Lithium and Alzheimer’s Disease: Experimental, Epidemiological, and Clinical Findings

Alzheimer’s disease (AD) represents one of the greatest health-care challenges of the twenty-first century. Besides known pathologies such as intracellular accumulation of neurofibrillary tangles and extracellular deposition of amyloid-beta plaques, other factors, such as dysregulated GSK-3 activity, mitochondrial dysfunction, inflammation, and oxidative stress, have been shown to play a role in the pathogenesis of AD. Over the last two decades, the evidence accumulated for a neuroprotective effect of lithium, as an important mechanism of this ion in mood disorders, reflected by an increase in cerebral gray matter volume in lithium-treated subjects. Neurobiological mechanisms of lithium neuroprotective actions may also be relevant to the pathogenesis and treatment of AD, and they will be delineated. In most epidemiological studies, a negative association between lithium use and dementia has been shown, including two most recent papers regarding a concentration of lithium in drinking water. In this article, the results of initial studies using lithium in the treatment of dementia and showing some promise will also be presented. Therefore, considering the current paucity of treatments for the AD, further testing of lithium as a disease-modifying treatment in this illness may be warranted

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

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

The association of glycogen synthase kinase-3beta (GSK-3β) gene polymorphism with kidney function in long-term lithium-treated bipolar patients

BACKGROUND: Most bipolar patients experience a reduction in urinary concentrating ability within a few weeks of starting lithium treatment. This phenomenon may be connected with the effect of lithium on the glycogen synthase kinase-3beta (GSK-3β) present in the renal tubules. The GSK-3β gene is located on chromosome 3q13 and possesses a functional -50 C/T polymorphism. In the present study, we estimated this polymorphism in a group of long-term lithium-treated patients and assessed its association with various parameters of kidney function, including novel markers of kidney injury such as serum neutrophil gelatinase-associated lipocalin (NGAL) and urinary beta2-microglobulin (β2-MG). METHODS: The study comprised 78 patients with bipolar mood disorder (25 males, 53 females), aged 36 to 82 (60 ± 11) years. The mean duration of bipolar illness was 6 to 50 (24 ± 10) years, and the patients have been receiving lithium for 5 to 38 (16 ± 9) years. All the patients had the following features, regarded as the phenotypes of kidney functions measured: urine examination for specific gravity evaluation, serum creatinine concentration, and estimated glomerular filtration rate (eGFR) evaluation, as well as the serum concentrations of NGAL and urinary β2-MG. Genotyping of GSK-3β gene -50 C/T polymorphism was done by polymerase chain reaction analysis. RESULTS AND DISCUSSION: Thirty-four patients (6 males, 28 females) had the T/T genotype, 37 patients (16 males, 21 females) had the T/C genotype, and 7 patients (3 males, 4 females) had the C/C genotype. Patients homozygous for C allele had significantly higher urine specific gravities (1.019 ± 0.008) compared to the remaining genotypes (1.013 ± 0.007) (p = 0.035), with no influence of the duration of lithium treatment. Other parameters of kidney function (serum creatinine, eGFR, serum NGAL, and urinary β2-MG levels) were not different between genotypes and, again, were not affected by the duration of lithium treatment. There was no correlation between urine specific gravity and other kidney function parameters. The results of our study indicate that the GSK-3β genotype may be connected with lithium-induced impairment of renal concentrating ability in long-term lithium-treated bipolar patients. Limitations of the study include small size of the sample, small number of C/C genotype patients, and a lack of multiple testing analysis of genotypic differences in various measures of kidney function

Lithium and bipolar depression

Kelly1 has recently disputed the recommendations of several international guidelines on the use of lithium in bipolar depression. In his scrutiny, the author points to three main errors that seem to have affected systematically ten international guidelines, namely the Woozle effect (evidence by citation), reference inflation (inappropriate citation of pivotal, generally old, studies) and belief perseverance (inability to modify evidence‐based recommendations despite the presence of contrary data). We concur with the author that the evidence supporting the effectiveness of lithium in acute bipolar depression, and to a lesser degree also in major depressive episodes, remains inadequate.2, 3 A different matter is, in our opinion, to label guidelines recommendations as inaccurate or biased, even if, as the author stated, no deceptive intentions were present

Postpartum depression : bipolar or unipolar? Analysis of 434 Polish postpartum women

Objective: To assess the prevalence of soft bipolar features in a sample of women with postpartum depressive symptoms, as well as to compare the sociodemographic and obstetric characteristics of subjects with bipolar or unipolar postpartum depressive symptomatology. Methods: Four hundred and thirty-four participants were enrolled in this cross-sectional study. Postpartum depression (PPD) symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS), while the Mood Disorder Questionnaire (MDQ) was used to screen for bipolarity features. Results: Of the 434 participants, 66 (15.2%) scored ≥ 13 points on the EPDS, thus fulfilling the screening criteria, and 103 scored ≥ 7 points on the MDQ. In comparison with non-depressed subjects, the women who scored positively on the EPDS were significantly more likely to exhibit symptoms of bipolar spectrum disorders (38 vs. 21%; chi-square test, p = 0.015). Women with bipolar PPD symptomatology were significantly younger than those exhibiting unipolar PPD symptoms (31.0±4.8 years vs. 28.5±4.1 years; t-test, p = 0.03). The groups did not differ in terms of obstetric characteristics. Conclusion: Our findings suggest that patients with PPD symptomatology may be more likely to exhibit soft bipolarity features as compared with non-depressed women

Guidelines for the use of second-generation long-acting antipsychotics

Long-acting injectable antipsychotics constitute a valuable alternative for the treatment of psychotic disorders, mainly schizophrenia. They assure a more stable drug level, improve treatment compliance, and increase the chances for favorable and long-lasting improvement. Additionally, the long-acting second-generation antipsychotics combine the values of longacting injectable drugs with the values of atypical antipsychotics. Four second generation long-acting antipsychotics have been described: risperidone, olanzapine, aripiprazole and paliperidone. The indications for their use, treatment strategy, tolerance, and potential interactions are discussed