Mixed states and suicidal behavior: a systematic review

The objective of this study was to identify whether mixed states in bipolar disorder (BD) are associated with more frequent suicidal behavior when compared to manic/hypomanic and depressive episodes.

Method

We performed a systematic search of the scientific literature on the subject using the PubMed, ISI Web Of Science, PsycINFO and SciELO databases. The terms chosen for the search were (bipolar) AND (suicid*) AND (mixed). We selected original studies comparing suicidal behavior of patients in mixed states and suicidal behavior of patients in other BD phases.

Results

Sixteen papers fit the selection criteria. Twelve of the original 16 studies compared suicidal behavior in mixed states and pure mania, and the majority of these studies (n = 11) revealed that suicidal behavior was more frequent among individuals in mixed states. Five of the papers compared suicidal behavior between depressive and mixed phases of BD. One of these five papers reported more severe suicidal behavior in patients in mixed states and another described more frequent suicidal behavior in patients with pure depression. There were no significant statistical differences between groups in the remaining three of these five studies.

Conclusion

During acute BD episodes, suicidal behavior is more strongly associated with mixed states than with pure mania or hypomania. However, it was not possible to demonstrate that the association between suicidal behavior and mixed states is stronger than the association between suicidal behavior and depressive phases. The results hereby presented are worth considering in clinical practice to better evaluate suicide risk and to prevent suicide.

