Continuing Lithium Treatment Does Not Increase Kidney Failure

February 26, 2018 · Posted in Current Treatments · Comment 

kidneyA risk of long-term lithium treatment is that it can cause kidney damage. However, a new study suggests that continuing lithium treatment after a diagnosis of chronic kidney disease does not necessarily increase the risk of irreversible end-stage kidney disease, which is defined as either the need for either chronic dialysis or a kidney transplant.

The 2017 study by researcher Lars Kessing and colleagues in the journal Acta Psychiatrica Scandinavica used Danish health databases to track data from all individuals who received a diagnosis of chronic kidney disease between 1995 and 2012 and also had a history of lithium treatment (754 patients) or anticonvulsant treatment (5,004 patients). Kessing and colleagues found that patients who continued taking lithium after an initial diagnosis of chronic kidney disease had decreased rates of end-stage kidney disease. This also held true for those who continued anticonvulsant treatment after a diagnosis of kidney disease.

One point of uncertainty was introduced by the finding that the subset of participants who were taking lithium specifically to treat bipolar disorder did have a higher rate of end-stage kidney disease. This was not true of the participants who were taking anticonvulsants to treat bipolar disorder.

Kessing and colleagues concluded that after an initial diagnosis of chronic kidney disease, continuing lithium did not necessarily increase end-stage kidney disease. Switching to an anticonvulsant, as is sometimes the practice after a kidney disease diagnosis, may not confer any benefit.

Lithium Treatment Lowers Suicide Rate in People with Bipolar Disorder

February 23, 2018 · Posted in Current Treatments · Comment 

lithium

A large study that made use of a Swedish health database has shown that lithium reduces suicide rates in bipolar disorder. The study by researcher Jie Song and colleagues was published in the American Journal of Psychiatry in 2017.

The study included eight years of data from 51,535 people with bipolar disorder. During that time, there were 10,648 suicide-related events recorded, such as suicide attempts or completed suicides. The researchers compared suicide rates when patients were taking lithium to rates when they were off the drug, and found that lithium reduced attempted or completed suicide by 14%. Song and colleagues also looked at suicide rates for people taking valproate, and found that these were no better than when patients were off valproate, implying that treatment alone is not enough to reduce the suicide rate and the benefit is specific to lithium use.

Song and colleagues estimate that 12% of the suicide-related events among the patients included in the study might have been avoided if the patients had taken lithium for the entire study period. While there are other clinical considerations to make when selecting an appropriate treatment for a given patient, the researchers suggest that lithium treatment should be considered for patients with bipolar disorder who have expressed suicidal intentions or who are otherwise at risk for suicide.

In Danish Study, Higher Trace Levels of Lithium in Drinking Water in Certain Regions Do Not Seem to Prevent Bipolar Disorder

February 21, 2018 · Posted in Potential Treatments · Comment 

man drinking water

Previous studies have found that trace levels of lithium that occur naturally in the drinking water of certain regions are associated with lower rates suicide. Preliminary studies have also shown that lithium in drinking water is associated with lower dementia rates. The trace levels seen in drinking water are many hundreds of times lower than clinical doses of lithium prescribed for bipolar disorder, but they vary greatly according to locality.

A new study by researcher Lars Kessing and colleagues investigated whether chronic exposure to lithium in drinking water might protect against bipolar disorder, but found no evidence that this is the case in Denmark.

In an article published in the journal Bipolar Disorders in 2017, Kessing and colleagues describe findings from their analysis of data on 14,820 patients with a diagnosis of mania or bipolar disorder and (for each participant with bipolar disorder) 10 other age- and gender-matched control participants totaling 140,311. The researchers were able to look longitudinally at the participants’ exposure to trace levels of lithium in drinking water based on their municipalities of residence.

The investigators hoped to find evidence that greater exposure to lithium was associated with lower rates of bipolar disorder. Kessing and colleagues concluded that trace lithium levels higher than those in Denmark might be needed to find such a result.

Editor’s Note: Clinical studies of lithium treatment for children at high risk for bipolar disorder could help clarify whether even conventional therapeutic levels of lithium could reduce or delay the appearance of bipolar disorder.

Naturally Occurring Lithium in Texas Drinking Water Reduced Alzheimer’s Mortality Rates

February 19, 2018 · Posted in Potential Treatments · Comment 

woman drinking water

Several studies have found that trace levels of lithium that naturally occur in the drinking water of certain regions are associated with reductions in dementia compared to regions with less lithium in the water. The latest such study found that higher trace levels of lithium in certain Texas counties were associated with less mortality from Alzheimer’s disease compared to Texas counties with lower levels of lithium in the water.

The research by Val Andrew Fajardo and colleagues was published in the Journal of Alzheimer’s Disease in 2017. Fajardo’s team obtained 6,180 water samples from 234 of Texas’ 254 counties. They also calculated that there was an increase in the Alzheimer’s mortality rate from the period 2000–2006 to the period 2009–2015. However, regions with higher trace levels of lithium were negatively correlated with this increase, suggesting that the lithium in the water had a protective effect on people in those counties.

