A 2004 meta-analysis of previous research showed that lithium was better than placebo at preventing affective episodes and preventing manic episodes. The evidence for the drug’s efficacy in preventing depression was less clear. A new meta-analysis by E. Severus et al. (not yet published) confirms the previous findings and provides new evidence that lithium is also better than placebo at preventing depressions.
The study also suggested that lithium is better than anticonvulsant mood stabilizers at preventing relapse and recurrence, but this finding only reached statistical significance in the prevention of new manic and hypomanic episodes.
Editor’s Note: These findings highlight the desirability of greater lithium use. The drug is currently prescribed less often in the US than it is in Europe. In addition to lithium’s efficacy in the long-term preventative treatment of bipolar disorder, there is evidence that lithium is also the best agent for suicide prevention and for neuroprotective effects.
Suicide is a serious risk for people with mood disorders. We have noted before that various studies of lithium show that the drug lowers suicide risk in people with mood disorders. A 2013 meta-analysis by Andrea Cipriani et al. in the journal BMJ confirms this finding. The review of 48 randomized controlled trials comparing lithium with placebo or other active drugs in the long-term treatment of mood disorders showed that lithium reduces the risk of suicide and death from any cause.
Lithium was more effective than placebo at reducing number of suicides and deaths from any cause, and more effective than carbamazepine and anticonvulsants in general at reducing deliberate self-harm. The authors wrote that lithium seems to reduce risk of suicide and death by more than 60% compared to placebo.
Lithium may reduce suicide risk by preventing relapse of mood disorders, but it may also have other mechanisms of action, such as decreasing aggression or impulsivity.
One thing to note about these findings is that the reduction in suicide risk also applies to those with unipolar depression, not just those with bipolar disorder. There is a case to be made that lithium treatment could be targeted specifically to reduce suicide risk.
Lithium treatment is associated with a moderate incidence of hyperparathyroidism, usually observed as an elevated concentration of calcium in the blood in addition to elevated parathormone levels, and often associated with the development of a tumor (adenoma) of the parathyroid gland.
In a recent study by Van Melick et al. published in the International Journal of Geriatric Psychiatry, among 111 patients with an average age of 75 years, 24-hour calcium excretion was elevated in only 3% of the patients, but levels of parathormone were elevated in 48%. Duration of lithium treatment was associated with lower vitamin 25OH D. Vitamin D is important for healthy bones and good cognitive functioning.
Editor’s Note: Lithium-induced hyperparathyroid should be investigated in those with elevated calcium levels, and if found, surgical removal of the parathyroid gland may be indicated. Low vitamin D is common in the US population. It is also particularly low in patients with mania and elderly patients on who have been on lithium for more than ten years. (Levels are below normal in 77% of these elderly individuals.) Assessment of vitamin D levels in those on long-term lithium is advisable, in addition to monitoring the thyroid, kidney function, and calcium metabolism.
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.