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Cited by 413Treatment of Major DepressionSchizophrenia research and treatmentMental Health and Psychiatry

Treatment resistance in psychiatry: state of the art and new directions

Open access
Howes, Oliver D., Thase, Michael E., Pillinger, Toby·2022·Molecular Psychiatry
DOI 10.1038/s41380-021-01200-3PMC PMC8960394
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Abstract

Treatment resistance affects 20–60% of patients with psychiatric disorders; and is associated with increased healthcare burden and costs up to ten-fold higher relative to patients in general. Whilst there has been a recent increase in the proportion of psychiatric research focussing on treatment resistance ( R 2 = 0.71, p < 0.0001), in absolute terms this is less than 1% of the total output and grossly out of proportion to its prevalence and impact. Here, we provide an overview of treatment resistance, considering its conceptualisation, assessment, epidemiology, impact, and common neurobiological models. We also review new treatments in development and future directions. We identify 23 consensus guidelines on its definition, covering schizophrenia, major depressive disorder, bipolar affective disorder, and obsessive compulsive disorder (OCD). This shows three core components to its definition, but also identifies heterogeneity and lack of criteria for a number of disorders, including panic disorder, post-traumatic stress disorder, and substance dependence. We provide a reporting check-list to aid comparisons across studies. We consider the concept of pseudo-resistance, linked to poor adherence or other factors, and provide an algorithm for the clinical assessment of treatment resistance. We identify nine drugs and a number of non-pharmacological approaches being developed for treatment resistance across schizophrenia, major depressive disorder, bipolar affective disorder, and OCD. Key outstanding issues for treatment resistance include heterogeneity and absence of consensus criteria, poor understanding of neurobiology, under-investment, and lack of treatments. We make recommendations to address these issues, including harmonisation of definitions, and research into the mechanisms and novel interventions to enable targeted and personalised therapeutic approaches.

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Crossref · 10.1038/s41380-021-01200-3

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 42 cited sources checked · 0 supported · 0 flagged

  • Findingreasoning

    The number of prior treatment trials needed for a treatment resistance diagnosis is often undefined or inconsistent, ranging from 2 to 3 drugs for depression.

    “the number of treatment trials that an individual should receive prior to a diagnosis of treatment resistance is, for some criteria sets for OCD and depression, either not defined, or inconsistent, ranging between 2-3 different drugs for depression.”
    Quote in the paperSubstantial claim
  • Findingreasoning

    Criteria also vary markedly within the same diagnosis, especially for defining adequate pharmacotherapy and assessing treatment response.

    “Surprisingly, marked variation in criteria is also seen within the same psychiatric diagnoses, particularly regarding how adequate pharmacotherapy is defined and how response to treatment is assessed.”
    Quote in the paperSubstantial claim
  • Findingown data

    Treatment resistance research made up less than 1% of all psychiatric research output.

    “in absolute terms this is less than 1% of the total output and grossly out of proportion to its prevalence and impact.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The publication database used for the bibliometric analysis captures the relevant literature on treatment resistance in psychiatry.
  • Findingown data

    In the authors' bibliometric analysis of 2000-2019 publications, papers on treatment resistance in psychiatry increased significantly year on year after adjusting for total publication growth (β=0.84, R2=0.71, p<0.0001).

    “This shows a significant year-on-year increase in the number of papers published focussing on treatment resistance in psychiatry, after accounting for the increase in total number of publications over time (β=0.84, R 2 =0.71, p<0.0001, Figure 1).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The publication database used for the bibliometric analysis captures the relevant literature on treatment resistance in psychiatry.
  • Findingown data

    No operationalised definitions of treatment resistance were found for mania, panic disorder, PTSD, or substance dependence.

    “We were unable to identify operationalised definitions of treatment resistance for mania, panic disorder, post-traumatic stress disorder (PTSD), and substance dependence.”
    Quote in the paperSubstantial claim
  • May combine two claims. 17
  • Classified as probably not a substantial claim. 18
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    Three guidelines defined inadequate response absolutely as 'no effect', four used quantitative symptom scale thresholds, and fourteen used vague terms like 'inadequate' or 'minimal'.

    “Three defined inadequate treatment response in absolute terms using statements such as ‘no effect’, four recommended assessments of quantitative change in symptom severity using symptom rating scales and thresholds to define response, and fourteen used amorphous terms such as ‘inadequate’ or ‘minimal’ response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The systematic review found 23 consensus guidelines on treatment resistance definitions: 9 for schizophrenia, 10 for depression, 1 for bipolar depression, and 3 for OCD.

