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Background The development of lithium-associated kidney damage is still a matter of controversy. We have addressed this question by investigating the role of somatic comorbidity for developing kidney failure in lithium treated patients. Methods The study group comprised of 1741 adult patients with normal creatinine levels at the start of lithium treatment. Patients who developed severe renal failure (CKD stages 4–5, n = 109), were matched by sex, time on lithium and age at start of lithium, with 109 controls (CKD stages 1–2) that did not develop severe renal failure. Results Patients in CKD 4–5 did not differ significantly from controls (CKD 1–2) in sex (females/males were 76/33 in both groups), time on lithium (mean 9.8 years, SD 6.4; vs. 9.6, SD 6.2) or age at start of lithium (mean 61.6 years, SD 13.4; vs. 60.5 years, SD 12.3), respectively. However, comparisons between groups showed a significantly higher prevalence of somatic comorbidity (p Limitations Patients in our study group were relatively old and the findings are therefore not generalizable to patients starting lithium at an early age. The retrospective design, relying on available charts, did not allow to grade severity of comorbid conditions other than need for hospitalisation or chronic drug treatment. Conclusions Our findings emphasize the role of somatic comorbidity for renal damage in lithium treated patients and especially the role of cardiovascular comorbidity. Monitoring of somatic comorbidity should be taken into account in treatment recommendations and safety routines in long-term prophylactic lithium treatment.

The primary aim of this study was to estimate the prevalence of lithium associated end-stage renal disease (ESRD) and to compare the relative risk of ESRD in lithium users versus non-lithium users. Second, the role of lithium in the pathogenesis of ESRD was evaluated. We used the Swedish Renal Registry to search for lithium-treated patients with ESRD among 2644 patients with chronic renal replacement therapy (RRT)-either dialysis or transplantation, within two defined geographical areas in Sweden with 2.8 million inhabitants. The prevalence date was December 31, 2010. We found 30 ESRD patients with a history of lithium treatment. ESRD with RRT was significantly more prevalent among lithium users than among non-lithium users (p

Aim: The aim of the study was to evaluate serum brain-derived neurotrophic factor (BDNF) levels in a group of euthymic bipolar patients on long-term prophylactic lithium treatment and to delineate putative relationships between lithium efficacy and BDNF concentrations. Methods: 141 euthymic bipolar patients (51 male, 90 female) on long-term lithium treatment were studied. Three categories of prophylactic lithium response were delineated: excellent lithium responders (ER; 30 patients), partial lithium responders (PR; 61 patients) and lithium nonresponders (NR; 50 patients). The control group consisted of 75 age- and gender-matched healthy subjects. Results: The lithium-treated patients as a whole group had lower BDNF levels compared to the healthy controls. However, after breaking down the patients into ER, PR and NR, it appeared that only NR had significantly lower BDNF levels compared with the healthy control subjects. No association between the age of the patients, duration of bipolar illness, and serum lithium and BDNF levels was found. Conclusion: The results point to a relationship between lithium prophylactic efficacy and plasma BDNF levels in euthymic bipolar patients where lithium NR had reduced BDNF levels. These findings suggest that serum BDNF is associated with lithium efficacy in bipolar disorder.

FYNbelongs to the protein kinase family that phosphorylates NMDA receptor subunits, participating in the regulation ofion transmission and BDNF/TrkB signal transduction pathway. Lithium inhibits glutamatergic transmission via NMDA receptors, exerting neuroprotective effect against excitotoxicity. The aim of this study was to find possible association of three polymorphisms of FYN gene with prophylactic lithium response in the group of bipolar patients. We analyzed 101 bipolar patients treated with lithium carbonate for 5‐27 years (mean 15 years). Twenty-four patients were identified as excellent lithium responders (ER), 51 patients as partial responders (PRs), and 26 patients were non-responders. Genotypes of the three analyzed polymorphisms were established by PCR-RFLP. Statistical analysis was done with Statistica. No significant differences in genotype distribution and allele frequencies were observed between T/G and A/G FYN polymorphisms and lithium response. We observed a trend toward association of TT genotype and T allele of T/C polymorphism with worse lithium response. The results of the study demonstrated only marginal association between FYN polymorphisms and prophylactic lithium response in bipolar patients. The results are discussed in light of our previous studies on FYN gene in bipolar illness and BDNF gene in lithium response. Copyright # 2009 John Wiley & Sons, Ltd.

