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Usefulness of lithium in the prophylaxis of bipolar disorders has been challenged for five major reasons. The authors review the empirical basis of these criticisms and come to the following conclusions.1. Lithium efficacy is high and beyond reasonable doubt in classic manic-depressive illness. Bipolar patients presenting atypical features show a much poorer response rate to lithium. 2. There is no empirical evidence for a loss of lithium efficacy over time. 3. There is little evidence for discontinuation-induced refractoriness to lithium. 4. Lithium withdrawal phenomena are well established but seem to be rather specific to certain subsgroups. Withdrawal phenomena seem to be common in atypical bipolar disorder but rare in fully stabilized classic manic-depressive illness. 5. Other factors limiting lithium efficacy in clinical practice (e.g.,non-compliance)are not specific to lithium. In conclusion, prophylactic lithium does have major drawbacks and there is a clear need for ore efficacious alternatives in non-classic bipolars. Compared to existing alternatives, lithium currently is to be considered the golden standard. This status might, however, be challenged by major alternative mood-stabilizers that are presently under clinical investigation. [ABSTRACT FROM AUTHOR]

Prophylactic treatment with lithium has been reported to prevent haloperidol-induced dopamine (DA) receptor supersensitivity. If such an effect exists, then lithium may be useful in the prevention of tardive dyskinesia, which is related to the neuroleptic-induced DA hyperfunction. In the experiments reported here chronic lithium administration had no effect on DA synthesis or utilization in the nigrostriatal, mesolimbic, or mesocortical DA pathways in the rat brain. Similarly, lithium had no effect on the increase in DA metabolism induced by the acute administration of haloperidol. Also, chronic lithium treatment failed to modify the biochemical tolerance which developed after prolonged administration of the neuroleptic drug. Supersensitivity of the presynaptic DA receptors, which was induced by prolonged exposure to haloperidol, likewise was unaffected by prophylactic lithium treatment. We conclude that lithium does not affect changes in DA metabolism or receptor supersensitivity induced by haloperidol. These results do not support the use of lithium in neurological disorders that may be related to neuroleptic-induced DA receptor supersensitivity. [ABSTRACT FROM AUTHOR]

Background: Lithium is effective in the long-term treatment of bipolar disorder. Concerns have been raised about non-responsiveness after discontinuation and resuming previously effective lithium prophylaxis. We reviewed the available literature on this so-called lithium-discontinuation-induced treatment refractoriness (LDITR). Results: We found 11 case reports and six cohort studies including 403 patients addressing LDITR, and one nation-wide register study providing some additional data on LDITR. Pooling all cohort studies, the percentages of non-responders during re-treatment with lithium ranged from 3.6 to 27.7%, with an average of 17.3%. Non-responsiveness was associated with longer duration of lithium treatment before discontinuation, longer duration of bipolar disorder before start of lithium, faster tapering off lithium, and longer duration of discontinuation. Conclusions: There may be a subgroup in whom lithium discontinuation-induced treatment refractoriness exists. However, the vast majority of people respond when lithium is restarted. Moreover, it may be necessary to continue lithium beyond the first relapses to restore long-term prophylactic efficacy. [ABSTRACT FROM AUTHOR]

Background: Multiple traumatic experiences, particularly in childhood, may predict and be a risk factor for the development of complex post-traumatic stress disorder (cPTSD). Unfortunately, individuals with bipolar disorder (BP) are more likely to have suffered traumatic events than the general population. Consequently, cPTSD could be comorbid with BD, and this may negatively affect psychopathological manifestations. To date, no one has explored whether such comorbidity also affects the response to treatment with mood stabilizers in BD patients. Results: Here, a cross-sectional study was carried out by comparing the response to treatment, measured by the Alda scale, in a cohort of 344 patients diagnosed with BD type I and II, screened for the presence (or absence) of cPTSD using the International Trauma Questionnaire. The main result that emerged from the present study is the poorer response to mood stabilizers in BD patients with comorbid cPTSD compared with BD patients without cPTSD. Conclusions: The results collected suggest the need for an add-on therapy focused on trauma in BD patients. This could represent an area of future interest in clinical research, capable of leading to more precise and quicker diagnoses as well as suggesting better tailored and more effective treatments. [ABSTRACT FROM AUTHOR]

Background: The phenomenon of preventing the recurrences of mood disorders by the long-term lithium administration was discovered sixty years ago. Such a property of lithium has been unequivocally confirmed in subsequent years, and the procedure makes nowadays the gold standard for the pharmacological prophylaxis of bipolar disorder (BD). The efficacy of lithium prophylaxis surpasses other mood stabilizers, and the drug has the longest record as far as the duration of its administration is concerned. The continuation of lithium administration in case of good response could be a lifetime and last for several decades. The stability of lithium prophylactic efficacy in most patients is pretty steady. However, resuming lithium after its discontinuation may, in some patients, be less efficient. Main body: In the article, the clinical and biological factors connected with the prophylactic efficacy of long-term lithium administration are listed. Next, the adverse and beneficial side effects of such longitudinal treatment are presented. The main problems of long-term lithium therapy, which could make an obstacle to lithium continuation, are connected with lithium's adverse effects on the kidney and, to lesser extent, on thyroid and parathyroid functions. In the paper, the management of these adversities is proposed. Finally, the case reports of three patients who have completed 50 years of lithium therapy are described. Conclusions: The authors of the paper reckon that in the case of good response, lithium can be given indefinitely. Given the appropriate candidates for such therapy and successful management of the adverse effects, ultra-long term lithium therapy is possible and beneficial for such patients. [ABSTRACT FROM AUTHOR]

Background: Lithium is an essential psychopharmaceutical, yet side effects and concerns about severe renal function impairment limit its usage. Aims: Our objectives were to quantify the occurrence of chronic kidney disease stage 4 or higher (CKD4 +) within a lithium-treated population, using age- and time-specific cumulative incidence and age-specific lifetime risk as measures of disease occurrence. Additionally, we aimed to investigate the association between the duration of lithium treatment and the risk of CKD4 +. Methods: We identified patients from the Sahlgrenska University Hospital's laboratory database. We conducted a retrospective cohort study employing cumulative incidence functions that account for competing deaths to estimate cumulative and lifetime risk of CKD4 +. A subdistribution hazards model was employed to explore baseline covariates. For measuring the association between the duration of lithium treatment and CKD4 + occurrence, we used a matched 1:4 case–control study design and logistic regression. Results: Considering a 90-year lifetime horizon, the lifetime risk of CKD4 + for patients initiating lithium treatment between ages 55 and 74 ranged from 13.9% to 18.6%. In contrast, the oldest patient group, those starting lithium at 75 years or older, had a lower lifetime risk of 5.4%. The 10-year cumulative risk for patients starting lithium between ages 18 and 54 was minimal, ranging from 0% to 0.7%. Pre-treatment creatinine level was a predictive factor, with a hazard ratio of 4.6 (95% CI 2.75–7.68) for values within the upper third of the reference range compared to the lower third. Moreover, twenty or more years of lithium exposure showed a strong association with an increased risk of CKD4 + compared to 1–5 years of lithium use, with an odds ratio of 6.14 (95% CI 2.65–14.26). Conclusions: The risk of CKD4 + among lithium-treated patients exhibited significant age-related differences. Patients under 55 years old had negligible 10-year risk, while the lifetime risk for those aged 75 and older was limited. Duration of lithium treatment, especially exceeding 20 years, emerged as a significant risk factor. For individual risk assessment and prediction, consideration of age, pre-treatment creatinine levels, and the chosen time horizon for prediction is essential. [ABSTRACT FROM AUTHOR]

