From a Contributing Editor, Colleague and Friend of the Editor

Sixty-seven years ago, Australian psychiatrist John Cade published his case series on manic patients treated with lithium – truly the dawn of the modern era in psychopharmacology. Two decades passed before lithium came to Canada, and almost three before it came to the United States. In the treatment of mania, it was the first significant drug alternative to the only other enduring treatment from that time – electroconvulsive therapy.

Dr. John Cade (and Lithium)

Today, however, lithium suffers from under-promotion (there is no money to be made on it by the pharmaceutical industry) and under-exposure in the training of residents despite the evidence of its benefit that continues to emerge.

Here is a new paper that looks at suicide and self-harm during maintenance treatment of people with bipolar disorder treated with lithium, valproate or the increasingly popular second-generation antipsychotic drugs. And here is an old paper that reminds us what a difference lithium had already made in the economics of mental illness by 1980.

– David Goldbloom, OC, MD, FRCP(C)

“Self-Harm, Unintentional Injury, and Suicide in Bipolar Disorder During Maintenance Mood Stabilizer Treatment”

Joseph Hayes et al., JAMA Psychiatry

Online First, 11 May 2016


Dr. Joseph Hayes

Why did they do this study?

Hayes et al. explain:

Self-harm is a major cause of morbidity in bipolar disorder (BPD), and drug treatments that reduce suicidal and nonsuicidal self-harm could improve quality of life for individuals with BPD and their families. Furthermore, individuals who self-harm have a substantially increased suicide risk. Bipolar disorder is associated with an annual risk of suicidal acts that is 10 times that of the general population and a lifetime risk of suicide that is almost 15 times greater. Randomized clinical trials of maintenance medication show that drugs like lithium, valproate sodium, olanzapine, and quetiapine fumarate can stabilize mood. However, balancing the relative benefits and potential risks of these medications is not straightforward, and potential drug effects on self-harm have been underexamined in this regard.

Because trials often exclude those with a history of suicidal behavior, drug effects on self-harm have been difficult to quantify due to low event rates. The findings of a meta-analysis of 48 trials suggested that suicide was less likely in people prescribed lithium than placebo or active comparator groups but found no difference in self-harm rates. The results of observational studies have suggested that lithium use may reduce fatal and nonfatal self-harm compared with maintenance treatment alternatives, most commonly anticonvulsant medication, but the findings have not always been consistent. After a warning from the US Food and Drug Administration that anticonvulsant medications carry an increased risk of suicidal self-harm, a number of studies investigated this issue in BPD. A meta-analysis that included only patients with BPD and several observational studies did not replicate this finding. There are sparse data on the association between antipsychotic medication use and self-harm. Small retrospective cohorts have shown no difference in suicidal self-harm in patients taking olanzapine or quetiapine and have demonstrated higher rates of suicide attempts in those prescribed second-generation antipsychotics compared with lithium or valproate.

The problem with measuring the impact of our treatments on suicide and self-harm is the rarity of these events in study populations. However, the authors used electronic health records data from 1995 to 2013 to study a nationally representative UK sample of over 6,000 people with bipolar disorder treated with lithium, valproate, quetiapine or olanzapine.

What did they find?

Here is the cumulative self-harm rate:

The authors note:

To our knowledge, this investigation is the largest naturalistic longitudinal study of fatal and nonfatal self-harm rates in individuals with BPD treated with lithium, valproate, olanzapine, or quetiapine. We found increased rates of self-harm in individuals prescribed valproate, olanzapine, or quetiapine compared with those prescribed lithium.

To summarize their findings: The difference for self-harm was significant in favour of lithium, whereas with suicide, the rates were too low to show differences by individual drugs.

This echoes an American database study from 13 years ago comparing suicide attempts and suicide in patients treated with lithium versus valproate, showing a clear therapeutic advantage to lithium:

And, from even further back, a worthy early analysis of the economic, let alone personal, positive impact of lithium:

In this study, Ann Reifman and Dr. Richard Wyatt examined the costs of treatment prior to and subsequent to the availability of lithium in the United States. It has a back-of-the-envelope feel to it compared to modern, statistically sophisticated health economics studies whose methodologies are comprehensible by few of us. While this 1980 study is full of big assumptions, it estimates that the decade 1969-1979 led to lithium-attributed savings in medical costs of $2.88 billion and productivity gains of $1.28 billion in the U.S.

Lithium is cheap and effective. As with MAOIs, tricyclic antidepressants, first-generation antipsychotics, and ECT, are the next generation of psychiatrists familiar and comfortable with its science, use, benefits and risks?

Some thoughts:

1. The enduring value of lithium – as well as that of ECT – is a sobering reminder that the neuroscience revolution has yet to generate new drugs that significantly outperform the antipsychotics, antidepressants, anxiolytics and mood stabilizers that were available in the 1960s.

2. Nevertheless, the older drugs didn’t work for everyone and were often difficult to tolerate, which means that for patients we need a broad, evidence-based menu that will allow us to match patients to treatments.

3. Biomarkers that allow us to predict with confidence who will respond to what remain a worthy pursuit but to date an elusive goal.


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