Lithium Prophylaxis Research Articles

Long-Term Lithium Therapy: Side Effects and Interactions

Lithium remains the drug of first choice for prophylactic treatment of bipolar disorder, preventing the recurrences of manic and depressive episodes. The longitudinal experiences with lithium administration greatly exceed those with other mood stabilizers. Among the adverse side effects of lithium, renal, gastrointestinal, neurological, thyroid, metabolic, cognitive, dermatological, cardiologic, and sexual are listed. Probably, the most important negative effect of lithium, occurring mostly after 10-20 years of its administration, is interstitial nephropathy. Beneficial side-effects of long-term lithium therapy also occur such as anti-suicidal, antiviral, and anti-dementia ones. Pharmacokinetic and pharmacodynamic interactions of lithium, mostly those with other drugs, may have an impact on the success of long-term lithium treatment. This paper makes the narrative updated review of lithium-induced side-effects and interactions that may influence its prophylactic effect in bipolar disorder. Their description, mechanisms, and management strategies are provided. The papers appearing in recent years focused mainly on the long-term lithium treatment are reviewed in detail, including recent research performed at Department of Psychiatry, Poznan University of Medical Sciences, Poland. Their own observations on ultra-long lithium treatment of patients with bipolar disorder are also presented. The review can help psychiatrists to perform a successful lithium prophylaxis in bipolar patients.

Studies on candidate genes for lithium prophylaxis performed at the Poznan University of Medical Sciences

Lithium is a drug of choice as a mood-stabilizer for the maintenance treatment of bipolar disorder. The prophylactic efficacy of lithium can be determined by genetic factors, partially related to a predisposition to bipolar disorder. In the field of psychiatric genetics, the first decade of the 21st century was dominated by the "candidate gene" research. In this paper, the studies on candidate genes connected with lithium prophylaxis performed at the Poznań University of Medical Sciences in 2005-2018 are presented. During this time, the polymorphisms of multiple genes have been investigated, many of which are also connected with a predisposition to bipolar illness. The associations with lithium prophylactic efficacy were found for the polymorphisms in 5HTT, ACP1, ARNTL, BDNF, COMT, DRD1, FKBP5, FYN, GLCC, NR3C1, and TIM, genes, but not those in 5HT2A, 5HT2C, DRD2, DRD3, DRD4, GRIN2B, GSK-3β, MMP-9, and NTRK2 genes. The polymorphism of the GSK-3β gene was found to be associated with the kidney side-effects occurring during lithium therapy. Possible roles for these genes in both the mechanism of lithium prophylactic activity and pathogenesis of bipolar mood disorder were discussed.

Lithium Biological Action Mechanisms after Ischemic Stroke.

Lithium is a source of great scientific interest because although it has such a simple structure, relatively easy-to-analyze chemistry, and well-established physical properties, the plethora of effects on biological systems-which influence numerous cellular and molecular processes through not entirely explained mechanisms of action-generate a mystery that modern science is still trying to decipher. Lithium has multiple effects on neurotransmitter-mediated receptor signaling, ion transport, signaling cascades, hormonal regulation, circadian rhythm, and gene expression. The biochemical mechanisms of lithium action appear to be multifactorial and interrelated with the functioning of several enzymes, hormones, vitamins, and growth and transformation factors. The widespread and chaotic marketing of lithium salts in potions and mineral waters, always at inadequate concentrations for various diseases, has contributed to the general disillusionment with empirical medical hypotheses about the therapeutic role of lithium. Lithium salts were first used therapeutically in 1850 to relieve the symptoms of gout, rheumatism, and kidney stones. In 1949, Cade was credited with discovering the sedative effect of lithium salts in the state of manic agitation, but frequent cases of intoxication accompanied the therapy. In the 1960s, lithium was shown to prevent manic and also depressive recurrences. This prophylactic effect was first demonstrated in an open-label study using the "mirror" method and was later (after 1970) confirmed by several placebo-controlled double-blind studies. Lithium prophylaxis was similarly effective in bipolar and also unipolar patients. In 1967, the therapeutic value of lithemia was determined, included in the range of 0.5-1.5 mEq/L. Recently, new therapeutic perspectives on lithium are connected with improved neurological outcomes after ischemic stroke. The effects of lithium on the development and maintenance of neuroprotection can be divided into two categories: short-term effects and long-term effects. Unfortunately, the existing studies do not fully explain the lithium biological action mechanisms after ischemic stroke.

