Prevention of Suicidal Behavior in Bipolar Disorder
Abstract
Background:
Excess mortality is a critical hallmark of bipolar disorder (BD) due to co-occurring general medical disorders and especially from suicide. It is timely to review of the status of suicide in BD and to consider the possibility of limiting suicidal risk.
Methods:
We carried out a semi-systematic review of recent research reports pertaining to suicide in BD.
Findings:
Suicide risk in BD is greater than with most other psychiatric disorders. Suicide rates (per 100,000/year) are approximately 11 and 4 in the adult and juvenile general populations, but over 200 in adults, and 100 among juveniles diagnosed with BD. Suicide attempt rates with BD are at least 20 times higher than in the adult general population, and over 50 times higher among juveniles. Notable suicidal risk factors in BD include: previous suicidal acts, depression, mixed–agitated-dysphoric moods, rapid mood-shifts, impulsivity, and co-occurring substance abuse. Suicide-preventing therapeutics for BD remain severely underdeveloped. Evidence favoring lithium treatment is stronger than for other measures, although encouraging findings are emerging for other treatments.
Conclusions:
Suicide is a leading clinical challenge for those caring for BD patients. Improved understanding of risk and protective factors combined with knowledge and close follow-up of BD patients should limit suicidal risk. Ethically appropriate and scientifically sound studies of plausible medicinal, physical, and psychosocial treatments aimed at suicide prevention specifically for BD patients are urgently needed.
Reprinted from Bipolar Disord 2021; 23:14–23, with permission from John Wiley and Sons. Copyright © 2021
INTRODUCTION
Risk of suicide is extraordinarily high among patients diagnosed with bipolar disorder (BD). Given the clinical and public health significance of the problem and recent progress in understanding the nature, epidemiology, risk factors, and efforts aimed at prevention related to suicidal behavior in BD patients, we have undertaken the present review. It is a semi-systematic overview of the broad topic of suicide, based on selected citations of recent research reports, backed by systematic reviews of the PubMed literature database for specific topics. We concentrated on suicide and attempts rather than more elusive suicidal ideation, and emphasize research findings specifically applicable to bipolar disorder (BD) when available.
EPIDEMIOLOGY
Overview
The international, age-standardized mortality rate (SMR) for suicide decreased by one-third between 1990 and 2016,1 from 16.6 to 11.2 deaths per 100,000 person-exposure years (100k PEY), as did years of life lost, from 697 to 458 per 100k PEY.1 These trends have not been consistent across all regions, as some countries have experienced major increases in suicide risk in recent decades.2,3 Although increases in some countries may be attributable to better case finding, that is, less likely for the US where suicide rates rose by one-third in 1999–2018, from 10.5 to 14.2 per 100k PEY, and did so across virtually all age groups and regions, although retaining marked differences in rates among regions (rural > urban), the sexes (males > females), and ethnic groups (Native > Caucasian > Hispanic > African).4 Moreover, in the US, between 2006 and 2015, both fatal and nonfatal suicidal acts increased by 10%, with a rise in suicide attempts especially noteworthy among women, adolescents, and older adults (65–74 years).4 Moreover, the lethality of suicidal acts (fatalities per attempts) increased by 13% in both sexes.5
In the US, increased suicidal risks have been associated with an epidemic of opioid abuse and the potential lethality of their overdoses in recent years.4 Poverty, especially in young persons, is an important risk factor for suicide 6 as are other economic and geographical factors that limit access to adequate health care.7 However, the US experience is not generalizable, notably as firearm ownership is widespread and unregulated in most states and suicide by gunshot accounts for 75% of all cases.8
According to US-CDC nomenclature, suicide risk follows a hierarchy starting with ideation, to preparatory behavior, and to self-directed violence—all of which can be considered as having clear suicidal intent or not or being unknown, with or without injury, interrupted by self or others, or fatal.9 Estimated annual rates of suicidal ideation in the US general population have recently averaged 4.5%; plans were made by an average of 1.3% of adults, about 0.62% made an attempt, and 0.02% died by suicide, indicating a ratio of ideation to fatalities of about 225 and of attempts to suicides of approximately 30.10,11 The ratio of attempts/suicides (A/S) is negatively correlated with greater lethality and can serve as an “index of lethality.” This ratio in mood disorder patients probably is well below 10, indicating at least three times greater lethality per suicidal act than in general population samples.12,13
Suicidal Risks with Bipolar Disorder
Although most psychiatric disorders present some suicidal risk, major mood disorders carry especially high rates.14–16 BD generally, and major depressive disorder (MDD) severe enough to require hospitalization, bear the highest reported rates among psychiatric disorders for suicide attempts and suicides. This risk is even higher with substance abuse, as commonly co-occurs with major mood disorders, and especially with more than one substance.14,16–18 The suicide-associated SMR in these high-risk clinical conditions can reach 20 times that in the age- and sex-matched general population,14,16 but may be even higher since the general population includes mood-disordered persons. If approximately half of all suicides are attributable to mood disorders, a more appropriate SMR for these diagnostic groups compared to a general population with mood disorders excluded may be as high as 40-fold. Recent data on suicidal risks among adults and juveniles with BD are summarized in Table 1 based on official reports3,4 and six studies.16,18–22
| Population | Rate per 100 k PEY [95%CI] | | |
|---|---|---|---|
| Attempts (A) | Suicides (S) | Lethality (A/S Ratio) | |
| General: overall | 600 [533-672] | 10.8 [9.6-12.1] | 55.6 [46.1-67.6] |
| General: juveniles | 380 [318-449] | 3.77 [3.15-4.45] | 101 [91-112] |
| Adults with BD | 4240 [3780-4700] | 212 [189-235] | 20.0 [17.5-22.9] |
| Juveniles with BD | 6550 [6040-7100] | 124 [57-236] | 52.8 [44.4-63.4] |
It is especially notable that suicide risk remains high among BD patients despite the growing array of effective psychopharmacological and psychosocial treatments available for the disorder.23,24 Indeed, up to 60% of persons with BD attempt suicide at some time, and suicide fatalities occur in 5%–20% of adults with BD.25–27 The high suicidal risk with BD is further underscored by findings that the rate of suicide attempts is approximately twice that associated with MDD, in which suicidal risk varies greatly with illness severity.16 The ratio of attempts/suicides also is much lower (greater lethality) in BD than MDD patients, indicating that BD patients not only present a higher risk of suicidal acts but also attempt suicide with greater intent to die or use relatively violent methods.
