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.     

Lithium treatment during pregnancy, delivery, and lactation: an update

Because prophylactic lithium treatment is often given to manic depressive women of fertile age, the answers to five questions are pressing: (1) Does lithium administration during pregnancy expose the unborn child to risk of malformations? (2) Does such exposure lead to later developmental anomalies? (3) Do changes in the pharmacokinetics of lithium during pregnancy and delivery require special precautions? (4) Does lithium treatment during pregnancy exert other effects? (5) Is it advisable that women in lithium treatment breastfeed their infants? The author discusses these questions in the light of present-day knowledge and proposes guidelines for lithium treatment during pregnancy, delivery, and lactation.     

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 lithium clinic for bipolar patients: 2-year outcome of the first 148 patients.

OBJECTIVE: This paper describes the outcome for the first 148 patients referred to a lithium clinic. METHOD: Two-year follow-up data from treatment charts are reported for all patients entering a lithium clinic in the study period. RESULTS: Lithium was given as the only mood stabilizer in 132 (89.2%) of the cases. Thirty-two (21.6%) patients were readmitted with a new affective disorder episode. Twenty-nine (19.6%) patients discontinued treatment prematurely. Variables predicting the recurrence of new affective disorder episodes as well as premature discontinuation of treatment were identified. CONCLUSION: The majority of bipolar patients received lithium for prophylaxis against recurrent affective disorder episodes. The outcome was moderate but comparable to the 30-40% improvement usually reported in follow-up studies of bipolar patients given long-term prophylactic treatment with lithium. Better long-term treatment results for bipolar patients depend on both the development of more effective mood stabilizing drugs or drug combinations and the improvement of patients' adherence to treatment.     

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.     

Lithium prophylaxis in recurrent affective disorders

The possibility of a prophylactic action of lithium in recurrent affective illness has been a subject of significant controversy, perhaps because of some valid methodological critiques and also because we are dealing with a relatively new possibility, that of prophylactic chemotherapy.In the history of science, new technologies have had profound impact on theory and research methods. This is especially true in medicine, where new treatments often have far-ranging effects on theoretical concepts, as well as important consequences for the diagnosis and treatment of patients. Within psychiatry, such changes are currently occurring in the treatment of the affective disorders. The therapeutic activity of lithium in this context has been of profound significance in investigating issues of symptomatology, diagnosis, and prognosis of these disorders, as have studies of the pharmacology and modes of action of psychotropic drugs found effective in affective disorders.Now, quite apart from the still-debated issue of the therapeutic efficacy of lithium for an acute manic episode, we must here direct our attention to the even more hotly debated issue of the prophylactic activity of lithium against recurrences of both manic and depressive episodes. If the reports that indicate such prophylactic effects should be fully corroborated, then we will have reached an important ear, one wherein the idealized goal of prevention of episodes of mental illness can, for the first time in psychiatry, realistically be entertained.Before we look at the data on prophylaxis, we should briefly restate the consensus regarding the action of lithium on a current manic or depressive episode. In regard to mania, a conclusion based on the available literature (not unanimous, but accepted) is that lithium is superior to placebo. When compared to other effective antipsychotic agents, the consensus is that in general it might be equivalent to chlorpromazine or haloperidol in regard to outcome, but not in regard to speed of action. With depression, the situation is much less clear. The open studies, even by weight of numbers, imply no clear efficacy. The most recent controlled study, by Mendels et al., ¹ compared lithium and desipramine in a total of 24 patients and found the drugs equipotent. However, a significant critical issue was the absence of a placebo group for comparative purposes.     

Differential efficacy of lithium and carbamazepine in the prophylaxis of bipolar disorder: results of the MAP study