Genetic polymorphisms influencing response to lithium in early-onset Bipolar disorder from south India.

Early-onset Bipolar disorder (EOBD), has a more malignant course with high recurrence risk and there is a need for population-specific pharmaco-genomic study. This study is a prospective and retrospective observational study. Both newly diagnosed patients and those on follow-up with a diagnosis of bipolar I disorder with onset before 18 years of age and on lithium prophylaxis as part of treatment-as-usual were recruited for the study. Response to treatment was assessed at the end of two years follow up using ALDA scale. Ten single nucleotide polymorphisms associated with treatment response based on previous studies were chosen for analysis. Of 162 who had EOBD, sixty-four fulfilled inclusion criteria and fifty-seven completed the study. TT and TG genotypes of rs75222709 on AL157359.3 gene were found to be significantly different between non-responders(N = 43) and healthy controls (N=220). The frequency of the GA genotype of the single nucleotide polymorphism rs17204573 of the RORA (Retinoic Acid related orphan receptor alpha) gene was significantly lower among subjects (27.3%, N = 54) as compared to controls (42.9%, OR:0.5, CI: 0.26-0.96, p value 0.035). However, the significance of both disappeared after Bonferroni correction. Among clinical factors female gender was significantly associated with lithium non-response. Although conducting pharmaco-genomic studies with large sample size is a challenge for low and middle-income countries, future studies can help improve the long-term outcome of youth with EOBD.

Management of Psychiatric Disorders during the Perinatal Period.

Management of Psychiatric Disorders during the Perinatal Period.

Lithium treatment in the era of personalized medicine

In 1949, an Australian psychiatrist, John Cade, reported on the antimanic efficacy of lithium carbonate, which is regarded as an introduction of lithium into contemporary psychiatry. Since the 1960s, lithium has been a precursor of mood stabilizers and has become first-choice drug for the prevention of affective episodes in mood disorders. For nearly four decades, lithium has also been used for the augmentation of antidepressant drugs in treatment-resistant depression. The knowledge of clinical and biological factors connected with the capability of long-term lithium treatment to prevent manic and depressive recurrences makes an important element of the personalized medicine of mood disorders. Excellent prophylactic lithium responders can be characterized by distinct mood episodes, with full remissions between them, the absence of other psychiatric morbidity, and the family history of bipolar illness. In recent years, many other clinical and biological factors connected with such a response have been identified, helping to select the best candidates for lithium prophylaxis. The antisuicidal effect of lithium during its long-term administration has been demonstrated and should also be taken into account as the element of personalized medicine for the pharmacological prophylaxis of patients with mood disorders. Several studies pertaining to personalized medicine were also dedicated to lithium treatment of acute mood episodes. Lithium still has a value in the treatment of mania and bipolar depression. However, it seems that the more important indication would be the augmentation of antidepressant drugs in treatment-resistant depression. The factors connected with the efficacy of lithium in these conditions are reviewed.

Assessment of lithium-related knowledge and attitudes among patients with bipolar disorder on long-term lithium maintenance treatment.

Background:Gaps in lithium-related knowledge among bipolar disorder (BD) patients on lithium prophylaxis may pose safety concerns and could adversely influence attitudes to lithium.Objective:To assess the lithium-related knowledge and attitudes among patients with BD.Materials and Methods:This was a cross-sectional, observational study assessing euthymic, adult outpatients with BD on lithium prophylaxis (≥1 year) using a semi-structured pro forma, lithium questionnaire for knowledge, lithium attitude questionnaire (LAQ), and medication adherence rating scale (MARS).Results:Descriptive analysis revealed several deficits in knowledge, including lack of critical safety information or need for periodic blood tests. Lower knowledge group had significantly more negative attitudes. Favorable attitude toward lithium (lower LAQ score) was significantly associated with the number of psychiatric follow-ups in the last year and MARS score.Conclusion:There were critical deficits in lithium-related knowledge among the patients. Lower lithium knowledge was associated with negative lithium attitudes. Educative interventions should be delivered periodically to regular lithium users.