RISK FACTORS
Identification of risk factors for suicidal behavior in BD as in other psychiatric conditions is essential for treatment selection and risk mitigation, as well as for research. In the general population, commonly cited suicide risk factors include: male gender in most cultures, Caucasian or Native-American ethnicity (Hispanic and, especially, African Americans present lower risks), and older age (>75 years). Many other factors have been described, but can be confounded by the presence of psychiatric illness, including living alone, being divorced, having no children, and being unemployed or impoverished.16,25
For mood disorder patients, previous suicide attempt is a most powerful predictor of future suicidal behavior: approximately, 40% of people die of suicide after a previous suicide attempt.2,26–28 Moreover, risk of suicide after an attempt has been estimated at 1.6% within a year of an attempt and about 4% within 5 years, whereas the risk for an another attempt was about 16% within 1 year.28,29 We found in an international mood-disorder population of about 8,500 subjects, a repeated suicide attempt in 13% of the cases.30 In addition, as in the general population of most countries, men are more likely to complete suicide and women to attempt it.2,16,25,29 Risk of suicidal behavior is especially high at younger ages, particularly within the initial few years after illness onset, and sometimes even before diagnosis.25,29–32 Younger age at illness onset is also associated with suicidal risk with BD, but its significance is confounded by longer risk exposure.15
In our recent study of more than 6,000 psychiatric patients evaluated at a European psychiatric research center, the highest rate of suicide was among patients diagnosed with DSM-5 BD with psychotic features, type I BD, and BD with mixed features, with rates that were nearly 20 times above international general-population rates.16 Risks were lower in type II BD, and even lower among MDD patients unless they had been hospitalized. This study confirmed high suicide risk with substance abuse disorders and far lower risk with anxiety-related and attention-deficit disorders.16 Rates of suicide may be somewhat higher among BD-I than BD-II patients, but their rates of suicide attempts are similar, as seems consistent with the prominence of depressive morbidity in BD-II.18,30
The key contributor to suicidal risk in BD is depressive morbidity. Of note, depressive or dysphoric-dysthymic morbidity accounts for three quarters of the 40%–50% of time ill among clinically treated BD patients,31 exposing patients to greater and more prolonged risk. Not only has higher suicide risk been reported in association with the predominant depressive polarity of BD33 but also bipolar depression is difficult to treat, especially if mixed or agitated-dysphoric features are present adding to an inclination to self-destructive actions.15,25,32–34 In contrast, suicidal behavior is uncommon in association with relatively pure manic, and especially hypomanic, states without mixed-depressive features. Since depression is the most likely mood state associated with suicide risk in BD, a major effort should be directed toward its treatment when suicidal thoughts or behaviors are present and toward efforts to limit future risk of bipolar depression. However, the effectiveness of most treatments offered for bipolar depression remains unsatisfactory, and use of antidepressants may be associated with inducing or worsening of agitation and mixed states, which can add to suicidal risk.35
Other clinical features associated with risk of suicide behavior in BD include depressive initial episodes which are strongly or moderately correlated with later predominant depressive morbidity, as well as treatment-resistant depressions, hopelessness, and dysthymic or cyclothymic (but not hyperthymic) temperament, impulsivity, and aggressiveness, lack of interpersonal or clinical support, psychiatric hospitalization, borderline personality features, but inconsistently with features associated with narcissistic personality disorder (Table 2).15,25,27,36–39 Family history of suicidal behavior, as well as childhood trauma, emotional abuse and neglect, as well as gender confusion also represent important predictors of later suicidal behavior.2,8 Quantitative estimates of associations of a range of clinical factors with risk of suicide and attempts are provided as the ratio of their presence in mood disorder patients with versus without suicidal acts (Table 2). In summary, suicidal acts are likely to be associated with multiple factors interacting at genetic, physiological, psychological, and environmental levels, and their effects can fluctuate greatly over time, especially in BD.2
| Factors | Relative Risk [95%CI] |
|---|---|
| Strongly Associated (RR 1.5-4.0) | |
| Bipolar diagnosis | 4.0 [3.7-4.3] |
| Ever psychiatrically hospitalized | 2.8 [2.5-3.1] |
| Co-occurring substance abuse (any) | 2.3 [2.2-2.4] |
| Separated or divorced | 2.3 [2.1-2.4] |
| Family history of suicide | 2.1 [2.0-2.2] |
| Treated with an antipsychotic | 2.0 [1.8-2.2] |
| Alcohol abuse | 1.9 [1.7-2.2] |
| Mixed features | 1.7 [1.5-1.9] |
| Family history of bipolar disorder | 1.7 [1.5-1.8] |
| Unemployment | 1.6 [1.4-1.8] |
| Early onset (≤25 years) | 1.5 [1.4-1.6] |
| Greater proportion of time ill | 1.5 [1.4-1.6] |
| Moderately Associated (RR 1.2-1.4) | |
| Multiple depressions (≥4) | 1.4 [1.3-1.6] |
| Lack of children | 1.4 [1.2-1.6] |
| Early abuse | 1.4 [1.3-1.5] |
| Smoking tobacco | 1.4 [1.3-1.5] |
| Diagnosis of BD-I vs. BD-II | 1.3 [1.2-1.4] |
| Co-occurring attention disorder | 1.3 [1.2-1.4] |
| Dysthymic or cyclothymic temperament | 1.3 [1.2-1.4] |
| More years of illness | 1.2 [1.1-1.3] |
| Younger current age (≤40 years) | 1.2 [1.1-1.3] |
| Severe current depression (HDRS ≥20) | 1.2 [1.1-1.3] |
These recalculated and modified data are based on 3284 major mood-disorder patients with versus without suicide or attempts; all factors listed were significantly associated with suicidal behavior (χ2 = 4.83-195, p = 0.03-0.0001).15 Factors significantly more associated with BD than MDD included: % of time depressed, total proportion of time ill, alcohol abuse, ≥4 depressive episodes, more dysthymic or cyclothymic temperament, and early abuse. Additional analyses of factors associated with suicidal behavior in BD were reported by others.24,26
ASSESSMENT
In efforts to limit suicidal risk in BD patients, it is important to recognize that even relatively close clinical monitoring may fail to detect emerging risk of self-harm, even within one to a few days prior to a suicidal act.25 This failure to detect suicidal risk may be related to rapid fluctuations of mood and behavior, as well as impulsivity, both of which are characteristic of many BD patients. Most standard rating scales for depression include an item evaluating levels of suicidal risk, ranging from passive ideation to a recent attempt, and some rating methods specifically address the level and type of suicidal ideation, planning, and behavior, although not specifically in BD patients.40,41 Relying on use of clinical rating scales may not be sufficient, and thorough clinical evaluation should be accompanied by sustained assessment of current mood and irritability, previous suicidal ideation, emerging intention and behavior, and current suicidal preparation and planning, access to lethal means including firearms, and relationships with family members and friends.
