 special issues on stress and behavior [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ] and on depression [ 2 , 3 , 4 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ], we are proud that the stunning progress presented here found its home in our pages. From inception in 1996, we have aimed at making Molecular Psychiatry promote the integration of molecular medicine and clinical psychiatry [ 63 ]. It is particularly rewarding to see that goal achieved so spectacularly in this second 2020 special issue on MDD, a disorder of gene-environment interactions that represents a pressing public health challenge, with an ever increasing impact on society [ 64 , 65 , 66 ]. We are privileged to have in these two 2020 depression special issues four remarkable papers from Paul Greengard’s teams that provide substantial new data on the mechanisms of antidepressant action [ 1 , 2 , 3 , 4 ]. Such profound advances in basic science are needed to facilitate and guide future translational efforts needed to advance therapeutics [ 67 , 68 ].

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Licinio, J., Wong, ML. Advances in depression research: second special issue, 2020, with highlights on biological mechanisms, clinical features, co-morbidity, genetics, imaging, and treatment. Mol Psychiatry 25 , 1356–1360 (2020). https://doi.org/10.1038/s41380-020-0798-1

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• Spring 2024 | VOL. 22, NO. 2 Autism Across the Lifespan CURRENT ISSUE pp.147-262
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Prognosis and Improved Outcomes in Major Depression: A Review

• Christoph Kraus ,
• Bashkim Kadriu ,
• Rupert Lanzenberger ,
• Carlos A. Zarate Jr. , and
• Siegfried Kasper

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Treatment outcomes for major depressive disorder (MDD) need to be improved. Presently, no clinically relevant tools have been established for stratifying subgroups or predicting outcomes. This literature review sought to investigate factors closely linked to outcome and summarize existing and novel strategies for improvement. The results show that early recognition and treatment are crucial, as duration of untreated depression correlates with worse outcomes. Early improvement is associated with response and remission, while comorbidities prolong course of illness. 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 (TNFα)). However, their integration into routine clinical care has not yet been fully elucidated, and more research is needed in this regard. Genetic findings suggest that testing for CYP450 isoenzyme activity may improve treatment outcomes. Strategies such as managing risk factors, improving clinical trial methodology, and designing structured step-by-step treatments are also beneficial. Finally, drawing on existing guidelines, we outline a sequential treatment optimization paradigm for selecting first-, second-, and third-line treatments for acute and chronically ill patients. Well-established treatments such as electroconvulsive therapy (ECT) are clinically relevant for treatment-resistant populations, and novel transcranial stimulation methods such as theta-burst stimulation (TBS) and magnetic seizure therapy (MST) have shown promising results. Novel rapid-acting antidepressants, such as ketamine, may also constitute a paradigm shift in treatment optimization for MDD.

(Reprinted from Transl Psychiatry . 2019 Apr 3; 9(1):127. Open access; is licensed under a Creative Commons Attribution 4.0 International License)

Depression: a major and relentless burden

Major depressive disorder (MDD) is the most common psychiatric disease and a worldwide leading cause of years lived with disability ( 1 , 2 ). In addition, the bulk of suicides are linked to a diagnosis of MDD. Despite the high prevalence rate of MDD and ongoing efforts to increase knowledge and skills for healthcare providers, the illness remains both underdiagnosed and undertreated ( 3 ). Many novel strategies with potentially broad impact are not yet ready for ‘prime time’, as they are either in early experimental stages or undergoing regulatory processes for approval. This review sought to: (1) provide a synopsis of key factors associated with outcomes in MDD, and (2) synthesize the existing literature on novel treatment strategies for depression. A literature search was conducted using the search terms ‘depression’, ‘antidepressant’, ‘outcome’, ‘predictor’, ‘(bio)marker’, ‘treatment-resistant depression (TRD)’, and ‘chronic depression’ in addition to combinations of these terms. The search was conducted in PubMed, Scopus, and Google Scholar with no restrictions on time period and concluded in October 2018. Notably, we defined ‘outcomes’ loosely, as either disease course (i.e., treatment resistance, chronic depression) or response/remission to treatment.

Prognostic variables for treatment outcomes in MDD

Clinical variables.

Clear evidence of an inverse relationship between duration of episode and treatment outcome (either response or remission) underscores the importance of early intervention in MDD ( 4 ) ( Table 1 ). In particular, replicable prospective and retrospective studies indicate that shorter duration of untreated disease—both in terms of first and recurrent episodes—is a prognostic factor indicating better treatment response and better long-term outcomes ( 5 – 10 ), although not all studies have found such an association ( 11 ). Another important clinical variable is time to antidepressant response. For instance, one meta-analysis found that early improvement was positively linked to antidepressant treatment outcome in 15 of 16 studies ( 9 ). Early response to antidepressant treatment appears to occur independently of treatment modality ( 12 , 13 ) or outcome parameters ( 14 , 15 ). Another study found that early improvement in work productivity was a significant positive predictor of higher remission rates after three and seven months of treatment ( 16 ). Similarly, imaging studies found that early response to treatment correlated with default mode network deactivation in the posterior cingulate ( 17 ), as well as thickening of gray matter in the anterior cingulate cortex (ACC) ( 18 ). Interestingly, two recent meta-analyses found that initial improvement was linked to response and outcome but failed to be associated with treatment resistance ( 19 , 20 ). This suggests that TRD—defined loosely here as non-response to at least two adequate antidepressant trials—and chronic depression (roughly defined here as non-response to any treatment) may have similar response slopes in the earliest treatment stages.

TABLE 1. Candidate markers associated with treatment outcomes

BDNF brain-derived neurotrophic factor, CRP c-reactive protein, EEG electroencephalography, IL-6 interleukin-6, OCD obsessive-compulsive disorder, PET positron emission tomography, PTSD post-traumatic stress disorder, rsfMRI resting-state functional MRI, SLC6A4 solute carrier family 6 member 4, sMRI structural MRI, TNFα tumor necrosis factor alpha, TSPO translocator protein, 5-HT1A serotonin-1A receptor, MAO-A monoamine oxidase A, SERT serotonin transporter

a Representative examples with meta-analytic evidence

TABLE 1. Candidate markers associated with treatment outcomes

In addition, lower baseline function and quality of life—including longer duration of the current index episode—have been associated with lower remission rates to various types of antidepressant treatments ( 21 , 22 ). This is in line with results from a previous study that found that baseline function predicted antidepressant response in TRD patients ( 23 ). Worse outcomes in more severely ill patients at baseline were also reported in elderly patients treated in primary-care settings ( 24 ). In contrast, several controlled clinical studies found that elevated baseline severity correlated with improved response and remission rates ( 25 ). Two naturalistic studies with broad inclusion criteria similarly found that remission correlated with higher baseline scores ( 4 , 26 ). However, this discrepancy might be explained by variations in outcome according to parameter. 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 patients ( 4 ).

Psychosocial Variables

The influence of sociodemographic factors such as age, age of onset, gender, and number of previous episodes on treatment outcome has been investigated with mixed results ( 4 , 27 , 28 ). One study found that females had higher remission rates ( 21 ), but this was not confirmed by another prospective study ( 27 ). Others have found that stress related to high occupational levels might impair outcomes ( 29 ). The European “Group for the Study of Resistant Depression” (GSRD) multi-site study found that age at first treatment (i.e., early-onset and early treatment), age, timespan between first and last episode (i.e., duration of illness), suicidality, and education level were all important variables for outcome ( 30 ). Notably, authors of long-lasting longitudinal studies have suggested that recall bias may influence the age of onset variable ( 31 , 32 ); given the cognitive deficits associated with acute episodes of MDD, retrospective studies must hence address the factor of memory bias in data collection.

Environmental Stress and Stressful Life Events (SLEs)

High stress levels significantly influence outcomes in MDD patients who are prone to vulnerable states, such as those with high levels of neuroticism ( 33 , 34 ). A meta-analysis found that history of childhood maltreatment was associated with elevated risk of developing recurrent and persistent depressive episodes, as well as with lack of response or remission during treatment ( 35 ). Another meta-analysis confirmed the detrimental impact of childhood maltreatment (emotional physical or sexual maltreatment or neglect) as a predisposing risk factor for severe, early-onset, and treatment-resistant depression ( 36 , 37 ). Studies also found gender-specific effects; in particular, at lower stress levels females were at higher risk of MDD than males ( 34 ). Moreover, twin studies have suggested a differential reactivity of gender in response to type of SLE ( 38 ). 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. Subjects with more SLEs exhibited greater cognitive symptoms at baseline but not significantly more mood or neurovegetative symptoms. These patients also had greater cognitive symptom reduction in response to escitalopram but not nortriptyline ( 39 ). This suggests that SLEs may have a cognitive domain-specific impact in MDD, but more data are needed to elucidate this issue.

Psychiatric and Physical Comorbidities

Psychiatric comorbidity has been shown to influence outcome in both treated and untreated patients ( 40 , 41 ). 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 strategies ( 42 , 43 ). Worse outcomes have also been reported for MDD patients with comorbid drug or alcohol use disorders, post-traumatic stress disorder (PTSD), and “double depression” (depression and dysthymia) ( 26 , 41 ). Data from the Sequential Treatment Alternatives to Relieve Depression (STAR*D) study, which included patients who were seeking medical care in routine medical or psychiatric outpatient treatment, indicate that roughly one-third (34.8%) of all MDD patients are free of any comorbidity; the most frequent comorbid Axis-I disorders are social phobia (31.3%), generalized anxiety disorder (23.6%), PTSD (20.6%), and obsessive-compulsive disorder (14.3%) ( 21 ). A large recent study found that clinically diagnosed personality disorder was associated with negative outcomes (with regard to remission and persistent depressive symptoms) six months after diagnosis in MDD subjects enrolled in primary care ( 44 ). Moreover, meta-analytic studies indicate that comorbid personality disorder increases the likelihood of poorer outcomes ( 45 , 46 ); it should be noted, though, that negative studies have also been reported ( 40 ).

MDD and several physical diseases—including cardiovascular disease and diabetes—appear to have bidirectional effects on disease trajectory ( 47 , 48 ), yet pathophysiologic links are most likely complex and have to be elucidated. In addition, depression appears to be linked to hormonal diseases, including hypothyroidism ( 49 ). A number of physical disabilities and medical comorbidities have been shown to significantly impact outcome measures in MDD ( 50 ), particularly in elderly subjects ( 51 ). This connection appears to be relevant at any stage of the disease, as number of physical comorbidities did not separate TRD from non-TRD patients ( 52 ). Links between MDD and pain have also been noted; subjects with elevated levels of baseline pain due to chronic conditions had longer depressive episodes, delayed remission ( 53 ) and, most importantly, elevated suicide risk ( 54 , 55 ). Interestingly, a prospective, 12-month study of older patients found that elderly patients with atrial fibrillation exhibited better remission rates ( 56 ). Patients with chronic pulmonary diseases had worse outcomes in uncontrolled treatment settings than those without these diseases. This difference was absent in the intervention group, in which depression care managers helped physicians with guideline-concordant recommendations and helped patients adhere to treatment ( 56 ). Further longitudinal studies on shared pathophysiology with physical diseases are needed to confirm such associations.

Neuroimaging Markers of Treatment Outcomes

Structural markers of antidepressant treatment outcomes suggest that hippocampal volumes are related to response and remission ( 57 , 58 ). One study found that low baseline hippocampal volumes were related to impaired treatment outcomes after 3 years ( 59 ); a meta-analysis confirmed that low baseline hippocampal volumes are associated with negative outcomes ( 60 ). However, negative studies have also been reported ( 61 , 62 ). The volume of other brain regions, including the anterior cingulate or orbito-frontal cortices, have also been shown to be decreased in MDD subjects ( 63 ), but more longitudinal neuroimaging trials with antidepressants are needed to clarify this association. Interestingly, several studies, including one meta-analysis ( 64 ), found significant hippocampal volume increases after ECT ( 65 – 67 ), although the relationship to antidepressant response has yet to be confirmed ( 64 , 68 ).

The largest functional magnetic resonance imaging (fMRI) study of MDD patients conducted to date reported neurophysiological subtypes based on connectivity patterns within limbic and frontostriatal brain areas ( 69 ). In subset analyses, connectivity patterns plus subtype classifications predicted response to repetitive transcranial magnetic stimulation (rTMS) treatment with higher accuracy (89.6%) than clinical characteristics alone. Other task-based and resting-state fMRI studies found that ACC activity (including pregenual activity) predicted treatment response ( 70 ), a finding corroborated by an expanded electroencephalography study ( 71 ) as well as a meta-analysis ( 60 ). While these interesting results suggest that fMRI measures could ultimately help classify biological subtypes of depression, these methods are far from ready for clinical application and results will have to be reproduced. However, given its easy implementation and the short time needed to acquire measurements, fMRI appears to be a promising tool for identifying imaging biomarkers.

Positron emission tomography (PET) studies have identified altered serotonin-1A (5-HT 1A ) receptor and 5-HT transporter (SERT) binding potentials, an index of protein concentration, at baseline and in TRD patients ( 72 – 75 ). Most of these results found reduced baseline SERT levels and elevated baseline 5-HT 1A heteroreceptors in MDD patients (depending on PET methodology for 5-HT 1A ); non-remitters had lower 5-HT 1A autoreceptor binding in the serotonergic raphe nuclei ( 75 ), as well as lower SERT ( 76 ). Reduced global 5-HT 1A receptor binding has also been observed after ECT ( 77 ). High costs, technical and methodological challenges, lack of dedicated PET centers with 11 C-radiochemistry, small sample sizes, small effect sizes, and unclear cutoff values have heretofore prevented the broader clinical application of these tools in MDD compared to disorders such as Alzheimer’s and Parkinson’s disease. An earlier [ 18 F]FDG PET study of unmedicated MDD patients was consistent with the aforementioned fMRI results, demonstrating increased glucose turnover in the orbito-frontal and posterior cingulate cortices and amygdala and decreased turnover in the subgenual ACC and dorsolateral prefrontal cortex ( 78 ). A later study corroborated these results and found that glucose turnover was differentially affected by cognitive behavioral therapy or venlafaxine ( 79 ). Interestingly, several studies detected microglial activation by labeling translocator protein (TSPO) with PET, using TSPO radioligands like 18 F-FEPPA. Microglial activation is closely linked to brain tissue damage, traumatic brain injury, neuroinflammation, and increased metabolic demands. Increased TSPO binding in MDD patients has been observed in the ACC, insula, and prefrontal cortex ( 80 ). In addition, TSPO binding has also been shown to positively correlate with length of illness and time without anti-depressant treatment, and to negatively correlate with SSRI treatment ( 80 ). Elevated TSPO levels in unmedicated, acutely ill MDD patients have now been reported in at least two independent datasets ( 81 , 82 ). However, TSPO-positive MDD patients may reflect a specific subtype (i.e., associated with neuroinflammation) and may, thus, respond better to treatments that target neuroinflammation. For a graphical summary of these findings see Fig. 1 .

FIGURE 1. Summary of imaging findings and their relationship with outcome

Imaging findings exhibiting unidirectional (left) relationships with outcome in MDD vs. bidirectional (right). fMRI, functional magnetic resonance imaging; PET, positron emission tomography; EEG electroencephalography; 5-HT1A, serotonin-1A receptor; SERT, serotonin transporter; MAO-A monoamine oxidase-A; BP ND , nondisplaceable binding potential; V T , volume of distribution. A color version of the figure, as originally published, appears in the online version of this article ( focus.psychiatryonline.org ).

Blood-Based Markers of Disease Outcomes

Consistent with neuroinflammatory processes, elevated levels of C-reactive protein (CRP), tumor necrosis factor alpha (TNFα), and interleukin-6 (IL-6) have been reported in a subset of MDD patients. In particular, elevated levels of CRP, a well-established marker of increased proinflammatory state in blood, was shown to be associated with MDD and increased risk for psychological distress in cross-sectional samples of the general population ( 83 ). A longitudinal study found that lower CRP levels were associated with quicker response to SSRIs, an association not observed for SSRI-bupropion combination therapy ( 84 ). Interestingly, elevated CRP levels have been shown to be more pronounced in female versus male MDD patients ( 85 ). Similar findings have been observed for IL-6 and TNFα. One meta-analysis found that all three were significantly elevated at baseline in MDD patients, but their treatment trajectories differed ( 86 ); IL-6 levels decreased with antidepressant treatment, but outcomes were indistinguishable. In the same meta-analysis, persistingly high TNFα levels identified TRD patients ( 86 ). Notably, heterogeneity was high within the pooled studies. Another study noted that levels of acute phase protein complement C3 significantly differentiated between atypical and melancholic MDD subtypes ( 87 ). MDD patients have also been shown to have altered levels of peripheral adipokines and bone inflammatory markers; these deficits were corrected with ketamine treatment ( 88 , 89 ).

