Treatment-Resistant Depression

(TRD): Advances in Prefrontal

Cortex-Targeted Therapies (2025)
Emerging Approaches and Clinical Implications

Presented by : [Link] Srinivasan,MBBS

SRI CHAMUNDESHWARI MEDICAL COLLEGE, HOSPITAL & RESEARCH INSTITUTE

14/02/2025
INTRODUCTION TO TRD

What is Treatment-Resistant Depression?

Definition: TRD is a severe form of major depressive disorder (MDD) where
patients do not achieve remission after at least two adequate trials of
antidepressant medications.

Prevalence: Approximately 30% of MDD patients are

treatment-resistant.

Impact:
- Increased risk of suicide and comorbidities
- Higher healthcare costs due to prolonged treatment
- Reduced quality of life
 Understanding the Neurobiology of TRD
Key Brain Regions Involved:

- Prefrontal Cortex (PFC): Regulates mood

decision-making, and cognitive control.
- Amygdala: Involved in emotional processing (often
hyperactive in TRD).
- Hippocampus: Linked to memory and stress response
(often atrophied in TRD).

PFC Dysfunction in TRD:

- Hypoactivity in the dorsolateral PFC (dlPFC): Impairs

cognitive control.
- Hyperactivity in the ventromedial PFC (vmPFC):
Associated with rumination and negative emotions.

Neurotransmitter Imbalances:

- Serotonin, dopamine, and glutamate dysregulation.

 The Role of the Prefrontal Cortex in TRD
Functions of the PFC:

- Mood regulation

- Decision-making and problem-solving

- Cognitive control and emotional regulation

Evidence of PFC Dysfunction in TRD:

- Neuroimaging studies show reduced activity in the dlPFC and increased activity in the vmPFC.

- PFC dysfunction correlates with symptoms like anhedonia, poor concentration, and emotional
dysregulation.

Potential for Neuromodulation:

- Restoring PFC activity can improve mood and cognitive symptoms in TRD.
 PFC Dysfunction
↓
Impaired Executive Function
↓
Difficulty in Decision Making
↓
Reduced Emotional Regulation
↓
Persistent Negative Thoughts
↓
Increased Anxiety and Stress
↓
Worsening Depression Symptoms
↓
Treatment-Resistant Depression
 Current Treatment Options for TRD
Pharmacotherapy:

- SSRIs (e.g., fluoxetine, sertraline)

- SNRIs (e.g., venlafaxine, duloxetine)

- Atypical antipsychotics (e.g., aripiprazole, quetiapine)

Psychotherapy:

- Cognitive Behavioral Therapy (CBT)

- Dialectical Behavior Therapy (DBT)

Limitations of Current Treatments:

- Low remission rates (only 30-40% of TRD patients respond to standard treatments).

- Side effects (e.g., weight gain, sexual dysfunction, sedation).

- High relapse rates.

 Emerging PFC-Targeted Therapies for TRD
Categories of Interventions:

1. Non-invasive brain stimulation: TMS, tDCS

2. Invasive neuromodulation: DBS, VNS

3. Pharmacological approaches: Ketamine, psychedelics

4. Emerging technologies: AI-driven neurofeedback, digital

therapeutics

Rationale: Directly modulate PFC activity to restore mood regulation and cognitive control.
 TMS: Revitalizing the Dorsolateral PFC
Mechanism: Magnetic pulses stimulate hypoactive dlPFC to enhance synaptic
plasticity.

2025 Advances:

- Personalized targeting: fMRI-guided coil placement.

- Theta-burst stimulation (TBS): 3-minute protocols with efficacy matching

traditional TMS.

Efficacy: 50–60% response rate in TRD.

 TBS: Faster, Smarter TMS

Mechanism: Delivers bursts of high-frequency magnetic pulses to mimic

natural brain rhythms.

Advantages:

- 90% reduction in session time (3 vs. 37 minutes).

- Improved patient adherence and clinic throughput.

2025 Status: FDA-approved for TRD; covered by Medicare/private insurers.

 tDCS: Portable PFC Modulation

Mechanism: Low-intensity electrical current enhances (anodal) or inhibits

(cathodal) PFC activity.

2025 Innovations:

- Wearable devices: At-home tDCS kits with app-guided protocols.

- Combination therapy: Paired with CBT for synergistic effects.

Limitations: Variable efficacy; requires daily sessions for 4–6 weeks.