    “This identified 23 guidelines: 9 for schizophrenia; 10 for depression; 1 for the depressed phase of bipolar affective disorder; and 3 for OCD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Criteria for inadequate treatment response varied widely across the 23 guidelines and were absent in two definitions.

    “Of the 23 guidelines identified, we observed that criteria for defining inadequate treatment response varied widely and were not provided in two definitions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Medication adherence is rarely a criterion for treatment resistance, and only one guideline recommended plasma drug level checks.

    “Table 1 shows that assessment of medication adherence is rarely included as a criterion for treatment resistance, and only one guideline recommended checking plasma drug levels to assess adherence.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Findingown data

    Across disorders and guidelines, treatment resistance definitions share three core requirements: correct diagnosis, adequate treatment, and inadequate response.

    “These highlight three core components required to establish treatment resistance seen across disorders and guidelines; these are that the correct diagnosis has been made, that adequate treatment has been given, and that there has been inadequate response (see Figure 2).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    Research and industry interest in treatment resistance has increased markedly.

    “Whilst there has been a marked increase in research and industry interest in treatment resistance”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Findingnone given

    Definitions of treatment resistance vary markedly and lack clear criteria both within and between disorders.

    “There is both marked variation and lack of clear criteria in the definition of treatment resistance both within and between disorders”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Findingnone given

    Treatment resistance carries major functional impairment and substantial economic and social costs.

    “associated with substantial functional impairment and economic and social costs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Findingnone given

    Only three pharmacological interventions are licensed for treatment resistance.

    “There are only three pharmacological interventions licensed for treatment resistance”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The LuAF35700 monotherapy trial for treatment resistant schizophrenia failed to show superiority over risperidone or olanzapine, though full results are unpublished.

    “The headline results of this study indicate that it failed to demonstrate superiority over risperidone or olanzapine (clinical trials identifier: NCT02717195), although the full trial results remain to be published.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    Clinical trials are currently testing fifteen new interventions for treatment-resistant psychiatric conditions.

    “However, fifteen novel interventions are currently being examined in clinical trials of treatment resistant psychiatric conditions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Findingnone given

    The proportion of psychiatric research devoted to treatment resistance is very low relative to its burden.

    “the proportion of psychiatric research in this field remains very low relative to its burden.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    A clinicaltrials.gov search identified 15 currently recruiting phase 2 or 3 studies for treatment resistant schizophrenia, depression, bipolar disorder, and OCD.

    “We identified 15 studies currently recruiting, covering treatments for schizophrenia, depression, bipolar affective disorder, and OCD.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Direct medical costs for treatment resistant depression are 2 to 6 times higher than for other MDD patients, and rise with chronicity and severity.

    “Direct medical costs associated with TRD are estimated to be 2-6 times higher compared with other patients with MDD, 42, 43 with costs increasing with chronicity and severity of TRD. 44”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [42] Corey-Lisle PK, Birnbaum HG, Greenberg PE, Marynchenko MB, Claxton AJ. Identification of a claims data “signature” and economic consequences for treatment-resistant depression. J Clin Psychiatry. 2002;63:717–26. source

      Not checked in the free run.

    • cites [43] Crown WH, Finkelstein S, Berndt ER, Ling D, Poret AW, Rush AJ, et al. The impact of treatment-resistant depression on health care utilization and costs. J Clin Psychiatry. 2002;63:963–71. source

      Not checked in the free run.

    • cites [44] Reich D, Nalls MA, Kao WHL, Akylbekova EL, Tandon A, Patterson N et al. Reduced neutrophil count in people of African descent is due to a regulatory variant in the duffy antigen receptor for chemokines gene. PLoS Genet. 2009;5:e1000360. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clozapine is the only drug licensed as monotherapy for a treatment resistant psychiatric condition, specifically treatment resistant schizophrenia, based on two studies.

    “To date, the only drug that has been licensed as monotherapy for a treatment resistant condition in psychiatry is clozapine for TRS, which gained regulatory approval on the basis of 2 studies. 12, 79”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45:789–96. source

      Not checked in the free run.

    • cites [79] Claghorn JL, Abuzzahab FS, Wang R, Larson C, Gelenberg AJ, Klerman GL, et al. The current status of clozapine. Psychopharmacol Bull. 1983;19:138–40.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Immune dysregulation may contribute to the pathogenesis of schizophrenia and depression, and immune alterations are hypothesised to occur in a subgroup linked to poor treatment response.