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. BDNF blood levels most likely stem from peripheral tissue. While these peripheral levels are linked to central levels, the question of whether BDNF is actively transported through the blood–brain barrier remains controversial ( 90 ). Compelling evidence suggests that BDNF levels are decreased at baseline in MDD patients and elevated in response to pharmacological ( 90 , 91 ) treatments as well as ECT ( 92 ). A meta-analysis found that increased BDNF levels in response to treatment successfully stratified responders and remitters compared to non-responders ( 93 ).

Outcome and Genetic and Epigenetic Links

Heritable risk for MDD is between 30 and 40%, with higher rates in women. A large, collaborative genome-wide association study (GWAS) detected 44 significant loci associated with MDD ( 94 ). 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. The authors suggested that alternative splicing could lead to shifts in the proportion of isoforms and altered biological functions of these proteins ( 94 ).

Hypothesis-driven approaches with candidate genes have provided initial insights into the influence of single-nucleotide polymorphisms (SNPs). It is beyond the scope of this manuscript to review the large number of candidate genes; here, we outline only several representative genes (see Table 1 for meta-analytic evidence of treatment outcomes). These include synaptic proteins involved in stress response, antidepressant binding structures, or neuroplasticity (e.g., CRH receptor 1 ( CRHR1 )), the sodium-dependent serotonin transporter ( SLC6A4 ), and BDNF ( 95 ). The aforementioned multicenter GSRD study also found that combining clinical and genetic variables explained antidepressant response better than SNPs alone in a random forest algorithm ( 96 ). In that study, regulatory proteins such as ZNF804A (associated with response) and CREB1 (associated with remission), as well as a cell adhesion molecule (CHL1, associated with lower risk of TRD), were linked to antidepressant treatment outcomes. Another interesting candidate gene is FK506 binding protein 5 ( FKBP5 ), which was found to moderate the influence of standard treatments in an algorithm lasting up to 14 weeks ( 97 ); FKBP5 is known to influence HPA axis reactivity ( 98 ), treatment response ( 99 ), and epigenetic mechanisms in response to environmental stressors ( 100 ). Another relevant avenue of research is drug-drug interactions and gene isoforms in the cytochrome P450 pathway (CYP450), which could account for insufficient amounts of a given drug reaching the brain or, conversely, result in exceedingly high plasma values, making subjects more vulnerable to treatment side effects ( 101 , 102 ). Several commercially available kits categorize patients according to their phenotypic status (e.g., CYP2D6, 2C19, CYP3A4). This led to the introduction of phenotype categories—“poor”, “intermediate”, “extensive (normal)”, and “ultrarapid” metabolizers—based on CYP450 isoenzyme status and their relationship to plasma levels at fixed doses ( 102 ). A large naturalistic study of CYP2C19 isoforms found that treatment success with escitalopram was less frequent in “poor” (CYP2C19Null/Null) and “ultrarapid” metabolizers (CYP2C19*1/*17 or CYP2C19*17/*17) ( 103 ).

Clinical Subgroups, TRD, and Treatment Outcomes

While some studies have suggested that depressive subtypes in MDD—including anxious, mixed, melancholic, atypical, and psychotic depression—respond differently to antidepressant treatment, this literature is mixed. For instance, some studies found that melancholic patients initially present with high levels of severity and may respond less well to SSRI treatment than to venlafaxine or tricyclic antidepressants ( 104 ), but other studies did not support this finding ( 105 ). No association was found between subgroups and clinical outcomes in a parallel design, uncontrolled study investigating sertraline, citalopram, and venlafaxine ( 106 ), which found that near equal percentages of patients who met criteria for a pure-form subtype (39%) also had more than one subtype (36%), making these psychopathological subtypes difficult to classify.

It should be noted that treatment success might have more discriminatory power for identifying subgroups than psychopathological subgroup stratification. Although a wide range of definitions exists specifying the number of failed trials necessary to diagnose TRD ( 107 ), the core definition of TRD centers around a lack of improvement in response to consecutive, adequate antidepressant treatments. Resistance occurs at alarmingly high rates and is thought to affect 50–60% of all treated patients ( 107 ). Unsurprisingly, this group of patients has dramatically worse outcomes than those who respond to antidepressants, and factors that are associated with TRD overlap with many of those presented above ( 28 ). Cross-sectional data from the GSRD ( 108 ) 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 treatment ( 28 ). 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 population ( 109 ). Taken together, the evidence indicates that TRD patients need special attention, as outcomes in these individuals are significantly worse.

Novel and existing strategies to improve treatment outcomes

Early identification, prevention, and early treatment.

Numerous programs for suicide prevention exist ( 110 ), and recognizing acute depressive symptoms is just one of many important facets of such work. Screening tools for early identification of depressed patients can be helpful ( 111 ), and such instruments can start with as few as two items—for instance, the Patient Health Questionnaire-2 ( 112 ) or Ask Suicide-Screening Questions (asQ’em) ( 113 )—and proceed to more detailed instruments if initial screens are positive. Positive screening should be followed by a diagnostic interview to determine whether patients meet criteria for MDD ( 111 ). In the general population, two large independent studies that used only clinical variables were nevertheless able to accurately predict depression within 1–3 years ( 114 ). In addition, long-term monitoring of vulnerable subjects with known SLEs may further improve the ability to identify at-risk individuals early in their course of illness. As noted above, duration of untreated disease is a negative predictor of treatment outcomes. Because the advantages of early intervention in MDD have been demonstrated ( 115 ), efforts to achieve early treatment might also help slow disease progression in individuals with TRD; however, this hypothesis has not been sufficiently tested.

Modeling Environmental Impact on Predisposition

As noted above, severe SLEs constitute an important risk factor. Elegantly designed studies have demonstrated that genetic predisposition, in concert with SLEs, might account for increased vulnerability to MDD ( 100 ). 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 SLEs ( 116 , 117 ). However, studies have been quite inconsistent and yielded small effect sizes, including a negative result in 252 patients enrolled in the GSRD study ( 118 ). It should be noted that counter-regulatory mechanisms or resilience factors, such as social support, may exist that counter SLEs. Nevertheless, preliminary research suggests that the impact of SLEs on MDD may depend on measurable factors such as gender and the timing of exposure ( 119 ). Both genes and the environment are complex systems with frequent opportunity for interaction and elaborate compensatory mechanisms. While the complexity of genetic susceptibility in MDD can be tackled through enormous collaborative projects ( 94 ), the interactions between genetic susceptibility and environmental factors have yet to be determined. Properly powered gene×environment interaction projects may exceed current research capabilities, and large longitudinal studies will certainly be needed ( 120 ).

Developing Markers for Subgroup Identification and Disease Course

Pioneering research on biological differences—for instance, between patients with atypical versus melancholic depression—suggests differential HPA axis or autonomous nervous system reactivity ( 121 , 122 ), though the subtype results have been only moderately consistent across time and are prone to low group specificity ( 123 – 125 ). However, at least one study demonstrated the more reliable stability of extreme types over a 2-year period ( 87 ). 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 controls ( 126 ). Using fMRI and biological variables, another study found that MDD subjects could be divided into low/high appetite groups with distinctive correlations between neuronal activity and endocrine, metabolic, and immune states ( 127 ). Other research groups have tried to overcome conventional psychopathological subgroups and model biotypes using resting-state fMRI ( 69 ). Molecular and functional neuroimaging, as well as epigenetic studies, are promising approaches for separating subgroups and may be better suited to identifying screening markers (see Fig. 2 ) that are exclusively valid in certain subgroups with higher predictive power.

FIGURE 2. Applicability of candidate markers in MDD

Candidate disease markers can be applied in clinically meaningful ways. While only candidate markers are presently available, sorting these according to their potential applications may facilitate the development of clinically applicable disease markers. The outline follows the classification of markers as suggested by others ( 200 ) (modified and reprinted with permission from Springer). A color version of the figure, as originally published, appears in the online version of this article ( focus.psychiatryonline.org ).

These approaches highlight the feasibility of linking and stratifying psychopathological categories with biological variables, a goal further supported by the Research Domain Criteria (RDoc), which seek to link dimensions of observable behavior with neurobiological systems ( 128 ). In the search for biomarkers, subgroup- or domain-specific classifications using unidimensional variables might improve subgroup stratification ( 129 ). Moreover, applying markers to other categories could boost the utility of existing markers that have failed in any given category (see Fig. 2 for established markers). As a field, the focus is largely on staging and prediction markers, but ‘predisposition’ or ‘recurrence’ markers may equally be worth investigating. 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.

The most important outcome of successful subgroup stratification and staging markers would be that patients and their relatives would receive valuable information at treatment onset about how their disease is likely to improve or worsen. Toward this end, the development of staging methods provides promising solutions. Currently, at least five different methods exist ( 130 ) that, to date, have not been evaluated thoroughly enough for clinical implementation. Continuous variables—as obtained by the Maudsley Method and Massachusetts General Hospital Staging Model—appear to provide greater staging advantages than categorical variables. It should be noted here that data indicate that research in severely ill, suicidal, and TRD subjects is safe to conduct in controlled inpatient settings ( 131 ). Presently, patients in various stages of disease and/or treatment history are lumped together and compared in statistical analyses. We propose that staging should be more thoroughly integrated into clinical trial design.

Algorithm- and Guideline-Based Treatments

Despite the availability and distribution of a variety of expert-based guidelines, only a fraction of patients are actually treated according to guidelines ( 132 ) (see Table 2 for current guidelines (≤10 years)). New guidelines – particularly for TRD – and more rigorous implementation of guideline-based care are needed. Improvements in currently available treatments have been conducted using treatment algorithms and following sequential treatment strategies, with standardized instructions for therapeutic decision-making. In the past two decades, large, collaborative studies using treatment-based algorithms have introduced standardized, sequential treatments; these include the Texas Medication Algorithm Project ( 133 ), the STAR*D trial ( 21 ), and the German algorithm project ( 134 ). Indeed, evidence suggests that algorithm-based treatments improve treatment outcomes ( 135 ) and are cost effective ( 136 ). Here, we considered current clinical treatment guidelines to create a sequential treatment optimization scheme of recommended treatments. While there is no fixed time-frame, first- and second-line treatments are recommended sequentially during the first episode and within 3 months (see Fig. 3 , which also illustrates the need for more third- and fourth-stage treatment options). Figure 4 , illustrates potential reasons for “pseudoresistance” ( 42 ) that should be ruled out during this time-frame.

TABLE 2. Currently available guidelines and consensus papers

a As of October 2018

TABLE 2. Currently available guidelines and consensus papers

FIGURE 3. Sequential treatment optimization scheme for major depression

A sequential treatment optimization scheme was generated based on antidepressant treatment guidelines (see Table 2 ). Treatment optimization is possible for patients being treated for the first time but also for patients with insufficient response to first- or second-stage therapies. a Treatment response curves for four common types of patients highlight the importance of sequentially introducing the next step upon non-response to previous steps. b Currently available treatments are listed in neuroscience-based nomenclature (201) with treatment lines corresponding to improvement curves in a. Although current classifications vary, patients classified as having treatment-resistant depression (TRD) are eligible for second- or third-stage therapies. 5-HT1A and similar: serotonin receptor subtypes; DBS: deep brain stimulation; DAT: dopamine transporter; D2: dopamine receptor D2; ECT: electroconvulsive therapy; MAO: monoamine oxidase; NET: noradrenaline transporter; SERT: serotonin transporter; TBS: theta-burst stimulation; rTMS: repetitive transcranial magnetic stimulation; DA: dopamine; NE: norepinephrine. A color version of the figure, as originally published, appears in the online version of this article ( focus.psychiatryonline.org ).

FIGURE 4. Easily overlooked but efficiently modified factors potentially confounding response to antidepressant treatment (pseudoresistance)

Points—in random order—follow earlier suggestions by Dold and Kasper (2017) ( 202 ). A color version of the figure, as originally published, appears in the online version of this article ( focus.psychiatryonline.org ).

Reducing Placebo Response in Clinical Trials While Harnessing Placebo Effects in Clinical Treatment

The issue of placebo response in antidepressant trials has become increasingly important ( 137 , 138 ). Indeed, the contribution of placebo effects to early response needs to be systematically studied in order to disentangle biological therapy-induced effects from psychologically induced effects. Strikingly, in the brain, anatomically similar regions that mediate placebo response are affected by MDD (for a comprehensive review, see ref.) ( 139 ). Several mechanisms contribute to placebo response, including patients’ expectations of benefits, behavioral conditions, and the quality of patient-physician interactions ( 139 ). Strategies for reducing placebo response could lead to better discrimination between effective treatments in clinical trials; such strategies include extending trial duration, excluding placebo responders by including a placebo run-in, or using randomized run-in and withdrawal periods ( 138 , 139 ). Others have suggested using more thorough criteria to select study participants ( 140 ). On the other hand, when antidepressant agents are used clinically, placebo effects must be taken advantage of by harnessing patients’ expectations and learning mechanisms to improve treatment outcomes ( 141 ).

Novel Antidepressant Treatments

The recent discovery that glutamatergic-based drugs are uniquely capable of rapidly and robustly treating mood disorders has ushered in a new era in the quest to develop novel and effective antidepressants ( 142 – 144 ). In this regard, the prototypic glutamatergic modulator ketamine has catalyzed research into new mechanistic approaches and offered hope for the development of novel, fast-acting antidepressants. While ketamine’s underlying mechanism of action remains the subject of active investigation, several theories have been propsed ( 144 ). These include N-methyl- d -aspartate receptor (NMDAR)-dependent mechanisms, such as the inhibition of NMDARs on gamma aminobutyric acid (GABA)-ergic interneurons, the inhibition of spontaneous NMDAR-mediated transmission, the inhibition of extrasynaptic NMDARs, the inhibition of lateral habenula neurons, and GABA B receptor expression/function ( 144 ). 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 activation ( 145 ). Among those theories, a leading hypothesis remains that NMDAR antagonism increases BDNF synthesis, a process mediated by decreased phosphorylation of eukaryotic elongation factor-2 and the subsequent activation of the mammalian target of rapamycin pathway by BDNF activation of the TrkB receptor ( 146 , 147 ). These putative mechanisms of action are not mutually exclusive and may complement each other to induce potentiation of excitatory synapses in affective-regulating brain circuits, resulting in improved depressive symptoms.

The initial serendipitous discovery that a single, subanesthetic-dose ketamine infusion has rapid-acting antidepressant effects in MDD ( 148 ), a finding subsequently confirmed by numerous randomized trials, has been hailed as one of the most important discoveries in psychiatry in the last decades ( 149 ). The initial proof-of-concept studies demonstrated that a single dose of ketamine (0.5 mg/kg, IV) administered over 40 min led to rapid, robust, and relatively sustained antidepressant effects in TRD—both MDD ( 150 – 153 ) and bipolar depression ( 154 , 155 ). In research settings, studies of TRD patients found response rates of >70% within 24 h post-infusion ( 153 ), with about 50–70% of participants exhibiting a variable duration of response ( 156 , 157 ). Ketamine has also been shown to be superior to any blinding counterpart ( 158 ). Off-label ketamine use has also been associated with significant and rapid (one to four hours) antisuicidal effects ( 150 , 159 , 160 ), a finding supported by a large, recent metanalysis showing that ketamine exerted rapid (within hours) and sustained (up to 7 days) improvements in suicidal thoughts compared to placebo ( 161 ).

Esketamine hydrochloride.

The ketamine enantiomer esketamine received approval by the FDA for TRD and is currently undergoing further Phase III clinical trials. A Phase II, 10-week, clinical trial of flexibly dosed intranasal esketamine (28 mg/56 mg or 84 mg) found that, in TRD patients, this agent demonstrated rapid and clinically relevant improvements in depressive symptoms compared to placebo ( 162 ). Strikingly, 65% of TRD patients met response criteria through Day 57. In another Phase II proof-of-concept, multi-site, 4-week, double-blind study, standard treatment plus intra-nasal esketamine (84 mg) was compared to standard treatment plus placebo in individuals with MDD at imminent risk of suicide ( 163 ). The authors found a rapid antisuicidal effect, as assessed via the Montgomery-Åsberg Depression Rating Scale Suicide Item score at 4 h.

Other rapid acting and novel antidepressants.

