Six predictors could help determine the amount of lithium needed to treat patients with bipolar disorder


Six predictors could help determine the amount of lithium needed to treat patients with bipolar disorder, according to a large study led by researchers at Karolinska Institutet in Sweden.

The study, published in the journal The Lancet Psychiatry, also pinpoints genetic markers that seem to influence how quickly the body eliminates lithium from its system.

“Our model could already now be used to predict how much lithium a patient with bipolar disorder will need. This could cut valuable time spent on finding the right dose for each patient, potentially with life-saving impact,” says Martin Schalling, professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet and the study’s senior author.

Lithium is one of the most important treatments for patients with bipolar disorder, a condition that has been linked to an increased risk of suicide. The chemical substance works as a mood stabilizer and reduces episodes of depression and mania.

How much is needed vary greatly between individuals and finding the right dose for each patient is key as too much can be toxic while too little is ineffective. To minimize the risk of side-effects, clinicians tend to initiate treatment at low doses that increase over time, meaning it could take months before the treatment has an effect.

To overcome this, researchers have long sought to find a model that could predict dose response in individual patients. Previous studies have identified markers such as age, sex and kidney function as possible predictors of how quickly the body eliminates lithium from its system (lithium clearance), which can be used to determine the amount needed on a daily basis. However, most studies have been limited by small sample sizes.

In the current study, the researchers examined electronic health records and registry data from a total of 2,357 patients with bipolar disorder, which may represent the largest sample size for this kind of study to date. Both men and women in ages ranging from 17 to 89 were included, mainly of European ancestry.

The study found associations between the speed of lithium clearance and age, sex, kidney function (measured as eGFR), serum lithium concentrations and medication with diuretics and substances targeting the renin-angiotensin-aldosterone system (RAAS), which could be used to treat hypertension and other conditions.

“Our findings suggest that older patients, women, patients with reduced kidney function, and those taking certain medications require lower doses of lithium. Interestingly, we also discovered that the amount of lithium taken and lithium concentrations in the blood do not seem to be completely proportional, which goes somewhat against current thinking.

Our model based on these predictors explained around 50–60% of the variance in lithium clearance, which is better than previous models and could be used to inform treatment decision,” says first author Vincent Millischer, a postdoctoral researcher at the Department of Molecular Medicine and Surgery, Karolinska Institutet, and resident in psychiatry at the Medical University of Vienna.

The study also found associations between a lower lithium clearance and one genetic locus on chromosome 11 and could also show that genetic variants affecting BMI and kidney function were associated with lithium clearance. Even though adding the genetic markers only marginally improved the model’s predictive capability, the researchers say it opens the opportunity of personalized medicine in lithium treatment in the future.

“Next, we will test our model in a clinical trial to see if it can reduce the time it takes to find the right amount of lithium for each patient,” Martin Schalling says. “If the outcome is positive, we will develop a digital app that could be used by psychiatrists in the future to help assess lithium dosage for patients with bipolar disorder.”

Bipolar Disorder (BD) is a chronic disorder characterized by recurrent mood fluctuations. It is associated with both high morbidity and mortality (Carvalho et al., 2020), hence long-term prophylactic maintenance treatment is recommended (Vieta et al., 2011). Lithium, introduced in 1949 (Cade, 1949), remains probably the most effective drug for long-term therapy in BD, preventing both depressive and manic recurrences and reducing the risk of suicide, dementia and all-cause mortality (Geddes et al., 2004; Del Matto et al., 2020; Severus et al., 2014; Miura et al., 2014). It is consequently recommended as first line treatment in most guidelines (Yatham et al., 2018; Malhi et al., 2015; Grunze et al., 2013; Verdolini et al., 2020), either as monotherapy or combination (Wingård et al., 2019).

Despite the long-term effectiveness of lithium, there are concerns regarding its safety profile. Aside from the narrow therapeutic index, the need for monitoring, and some frequent side effects such as diarrhea, polydipsia and tremor, lithium’s toxicity profile includes an increased risk of renal failure and reduced urine-concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain (McKnight et al., 2012; Tondo et al., 2017).

Weight gain is among the most distressing lithium-associated side effects for patients (Gitlin, 2016). In one study, despite ranking third in frequency, it ranked first among patients’ rating of bothersome side effects of lithium use and second amongst bothersome side effects leading to lithium discontinuation (Gitlin et al., 1989).

Nevertheless, weight gain remains as one of the less studied complications related with lithium treatment. Besides this, there is a high prevalence of weight gain and weight-related conditions due to other medications used to treat BD. Among these, metabolic syndrome (around 37 %) (Vancampfort et al., 2013), obesity (around 21 %) (Krishnan, 2005), type 2 diabetes mellitus (around 14 %) and non-alcoholic fatty liver disease (22–42 %,) are prominent (Soto-Angona et al., 2020; Vancampfort et al., 2016).

These associated comorbidities lead to cardiovascular disease and higher premature mortality in BD patients (Correll et al., 2017; Staudt Hansen et al., 2019; Kessing et al., 2015; Hayes et al., 2015). People with BD who suffer weight-gain and related comorbidities also have a worse clinical course, more depression, associated physical comorbidities, and higher suicide rates (Hayes et al., 2015; Fagiolini et al., 2003; Torrent et al., 2008).

To date, findings about lithium-induced weight gain are controversial and inconsistent (Gitlin, 2016; McKnight et al., 2012). In fact, definitions of weight change and duration of observation differ across studies, precluding any simple averaging of lithium-induced weight gain. From the available studies, it is also unclear whether weight gain correlates with lithium dose or levels (Gitlin, 2016).

Furthermore, the majority of studies include BD patients concurrently treated with psychotropic medications other than lithium, such as antipsychotics, valproate, and some antidepressants, which might contribute to weight gain (Torrent et al., 2008). Finally, genetic factors may be much more relevant than lithium itself (Bopp et al., 2019).

In this context, lithium-induced weight change is of increasing scientific and clinical interest for both patients and practitioners, considering that weight gain is usually one of the most dreaded side effects for patients and that in many occasions, it is the main reason for treatment discontinuation (Gitlin et al., 1989).

To provide evidence-based information for decision-making and accurate information to patients and professionals, the primary aim of this study is to systematically investigate whether lithium induces weight change and, if so, to quantify the magnitude of this association, compared to active comparators or placebo. The secondary aim of this study is to examine whether lithium-induced weigh change is moderated by duration of lithium therapy.

reference link :

More information: “Improving lithium dose prediction using population pharmacokinetics and pharmacogenomics: a cohort genome-wide association study in Sweden”, The Lancet Psychiatry (2022). … (22)00100-6/fulltext


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