There is some evidence that lithium can affect brain structure, particularly the size of various parts of the brain. A study by Hajek et al. presented at the 2013 meeting of the International Society of Bipolar Disorders examined patients with bipolar disorder who had either received lithium for at least two years (37 patients) or had received under three months of treatment with lithium (19 patients), and compared the size of the hippocampus in these two groups and one control group (50 people). The patients with bipolar disorder all had the disorder for at least 10 years (25 years on average) and had had a minimum of five episodes.
Those treated with lithium long-term had greater hippocampal volume than the non-lithium patients (despite having spent more time in episodes of illness), and equal volume to healthy controls. Measurements were collected via magnetic resonance imaging (MRI), and analyses were done two different ways to avoid being confounded by the changes lithium may have on water balance in the brain, a phenomenon that was recently found to affect MRI images.
Editor’s Note: These data add to the large number of studies in animals and humans indicating that lithium, in addition to preventing episodes and suicides, may have neurotrophic and neuroprotective effects.
Oxidative stress has been implicated in a wide range of illnesses, but what is it exactly? Our bodies use the oxygen we breathe to burn the fuel we get from food, and while this is a natural process, it produces byproducts known as free radicals, which are unstable molecules that can strip electrons from other molecules in a process called oxidation. Antioxidants (such as vitamin C) act as a source of electrons, helping keep other cells stable and healthy. Oxidative stress refers to the stress on our bodies from the normal effects of free radicals combined with environmental stressors like tobacco smoke or radiation.
In work presented at the 2013 meeting of the Society of Biological Psychiatry, Anna Andreason showed that over-activity of neurons increases oxidative stress through the production of reactive oxygen species (ROS). These are a type of free radicals that can damage cells in two ways: nitrosylation of proteins (adding nitric oxide to a thiol molecule), and oxidation, which results in more lasting effects on synaptic structures. The chemical compound rotenone damages mitochondria by producing ROS, and Andreason found that lithium was able to reverse this production and reverse the adverse effects of oxidative stress.
Lithium Has an Amazing Array of Positive Effects
Editor’s Note: The ability of lithium to protect mitochondria (the energy storehouse of a cell) adds to an increasingly long list of lithium’s neurotropic and neuroprotective benefits. Lithium increases cell survival factors BDNF and Bcl-2, increases markers of neuronal integrity such as N-Acetylaspartic acid (NAA), increases the volume of the hippocampus and cortex, and now helps protect mitochondria from oxidative stress. Lithium also increases the length of telomeres, which cap the ends of chromosome and protect them from damage during the DNA replication that occurs each time a cell divides. Short telomeres are associated with many kinds of medical and psychiatric diseases, as well as shorter life spans. No wonder that in addition to preventing mania and depression it has other clinical benefits, such as preventing memory deterioration, medical mortality, and suicide.
Willem Nolen, a researcher who has spent 40 years studying unipolar and bipolar disorder, recently retired from his position at Groningen Hospital in the Netherlands. In February, his retirement was celebrated with a symposium where he and other researchers discussed some of their important findings from the last several decades.
Nolen recently published a double-blind randomized study showing that in patients who were initially responsive to monotherapy with quetiapine (Seroquel), continuing the drug (at doses of 300-800mg/night) or switching to lithium were both more effective than switching to placebo over 72 weeks of long-term follow-up.
This study shows that quetiapine, which is only FDA-approved for long-term preventative treatment when used in combination with lithium or valproate (Depakote), also has efficacy when used as monotherapy.
Lithium is Highly Effective in Long-term Prevention
Nolen’s work also adds to an impressive amount of literature showing that lithium is highly effective in long-term prevention. This case is especially noteworthy because lithium was effective even in patients who had initially been selected for their response to quetiapine. (Studies that use this kind of “enriched sample” can only claim that quetiapine has long-term efficacy in those patients who initially respond well to the drug.) The data on lithium are even more impressive since the patients in this study were not enriched for lithium response.