Lithium pharmacogenetics. Two decades of studies

Pharmacogenetic research aims to elucidate associations of genetic variants and individual effects of pharmacotherapy. Personalised expected response to medications might be useful in prognosis for polygenetically determined disorders. In bipolar disorder (BP), that is partly hereditary polygenic disorder, a subgroup of patients excellently responding to lithium prophylaxis was described. During the last 20 years molecular technology allowed to investigate genome of patients treated with lithium and candidate association studies characterised them more precisely than clinical features. The role of several neurotransmitters’ pathways, second messengers, neuroprotection involved genes and clock genes associations were discovered. Further laboratory technics development enables us to perform genome-wide association studies (GWAS) and polygenic risk score (PRS) analyses. We aimed to review research on genes involved in lithium treatment efficacy and safety. PubMed for English papers, articles published in Polish and reference lists from full-text available papers were searched. Pharmacogenetic findings for lithium treatment effects might help develop new personalised strategies and consequently better symptom reduction. So far, chronicity and recurrent course of bipolar disorder impair the functioning of numerous patients and strongly increase the risk of suicide.

Faut-il annoncer un diagnostic de trouble bipolaire à un patient qui n’a jamais connu la dépression ? Une revue systématique actualisée sur la manie récurrente

Bipolar disorder (BD) is a severe and recurrent mood disorder. It is characterized by episodic changes in mood and energy/activity levels that are increased during mania/hypomania or decreased during depression. Recurrent mania (RM) is a mood disorder, which would be defined by at least two manic/hypomanic without depressive episodes. Despite a rich body of clinical descriptions, RM is still not integrated into the latest editions of disease classifications and continues to be subsumed under BD in clinical practice. We conducted a systematic review of the literature to pool data about RM prevalence within BD groups, identify differences between RM and BD and develop reliable knowledge about specificities of RM. Furthermore, we sought to identify the methodological bias inherent to RM studies. Relevant publications were identified by a systematic search of PubMed, Embase, ScienceDirect and PsychInfo databases according to PRISMA criteria, with no limitation of date. The following MESH terms were used: (mania OR manic) AND (unipolar) NOT (depress*) OR ("unipolar mania" OR "unipolar manic" NOT "depress*"). Twenty-three (23) of 186identified studies met eligibility criteria for our systematic review. The total sample included 1118RM subjects among 4796BD subjects. The weighted mean of RM prevalence was 23.2%. Compared to BD, RM was characterized by a predominance of men, an earlier age at illness onset, less rapid cycles and seasonal variations, longer manic episodes, less specific clinical features (suicide attempts, anxious disorders, catatonic symptoms, irritability, hyperactivity, racing thoughts), less family history of depression, more addictive comorbidities and worse response to lithium prophylaxis (P<0.05). However, many studies failed to replicate these significant differences. RM studies were mainly retrospective. The major bias of RM studies were the lack of consensus on the defining criteria for RM and the risk of unreported depressive episodes, both in charts that were reviewed in retrospective studies and in prospective studies with insufficient follow-up duration. Although the literature on RM remains sparse, many authors agree that RM should be distinguished from BD. RM would concern almost 1 in 4 BD patients. Furthermore, several clinical variables could differentiate this mood disease from BD and may orient the specific therapeutic choice. However, clinical criteria are still not reliable enough to make a diagnosis of RM. Further studies are required to replicate the results of existing studies and to adjust for the effect of methodological biases.