Keywords
Bipolar disorder; suicide; systematic review

Article	Location	Objective	Method	Samples	Sociodemographic factors	Mx evaluation	Assessment of suicidal behavior	Suicidal behavior results
Young²⁰20. Young AH, Eberhard J. Evaluating depressive symptoms in mania: a naturalistic study of patients with bipolar disorder. Neuropsychiatr Dis Treat. 2015;11:1137-43.	Centers in Australia, Brazil, Canada, Germany, Italy, Spain, Turkey, and the UK.	To evaluate BD-I manic patients who met the DSM-5 criteria for BD-I “with mixed features.”	The study surveyed psychiatrists and their BD-I manic patients. Data were stratified and characteristics were compared between PM and mMX subgroups.	1,035 BD-I: 348 mMX, 687 PM	Mean age (y): 40; Female gender (%): 52; Employed (%): 44	DSM-5	Number of patients with at least one suicide attempt	mMX (38%) > PM (9%)
Reinares²¹21. Reinares M, Bonnín Cdel M, Hidalgo-Mazzei D, Undurraga J, Mur M, Nieto E, et al. Making sense of DSM-5 mania with depressive features. Aust N Z J Psychiatry. 2015;49:540-9.	Catalonia, Spain.	To compare manic patients with and without mixed features to validate the relevance of the DSM-5 mixed specifier.	Bipolar patients presenting a manic episode were evaluated and systematically assessed for a 6-month period.	169 BD-I: 46 mMX, 123 PM	Mean age (y): mMX = 41.85, PM = 44.35; Female gender (%): mMX = 43.3, MP = 45.7; Married (%): PM = 35.8, mMX = 141.3; Employed (%): PM = 29, mMX = 19	DSM-5	Number of patients with suicidal ideation	mMX (26.1%) > PM (12.3%)
Shim²²22. Shim IH, Woo YS, Jun TY, Bahk WM. A reevaluation of the possibility and characteristics in bipolar mania with mixed features: a retrospective chart review. Psychiatry Res. 2014;215:335-40.	Seoul, South Korea	To reevaluate the feasibility of diagnosing a bipolar mixed mania and to elucidate the clinical characteristics, treatment response, and course of the illness.	BD-I manic inpatients were divided according to Cincinnati criteria. Charts were reviewed for demographic and clinical characteristics.	171 BD-I: 67 PM, 79 PMX, 25 DMX	Mean age (y): PM = 41.8, PMX = 35.2, DMX = 33.2; Female gender (%): PM = 40.3, PMX = 70.9, DMX = 68; Married (%): PM = 59.7, PMX = 46.8, DMX = 52	Cincinnati criteria	Number of patients with suicidal ideation or with at least one suicide attempt	DMX (28%) > PM (0%); PMX (5.1%) = PM (0%); DMX (28%) > PMX (5.1%)
Cassidy²³23. Cassidy F, Ahearn E, Carroll BJ. Concordance of self-rated and observer-rated dysphoric symptoms in mania. J Affect Disord. 2009;114:294-8.	USA	To examine whether patients’ depression self-ratings agree with observer ratings and whether patients rate their depressive symptoms differently during manic and mixed episodes.	Patients’ depression self-ratings were compared with observer ratings, as were differences between the manic and mixed subtypes.	94 BD-I: 65 PM, 29 Mmx	Mean age (y): 40.9; Female gender (%): 39.4; Ethnic group (%): Whites: 57.4, Blacks: 42.6	ROC-derived	Mean scores on the suicide items of HAM-D and CDS scales	HAM-D: mMX (0.759) > PM (0); CDS: mMX (0.759) > PM (0.108)
Schwartzmann²⁴24. Schwartzmann AM, Amaral JA, Issler C, Caetano SC, Tamada RS, Almeida KM, et al. A clinical study comparing manic and mixed episodes in patients with bipolar disorder. Rev Bras Psiquiatr. 2007;29:130-3.	São Paulo, Brazil	To compare severity between mixed and pure manic episodes.	BD-I mixed and pure manic patients were compared for sociodemographic data and clinical characteristics.	49 BD-I: 29 MX, 20 PM	Mean age (y): PM = 42, MX = 34.8; Female gender (%): MX = 72.4, PM = 80	DSM-IV	Number of patients with at least one suicide attempt	MX (6.9%) = PM (0%)
Cassidy⁵5. Cassidy F, Carroll BJ. Frequencies of signs and symptoms in mixed and pure episodes of mania: implications for the study of manic episodes. Prog Neuropsychopharmacol Biol Psychiatry. 2001;25:659-65.	Butner, North Carolina, USA	To compare frequencies of the 20 signs and symptoms of SMS between pure and mixed mania. Subtypes were determined by the ROC-derived criteria.	BD inpatients were diagnosed as manic or mixed using the ROC-derived criteria. Frequencies of each sign or symptom of SMS were compared.	363 BD: 280 PM, 83 MX	Mean age (y): 42.1; Female gender (%): 52; Ethnic group (%): Whites: 58.7, Blacks: 40.8, American Indian: 0.3, Asian American: 0.3.	ROC-derived	Number of patients with suicidal ideation according to the SMS suicide item	High threshold (≥ 2 points): MX (31.3%) > PM (0.7%); Low threshold (1 point): MX (49.4%) > PM (4.6%)