Nolen has also conducted multiple studies of lithium, but optimal doses and target blood levels of the drug remain controversial. The therapeutic range of lithium is usually considered to be 0.6 to 1.2 meq/L, but some have argued that lower levels may still be effective. In a new analysis of those patients in the quetiapine study who were switched to lithium treatment, Nolen found that only lithium levels above 0.6 meq/L produced better results than placebo in long-term prophylaxis. Read more
A 2012 study by Kemp et al. in the journal Bipolar Disorders found that lamotrigine added to combination treatment with lithium and valproate was no more effective than placebo in patients with rapid cycling bipolar disorder. Only 14% (19 out of 133) of rapid cycling patients stabilized upon initial treatment with the open combination of lithium and valproate, a startlingly low rate. In the next phase of the study, 49 patients who were not stabilized were given adjunctive treatment with either lamotrigine (n=23) or placebo (n=26) on a double-blind basis, but no significant difference was observed.
Editor’s Note: This study has two pieces of not-so-good news. The first is that it was so difficult to stabilize these patients with rapid cycling bipolar disorder. The second is that the add-on of lamotrigine, which is highly effective in the prevention of depressions in bipolar disorder, was in this case no more effective than placebo.
This study again demonstrates that rapid cycling bipolar disorder is difficult to treat, and even the use of three proven mood stabilizers in combination is not always effective. Many doctors would recommend an atypical antipsychotic as the next clinical option.
In a poster at the 5th Biennial Conference of the International Society for Bipolar Disorders, researchers from the Netherlands including E.J. Regeer described the prevalence of hypercalcemia (high calcium levels) in patients with bipolar disorder who are treated with lithium. In a study of 314 patients taking lithium, Regeer and colleagues found that calcium levels were elevated in 15.6% of the patients, and the length of time patients had been treated with lithium was significantly related to the degree of hypercalcemia. It is recommended that blood levels of calcium be monitored in patients on lithium.
The researchers recommended testing for parathyroid hormone in blood in order to exclude other causes of hypercalcemia. They also suggested that when lithium cannot safely be discontinued or when its discontinuation does not resolve the hypercalcemia, other treatment for high blood calcium, including removal of the parathyroid, may be necessary.
Lithium Discontinuation Results in Only Modest Improvement in Renal Function Compared to Continued Treatment
Lithium is one of the most important treatments available for bipolar disorder. Unfortunately long-term use can be complicated by renal (kidney) dysfunction and, in rare cases, renal failure. A 2012 study by Rej et al. of geriatric patients with a history of lithium use and symptoms of chronic renal failure found that after two years, differences in outcomes for patients who continued lithium use versus stopping this treatment were not significantly different, though the lithium continuers had slightly less renal function after 60 months.
Editor’s Note: This study addresses one of the important unanswered questions about what to do when kidney function starts to diminish (observed as high levels of creatinine (Cr) or low Cr clearance) in patients on chronic lithium treatment.
The findings of Rej et al. suggest that the advantages of discontinuing lithium are not huge. Renal function may deteriorate a bit less (or not at all) in those who stop lithium. However, if someone is highly responsive to lithium and the “creatinine creep” upwards is slow, that patient might be able to proceed with careful monitoring and lithium continuation. Where other treatment options are readily available, the discontinuation route might be a good choice.
This study brings some much-needed randomized longitudinal data (if not a definitive recommendation) to bear on a difficult clinical decision that may have to be addressed when lithium is used in long-term approaches to bipolar disorder.
Lithium is one of the most important treatments available for bipolar disorder. A small percentage of patients who initially respond well to lithium may develop resistance to the drug over time. Some develop tolerance to the drug’s therapeutic effects over a period of years, seen as a gradual breaking through of manic or depressive episodes that increase in severity or frequency. Others who are good long-term responders to lithium, but stop taking lithium and then suffer relapses, fail to respond as well as they had before. In a few instances, the drug no longer helps at all. This latter form of acquired lithium resistance is called lithium discontinuation-induced refractoriness.
In a review article published in the Journal of Affective Disorders in 2011, this editor (Robert Post) analyzed case series and case reports that depicted these two different types of acquired lithium resistance and reported that each must be addressed in a different way. In the case of tolerance development, a temporary break from lithium may theoretically restore its effectiveness, but the typical way to treat this situation is to add additional drugs with different mechanisms of action that are not affected by the tolerance.
