Acta Neuropsychiatrica 2014 All rights reserved DOI: 10.1017/neu.2014.42
© Scandinavian College of Neuropsychopharmacology 2014 ACTA NEUROPSYCHIATRICA
Risk of bipolar disorder and psychotic features in patients initially hospitalised with severe depression Nakamura K, Iga J, Matsumoto N, Ohmori T. Risk of bipolar disorder and psychotic features in patients initially hospitalised with severe depression.
Objective: Severe depression may be a risk factor for diagnostic conversion into bipolar disorder (BD), and psychotic depression (PD) has been consistently associated with BD. The aims of the present study were to investigate the stability of the diagnosis of severe depression and the differences between PD and non-psychotic severe depression (non-PD), as well as to assess the effectiveness of electroconvulsive therapy (ECT). Methods: Patients who were hospitalised for severe depression (diagnosed according to ICD-10) both with and without psychotic symptoms (n = 89; mean age = 55.6 years, SD = 13.9) from 2001 to 2010 were retrospectively assessed. Results: By the 75th month of follow-up assessments, 11(12.4%) patients had developed BD. Among these 11 converters, nine had developed BD within 1 year after admission. Only sub-threshold hypomanic symptoms were significantly related to developing BD. The number of depressive episodes and history of physical diseases were significantly increased in non-PD compared with PD patients, whereas ECT was significantly increased in PD compared with non-PD patients. There was a significant association between length of stay at the hospital and the number of days between admission and ECT. Conclusion: Sub-threshold hypomanic symptoms may represent a prodrome of BD or an indicator of an already manifest phenotype, especially in older patients, which suggests cautious use of antidepressants. In severe depression, non-PD may often occur secondary to physical diseases and patients may experience increased recurrences compared with PD patients, which may be a more ‘primary’ disorder and often requires ECT treatments. ECT is effective for severe depression regardless of the presence of any psychotic feature; the earlier ECT is introduced, the better the expected treatment outcome.
Kimiya Nakamura, Junichi Iga, Naoki Matsumoto, Tetsuro Ohmori Department of Psychiatry, Course of Integrated Brain Sciences, University of Tokushima School of Medicine, Tokushima Japan
Keywords: bipolar disorder; co-morbidity; depression; psychosis Junichi Iga, Department of Psychiatry, Course of Integrated Brain Sciences, University of Tokushima School of Medicine, Tokushima 770-8503, Japan. Tel: + 81-86-633-7130; Fax: + 81-86-633-7131; E-mail: [email protected] Accepted for publication December 1, 2014
Significant outcomes
∙ ∙ ∙
Sub-threshold hypomanic symptoms may represent a prodrome of bipolar disorder. Non-psychotic severe depression may often occur secondary to physical diseases. Electroconvulsive therapy is effective for severe depression regardless of the presence of any psychotic features.
Limitations
∙ ∙ ∙
The present study utilised a retrospective design and lacked a structured interview for diagnoses. The findings refer to severe, hospitalised cases, and therefore cannot be generalised to outpatient or community samples. Treatment was not controlled for this study. 1
Nakamura et al. Introduction
Many cases of bipolar disorder (BD) present with depressive episodes at onset, accounting for more than half of the initial episodes (1). Misdiagnosis of BD may imply a variety of negative outcomes such as inadequate use of antidepressants, a greater number of recurrences, longer episodes, and a higher level of social impairment (2). A severe depressive episode (severe depression, as diagnosed by ICD-10) may be a risk factor for diagnostic conversion into BD (3), and severe depression with psychotic symptoms [psychotic depression (PD)] has been consistently associated with BD (4,5). The rate of diagnostic conversion from severe depression to BD and its clinical variables are informative for selecting treatment options, because some options such as lithium or atypical antipsychotic augmentation and modified electroconvulsive therapy (ECT) are known to be effective for both severe depression and BD. PD is known to have a higher number of depressive episodes, a higher number of admissions to hospitals, longer length of episodes, and more impaired performance in activities of daily living, as well as a higher suicide rate and mortality compared with non-psychotic depression (non-PD) (6–9). However, whether PD is best considered to be separate from non-PD or simply a more severe form of depression remains unsettled. Therefore, the aims of the present study were to examine the stability of diagnosis of severe depression within an inpatient setting and to compare the clinical characteristics of psychotic and non-psychotic severe depression, as well as to assess the effectiveness of ECT.
