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Cited by 139Treatment of Major DepressionAnxiety, Depression, Psychometrics, Treatment, Cognitive ProcessesPsychological Treatments and Disorders

Patients with anxious depression: overview of prevalence, pathophysiology and impact on course and treatment outcome

Open access
Gaspersz, Roxanne, Nawijn, Laura, Lamers, Femke, Penninx, Brenda W.J.H.·2018·Current Opinion in Psychiatry
DOI 10.1097/yco.0000000000000376
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Abstract

PURPOSE OF REVIEW: Major depressive disorder with a comorbid anxiety disorder or with significant anxiety symptoms (here called anxious depression) is common and has been associated with poor clinical course trajectories. However, various dichotomous as well as dimensional definitions have been used to label anxious depression and it remains unclear to which extent these result in inconsistent findings. This review provides an overview of recent literature on the impact of anxiety in depressed patients on clinical course trajectories, treatment outcomes, and underlying neurobiological dysregulations. RECENT FINDINGS: Anxious depression seems associated with poorer clinical course trajectories and treatment nonresponse as compared with 'pure' depression, regardless of which definition is used. Recent studies have attempted to determine specific efficacy of novel pharmacological treatments for anxious depressed patients, but have not been conclusive because of the insufficient number of studies and differences in definitions and assessment of anxious depression. Neurobiology studies suggest that anxious depression is associated with increased immune dysregulation, more cortical thinning, and corticolimbic dysfunctions as compared with 'pure' depression. SUMMARY: Anxious depression appears to be a common and clinically relevant subtype of depression as it predicts poorer course trajectories. As populations with anxious depression may benefit from specific treatment regimens, further research is necessary to better delineate its definition and neurobiology. The relatively new Diagnostic and Statistical Manual of Mental Disorders-5 anxious distress specifier is a welcome development and should be further investigated and compared against other anxiety constructs.

AI snapshot

Written from the paper’s full text.

TL;DR

Anxious depression—defined variably as MDD with a comorbid anxiety disorder, elevated anxiety symptoms, or DSM-5 anxious distress—is common and associated with poorer clinical course and treatment outcomes. Recent evidence suggests a distinct neurobiological profile involving immune dysregulation, cortical thinning, and altered corticolimbic connectivity, but definitional heterogeneity limits conclusions.

Key findings

  • Prevalence is high across definitions: 42–78% of depressed patients have cooccurring anxiety; in lifetime MDD, 46% had at least one lifetime anxiety disorder, and in 12-month MDD, 52% had lifetime anxiety disorders and 42% had 12-month anxiety disorders. Dimensional studies found 53% of 2876 STAR*D MDD patients and 70% of 375 Chinese MDD patients had anxious depression; DSM-5 anxious distress prevalence ranged from 54 to 78%.
  • Anxious depression is associated with poorer course trajectories: greater depression chronicity and severity, higher suicide risk, lower quality of life, impaired social/occupational dysfunction, higher readmission rates, and lower remission rates. The DSM-5 anxious distress specifier outperformed DSM-4-based anxiety disorder comorbidity in predicting subsequent chronicity, longer time to remission, and greater functional disability.
  • Treatment findings are mixed: traditional antidepressants may be less effective for maintaining response/remission and may cause more side effects in anxious depression. Novel agents show inconsistent results; single-infusion ketamine was more effective in anxious than nonanxious depression, and vilazodone was more effective in 708 anxious versus 155 nonanxious patients, but evidence remains insufficient to establish specific efficacy.
  • Neurobiological studies suggest increased immune dysregulation (e.g., higher monocyte counts, higher innate cytokine production capacity), HPA-axis dysregulation, more cortical thinning in orbitofrontal/anterior cingulate cortex, insula, and temporal lobes, and increased corticolimbic functional connectivity compared with nonanxious MDD.

Methods

  • Narrative review of recent literature on anxious depression, covering prevalence, clinical course trajectories, treatment outcomes, and underlying neurobiological dysregulations.
  • Synthesizes large epidemiological and clinical studies and pharmacological trials, including a 74,045-adult 24-country study, STAR*D (n=2876), a European multicenter study (n=1346), and various randomized/post hoc treatment studies.
  • Main analysis is qualitative synthesis, with attention to whether findings depend on the definition or assessment method used for anxious depression; no meta-analysis or systematic search strategy is described.

