Recent studies have indicated that bipolar disorder is associated with changes to brain volume, including thinning of the cortex. In research presented at the 2016 meeting of the Society of Biological Psychiatry, researcher Noha Abdel Gawad reported that four weeks of lithium treatment increased cortical thickness in the left superior frontal gyrus. This is the third replication of this finding.
Other research has established that lithium treatment also increases the volume of the hippocampus in people with bipolar disorder. Together the findings provide strong evidence that lithium treatment protects neurons and can reverse brain changes associated with bipolar disorder.
Telomeres are repeated DNA sequences that sit at the end of chromosomes and protect the DNA as it is replicated. Depressive episodes and age can reduce the length of telomeres. Lithium treatment increases telomere length. At the 2016 meeting of the Society of Biological Psychiatry, researcher Martin Schalling reported that the longer a patient takes lithium, the more their telomere length increases.
According to Schalling, people who respond well to lithium treatment show greater increases in telomere length than those who respond poorly to lithium.
While some cancers are associated with long telomeres, lithium use has not been found to increase cancer risk. In fact, lithium treatment can decrease the risk of certain cancers of the gastrointestinal, respiratory, and endocrine systems.
Patients with bipolar disorder often show increases in signs of inflammation, including levels of the proteins IL-2, IL-4, Il-6, IL-10 and tumor necrosis factor in their blood. Lithium is the most effective treatment for bipolar disorder, but it is not yet clear how it works. A recent study by researcher Joao de Quevado and colleagues determined that lithium can reduce the same inflammatory markers in rats.
Rats were treated with amphetamine to induce mania-like behavior, which was accompanied by increases in some of the same inflammatory markers in the blood and brain that are increased in people with bipolar disorder. Lithium treatment reduced both the manic behavior and levels of these inflammatory proteins in the rats.
The researchers concluded that lithium may treat mania by reducing inflammation.
Lithium is one of the most effective medications for bipolar disorder, but it has other benefits as well. At a 2015 scientific meeting, Ronald Fieve reported that among 1021 psychiatric outpatients, 570 who received long-term lithium treatment for their psychiatric illnesses had a significantly lower likelihood of certain medical conditions compared to the other outpatients who did not receive lithium therapy. The medical conditions that lithium made less likely were seizures, amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease, dementia, and heart attack.
It is not yet know how lithium decreases these medical conditions. It may be by increasing the length of telomeres. Telomeres are repeated DNA sequences that sit at the end of chromosomes and protect them during cell replication. Telomeres get shorter with aging and with stressors or psychiatric illnesses. Lithium directly increases the enzyme telomerase, which maintains telomere length. This may be one reason lithium use provides some protection from seizures, heart attacks, and other conditions.
Lithium is the treatment of choice for adults with bipolar disorder, but has rarely been studied in children or adolescents. One of the first double-blind placebo-controlled trials of lithium for the treatment of mania in children and teens aged 7–17 showed that the drug produced greater improvement in mania than did placebo. Side effects included blurred vision, abdominal pain, diarrhea, nausea, vomiting, fatigue, thirst, increased thyroid-stimulating hormone, decreased appetite, dizziness, sedation, tremor, increased urination, and rash.
In the study by researcher Adelaide S. Robb and colleagues, which was presented at the 2015 meeting of the American Academy of Child and Adolescent Psychiatry, doses began at 300mg twice a day, were based on each child’s weight, and were slowly increased.
At the same meeting, researcher Russell Scheffer presented data on 41 children who continued lithium treatment for 16 weeks with good results. The mean dose was 27.8 +/- 6.7 mg/kg per day.
At the 2015 meeting of the International Society for Bipolar Disorders, researcher Martin McInnis described how stem cells can be used to identify biochemical abnormalities in patients with bipolar disorder. In this research, the stem cells, or IPSCs (for induced pluripotential stem cells), are created when cells from skin fibroblasts, which produce connective tissue, are treated with chemicals that cause them to de-differentiate back into stem cells.
McInnis identified several abnormalities in the stem cells of patients with bipolar disorder. Stem cells with the gene CACNA1C, which is associated with vulnerability to bipolar disorder, fired more rapidly than non-CACNA1C stem cells. There were other abnormalities at the NMDA glutamate receptor and an imbalance of the neurotransmitter GABA in the cells. When the cells were treated with lithium, some of these abnormalities were reversed. In the cells with the CACNA1C gene, lithium normalized the firing rate. Lithium aslo re-balanced the distribution of GABA in the cells.
McInnis hopes that this stem cell research will shed light on the abnormalities associated with bipolar disorder, help explain how lithium corrects some of these, and lead to the development of new therapeutic approaches.