was included in the criteria for a manic or hypomanic episode in BD. A total of 336 patients with depression consistent with the ICD-10 diagnostic criteria (F32 and F33 at intake) were hospitalised from 2001 to 2010 in a psychiatric ward at Tokushima University Hospital, whose Institutional Review Board approved the study. Ultimately, 89 of the 336 (26.5%) inpatients (28 men [31.5%] and 61 women [68.5%]) with a primary diagnosis of severe depression (PD: n = 33 [37.1%]; non-psychotic severe depression: n = 56 [62.9%]) consistent with the ICD-10 criteria (F32.2, F32.3, F33.2, F33.3) were enrolled in the study. Patients with diagnosis of mood disorders due to a general medical condition were excluded. Mean age of the patients at their initial hospitalisation was 55.7 ± 13.9 years (range: 16–82 years). Mean follow-up time was 74.8 ± 37.7 months (range: 15–137 months). The sample included in the study consisted of patients examined and diagnosed by individual consultant psychiatrists in our department. Their diagnoses at intake were also checked by various psychiatrists during a conference. Follow-up assessments were made regularly (at least every 3 months) by individual consultant psychiatrists. A retrospective chart review was independently conducted by at least two trained psychiatrists (N.M., N.K., and J.I.). Student’s t-test, Fisher’s exact test, and the linear regression tests were used for analyses. p < 0.05 was considered to be significant. Diagnostic conversions were evaluated using survival analyses.
Results BD converters versus non-converters
Materials and methods
A retrospective chart review of patient medical records was performed. We reviewed age at onset, duration of observations, number of depressive episodes, time spent within a psychiatric ward, history of suicide attempts and psychotic symptoms at admission, family history of any psychiatric disorders, ECT during hospitalisation, use of mood stabilisers at discharge, and sub-threshold hypomanic symptoms during hospitalisation. We defined sub-threshold hypomanic symptoms as a depressive episode with sub-threshold hypomania (hypomania without impairment, or the presence, over at least several days, of persistent elation or irritability with three or more manic symptoms, but an insufficient number of symptoms to meet full criteria for hypomania (10)). A manic or hypomanic episode during antidepressant treatment that met the criteria even after stopping antidepressants 2
By the 75th month of follow-up, diagnostic conversion from severe depression to BD was observed in 11 patients (12.4% of the total sample), of which nine patients (81.8% of the converters) had their diagnosis changed within 1 year after admission (Fig. 1). Among the 11 converters, four patients’ diagnoses changed because of manic or hypomanic episodes during their antidepressant treatment, but they met the criteria even after discontinuing their antidepressants. In addition, among the 11 converters, five patients had manic episodes and six of them had hypomanic episodes. The mean time between admission and diagnostic conversion was 7.9 ± 13.3 months. Comparison of clinical variables related to patients who had (or did not have) their diagnosis converted from severe depression to BD is presented in Table 1. Only one patient had a family history of BD within our sample. Patients who had their diagnosis changed to BD were characterised by
Bipolar disorder and psychosis in severe depression Table 1. Comparison of clinical variables related to patients who had (or did not have) their diagnosis converted from severe depression to BD Conversion (n = 11)
Fig. 1. Survival analysis illustrating the percentage of 11 patients who eventually developed bipolar disorder (BD).
a significantly higher frequency of sub-threshold hypomanic symptoms during hospitalisation (converters: 63.6% vs. non-converters: 5.1%, p < 0.001). The groups did not differ in any other characteristics.
Age at onset (years) 48.1 ± 16.6 Duration of observation after admission 70.0 ± 31.3 (months) Number of depressive episodes 1.73 ± 0.79 Time spent in a psychiatric ward (in days) 128.3 ± 70.3 History of suicide attempts (with/without) 2 (18.2%) History of psychotic features (with/without) 3 (27.3%) Family history of any psychiatric diseases 6 (54.5%) (with/without) Electroconvulsive therapy during 1 (9.1%) hospitalisation (with/without) Use of mood stabilisers at discharge 2 (18.2%) (with/without) Sub-threshold hypomanic symptoms 7 (63.6%) during hospitalisation (with/without)
p-value
49.5 ± 15.4 75.5 ± 38.7
0.80 0.66
1.88 ± 0.98 146.3 ± 116.4 16 (20.5%) 30 (38.5%) 32 (41.0%)
0.61 0.62 1.00 0.76 0.58
13 (16.7%)
1.00
20 (25.6%)
1.00
4 (5.1%)
< 0.001
Student’s t-test and Fisher’s exact test were used for analyses.