Objectives The therapeutic action of lithium in bipolar mood disorder may be connected with its effect on biological rhythms. In the present study, an attempt was made to investigate an association between multiple single nucleotide polymorphisms (SNPs) and their haplotypes pertaining to four genes involved in regulation of biological rhythms [circadian locomotor output cycle kaput (CLOCK), aryl hydrocarbon receptor nuclear translocator-like (ARNTL), timeless circadian clock (TIMELESS), period circadian clock 3 (PER 3)], and the efficacy of lithium prophylaxis. Methods The study was performed on 115 patients with bipolar mood disorder (45 males, 70 females) with a mean age of 52 ± 12 years, with lithium prophylaxis for 22 ± 8 years, recruited from the outpatients in the Department of Psychiatry, Poznan University of Medical Sciences. The assessment of the lithium prophylactic response was made retrospectively using the Alda scale. Genotyping was done for nine SNPs of the CLOCK gene, 18 SNPs of the ARNTL gene, six SNPs of the timeless circadian clock (TIM) gene, and nine SNPs of the PER3 gene. Results An association with the degree of lithium prophylaxis was found for six SNPs and three haplotype blocks of the ARNTL gene, and two SNPs and one haplotype block of the TIM gene. No association with SNPs or haplotypes of the CLOCK and PER3 genes was observed. Conclusions The results suggest that the ARNTL and TIM genes may be associated with the lithium prophylactic response in bipolar illness. This association may be related to the role of these genes in the predisposition to bipolar mood disorder. Of special interest may be polymorphisms of these genes involved both in the predisposition to bipolar mood disorder and the lithium response.

Objectives: The aim of this study was to systematically integrate the available evidence on response prediction to prophylactic lithium based on clinical factors. Methods: Each clinical variable that was related to lithium response in at least one prior study was examined with respect to response prediction. If several studies were located for the same variable, results were integrated using the meta-analytic approach as suggested by DerSimonian and Laird which was developed for substantial heterogeneity in primary studies. Results: Of 42 potential clinical predictors investigated, five variables were identified as possible response predictors of prophylactic lithium: [1] An episodic pattern of mania-depression-interval, and [2] a high age of illness onset were identified as potentially protective against a recurrence under lithium. [3] A high number of previous hospitalizations, [4] an episodic pattern of depression-mania-interval, and [5] continuous cycling were identified as potential risk factors. Six further variables were found to be significantly related to lithium response, though calculation of fail-safe numbers indicates that current evidence is not sufficient to hold these variables as reliable predictors of lithium response. All effect-sizes relating clinical predictors to response were small to moderate. Conclusions: Although a few variables are quite robustly supported as response-predictors in this review, a more in-depth analysis of each potential predictor is needed. As none of the potential predictors had a very strong impact on response, prediction of lithium response should be based on a multitude of variables.

The neuroplasticity hypothesis of bipolar disorder indicates that the BDNF/Trk signaling pathway is associated with the pathogenesis of this illness and treatment with mood stabilizers, such as lithium. This paper describes a relationship between response to lithium prophylaxis and polymorphisms of two functionally connected genes: BDNF and NTRK2, in bipolar illness. Analyses of four SNPs of the BDNF gene (rs2030324, rs988748, rs6265 [Val66Met]and rs2203877) and three of the NTRK2 gene (rs1187326, rs2289656, rs1187327) were performed in the 108 bipolar patients, classified as excellent responders (23%), partial responders (51%) and nonresponders (26%) to lithium. An association of C/G (rs988748) and G/A (rs6265) polymorphisms of the BDNF gene with a degree of prophylactic lithium response were found. No association with lithium response was revealed with the polymorphism of NTRK2 gene, neither with interaction of BDNF and NTRK2 genes.

