Skip to main content Accessibility help
×
Home

Association between antidepressant resistance in unipolar depression and subsequent bipolar disorder: cohort study

  • Cheng-Ta Li (a1), Ya-Mei Bai (a2), Yu-Lin Huang (a3), Ying-Sheue Chen (a4), Tzeng-Ji Chen (a5), Ju-Yin Cheng (a4) and Tung-Ping Su (a6)...

Abstract

Background

People with major depressive disorder who fail to respond to adequate trials of antidepressant treatment may harbour hidden bipolar disorder.

Aims

We aimed to compare the rates of a change in diagnosis to bipolar disorder among people with major depressive disorder with stratified responses to antidepressants during an 8-year follow-up period.

Method

Information on individuals with major depressive disorder identified during 2000 (cohort 2000, n = 1485) and 2003 (cohort 2003, n = 2459) were collected from a nationally representative cohort of 1 000 000 health service users in Taiwan. Participants responding well to antidepressants were compared with those showing poor responses to adequate trials of antidepressants.

Results

In 7.6–12.1% of those with a diagnosis of unipolar major depressive disorder this diagnosis was subsequently changed to bipolar disorder, with a mean time to change of 1.89–2.98 years. Difficult-to-treat participants presented higher rates of change to a bipolar diagnosis (25.6% in cohort 2000; 26.6% in cohort 2003) than easy-to-treat participants (8.8–8.9% in cohort 2000; 6.8–8.6% in cohort 2003; P<0.0001). Regression analysis showed that the variable most strongly associated with the change in diagnosis was antidepressant use history. The difficult-to-treat participants were associated most with diagnostic changing (cohort 2000: odds ratio (OR) = 1.88 (95% CI 1.12–3.16); cohort 2003: OR = 4.94 (95% CI 2.81–8.68)).

Conclusions

This is the first large-scale study to report an association between antidepressant response history and subsequent change in diagnosis from major depressive disorder to bipolar disorder. Our findings support the view that a history of poor response to antidepressants in unipolar depression could be a useful predictor for bipolar diathesis.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Association between antidepressant resistance in unipolar depression and subsequent bipolar disorder: cohort study
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Association between antidepressant resistance in unipolar depression and subsequent bipolar disorder: cohort study
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Association between antidepressant resistance in unipolar depression and subsequent bipolar disorder: cohort study
      Available formats
      ×

Copyright

Corresponding author

Tung-Ping Su, Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, 11217, Taiwan. Email: tomsu0402@gmail.com

Footnotes

Hide All

See editorial, pp. 5–6, this issue.

Declaration of interest

None.

