Lithium therapy for unipolar and bipolar depression among the middle-aged and older adult patient subpopulation

Affective disorders are a major cause of morbidity and disability among middle-aged and older people. Thus, the prophylaxis of both unipolar depression and bipolar disorder in this patient subpopulation is an important task of psychiatrists and other physicians. Although lithium remains an effective prophylactic and treatment agent in younger individuals with bipolar disorder, its prophylactic efficacy and tolerability has not been thoroughly investigated among middle aged and older people with unipolar depression and bipolar disorder. Our study is based on a mirror-image design that compared the clinical course with lithium treatment and the clinical course prior to lithium treatment based on a retrospective chart review. We examined the results obtained with long-term lithium maintenance in a group of 60 middle-aged and older adult patients (age >60 years) with unipolar depression and bipolar disorder. More specifically, we analyzed changes of frequency, severity, and duration of depressive or manic relapses, rate and duration of hospitalizations and suicidal behavior (thoughts or attempts), and various assessments of outcome. A significant reduction was found on all indices during lithium therapy compared to before lithium treatment, attesting to the prophylactic efficacy of long-term lithium in unipolar depression and bipolar disorder. The range of side effects in our sample was similar to that found in other reports in this age group. The probability of relapse and recurrence in patients with bipolar disorder and with unipolar depression can be significantly decreased by lithium prophylaxis. Further investigation is mandated to confirm these findings under double-blind conditions.     

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.     

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.     

The effect of pharmacotherapy on suicide rates in bipolar patients

Suicide is a complex and multicausal human behavior and also a great challenge for psychiatry. We review the evidence available concerning pharmacological prevention of suicide in bipolar disorder patients. Several clinical trials provide evidence that effective acute and long-term treatment of bipolar depression provides a strong protection against suicide, suicide attempts, and probably against other complications of this disorder. Current major mood disorder is the most important risk factor of suicide, and bipolar II patients carry the highest risk. In bipolar patients suicidal behavior is most likely to occur during pure or mixed depressive episodes. Since bipolar disorder is a highly recurrent illness, adequate long-term pharmacotherapy is needed to prevent suicidal behavior.     

Suicidal risk in bipolar I disorder patients and adherence to long-term lithium treatment

Objectives:  Among the well-established treatments for bipolar disorder (BPD), lithium continues to offer an unusually broad spectrum of benefits that may include reduction of suicidal risk.
Methods:  We examined the association of suicidal acts with adherence to long-term lithium maintenance treatment and other potential risk factors in 72 BP I patients followed prospectively for up to 10 years at a Mood Disorders Research Center in Spain.
Results:  The observed rates of suicide were 0.143, and of attempts, 2.01%/year, with a 5.2-fold (95% CI: 1.5–18.6) greater risk among patients consistently rated poorly versus highly adherent to lithium prophylaxis (11.4/2.2 acts/100 person-years). Treatment non-adherence was associated with substance abuse, being unmarried, being male, and having more hypomanic–manic illness and hospitalizations. Suicidal risk was higher with prior attempts, more depression and hospitalization, familial mood disorders, and being single and younger, as well as treatment non-adherence, but with neither sex nor substance abuse. In multivariate analysis, suicidal risk was associated with previous suicidality > poor treatment adherence > more depressive episodes > younger age.
Conclusions:  The findings support growing evidence of lower risk of suicidal acts during closely monitored and highly adherent, long-term treatment with lithium and indicate that treatment adherence is a potentially modifiable factor contributing to antisuicidal benefits.     

Psychopharmacologic strategies for the prevention of suicidal behavior in bipolar patients

Current pharmacological strategies for the prevention of the suicide behavior in bipolar patients are reviewed. Additionally, these studies are discussed in the context of a stress–diathesis model, to explore whether this model explains the empirical fact that some drugs appear to have antisuicidal properties while others do not. A review of the relevant literature suggests that lithium and serotonin enhancing antidepressants reduce suicidal behavior in bipolar patients. A stress–diathesis model explains the differential effect of such medications compared to other antidepressants or mood stabilizers by proposing additional effects of these medications on the diathesis for suicidal behavior. This effect may be mediated by augmentation of serotonergic function, which is linked to suicidal behavior. Serotonergic enhancing drugs therefore can potentially reduce suicidal behavior.     