For over half a century, it has been widely known that lithium is the most efficacious maintenance treatment for bipolar disorder. Despite thorough research on the long-term effects of lithium on renal function, a number of important questions relevant to clinical practice remain. The risk of polyuria, reflecting renal tubular dysfunction, is seen in a substantial proportion of patients treated with long term lithium therapy. The duration of lithium may be the most important risk factor for lithium-induced polyuria. Most, but not all, studies find that lithium is associated with higher rates of chronic kidney disease compared to either age matched controls or patients treated with other mood stabilizers. Age, duration of lithium therapy and medical disorders such as hypertension and diabetes mellitus are risk factors for chronic kidney disease in lithium-treated patients. The relationship between polyuria and chronic kidney disease is inconsistent but poorly studied. Although not all studies agree, it is likely that lithium may increase the risk for end stage renal disease but in a very small proportion of treated patients. Patients whose renal function is relatively preserved will show either no progression or improvement of renal function after lithium discontinuation. In contrast, patients with more renal damage frequently show continued deterioration of renal function even after lithium discontinuation. Optimal management of lithium treatment requires obtaining a baseline measure of renal function (typically estimated glomerular filtration rate [eGFR]) and regular monitoring of eGFR during treatment. Should the eGFR fall rapidly or below 60 ml/minute, patients should consider a consultation with a nephrologist. A decision as to whether lithium should be discontinued due to progressive renal insufficiency should be made using a risk/benefit analysis that takes into account other potential etiologies of renal dysfunction, current renal function, and the efficacy of lithium in that individual patient. [ABSTRACT FROM AUTHOR]

Lithium is one of the most effect mood-stabilizing drugs prescribed especially for bipolar disorder. Lithium has wide range effects on different molecular factors and neural transmission including dopaminergic signaling. On the other hand, mesolimbic and mesocortical dopaminergic signaling is significantly involved in the pathophysiology of neuropsychiatric disorders. This review article aims to study lithium therapeutic mechanisms, dopaminergic signaling, and the interaction of lithium and dopamine. We concluded that acute and chronic lithium treatments often reduce dopamine synthesis and level in the brain. However, some studies have reported conflicting results following lithium treatment, especially chronic treatment. The dosage, duration, and type of lithium administration, and the brain region selected for measuring dopamine level were not significant differences in different chronic treatments used in previous studies. It was suggested that lithium has various mechanisms affecting dopaminergic signaling and mood, and that many molecular factors can be involved, including brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), β-catenin, protein kinase B (Akt), and glycogen synthase kinase-3 beta (GSK-3β). Thus, molecular effects of lithium can be the most important mechanisms of lithium that also alter neural transmissions including dopaminergic signaling in mesolimbic and mesocortical pathways. [ABSTRACT FROM AUTHOR]

Background: Response to lithium (Li) is highly variable in bipolar disorders (BD). Despite decades of research, no clinical predictor(s) of response to Li prophylaxis have been consistently identified. Recently, we developed epigenetic Methylation Specific High-Resolution Melting (MS-HRM) assays able to discriminate good responders (GR) from non-responders (NR) to Li in individuals with BD type 1 (BD-I). This study examined whether a combination of clinical and epigenetic markers can distinguish NR from other types of Li responders. Methods: We recorded clinical variables that are potentially associated with Li response in 64 individuals with BD-I. MS-HRM assays were performed on DNA isolated from peripheral blood. We used backward stepwise logistic regression analyses, followed by receiver operating characteristic (ROC) curve analysis to estimate the performance of the clinical variables, alone then in combination with the epigenetic biomarkers, to identify GR and partial responders (PaR) vs NR. Results: Polarity at onset, psychotic symptoms at onset and family history of BD classified correctly 70% of individuals according to their Li response (PaR + GR = 86%; NR = 35%). When combined with the epigenetic biomarkers, these three clinical variables plus alcohol misuse (and one DMR: Differentially Methylated Region) correctly classified 86% of individuals, improving the prediction of PaR + GR (93%) and of NR (70%). The ROC analysis demonstrated an improvement in the area under the curve from 0.75 (clinical variables alone) to 0.87 (combination of clinical and epigenetic markers). Conclusions: Combining clinical predictors and DNA methylation markers of Li response may have greater utility in clinical practice than relying on clinical characteristics alone. [ABSTRACT FROM AUTHOR]

HIV-associated neurocognitive disorders (HAND) persist in the era of antiretroviral therapy (ART). Thus, ART does not completely halt or reverse the pathological processes behind HAND. Adjuvant mitigating treatments are, therefore, prudent. Lithium treatment is known to promote neuronal brain–derived neurotrophic factors (BDNF). Lithium is also an inhibitor of glycogen synthase kinase-3 beta (GSK-3-β). We analyzed biomarkers obtained from participants in a randomized placebo-controlled trial of lithium in ART-treated individuals with moderate or severe HAND. We assayed markers at baseline and 24 weeks across several pathways hypothesized to be affected by HIV, inflammation, or degeneration. Investigated biomarkers included dopamine, BDNF, neurofilament light chain, and CD8 + lymphocyte activation (CD38 + HLADR +). Alzheimer's Disease (AD) biomarkers included soluble amyloid precursor protein alpha and beta (sAPPα/β), Aβ38, 40, 42, and ten other biomarkers validated as predictors of mild cognitive impairment and progression in previous studies. These include apolipoprotein C3, pre-albumin, α1-acid glycoprotein, α1-antitrypsin, PEDF, CC4, ICAM-1, RANTES, clusterin, and cystatin c. We recruited 61 participants (placebo = 31; lithium = 30). The age baseline mean was 40 (± 8.35) years and the median CD4 + T-cell count was 498 (IQR: 389–651) cells/μL. Biomarker concentrations between groups did not differ at baseline. However, both groups' blood dopamine levels decreased significantly after 24 weeks (adj. p < 002). No other marker was significantly different between groups, and we concluded that lithium did not confer neuroprotection following 24 weeks of treatment. However, the study was limited in duration and sample size. [ABSTRACT FROM AUTHOR]