Table 2. Comparison of clinical variables in patients with non-psychotic (non-PD) versus psychotic depression (PD)
PD versus non-psychotic severe depression
Among 89 inpatients with primary diagnosis of severe depressive episodes, 33 (37.1%) were diagnosed with PD (F32.3, F33.3), while 56 (62.9%) were diagnosed as non-PD (F32.2, F33.2). A comparison of clinical variables related to patients with PD and non-PD is presented in Table 2. The mean age at onset of severe depression was 49.3 ± 15.5 years (range: 13–79 years). The proportion of women in the sample was significantly higher than that of men (28 men [31.5%] and 61 women [68.5%], p < 0.001). Number of depressive episodes (PD: 1.55 ± 0.71 vs. non-PD: 2.05 ± 1.03, p = 0.02) and history of physical diseases (PD: 36.4% vs. non-PD: 66.1%, p < 0.01) were significantly increased in non-PD patients compared with PD patients, whereas ECT during hospitalisation was significantly increased in PD patients compared with non-PD patients (PD: 27.3% vs. non-PD: 8.9%, p = 0.03). The groups did not differ in other characteristics. Table 3 lists the results regarding the association between physical diseases and PD and non-PD. Digestive diseases such as chronic hepatitis C and duodenal and gastric ulcer, as well as orthopaedic diseases such as bone fracture and rupture, are frequent in both non-PD and PD patients. Digestive diseases, thyroid gland diseases, cardiovascular diseases, and hypertension showed tendencies to be more frequent in non-PD than in PD patients. The number of physical diseases in total was significantly increased in non-PD compared with PD patients (p < 0.03). There were no significant differences in
No conversion (n = 78)
Age of onset (years) Male gender (%) Number of depressive episodes Time spent in a psychiatric ward (days) History of suicide attempts (with/without) Family history of any psychiatric disease (with/without) History of physical diseases (with/without) Electroconvulsive therapy during hospitalisation (with/without) Use of mood stabilisers at discharge (with/without) Diagnostic conversion to bipolar disorder (with/without)
non-PD (n = 56)
PD (n = 33)
p
48.1 ± 14.9 21 (37.6%) 2.05 ± 1.03 145.0 ± 114.5
51.5 ± 16.3 7 (26.9%) 1.55 ± 0.71 142.6 ± 108.1
0.31 0.16 0.02 0.92
13 (23.2%)
5 (15.2%)
0.42
23 (41.1%)
15 (45.5%)
0.82
37 (66.1%)
12 (36.4%)
< 0.01
5 (8.9%)
9 (27.3%)
0.03
11 (19.6%)
11 (33.3%)
0.20
8 (14.3%)
3 (9.1%)
0.74
The Student t-test and Fisher’s exact test were used for analyses.
the length of stay in a hospital between PD and non-PD patients treated with ECT. However, there were significant correlations between the length of stay in a hospital and the number of days from admission to ECT (linear regression test n = 14, r2 = 0.58, p < 0.01, Fig. 2) and between length of episode and the days from onset to ECT (linear regression test n = 14, r2 = 0.82, p < 0.0001). There was a modest but non-significant correlation between the number of days from onset to ECT and the number of ECT treatments (linear regression test n = 14 r2 = 0.27 p = 0.06). 3
Nakamura et al. Table 3. Associations between physical diseases and presence of non-psychotic (non-PD) versus psychotic depression (PD)
Digestive diseases Orthopaedic diseases Cardiovascular diseases Hypertension Cancers Thyroid gland diseases Stroke Respiratory diseases Diabetes Stroke Others Total
Total
non-PD (n = 56)
PD (n = 33)
p-value
18 12 10 7 6 4 2 3 3 2 17 84
15 7 9 6 4 4 1 3 2 1 15 67
3 5 1 1 2 0 1 0 1 1 2 17
0.11 0.76 0.16 0.42 1.00 0.29 1.00 0.55 1.00 1.00 0.05 0.02
Fisher’s exact test was used for analyses.
Fig. 2. Significant correlation between the days from admission to electroconvulsive therapy (ECT) and length of stay at the hospital (in days) (linear regression test: r2 = 0.58, p = 0.0016).