Quality of life for patients diagnosed with bipolar disorder: Lifestyle and treatment

BackgroundAlthough bipolar disorder (BP) is associated with impaired quality of life (QOL), little is known about the clinical features associated with QOL. Better knowledge about this relationship may improve treatment. MethodsThis cross-sectional and retrospective study of 160 bipolar outpatients is part of an extensive study battery that includes patient-rated QOL with the World Health Organization QOL-100. The subscale “overall QOL” was used for analysis. QOL was divided into subgroups denoted “low”, “mid”, and “high”. Clinical data such as disease-specific factors, treatment efforts, and lifestyle were gathered from personal interviews and medical records. ResultsCompared to mid QOL, single analysis adjusted for age and sex revealed that low QOL was associated with BP II diagnosis, no previous hospitalization, low grade of current lithium medication, high grade of current antiepileptic medication, short disease duration with lithium, long disease duration without lithium, inactive lifestyle, high BMI, young age, and pre-menopausal women. Compared to mid QOL, high QOL was associated with a hypomanic/manic first affective episode, low BMI, non-smoker, and not currently using anxiolytic or sedatives. LimitationsNo longitudinal QOL data were collected. ConclusionsQOL for bipolar patients is determined by serval factors that potentially could be altered. To improve QOL, lithium prophylaxis and lifestyle factors seem the most promising.

28.1 THE DEVELOPMENTAL TRAJECTORY OF BIPOLAR DISORDER: LATEST OBSERVATIONS FROM THE CANADIAN FLOURISH HIGH-RISK STUDY

The goal of this session is to present new data mapping with the emergent course of bipolar disorder (BD) in the high-risk offspring of affected parents subgrouped by parental response to lithium prophylaxis.

Lithium prophylaxis in early-onset Bipolar disorder: a descriptive study.

Subjects fulfilling DSM 5 criteria of Bipolar I disorder with onset before 18 years on Lithium prophylaxis were included. A total of 575 subjects with Bipolar Disorder were screened, 141 had early-onset Bipolar disorder, 72 patients were on Lithium and 52 provided informed consent and entered the study. Thirty-four were in the prospective group, and 18 were in the retrospective arm. Mean age at onset was 16.13 (1.40) years. About 31% (n = 16) were initiated on Lithium following first episode. Mean age at initiating lithium was 19.73 (3.82) years. Clinical profile and treatment response of early-onset bipolar disorder in the Indian context needs further study.

Peripheral insulin-like growth factor and glutamate-related antibodies in bipolar disorder and lithium prophylaxis

Peripheral insulin-like growth factor and glutamate-related antibodies in bipolar disorder and lithium prophylaxis

Challenging the Negative Perception of Lithium and Optimizing Its Long-Term Administration.

The use of lithium for the prevention of recurrences in mood disorders has a 55-year history. Nowadays, lithium is universally accepted as the first-choice mood-stabilizer (MS) for maintenance treatment of bipolar disorder. In addition to its mood-stabilizing properties, lithium exerts anti-suicidal, immunomodulatory and neuroprotective action which may further substantiate its clinical usefulness. Despite these facts, the use of lithium in mood disorders has been greatly underutilized. The reasons include the introduction and promoting other MS as well as a perception of lithium as a “toxic drug” due to its side effects, mainly thyroid, renal and cognitive disturbances. The trends in lithium prescription in recent decades show relative stability or a decline at the expense of other mood-stabilizing drugs, both first generation (valproate) and second generation (olanzapine, quetiapine, lamotrigine). In this review article, the negative perception of lithium by some clinicians will be challenged. First, the data showing lithium superiority over other MS will be presented. Second, the lithium-induced side effects which can make a challenge for a more frequent application of this drug will be delineated, and their proper management described. Finally, an issue of benefits of long-term administration of lithium will be discussed, including the phenomenon of the “excellent lithium responders” (ER) as well as a subject of starting lithium prophylaxis early in the course of the illness. This review article is based on the 47-year experience with lithium therapy by the author of the article.

Lithium Clinics in Berlin and Dresden: a 50-Year Experience.

