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

The concept of spectrum of bipolar affective illness

Prekursorem współczesnej klasyfikacji psychiatrycznej jest Emil Kraepelin, który w 1899 roku oddzielił zaburzenie maniakalno-depresyjne (manisch-depressives Irrensein) od grupy zaburzeń dementia praecox. W historii klasyfikacji psychiatrycznej XX wieku znaczącym wydarzeniem było rozdzielenie zaburzeń afektywnych jedno- i dwubiegunowych. W połowie lat 70. ubiegłego wieku zaczęto wyróżniać typy zaburzeń afektywnych dwubiegunowych: typ I i II, przebieg z szybką zmianą faz i choroba sezonowa. Wyniki badań epidemiologicznych przy zastosowaniu szerszych kryteriów dwubiegunowości zaczęły wskazywać na znacznie częstsze, obejmujące kilka procent populacji, rozpowszechnienie zaburzeń afektywnych dwubiegunowych niebędących chorobą typu I. Opracowano również nowe skale do pomiaru dwubiegunowości, na przykład Kwestionariusz Zaburzeń Nastroju. Wprowadzono też pojęcie „spektrum” choroby afektywnej dwubiegunowej, które ma obecnie kilka znaczeń. Jedno z nich dotyczy przestrzeni diagnostycznej między chorobą afektywną dwubiegunową typu II i depresją nawracającą. W polskim badaniu DEP-BI stwierdzono, że tak rozumiane spektrum choroby afektywnej dwubiegunowej występuje u 12% pacjentów leczonych przez psychiatrów z powodu depresji. Koncepcja spektrum choroby afektywnej dwubiegunowej amerykańskiego badacza, Hagopa Akiskala, oznacza continuum zaburzeń, które, poza klasyczną postacią choroby afektywnej dwubiegunowej (bipolar I), miałyby obejmować wszystkie postacie chorób afektywnych mające kliniczne cechy "dwubiegunowości" Autor ten przedstawił 7 podtypów spektrum choroby afektywnej dwubiegunowej (od I do IV, stosując również wartości pośrednie, np. I ½ ), gdzie głównym kryterium umieszczenia na jej continuum było nasilenie objawów (cech) związanych ze wzmożonym nastrojem. W ostatnich badaniach dotyczących spektrum choroby afektywnej dwubiegunowej wskazuje się na znaczenie takich postaci klinicznych, jak depresyjny stan mieszany i często nawracająca depresja oraz na rolę takich narzędzi badawczych, jak Hipomania Checklist (HCL-32) i "indeks dwubiegunowości".Emil Kraepelin became a precursor of contemporary psychiatric classification by separating in 1899 manic-depressive disorder (manisch-depressives Irrensein) from a group of disorders called "dementia praecox". In the 20th century history of psychiatric classification, a separation of unipolar from bipolar affective disorders made a significant event. From mid 1970s, the types of bipolar mood disorder have been distinguished such as bipolar I and bipolar II, rapid cycling and seasonal disorder. Epidemiological studies using broader criteria of bipolarity have pointed at more frequent prevalence of bipolar mood disorders (non-bipolar I), as several percent of the population. New tools for measuring bipolarity have been elaborated, such as e.g. Mood Disorders Questionnaire. The term "bipolar spectrum" has been introduced, which is used in various sense. One meaning denotes diagnostic space between bipolar illness type II and unipolar depression. In Polish DEP-BI study it was found that the frequency of bipolar spectrum conceived in this way accounts for 12% of patients treated by psychiatrists for depression. The concept of bipolar spectrum introduced by Hagop Akiskal covers a continuum of disturbances, which, beginning from classic form of illness (bipolar I) extends to all types of affective disturbances having bipolar features. This author presented 7 subtypes of bipolar spectrum (from I to II including also intermediates, like I ½ ) where the main criterion for placing on continuum is intensity of features connected with elevated mood. In recent studies on bipolar spectrum, a significance of such clinical types as mixed depression and frequently recurrent depression, and a role of such tools as Hypomania Checklist (HCL-32) and bipolarity index have been pointed out

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 influence of the first generation mood-stabilizing drugs (lithium,valproate, carbamazepine) on body weight and carbohydrate metabolism in patients with bipolar affective disorder

