Empagliflozin for Depression: Effective Adjunct with SSRIs (2024 Clinical Trial)

Major Depressive Disorder (MDD) impacts millions globally, making it a significant public health challenge.

Traditional treatments like Selective Serotonin Reuptake Inhibitors (SSRIs) don’t work for everyone, highlighting the need for innovative approaches.

Recent clinical trials exploring the use of empagliflozin, a medication originally used to lower blood sugar in diabetes patients, have shown promising results as an adjunctive therapy in treating MDD, offering new hope for those struggling with this condition.

Highlights:

1. Prevalence of MDD: Affects an estimated 300 million people worldwide annually, leading to significant disability.
2. Limitations of Current Treatments: About 40% of MDD patients do not respond to first-line treatments like SSRIs.
3. Empagliflozin’s Dual Role: Originally developed for type 2 diabetes, empagliflozin has shown potential in reducing depressive symptoms due to its neuromodulating and anti-inflammatory properties.
4. Clinical Trial Success: A recent study indicated that empagliflozin, when used alongside citalopram, significantly reduced depressive symptoms compared to a placebo group.

Source: BMC Psychiatry (2024)

Empagliflozin: History, Medical Uses, Mechanisms (Overview)

Empagliflozin is a pharmaceutical medication primarily known for its role in managing type 2 diabetes mellitus.

History & Medical Uses

Empagliflozin, marketed under the brand name Jardiance among others, was first approved for medical use in the United States in 2014.

It belongs to a class of medications known as sodium-glucose cotransporter 2 (SGLT2) inhibitors, which are used to lower blood sugar levels in people with type 2 diabetes.

By inhibiting SGLT2, empagliflozin reduces glucose reabsorption in the kidney, leading to the excretion of glucose through the urine and, consequently, a reduction in blood glucose levels.

Mechanisms of Action

• SGLT2 Inhibition: Empagliflozin’s primary mechanism involves inhibiting the SGLT2 protein in the kidneys, which is responsible for reabsorbing glucose back into the bloodstream. By blocking this protein, empagliflozin allows for increased glucose excretion, thereby lowering blood glucose levels.
• Cardiovascular & Renal Benefits: Beyond its glucose-lowering effect, empagliflozin has demonstrated significant cardiovascular and renal benefits. It reduces the risk of cardiovascular death in people with type 2 diabetes and has shown a protective effect on kidney function, slowing the progression of kidney disease.

Antidepressant Potential

The exploration of empagliflozin as a treatment for MDD is a relatively recent development, grounded in the drug’s potential anti-inflammatory and neuromodulatory effects.

The rationale for its use in depression includes:

• Anti-inflammatory Properties: Chronic inflammation is increasingly recognized as a significant factor in the pathophysiology of depression. Empagliflozin’s ability to reduce systemic inflammation could potentially mitigate the inflammatory processes associated with MDD.
• Neuromodulatory Effects: Empagliflozin may influence neurobiological pathways relevant to mood regulation. It has been suggested that the drug can reduce oxidative stress and improve endothelial function, which in turn could have positive effects on brain health and mood.
• Impact on Neurotransmitter Systems: There is emerging evidence that empagliflozin may affect neurotransmitter systems implicated in depression, such as reducing glutamate toxicity and enhancing the signaling of neuroprotective factors like brain-derived neurotrophic factor (BDNF).

Major Findings: Adjunct Empagliflozin & Citalopram for Major Depression (2024 Trial)

Zandifar et al. evaluated the effect of adjunct empagliflozin to conventional SSRI (citalopram) treatment for major depressive disorder (MDD) – below were the major findings.

1. Significant Depression Reduction

The clinical trial’s most notable finding was the significant reduction in depression severity among participants receiving empagliflozin in combination with citalopram, compared to those who were administered a placebo alongside citalopram.

Depression severity was measured using the Hamilton Depression Rating Scale (HDRS), a widely recognized tool in clinical research for evaluating depression outcomes.

At the study’s outset, HDRS scores were comparable between both groups, ensuring a balanced baseline for assessing treatment effects.

• Baseline HDRS Scores: Participants started with similar levels of depression severity, with average HDRS scores around 28 for both groups, indicating moderate to severe depression.
• Week 4 HDRS Scores: By week 4, a marked difference emerged. The empagliflozin group showed a significant decrease in HDRS scores (average ~13.76), suggesting a rapid improvement in depressive symptoms. In contrast, the placebo group’s scores averaged around 20.20, indicating a slower and less pronounced improvement.
• Week 8 HDRS Scores: The most striking difference was observed by week 8, where the empagliflozin group’s average HDRS score dropped to 7.00, moving into the range considered to be in remission. Meanwhile, the placebo group’s scores decreased to an average of 13.42, still reflecting moderate depression.

2. Statistical Significance & Clinical Relevance

The differential change in depression (HDRS) scores between the empagliflozin and placebo groups was statistically significant, with a p-value of 0.0001 using repeated-measures ANOVA.

This indicates a highly significant improvement in depression symptoms over time for those treated with empagliflozin.

The clinical relevance of these findings is profound, suggesting that empagliflozin, when used as an adjunct therapy, can accelerate and enhance the reduction of depressive symptoms in individuals with MDD.