Discussion
The rate of the conversion from severe depressive episode to BD in our group of patients was 1.99% per year (12.4÷74.8 × 12). Despite the higher onset age of our patients, this finding was comparable with previously published results, which report a lower age at onset and longer follow-up periods (3,4,11–13). Akin to previously reported data showing higher rates of diagnostic conversion or progression early in follow-up (14), our analysis showed a more rapid progression in the first year of follow-up, followed by a slower, linear decline thereafter (Fig. 1). Importantly, most diagnostic conversions (9/11) occurred during the first year after admission. This result indicates that patients with severe depression should be monitored through careful observation of their manic symptoms, especially during the first year after admission. Recently, sub-threshold hypomanic symptoms during depressive episodes were reported to be associated with the diagnostic conversion to BD (10,14). Consistently, sub-threshold hypomanic symptoms often accompany 4
bipolar depressive episodes (15). In the present study, 11/89 (12.4%) patients with severe depression presented with sub-threshold hypomanic symptoms during hospitalisation, and 7/11 (63.6%) patients who had sub-threshold hypomanic symptoms converted to BD. These findings are comparable with a previous report, which showed that two-thirds of patients who experienced bipolar depressive episodes had subthreshold hypomanic symptoms (15). The rate of PD in the present sample (37.1%) fell in line with findings from several studies of inpatients with major depressive episodes (16,17). The distribution of sex (37% males in non-PD, and 26.9% in PD) was also in line with findings from several studies on non-PD (18) and PD patients (19). The number of depressive episodes was significantly increased in non-PD compared with PD patients (PD: 1.55 ± 0.71 vs. non-PD: 2.05 ± 1.03, p = 0.02) in our sample. This finding was inconsistent with previous studies, because the severity of a depressive episode was reported to predict shorter time to recurrence and a higher number of recurrences (20,21); this result may imply that our sample with non-psychotic severe depression was more severe than that of previous studies, and non-psychotic ‘very’ severe depression might have a higher number of episodes compared with PD. A recent population-based historical prospective cohort study from Danish registers revealed that diagnostic conversion to BD was prevalent among patients with PD (22); however, the rate of diagnostic conversion from PD to BD in our sample was not higher compared with non-PD patients. This inconsistency may be due to our small sample size. The low conversion rate and low number of depressive episodes among PD patients may also be explained by the studied population’s relatively older age and fewer episodes of depression, because occurrence of the first depressive episode at a younger age and recurrent depressive episodes are known to increase the risk of conversion to BD. A history of physical diseases was significantly increased in non-PD compared with PD patients (PD: 36.4% vs. non-PD: 66.1%, p < 0.01). In the present study, digestive diseases including chronic hepatitis C and duodenal and gastric ulcer, as well as orthopaedic diseases such as bone fracture and rupture, frequently occurred in both non-PD and PD patients. Furthermore, digestive diseases, thyroid gland diseases, cardiovascular diseases, and hypertension were more prevalent in nonPD than in PD patients. Although interferon-induced depression was not included in our sample, chronic hepatitis C may be associated with severe depression (23,24). Recent evidence supports an association between depression and increased risk of fracture and bone loss, which may be mediated by antidepressants (25,26). Diseases with a vascular pathogenesis such
Bipolar disorder and psychosis in severe depression as cardiovascular diseases and hypertension were associated with non-psychotic severe depression (19,27). Moreover, a recent register-based study revealed that a history of physical diseases such as ischaemic heart disease, hypertension, stroke, and chronic lower pulmonary disease increased the risk for the subsequent development of non-PD compared with psychotic severe depression (19). The present findings, noting differences in the two, add some support to the hypothesis that non-psychotic severe depression may often occur secondary to physical diseases (environmental risk factor) compared with PD, which, in contrast, may be a more ‘primary’ disorder, characterised by a stronger genetic predisposition (28–30). ECT during hospitalisation was significantly increased in PD patients compared with non-PD patients (PD: 27.3% vs. non-PD: 8.9%, p = 0.03), because the days from admission to ECT were not significantly different between PD and non-PD patients. This result suggests that PD often occurred without life events such as a history of physical disease, and often became treatment-refractory and required ECT. Although we could not find significant differences in the length of stay in the hospital and the length of episodes between PD and non-PD treated with ECT, there were significant correlations between length of stay in the hospital and the number of days from admission to ECT (see Fig. 2) and between the length of episodes and the number of days from onset to ECT. These findings suggest that ECT is effective for severe depression, regardless of the diagnostic conversion to BD or the presence of psychotic features, which falls in line with the previous reports (31–34). The main limitation of our study is that patients were retrospectively studied; therefore, we could not conduct structured interviews for diagnoses, which could have increased diagnostic uncertainty. The present findings are limited to severe hospitalised cases, and therefore cannot be generalised to outpatient or community samples. Finally, treatment was not controlled for this study, and patients received a variety of treatments during follow-up. Acknowledgements
Dr. Kimiya Nakamura and Dr. Naoki Matsumoto contributed to the acquisition and analysis of data. Dr. Junichi Iga contributed to the conception and design of the research plan. Prof. Tetsuro Ohmori contributed to the final approval of the manuscript submitted for publication. Financial Support None.
