Bipolar disorder, a mental health condition characterized by recurrent episodes of depression and mania/hypomania, has been a challenging condition to understand and treat effectively. Lithium, a medication that has been a mainstay in bipolar disorder treatment for six decades, has shown promise in reducing the frequency of mood episodes and providing other potential benefits. However, the precise mechanisms by which lithium works to stabilize mood have remained elusive.
A recent study published in Psychopharmacology helps shed light on this mystery by examining the impact of lithium on a core psychological process often impaired in bipolar disorder: emotion regulation. This study provides valuable insights into the effects of lithium on the brain during emotion regulation and may pave the way for better understanding bipolar disorder and the development of more effective treatments.
Bipolar disorder is a complex mental health condition characterized by extreme mood swings, including periods of depression and mania or hypomania. These mood shifts can have a profound impact on an individual’s life, affecting their mood, motivation, cognition, and behavior. Lithium, a medication that has been used to treat bipolar disorder for many years, has shown efficacy in reducing the frequency of these mood episodes.
Despite its long history of use, researchers have been keen to uncover the precise neurochemical pathways through which lithium exerts its mood-stabilizing effects. Understanding these mechanisms could help predict patients’ responses to lithium treatment and potentially lead to the development of more effective treatments, particularly for individuals who do not respond well to existing mood-stabilizing medications.
“Bipolar disorder is a mental health condition where individuals experience episodes both of depression and of mania,” said study author Marieke Martens, a senior postdoctoral researcher at the University of Oxford. “Lithium is one of the core treatments for this disorder, but it can be a difficult drug to take long term.”
“The effects of lithium were discovered by accident, and it is not known how its effects come about in stabilising mood. We therefore wanted to find out how lithium affected the way the brain regulates emotions, a psychological process that is impaired in bipolar disorder. This would be a first step towards further treatment development.”
One prevailing theory in the field of bipolar disorder research suggests that difficulties in emotional regulation contribute to the underlying psychopathology of the disorder. Emotion regulation refers to the ability to modulate one’s emotional responses to various stimuli, and it plays a crucial role in maintaining emotional balance. Dysregulation of emotions can lead to extreme mood states, such as mania or depression, which are characteristic of bipolar disorder.
Evidence from structural and functional neuroimaging studies has indicated that disruptions in the fronto-limbic network, a network of brain regions involved in emotional regulation, may underlie emotion regulation difficulties in bipolar disorder. Structural changes, such as differences in brain volume in areas like the anterior cingulate cortex (ACC) and grey matter reductions in the prefrontal cortex, have been observed in individuals with bipolar disorder. Functionally, individuals with bipolar disorder have shown differences in brain activation patterns during emotional regulation tasks compared to healthy individuals.
One commonly used strategy for emotional regulation is cognitive reappraisal, in which individuals consciously reinterpret emotionally disturbing stimuli to reduce their emotional impact. Healthy individuals engage specific brain regions during this process, including the anterior prefrontal cortex, dorsolateral prefrontal cortex, and ventrolateral prefrontal cortex, among others.
In order to investigate the effects of lithium on emotion regulation, the researchers conducted a study with 36 healthy participants, who were carefully selected based on specific criteria to ensure their suitability for the research. Participants were excluded if they had any psychiatric disorders, medical contraindications, or were taking psychotropic medications. This rigorous screening process aimed to create a homogeneous group of participants to study the direct effects of lithium.
The research design followed a double-blind randomized approach, ensuring that neither the participants nor the researchers knew who received lithium and who received a placebo. The participants received either lithium or a placebo for 10-12 days, and the dosage of lithium was gradually increased to reach a steady state.
During the study, participants underwent various assessments, including behavioral assessments, mood questionnaires, and magnetic resonance imaging (MRI) scans. These assessments allowed the researchers to measure both subjective and objective changes associated with lithium treatment.
The researchers found that cognitive reappraisal was associated with specific patterns of brain activation in healthy participants. This included increased activation in regions associated with cognitive control, such as the prefrontal cortex, as well as decreased activation in regions related to emotional reactivity, including the amygdala.
Lithium administration led to altered brain activation patterns during emotion regulation tasks. Specifically, participants who received lithium showed decreased activation in prefrontal areas, such as the anterior prefrontal cortex and superior frontal gyrus, as well as the angular gyrus. These changes were observed when participants engaged in cognitive reappraisal compared to passive viewing of emotional stimuli.
An exploratory analysis of brain connectivity revealed differences between the lithium and placebo groups during emotion regulation. The lithium group exhibited increased connectivity between certain brain regions, including the right superior temporal gyrus, during reappraisal compared to the placebo group.
“Our study provides the first experimental evidence that lithium influences the brain processes that underlie how we regulate our emotions,” Martens told PsyPost. “For example, lithium altered activity of, and connectivity between, brain regions important for emotional processing (like the prefrontal cortex and the angular gyrus) compared to placebo, when participants actively tried to downregulate provoked negative emotions whilst being in an MRI brain scanner (for example by thinking that a picture of a man with blood stains could be an actor wearing makeup for a movie rather than a victim of assault). This gives us a clue about how lithium might be working at a psychological level – which means that future drug development could focus on novel compounds that do something similar, but then more effectively without causing troublesome side effects.”
“Even though we expected that lithium would influence the brain processes underlying emotional regulation, some of our results were in the opposite direction. For example, we predicted that lithium would increase activation of certain brain regions important for the regulation of emotions (like the anterior prefrontal cortex), as this would suggest enhanced cognitive control over emotions (which would be beneficial when someone has difficulties regulating their emotions as in bipolar disorder).”
“However, what we found was the opposite: lithium reduced activity in the anterior prefrontal cortex,” Martens continued. “We do not fully understand yet why this was the case. One explanation could be that because the healthy volunteers in our study sample already used effective emotional regulation strategies prior to treatment, lithium may have led to a disturbance in this process instead of an improvement (i.e., “too much of a good thing”). A future study exploring the effects of lithium in patients with bipolar disorder (or a group with impaired emotional regulation) could help us solve this.”
The study’s results remained consistent when accounting for gray matter differences and controlling for potential confounding factors related to brain activity. But while this study provides valuable insights into the effects of lithium on emotion regulation, it is not without limitations. “For example, even though lithium influenced brain activity related to emotional regulation, the participants themselves did not report a subjective change in how they were feeling after actively trying to regulate their emotions,” Martens explained.
“But perhaps maybe even more important, the study will need to be repeated in patients with bipolar disorder before we can draw any conclusions on the effects of lithium on emotional regulation in patients with this disorder. As said before, healthy volunteers may have an already near-optimal ability to regulate their emotions and so the effects of lithium may not accurately represent what would be seen with treatment in bipolar disorder.”
“The reason for doing this initial study in healthy volunteers was that this aids isolating the mechanisms behind lithium treatment without the complications of disorder-related factors (i.e., disorder severity, duration, state, and/or history of medication) which would also be expected to affect brain activity,” Martens said. “Another limitation is that 11 days of lithium treatment is not representative of real clinical practice, as lithium is usually given over longer periods of time. Therefore, future studies should validate the present evidence in a large patient sample, with a longer treatment administration.”
“We like to thank all participants for taking part in this study, as without them none of this would have been possible! If you are interested in taking part in studies like these yourself, please have a look at https://perloxford.com/participate-in-research/”
The study, “Effect of lithium administration on brain activity under an emotion regulation paradigm in healthy participants: a functional magnetic resonance imaging study“, was authored by Pilar Artiach Hortelano, Marieke A. G. Martens, Abigail Pringle, and Catherine J Harmer.