Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review

Objectives:  To update and extend comparisons of rates of suicides and suicide attempts among patients with major affective disorders with versus without long-term lithium treatment.
Methods:  Broad searching yielded 45 studies providing rates of suicidal acts during lithium treatment, including 34 also providing rates without lithium treatment. We scored study quality, tested between-study variance, and examined suicidal rates on versus off lithium by meta-analytic methods to determine risk ratios (RRs) and 95% confidence intervals (CI).
Results:  In 31 studies suitable for meta-analysis, involving a total of 85,229 person-years of risk-exposure, the overall risk of suicides and attempts was five times less among lithium-treated subjects than among those not treated with lithium (RR = 4.91, 95% CI 3.82–6.31, p < 0.0001). Similar effects were found with other meta-analytic methods, as well as for completed versus attempted suicide, and for bipolar versus major mood disorder patients. Studies with higher quality ratings, including randomized, controlled trials, involved shorter exposures with somewhat lesser lithium superiority. Omitting one very large study or those involving lithium-discontinuation had little effect on the results. The incidence-ratio of attempts-to-suicides increased 2.5 times with lithium-treatment, indicating reduced lethality of suicidal acts. There was no indication of bias toward reporting positive findings, nor were outcomes significantly influenced by publication-year or study size.
Conclusions:  Risks of completed and attempted suicide were consistently lower, by approximately 80%, during treatment of bipolar and other major affective disorder patients with lithium for an average of 18 months. These benefits were sustained in randomized as well as open clinical trials.     

Clinical predictors of suicidal acts after major depression in bipolar disorder: a prospective study

Objective:  This study determined the clinical predictors of suicidal behavior during a 2-year follow-up of patients with bipolar disorder presenting with a major depressive episode (MDE).
Method:  Sixty four patients with DSM-III-R bipolar disorder were assessed at presentation for treatment of an MDE. Correlates of past suicidal behavior were determined by comparing patients with and without a history of suicide attempts using a t -test, Wilcoxon test or chi-squared test of independence on individual explanatory variables. Putative predictors of attempts during the follow-up period were tested separately using Cox proportional hazards regression analysis.
Results:  Twelve of 64 patients had at least one suicide attempt in the follow-up period, five of them attempted in the first 2 months and seven around or shortly after the 1-year follow-up visit. All attempters had a history of past suicide attempts. Most predictors of future suicidal behavior were correlates of past suicidal behavior. Family history of suicide acts and comorbid borderline personality disorder predicted early attempts, while younger age, high hostility scores, number of past attempts, subjective pessimism as reflected in depression and suicidal ideation, and few reported reasons for living predicted suicidal acts during the whole period.
Conclusion:  In this data set of bipolar patients we noted an intriguing picture of two clusters of suicide attempts. Hostility was the strongest risk factor. These findings may have implications in both the identification of at-risk patients and the timing of clinical interventions including aggressive pharmacotherapeutic prophylaxis to prevent relapse or recurrence of depressive symptomatology.     

Adherence to lithium in naturalistic settings: results from a nationwide pharmacoepidemiological study

Objectives:  To estimate adherence to lithium in a nationwide sample of all patients treated with lithium and to characterize adherence according to gender and age.
Methods:  Adherence to lithium was estimated using data obtained by linking Medicinal Product Statistics with the Danish Medical Register on Vital Statistics, identifying all persons who received lithium among the 5.3 million persons living in Denmark during the period 1995 to 2000 inclusive.
Results:  The median time to discontinuation of lithium was 181.0 days [95% confidence interval (CI) 135.7–181.0] and 25% of patients stopped treatment with lithium within 45.2 days. Adherence to lithium was significantly poorer for women (135.7 days; 95% CI 90.5–135.7) than for men (316.7 days; 95% CI 271.4–407.1) and for younger (18–39 years) and older (≥60 years) patients compared to middle-aged patients.
Conclusions:  The results highlight the need for increased focus on long-term adherence to lithium with intensified psychological support, especially among younger and older female patients.     