Questions about possible precipitating factors are highly relevant and should address recent life events such as economic distress, general medical illnesses, romantic disappointments, humiliation, or suicide of a close friend or relative. In addition, clinical and demographic factors contributing to, or sparing suicidal risk require attention, including marriage, children, personal relationships, employment, and religious interests. In general, it is important not to avoid the topic of suicide with patients, as it can helpfully be addressed cautiously and repeatedly.42,43 If several risk factors are identified or increasing, it may be necessary to arrange for psychiatric hospitalization. In general, it is important not to avoid the topic of suicide with patients, as it can helpfully be addressed cautiously and repeatedly.37
TREATMENT
Challenges for Studies of Suicide Prevention
Scientifically sound information concerning the effectiveness of interventions aimed at reducing suicidal risk, specifically in BD, continues to be very limited. This circumstance reflects major ethical challenges of designing safe, ethical control conditions for clinical trials, the low incidence of suicidal behavior, and difficulties in recruiting and retaining study subjects. A particular paradox is that measurement of the effectiveness of suicide-preventing interventions involves more nonevents (lack of suicidal behaviors). The major source of information about effects of treatment is suicidal behavior noted in clinical studies designed for other purposes, including long-term, randomized, and even placebo-controlled treatment trials, such as with lithium, in which suicidal acts typically are reported among “adverse events.”23,24,30 Such efforts may improve with wider inclusion of assessment methods aimed explicitly at identifying suicidal behavior in treatment trials.
Studies of events as rare as suicidal acts require either very large samples or prolonged exposure and observation to provide sufficient numbers of events for statistical analysis. A prevalent alternative is use of meta-analysis to pool data from many studies so as to increase statistical power. A major problem with this type of analysis is the lack of homogeneity among studies, including in their acquisition of incidental data. Even with adequate sampling, studies with suicidal behavior as an explicit outcome measure remain rare. Therefore, alternative surrogate measures often are employed. These include suicide threats, need to intervene clinically to avoid suicidal behavior, or even self-reported suicidal ideation, which can be particularly unreliable. In addition, ethical considerations usually require comparisons between similarly plausible alternative and active interventions.
Even widely employed clinical methods of managing suicidal persons rarely are adequately supported by empirical research evidence, and studies specifically aimed at suicide prevention with BD patients are especially rare. This circumstance leaves tension between the obligation to intervene clinically, often rapidly, despite a lack of secure evidence about how best to do it.30,43 Several types of treatments have been considered for their potential ability to reduce the risk of suicide in BD patients. They include antidepressants, lithium, mood-altering anticonvulsants, antipsychotics, anxiolytics, as well as ECT and other emerging methods of brain stimulation, and various types of psychotherapies.
Antidepressants
Antidepressant treatment for bipolar depression remains controversial, inadequately studied for short- and especially for long-term use, may have emotionally destabilizing effects, and lacks explicit regulatory approval for use in BD, with the exception of the combination of fluoxetine with olanzapine.23,24,35 Antidepressants may even increase suicidal risk, especially when dysphoric agitation, anger, restlessness, irritability, or insomnia emerge, and in mood states with mixed features, including dysphoric mania and agitated depression.30,33,34,43 Evidence of lower suicidal risk during treatment with an antidepressant than with a placebo is based largely on questionable use of suicide-related items in depression rating scales, which are weighted toward suicidal ideation rather than behavior and likely to be contaminated by overall impressions of general clinical improvement.40,41 In addition, efforts to correlate increased use of modern antidepressants with decreasing suicide rates in regional populations (“ecological” studies) have proved to be potentially misleading and inconsistent.44
Suicide rates pooled across large meta-analyses of randomized controlled trials (RCTs) of antidepressants against placebo were similar across treatments and were substantial, despite efforts to exclude suicidal subjects from most trials.45 Suicide rates in these RCTs averaged 862/100k PEY, or more than 80 times above the general population rate of approximately 10.6/100k PEY, and well above an estimated rate of about 100/100k PEY in clinically managed outpatients with a major affective disorder.12,16 Based on retrospective analyses, findings pooled from RCTs of antidepressants have found increased risks compared to placebo in young patients, decreased risks in older adults, and no difference overall across all ages.46,47 These age-selective differences remain unexplained and, moreover, none of the studies was specific to BD patients, or was suicidal behavior an explicit, a priori outcome measure.
Overall, currently available research findings derived from observations of large numbers of subjects treated with antidepressants do not provide compelling support for either an increase or decrease in suicide ideation or behavior with antidepressant treatment in mood disorder patients generally, nor specifically in BD. Indeed, the efficacy of antidepressant treatment for bipolar depression remains unresolved and far less well studied than with MDD.35 It may be that suicidal ideation and possibly suicide attempts are increased with antidepressant treatment in juvenile and young-adult depressed patients treated with antidepressants, but decreased in older depressed adults,46,47 although this post hoc impression lacks verification with prospective trials using explicit suicide assessments, and has not been extended to BD patients.
Lithium
Suicidal risk was reduced during long-term treatment of BD patients with lithium in several studies,48–53 and its overall clinical value in the treatment of BD was reviewed recently.54 In meta-analyses including data from 34 trials (8 were RCTs against placebo) of long-term treatment with lithium for a major mood disorder in more than 110,000 PEY of risk, pooled rates of suicide and attempts were five times lower during treatment with lithium compared to no treatments or other treatments, and six-fold with BD specifically.48,50 An important issue with lithium treatment is its discontinuation. We noted that rates of suicidal behavior increased as much as 20-fold within several months of discontinuing lithium maintenance treatment and were twice greater with abrupt or rapid, compared to gradual discontinuation over ≥2 weeks, before declining to rates encountered before lithium treatment.48
Based on the findings of the preceding and other studies, an authoritative European Psychiatric Association review recommended long-term lithium treatment of BD patients as a means of reducing risk of suicidal behavior.52 Nevertheless, with the exception of clozapine for schizophrenia, no treatment has regulatory recognition of an antisuicidal effect, including lithium. Again, a notable limitation of support for lithium is that the trials just considered were designed to test for clinical efficacy but not explicitly to detect suicidal acts, which appeared incidentally among reported adverse effects.