Based on the success of ketamine, other rapid-acting or novel antidepressant substances within the glutamatergic/GABA neurotransmitter systems are being developed, several of which are in Phase III clinical trials. A prototype novel substance is AV-101 (L-4-cholorkynurenine). This is a potent selective antagonist at the glycine-binding site of the NMDAR NR1 subunit and has demonstrated antidepressant-like effects in animal models, while human Phase II studies are currently ongoing ( 164 ). Brexanolone is a formulation of the endogenous neurosteroid allopregnanolone, which modulates neuronal activation of GABA A receptors and has met positive endpoints in Phase III, leading to FDA approval for postpartum depression. A comparable substance is under development for MDD ( 165 ). In addition, serotonergic agonists have been studied as our understanding of their mechanism of action (e.g., their effects on glutamate release or plasticity) has increased ( 166 ). Encouraging results have been seen for the serotonin 2A receptor agonist psilocybin ( 167 ), but these findings need to be replicated in larger systematic clinical trials. Initial positive trials of add-on agents—such as buprenorphine ( 168 , 169 ), rapastinel ( 170 ), or scopolamine ( 145 )—have also been conducted. However, it is beyond the scope of this manuscript to review all of these findings, and we refer the interested reader to recent comprehensive reviews of this subject ( 144 , 145 , 165 , 171 ).

Transcranial Stimulation Paradigms

In contrast to pharmaceutical treatments that exert their efficacy at the molecular level, electrical stimulation techniques target entire neuronal circuits. TMS of the (left) dorsolateral prefrontal cortex has been FDA-approved since 2008 to treat depression in patients who failed to respond to one standard antidepressant treatment. Apart from transient local skin and muscle irritation at the stimulation site and headaches, it is a very safe technique with few side effects. Studies have repeatedly demonstrated the superiority of rTMS over sham procedures, though effect sizes have been moderate ( 172 – 174 ). Initial studies suggest that rTMS is also effective in TRD but the data are too few to draw definitive conclusions ( 175 , 176 ). Improvements in rTMS techniques known as theta-burst stimulation (TBS) provide significantly shortened treatment times (3 min for TBS versus 37 min for rTMS) and hence allow more patients to be treated per day. A large non-inferiority trial of 414 moderately resistant MDD patients found that TBS was at least as effective as rTMS in reducing depressive symptoms ( 177 ).

Electroconvulsive Therapy (ECT)

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. It is also one of the most effective antidepressant therapies ( 178 ), yielding response rates of ∼80%, remission rates of ∼75% ( 179 ), and antisuicidal effects ( 180 ). Remission is achieved by about 30% of patients within six ECT sessions ( 179 ). ECT also reduces the risk of readmission ( 181 ) and is likewise safe to use in depressed elderly subjects ( 182 ). The side effects of ECT include intermediate disorientation, impaired learning, and retrograde amnesia, all of which usually resolve ( 183 ). The optimal anatomic location of the stimulus electrodes is a topic of current debate ( 184 , 185 ). Recent evidence suggests that all three methods for electrode placement (bifrontal, bitemporal, and unilateral) show clinically significant effects ( 186 ). While no difference in cognitive side effects was observed, bitemporal placement should be considered the first-line choice for urgent clinical situations. Despite its clinical efficacy, ECT remains underutilized. Its use is declining ( 187 ) because it needs to be administered in hospital settings under anesthesia, and partly because of misleading portrayals of the procedure itself. Adjusting the dose of electrical stimuli (e.g., through refined electrode placement or individually adjusted pulse amplitudes) may improve ECT’s side effect profile.

Magnetic Seizure Therapy (MST)

MST uses high doses of rTMS to induce seizures ( 188 ). The electromagnetically induced electrical field generated by MST is unifocal and variable, as there are individual differences in the degree to which the skull provides electrical resistance ( 189 ). As an advantage over ECT, MST is associated with a more superficial stimulation, which exerts less impact on the medial-temporal lobe where cognitive side effects are thought to be elicited. To date, few research sites across the world have used MST, with a concomitant dearth of open-label trials. Nevertheless, the preliminary treatment data suggest that results obtained with MST are similar to those obtained with ECT but with a more favorable side effect profile ( 190 , 191 ).

Vagus Nerve Stimulation (VNS)

VNS is a surgically implanted pacemaker-like device attached to a stimulating wire threaded along the left vagus nerve. 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. In such cases, it has been shown to have superior long-term effects over conventional psychopharmacological treatment ( 192 ). A recent, large, observational, adjunctive, open-label, naturalistic study followed TRD patients over 5 years ( 193 ). 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).

Deep-Brain Stimulation (DBS)

DBS involves the neurosurgical implantation of electrodes and has become clinically routine in the treatment of Parkinson’s disease and Dystonia. The technique is safe, removable, and does not cause lasting neuronal lesions. In TRD, anatomical targets include the subgenual cingulate, nucleus accumbens, habenula, and medial forebrain bundle. Clinical trials typically only enroll severely ill TRD patients whose current episode has lasted >12 months, whose age of onset is <45 years, and who have failed to respond to at least four adequate prior treatment trials of standard antidepressants, ECT, and/or psychotherapy. Initial open-label or single-blind trials found that DBS had both rapid and sustained antidepressant effects ( 194 – 196 ). In contrast, one large and one smaller sham-controlled clinical study both failed to achieve their primary endpoints of symptom reduction ( 197 , 198 ). To date, the number of MDD patients treated with DBS has been very small compared to other treatment options, including ECT and TMS. 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 detected ( 199 ).

Conclusions

Although enormous progress has been made in measuring, predicting, and improving outcomes, depression remains a relentless disease that places a heavy burden on both individuals and society. The research reviewed above indicates that early recognition and early adequate treatment at illness onset are preferable to watch-and-wait strategies. The studies reviewed above also underscore the manner in which SLEs, as well as physical and psychiatric comorbidities, contribute to impaired outcomes. Together, these factors contribute toward treatment resistance, which has gained a substantial amount of importance as a patient-stratifying variable.

This paper also reviewed biological markers, where research has grown exponentially to encompass enormous projects with potentially tens of thousands of subjects enrolled in real world studies. In parallel, studies exploring the underlying genetics of depression have evolved from early candidate gene studies of neurotransmitters, stress, or gene-regulatory systems to large GWAS that help reveal potential new pathways and treatment targets. Moreover, the burgeoning field of proteomics has found promising target molecules. Nevertheless, despite the wealth of recent work in this area, no single biomarker has yet been used in clinical applications. A substantial need exists for replication and, because many biomarker studies are currently open-label, for controlled studies. 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.

Above, we also outlined efforts to optimize outcomes. 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. Successful subgroup identification, and the ability to use this information in clinical settings, is crucial to improving future treatment paradigms. While recent research has increasingly focused on TRD, we wish to reiterate that no standard definition of TRD presently exists. 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. In this context, this manuscript also reviews novel treatments and brain stimulation techniques that have demonstrated rapid antidepressant effects in TRD, including ketamine, esketamine, ECT, MST, TMS/TBS, VNS, DBS, and others. When ttreating 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. If acuity supersedes chronicity, one could consider fast-acting interventions such as ketamine or ECT/MST.

This review, though comprehensive, was not able to consider several lines of evidence on outcome prediction and treatment improvement. In particular, we focused on clinical outcomes in humans and were, thus, unable to fully explore the highly valuable advances made in translational science. Similarly, it was beyond the scope of this manuscript to review the richness of results from animal research and their relevance to MDD. Moreover, given the amount of literature, we were not able to incorporate many proteomic, genetic, or psychopharmacological findings.

Taken together, this review outlines important clinical, psychosocial, and biological factors associated with response and remission to antidepressant treatment (see Table 3 ). Recent studies have led to important insights into neurobiological disease markers that could result in improved disease stratification and response prediction in the near future. Key discoveries into novel rapid-acting substances, in concert with improvements in brain stimulation techniques, may also result in significantly improved treatment outcomes in formerly hard-to-treat patients.

TABLE 3. Key points of strategies to improve outcomes in MDD

TABLE 3. Key points of strategies to improve outcomes in MDD

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Type 1 diabetes FAQs

Endocrinologist Yogish Kudva, M.B.B.S., answers the most frequently asked questions about type 1 diabetes.

Hi, I'm Dr. Yogish C Kudva. I'm an endocrinologist at Mayo Clinic and I'm here to answer some of the important questions you may have about type one diabetes.

The best current treatment for type one diabetes is an automated insulin delivery system. This system includes a continuous glucose monitor, insulin pump, and a computer algorithm that continually adjusts insulin responding to the continuous glucose monitoring signal. The patient still has to enter information about the amount of carbohydrate he or she eats at mealtimes to provide the meal time related insulin.

Testing using a glucose meter is not enough because glucose measurements in people with type one diabetes, vary from normal to low and normal to high very rapidly in the course of a day, a continuous glucose monitor is needed to assess whether treatment is effective and also to determine how to improve treatment.

Current guidelines recommend use of a continuous glucose monitor. The percentage of time that is spent daily with glucose between 70 and 180 milligram per deciliter is the main measurement of appropriate treatment. This percentage should be 70% or higher daily. In addition, percentage of time spent with glucose below 70 should be less than four percent and greater than 250 should be less than five percent. Clearly, hemoglobin A1C testing to evaluate adequacy of treatment is not enough.

In certain people with type one diabetes transplantation can be undertaken. This could be pancreas transplantation or transplantation of insulin making cells called islet. Islet transplantation is considered research in the US. Pancreas transplantation is available as a clinical treatment. These patients with hypoglycemia unawareness may benefit from a pancreas transplant. People with type one diabetes who develop recurrent diabetic ketoacidosis may also benefit from a pancreas transplant. People with type one diabetes who have developed kidney failure, could have their lives transformed by transplantation of both the pancreas and the kidney.

There is active research going on to prevent type one diabetes from happening in children and adults who are less than 45 years old. People who are eligible for such research studies are people who have a positive antibody test for type one diabetes and are willing to be in such studies. The treatment being tested is medication that suppresses the immune system. Willing participants would be randomized to receive immune suppressive treatment or placebo treatment. Placebo looks like the medication, but does not do the same thing in the body. Initial research studies have been successful in decreasing the risk of development of type one diabetes in people that have received the immune system suppressing treatment and therefore, larger studies are now being undertaken.

Try to be informed about research going on and treatments that may be approved for type one diabetes. You can get this information through already available publications. Make sure that at least annually you see a physician who is an expert on your disorder. Never hesitate to ask your medical team any questions or concerns you have. Being informed makes all the difference. Thanks for your time and we wish well.

Type 1 diabetes symptoms often start suddenly and are often the reason for checking blood sugar levels. Because symptoms of other types of diabetes and prediabetes come on more gradually or may not be easy to see, the American Diabetes Association (ADA) has developed screening guidelines. The ADA recommends that the following people be screened for diabetes:

• Anyone with a body mass index higher than 25 (23 for Asian Americans), regardless of age, who has additional risk factors. These factors include high blood pressure, non-typical cholesterol levels, an inactive lifestyle, a history of polycystic ovary syndrome or heart disease, and having a close relative with diabetes.
• Anyone older than age 35 is advised to get an initial blood sugar screening. If the results are normal, they should be screened every three years after that.
• Women who have had gestational diabetes are advised to be screened for diabetes every three years.
• Anyone who has been diagnosed with prediabetes is advised to be tested every year.
• Anyone who has HIV is advised to be tested.

Tests for type 1 and type 2 diabetes and prediabetes

A1C test . This blood test, which doesn't require not eating for a period of time (fasting), shows your average blood sugar level for the past 2 to 3 months. It measures the percentage of blood sugar attached to hemoglobin, the oxygen-carrying protein in red blood cells. It's also called a glycated hemoglobin test.

The higher your blood sugar levels, the more hemoglobin you'll have with sugar attached. An A1C level of 6.5% or higher on two separate tests means that you have diabetes. An A1C between 5.7% and 6.4% means that you have prediabetes. Below 5.7% is considered normal.

• Random blood sugar test. A blood sample will be taken at a random time. No matter when you last ate, a blood sugar level of 200 milligrams per deciliter (mg/dL) — 11.1 millimoles per liter (mmol/L) — or higher suggests diabetes.
• Fasting blood sugar test. A blood sample will be taken after you haven't eaten anything the night before (fast). A fasting blood sugar level less than 100 mg/dL (5.6 mmol/L) is normal. A fasting blood sugar level from 100 to 125 mg/dL (5.6 to 6.9 mmol/L) is considered prediabetes. If it's 126 mg/dL (7 mmol/L) or higher on two separate tests, you have diabetes.

Glucose tolerance test . For this test, you fast overnight. Then, the fasting blood sugar level is measured. Then you drink a sugary liquid, and blood sugar levels are tested regularly for the next two hours.

A blood sugar level less than 140 mg/dL (7.8 mmol/L) is normal. A reading of more than 200 mg/dL (11.1 mmol/L) after two hours means you have diabetes. A reading between 140 and 199 mg/dL (7.8 mmol/L and 11.0 mmol/L) means you have prediabetes.

If your provider thinks you may have type 1 diabetes, they may test your urine to look for the presence of ketones. Ketones are a byproduct produced when muscle and fat are used for energy. Your provider will also probably run a test to see if you have the destructive immune system cells associated with type 1 diabetes called autoantibodies.

Your provider will likely see if you're at high risk for gestational diabetes early in your pregnancy. If you're at high risk, your provider may test for diabetes at your first prenatal visit. If you're at average risk, you'll probably be screened sometime during your second trimester.

• Care at Mayo Clinic

Our caring team of Mayo Clinic experts can help you with your diabetes-related health concerns Start Here

Depending on what type of diabetes you have, blood sugar monitoring, insulin and oral drugs may be part of your treatment. Eating a healthy diet, staying at a healthy weight and getting regular physical activity also are important parts of managing diabetes.

Treatments for all types of diabetes

An important part of managing diabetes — as well as your overall health — is keeping a healthy weight through a healthy diet and exercise plan:

Healthy eating. Your diabetes diet is simply a healthy-eating plan that will help you control your blood sugar. You'll need to focus your diet on more fruits, vegetables, lean proteins and whole grains. These are foods that are high in nutrition and fiber and low in fat and calories. You'll also cut down on saturated fats, refined carbohydrates and sweets. In fact, it's the best eating plan for the entire family. Sugary foods are OK once in a while. They must be counted as part of your meal plan.

Understanding what and how much to eat can be a challenge. A registered dietitian can help you create a meal plan that fits your health goals, food preferences and lifestyle. This will likely include carbohydrate counting, especially if you have type 1 diabetes or use insulin as part of your treatment.

Physical activity. Everyone needs regular aerobic activity. This includes people who have diabetes. Physical activity lowers your blood sugar level by moving sugar into your cells, where it's used for energy. Physical activity also makes your body more sensitive to insulin. That means your body needs less insulin to transport sugar to your cells.

Get your provider's OK to exercise. Then choose activities you enjoy, such as walking, swimming or biking. What's most important is making physical activity part of your daily routine.

Aim for at least 30 minutes or more of moderate physical activity most days of the week, or at least 150 minutes of moderate physical activity a week. Bouts of activity can be a few minutes during the day. If you haven't been active for a while, start slowly and build up slowly. Also avoid sitting for too long. Try to get up and move if you've been sitting for more than 30 minutes.

Treatments for type 1 and type 2 diabetes

Treatment for type 1 diabetes involves insulin injections or the use of an insulin pump, frequent blood sugar checks, and carbohydrate counting. For some people with type 1 diabetes, pancreas transplant or islet cell transplant may be an option.

Treatment of type 2 diabetes mostly involves lifestyle changes, monitoring of your blood sugar, along with oral diabetes drugs, insulin or both.

Monitoring your blood sugar

Depending on your treatment plan, you may check and record your blood sugar as many as four times a day or more often if you're taking insulin. Careful blood sugar testing is the only way to make sure that your blood sugar level remains within your target range. People with type 2 diabetes who aren't taking insulin generally check their blood sugar much less often.

People who receive insulin therapy also may choose to monitor their blood sugar levels with a continuous glucose monitor. Although this technology hasn't yet completely replaced the glucose meter , it can lower the number of fingersticks necessary to check blood sugar and provide important information about trends in blood sugar levels.

Even with careful management, blood sugar levels can sometimes change unpredictably. With help from your diabetes treatment team, you'll learn how your blood sugar level changes in response to food, physical activity, medications, illness, alcohol and stress. For women, you'll learn how your blood sugar level changes in response to changes in hormone levels.