Cassidy²⁵25. Cassidy F, Murry E, Forest K, Carroll BJ. Signs and symptoms of mania in pure and mixed episodes. J Affect Disord. 1998;50:187-201.	Butner, North Carolina, USA	To compare frequencies of the 20 signs and symptoms of SMS between pure and mixed mania. Subtypes were determined with the DSM-III-R.	BD inpatients were diagnosed as manic or mixed using the DSM-III-R criteria. Frequencies of each sign or symptom of SMS were compared.	316 BD-I: 273 PM, 43 MX	Mean age (y): 42.2; Female gender (%): 53.2; Ethnic group (%): Whites: 57, Blacks: 42.4, Oriental: 0.3, American Indian: 0.3	DSM-III-R	Number of patients with suicidal ideation according to the SMS suicide item	High threshold (≥ 2 points): MX (39.5%) > PM (1.8%); Low threshold (1 point): MX (58.8%) > PM (8.8%)
Goldberg²⁶26. Goldberg JF, Garno JL, Leon AC, Kocsis JH, Portera L. Association of recurrent suicidal ideation with nonremission from acute mixed mania. Am J Psychiatry. 1998;155:1753-5.	New York, USA	To examine suicidality in relation to acute symptom remission in inpatients with mixed and pure BD.	Using chart review, the authors assessed suicidality, other psychopathology, treatment, and remission of BD-I inpatients.	184 BD-I: 77 PM, 107 MX	Mean age (y): 40.4; Female gender (%): 53.8; Ethnic group (%): Whites: 72.3	Cincinnati criteria	Number of patients with suicidal ideation or with at least one suicide attempt	MX (57.9%) > PM (1.3%)
Dilsaver²⁷27. Dilsaver SC, Chen YW, Swann AC, Shoaib AM, Tsai-Dilsaver Y, Krajewski KJ. Suicidality, panic disorder and psychosis in bipolar depression, depressive-mania and pure-mania. Psychiatry Res. 1997;73:47-56.	Harris County, Texas, USA	To assess links between suicidality, panic disorder, psychosis, bipolar depression, depressive-mania, and pure-mania.	BD inpatients in different illness phases were evaluated. Suicidality, intra-episode panic disorder, and psychotic features were ascertained.	129 BD: 53 MDE, 32 MX, 44 PM	Mean age (y): MDE = 34, PM = 33.4,, MX = 32.1; Female gender (%): MDE = 64.1, PM = 54.5, MX = 56.3	RDC mania + RDC major depression	Number of patients with a score ≥ 3 in the SADS suicide item	MX (56.3%) > PM (2.3%)
Perugi⁷7. Perugi G, Akiskal HS, Micheli C, Musetti L, Paiano A, Quilici C, et al. Clinical subtypes of bipolar mixed states: validating a broader European definition in 143 cases. J Affect Disord. 1997;43:169-80.	Pisa, Italy	To validate and clinically characterize mixed bipolar states derived from the concepts of Kraepelin and the Vienna School, using the Pisa criteria.	MX patients diagnosed according to Pisa criteria were compared with DSM-III-R PM patients.	261 BD-I: 118 PM, 143 MX	Mean age (y): MX = 37.3, PM = 39.3; Female gender (%): MX = 60.1, PM = 56.8	Pisa criteria	Number of patients with at least one suicide attempt	MX (14.7%) > PM (0%)
Strakowski²⁸28. Strakowski SM, McElroy SL, Keck PE Jr, West SA. Suicidality among patients with mixed and manic bipolar disorder. Am J Psychiatry. 1996;153:674-6.	Cincinnati, Ohio, USA	To determine whether suicidality in mania is associated with increasing depression in general or with the presence of a mixed state per se.	Categorical and dimensional assessments of BD-I inpatients were performed. Mixed and manic bipolar subtypes were compared.	91 BD-I: 57 PM, 34 MX	Mean age (y): 26; Female gender (%): 43; Ethnic group (%): Caucasian: 55, African-American: 40, Not specified: 5	DSM-III-R	Number of patients with a score > 1 in the HAM-D suicide item	MX (26%) > PM (7%)
Dilsaver²⁹29. Dilsaver SC, Chen YW, Swann AC, Shoaib AM, Krajewski KJ. Suicidality in patients with pure and depressive mania. Am J Psychiatry. 1994;151:1312-5.	Houston, Texas, USA	To determine the rate and severity of suicidality among patients with pure and depressive mania.	Severity of current suicidality was compared between patients with pure and depressive mania.	93 BD-I: 49 PM, 44 MX	Mean age (y): PM = 35.2, MX = 32.8; Female gender (%): 61.3; Ethnic group (%): Caucasians: 60.2, African-Americans: 29, Hispanics: 7.5, Not specified: 3.2	RDC mania + RDC major depression	Number of patients with a score ≥ 3 in the SADS suicide item	MX (54.5%) > PM (2%)

