Cellular Transport and the Inorganic Biochemistry of Lithium (N.J. Birch)
The chemistry of lithium is unusual. Lithium atoms are very small, highly polarized, and have a high charge density. The chemical and biochemical properties of lithium are similar to those of magnesium, with which it shares a “diagonal relationship” in the periodic table. Because magnesium plays a crucial role in the regulation of biochemical systems, it has been theorized that lithium influences magnesium-dependent processes.
Too many Americans rely on bottled or home-filtered water for their drinking needs. Most filtered and bottled waters provide little or no magnesium. Even most tap water is devoid of this critical mineral
Lithium can be transported across membranes in five different ways. Of these, passive flux is important for the entry of lithium into cells, and sodium-lithium countertransport for the extrusion of lithium from cells. Lithium can presumably replace sodium in the sodium-sodium countertransport system, although the biological significance of the latter process is still unclear.
It appears that the concentration of lithium in cells does not reach the levels predicted by the Nernst equation. Rather, the (inside the cell) intracellular lithium concentration is considerably lower than its concentration in blood or (outside the cell) extracellular fluid. This is important for the models which have been proposed for its mechanism of action, as these must be able to explain the effects of lithium at intracellular concentrations of 0.1 mmol/l (i.e. similar to those seen in patients on lithium (preventative treatment) prophylaxis).
One hypothesis suggests that the biological effects of lithium are due to the role it plays at the cell periphery, where, for example, it may influence cell recognition, cell signaling mechanisms at the cell membrane, and certain immunological processes.
Lithium as a Trace Element (K. Lehmann)
In humans endogenous serum lithium levels normally range from 0.14-8.6 micromol/l, with a maximum level of 15.8 micromol/l. These lithium serum levels are 3 orders of magnitude lower than those necessary for therapeutic/prophylactic treatment (of bipolar). Scientists suspect that endogenous lithium in the human body has a physiological function, although sufficient evidence of this is still lacking.
Daily lithium intake in humans is dependent on both diet and the use of medications that contain lithium. With the latter, a total of 15 micromol to 0.66 mmol of lithium may be administered per day.
Effects of Lithium on Neurotransmitters and Second Messenger Systems (D. van Calker)
Studies examining the effect of lithium ions on the synthesis and metabolism of neurotransmitters have, thus far, yielded inconsistent results, failing to shed any light on the mechanism of action of lithium in vivo. Lithium ions prevent the development of functional supersensitivity to dopamine and acetylcholine receptor stimulation, most likely by influencing second messenger systems.
Lithium ions increase basal cAMP levels and inhibit the neurotransmitter-stimulated accumulation of cAMP in the brain and other tissues. Acute administration of lithium inhibits the stimulation of adenylyl cyclase, most likely through direct competition with magnesium, whose hydrated ionic radius is similar to that of lithium. The effects of chronic lithium treatment, however, probably result from (a) the modification of gene expression among components of the adenylyl cyclase system, especially G protein subunits (G_i, G_s), as well as from (b) a stabilization of the inactive trimeric form of the Gi protein. Lithium has been found to increase basal cAMP levels, which is most likely due to attenuation of the Gi protein and an increase – probably resulting from the effects of lithium on gene transcription – in the levels of adenylyl cyclase type I and type II mRNA.
At therapeutically relevant concentrations, lithium ions inhibit the hydrolysis of inositol mono-phosphatase to inositol. This leads to a depletion of inositol and a strong increase in diacylglycerol (DAG) in susceptible cells and tissues, depending on species and tissue type. Susceptibility is determined by the activity of a high-affinity inositol transport system, as well as by the degree to which the inositolphospholipid (IP) second messenger system is hormonally stimulated. Pronounced inositol depletion can lead to an inhibition of the IP system in affected cells, which is probably a result of attenuated IP synthesis and/or the activation of protein kinase C (PKC) through the accumulation of DAG.
Lithium exposure facilitates the activation of certain PKC isozymes, chronic activation of which can result in a downregulation of PKC activity (i.e. a constitutive activation and redistribution in the cell nucleus). This process is probably responsible for the diverse effects of lithium on the release of neurotransmitters, the inhibition of receptor sensitization and certain membrane transport processes. By influencing transcription factors such as c-fos, this process could also be responsible for the lithium-induced changes in gene transcription which have been observed.