单、双相抑郁症自杀行为遗传效应的比较研究

目的　探讨单、双相抑郁症患者自杀行为的遗传效应有否差异。方法　对1 1 5例单相抑郁症及1 84例双相抑郁症患者应用家族史法进行研究,用多基因阈值理论进行遗传率的估算。结果　单、双相抑郁症患者自杀危险性均较其一级亲属高;患者一级亲属自杀危险性均较对照组一级亲属高;单相抑郁症患者自杀危险性较双相抑郁症患者高;单相抑郁症患者一级亲属自杀危险性较双相抑郁症患者一级亲属高;单相抑郁症患者自杀行为的加权平均遗传率及标准误较双相抑郁症的高,均有显著性差异。结论　单、双相抑郁症患者自杀行为均有明显的遗传效应;单、双相抑郁症患者自杀行为遗传效应存在差异,更应注意对单相抑郁症患者及一级亲属自杀行为进行监测、预防。     

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.     

When do antidepressants worsen the course of bipolar disorder?

Bipolar disorder may be more prevalent than previously believed. Because a substantial number of patients with bipolar disorder present with an index depressive episode, it is likely that many are misdiagnosed with unipolar major depression. Even if a correct diagnosis is made, depressive symptoms in bipolar disorder are notoriously difficult to treat. Patients are often treated with antidepressants, which, if used improperly, are known to induce mania and provoke rapid cycling. This article explores diagnostic conundrums in bipolar depression and their possible solutions, based on current research evidence. It also elucidates current evidence regarding the risks and benefits associated with antidepressant use and evaluates alternative treatment regimens for the depressed bipolar population, including the use of traditional mood stabilizers such as lithium, novel anticonvulsants such as lamotrigine, and atypical antipsychotics.     

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.     

Pediatric Depression: An Evidence-Based Update on Treatment Interventions

The combination of depression and activation presents clinical and diagnostic challenges. It can occur, in either bipolar disorder or major depressive disorder, as increased agitation as a dimension of depression. What is called agitation can consist of expressions of painful inner tension or as disinhibited goal-directed behavior and thought. In bipolar disorder, elements of depression can be combined with those of mania. In this case, the agitation, in addition to increased motor activity and painful inner tension, must include symptoms of mania that are related to goal-directed behavior or manic cognition. These diagnostic considerations are important, as activated depression potentially carries increased behavioral risk, especially for suicidal behavior, and optimal treatments for depressive episodes differ between bipolar disorder and major depressive disorder.     

Bipolar disorders and suicidal behaviour

Rihmer Z, Kiss K. Bipolar disorders and suicidal behaviour. Bipolar Disord 2002: 4(Suppl. 1): 21–25. © Blackwell Munksgaard, 2002
Major depressive disorder is the leading cause of suicide, particularly in the absence of adequate treatment. The aim of this paper is to analyse the relationship between different forms of major mood disorders and suicidal behaviour. Population-based epidemiological surveys as well as clinical studies on the clinically explorable suicide risk factors in bipolar and unipolar depressive disorders are reviewed. The present literature shows that patients with bipolar disorders are at higher risk of attempted and completed suicide than that of patients with unipolar major depression. Contrasting only bipolar I and bipolar II patients, current findings indicate that the rate of prior suicide attempt is higher in bipolar II patients, and bipolar II disorder is overrepresented in depressed suicide victims. Among patients with different clinical manifestations of major mood disorders (unipolar major depression, bipolar I and bipolar II disorder), bipolar patients in general, and bipolar II subjects in particular carry the highest risk of suicide.     

Bipolar depression and suicidal behavior

Suicide is a frequent and tragic consequence of bipolar depression. The prevention of suicidal behavior (SB) need an assessment of vulnerability traits related related to SB (personal suicide history, impulsive traits...), characteristics of depression (mixed depression, subtype of bipolar disorder...), psychiatric comorbidities and stressors psycho-social. Meanwhile, the characteristics of suicidal behavior (ie: severe or multiple attempts) suggest a diagnosis of bipolar disorder rather than major depressive disorder. In addition to a correct screening of bipolar disorders and assessment of suicidal behavior, the removal of lethal means, networking and treatment of depression reduces the risk of suicidal behavior. Finally, lithium may have a particular interest in subjects at high risk of suicide.     

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.     

Does psychomotor agitation in major depressive episodes indicate bipolarity?

