International Journal of Psychiatry in Clinical Practice, 2008; 12(2): 142146
SHORT REPORT
The bipolar diathesis of treatment-resistant major depressive disorder
YOUNG SUP WOO, JEONG-HO CHAE, TAE-YOUN JUN, KWANG-SOO KIM & WON-MYONG BAHK
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Department of Psychiatry, College of Medicine, The Catholic University of Korea, Seoul, Korea
Abstract Objective. In this study, we determined the prevalence of bipolarity in patients with treatment-resistant depression (TRD) by investigating demographic and clinical characteristics, diagnostic subtypes and illness outcome of patients with resistant depression. Methods. A medical record review of patients who were admitted to a university hospital with the diagnosis of major depressive disorder (MDD) was conducted. DSM-IV diagnoses at the index hospitalization and 6 months after discharge and detailed clinical information were obtained. We categorized subjects into a TRD group or a non-TRD group and re-evaluated the patients using the criteria for bipolar spectrum disorders. Results. There were 281 patients diagnosed with MDD. At discharge, the number of patients who fulfilled the criteria for BSD was higher in the TRD group (47.1%) than in the non-TRD group (3.8%) (P B0.001). At the end of the 6-month follow-up period, the diagnoses of 38 patients were changed; 18 (26.5%) of the TRD group were subsequently classified as having a bipolar disorder, as were seven (3.3%) in the non-TRD group (P B0.001). There was no difference between these two groups for other clinical and demographic variables. Conclusion. The findings of this study suggest that many patients with TRD have a bipolar diathesis.
Key Words: Treatment-resistant depression, bipolar spectrum disorder, bipolarity
Introduction With regard to the pharmacological treatment of major depressive disorder (MDD), specific medications for this disorder have been developed over the past two decades. However, despite significant psychopharmacological advances, roughly one-third of patients with MDD do not respond to antidepressant treatment, and about half have only a partial response [13]. Those patients with treatment-resistant depression (TRD) have a major impact on health care utilization and costs due to their extensive use of medical services. The total annual depression-related costs over a 5-year period were significantly higher for patients with TRD compared with those who did not have TRD [4]. Several patient- and treatment-related risk factors have been identified that increase the likelihood of poor response to antidepressant treatment [5]. Patient-related risk factors include disease severity [5] and concomitant medical or psychiatric disorders, such as alcohol abuse [6] and anxiety disorders [7]. Some reports also suggest that an older age and chronicity are associated with a poor treatment response [5]. In addition, atypical features have also been associated with refractoriness [8].
Treatment-related risk factors include an inadequate dose and duration of antidepressant treatment, inaccurate diagnosis or misdiagnosis and treatment noncompliance [4,5]. The inaccurate diagnosis of bipolar depression as ‘‘unipolar’’ MDD is common [9,10], and delayed or inappropriate treatment can be associated with a poor prognosis [11,12]. Antidepressants are less effective for treating bipolar depression than they are for the treatment of MDD. A study on the relationship between episode duration and antidepressant treatment concluded that antidepressant treatment might not reduce the length of a depressive episode in patients with bipolar depression [13]. There is also a concern that bipolarity in some patients with MDD may lead to chronicity and treatment refractoriness. Akiskal and Mallya [14] reported that patients who respond to lithium and/or low-dose neuroleptic augmentation might have a bipolar diathesis. In another study, patients who relapsed on previous successful antidepressants were more likely to have clinical features suggestive of bipolarity such as atypical symptoms of depression, postpartum episodes and a family history of bipolarity [15].
Correspondence: Won-Myong Bahk, M.D., Department of Psychiatry, College of Medicine, The Catholic University of Korea, #62 Yoido-Dong, Youngdeungpo-Gu, Seoul 150-713, Korea. Tel: 82 2 37791250. Fax: 82 2 780 6577. E-mail: [email protected]
(Received 7 May 2007; accepted 27 September 2007) ISSN 1365-1501 print/ISSN 1471-1788 online # 2008 Taylor & Francis DOI: 10.1080/13651500701749867
Bipolarity of treatment-resistant depression In the present study, we investigated the clinical and sociodemographic features of patients who were admitted to the psychiatric unit of a university hospital with MDD. We compared the prevalence of bipolarity in the TRD patients with patients who did not have TRD.