Footnotes

References

Hide All
1 Fava, M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry 2003; 53: 649–59.
2 Eaton, WW, Shao, H, Nestadt, G, Lee, HB, Bienvenu, OJ, Zandi, P. Population-based study of first onset and chronicity in major depressive disorder. Arch Gen Psychiatry 2008; 65: 513–20.
3 Moller, HJ. Outcomes in major depressive disorder: the evolving concept of remission and its implications for treatment. World J Biol Psychiatry 2008; 9: 102–14.
4 Bschor, T. Therapy-resistant depression. Expert Rev Neurother 10: 7786
5 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.
6 Kornstein, SG, Schneider, RK. Clinical features of treatment-resistant depression. J Clin Psychiatry 2001; 62 (suppl 16): 1825.
7 Inoue, T, Nakagawa, S, Kitaichi, Y, Izumi, T, Tanaka, T, Masui, T, et al. Long-term outcome of antidepressant-refractory depression: the relevance of unrecognized bipolarity. J Affect Disord 2006; 95: 61–7.
8 Akiskal, HS, Mallya, G. Criteria for the “soft” bipolar spectrum: treatment implications. Psychopharmacol Bull 1987; 23: 6873.
9 Correa, R, Akiskal, H, Gilmer, W, Nierenberg, AA, Trivedi, M, Zisook, S. Is unrecognized bipolar disorder a frequent contributor to apparent treatment resistant depression? J Affect Disord 2010; 127: 10–8.
10 Ghaemi, SN, Ko, JY, Goodwin, FK. “Cade's disease” and beyond: misdiagnosis, antidepressant use, and a proposed definition for bipolar spectrum disorder. Can J Psychiatry 2002; 47: 125–34.
11 Sharma, V, Khan, M, Smith, A. A closer look at treatment resistant depression: is it due to a bipolar diathesis? J Affect Disord 2005; 84: 251–7.
12 Huang, KL, Su, TP, Chen, TJ, Chou, YH, Bai, YM. Comorbidity of cardiovascular diseases with mood and anxiety disorder: a population based 4-year study. Psychiatry Clin Neurosci 2009; 63: 401–9.
13 National Health Research Institutes. National Health Insurance Research Database, Taiwan. NHRI, 2007 (http://w3.nhri.org.tw/nhird//en/Research.html).
14 National Center for Health Statistics. International Classification of Diseases (9th Rev. Clinical Modification) (ICD-9-CM). NCHS, 2010 (http://www.cdc.gov/nchs/icd/icd9cm.htm).
15 Correa, R, Akiskal, H, Gilmer, W, Nierenberg, AA, Trivedi, M, Zisook, S. Is unrecognized bipolar disorder a frequent contributor to apparent treatment resistant depression? J Affect Disord 2010; 126: 10–8.
16 Hantouche, EG, Akiskal, HS, Lancrenon, S, Allilaire, JF, Sechter, D, Azorin, JM, et al. Systematic clinical methodology for validating bipolar-II disorder: data in mid-stream from a French national multi-site study (EPIDEP). J Affect Disord 1998; 50: 163–73.
17 Goodwin, G, Fleischhacker, W, Arango, C, Baumann, P, Davidson, M, de Hert, M, et al. Advantages and disadvantages of combination treatment with antipsychotics: ECNP Consensus Meeting, March 2008, Nice. Eur Neuropsychopharmacol 2009; 19: 520–32.
18 Papakostas, GI. Managing partial response or nonresponse: switching, augmentation, and combination strategies for major depressive disorder. J Clin Psychiatry 2009; 70 (suppl 6): 1625.
19 Papakostas, GI. Pharmacologic and therapeutic strategies in treatment-resistant depression. Switching antidepressants vs. conventional augmentation strategies. CNS Spectr 2009; 14: 11–4.
20 Shelton, RC, Osuntokun, O, Heinloth, AN, Corya, SA. Therapeutic options for treatment-resistant depression. CNS Drugs 2010; 24: 131–61.
21 Dudek, D, Rybakowski, JK, Siwek, M, Pawłowski, T, Lojko, D, Roczan, R, et al. Risk factors of treatment resistance in major depression: Association with bipolarity. J Affect Disord 2010; 126: 268–71.
22 Akiskal, HS, Maser, JD, Zeller, PJ, Endicott, J, Coryell, W, Keller, M, et al. Switching from ‘unipolar’ to bipolar II. An 11-year prospective study of clinical and temperamental predictors in 559 patients. Arch Gen Psychiatry 1995; 52: 114–23.
23 Holma, IAK, Holma, KM, Melartin, TK, Isometsä, ET. Maintenance pharmacotherapy for recurrent major depressive disorder: 5-year follow-up study. Br J Psychiatry 2008; 193: 163–4.
24 Holma, KM, Melartin, TK, Holma, IAK, Isometsä, ET. Predictors for switch from unipolar major depressive disorder to bipolar disorder type I or II: a 5-year prospective study. J Clin Psychiatry 2008; 69: 1267–75.
25 Angst, J, Sellaro, R, Stassen, HH, Gamma, A. Diagnostic conversion from depression to bipolar disorders: results of a long-term prospective study of hospital admissions. J Affect Disord 2005; 84: 149–57.
Type Description Title
PDF
Supplementary materials

Li et al. supplementary material
Supplementary Material

 PDF (35 KB)
35 KB

Association between antidepressant resistance in unipolar depression and subsequent bipolar disorder: cohort study

  • Cheng-Ta Li (a1), Ya-Mei Bai (a2), Yu-Lin Huang (a3), Ying-Sheue Chen (a4), Tzeng-Ji Chen (a5), Ju-Yin Cheng (a4) and Tung-Ping Su (a6)...

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed

Association between antidepressant resistance in unipolar depression and subsequent bipolar disorder: cohort study

  • Cheng-Ta Li (a1), Ya-Mei Bai (a2), Yu-Lin Huang (a3), Ying-Sheue Chen (a4), Tzeng-Ji Chen (a5), Ju-Yin Cheng (a4) and Tung-Ping Su (a6)...
Submit a response

