The New News About Lithium

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


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.

About fifteen percent of people taking lithium develop a thyroid deficiency, which can readily be corrected with thyroid hormone replacement. Diabetes insipidus, a hormone disorder characterized by thirst and heavy urination, can be minimized with amiloride.

Creatinine increases may occur with long-term lithium use. These usually start after 30 years of taking the drug and tend not to progress to end-stage renal disease in people taking lithium, as they do in people taking anticonvulsants.

Hyperparathyroidism (high levels of calcium) is rare and can be treated with surgery. Tremor can be treated with propranolol. Weight gain on lithium is usually minimal.

Predicting a Good Response to Lithium

Research has found that some people are more likely to have a good response to lithium treatment than others. A family history of mood disorders, especially bipolar disorder, is one of the number one predictors. Lack of anxiety and substance abuse comorbidity also predict a better response to lithium.

People who have euphoric manias respond better to lithium than the two-thirds of women and 40% of men who have dysphoric (anxious, irritable) manias. Those who have discrete mood episodes separated by well intervals in between are also more likely to respond well to lithium.

The pattern of a person’s manias and depressions may also affect whether they respond well to lithium. Mania followed by depression and then a well interval (a pattern known as M-D-I) is associated with a better lithium response than depression followed by mania and then a well interval (D-M-I).

Starting ongoing preventative treatment with lithium after fewer mood episodes predicts a better response than beginning later in the course of illness, after many episodes.
It is notable that perhaps the majority of people with bipolar illness in the US do not fit this profile. For these patients, lithium would need to be augmented with an anticonvulsant drug, a mood stabilizer (lamotrigine, valproate, or carbamazepine), or an atypical antipsychotic.

New Principles of Treatment

A 2013 article by Lars V. Kessing and colleagues in the British Journal of Psychiatry showed that after a first episode of mania, patients randomized to receive two years of comprehensive treatment involving medications, psychotherapy, psycho-education, and illness monitoring had fewer relapses over a period of six years than patients who received treatment as usual. That is, early excellent treatment can improve the long-term course of illness.

At the 2016 meeting of the International Society of Bipolar Disorders, researcher Lakshmi Yatham emphasized the importance of starting ongoing preventative treatment after a first mania. Yatham and colleagues found that cognitive deficits associated with a first mania recover over the course of the next year, but only if the patient experiences no further episodes during this period.

A 2017 study by Michael Berk and colleagues in the British Journal of Psychiatry found that when patients were randomized to one year of lithium or quetiapine following a first mania, both groups improved considerably, but had some residual symptoms.

However, after the first six months, lithium brought about more improvement than quetiapine on all measures, including mania, depression, functioning, cognition, and brain imaging. Thus, preventive treatment should begin after a first manic episode, and use of lithium should definitely be considered.

The recurrence of stressors, mood episodes, and bouts of substance use can snowball, making episodes, stressors, and substance use more likely to occur and to become more severe in the future. This process is called sensitization, and it drives illness progression.

Unfortunately, sensitization is based on memory-like epigenetic changes to the shape of DNA that can have a lasting effect on gene transcription and vulnerability to illness, even for a patient’s offspring. This means limiting stress and substance abuse and using preventive medication to avoid episodes is not only important to recovery, but can also reduce the accumulation of adverse epigenetic marks on DNA.

If substance abuse cannot be prevented, it should be treated using off label treatments if necessary, since there are no US Food and Drug Administration-approved treatments for the combination of substance abuse and bipolar disorder.

Illness education should be paired with treatment at all stages of bipolar disorder (early, mid, and late). It can help patients better understand and monitor their illness and adhere to ongoing preventive treatment.

Psychotherapy can also help prevent episodes, modulate stressors, and reduce the risk of suicide.

It is also important to be alert to emerging symptoms in children at high risk for bipolar disorder due to their family history. Interventions involving lifestyle improvements (such as nutritious diet, regular exercise, and good sleep habits), psychosocial therapy, or medication may be needed. Early, effective treatment may prevent the onset of full-blown illness or lessen its severity.


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