Methods
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Subjects This retrospective investigation was performed by reviewing the medical records of patients at St. Mary’s Hospital, The Catholic University of Korea, who were patients consecutively hospitalized in the psychiatric ward (index hospitalization) due to the severity of their illness from January 2002 to June 2005. A psychiatrist (YSW) who was not involved in the clinical care of the patients and was blind to patient identity performed the medical record review. The institutional review board (IRB) reviewed and approved the protocol, and the study was conducted in accordance with good clinical practices and the Helsinki Declaration. The patients were at least 18 years old and they were clinically diagnosed with MDD according to DSM-IV at the index hospitalization. A structured interview to confirm the diagnosis was not used. Patients admitted with an adverse event or other diagnostic or environmental etiologies were excluded. To be eligible for assessment, patients were required to have had at least 6 months of follow-up care. Definitions and clinical data Treatment resistance was defined as failure to respond to two adequate trials of antidepressants. The adequacy of the pharmacotherapy was determined using the criteria described by Nierenberg and Amsterdam [16]. A treatment response was defined as a 50% decrease in the score on the 17-item Hamilton Depression Scale (HDRS) from the baseline score [17]. We used the diagnostic criteria suggested by Ghaemi et al. [18] to define bipolar spectrum disorder (BSD) (Table I). Detailed clinical information, including sociodemographic data, age at illness onset, duration of the mood disorder, nature of symptoms, and severity of symptoms on admission using the HDRS and the Clinical Global Impression-Bipolar (CGI-BP) scales were obtained. In addition, psychiatric comorbidity, psychiatric family history in first-degree relatives, treatment lag (the interval between emergence of acute mood symptoms and initiation of treatment seeking) and DSM-IV diagnoses at the index hospitalization and 6 months after discharge were obtained. Medical records were re-evaluated to verify the clinical diagnosis according to the DSM-IV and determine which patients had TRD or BSD
143
Table I. A proposed definition of bipolar spectrum disorder. A At least one major depressive episode B No spontaneous hypomanic or manic episodes C Either of the following, plus at least two items from criterion D, or both of the following plus one item from criterion D: 1. A family history of bipolar disorder in a first-degree relative 2. Antidepressant-induced mania or hypomania D If no items from criterion C are present, six of the following nine criteria are needed: 1. Hyperthymic personality (at baseline, nondepressed state) 2. Recurrent major depressive eisodes (3) 3. Brief major depressive episodes (on average, B3 months) 4. Atypical depressive features (increased sleep or appetite) 5. Psychotic major depressive episodes 6. Early age of onset of major depressive episode (Bage 25) 7. Postpartum depression 8. Antidepressant tolerance (‘wear-off’, acute but not prophylactic response) Adapted from Ghaemi et al. [18].
according to the criteria reported by Ghaemi et al. [18]. We divided the subjects into a TRD group or a non-TRD group based on their history and the clinical features at the time of discharge from the index hospitalization. Statistical analysis Sociodemographic and clinical information were compared between the TRD group and non-TRD group. The baseline data (HDRS, CGI score and other continuous variables) distribution did not differ significantly from normal (Kolmogorov Smirnov test) and were analyzed using the independent t-test. Categorical variables were analyzed with a chi-square test or a Fisher’s exact test. The tests were considered significant when the P values were less than 0.05 (two-tailed). Results The medical records of 487 patients admitted with the diagnosis of MDD were reviewed. We identified 281 patients who fulfilled the eligibility criteria and excluded 206 patients for reasons of an indistinct diagnosis, insufficient follow-up and absence of conclusive clinical data. Sixty-eight patients were included in the TRD group and 213 patients were included in the non-TRD group. The clinical and sociodemographic data for these two groups is presented in Table II. There were no group differences in any of the sociodemographic and baseline clinical variables. Patients with axis II comorbidity were more common in the TRD group, but this difference was not statistically significant (P 0.063). The diagnosis of all patients with axis II comorbidity was confined to cluster B personality disorders. Among the patients with the diagnosis of MDD at the index hospitalization, the number of patients who fulfilled the criteria for the bipolar
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Table II. Demographic and clinical characteristics of patients with major depression diagnosed during the study period. TRD group (n 68)
P value
Sex Male Female
16 (23.5%) 52 (76.5%)
Onset age
45.87916.96
46.86916.44
0.792
1.5093.55
0.6692.63
0.074
Treatment lag (years)
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Non-TRD group (n 213)
Marital status Married Unmarried Divorced Widowed Family history of psychiatric disorder
50 14 1 3 13
Comorbidity Medical Psychiatric (Axis I) Psychiatric (Axis II)
21 (30.9%) 7 (10.3%) 7 (10.3%)
CGI-BP-severity score at hospitalization HDRS score at hospitalization
(73.5%) (20.6%) (1.5%) (4.4%) (19.1%)
62 (29.1%) 151 (70.9%)
171 28 7 7 32
0.438
(80.3%) (13.1%) (3.3%) (3.3%) (15.0%)
0.449
75 (35.2%) 28 (13.1%) 9 (4.2%)
0.512 0.674 0.063
0.393
4.8191.29
4.6991.14
0.489
29.3896.57
28.9297.19
0.635
TRD, treatment-resistant depression; CGI-BP, Clinical Global Impression-Bipolar; HDRS, Hamilton Depression Rating Scale.