The inhibitory effects of chronic lithium treatment on the PI system have also been demonstrated in humans. Peripheral cells from manic-depressive patients show increased hormonal sensitivity in the phosphoinositide (PI) system. Thus, it appears that lithium ions might compensate for the hyperactivity of the PI system which is associated with illness in these patients.
The Effect of Lithium on Serotoninergic Function (B. Müller-Oerlinghausen)
In animal experiments, lithium administration results in a net rise in 5-HT activity, which is probably caused presynaptically by an increase in the release and transformation of 5-HT precursors, an increase in the release of 5-HT, and by the functional antagonism between lithium and inhibitory presynaptic 5-HT1A receptors.
However, there are considerable differences in the amount of time which elapses before each of the different effects occurs.
An increase in 5-HT uptake in the thrombocytes of depressive patients, but not in those of healthy test subjects, has been observed.
In several studies of patients and healthy volunteers on short-term lithium therapy, neuroendocrine stimulation (e.g. with fenfluramine or tryptophan) led to increased prolactine or cortisol responses via serotoninergic transmission.
The presumably adaptive mechanisms which tend to emerge after chronic lithium administration (e.g. a decrease in the number and sensitivity of postsynaptic 5-HT receptors) probably result in a stabilization of serotoninergic neurotransmission rather than a unidirectional increase in 5-HT activity.
The Effects of Lithium on the Hematopoietic System (V.S. Gallicchio)
Lithium increases the number of neutrophil and eosinophil granulocytes, but probably not that of monocytes, basophil granulocytes, thrombocytes or erythrocytes / reticulocytes in peripheral blood. Whereas lithium increases the number of pluripotent stem cells in bone marrow, as well as of granulocyte-macrophage and megakaryocyte precursors, it probably reduces the number of erythrocyte progenitor cells.
Researchers suspect that these phenomena result from both the direct and indirect effects of lithium on cells, including an increase in the number of macrophages that produce growth factors and cytokines. A lithium-induced increase in bone marrow activity also appears to play a role in this context. A decline in erythropoiesis during lithium therapy may be due to inhibition of cAMP which, in turn, inhibits prostaglandin E production.
Thus, lithium can be used to treat toxic impairment of the hematopoietic system, whether this damage be caused by chemotherapy, radiation, antiviral medication, or granulocytopenia induced by carbamazepine or neuroleptics. To date there has been no scientific evidence that lithium can cause leukemia.
The Effects of Lithium on the Immune System (V.S. Gallicchio)
In humans lithium therapy may lead to an increase in immunoglobulin synthesis by B-lymphocytes. However, the results of in vitro experiments and animal testing are contradictory.
Lithium stimulates the proliferation of T-lymphocytes and appears to increase the phagocytic activity of macrophages, but only at doses higher than those prescribed for medical treatment.
Experimental evidence suggests that lithium can increase cytokine production. This has been confirmed in the case of interleukin-2. Moreover, lithium potentiates tumor necrosis factor-mediated cytotoxicity. In high doses, lithium inhibits cyclic AMP (cAMP), which leads to an increase in the synthesis of interferon products.
It appears that lithium influences the immune system in part by reducing intracellular concentrations of cAMP and inositol phosphate.
Because of the high doses involved, the potential usefulness of lithium in the treatment of inflammatory and auto-immune diseases is still unclear. However, because it can increase interleukin-2 production, as well as potentiate killer cell activity, high-dose lithium has been used in the treatment of various cancers. Recent evidence also indicates that, by inhibiting T-suppressor cells lithium can reduce the severity of graft-versus-host reactions following transplants.
Of great importance is the potential use of lithium in the treatment of immune deficiency syndromes such as AIDS. In vitro experiments have shown that lithium can lead to a more robust immune response in patients with AIDS. The direct antiviral effects of lithium, e.g. in herpes virus infections, are already being utilized in clinical practice.
Chronobiological Aspects of Lithium Prophylaxis (B. Pflug)
Repetitive variations with a periodicity of approximately 24 hours are part of the circadian system. This system can be found among single-celled organisms, plants, animals, and humans. In humans the circadian system is based on a number of oscillators of varying strengths which exert mutual influence on one another. The main pacemaker of this multi-oscillatory system is the nucleus suprachiasmaticus.
Lithium ions are chronobiologically active. They influence the circardian system by modifying phase relationships and lengthening the free-running period.