Treatment adherence with antipsychotic medications in bipolar disorder

OBJECTIVES: Atypical antipsychotic medications are a relatively new, increasingly prominent component of the treatment armamentarium for bipolar disorder. Information on adherence with antipsychotics among individuals with bipolar disorder in general, and atypical antipsychotics in particular, is currently quite limited. Using data from the VA National Psychosis Registry, we examined adherence with antipsychotic medications among patients with bipolar disorder (n = 73,964). METHODS: Antipsychotic medication adherence among veterans with bipolar disorder was evaluated using the medication possession ratio and categorizing patients into three groups: fully adherent, partially adherent and non-adherent. We compared characteristics of bipolar patients who received versus those who did not receive antipsychotic medication, and also identified predictors of poor adherence with antipsychotic medications. RESULTS: Approximately 45% (n = 32,993) of all individuals with bipolar disorder were prescribed antipsychotic medication. Individuals who were prescribed antipsychotic medications were younger and more often had comorbid substance abuse or post-traumatic stress disorder compared to individuals with bipolar disorder who were not prescribed antipsychotic medication. Just over half (51.9%) of individuals appear to be fully adherent with antipsychotic medications, while 48.1% of individuals are either partially adherent or non-adherent with antipsychotic medications. Factors associated with treatment non-adherence were younger age, minority ethnicity, comorbid substance abuse and homelessness. CONCLUSIONS: Treatment non-adherence is a major issue for close to half of individuals with bipolar disorder prescribed antipsychotic medication. Additional studies are needed to better understand treatment adherence within the full range of pharmacologic therapies among individuals with bipolar disorder.     

Current Issues in Danish Psychiatry

The purpose of this prospective study of 133 affective disorder patients consecutively referred to start lithium treatment was to identify predictors of importance for non-adherence. The non-adherent group was defined as the 56 (42.1%) of the patient who disrupted lithium during the two years. The non-adherent patients had more readmissions during the two years than the patients adherent to lithium. Young age and male sex only showed a weak association to non-adherence. Social background variables such as educational level, social class etc., indices for social stability and support, and recent life events did not show any association to non-adherence. Not married individuals were more frequently non-adherent. Inadequate level of information of treatment only showed a weak association to non-adherence. Many earlier admissions to psychiatric hospitals were significantly associated to non-adherence. The diagnostic subgroups, the character of the index episode and free intervals were not of importance, however, concomitant symptoms concerning substance abuse was significantly associated to non-adherence. In the multivariate logistic analysis the individual probability of non-adherence if abuse (alcohol, drugs, cigarettes) and many admissions were calculated to 0.89. In consequence of the results potentially non-adherent patients are either offered intensive control and support or are not offered long-term lithium treatment at all.     

Suicidal ideation and suicide attempts in homeless mentally ill persons

BACKGROUND: Despite reports of high rates of suicidal behavior among mentally ill homeless persons, it remains unknown whether the well-established suicide risks of increased age and comorbid psychiatric and substance abuse disorders ("dual diagnosis") documented in the general population are also markers for increased suicide risk among homeless persons. METHODS: Data from a multi-site outreach program (ACCESS) (N = 7,224) were used to investigate whether rates of serious suicidal ideation and recent suicide attempts varied with the age and substance abuse diagnosis(es) (drug abuse and/or alcohol abuse disorders) among homeless mentally ill clients. RESULTS: The prevalence of 30-day suicidal ideation and suicide attempts (37.5 % and 7.9 %, respectively) was extremely high. Although the risk of serious suicidal ideation and suicide attempts was greater among the younger compared with the older homeless mentally ill clients, risks were not significantly increased by co-morbid alcohol and/or drug abuse. However, a significant interaction between age and co-morbid substance abuse was observed showing that among older clients but not younger clients, those with drug and alcohol abuse were at significantly greater risk of suicidal ideation than those without substance use problems, controlling for confounding factors. CONCLUSION: Efforts to prevent suicide should recognize that among homeless people with mental illness, young-middle-aged (30- to 39-year-old) clients are at greatest risk of suicidal behavior. Among older clients the presence of both drug and alcohol abuse significantly increases suicide risk. These patterns are of special importance because they are quite different from those that are well documented in non-homeless populations.     