Article	Location	Objective	Method	Samples	Sociodemographic factors	Mx evaluation	Assessment of suicidal behavior	Suicidal behavior results
Holma³⁰30. Holma KM, Haukka J, Suominen K, Valtonen HM, Mantere O, Melartin TK, et al. Differences in incidence of suicide attempts between bipolar I and II disorders and major depressive disorder. Bipolar Disord. 2014;16:652-61.	Finland	To investigate differences in the risk of suicide attempts between MDD and BD.	Incidence rates for suicide attempts during various illness phases were compared between patients from two different cohorts.	249 MDD, 147 BD: 106 MDE, 41 MX	Mean age (y): MDD = 40.1, MDE = 38.3, MX = 33.6; Female gender(%): MDD = 74.3, BD = 52.8, MX = 63.4; Married (%): MDD = 52.6, MDE = 43.4, MX = 34.1	DSM IV or Benazzi & Akiskal	Suicidal ideation based on SSI score	SSI percentile 50: MX(8) = MDE(5)
Valtonen³¹31. Valtonen HM, Suominen K, Mantere O, Leppämäki S, Arvilommi P, Isometsä E. Suicidal behaviour during different phases of bipolar disorder. J Affect Disord. 2007;97:101-7.	Espoo, Finland	To investigate the differences in prevalence and risk factors for suicidal behavior during different phases of BD.	Suicidal ideation of BD patients was measured. Prevalence and risk factors for suicidal ideation and attempts during different phases were investigated.	144 BD: 15 MX, 24 dMX, 105 MDE	Mean age (y): MDE: 38.4, MX: 36, dMX: 32.4; Female gender (%): MDE: 53.3, MX:53.3, dMX: 70.8; Married (%): MDE: 42.8, MX: 26.7, dMX: 37.5	DSM IV and Benazzi & Akiskal	Suicidal ideation based on SSI score	SSI percentile 50: MX (12.0) > dMX (6.5) > MDE (5.0)
Perugi³²32. Perugi G, Akiskal HS, Micheli C, Toni C, Madaro D. Clinical characterization of depressive mixed state in bipolar-I patients: Pisa-San Diego collaboration. J Affect Disord. 2001;67:105-14.	Pisa, Italy	To delineate the clinical profiles of depressive mixed states in the context of BD-I.	The authors studied patients who either met Pisa criteria for bipolar mixed state or DSM-III-R criteria for major depressive episode.	154 BD-I: 118 MX (32 MS-D, 86 MS-DSM), 36 MD-B	Mean age (y): MS-D = 36.3, MS-DSM = 37.7, MD-B = 42.3; Female gender (%): MS-D = 50, MS-DSM = 65.1, MD-B = 52.8; Unemployed (%): MS-D = 12.5, MS-DSM = 8.6, MD-B = 9.4. Married (%): MS-D = 34.4, MS-DSM = 46.5, MD-B = 60	Pisa criteria	Average score on HAM-D suicide item	D-MS (1.04 SD 1.35) = MS-DSM (1.47 SD 1.49) = B-MD (0.73 SD 0.93)
Ciapparelli³³33. Ciapparelli A, Dell’Osso L, Tundo A, Pini S, Chiavacci MC, Di Sacco I, et al. Eletroconvulsive therapy in medication-neuroresponsive patients with mixed mania and bipolar depression. J Clin Psychiatry. 2001;62:552-5.	Pisa, Italy	To investigate the effectiveness of ECT in medication-nonresponsive patients with mixed mania and bipolar depression.	Patients with mixed mania and bipolar depression assigned for ECT were evaluated the day before starting ECT, 48h after third session, and a week after last session.	64 BD-I: 41 MX, 23 MDE	Mean age (y): MX = 38, MDE = 40.5; Female gender (%): MX = 37, MDE = 39	DSM-IV	Average score on MADRS suicidal ideation item	MX (2.9 SD 1.8) = MDE (3.3 SD 1.5)
Dilsaver²⁷27. Dilsaver SC, Chen YW, Swann AC, Shoaib AM, Tsai-Dilsaver Y, Krajewski KJ. Suicidality, panic disorder and psychosis in bipolar depression, depressive-mania and pure-mania. Psychiatry Res. 1997;73:47-56.	Harris County, Texas, USA	To, assess links between suicidality, panic disorder, psychosis, bipolar depression, depressive-mania, and pure-mania.	BD inpatients in different illness phases were evaluated. Suicidality, intra-episode panic disorder, and psychotic features were ascertained.	129 BD: 53 MDE, 32 MX, 44 PM	Mean age (y): MDE = 34, PM = 33.4, MX = 32.1; Female gender (%): MDE = 64.1, PM = 54.5, MX = 56.3	RDC mania + RDC major depression	Number of patients with a score ≥ 3 on the SADS suicide item	MX (56.3%) < MDE (79.3%)

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[1] Correspondence: Renata Reis Lage. Instituto de Psiquiatria, Universidade Federal do Rio de Janeiro Av. Venceslau Brás, 71, fundos 22290-140 - Rio de Janeiro, RJ - Brazil Tel.: +55 (27) 996536333 E-mail: renatareislage@hotmail.com