The researchers controlled for gender, race, education, rural living, and air pollution. Physical inactivity, obesity, and type 2 diabetes seemed to be confounding factors. Obesity and type 2 diabetes were positively correlated with Alzheimer’s mortality and negatively correlated with lithium levels in drinking water, meaning that it is possible that lithium also protects against these conditions.

Lithium in Drinking Water May Reduce Dementia

February 16, 2018 · Posted in Potential Treatments · Comment 

New research suggests that higher trace levels of lithium in drinking water can reduce dementia rates in the general population. In a 2017 article in the Archives of General Psychiatry, researcher Lars Kessing and colleagues compared data on 73,731 patients in Denmark with a diagnosis of dementia to 733,653 control participants without this diagnosis between the years 1970 and 2013. They were able to match the data to recorded levels of trace lithium in the drinking water in participants’ municipalities of residence.

Lithium levels in the water ranged from 0.6 micrograms per liter to 30.7 micrograms per liter in 151 different locations throughout Denmark. Compared to those exposed to 2.0 to 5.0 micrograms of lithium per liter of water, those exposed to more than 15.0 micrograms per liter had a lower incidence rate of dementia. However, those exposed to 5.1 to 10.0 micrograms per liter had a higher incidence of dementia. The same relationship was also found between lithium exposure levels and both Alzheimer’s disease and vascular dementia.

The lithium levels in the water were approximately 10,000 to 300 times lower than typical clinical doses (typically 900–1500mg/day, which produce concentrations ranging from 0.6 to 1.2 meq/L in patients’ blood). The minute exposures to lithium in the drinking water occurred over decades in the Danish study, and suggest that there may be long-term positive effects to chronic lifetime exposure to very low lithium levels.

These data follow others regarding exposure to trace lithium. In 2011, researcher Orestes V. Forlenza and colleagues reported in the British Journal of Psychiatry that low dose lithium (150–600mg/day) over a period of one year decreased the progression of mild cognitive impairment compared to placebo, while researcher Marielza Andrade Nunes and colleagues reported in the journal Current Alzheimer’s Research in 2013 that an even smaller dose (0.3mg/day) over a period of 15 months slowed the progression of Alzheimer’s dementia. Thus, low or microscopic doses consumed over long periods could slow cognitive deterioration.

Making Lithium Treatment More Tolerable For Patients

November 9, 2017 · Posted in Current Treatments · Comment 

taking lithiumIn a slideshow at Psychiatric Times, Chris Aiken describes seven ways to improve lithium’s tolerability.  Since many researchers, including BNN Editor-in-Chief Robert M. Post, have suggested that lithium should be used more often as a treatment for bipolar disorder, ways of making its side effects more manageable are of great interest. Here we summarize Dr. Aiken’s seven points and add a few perspectives of our own.

Aiken writes that “when it comes to the side effects that matter most to patients—sedation, weight gain, and cognition—lithium’s tolerability ranks right behind lamotrigine.”  In fact, lithium plus lamotrigine is an excellent combination, as lithium excels at preventing manias while lamotrigine excels at depression prevention.

Post’s philosophy is that many of lithium’s side effects can be avoided in the first place through judicious dose titration. He suggests gradually increasing dosage, and stopping before side effects become difficult, or reducing a dosage that has already become a problem. The idea is to avoid lithium side effects even if blood levels of lithium remain below clinically therapeutic levels. Post suggests using lithium at whatever dose is not associated with side effects.

Many of lithium’s positive therapeutic effects emerge at low doses, and if this improvement is insufficient, the rest of the needed efficacy can be achieved by adding other medications. As noted above, lamotrigine is a good option for break-through depression, as is lurasidone. For breakthrough mania, the mood stabilizers valproate and carbamazepine or an atypical antipsychotic can be added to lithium.

A little-appreciated option for enhancing lithium’s mood stabilizing effects is nimodipine, a dihydropyridine calcium blocker. It has both antimanic and antidepressant efficacy without lithium’s side effects. Research showed that a year on the combination of lithium and nimodipine was more effective than a year of either drug alone.

If a patient taking lithium experiences a tremor at a dose that is not fully effective, nimodipine can be added in order to lower the lithium dose enough to eliminate the tremor.
Nimodipine specifically blocks the calcium influx gene CACNA1C that has been repeatedly been associated with the vulnerability to bipolar disorder and depression.

If side effects do occur on lithium, they can often be managed. The following suggestions are adapted from Aiken’s article with input from Post. Read more

The New News About Lithium

November 7, 2017 · Posted in Current Treatments, Peer-Reviewed Published Data · Comment 

lithium

Robert M. Post, Editor-in-Chief of the BNN, recently published an open access article in the journal Neuropsychopharmacology, “The New News About Lithium: An Underutilized Treatment in the United States.” Here we summarize the main points of the publication, including: the multiple benefits of lithium, its relative safety, predictors of lithium responsiveness, and principles for treatment.

Benefits of lithium

Lithium prevents both depressions and manias in bipolar disorder, and also prevents depressions in unipolar disorder and can augment antidepressant effects acutely. In addition to these mood benefits, lithium has anti-suicide effects. Lithium also enhances the efficacy of atypical antipsychotics and other mood stabilizers when used in combination with them.