Besides daily blood sugar monitoring, your provider will likely recommend regular A1C testing to measure your average blood sugar level for the past 2 to 3 months.

Compared with repeated daily blood sugar tests, A1C testing shows better how well your diabetes treatment plan is working overall. A higher A1C level may signal the need for a change in your oral drugs, insulin regimen or meal plan.

Your target A1C goal may vary depending on your age and various other factors, such as other medical conditions you may have or your ability to feel when your blood sugar is low. However, for most people with diabetes, the American Diabetes Association recommends an A1C of below 7%. Ask your provider what your A1C target is.

People with type 1 diabetes must use insulin to manage blood sugar to survive. Many people with type 2 diabetes or gestational diabetes also need insulin therapy.

Many types of insulin are available, including short-acting (regular insulin), rapid-acting insulin, long-acting insulin and intermediate options. Depending on your needs, your provider may prescribe a mixture of insulin types to use during the day and night.

Insulin can't be taken orally to lower blood sugar because stomach enzymes interfere with insulin's action. Insulin is often injected using a fine needle and syringe or an insulin pen — a device that looks like a large ink pen.

An insulin pump also may be an option. The pump is a device about the size of a small cellphone worn on the outside of your body. A tube connects the reservoir of insulin to a tube (catheter) that's inserted under the skin of your abdomen.

Continuous glucose monitor and insulin pump

A continuous glucose monitor, on the left, is a device that measures your blood sugar every few minutes using a sensor inserted under the skin. An insulin pump, attached to the pocket, is a device that's worn outside of the body with a tube that connects the reservoir of insulin to a catheter inserted under the skin of the abdomen. Insulin pumps are programmed to deliver specific amounts of insulin automatically and when you eat.

A continuous glucose monitor, on the left, is a device that measures blood sugar every few minutes using a sensor inserted under the skin. An insulin pump, attached to the pocket, is a device that's worn outside of the body with a tube that connects the reservoir of insulin to a catheter inserted under the skin of the abdomen. Insulin pumps are programmed to deliver specific amounts of insulin continuously and with food.

A tubeless pump that works wirelessly is also now available. You program an insulin pump to dispense specific amounts of insulin. It can be adjusted to give out more or less insulin depending on meals, activity level and blood sugar level.

A closed loop system is a device implanted in the body that links a continuous glucose monitor to an insulin pump. The monitor checks blood sugar levels regularly. The device automatically delivers the right amount of insulin when the monitor shows that it's needed.

The Food and Drug Administration has approved several hybrid closed loop systems for type 1 diabetes. They are called "hybrid" because these systems require some input from the user. For example, you may have to tell the device how many carbohydrates are eaten, or confirm blood sugar levels from time to time.

A closed loop system that doesn't need any user input isn't available yet. But more of these systems currently are in clinical trials.

Oral or other drugs

Sometimes your provider may prescribe other oral or injected drugs as well. Some diabetes drugs help your pancreas to release more insulin. Others prevent the production and release of glucose from your liver, which means you need less insulin to move sugar into your cells.

Still others block the action of stomach or intestinal enzymes that break down carbohydrates, slowing their absorption, or make your tissues more sensitive to insulin. Metformin (Glumetza, Fortamet, others) is generally the first drug prescribed for type 2 diabetes.

Another class of medication called SGLT2 inhibitors may be used. They work by preventing the kidneys from reabsorbing filtered sugar into the blood. Instead, the sugar is eliminated in the urine.

Transplantation

In some people who have type 1 diabetes, a pancreas transplant may be an option. Islet transplants are being studied as well. With a successful pancreas transplant, you would no longer need insulin therapy.

But transplants aren't always successful. And these procedures pose serious risks. You need a lifetime of immune-suppressing drugs to prevent organ rejection. These drugs can have serious side effects. Because of this, transplants are usually reserved for people whose diabetes can't be controlled or those who also need a kidney transplant.

Bariatric surgery

Some people with type 2 diabetes who are obese and have a body mass index higher than 35 may be helped by some types of bariatric surgery . People who've had gastric bypass have seen major improvements in their blood sugar levels. But this procedure's long-term risks and benefits for type 2 diabetes aren't yet known.

Treatment for gestational diabetes

Controlling your blood sugar level is essential to keeping your baby healthy. It can also keep you from having complications during delivery. In addition to having a healthy diet and exercising regularly, your treatment plan for gestational diabetes may include monitoring your blood sugar. In some cases, you may also use insulin or oral drugs.

Your provider will monitor your blood sugar level during labor. If your blood sugar rises, your baby may release high levels of insulin. This can lead to low blood sugar right after birth.

Treatment for prediabetes

Treatment for prediabetes usually involves healthy lifestyle choices. These habits can help bring your blood sugar level back to normal. Or it could keep it from rising toward the levels seen in type 2 diabetes. Keeping a healthy weight through exercise and healthy eating can help. Exercising at least 150 minutes a week and losing about 7% of your body weight may prevent or delay type 2 diabetes.

Drugs — such as metformin, statins and high blood pressure medications — may be an option for some people with prediabetes and other conditions such as heart disease.

Signs of trouble in any type of diabetes

Many factors can affect your blood sugar. Problems may sometimes come up that need care right away.

High blood sugar

High blood sugar ( hyperglycemia in diabetes ) can occur for many reasons, including eating too much, being sick or not taking enough glucose-lowering medication. Check your blood sugar level as directed by your provider. And watch for symptoms of high blood sugar, including:

• Urinating often
• Feeling thirstier than usual
• Blurred vision
• Tiredness (fatigue)
• Irritability

If you have hyperglycemia, you'll need to adjust your meal plan, drugs or both.

Increased ketones in your urine

Diabetic ketoacidosis is a serious complication of diabetes. If your cells are starved for energy, your body may begin to break down fat. This makes toxic acids known as ketones, which can build up in the blood. Watch for the following symptoms:

• Stomach (abdominal) pain
• A sweet, fruity smell on your breath
• Shortness of breath

You can check your urine for excess ketones with a ketones test kit that you can get without a prescription. If you have excess ketones in your urine, talk with your provider right away or seek emergency care. This condition is more common in people with type 1 diabetes.

Hyperglycemic hyperosmolar nonketotic syndrome

Hyperosmolar syndrome is caused by very high blood sugar that turns blood thick and syrupy.

Symptoms of this life-threatening condition include:

• A blood sugar reading over 600 mg/dL (33.3 mmol/L)
• Extreme thirst
• Vision loss
• Hallucinations

This condition is seen in people with type 2 diabetes. It often happens after an illness. Call your provider or seek medical care right away if you have symptoms of this condition.

Low blood sugar (hypoglycemia)

If your blood sugar level drops below your target range, it's known as low blood sugar ( diabetic hypoglycemia ). If you're taking drugs that lower your blood sugar, including insulin, your blood sugar level can drop for many reasons. These include skipping a meal and getting more physical activity than normal. Low blood sugar also occurs if you take too much insulin or too much of a glucose-lowering medication that causes the pancreas to hold insulin.

Check your blood sugar level regularly and watch for symptoms of low blood sugar, including:

• Heart palpitations
• Slurred speech

Low blood sugar is best treated with carbohydrates that your body can absorb quickly, such as fruit juice or glucose tablets.

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Clinical trials

Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition.

Lifestyle and home remedies

Diabetes is a serious disease. Following your diabetes treatment plan takes total commitment. Careful management of diabetes can lower your risk of serious or life-threatening complications.

• Commit to managing your diabetes . Learn all you can about diabetes. Build a relationship with a diabetes educator. Ask your diabetes treatment team for help when you need it.
• Choose healthy foods and stay at a healthy weight. If you're overweight, losing just 7% of your body weight can make a difference in your blood sugar control if you have prediabetes or type 2 diabetes. A healthy diet is one with plenty of fruits, vegetables, lean proteins, whole grains and legumes. And limit how much food with saturated fat you eat.

Make physical activity part of your daily routine. Regular physical activity can help prevent prediabetes and type 2 diabetes. It can also help those who already have diabetes to maintain better blood sugar control. A minimum of 30 minutes of moderate physical activity — such as brisk walking — most days of the week is recommended. Aim for at least 150 minutes of moderate aerobic physical activity a week.

Getting regular aerobic exercise along with getting at least two days a week of strength training exercises can help control blood sugar more effectively than does either type of exercise alone. Aerobic exercises can include walking, biking or dancing. Resistance training can include weight training and body weight exercises.

Also try to spend less time sitting still. Try to get up and move around for a few minutes at least every 30 minutes or so when you're awake.

Lifestyle recommendations for type 1 and type 2 diabetes

Also, if you have type 1 or type 2 diabetes:

• Identify yourself. Wear a tag or bracelet that says you have diabetes. Keep a glucagon kit nearby in case of a low blood sugar emergency. Make sure your friends and loved ones know how to use it.
• Schedule a yearly physical and regular eye exams. Your regular diabetes checkups aren't meant to replace yearly physicals or routine eye exams. During the physical, your provider will look for any diabetes-related complications and screen for other medical problems. Your eye care specialist will check for signs of eye damage, including retinal damage (retinopathy), cataracts and glaucoma.

Keep your vaccinations up to date. High blood sugar can weaken your immune system. Get a flu shot every year. Your provider may recommend the pneumonia and COVID-19 vaccines, as well.

The Centers for Disease Control and Prevention (CDC) also currently recommends hepatitis B vaccination if you haven't previously had it and you're an adult ages 19 to 59 with type 1 or type 2 diabetes.

The most recent CDC guidelines suggest vaccination as soon as possible after diagnosis with type 1 or type 2 diabetes. If you are age 60 or older, have been diagnosed with diabetes, and haven't previously received the vaccine, talk to your provider about whether it's right for you.

• Pay attention to your feet. Wash your feet daily in lukewarm water. Dry them gently, especially between the toes. Moisturize with lotion, but not between the toes. Check your feet every day for blisters, cuts, sores, redness or swelling. Talk to your provider if you have a sore or other foot problem that doesn't heal quickly on its own.
• Control your blood pressure and cholesterol. Eating healthy foods and exercising regularly can help control high blood pressure and cholesterol. Drugs may be needed, too.
• Take care of your teeth. Diabetes may leave you prone to more-serious gum infections. Brush and floss your teeth at least twice a day. And if you have type 1 or type 2 diabetes, schedule regular dental exams. Talk to your dentist right away if your gums bleed or look red or swollen.
• If you smoke or use other types of tobacco, ask your provider to help you quit. Smoking increases your risk of many diabetes complications. Smokers who have diabetes are more likely to die of cardiovascular disease than are nonsmokers who have diabetes. Talk to your provider about ways to stop smoking or to stop using other types of tobacco.

If you drink alcohol, do so responsibly. Alcohol can cause either high or low blood sugar. This depends on how much you drink and if you eat at the same time. If you choose to drink, do so only in moderation — one drink a day for women and up to two drinks a day for men — and always with food.

Remember to include the carbohydrates from any alcohol you drink in your daily carbohydrate count. And check your blood sugar levels before going to bed.

• Take stress seriously. The hormones your body may make in response to long-term stress may prevent insulin from working properly. This will raise your blood sugar and stress you even more. Set limits for yourself and prioritize your tasks. Learn relaxation techniques. And get plenty of sleep.

Alternative medicine

Many substances have been shown to improve the body's ability to process insulin in some studies. Other studies fail to find any benefit for blood sugar control or in lowering A1C levels. Because of the conflicting findings, there aren't any alternative therapies that are currently recommended to help everyone to manage blood sugar.

If you decide to try any type of alternative therapy, don't stop taking the drugs that your provider has prescribed. Be sure to discuss the use of any of these therapies with your provider. Make sure that they won't cause bad reactions or interact with your current therapy.

Also, no treatments — alternative or conventional — can cure diabetes. If you're using insulin therapy for diabetes, never stop using insulin unless directed to do so by your provider.

Coping and support

Living with diabetes can be difficult and frustrating. Sometimes, even when you've done everything right, your blood sugar levels may rise. But stick with your diabetes management plan and you'll likely see a positive difference in your A1C when you visit your provider.

Good diabetes management can take a great deal of time and feel overwhelming. Some people find that it helps to talk to someone. Your provider can probably recommend a mental health professional for you to speak with. Or you may want to try a support group.

Sharing your frustrations and triumphs with people who understand what you're going through can be very helpful. And you may find that others have great tips to share about diabetes management.

Your provider may know of a local support group. You can also call the American Diabetes Association at 800-DIABETES ( 800-342-2383 ) or the Juvenile Diabetes Research Foundation at 800-533-CURE ( 800-533-2873 ).

Preparing for your appointment

You're likely to start by seeing your health care provider if you're having diabetes symptoms. If your child is having diabetes symptoms, you might see your child's health care provider. If blood sugar levels are very high, you'll likely be sent to the emergency room.

If blood sugar levels aren't high enough to put you or your child immediately at risk, you may be referred to a provider trained in diagnosing and treating diabetes (endocrinologist). Soon after diagnosis, you'll also likely meet with a diabetes educator and a registered dietitian to get more information on managing your diabetes.

Here's some information to help you get ready for your appointment and to know what to expect.

What you can do

• Be aware of any pre-appointment restrictions. When you make the appointment, ask if you need to do anything in advance. This will likely include restricting your diet, such as for a fasting blood sugar test.
• Write down any symptoms you're experiencing, including any that may seem unrelated.
• Write down key personal information, including major stresses or recent life changes. If you're monitoring your glucose values at home, bring a record of the glucose results, detailing the dates and times of testing.
• Make a list of any allergies you have and all medications, vitamins and supplements you're taking.
• Record your family medical history. Be sure to note any relatives who have had diabetes, heart attacks or strokes.
• Bring a family member or friend, if possible. Someone who accompanies you can help you remember information you need.
• Write down questions to ask your provider. Ask about aspects of your diabetes management you're unclear about.
• Be aware if you need any prescription refills. Your provider can renew your prescriptions while you're there.

Preparing a list of questions can help you make the most of your time with your provider. For diabetes, some questions to ask include:

• Are the symptoms I'm having related to diabetes or something else?
• Do I need any tests?
• What else can I do to protect my health?
• What are other options to manage my diabetes?
• I have other health conditions. How can I best manage these conditions together?
• Are there restrictions I need to follow?
• Should I see another specialist, such as a dietitian or diabetes educator?
• Is there a generic alternative to the medicine you're prescribing?
• Are there brochures or other printed material I can take with me? What websites do you recommend?

What to expect from your doctor

Your provider is likely to ask you many questions, such as:

• Can you describe your symptoms?
• Do you have symptoms all the time, or do they come and go?
• How severe are your symptoms?
• Do you have a family history of preeclampsia or diabetes?
• Tell me about your diet.
• Do you exercise? What type and how much?

Diabetes care at Mayo Clinic

• Ferri FF. Diabetes mellitus. In: Ferri's Clinical Advisor 2022. Elsevier; 2022. https://www.clinicalkey.com. Accessed May 7, 2022.
• Classification and diagnosis of diabetes: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S002.
• Papadakis MA, et al., eds. Diabetes mellitus. In: Current Medical Diagnosis & Treatment 2022. 61st ed. McGraw Hill; 2022. https://accessmedicine.mhmedical.com. Accessed May 4, 2022.
• Diabetes risk factors. Centers for Disease Control and Prevention. https://www.cdc.gov/diabetes/basics/risk-factors.html. Accessed June 2, 2022.
• Cunningham FG, et al. Diabetes mellitus. In: Williams Obstetrics. 25th ed. McGraw-Hill Education; 2018. https://accessmedicine.mhmedical.com. Accessed June 2, 2022.
• Diabetes and DKA (ketoacidosis). American Diabetes Association. https://www.diabetes.org/diabetes/dka-ketoacidosis-ketones. Accessed May 4, 2022.
• Diabetes Canada Clinical Practice Guidelines Expert Committee. Complementary and alternative medicine for diabetes. Canadian Journal of Diabetes. 2018; doi:10.1016/j.jcjd.2017.10.023.
• Nimmagadda R. Allscripts EPSi. Mayo Clinic. June 16, 2022.
• Jameson JL, et al., eds. Diabetes mellitus: Diagnosis, classification and pathophysiology. In: Harrison's Principles of Internal Medicine. 20th ed. McGraw-Hill Education; 2018. https://accessmedicine.mhmedical.com. Accessed June 2, 2022.
• Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S009.
• Facilitating behavior change and well-being to improve health outcomes: Standards of medical care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S005.
• AskMayoExpert. Type 1 diabetes mellitus. Mayo Clinic; 2021.
• Glycemic targets: Standards of Medical Care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S012.
• Comprehensive medical evaluation and assessment of comorbidities: Standards of Medical Care in Diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S004.
• Prevention or delay of type 2 diabetes and associated comorbidities: Standards of Medical Care in diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S003.
• Obesity and weight management for the prevention and treatment of type 2 diabetes: Standards of Medical Care in Diabetes — 2022. Diabetes Care. 2022; doi:10.2337/dc22-S008.
• Diabetes technology. Standards of Medical Care in Diabetes — 2022. 2022; doi:10.2337/dc22-S007.

