Risk factors for suicide attempts in patients with bipolar disorder misdiagnosed with major depressive disorder: results from a national survey in China

Background: Bipolar disorder (BD) is a kind of mental disorder with the greatest risk of suicide, but it is often misdiagnosed as major depressive disorder (MDD) clinically. This study aimed to analyze the sociodemographic factors and clinical characteristics associated with suicide attempts (SA) in patients with BD misdiagnosed with MDD in China. Methods: A total of 1487 MDD patients were consecutively enrolled in 13 mental health centers in China. Data on patients’ sociodemographic and clinical characteristics were collected using a standardized protocol. Of these, 306 BD patients were misdiagnosed with MDD according to the Mini International Neuropsychiatric Interview (MINI). Suicide attempters and non-attempters were classified by the suicidality module of the MINI. Multiple logistic regression analyses were performed to assess the association between the independent variables of interest and SA in BD patients misdiagnosed with MDD. Results: Of the 306 BD patients misdiagnosed with MDD, 225 (73.5%) were non-attempters and 81 (26.5%) were attempters. Compared to non-attempters, attempters were older (Z =2.2, p = 0.03) and had more admissions(χ2 =6.1, p = 0.013), more frequent depressive episodes, more atypical characteristics (e.g. increased appetite, weight gain, and more sleep time)(χ2 = 5.8, p = 0.016), more suicidal ideation (χ2 = 27.3, p < 0.001), more psychotic symptoms (χ2 = 7.4, p = 0.006) and more seasonal depressive episodes (χ2 = 5.6, p = 0.018). Multiple logistic regression analyses revealed that attempters were characterized by more suicidal ideation (OR = 5.7, 95% CI: 2.6–12.5) and frequent depressive episodes (OR = 2.4, 95% CI: 1.3–4.6). The limitations of this study include its cross-sectional design and data collection by suicide attempters’ retrospective recall. Conclusions: The findings of this study suggest that BD patients misdiagnosed with MDD are at


Background
Suicide is a major public health problem throughout the world (Nordentoft 2011). Although China's suicide rate dropped significantly from 2002 to 2015, the rate of decline has slowed or even reversed in certain groups, underscoring the urgent need for targeted suicide prevention programs (Jiang et al. 2018). Suicidal behavior is becoming a great challenge for psychiatry, other fields of medicine, and society as a whole, owing to the difficulty in predicting suicidal behavior. Thus, suicide prediction and prevention are receiving increasing attention (Gonda et al. 2012).
There are many reasons for suicide, but suicide is almost always associated with potential mental disorders (Wasserman et al. 2012),about 50-90% of suicide deaths can establish a diagnosis of mental illness, with mood disorders being the most common (Cavanagh et al. 2003 Patients with major affective disorder (MAD), that is, major depressive disorder (MDD), bipolar disorder (BD), are highly vulnerable to suicidal behavior (Pompili et al. 2008). Furthermore, patients with BD are at a higher risk of suicidal behavior than those with other mental disorders ( However, the first episode of BD is usually a depressive episode, manic or hypomanic episode often occurs after the depressive episode which is more frequent than manic or hypomanic episode (Solomon et al. 2006;Judd et al. 2003). Moreover, manic or hypomanic episode is usually retrospectively established, and there will be memory bias (Perlis 2005;Yen et al. 2007). Therefore, BD patients are often misdiagnosed as major depressive disorder (MDD) and may not receive adequate or appropriate treatment (Hirschfeld et al. 2003). It is possible that only receiving a single antidepressant treatment will lead to emotional instability, induce manic episode, and even increase the risk of suicide (Birnbaum et (Daveney et al. 2019). Therefore, the suicide-related problems in BD patients misdiagnosed with MDD need more attention.
Currently, suicide risk factors are often studied in relation to attempted suicide rather than committed suicide (Holma et al. 2010).
A previous suicide attempt is a strong predictor of a completed suicide (Bega et al. 2012). Thus, studying SA is pivotal to identifying those at risk of future completion (Suominen et al. 2004).SA is an important proxy outcome when investigating the risk factors for suicide (Holma et al. 2010 Patients who met the study criteria were invited to participate in the study.