During manic-depressive episodes a variety of circadian rhythm dysfunctions have been observed. The chronobiological effects of lithium salts help explain their efficacy in the treatment of manic-depressive disorders.
The Psychological Approach to the Effects of Lithium Prophylaxis (W. Classen)
The main effect of long-term lithium treatment is based on the modification of behavior and perception. These effects can be explained within psychological models and need not be reduced to other, lower levels of explanation.
Over the last 25 years, animal studies, psychophysiological investigations in humans, and routine clinical observation have led to the development of models which help explain the psychological effects of lithium salts. The phenomenological model developed by Kropf integrates concepts of genetic disease, aspects of the illness described in psychological terms, as well as the acute and chronic effects of lithium.
Among healthy test subjects lithium can cause fatigue, apathy, irritability, alternation between increased and decreased susceptibility to external stimuli, and general feelings of illness along with negative thinking, dysphoria, and lethargy.
Depressive patients exhibit a rigid and non-regulable behavioral repertoire, both during acute episodes and over the long term. This indicates a change in mental functions, such as cognition, perception, emotions, and the ability to structure thoughts and process information. Lithium most likely modulates these processes by raising the perception threshold for various stimuli and improving information processing structures.
The aggression-dampening effect of lithium which has been observed in human and animal studies is probably due to changes in the perception of aggression-inducing stimuli, as well as to improved control over aggressive impulses accompanied by a reduction in the number of aggressive behavioral patterns.
The Pharmacokinetics of Lithium Salts (K. Lehmann)
The kinetics of lithium are determined by the fact that it is a simple, monovalent cation (Positive). The anion and/or the galenic formulation chosen for the final drug product primarily influence the resorption phase. This needs to be taken into account when initiating lithium treatment or changing a patient’s prescription. The primary route of lithium elimination is renal (via glomerular filtration). Between 70-80% is reabsorbed in the proximal tubule. The overall elimination half-life of lithium is approximately 24 hours.
The exogenous clearance of lithium (ca. 19-20%) is approximately equal to the endogenous clearance of the drug in patients with normal renal function.
The renal clearance of lithium is subject to manifold influences, the most significant of which are (a) changes in electrolyte levels and (b) the secretion of aldosterone.
Impaired kidney function and age-related decreases in renal clearance can lead to a dramatic rise in serum lithium levels.
Lithium is distributed slowly and unevenly in the human body. Distribution is usually complete within 12 hours of first ingestion. During lithium therapy, steady state concentrations are generally reached within 4-7 days of repeated oral application in patients with normal renal function.
Exact drug monitoring is absolutely essential not only in all problem cases or when medication(s) are adjusted or switched, but also during routine follow-up exams.
The efficacy of lithium
The main goal of treatment in patients with bipolar disorder is to prevent recurrences and suicidal acts. Of the variety of drugs now available to treat this condition, lithium has been shown to be the most efficacious in the long-term treatment of bipolar disorder. The earliest controlled studies were performed in the 1960s and demonstrated response rates of 70 to 80%. However, later studies were not always able to replicate these findings. This led to a growing critique of lithium treatment, primarily from researchers in the United States. Some US researchers also advanced the hypothesis that long-term lithium treatment would lose its efficacy over time, or after discontinuation and subsequent reinstallation. However, this hypothesis was based on preliminary findings in small patient groups and could not be replicated elsewhere.
In a large sample of 163 bipolar patients on long-term lithium treatment, the IGSLI demonstrated that it was indeed possible for patients who had shown an excellent primary response to remain stable for decades, regardless of discontinuations (Grof 1999). During the 1990s, it became evident that the decrease in response rates observed previously had been due to the widespread use of lithium in naturalistic, and therefore less controlled, settings. The introduction of modern diagnostic systems (DSM III R, ICD 10) had also broadened the criteria of bipolar disorder, thus leading to a more heterogeneous group of patients.
Different subtypes of bipolar disorder
The IGSLI is currently working on the hypothesis that the diagnosis of bipolar subtypes may help achieve maximal response in patients on long-term treatment. When used to treat the classical type of bipolar illness (i.e. without psychiatric comorbidity and without mood-incongruent psychotic features), lithium is superior to other treatment options. However, lithium is less effective in patients with atypical bipolar disorder, which is characterised by mood-incongruent psychotic features, substance abuse, anxiety disorders or other psychiatric comorbidity, and frequently by residual non-affective symptoms between episodes. Results from several other European research groups support this hypothesis.