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Perinatal Depression

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Perinatal depression is a mood disorder that occurs during pregnancy and after childbirth. The symptoms can range from mild to severe. In rare cases, the symptoms are severe enough that a mother and her baby’s health and well-being may be at risk.

Perinatal depression can be treated. Learn about the signs and symptoms, risk factors, treatments, and ways you or a loved one can get help.

What is perinatal depression?

Perinatal depression includes depression that occurs during pregnancy (prenatal depression) and in the weeks after childbirth (postpartum depression). Most episodes of perinatal depression begin within 4−8 weeks after the baby is born. Women and other pregnant and postpartum people with perinatal depression experience extreme sadness, anxiety, and fatigue that may make it difficult to carry out daily tasks, including caring for themselves or others.

How is postpartum depression different from “baby blues”?

“Baby blues” is a term used to describe mild and short-lasting mood changes and feelings of worry, unhappiness, and exhaustion that many women experience in the first 2 weeks after giving birth. Babies require around-the-clock care, so it’s normal for new mothers to feel tired or overwhelmed sometimes.

Mood changes and feelings of anxiety or unhappiness that are severe or last longer than 2 weeks after childbirth may be signs of postpartum depression. Women with postpartum depression generally will not feel better without treatment.

What are the signs and symptoms of perinatal depression?

Some women experience a few symptoms of perinatal depression, while others experience several symptoms. Some of the more common symptoms include:

• Persistent sad, anxious, or “empty” mood most of the day, nearly every day, for at least 2 weeks
• Feelings of hopelessness or pessimism
• Feelings of irritability, frustration, or restlessness
• Feelings of guilt, worthlessness, or helplessness
• Loss of interest or pleasure in hobbies and activities
• Fatigue or abnormal decrease in energy
• Being restless or having trouble sitting still
• Difficulty concentrating, remembering, or making decisions
• Difficulty sleeping (even when the baby is asleep), waking early in the morning, or oversleeping
• Abnormal changes in appetite or unplanned weight changes
• Physical aches or pains, headaches, cramps, or digestive problems that do not have a clear physical cause and do not go away with treatment
• Trouble bonding or forming an emotional attachment with the baby
• Persistent doubts about the ability to care for the baby
• Thoughts of death or harming oneself or the baby or suicide attempts

Women who experience any of these symptoms should see a health care provider. A provider can determine whether the symptoms are due to perinatal depression or something else.

What is postpartum psychosis?

Postpartum psychosis is a serious mental illness that can occur after childbirth. Women with postpartum psychosis may experience delusions (thoughts or beliefs that are not true), hallucinations (seeing, hearing, or smelling things that are not there), mania (a high, elated mood that often seems out of touch with reality), paranoia, and confusion.

Postpartum psychosis is a psychiatric emergency that requires hospitalization. Women experiencing symptoms of postpartum psychosis should seek immediate help by calling 911 or going to the nearest emergency room. Recovery is possible with professional help.

What are the risk factors for perinatal depression?

Perinatal depression is a medical condition that can affect any woman or pregnant and postpartum person, regardless of age, race, ethnicity, income, culture, or education. A woman is not to blame or at fault for having perinatal depression: It is not caused by anything she has or has not done.

Perinatal depression does not have a single cause. Research suggests that genetic and environmental factors contribute to the disorder. Specific factors contributing to perinatal depression can include:

• Life stress (for example, demands at work or experiences of past trauma)
• Physical and emotional demands of childbirth and caring for a new baby
• Changes in hormones that occur during and after pregnancy

In addition, women are at increased risk for perinatal depression if they have a personal or family history of depression or bipolar disorder or if they experienced depression with a previous pregnancy. Women with a history of perinatal depression should consult a health care provider to develop a plan for follow-up care in case a depressive episode reoccurs.

How is perinatal depression treated?

Treating perinatal depression is critical for the health of the mother and her baby, as the disorder can have serious effects on both. However, with proper treatment, most women feel better and their symptoms improve.

Treatment for perinatal depression usually includes therapy, medication, or a combination of therapy and medication.

Researchers continue to study treatment options for perinatal depression. A health care provider can explain the different treatments and help you choose the best one based on your symptoms. Learn more about approaches for treating depression .

Learn about ways to get help and find a health care provider or access treatment.

If you or someone you know is struggling or having thoughts of suicide, call or text the 988 Suicide and Crisis Lifeline   at 988 or chat at 988lifeline.org   . In life-threatening situations, call 911 .

Psychotherapy

Several types of psychotherapy (also called talk therapy or counseling) can help women with perinatal depression by teaching them new ways of thinking and behaving and helping them change habits that contribute to depression. Evidence-based therapies for perinatal depression include cognitive behavioral therapy and interpersonal therapy.

• Cognitive behavioral therapy (CBT) : With CBT, people learn to challenge and change unhelpful thoughts and behaviors to improve their depressive and anxious feelings. People also learn different ways of reacting to situations. CBT can be conducted individually or with a group of people who have similar concerns.
• Interpersonal therapy (IPT) : IPT is based on the idea that interpersonal and life events impact mood and vice versa. IPT aims to help people improve their communication skills within relationships, form social support networks, and develop realistic expectations to better deal with crises or other issues contributing to their depression.

Learn more about psychotherapy .

Medications used for depression (antidepressants) can effectively treat perinatal depression when used alone or in combination with psychotherapy. Antidepressants work by changing how the brain produces or uses certain chemicals involved in mood or stress.

Antidepressants take time—usually 4−8 weeks—to work. Problems with sleep, appetite, and concentration often improve before mood lifts. It is important to give a medication a chance to work before deciding whether it is right for you. You may need to try several medications to find the best one.

The U.S. Food and Drug Administration (FDA) has approved a medication called brexanolone specifically to treat severe postpartum depression. Brexanolone, which is administered through an IV during a brief hospital stay, appears to work differently than traditional antidepressants by rapidly altering a brain chemical that may play an important role in regulating the body’s vulnerability to depression and anxiety.

More recently, the FDA approved a pill called zuranolone as the first oral medication for postpartum depression in adults. Zuranolone acts on similar brain receptors to brexanolone. In clinical trials, the pill reduced depressive symptoms in women with severe postpartum depression more quickly than traditional antidepressants.

Note : In some cases, people under 25 years may experience an increase in suicidal thoughts or behavior when taking antidepressants, especially in the first few weeks after starting or when the dose is changed. The FDA advises that patients of all ages taking antidepressants be watched closely, especially during the first few weeks of treatment.

The risk of birth defects and other problems for babies of mothers who take antidepressants during pregnancy is very low. However, women should always let a health care provider know if they are pregnant or nursing and work with the provider to minimize the baby’s exposure to medication and weigh the risks and benefits of available treatment options. Find more information on medications during and after pregnancy on the FDA website  .

All medications can have side effects. Talk to a health care provider before starting or stopping any medication. Learn more about antidepressants .

Learn about specific medications like brexanolone and zuranolone, including the latest approvals, side effects, warnings, and patient information, on the FDA website  .

How can I find help for perinatal depression?

Visit a mental health professional.

If you think you have perinatal depression, start by making an appointment with a health care provider. This could be a primary care doctor or a mental health professional who specializes in diagnosing and treating mental disorders (for example, a psychologist, psychiatrist, or social worker). A health care provider will examine you and talk to you about treatment options and next steps, including options if you are pregnant or nursing.

Communicating well with a health care provider can improve your care and help you both make good choices about your health. Find tips for talking with a health care provider to improve your care and get the most out of your visit. For additional resources, including questions to ask a provider, visit the Agency for Healthcare Research and Quality website  .

The Substance Abuse and Mental Health Services Administration has an online treatment locator  to help you find mental health services in your area.

Join a support or advocacy group

Support or advocacy groups can be an important source of help and information. One example of this type of group is Postpartum Support International   ; you can find others through online searches.

Contact the National Maternal Mental Health Hotline

This hotline offers free, confidential mental health support for mothers and their families before, during, and after pregnancy. Call or text 1-833-9-TLC-MAMA ( 1-833-852-6262 ) to connect with counselors 24 hours a day, 7 days a week. English- and Spanish-speaking counselors are available.

How can family and friends provide help for perinatal depression?

It is essential to understand that perinatal depression is a medical condition that impacts the mother, the child, and the family. Treatment is central to recovery.

Spouses, partners, family members, and friends may be the first to recognize signs of depression in a new mother. Family and friends can provide help in many ways that include:

• Encouraging discussion with a health care provider
• Helping get to appointments
• Offering emotional or practical support
• Assisting with daily tasks such as caring for the baby or home

Where can I learn more about depression in women?

The following agencies have additional information on depression in women:

• Action Plan for Depression and Anxiety During Pregnancy and After Birth  ( Eunice Kennedy Shriver National Institute of Child Health and Human Development)
• Depression Among Women  (Centers for Disease Control and Prevention)
• Perinatal Depression: Preventive Interventions   (U.S. Preventive Services Task Force)
• Postpartum Depression  (Office on Women’s Health)
• Women and Depression  (U.S. Food and Drug Administration)

For more information on postpartum depression, also see:

• Postpartum Depression  (MedlinePlus, National Library of Medicine)
• Talking Postpartum Depression videos  (Office on Women’s Health) 

What are clinical trials and why are they important?

Clinical trials are research studies that look at ways to prevent, detect, or treat diseases and conditions. These studies help show whether a treatment is safe and effective in people. Some people join clinical trials to help doctors and researchers learn more about a disease and improve health care. Other people, such as those with health conditions, join to try treatments that aren’t widely available.

NIMH supports clinical trials across the United States. Talk to a health care provider about clinical trials and whether one is right for you. Learn more about  participating in clinical trials .

For more information

MedlinePlus   (National Library of Medicine) ( en español  )

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health NIH Publication No. 23-MH-8116

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Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions

Roger s. mcintyre.

1 Brain and Cognition Discovery Foundation, Toronto ON, Canada

2 Department of Psychiatry, University of Toronto, Toronto ON, Canada

3 Department of Pharmacology and Toxicology, University of Toronto, Toronto ON, Canada

Mohammad Alsuwaidan

Bernhard t. baune.

4 Department of Psychiatry, University of Münster, Münster Germany

5 Department of Psychiatry, University of Melbourne, Melbourne VIC, Australia

Michael Berk

6 Deakin University IMPACT Institute, Geelong VIC, Australia

Koen Demyttenaere

7 Department of Psychiatry, Faculty of Medicine, KU Leuven, Leuven Belgium

Joseph F. Goldberg

8 Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York NY, USA

Philip Gorwood

9 Department of Psychiatry, Sainte‐Anne Hospital, Paris France

10 Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

11 Institute for Health Innovation and Technology, National University of Singapore, Singapore

Siegfried Kasper

12 Department of Psychiatry and Psychotherapy and Center of Brain Research, Molecular Neuroscience Branch, Medical University of Vienna, Vienna Austria

Sidney H. Kennedy

Josefina ly‐uson.

13 Department of Psychiatry and Behavioral Medicine, University of The Philippines College of Medicine, Manila The Philippines

Rodrigo B. Mansur

R. hamish mcallister‐williams.

14 Northern Center for Mood Disorders, Translational and Clinical Research Institute, Newcastle University, and Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust, Newcastle upon Tyne UK

James W. Murrough

Charles b. nemeroff.

15 Department of Psychiatry, Dell Medical School, Austin TX, USA

Andrew A. Nierenberg

16 Dauten Family Center for Bipolar Treatment Innovation, Massachusetts General Hospital, Boston MA, USA

Joshua D. Rosenblat

Gerard sanacora.

17 Department of Psychiatry, Yale University, New Haven CT, USA

Alan F. Schatzberg

18 Department of Psychiatry, Stanford University School of Medicine, Stanford CA, USA

Richard Shelton

19 Department of Psychiatry, University of Alabama at Birmingham, Birmingham AL, USA

Stephen M. Stahl

20 Department of Psychiatry, University of California, San Diego CA, USA

Madhukar H. Trivedi

21 Department of Psychiatry, University of Illinois Chicago, Chicago IL, USA

Eduard Vieta

22 Department of Psychiatry and Psychology, Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona Spain

Maj Vinberg

23 Mental Health Centre, Northern Zealand, Copenhagen University Hospital ‐ Mental Health Services CPH, Copenhagen Denmark

Nolan Williams

Allan h. young.

24 Department of Psychological Medicine, King's College London, London UK

25 Department of Psychiatry, University of Campania “Luigi Vanvitelli”, Naples Italy

Treatment‐resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision‐making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision‐making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo‐resistant (e.g., due to inadequacy of treatment trials or non‐adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non‐response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co‐administered with an antidepressant) are established as efficacious in the management of TRD. Some second‐generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine‐fluoxetine combination has been studied in FDA‐defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA‐approved for individuals with TRD, with accelerated theta‐burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non‐inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual‐based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.

It is amply documented that major depressive disorder (MDD) is highly prevalent and associated with substantial burden and economic costs 1 , 2 , 3 , 4 , 5 . According to the World Health Organization (WHO), MDD is the single largest contributor to loss of healthy life, and this contribution has apparently further increased during the COVID‐19 pandemic 6 , 7 , 8 .

Notwithstanding the evidence supporting the efficacy of conventional antidepressants as well as manual‐based psychotherapies and specific neurostimulation modalities, the majority of individuals with MDD are inadequately responsive to first‐line treatments. Moreover, a substantial proportion of them fail multiple antidepressant interventions, resulting in what is described as treatment‐resistant depression (TRD) 5 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 .

Although non‐response is a common outcome of treatment with multiple conventional antidepressants, a consensus definition of TRD with predictive utility does not currently exist. Instead, a host of definitions have been proposed, differing in their conceptual framework, operational criteria and working assumptions. This heterogeneity of definitions has resulted in a wide range of estimates of the prevalence of TRD 16 . The proportion of people with TRD would be expected to be higher when multidimensional definitions are used, especially those including patient‐reported outcomes 17 , 18 .

There are multiple serious public health implications associated with TRD, which provide the impetus for a specific focus on its detection and algorithmic management. First, TRD is common in the general population: based on international epidemiological estimates, it is extrapolated that more than 100 million people globally meet one or more definitions of this condition 19 . In addition, cost of illness studies have documented staggering direct and indirect economic costs associated with MDD, of which more than half globally are attributable to TRD 20 .

The relatively higher cost of illness attributed to TRD is directly due to higher health care utilization and the need for higher intensity treatments 20 , 21 , 22 , 23 . Higher indirect costs are also reported in TRD as a consequence of relatively greater impairment in psychosocial function, greater need for disability benefits, higher workplace disability and absenteeism, as well as the negative impact on carers 10 , 21 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 . Moreover, the rate of suicidality, including completed suicide, is disproportionately higher in TRD populations 36 .

Additional public health implications of TRD relate to the established association between MDD and multiple common and chronic non‐communicable physical diseases 37 , 38 , 39 . For example, it is established that MDD is a risk factor for cardiovascular disease, obesity and type 2 diabetes mellitus, and this is especially apparent in individuals with more severe and/or persistent depressive syndromes, which are over‐represented in TRD populations 40 , 41 .

Notwithstanding the foregoing public health implications of TRD, relatively few interventions have been established as efficacious for persons having multiple failed trials with conventional antidepressants. Instead, the emphasis of treatment development in depressive disorders has been on non‐TRD populations. In addition, prevention of TRD is not a national health policy priority in any country worldwide, nor is progress in its management a quality outcome measure in any national public health care system.

Currently, more than 90 clinical practice guidelines are available that aim to provide decision support to clinicians caring for adults with mood disorders, originating from 83 countries and published in 27 languages 42 . Most of them have been produced in high‐income countries and integrate scientific evidence with expert opinion 42 , 43 , 44 , 45 . Major limitations of extant guidelines, as it specifically relates to TRD, are that they do not adopt a consensus definition of this condition, and are not consistent in their selection or sequencing of recommendations.