Limitations

  • The paper states that various dichotomous and dimensional definitions and assessment instruments are used, no uniform definition has been established, and different definitions do not necessarily capture the same patients (e.g., DSM-5 anxious distress specifier poorly overlapped with DSM-4-based anxiety disorders, Cohen κ = 0.09).
  • The paper states that treatment studies are scarce, often use post hoc analyses with limited sample sizes, and not all directly compare anxious with nonanxious depression, so current evidence is insufficient to establish whether novel pharmacological treatments are specifically beneficial.
  • The paper states that neuroimaging and biological studies are limited and use various definitions; evident from the text, the review also lacks a described systematic search or risk-of-bias assessment and excludes bipolar depression and DSM-4 mixed anxious-depressive disorder.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1097/yco.0000000000000376

Cites

83 of 83 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 78 cited sources checked · 0 supported · 0 flagged

  • Interpretationcitation

    Various scales and different cutoff points to determine relevant anxiety symptoms have been used, resulting in heterogeneity in the dimensional definition of anxious depression.

    “However, various scales and different cutoff points to determine relevant anxiety symptoms have been used, resulting in heterogeneity in the dimensional definition as well [2,3].”
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  • Premisecitation

    A measure of the DSM-5 anxious distress specifier, the DSM-5 anxious distress specifier interview, had comparable validity as the HAM-A in measuring anxiety in depression.

    “and that a measure of the DSM-5 anxious distress specifier, the DSM-5 anxious distress specifier interview, had comparable validity as the HAM-A in measuring anxiety in depression [28 & ].”
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  • Interpretationcitation

    Anxious depression, defined as major depressive disorder with a comorbid anxiety disorder or with significant anxiety symptoms, is common.

    “The cooccurrence of anxiety in depression is common [1]”
    • Also stated in: § KEY POINTS · plain
      “Despite heterogeneity in diagnostic criteria and assessment instruments, anxious depression is common: 42-78% of all depressed patients suffer from cooccurring anxiety.”
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  • Premisecitation

    In the STAR*D study, 53% of 2876 MDD patients had anxious depression defined as MDD and a HAM-D ASF score of at least 7.

    “The Sequenced Treatment Alternatives to Relieve Depression study showed that 53% of 2876 MDD patients had anxious depression (MDD and a HAM-D ASF score !7) [12]”
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  • Premisecitation

    Of persons with lifetime MDD, 46% had at least one lifetime anxiety disorder.

    “Of persons with lifetime MDD, 46% had at least one lifetime anxiety disorder, and of those with a 12-month MDD, 52% had lifetime anxiety disorders and 42% had 12-month anxiety disorders [30].”
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    Premisecitation

    The DSM-5 includes a new anxious distress specifier to acknowledge the clinical significance of prominent anxiety features in MDD.

    “The DSM-5 includes a new anxious distress specifier to acknowledge the clinical significance of prominent anxiety features in MDD [22].”
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    Interpretationnone given

    Neurobiology studies suggest that anxious depression is associated with increased immune dysregulation, more cortical thinning, and corticolimbic dysfunctions compared with pure depression.

    “Neurobiology studies suggest that anxious depression is associated with increased immune dysregulation, more cortical thinning, and corticolimbic dysfunctions as compared with 'pure' depression.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    No uniform definition of anxious depression has been established.

    “Although it has been suggested that a dimensional definition of anxious depression is clinically most relevant [2,3,21 & ], up until now, no uniform definition has been established.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Various definitions for anxious depression are used across studies, making results not always directly comparable.

    “Consequently, various definitions for anxious depression are being used across studies, making results not always directly comparable.”
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    Premisecitation

    The term anxious depression has been used interchangeably in recent literature to denote three common dichotomous anxiety-depression definitions: MDD with a comorbid full-blown anxiety disorder, MDD with anxiety symptoms measured as an above-cutoff score on an anxiety severity scale, and MDD with the DSM-5 anxious distress specifier.

