Skip to content

Comorbidity and primary care

TL;DR — GAD is a primary-care disorder that primary care mostly does not diagnose. In a 20,000-patient German study, physicians recognised clinically significant emotional problems in 72.5% of pure-GAD patients but reached the correct diagnosis in only 34.4% (vs 64.3% for major depressive episode), and few of those recognised were prescribed medication or referred (Wittchen 2002, PMID 12044105). In 965 US primary-care patients, 7.6% (95% CI 5.9–9.4) had GAD, 19.5% had ≥1 anxiety disorder, and 41% of those with an anxiety disorder reported no current treatment (Kroenke 2007, PMID 17339617). Comorbidity is the norm at lifetime scale — 81.9% lifetime comorbidity, 63.0% with mood disorders (Ruscio 2017, PMID 28297020) — but not at the point-prevalence scale that primary care sees: 3.8% pure GAD vs 1.6% comorbid GAD/MDE in the same German sample (Wittchen 2002, PMID 12044105). The comorbid state is measurably worse on every axis: painful physical symptoms in 78.0% of GAD+MDD vs 59.0% of GAD alone vs 28.3% of controls (Romera 2010, PMID 20541811); HRQoL impairment greater than either disorder alone (Revicki 2012, PMID 22154706). The strongest intervention evidence is organisational rather than pharmacological: the CALM trial (1,004 patients, 17 clinics) improved anxiety symptoms with NNT 5.27 for response and 5.50 for remission at 12 months versus usual care (Roy-Byrne 2010, PMID 20483968), with GAD showing sustained benefit at 6, 12 and 18 months (Craske 2011, PMID 21464362). This condition treats comorbid depression as a cross-linked neighbouring state, not as part of GAD.

What primary care sees

Metric Value Source
GAD prevalence among primary-care attenders 7.6% (95% CI 5.9–9.4) Kroenke 2007, PMID 17339617
Any anxiety disorder among attenders 19.5% (17.0–22.1) Kroenke 2007, PMID 17339617
GAD as proportion of primary-care attenders (European) ~8%; GAD present in 22% of primary-care patients complaining of anxiety problems Wittchen 2002, PMID 12497648
Pure GAD / pure MDE / comorbid GAD+MDE 3.8% / 4.4% / 1.6% of >20,000 patients Wittchen 2002, PMID 12044105
Screened positive for GAD (HADS-A) in Spanish primary care 22% of 7,152; confirmed GAD 14% (MINI); GAD+MDD 8%, GAD alone 6% Romera 2010, PMID 20541811
Anxiety-disorder patients reporting no current treatment 41% Kroenke 2007, PMID 17339617
Physician correct diagnosis, pure GAD 34.4% (vs 64.3% MDE; 85.4% recognition of emotional problems in comorbid GAD/MDE) Wittchen 2002, PMID 12044105
Adequately treated (North America / Europe review) 20–32% Revicki 2012, PMID 22154706
Median annual medical cost, GAD vs primary-care patients without US $2,375 vs $1,448 Revicki 2012, PMID 22154706

The recognition gap is specific: it is not that GAD patients are invisible — three-quarters are seen to have an emotional problem — but that the problem is named as something else (Wittchen 2002, PMID 12044105). The classic mechanism proposed for GAD's disproportionate health-care utilisation is that it acts as a precursor or concurrent modifier of other disorders rather than driving cost directly (Roy-Byrne 1997, PMID 9133491).

The comorbidity structure

Comorbidity Magnitude Source
Lifetime any disorder 81.9% (SE 0.7) Ruscio 2017, PMID 28297020
Lifetime mood disorder 63.0% (SE 0.9) Ruscio 2017, PMID 28297020
Lifetime other anxiety disorder 51.7% (SE 0.9) Ruscio 2017, PMID 28297020
Community sample with no other DSM-IV diagnosis Only 17.1% of 105 GAD cases; most frequent comorbidity MDD at 70.4% Faravelli 2012, PMID 22578985
Older adults ≥55, past-year GAD without any Axis I/II comorbidity 0.53% of a 2.80% total Mackenzie 2011, PMID 21427639
Children/adolescents, comorbid anxiety disorder 57.6% Mohammadi 2020, PMID 32470794
Personality disorder and remission Any PD: 30% lower likelihood of GAD remission; avoidant 34%, dependent 14% Massion 2002, PMID 11982447
Pre-existing MDD as a risk factor for GAD (claims) OR 5.06 (95% CI 5.03–5.08) — the strongest of all retrospectively assessed risk factors, ahead of family problems (2.83), SARS-CoV-2 infection (2.53), employment difficulties (2.48) and ADHD (2.19) Druet-Cabanac 2025, PMID 40611531