In addition, extant guidelines vary in how they define an adequate antidepressant regimen and frequently conflate the treatment of TRD with non‐TRD populations (i.e., partial responders to antidepressants). For example, second‐generation antipsychotics (SGAs), of which most have not been proven to be effective in TRD, are often recommended for this condition in combination with antidepressants, despite their evidentiary base comprised largely of populations defined as partial responders to antidepressants.

Herein, we aim to provide a synthesis of current definitions of TRD, with an emphasis on their limitations, and recommendations for the development of an improved consensus definition; to summarize best estimates of the prevalence of TRD on the basis of current definitions; to review the available evidence on risk factors for TRD; to provide recommendations concerning the detection and management of TRD, based on research evidence when available and opinions from international experts; and to review investigational interventions for TRD. We do not intend to review and/or supplant existing recommendations for depression which is not treatment‐resistant 44 , 45 , 46 , 47 , 48 .

DEFINITIONS OF TREATMENT‐RESISTANT DEPRESSION

The absence of a consensus and validated definition of TRD is a major limitation from the viewpoints of translational research, treatment development, as well as clinical and policy decision‐making. Indeed, the pathway towards more targeted treatments in psychiatry requires a more precise delineation of the phenotype being evaluated 49 , 50 , 51 .

The lack of a consensus definition results in the heterogeneity of populations enrolled in clinical trials evaluating new interventions for TRD, greatly limiting the interpretability and generalizability of the results. At a clinical level, the heterogeneity of patient samples contributes to differences in recommendations on the sequencing of treatments for people not responding to conventional first‐line antidepressants. Disparity in practice behavior is likely compromising optimal health outcomes amongst those living with and receiving interventions for TRD. Moreover, from a policy perspective, reimbursement and access to treatment for populations with TRD will understandably vary in the absence of a universal definition, further compromising real‐world outcomes in these patients.

The definition of TRD adopted by the US Food and Drug Administration (FDA) 52 and the European Medicines Agency (EMA) 53 is failure to respond to two or more antidepressant regimens despite adequate dose and duration and adherence to treatment. These regulatory agencies recognize the lack of precision of this definition and its overlap with definitions of “partial response” to antidepressant treatment 53 . The EMA definition, contrary to the FDA one, explicitly states that the failed antidepressants can be from the same or different mechanistic classes. Limitations of the FDA and EMA definitions are that they do not explicitly operationalize non‐response, and do not consider psychotherapeutic interventions, regarded as first‐line treatments for mild or moderate depression by most guidelines 48 .

Other definitions of TRD have tried to overcome one or more of the above drawbacks (see Table  1 , ​ ,2). 2 ). A commonly cited framework for the definition of inadequate response to antidepressants is the Thase and Rush staging model 54 , 55 . This model does not define TRD categorically, but instead operationalizes and tacitly implies TRD along a continuum of failed antidepressant trials. Stage I is defined by failure of at least one adequate trial of one major class of antidepressants; stage II by failure of at least two adequate trials of at least two distinctly different classes of antidepressants; stage III by stage II resistance plus failure of an adequate trial of a tricyclic antidepressant (TCA); stage IV by stage III resistance plus failure of an adequate trial of a monoamine oxidase inhibitor (MAOI); and stage V by stage IV resistance plus failure of a course of bilateral electroconvulsive therapy (ECT). In the text of the reference paper, it is made clear that the first trial should be a 4‐week one with a selective serotonin reuptake inhibitor (SSRI) in moderate dosages 54 .

Definitions of treatment‐resistant depression (TRD)

FDA – US Food and Drug Administration, EMA – European Medicines Agency, GSRD – European Group for the Study of Resistant Depression, DM‐TRD – Dutch Measure for quantification of Treatment Resistant Depression, MGH‐S – Massachusetts General Hospital Staging, ECT – electroconvulsive therapy

Options for management of treatment‐resistant depression (TRD)

Strengths of the Thase and Rush model are its simplicity, pragmatism, and close proximity to behavior in everyday clinical practice. In addition, this model prioritizes treatments that are better tolerated, which is in line with clinical practice guidelines and treatment algorithms. A first limitation of the model is that “failure” of treatment trials is not operationalized. Furthermore, the model reflects some non‐validated assumptions: for instance that, in a patient initially not responding to an SSRI, a non‐classmate antidepressant is more likely to be efficacious as a next‐step treatment strategy; or that MAOI exposure should be limited to populations with treatment resistance. In addition, there is no explicit consideration of depression features such as duration and severity of the index episode, and no mention of psychotherapeutic interventions. Finally, although augmentation or combination strategies are mentioned in the text of the reference paper 54 , they are not explicitly included in the staging model.

The Maudsley Staging Model (MSM) was developed to improve upon the limitations of the Thase and Rush model 56 . It defines treatment resistance as failure to attain significant level of improvement (i.e., clinical remission) from an accurately diagnosed depressive episode following treatment with an antidepressant given at an adequate dose for a minimum of six weeks. Three dimensions of resistance are included: treatment failure, duration of the depressive episode, and severity of depression 56 .

A maximum of seven points can be assigned for the treatment dimension: one point for failure on 1‐2 medications; two points for failure on 3‐4 medications; three points for failure on 5‐6 medications; four points for failure on 7‐10 medications; five points for failure on more than 10 medications. One further point is assigned if augmentation treatment has failed, and one further point if ECT has not been effective. A maximum of three points can be assigned for the duration of the depressive episode: one if the episode is acute (up to 12 months); two if it is subacute (from 13 to 24 months); three if it is chronic (more than 24 months). A maximum of five points can be assigned for the severity of depression: one if it is subsyndromal; two if it is mild; three if it is moderate; four if it is severe without psychosis; and five if it is severe with psychosis. The overall staging of TRD is defined as mild (total score between 3 and 6), moderate (total score between 7 and 10) or severe (total score between 11 and 15).

Thus, in the MSM, resistance is assessed on the basis not only of treatment but also of illness variables, which has been reported to be useful in predicting short‐ and intermediate‐term outcomes in TRD populations 57 , 58 . Overall, the threshold for the definition of TRD is low, requiring failure of just one adequate treatment. Failure of treatment is not operationalized, although a discussion of the complexity of defining clinical remission is provided in the text of the main paper presenting the model 56 . The assignment of scorings is in some respects arbitrary: for instance, a differential weighting is assigned to populations who fail at least five vs. less than five treatments, in the absence of validation. Failure of manual‐based psychotherapies is not considered.

The European Group for the Study of Resistant Depression (GSRD) 14 separately defined non‐response (failure to respond to one trial of 6‐8 week duration of any antidepressant treatment); TRD (failure to respond to two or more adequate trials of different classes of antidepressants, with five different levels of resistance depending on the overall duration of trials); and chronic resistant depression (failure to respond to several antidepressant trials, including augmentation strategies, of the overall duration of at least 12 months) 14 .

Strengths of the GSRD staging method are the explicit definition of treatment non‐response as a reduction of less than 50% in the total score on the Hamilton Depression Rating Scale (HAM‐D) 59 or the Montgomery‐Åsberg Depression Rating Scale (MADRS) 60 , and the lack of any implicit hierarchy of efficacy of antidepressants. Limitations are the lack of validation of any of the provided time‐based subcategories, including the definition of chronic depression based on a duration of at least one year, which is considerably briefer than what is generally accepted (i.e., longer than two years).

The Dutch Measure for quantification of Treatment Resistant Depression Model (DM‐TRD) was developed to improve upon the point system proposed in the MSM 61 . To the variables considered in that system, this model adds functional impairment (with a score from 0, no impairment, to 3, severe impairment); comorbid anxiety symptoms (with a score from 0, not present, to 1, fulfilling criteria for at least one DSM‐IV anxiety disorder); comorbid personality disorder (with a score from 0, not present, to 1, present based on formal interview); psychosocial stressors (with a score of 0, no psychosocial stressor, or 1, at least one psychosocial stressor); several categories of augmentation/combination regimens (with a score from 0, not used, to 3, five or six medications); use of psychotherapy (with a score from 0, not used, to 2, at least two empirically supported psychotherapies); and intensified treatment (with a score from 0, not used, to 2, inpatient treatment). The maximum total score becomes 27.

This model is the most comprehensive in terms of variables included, although physical comorbidities and childhood adversities are not considered. As in the MSM, the threshold for the definition of TRD is low, requiring failure of just one adequate treatment, and non‐response is not operationalized. The predictive validity of the model has been supported to some extent 61 .

The Massachusetts General Hospital Staging Model (MGH‐S) definition of TRD integrates the number of failed trials with the intensity/optimization of each trial, without assumptions on the hierarchy of antidepressant classes 62 . One point is assigned for non‐response to each adequate trial of a marketed antidepressant (duration of at least six weeks and adequate dosage). Half a point is assigned for each trial based on optimization of dose, optimization of duration, or an augmentation/combination strategy. Three points are assigned for non‐ response to ECT.

Limitations of the MGH‐S include the lack of operationalization of “failure” of trials; the arbitrary scores attributed to treatments; the fact that optimization of dose or duration of treatment is weighted equally as augmentation/combination strategies (which is not empirically supported); and the assignment of one point for each failed antidepressant, which may generate a very high total score 63 .

None of the extant TRD definitions are universally accepted and/or implemented at point‐of‐care in clinical practice 11 , 32 , 64 , 65 , 66 , 67 , 68 . In addition, no existing TRD definition is supported by an external validator and/or biomarker. Most TRD definitions do not explicitly consider failure of manual‐based psychotherapies in their hierarchical characterization of treatment resistance. As psychotherapeutic interventions are recommended as first‐line treatments in persons presenting with depression of mild or moderate severity, any working definition of TRD with clinical utility will need to explicitly include non‐response to these interventions.

Also, common across most definitions of TRD is the absence of a quantifiable and consensus endpoint defining response versus non‐response to antidepressants. An additional limitation is that the definition of outcome is based on a clinician assessment, while patient‐reported outcomes are not considered. Indeed, even amongst patients classified as “responders”, many continue to manifest debilitating residual symptoms 69 , 70 . This was highlighted in the STAR*D trial, in which it was observed that only 10% of persons “in remission” were fully asymptomatic 71 . If, for example, a person is classified as “responder” to treatment but continues to experience cognitive deficits that are impairing, it would be incorrect to consider this an adequate antidepressant response 72 .

None of the extant definitions of TRD includes reference to quality of life. This is a major limitation, given the importance assigned to this variable by persons with lived experience 73 . The predictive utility of quality of life as a critical outcome measure when defining TRD is underscored by the observation that persons remitting with antidepressants who continue to report decreased quality of life are at greater risk of relapse and recurrence 74 , 75 .

Further drawbacks of existing TRD definitions are that they fail to take into consideration the social, economic, anamnestic (e.g., adverse childhood experiences) and interpersonal factors which, alone or in combinations, are known to moderate antidepressant response 1 , 44 , 47 , 71 , 75 , 76 , 77 , 78 , 79 , 80 , 81 . Furthermore, an unintended consequence of a TRD framework that is hierarchical is encouraging multiple unproven treatment strategies, with polypharmacy and the possibility of associated safety and tolerability concerns 70 , 75 .

Moreover, results of a recent analysis in the WHO World Mental Health Surveys underscores that persistence with next‐step treatments is uncommon in persons with MDD 82 . Also, in those who do switch to next‐step treatments, a considerable treatment delay (i.e., 6‐9 months) elapses before switching occurs 82 , 83 .

An example of a patient‐centric framework describing persons with multiple antidepressant failures is the construct of difficult‐to‐treat depression (DTD) 84 . This construct relies on a biopsychosocial approach when considering causal, perpetuating and treatment factors of poor outcomes in depression 70 . The therapeutic emphasis in DTD pivots away from symptomatic remission towards symptomatic control, functional recovery and quality of life improvement as part of chronic disease management 70 .

For several patients, despite non‐remission status, more modest improvement in overall depressive symptom severity may result in significant self‐assessed improvement in well‐being 85 , 86 , 87 . For example, an approximate 35% improvement from baseline in total MADRS score may be associated with significant improvement of quality of life in persons with TRD 87 . These data support the notion that more modest improvements in symptom severity in persons with TRD may be clinically meaningful, and invite the need for multidimensional definitions that are not solely dependent on threshold symptomatic improvement 86 , 88 , 89 .

Surveys of persons with lived depression experience have highlighted the importance of dimensional symptomatic outcomes in addition to categorical ones 90 , 91 . For example, alleviation of emotional blunting, anhedonia, anxiety and rumination are often prioritized by persons living with depression over full symptomatic remission 92 . Shared‐decision making, patient‐centered care focusing on specific symptoms of concern, and integrating treatment modalities become paramount in DTD, in keeping with the guiding principles of chronic disease management 84 , 93 , 94 , 95 , 96 . Although DTD is not currently recognized by regulators as a pathway for treatment approval and marketing authorization, it more closely approximates real‐world presentations and outcomes among persons with TRD, and could serve as a clinical heuristic or even a framework informing the further characterization of TRD.

Overall, there is a confluence of research, clinical, policy, and public health reasons to have a validated and universal TRD definition. Existing definitions would be best characterized as frameworks that vary in their constituent variables and working assumptions. The existing TRD frameworks reviewed herein have not provided any substantive insight into the pathogenesis, treatment discovery and development, or clinical care of persons with TRD.

Moreover, there is no compelling evidence that any of the foregoing TRD frameworks have been implemented at large scale by the clinical or research community. A consensus definition of TRD at the very least will need to provide a quantifiable endpoint defining response, integrate manual‐based psychotherapies, empirically validate assumptions surrounding differential treatment weighting, and integrate multiple factors known to influence antidepressant response. A TRD definition that is consistent across disparate clinical care ecosystems, and fulfills both research and clinical needs, is badly needed.

PREVALENCE OF TREATMENT‐RESISTANT DEPRESSION

Differences in the definition of TRD have resulted in highly variable estimates of its prevalence rate 99 . TRD is often stated to affect approximately 30% of persons receiving antidepressant treatment in research settings, while its prevalence in real world practice is estimated to range between 6 and 55% 32 , 98 , 99 , 100 , 101 .

Most individuals with MDD access mental health care initially through the primary care system, where measurement‐based care is rarely implemented 102 , 103 , 104 . A tentative estimate of the prevalence of TRD in primary care can be made only indirectly by using a “depression treatment cascade” approach 105 . Approximately 10‐15% of patients in primary care present with clinically significant depressive symptoms, and only about half of these cases are diagnosed, of which an estimated 25% are prescribed an antidepressant 106 . Replicated evidence indicates that, of those prescribed antidepressants, the majority discontinue treatment prematurely. Hence, only about 5‐7% of persons with depression treated in primary care settings would be expected to achieve remission 106 . The foregoing cascade approach – which integrates aspects of misdiagnosis, non‐adherence, inadequate treatment trials, as well as implementation gaps – underscores the high prevalence of poor outcomes of depression in primary care, of which a significant percentage would be expected to meet criteria for TRD 10 , 30 , 64 , 71 , 107 , 108 .

A more precise estimate of the prevalence of TRD can be done by referring to the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, a National Institute of Mental Health (NIMH)‐sponsored multisite study (18 primary care and 23 psychiatric care settings) carried out in the US 33 . All eligible subjects enrolled in the STAR*D trial initiated treatment with citalopram. After a 12‐week trial (level 1 treatment), those persons not in remission were randomly assigned to one of seven switch/combination approaches (level 2). Non‐response to a switch/combination level 2 treatment resulted in randomization to further treatments (levels 3 and 4). The FDA and EMA definitions of TRD would align with failure to level 1 and 2 treatments in the STAR*D trial. On this basis, it can be estimated that approximately 55% of persons with MDD would meet the FDA/EMA criteria for TRD (i.e., inadequate response to two or more antidepressants despite adequate treatment intensity and duration) 33 .

In summary, while it is often stated that TRD is affecting approximately 30% of persons receiving antidepressant treatment, a more stringent and multidimensional definition of this condition emphasizing symptomatic remission increases this estimate to about 55%.

RISK FACTORS FOR TREATMENT‐RESISTANT DEPRESSION

Many factors have been identified as being associated with reduced antidepressant response, but relatively few are established as risk factors specifically for TRD. In addition, most factors identified as negatively affecting antidepressant outcomes are reported in small studies and are described with a particular antidepressant intervention. Amongst the relatively few studies that have sought to identify factors associated with TRD, most are limited by the inconsistent definition of this condition, and primarily evaluate outcomes with monoamine‐based antidepressants.

