Lithium, manic depression and beyond

This essay was written by Qiling Xu and was first published in the 2010 Mill Hill Essays.

A survey of the prevalence of treated and untreated mental disorders in the adult population aged 16 and over in England was carried out in 2007. It found that nearly one person in four had at least one mental disorder and that one person in eighteen reported having attempted suicide. Depression is one of the commonest mental disorders and it has been predicted that by the year 2020 depression will form the second greatest contribution to the worldwide burden of disease. The illness is characterised by sadness, loss of interest in activities and decreased energy. Depression is different from normal mood changes that are part of our daily life.

A severe form is manic depression – also called bipolar disorder – in which the mood swings from exaggerated elation (“mania”) to feeling low or irritable (“depressed”). Depressive disorders and schizophrenia are responsible for sixty percent of suicides, with manic depression the third leading cause of death in 15-24 year olds. The causes of depression are complex and include psychological, social and genetic factors. First-line treatments for depression are medication, psychotherapy, or a combination of both, together with support groups for vulnerable individuals.

Remarkably, a simple chemical compound – lithium salt – is highly effective in the treatment of bipolar disorder. Lithium is a naturally occurring element, in the same group of alkali metals as sodium and potassium in the chemical periodic table. On its own lithium is a highly reactive metal, but it is normally found as a salt, a chemical compound in which the positively charged lithium ion is associated with a negatively charged cation; it is the lithium ion that is the therapeutically active component.

The use of lithium salts for treating mental illness such as manic disorder was known in the 19th century but rediscovered in the mid-20th century by an Australian psychiatrist, John Cade. As described in his seminal study “Lithium salts in the treatment of psychotic excitement”, published in the Medical Journal of Australia in 1949, he first experimented with guinea pigs to analyse the toxicity and protective effect of lithium salts and found that the treated animals became lethargic. He then presented in detail the results of treatment of ten manic patients. This is an excerpt from case I:

a male, aged fifty-one years, who had been in a state of chronic manic excitement for five years, restless, dirty, destructive, mischievous and interfering, …His response was highly gratifying. …with lithium citrate he steadily settled down and in three weeks was enjoying the unaccustomed surroundings of the convalescent ward. …He was soon back working happily at his old job.

The patient was readmitted several months later due to not taking the lithium medication and was treated again. He was soon better, and returned to home and work. John Cade also reported the sedative effect of lithium treatment on six patients with dementia:

Although there was no fundamental improvement in dementia, three patients, who were usually restless, noisy and shouting nonsensical abuse, lost their excitement and restlessness and became quiet and amenable for the first time for years.

Based on these findings, John Cade suggested that lithium salts should be used for treatment as an alternative to involuntary confinement of psychopathic mental patients.

Following these pioneering studies, Mogens Schou and co-workers carried out the first rigorously-controlled clinical trials of lithium that firmly established that it has a mood-stabilising effect. In the 1970s the U.S. Food and Drug Administration approved its use in treating bipolar disorder. Today, lithium is used mainly to help patients by reducing both the number and the severity of manic and depression states, giving them more emotional control and greater capability in coping with problems. John Cade’s work has thus been hailed as the beginning of the modern psychopharmacological era, and it opened the door to treatment that has saved many lives and improved the quality of life of millions with manic depression.

The finding that lithium is highly effective for the treatment of manic depression raises the question of how it exerts its therapeutic effects. Lithium has been found to alter the amount of many different biochemical components of the functioning brain, including substances that relay (or “signal”) information between nerves. These alterations could in turn underlie the changes in mood. It can be difficult to guarantee effective treatment as it is necessary to achieve the appropriate level of lithium in the body: if the dose is too low, it won’t work; if too high, it has unwanted side-effects, or toxicity. Lithium toxicity often leads to poor compliance in patients, who need to have regular blood tests to make sure they are getting the right dose. Alcohol use is discouraged because it interferes with the efficacy of the lithium medication.

It is therefore important to uncover whether the beneficial effects of lithium are due to it acting on one specific target that has several roles in the brain, or instead are due to it acting on many targets. If just one or a small number of targets of lithium are responsible for the beneficial effects, then new drugs could be devised that are more specific for these targets. There is emerging evidence that one particular target of lithium underlies many of its effects on mood. Before discussing this, the stage will be set by a brief summary of key aspects of brain development and maintenance, as many psychiatric diseases, including bipolar disorder, have their origins in foetal development.

The adult human nervous system is very complex and consists of over one hundred billion neurons (nerve cells) of hundreds of different types, and five to ten times as many other cells (glial cells). The nervous system is formed progressively during development, starting from the induction of a simple sheet of neural cells that are the progenitors, or ‘stem cells’, that give rise to all of the different types of nerve and glial cells. These progenitors proliferate and differentiate in a highly orchestrated manner to generate appropriate cell types at the correct time and place. During their differentiation, cells will migrate to specific locations, and each neuron extends long branches that form connections with specific neurons, and in some cases with other cell types. During the process of making connections brain cells are linked through specialised junctions called synapses. A synapse is the club-shaped tip of a nerve branch which almost touches another cell and thereby allows the transmission of signals, and hence information, between the two nerve cells. The signals can be electrical or chemical. The chemical signals carried by molecules are called neurotransmitters and many antidepressant drugs act to increase the amount of neurotransmitters in the brain.

