Lithium May Best Newer Drugs at Reducing Self-harm in BD

Fran Lowry

May 16, 2016

In a study of more than 6500 patients with bipolar disorder, those taking lithium (multiple brands) had lower rates of self-harm and unintentional injury than those taking alternative mood stabilizers such as valproate (Depacon, AbbVie Inc), olanzapine (Zyprexa, Eli Lilly and Company) or quetiapine (Seroquel, AstraZeneca Pharmaceuticals LP).

The finding, published online May 11 in JAMA Psychiatry, augments results form limited trials and smaller observational studies and supports the hypothesis that lithium reduces impulsive aggression in addition to stabilizing mood, the authors state.

"People with bipolar disorder are 15 times more likely to die by suicide and six times more likely to die by accidental injury than the general population," lead author Joseph F. Hayes, MD, from University College London, United Kingdom, told Medscape Medical News.

"Understanding if drug treatment can affect these negative outcomes is therefore very important," Dr Hayes said. "In randomized controlled trials, drug effects on these outcomes have been difficult to quantify, and people with a history of self-harm have often been excluded, and well-designed observational, or real-life, studies are likely to be our best opportunity to study these effects."

Dr Joseph Hayes


In the current study, which was a propensity score (PS)–adjusted and PS-matched longitudinal cohort study, he and his team analyzed data from electronic health records on a nationally representative sample of 6671 patients with bipolar disorder.

The data were collected between January 1, 1995, and December 31, 2013.

Of the patients in the sample, 2148 were prescribed lithium; 1670 were prescribed valproate; 1477, olanzapine; and 1376 quetiapine as maintenance mood stabilizer treatment.

The duration of drug exposure ranged from 28 days to 17 years, 11 days.

Patients prescribed lithium tended to be older than those taking the other study drugs. More years of follow-up data were available for the patients prescribed lithium, and they were less likely to have been treated for depression, anxiety, or self-harm before their entry into the cohort.

Overall, the rate of self-harm in the cohort reported to primary care physicians was 340 per 10,000 person-years at risk (PYAR).

Self-harm rates were lower in patients prescribed lithium than in those prescribed the newer agents.

Table. Self-harm Rates for Lithium vs New Agents per 10,000 PYAR

Drug Self-harm Rates per 10,000 PYAR 95% Confidence Interval
Lithium 205 175 - 241
Valproate 392 334 - 460
Olanzapine 409 345 - 483
Quetiapine 582 489 - 692


The reduced rates of self-harm in patients taking lithium in comparison with those taking the other agents persisted after adjusting for propensity score, age, calendar year, and primary care practice (hazard ratio [HR], 1.40; 95% CI, 1.12 - 1.74 for valproate, olanzapine, or quetiapine vs lithium) and propensity score matching (HR, 1.51; 95% CI, 1.21 - 1.88).

In addition, after propensity score adjustment, unintentional injury rates were lower with lithium than with valproate (HR, 1.32; 95% CI, 1.10 - 1.58) and quetiapine (HR, 1.34; 95% CI, 1.07 - 1.69) but not olanzapine.

The suicide rate in the cohort was 14 (95% CI, 9 - 21) per 10,000 PYAR.

"This rate of suicide was lower in the lithium group than for the other drugs, but there were too few events to allow accurate estimates," Dr Hayes noted.

"The high rate of injuries requiring emergency department or GP contact in our study was surprising and represents significant morbidity in this patient group," he said.

"Although this study suggests lithium may have more impact on self-harm than other drugs, this is only part of the picture," Dr Hayes said.

"Two recent meta-analyses have suggested that lithium should be used first-line for maintenance treatment of bipolar disorder because of its superior mood stabilizing properties. However, there are concerns about the potential side effects of lithium, especially potential effects on the kidney and thyroid. There is some evidence that if levels are carefully monitored, the risk of adverse effects is dramatically reduced, but benefits and potential risks need to be balanced for the individual patient," he said.

Currently, the best use of lithium is not being studied, at least in the United Kingdom, Dr Hayes added.

"Further research needs to go into understanding the potential side effects of lithium and the other commonly used mood stabilizers in the long term, as patients often take these drugs for years. We also need to understand if particular patient characteristics mean that they are more likely to benefit from lithium or experience side effects," he said.

For now, physicians should discuss with their patients the possiblity of commencing therapy with lithium early on. "The evidence we are accruing shows lithium in a positive light compared to newer drugs that have been intensively marketed. Lithium's bad reputation needs to be challenged with both clinicians and the public," Dr Hayes said.

Study May Encourage More Use of Lithium

Commenting on this study for Medscape Medical News, R. Scott Hamilton, MD, from the Order of the Sisters of St. Francis OSF Health Care, Normal, Illinois, said he is now taking a renewed interest in lithium and may start to use it more often.

Dr R. Scott Hamilton

"This was a very interesting and important paper because it supports the idea that lithium reduces suicidal behavior compared to the other medications and also supports the explanation that suicidal behaviors are impulsive actions and that lithium has a special, preferential effect against such behaviors," Dr Hamilton said.

"I have many patients who do various things to harm themselves, so having some way of diminishing that is very helpful. I think these data should encourage practitioners to use lithium more often," he said.

Lithium was used widely in the 1960s and 1970s, but its use has declined since the advent of the newer antipsychotics, Dr Hamilton said.

"When I trained back in the 1980s, lithium was used a lot, but it has fallen into disfavor. I think that some of these data support the idea of using lithium more often than we have been. I haven't been using it as much because of the other choices that are available to us now, but maybe I'll start using it a bit more," he said.

He added that a strength of the study is that it was not sponsored by a pharmaceutical company.

"All of the drugs in this study are no longer on patent, and the study is not sponsored by one drug company. Sometimes that raises suspicion about whether the results are valid, but these are all older medications, so there doesn't appear to be a profit motive as far as the study goes," Dr Hamilton said.

Dr Hayes is supported by a Medical Research Council Population Health Scientist fellowship. Dr Hamilton reports no relevant financial relationships.

JAMA Psychiatry. Published online May 11, 2016. Full text


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