Methods Subjects
The DASP is a national study that was initiated by the Chinese Society of Psychiatry (CSP),which aimed to develop and test the usefulness of screening tools for patients with BD treated for MDD(Hu years, (ii)diagnosed with DSM-IV or ICD-10 MDD based on a review of medical records, (iii) satisfied the major depressive episode criteria, and (iv) understood the aims of the study and were able to provide informed consent. The exclusion criteria were as follows: (i) a past diagnosis of BD, (ii) in remission state, (iii) in a manic (or hypomanic) episode, (iv) a history of or ongoing significant medical or neurological condition(s), (v) depressive disorders secondary to a general medical or neurological condition, or (vi) had received electroconvulsive therapy (ECT) in the past month. The study protocol was approved by the Clinical Research Ethics Committees of the respective study centers. Written consent was obtained from patients or their guardians for those who were younger than 18 years of age as long as they verbally agreed to participate.

Instruments and assessment procedure
Patients who fulfilled the study criteria were invited to participate in the study. Patients' general sociodemographic and clinical data were collected using a questionnaire designed for the study in a The suicidality module of MINI includes the following specific questions that assess SA:C1-5"Did you attempt suicide within the past month?"; C1-6 "In your lifetime, did you ever make a suicide attempt?". Patients who responded "yes" to both or one of the items were classified as the suicideattempted group; those who answered "no" to both questions, they were classified as the nonsuicide-attempted group.
Prior to the study, all thirteen raters were trained in the use of the BD diagnostic instrument on20 patients with MDD. The kappa values of all instruments were above 0.85 for each rater. Wherever possible, the same raters evaluated the same group of patients throughout the study.

Statistical procedures
Statistical analyses were performed using SAS 9.13 (SAS Institute Inc., Cary, North Carolina). Mann-Whitney U tests were used for continuous variables non-normally distributed. Continuous variables were presented as mean ± standard deviation (SD). Categorical variables, such as sex, marital status, were expressed as percentages (%) and compared using the Chi-square. For potential risk factors, variables with a P-value of less than 0.1 in a univariate analysis were selected and included in a multivariate logistic regression model. Odds ratio (OR) and 95% CI were evaluated to assess associations between risk factors and SA for the BD patients misdiagnosed with MDD. All tests were

Results
Description of samples A total of 1,487 patients diagnosed with MDD from 13 study sites were enrolled based on the diagnostic criteria. Of them, 309 patients were re-diagnosed to BD according to the MINI V5.0. After excluding three patients due to lack of information on the suicidal module of MINI, 306 patients were included in analyses. The incidence of SA was15.6% (183/1178) in MDD patients. Of the BD patients, 26.5% (81/306) were suicide attempters and 73.5% (225/306) were not.

Correlates of SA
A multiple logistic regression analysis demonstrated that more depressive episodes with suicide ideation (β = 1.7, OR = 5.7, p < 0.001) and more frequent depressive episode (> 4 in past year) (β = 0.9, OR = 2.4, p = 0.007) were associated with SA in BD patients misdiagnosed with MDD (Table 3).  In a study involving 387 patients with BD rapid circulation type, more than 41% patients had SA at least once (Gao et al. 2009

Conclusion
In conclusion, this study found that among BD patients misdiagnosed as MDD, the prevalence rate of SA was 26.5%, which was associated with suicidal ideation and more frequent depressive episodes.
Focusing on these two risk factors might help clinicians to identify patients at a high risk for SA and implement effective preventive interventions to prevent suicides.

Acknowledgments
The study was initiated by the Chinese Society of Psychiatry (CSP) with support from AstraZeneca China. AstraZeneca China had no role in the study design or the generation or interpretation of the results. The authors are grateful to all the clinicians who helped to organize the study in each study site.

Funding
The data analysis and submission of the manuscript were partially supported by the National Natural

Availability of data and materials
The datasets generated and/or analyzed during the present study are not publicly available.

Ethics approval and consent to participate
The study protocol was approved by the Clinical Research Ethics Committees of the respective study centers. Written consent was obtained from patients or their guardians for those who were younger than 18 years of age as long as they verbally agreed to participate.

Consent for publication
Not applicable.