What is the role of GABA (Gamma-Aminobutyric Acid) and glutamate in depression and how does Auvelity (dextromethadone) work in treating it?

GABA and Glutamate in Depression: Mechanisms and Auvelity's Role

Auvelity (dextromethorphan-bupropion) is FDA-approved for major depressive disorder and works by modulating glutamatergic neurotransmission through NMDA receptor antagonism, addressing the glutamate-GABA imbalance that characterizes treatment-resistant depression. 1

The Glutamate-GABA Imbalance in Depression

Elevated Glutamate as a Marker of Severe Depression

Depression involves a fundamental disruption in the balance between excitatory glutamate and inhibitory GABA neurotransmission in the brain. Medication-free patients with chronic, symptomatic major depressive disorder demonstrate elevated glutamate (Glu) and Glx (glutamate + glutamine) levels in the ventromedial prefrontal cortex/anterior cingulate cortex, with the highest levels correlating with more severe depression. 2

• Higher glutamate levels directly correlate with depression severity, particularly in males with MDD 2
• This elevation appears most pronounced in untreated, severe cases rather than medicated patients 2

GABA Deficiency and Disinhibition

Low GABA levels in depression lead to disinhibition of glutamate release, creating a vicious cycle of excitotoxicity. 2

• Cortical GABA levels are reduced in unipolar depression (though not consistently in bipolar depression) 3
• The combination of low GABA and high glutamate suggests that GABAergic interneuron dysfunction removes normal inhibitory control over glutamatergic neurons 2
• This model explains why NMDA receptor antagonism (blocking excessive glutamate signaling) produces antidepressant effects 2

Glutamatergic System as a Therapeutic Target

NMDA Receptor Antagonism Shows Greatest Promise

Among glutamatergic targets, NMDA receptor antagonism has demonstrated the most robust evidence for treating depression, with multiple FDA-approved agents now available. 1

The glutamatergic system has emerged as the most promising non-monoaminergic target because:

• Approximately one-third to one-half of patients respond poorly to traditional monoamine-based antidepressants 4
• NMDA receptor antagonists work rapidly, often within hours to days rather than weeks 1
• Antidepressant efficacy correlates with reduction of elevated vmPFC/ACC glutamate levels 2

Auvelity: Mechanism and Clinical Application

Unique Dual Mechanism

Auvelity combines dextromethorphan (NMDA receptor antagonist) with bupropion (which inhibits dextromethorphan metabolism and provides additional norepinephrine-dopamine reuptake inhibition), creating a novel approach to glutamate modulation. 1

• Dextromethorphan acts as an uncompetitive NMDA receptor antagonist, reducing excessive glutamatergic neurotransmission 1
• Bupropion serves dual purposes: it increases dextromethorphan bioavailability by inhibiting CYP2D6 metabolism and provides complementary monoaminergic effects 1
• This combination demonstrated positive results particularly in patients with cognitive dysfunction 1

Clinical Positioning

Auvelity is FDA-approved for major depressive disorder (not specifically limited to treatment-resistant cases), distinguishing it from esketamine which is approved only for TRD. 1

Key advantages over other glutamatergic agents:

• Oral administration (unlike esketamine's intranasal route or ketamine's IV route)
• Does not require specialized monitoring settings
• May be particularly beneficial for depressed patients with prominent cognitive symptoms 1

Other Glutamatergic and GABAergic Agents

Ketamine and Esketamine

Esketamine (Spravato) is FDA-approved specifically for treatment-resistant depression and has the most robust evidence among NMDA antagonists, though concerns about long-term safety and abuse potential exist. 1

• Ketamine and esketamine generate rapid responses across multiple trials 1
• Esketamine requires administration in certified healthcare settings with post-dose monitoring 1
• Some safety concerns have emerged with esketamine use 1

NMDA-Glycine Site Modulators

D-cycloserine and apimostinel, which modulate the NMDA receptor's glycine site, show promising initial safety and efficacy profiles warranting further investigation. 1

GABAergic Approaches

Brexanolone (Zulresso), a synthetic neurosteroid with positive GABAA receptor modulation, is FDA-approved for postpartum depression but has significant practical limitations. 1

• Brexanolone represents the most promising GABA modulator for depression 1
• Requires continuous IV infusion over 60 hours in a certified healthcare facility 1
• Safety concerns similar to esketamine have emerged 1

Baclofen, a GABA-B receptor agonist, shows promise for alcohol use disorder in patients with liver disease but is not established for primary depression treatment. 5

Clinical Implications and Treatment Algorithm

When to Consider Glutamatergic Agents

Consider glutamate-modulating treatments when:

• Patients have failed 1-2 adequate trials of monoaminergic antidepressants 1
• Severe depression with elevated symptom burden (likely reflecting high glutamate) 2
• Prominent cognitive dysfunction accompanies depression 1
• Rapid response is clinically necessary

Practical Selection Strategy

For treatment-resistant depression requiring rapid response with specialized monitoring available, esketamine is the evidence-based choice; for patients needing oral therapy with cognitive symptoms, Auvelity offers a practical alternative. 1

1. First consideration: Esketamine for documented TRD with ability to access certified treatment centers 1
2. Second consideration: Auvelity for MDD (including TRD) when oral therapy preferred or cognitive symptoms prominent 1
3. Investigational options: D-cycloserine or apimostinel in research settings 1

Critical Caveats

• The glutamate elevation seen in medication-free severe depression may normalize with treatment, making baseline glutamate levels a potential biomarker for treatment selection 2
• Antidepressant treatments (both monoaminergic and glutamatergic) appear to raise cortical GABA levels and reduce excessive glutamate signaling 3
• Male patients may show more pronounced glutamate elevation and potentially greater response to glutamatergic interventions 2
• Avoid confusing Auvelity's dextromethorphan component with dextromethadone (which doesn't exist as an antidepressant) - the correct drug is dextromethorphan combined with bupropion 1