spectrum disorder at the index hospitalization was higher in the TRD group (32/68, 47.1%) than in the non-TRD group (8/213, 3.8%; P 0.000) (Figure 1). At the end of a 6-month follow-up period, the diagnosis of 38 patients was changed, mainly to a diagnosis of bipolar disorder (25/281, 8.9%). The number of patients whose diagnoses was changed to bipolar disorder was significantly higher in the TRD group than in the non-TRD group (18/ 68, 26.5% vs. 7/213, 3.3%; P 0.000) (Table III). The remaining 13 patients were subsequently diagnosed with schizophrenia, personality disorder and anxiety disorder. Discussion Dunner et al. [19], who defined bipolarity as varying degrees of mania and hypomania, originally proposed the concept of BSD. Klerman [20], Akiskal [21], and later Ghaemi et al. [18] further developed 96.2
100 80 60
52.9
47.1
TRD Non-TRD
40 20 3.8 0
BSD
Non-BSD
Figure 1. Prevalence rate of bipolar treatment-resistant major depression in bipolar spectrum disorder and non-bipolar spectrum disorder. TRD, treatment resistant major depression; BSD, bipolar spectrum disorder.
the concept of bipolarity. Several investigators have suggested that the true rate of BSD is higher than currently reported [22,23]. Goodwin and Ghaemi suggested that a broad spectrum of the bipolar disorder may be present in 25% of the population and may be as common as unipolar MDD [22]. However, BSD is often misdiagnosed because the symptoms overlap with other psychiatric disorders, particularly ‘‘unipolar’’ MDD [23,24]. Hantouche et al. [23] found that the number of patients with broadly defined bipolar disorders markedly increased when a systematic approach was used for the diagnosis of MDD patients. They diagnosed 70 of 250 patients (28%) as bipolar at the end of visit one. During the second visit, a more sophisticated assessment of soft bipolarity was utilized and related measures were used for confirmation of the diagnosis. At the end of the second visit, 137 patients (55%) were classified as having bipolar I disorder (n 15, 6%), bipolar II disorder (n 100, 40%), and ‘‘pseudo-unipolar depression’’ [25] (n 22, 9%). Only 113 patients (45%) strictly conformed to the diagnosis of unipolar depression. The results of this study showed that the diagnosis of BSD and a change of diagnosis to bipolar disorder were more common in patients with TRD. These results are consistent with previous reports, suggesting that bipolarity may be a significant cause of treatment resistance [14,26]. Sharma et al. [26] reevaluated 61 patients who were seen consecutively at a mood disorders clinic with the diagnosis of unipolar treatment-resistant depression. At intake, 35% (n 21) of the patients were diagnosed as having bipolar disorder. At the follow-up, there was a 59% (n 36) prevalence of bipolar disorder. Of the patients with MDD at follow-up, 13 patients (52%) were classified as having BSD. The prevalence rate of
Bipolarity of treatment-resistant depression
145
Table III. Prevalence rate of bipolar disorder in the TRD group versus the non-TRD group. Non-TRD (n 213)
TRD (n 68) BSD (n 32) Follow- up
Diagnostic Change to BPD, N (%)
Non-BSD (n 36)
18 (26.5) 17 (53.1)
BSD (n 8)
Non-BSD (n 205)
Significance
7 (3.3) 1 (2.8)
0.000*
1 (12.5)
6 (2.9)
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TRD, treatment-resistant major depression; BSD, bipolar spectrum disorder; BPD, bipolar disorder; *P B0.001.
