Bipolar disorder is a mental health condition estimated to affect between 1% and 3% of people worldwide. Its main symptoms include extreme mood swings, ranging from periods of high activity and emotional high (i.e., mania) to depressive periods marked by a low mood, reduced motivation and a loss of interest in everyday activities.
Bipolar disorder typically cannot be treated solely with psychotherapy, although some approaches and lifestyle adjustments can help affected individuals to better manage the condition. Its effective treatment also heavily relies on medications that stabilize mood, reduce anxiety, or treat acute mania and psychosis (i.e., a state that entails losing touch with reality, hallucinations and/or false beliefs).
One particular mood stabilizer called lithium has long been considered the most effective drug for regulating the mood fluctuations associated with bipolar disorder. While many patients respond well to lithium, others are forced to discontinue it, either because it does not work for them or due to side effects that are difficult to manage.
Researchers at Niuvanniemi Hospital in Finland, Karolinska Institute in Sweden and Stockholm City Council recently carried out a large-scale observational study exploring the effectiveness of other available treatments for bipolar disorder over time, when these are taken in conjunction with lithium or instead of it. Their findings, published in Nature Mental Health, highlight specific treatment plans and combinations of drugs that appeared to be linked to fewer relapses and psychiatric hospital admissions.
“This study grew out of a very practical problem I faced in my clinical practice,” Johannes Lieslehto, first author of the paper, told Medical Xpress. “Lithium is widely considered the gold-standard treatment for bipolar disorder, but in real life many patients either do not respond sufficiently or cannot tolerate it. At the same time, clinicians often need to combine medications or switch strategies, yet there is surprisingly little high-quality evidence on which specific combinations work best in the long term.”
Pinpointing effective bipolar treatments beyond lithium
The main goal of this research study was to identify treatment strategies that tend to be particularly effective, particularly in cases where lithium alone does not treat all symptoms or needs to be discontinued. To do this, Lieslehto and colleagues analyzed a large pool of data collected from over 160,000 people who were being treated for bipolar disorder in Sweden and Finland, over the course of several years.
“What makes our approach a bit different is that we compared each patient to themselves over time,” explained Lieslehto. “So, instead of comparing different people who were taking different medications, we looked at how the same person did during periods when they were on different treatments. This approach helps reduce bias, because factors like genetics, illness severity, or lifestyle are naturally controlled for (i.e., they don’t change within the same person).”
To gain insight into the effectiveness of different treatment plans, the researchers specifically looked at relapse rates. These were measured by looking at psychiatric hospitalization records, which offer an indication of whether a patient started struggling with symptoms again and required medical care.
The team’s analyses ultimately led to the identification of specific drug combinations and treatment strategies that were linked to a lower risk of relapse and hospitalization. These treatments often included clozapine or other antipsychotic medications, particularly long-acting drugs that patients received periodically via injections.
“We also identified specific treatment options for patients who discontinue lithium, such as combinations like quetiapine with lamotrigine or olanzapine with valproate, which were linked to better outcomes,” said Lieslehto. “Clinically, the key message is that there are viable alternatives when lithium is not sufficient or cannot be used. Importantly, the results also highlight that the way medications are combined matters. Not all combinations are equally effective. Importantly, however, these findings are observational and should be interpreted carefully.”
Informing future research and clinical decision-making
The insight gathered by Lieslehto and colleagues could soon prove useful for clinical psychiatrists, as it could offer some guidance for the treatment of lithium-resistant bipolar disorder. Nonetheless, the team’s findings need to be validated in randomized clinical trials before they can be broadly applied in psychiatric settings or used to update official treatment protocols.
“In the future, we would like to study outcomes beyond hospitalization, such as functional recovery and quality of life, to get a more complete picture of treatment effectiveness,” added Lieslehto. “We are also increasingly interested in more personalized approaches. For example, combining clinical data with genetic information or other biomarkers to better predict (e.g., using machine learning) which treatment works best for a given individual.”