Sole litu, walproiniany i karbamazepina należą do leków normotymicznych I generacji. Podstawowym wskazaniem do ich zastosowania jest farmakologiczna profilaktyka nawrotów choroby afektywnej dwubiegunowej. W związku z tym u większości pacjentów należy je podawać przez długi okres. Występowanie działań niepożądanych, a wśród nich metabolicznych efektów ubocznych, jest częstszym powodem zaprzestania leczenia. Przejawiają się one między innymi wzrostem masy ciała oraz zaburzeniami gospodarki węglowodanowej. Szczególnie ten pierwszy efekt, silnie wyrażony już od początku leczenia litem czy walproinianami, często prowadzi do zaprzestania terapii. Wzrost masy ciała i hiperglikemia mogą postępować w trakcie leczenia. Przekłada się to również na podwyższenie ryzyka chorób układu krążenia u tych pacjentów.Lithium, valproate, carbamazepine belong to the first generation of mood-stabilizing drugs. They are mainly indicated as the pharmacological prophylaxis of relapse in bipolar affective disorder. Accordingly, these drugs must be given in a majority of patients for a long time. A common reason for discontinuation of treatment are adverse effects, including undesirable metabolic side effects. Their manifestation are: weight gain and abnormalities in carbohydrate metabolism. Particularly weight gain, occurring from the early stages of lithium or valproate therapy, often leads to discontinuation of treatment. Weight gain and hyperglicaemia may increase during therapy. This may also result in the increase of cardiovascular risk in these patients

Psychotic disorders as a complication of interferon-a treatment of hepatitis C

Summary Low-dose long-term interferon-a is a standard therapy for hepatitis C and is often associated with neuropsychiatric side effects, most frequently depression, mild cognitive impairment and fatigue which disappear with cessation of such treatment. Psychotic disorders are a rare complication of the treatment and usually resolve with its termination. In this paper, a review of the literature on interferon-a-induced psychotic disorders in hepatitis C patients has been performed. Epidemiology, predisposing factors, clinical picture, treatment and mechanisms of this serious neuropsychiatric complication have been discussed. Also, an own case of chronic schizophreniform psychosis and dementia following such treatment is described. interferon-a / psychotic disorders / clinical factors / treatment / mechanism

RISK FACTORS FOR NONCOMPLIANCE WITH ANTIPSYCHOTIC MEDICATION IN LONG-TERM TREATED CHRONIC SCHIZOPHRENIA PATIENTS

Background: The attitudes of schizophrenic patients toward medications directly impact the treatment compliance. Although noncompliance represents a serious concern in long-term schizophrenia treatment, a detailed information on the factors that impair compliance is still limited. The present study aims to assess the factors related to noncompliance with antipsychotics agents, in longterm treated chronic paranoid schizophrenia patients. Subjects and methods: Two groups of such patients (total number n=162) were analyzed and compared: 1). patients with symptomatic remission on haloperidol (n=32), clozapine (n=40) or olanzapine (n=45), and 2). drug resistant patients (n=45). The mean duration of the disease was 19.3 years. Results: Altogether, in our patient sample, a better drug attitude was found in the olanzapine and clozapine groups. Our findings have also revealed that worse attitude toward antipsychotics correlated with an earlier onset of schizophrenia, younger patient age, shorter duration of the disease, higher burden of symptoms, treatment with a typical antipsychotics, and higher severity of akathisia. Conclusion: Our results suggest that detecting factors that influence the patient’s attitude toward medications might be helpful for designing targeted educational strategies in chronic schizophrenia patients (particularly those with the high risk of noncompliance), and further trials are warranted to explore this topic

RISK FACTORS FOR NONCOMPLIANCE WITH ANTIPSYCHOTIC MEDICATION IN LONG-TERM TREATED CHRONIC SCHIZOPHRENIA PATIENTS

Background: The attitudes of schizophrenic patients toward medications directly impact the treatment compliance. Although noncompliance represents a serious concern in long-term schizophrenia treatment, a detailed information on the factors that impair compliance is still limited. The present study aims to assess the factors related to noncompliance with antipsychotics agents, in longterm treated chronic paranoid schizophrenia patients. Subjects and methods: Two groups of such patients (total number n=162) were analyzed and compared: 1). patients with symptomatic remission on haloperidol (n=32), clozapine (n=40) or olanzapine (n=45), and 2). drug resistant patients (n=45). The mean duration of the disease was 19.3 years. Results: Altogether, in our patient sample, a better drug attitude was found in the olanzapine and clozapine groups. Our findings have also revealed that worse attitude toward antipsychotics correlated with an earlier onset of schizophrenia, younger patient age, shorter duration of the disease, higher burden of symptoms, treatment with a typical antipsychotics, and higher severity of akathisia. Conclusion: Our results suggest that detecting factors that influence the patient’s attitude toward medications might be helpful for designing targeted educational strategies in chronic schizophrenia patients (particularly those with the high risk of noncompliance), and further trials are warranted to explore this topic

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