BACKGROUND: Kraepelin's partial interpretation of agitated depression as a mixed state of "manic-depressive insanity" (including the current concept of bipolar disorder) has recently been the focus of much research. This paper tested whether, how, and to what extent both psychomotor symptoms, agitation and retardation in depression are related to bipolarity and anxiety. METHOD: The prospective Zurich Study assessed psychiatric and somatic syndromes in a community sample of young adults (N = 591) (aged 20 at first interview) by six interviews over 20 years (1979-1999). Psychomotor symptoms of agitation and retardation were assessed by professional interviewers from age 22 to 40 (five interviews) on the basis of the observed and reported behaviour within the interview section on depression. Psychiatric diagnoses were strictly operationalised and, in the case of bipolar-II disorder, were broader than proposed by DSM-IV-TR and ICD-10. As indicators of bipolarity, the association with bipolar disorder, a family history of mania/hypomania/cyclothymia, together with hypomanic and cyclothymic temperament as assessed by the general behavior inventory (GBI) [15], and mood lability (an element of cyclothymic temperament) were used. RESULTS: Agitated and retarded depressive states were equally associated with the indicators of bipolarity and with anxiety. Longitudinally, agitation and retardation were significantly associated with each other (OR = 1.8, 95% CI = 1.0-3.2), and this combined group of major depressives showed stronger associations with bipolarity, with both hypomanic/cyclothymic and depressive temperamental traits, and with anxiety. Among agitated, non-retarded depressives, unipolar mood disorder was even twice as common as bipolar mood disorder. CONCLUSION: Combined agitated and retarded major depressive states are more often bipolar than unipolar, but, in general, agitated depression (with or without retardation) is not more frequently bipolar than retarded depression (with or without agitation), and pure agitated depression is even much less frequently bipolar than unipolar. The findings do not support the hypothesis that agitated depressive syndromes are mixed states. LIMITATIONS: The results are limited to a population up to the age of 40; bipolar-I disorders could not be analysed (small N).     

50 years lithium treatment

Answers have been sought to the following questions of current interest: Does lithium have a prophylactic action? The claim that such an action has never been demonstrated was based on wrong assumptions, biased selection of references, and unjustified generalizations. What effect does long-term lithium treatment have on the patients' suicidal behavior? There is a close association between long-term lithium treatment, on the one hand, and lowered mortality and reduced suicidal behavior, on the other; no such association has been demonstrated for other mood stabilizers. What are the effects of lithium when given during pregnancy and lactation? The risk/benefit ratio of lithium is lower than that of the anticonvulsant drugs. Are new drugs about to oust lithium? Among contending drugs the anticonvulsants carbamazepine and valproate have attracted particular interest, but the evidence for a prophylactic action in typical bipolar disorder is weak or missing. What are the requirements of the designs of future comparative trials? In order to prove new drugs prophylactically superior to lithium, trial designs must be such that they provide valid information; some proposals are outlined here. Which drug or drugs should be used for prophylactic treatment? In addition to prophylactic superiority over lithium the new drugs must be as good as or better than lithium as regards a number of other properties, including risk/benefit ratio during pregnancy and lactation, and a close association between long-term treatment and lowered suicidal behavior. The most urgent problem at the present time is to compare in a just and balanced manner the prophylactic efficacy and other relevant properties of new drugs with those of lithium. Many manic-depressive patients' health and sometimes life depend on whether at any time they are given the best prophylactic drug available.     

The mood spectrum in unipolar and bipolar disorder: arguments for a unitary approach

OBJECTIVE: This study examined the extent to which individuals with a lifetime diagnosis of recurrent unipolar disorder endorse experiencing manic/hypomanic symptoms over their lifetimes and compared their reports with those of patients with bipolar I disorder. METHOD: The study group included 117 patients with remitted recurrent unipolar depression and 106 with bipolar I. Subjects had their clinical diagnosis confirmed by the Mini International Neuropsychiatric Interview and were administered the Structured Clinical Interview for the Mood Spectrum, which assesses lifetime symptoms, traits, and lifestyles that characterize threshold and subthreshold mood episodes as well as "temperamental" features related to mood dysregulation. RESULTS: The patients with recurrent unipolar depression endorsed experiencing a substantial number of manic/hypomanic symptoms over their lifetimes. In both patients with recurrent unipolar depression and patients with bipolar I disorder, the number of manic/hypomanic items endorsed was related to the number of depressive items endorsed. In the group with recurrent unipolar depression, the number of manic/hypomanic items was related to an increased likelihood of endorsing paranoid and delusional thoughts and suicidal ideation. In the bipolar I group, the number of lifetime manic/hypomanic items was related to suicidal ideation and just one indicator of psychosis. CONCLUSIONS: The presence of a significant number of manic/hypomanic items in patients with recurrent unipolar depression seems to challenge the traditional unipolar-bipolar dichotomy and bridge the gap between these two categories of mood disorders. The authors argue that their mood spectrum approach is useful in making a more accurate diagnostic evaluation in patients with mood disorders.