Conflicts of Interest None. Ethical Standards The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.
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© Scandinavian College of Neuropsychopharmacology 2014 ACTA NEUROPSYCHIATRICA
Risk of bipolar disorder and psychotic features in patients initially hospitalised with severe depression Nakamura K, Iga J, Matsumoto N, Ohmori T. Risk of bipolar disorder and psychotic features in patients initially hospitalised with severe depression.
Objective: Severe depression may be a risk factor for diagnostic conversion into bipolar disorder (BD), and psychotic depression (PD) has been consistently associated with BD. The aims of the present study were to investigate the stability of the diagnosis of severe depression and the differences between PD and non-psychotic severe depression (non-PD), as well as to assess the effectiveness of electroconvulsive therapy (ECT). Methods: Patients who were hospitalised for severe depression (diagnosed according to ICD-10) both with and without psychotic symptoms (n = 89; mean age = 55.6 years, SD = 13.9) from 2001 to 2010 were retrospectively assessed. Results: By the 75th month of follow-up assessments, 11(12.4%) patients had developed BD. Among these 11 converters, nine had developed BD within 1 year after admission. Only sub-threshold hypomanic symptoms were significantly related to developing BD. The number of depressive episodes and history of physical diseases were significantly increased in non-PD compared with PD patients, whereas ECT was significantly increased in PD compared with non-PD patients. There was a significant association between length of stay at the hospital and the number of days between admission and ECT. Conclusion: Sub-threshold hypomanic symptoms may represent a prodrome of BD or an indicator of an already manifest phenotype, especially in older patients, which suggests cautious use of antidepressants. In severe depression, non-PD may often occur secondary to physical diseases and patients may experience increased recurrences compared with PD patients, which may be a more ‘primary’ disorder and often requires ECT treatments. ECT is effective for severe depression regardless of the presence of any psychotic feature; the earlier ECT is introduced, the better the expected treatment outcome.
Kimiya Nakamura, Junichi Iga, Naoki Matsumoto, Tetsuro Ohmori Department of Psychiatry, Course of Integrated Brain Sciences, University of Tokushima School of Medicine, Tokushima Japan
Keywords: bipolar disorder; co-morbidity; depression; psychosis Junichi Iga, Department of Psychiatry, Course of Integrated Brain Sciences, University of Tokushima School of Medicine, Tokushima 770-8503, Japan. Tel: + 81-86-633-7130; Fax: + 81-86-633-7131; E-mail: [email protected] Accepted for publication December 1, 2014
Significant outcomes
∙ ∙ ∙
Sub-threshold hypomanic symptoms may represent a prodrome of bipolar disorder. Non-psychotic severe depression may often occur secondary to physical diseases. Electroconvulsive therapy is effective for severe depression regardless of the presence of any psychotic features.
Limitations
∙ ∙ ∙
The present study utilised a retrospective design and lacked a structured interview for diagnoses. The findings refer to severe, hospitalised cases, and therefore cannot be generalised to outpatient or community samples. Treatment was not controlled for this study. 1
Nakamura et al. Introduction
Many cases of bipolar disorder (BD) present with depressive episodes at onset, accounting for more than half of the initial episodes (1). Misdiagnosis of BD may imply a variety of negative outcomes such as inadequate use of antidepressants, a greater number of recurrences, longer episodes, and a higher level of social impairment (2). A severe depressive episode (severe depression, as diagnosed by ICD-10) may be a risk factor for diagnostic conversion into BD (3), and severe depression with psychotic symptoms [psychotic depression (PD)] has been consistently associated with BD (4,5). The rate of diagnostic conversion from severe depression to BD and its clinical variables are informative for selecting treatment options, because some options such as lithium or atypical antipsychotic augmentation and modified electroconvulsive therapy (ECT) are known to be effective for both severe depression and BD. PD is known to have a higher number of depressive episodes, a higher number of admissions to hospitals, longer length of episodes, and more impaired performance in activities of daily living, as well as a higher suicide rate and mortality compared with non-psychotic depression (non-PD) (6–9). However, whether PD is best considered to be separate from non-PD or simply a more severe form of depression remains unsettled. Therefore, the aims of the present study were to examine the stability of diagnosis of severe depression within an inpatient setting and to compare the clinical characteristics of psychotic and non-psychotic severe depression, as well as to assess the effectiveness of ECT.
