Bipolar disorder is a mental illness characterized by extreme mood swings between depression and mania.
While antidepressants are commonly prescribed to treat the depressive symptoms, they can also trigger manic episodes in some patients.
New research suggests having a certain gene may increase this risk.
Key Facts:
- Antidepressants can cause manic episodes, called treatment emergent mania (TEM), in people with bipolar disorder.
- Around 30% of people with bipolar disorder experience TEM when taking antidepressants.
- A gene called 5-HTTLPR seems to be associated with higher risk of TEM. People with a particular variant of this gene may be more vulnerable.
- Knowing someone’s genetic risk could help guide treatment and determine when antidepressants should be avoided in bipolar disorder.
Source: J Clin Psychopharmacol. 2023 Sept-Oct
The Dilemma of Treating Bipolar Depression: Mania
Bipolar disorder is a mental health condition characterized by extreme shifts in mood and energy levels.
People swing between periods of severe depression and mania – an abnormally elevated mood state.
These manic episodes involve symptoms like euphoria, impulsiveness, racing thoughts, and risky behavior.
While mania is the most well-known aspect of bipolar disorder, most people spend more time depressed.
Depression causes feelings of sadness, emptiness, fatigue, and suicidal thoughts.
This depressed state is often the main target for treatment.
However, treating bipolar depression poses a major dilemma.
Antidepressant medications effectively relieve depressive symptoms, but can also trigger manic switches in some individuals.
This phenomenon is called treatment emergent mania (TEM).
About 30% of people with bipolar disorder experience TEM when taking antidepressants.
Clearly, antidepressants provide important benefits in bipolar depression, but also carry substantial risks.
Clinicians are faced with the challenge of balancing these pros and cons on a patient-by-patient basis.
5-HTTPLR Gene & Treatment Emergent Mania
Recent research has begun unraveling the biology behind TEM to understand why some people are more vulnerable than others.
Several studies have implicated a gene called 5-HTTLPR, which codes for a protein that transports serotonin.
Serotonin is a neurotransmitter involved in regulating mood.
Antidepressants work by increasing serotonin levels in the brain.
However, this effect on serotonin signaling appears to backfire in some patients with bipolar disorder, flipping the mood switch from depression to mania.
The 5-HTTLPR gene comes in short and long variants.
Having two copies of the short variant leads to reduced expression of the serotonin transporter protein.
This dampened serotonin signaling seems to escalate the risk of TEM when taking antidepressants.
In a new meta-analysis, researchers compiled data from seven studies examining links between 5-HTTLPR and TEM.
They found that the short variant of 5-HTTLPR was associated with a 43% higher likelihood of developing TEM compared to the long variant.
Although not a huge effect, this relationship was statistically significant.
While more research is still needed, these findings suggest that genetics may contribute to the tricky balance between risks and rewards with antidepressant treatment in bipolar disorder.
In the future, testing for this serotonin transporter gene could potentially help guide medication decisions.
Personalized Medicine for Bipolar Depression: The Big Picture
Beyond just this single gene, the broader goal is to develop risk models that integrate both genetic and clinical factors.
These models could estimate an individual’s vulnerability to TEM based on their unique set of biological and environmental risk characteristics.
Here are some of the key factors that might be included:
Clinical Factors:
- Type of bipolar disorder (bipolar I vs bipolar II)
- Gender
- Age of onset
- Number of prior depressive episodes
- Concurrent medication use
- Class of antidepressant prescribed
Genetic Factors:
- Metabolizer status for cytochrome P450 enzymes, which break down medications
- Serotonin transporter gene variant
- Other gene variants identified through genome-wide association studies
By analyzing how these variables interact, a multi-factor risk model could generate individualized risk assessments.
For instance, a 20-year old bipolar II woman with the 5-HTTLPR short variant and a poor metabolizer genotype would be flagged as high-risk.
In contrast, a 50-year old bipolar I man with the long 5-HTTLPR variant and extensive metabolizer status would be low-risk.
In essence, the goal is to move away from the one-size-fits-all approach to more personalized medicine when treating bipolar disorder.
This could allow doctors to avoid prescribing antidepressants to patients with an unfavorable risk profile.
Ultimately, personalized risk stratification aims to improve safety and optimize the benefit/risk ratio of medications like antidepressants in this population.
Hopes for the Future of Bipolar Treatment
The dilemma around antidepressant use in bipolar disorder has burdened patients and doctors alike for decades.
By illuminating the biological underpinnings of treatment emergent mania, emerging research brings new promise for individualized care.
While still in its early stages, genetic testing holds potential to guide clinical decisions and prevent disastrous manic switches.
Beyond just 5-HTTLPR, exploring additional genes and clinical variables might someday offer a comprehensive map of each patient’s risk landscape.
Advanced machine learning algorithms are also poised to revolutionize bipolar treatment.
These artificial intelligence models could process diverse information – from demographics to family history to genetics – to generate data-driven risk predictions.
Although much work remains, researchers are optimistic that personalized medicine will transform our ability to safely and effectively treat bipolar depression.
In the future, treatment for bipolar disorder may come to mirror the approach in cancer.
Doctors routinely do genetic testing on tumors to identify targeted therapies and avoid one-size-fits-all chemotherapy.
Similarly, testing for mania risk genes could steer bipolar patients away from medications likely to trigger that downward spiral toward mania.
With thoughtful use of antidepressants only when the benefits clearly outweigh the risks, patients with bipolar disorder can maintain hope for managing this profoundly difficult illness.
While the tunnel may seem dark at times, scientific discoveries continue to shed light on the path forward.
References
- Study: Antidepressant-associated treatment emergent mania
- Authors: Nicolas A. Nunez et al. (2023)