    “Generally, the term 'anxious depression' has been used interchangeably in recent literature to denote three common dichotomous anxiety-depression definitions: major depressive disorder (MDD) with a comorbid full-blown anxiety disorder, MDD with anxiety symptoms measured as an above cutoff score on an anxiety severity scale [2], and MDD with the Diagnostic and Statistical Manual of Mental Disorders”
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    Premisecitation

    Of the five DSM-5 anxious distress specifier symptoms, four are typical for generalized anxiety disorder and one for panic disorder.

    “Of these, four out of five symptoms are typical for generalized anxiety disorder (GAD) and one for panic disorder [23].”
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    Interpretationreasoning

    Anxious depression appears to be a common and clinically relevant subtype of depression because it predicts poorer course trajectories.

    “Anxious depression appears to be a common and clinically relevant subtype of depression as it predicts poorer course trajectories.”
    Quote in the paperSubstantial claim

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    Interpretationnone given

    Anxious depression is associated with poorer clinical course trajectories and treatment nonresponse compared with pure depression, regardless of which definition is used.

    “Anxious depression seems associated with poorer clinical course trajectories and treatment nonresponse as compared with 'pure' depression, regardless of which definition is used.”
    Quote in the paperSubstantial claim

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    Premisecitation

    A recent study examining the validity of the DSM-5 anxious distress specifier suggests that the specifier is a generic anxiety marker, as it did not show specificity with GAD and panic disorder.

    “However, a recent study examining the validity of the specifier suggests that the specifier is a generic anxiety marker, as it did not show specificity with GAD and panic disorder [24 & ].”
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    Premisecitation

    Of those with a 12-month MDD, 52% had lifetime anxiety disorders and 42% had 12-month anxiety disorders.

    “Of persons with lifetime MDD, 46% had at least one lifetime anxiety disorder, and of those with a 12-month MDD, 52% had lifetime anxiety disorders and 42% had 12-month anxiety disorders [30].”
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    Interpretationcitation

    Generally the onset of anxiety disorders precedes the onset of depression, suggesting that a temporal priority of anxiety disorders may contribute to the development of depression.

    “Recent as well as other previous studies [4,[33][34][35] also showed that generally the onset of anxiety disorders precedes the onset of depression, suggesting that a temporal priority of anxiety disorders may contribute to the development of depression [36,37].”
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    Premisecitation

    Different definitions of anxious depression do not necessarily capture the same patients; the DSM-5 anxious distress specifier poorly overlapped with comorbid DSM-4-based anxiety disorders (Cohen k = 0.09).

    “It is important to note that different definitions do not necessarily capture the same patients though; the DSM-5 anxious distress specifier, for example, poorly overlapped with comorbid DSM-4-based anxiety disorders (Cohen k ¼ 0.09) [24 & ].”
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    Premisecitation

    Of those with lifetime comorbid anxiety disorder and MDD, 68% reported an earlier occurrence of their first anxiety disorder versus their MDD, 13.5% had anxiety follow after MDD onset, and 18.5% had parallel occurrence.

    “In terms of temporal order, of those with lifetime comorbid anxiety disorder and MDD, 68% reported an earlier occurrence of their first anxiety disorder versus their MDD, whereas in 13.5% anxiety followed after MDD onset, and in 18.5% the occurrence of the anxiety disorder was parallel to that of depression [30].”
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    Interpretationcitation

    Depressed patients with anxiety symptoms measured with the HAM-D ASF or HAM-A generally have greater depression chronicity and severity, higher suicide ideation and risks, and lower quality of life than MDD patients without anxiety.

    “Either measured with the HAM-D ASF score or HAM-A, depressed patients with anxiety symptoms generally have greater depression chronicity and severity [1,5,6], higher suicide ideation and risks [1,8,9], and lower QOL than MDD patients without anxiety.”
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    Interpretationcitation

    Anxious depression defined with the anxious distress specifier was associated with greater depression severity, higher suicidal ideation, decreased quality of life, greater self-reported impairment, severe insomnia, and increased incidence of cardiovascular disease.

    “Also anxious depression defined with the anxious distress specifier was associated with greater depression severity, higher suicidal ideation, decreased QOL, greater self-reported impairment, severe insomnia [10,40], and increased incidence of cardiovascular disease [43].”
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    Premisecitation

    Another study observed a higher suicide risk and greater dysfunction in patients with MDD and at least two anxiety disorders compared with those with a comorbid social anxiety disorder.

