Alternatives to lithium for preventive treatment of bipolar disorder

The authors review the research literature on drug treatment for the prevention of recurrences in bipolar disorder, emphasizing the available alternatives to lithium therapy. They discuss the need for alternative treatments and the current status of promising agents. Carbamazepine receives special attention because of its status as the most promising backup treatment for lithium. The authors conclude that despite the extensive literature on carbamazepine, there is strong need for carefully designed, prospective, double-blind studies to establish the efficacy of carbamazepine alone and in combination with lithium as a prophylactic treatment for bipolar disorder. Difficulties in developing and evaluating preventive maintenance are discussed.     

Alternatives to lithium and divalproex in the maintenance treatment of bipolar disorder

Objectives: The role of lithium carbonate in the maintenance treatment of bipolar disorder is well established. Unfortunately, many patients fail to respond adequately to this agent or are unable to tolerate its adverse effects. Divalproex has become a commonly used alternative to lithium, but it also is ineffective or poorly tolerated in many patients. This article attempts to review the available data on maintenance therapy in bipolar disorder with a variety of anticonvulsants and antipsychotics (both conventional and novel), with reference to relevant studies in acute mania and bipolar depression as well.
Methods: Evidence on maintenance therapy and relevant acute-phase data were collected using MEDLINE database searches.
Results: Data on maintenance therapy with agents other than lithium and divalproex are sparse, and often derived from open, uncontrolled studies. Implications and flaws of available data are discussed.
Conclusions: Other than lithium, there are few robust double-blind data to support the use of a variety of agents in the maintenance phase. However, uncontrolled data suggest that a number of agents merit further study.     

Response to lithium treatment in bipolar disorder as a pharmacogenetic phenotype

Family, twin, and adoption studies have provided consistent evidence supporting the role of genes in the predisposition to bipolar disorder (BD). Lithium has been one of the most commonly prescribed prophylactic treatments for BD and although it is a clearly effective mood stabilizer, its effectiveness tends to vary depending on clinical presentation and side-effect profile. Pharmacogenetic studies can be useful to elucidate genetic factors that may play a role in modulating lithium response. This strategy has provided hope for advancements in understanding the genetics of lithium responsive BD, and eventually, setting up the foundations for a more personalized treatment of BD patients. This article briefly reviews possible molecular mechanisms of lithium action and discusses genetic studies that have focused on lithium response. Although data examining the pharmacogenetics of BD remain scarce, the study of lithium response is an important and promising avenue to better understanding the BD phenotype, as well as genetic mechanisms that may be involved in BD and mood stabilization.     

Risk of recurrence following discontinuation of lithium treatment in bipolar disorder.

Episode recurrence in bipolar disorder following discontinuation of stable maintenance treatment with lithium salts was analyzed from 14 studies involving 257 patients with bipolar I disorder. More than 50% of new episodes of illness occurred within 10 weeks of stopping an average of 30 months of treatment. By survival analysis of 124 cases in which the time to a new episode was known, the computed time to 50% failure of remission was 5.0 months after stopping therapy; the time to 25% recurrence of mania was 5.2 times earlier than for depression (2.7 vs 14 months). In 16 patients with a mean cycle length before treatment of 11.6 months, the time to a new episode when off lithium therapy was only 1.7 months. Risk of early recurrence of bipolar illness, especially of mania, evidently is increased following discontinuation of lithium use and may exceed that predicted by the course of the untreated disorder. The basis and management of risks associated with discontinuing effective long-term mood-stabilizing treatment require further study.     

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.     

Carbamazepine versus lithium in the prophylaxis of bipolar affective disorder.