Age comparison of treatment adherence with antipsychotic medications among individuals with bipolar disorder

BACKGROUND: Few studies have evaluated medication adherence among older vs younger individuals with bipolar disorder (BPD). We compared adherence with antipsychotic medication among older (age 60 and older) and younger individuals using a large case registry (n = 73,964). METHODS: Adherence was evaluated using the medication possession ratio (MPR) for patients receiving antipsychotic medication. RESULTS: Twenty six thousand five hundred and thirty younger individuals (mean age 46.9) and 6,461 older individuals (mean age 69.2) were prescribed antipsychotic medication. Among older individuals, 61.0% (n = 3,350) were fully adherent, while 19.0% (n = 1,043) were partially adherent and 20.0% (n = 1,098) were non-adherent. Among younger individuals, 49.5% (n = 10,644) were fully adherent, while 21.8% (n = 4,680) were partially adherent, and 28.7% (n = 6,170) were non-adherent. As with younger patients, comorbid substance abuse and homelessness predicted non-adherence among older patients with BPD. CONCLUSION: Older individuals with BPD were more adherent with antipsychotic medications compared to younger individuals. However, a substantial proportion (approximately 39%) of older patients with BPD still have difficulties with adherence.     

Arguments for the specificity of the antisuicidal effect of lithium

Affective disorders are characterized by first a high recurrence risk, second a 30-50 times increased suicide risk and third a 2- to 3 times increased overall mortality. In contrast to a populistic belief no scientific evidence exists that antidepressant treatment, particularly long-term treatment, could reduce the the risk of suicidal acts in depressive patients with a history of suicide attempts. Data, however, coming from international, systematic, retrospective analyses of well-documented long-term courses of illness in reliably diagnosed patients, and from a large national, prospective long-term trial on the prophylactic efficacy of lithium versus carbamazepine and amitriptyline has accumulated in the last 10-15 years strongly supporting a (possibly specific) antisuicidal effect of lithium. The large collaborative IGSLI study (International Group for the Study of Lithium-treated Patients) covering 5,616 patient years clearly showed that adequate long-term lithium treatment significantly reduces and even normalizes the excess mortality of patients with affective disorders. A metaanalysis on 17,000 patients pooled from 28 studies demonstrated that the rate of suicidal acts is 8.6 fold higher in patients without lithium as compared to those with regular lithium treatment. A post-hoc analysis of a large multicenter, controlled long-term trial found no suicidal acts in 146 patients randomized to lithium compared to 9 suicidal acts in 139 patients randomized to carbamazepine. Reanalysis of the data from the IGSLI study supports the concept of the specificity of lithium, i.e., evidence could be provided that lithium also reduces suicidal behavior in patients who do not benefit from the lithium treatment in terms of episode reduction. CONCLUSION: Lithium has to be considered as a first line mood stabilizer in affective disorders, particularly in patients with a history of suicide attempts. Extreme caution is required when lithium is discontinued or a patient is switched to another mood stabilizer, because such a patient might have been protected against suicidal impulses in spite of an incomplete response as to the number and quality of depressive/manic episodes.     

A comparison of the medical lethality of suicide attempts in bipolar and major depressive disorders

Objectives:  Among mood disorders, bipolar disorder (BPD) is often noted to involve the highest rates of suicide attempts and possibly of completion. This study sought to determine whether suicide attempters with BPD exhibit suicide attempts with higher lethality than attempters with major depressive disorder (MDD) and to explore differences in clinical features associated with suicidal acts.
Methods:  Mood disordered suicide attempters were interviewed about Axis I and II diagnoses, lifetime history of suicide attempts, suicidal intent, suicidal ideation, the medical lethality of their most severe suicide attempt, severity of depression, hopelessness, lifetime aggression, and impulsivity.
Results:  The maximum lethality of suicidal acts tended to be higher among BPD attempters compared with those with MDD. However, there were no differences in the number of suicide attempts, intent to die or suicidal ideation. Suicide attempters with BPD reported higher levels of aggression and impulsivity but less hopelessness compared with MDD attempters. These differences could not be explained by Cluster B personality disorder comorbidity. Of note, within the BPD group, but not the MDD group, males reported suicidal acts with higher lethality. Multivariate analyses suggested that risk for more lethal suicide attempts is associated with BPD and male sex and that bipolar males appear to be especially vulnerable to these behaviors.
Conclusions:  Males with BPD make more lethal suicide attempts than females with BPD, an effect not observed among the MDD sample. Our findings suggest that higher rates of suicidal behavior in BPD may be due to a specific effect of BPD on males, leading to more dangerous suicidal behaviors. This effect, together with the larger proportion of males in the BPD group compared with the MDD group may lead to higher rates of reported attempted and completed suicide.     