BSD and the change of the diagnosis to bipolar disorder in TRD patients were higher in the study of Sharma et al. [26] than in the present study. It is difficult to compare our results with the findings of Sharma et al. [26] because the length of follow-up was different. Moreover, there was no non-TRD control group in the Sharma study because all patients were referred for assessment and treatment of TRD. They proposed that the high occurrence rate in their study was likely due to their sample being biased towards having an overrepresentation of patients with a bipolar diathesis [26]. The findings from the present study have important clinical implications. Patients who have TRD should have an exhaustive assessment to rule out bipolarity. As patients may have difficulty in recalling any hypomanic episodes and seldom seek treatment for hypomania, recognition of bipolar II disorder and the softer variants of bipolarity must be considered during assessment or treatment of an MDD, especially in the case of TRD. A clear limitation of the present study was the retrospective design. Retrospective medical record reviews cannot control for differences in baseline characteristics not captured in the medical records (such as number of prior episodes and length of each episode) and raise questions about the accuracy of diagnosis. Evaluation of patients using a structured interview could be used to confirm the current diagnosis. We did not assess the frequency of each clinical feature included in the criteria for bipolar spectrum disorder. However, assessment of demographic and clinical features, distinguishing BSD or bipolar depression from MDD, was beyond the goals of this study. A second limitation was the omission of information regarding the pharmacotherapy, except for the information required to define treatment-resistance. The class or dose of antidepressants previously or currently used may have been related to the course of the depressive episodes or might have induced manic or hypomanic episodes. In addition, the data were collected only from patients who were hospitalized; this may have biased the sample since patients with less severe symptoms were not included. TRD is common and associated with considerable personal and social burdens. The results of the present study indicated that bipolarity is present in a substantial portion of patients with treatment
resistance. Our results suggest that patients with TRD should be assessed for bipolarity. Further studies with larger patient samples and extended follow-up are needed to determine the relationship between treatment resistance and bipolarity. Key points . A considerable number of patients with treatment-resistant depression fulfilled the criteria for bipolar spectrum disorder . Diagnoses of patients with treatment-resistant depression were more frequently changed to bipolar disorder . A large number of patients with treatmentresistant depression have a bipolar diathesis Statement of interest We declare that we have no proprietary or financial interest in any aspect of this article. This study received no public financial support. We declare that they have no competing interests. References [1] Amsterdam JD, Hornig-Rohan M. Treatment algorithms in treatment-resistant depression. Psychiatr Clin North Am 1996;19:37186. [2] Fawcett J. Progress in treatment-resistant depression and treatment-refractory depression: we still have a long way to go. Psychiatr Ann 1994;24:2146. [3] Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am 1996;19:179200. [4] Crown WH, Finkelstein S, Berndt ER, et al. The impact of treatment-resistant depression on health care utilization and costs. J Clin Psychiatry 2002;63:96371. [5] Kornstein SG, Schneider RK. Clinical features of tretmentresistant depression. J Clin Psychiatry 2001;62(Suppl 16): 1825. [6] Castaneda R, Sussman N, Westreich L, Levy R, O’Malley M. A review of the effects of moderate alcohol intake on the treatment of anxiety and mood disorders. J Clin Psychiatry 1996;57:20712. [7] McLeod JD, Kessler RC, Landis KR. Speed of recovery from major depressive episodes in a community sample of married men and women. J Abnorm Psychol 1992;101:277 86. [8] Benazzi F. Should mood reactivity be included in the DSMIV atypical specifier? Eur Arch Psychiatry Clin Neurosci 2002;252:13540. [9] Manning JS, Haykal RF, Connor PD, Akiskal HS. On the nature of depressive and anxious states in a family practice /
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Y.S. Woo et al. setting: the high prevalence of bipolar II and related disorders in a cohort followed longitudinally. Compr Psychiatry 1997;38:1028. Hirschfeld RM, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we really come? Results of the National Depressive and Manic-Depressive Association 2000 survey of individuals with bipolar disorder. J Clin Psychiatry 2003;64:16174. Wehr TA, Goodwin FK. Can antidepressants cause mania and worsen the course of affective illness? Am J Psychiatry 1987;144:140311. Goldberg JF, Ernst CL. Features associated with the delayed initiation of mood stabilizers at illness onset in bipolar disorder. J Clin Psychiatry 2002;63:98591. Frankle WG, Perlis RH, Deckersbach T, et al. Bipolar depression: relationship between episode length and antidepressant treatment. Psychol Med 2002;32:141723. Akiskal HS, Mallya G. Criteria for the ‘‘soft’’ bipolar spectrum: treatment implications. Psychopharmacol Bull 1987;23:6873. Sharma V. Loss of response to antidepressants and subsequent refractoriness: diagnostic and treatment issues. J Affect Disord 2001;64:99106. Nierenberg AA, Amsterdam JD. Treatment-resistant depression: definition and treatment approaches. J Clin Psychiatry 1990;51((Suppl)):3947. Angst J, Delini-Stula A, Stabl M, Stassen HH. Is a cut-off score a suitable measure of treatment outcome in short-term trials in depression? A methodological meta-analysis. Hum Psychopharmacol 1993;8:3117. /
