Suicide is a major public health issue worldwide with more than 800,000 people dying from this cause annually.1 It is a complex, multifaceted phenomenon accounting for both distal and proximal risk factors.2 Among these latter factors, psychiatric disorders are major contributing factors to the precipitation of suicide, with mood disorders ranking first.3 Bipolar disorders (BD) and unipolar major depressive disorder are important contributors to suicide risk in people who are vulnerable.3,4 A recent systematic review showed that during acute phases of BD, suicidal behavior is more strongly associated with mixed states than with pure mania or hypomania.5
The mixed state in mood disorders represents a severe presentation of BD with longer hospital stays,6 occurring at a younger age,7 and with a high percentage of depressive symptoms during mania.8 Up to 72% of patients who experience mania with depressive symptoms, according to Vieta et al.,9 experience anxiety, irritability, and agitation.
It appears that people who experience mania with depressive symptoms are at higher risk of suicide and present a higher lifetime history of suicidality,8 might have a higher prevalence of suicide risk in the long term (10-year follow-up),10 and they are more likely to attempt suicide after experiencing a manic episode with depressive symptoms versus a “pure” manic episode.11 It is noteworthy that early onset and suicide risk are associated with high mixed state index scores such as onset before age 16 years, head trauma, and suicide attempts.12 The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5),13 includes a new “with mixed features” specifier for hypomanic, manic, or depressive episodes, moving from a categorical to a dimensional approach. This has allowed for a more precise recognition of mixed states using a specifier indicating the presence of symptoms of the opposite pole, which is applicable to episodes of both depression and hypomania. It is also applicable in the context of both unipolar and bipolar lifetime diagnoses, and it addresses the convergence of predominantly depressive and manic mixed states.
There is no doubt that mixed states are clinical conditions with a greater predisposition to suicide risk. In episodes of mania with depressive symptoms, when depression may switch into mania and when rapid or unexpected change in moods are associated with dysphoria and agitation, it is imperative to monitor suicide risk.14 Although suicide in mood disorders in general and BD in particular has been studied extensively in the literature, little emphasis has been placed on suicide risk factors in mixed states. Moreover, summaries of risk factors for suicidal behavior in patients presenting mixed states are scarce.
This article will provide a broader picture of features commonly associated with suicide risk in mixed states as well as measures that can help clinicians in the prevention of suicide.
Clinical Features Associated with Suicidal Behaviors in Mixed States
Mania with Mixed Features
In 1994, Dilsaver et al.15 analyzed a sample of 93 patients affected by bipolar I disorder (BD-I; n = 75) or schizoaffective disorder (n = 18) to determine the rate and severity of suicidality among patients with pure and depressive mania. They reported that those affected by depressive mania were more at risk of presenting suicidal behavior compared to those with pure mania [24 vs 1, X2(1) = 32.50, P = .0001].
In 1998, a study reported that, among a sample of 316 inpatients meeting DSM-III-R16 criteria for BD, those presenting mixed states presented a higher risk of suicidal behavior compared to those with pure mania.17 Cassidy et al.17 were one of the first to suggest that mania was “not a purely euphoric state” and found significant rates of dysphoria, lability, anxiety, and irritability among the “pure” manic patients according to the DSM-III.18 Similarly, Perugi et al.19 analyzed differences between patients with pure mania (N = 118) and a group with mixed features (N = 143). They reported that those diagnosed with a mixed state presented a higher risk of attempting suicide than those with pure mania (14.7% vs 0%, X2(1) = 16.21, P = .0001).