Background: Lithium-induced nephrotoxicity has long been debated. However, it has been rarely explored in Asian populations. The aim of the present study was to assess the effect of lithium maintenance therapy on estimated glomerular filtration rate (eGFR) in Korean patients diagnosed with a psychiatric illness. Methods: This was a single-centered, retrospective study that included patients treated with lithium or comparator drug (valproate) in Samsung Seoul Medical Center between November 1994 and July 2020. Patients diagnosed with ICD codes F20-33 who had ≥ 6 months of exposure to lithium or valproate were included. Patients had to have ≥ 1 baseline and ≥ 2 post-baseline eGFR data with post-baseline data having an interval of at least 30 days. Chronic kidney disease (CKD) was defined as CKD stage 3 (eGFR < 60 mL/min/1.732). To be considered as CKD, the threshold had to be met at two consecutive post-baseline measurements. Those treated with both lithium and valproate, diagnosed with CKD stages 3–5, diagnosed with a renal disease, or received kidney transplantation were excluded. Results: A total of 766 patients were included (242 treated with lithium and 524 with valproate). Two (0.8%) in the lithium group and 8 (1.5%) in the valproate group developed CKD stage 3. None developed CKD stages 4–5. Median yearly eGFR change was − 1.3 mL/min/1.732 (IQR: − 6.8, 1.7) for the lithium group and − 1.1 mL/min/1.732 (IQR: − 4.5, 1.5) for the valproate group, showing no significant difference between the two groups (p = 0.389). The rate of decline was more rapid for those with CKD in both groups. eGFR values of lithium and valproate groups did not show significant differences during a follow-up duration of 15 years or more. A significant negative correlation between baseline eGFR and yearly eGFR change was identified in a linear regression analysis. Conclusions: In Korean patients, treatment with lithium did not increase the risk of developing CKD compared to treatment with valproate. Prevalence of CKD was lower than those previously reported in western populations. Low baseline eGFR showed significant correlation with changes in renal function. [ABSTRACT FROM AUTHOR]

Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen's kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and Würzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [− 0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures. [ABSTRACT FROM AUTHOR]

Objective: To identify possible socio-demographic and clinical factors associated with Good Outcome (GO) as compared with Poor Outcome (PO) in adult patients diagnosed with Bipolar Disorder (BD) who received long-term treatment with lithium. Methods: A comprehensive search of major electronic databases was performed to identify relevant studies that included adults patients (18 years or older) with a diagnosis of BD and reported sociodemographic and/or clinical variables associated with treatment response and/or with illness outcome during long-term treatment to lithium (> = 6 months). The quality of the studies was scored using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies from the National Institute of Health. Results: Following review, 34 publications (from 31 independent datasets) were eligible for inclusion in this review. Most of them (n = 25) used a retrospective design. Only 11 studies were graded as good or borderline good quality. Forty-three potential predictors of outcome to lithium were identified. Four factors were associated with PO to lithium: alcohol use disorder; personality disorders; higher lifetime number of hospital admissions and rapid cycling pattern. Two factors were associated with GO in patients treated with lithium: good social support and episodic evolution of BD. However, when the synthesis of findings was limited to the highest (good or borderline good) quality studies (11 studies), only higher lifetime number of hospitalization admissions remained associated with PO to lithium and no associations remained for GO to lithium. Conclusion: Despite decades of research on lithium and its clinical use, besides lifetime number of hospital admissions, no factor being consistently associated with GO or PO to lithium was identified. Hence, there remains a substantial gap in our understanding of predictors of outcome of lithium treatment indicating there is a need of high quality research on large representative samples. [ABSTRACT FROM AUTHOR]

Deals with a study that assesses whether polarity of recurrence is related to serum lithium level in patients with bipolar disorder. Methods applied in the study; Result of the study; Conclusion.

Background: When evaluating the long-term treatment response to mood stabilizers using the Alda scale, mood stabilizer combination therapy is typically considered a confounding factor, and patients receiving combination therapy are excluded from the analysis. However, this may result in bias if those under combination therapy are worse treatment responders. This study aims to explore whether the Alda scale is applicable to patients taking lithium and valproate combination therapy. We compared long-term treatment response in patients receiving monotherapy and combination therapy of the two drugs, and investigated clinical correlates of the responses to each drug. Methods: The study subjects consisted of 102 patients with bipolar I (BD-I) or bipolar II (BD-II) disorder who had been undergoing maintenance treatment with lithium and/or valproate for more than 2 years at a single specialized bipolar disorder clinic. Long-term treatment response was measured using the Alda scale and compared among the lithium monotherapy group, the valproate monotherapy group, and the mood stabilizer combination group. Clinical correlates of long-term treatment response were evaluated in lithium users and valproate users separately. Results: There were no significant differences in terms of baseline illness characteristics among groups. The combination group showed the worst treatment response for all the response measurements applied. This group also had the higher rate of 'poor responder' with a statistically significant difference compared to valproate group. Older age at onset and (hypo)manic episode at onset showed significant positive associations with total Alda score in lithium users, while comorbid anxiety disorders, obsessive–compulsive disorder and mixed episode showed significant negative associations in valproate users. Conclusions: The combination group had poorer long-term treatment response but did not show distinct clinical characteristics compared to the monotherapy groups. When exploring the long-term effects of mood stabilizers, excluding patients undergoing combination treatment could result in bias because they may represent a poor response group. The long-term treatment responses of lithium and valproate had different clinical correlates. [ABSTRACT FROM AUTHOR]

Lithium (Li) is the cornerstone maintenance treatment for bipolar disorders (BD), but response rates are highly variable. To date, no clinical or biological marker is available to reliably define eligibility criteria for a maintenance treatment with Li. We examined whether the prophylactic response to Li (assessed retrospectively) is associated with distinct blood DNA methylation profiles. Bisulfite-treated total blood DNA samples from individuals with BD type 1 (15 excellent-responders (LiERs) versus 11 non-responders (LiNRs)) were used for targeted enrichment of CpG rich genomic regions followed by high-resolution next-generation sequencing to identify differentially methylated regions (DMRs). After controlling for potential confounders we identified 111 DMRs that significantly differ between LiERs and LiNRs with a significant enrichment in neuronal cell components. Logistic regression and receiver operating curves identified a combination of 7 DMRs with a good discriminatory power for response to Li (Area Under the Curve 0.806). Annotated genes associated with these DMRs include Eukaryotic Translation Initiation Factor 2B Subunit Epsilon (EIF2B5), Von Willebrand Factor A Domain Containing 5B2 (VWA5B2), Ral GTPase Activating Protein Catalytic Alpha Subunit 1 (RALGAPA1). Although preliminary and deserving replication, these results suggest that biomarkers of response to Li may be identified through peripheral epigenetic measures. [ABSTRACT FROM AUTHOR]

