Antisuicide properties of psychotropic drugs: a critical review

The authors consider the extent to which psychotropic medications demonstrate benefits in the prevention of suicidal behavior in psychiatric patients. Results of a MedLine search are critically reviewed for lithium, divalproex and other anticonvulsants, conventional and atypical antipsychotics, and antidepressants. The existing literature is almost entirely limited to noncontrolled, often retrospective studies that do not control for potential biases in treatment selection, the use of multiple medications, the impact of medication nonadherence, and nonrandomized treatment discontinuations. Nevertheless, an extensive literature has arisen regarding observed reductions in suicidal behavior with lithium for mood disorders and, to a lesser extent, with clozapine for schizophrenia. A substantially smaller literature suggests more negative than positive data with divalproex or carbamazepine in bipolar disorder, while minimal information exists regarding suicidality with atypical antipsychotics other than clozapine. Studies of antidepressants have mostly been short-term and have focused more on whether they induce (rather than ameliorate) suicidal thoughts or behaviors. The sum of existing studies is generally inconclusive about whether antidepressants appreciably reduce risk for suicide completions. Relatively little is known about pharmacotherapy effects on suicidal ideation as distinct from behaviors. Possible mechanistic considerations for understanding antisuicide properties include a therapeutic impact on depression, impulsivity, or aggression, potentially mediated through serotonergic or other neuromodulatory systems. Recommendations are provided to guide future research as well as clinical practice.     

Antidepressants and suicidal behavior in bipolar disorder

Patients with bipolar disorder are at very high risk for suicidal ideation, non-fatal suicidal behaviors and suicide and are frequently treated with antidepressants. However, no prospective, randomized, controlled study specifically evaluating an antidepressant on suicidality in bipolar disorder has yet been completed. Indeed, antidepressants have not yet been shown to reduce suicide attempts or suicide in depressive disorders and may increase suicidal behavior in pediatric, and possibly adult, major depressive disorder. Available data on the effects of antidepressants on suicidality in bipolar disorder are mixed. Considerable research indicates that mixed states are associated with suicidality and that antidepressants, especially when administered as monotherapy, are associated with both suicidality and manic conversion. In contrast, growing research suggests that antidepressants administered in combination with mood stabilizers may reduce depressive symptoms in patients with bipolar depression. Further, the only prospective, long-term study evaluating antidepressant treatment and mortality in bipolar disorder, although open-label, found antidepressants and/or antipsychotics in combination with lithium, but not lithium alone, reduced suicide in bipolar and unipolar patients (Angst F, et al. J Affect Disord 2002: 68: 167–181). We conclude that antidepressants may induce suicidality in a subset of persons with depressive (and probably anxious) presentations; that this induction may represent a form of manic conversion, and hence a bipolar phenotype, and that lithium's therapeutic properties may include the ability to prevent antidepressant-induced suicidality.     

Risk of suicide in mood disorders

Suicide is commonly associated with mood disorders. Risk factors for suicide in mood disorders can be organized according to whether their effect is on the threshold or diathesis for suicidal acts or whether they serve mainly as triggers or precipitants of suicidal acts. Predisposition to suicidal behavior or diathesis is a key element that helps to differentiate patients who are at high risk versus those at lower risk. The objective severity of mood disorders does not identify depressed patients at high risk for suicide attempt. There is a lack of agreement over the suicide risk associated with characteristics of depression such as psychotic features, agitation, or anxiety, or mixed mood states as part of bipolar disorder. Risk factors affecting the diathesis for suicidal behavior include family history of suicide, low cerebrospinal fluid 5-hydroxyindolacetic acid, alcohol and/or substance abuse, cluster B personality disorder, high past impulsivity and aggression, chronic physical illness particularly involving the brain, marital isolation, parental loss before age 11, childhood history of physical and sexual abuse, hopelessness, and not living with a child under age 18. Most common precipitants of suicidal acts in mood disorders include interpersonal losses or conflicts, financial trouble, and job problems. Identification of high risk patients and effective treatment are required for suicide prevention to reduce morbidity and mortality in affective disorders.     