Until recently, it was believed that once the mature nervous system is formed, no new neurons can be generated. We now know that in specific regions of the adult brain, stem cells are present which differentiate to form neurons and may have important roles in specific functions such as learning and memory. In addition, the existing neural stem cells may enable some replacement of cells that have been lost due to injury or disease. Some of the factors that regulate nervous system development may thus have continued roles that maintain the functionality of the mature brain.

During the development of many animal species, including humans, there is an overproduction of neurons that compete with each other to make connections to the appropriate target, and the excess neurons are eliminated by a process of programmed cell death, termed apoptosis. This elimination occurs because neurotrophic factors – signaling proteins that are required for the survival and growth of nerve cells – are present only in small amounts. Consequently, during normal development not all nerve cells are able to receive sufficient neurotrophic support, and the others undergo cell death. An abnormally low level of neurotrophic factors leads to increased apoptosis and loss of nerve cells in the developing or mature nervous system, and this is one of the common pathologies underlying many neurodegenerative diseases.

Brain Derived Neurotrophic Factor (BDNF) is one of the neurotrophic factors with important roles in the developing and mature nervous system. It helps to support the survival and growth of existing neurons and the differentiation of new neurons from stem cells. BDNF is present in areas of the brain that are crucial for learning, memory, emotion and higher order thinking. Defects in the BDNF gene and its regulators are associated with a milieu of mental disorders such as depression, schizophrenia and dementia, as well as neurodegenerative diseases including Alzheimer’s disease and Huntington’s disease.

Studies of the postmortem brain from bipolar patients have shown that in the prefrontal cortex – an area associated with judgement and executive function – there is a significant increase in the levels of proteins that affect apoptotic cell death. Intriguingly, several lines of evidence show that lithium treatment leads to increased production of BDNF in the brains of patients with bipolar disorder. Lithium may therefore exert its effect in part by activating neurotrophic signalling that protects cells from apoptosis. Bipolar patients have different levels of response to lithium treatment, with around one third of them seeing total remission of symptoms. Comparative studies have revealed that plasma BDNF levels in these patients were higher than in the patients who respond less well to lithium, but the same as those of healthy controls. Excellent responders may constitute a specific subgroup of bipolar patients for whom longterm lithium administration can produce complete normality.

Lithium decreases GSK-3 activity in several ways
Figure 1 Lithium decreases GSK-3 activity in several ways

GSK-3 is inactivated by specific enzymes that add a phosphate, and this can be reversed by dephosphorylating enzymes. Lithium inhibits the dephosphorylation, and consequently GSK-3 is less active. Magnesium ions (Mg2+) are required for activated GSK-3 to phosphorylate substrates required in a diverse array of biological functions. By competing with Mg2+, lithium ions block the function of activated GSK-3. As a consequence of these inhibitory effects, GSK-3 can no longer regulate many important biological processes.

The emerging links between lithium and neurotrophic factors are encouraging advances but they do not address the direct mechanism by which lithium acts. Chemically, lithium exerts its action by competing with magnesium (another metal ion) for binding, thus inhibiting various magnesium-dependent enzymes. Many of these enzymes are involved in the propagation of chemical signals required for cell survival, proliferation and differentiation. Some of them are implicated in neurological functions.

Lithium can also inhibit some metabolic enzymes, including one called glycogen synthase kinase 3 (GSK-3) (see figure 1). GSK-3 is an enzyme initially discovered to be involved in the regulation of glucose metabolism but is also found to be a component of several pathways that relay chemical signals from outside cells (extracellular) to the cell nucleus. In the mid 1990s, researchers found that lithium administration to developing frog embryos had the same effect as did loss of function of GSK-3. This led them to the discovery that GSK-3 was directly inhibited by lithium. Since then, GSK-3 has emerged as a key target that is central to the effects of lithium treatment.

GSK-3 is involved in several diverse cellular processes and it is likely that several of these contribute to the therapeutic effects of lithium. One of these processes is regulation of the activity of specific transcription factors, proteins that act as molecular switches to turn particular genes on or off. An important and well-understood example is the Wnt signaling pathway. The Wnt pathway came to light in studies of embryo development and was found to have essential roles in promoting the survival, proliferation, differentiation and migration of cells in many different tissues including nerve tissue, as well as in synapse formation in the nervous system. In essence, the Wnt pathway involves the inhibition of an inhibitor, leading to activation of a transcription factor. In the absence of Wnt signals, GSK- 3 comes together with other proteins and causes a critical mediator of the pathway, a protein called beta-catenin, to be rapidly removed by degradation. The binding of Wnt signaling molecules to receptors on the cell surface leads to blocking of the function of GSK-3. Consequently, betacatenin can now accumulate, move into the cell nucleus and assemble with other proteins to switch on specific target genes. The mode of action of lithium on the Wnt pathway is illustrated in Figure 2.

Effect of lithium on the wnt pathway
Figure 2 Effect of lithium on the wnt pathway.