Lithium is good for the brain. It has been shown to reduce the incidence of dementia. Lithium increases the volume of the hippocampus and cortex, and can increase the production of new neurons and glia. It also protects neurons. In animals, lithium has been shown to reduce lesion size in neurological syndromes that are models for human disorders such as AIDS-related neurotoxicity, ischemic/hemorrhagic stroke, traumatic brain/spinal cord injury, Huntington’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), fragile X syndrome, Parkinson’s disease, retinal degeneration, multiple sclerosis, alcohol-induced degeneration, Down’s syndrome, spinocerebellar ataxia-1, and irradiation.

Lithium’s benefits include more general ones as well. It can increase the length of telomeres, bits of DNA on the ends of chromosomes that protect them during replication. Short telomeres have been linked to various illnesses and the aging process. Lithium also decreases the incidence of several medical illnesses and enhances survival.

Side Effects Are Often Benign, Treatable

Lithium side effects are more benign than many people think. Even low levels of lithium may be therapeutically sufficient. Read more

Lithium Responders and Non-Responders Have Different Neuron Characteristics

May 22, 2017 · Posted in Current Treatments · Comment 
after hyperpolarization

After hyperpolarization (via Wikimedia Commons)

A 2017 study in the journal Molecular Psychiatry suggests that by observing the neurons of a person with bipolar disorder, you can predict whether they will respond to lithium treatment. The drug is effective in approximately 30% of those to whom it is prescribed.

Researchers led by Shani Stern and Renata Santos used stem cell research to analyze neurons from people with bipolar disorder and healthy controls.

People with bipolar disorder shared some neuron features, namely a large, fast after-hyperpolarization (a phase in which the cell’s membrane changes), which is followed by a resting period before the neuron can fire again. The large, fast hyperpolarization in people with bipolar disorder speeds up this cycle, leading to fast and sustained neuron firing. This replicated previous findings by the same researchers, which found that people with bipolar disorder are more sensitive to stimuli. In people with bipolar disorder, the threshold for a neuron to fire drops with each subsequent after-hyperpolarization.

Chronic lithium treatment reduced this hyperexcitability in some patients—and these were the patients who had a good response to lithium treatment.

Among the study participants with bipolar disorder, there were differences in the neuron profiles of those who responded well to lithium versus those who did not.

Stern and colleagues programmed a computer to recognize the electrophysiological features of neurons from lithium responders and non-responders. The computer could then analyze the neurons of a patient whose response to lithium was unknown and predict with a greater than 92% success rate whether that patient had responded well to lithium treatment.

Lithium May Reduce Cancer Risk

April 17, 2017 · Posted in Current Treatments · Comment 

smiling senior asian man

New research suggests that cumulative exposure to lithium may correlate with reduced cancer risk in patients with bipolar disorder. A 2016 article by Yi-Hsin Yang and colleagues in the British Journal of Psychiatry reports findings from a Taiwanese population database study of 4,729 adult patients with bipolar disorder, 115 of whom were diagnosed with cancer. Those who had been prescribed lithium (with or without anticonvulsants) had lower rates of cancer (1.96%) than those who received only anticonvulsants (2.65%).

Incidence of cancer was higher among the patients with bipolar disorder than the general population in the study. Other studies have indicated that cancer risk is higher among people with bipolar disorder than those without.

Those people who took a recommended maintenance lithium dose for 215 days or longer had a 44.8% lower risk of cancer than those who took only anticonvulsants.

Lithium May Work by Restoring Dendritic Spines

April 14, 2017 · Posted in Current Treatments, Neurobiology, Theory · Comment 
spines on a dendrite

spines on a dendrite

New research on mice clarifies lithium’s effects on neurons and suggests how it can lead to improved symptoms. Dendrites are the long projections on neurons that seem to reach out to form synapses with other neurons. The surface of these dendrites is covered in mushroom-shaped spines that help create these synaptic connections. A 2016 article by research Ben Cheyette and colleagues in the journal Molecular Psychiatry reports that in mice with a genetic mutation common to people with autism, schizophrenia, and bipolar disorder, lithium restored healthy numbers of the mushroom-shaped spines. The lithium treatment also reversed symptoms such as lack of interest in social interactions, lack of motivation, and anxiety in the mice.

Cheyette and colleagues first identified a genetic mutation that affects signaling in what is known as the brain’s Wnt pathway. The mutation, while rare, is 80% more common in people with bipolar disorder, autism, and schizophrenia than in people without these disorders.

When the mice were given a similar mutation, they exhibited symptoms such as anxiety, decreased sociability, and lack of motivation. They also had reduced numbers of dendritic spines and impaired Wnt signaling.

Lithium can improve Wnt signaling by blocking an enzyme called GSK-3 beta that impairs the signaling.

Treating the mice with lithium restored their dendritic spines and improved their behavior.

Wnt signaling and dendritic spines may offer the key to lithium’s success in treating a variety of psychiatric disorders in people.

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