Neutrophil-to-lymphocyte ratio predicting suicide risk in euthymic patients with bipolar disorder: Moderatory effect of family history

BackgroundNeutrophil-to-lymphocyte ratio (NLR) has been independently related to bipolar disorder (BD) and factors associated with suicidal risk. The aim of our study was to explore the relationship between NLR and suicide risk in euthymic BD patients. We also sought to propose a model of interaction between NLR and stress–diathesis factors, leading to suicidal risk in BD.MethodsThe study group consisted of 83 patients diagnosed with BD (36 suicide attempters; 47 suicide non-attempters), compared to the healthy control group (n = 73) and matched according to age, gender, and body mass index (BMI). NLR was measured according to the complete blood count. Mood symptoms have been assessed by Young Mania Rating Scale and Montgomery–Asberg Depression Rating Scale. Early trauma and acute stress were evaluated by Early Trauma Inventory Self Report–Short Form and List of Threatening Experiences Questionnaire, respectively. Suicide risk has been assessed by Suicide Behaviors Questionnaire-Revised (SBQ-R).ResultsSignificant correlation was found between NLR and SBQ-R score. The main effects of suicide attempts on NLR, after covarying for confounders, were observed, indicating increased NLR in BD suicide attempters compared to healthy controls. We found significant moderatory effects of family history on NLR relationship to suicidal risk, with NLR being significant positive predictor of suicidal risk only in the patients with positive family history of suicide attempts.ConclusionsThe results suggest an enhancing effect of positive family history of suicide attempts on predictive effect of NLR on suicide risk. Our data support the idea that immune markers can predict suicide attempt risk in BD, but only in the subpopulation of BD patients with family history of suicide attempts. This could lead to prevention in suicide behavior in the patient population at particular risk of suicide.     

Illness characteristics and their association with prescription patterns for bipolar I disorder

Introduction: The present study explores the relationships among psychotropic medications, illness-related parameters, patient demography, suicidality, and levels of functioning in a voluntary bipolar case registry. Methods: Four hundred and fifty-seven subjects with bipolar I disorder were selected from a voluntary registry for subjects with bipolar illness. Demographic characteristics, psychotropic medications, age at onset of illness, duration of illness, number of hospitalizations, the ability to live independently, employment and driving status as well as the history of suicidal attempts were obtained through a structured phone interview. Results: Subjects treated with antidepressants had a shorter duration of illness, while patients treated with antipsychotic drugs had an earlier onset of illness. The number of hospitalizations for mania was fewer among patients taking a combination of lithium and carbamazepine as compared to patients not receiving them, while subjects taking neuroleptics had more hospitalizations as compared to subjects not receiving them. The number of psychotropic agents prescribed correlated positively with the number of hospitalizations for depressive episodes. Curiously, no correlations were found between the types of psychotropic agents prescribed and the levels of functioning or a history of suicidal attempts. Interestingly, our results suggest that more than half of the subjects were unable to live independently or to work due to their illness. Also, more than 50% of the subjects had at least one suicidal attempt, the majority occurred during depressive episodes. Conclusions: Our results suggest that subjects with bipolar I disorder have high rate of suicidal attempts and may have serious functional impairments.     

Social phobia is associated with suicide attempt history in bipolar inpatients

OBJECTIVES: In an attempt to reduce the phenotypical heterogeneity in an ongoing genetic study of suicidal behavior, we investigated the impact of comorbid anxiety disorders on suicidal behavior in bipolar disorder (BD) patients. METHODS: Anxiety disorders were compared in 406 BD I and BD II patients with or without lifetime history of suicide attempt. RESULTS: Among anxiety disorders, only social phobia (SP) was significantly associated with history of suicide attempt in BD [p<0.001, odds ratio 4.26 (2.284-7.946)]. Moreover, onset of SP was found to precede onset of BD. CONCLUSIONS: This result suggests that SP is an important risk factor for suicidal behavior in BD. Further studies are required to determine whether comorbid SP may help to identify a more homogeneous BD sub-group, especially when studies of suicidal behavior are conducted. A second question is whether SP identifies a sub-group of subjects with BD who have a more severe illness course and whether treatment of SP with selective serotonin reuptake inhibitor (SSRI) antidepressants is associated with improvement or worsening of the course of BD.     