was included in the criteria for a manic or hypomanic episode in BD. A total of 336 patients with depression consistent with the ICD-10 diagnostic criteria (F32 and F33 at intake) were hospitalised from 2001 to 2010 in a psychiatric ward at Tokushima University Hospital, whose Institutional Review Board approved the study. Ultimately, 89 of the 336 (26.5%) inpatients (28 men [31.5%] and 61 women [68.5%]) with a primary diagnosis of severe depression (PD: n = 33 [37.1%]; non-psychotic severe depression: n = 56 [62.9%]) consistent with the ICD-10 criteria (F32.2, F32.3, F33.2, F33.3) were enrolled in the study. Patients with diagnosis of mood disorders due to a general medical condition were excluded. Mean age of the patients at their initial hospitalisation was 55.7 ± 13.9 years (range: 16–82 years). Mean follow-up time was 74.8 ± 37.7 months (range: 15–137 months). The sample included in the study consisted of patients examined and diagnosed by individual consultant psychiatrists in our department. Their diagnoses at intake were also checked by various psychiatrists during a conference. Follow-up assessments were made regularly (at least every 3 months) by individual consultant psychiatrists. A retrospective chart review was independently conducted by at least two trained psychiatrists (N.M., N.K., and J.I.). Student’s t-test, Fisher’s exact test, and the linear regression tests were used for analyses. p < 0.05 was considered to be significant. Diagnostic conversions were evaluated using survival analyses.
Results BD converters versus non-converters
Materials and methods
A retrospective chart review of patient medical records was performed. We reviewed age at onset, duration of observations, number of depressive episodes, time spent within a psychiatric ward, history of suicide attempts and psychotic symptoms at admission, family history of any psychiatric disorders, ECT during hospitalisation, use of mood stabilisers at discharge, and sub-threshold hypomanic symptoms during hospitalisation. We defined sub-threshold hypomanic symptoms as a depressive episode with sub-threshold hypomania (hypomania without impairment, or the presence, over at least several days, of persistent elation or irritability with three or more manic symptoms, but an insufficient number of symptoms to meet full criteria for hypomania (10)). A manic or hypomanic episode during antidepressant treatment that met the criteria even after stopping antidepressants 2
By the 75th month of follow-up, diagnostic conversion from severe depression to BD was observed in 11 patients (12.4% of the total sample), of which nine patients (81.8% of the converters) had their diagnosis changed within 1 year after admission (Fig. 1). Among the 11 converters, four patients’ diagnoses changed because of manic or hypomanic episodes during their antidepressant treatment, but they met the criteria even after discontinuing their antidepressants. In addition, among the 11 converters, five patients had manic episodes and six of them had hypomanic episodes. The mean time between admission and diagnostic conversion was 7.9 ± 13.3 months. Comparison of clinical variables related to patients who had (or did not have) their diagnosis converted from severe depression to BD is presented in Table 1. Only one patient had a family history of BD within our sample. Patients who had their diagnosis changed to BD were characterised by
Bipolar disorder and psychosis in severe depression Table 1. Comparison of clinical variables related to patients who had (or did not have) their diagnosis converted from severe depression to BD Conversion (n = 11)
Fig. 1. Survival analysis illustrating the percentage of 11 patients who eventually developed bipolar disorder (BD).
a significantly higher frequency of sub-threshold hypomanic symptoms during hospitalisation (converters: 63.6% vs. non-converters: 5.1%, p < 0.001). The groups did not differ in any other characteristics.
Age at onset (years) 48.1 ± 16.6 Duration of observation after admission 70.0 ± 31.3 (months) Number of depressive episodes 1.73 ± 0.79 Time spent in a psychiatric ward (in days) 128.3 ± 70.3 History of suicide attempts (with/without) 2 (18.2%) History of psychotic features (with/without) 3 (27.3%) Family history of any psychiatric diseases 6 (54.5%) (with/without) Electroconvulsive therapy during 1 (9.1%) hospitalisation (with/without) Use of mood stabilisers at discharge 2 (18.2%) (with/without) Sub-threshold hypomanic symptoms 7 (63.6%) during hospitalisation (with/without)
p-value
49.5 ± 15.4 75.5 ± 38.7
0.80 0.66
1.88 ± 0.98 146.3 ± 116.4 16 (20.5%) 30 (38.5%) 32 (41.0%)
0.61 0.62 1.00 0.76 0.58
13 (16.7%)
1.00
20 (25.6%)
1.00
4 (5.1%)
< 0.001
Student’s t-test and Fisher’s exact test were used for analyses.