The pure-versus-comorbid dispute is a sampling artefact, and both sides are right about their own data. Lifetime comorbidity in an epidemiological survey (81.9%) and point-prevalence pure GAD in a primary-care day survey (3.8% vs 1.6% comorbid) are compatible: comorbidity accumulates over a lifetime, and at any given consultation many patients have GAD alone. Quoting either as "the" comorbidity rate is the error. See the diagnostic boundary.

Who seeks treatment, and does it help?

Two large surveys answer questions that trials cannot.

Treatment-seeking correlates. In NESARC-III, using DSM-5 criteria and the AUDADIS-5, comorbid depression, panic disorder and PTSD were each uniquely associated with higher rates of GAD-related treatment seeking, as were several specific symptoms — fatigue, panic attacks, reassurance-seeking and interpersonal avoidance (Zech 2024, PMID 39047416). The clinical implication is uncomfortable: the pure-GAD patient, who impairs as much as a pure-MDD patient (Hoffman 2008, PMID 17146763), is the least likely to present.

Perceived helpfulness. Community epidemiological surveys in 23 countries (WHO World Mental Health), DSM-5 GAD assessed by CIDI 3.0 (Stein 2021, PMID 34372811):

Finding Value
Overall GAD prevalence in these surveys 4.5% (2.8% in low/middle-income, 5.3% in high-income countries)
Ever obtained treatment for GAD 34.6% overall — 19.2% in low/middle-income, 38.4% in high-income countries
Of those treated, perceived the treatment helpful 70%, and comparably so in low/middle- and high-income countries
Modelled probability of eventually obtaining helpful treatment if the patient persisted with up to 10 professionals Virtually all patients
Estimated proportion who would persist that long 29.7%

That last pair is the most actionable finding in this whole condition. Treatment for GAD is helpful when patients find the right treatment, and the binding constraint is persistence through unhelpful encounters, not the absence of effective treatments. Most predictors of obtaining helpful treatment operated through persistence rather than through encounter-level helpfulness (Stein 2021, PMID 34372811). It also converts the treatment-gap tables above from a supply problem into a supply-and-persistence problem.

Substance use as a comorbidity

Finding Value Source
Lifetime prevalence of GAD with a substance use disorder vs GAD without 2.04% vs 2.10% — i.e. GAD-SUD constitutes about half of all lifetime GAD Alegría 2010, PMID 20923623 (NESARC, N=43,093)
Psychiatric comorbidity Higher in GAD-SUD than GAD-only, particularly across the externalizing spectrum; higher disability; more use of alcohol and drugs to relieve anxiety Alegría 2010, PMID 20923623
Treatment-seeking Equally low in GAD-SUD and GAD-only, and both groups equally likely to receive pharmacological treatment for anxiety Alegría 2010, PMID 20923623
GAD among people seeking outpatient substance-abuse treatment Studied directly Smith 2010, PMID 19733441
Pharmacotherapy for anxiety with comorbid alcohol use disorder Cochrane review Ipser 2015, PMID 25601826

The half-of-all-GAD figure (Alegría 2010, PMID 20923623) sits awkwardly beside the treatment literature, which excludes substance use disorders routinely — the Cochrane antidepressant review excluded studies including participants with regular benzodiazepine use and enrolled few with secondary psychiatric comorbidity (Kopcalic 2025, PMID 39880377). The gabapentinoid misuse literature makes this more than academic: opioid use disorder is the greatest risk factor for gabapentinoid misuse, and pregabalin is a first-line-adjacent GAD drug (red flags and safety concerns; Evoy 2021, PMID 33215352).