Non-adherence with long-term prophylaxis: a 6-year naturalistic follow-up study of affectively ill patients

In a retrospective 6-year follow-up, we assessed the reasons for and the frequency and consequences of non-adherence in 76 affectively ill patients receiving lithium prophylaxis in two lithium clinics. Thirty-eight bipolar (50%), 21 unipolar (27.6%) and 17 schizoaffective patients (22.4%) diagnosed according to DSM-III-R, were investigated with a specialized follow-up documentation. Of the patients 53.9% discontinued prophylaxis at some time; 43.2% of the discontinuations occurred during the first 6 months. In contrast to other studies the main reason reported for non-adherence was resistance against long-term treatment. According to the Lithium Attitudes Questionnaire non-adherent patients showed significantly less acceptance of the prophylaxis in general, of the effectiveness of lithium and of the severity of their illness than adherent patients. In a multivariate analysis of various parameters, only the negative attitude to prophylaxis correlated significantly with non-adherence. Significant correlation was found between treatment outcome and duration of initial prophylaxis. During the 6-year follow-up only the adherent patients showed a significant reduction of the number and duration of admissions. Our findings confirmed non-adherence as a major problem in the effectiveness of lithium prophylaxis. The authors recommend prospective investigations of attitudes and the impact of psychoeducation on long-term adherence.     

Identifying and improving non-adherence in bipolar disorders

Objectives:  To review the definition of non-adherence, its clinical and economic impact and identify its role and impact in clinical practice.
Methods:  A selective review of the literature as conducted of articles and literature known to the authors.
Results:  There is a paucity of studies examining specifically treatment non-adherence and its consequences in bipolar disorder. Few studies have systematically examined ways in which treatment adherence can impact treatment and improve outcome.
Conclusion:  Non-adherence is common in the management of bipolar disorder. Clinicians and Researchers alike need to remain alert and be aware of issues related to non-adherence – in particular suicide. Like other course-modifiers non-adherence has to be considered, sought and addressed, and this is perhaps best done by including psychoeducation in routine clinical care.     

What is the optimal serum lithium level in the long-term treatment of bipolar disorder – a review?

Objectives:  There is substantial uncertainty about the most efficacious serum lithium level for the long-term treatment of bipolar disorder (BD). This review focuses on the available evidence taking into consideration the effects of previous lithium history, changes in lithium level and polarity of relapse or recurrence.
Methods:  We conducted a MEDLINE search, using the MeSH Terms 'bipolar disorder' and 'lithium' together with 'randomized controlled trial' or 'controlled clinical trial' covering the time span from 1966 to March 2006. We only included studies reporting on the long-term treatment of mood disorders where patients with BD were examined as a separate group and were assigned to precisely specified target ranges of lithium level.
Results:  The minimum efficacious serum lithium level in the long-term treatment of bipolar disorder was 0.4 mmol/L with optimal response achieved at serum levels between 0.6–0.75 mmol/L. Lithium levels >0.75 mmol/L may not confer additional protection against overall morbidity but may further improve control of inter-episode manic symptoms. Abrupt reduction of serum levels of more than 0.2 mmol/L was associated with increased risk of relapse.
Conclusions:  In the long-term treatment of bipolar disorder clinicians should initially aim for serum lithium levels of 0.6–0.75 mmol/L, while higher levels may benefit patients with predominantly manic symptoms.     