The first large, randomized, double-blind study of lithium in children and teens has shown that as in adults, the drug can reduce mania with minimal side effects. The study by researcher Robert Findling was published in the journal Pediatrics in October. Lithium is the best available treatment for adults, but until now little research had been done on treatments for children and teens with bipolar disorder.
In the study, 81 participants between the ages of 7 and 17 with a diagnosis of bipolar I disorder and manic or mixed episodes were randomized to receive either lithium or placebo for a period of eight weeks. By the end of the study, those patients taking lithium showed greater reductions in manic symptoms than those taking placebo. Among those taking lithium, 47% scored “much improved” or “very much improved” on a scale of symptom severity, compared to 21% of those taking placebo.
Dosing began at 900mg/day for most participants. (Those weighing less than 65 lbs. were started at 600mg/day.) Dosing could be gradually increased. The mean dose for patients aged 7–11 was 1292mg/day, and for patients aged 12–17 it was 1716mg/day.
Side effects were minimal. There were no significant differences in weight gain between the two groups. Those taking lithium had significantly higher levels of thyrotropin, a peptide that regulates thyroid hormones, than those taking placebo. If thyroid function is affected in people taking lithium, the lithium dosage may be decreased, or patients may be prescribed thyroid hormone.
Earlier this year we described a 2015 study by Harald Aiff and colleagues that suggested that long-term lithium use was associated with a risk of kidney failure. That study, published in the Journal of Psychopharmacology, included 630 patients who had taken lithium for at least 10 years. One-third of these patients had evidence of kidney dysfunction, and in 5%, the impairment was severe. Two new studies provide some data that suggest these risks may not be lithium-specific and are comparable to risks that come with taking other medications.
The first, by Stefan Clos et al. in The Lancet Psychiatry, included 1,120 patients followed for up to 12 years. On average, these patients had been exposed to lithium for a little over 4.5 years. Clos and colleagues determined patients’ estimated glomerular filtration rate (eGFR), a measure of how well the blood is filtered by the kidneys. The researchers concluded that there was “no effect of stable lithium maintenance therapy on the rate of change of eGFR over time” compared to other drugs such as quetiapine, olanzapine, or valproate.
The second new study, by Lars Vedel Kessing and colleagues in the journal JAMA Psychiatry, included 26,731 patients exposed to lithium and 420,959 exposed to anticonvulsants. Kessing and colleagues concluded that both exposure to lithium and exposure to an anticonvulsant were associated with an increased rate of chronic kidney disease, but lithium was not associated with end-stage kidney disease (the kind that requires dialysis or renal transplantation).
The three studies taken together suggest the following: Taking lithium for an average of 4–5 years does not affect kidney functioning, and longer exposure may not harm kidney function any more than other medications (such as anticonvulsants) would. However, kidney functioning (in terms of eGFR) does decline with age, and is also lower among those with higher baseline eGRF, those with other illnesses, those taking other drugs that affect the kidneys, and those who experience an episode of lithium toxicity. Read more
Studies of rodents with depression-like behaviors revealed that the combination of low (sub-therapeutic) doses of lithium and infusions of ketamine produced antidepressant-like effects. Researchers believed this might mean that in humans, lithium might have a unique effect potentiating the effects of ketamine.
In a small study by Mark J. Niciu presented at the 2015 meeting of the Society for Biological Psychiatry, patients with bipolar depression taking lithium or valproate mood stabilizers were given ketamine infusions or control infusions. In the 23 patients taking lithium and the 13 taking valproate, ketamine’s antidepressant effects were significantly better than placebo, but there was no difference between lithium and valproate with regard to these antidepressant effects. These preliminary data in a small number of subjects do not support the proposition that lithium augments the effects of ketamine in depression.
Lithium inhibits the enzyme glycogen synthase kinase 3, which has been implicated in dementia. To study whether lithium may prevent cognitive decline, researchers led by Tobias Gerhard looked at the medication histories of patients with bipolar disorder who were 50 years of age or older. In their article published in the British Journal of Psychiatry, those patients who had taken lithium 301–365 days out of the previous year had substantially lower risk of dementia than those who had not taken lithium during that time. Patients who had 300 or fewer days of lithium use did not have a significant reduction in dementia risk, nor did patients who were prescribed anticonvulsant drugs.
Editor’s Note: These data are consistent with those of Lars Kessing and colleagues, which suggest that patients in Denmark who renewed their lithium prescriptions were less likely to receive a diagnosis of dementia in old age.
In 2011, Orestes V. Forlenza and colleagues also reported in the British Journal of Psychiatry that compared to placebo, a very small dose of lithium, 150 mg/day, slowed the progression of mild cognitive impairment over one year.