3. Safety & Tolerability

Another critical aspect of the study’s findings relates to the safety and tolerability of empagliflozin as an adjunctive treatment.

The occurrence of side effects was closely monitored throughout the trial, with particular attention to those commonly associated with SGLT2 inhibitors, such as urinary symptoms.

Only two patients in the empagliflozin group reported mild urinary symptoms, which improved without intervention and did not necessitate discontinuation of the treatment.

No significant adverse effects were reported, underscoring empagliflozin’s tolerability and safety when used in this new context.

(Related: Semaglutide & Empagliflozin May Treat Cognitive Deficits in Obesity)

Empagliflozin for Depression with Citalopram (2024 Trial)

The primary objective of this study was to evaluate the effectiveness of empagliflozin, alongside citalopram, in reducing the severity of depressive symptoms in outpatients with moderate to severe MDD.

This investigation was motivated by the need for alternative treatments due to the partial response or tolerance issues observed with existing antidepressant medications.

Methods

• Study Design: An 8-week randomized, double-blind, placebo-controlled, parallel-group clinical trial.
• Participants: 90 outpatients aged 18–60 years, diagnosed with moderate to severe MDD (HDRS ≥ 17), who had not taken related medication for at least the last two months.
• Intervention: Participants were randomly divided into two groups to receive either empagliflozin (10 mg daily) combined with citalopram (40 mg daily) or a placebo combined with citalopram (40 mg daily).
• Randomization: Utilized a permuted block randomization method to ensure equal distribution.
• Assessments: Depression severity was measured using the Hamilton Depression Rating Scale (HDRS) at baseline, week 4, and week 8.

Findings

• Depression Severity Reduction: The empagliflozin group showed a significantly greater reduction in HDRS scores over time compared to the placebo group. By week 8, the empagliflozin group’s average HDRS score indicated remission of depressive symptoms, while the placebo group remained in the moderate depression category.
• Statistical Analysis: Repeated-measures ANOVA revealed a significant time-treatment interaction (p = 0.0001), indicating the empagliflozin group’s depressive symptoms improved more substantially over time than the placebo group’s.
• Safety & Tolerability: Empagliflozin was well-tolerated with minimal side effects. Only two participants in the empagliflozin group reported mild, non-severe urinary symptoms, which did not require intervention or discontinuation of the drug.

Limitations

• Sample Size & Duration: The study’s relatively small sample size and short duration limit the generalizability and long-term efficacy understanding of empagliflozin as an adjunctive treatment for MDD.
• Lack of Comprehensive Biomarker Analysis: The study did not include an analysis of biomarkers that could elucidate the biological mechanisms underlying the observed antidepressant effects of empagliflozin.
• Narrow Participant Profile: The exclusion of individuals with concurrent major psychiatric disorders, substance use, or significant medical comorbidities may limit the applicability of the findings to a broader MDD population.
• Absence of Follow-Up: Without a follow-up period, the study does not provide information on the sustainability of the therapeutic effects or the long-term safety profile of empagliflozin in MDD patients.

Combining Empagliflozin with SSRIs for Depression: Potential Benefits

Combining empagliflozin with a Selective Serotonin Reuptake Inhibitor (SSRI) represents a novel approach to treating Major Depressive Disorder (MDD) that may offer enhanced therapeutic benefits compared to using either treatment as a standalone.

This synergistic potential arises from addressing multiple pathophysiological aspects of depression simultaneously, leveraging the unique mechanisms of action of each drug.

Complementary Mechanisms of Action

SSRIs primarily function by increasing serotonin levels in the brain, which can improve mood and emotional regulation. However, SSRIs do not address all the complex biological factors contributing to depression, such as inflammation and insulin resistance, which are increasingly recognized in the pathophysiology of MDD.

Empagliflozin targets these additional pathophysiological aspects. Its anti-inflammatory properties and effects on glucose metabolism could address underlying conditions that SSRIs do not, potentially offering a more comprehensive treatment strategy for depression.

Enhanced Neuroprotective Effects

The combination of empagliflozin and SSRIs may offer enhanced neuroprotective effects.

Empagliflozin’s potential to reduce oxidative stress and inflammation, combined with the neurotrophic effects of SSRIs, could synergistically promote brain health, potentially leading to improved outcomes in depression treatment.

Comorbid Conditions

Patients with MDD often have comorbid metabolic conditions such as diabetes and obesity, which can exacerbate depressive symptoms.

Empagliflozin, by managing blood glucose levels and offering cardiovascular benefits, can improve overall physical health, which is closely linked to mental health.

When combined with an SSRI, this approach not only targets the psychological aspects of depression but also the physical health challenges that may contribute to the disorder.

Potential for Improved Treatment Response

Combining empagliflozin with an SSRI may improve treatment response in patients who are partially or non-responsive to SSRIs alone.

By targeting multiple mechanisms associated with depression, this combination could enhance the effectiveness of treatment, offering relief to a broader population of patients with MDD.

Reduction of Side Effects

Empagliflozin’s positive effects on weight and metabolic health could counteract some of the common side effects associated with SSRIs, such as weight gain and sexual dysfunction.