Suicidal Behavior in Mood Disorders: Response to Pharmacological Treatment

Suicidal behavior is strongly associated with depression, especially if accompanied by behavioral activation, dysphoria, or agitation. It may respond to some treatments, but the design of scientifically sound, ethical trials to test for therapeutic effects on suicidal behavior is highly challenging. In bipolar disorder, and possibly also unipolar major depression, an underprescribed medical intervention with substantial evidence of preventive effects on suicidal behavior is long-term treatment with lithium. It is unclear whether this effect is specifically antisuicidal or reflects beneficial effects of lithium on depression, mood instability, and perhaps aggression and impulsivity. Antisuicidal effects of anticonvulsant mood stabilizers (carbamazepine, lamotrigine, valproate) appear to be less than with lithium. Further evaluation is needed for potential antisuicidal effects of atypical antipsychotics with growing evidence of efficacy in depression, particularly acute bipolar depression, while generally lacking risk of inducing agitation, mania, or mood instability. Short-term and long-term value and safety of antidepressants are relatively secure for unipolar depression but uncertain and poorly tested for bipolar depression; their effects on suicidal risk in unipolar depression may be age-dependent. Sedative anxiolytics are virtually unstudied as regards suicidal risks. Adequate management of suicidal risks in mood disorder patients requires comprehensive, clinically skillful monitoring and timely interventions.     

Prospective study of clinical predictors of suicidal acts after a major depressive episode in patients with major depressive disorder or bipolar disorder

OBJECTIVE: The authors investigated the predictive potential of a stress-diathesis model for suicidal behavior based on correlates of past suicidal acts. In this model, suicidal acts are precipitated by stressors such as life events or a major depressive episode in the setting of a propensity for acting on suicidal urges. This diathesis is expressed as the tendency to develop more pessimism in response to a stressor and/or the presence of aggressive/impulsive traits. The predictive potential of the diathesis was tested by determining whether clinical correlates of past suicidal behavior predict suicidal acts during a 2-year follow-up of patients with a major depressive episode. METHOD: Patients with DSM-III-R major depressive disorder or bipolar disorder (N=308) were assessed at presentation for treatment of a major depressive episode. Potential predictors of suicidal acts in the 2 years after study enrollment were identified on the basis of an association with previous suicidal behavior and were tested by using Cox proportional hazards regression analysis. In addition, pessimism and aggression/impulsivity factors were generated, and their predictive ability was tested by using Cox proportional hazards regression analysis. RESULTS: The three most powerful predictors of future suicidal acts were a history of suicide attempt, subjective rating of the severity of depression, and cigarette smoking, each of which had an additive effect on future risk. The pessimism and aggression/impulsivity factors both predicted suicidal acts, and each factor showed an additive effect. CONCLUSIONS: In addition to obtaining a history of suicidal behavior, clinicians may find it useful to assess patients' current level of pessimism, aggressive/impulsive traits, and comorbidity with substance use disorders, including nicotine-related disorders, to help identify patients at risk for suicidal behavior after major depression. Interventions such as aggressive pharmacotherapeutic prophylaxis to prevent relapse or recurrence of depressive symptoms may protect such at-risk individuals from future suicidal behavior.     

Family Environment and Suicidal Ideation Among Bipolar Youth

The objective of this study was to examine the association between family environment and suicidal ideation among youth with bipolar disorder. Subjects included 446 bipolar (BP) youth (age 7–17) enrolled in the Course and Outcome of Bipolar Youth study. Current suicidal ideation, family functioning and family stress were assessed at intake. BP youth with current suicidal ideation reported more conflict with their mother and less family adaptability. Ideators endorsed more stressful family events over the prior year and higher rates of specific familial stressors. Clinicians treating bipolar youth should consider family stress when conducting suicide risk assessment. Treatment goals may include enhancing family communication and addressing issues of loss.     