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[18] 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;47:12534. [19] Dunner DL, Gershon ES, Goodwin FK. Heritable factors in the severity of affective illness. Sci Pro Am Psychiatric Assn 1970;123:1878. [20] Klerman GL. The spectrum of mania. Compr Psychiatry 1981;22:1120. [21] Akiskal HS. The prevalent clinical spectrum of bipolar disorders: beyond DSM-IV. J Clin Psychopharmacol 1996; 16(Suppl 1):414S. [22] Goodwin FK, Ghaemi SN. The difficult-to-treat patient with bipolar disorder. In: Dewan MJ, Pies RW, editors. The under-recognized bipolar spectrum disorder difficult-to-treat psychiatric patient. Washington, DC: American Psychiatric Press; 2001. p 739. [23] Hantouche EG, Akiskal HS, Lancrenon S, 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;50:16373. [24] Dunner DL. Clinical consequences of under-recognized bipolar spectrum disorder. Bipolar Disord 2003;5:45663. [25] Akiskal HS, Downs J, Jordan P, Watson S, Daugherty D, Pruitt DB. Affective disorders in referred children and younger siblings of manic-depressives: Mode of onset and prospective course. Arch Gen Psychiatry 1985;42:9961003. [26] Sharma V, Khan M, Smith A. A closer look at treatment resistant depression: is it due to a bipolar diathesis? J Affect Disord 2005;84:2517. /
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SHORT REPORT
The bipolar diathesis of treatment-resistant major depressive disorder
YOUNG SUP WOO, JEONG-HO CHAE, TAE-YOUN JUN, KWANG-SOO KIM & WON-MYONG BAHK
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of Waterloo on 01/05/15 For personal use only.
Department of Psychiatry, College of Medicine, The Catholic University of Korea, Seoul, Korea
Abstract Objective. In this study, we determined the prevalence of bipolarity in patients with treatment-resistant depression (TRD) by investigating demographic and clinical characteristics, diagnostic subtypes and illness outcome of patients with resistant depression. Methods. A medical record review of patients who were admitted to a university hospital with the diagnosis of major depressive disorder (MDD) was conducted. DSM-IV diagnoses at the index hospitalization and 6 months after discharge and detailed clinical information were obtained. We categorized subjects into a TRD group or a non-TRD group and re-evaluated the patients using the criteria for bipolar spectrum disorders. Results. There were 281 patients diagnosed with MDD. At discharge, the number of patients who fulfilled the criteria for BSD was higher in the TRD group (47.1%) than in the non-TRD group (3.8%) (P B0.001). At the end of the 6-month follow-up period, the diagnoses of 38 patients were changed; 18 (26.5%) of the TRD group were subsequently classified as having a bipolar disorder, as were seven (3.3%) in the non-TRD group (P B0.001). There was no difference between these two groups for other clinical and demographic variables. Conclusion. The findings of this study suggest that many patients with TRD have a bipolar diathesis.
Key Words: Treatment-resistant depression, bipolar spectrum disorder, bipolarity
Introduction With regard to the pharmacological treatment of major depressive disorder (MDD), specific medications for this disorder have been developed over the past two decades. However, despite significant psychopharmacological advances, roughly one-third of patients with MDD do not respond to antidepressant treatment, and about half have only a partial response [13]. Those patients with treatment-resistant depression (TRD) have a major impact on health care utilization and costs due to their extensive use of medical services. The total annual depression-related costs over a 5-year period were significantly higher for patients with TRD compared with those who did not have TRD [4]. Several patient- and treatment-related risk factors have been identified that increase the likelihood of poor response to antidepressant treatment [5]. Patient-related risk factors include disease severity [5] and concomitant medical or psychiatric disorders, such as alcohol abuse [6] and anxiety disorders [7]. Some reports also suggest that an older age and chronicity are associated with a poor treatment response [5]. In addition, atypical features have also been associated with refractoriness [8].
Treatment-related risk factors include an inadequate dose and duration of antidepressant treatment, inaccurate diagnosis or misdiagnosis and treatment noncompliance [4,5]. The inaccurate diagnosis of bipolar depression as ‘‘unipolar’’ MDD is common [9,10], and delayed or inappropriate treatment can be associated with a poor prognosis [11,12]. Antidepressants are less effective for treating bipolar depression than they are for the treatment of MDD. A study on the relationship between episode duration and antidepressant treatment concluded that antidepressant treatment might not reduce the length of a depressive episode in patients with bipolar depression [13]. There is also a concern that bipolarity in some patients with MDD may lead to chronicity and treatment refractoriness. Akiskal and Mallya [14] reported that patients who respond to lithium and/or low-dose neuroleptic augmentation might have a bipolar diathesis. In another study, patients who relapsed on previous successful antidepressants were more likely to have clinical features suggestive of bipolarity such as atypical symptoms of depression, postpartum episodes and a family history of bipolarity [15].