Since patients usually undergo close clinical monitoring during long-term treatment with lithium or clozapine to limit medical risks associated with these agents, such extra attention might help to limit suicidal risk by increasing interpersonal support and facilitating early identification of relevant emerging symptoms before suicidal behavior occurs. However, this possibility was not supported in the InterSePT trial for schizophrenia patients, in which clinician contact time was similar with both clozapine and the comparitor treatment olanzapine.55
Effectiveness of lithium treatment in preventing suicide may be associated with reduced impulsivity and aggressiveness in bipolar depressive or dysphoric-agitated mixed states, or lithium may have specific effects against suicide independent of mood-stabilizing actions. Suicidal risk sometimes was found to be reduced even among patients whose mood-disorder symptoms had not responded well to lithium,53,56 although not always.53,57
Anticonvulsants
Research that has evaluated suicidal risks during treatment of BD patients with proved or putative mood-stabilizing anticonvulsants, and their comparison to lithium remains sparce.30,58,59 Nevertheless, two studies found nearly three-fold lower average risks of suicidal behavior with lithium than with carbamazepine or valproate among BD or schizoaffective disorder patients.60,61 They were included in a meta-analysis of suicidal behavior in six direct comparisons of treatment with lithium (31 months) or an anticonvulant (19 months) involving more than 30,000 BD patients.62 The rate of suicidal acts averaged 300/100k PEY during treatment with lithium versus 900/100k PEY with anticonvulsants (mostly valproate, much less carbamazepine or lamotrigine), to yield a pooled risk ratio of 2.86 (95% CI: 2.29–3.57; p<0.0001), favoring lithium by nearly three-fold.62 In general, some anticonvulsants may have beneficial effects on suicidal behavior in BD patients, although their relative effects are untested.63–66
In an FDA meta-analysis of placebo-controlled RCTs involving 11 anticonvulsants, suicidal ideation and behavior were found to be more prevalent than with placebo in epilepsy patients, although not with psychiatric applications.67 Lack of increased suicidal risk among psychiatric patients, and even indications of suicide-sparing benefit were supported by other studies.63–66 The apparent worsening of suicidal status during anticonvulsant treatment of epilepsy patients remains unexplained, and the plausible expectation that mood-stabilizing anticonvulsants might reduce suicidal risk in BD patients has some support.63–66
Antipsychotics
Most studies of associations between treatment with antipsychotic medicines and suicidal risk involve patients with primary psychotic disorders, and most recent research pertaining to BD patients involves second-generation antipsychotics (SGAs). The first and only US FDA-approved treatment of any kind with an antisuicide indication was clozapine for schizophrenia patients based mainly on a remarkable randomized trial (InterSePT) comparing it with olanzapine among schizophrenia patients at relatively high suicidal risk.55 This trial found longer time to intervention for emerging suicidal risk and reduced rates of suicide attempts, without a reduction in suicides, which were rare with either treatment. Later pharmacoepidemiological studies and their meta-analyses have sometimes yielded evidence of reduction in all-cause mortality and risk of suicide attempts with clozapine,68 whereas sparing of suicide mortality has been found in some69 but not all studies.70 Moreover, similar benefits have been found with antipsychotics other than clozapine.69,71 Potential benefits of clozapine specifically in BD, including suicide prevention, require testing.
An emerging approach to treating BD patients is use of SGA agents for treatment of acute bipolar depression (notably with cariprazine, lurasidone, olazapine-with-fluoxetine, and quetiapine); most (lurasidone is untested) also are effective for mania.72 Having combined efficacy for both mania and bipolar depression should provide extra clinical safety, particularly in treating BD patients in agitated-dysphoric mixed states with very high suicidal risks. However, whether SGA treatment, including with clozapine, may reduce risks of suicidal behavior in BD patients remains uncertain. A caveat is that some SGAs have substantial risks of inducing akathisia or restlessness and agitation, which may increase suicidal risk.72,73
In summary, treatment with modern antipsychotic drugs, especially clozapine, has been associated with substantial reduction in suicide-related behaviors and mortality in suicidal schizophrenia patients. In addition, several SGAs can improve bipolar depression as well as mania, with low risks of inducing agitation or mood switches. Nevertheless, such drugs require specific testing for antisuicidal effects as well as for long-term clinical effectiveness and safety in BD patients.
Anxiolytics and Sedatives
Very limited available evidence does not indicate that antianxiety agents alter suicidal risk in patients with anxiety disorders or other psychiatric illnesses during either short- or long-term treatment,65,74 and the low risk of suicide with anxiety disorders complicates searching for such relationships.16 Antianxiety agents commonly are used as secondary treatments for a variety of psychiatric disorders, and rarely have been investigated as a sole pharmacological intervention in mood disorders. In evaluating potential effects of benzodiazepines on suicidal behavior, it is important to consider that discontinuating benzodiazepine treatment, especially rapidly, may induce a withdrawal syndrome and increase suicidal risk, and that behavioral disinhibition associated with benzodiazepine use might favor impulsive and aggressive behaviors, particularly when combined with alcohol, and with co-occurring personality-disorder features.75,76
Ketamine
The glutamate NMDA-receptor antagonist ketamine administered parenterally and its active isomer, esketamine given intranasally, have growing evidence of effective and rapid reduction in depressive symptoms in depressed patients, including those with BD, even when other treatments have been ineffective. Such effects have been documented within minutes of administration and can persist for at least several days.77 More than a dozen controlled trials also have reported rapid beneficial effects on suicidal symptoms, at least on ratings of suicidal ideation, including in patients with BD.78–80 Whether such effects occur with intranasal esketamine, are sustained, and extend further to suicidal behavior remain under investigation.
In these trials, the dose of ketamine (usually administered intravenously [IV]) has averaged 0.5 mg/kg. Control treatments were a potent sedative, or saline alone or with an added bitter compound when compared with esketamine to support blinding. Findings from several RCTs included significantly reduced ratings of suicidal ideation within 12 hours that were highly significant by 24 hours, and persisted up to 3 days, although statistical separation of responses to ketamine versus controls was significant in only 40% of trials individually.43,80 Risk of inducing mood switching with ketamine for bipolar depressed patients remains uncertain, but it has been used successfully in depressed BD patients with mixed symptoms.79
In general, this promising and remarkably rapidly acting treatment for otherwise poorly treatment-responsive depression, including in BD, requires further study to test for short-term and sustained benefits against suicidal behavior in general, including with intranasal rather than intravenous administration, and with BD patients in particular.
Psychotherapy and Other Interventions
Specific and reproducible forms of psychotherapy have had some evaluation for ability to reduce suicidal risks. Notably, they include cognitive-behavioral therapy (CBT) and dialectical behavior therapy (DBT).81,82 In nearly a dozen randomized trials, CBT has reduced recurrences of self-injurious behaviors for 6–12 months compared to treatment as usual, with nonsignificantly fewer suicides during follow-up over 24 months.81,82 DBT has been evaluated mainly among persons diagnosed with borderline personality disorder, for whom research findings are encouraging but not definitive.82 Also acceptance and commitment therapy (ACT), a mindfulness-based behavior therapy, has been reported to reduce suicide risk in a large group of veterans with post-traumatic stress disorder and alcohol abuse.83 A recent systematic review mainly of the effects of CBT and DBT in patients with suicidal risk reported a reduction of 55.0% for suicidal ideation and by 37.5% for suicide attempts by 37.5% in patients who had attempted suicide.81 None of these psychotherapies or any other has been evaluated adequately for potential antisuicidal effects in BD patients.