Introduction: Lithium is a medication indicated for the treatment of bipolar disorder and treatment-resistant depression, with a narrow therapeutic index. Overdose, either acute or chronic can result in neurological symptoms, requiring dialysis and admission to intensive care in some cases. Lithium toxicity is avoidable with careful monitoring. However, we have noted several recent cases of lithium toxicity in our local service and thus sought to investigate this issue in a more systematic manner. Aim: We aimed to quantify the incidence of lithium toxicity in our local population over a single year and identify the patients most at risk. We also aimed to generate clinical recommendations on the prevention of lithium toxicity to improve patient safety. Method: We identified the incidence of lithium toxicity in our local population, by searching the hospital pathology database for patients with serum lithium levels greater than 1.0 mmol/L. We examined the available clinical notes for these patients. Results: We identified 74 serum lithium readings above 1.0 mmol/L measured in 44 individual patients. The highest recorded level was 3.2 mmol/L. Of these, 11 patients were aged 65 years or older. Hospital admission was required in 14 cases. There were missing data of note: 29.5% had no renal function/eGFR measurement at time of toxicity and 52.3% without a baseline eGFR. Conclusion: Lithium toxicity is common in our population. Given the narrow therapeutic index, this demonstrates the need for careful monitoring and prescribing, especially patients aged 65 and over. [ABSTRACT FROM AUTHOR]

Lithium compounds have been widely used in psychopharmacology, particularly in the treatment of bipolar disorder. Their normothymic and neuroprotective properties when used at high doses have been well established. However, a number of observations suggest that environmentally relevant lithium doses may also exert beneficial health effects, leading to a decrease in the rate of suicides and levels of violence. Despite the fact that this element is not officially considered to be a micronutrient, some authors have suggested provisional recommended intakes set at 1000 μg/day for a 70-kg adult (14.3 μg/kg body weight). The present paper reviews the biological action of lithium, its bioavailability and metabolism, and content in different foodstuffs and water. It also assesses epidemiological data on potential correlations between lithium intake and suicide rate as well as examines the concept of fortifying food with this element as a strategy in the primary prevention of mood disorders and pre-suicidal syndrome. [ABSTRACT FROM AUTHOR]

Purpose: Lithium (Li), the first-line treatment of bipolar disorder, was first developed as an immediate-release form with a routine therapeutic drug monitoring 12 h after the last dose. In Europe, the most commonly prescribed form is a sustained release (srLi). Yet no pharmacokinetics (PK) study has been published of srLi, administered once a day, in adults. The present study describes srLi PK in the serum and erythrocytes of bipolar patients.Methods: To assess srLi PK, we studied prospectively 17 French bipolar patients on a median dose of 1000 mg (600-1600) for at least 2 years. Serum (S), erythrocyte (E) concentrations, and urinary (U) amount were collected over 8 h after 15 days of morning intake using monitoring electronic medical system (MEMs). Population PK parameters were estimated using the SAEM algorithm (MONOLIX 4.3.3 software).Results: Using a population approach, we built a PK population model of srLi including one S compartment (VS = 23.0 L, ClS = 1.21 L h−1), one E compartment (VE = 64.7 L, ClSE = 3.63 L h−1, ClES = 9.46 L h−1), and one U compartment (F = 0.62) and estimate the ratio of concentrations to Li in E over S at 0.38 with 27% between-subject variability.Conclusion: This is a PK model of srLi once a day in bipolar patients using a population approach simultaneously describing Li concentrations in serum, erythrocytes, and urine which provide an estimate of the ratio of concentration in erythrocyte over serum and its between-subject variability (BSV). [ABSTRACT FROM AUTHOR]

Personalized medicine (personalized psychiatry in a specific setting) is a new model towards individualized care, in which knowledge from genomics and other omic pillars (microbiome, epigenomes, proteome, and metabolome) will be combined with clinical data to guide efforts to new drug development and targeted prescription of the existing treatment options. In this review, we summarize pharmacogenomic studies in mood disorders that may lay the foundation towards personalized psychiatry. In addition, we have discussed the possible strategies to integrate data from omic pillars as a future path to personalized psychiatry. So far, the progress of uncovering single nucleotide polymorphisms (SNPs) underpinning treatment efficacy in mood disorders (e.g., SNPs associated with selective serotonin re-uptake inhibitors or lithium treatment response in patients with bipolar disorder and major depressive disorder) are encouraging, but not adequate. Genetic studies have pointed to a number of SNPs located at candidate genes that possibly influence response to; (a) antidepressants COMT, HTR2A, HTR1A, CNR1, SLC6A4, NPY, MAOA, IL1B, GRIK4, BDNF, GNB3, FKBP5, CYP2D6, CYP2C19, and ABCB1 and (b) mood stabilizers (lithium) 5- HTT, TPH, DRD1, FYN, INPP1, CREB1, BDNF, GSK3β, ARNTL, TIM, DPB, NR3C1, BCR, XBP1, and CACNG2. We suggest three alternative and complementary strategies to implement knowledge gained from pharmacogenomic studies. The first strategy can be to implement diagnostic, therapeutic, or prognostic genetic testing based on candidate genes or gene products. The second alternative is an integrative analysis (systems genomics approach) to combine omics data obtained from the different pillars of omics investigation, including genomics, epigenomes, proteomics, metabolomics and microbiomes. The main goal of system genomics is an identification and understanding of biological pathways, networks, and modules underlying drug-response. The third strategy aims to the development of multivariable diagnostic or prognostic algorithms (tools) combining individual's genomic information (polygenic score) with other predictors (e.g., omics pillars, neuroimaging, and clinical characteristics) to finally predict therapeutic outcomes. An integration of molecular science with that of traditional clinical practice is the way forward to drug discoveries and novel therapeutic approaches and to characterize psychiatric disorders leading to a better predictive, preventive, and personalized medicine (PPPM) in psychiatry. With future advances in the omics technology and methodological developments for data integration, the goal of PPPM in psychiatry is promising. [ABSTRACT FROM AUTHOR]

Despite its virtually universal acceptance as the gold standard in treating bipolar disorder, prescription rates for lithium have been decreasing recently. Although this observation is multifactorial, one obvious potential contributor is the side effect and toxicity burden associated with lithium. Additionally, side effect concerns assuredly play some role in lithium nonadherence. This paper summarizes the knowledge base on side effects and toxicity and suggests optimal management of these problems. Thirst and excessive urination, nausea and diarrhea and tremor are rather common side effects that are typically no more than annoying even though they are rather prevalent. A simple set of management strategies that involve the timing of the lithium dose, minimizing lithium levels within the therapeutic range and, in some situations, the prescription of side effect antidotes will minimize the side effect burden for patients. In contrast, weight gain and cognitive impairment from lithium tend to be more distressing to patients, more difficult to manage and more likely to be associated with lithium nonadherence. Lithium has adverse effects on the kidneys, thyroid gland and parathyroid glands, necessitating monitoring of these organ functions through periodic blood tests. In most cases, lithium-associated renal effects are relatively mild. A small but measurable percentage of lithium-treated patients will show progressive renal impairment. Infrequently, lithium will need to be discontinued because of the progressive renal insufficiency. Lithium-induced hypothyroidism is relatively common but easily diagnosed and treated. Hyperparathyroidism from lithium is a relatively more recently recognized phenomenon. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) is a chronic psychiatric illness with an unknown etiology. Lithium is considered the cornerstone in the management of BD, though about 50-60 % of patients do not respond sufficiently to chronic treatment. Insulin-like growth factor 1 ( IGF1) has been identified as a candidate gene for BD susceptibility, and its low expression has been suggested as a putative biomarker for lithium unresponsiveness. In this study, we examined the in vitro effects of insulin-like growth factor 1 (IGF-1) on lithium sensitivity in lymphoblastoid cell lines (LCLs) from lithium responder (R) and non-responder (NR) bipolar patients. Moreover, we evaluated levels of microRNA let-7c, a small RNA predicted to target IGF1. We found that exogenous IGF-1 added to serum-free media increased lithium sensitivity selectively in LCLs from NR BD patients. However, no significant differences were observed when comparing let-7c expression in LCLs from R vs. NR BD patients. Our data support a key role for IGF-1 in lithium resistance/response in the treatment of bipolar disorder. [ABSTRACT FROM AUTHOR]