In a randomized clinical trial with an observation period of 2.5 years, the differential efficacy of lithium versus carbamazepine was compared in 171 bipolar patients (DSM-IV). In order to investigate the efficacy of the two drugs in clearly defined subsamples, a series of subgroup analyses was carried out. First, patients with a bipolar I disorder (n = 114) were analyzed separately. In these patients, lithium was superior to carbamazepine. In contrast, carbamazepine was at least equally as efficacious as lithium in the subsample of patients with bipolar II disorder or bipolar disorder not otherwise specified (n = 57). In a second analysis on differential efficacy, the whole sample was subdivided into a classical subgroup (bipolar I patients without mood-incongruent delusions and without comorbidity; n = 67) and a nonclassical subgroup including all other patients (n = 104). Classical bipolar patients had a significantly lower hospitalization rate under lithium than under carbamazepine prophylaxis (26 vs. 62%, p = 0.012). For the nonclassical group, a tendency in favor of carbamazepine was found. In a third step, we analyzed the impact of episode sequence on differential efficacy. In a global view, the episode sequence prior to the index episode was not correlated to differential efficacy. Our results might, however, indicate that patients with an episode sequence of mania-depression-free interval responded better to lithium. Besides differential efficacy, suicidal behavior and patients' satisfaction with treatment were investigated. Regarding suicidal behavior, a trend in favor of lithium was found. The data on patients' satisfaction were significantly in favor of carbamazepine. In conclusion, lithium appears to be superior to carbamazepine in classical bipolar cases and might have additional impact on proneness to suicide. The distinctly larger group of patients with nonclassical features might profit more from carbamazepine which seems to be well accepted by the patients. Hence, treatment alternatives to lithium are desirable for the majority of bipolar patients.     

Lithium and suicide prevention in bipolar disorder

IntroductionBipolar disorder (BD) is a severe and recurrent psychiatric disorder. The severity of prognosis in BD is mainly linked to the high rate of suicide in this population. Indeed, patients with BD commit suicide 20 to 30 times more frequently than the general population, and half of the BD population with an early age of onset have a history of suicide attempt. International therapeutic guidelines recommend lithium (Li) as the first-line treatment in BD for its prophylactic action on depressive or manic episodes. In addition, Li is the only mood stabilizer that has demonstrated efficacy in suicide prevention. This effect of Li is unfortunately often unknown to psychiatrists. Thus, this review aims to highlight evidence about the preventive action of Li on suicide in BD populations.MethodsWe conducted a literature search between April 1968 and August 2014 in PubMed database using the following terms: “lithium” AND “suicide” OR “suicidality” OR “suicide attempt”.ResultsAs confirmed by a recent meta-analysis, many studies show that Li has a significant effect on the reduction of suicide attempts and deaths by suicide in comparison to antidepressants or other mood-stabilisers in BD populations. Studies have demonstrated that long-term treatment with Li reduces suicide attempts by about 10% and deaths by suicide by about 20%. The combination of Li and an antidepressant could reduce suicidal behaviours by reducing suicidal ideation prior to depressive symptoms. It appears crucial for Li efficacy in suicide prevention to maintain the Li blood concentrations in the efficient therapeutic zone and to instate long-term Li treatment. The “impulsive-aggressive” endophenotype is associated with suicide in BD. The specific action of Li on the 5-HT serotoninergic system could explain the specific anti-suicidal effects of Li via the modulation of impulsiveness and aggressiveness. Furthermore, genetic variants of the glycogen synthase kinase 3α/β (GSK3α and β; proteins inhibited by Li) seem to be associated with more impulsiveness in BD populations.ConclusionThe anti-suicidal effect of Li has been very well demonstrated. By its specific action on the serotoninergic system, treatment with Li significantly reduces “impulsive-aggressive” behaviour which is a vulnerability factor common to suicide and BD. Long-term appropriately modulated treatment with Li seems to have considerable impact on the reduction of suicidal behaviours, suicidal ideation and death by suicide in the BD population.     

Prevention of suicidal activity in patients with affective disorders by treatment with lithium]

The authors expressed in 1984 the assumption that lithium is the drug of the phenomenon of suicidal action in affective disorders. In the present paper the authors describe in a group of 56 patients with affective disorders in the course of lithioprophylaxis a marked decline of the suicide rate at the 4% level of significance. Therefore the authors are still in favour of the view that lithium is the drug in suicidal behaviour in affective disorders. This mechanism can be explained by the antiaggressive as well as prophylactic action of lithium. In the authors' opinion it is possible that the mechanism of this action may be conditioned by the interference of lithium with the dysfunction of the central serotonergic system.     

Mortality during initial and during later lithium treatment

We have previously shown that the mortality of patients with recurrent affective disorders in long-term lithium treatment is not higher than that of the general population. In the present study on 471 patients from Denmark and Germany, we examined mortality during the initial year of lithium treatment and during later lithium treatment. During initial lithium treatment, the total mortality was twice as high as in the general population (difference not significant) and the mortality due to suicide 16 times higher. During later lithium treatment, the mortality rates did not differ from those in the general population. Our results indicate that patients with frequent, often severe recurrences, those chosen for prophylactic lithium treatment, are at risk of high mortality, which then diminishes as the prophylactic action of the treatment takes effect.     