Impulsivity: a link between bipolar disorder and substance abuse

Background:  Substance abuse is present in most patients with bipolar disorder and associated with poor treatment outcome and increased risk of suicide. Increased impulsivity may be a link between bipolar disorder and substance abuse.
Methods:  First, we compared impulsivity as a stable trait (Barratt Impulsiveness Scale, BIS) and as state-dependent behavioral laboratory performance (Immediate Memory–Delayed Memory task, derived from the Continuous Performance Task) in interepisode bipolar and non-bipolar subjects with and without substance abuse. Secondly, we compared impulsivity in interepisode and manic bipolar subjects with and without substance abuse.
Results:  The BIS scores were increased in interepisode bipolar disorder and in subjects with histories of substance abuse, and were increased further in interepisode bipolar subjects with substance abuse. Performance impulsivity was increased in subjects with substance abuse, regardless of whether they had bipolar disorder. Among subjects with bipolar disorder, after correction for age, BIS scores were increased in those with substance abuse. Performance impulsivity was increased in manic compared with interepisode subjects, regardless of substance abuse history, and was increased in interepisode subjects with substance abuse similarly to manic subjects without substance abuse. These differences could not be accounted for by age, gender, or course of illness.
Conclusions:  Trait impulsivity is increased additively in bipolar disorder and substance abuse. Performance impulsivity is increased in interepisode bipolar disorder only if a history of substance abuse is present. This increased predisposition to impulsivity when not manic may contribute to the decrement in treatment outcome and compliance, and increased risk for suicide and aggression, in bipolar disorder with substance abuse.     

Prevalence of and risk factors for suicide-related outcomes in the World Health Organization World Mental Health Surveys Japan

Aim:  Suicide is a major public health concern in Japan but little is known about the prevalence of and risk factors for suicidal ideation, plans, and attempts. The aim of the present study was to clarify the prevalence of and risk factors for important suicide-related outcomes.
Methods:  Important suicide-related outcomes and risk factors were assessed in face-to-face interviews with 2436 adult respondents in seven areas as part of the World Health Organization (WHO) World Mental Health Survey Initiative. Mental disorders were assessed with the WHO Composite International Diagnostic Interview (CIDI).
Results:   The lifetime prevalence estimates of suicidal ideation, plans, and attempts were 10.9%, 2.1%, and 1.9%, respectively. Risk of suicide plans and attempts was highest when suicidal ideation occurred at an early age and within the first year of ideation. In middle-aged individuals, the period after first employment and the presence of mental disorders were risk factors.
Conclusions:  Risk of suicide plans and attempts is highest when suicidal ideation occurred at an earlier age and within the first year of ideation. Mental disorders are as predictive of the suicide-related outcomes examined here, and comorbidity is an important predictor.     

Sex differences in clinical predictors of suicidal acts after major depression: a prospective study

OBJECTIVE: Whether sex differences exist in clinical risk factors associated with suicidal behavior is unknown. The authors postulated that among men with a major depressive episode, aggression, hostility, and history of substance misuse increase risk for future suicidal behavior, while depressive symptoms, childhood history of abuse, fewer reasons for living, and borderline personality disorder do so in depressed women. METHOD: Patients with DSM-III-R major depression or bipolar disorder seeking treatment for a major depressive episode (N=314) were followed for 2 years. Putative predictors were tested with Cox proportional hazards regression analysis. RESULTS: During follow-up, 16.6% of the patients attempted or committed suicide. Family history of suicidal acts, past drug use, cigarette smoking, borderline personality disorder, and early parental separation each more than tripled the risk of future suicidal acts in men. For women, the risk for future suicidal acts was sixfold greater for prior suicide attempters; each past attempt increased future risk threefold. Suicidal ideation, lethality of past attempts, hostility, subjective depressive symptoms, fewer reasons for living, comorbid borderline personality disorder, and cigarette smoking also increased the risk of future suicidal acts for women. CONCLUSIONS: These findings suggest that the importance of risk factors for suicidal acts differs in depressed men and women. This knowledge may improve suicide risk evaluation and guide future research on suicide assessment and prevention.     

Association of comorbid posttraumatic stress disorder and major depression with greater risk for suicidal behavior

OBJECTIVE: Posttraumatic stress disorder (PTSD) increases the risk of suicidal behavior; a major depressive episode also increases the risk for suicidal behavior. The authors' goal was to examine the effect of comorbid PTSD and major depressive episode on suicidal behavior. METHOD: Inpatients with a diagnosis of major depressive episode (N=156) were assessed for PTSD, suicidal behavior, and clinical risk factors for suicidal acts. RESULTS: Patients with comorbid major depressive episode and PTSD were more likely to have attempted suicide, and women with both disorders were more likely to have attempted suicide than men with both disorders. Cluster B personality disorder and PTSD were independently related to history of suicide attempts. CONCLUSIONS: The greater rate of suicide attempts among patients with comorbid PTSD and major depressive episode was not due to differences in substance use, childhood abuse, or cluster B personality disorders.     