Another report showed that among a sample of patients with BD-I diagnosed with mania, those with mixed mania presented higher scores on suicidality items evaluated both with the Hamilton Depression Rating Scale and the self-rated Carroll Depression Scale compared to those with pure mania.20 Among a sample of 169 adult patients affected by BD-I, it was found that those presenting with mania with mixed features were at higher risk of experiencing suicidal ideation.21 Similarly, another study found that among a sample of 171 inpatients diagnosed with BD-I, those receiving a diagnosis of mania with mixed features were at higher risk of having a history of suicidal behavior related to mania.22
Anxiety, Psychomotor Agitation, Irritability
Eberhard and Weiller23 investigated the relationship between suicidality and anxiety, irritability, and agitation (AIA) symptoms in patients with BD-I experiencing mania with depressive symptoms using data from a previous naturalistic study. They found that suicidal ideation had a greater incidence in the severe AIA group (120 of 167 patients; 71.9%) than in the mild AIA group (50 of 105 patients; 47.6%).23 The mean number of suicide attempts in patients with BD-I mania with mixed features was significantly higher in the severe AIA group than in the mild AIA group (0.84 vs 0.34 suicide attempts, respectively; P = .05; N = 162). Lifetime suicide attempts were also found to be higher in the severe AIA group. In a naturalistic study, Berk et al.24 suggested an association between irritability and suicidality among bipolar patients in a mixed phase.
Benazzi25 investigated the role of racing/crowded thoughts in a sample of 374 consecutive BP-II outpatients presenting with a major depressive episode. He reported that racing/crowded thoughts, psychomotor agitation, and more talkativeness were independent predictors of suicidal ideation.25,26
Considering that mental activation, irritability, and psychomotor agitation are often present in a depressive mixed state (DMX), Akiskal and Benazzi27 tested all the noneuphoric hypomanic symptoms of DMX as possible precursors to suicidality. They found that irritability, psychomotor agitation, and racing/crowded thoughts were present in a significantly higher percentage in DMX than in non-DMX. Racing/crowded thoughts were found to be the only significant independent predictor of suicidal ideas (odds ratio [OR] = 1.81, 95% confidence interval [CI] = 1.12–2.94, P = .015 in the BP-II sample; OR = 1.87, 95% CI = 1.12–3.11, P = .016 in the MDD sample).27
Severity of Intra-Episodic Depressive Symptoms
Several studies support the hypothesis that the presence and severity of depressive symptoms in mixed states might be the main risk factors for suicidal behavior. Strakowski et al.28 analyzed the severity of depressive symptoms in a clinical population of patients affected by manic and mixed symptoms. Interestingly, they found that suicidality was more common in mixed than manic BD. After adjusting for total depression scores, the association with affective state did not persist, and only the Hamilton Depression Rating Scale total score (not the Young Mania Rating Scale) remained associated with suicidal ideation. Thus, the severity of depressive symptoms in mania, rather than the presence of a mixed state per se, was associated with suicidal behavior.28 This evidence supported a dimensional approach to describing the affective states of BD and emphasizes the need to assess suicidality in all bipolar patients, regardless of the current affective phase. Likewise, a report from the EPIMAN study, involving 104 patients with acute manic symptoms, divided patients with pure mania from patients with dysphoric mania based on the number of depressive symptoms (dysphoric mania if more than three depressive symptoms were present).29 Their analysis showed that there was no significant difference in the rate of lifetime suicide attempts between patients with pure and dysphoric mania, suggesting that the association between mixed states and suicidal behaviors could be related to the severity of depressive symptoms.29 In 1997, Dilsaver et al.15 found that among a sample of 129 patients diagnosed with BD-I, those presenting with a depressive episode were at higher risk of suicidality compared to those presenting other phases.