Somatic presentation

  • Pain. Painful physical symptoms (VAS >30) were present in 59.0% of GAD alone versus 28.3% of controls (p<0.001), and 78.0% of GAD+MDD versus 59.0% of GAD alone (p<0.001); PPS were significantly associated with functional and health-status impairment in both groups (Romera 2010, PMID 20541811).
  • Somatic symptom scales travel with the GAD-7. The PHQ-15 is equal or superior to other brief somatic measures, and the PHQ-9/GAD-7/PHQ-15 triad was designed to be used together because depression, anxiety and somatisation are each present in ≥5–10% of primary-care patients and frequently co-occur (Kroenke 2010, PMID 20633738).
  • Functional somatic syndromes. Meta-analytic integration across 244 studies found IBS, non-ulcer dyspepsia, fibromyalgia and chronic fatigue syndrome moderately but highly significantly associated with anxiety and depression versus both healthy and organically ill controls, with the association holding when depression was measured without somatic items (Henningsen 2003, PMID 12883101). Fibromyalgia showed lower anxiety scores than IBS. A prospective analysis has since examined associations between MDD, GAD, fibromyalgia and ME/CFS (Thomas 2025, PMID 40785390).
  • Medical settings miss it. Among 180 veterans with cardiopulmonary disease meeting criteria for anxiety, depression or PTSD on the MINI, only 39% had a mental-health diagnosis documented in the medical record (Ratcliff 2017, PMID 28807139).

What improves care

Intervention Design Result
CALM (Roy-Byrne 2010, PMID 20483968) 1,004 patients with panic, GAD, social anxiety or PTSD (± major depression), 17 clinics, 4 US cities; choice of CBT, medication or both, web-based outcome monitoring, non-expert care managers; blinded follow-up to 18 months BSI-12 group differences −2.49 (−3.59 to −1.40) at 6 months, −2.63 at 12, −1.63 at 18; response 63.66% vs 44.68% and remission 51.49% vs 33.28% at 12 months; NNT 5.27 (response), 5.50 (remission)
CALM, disorder-specific (Craske 2011, PMID 21464362) Same trial; principal GAD n=549 of 1,004 CALM superior for principal GAD at 6 months (−1.61, −2.42 to −0.79), 12 months (−2.34, −3.22 to −1.45) and 18 months (−2.37, −3.24 to −1.50); also superior for principal panic and social anxiety; effect sizes favoured CALM for comorbid disorders but were mostly not significant
Telephone stepped collaborative care (Rollman 2017, PMID 27714649) 329 referred patients; 250 highly anxious randomised to 12 months of centralised telephone collaborative care vs usual care At 12 months: mental HRQoL ES 0.38 (0.13–0.63, p=0.003), anxiety (SIGH-A) ES 0.30 (0.05–0.55, p=0.02), mood ES 0.45 (0.19–0.71, p=0.001); larger and durable effects in African-American patients (ES 0.70–1.14) and men (0.43–0.93)
Online collaborative care (Rollman 2018, PMID 29117275) 704 randomised from 2,884 referred across 26 practices; computerised CBT ± internet support group vs usual care, 6 months guided access Mental HRQoL and PROMIS depression/anxiety at 6 months with durability assessed at 12; 84.4% started the CCBT program (mean 5.4 of 8 sessions)
Quality of care and satisfaction (Stein 2011, PMID 21367351) CALM secondary analysis Quality of and patient satisfaction with primary-care anxiety treatment
Cost (Joesch 2012, PMID 22152230) CALM economic analysis Incremental benefits and costs of the CALM model
Equity (Chavira 2014, PMID 24660674) CALM secondary analysis Treatment engagement and CBT response among Latino patients
Contemporary collaborative care PARTNERs telephone collaborative care (Ishrat Husain 2023, PMID 36855791); COMET cluster-randomised stepped care (Heddaeus 2025, PMID 39908421) The model continues to be tested at system scale

The collaborative-care literature is the strongest practical evidence in this whole condition — NNT ~5 for response is better than any single drug's NNT (compare NNTB 7 for antidepressant response; Kopcalic 2025, PMID 39880377) — and it is delivered by reorganising care rather than by adding a treatment.

What is still missing

  1. No GAD-without-depression treatment estimate. The Cochrane antidepressant review excluded serious comorbidity and included few participants with secondary psychiatric comorbidity (Kopcalic 2025, PMID 39880377); the psychological/pharmacological network allowed all comorbidities (Chen 2019, PMID 31494377). Neither yields a stratified answer (OQ-2 in OPEN-QUESTIONS.md).
  2. No demonstration that screening changes outcomes. Accuracy is characterised (Aktürk 2025, PMID 40130828); benefit is not (O'Connor 2023, PMID 37338868) — even though the USPSTF recommends screening adults (USPSTF 2023, PMID 37338866). See screening and measurement.
  3. One protocol designed for the comorbid case. Emotion regulation therapy was trialled deliberately in GAD with and without co-occurring depression (43% comorbid MDD) and produced large effects on both (Mennin 2018, PMID 29504794) — an approach the rest of the field has not adopted.