    “Another study observed a higher suicide risk and greater dysfunction in patients with MDD and at least two anxiety disorders compared with those with a comorbid SAD [29].”
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    Interpretationcitation

    MDD with comorbid anxiety disorders is associated with chronic course trajectories and poor clinical outcomes in clinical samples.

    “Substantial evidence suggests that MDD with comorbid anxiety disorders is associated with chronic course trajectories [7,35] and poor clinical outcomes [4,29,31 && ,32,41,42] in clinical samples.”
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    Premisecitation

    Higher likelihood to experience antidepressant side-effects was observed only in MDD cases with comorbid panic disorder versus those without, but not in those with comorbid social anxiety disorder or GAD.

    “Another recent study reported a higher likelihood to experience antidepressant side-effects only in MDD cases with comorbid panic disorder versus those without, but not in those with comorbid SAD or GAD [50].”
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    Interpretationreasoning

    Overall, anxious depression seems to be associated with poorer course trajectories and worse clinical outcomes.

    “Overall, anxious depression seems to be associated with poorer course trajectories and worse clinical outcomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Patients with dimensionally defined anxious depression did respond to traditional antidepressants, but were unable to maintain response or remission and suffered from greater frequency of side-effects than patients with nonanxious depression.

    “A previous, large review [14] showed that patients with dimensionally defined anxious depression did respond to traditional antidepressants, but that they were unable to maintain response or remission and suffered from greater frequency of side-effects than patients with nonanxious depression [14].”
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    Interpretationcitation

    Some atypical agents may have an unfavorable side-effect profile, limiting their use in depressed patients with comorbid anxiety as they may suffer from greater side-effects.

    “Some of the atypical agents may have an unfavorable side-effect profile [52], limiting its use in depressed patients with comorbid anxiety as they may suffer from greater side-effects [14].”
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    Premisecitation

    Presence of DSM-5 based anxious distress predicted subsequent poor treatment outcomes and a greater frequency of antidepressant side-effects in depressed patients who received adequate antidepressant treatment, whereas presence of comorbid DSM-4-based anxiety disorders did not.

    “Recently, one study showed that within MDD patients, the presence of (DSM-5 based) anxious distress predicted subsequent poor treatment outcomes and a greater frequency of antidepressant side-effects in depressed patients who received adequate antidepressant treatment, whereas presence of comorbid DSM-4-based anxiety disorders did not [38].”
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    Premisecitation

    Decreased venous blood basophil counts and increased fragmented neutrophils were observed in patients with MDD and higher levels of anxiety.

    “Also, decreased venous blood basophil counts and increased fragmented neutrophils were observed in patients with MDD and higher levels of anxiety [66].”
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    Premisecitation

    Vilazodone was more effective in 708 patients with anxious depression than in 155 patients with nonanxious depression, although the sample size of those with nonanxious depression was very small.

    “Also, vilazodone -a serotonin reuptake inhibitor and 5-hydroxytryptamine 1A receptor partial antagonist -was more effective in 708 patients with anxious depression than in 155 patients with nonanxious depression, although the sample size of those with nonanxious depression was very small [59].”
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    Premisecitation

    Another study found efficacy for quetiapine therapy in patients with anxious depression, but did not directly compare with a nonanxious depressed patient group and the sample size was very small (n = 9).

    “Another study also found efficacy for quetiapine therapy in patients with anxious depression, but did not directly compare this with a nonanxious depressed patient group and the sample size was very small (n ¼ 9) [54].”
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    Interpretationreasoning

    These alterations in white blood cell subset counts indirectly point to alterations in the immune system, suggesting a role of inflammation in the pathophysiology of anxious depression.

    “These alterations in white blood cell subset counts indirectly point to alterations in the immune system, suggesting a role of inflammation in the pathophysiology of anxious depression.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    The combination of MDD diagnosis and dimensional anxiety measures proved the best fit with functional connectivity patterns, whereas anxiety disorder diagnosis did not add to the model.

    “Interestingly, the combination of MDD diagnosis and dimensional anxiety measures proved the best fit with functional connectivity patterns, whereas anxiety disorder diagnosis did not add to the model [21 & ].”
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    Premisecitation

    MDD diagnosis was associated with reduced functional connectivity between the ACC and striatum and limbic/paralimbic reactivity, whereas both GAD diagnosis and dimensional anxious arousal and distress levels were associated with increased ACC-striatal connectivity and limbic/paralimbic reactivity.