Goldberg et al.30 analyzed a population of more than 1,000 patients affected by BD during a major depressive episode defined according to the DSM-IV criteria.31 They divided the population into three groups, evaluating the number of manic symptoms presented during the depressive episode: pure depressive (absence of manic symptoms), subsyndromal mania (one or three definite manic symptoms), or full mixed episode (four or more definite manic symptoms). The results showed that patients with both subsyndromal (43.7%; relative risk [RR] = 1.11, 95% CI = 0.87–1.41) and full mixed states (53.6%; RR = 1.49, 95% CI = 1.08–2.04) attempted suicide more frequently. Moreover, subsyndromal mixed states were associated with greater lifetime illness severity, particularly more extensive suicide attempts.30 These findings suggested that not only depression but the presence of manic features (at even a subthreshold level) during bipolar depression might confer an increased lifetime risk for suicide attempts.30
Valtonen et al.,32 in the context of the Jorvi Bipolar Study, studied a sample of 191 patients diagnosed with BD (90 BD-I, 101 BD-II), measuring suicidal ideation with several scales. They reported that the level of suicidal ideation correlated with the level of hopelessness (Beck Hopelessness Scale; r = 0.45, P = .004) and subjective ratings of depression (Beck Depression Inventory [BDI]; r = 0.35, P = .03) during mixed phases. They also reported that a subjective rating of severity of depression (BDI) and younger age predicted suicide attempts during mixed phases. Also, it was shown that the incidence of suicide attempts was 37 times higher (95% CI, RR: 11.8–120.3) during combined mixed and depressive mixed states and 18 times higher (95% CI, 6.5–50.8) during major depressive phases.32
Young and Eberhard8 evaluated patients with BD-I who had mania with depressive symptoms and who met the new “with mixed features” specifier of the DSM-5.13 Patients with three or more depressive symptoms were also significantly more likely to have made at least one suicide attempt during their lifetime and during their current manic episode compared to those with zero to two depressive symptoms.8
Time Spent in a Depressive Phase
Several studies have suggested that time spent in a depressive phase could be associated with a greater risk of suicidal behavior. Khalsa et al.33 assessed 216 BP-I patients (based on the DSM-IV)31 and confirmed that factors associated with suicidality included a higher proportion of time ill overall, more time in depressed-dysphoric morbidity, higher initial depression symptom ratings, any Axis I comorbidity, and prior suicide attempts. Also, a relationship between the number of suicide attempts in the previous year and the number of intra-depressive hypomania symptoms and Multiple Visual Analog Scales of Bipolarity activation scores were found.34
Holma et al.35 reported that the higher incidence of suicide attempts among a sample of patients affected by BD compared to unipolar depression was related to more time spent depressed among patients with BD.
A recent study suggested that the higher risk of suicidal behavior found among patients with mixed states could be related to more time spent depressed.36 In a sample of 429 participants with BD, the rate of suicidal behavior was higher for people with a history of mixed state experiences than people without a history (7.4 vs 4.6 per 100 person-years; RR = 1.61). Those patients spent a greater proportion of time depressed than people with no history of mixed states; the mean proportion of time spent depressed was 46.3% for people with a history of mixed states and 28.2% for those without.36
The present overview of the literature summarizes most of the existing literature on the risk factors for suicidal behavior among patients presenting with mixed states. Despite the lack of original investigations aimed at evaluating common features associated with suicidal behavior in mixed states, several risk factors can be outlined from the existing literature.
Previous studies highlighted that bipolar patients experiencing anxiety, psychomotor agitation, and irritability might present a higher risk of both suicidal ideation and suicide attempt.23,24 Also, other specific symptoms of activation such as racing/crowded thoughts might be related to a higher risk of suicidal behavior in patients presenting mixed states.25,26,37 As highlighted recently, the role of irritability might be clarified in further studies, as it is not yet clear what its role might be in conferring higher risk of suicidal behavior in both adult and adolescent populations affected by mood disorders.38,39
Patients who experience depressive symptoms during an episode of mania face even greater challenges than during other phases of illness. Mania with depressive symptoms is often associated with higher rates of suicide, more frequent episodes of longer duration, more frequent relapses, a longer time to reach symptomatic remission, more severe anxiety, irritability, or agitation.8 Furthermore, due to the combination of a depressed mood (eg, feelings of hopelessness) with the impulsivity and hyperactivity of mania, these patients are at an increased risk of suicide.6 Clinicians should pay particular attention to anxiety, irritability, or agitation, which are important warning signs that indicate the presence of depressive symptoms within an episode of mania. Almost three-quarters (72%) of patients who experience mania with depressive symptoms suffer from anxiety, irritability, and agitation.39 These findings are of particular importance as they match with classical suicidology research, which points to the understanding of the mental pain of people who are suicidal. Jobes40 reported that the above-mentioned features of mixed states as components of a patient's suicide risk should be explored collaboratively with the patient. In consideration of the high risk of suicidal behavior linked to these symptoms, their assessment is important for the diagnosis and treatment of patients presenting mixed episodes.