The long-term course of rapid-cycling bipolar disorder

BACKGROUND: Rapid cycling among patients with bipolar affective disorders is important because of its implications for long-term prognosis and for the use of antidepressants. To our knowledge, no prospective study has, as yet, described the course of this phenomenon beyond 5 years. METHODS: From 345 patients with bipolar I or bipolar II disorder followed up for a mean (SD) of 13.7 (6.1) years as part of the National Institute of Mental Health Collaborative Depression Study, 89 (25.8%) were identified who, during 1 or more years of follow-up, manifested a pattern that met DSM-IV criteria for rapid cycling. These patients were compared with the remaining bipolar patients by demographics, overall affective morbidity, morbidity during specific treatment conditions, and the likelihood of suicidal behavior. Analyses assessed whether the use of tricyclic antidepressants for depressive symptoms was associated with the persistence of rapid cycling or with tendencies to switch from depressive to manic or hypomanic phases. RESULTS: The 89 patients who showed a rapid cycling pattern were significantly more likely to have had an illness onset before 17 years of age and were more likely to make serious suicide attempts. In 4 of 5 cases, rapid cycling ended within 2 years of its onset. Resolutions were not associated with decreases in tricyclic antidepressant use. Throughout follow-up, patients prone to rapid cycling experienced more depressive morbidity than other bipolar patients, particularly when lithium carbonate was being used without tricyclic antidepressants. The use of these antidepressants was not more likely in the weeks preceding shifts from depression to mania or hypomania. CONCLUSIONS: These results indicate that bipolar patients who develop a rapid cycling pattern suffer substantial depressive morbidity and are at high risk for serious suicide attempts. These findings do not implicate tricyclic antidepressants or, by inference, serotonin reuptake inhibitors in the promotion of affective instability.     

Antidepressants--do they decrease or increase suicidality?

Based on an intensive review of the literature, the question was analyzed as to whether antidepressants have an influence on suicidality and whether there are specific differences between certain subgroups of antidepressants. In general, antidepressants reduce suicidal ideations in depressive patients. A faster onset of this kind of action in serotonin-reuptake inhibitors is not yet completely proved. The hypothesis, described by clinicians, of a specific suicidality-increasing risk being associated with a certain group of antidepressants (e.g., antidepressants with a drive-enhancing, non-sedating clinical profile, drugs with a certain biochemical mode of action) has hitherto not been confirmed in control-group studies. An unspecific induction of suicidality, observable also under other psychoactive drugs, appears to be quite rare and occurs only under predisposing conditions, such as personality disorders and comedication with other drugs.     

Perspectives on lithium treatment of bipolar disorder: action, efficacy, effect on suicidal behavior

Objective: To review studies of (A) whether lithium has a prophylactic action in bipolar disorder, (B) the efficacy of prophylactic lithium treatment in comparison with the efficacy of treatment with anticonvulsant drugs, and (C) the effect of lithium treatment on suicidal behavior.
Methods: Analysis of all relevant publications.
Results: (A) The claim that a prophylactic action of lithium has never been satisfactorily demonstrated is based on wrong assumptions, biased selection of references, and unjustified generalizations. (B) In typical bipolar disorder lithium is significantly more efficacious than carbamazepine; in atypical bipolar disorder there is a non-significant trend for carbamazepine to be better than lithium. Valproate has not been proven prophylactically efficacious in typical bipolar disorder; in atypical bipolar disorder it may have an effect, but it has not been compared with that of lithium. (C) A significant association has been found between prophylactic lithium treatment, on the one hand, and reduced mortality and suicidal behavior, on the other. No such association has been reported for prophylactic treatment with other mood stabilizers.
Conclusion: In bipolar disorder the choice of prophylactic drug must be based on a weighing of efficacy against tolerability, interactions, ease of management, use during pregnancy and lactation, and expense. Lithium should be the preferred prophylactic drug in patients with typical bipolar disorder and in patients who are at high risk of committing suicide, that is, patients with severe depressions or depressions combined with persistent suicidal ideas or with suicide attempts in the past.     