Discontinuing lithium maintenance treatment in bipolar disorders: risks and implications

Objective: To review research findings on clinical effects of discontinuing lithium maintenance treatment.
Methods: Data from studies reported since 1970 plus our recent findings were updated.
Results: Discontinuing lithium maintenance treatment led to marked increases of early affective morbidity and suicidal risk. Gradual discontinuation markedly reduced early recurrences of mania or depression, did so more in bipolar II than I disorder patients, and also tended to reduce suicidal risk. Similar effects were found in pregnant and nonpregnant women after lithium discontinuation. Long-term retreatment with lithium following discontinuation was only slightly less effective than in initial trials.
Conclusions: Recurrences increased sharply soon after discontinuing lithium, but were markedly limited and not merely delayed, by slow discontinuation. Similar reactions may follow discontinuation of other drugs, evidently as responses to long-term pharmacodynamic adaptations. Discontinuing treatment is not equivalent to not-treating. Post-discontinuation relapse risk has implications for the design, management, and interpretation of protocols involving discontinuation of long-term treatments that should be considered in both clinical management and research.     

Phenotypic spectra of bipolar disorder in responders to lithium versus lamotrigine

Objective:  We conducted a study of clinical presentation and family history in patients responsive to either of two commonly used mood stabilizers, lithium and lamotrigine.
Methods:  The sample included 164 subjects from 21 families of bipolar probands, 14 responders to lithium and seven to lamotrigine. Diagnostic information on first-degree relatives was obtained in a blind fashion through a combination of direct interviews (SADS-L) and family history assessments (FH-RDC).
Results:  The probands differed with respect to clinical course (episodic in the lithium group, rapid cycling in the lamotrigine group), and comorbidity (panic attacks and substance abuse in the lamotrigine group). The relatives of lithium responders had significantly higher risk of bipolar disorder while relatives of lamotrigine responders had higher prevalence of schizoaffective disorder, major depression and panic attacks.
Conclusions:  These findings suggest that lithium- and lamotrigine-responsive patients differ with respect to course of illness, comorbidity and family history and may represent distinct subtypes of bipolar disorder.     

Suicidality, depression, and substance abuse in adolescence

The authors assessed the occurrence of suicidal ideation, suicide attempts, major depression, and substance abuse in a sample of 424 apparently healthy college students 16-19 years old. Major depression and substance abuse were independent and interactive risk factors for suicidal ideation and for suicide attempts; substance abuse had a particularly deleterious effect on men. A prolonged desire to be dead was a more specific risk factor for a suicide attempt than was a thought of suicide. The authors conclude that suicidal ideation in the presence of major depression and/or substance abuse in older adolescents should call forth greater concern for lethality.     

Prospective prediction of first lifetime suicide attempts in a multi-site study of substance users

Although considerable empirical work has been devoted to identifying risk factors for suicide attempts, most longitudinal research has studied recurrent attempts rather than first lifetime attempts. The present study sought to examine prospective predictors of first lifetime suicide attempts among adults receiving treatment for substance use. Data were drawn from the National Treatment Improvement Evaluation Study, a study of addiction treatment programs. Data were collected at treatment intake, treatment exit, and one year post-treatment. Patients (n = 3518) with no lifetime history of suicide attempts at treatment intake were followed at treatment exit and one year post-treatment, when they reported on the occurrence of suicide attempts since the prior assessment. Prospective suicidal behavior was assessed using logistic regression in relation to sociodemographic variables, health-related work impairment, history of psychiatric treatment utilization, history of suicidal ideation, history of depressive symptoms, substance use, and childhood abuse, assessed at intake. Health-related work impairment, history of suicidal ideation, and childhood physical abuse significantly predicted first lifetime attempts in a multivariate analysis. Suicidal ideation, health-related functional impairments, and childhood physical abuse may be particularly important in assessing risk for first lifetime suicide attempts. Findings suggest that future clinical work and research would benefit from considering these factors when identifying individuals at heightened risk of making a first suicide attempt.