Introduction: Brain-derived neurotrophic factor (BDNF) has been involved in the pathogenesis of bipolar mood disorder and in the mechanism of mood-normalizing action of lithium. The aim of this study was to find a possible association between lithium prophylactic effect in bipolar patients and two polymorphisms of BDNF gene. Methods: Eighty-eight patients (35 males, 53 females) with bipolar illness were studied. Duration of lithium prophylaxis ranged between 5-27 years (mean 15 years). Three categories of prophylactic lithium response were delineated: excellent responders (ER), partial responders (PR) and non-responders (NR). All patients were genotyped for two polymorphisms of BDNF gene: Val66Met and -270C/T. Results: The Val/Met genotype of Val66Met polymorphism occurred more frequently (p = 0.037) and there was a trend for a higher incidence of Met allele (p = 0.076), in ER than in NR. A trend for C/T genotype and T allele of -270C/T polymorphism was observed to occur more frequently in ER than in NR (p = 0.057 and p = 0.065, respectively). Conclusion: The data obtained suggest that polymorphism of BDNF gene may be connected with a quality of lithium prophylaxis.

Though the pathogenesis of postoperative cognitive dysfunction (POCD) remains unclear, evidence is accumulating for a pivotal role of neuroinflammation in the disease process. Advanced age and severe surgical trauma are two main risk factors for POCD. Lithium, a neuroprotective agent, can alleviate peripheral surgery-induced memory impairment in aged rats. The results of in vivo and in vitro experiments also showed that toll like receptor 4 (TLR4) was associated with the occurrence and development of neuroinflammation and POCD. So we hypothesized that inhibition of TLR4 signaling in the hippocampus maybe involved in the protective effects of prophylactic lithium on the occurrence of inflammation and POCD. In the present study, we incubated BV-2 microglia with 1μg/ml lipopolysaccharide (LPS) to mimic neuroinflammation in vitro. We found that pretreatment with 10mM of lithium or 100nM of TLR4 siRNA could inhibit the tumor necrosis factor (TNF)-α and TLR4 mRNA expression induced by LPS in BV-2 microglia. Furthermore, combination of prophylactic lithium and TLR4 siRNA even decreased their mRNA expression to the baseline levels, which showed that TLR4 signaling may be vital in protective effects of prophylactic lithium on neuroinflammation. So we further undergone the in vivo experiment. Then, we firstly demonstrated that prophylactic 2mM/kg of lithium alleviated splenectomy-induced cognitive impairments, decreased splenectomy-associated systemic, central, and hippocampal TNF-α and interleukin (IL)-1β expression and reduced the increase of CD11b(+) area in hippocampal CA1 region caused by the surgery. Then, we also found that splenectomy merely increased hippocampal TLR2 and TLR4 mRNA levels in aged rats. At last, we confirmed that prophylactic lithium reduced the increased levels of hippocampal TLR4/NF-κB induced by splenectomy. Taken together, these results demonstrate that TLR4 signaling inactivation may contribute to the protective effects of prophylactic lithium on the occurrence of POCD by inhibiting systemic inflammation and especially neuroinflammation.

Postoperative cognition impairment is a perishing complication in elderly patients undergone surgeries. Lithium is widely used in psychiatric patients for its role in neuronal protection, whereas whether or not it could attenuate surgery-associated postoperative cognition dysfunction used prophylactically is not well defined. After approval by the Institutional Animal Care and Use Committee, 48 male Sprague-Dawley rats aged 18months old were randomly divided into three groups with 16 each: i, no surgeries and drugs were given; ii, surgical procedures were performed only without drug delivery; iii, prophylactic 2mM/kg lithium chloride was given intraperitoneally once a day for seven days before surgeries. The change in spatial memory was assessed with Morris Water Maze (MWM), and the activation of PI3K/AKT/mTOR pathway was detected, and the levels of hippocampal glycogen synthase kinase-3β (p-GSK-3β) phosphorylation at serine 9 and interleukin-1β (IL-1β) were measured. The MWM detection showed that both swimming latency and distance were considerably prolonged by the surgeries, but these changes could be markedly shortened by prophylactic lithium administration. Meanwhile, the changes in the hippocampal PI3K cascades and p-GSK-3β and IL-1β expression displayed corresponding changes that were parallel to the alterations of spatial memory, and inhibition of PI3K and GSK-3β suggested upstream PI3K activation leads to downstream change in p-GSK-3β and IL-1β. These results indicate, at least in part, that prophylactic lithium can alleviate surgery-associated impairment of the spatial memory in aged rats which is strongly associated with the reduced levels of hippocampal p-GSK-3β and IL-1β resulted from the activation of PI3K/AKT/mTORC2 pathway.