    “Fitting with previous literature, MDD diagnosis was associated with reduced functional connectivity between the ACC and striatum and limbic/paralimbic reactivity, whereas both GAD diagnosis and dimensional anxious arousal and distress levels were associated with increased ACC-striatal connectivity and limbic/paralimbic reactivity.”
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    Interpretationreasoning

    Cortical thinning in these regions has also been observed in MDD relative to controls, and thus seems regionally similar but more severe in anxious depression.

    “Cortical thinning in these regions have also been observed in MDD relative to controls [75], and thus seem regionally similar but more severe in anxious depression.”
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    Premisecitation

    Both anxiety dimensions and comorbid anxiety within MDD were associated with increased functional connectivity between limbic-striatal and prefrontal regions, although decreased fronto-striatal functional connectivity has also been observed.

    “Both anxiety dimensions and comorbid anxiety within MDD were associated with increased functional connectivity between limbic-striatal and prefrontal regions [21 & ,78-81], although decreased fronto-striatal FC has also been observed [79].”
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    Interpretationreasoning

    Despite the limited number of neuroimaging and biological studies and various definitions and assessment of anxious depression, anxious depression seems to be associated with a distinct neurobiological profile, showing increased immune dysregulation, more severe thinning in temporal and prefrontal areas, and increased corticolimbic functional connectivity patterns compared with nonanxious MDD.

    “Taken together, despite the limited number of neuroimaging and biological studies and various definitions and assessment of anxious depression, anxious depression seems to be associated with a distinct neurobiological profile, showing increased immune dysregulation, more severe thinning in temporal and prefrontal areas, and increased corticolimbic functional connectivity patterns compared with non”
    Quote in the paperSubstantial claim

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    Interpretationcitation

    Functional connectivity deficits associated with anxiety may vary with symptom levels and are not diagnosis specific.

    “This suggests that functional connectivity deficits associated with anxiety may vary with symptom levels and are not diagnosis specific.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    Poorer clinical and treatment outcomes as well as distinct neurobiological correlates were observed in persons with anxious depression versus persons with pure (nonanxious) depression.

    “Poorer clinical and treatment outcomes as well as distinct neurobiological correlates were observed in persons with anxious depression versus persons with 'pure' (nonanxious) depression.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    Evidence demonstrates that anxious depression is common and clinically relevant.

    “Evidence demonstrates that anxious depression is common and clinically relevant.”
    Quote in the paperSubstantial claim
34 of 34

Claims other papers make about this one

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Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting thresholds for the DSM-5 anxious distress specifier

    Minor

    The introduction defines the specifier as requiring three of five anxiety symptoms, but the diagnostic assessment section says it requires at least two of the five.

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Related

Authors
Gaspersz, R., Nawijn, L., Lamers, F., & Penninx, B. W. J. H.
Affiliations
Amsterdam Neuroscience (NL)
Corresponding author
Gaspersz, Roxanne
ORCID
Venue
Current Opinion in Psychiatry
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-01
Volume
31
Issue
1
Pages
17-25
ISSN
0951-7367 (ISSN-L)
DOI
10.1097/yco.0000000000000376
OpenAlex
W2767830383
Cited by
139
References
85
Citations by year
2026: 11 · 2025: 14 · 2024: 25 · 2023: 19 · 2022: 15 · 2021: 21 · 2020: 12 · 2019: 16 · 2018: 6
FWCI
1.18
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Current Opinion in Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion)
Funders
European Commission
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
  • Social Sciences › Psychology › Clinical Psychology › Psychological Treatments and Disorders
Keywords
anxious depression, major depressive disorder, anxiety comorbidity, treatment non-response, neurobiology of depression, immune dysregulation, cortical thinning
MeSH terms
Antidepressive Agents, Anxiety, Anxiety Disorders, Depressive Disorder, Major, Major Depressive Disorder, Humans, Anti-Anxiety Agents, Comorbidity, Prevalence, Treatment Outcome, Disease Progression, Diagnostic and Statistical Manual of Mental Disorders

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