This could improve adherence to treatment and overall patient satisfaction.

How Empagliflozin May Help Treat Depression (Mechanisms)

Empagliflozin, primarily known for its role in managing type 2 diabetes, has shown promise as an adjunctive treatment for Major Depressive Disorder (MDD), leveraging both direct and indirect mechanisms to exert antidepressant effects.

These mechanisms encompass a broad spectrum of biological processes, including inflammation modulation, weight management, blood sugar regulation, hormonal balance, and neurotransmitter activity.

Inflammation Reduction

Chronic inflammation is a recognized contributor to the pathophysiology of depression.

Empagliflozin can lower systemic inflammation, as evidenced by reductions in inflammatory markers like C-reactive protein (CRP) and interleukin-6 (IL-6).

This anti-inflammatory action may help alleviate the neuroinflammation often seen in patients with MDD, contributing to its antidepressant effects.

Weight Management

Obesity and weight gain are both risk factors and consequences of depression.

Empagliflozin promotes weight loss through increased glucose excretion in the urine, addressing one of the atypical symptoms of depression (i.e., weight gain) and potentially improving patients’ self-esteem and overall quality of life.

Blood Sugar Regulation

Fluctuations in blood sugar levels can affect mood and energy levels, contributing to the symptoms of depression.

By improving glycemic control, empagliflozin can stabilize these fluctuations, indirectly supporting mood stabilization and reducing the depressive symptoms associated with metabolic dysregulation.

Hormonal Balance

Depression has been linked to dysregulation in the hypothalamic-pituitary-adrenal (HPA) axis, leading to imbalances in stress hormones like cortisol.

Empagliflozin may have a modulating effect on this axis, potentially normalizing cortisol levels and mitigating the stress response that can exacerbate depression symptoms.

Neurotransmitter Activity

While empagliflozin’s primary action is not directly on neurotransmitters, its systemic effects can indirectly influence neurotransmitter systems involved in mood regulation, such as serotonin, dopamine, and glutamate.

For example, by reducing systemic inflammation and oxidative stress, empagliflozin may improve the functionality of these neurotransmitter systems, enhancing mood and cognitive function.

Cardiovascular & Neuroprotective Effects

Empagliflozin’s cardiovascular benefits, including reducing the risk of heart failure and improving endothelial function, may contribute to its antidepressant effects by improving overall physical health, which is closely linked to mental health.

Additionally, its neuroprotective properties, such as reducing oxidative stress and enhancing vascular health, may support brain health and resilience against depressive symptoms.

Which Patients May Respond Best to Adjunct Empagliflozin for Depression?

The combination of empagliflozin with an SSRI for the treatment of Major Depressive Disorder (MDD) opens up new avenues for personalized medicine, targeting specific patient demographics and depressive subtypes that might benefit the most from this novel treatment strategy.

Given the unique mechanisms of action of empagliflozin and its potential synergistic effects with SSRIs, certain groups of patients could be ideally suited for this combination therapy.

1. Treatment-Resistant Depression

Individuals who have not responded adequately to multiple courses of traditional antidepressants, including SSRIs or SNRIs alone, might benefit significantly from the addition of empagliflozin.

This group often struggles to find effective treatment options, and the combination approach could offer a new avenue for relief.

2. Comorbid Metabolic Disorders

Those suffering from MDD and concurrent metabolic conditions, such as type 2 diabetes or metabolic syndrome, could be particularly suited for this therapy.

Empagliflozin’s efficacy in managing blood glucose levels and providing cardiovascular benefits could simultaneously address their depressive symptoms and metabolic health, potentially leading to improved overall outcomes.

3. High Inflammation

Individuals with MDD who show elevated levels of inflammatory biomarkers (e.g., CRP, IL-6) might respond well to the anti-inflammatory effects of empagliflozin.

This subgroup could particularly benefit from the combined anti-inflammatory and antidepressant effects of empagliflozin and SSRIs.

4. Depressive Symptoms with Atypical Features

Atypical depression, characterized by mood reactivity, weight gain, hypersomnia, and leaden paralysis, might be responsive to this combination therapy.

Empagliflozin’s impact on weight and metabolic health could be particularly beneficial for patients who experience these atypical depressive symptoms.

5. Middle-Aged to Elderly Patients

This demographic often presents with a higher prevalence of comorbid conditions, including cardiovascular diseases and type 2 diabetes, alongside depression.

The cardioprotective and antihyperglycemic effects of empagliflozin, combined with the mood-stabilizing effects of SSRIs, could offer dual benefits.

6. High Cardiovascular Risk

Depression has been linked to an increased risk of cardiovascular diseases.

Patients with MDD who are also at high risk for cardiovascular events might find the combination of empagliflozin and an SSRI particularly advantageous due to the cardiovascular benefits of empagliflozin.

Conclusion: Empagliflozin for the Treatment of Depression

References

• Paper: Efficacy of empagliflozin as adjunctive therapy to citalopram in major depressive disorder: a randomized double-blind, placebo-controlled clinical trial (2024)
• Authors: Atefeh Zandifar et al.

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