The lithium paradox: declining prescription of the gold standard treatment for bipolar disorder

I read with great interest two studies recently published in Acta Psychiatrica Scandinavica. First, in the authoritative review by Ghaemi, lithium was evaluated as one of the few available drugs in psychiatry with disease modifying—and not just symptomatic—effects, improving both the course of illness and quality of life. This is not surprising considering the amount of evidence highlighting that lithium has wellestablished benefits in terms of prevention of mood relapses, neuroprotection, and anti-suicidal properties. As a whole, the review by Ghaemi represents an additional confirmation about the role of lithium as the gold standard for treatment of bipolar disorders (BD). Second, in an epidemiological study based on nationwide Finnish registers (N = 26,395), Poranen and colleagues analyzed the trends on lithium prescription for BD. The authors estimated that the rates of lithium use during the 3 months following the first diagnosis of BD varied between 5.9% and 6.5%, with the overall prevalence decreasing from the 1996–2000 (12.1%) to the 2016–2018 (4.1%) sub-cohorts. This study made clear the lithium paradox: while the evidence on lithium effectiveness is growing, its prescription is decreasing. The Finnish data are not the only example of this trend; other epidemiological studies have shown a counterintuitive decline of lithium prescription over the last years in different geographical areas. Data from the US National Ambulatory Medical Care Survey showed that substantial changes occurred in the treatment of BD across the years, with second-generation antipsychotics (SGAs) progressively supplanting traditional mood stabilizers. The use of lithium for BD declined from 30.4% in 1997–2000 to 17.6% in 2013–2016 periods (adjusted odds ratio [OR]: 0.46; 95% CI: 0.29–0.71), while, comparing the same periods, the use of SGAs had more than quadrupled. Similar data have been reported in the United Kingdom, in which prescription of lithium for BD declined from 30.6% in 2001 to 16.0% in 2018. On the other hand, the use of SGAs increased from 36.7% in 2001 to 45.3% in 2018. Low rates of lithium prescription were also estimated in Hong Kong, with antipsychotics representing the most frequently prescribed monotherapy. In addition, a study analyzing prescribing patterns in BD in Scotland between 2009 and 2016 has shown that, surprisingly, the most common treatment for BD was monotherapy with an antidepressant (prescribed in about one quarter of patients), while only 6% of patients were receiving lithium monotherapy, with rates progressively decreasing (OR: 0.83; 95% CI: 0.82– 0.85). This study further documented a significant increase in antipsychotic prescription (OR: 1.16; 95% CI: 1.15–1.18). Some possible reasons for the widespread declining trend on lithium prescription can be hypothesized. The introduction over the last years of SGAs with some benefit also for BD, might have led clinicians to overestimate their effectiveness. Moreover, although SGAs also require regular clinical monitoring, these agents are easier to manage than lithium, considering its narrow therapeutic window. In addition, the lack of clinical experience and education about lithium long-term tolerability and sequalae, might have reduced the confidence on its clinical advantages. Similarly, possible misconceptions about the reduced efficacy of lithium for specific BD-related characteristics, such as mixed features, may explain its reduced prescription. Finally, it is worth mentioning that lithium is an old drug, with little or no interests by pharmaceutical companies in promoting or marketing it. The reduction of lithium prescription worldwide, despite its documented superiority over other pharmacological agents, suggests that the majority of patients with BD are missing out on the best available pharmacological option. This represents an important incongruity between evidence-based recommendations and clinical practice in psychiatry. The role of education, as well as the establishment of a specialized clinical staff, might be central in reversing this concerning trend. Efforts in improving training on lithium should represent a priority of postgraduate and residency programs around the world in the next years. Received: 23 October 2022 Revised: 6 December 2022 Accepted: 12 December 2022