Other clinical interventions have been employed empirically with the aim of reducing risk of suicide, although the extent of their scientifically credible assessment has been variable and the design of comparison-control conditions often has been difficult. They include rapid hospitalization which is often clinically necessary for an acutely suicidal patient. However, the days and weeks following psychiatric hospitalization carry greatly increased risks of suicide and attempts, especially when the index hospitalization was to prevent impending suicidal behavior.84
Among physical treatments, electroconvulsive therapy (ECT) is considered clinically to be highly effective for acutely suicidal patients, although research to support long-lasting suicide-preventing effects of even repeated ECT is very limited.85,86 Other neurostimulating treatments, including repeated transcranial magnetic stimulation (rTMS),87–89 vagal nerve stimulation,90 and other experimental forms of superficial or deep brain stimulation (DBS),91 may be effective for the treatment bipolar depression, whereas effects on suicidal behavior in BD patients require testing. Treatments relevant to preventing suicidal risks in BD are summarized in Table 3.30,33,43
| Treatment | Timing | Findings | Limitations |
|---|---|---|---|
| Antidepressants | Effects on BD suicide risk not established | Inconsistent findings re. suicidal risks in trials for MDD; little research in BD; may increase risk of nonlethal suicidal risks at age <25 yrs, but risk decrease in older adults | Lack of matched exposure times with vs. without antidepressants; suicidal status usually assessed passively & incidentally as an adverse effect rather than an explicit outcome measure |
| Antipsychotics | May have short-term benefits; clozapine not tested in mood disorders | Clozapine: only FDA-recognized “antisuicidal” treatment; other second-generation antipsychotics not adequately evaluated | Effects on suicidal risk based on 1 controlled trial with no reduction in (rare) suicides, only in schizophrenia; status of other modern antipsychotics on suicidal risk is unclear |
| Anxiolytics & sedatives | May be beneficial short term | Very limited, inconclusive research | Potential disinhibition to increase suicidal risk;risk of abuse/dependence |
| Anticonvulsants | Short- and long-term effects not established | Anticonvulsants may be less effective than lithium; valproate most studied | Suicidal behaviors have usually been incidental events, not explicit outcomes |
| Lithium | Probably effective long term, not tested short term | Consistent decrease in suicide risk in nonrandomized studies and in placebo-controlled, randomized trials | Incidentally identified suicidal events; risk of self-selection by acceptance & tolerance of treatment |
| Ketamine | Brief reduction in suicidal ideation for ca. 1 week; suitable for emergency intervention | Reduced suicidal ideation vs. saline or sedative controls as depression improved | No information about suicidal behavior; effects on ideation parallel brief mood improvement |
| ECT | Short-term benefit | Effective as an emergency measure | No apparent long-term benefit |
| Psychotherapy | CBT reduced self-injury recurrences up to 12 months. Crisis management useful as acute intervention | CBT reduced recurrences of self-injury by 14%–20% up to 12 mos; DBT ineffective | Testing of DBT lacked statistical power for BD, mostly tested in borderline syndrome |
| Hospitalization | Short-term benefit | Effective as an emergency measure | Untested for long-term benefit; suicide risk increases markedly shortly post-discharge |
Although suicide can only be prevented, patients with suicidal ideation or attempts may require immediate treatment, sometimes in a hospital emergency department. Some treatments described here may not be suitable for emergency treatment in the setting of acute suicidal risk. For instance, antidepressants may increase the agitation and dysphoria usually present in persons with suicidal ideation or a suicide attempt, and their beneficial actions for depression are typically slow to appear. Similarly, mood stabilizers may require a relatively long time to exert beneficial effects. Rapidly acting SGAs or anti-anxiety agents, instead, can be crucial in these circumstances. ECT has long been employed empirically for rapid effects on suicidal ideation and behavior, and ketamine shows promise of reducing suicidal ideation, at least, along with improvement of depression. Rapid hospitalization is widely used to deal with intense suicidal ideation, threats, or acts. Psychosocial interventions may be beneficial against suicidal ideation and behavior, but they are not well evaluated with BD and may not be adequate alone. In general, clinical management of suicidal patients should include a component of crisis intervention. This includes careful clinical assessment with mental state examination, assessment of risk, and protective factors, including support by relatives and friends, and possibly collaboration with other clinicians, especially those involved in management of substance abuse.92
CONCLUSIONS
Suicide cannot be "treated" but can be prevented. Research on treatments aimed at suicide prevention, not surprisingly, is very limited because of clinical and ethical problems arising when an inactive or ineffective treatment, such as a placebo condition, would be compared to an active experimental intervention, with death as a potential outcome. Although it is virtually impossible to know when a suicide has been prevented and to have confidence in efforts to assess suicidal ideation, self-injurious acts can be counted. For research, the rarity of suicide, even among psychiatrically ill persons, encourages reliance on such, more prevalent, surrogate outcome measures related to suicide, however, remotely. They include suicidal ideation with planning as a preparatory behavior, threats, self-injurious acts, and emergency interventions aimed at avoiding apparently impending suicidal behavior. The typically distant relationship of such measures to suicide can lead to misleading impressions and not prove therapeutic effects on suicide itself. Suicidal behaviors, including attempts, and interventions aimed at preventing progression from suicidal ideation to an attempt have been employed in the research assessment of treatments aimed at reducing risk of suicide, including comparisons before versus during an intervention or between two plausible interventions.
Many BD and other psychiatric patients at risk for suicide receive various treatments, often with the implied aim of limiting suicidal risk. However, the effects of very few have been tested adequately for effects on suicidal behavior, leaving their potential benefits and risks for BD patients uncertain. Among potential treatments, lithium has arguably the strongest support for having antisuicide effects in BD (and possibly also in MDD), although limitations and problems arise from its need for medical monitoring to avoid potentially severe adverse pathophysiological effects, toxic effects of overdosing, both public and professional skepticism about its routine clinical use, and lack of commercial interest in this unpatentable mineral natural product.
Some anticonvulsants may share antisuicidal effects with lithium, but these appear to be less substantial. Their limitations include severe teratogenic effects of valproate and carbamazepine, drug interactions with both, and lack of their regulatory approval for long-term prophylactic use in BD. SGAs occupy an interesting and growing place in the overall clinical management of BD in that most have antimanic effects and several are effective in acute bipolar depression. Nevertheless, their potential antisuicidal effects in BD remain unproved, and the tendencies of some to induce akathisia or agitation represent risk factors for suicide. Antidepressants continue to have a controversial position in the treatment of bipolar depression, as well as being remarkably poorly studied for that indication, particularly for long-term, prophylactic applications, in contrast to a massive research literature for their use in MDD. They may be effective and well-tolerated if mixed or agitated elements in bipolar depression are avoided during their use. Among experimental medicinal treatments, ketamine shows some promise, at least in rapidly reducing suicidal ideation along with depression in otherwise treatment-resistant BD patients.
Psychotherapy is typically combined with mood-stabilizing medicines as a supportive intervention in BD, although specific benefits against suicidal behavior of particular, protocol-guided forms of psychotherapy (such as CBT and DBT) remain inadequately evaluated for BD patients. ECT has a well-established empirical place in the clinical management of acutely suicidal BD patients. In addition, rTMS, VNS, DBS, and other physical treatments appear to have utility for depression and are of interest for assessment of their potenial antisuicide effects in BD.