After decades of research, the mechanism of action of lithium in preventing recurrences of bipolar disorder remains only partially understood. Lithium research is complicated by the absence of suitable animal models of bipolar disorder and by having to rely on in vitro studies of peripheral tissues. A number of distinct hypotheses emerged over the years, but none has been conclusively supported or rejected. The common theme emerging from pharmacological and genetic studies is that lithium affects multiple steps in cellular signaling, usually enhancing basal and inhibiting stimulated activities. Some of the key nodes of these regulatory networks include GSK3 (glycogen synthase kinase 3), CREB (cAMP response element-binding protein) and Na+-K+ ATPase. Genetic and pharmacogenetic studies are starting to generate promising findings, but remain limited by small sample sizes. As full responders to lithium seem to represent a unique clinical population, there is inherent value and need for studies of lithium responders. Such studies will be an opportunity to uncover specific effects of lithium in those individuals who clearly benefit from the treatment. [ABSTRACT FROM AUTHOR]

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Recent high-quality studies have confirmed the central role of lithium in the treatment of bipolar disorder and have established lithium as the drug of first choice for long-term prophylaxis in this condition. However, several indications for its use in unipolar major depression are also based on sound evidence. This includes lithium augmentation as a main strategy for depressed patients not responding to an antidepressant, lithium prophylaxis for recurrent unipolar depression as an alternative to prophylaxis with an antidepressant, and lithium's unique anti-suicidal properties. Lithium monotherapy, on the other hand, is not established for acute treatment of depression. Lithium therapy should be a core competency of every psychiatrist, enabling the safe use of lithium, to the benefit of our patients. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase (GSK3) is a constitutively active serine-threonine kinase associated to neurological and psychiatric disorders. GSK3 inhibition is considered a mediator of the efficacy of the mood-stabiliser lithium. This study aimed at comparing the central nervous system effect of lithium with the selective GSK3 inhibitors AZ1080 and compound A in biochemical, cellular, and behavioural tests. Collapsin response mediator protein 2 is a neuron-specific GSK3 substrate. Lithium, AZ1080, and compound A inhibited its phosphorylation in rat primary neurons with different pIC. After systemic treatments with lithium or GSK3 inhibitors to assess specific functional responses, phosphorylation was unchanged in adult rat brain, while it was strongly inhibited by GSK3 inhibitors in pups, differently from lithium. Lithium may exert neurotrophic effect by increasing brain-derived neurotrophic factor (BDNF) levels: in the present experimental conditions, lithium exerted opposite effects on plasma BDNF levels compared to GSK3 inhibitors, suggesting this effect might not be necessarily mediated by GSK3 inhibition alone. While plasma thyroid-stimulating hormone and luteinising hormone were not affected by lithium, they were decreased by selective inhibitors. GH and prolactin displayed similar responses towards reduction. Follicle-stimulating hormone levels were not altered by treatments, whereas melatonin was specifically increased by AZ1080. Lithium impaired mouse spontaneous locomotion and decreased amphetamine-induced hyper-locomotion. AZ1080 had no effects on locomotion, while compound A reduced spontaneous locomotor activity without effects on amphetamine-induced hyper-locomotion. The present results indicate that a broad correlation between the effects of lithium and selective GSK3 inhibitors could not be devised, suggesting alternative mechanisms, whereas overlapping results could be obtained in specific assays. [ABSTRACT FROM AUTHOR]

Background: Lithium is a mood stabilizer with both antidepressant and antimanic properties, however its mechanism of action is unclear. Identifying the genetic factors that influence lithium's therapeutic actions will be an important step to assist in identifying such mechanisms. We previously reported that lithium treatment of male mice has antidepressant-like effects in the C57BL/6J strain but that such effects were absent in the BALB/cJ strain. Objectives: This study aimed to assess the roles of both genetic and non-genetic factors such as sex and non-shared environmental conditions that may mediate differential behavioral responses to lithium. Methods: Mice were treated with lithium for 10 days and then tested in the forced swim test followed by lithium discontinuation and retesting to assess effects of lithium withdrawal. We also assessed effects of sex and cross-fostering on lithium response between the C57BL/6J and BALB/cJ strains, and antidepressant-like effects of lithium in the hybrid CB6F1/J strain that is derived from C57BL/6J and BALB/cJ parental strains. Results: Neither sex nor maternal care significantly influenced the differential antidepressant-like response to lithium. Withdrawal from lithium treatment reversed antidepressant-like effects in the C57BL/6J strain but had no effects in BALB/cJ mice. Lithium treatment did not result in antidepressant-like effects in the CB6F1/J strain. Conclusions: Genetic factors are likely primarily responsible for differential antidepressant-like effects of lithium in the C57BL/6J and BALB/cJ strains. Future studies identifying such genetic factors may help to elucidate the neurobiological mechanisms of lithium's therapeutic actions. [ABSTRACT FROM AUTHOR]

Lithium carbonate is used in the treatment of both psychiatric and nonpsychiatric disorders. The aim of this study was to explore the relationship between serum lithium, salivary lithium, and urinary lithium. Blood, saliva, and urine samples were collected from 50 patients, and estimation of serum, salivary, and urine lithium was done using an atomic absorption spectrophotometer. Mean serum lithium was 0.75 ± 0.25 mEq/L, mean salivary lithium was 1.91 ± 0.80 mEq/L, and mean urine lithium was 7.16 ± 4.84 mEq/L. A significant direct correlation was found between serum lithium and salivary lithium ( r = 0.695, p < 0.001). This correlation was higher in females ( r = 0.770, p < 0.001) when compared to males ( r = 0.665, p < 0.001). Even though a significant correlation was found between serum and salivary lithium levels, more studies are needed in this domain to establish salivary therapeutic monitoring as a feasible option for patients on lithium carbonate therapy. [ABSTRACT FROM AUTHOR]