eLetters

Diagnosing bipolar disorder in treatment-resistant depression

Gurdaval Singh, ST6 in General Adult Psychiatry
26 January 2012

Firstly, we would like to thank Li et al1 for their very informative and interesting cohort study on the association between antidepressant resistance in unipolar depression and subsequent bipolar disorder. The study had a number of highly commendable aspects including its elegant study design, large sample sizes and no investigator bias in determining bipolar symptoms. In addition, the naturalistic data obtained makes the study findings applicable to everyday clinical practice. However, we wondered whether the authors had considered the following points in relation to their study findings. The authors report an increase in the rate of diagnosis of bipolar disorder in the 2003 cohort study compared to 2000 cohort study. There area number of reports about a general trend towards overdiagnosing patients with bipolar disorder. Healey highlighted that the emergence of bipolar IIdisorder, bipolar disorders not otherwise specified (NOS) and cyclothymia have culminated in the prevalence of bipolar disorders growing from 0.1% of the population having bipolar I disorder to 5% or more when the definition of bipolar disorder encompasses the aforementioned community bipolar disorders.2 In the same paper, Healey continued by stating that there is the potential for creating a bipolar disorder "epidemic" due to people being diagnosed with the condition based on operational criteria that rely upon subjective judgements as opposed to an objective criterion of disability such as hospitalisation.2 Zimmerman et al conducted a study which essentially demonstrated that there was a significant problem with overdiagnosis of bipolar disorder by clinicians. Zimmerman and his colleagues recommended that clinicians use a standardised, validated approach in diagnosing this condition.3We wondered whether these factors have some bearing on the results of the study by Li et al1. Patients who did not respond to antidepressants (DTT: antidepressants altered ? 2 times) for whatever reason may have prompted clinicians to explore bipolarsymptoms more aggressively as with the general trend. This may partly contribute to the finding that there was a higher rate of conversion to a diagnosis of bipolar disorder in the DTT group compared to the other groups.The authors have looked into the co-morbid conditions, but it is not clearwhether they have considered the use of other psychotropic medications influencing the results. We wondered whether some of the study participants categorised in the easy to treat groups (ETT-1: no antidepressant treatment) and (ETT-2: one antidepressant treatment) and intermediate difficult to treat (ITT: antidepressant changed once) group were possibly already taking mood stabilisers or antipsychotics (possessing mood stabilising properties) for other reasons (such as to treat co-morbid conditions e.g. adjunctive treatment of anxiety which frequently occurs in everyday clinical practice4). If this was the case, it may go some way to explain why participants in one of these three groups had a lower rate of conversion to a diagnosis of bipolar disorder compared to the DTT group participants as these medications would mask theemergence of manic or hypomanic symptoms. A depressive illness emerges due to a complex interplay between biological, psychological and social factors. Those individuals suffering from a depressive episode where psychosocial factors predominate may be less responsive to antidepressant treatment compared to those individuals where biological factors predominate. In this study, those individuals classified in the DTT group may have largely had psychosocial factors culminating in their depressive episode. This may partly explain why DTT participants were less responsive to antidepressant medication compared tothe other groups. It would be interesting to find out whether individuals categorised in the easy to treat groups suffered from more depressive episodes that included features of the 'somatic syndrome'5 compared to theDTT group as they may have been more responsive to antidepressant treatment than DTT participants. When comparing the prevalence of bipolar disorder from 2000 to 2007, the authors included every bipolar disorder diagnosis reported by all clinicians. We wondered why the authors did not look at only those cases where bipolar disorder was diagnosed by a psychiatrist in making this comparison. If the authors are questioning the reliability and validity ofa bipolar diagnosis made by non-psychiatrists (as they did in this study by excluding these cases), surely including these cases in calculating thechange in prevalence of a bipolar diagnosis over the aforementioned time period would also be questionable? We assumed that the authors believed that diagnoses of bipolar disorder made by non-psychiatrists would be deemed less accurate. Although we could understand the authors' rationale for excluding diagnoses of bipolar disorder made by non-psychiatrists, we believed it would be interesting to know whether the study findings would alter if these diagnoses were also included. Although the authors do highlight that the primary objective of this studywas not to differentiate between subtypes of bipolar disorder, this would certainly be something to explore further in future research. The authors'approach to classifying participants as either suffering from bipolar I disorder or bipolar II disorder on the basis of whether or not they required hospitalisation seemed reasonably appropriate for the purposes ofthe study. The authors demonstrate that those individuals whose diagnosis was changed to bipolar disorder in both the cohort 2000 and cohort 2003 studies mostly had bipolar II disorder.1 This result supports Healey's finding that the increased prevalence of bipolar disorder is largely due to the inclusion of bipolar II diagnoses in calculating the prevalence.2 This makes us question whether we are diagnosing patients more with bipolar disorder if they are deemed to suffer from treatment-resistant depression.Based on the study findings, the authors propose that a history of poor response to antidepressants in individuals with major depression is a useful sign for predicting bipolar diathesis. This finding clearly has significant clinical implication. It highlights the importance of regularly checking for symptoms suggestive of hypomania or mania in this patient group in order to ensure that they receive the most appropriate treatment in a timely manner, but at the same time not falling into trap of over diagnosing it. The study is certainly worth repeating in order to see whether there is an ongoing upward trend in patients being diagnosed with bipolar disorder and whether the same results are produced. Future research in this area could also explore whether those individuals who have a poor response to antidepressant treatment have a positive family history of bipolar disorder as this would add further weight to the authors' conclusion. REFERENCES1. Li C-T, Ya-Mei Bai Y-M, Huang Y-L, Chen Y-S, Chen T-J, Ju-Yin ChengJ-Y, et al. Association between antidepressant resistance in unipolar depression and subsequent bipolar disorder: cohort study. Br J Psychiatry 2012; 200: 45-51.2. Healy D. The latest mania: selling bipolar disorder. PLoS Med 2006;3(4): e185. doi:10.1371/journal.pmed.0030185.3. Zimmerman M, Ruggero CJ, Chelminski I, Young D. Is bipolar disorderoverdiagnosed? J Clin Psychiatry 2008; 69(6): 935-940.4. Culpepper, L. Evidence for using atypical antipsychotics for mood and anxiety disorders. Prim Care Companion J Clin Psychiatry 2003; 5(3): 27-32.5. World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. WHO,1992.

... More

Conflict of interest: None declared

Write a reply

×

Reply to: Submit a response


Your details


Conflicting interests

Do you have any conflicting interests? *