Bipolar depression in a low-income primary care clinic

OBJECTIVE: This study estimated the proportion of patients attending an urban general medical practice with current major depression and a history of bipolar disorder and compared the history, presentation, and treatment of patients with unipolar and bipolar depression. METHOD: A group of 1,143 patients was assessed with measures of past and current mental health and treatment. Patients were partitioned into bipolar and unipolar groups based on a predefined cutoff on the Mood Disorder Questionnaire. The groups were compared on sociodemographic characteristics, depressive symptoms, comorbid mental disorders, and mental health treatment. RESULTS: Approximately one-quarter of the patients with major depression had lifetime bipolar depression. Patients with unipolar and bipolar depression did not significantly differ on background or health characteristics. Patients with bipolar depression were significantly more likely to report hallucinations, current suicidal ideation, and low self-esteem than patients with unipolar depression but less likely to report disturbed appetite. Patients with bipolar depression were significantly more likely to have an alcohol use disorder and to report inpatient psychiatric care and antipsychotic treatment during the past month than patients with unipolar depression. Nearly one-half of the patients with bipolar depression had taken an antidepressant in the last month, but most were not also being treated with an antipsychotic or mood stabilizer. CONCLUSIONS: Bipolar depression is common in urban general medicine practice. When patients took antidepressants, they seldom received concurrent antimanic medications. Because of the risks of treating bipolar disorder with antidepressant monotherapy, physicians should assess their depressed patients for mania before prescribing antidepressants.     

Atypical antipsychotics and suicide in mood and anxiety disorders

Abstract:  Globally, a million people commit suicide every year, and 10–20 million attempt it. Mood disorders, especially major depressive disorder (MDD) and bipolar disorder, are the most common psychiatric conditions associated with suicide. Primary (psychiatric and physical illness), secondary (psychosocial), and tertiary (demographic) risk factors for suicide have been identified. Comorbid psychiatric illness, particularly anxiety symptoms or disorders, significantly increase the risk of suicidal behavior. Current standard risk assessments and precautions may be of limited value, while assessing the severity of anxiety and agitation may be more effective in identifying patients at risk. Lithium is the medication that has most consistently demonstrated an antisuicidal effect. The effects of antidepressants and conventional antipsychotics on suicide risk are uncertain, but atypical antipsychotics appear promising. Atypical antipsychotics have beneficial effects on depressed mood both in patients with MDD and in patients with bipolar disorder. In addition, data in patients with schizophrenia have demonstrated a significant improvement in the incidence of suicidal behavior with clozapine compared with olanzapine. Electroconvulsive therapy appears to have an acute benefit on suicidality.     

Suicidal attempts in bipolar disorder: results from an observational study (EMBLEM)

Bellivier F, Yon L, Luquiens A, Azorin J‐M, Bertsch J, Gerard S, Reed C, Lukasiewicz M. Suicidal attempts in bipolar disorder: results from an observational study (EMBLEM).
Bipolar Disord 2011: 13: 377–386. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objectives: To compare patients with and without a history of suicidal attempts in a large cohort of patients with bipolar disorder and to identify variables that are associated with suicidal behavior. Methods: European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) is a two‐year, prospective, observational study that enrolled 3,684 adult patients with bipolar disorder and initiated or changed oral treatment for an acute manic/mixed episode. Of those, 2,416 patients were eligible for the two‐year follow‐up. Only baseline characteristics were studied in the present study, included sociodemographic data, psychiatric history and comorbidities, history of suicide attempts, history of substance use problems, compliance with treatment, inpatient admissions, and functional status. Symptom severity was assessed using the Clinical Global Impression–Bipolar Disorder (CGI‐BP) scale, the Young Mania Rating Scale (YMRS), and the 5‐item Hamilton Depression Rating Scale (HAMD‐5). A logistic regression model identified baseline variables independently associated with a history of suicidal behavior. Results: Of the 2,219 patients who provided data on their lifetime history of suicide attempts, 663 (29.9%) had a history of suicidal behavior (at least one attempt). Baseline factors associated with a history of suicidal behavior included female gender, a history of alcohol abuse, a history of substance abuse, young age at first treatment for a mood episode, longer disease duration, greater depressive symptom severity (HAMD‐5 total score), current benzodiazepine use, higher overall symptom severity (CGI‐BP: mania and overall score), and poor compliance. Conclusions: These factors may be considered as potential characteristics to identify subjects at risk for suicidal behavior throughout the course of bipolar disorder.     