The current statement is a systematic review of the available data concerning the efficacy of medication treatment of bipolar disorder (BP). A systematic MEDLINE search was made concerning the treatment of BP (RCTs) with the names of treatment options as keywords. The search was updated on 10 March 2012. The literature suggests that lithium, first and second generation antipsychotics and valproate and carbamazepine are efficacious in the treatment of acute mania. Quetiapine and the olanzapine-fluoxetine combination are also efficacious for treating bipolar depression. Antidepressants should only be used in combination with an antimanic agent, because they can induce switching to mania/hypomania/mixed states/rapid cycling when utilized as monotherapy. Lithium, olanzapine, quetiapine and aripiprazole are efficacious during the maintenance phase. Lamotrigine is efficacious in the prevention of depression, and it remains to be clarified whether it is also efficacious for mania. There is some evidence on the efficacy of psychosocial interventions as an adjunctive treatment to medication. Electroconvulsive therapy is an option for refractory patients. In acute manic patients who are partial responders to lithium/valproate/carbamazepine, adding an antipsychotic is a reasonable choice. The combination with best data in acute bipolar depression is lithium plus lamotrigine. Patients stabilized on combination treatment might do worse if shifted to monotherapy during maintenance, and patients could benefit with add-on treatment with olanzapine, valproate, an antidepressant, or lamotrigine, depending on the index acute phase. A variety of treatment options for BP are available today, but still unmet needs are huge. Combination therapy may improve the treatment outcome but it also carries more side-effect burden. Further research is necessary as well as the development of better guidelines and algorithms for the step-by-step rational treatment. [ABSTRACT FROM AUTHOR]

Little is known regarding the mechanisms underlying the complex etiology of mood disorders, represented mainly by major depressive disorder and bipolar disorder. The 1996 discovery that lithium inhibits glycogen synthase kinase-3 (GSK3) raised the possibility that impaired inhibition of GSK3 is associated with mood disorders. This is now supported by evidence from animal biochemical, pharmacological, molecular, and behavioral studies and from human post-mortem brain, peripheral tissue, and genetic studies that are reviewed here. Mood disorders may result in part from impairments in mechanisms controlling the activity of GSK3 or GSK3-regulated functions, and disruptions of these regulating systems at different signaling sites may contribute to the heterogeneity of mood disorders. This substantial evidence supports the conclusion that bolstering the inhibitory control of GSK3 is an important component of the therapeutic actions of drugs used to treat mood disorders and that GSK3 is a valid target for developing new therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: The effects of chronic lithium exposure on spatial memory in rats remain controversial. In this study a time course of the effects of lithium, administered systemically, on spatial memory acquisition in Morris water maze was investigated. Material and Methods: Lithium (600 mg/L) was administered to four groups of rats in their drinking water; the first group of animals received lithium for one week, the second group for two weeks, the third group for three weeks, and the fourth group for four weeks. As controls, four groups of animals received only normal drinking water for the same period of time. Toward the end of their lithium or water treatment, all animals were trained for four days; each day included one block and each block contained four trials. Test trials were conducted 48 hrs after completion of the lithium treatment. Escape latency, traveled distance and swimming speed were evaluated during testing trials. Brain tissues from animals were processed according to the standard protocols for immunohistochemical analysis. Results: Lithium treatment decreased escape latency and traveled distance, but not swimming speed, compared with controls, suggesting significant spatial memory acquisition enhancement by lithium. Quantitative analysis showed that lithium, particularly after four weeks of exposure, significantly increased the number and density of immunostained ChAT-containing (choline acetyltransferase) neurons in the medial septal area in comparison with control groups. There was also a significant correlation between the number of immunostained ChAT neurons and behavioral measures. Conclusion: These results suggest that chronic oral administration of lithium causes spatial memory acquisition improvement in rats and an increase in ChAT immunostaining levels in medial septal nuclei. [ABSTRACT FROM AUTHOR]

Lithium is established as an effective treatment of acute mania, bipolar and unipolar depression and as prophylaxis against bipolar disorder. Accumulating evidence is also delineating a neuroprotective and neurotrophic role for lithium. However, its primary effects on cognitive functioning remain ambiguous. The aim of this paper is to review and combine the relevant translational studies, focusing on the putative cognitive enhancement properties of lithium, specifically on learning, memory, and attention. These properties are also discussed in reference to research demonstrating a protective action of lithium against cognitive deficits induced by various challenges to the nervous system, such as stress, trauma, neurodegenerative disorders, and psychiatric disorders. It is suggested on the basis of the evidence that the cognitive effects of lithium are best expressed and should, therefore, be sought under conditions of functional or biological challenge to the nervous system. [ABSTRACT FROM AUTHOR]

Approximately one of six patients who seek treatment for bipolar disorder present with a rapid cycling pattern. In comparison with other patients who have bipolar disorder, these individuals experience more affective morbidity in both the immediate and distant future and are more likely to experience recurrences despite treatment with lithium or anticonvulsants. Particular care should be given to distinguishing rapid cycling bipolar disorder from attention-deficit hyperactivity disorder in children or adolescents and from borderline personality disorder in adults. Perhaps four of five cases of rapid cycling resolve within a year, but the pattern may persist for many years in the remaining patients. As with bipolar disorder in general, depressive symptoms produce the most morbidity over time. Controlled studies have not established that antidepressants provoke switching or rapid cycling, but neither have they been shown consistently to have benefits in bipolar illness. Successful management will often require a sequence of trials with mood stabilizer drugs, beginning with lithium in treatment-naive patients. Efforts to minimise adverse effects, and the recognition that full benefits may not be apparent for several months, will make the premature abandonment of a potentially helpful treatment less likely. Placebo-controlled studies so far provide the most support for the use of lithium and lamotrigine as prophylactic agents. The combination of lithium and carbamazepine, valproate or lamotrigine for maintenance has some support from controlled studies, as does the adjunctive use of olanzapine. [ABSTRACT FROM AUTHOR]

We previously reported an association between the functional polymorphism in the upstream regulatory region of the serotonin transporter gene (SERTPR) and the prophylactic efficacy of lithium in a sample of 201 Italian subjects affected by Mood disorders. The aim of the present study was to replicate analyses on an independent sample. In total, 83 subjects affected by Bipolar disorder were recruited in the Mood Disorders Clinic of the Eginition Hospital of the Athens University, Medical School Department of Psychiatry. All patients were administered with lithium as prophylactic therapy and they were prospectively observed for at least 3 years. Subjects were typed for their SERTPR variant using polymerase chain reaction techniques. SERTPR variants were associated with lithium outcome among those subjects who had few manic episodes before lithium treatment and, as a trend, among subjects who received a high daily dose of lithium (?1200?mg/die). In both cases, subjects with the l/l variant showed a higher probability to develop an illness episode within 3 years of prophylactic treatment with lithium. The present study confirmed our previous observation of a better response of SERTPR*l/s carriers, but could not confirm a poor efficacy in subjects with the SERTPR*s/s genotype. Notwithstanding the conflicting results, SERTPR variants are a possible liability factor for lithium long-term efficacy in mood disorders. Further studies on independent and large samples are required to determine the reliability and direction of the possible association between SERTPR variants and lithium outcome.The Pharmacogenomics Journal (2004) 4, 267-273. doi:10.1038/sj.tpj.6500252 Published online 27 April 2004 [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) is a major psychiatric condition that commonly requires prophylactic and episodic treatment. There is important variability in the therapeutic response and side-effect profiles to currently available pharmacological agents. Pharmacogenetics have provided new hopes to develop more efficient treatment strategies tailored to the individual patient's needs. This review assesses nonsystematically studies using pharmacogenetic strategies in BD. Most of these studies have focused on patients selected according to lithium response, and more recently, a growing number of studies have been investigating genetic factors in mixed samples of patients classified according to response to antidepressant treatment. Although previous clinical and family studies support the use of pharmacogenetic strategies both to increase phenotype homogeneity as well as to identify genetic factors that may mediate response to treatment, most molecular studies carried out to date are still preliminary and in need of external validation. A major problem has been comparability between studies, in part, because of differences in the criteria used to define response. More attention should be paid to standardize the criteria for drug response definition.The Pharmacogenomics Journal (2004) 4, 161-170. doi:10.1038/sj.tpj.6500245 Published online 13 April 2004 [ABSTRACT FROM AUTHOR]