In those who stop effective lithium treatment and experience relapses that are no longer responsive when lithium is re-instituted, it is not clear what the best treatment approaches are. Therefore the most conservative approach to preventive treatment with lithium is to avoid discontinuing the drug. This would appear to be a generally sound principle for the treatment of recurrent unipolar or bipolar illness. When things are going well, do not change the regimen; leave well-enough alone. Conversely, when treatment is not optimal, as in the case of loss of drug responsiveness via tolerance, a more aggressive exploration of treatment options would be warranted.
Patients should be aware of the multiple dangers of stopping effective treatment with lithium. These include: likely relapse, perhaps the necessity of hospitalization, an increased risk of suicide, and the loss of responsiveness to lithium that appears to occur in approximately 15% of patients who stop lithium when it is working effectively.
Telomeres sit at the ends of strands of DNA at each chromosome. Various events make telomeres decrease in length: cell division/replication, stress, aging, and depressive episodes in Bipolar II disorder.
Martin Schalling, a professor of medical genetics at the Karolinska Institutet in Sweden, has found that lithium treatment lengthens telomeres.
Editor’s Note: This finding by Schalling, which will soon be published, adds to the list of beneficial neurobiological effects of lithium, including increasing cell survival factors BDNF and Bcl-2, decreasing cell death factors BAX and p53, increasing marker of neuronal integrity NAA, and possibly increasing hippocampal and cortical grey matter volumes.
Clinically, lithium decreases recurrence of manic and depressive episodes (mania more than depression), decreases suicidality, and may slow cognitive deterioration in those with mild cognitive impairment.
These clinical and neurobiological benefits to lithium treatment should be factored in to calculations of the risk/benefit ratio for lithium use in long-term preventative treatment of bipolar disorder.
Studies have indicated that lithium increases gray matter and the volume of the cortex and hippocampus in patients with bipolar I disorder. A poster presented by S. Selek et al. at the 5th Biennial Conference of the International Society for Bipolar Disorders described a longitudinal study of fronto-limbic brain structures in patients with bipolar I disorder during lithium treatment.
This study reported that patients whose illness failed to respond to lithium had smaller right amygdalas than euthymic bipolar I patients or healthy controls. After treatment with lithium, those who responded well to the drug showed significant enlargement of the left prefrontal cortex and the left dorsolateral prefrontal cortex, while those who responded poorly to lithium showed decreases in the volume of their left hippocampus and right anterior cingulate cortex.
Editor’s Note: This is one of several studies that suggest a relationship between volume of brain regions and degree of response to lithium. These data add to the remarkably consistent literature suggesting that lithium may have neurotrophic and neuro-protective effects, potentially because of the drug’s ability to increase neuroprotective factors such as BDNF and Bcl-2 while decreasing cell death factors such as BAX and p53.
Blüml et al. reported in the Journal of Psychiatric Research in 2013 that among 226 counties in Texas, the ones with higher trace levels of lithium in the public water supply had lower rates of completed suicide in the general population than did the counties with lower lithium levels. The naturally occurring lithium levels in public water supplies in the geographic regions described in this study ranged from 2.8 to 219 ?g/l or 0.00043 to 0.0315 mmol/l (much lower than the levels used to treat bipolar disorder).
This is the fourth positive study describing this effect, including two in Texas, one in Japan, and one in Austria. (One study from part of England failed to show this relationship, though levels measured in that study had a much lower and restricted range, from less than 1 to 21 ?g/l.) The most recent studies have collected more water samples and used more sophisticated statistical analyses to control for socioeconomic and a variety of other demographic effects on suicide.
Editor’s Note: Why higher trace levels of lithium occurring naturally in the water supply should have this anti-suicide effect in the general population is unknown, but it is a fascinating finding. It also gives indirect credence to the clinical findings in patients with unipolar and bipolar disorder that lithium (albeit in the much higher levels achieved with medication) has anti-suicide effects.