Correspondence: Won-Myong Bahk, M.D., Department of Psychiatry, College of Medicine, The Catholic University of Korea, #62 Yoido-Dong, Youngdeungpo-Gu, Seoul 150-713, Korea. Tel: 82 2 37791250. Fax: 82 2 780 6577. E-mail: [email protected]
(Received 7 May 2007; accepted 27 September 2007) ISSN 1365-1501 print/ISSN 1471-1788 online # 2008 Taylor & Francis DOI: 10.1080/13651500701749867
Bipolarity of treatment-resistant depression In the present study, we investigated the clinical and sociodemographic features of patients who were admitted to the psychiatric unit of a university hospital with MDD. We compared the prevalence of bipolarity in the TRD patients with patients who did not have TRD.
Methods
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of Waterloo on 01/05/15 For personal use only.
Subjects This retrospective investigation was performed by reviewing the medical records of patients at St. Mary’s Hospital, The Catholic University of Korea, who were patients consecutively hospitalized in the psychiatric ward (index hospitalization) due to the severity of their illness from January 2002 to June 2005. A psychiatrist (YSW) who was not involved in the clinical care of the patients and was blind to patient identity performed the medical record review. The institutional review board (IRB) reviewed and approved the protocol, and the study was conducted in accordance with good clinical practices and the Helsinki Declaration. The patients were at least 18 years old and they were clinically diagnosed with MDD according to DSM-IV at the index hospitalization. A structured interview to confirm the diagnosis was not used. Patients admitted with an adverse event or other diagnostic or environmental etiologies were excluded. To be eligible for assessment, patients were required to have had at least 6 months of follow-up care. Definitions and clinical data Treatment resistance was defined as failure to respond to two adequate trials of antidepressants. The adequacy of the pharmacotherapy was determined using the criteria described by Nierenberg and Amsterdam [16]. A treatment response was defined as a 50% decrease in the score on the 17-item Hamilton Depression Scale (HDRS) from the baseline score [17]. We used the diagnostic criteria suggested by Ghaemi et al. [18] to define bipolar spectrum disorder (BSD) (Table I). Detailed clinical information, including sociodemographic data, age at illness onset, duration of the mood disorder, nature of symptoms, and severity of symptoms on admission using the HDRS and the Clinical Global Impression-Bipolar (CGI-BP) scales were obtained. In addition, psychiatric comorbidity, psychiatric family history in first-degree relatives, treatment lag (the interval between emergence of acute mood symptoms and initiation of treatment seeking) and DSM-IV diagnoses at the index hospitalization and 6 months after discharge were obtained. Medical records were re-evaluated to verify the clinical diagnosis according to the DSM-IV and determine which patients had TRD or BSD
143
Table I. A proposed definition of bipolar spectrum disorder. A At least one major depressive episode B No spontaneous hypomanic or manic episodes C Either of the following, plus at least two items from criterion D, or both of the following plus one item from criterion D: 1. A family history of bipolar disorder in a first-degree relative 2. Antidepressant-induced mania or hypomania D If no items from criterion C are present, six of the following nine criteria are needed: 1. Hyperthymic personality (at baseline, nondepressed state) 2. Recurrent major depressive eisodes (3) 3. Brief major depressive episodes (on average, B3 months) 4. Atypical depressive features (increased sleep or appetite) 5. Psychotic major depressive episodes 6. Early age of onset of major depressive episode (Bage 25) 7. Postpartum depression 8. Antidepressant tolerance (‘wear-off’, acute but not prophylactic response) Adapted from Ghaemi et al. [18].