Patterns of concomitant psychotropic medication use during a 2-year study comparing clozapine and olanzapine for the prevention of suicidal behavior

BACKGROUND: Results from the International Suicide Prevention Trial (InterSePT) indicate that clozapine is more effective than olanzapine in reducing suicidal behavior in schizophrenic and schizoaffective patients. However, because InterSePT allowed the uncontrolled use of concomitant psychotropic medications (CPMs), it is possible that the antisuicidal effect of clozapine may have been influenced by greater use of such agents. This article describes the use patterns of CPMs during InterSePT and examines whether CPM use may have affected study outcome. METHOD: In this study, 479 patients received clozapine and 477 patients received olanzapine. Concomitant psychotropic medications were grouped into 4 classes: antipsychotics, antidepressants, sedatives/anxiolytics, and mood stabilizers. The doses of each CPM were converted into dosage equivalents of standard reference drugs. An analysis of covariance was performed to compare mean daily doses of CPMs between the 2 groups over the 2-year treatment period. The duration of treatment for each patient was 2 years, with the first patient entering the study in March 1998 and the last patient completing treatment in February 2001. RESULTS: Approximately 90% of patients in both treatment groups received at least 1 CPM. The mean +/- SD number of CPMs per patient was 3.8 +/- 2.90 in the clozapine group and 4.2 +/- 3.16 in the olanzapine group. For each CPM class, the mean daily dose was statistically significantly lower in the clozapine group (antipsychotics, p <.001; antidepressants, p <.01; sedatives/anxiolytics, p <.001; mood stabilizers, p <.05). Analyses of CPM use by study intervals, suicide attempters versus nonattempters, study completers versus noncompleters, and geographic region resulted in similar findings. CONCLUSION: The results support the conclusion that the effects of clozapine in reducing the risk of suicidal behavior derive from its intrinsic pharmacology and not from the influence of concomitant psychotropic medications.     

Hopelessness and suicidal risk in bipolar disorder. A study in clinically nonsyndromal patients

Objective

Attempted suicide and death due to suicide are not uncommon among patients with bipolar disorder. Although some risk factors for suicidality in bipolar patients have been identified, little is known about hopelessness and other possible trait or diathesis-related factors. Consequently, the objective of this study was to investigate variables associated with suicidal risk in clinically nonsyndromal bipolar patients.

Methods

A sample of 102 outpatients with a diagnosis of bipolar disorder according to International Classification of Diseases, 10th Revision criteria during nonsyndromal stage were evaluated. On the basis of suicidal history, patients were divided into suicide attempt, suicidal ideation, and nonsuicidal groups. Sociodemographic, clinical, and psychopathological variables were assessed.

Results

As compared with the nonsuicidal group, female sex, combined psychopharmacologic treatment, and hopelessness were independently associated with suicide attempt. Hopelessness and insight into having a mental disorder were independently associated with history of suicidal ideation.

Conclusions

Patients with bipolar disorder and suicidal history are characterized by the presence of hopelessness, which probably confers greater vulnerability for suicidal behavior in the presence of stress factors. This identification of the risk profile for suicidal behavior in nonsyndromal bipolar patients adds complementary information to risk factors established for suicidality during acute phases of the disease, allows for differentiated preventive and treatment approaches of patients at risk, and suggests psychotherapy as an advisable intervention in this group of patients.