Herein, we endeavour to identify factors that are associated with TRD. As most studies have evaluated factors associated with reduced response to conventional antidepressants rather than TRD, we provide clarity and attempt to separate these two aspects.

Sociodemographic factors

It is established that older persons more frequently fail multiple monoamine‐based antidepressant treatments, which may be taken as evidence that TRD is more common in this subpopulation 109 , 110 . However, there is no evidence of an attenuated response in older adults with depression receiving manual‐based psychotherapeutic treatments 111 , and the efficacy of ECT does not seem to be reduced as a function of age 112 . It is also reported that repetitive transcranial magnetic stimulation (rTMS) may have similar (or potentially greater with increased pulse dose) efficacy in older adults with MDD 113 .

It is not established whether female sex is a risk factor for TRD 114 . Whether depression during reproductive life events (e.g., peripartum onset depression) is more likely to be treatment‐resistant is also not sufficiently established 115 . It is, however, well known that females are affected by depression at twice the rate of males, and are more likely to be prescribed antidepressants 116 . Consequently, females would be expected to represent the majority within a TRD population, although it remains uncertain whether their relative risk is higher.

Socioeconomic position is a risk factor for TRD in persons receiving monoamine‐based antidepressants. For example, in the STAR*D trial, persons meeting level 2 criteria (i.e., inadequate response to two sequential antidepressant regimens) were more likely to report lower income and dependence on the public health system 117 . In addition, persons of lower educational attainment or unemployed are found to be more often resistant to multiple sequential antidepressant strategies 17 , 118 .

Future research should evaluate whether racial and/or ethnic factors contribute to the occurrence of TRD, and also endeavour to explore whether sexual orientation and/or gender identity, marital status, interpersonal connectedness, and measures of loneliness are risk factors for TRD.

Adverse experiences and trauma

It is well established that childhood maltreatment is associated with greater severity of depression, earlier age at onset, cognitive dysfunction, presence of psychotic symptoms, and physical/psychiatric comorbidities, each of which is also associated with attenuated response to antidepressants and manual‐based psychological interventions 119 , 120 , 121 , 122 , 123 .

There are also studies providing evidence that a reported history of childhood emotional abuse is associated with recurrent depression, persistent depression, as well as treatment resistance to antidepressants 124 . The international Study to Predict Optimized Treatment for Depression (iSPOT‐D) reported that, amongst adults with MDD and a history of trauma between the ages of 4 and 7 years, only 15.9% achieved remission after 8 weeks of treatment with escitalopram, sertraline or venlafaxine, compared to 84.1% in individuals with no history of childhood trauma 125 .

The attenuated response to antidepressants in persons with a history of childhood maltreatment may not, however, occur with all antidepressants. For example, preliminary evidence suggests that response to vortioxetine or ketamine treatment in depression is not reduced in persons with trauma, suggesting different outcomes as a function of the putative mechanism of action of medications 126 , 127 .

More in general, life stress events have been directly associated with a poorer response to commonly prescribed antidepressants, as well as with a greater occurrence of suicidal behavior and comorbidities and a greater severity of symptoms, which are variables that could mediate the association with an attenuated response to antidepressants and possibly to TRD 128 .

Clinical factors

Greater baseline severity is a highly replicated risk factor for TRD, and is indeed included in some frameworks as a variable in the hierarchical characterization of the condition. Illness duration is also highly associated with TRD, with replicated evidence indicating that the length of a depressive episode is inversely proportional to the probability of treatment response 129 .

Evidence also suggests that some phenomenological characteristics of depression may be associated with treatment resistance. Psychotic symptoms affect approximately 20% of adults with MDD and are highly associated with TRD 130 . Mixed features are reported to be present in approximately 25% of persons with MDD and are associated with attenuated antidepressant response, although it remains to be determined whether they are a risk factor specifically for TRD 47 , 131 .

Anhedonia is a core component of depression endorsed by 35‐75% of patients, and may be a risk factor for TRD in persons whose treatment history is delimited to SSRIs 132 , 133 . Cognitive deficits in MDD are prevalent, persistent, and often progressively increase as a function of illness severity and duration; they are associated with attenuated response to select antidepressants, and may represent a risk factor for TRD 72 , 134 , 135 , 136 .

Anxiety symptoms are frequently reported in TRD populations, and their presence in MDD is associated with a more severe illness presentation, lower probability of remission, comorbidities and suicidality 137 , 138 , 139 , 140 . Results from the STAR*D trial indicate that persons presenting with anxious depression exhibit attenuated antidepressant response and are more likely to develop TRD 141 . The GSRD study also reported that anxiety disorders were over‐represented in persons meeting criteria for TRD 142 .

It is well established that TRD populations have a higher rate of psychiatric and physical comorbidities as compared to non‐TRD populations 143 . In addition, TRD is a risk factor for incident physical comorbidities, such as cardiovascular disease, type 2 diabetes mellitus, osteoporosis, and metabolic syndrome 40 , 144 , 145 , 146 . Evidence indicates that the foregoing physical diseases are in their turn risk factors for TRD 145 , 147 , 148 , 149 , 150 , 151 , 152 .

DETECTION OF TREATMENT‐RESISTANT DEPRESSION

The assessment of an individual with MDD towards personalization of treatment selection and sequencing has been previously reviewed in this journal 13 . Herein, we specifically focus on the assessment process aimed to confirm that TRD is present, and to rule out the possibility of pseudo‐resistance.

Reviewed herein are the most common modifiable contributors to pseudo‐resistance, including inaccuracy of the MDD diagnosis, inadequacy of current and past treatment trials, inaccurate assessment of response, and individual differences in the metabolism of antidepressants 153 , 154 .

Accurate diagnosis of MDD

Inaccuracy of the MDD diagnosis is a common reason for pseudo‐resistance. It is estimated that approximately half of individuals with MDD are not correctly diagnosed 155 . A not uncommon scenario in clinical practice is the depressed patient presenting with resistance to multiple sequential antidepressants whose correct diagnosis should be bipolar disorder instead of MDD 156 .

For most individuals with bipolar disorder, depression is the index presentation, which warrants reconsideration of the MDD diagnosis in any person presenting with TRD. Indeed, it is reported that individuals prescribed multiple failed antidepressant trials (i.e., TRD) have a much greater likelihood of an underlying diagnosis of bipolar disorder as compared to persons prescribed a single antidepressant trial 157 . Furthermore, it is reported that the transition from a diagnosis of MDD to one of bipolar disorder occurs at a rate of approximately 1‐3% per year, indicating that diagnostic assessment must be reconsidered in all TRD presentations 130 , 158 , 159 .

Multiple screening tools for bipolar disorder have been validated, including the Rapid Mood Screener (RMS) 160 , the Patient Mania Questionnaire (PMQ) 161 , the Mood Disorder Questionnaire (MDQ) 162 , and the Hypomania Checklist‐32 163 . Although screening tools are not sufficient to diagnose bipolar disorder, they can be used routinely in clinical practice and, if positive, warrant a more comprehensive assessment of the possible presence of bipolar disorder.

In addition to screening for bipolar disorder, relevant comorbid conditions should be diagnosed and managed if present. They include substance and alcohol use disorders, anxiety disorders, personality disorders, and some physical diseases such as hypothyroidism.

Determining the adequacy of treatment trials

The adequacy of an antidepressant treatment refers to the choice of medication, its dose, the duration of treatment, and the patient's adherence. A comprehensive and precise characterization of current and past medication regimens is required in order to confirm the presence of TRD, and can be captured by several instruments.

The Antidepressant Treatment History Form (ATHF) is a data capture instrument suitable for implementation at point‐of‐care. It was originally developed in studies of ECT and has subsequently undergone a broader clinical and research application 164 . It has explicit criteria for evaluating response to pharmacological and neurostimulation treatments, and is also available in a shorter version (the ATHF‐Short Form, ATHF‐SF) 165 . Other instruments that capture and record current and prior antidepressant regimens are the self‐rated Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (ATRQ) 166 and the Maudsley Treatment Inventory 56 .

First of all, the appropriateness of the antidepressant regimen needs to be confirmed. It is well established that a knowledge‐implementation gap exists between what are proven treatment strategies in MDD and what are actually implemented 42 . The adequacy of the dose of the medication has then to be considered: dosing recommendations are established for all approved antidepressants and are described in their respective product monographs.

The adequate duration of an antidepressant trial is generally considered to be 4‐6 weeks at optimal dosing, although 60% of persons who achieved remission in the STAR*D trial with level 1 treatment did so after week 6 of treatment, indicating that a subpopulation of adults with MDD may require longer treatment trials 167 , 168 .

Adherence to treatment has also to be assessed. A replicated observation is the high rate of non‐adherence to antidepressants in persons with MDD. Persons with less than 80% adherence to antidepressant regimen recommendations are commonly defined as non‐adherent 169 . Using this definition, about 30‐50% of persons prescribed with antidepressants are non‐adherent in acute phase treatment 169 . Assessing adherence to therapy includes pill counts and patient self‐report. Digital sensor systems have been used in academic studies to document adherence, but are not readily available for clinical implementation.

Assessing outcome of previous antidepressant trials

Defining TRD implies quantification of therapeutic outcome with previous antidepressant treatments. However, as already stated, most definitions of TRD do not provide a quantifiable and consensus endpoint defining response versus non‐response to antidepressants. An exception is the GSRD staging method 14 , which explicitly defines treatment non‐response as a reduction of less than 50% in the total score on the HAM‐D or the MADRS. This may represent a useful reference in ordinary clinical practice.

However, it is noticed that, in some patients, a reduction of total MADRS score of about 35% may be associated with significant improvement of quality of life 87 , supporting the need for multidimensional definitions that are not solely dependent on threshold symptomatic improvement 86 , 88 , 89 . The use of measures such as the World Health Organization‐Five Well‐Being Index (WHO‐5) may be suggested for this purpose 170 . More in general, therapeutic endpoints that integrate patient‐reported outcomes along with symptomatic measures may provide a more precise characterization of response to treatment 82 .

Although “failure” of one or more antidepressant trials is an integral part of all definitions of TRD, it must be acknowledged that there is no consensus in the field about how this “failure” should be defined and ascertained. Overcoming this major limitation is an obvious priority for future research on TRD.

Pharmacogenomic testing and evaluating antidepressant blood levels

Evidence indicates that a subset of MDD patients presenting with TRD may exhibit a failed antidepressant response as a consequence of a suboptimal bioavailability of the administered antidepressant, due to rapid metabolizer status 171 , 172 , 173 , 174 . Available evidence indicates that allelic variations of cytochromes P450‐2D6 (CYP2D6) and P450‐2C19 (CYP2C19) are especially associated with antidepressant outcome. In particular, CYP2D6 phenotypes may be important in some patients taking TCAs and venlafaxine, and CYP2C19 phenotypes in some individuals receiving TCAs, citalopram, escitalopram and sertraline 171 . Although pharmacogenetic testing cannot be recommended as a routine assessment in TRD, some preliminary evidence does suggest that, in select circumstances, it may be warranted.

Furthermore, blood levels should be monitored in non‐responding persons receiving some TCAs (i.e., imipramine, desipramine, nortriptyline), as therapeutic levels/windows have been established for these agents 175 , 176 , 177 .

MANAGEMENT OF TREATMENT‐RESISTANT DEPRESSION

Herein, we review tactics which can be considered for managing TRD once the presence of this condition is confirmed. These tactics include extending the current antidepressant trial, switching antidepressants, combining antidepressants, use of esketamine/ketamine, and neurostimulation (see Table 2).

Although manual‐based psychotherapies are not proven to be efficacious as a standalone intervention in TRD, their efficacy in combination with antidepressants is briefly reviewed. Also, we briefly review the evidence for other strategies (e.g., lithium, thyroid hormone) that are better established in patients with partial response to TCAs and MAOIs rather than principally studied in TRD.

We also review data for SGAs, despite the fact that – with the exception of the olanzapine‐fluoxetine combination – these medications are not approved for TRD, but only for individuals with MDD exhibiting partial response to an index antidepressant.

Extending the antidepressant trial

As mentioned earlier, results from the STAR*D trial indicated that a proportion of individuals who responded to level 1 treatment did so after week 6. A systematic review of available studies sought to evaluate the likelihood of response during weeks 5‐8 and 9‐12 in individuals with MDD not responding after four weeks 178 . It was concluded that approximately 20% of patients with MDD not responding in the first four weeks responded during weeks 5‐8, while approximately 10% responded during weeks 9‐12 178 .

However, it is not established that extending an antidepressant trial in patients defined as having TRD results in any considerable likelihood of treatment success. In addition, persons with lived depression experience prioritize rapidity of antidepressant action, so that prolonging antidepressant trials for an additional one to two months is unlikely to be acceptable in most cases of TRD 92 .

Switching antidepressants

Meta‐analytic data are conflicting as to whether switching antidepressants increases the likelihood of response in TRD 179 , 180 . A related but separate concept that would justify switching class of antidepressants is that of “broadening the spectrum of efficacy”. For example, a patient prescribed an SSRI who continues to manifest debilitating anhedonia, fatigue, and psychomotor retardation may exhibit significant improvement when switching to an antidepressant with a different mechanism of action 181 , 182 .

Overall, switching antidepressants may be considered in some cases of TRD, and the new agent should be a “non‐classmate” antidepressant.

Combining antidepressants

Persons with TRD are commonly treated with antidepressant polypharmacy, but few relevant studies have been conducted specifically in populations with TRD 183 , 184 , 185 , 186 , 187 .

Results from a meta‐analysis have supported the efficacy of adding mirtazapine or bupropion in persons with “early‐stage” TRD (i.e., non‐response to one adequate pharmacological or psychological therapy for depression) 188 . As mentioned earlier, level 2 treatment (i.e., TRD) from the STAR*D trial included seven possible switch/augmentation strategies in adults with non‐psychotic depression not achieving remission with citalopram. The three augmentation approaches were bupropion, buspirone, and cognitive therapy. The proportion of patients achieving remission after receiving bupropion combined with citalopram was 39.0%, compared to 25.5% when switching to bupropion sustained release (SR) monotherapy 33 .

A recent meta‐analysis concluded that alpha‐2 autoreceptor antagonists (i.e., mirtazapine, mianserin, trazodone) combined with SSRIs are superior to monotherapy in mixed populations including TRD, but the composition of the patient samples studied precludes any definite interpretation of the finding 189 .

Overall, data supporting the combination of antidepressants as an efficacious treatment strategy is modest in TRD populations.

Ketamine/esketamine

Intravenous (IV) racemic ketamine has been found to rapidly improve depressive symptoms and suicidal ideation in adults with TRD, and its efficacy has been confirmed in real‐world patient samples. Clinically meaningful benefit has been observed in both single and multiple infusion studies 190 , 191 , 192 , 193 . Intranasal esketamine spray co‐initiated with an antidepressant has also demonstrated rapid clinically meaningful efficacy in patients with TRD. Unlike IV ketamine, there are also data demonstrating long‐term (i.e., greater than 3‐year) safety and tolerability for esketamine 194 , 195 .

Item analysis indicates that ketamine and esketamine not only significantly improve overall symptoms of TRD, but also specific depressive symptoms that are over‐represented in adults with TRD, such as anhedonia 196 , 197 , 198 , 199 . Meta‐analytic data also indicate that glutamatergic treatment strategies may be superior to antipsychotic agents in adults with TRD 200 , 201 .

In 2019, the FDA approved intranasal esketamine spray combined with antidepressants in adults with TRD, with subsequent approvals by other regulators globally (e.g., EMA). Less evidence is available for ketamine and/or its derivatives delivered through other routes of administration 191 . Moreover, the concomitant administration of ketamine and psychological interventions (“ketamine‐assisted” therapy) is insufficiently characterized and as such cannot be recommended for TRD 202 .

Results from the recent ESCAPE‐TRD trial indicate that intranasal esketamine combined with an antidepressant is significantly more effective than quetiapine XR in TRD, with a remission rate at week 8 of 27.1% vs. 17.6% (p=0.003) 203 . Remission rates continued to increase in both arms after the primary endpoint, with a significantly greater proportion of patients in remission at week 32 in the intranasal esketamine than in the quetiapine XR arm (55% vs. 37%, p<0.001) 203 .

Preliminary evidence indicates that the effectiveness of IV ketamine in individuals with TRD and history of non‐response to neurostimulation (i.e., ECT or rTMS) is not reduced as compared to individuals with TRD and no prior neurostimulation treatment 204 . Available evidence also indicates that the efficacy of ketamine/esketamine in the acute treatment of TRD is also apparent in individuals with greater degrees of antidepressant resistance 205 .