The present overview also provides a summary of evidence suggesting that depression severity and time spent in a depressive phase might enhance the risk of lifetime suicidal behavior. This finding might be related to the evidence that depressive phases of BD-I and BD-II as well as unipolar depression are not being fully or even satisfactorily controlled with available treatments.41,42
The findings from the present overview also have implications for the treatment of mixed states, supporting the recommendation that antidepressant monotherapy should not be an option for the treatment of patients with mixed depression of any type (unipolar, BP-I, or BP-II).43 Mood-stabilizing agents might be needed to control these symptoms before using antidepressants; antidepressants used alone (ie, not protected by mood-stabilizing agents) can increase intra-major depressive episode manic/hypomanic symptoms, sometimes leading to (or increasing) suicidality.25,44 Given the suicide preventive properties of lithium and its neuroprotective effects, as well as its long-term preventive efficacy, lithium might be a valuable option in patients presenting symptoms of activation (such as anxiety, psychomotor agitation, and irritability), and more studies are needed to test its efficacy in mixed states.43,45,46
One of the major limitations of this overview is related to the analysis of articles assessing patients through different diagnostic criteria. For instance, the transition from DSM-IV-TR47 to DSM-513 represents a breakthrough for the diagnostic criteria for mixed states. Furthermore, scholars worldwide have referred to mixed states with different names such as “mixed depression” and “agitated-depression.”
Suicide in BD-I is a major public health problem. The first DSM-513 criteria for BD “with mixed features” seek to capture the fact that a significant number of patients have mania or hypomania with depressive symptoms. Manic episodes with depressive symptoms are generally more severe and are associated with a poorer prognosis than pure manic episodes. Clinicians should pay particular attention to episodes of mania with depressive symptoms, especially when depression switches into mania and when volatile and erratic moods are associated with dysphoria and agitation; it is imperative to monitor suicide risk. There is a lack of education, awareness, and understanding among psychiatrists and other health care professionals around suicide risk and prevention in patients with BD-I, specifically those who experience mania with depressive symptoms. The key is to recognize patients experiencing mania with depressive symptoms and stabilize their mood through medication. Indeed, the use of this type of medication in those patients can increase the risk of “switch” and lead the patients to a condition of intollerable instability that can increase suicide risk. Therefore, relieving dysphoria, which is an emotional state marked by anxiety, depression, and restlessness, is a priority for psychiatric treatment.
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- Young AH, Eberhard J. Evaluating depressive symptoms in mania: a naturalistic study of patients with bipolar disorder. Neuropsychiatr Dis Treat. 2015;11:1137–1143. doi:10.2147/NDT.S82532 [CrossRef] PMID:25995638
- Vieta E, Grunze H, Azorin J-M, Fagiolini A. Phenomenology of manic episodes according to the presence or absence of depressive features as defined in DSM-5: results from the IMPACT self-reported online survey. J Affect Disord. 2014;156:206–213. doi:10.1016/j.jad.2013.12.031 [CrossRef] PMID:24439831
- González-Pinto A, Barbeito S, Alonso M, et al. Poor long-term prognosis in mixed bipolar patients: 10-year outcomes in the Vitoria prospective naturalistic study in Spain. J Clin Psychiatry. 2011;72(5):671–676. doi:10.4088/JCP.09m05483yel [CrossRef] PMID:20868631
- Isometsä E, Sund R, Pirkola S. Post-discharge suicides of inpatients with bipolar disorder in Finland. Bipolar Disord. 2014;16(8):867–874. doi:10.1111/bdi.12237 [CrossRef] PMID:25056223
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