Table 2. Comparison of clinical variables in patients with non-psychotic (non-PD) versus psychotic depression (PD)
PD versus non-psychotic severe depression
Among 89 inpatients with primary diagnosis of severe depressive episodes, 33 (37.1%) were diagnosed with PD (F32.3, F33.3), while 56 (62.9%) were diagnosed as non-PD (F32.2, F33.2). A comparison of clinical variables related to patients with PD and non-PD is presented in Table 2. The mean age at onset of severe depression was 49.3 ± 15.5 years (range: 13–79 years). The proportion of women in the sample was significantly higher than that of men (28 men [31.5%] and 61 women [68.5%], p < 0.001). Number of depressive episodes (PD: 1.55 ± 0.71 vs. non-PD: 2.05 ± 1.03, p = 0.02) and history of physical diseases (PD: 36.4% vs. non-PD: 66.1%, p < 0.01) were significantly increased in non-PD patients compared with PD patients, whereas ECT during hospitalisation was significantly increased in PD patients compared with non-PD patients (PD: 27.3% vs. non-PD: 8.9%, p = 0.03). The groups did not differ in other characteristics. Table 3 lists the results regarding the association between physical diseases and PD and non-PD. Digestive diseases such as chronic hepatitis C and duodenal and gastric ulcer, as well as orthopaedic diseases such as bone fracture and rupture, are frequent in both non-PD and PD patients. Digestive diseases, thyroid gland diseases, cardiovascular diseases, and hypertension showed tendencies to be more frequent in non-PD than in PD patients. The number of physical diseases in total was significantly increased in non-PD compared with PD patients (p < 0.03). There were no significant differences in
No conversion (n = 78)
Age of onset (years) Male gender (%) Number of depressive episodes Time spent in a psychiatric ward (days) History of suicide attempts (with/without) Family history of any psychiatric disease (with/without) History of physical diseases (with/without) Electroconvulsive therapy during hospitalisation (with/without) Use of mood stabilisers at discharge (with/without) Diagnostic conversion to bipolar disorder (with/without)
non-PD (n = 56)
PD (n = 33)
p
48.1 ± 14.9 21 (37.6%) 2.05 ± 1.03 145.0 ± 114.5
51.5 ± 16.3 7 (26.9%) 1.55 ± 0.71 142.6 ± 108.1
0.31 0.16 0.02 0.92
13 (23.2%)
5 (15.2%)
0.42
23 (41.1%)
15 (45.5%)
0.82
37 (66.1%)
12 (36.4%)
< 0.01
5 (8.9%)
9 (27.3%)
0.03
11 (19.6%)
11 (33.3%)
0.20
8 (14.3%)
3 (9.1%)
0.74
The Student t-test and Fisher’s exact test were used for analyses.
the length of stay in a hospital between PD and non-PD patients treated with ECT. However, there were significant correlations between the length of stay in a hospital and the number of days from admission to ECT (linear regression test n = 14, r2 = 0.58, p < 0.01, Fig. 2) and between length of episode and the days from onset to ECT (linear regression test n = 14, r2 = 0.82, p < 0.0001). There was a modest but non-significant correlation between the number of days from onset to ECT and the number of ECT treatments (linear regression test n = 14 r2 = 0.27 p = 0.06). 3
Nakamura et al. Table 3. Associations between physical diseases and presence of non-psychotic (non-PD) versus psychotic depression (PD)
Digestive diseases Orthopaedic diseases Cardiovascular diseases Hypertension Cancers Thyroid gland diseases Stroke Respiratory diseases Diabetes Stroke Others Total
Total
non-PD (n = 56)
PD (n = 33)
p-value
18 12 10 7 6 4 2 3 3 2 17 84
15 7 9 6 4 4 1 3 2 1 15 67
3 5 1 1 2 0 1 0 1 1 2 17
0.11 0.76 0.16 0.42 1.00 0.29 1.00 0.55 1.00 1.00 0.05 0.02
Fisher’s exact test was used for analyses.
Fig. 2. Significant correlation between the days from admission to electroconvulsive therapy (ECT) and length of stay at the hospital (in days) (linear regression test: r2 = 0.58, p = 0.0016).