    “Converging lines of genetic, post-mortem, and pre-clinical evidence suggest immune dysregulation may play a role in the pathogenesis of both schizophrenia 63–67 and depression, 68, 69 and it is hypothesised that immune alterations are seen only in a proportion of these patients (immune/inflammatory subgroups) and are linked to poor treatment response. 67, 70–72”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [63] Howes OD, McCutcheon R. Inflammation and the neural diathesis-stress hypothesis of schizophrenia: a reconceptualization. Transl Psychiatry. 2017;7:e1024. source

      Not checked in the free run.

    • cites [64] Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014;511:421–7. source

      Not checked in the free run.

    • cites [65] Marques TR, Ashok AH, Pillinger T, Veronese M, Turkheimer FE, Dazzan P et al. Neuroinflammation in schizophrenia: meta-analysis of in vivo microglial imaging studies. Psychol Med. 2018;49:1–11. source

      Not checked in the free run.

    • cites [66] Pillinger T, D’Ambrosio E, McCutcheon R, Howes OD. Is psychosis a multisystem disorder? A meta-review of central nervous system, immune, cardiometabolic, and endocrine alterations in first-episode psychosis and perspective on potential models. Mol Psychiatry. 2018;24:776–94. source

      Not checked in the free run.

    • cites [67] Pillinger T, Osimo EF, Brugger S, Mondelli V, McCutcheon RA, Howes OD. A meta-analysis of immune parameters, variability, and assessment of modal distribution in psychosis and test of the immune subgroup hypothesis. Schizophr Bull. 2018;45:1120–33. source

      Not checked in the free run.

    • cites [68] Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56. source

      Not checked in the free run.

    • cites [69] Benros ME, Waltoft BL, Nordentoft M, Ostergaard SD, Eaton WW, Krogh J, et al. Autoimmune diseases and severe infections as risk factors for mood disorders a nationwide study. Jama Psychiatry. 2013;70:812–20. source

      Not checked in the free run.

    • cites [70] Mondelli V, Ciufolini S, Murri MB, Bonaccorso S, Di Forti M, Giordano A, et al. Cortisol and inflammatory biomarkers predict poor treatment response in first episode psychosis. Schizophr. Bull. 2015;41:1162–70. source

      Not checked in the free run.

    • cites [71] Fillman SG, Weickert TW, Lenroot RK, Catts SV, Bruggemann JM, Catts VS, et al. Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca’s area volume. Mol Psychiatry. 2016;21:1090–8. source

      Not checked in the free run.

    • cites [72] Osimo EF, Pillinger T, Rodriguez IM, Khandaker GM, Pariante CM, Howes OD. Inflammatory markers in depression: a meta-analysis of mean differences and variability in 5166 patients and 5,083 controls. Brain Behav Immun. 2020;87:901–9. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Hospitalisation costs and total health resource use for treatment resistant schizophrenia are ten times higher than for non-resistant schizophrenia, and up to 80% of US yearly schizophrenia health costs are attributed to it.

    “It has been estimated that hospitalisation costs and total health resource utilisations for TRS are 10-fold higher than those for non-TRS and that up to 80% of the total yearly health costs associated with schizophrenia in the USA are attributed to TRS. 41”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Kennedy JL, Altar CA, Taylor DL, Degtiar I, Hornberger JC. The social and economic burden of treatment-resistant schizophrenia: a systematic literature review. Int Clin Psychopharmacol. 2014;29:63–76. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Model 1 holds that treatment resistant illness shares the same neurobiology as responsive illness but has more severe pathophysiological changes, making standard treatment inadequate.

    “The first possibility (Figure 5A) is that the treatment resistant form of a given psychiatric illness has the same underlying neurobiology as the treatment responsive illness, but the pathophysiological alterations are more severe such that standard treatment is inadequate.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    Model 2 holds that treatment resistance is neurobiologically distinct from treatment responsive illness.

    “Alternatively, treatment resistance could be neurobiologically distinct from treatment responsive illness (Figure 5B).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The literature proposes three broad disease models for treatment resistance.

    “There are three broad disease models proposed by the literature to explain treatment resistance, summarised in Figure 5 (see eAppendix 3 for search details). 48–51”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [48] Potkin SG, Kane JM, Correll CU, Lindenmayer JP, Agid O, Marder SR, et al. The neurobiology of treatment-resistant schizophrenia: paths to antipsychotic resistance and a roadmap for future research. NPJ Schizophr. 2020;6:1. source

      Not checked in the free run.

    • cites [49] Trivedi MH, Hollander E, Nutt D, Blier P. Clinical evidence and potential neurobiological underpinnings of unresolved symptoms of depression. J Clin Psychiatry. 2008;69:246–58. source

      Not checked in the free run.