according to the criteria reported by Ghaemi et al. [18]. We divided the subjects into a TRD group or a non-TRD group based on their history and the clinical features at the time of discharge from the index hospitalization. Statistical analysis Sociodemographic and clinical information were compared between the TRD group and non-TRD group. The baseline data (HDRS, CGI score and other continuous variables) distribution did not differ significantly from normal (Kolmogorov Smirnov test) and were analyzed using the independent t-test. Categorical variables were analyzed with a chi-square test or a Fisher’s exact test. The tests were considered significant when the P values were less than 0.05 (two-tailed). Results The medical records of 487 patients admitted with the diagnosis of MDD were reviewed. We identified 281 patients who fulfilled the eligibility criteria and excluded 206 patients for reasons of an indistinct diagnosis, insufficient follow-up and absence of conclusive clinical data. Sixty-eight patients were included in the TRD group and 213 patients were included in the non-TRD group. The clinical and sociodemographic data for these two groups is presented in Table II. There were no group differences in any of the sociodemographic and baseline clinical variables. Patients with axis II comorbidity were more common in the TRD group, but this difference was not statistically significant (P 0.063). The diagnosis of all patients with axis II comorbidity was confined to cluster B personality disorders. Among the patients with the diagnosis of MDD at the index hospitalization, the number of patients who fulfilled the criteria for the bipolar
144
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Table II. Demographic and clinical characteristics of patients with major depression diagnosed during the study period. TRD group (n 68)
P value
Sex Male Female
16 (23.5%) 52 (76.5%)
Onset age
45.87916.96
46.86916.44
0.792
1.5093.55
0.6692.63
0.074
Treatment lag (years)
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Non-TRD group (n 213)
Marital status Married Unmarried Divorced Widowed Family history of psychiatric disorder
50 14 1 3 13
Comorbidity Medical Psychiatric (Axis I) Psychiatric (Axis II)
21 (30.9%) 7 (10.3%) 7 (10.3%)
CGI-BP-severity score at hospitalization HDRS score at hospitalization
(73.5%) (20.6%) (1.5%) (4.4%) (19.1%)
62 (29.1%) 151 (70.9%)
171 28 7 7 32
0.438
(80.3%) (13.1%) (3.3%) (3.3%) (15.0%)
0.449
75 (35.2%) 28 (13.1%) 9 (4.2%)
0.512 0.674 0.063
0.393
4.8191.29
4.6991.14
0.489
29.3896.57
28.9297.19
0.635
TRD, treatment-resistant depression; CGI-BP, Clinical Global Impression-Bipolar; HDRS, Hamilton Depression Rating Scale.
spectrum disorder at the index hospitalization was higher in the TRD group (32/68, 47.1%) than in the non-TRD group (8/213, 3.8%; P 0.000) (Figure 1). At the end of a 6-month follow-up period, the diagnosis of 38 patients was changed, mainly to a diagnosis of bipolar disorder (25/281, 8.9%). The number of patients whose diagnoses was changed to bipolar disorder was significantly higher in the TRD group than in the non-TRD group (18/ 68, 26.5% vs. 7/213, 3.3%; P 0.000) (Table III). The remaining 13 patients were subsequently diagnosed with schizophrenia, personality disorder and anxiety disorder. Discussion Dunner et al. [19], who defined bipolarity as varying degrees of mania and hypomania, originally proposed the concept of BSD. Klerman [20], Akiskal [21], and later Ghaemi et al. [18] further developed 96.2
100 80 60
52.9
47.1
TRD Non-TRD
40 20 3.8 0
BSD
Non-BSD
Figure 1. Prevalence rate of bipolar treatment-resistant major depression in bipolar spectrum disorder and non-bipolar spectrum disorder. TRD, treatment resistant major depression; BSD, bipolar spectrum disorder.
the concept of bipolarity. Several investigators have suggested that the true rate of BSD is higher than currently reported [22,23]. Goodwin and Ghaemi suggested that a broad spectrum of the bipolar disorder may be present in 25% of the population and may be as common as unipolar MDD [22]. However, BSD is often misdiagnosed because the symptoms overlap with other psychiatric disorders, particularly ‘‘unipolar’’ MDD [23,24]. Hantouche et al. [23] found that the number of patients with broadly defined bipolar disorders markedly increased when a systematic approach was used for the diagnosis of MDD patients. They diagnosed 70 of 250 patients (28%) as bipolar at the end of visit one. During the second visit, a more sophisticated assessment of soft bipolarity was utilized and related measures were used for confirmation of the diagnosis. At the end of the second visit, 137 patients (55%) were classified as having bipolar I disorder (n 15, 6%), bipolar II disorder (n 100, 40%), and ‘‘pseudo-unipolar depression’’ [25] (n 22, 9%). Only 113 patients (45%) strictly conformed to the diagnosis of unipolar depression. The results of this study showed that the diagnosis of BSD and a change of diagnosis to bipolar disorder were more common in patients with TRD. These results are consistent with previous reports, suggesting that bipolarity may be a significant cause of treatment resistance [14,26]. Sharma et al. [26] reevaluated 61 patients who were seen consecutively at a mood disorders clinic with the diagnosis of unipolar treatment-resistant depression. At intake, 35% (n 21) of the patients were diagnosed as having bipolar disorder. At the follow-up, there was a 59% (n 36) prevalence of bipolar disorder. Of the patients with MDD at follow-up, 13 patients (52%) were classified as having BSD. The prevalence rate of
Bipolarity of treatment-resistant depression
145
Table III. Prevalence rate of bipolar disorder in the TRD group versus the non-TRD group. Non-TRD (n 213)
TRD (n 68) BSD (n 32) Follow- up
Diagnostic Change to BPD, N (%)
Non-BSD (n 36)
18 (26.5) 17 (53.1)
BSD (n 8)
Non-BSD (n 205)
Significance
7 (3.3) 1 (2.8)
0.000*
1 (12.5)
6 (2.9)
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TRD, treatment-resistant major depression; BSD, bipolar spectrum disorder; BPD, bipolar disorder; *P B0.001.