Open questions

  • What works for GAD without comorbid depression? Trial inclusion criteria make this unanswerable from existing data (Kopcalic 2025, PMID 39880377; Chen 2019, PMID 31494377).
  • Why is GAD correctly diagnosed in 34.4% of cases when the emotional problem is recognised in 72.5% (Wittchen 2002, PMID 12044105)? Is this a criteria problem, a training problem, or an incentive problem?
  • Does collaborative care work because of care coordination, treatment choice, or measurement-based follow-up? CALM bundled all three (Roy-Byrne 2010, PMID 20483968). A PubMed search rerun on 2026-09-02 located no GAD-specific dismantling trial separating those components; their individual contributions remain a dated evidence gap.
  • If persistence through unhelpful encounters is the binding constraint (Stein 2021, PMID 34372811), what intervention increases persistence? Nothing in the collaborative-care literature was designed to test that directly.
  • Should the treatment literature stop excluding substance use disorders, given that GAD-SUD is half of all lifetime GAD (Alegría 2010, PMID 20923623)?
  • Are painful physical symptoms a GAD feature, a depression feature, or a marker of the comorbid state (Romera 2010, PMID 20541811)?
  • Should treatment target the comorbid state directly rather than sequentially? ERT is the only GAD protocol built on that premise (Mennin 2018, PMID 29504794).