A 12-month double-blind trial of carbamazepine vs lithium, given as sole treatment for the prophylaxis of bipolar affective disorder, was carried out in 31 patients. All were previously stable on lithium; 15 were switched over to carbamazepine and 16 remained on lithium. Although the overall relapse rate was similar in the 2 groups (6 on carbamazepine, 8 on lithium), nearly all the relapses in carbamazepine occurred in the first month, probably precipitated by lithium withdrawal. Two patients on carbamazepine developed a rash and were withdrawn. More side effects were noted during the early stages on carbamazepine. Patients on lithium tended to gain weight (+4 kg) compared with carbamazepine (-3.1 kg). It is concluded that carbamazepine is as effective as lithium in the prophylaxis of bipolar affective disorder; changeover from lithium to carbamazepine should be done slowly.     

Pharmacogenetics of lithium response in bipolar disorder

Lithium is the first-line treatment for bipolar disorder. In the past, genetic studies have attempted to identify factors associated with positive treatment response or side effects. Several research groups have shown that familial factors, family history of primary bipolar disorder, and negative family history of schizophrenia in particular, correlate well with prophylactic lithium response. Conversely, studies of lithium responsive patients and their families can assist genetic research of bipolar disorder. Lithium responders appear to suffer from a form of bipolar disorder that is more genetically based and more homogeneous. In a series of family studies, the author and his colleagues have confirmed the differences in family histories of lithium responders and nonresponders and shown that the mode of inheritance in lithium responders is compatible with a major-gene model. Subsequently, they initiated an international collaborative study to map the gene(s) predisposing to the illness or treatment response, or both, using both linkage and association strategies. To date, a sample of 32 families, 138 unrelated patients and 163 control subjects has been studied. In these studies, they found support for the role of phospholipase C in lithium responsive bipolar disorder.     

家庭干预辅助碳酸锂治疗康复期双相情感障碍的效果

目的 探讨家庭干预辅助碳酸锂治疗康复期双相情感障碍的效果,为提高治疗效果提供参考。 方法 选取2018年1月-12月在佛山市第三人民医院住院治疗出院后2个月、符合《精神障碍诊断与统计手册（第5版）》（DSM-5）双相情感障碍诊断标准、病情稳定且持续服用碳酸锂治疗的患者68例,采用随机数字表法分为研究组和对照组各34例,两组均接受碳酸锂治疗,研究组采用家庭干预辅助碳酸锂治疗,两组均治疗4个月,其中家庭干预每两周一次。于干预前后采用焦虑自评量表(SAS)和抑郁自评量表(SDS)评定患者的焦虑和抑郁症状,干预后采用世界卫生组织生存质量测定简表（WHOQOL-BREF）评定患者的生活质量。 结果 干预后研究组SAS、SDS总评分低于对照组[（47.21±2.79）分vs.（52.79±2.42）分,（53.32±2.43）分vs.（56.41±3.49）分,t=8.813、4.231,P均<0.01]。研究组WHOQOL-BREF的生理、心理、社会关系领域评分以及总评分均高于对照组,差异有统计学意义[（5.62±0.63）分vs.（4.29±0.35）分,（12.42±4.24）分vs.（5.38±1.34）分,（3.46±0.34）分vs.（1.38±0.53）分,（39.14±11.21）分vs.（29.19±4.42）分,t=4.815~19.260,P均<0.01]。 结论 家庭干预辅助碳酸锂治疗康复期双相情感障碍患者的效果可能优于单用碳酸锂治疗,其生活质量更高。     

Maintenance treatment in bipolar disorder: a reassessment of lithium as the first choice

Objective:  In consideration of the declining use of lithium over the past several decades, this review focuses on three topics to argue for lithium's status as first choice as the maintenance treatment of bipolar disorder.
Methods:  This review (i) describes success rates for patients assigned to lithium and those assigned to placebo in early (1973–1976) and recent (2000–2003) trials, as well as those assigned to alternative mood stabilizers versus placebo; (ii) summarizes the results of studies that compared lithium to alternative mood stabilizers by the degree of weight gain during maintenance therapy; and (iii) reviews evidence that lithium exhibits unique antisuicidal properties.
Results:  Differing success rates in early and more recent maintenance trials strongly suggest a cohort effect in which the lithium responders are relatively unavailable for recent maintenance trials. Moreover, among mood stabilizers studied in randomized trials, lithium appears least likely to cause substantial weight gain, and a considerable literature has developed to suggest that lithium has antisuicidal effects that extend beyond its benefits in relapse prevention.
Conclusion:  The evidence reviewed here strongly supports the consideration of lithium when prophylactic treatment is first begun for a bipolar patient.     