Although lithium's serendipitous discovery as a medication for depression dates back more than 200 years, the first scientific evidence that it prevents mania and depression arose only in the 1960s. However, at that time there was a lack of knowledge about how to administer and monitor lithium therapy safely and properly. The lithium clinics in Dresden and Berlin were remarkably similar in their beginnings in the late 1960s regarding patient numbers and scientific expertise without being aware of one another due to the Iron Curtain separating Germany into a western and eastern part until 1990. In what were initially lithium-care programs run independently from one another, the lithium clinics embedded in academic settings in Dresden and Berlin represent a milestone in the history of psychopharmacological treatment of affective disorders in Germany and trailblazers for today's lithium therapy. Nowadays, lithium's clinical applications are unquestioned, such as its use in strategies to prevent mood episodes and suicide, and to treat depression. The extensively documented knowledge of lithium treatment is the fruit of more than 50 years of observing disease courses and of studying side effects and influencing factors of lithium prophylaxis. Its safe and proper administration-in determining the correct indication, baseline and follow-up examinations, recommended dosages, monitoring, or the management of side effects-is well established. Subsequently, both national and international guidelines continue recommending lithium as the gold standard in treating patients with unipolar and bipolar disorders.

Clinical factors associated with lithium treatment response in bipolar disorder patients from India.

Bipolar Disorder (BD) is a chronic and disabling psychiatric illness with waxing and waning course. Lithium is the mainstay of treatment for Bipolar disorder (BD). There is limited literature on the clinical markers of Lithium treatment response from south Asia. Two hundred and ten individuals with BD I and a history of at least 6 months of treatment with Lithium were recruited from the outpatient services of the National Institute of Mental Health and Neurosciences (NIMHANS) after obtaining informed consent. A diagnosis of BD I was made according to the DSM-IV criteria. The characterization of response to lithium prophylaxis was done using NIMH Retrospective Life Chart and "Retrospective Criteria of Long Term Treatment Response in Research Subjects with Bipolar Disorder" scale. There were 132 (62.86%) good responders and 78 (37.14%) non-responders. Good responders were noted to have less number of hospitalizations and more onset episode of depression than non-responders. Using continuous phenotype, Lithium response was inversely correlated with total number of episodes, number of episodes of mania/ depression, number of hospitalisations and presence of suicide attempt. Multivariate analysis only revealed number of episodes and hospitalization to be associated with Lithium response. Our Lithium response rates were higher than what have been reported in the few previous studies. Illness severity was the only factor associated with Lithium response. There is a need to examine this question in larger prospective samples and to focus on biological/ molecular markers of treatment response.

Hyper- and hypocortisolism in bipolar disorder - A beneficial influence of lithium on the HPA-axis?

BackgroundA hyperactive hypothalamic-pituitary-adrenal axis (HPA-axis) is a well-known phenomenon in bipolar disorder (BD). However, hypocortisolism has also been described and found associated with depression, low quality of life and cardiovascular risk factors in BD patients. Although the pathophysiology related to hypocortisolism in BD is largely unknown, hypocortisolism is associated with chronic stress exposure and after inducing an initial rise in cortisol long-term stress may result in a transition to hypocortisolism. BD patients are throughout life often exposed to chronic stress. We therefore hypothesized that higher age would be associated with lower HPA-axis activity especially among patients without previous mood stabilizing treatment. MethodsThis cross-sectional study consisted of 159 bipolar outpatients and 258 controls. A low-dose-dexamethasone-suppression-test (DST) was used to measure HPA-axis activity. ResultsPatients with BD showed a negative association between post DST cortisol and age (−3.0 nmol/l per year; p=0.007). This association gradually increased in subgroups that were naïve to lithium (−7.7 nmol/l per year; p=0.001) and “all mood stabilizers” (−11.4 nmol/l per year; p=0.004). Patients exhibiting hypercortisolism were characterized by younger age and female gender, whereas patients exhibiting hypocortisolism were characterized by long disease duration without prophylactic lithium treatment as well as absence of current lithium medication. LimitationsCross sectional study design. ConclusionsThere was a negative association between HPA-axis activity and age in BD, rendering BD patients at risk for developing hypocortisolism. This association was most pronounced among patients without previous or current lithium prophylaxis.

Childhood trauma and mixed episodes are associated with poor response to lithium in bipolar disorders.