References

  1. Wittchen HU, et al. Generalized anxiety and depression in primary care: prevalence, recognition, and management. J Clin Psychiatry. 2002;63 Suppl 8:24-34. PMID 12044105
  2. Wittchen HU. Generalized anxiety disorder: prevalence, burden, and cost to society. Depress Anxiety. 2002;16:162-71. PMID 12497648
  3. Kroenke K, et al. Anxiety disorders in primary care: prevalence, impairment, comorbidity, and detection. Ann Intern Med. 2007;146:317-25. PMID 17339617
  4. Kroenke K, et al. The Patient Health Questionnaire Somatic, Anxiety, and Depressive Symptom Scales: a systematic review. Gen Hosp Psychiatry. 2010;32:345-59. PMID 20633738
  5. Ruscio AM, et al. Cross-sectional Comparison of the Epidemiology of DSM-5 Generalized Anxiety Disorder Across the Globe. JAMA Psychiatry. 2017;74:465-475. PMID 28297020
  6. Romera I, et al. Generalized anxiety disorder, with or without co-morbid major depressive disorder, in primary care: prevalence of painful somatic symptoms, functioning and health status. J Affect Disord. 2010;127:160-8. PMID 20541811
  7. Revicki DA, et al. Humanistic and economic burden of generalized anxiety disorder in North America and Europe. J Affect Disord. 2012;140:103-12. PMID 22154706
  8. Roy-Byrne PP, Katon W. Generalized anxiety disorder in primary care: the precursor/modifier pathway to increased health care utilization. J Clin Psychiatry. 1997;58 Suppl 3:34-8. PMID 9133491
  9. Faravelli C, et al. Generalized anxiety disorder: is there any specific symptom? Compr Psychiatry. 2012;53:1056-62. PMID 22578985
  10. Mackenzie CS, et al. Prevalence and correlates of generalized anxiety disorder in a national sample of older adults. Am J Geriatr Psychiatry. 2011;19:305-15. PMID 21427639
  11. Mohammadi MR, et al. Generalized anxiety disorder: Prevalence, predictors, and comorbidity in children and adolescents. J Anxiety Disord. 2020;73:102234. PMID 32470794
  12. Massion AO, et al. Personality disorders and time to remission in generalized anxiety disorder, social phobia, and panic disorder. Arch Gen Psychiatry. 2002;59:434-40. PMID 11982447
  13. Druet-Cabanac A, et al. Generalized anxiety disorder: epidemiology, burden, and comorbid depression. Curr Med Res Opin. 2025;41:1053-1064. PMID 40611531
  14. Henningsen P, et al. Medically unexplained physical symptoms, anxiety, and depression: a meta-analytic review. Psychosom Med. 2003;65:528-33. PMID 12883101
  15. Thomas NS, et al. Prospective associations between major depressive disorder, generalized anxiety disorder, fibromyalgia, and myalgic encephalomyelitis/chronic fatigue syndrome. Psychol Med. 2025;55:e232. PMID 40785390
  16. Ratcliff CG, et al. Recognition of anxiety, depression, and PTSD in patients with COPD and CHF: Who gets missed? Gen Hosp Psychiatry. 2017;47:61-67. PMID 28807139
  17. Roy-Byrne P, et al. Delivery of evidence-based treatment for multiple anxiety disorders in primary care: a randomized controlled trial. JAMA. 2010;303:1921-8. PMID 20483968
  18. Craske MG, et al. Disorder-specific impact of coordinated anxiety learning and management treatment for anxiety disorders in primary care. Arch Gen Psychiatry. 2011;68:378-88. PMID 21464362
  19. Rollman BL, et al. Telephone-Delivered Stepped Collaborative Care for Treating Anxiety in Primary Care: A Randomized Controlled Trial. J Gen Intern Med. 2017;32:245-255. PMID 27714649
  20. Rollman BL, et al. Effectiveness of Online Collaborative Care for Treating Mood and Anxiety Disorders in Primary Care: A Randomized Clinical Trial. JAMA Psychiatry. 2018;75:56-64. PMID 29117275
  21. Stein MB, et al. Quality of and patient satisfaction with primary health care for anxiety disorders. J Clin Psychiatry. 2011;72:970-6. PMID 21367351
  22. Joesch JM, et al. Incremental benefits and cost of coordinated anxiety learning and management for anxiety treatment in primary care. Psychol Med. 2012;42:1937-48. PMID 22152230
  23. Chavira DA, et al. Treatment engagement and response to CBT among Latinos with anxiety disorders in primary care. J Consult Clin Psychol. 2014;82:392-403. PMID 24660674
  24. Ishrat Husain M, et al. A Collaborative-Care Telephone-Based Intervention for Depression, Anxiety, and at-Risk Drinking in Primary Care: The PARTNERs Randomized Clinical Trial. Can J Psychiatry. 2023;68:732-744. PMID 36855791
  25. Heddaeus D, et al. Collaborative and Stepped Care for Mental Disorders: Results of a Cluster-Randomized Controlled Trial in Outpatient Care (The COMET Study). Dtsch Arztebl Int. 2025;122:127-134. PMID 39908421
  26. Mennin DS, et al. A randomized controlled trial of emotion regulation therapy for generalized anxiety disorder with and without co-occurring depression. J Consult Clin Psychol. 2018;86:268-281. PMID 29504794
  27. Kopcalic K, et al. Antidepressants versus placebo for generalised anxiety disorder (GAD). Cochrane Database Syst Rev. 2025;1:CD012942. PMID 39880377
  28. Chen TR, et al. Pharmacological and psychological interventions for generalized anxiety disorder in adults: A network meta-analysis. J Psychiatr Res. 2019;118:73-83. PMID 31494377
  29. Aktürk Z, et al. Generalized Anxiety Disorder 7-item (GAD-7) and 2-item (GAD-2) scales for detecting anxiety disorders in adults. Cochrane Database Syst Rev. 2025;3:CD015455. PMID 40130828
  30. O'Connor EA, et al. Anxiety Screening: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2023;329:2171-2184. PMID 37338868
  31. US Preventive Services Task Force. Screening for Anxiety Disorders in Adults. JAMA. 2023;329:2163-2170. PMID 37338866
  32. Zech JM, et al. Correlates of treatment-seeking in DSM-5 generalized anxiety disorder: Findings from the National Epidemiologic Survey on Alcohol and Related Conditions-III. J Anxiety Disord. 2024;106:102909. PMID 39047416
  33. Stein DJ, et al. Perceived helpfulness of treatment for generalized anxiety disorder: a World Mental Health Surveys report. BMC Psychiatry. 2021;21:392. PMID 34372811
  34. Alegría AA, et al. Comorbidity of generalized anxiety disorder and substance use disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2010;71:1187-95. PMID 20923623
  35. Smith JP, et al. Comorbidity of generalized anxiety disorder and alcohol use disorders among individuals seeking outpatient substance abuse treatment. Addict Behav. 2010;35:42-5. PMID 19733441
  36. Ipser JC, et al. Pharmacotherapy for anxiety and comorbid alcohol use disorders. Cochrane Database Syst Rev. 2015;1:CD007505. PMID 25601826
  37. Hoffman DL, et al. Human and economic burden of generalized anxiety disorder. Depress Anxiety. 2008;25:72-90. PMID 17146763
  38. Evoy KE, et al. Abuse and Misuse of Pregabalin and Gabapentin: A Systematic Review Update. Drugs. 2021;81:125-156. PMID 33215352