In conclusion, this brief overview of the complex topic of suicide in BD supports the impression that the cornerstone of suicide prevention in BD and other patients at risk remains careful, detailed, repeated, and ongoing clinical assessment of risk and protective factors and of sometimes rapidly changing states of mood and behavior among BD patients.
Footnotes
ORCID
Leonardo Tondo https://orcid.org/0000-0002-1624-0522
Ross J. Baldessarini https://orcid.org/0000-0001-9718-8211
References
1.
Naghavi M; (Global Burden of Disease Self-Harm Collaborators). Global, regional, and national burden of suicide mortality 1990 to 2016: systematic analysis for the Global Burden of Disease Study 2016. BMJ. 2019;364(6 Feb):l94.
2.
Turecki G, Brent DA, Gunnell D, et al. Suicide and suicidal risk: a primer. Nature Rev Dis Prim. 2019;5(1):74-95.
3.
WHO (World Health Organization). Suicide rates in 183 countries, 2020. https://www.who.int/mental_health/prevention/suicide/estimate/en. Accessed 21 Apr 2020
4.
CDC (US Centers for Disease Control and Prevention). Estimated rate of suicide attempts in the US, 2020. www.cdc.gov/violenceprevention/pdf/suicides-datasheet-1.pdf. Accessed 21 Apr 2020
5.
Wang J, Sumner SA, Simon TR, et al. Trends in the incidence and lethality of suicidal acts in the United States, 2006 to 2015. JAMA Psychiatry. 2020;77(7):1-10.
6.
Hoffmann JA, Farrell CA, Monuteaux MC, Fleegler EW, Lee LK. Association of pediatric suicide with county-level poverty in the United States, 2007–2016. JAMA Pediatrics. 2020;174(3):287-294.
7.
Tondo L, Albert MJ, Baldessarini RJ. Suicide rates in relation to health-care access in the United States: an ecological study. J Clin Psychiatry. 2006;67(4):517-523.
8.
Conner A, Azrael D, Miller M. Suicide case-fatality rates in the United States, 2007 to 2014: nationwide population-based study. Ann Intern Med. 2019;171(12):885-895.
9.
Crosby AE, Ortega L, Melanson C. Self-directed violence surveillance: uniform definitions and recommended data elements, Version 1.0. Atlanta: US National Center for Injury Prevention and Control, Centers for Disease Control and Prevention (CDC), 2011.
10.
Kessler RC, Berglund P, Borges G, Nock M, Wang PS. Trends in suicide ideation, plans, gestures, and attempts in the United States, 1990–1992 to 2001–2003. JAMA. 2005;293(20):2487-2495.
11.
Park-Lee E, Hedden SL, Lipari RN. Suicidal thoughts and behavior in 33 metropolitan statistical areas update: 2013 to 2015. CBHSQ Report. Rockville, MD: US Substance Abuse and Mental Health Services Administration; 2018. https://www.samhsa.gov/data/sites/default/files/report_3452/ShortReport-3452.html; Accessed 22 Jan 2020
12.
Tondo L, Lepri B, Baldessarini RJ. Suicidal risks among 2826 major affective disorder patients. Acta Psychiatr Scand. 2007;116(6):419-428.
13.
Tondo L, Lepri B, Baldessarini RJ. Suicidal status during antidepressant treatment in 789 Sardinian patients with major affective disorder. Acta Psychiatr Scand. 2008;118(2):106-115.
14.
Harris EC, Barraclough B. Excess mortality of mental disorder. Br J Psychiatry. 1998;173(7):11-53.
15.
Baldessarini RJ, Tondo L, Pinna M, Nuñez N, Vázquez GH. Suicidal risk factors in major affective disorders. Br J Psychiatry. 2019;215(7):621-626.
16.
Baldessarini RJ, Tondo L. Suicidal risks in psychiatric disorders. J Affect Disord. 2020;271(4):66-73.
17.
Schaffer A, Isometsä ET, Tondo L, et al. International Society for Bipolar Disorders Task Force on Suicide: meta-analyses and meta-regression of correlates of suicide attempts and suicide deaths in bipolar disorder. Bipolar Disord. 2015;17(1):1-16.
18.
Tondo L, Pompili M, Forte A, Baldessarini RJ. Suicide attempts in bipolar disorders: comprehensive review of 101 reports. Acta Psychiatr Scand. 2016;133(3):174-186.
19.
Geulayov G, Casey D, McDonald KC, et al. Incidence of suicide, hospital-presenting non-fatal self-harm, and community-occurring non-fatal self-harm in adolescents in England (the iceberg model of self-harm): retrospective study. Lancet Psychiatry. 2018;5(2):167-174.
20.
Döme P, Rihmer Z, Gonda X. Suicide risk in bipolar disorder: brief review. Medicina (Kaunas). 2019;55(8):403-410.
21.
Spiller HA, Ackerman JP, Spiller NE, Casavant MJ. Sex- and age-specific increased in suicide attempts by self-poisoning in the United States among youth and young adults from 2000 to 2018. J Pediatrics. 2019;210(7):201-208.
22.
Glenn CR, Kleiman EM, Kelerman J, et al. Annual research review: meta-analytic review of worldwide suicide rates in adolescents. J Child Psychol Psychiatry. 2020;61(3):294-308.
23.
Baldessarini RJ. Chemotherapy in Psychiatry, (3rd edn). New York: Springer Press; 2013.
24.
Baldessarini RJ, Tondo L, Vázquez GH. Treatment of bipolar disorder. Mol Psychiatry. 2019;24(2):196-217.
25.
Jones S, Riste L, Barrowclough C, et al. Reducing relapse and suicide in bipolar disorder: practical clinical approaches to identifying risk, reducing harm and engaging service users in planning and delivery of care. Chapter 5 in the PARADES (Psychoeducation, Anxiety, Relapse, Advance Directive Evaluation and Suicidality) program. Southampton (UK): NIHR Journals Library, 2018; pp 149-181.
26.
Malhi GS, Outhred T, Das P, Morris G, Hamilton A, Mannie Z. Modeling suicide in bipolar disorders. Bipolar Disord. 2018;20(4):334-348.
27.
Tondo L, Baldessarini RJ, Barbuti M, Colombini P, Angst J, Azorin JM. Factors associated with single versus multiple suicide attempts in depressive disorders. J Affect Disord. 2020; in press. 28.
28.
Carroll R, Metcalfe C, Gunnell D. Hospital presenting self-harm and risk of fatal and non-fatal repetition: systematic review and meta-analysis. PLoS One. 2014;9(2):e89944-e89953.
29.
Dong M, Lu L, Zhang L, et al. Prevalence of suicide attempts in bipolar disorder: systematic review and meta-analysis of observational studies. Epidemiol Psychiatr Sci. 2019;29(10):e63.
30.
Tondo L, Baldessarini RJ. Suicide in bipolar disorder. Chapt 37 in Yildiz A, Nemeroff C, Ruiz P (editors). The Bipolar Book: History, Neurobiology, and Treatment. New York: Oxford University Press, 2015, pp 509-528.