Reliable predictors of response to lithium are still lacking in bipolar disorders (BDs). However, childhood trauma has been hypothesized to be associated with poor response to lithium. We included 148 patients with BD, euthymic when retrospectively and clinically assessed for response to lithium and childhood trauma using reliable scales. According to the 'Alda scale', the sample consisted in 20.3% of excellent responders, 49.3% of partial responders and 30.4% of non-responders to lithium. A higher level of physical abuse significantly correlated with a lower level of response to lithium (P = 0.009). As compared to patients not exposed to any abuse, patients with at least two trauma abuses (emotional, physical or sexual) were more at risk of belonging to the non-responders group (OR = 4.91 95% CI (1.01-27.02)). Among investigated clinical variables, lifetime presence of mixed episodes and alcohol misuse were associated with non-response to lithium. Multivariate analyses demonstrated that physical abuse and mixed episodes were independently associated with poor response to lithium (P = 0.005 and P = 0.013 respectively). Childhood physical abuse might be involved in a poor future response to lithium prophylaxis, this effect being independent of the association between clinical expression of BD and poor response to lithium.

Postpartum Psychosis: Madness, Mania, and Melancholia in Motherhood.

Psychosis or mania after childbirth is a psychiatric emergency with risk for suicide and infanticide. The authors reviewed the epidemiologic and genetic research and physiological postpartum triggers (endocrine, immunological, circadian) of psychosis. They also summarized all systematic reviews and synthesized the sparse clinical studies to provide diagnostic recommendations, treatment options, and strategies for prevention. The incidence of first-lifetime onset postpartum psychosis/mania from population-based register studies of psychiatric admissions varies from 0.25 to 0.6 per 1,000 births. After an incipient episode, 20%-50% of women have isolated postpartum psychosis. The remaining women have episodes outside the perinatal period, usually within the bipolar spectrum. Presumably, the mechanism of onset is related to physiological changes after birth (e.g., hormonal, immunological, circadian), which precipitate disease in genetically vulnerable women. Some women have treatable causes and comorbidities, such as autoimmune thyroiditis or infections. N-methyl-d-aspartate-encephalitis or inborn errors of metabolism may present after birth with psychosis. Fewer than 30 publications have focused on the treatment of postpartum psychosis. The largest study (N=64) provided evidence that lithium is highly efficacious for both acute and maintenance treatment. Another report (N=34) described successful ECT treatment. Inpatient care is usually required to ensure safety, complete the diagnostic evaluation, and initiate treatment. The relapse risk after a subsequent pregnancy for women with isolated postpartum psychoses is 31% (95% CI=22-42). Strategies for prevention of postpartum psychosis include lithium prophylaxis immediately postpartum and proactive safety monitoring. Postpartum psychosis offers an intriguing model to explore etiologic contributions to the neurobiology of affective psychosis.

Ultrasonographically Measured Change in Thyroid Status in Lithium Treated Adult Patients with Mood Disorder.

Background:Lithium, which is frequently used in the treatment of mood disorder, can lead to various types of thyroid dysfunctions. Although clinical examination and biochemical assessment are fundamental to any thyroid work-up of lithium-treated patients, assessment findings vary widely depending on the investigator. Ultrasonographic measurement of thyroid volume has, therefore, been performed in lithium treatment populations and found to be a sensitive tool.Aim:We aimed to determine and compare thyroid gland volume using Ultrasonography and laboratory parameters, (thyroid-stimulating hormone [TSH], T3, and T4) in long-term lithium and other mood stabilizers treated patients with mood disorder.Materials and Methods:In this cross-sectional study, we performed ultrasonography examinations and thyroid function test of 30 patients on lithium treatment and 30 patients on other mood stabilizers.Results:The ultrasonographically measured thyroid volume was significantly increased in patients receiving lithium therapy as compared to the patients receiving other mood stabilizers. The total triiodothyronine (T3) was significantly increased with trends toward increased total thyroxine (T4) and decreased TSH in patients receiving lithium therapy as compared to the patients receiving other mood stabilizers.Conclusion:These results highlight the need of including ultrasonographic measurement of thyroid volume as a part of standard thyroid work-up before initiating lithium prophylaxis and during follow-up. Additional studies on the incidence and mechanism of lithium associated hyperthyroidism are needed.