BSD and the change of the diagnosis to bipolar disorder in TRD patients were higher in the study of Sharma et al. [26] than in the present study. It is difficult to compare our results with the findings of Sharma et al. [26] because the length of follow-up was different. Moreover, there was no non-TRD control group in the Sharma study because all patients were referred for assessment and treatment of TRD. They proposed that the high occurrence rate in their study was likely due to their sample being biased towards having an overrepresentation of patients with a bipolar diathesis [26]. The findings from the present study have important clinical implications. Patients who have TRD should have an exhaustive assessment to rule out bipolarity. As patients may have difficulty in recalling any hypomanic episodes and seldom seek treatment for hypomania, recognition of bipolar II disorder and the softer variants of bipolarity must be considered during assessment or treatment of an MDD, especially in the case of TRD. A clear limitation of the present study was the retrospective design. Retrospective medical record reviews cannot control for differences in baseline characteristics not captured in the medical records (such as number of prior episodes and length of each episode) and raise questions about the accuracy of diagnosis. Evaluation of patients using a structured interview could be used to confirm the current diagnosis. We did not assess the frequency of each clinical feature included in the criteria for bipolar spectrum disorder. However, assessment of demographic and clinical features, distinguishing BSD or bipolar depression from MDD, was beyond the goals of this study. A second limitation was the omission of information regarding the pharmacotherapy, except for the information required to define treatment-resistance. The class or dose of antidepressants previously or currently used may have been related to the course of the depressive episodes or might have induced manic or hypomanic episodes. In addition, the data were collected only from patients who were hospitalized; this may have biased the sample since patients with less severe symptoms were not included. TRD is common and associated with considerable personal and social burdens. The results of the present study indicated that bipolarity is present in a substantial portion of patients with treatment
resistance. Our results suggest that patients with TRD should be assessed for bipolarity. Further studies with larger patient samples and extended follow-up are needed to determine the relationship between treatment resistance and bipolarity. Key points . A considerable number of patients with treatment-resistant depression fulfilled the criteria for bipolar spectrum disorder . Diagnoses of patients with treatment-resistant depression were more frequently changed to bipolar disorder . A large number of patients with treatmentresistant depression have a bipolar diathesis Statement of interest We declare that we have no proprietary or financial interest in any aspect of this article. This study received no public financial support. We declare that they have no competing interests. References [1] Amsterdam JD, Hornig-Rohan M. Treatment algorithms in treatment-resistant depression. Psychiatr Clin North Am 1996;19:37186. [2] Fawcett J. Progress in treatment-resistant depression and treatment-refractory depression: we still have a long way to go. Psychiatr Ann 1994;24:2146. [3] Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am 1996;19:179200. [4] Crown WH, Finkelstein S, Berndt ER, et al. The impact of treatment-resistant depression on health care utilization and costs. J Clin Psychiatry 2002;63:96371. [5] Kornstein SG, Schneider RK. Clinical features of tretmentresistant depression. J Clin Psychiatry 2001;62(Suppl 16): 1825. [6] Castaneda R, Sussman N, Westreich L, Levy R, O’Malley M. A review of the effects of moderate alcohol intake on the treatment of anxiety and mood disorders. J Clin Psychiatry 1996;57:20712. [7] McLeod JD, Kessler RC, Landis KR. Speed of recovery from major depressive episodes in a community sample of married men and women. J Abnorm Psychol 1992;101:277 86. [8] Benazzi F. Should mood reactivity be included in the DSMIV atypical specifier? Eur Arch Psychiatry Clin Neurosci 2002;252:13540. [9] Manning JS, Haykal RF, Connor PD, Akiskal HS. On the nature of depressive and anxious states in a family practice /
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