Distinguishing between subtypes may also be useful for evaluating the prognosis of bipolar women during pregnancy. In a retrospective study, the IGSLI demonstrated that in women with typical, or type I bipolar disorder, the risk of recurrence during pregnancy was markedly lower than had been expected in light of the normal clinical course of the disease. Exploring the underlying protective mechanisms in such cases may help lead to a new understanding of the pathophysiology of affective disorders and to new approaches to treatment and prevention.
The spectrum of therapeutic options has broadened since the emergence of anticonvulsants as a means of treating affective disorders. Applying lithium and anticonvulsants in a more differential manner might bring considerable benefits, especially to the large number of patients whose illness differs significantly from the classical type of bipolar disorder and who belong to the bipolar spectrum.
This site Nevertheless, recently released, high-quality guidelines and overviews underscore the fact that lithium is still the first-line treatment in the prophylaxis of bipolar affective disorder.
High-dose thyroxine research
The problem of refractory recurrent affective illness deserves special attention, since a relatively high percentage of patients have a less than adequate response to standard prophylactic agents. For one decade now, the IGSLI has been engaged in research on high-dose thyroxine as an add-on therapy in refractory patients, especially in lithium-nonresponders. The “Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of Levothyroxine as Add-on Therapy in Bipolar Depression” (Sponsor: The Stanley Medical Research Institute of the Stanley Foundation, Bethesda, MD, USA; Grant ID #02T-238) started recently as a cooperation of several IGSLI members and other European and US research centers:
Investigators and participating study sites are:
Charité University Medical Center Berlin, Germany: Michael Bauer (P.I.), Martin Schäfer, Mazda Adli, Johanna Sasse, Igor Sutej
Ludwig-Maximilians-Universität Munich, Germany: Heinz Grunze; Emanuel Severus
Technische Universität Dresden, Germany: Tom Bschor
University Medical Center Utrecht, The Netherlands: Ralph Kupka, Willem A. Nolen
University of California Los Angeles (UCLA), USA: Mark Frye, Lori Altshuler
Stanford University School of Medicine, Stanford, USA: Natalie Rasgon
Statistical Consultant: Michael Smolka, Central Institute of Mental Health, University Heidelberg, Germany.
New Technologies to Improve Longitudinal Research in Bipolar Disorder
Longitudinal studies are an optimal approach to understand the variable course and outcome of mood disorders. However, longitudinal studies have been limited by missing and unbalanced data values collected at unequal time intervals and by reliance on paper-based forms for data collection. To overcome methodological limitations, several IGSLI centers collect data for longitudinal studies using a validated computer-based system (ChronoRecord). Using software available in English, German and Spanish and being translated into Czech and Polish, patients record mood, medications, sleep, life events, and menstrual data onto a home computer every day. Weight is entered weekly. This technology facilitates compilation of data from multiple IGSLI centers into a large database for analysis. Automation of data collection can reduce missing data, eliminate errors associated with data entry and allows the use of familiar statistical techniques for analysis. Additionally, ongoing feedback is provided for patients and researchers in the form of graphical mood charts and statistical analyses. For more information on ChronoRecord visit www.chronorecord.org.
Neuroprotective Effects of Lithium
Some affective disorders appear to be accompanied by persistent neurocognitive impairment, an increased risk for mild cognitive impairment and morphological changes in the brain. Imaging, neuropsychological and postmortem brain studies suggest that there are abnormalities in specific brain regions in bipolar disorders.
There is accumulating literature on neuroprotective effects of lithium which mainly stems from studies with cell cultures and animal research. Chronic but not acute lithium treatment appears to have robust neuroprotective effects against a variety of insults including glutamatergic damage, ischemia, neurodegeneration and oxidative stress. The effects of lithium include prevention of cellular damage and loss as well as in some instances, reversal of damage after subsequent treatment with lithium. The mechanisms for the neuroprotective effects of lithium appear to be diverse.
At present little is known about the potential neuroprotective effects of lithium treatment in bipolar patients. A number of studies indicate that chronic lithium treatment may correct some of the previously reported neurocognitive abnormalities in these patients.
IGSLI currently conducts a multi-center cross-sectional study which aims at evaluating the potential of lithium in the prevention of neurocognitive impairment and volume changes of specific brain areas in patients with bipolar disorders.