    • cites [50] Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology. 2012;62:63–77. source

      Not checked in the free run.

    • cites [51] Coplan JD, Gopinath S, Abdallah CG, Berry BR. A neurobiological hypothesis of treatment-resistant depression - mechanisms for selective serotonin reuptake inhibitor non-efficacy. Front Behav Neurosci. 2014;8:189. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with treatment resistant depression are twice as likely to be hospitalised and have more psychiatric outpatient visits than non-resistant MDD patients.

    “Patients with TRD are twice as likely to be hospitalised compared with non-TRD patients, and require increased numbers of psychiatric outpatient visits. 43”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Crown WH, Finkelstein S, Berndt ER, Ling D, Poret AW, Rush AJ, et al. The impact of treatment-resistant depression on health care utilization and costs. J Clin Psychiatry. 2002;63:963–71. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the USA, annual direct medical costs for treatment resistant schizophrenia are conservatively over $34 billion.

    “In the USA, annual direct medical costs associated with TRS are conservatively estimated at over $34 billion. 41”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Kennedy JL, Altar CA, Taylor DL, Degtiar I, Hornberger JC. The social and economic burden of treatment-resistant schizophrenia: a systematic literature review. Int Clin Psychopharmacol. 2014;29:63–76. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Thirty percent of patients with treatment resistant depression attempt suicide during their lifetime.

    “and 30% of TRD patients attempt suicide in their lifetime. 47”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Bergfeld IO, Mantione M, Figee M, Schuurman PR, Lok A, Denys D. Treatment-resistant depression and suicidality. J Affect Disord. 2018;235:362–7. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mean quality of life is about 20% lower in treatment resistant schizophrenia and 25-40% lower in treatment resistant depression than in responsive or remitted patients.

    “the mean quality of life is estimated to be 20% lower in TRS compared with non-TRS. 41 Mean quality of life is approximately 25-40% lower in patients with TRD compared with patients who respond to treatment or who are in remission; 46”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [41] Kennedy JL, Altar CA, Taylor DL, Degtiar I, Hornberger JC. The social and economic burden of treatment-resistant schizophrenia: a systematic literature review. Int Clin Psychopharmacol. 2014;29:63–76. source

      Not checked in the free run.

    • cites [46] Mrazek DA, Hornberger JC, Altar CA, Degtiar I. A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996–2013. Psychiatr Serv. 2014;65:977–87. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Electroconvulsive therapy has widespread regulatory approval for treatment resistant depression and mania.

    “Electroconvulsive therapy (ECT) has widespread regulatory approval for treatment resistant depression and mania.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Marked heterogeneity in treatment resistance definitions could produce heterogeneous study populations and limit research validity.

    “there is marked heterogeneity in definitions used. This could lead to heterogeneity of study populations, which in turns limits the validity of research.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Efforts to identify treatment-resistant schizophrenia using genetics and neuroimaging are ongoing.

    “Efforts to identify TRS based on genetics and neuroimaging are on-going, 94, 95”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [94] Wimberley T, Gasse C, Meier SM, Agerbo E, MacCabe JH, Horsdal HT. Polygenic risk score for schizophrenia and treatment-resistant schizophrenia. Schizophr Bull. 2017;43:1064–1069. source

      Not checked in the free run.

    • cites [95] Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161:1–56. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationcitation

    A transdiagnostic approach focused on symptom domains might help identify common mechanisms underlying response and resistance.

    “a transdiagnostic approach focussed on symptom domains, such as psychosis in schizophrenia and bipolar affective disorder, or depression in major depressive disorder and bipolar affective disorder, 93 might help disentangle common underlying mechanisms linked to response and resistance.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] Jauhar S, Nour MM, Veronese M, Rogdaki M, Bonoldi I, Azis M, et al. A test of the transdiagnostic dopamine hypothesis of psychosis using positron emission tomographic imaging in bipolar affective disorder and schizophrenia. JAMA Psychiatry. 2017;74:1206–1213. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High doses of venlafaxine or olanzapine may be effective in treatment resistant depression and schizophrenia, respectively.

    “there is also some evidence that high doses of certain antidepressants (e.g. venlafaxine) 53, 89 or antipsychotics (e.g. olanzapine) 52 can be effective strategies in the management of treatment resistant depression and schizophrenia respectively.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [53] Poirier MF, Boyer P. Venlafaxine and paroxetine in treatment-resistant depression—double-blind, randomised comparison. Br J Psychiatry. 1999;175:12–16. source

      Not checked in the free run.