31.
Forte A, Baldessarini RJ, Tondo L, Vázquez GH, Pompili M, Girardi P. Long-term morbidity in bipolar-I, bipolar-II, and unipolar major depressive disorders. J Affect Disord. 2015;178(6):71-78.
32.
Pallaskorpi S, Suominen K, Rosenström T, et al. Predominant polarity in bipolar I and II disorders: five-year follow-up study. J Affect Disord. 2019;246(3):806-813.
33.
Tondo L, Vázquez GH, Baldessarini RJ. Suicidal behavior associated with mixed features in major mood disorders. Psychiatr Clin No Am. 2020;43(1):83-93.
34.
Vázquez GH, Lolich M, Cabrera C, et al. Mixed symptoms in mood disorders: systematic review. J Affect Disord. 2018;225(1):756-760.
35.
Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. International Society for Bipolar Disorders (ISBD) task force report on antidepresant use in bipolar disorders. Am J Psychiatry. 2013;170(11):1249-1262.
36.
Blasco-Fontecilla H, Baca-Garcia E, Dervic K, et al. Specific features of suicidal behavior in patients with narcissistic personality disorder. J Clin Psychiatry. 2009;70(11):1583-1587.
37.
Ansell EB, Markowitz JC, Sanislow CA, et al. Personality disorder risk factors for suicide attempts over 10 years of follow-up. Personal Disord. 2015;6(2):161-167.
38.
Coleman D, Lawrence R, Parekh A, et al. Narcissistic personality and suicidal behavior in mood disorders. J Psychiatr Res. 2017;85(2):24-28.
39.
Zimmerman M, Balling C, Chelminski I, Dalrymple K. Patients with borderline personality disorder and bipolar disorder: a descriptive and comparative study. Psychol Med. 2020: [published online ahead of print March 17, 12 pp].
40.
Coric V, Stock EG, Pultz J, Marcus R, Sheehan DV. Sheehan Suicidality Tracking Scale (Sheehan-STS): preliminary results from a multicenter clinical trial in generalized anxiety disorder. Psychiatry (Edgmont). 2009;6(1):26-31.
41.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007;164(7):1035-1043.
42.
Miller JN, Black DW. Bipolar disorder and suicide: review. Curr Psychiatry Rep. 2020;22(2):6.
43.
Tondo L, Baldessarini RJ. Suicide in psychiatric disorders: rates, risk factors and therapeutics. In Vázquez GH, Zarate CA, Jr., Brietzke E (editors). Ketamine in Treatment Resistant Depression: Neurobiology and Applications. New York: Elsevier-Academic Press, 2020, in press.
44.
Baldessarini RJ, Tondo L, Strombom I, et al. Analysis of ecological studies of relationships between antidepressant utilization and suicidal risk. Harv Rev Psychiatry. 2007;15(4):133-145.
45.
Braun C, Bschor T, Franklin J, Baethge C. Suicides and suicide attempts during long-term treatment with antidepressants: meta-analysis of 29 placebo-controlled studies including 6934 patients with major depressive disorder. Psychother Psychosomat. 2016;85(3):171-179.
46.
Hammad TA, Laughren TP, Racoosin JA. Suicide rates in short-term randomized controlled trials of newer antidepressants. J Clin Psychopharmacol. 2006;26(2):203-207.
47.
Barbui C, Esposito E, Cipriani A. Selective serotonin reuptake inhibitors and risk of suicide: systematic review of observational studies. CMAJ. 2009;180(3):291-297.
48.
Tondo L, Baldessarini RJ, Hennen J, Floris G, Silvetti F, Tohen M. Lithium treatment and risk of suicidal behavior in bipolar disorder patients. J Clin Psychiatry. 1998;59(8):405-414.
49.
Angst J, Angst F, Gerber-Werder R, Gamma A. Suicide in 406 mood-disorder patients with and without long-term medication: 40 to 44 years’ follow-up. Arch Suicide Res. 2005;9(3):279-300.
50.
Baldessarini RJ, Tondo L, Davis P, Pompili M, Goodwin FK, Hennen J. Decreased risk of suicides and attempts during long-term lithium treatment: meta-analytic review. Bipolar Disord. 2006;8(5:2):625-639.
51.
Müller-Oerlinghausen B, Ahrens B, Felber W. Suicide-preventive and mortality-reducing effect of lithium. In: Bauer M, Grof P, Müller-Oerlinghausen B, eds. Lithium in Neuropsychiatry. London: Informa Healthcare; 2006:79-192.
52.
Lewitzka U, Bauer M, Felber W, Müller-Oerlinghausen B. Anti-suicidal effect of lithium: current state of research and its clinical implications for the long-term treatment of affective disorders (German). Nervenarzt. 2013;84(3):294-306.
53.
Del Matto L, Muscas M, Murru A, et al. Lithium and suicide prevention in mood disorders and the general population: systematic review. Neurosci Biobehav Rev. 2020;116(6):142-153.
54.
Tondo L, Alda M, Bauer M, et al. Clinical use of lithium salts: guide for users and prescribers. Int J Bipolar Disord. 2019;7(1):16-25.
55.
Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60(1):82-91.
56.
Müller-Oerlinghausen B, Lewitzka U. Lithium reduces pathological aggression and suicidality: mini-review. Neuropsychobiology. 2010;62:43-49.
57.
Manchia M, Hajek T, O'Donovan C, et al. Genetic risk of suicidal behavior in bipolar spectrum disorder: analysis of 737 pedigrees. Bipolar Disord. 2013;15(5):496-506.
58.
Oquendo MA, Galfalvy HC, Currier D, et al. Treatment of suicide attempters with bipolar disorder: randomized clinical trial comparing lithium and valproate in the prevention of suicidal behavior. Am J Psychiatry. 2011;168(10):1050-1056.
59.
Søndergård L, Lopez AG, Andersen PK, Kessing LV. Mood-stabilizing pharmacological treatment in bipolar disorders and risk of suicide. Bipolar Disord. 2013;10(1):87-94.
60.
Thies-Flechtner K, Müller-Oerlinghausen B, Seibert W, Walther A, Greil W. Effect of prophylactic treatment on suicide risk in patients with major affective disorders: data from a randomized prospective trial. Pharmacopsychiatry. 1996;29(3):103-107.
61.
Goodwin FK, Fireman B, Simon GE, Hunkeler EM, Lee J, Revicki D. Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA. 2003;290(11):1467-1473.
62.
Baldessarini RJ, Tondo L. Meta-analytic comparison of antisuicidal effects of lithium versus anticonvulsants. Pharmacopsychiatry. 2009;42(2):72-75.
63.
Gibbons RD, Hur K, Brown CH, Mann JJ. Relationship between antiepileptic drugs and suicide attempts in patients with bipolar disorder. Arch Gen Psychiatry. 2009;66(12):1354-1360.