Safety concerns attributable to long‐term ketamine/esketamine exposure include potential for abuse and misuse, tolerance and withdrawal, effects on liver function, and possibly kidney and/or urogenital toxicity 206 . The risks for the foregoing safety concerns would be expected to be mitigated when administering ketamine/esketamine under medical supervision in accordance with best practices 205 .

Second‐generation antipsychotics

The only SGA evaluated in patients failing two or more prior antidepressant treatments (i.e., TRD) is the fixed dose olanzapine‐fluoxetine combination 207 , 208 , 209 . The other SGAs assessed in MDD (i.e., aripiprazole, brexpiprazole, cariprazine, risperidone and quetiapine XR) have been studied only in patients with a partial response to at least one antidepressant 187 , 201 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 .

Head‐to‐head comparisons of SGAs as augmentation in TRD are not available, nor are long‐term recurrence prevention data. The absence of long‐term data with SGAs is a point of differentiation with esketamine, which has long‐term multi‐year establishment of efficacy and safety 195 . Limitations of longer‐term use of SGAs in MDD relate to tolerability and safety concerns (e.g., metabolic dysregulation, weight gain, and extrapyramidal adverse effects) 225 .

Relatively few studies have compared the antipsychotic augmentation of antidepressants versus the combination of antidepressants in patients presenting with suboptimal antidepressant response. The VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST‐D) trial was a multisite randomized, single‐blind, parallel‐assignment trial of depression unresponsive to at least one course of antidepressant treatment 226 . Eligible subjects were randomly assigned to one of three treatments: switch to bupropion SR, augmentation of current treatment with bupropion SR, or augmentation of current treatment with aripiprazole. The remission rate at week 12 was higher for the aripiprazole group (28.9%) compared with the switch to bupropion SR group (22.3%), but not with the bupropion SR add‐on group (26.9%). Response rates were significantly higher for the aripiprazole group (74.3%) than for both bupropion SR monotherapy and bupropion SR augmentation groups (62.4% and 65.6%, respectively) 226 .

The VAST‐D trial results replicate and extend the efficacy and tolerability of SGAs in individuals with MDD partially responding to antidepressants. As mentioned earlier, there are insufficient data for SGAs in TRD. However, results of the ESCAPE‐TRD trial suggest superiority of intranasal esketamine to quetiapine XR.

Neurostimulation

Neurostimulatory treatments evaluated in TRD include vagus nerve stimulation (VNS), ECT, rTMS, magnetic seizure therapy, deep brain stimulation, and transcranial direct current stimulation 227 , 228 , 229 , 230 , 231 , 232 , 233 .

VNS has proven to be efficacious in patients with higher‐order TRD (i.e., equal or greater than four prior antidepressants), and has also demonstrated durability of effect with maintenance treatment 234 , 235 , 236 . The FDA has approved VNS in TRD patients with a history of at least four prior failed antidepressants.

ECT is a well‐established therapeutic intervention in the treatment of TRD, with an average open‐label remission rate of 48% in non‐psychotic depression 237 . Efficacy may be higher in individuals with psychotic depression. Many modifications to the implementation of ECT have retained efficacy in TRD with improved tolerability profile (e.g., bilateral brief pulse ECT vs. right unilateral ultra‐brief pulse ECT) 238 .

Results from systematic reviews and meta‐analyses consistently support the efficacy of rTMS in TRD 233 . Results also indicate that greater severity at baseline and higher number of prior antidepressant failures are associated with attenuated rTMS efficacy 239 , 240 , 241 , 242 , 243 . The cost‐effectiveness of rTMS in adults with TRD is well established, and possibly higher compared to ECT, but available evidence also shows that ECT may be more effective than conventional rTMS in the acute and recurrence prevention treatment of TRD 244 , 245 , 246 .

Newer forms of rTMS are being validated, including conventional intermittent theta burst stimulation (iTBS), whose efficacy in adults with TRD when compared to sham treatment is well established 247 , 248 . An accelerated high‐dose iTBS protocol with magnetic resonance imaging (MRI)‐guided functional connectivity targeting (Stanford neuromodulation therapy, SNT) has been found, in a double‐blind randomized controlled trial (RCT), to be significantly superior relative to sham treatment four weeks after the end of the five‐day protocol. The significant benefit observed was evident despite an average of five prior antidepressant medication trials 249 . The SNT approach was recently cleared by the FDA for TRD.

In addition, results from RCTs have supported the efficacy of magnetic seizure therapy, with additional evidence demonstrating continuation of effect 250 , 251 . A Cochrane review did not identify a significant difference between this therapy and ECT in adults with TRD 252 .

Results of RCTs have not documented the efficacy of deep brain stimulation, when compared to sham treatment, in TRD 253 , 254 , 255 , 256 , 257 . Transcranial direct current stimulation is associated with variable outcomes across RCTs in the treatment of adults with TRD: the heterogeneity in response may be due to the broad range of treatment resistance included in the original trials, from treatment‐naïve to ECT failing individuals 258 .

In summary, of the foregoing neurostimulation modalities, ECT, rTMS, VNS and SNT are recommended in adults with TRD. Although there is a lack of head‐to‐head comparator data of proven treatments in TRD, preliminary evidence suggests that ECT may be non‐inferior when compared to IV racemic ketamine in adults with TRD 259 .

Psychotherapeutic interventions

There are multiple reasons for considering psychotherapeutic interventions in persons with TRD. For example, evidence indicates that these interventions are a preferred treatment option over pharmacotherapy amongst persons with lived depression experience 73 , 260 , 261 . Residual symptoms and comorbidities in persons with TRD are frequently amenable to psychological treatments. Psychotherapies, when combined with pharmacological treatments, are conceptually supported insofar as they facilitate learning, coping and resilience mechanisms that synergize with the hypothesized biological mechanisms of action of antidepressants 262 . Finally, individuals with persistent depression and history of trauma, both of which are more common in TRD populations, exhibit significant response rates with psychological interventions 263 , 264 .

Notwithstanding the rationale for use of psychotherapies in TRD, data supporting them as standalone interventions in TRD are limited 265 , 266 . Available evidence does, however, support the efficacy of adjunctive psychological interventions in persons with TRD 267 , 268 , 269 , 270 , 271 .

The psychotherapeutic modalities most frequently investigated include cognitive behavioral therapy (CBT), interpersonal psychotherapy, and mindfulness‐based cognitive therapy 272 . Meta‐analytic data have determined that psychotherapy added to ongoing treatment as usual (TAU) had a moderate and significant effect size (Hedges’ g=0.42) in comparison with TAU alone in TRD 272 .

Overall, the available evidence indicates that manual‐based psychotherapies are effective in persons with TRD when combined with antidepressants. There is insufficient evidence about combining these interventions in persons with a higher number of prior antidepressant failures and/or ECT non‐response. Patient preference, potential for scalability with digital solutions, and efficacy in the treatment of comorbidities (e.g., anxiety disorders) are additional rationales for considering psychotherapies in patients with TRD. Preliminary evidence suggests that CBT may be capable of prolonging the effect observed in adults with TRD who acutely benefited from ketamine treatment 202 .

However, a recent European study that rigorously defined TRD failed to demonstrate the efficacy of adjunctive psychological treatment 266 . It may be surmised that patient characteristics and the type of psychological intervention are critical moderators of efficacy in TRD populations.

INVESTIGATIONAL INTERVENTIONS IN TREATMENT‐RESISTANT DEPRESSION

The public health implications of TRD provide the impetus for the development of new interventions specifically for this subpopulation. It is noteworthy that enrollment in most clinical trials of investigational agents in MDD exclude patients with TRD, especially those with a high number of failed prior antidepressant trials in the current episode, or those who have failed ECT or IV ketamine in this episode.

The class of agents imprecisely referred to as psychedelics has received the most attention as a potential investigational intervention in TRD 273 . Preliminary evidence suggests that psilocybin, combined with psychotherapy, may offer rapid and possibly sustained symptom relief in adults with TRD. For example, a phase 2 double‐blind trial randomly assigned adults with TRD to receive a single dose of psilocybin 25 mg, 10 mg or 1 mg (control) along with psychological support 274 . All persons had failed at least two prior treatments before enrollment. Participants receiving the 25 mg dose, but not the 10 mg dose, exhibited a significantly greater least‐squares mean change from baseline to week 3 compared with the 1 mg dose. The response and remission rates for the participants receiving the 25 mg dose were 37% and 29%, respectively 274 .

Several methodological problems affect available controlled trials with psilocybin in TRD. Aspects of unblinding as well as expectancy are undoubtedly contributing to the observed effects, as are the psychotherapeutic modalities that are considered integral to the process of taking psychedelics. Nevertheless, the results of available RCTs with psilocybin have provided the impetus for evaluating this drug in phase 3 pivotal trials for TRD 275 . Deconstructing the contribution of psychotherapy from the psychedelic intervention will be an inexact yet necessary endeavor in order to interpret study findings and provide appropriate treatment and implementation recommendations. Moreover, the psychotherapy that is currently combined with psychedelics does not have a standardized evidence‐based protocol.

Additional investigational interventions in TRD include lithium, thyroid hormone, buspirone, L‐methylfolate, S‐adenosylmethionine, anti‐inflammatory agents (e.g., COX‐2 inhibitors, minocycline, statins, and tumor necrosis factor‐alpha antagonists), zuranolone and dextromethorphan‐bupropion combination 276 , 277 , 278 , 279 , 280 . The extant evidence supporting lithium and thyroid hormone largely refers to their combination with TCAs and MAOIs in patients with partial response to these agents. Medications that have been studied in TRD and demonstrated not to be efficacious are pindolol and buprenorphine 281 , 282 .

Despite the widespread prescription of multiple psychotropic agents off‐label in patients with TRD, there are no rigorous studies with large samples establishing the efficacy of any of the foregoing strategies.

CONCLUSIONS

Amongst individuals meeting criteria for MDD with access to high‐quality measurement‐based care, at least 30% will meet criteria for TRD. This estimate is derived from efficacy and/or effectiveness research findings. The prevalence of TRD in real world practice is not known, but would be expected to be higher, due to knowledge‐implementation gaps, barriers to access, and illness presentation complexity 283 .

With respect to illness presentation complexity, most individuals with TRD encountered in clinical practice would not be eligible for most clinical research studies, on the basis of illness characteristics (e.g., severity, number of prior episodes, suicidality), comorbidity and treatment history 13 , 284 .

Multiple definitions of TRD have been proposed and are reviewed herein. The lack of a universal definition of TRD is a barrier to advancing mechanistic and translational research, as well as to identifying innovative and precision‐based therapeutics. In addition, public policy decisions, as well as clinical decision‐making, would be benefited by a more precise and valid definition of TRD. For example, considerations for reimbursement in TRD which are critical for access to treatment are limited by the fact that multiple definitions of this condition exist. Hence, decisions by policy makers on whether to include treatments for TRD as part of a reimbursement schedule are highly variable across jurisdictions. From a clinical perspective, the lack of a universal definition of TRD contributes to heterogeneity in treatment selection and sequencing. This heterogeneity is also reflected in clinical practice guidelines for MDD, that have different recommendations with respect to selection and sequencing of treatments for adults with TRD.

Consensus exists that the lack of a clinically meaningful improvement with a minimum of two antidepressants should be retained in any working definition of TRD. A quantifiable endpoint defining non‐response should be provided. A comprehensive and conceptually valid definition of TRD with clinical utility should also include aspects of patient‐reported outcomes, psychosocial function, as well as dimensional outcomes (e.g., anhedonia) 285 .

The related, but separate, notion of DTD seems more aligned with the realities of the clinical ecosystem, and with patient experience of depression and sequential non‐response to treatments 94 , 286 . A compelling case is made that TRD is potentially judgmental insofar as it may be interpreted as blaming the patient. Instead, DTD is agnostic and represents a patient‐centered and pragmatic approach to identifying therapeutic targets 84 . The construct of DTD could serve as a useful framework informing further characterization of TRD.

The variability in antidepressant response is widely recognized 287 . A confluence of sociodemographic and clinical characteristics is known to moderate this response. Clinicians are encouraged to identify modifiable factors that attenuate antidepressant outcomes and allocate resources to these factors in patients prescribed antidepressants. For example, non‐adherence, illness and treatment illiteracy, stigma, and attitude towards treatment are modifiable with psychoeducation efforts and possibly peer‐support 73 .

In addition, psychiatric and physical comorbidities not only attenuate antidepressant response but may also be a consequence of TRD. Targeting comorbidities at the same time as depressive symptoms would be predicted to improve treatment outcomes as well as reduce cost and health resource utilization in adults with MDD. In addition, closing the implementation‐knowledge gap with fidelity to evidence‐based treatments is a near‐term cost‐effective priority in the management of MDD today.

The evidence supports select SGAs, as well as rTMS and manual‐based psychotherapies (in combination), as proven strategies in adults who have failed one prior antidepressant. For individuals with TRD (failing multiple antidepressants), evidence is best for ketamine, esketamine, adjunctive psychotherapy, ECT and rTMS. Psychotherapeutic interventions in combination with antidepressants may offer partial symptomatic relief in persons with TRD, but their efficacy as monotherapy is not established. Combination antidepressants, switching antidepressant treatment, dose optimization and the use of a host of augmentation strategies (e.g., lithium, thyroid hormone) have mixed data supporting their usefulness 288 .

Intranasal esketamine combined with an antidepressant is the most rigorously evaluated pharmacologic strategy in the acute and maintenance treatment of adults with TRD. In addition to demonstrating acute efficacy, it has established relapse prevention, tolerability and safety in persons with TRD, with more than three years of maintenance data. IV racemic ketamine has also demonstrated robust rapid antidepressant efficacy in mostly acute studies. There are relatively few controlled studies, however, that have documented maintenance efficacy of repeat‐dose IV ketamine in adults with TRD 289 .

The relative efficacy of intranasal esketamine to ECT in TRD is unknown, but is currently being evaluated. Preliminary evidence suggests that ECT may be non‐inferior to IV racemic ketamine in the acute treatment of TRD 259 . Results from large and rigorous controlled studies comparing IV ketamine to ECT are expected to provide further decision support and inform recommendations for treatment sequencing in TRD 259 .

The investigational interventions in TRD that have received the most research, media and public attention have been psychedelics. Available evidence for psilocybin suggests acute efficacy that is rapid and sustained in well‐characterized samples of persons with TRD. Unanswered questions as to the contribution of integrated psychotherapy in persons receiving psilocybin have not only conceptual and clinical relevance, but are also critical to address from an implementation perspective.

Future research vistas with respect to pharmacological treatment are testing whether ketamine derivatives or other glutamatergic agents may be useful in TRD. Additionally, GABAergic agents (e.g., zuranolone), opioid receptor modulators, orexin antagonists, voltage‐gated ion channels modulators, anti‐inflammatories, as well as agents targeting cellular metabolic processes are also under investigation in TRD 290 .

It is recognized that TRD is an under‐researched clinical population with disproportionate morbidity and mortality. Mechanistically novel interventions that offer meaningful benefit may be eligible for FDA “breakthrough status”, incentivizing treatment discovery and development in this area.

Identifying biomarkers and biosignatures associated with TRD is an important future research vista. As reviewed herein, pharmacogenomic testing has preliminary support as a tactic in assessing TRD patients, especially in cases of medication poor tolerability. Notwithstanding, it cannot be recommended as a routine assessment in all persons presenting with TRD. It is anticipated that pharmacogenomics will advance, as will the ability to computationally interrogate multi‐omic data, providing insights into the neurobiology of TRD and also potentially informing patient stratification and precision therapeutics with clinical ecosystem application potential.

Digital psychiatry encompasses aspects of health care delivery, illness surveillance, disease management and treatment 291 , 292 , 293 , 294 . Multiple proprietary and academically led product developments are underway to identify digital therapeutics that may have application in TRD populations.

The next decade can reasonably expect the regulatory approval of innovative pharmacological treatments targeting systems implicated in the pathophysiology of depression. The foregoing, along with advances in the digital delivery of psychological interventions and refinement of parameters of neurostimulation (notably rTMS with accelerated protocols), hold promise to improve general health outcomes and cost‐effectiveness of care in TRD.

The extraordinary public health burden of TRD will unlikely be extinguished in the near future, but the proportion of individuals with debilitating symptoms of depression and dissatisfaction with treatment may be reasonably expected to be decreased with successful targeting of modifiable factors, reducing the knowledge‐implementation gap, and rapid adoption of innovations across therapeutic modalities.