    • cites [89] Nierenberg AA, Feighner JP, Rudolph R, Cole JO, Sullivan J. Venlafaxine for treatment-resistant unipolar depression. J Clin Psychopharmacol. 1994;14:419–423. source

      Not checked in the free run.

    • cites [52] Lerner V. High-dose olanzapine for treatment-refractory schizophrenia. Clin Neuropharmacol. 2003;26:58–61. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Most treatment resistance approaches treat illness as a single overarching symptom dimension, which may exclude patients with one disabling non-responsive symptom.

    “most approaches to treatment resistance consider the illness in terms of a single over-arching symptom dimension. However, these fail to recognise that some patients may have ongoing domain-specific disabling symptoms despite treatment, such as negative symptoms of schizophrenia or somatic symptoms of depression. Thus, definitions of treatment resistance based on global rating may exclude people”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Recent interest has been considerable in using blood immune markers to stratify schizophrenia and depression patients and find a subgroup whose symptoms might respond to immunotherapy.

    “there has been considerable recent interest in stratifying patients with schizophrenia and depression based on blood immune markers with a view to identifying a subgroup whose psychiatric symptoms may respond to immunotherapy. 67, 74, 75”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [67] Pillinger T, Osimo EF, Brugger S, Mondelli V, McCutcheon RA, Howes OD. A meta-analysis of immune parameters, variability, and assessment of modal distribution in psychosis and test of the immune subgroup hypothesis. Schizophr Bull. 2018;45:1120–33. source

      Not checked in the free run.

    • cites [74] Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70:31–41. source

      Not checked in the free run.

    • cites [75] McIntyre RS, Subramaniapillai M, Lee Y, Pan Z, Carmona NE, Shekotikhina M et al. Efficacy of adjunctive infliximab vs placebo in the treatment of adults with bipolar I/II depression: a randomized clinical trial. JAMA Psychiatry 2019;76:783–90. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    This variation and lack of clear criteria could make study populations heterogeneous and comparisons difficult.

    “which could lead to heterogeneity in the patients included in studies, making comparisons difficult.”
    Quote in the paperSubstantial claim
32 of 32

  • The paper relies on this without support.

    The publication database used for the bibliometric analysis captures the relevant literature on treatment resistance in psychiatry.

    “we conducted an analysis of scientific publications on treatment resistance in psychiatry between 2000-2019 inclusive (see eAppendix 1 for methods and full results).”

  • The paper relies on this without support.

    The prevalence of treatment resistance in psychiatric conditions is between 20% and 60%.

    “Given that the prevalence of treatment resistance in psychiatric conditions is 20 to 60%”

  • The paper relies on this without support.

    Treatment resistance is associated with a high burden.

    “and it is associated with high burden”
3 of 3

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References 138 · Cited by 413

Research works printed but not linked: 1

  1. Taylor D, Barnes T, Young A. The maudsley prescribing guidelines in psychiatry 13th edn. Wiley Blackwell; 2018.

Authors
Howes, O. D., Thase, M. E., & Pillinger, T.
Affiliations
  • King's College London (GB)
  • Philadelphia VA Medical Center (US)
Corresponding author
Howes, Oliver D.
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2021-07-13
Volume
27
Issue
1
Pages
58-72
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-021-01200-3
PMC
PMC8960394
OpenAlex
W3171833614
Cited by
413
References
138
Citations by year
2026: 80 · 2025: 113 · 2024: 115 · 2023: 72 · 2022: 31 · 2021: 2
FWCI
7.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • South London and Maudsley NHS Foundation Trust
  • Wellcome Trust (094849, 094849/Z/10/Z)
  • Maudsley Charity (094849/Z/10/Z)
  • National Institute for Health and Care Research
  • King's College London
  • H. Lundbeck A/S
  • Medical Research Council (094849/Z/10/Z, MR/N027078/1, MC_A656_5QD30_2135)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Social Sciences › Arts and Humanities › Philosophy › Mental Health and Psychiatry
Keywords
treatment resistance, mental illness, schizophrenia, major depressive disorder, bipolar disorder, obsessive-compulsive disorder, consensus recommendations, pseudoresistance, medication adherence, neurobiological model, non-pharmacological treatment, new drugs, personalized treatment, reporting checklist, health care costs
MeSH terms
Bipolar Disorder, Major Depressive Disorder, Depressive Disorder, Major, Humans, Obsessive-Compulsive Disorder, Psychiatry, Panic Disorder

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