Paul Grof has pioneered research in mood disorders since the 1960’s from University of Ottawa, Canada
Matching lithium to the right bipolar profile could reverse decades of decline
STUDY: Grof P, Pharmaceuticals 2026;19:527
STUDY TYPE: Review
FUNDING: Independent
Background
Lithium use in the U.S. has fallen from over 30% to below 15% of bipolar patients over the past three decades, even as guidelines rank it first line. This review argues the decline reflects misunderstanding, not evidence.
Who Responds
Paul Grof draws on six decades of clinical experience to make the case that lithium’s apparent loss of efficacy tracks directly with diagnostic drift. As DSM criteria expanded the bipolar category, lithium was increasingly prescribed to patients unlikely to respond — and when they didn’t, lithium’s reputation suffered. In the original double-blind trials, clinicians diagnosed using Kraepelinian criteria, emphasizing fully episodic courses and family history. That subset — roughly one-third of today’s broadly diagnosed bipolar patients — still responds as reliably as ever.
Safety and Tolerability
Dr. Grof explains that lithium is often better tolerated than expected, citing an unpublished study of 300 long-term responders. Their main complaint was thirst, and only 10% had other side effects, most of which were correctable. In his view, the main problematic risk is to the kidneys. I’ll add other points from recent posts here:
- Its medical risks are lower than thought
- Patients live longer Lithium Lowers Mortality in Bipolar Disorderon lithium than other mood stabilizers.
- Lithium has a low risk of weight gain and causes fatigue in 1:28 patients.
- Renal risks can be reduced by keeping the level below 0.8, avoiding toxicity, dosing all at night, and possibly using N-acetylcysteine and newer diabetes medications (SGLT2 inhibitors).
Practice Implications
- Look for classic bipolar disorder.
- Whether type I or type II, these patients are likely to have a full recovery and lasting recovery with lithium.
- These pearls on personalizing lithium showed up in the first clinical trial from 1951. Learn that history in the Carlat Podcast.
— Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