A predictor of clinical response to prophylactic lithium treatment in affective psychoses would be of considerable importance. In a pilot study, responders to prophylactic lithium medication, as compared with nonresponders, were characterized by a steeper slope of the amplitude/stimulus-intensity function (ASF slope) of the N1/P2 component of the auditory evoked potential. We tried to replicate this finding in 34 stabilized outpatients with affective illness who had been treated with lithium for at least 3 years. As in the pilot study, responders were again characterized by steeper ASF slopes than nonresponders. Since a steep ASF slope seems to indicate low central serotonergic function, it is speculated that a steep ASF slope characterizes those patients with a serotonin deficit who respond to serotonin agonists like lithium.

This review is based an relevant publications and addresses the following questions: Does lithium exert a recurrence-preventive, prophylactic action in manic-depressive illness? Has prophylactic treatment with anticonvulsants or antidepressants become preferable to lithium prophylaxis? Which drug or drugs should be first-choice prophylactic agent in bipolar and in unipolar manic-depressive illness?

The purpose of this study of 133 affective disorder patients consecutively referred to start prophylactic lithium treatment was to identify informative predictors of outcome. Non-adherence to treatment was mainly predicted by substance abuse and many earlier admissions. Non-response among the 78 patients adhering to lithium treatment was mainly predicted by female sex, young age and previously chronic course. The overall response rate was rather poor and an excess mortality rate was found. It is suggested that patients with substance abuse should not be offered prophylactic lithium treatment unless intensive control and support is practicable, and patients with a chronic course needa more effective treatment than lithium can offer.

Background Previously, we have found an association between the -48 A/G polymorphism of the dopamine receptor D1 (DRD1) gene and bipolar disorder. The aim of the present study was to investigate a possible association of this polymorphism with the quality of the prophylactic lithium response in bipolar patients. Methods Ninety-two patients (39 male, 53 female), aged 30-77 (mean: 54 years) were studied. They have received lithium for prophylactic purposes for 5-27 years (mean: 15 years). Twenty-four patients were identified as excellent lithium responders (ER), 48 patients as partial responders (PR), and 20 patients were non-responders (NR). They all were genotyped for -48 A/G polymorphism of the DRD1 gene. Results The frequency of G/G genotype in ER, PR, and NR patients was 21%, 48%, and 60%, respectively, and the frequency of G allele was 58%, 76%, and 80%, respectively. Discussion The results obtained suggest that the higher frequency of G allele, and G/G genotype, which has been associated with a predisposition to bipolar illness, is also connected with a poorer prophylactic effect of lithium.

Non-compliance is the most frequent cause of recurrence during prophylactic lithium treatment and is associated with poor response and high levels of suicidality. Non-compliance is a complex phenomenon and may have a number of causes. When manic-depressive patients fare badly under the conditions of so-called 'naturalistic' trials, this usually indicates that such conditions are inadequate for long-term maintenance treatment. Prophylactic lithium treatment must be accompanied by measures to sustain compliance and counteract drop-out, and these measures build on three cornerstones, namely information, support and supervision.

Introduction: Lithium has been found to be very effective in prophylactic treatment of affective disorders. However, approximately one-third of patients do not respond to this treatment, which does not become apparent until after a year or more of treatment. Therefore, predictors are needed to avoid a long and unsuccessful therapy with risk of severe side effects. Since lithium acts as a serotonin agonist in prophylactic treatment, a predictor of being able to identify patients with low serotonergic activity, who may be responders to lithium, is promising. To determine whether the loudness dependence (LDAEP) of primary, but not of secondary, auditory-cortex-evoked activity, which is inversely related to central serotonergic neurotransmission, could be such a predictor, responders and non-responders to prophylactic lithium treatment were compared. Methods: Thirty patients with uni- and bipolar affective disorders, who have taken a prophylactic lithium medication continuously for at least 3 years, were included in the study. Patients were classified as responders if they had no hospitalization within the past 3 years. Dipole source analysis allowing us to separate evoked activity of the primary and secondary auditory cortex was used. Results: The LDAEP of the primary, but not of the secondary, auditory cortex was significantly stronger in the responders to the lithium treatment than in the non-responders, implicating low serotonergic function in these patients. Discussion: This finding, which is in line with previous studies, suggests that loudness dependence of primary auditory-cortex-evoked activity could be a clinically relevant predictor of prophylactic treatment with lithium in affective disorders.