Rationale. Adverse cognitive effects associated with lithium are often implicated as contributing to vocational and social impairment, as well as medication noncompliance. As impaired cognitive functioning caused by lithium has clear clinical implications, it is important to determine whether evidence for or against impaired cognitive functioning exists in the literature. Objectives. An attempt is made to synthesize findings from previous studies, which assess a variety of cognitive domains, to determine whether conclusions can be drawn regarding lithium-associated cognitive impairment. The "reversibility" of neuropsychological impairment following lithium discontinuation and whether lithium administration has negative cumulative effects on cognition were also reviewed. Methods. Key word searches on "Medline" and "Psych Info" were completed for clinical articles that investigated the neuropsychological effects of lithium in clinical and normal populations between 1968 and 2000. Results. Despite methodological flaws, poor replicability and the subtle cognitive effects of lithium, five consistent findings emerged from the review; impairment on tasks of psychomotor speed, impaired functioning in the majority of studies examining verbal memory, no impairment on tasks of visuo-spatial constructional ability or attention/ concentration, and no negative cumulative effect. Conclusions. Many patients administered lithium carbonate complained of mental slowness. Lithium carbonate also appeared to have definite, yet subtle, negative effects on psychomotor speed. Studies reviewed also showed a trend toward impaired verbal memory. Recommendations with respect to future research, methodological and statistical problems, and additional clinical implications are presented. [ABSTRACT FROM AUTHOR]

Breakthrough depression is a common problem in the treatment of bipolar disorder. Only one, recently published, double-blind, placebo-controlled trial has examined the efficacy of divalproex in the prevention of depressive episodes in bipolar patients. This report describes, in further detail, the findings from that trial of the effect of divalproex on multiple dimensions of depressive morbidity in bipolar disorder. A randomized, double-blind, parallel-group, multicenter study was conducted over a 52-week maintenance period. Bipolar I patients, who may have been treated with open-label lithium or divalproex and who met recovery criteria within 3 months of onset of an index manic episode, were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2 : 1 : 1 ratio. Adjunctive paroxetine or sertraline for breakthrough depression was allowed in maintenance phase. Outcome measures were the rate of early discontinuation for depression, time to depressive relapse, proportion of patients with depressive relapse, mean change in Depressive Syndrome Scale score, proportion of patients receiving antidepressants, and time in the study. Among patients taking an antidepressant, a higher percentage of patients on placebo than divalproex discontinued early for depression. Patients who were previously hospitalized for affective episodes or took divalproex in the open period relapsed later on divalproex than on lithium during the maintenance period. Divalproex-treated patients had less worsening of depressive symptoms than lithium-treated patients during maintenance. Indices of severity of prestudy illness course predicted worse outcome in all treatment groups. Divalproex improved several dimensions of depressive morbidity and reduced the probability of depressive relapse in bipolar disorder, particularly in patients who had responded to divalproex when manic, and among patients with a more severe course of illness. [ABSTRACT FROM AUTHOR]

Beyond its prophylactic efficacy lithium has demonstrated possibly specific antisuicidal effects. Lithium significantly reduces the high excess mortality of patients with affective disorders. Appropriate lithium prophylaxis prevents ca. 250 suicides per year in Germany although lithium salts are prescribed within the National Health Scheme at low frequency (0.06% of the population). Rational treatment strategies most likely would demand for about 10 times higher prescription rates. Guidelines and algorithms for selecting an appropriate prophylactic strategy in affective disorders should take into consideration the suicide risk of an individual patient. [ABSTRACT FROM AUTHOR]

Experiences of early life stress are more prevalent among depressed patients than healthy controls. Neuropeptide Y (NPY) was suggested to play a role in the pathophysiology of depression. Consequently, we investigated in adult rats the effects of maternal deprivation for 3 h/day during postnatal days (PND) 2–14 and of dietary lithium during PND 50–83 on brain levels of NPY-like immunoreactivity (LI). Brain levels of corticotropin-releasing hormone (CRH) and serum corticosterone were also measured. Maternal deprivation reduced NPY-LI levels in the hippocampus and the striatum but increased NPY-LI and CRH-LI levels in the hypothalamus. Lithium treatment counteracted the effect of maternal deprivation in the hippocampus and striatum by increasing NPY-LI levels. In the hypothalamus, lithium tended to decrease CRH-LI but further increased levels of NPY-LI; it also increased serum corticosterone levels. The results suggest that early life stress has long-term effects on brain NPY with implications for the development of depression/vulnerability to stress, and that one therapeutic mechanism of action of lithium is to increase brain NPY. [Copyright &y& Elsevier]

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The evidence is reviewed for effective serum lithium concentrations for the acute and prophylactic treatment of mania and depression in patients with bipolar disorder. The efficacy of lithium in the treatment of acute manic episodes has been recognised for several decades, primarily using concentrations in the range of 0.8 to 2 mmol/L. The number of patients responding increases as the serum lithium concentration increases, although individual patients may respond at lower concentrations (<0.8 mmol/L). Lithium doses and serum concentrations similar to those used to treat acute mania have been studied in bipolar depression, with no evaluation of a relationship between concentration and clinical response. Several prospective controlled trials have evaluated this relationship in the prophylactic treatment of bipolar disorder. Maintaining higher serum lithium concentrations (0.8 to 1 mmol/L) improves the likelihood of good effect in prophylactic treatment, although individual patients may do well on lower concentrations. Despite the paucity of evidence to specifically support the efficacy of lithium at lower serum lithium concentrations in the elderly, lower target ranges (0.5 to 0.8 mmol/L) are commonly recommended due to an increased sensitivity to adverse effects, particularly neurotoxicity. The serum lithium concentrations recommended in adults have been applied to children; however, this has not been studied. Overall, the evidence suggests a relationship between serum lithium concentration and therapeutic effect, although the exact nature of this relationship is not clear. For example, it is not known why some people respond to lower concentrations and others do not. There are many factors that influence studies trying to elucidate this relationship. Many of these factors are related to the interpretation of the serum lithium concentration. In summary, patients have an increased chance of responding to lithium if 12-hour serum lithium concentrations at steady state are above 0.8 mmol/L. Many patients will respond to lower concentrations (0.4 to 0.7 mmol/L), but we are unable to identify these patients a priori. The relationship between serum lithium concentrations and adverse effects is also very important in determining appropriate target lithium concentrations. The current best advice is to individualise the target serum lithium concentrations based on efficacy and tolerability and to optimise the interpretation of these concentrations by ensuring within-patient consistency with respect to dosage schedule, lithium preparation and the timing of blood sampling. [ABSTRACT FROM AUTHOR]