In the absence of wnt signals, GSK-3 causes destruction of beta-catenin. Wnt proteins bind to their receptors on the cell membrane and activate the pathway. This leads to inhibition of GSK-3, such that beta-catenin is no longer destroyed, and can now move into the nucleus and activate specific genes. Since lithium inhibits GSK-3, it has the same effect as activation of wnt pathway.

Lithium is a potent inhibitor of GSK-3, and consequently it activates the Wnt pathway which in turn promotes cell survival. Activation of the Wnt pathway may also affect manic depression through additional mechanisms, for example the increased production of BDNF and an increased number of synapses. Indeed, a recent report demonstrates that beta-catenin can directly bind and activate the BDNF gene.

In addition to its relationship with the treatment of bipolar disorder, there is emerging evidence for links between the Wnt pathway and other neurological disorders. For example, GSK-3 and potential targets of the Wnt pathway have been linked to schizophrenia and autism. A search for genes switched on by beta-catenin has identified some of the known susceptibility genes for schizophrenia, autism and bipolar disorder.

Recently a gene called Disrupted in Schizophrenia-1 was discovered. When defective this gene increases the risk of having psychiatric disorders, and is an essential regulator of the proliferation of neural progenitor cells. A recent report reveals that this gene acts via inhibition of GSK-3 and modulation of the Wnt signaling pathway. Furthermore, several studies have identified GSK-3 as a mediator of the pathological effects of alcohol, and lithium is used in treating alcohol abuse. It is therefore not surprising that GSK-3 has emerged as a therapeutic target for the design of novel drugs for the treatment of bipolar disorder and other neurological diseases.

A major difficulty in devising new treatments for manic depression is that the underlying causes of the disorder are not yet understood. Emerging lines of evidence paint a multifaceted picture of causes and effects. The risk of bipolar disorder has been associated with viral infection and prenatal or perinatal stress. Mood switches in bipolar patients have been linked to impaired control of rhythmic activities such as the sleep/awake cycle in the brain. Genetic predisposition is also a major risk factor in the pathogenesis of bipolar disorder. Gene discovery efforts have been hampered by the complex mode of inheritance and the involvement of multiple genes. Genome-wide association studies aided by large-scale DNA sequencing (a separate topic in this volume) are a powerful approach to uncovering the secrets of genetic mutations and variations in bipolar patients.

Genetic variation may also contribute to different responses to lithium treatment and other antidepressant drugs. Investigating the genetics of lithium sensitivity has identified new molecules that modulate lithium sensitivity and thus offer new therapeutic targets for the treatment of manic depression and other mental disorders. Furthermore, the identification of risk genes for manic depression may provide a better understanding of the nature of pathogenesis and in turn may lead to a better therapeutic target. Many of the genes associated with bipolar disorder have also been associated with schizophrenia. These overlapping candidate genes may help to determine some of the common features such as psychosis, mania and suicidal feelings, and interestingly lithium is effective in reducing the frequency of suicide attempts in both diseases. There are reports of defects in the glial support cells in the brain in manic depression and schizophrenia, suggesting that these rather than nerve cells may be the affected cell type in some cases.

The multi-causal nature of bipolar disorder remains a major challenge for the diagnosis and treatment of this illness. Animal models have been developed to enable a better understanding of its pathology, and to identify therapeutic targets and better drugs for bipolar disorders. Investigating the genetics of lithium sensitivity has identified new molecules that modulate lithium sensitivity and thus offer new therapeutic targets.

Another important tool is the use of functional magnetic resonance imaging (fMRI), a brain scan technique that maps areas of brain activated by, for example, tasks or questions to the conscious person. This has enabled meaningful comparisons of brain images, which define the affected regions and provide a neurophysiological basis for understanding mental disorders such as bipolar disorder. A number of imaging studies suggest that structural abnormalities in the amygdala, basal ganglia and prefrontal cortex occur in patients with bipolar disorder. These are the brain areas associated with a variety of functions, including motor control, learning and emotion.

fMRI will also have a great impact on investigating a wide array of other brain lesions and aspects of mental health. A recent example is a study showing that fMRI could help doctors diagnose adults with autism by identifying structural differences in their brain, though it is not clear whether the regional differences are the cause or effect of the pathogenesis. Extension of this study to younger people will help to shed light and allow the identification of at-risk children more rapidly.

The discovery that lithium inhibits GSK-3 has paved the way to establishing that many mood disorders involve the activity of GSK-3 or GSK-3 regulated functions. Disruptions of these intricate regulating systems may contribute to the heterogeneity of the disorder. As a mood stabiliser, lithium will remain popular in treating bipolar disorder, although the side effects and toxicity remain a problem. Further research is needed to discover new drugs and ways of controlling GSK-3 activity in a tissue-specific manner to avoid unwanted effects of inhibition outside the nervous system.

Stephen Fry
Stephen Fry, the actor, comedian and author, has spoken publicly about his experience with bipolar disorder, which was also depicted in the documentary Stephen Fry: The Secret Life of the Manic-Depressive.

Courtesy of Lotte D’Hulster

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