64.
Smith EG, Søndergård L, Lopez AG, Andersen PK, Kessing LV. Association between consistent purchase of anticonvulsants or lithium and suicide risk: longitudinal cohort study from Denmark, 1995–2001. J Affect Disord. 2009;117(3):162-167.
65.
Yerevanian BI, Choi YM. Impact of psychotropic drugs on suicide and suicidal behaviors. Bipolar Disord. 2013;15(5):594-621.
66.
Fontoulakis KN, Gonda X, Baghai TC, et al. Report of the WPA section of pharmacopsychiatry on the relationship of antiepileptic drugs with suicidality in epilepsy. Int J Psychiatry Clin Pract. 2015;19(3):158-167.
67.
Mula M. Do anti-epileptic drugs increase suicide in epilepsy? 10 years after the FDA alert. Expert Rev Neurother. 2018;18(3):177-178.
68.
Wimberley T, MacCabe JH, Laursen TM, et al. Mortality and self-harm in association with clozapine in treatment-resistant schizophrenia. Am J Psychiatry. 2017;174(10):990-998.
69.
Taipale H, Tanskanen A, Mehtälä J, Vattulainen P, Correll CU, Tiihonen J. 20-year follow-up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20). World Psychiatry. 2020;19(1):61-68.
70.
Vermeulen JM, van Rooijen G, van de Kerkhof MPJ, Sutterland AL, Correll CU, de Haan L. Clozapine and long-term mortality risk in patients with schizophrenia: systematic review and meta-analysis of studies lasting 1.1–12.5 years. Schizophr Bull. 2019;45(2):315-329.
71.
Haukka J, Tiihonen J, Härkänen T, Lönnqvist J. Association between medication and risk of suicide, attempted suicide and death in nationwide cohort of suicidal patients with schizophrenia. Pharmacoepidemiol Drug Saf. 2008;17(7):686-696.
72.
Lindström L, Lindström E, Nilsson M, Höistat M. Maintenance therapy with second generation antipsychotics for bipolar disorder: systematic review and meta-analysis. J Affect Disord. 2017;213(4):138-150.
73.
Seemüller F, Schennach R, Mayr A, et al. Akathisia and suicidal ideation in first-episode schizophrenia. J Clin Psychopharmacol. 2012;32(5):694-698.
74.
Gaertner I, Gilot C, Heidrich P, Gaertner HJ. Case control study on psychopharmacotherapy before suicide committed by 61 psychiatric inpatients. Pharmacopsychiatry. 2002;35(2):37-43.
75.
D'Anci KE, Uhl S, Girardi G, Martin C. Treatments for prevention and management of suicide: systematic review. Ann Int Med. 2019;171(5):334-342.
76.
Gardner DL, Cowdry RW. Alprazolam-induced dyscontrol in borderline personality disorder. Am J Psychiatry. 1985;142(1):98-100.
77.
Molero P, Pamos-Quiroga JA, Martin-Santos R, Calvalo-Sánchez E, Gutiérrez-Rojas L, Meana JJ. Antidepressant efficacy and tolerability of ketamine and esketamine: critical review. CNS Drugs. 2018;32(5):411-420.
78.
Fu D-J, Ionescu DF, Li X, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptom in patients who have active suicidal ideation with intent: double-blind, randomized study. J Clin Psychiatry. 2020;81(3):19m13191-19m13198.
79.
McIntyre RS, Lipsitz O, Rodrigues NB, et al. Effectiveness of ketamine on anxiety, irritability, and agitation: implications for treating mixed features in adults with major depressive or bipolar disorder. Bipolar Disord. 2020. [published online ahead of print, May 12].
80.
Witt K, Potts J, Hubers A, et al. Ketamine for suicidal ideation in adults with psychiatric disorders: systematic review and meta-analysis of treatment trials. Aust N Z J Psychiatry. 2020;54(1):29-45.
81.
Hawton K, Witt KG, Salisbury TLT, et al. Psychosocial interventions following self-harm in adults: systematic review and meta-analysis. Lancet Psychiatry. 2016;3(8):740-750.
82.
Méndez-Bustos P, Calati R, Rubio-Ramírez F, Olié E, Courtet P, Lopez-Castroman J. Effectiveness of psychotherapy on suicidal risk: systematic review of observational studies. Front Psychol. 2019;10(2):277-286.
83.
Meyer EC, Walser R, Hermann B, et al. Acceptance and commitment therapy for co-occurring posttraumatic stress disorder and alcohol use disorders in veterans: pilot treatment outcomes. J Trauma Stress. 2018;31(5):781-789.
84.
Forte A, Buscajoni A, Fiorillo A, Pompili M, Baldessarini RJ. Suicidal risk following hospital discharge: a review. Harv Rev Psychiatry. 2019;27(4):209-216.
85.
Liang CS, Chung CH, Ho PS, Tsai CK, Chien WC. Superior antisuicidal effects of electroconvulsive therapy in unipolar disorder and bipolar depression. Bipolar Disord. 2018;20(6):539-546.
86.
Jørgensen MB, Rozing MP, Kellner CH, Osler M. Electroconvulsive therapy, depression severity and mortality: data from the Danish National Patient Registry. J Psychopharmacol. 2020;34(3):273-279.
87.
McGirr A, Karmani S, Arsappa R, et al. Clinical efficacy and safety of repetitive transcranial magnetic stimulation in acute bipolar depression. World Psychiatry. 2016;15(1):85-86.
88.
Tavares DF, Myczkowski ML, Alberto RL, et al. Treatment of bipolar depression with deep TMS: results from a double-blind, randomized, parallel group, sham-controlled clinical trial. Neuropsychopharmacology. 2017;42(13):2593-2601.
89.
Gold AK, Ornelas AC, Cirillo P, et al. Clinical applications of transcranial magnetic stimulation in bipolar disorder. Brain Behav. 2019;9(10):e01419.
90.
McAllister-Williams RH, Sousa S, Kumar A, et al. Effects of vagus nerve stimulation on the course and outcomes of patients with bipolar disorder in a treatment-resistant depressive episode: 5-year prospective registry. Int J Bipolar Disord. 2020;8(1):13-23.
91.
Gippert SM, Switala C, Bewernick BH, et al. Deep brain stimulation for bipolar disorder-review and outlook. CNS Spectr. 2017;22(3):254-257.
92.
Saunders KEA, Hawton K. Clinical assessment and crisis intervention for the suicidal bipolar disorder patient. Bipolar Disord. 2013;15(5):575-583.
Information & Authors
Information
Published In
History
Published in print: Fall 2023
Published online: 16 October 2023
Keywords
Authors
Metrics & Citations
Metrics
Citations
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
For more information or tips please see 'Downloading to a citation manager' in the Help menu.
View Options
View options
PDF/EPUB
View PDF/EPUBLogin options
Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.
Personal login Institutional Login Open Athens loginNot a subscriber?
PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.
Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).