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.     

A comparative study of morphine treatment regimen prior to mating and during late pregnancy

Pre-mating treatment of female rats with morphine may have long-term effects. In this study, we analyzed the effects of two types of morphine sulfate pre-treatment: during pre-mating (5.0 mg/kg on alternate days for a total of seven doses) and during pregnancy (3.5 mg/(kgday) for 5 days starting on day 17 of pregnancy during early lactation. In order to evaluate possible morphine-induced behavioral changes, dams were tested for maternal behavior and locomotor activity during early lactation, and striatal and hypothalamic concentrations of dopamine and their metabolites and serum levels of corticosterone were measured. Maternal behavior was disrupted only in animals treated with morphine sulfate during pregnancy and challenged acutely (1.5 mg/kg) during lactation. Pre-mating treatment with morphine sulfate-induced changes in responses with increased locomotor activity, striatal dopamine turnover and serum corticosterone levels. None of these parameters were affected by morphine sulfate pre-treatment during late pregnancy. These data suggest that morphine has specific long-term and sometimes addictive-like effects on actively reproductive female animals that vary with the pre-treatment period, late pregnancy being particularly sensitive for effects on maternal behavior.     

Ketamine for Treatment of Suicidal Ideation and Reduction of Risk for Suicidal Behavior

Ketamine, an NMDA receptor antagonist with efficacy as a rapid anti-depressant, has early evidence for action to reduce suicidal ideation. This review will explore several important questions that arise from these studies. First, how do we measure reductions in suicidal ideation that occur over minutes to hours? Second, are the reductions in suicidal ideation after ketamine treatment solely a result of its rapid anti-depressant effect? Third, is ketamine only effective in reducing suicidal ideation in patients with mood disorders? Fourth, could ketamine’s action lead us to a greater understanding of the neurobiology of suicidal processes? Last, do the reductions in depression and suicidal ideation after ketamine treatment translate into decreased risk for suicidal behavior? Our review concludes that ketamine treatment can be seen as a double-edged sword, clinically to help provide treatment for acutely suicidal patients and experimentally to explore the neurobiological nature of suicidal ideation and suicidal behavior.     

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.     

Pharmacogenetics of bipolar disorder

To review the pharmacogenetics of bipolar disorders, the authors searched databases for genetic association and linkage studies involving response to long-term prophylactic lithium treatment, as well as treatment with antidepressants or clozapine. Significant ethnic variations in the metabolism and efficacy of antidepressants, as well as clozapine, have been reported by several groups. Systematic studies suggest that that genetic factors affect the response to prophylactic lithium treatment. Numerous associations between the three traits of interest and candidate gene polymorphisms have been proposed. Among these, an association between the serotonin transporter gene and response to serotonin reuptake inhibitors appears robust. Considerable interest has also focused on serotonergic gene polymorphisms and response to clozapine. Response to pharmacotherapy in bipolar disorders may be mediated by genetic factors, but the role played by heritability is unknown.     

Psychopharmaka zur Behandlung suizidaler Patienten und zur Suizidprävention

Suicidality represents a frequent phenomenon in affective and psychotic disorders but the treatment of acute and chronic suicidality is still a controversial issue. Especially the efficacy of antidepressant and neuroleptic drugs for prevention of suicide continues to be debated. There is a lack of evidence due to limitations of methodological studies and ethical concerns are a major issue. Considering methodological problems in the conducted studies the often insufficiently valued differentiation between suicidal thoughts and actual suicidal behavior has to be emphasized. With the exception of lithium and clozapine suicide-preventing effects of antidepressants and neuroleptics could not yet be demonstrated. Regarding new antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) even the possible new onset of suicidal thoughts and ideations as an adverse effect needs to be stressed. Considering the frequent occurrence of suicidality the currently available evidence is undoubtedly insufficient. The improvement of study concepts and especially a more differentiated consideration of the vague term “suicidality” seems to be essential. An underrepresentation of the evidence-based therapeutic options with lithium and clozapine in the treatment of suicidal patients needs to be avoided.     

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.