Long-term lithium treatment in bipolar disorder is associated with longer leukocyte telomeres

Telomere shortening is a hallmark of aging and has been associated with oxidative stress, inflammation and chronic somatic, as well as psychiatric disorders, including schizophrenia and depression. Additionally, antidepressants have been found to protect against telomere shortening. However, pharmacological telomere studies are lacking in bipolar disorder (BD). Therefore, the objective of this study was to explore telomere length (TL) in patients with BD in the context of lithium treatment. We determined TL by quantitative real-time PCR using peripheral blood leukocytes. Participants were outpatients diagnosed with BD type 1 or 2 (n=256) and healthy controls (n=139). Retrospective case–control and case–case study designs were applied. Lithium response (LiR) was scored using the Alda-Scale. Lithium-treated BD patients overall, as well as those on lithium monotherapy, had 35% longer telomeres compared with controls (P<0.0005, partial η²=0.13). TL correlated positively with lithium treatment duration of >30 months (P=0.031, R²=0.13) and was negatively associated with increasing number of depressive episodes (P<0.007). BD patients responding well to lithium treatment had longer telomeres than those not responding well. This is the first study to report a positive effect of long-term lithium treatment on TL. Importantly, longer TL was also associated with a better LiR in BD patients. These data suggest that lithium exerts a protective effect against telomere shortening especially when therapeutically efficacious. We hypothesize that induction of telomerase activity may be involved in LiR in BD.     

Biological predictors of lithium response in bipolar disorder

In order to prescribe lithium appropriately to patients with bipolar disorder, predictors of lithium response are helpful. The present paper reviews the biological predictors of lithium response. As a positive predictor of lithium response, the following have been reported: strong loudness dependence of the auditory-evoked N1/P2-response; higher brain lithium concentration; lower inositol monophosphatase (IMPase) mRNA expression; higher serotonin-induced calcium mobilization; increased N-acetyl-aspartate peak and decreased myo-inositol peak; white matter hyperintensity; decreased intracellular pH; higher frequency of phospholipase C gamma-1 (PLCG1)-5 repeat and PLCG1-8 repeat; and C973A polymorphism in the inositol polyphosphate 1-phosphatase gene. In contrast the following have been reported as a predictor of negative lithium response: epileptiform abnormality of electroencephalography; human leukocyte antigen type A3; decreased phosphocreatine peak area after photic stimulation; and homozygotes for the short variant of the serotonin transporter gene. Most of the possible biological predictors of better lithium response, such as lower IMPase mRNA levels, white matter hyperintensity, lower brain intracellular pH, enhanced calcium response, and PLCG1-5 repeat had been detected as risk factors for bipolar disorder, suggesting that bipolar disorder responding well to maintenance lithium treatment is a distinct category having a certain neurobiological basis, although these findings need further replication. The search for biological predictors of lithium response is still in its infancy. Most of the laboratory or neuroimaging techniques used in these studies are not easily performed in clinical settings, so the development of an easy and useful laboratory test is needed.     

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.     

Optimizing lithium treatment in bipolar disorder: a review of the literature and clinical recommendations

While the past decade has witnessed a major proliferation of putative treatments for bipolar disorder, one medication--lithium--has proven its effectiveness through 50 years of clinical experience and scientific scrutiny. Unfortunately, because the generic compound, lithium, lacks the financial support of its newer, patented comparators, it is often neglected by clinicians who are exposed to continuing medical education (CME) and residency training programs that are heavily weighted towards the newer treatments. This article critically examines the medical literature on lithium's efficacy, anti-suicidal properties, and adverse effects. The authors present research-based recommendations for maximizing lithium's benefits and minimizing adverse effects associated with lithium in patients with bipolar disorder.