 Modern ECT: Precision Targeting for the PFC

Mechanism: Focal seizures modulate PFC and limbic hyperactivity.

Latest Advances:

- Ultrabrief pulse ECT: Reduced cognitive side effects (e.g., memory loss).

- Focal PFC stimulation: Avoids hippocampal overstimulation.

Efficacy: 70–80% response rate in severe TRD.

 DBS: Rewiring the PFC Network

Mechanism: Implanted electrodes stimulate PFC-connected regions (e.g.,

subcallosal cingulate).

2025 Innovations:

- Closed-loop DBS: Real-time adjustment based on neural biomarkers.

- AI-driven targeting: Machine learning optimizes electrode placement.

Challenges: Invasive; requires neurosurgical expertise.

 VNS: Indirect PFC Modulation

Mechanism: Vagus nerve stimulation enhances PFC connectivity via the

noradrenergic system.

2025 Advances:

● Non-invasive VNS: Transcutaneous devices (e.g., gammaCore).

● Combined with psychotherapy: Boosts emotional processing.

Efficacy: 40–50% response rate after 12 months.

 MST: A Safer Alternative to ECT

Mechanism: Uses TMS to induce focal seizures in the PFC, avoiding hippocampal
damage.

2025 Status: Phase III trials show 65% response rate with minimal cognitive side
effects.

Advantages: Outpatient procedure; no anesthesia required.

 Rapid-Acting PFC-Targeted Drugs
Ketamine/Esketamine:

Mechanism:
Glutamate modulation in the PFC → rapid synaptogenesis.
2025 Use: FDA-approved nasal spray with biweekly
maintenance dosing.

Psychedelics (Psilocybin/MDMA):

Mechanism: Enhance PFC-limbic connectivity and

neuroplasticity.
2025 Status: FDA breakthrough designation; Phase III trials
ongoing.
 Tech-Driven PFC Rehabilitation

Neurofeedback:
❏ Real-time fMRI/EEG trains patients to regulate PFC
activity.
❏ Example: NeuroRex headset (FDA-cleared in 2024).

AI-Driven Apps:
❏ Personalized cognitive exercises to strengthen dlPFC
function.
❏ Example: MoodFit app with VR-based exposure
therapy.
 Challenges and Limitations of PFC-Targeted Therapies

Individual Variability:
- Differences in PFC anatomy and functional connectivity.
- Personalized approaches are needed to optimize outcomes.
Cost and Accessibility:
- Advanced therapies (e.g., DBS, TMS) are expensive and require specialized equipment.
- Limited availability in rural or low-resource settings.
Ethical Concerns:

★ Invasive procedures (e.g., DBS) raise questions about patient autonomy and
long-term effects.

★ Psychedelic therapies require careful regulation and monitoring.

Side Effects:

★ Cognitive side effects (e.g., memory loss with ECT).

★ Physical side effects (e.g., headaches with tDCS).

 The Future of TRD Treatment: What’s Next?
Biomarker Development:

- Identifying neural, genetic, or blood-based biomarkers to predict treatment response.

Example: fMRI patterns or glutamate levels as predictors for ketamine response.

Combination Therapies:

- Pairing neuromodulation (e.g., TMS) with pharmacological treatments (e.g., ketamine).

- Synergistic effects to enhance remission rates.

Wearable and Digital Innovations:

- Portable tDCS devices for at-home use.

- AI-driven apps for real-time mood tracking and intervention.

Case Study: Successful PFC-Targeted Therapy in TRD
Patient Profile:
- 45-year-old female with a 10-year history of TRD.
- Failed trials of SSRIs, SNRIs, and psychotherapy.
Intervention:
- Theta-burst stimulation (TBS) targeting the dorsolateral PFC (dlPFC).
- 5 sessions per week for 6 weeks.
Outcome:
- 50% reduction in depressive symptoms (measured by MADRS score).
- Improved cognitive function and quality of life.
Takeaway:
- TBS is a promising, time-efficient option for TRD patients.
Conclusion
The Promise of PFC-Targeted Therapies
Key Takeaways:

1. TRD is a complex condition with significant unmet needs.

2. The prefrontal cortex is a critical target for innovative therapies.

3. Advances in neuromodulation, pharmacology, and digital

therapeutics are transforming TRD treatment.
Clinical Implications:

- Multidisciplinary care teams are essential for optimal outcomes.

- Patient education and shared decision-making improve treatment

adherence.
Thank You!
“Your mental health journey may be difficult,
but it’s worth it. ”