Sixty-eight bipolar patients in remission on lithium prophylaxis with adequate serum lithium levels were cross-sectionally studied to assess the relation of certain psychosocial variables (life events, social support and daily hassles) with psychopathology and psychosocial functioning. The daily hassles and number of life events were found to have significant positive correlation with Hamilton Depression Rating Scale (HDRS) scores while perceived social support score had significant negative correlation with general psychopathology score. In stepwise multiple regression analyses, psychosocial variables taken together explained 7% - 23% of variance in psychopathology and global functioning of these patients. We conclude that psychosocial variables may have a modest but significant relation with the clinical and psychosocial functioning of bipolar patients stabilized on lithium prophylaxis.

The search for predictors of outcome has not been particularly rewarding, and the use of lithium remains empirical: a trial of lithium is the most powerful predictor of outcome. However, lithium is a highly specific treatment for bipolar disorder. In non-bipolar affective disorder, factors of interest are correlates of bipolar disorder: mood-congruent psychotic features, retarded-endogenous profile, cyclothymic personality, positive family history of bipolar illness, periodicity, and normality between episodes of illness.

Background. The aim was to systematically integrate the available evidence on psychosocial and demographic factors associated with response prediction to prophylactic lithium.Method. Each psychosocial or demographic variable that was related to lithium response in at least one study was examined with respect to response prediction. If several studies were located for the same variable results were integrated using a meta-analytical approach. To account for heterogeneity of primary studies aggregation of results was based on a random-effects model.Results. Out of 27 psychosocial and demographic variables investigated in this review, nine variables were identified as significantly related to outcome under to prophylactic lithium: (1) high social status, (2) social support, (3) good compliance, and (4) dominance may be protective against a recurrence under lithium. In contrast, (5) stress, (6) high expressed emotions, (7) neurotic personality traits, (8) unemployment, and (9) a high number of life events were identified as possible risk factors for poor response.Conclusions. This systematic review shows a surprisingly high number of psychosocial variables to be related to lithium response. Effect sizes were, however, small to moderate. Many variables should, therefore, be considered simultaneously to predict response.

Lithium is one of the most commonly used drugs in the prophylaxis and treatment of bipolar disorder. The mechanisms of mood stabilization by lithium incorporate its effect on serotonergic neurotransmission. This paper investigates a relationship between response to lithium prophylaxis and polymorphisms in two genes: T102C of 5-HT2A receptor and G68C (Cys23Ser) of 5-HT2C serotonin receptor gene. Genotypes were estimated in 92 bipolar patients (39 males and 53 females) who have been taking lithium for at least 5 years. The patients were classified as excellent responders, partial responders and non-responders to lithium. The obtained results suggest that these polymorphisms may not be related to the degree of prophylactic lithium response.

We assessed performance on the Wisconsin Card Sorting Test (WCST), measuring executive functions, in 30 patients showing different prophylactic effect of lithium (excellent lithium responders-ER, partial responders-PR and non-responders-NR), and in fifty persons of their offspring (12 of ER, 26 of PR, and 12 of NR). Age- and gender head-to-head matched population consisted of 30 subjects for lithium group and 50 subjects for the offspring of lithium patients. In lithium patients, NR had significantly worse results compared to the remaining groups and to control subjects on perseverative errors (WCST-P) and conceptual responses (WCST-%conc). No differences were observed in the offspring of patients with different effect of lithium, however, they showed an impairment on WCST-P and WCST-%conc compared to matched healthy controls. Therefore, the favorable effect of lithium prophylaxis may be associated with a preservation of executive cognitive functions and the offspring of bipolar patients shows an impairment of such functions.