Discussion
The rate of the conversion from severe depressive episode to BD in our group of patients was 1.99% per year (12.4÷74.8 × 12). Despite the higher onset age of our patients, this finding was comparable with previously published results, which report a lower age at onset and longer follow-up periods (3,4,11–13). Akin to previously reported data showing higher rates of diagnostic conversion or progression early in follow-up (14), our analysis showed a more rapid progression in the first year of follow-up, followed by a slower, linear decline thereafter (Fig. 1). Importantly, most diagnostic conversions (9/11) occurred during the first year after admission. This result indicates that patients with severe depression should be monitored through careful observation of their manic symptoms, especially during the first year after admission. Recently, sub-threshold hypomanic symptoms during depressive episodes were reported to be associated with the diagnostic conversion to BD (10,14). Consistently, sub-threshold hypomanic symptoms often accompany 4
bipolar depressive episodes (15). In the present study, 11/89 (12.4%) patients with severe depression presented with sub-threshold hypomanic symptoms during hospitalisation, and 7/11 (63.6%) patients who had sub-threshold hypomanic symptoms converted to BD. These findings are comparable with a previous report, which showed that two-thirds of patients who experienced bipolar depressive episodes had subthreshold hypomanic symptoms (15). The rate of PD in the present sample (37.1%) fell in line with findings from several studies of inpatients with major depressive episodes (16,17). The distribution of sex (37% males in non-PD, and 26.9% in PD) was also in line with findings from several studies on non-PD (18) and PD patients (19). The number of depressive episodes was significantly increased in non-PD compared with PD patients (PD: 1.55 ± 0.71 vs. non-PD: 2.05 ± 1.03, p = 0.02) in our sample. This finding was inconsistent with previous studies, because the severity of a depressive episode was reported to predict shorter time to recurrence and a higher number of recurrences (20,21); this result may imply that our sample with non-psychotic severe depression was more severe than that of previous studies, and non-psychotic ‘very’ severe depression might have a higher number of episodes compared with PD. A recent population-based historical prospective cohort study from Danish registers revealed that diagnostic conversion to BD was prevalent among patients with PD (22); however, the rate of diagnostic conversion from PD to BD in our sample was not higher compared with non-PD patients. This inconsistency may be due to our small sample size. The low conversion rate and low number of depressive episodes among PD patients may also be explained by the studied population’s relatively older age and fewer episodes of depression, because occurrence of the first depressive episode at a younger age and recurrent depressive episodes are known to increase the risk of conversion to BD. A history of physical diseases was significantly increased in non-PD compared with PD patients (PD: 36.4% vs. non-PD: 66.1%, p < 0.01). In the present study, digestive diseases including chronic hepatitis C and duodenal and gastric ulcer, as well as orthopaedic diseases such as bone fracture and rupture, frequently occurred in both non-PD and PD patients. Furthermore, digestive diseases, thyroid gland diseases, cardiovascular diseases, and hypertension were more prevalent in nonPD than in PD patients. Although interferon-induced depression was not included in our sample, chronic hepatitis C may be associated with severe depression (23,24). Recent evidence supports an association between depression and increased risk of fracture and bone loss, which may be mediated by antidepressants (25,26). Diseases with a vascular pathogenesis such
Bipolar disorder and psychosis in severe depression as cardiovascular diseases and hypertension were associated with non-psychotic severe depression (19,27). Moreover, a recent register-based study revealed that a history of physical diseases such as ischaemic heart disease, hypertension, stroke, and chronic lower pulmonary disease increased the risk for the subsequent development of non-PD compared with psychotic severe depression (19). The present findings, noting differences in the two, add some support to the hypothesis that non-psychotic severe depression may often occur secondary to physical diseases (environmental risk factor) compared with PD, which, in contrast, may be a more ‘primary’ disorder, characterised by a stronger genetic predisposition (28–30). ECT during hospitalisation was significantly increased in PD patients compared with non-PD patients (PD: 27.3% vs. non-PD: 8.9%, p = 0.03), because the days from admission to ECT were not significantly different between PD and non-PD patients. This result suggests that PD often occurred without life events such as a history of physical disease, and often became treatment-refractory and required ECT. Although we could not find significant differences in the length of stay in the hospital and the length of episodes between PD and non-PD treated with ECT, there were significant correlations between length of stay in the hospital and the number of days from admission to ECT (see Fig. 2) and between the length of episodes and the number of days from onset to ECT. These findings suggest that ECT is effective for severe depression, regardless of the diagnostic conversion to BD or the presence of psychotic features, which falls in line with the previous reports (31–34). The main limitation of our study is that patients were retrospectively studied; therefore, we could not conduct structured interviews for diagnoses, which could have increased diagnostic uncertainty. The present findings are limited to severe hospitalised cases, and therefore cannot be generalised to outpatient or community samples. Finally, treatment was not controlled for this study, and patients received a variety of treatments during follow-up. Acknowledgements
Dr. Kimiya Nakamura and Dr. Naoki Matsumoto contributed to the acquisition and analysis of data. Dr. Junichi Iga contributed to the conception and design of the research plan. Prof. Tetsuro Ohmori contributed to the final approval of the manuscript submitted for publication. Financial Support None.
Conflicts of Interest None. Ethical Standards The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.
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