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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 o... [ABSTRACT FROM AUTHOR]

Background: Recent estimates of the cost of manic-depressive illness totaled roughly $45 billion in 1991. Using data from the Epidemiological Catchment Area (ECA) study, this study estimates the savings brought about by the use of lithium between 1970 and 1991. Methods: Total savings are the difference between estimated actual costs and projected costs had lithium never been introduced. Actual yearly costs were interpolated from data for 1970 and 1991, and projected costs were obtained by adjusting 1970 costs with Consumer Price Index (CPI) and population inflaters. All costs for 1970 were obtained using methods almost identical to those used to calculate the 1991 costs of manic-depressive illness, presented in a previous publication. All savings are presented in 1991 dollars. Results: Between 1970 and 1991, lithium saved over $170 billion, or roughly over $8 billion per year. Approximately $15 billion in direct costs, which included inpatient and outpatient care as well as research, was saved between 1970 and 1991. The savings are more dramatic for indirect costs, which include the lost productivity of wage-earners, homemakers, family caregivers, and individuals who are in institutions or who committed suicide; these totaled roughly $155 billion. Conclusions: Our results suggest that, although manic-depressive illness is still costly, lithium has been tremendously successful in treating the illness, and has provided enormous financial savings in the process. [ABSTRACT FROM AUTHOR]

For over 25 years lithium was regarded as the drug of choice for prophylactic treatment in patients with bipolar disorder. More recently its place in the long term management of this condition has been questioned. A number of long term naturalistic studies have revealed that lithium is less effective in clinical practice than would be anticipated from clinical trial data. A major factor contributing to this discrepancy is the poor adherence to medication shown by over a third of patients taking the drug long term. Another possible reason is a broadening of the diagnostic criteria for bipolar disorder to include patients with mood-incongruent psychotic symptoms and/or comorbid substance abuse. Following initially favourable reports from open studies, the anticonvulsant compounds carbamazepine and valproic acid (sodium valproate) have come to be widely used in the long term management of bipolar disorder. However, there is, thus far, little confirmatory evidence from controlled clinical trials to support this practice. The same is true for the use of the newer atypical antipsychotics and the newer anticonvulsants in the treatment of bipolar disorder. Until there is convincing evidence from controlled clinical trials that these alternatives are superior to lithium in improving the overall well-being of patients with bipolar disorder, it is my opinion that lithium remains the drug of choice. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the possible pharmacokinetic interaction between nefazodone and lithium. Methods: Twelve healthy volunteers received nefazodone 200 mg b.i.d. for 5 days. A 4-day washout phase followed from day 6 to day 9. From day 10 to day 20, escalating doses of lithium 250 mg b.i.d. to 500 mg b.i.d. were given; the daily dose of 1000 mg was obtained on day 13. From day 16 to day 20, nefazodone 200 mg b.i.d. was added to the lithium dosing regimen. Venous blood sampling was performed on days 5, 15 and 20 for 0- to 48-h-pharmacokinetic analysis. Nefazodone and its metabolites, hydroxynefazodone, mCPP and triazoledione were assayed by high-performance liquid chromatography (HPLC). Lithium was assayed by flame photometry. Results: Co-administration of nefazodone did not modify pharmacokinetic parameters of lithium at steady-state. Comparison of the area under the plasma or serum concentration-versus-time curve calculated from 0–12 h (AUC0–12) of nefazodone and hydroxynefazodone revealed no significant differences when nefazodone was administered alone or with lithium. The mean maximum peak plasma concentration Cmax and AUC0–12 of meta-chlorophenyl-piperazine (mCPP) were significantly reduced by 27% ( P <0.001) and 16% ( P <0.001) with the co-administration. The mean Cmax and AUC0–12 of triazoledione were reduced by 23% ( P <0.005) and 16% ( P <0.01) by the co-administration. Conclusion: Since there were no clinically significant changes in the pharmacokinetics of the parent compounds or metabolites, and the combination was well tolerated, no dosage adjustments of nefazodone or lithium are necessary when they are co-administered. [ABSTRACT FROM AUTHOR]

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Drug-induced diabetes insipidus is always of the nephrogenic type, i.e. unresponsiveness of the kidneys to the action of antidiuretic hormone. This condition is easily diagnosed by measuring urinary concentrating capacity during a thirst test (e.g. 12 hours of water deprivation) or by administration of a modified antidiuretic hormone, desmopressin, to demonstrate the renal unresponsiveness. Drug-induced nephrogenic diabetes insipidus is not a common disorder except in patients receiving treatment with lithium salts for affective disorders where it may affect about 10% of patients treated long term (15 years). Drug-induced nephrogenic diabetes insipidus caused by other drugs usually occurs in critically ill patients in intensive care units receiving a multitude of drugs dominated by antimicrobials and cytostatics. A search of the World Health Organization's adverse effect database revealed 359 reports of drug-induced diabetes insipidus. Lithium was the most common cause (159 reports) followed by foscarnet (15) and clozapine (10). Treatment is symptomatic in most patients and the offending drug should be stopped. If urine volumes exceed 4 L/day, treatment with thiazides and amiloride has been advocated, and nonsteroidal anti-inflammatory drugs, such as indomethacin, may be tried in severe cases. Prevention of lithium-induced nephrogenic diabetes insipidus is an important aspect of the treatment of affective disorders. In patients treated long term it appears to be only partly reversible upon lithium discontinuation. Close monitoring of the treatment aiming at 12-hour trough value of 0.4 to 0.6 mmol/L is recommended. Yearly measurement of the urinary volume/day is effective in making both the patient and the physician aware of the development of the drug-induced nephrogenic diabetes insipidus. The condition is a serious adverse effect because of the risk of developing dehydration and aggravation of drug intoxications. [ABSTRACT FROM AUTHOR]

An analysis of the single and multiple dose pharmacokinetics of lithium in 7 healthy volunteers is presented. A solution of lithium chloride was administered in single dose experiments and the same solution and a sustained release preparation were employed in multiple dose experiments, which were carried out at steady state. A fixed dose of 24 mmol was used in the single dose experiments and in the subsequent multiple dose experiments in the same subjects the same dose was administered once daily for a week. Distinct two-compartment characteristics were found, with a mean disposition rate constant (β) of 0.035 h±0.010 SD, corresponding to a mean biological half-life of about 19.8 h. The mean half-time of the distributory α-phase was about 1.15 h. The absorption of lithium from an orally administered solution took place with a half-time of about 0.15 h in the single dose experiments. The apparent volume of distribution of the central compartment (V) was 0.307 1 kg±0.046 SD, less than half that of V at equilibrium. V (V) was 0.8291 kg±0.184 SD and mean total body clearance was 27.6 ml kg h±4.7 SD. [ABSTRACT FROM AUTHOR]