Current and Emerging Pharmacotherapies in Patients With MDD

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Learn about atypical antipsychotics and the best strategies for using them to augment treatment for major depressive disorder (MDD) with inadequate response to initial therapy.

Defining Treatment Response in MDD​

Response to treatment is categorized to establish a clear framework for understanding inadequate responses:

1. Nonresponse: Less than 25% improvement in symptoms on standardized scales.
2. Partial or Inadequate Response: 25%-49% improvement with persistent functional impairments.
3. Response: ≥50% symptom improvement but without achieving remission.
4. Remission: Nearly symptom-free, with restored normal functioning.

Challenges in Achieving Remission​

• Only 20%-30% of patients achieve remission with each treatment trial.
• Residual symptoms often include low mood, anxiety, fatigue, reduced libido, and sleep disturbances.
• Functional problems like work impairment, cognitive deficits, and low energy persist even in remitted patients.

Implications of Inadequate Response​

Patients with insufficient symptom improvement face:

• Higher relapse rates.
• More chronic episodes with shorter intervals between them.
• Lower quality of life and increased risk of morbidity and suicide.

Adjusting Treatment Strategies​

Treatment regimens may need to be altered due to:

1. Intolerance: Side effects can compromise adherence.
2. Worsening Symptoms: Early detection of inadequate response is critical.

Recommendations from Major Guidelines​

1. American Psychiatric Association (APA, 2019):
   • After one failed monotherapy, switch to another agent with a different mechanism of action or augment with an additional medication.
2. CANMAT (Canada):
   • Advocates for early adjunctive treatments, particularly after the first or second inadequate response if tolerability permits.

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Enhancing Quality of Life and Functional Recovery​

1. Quality of Life Improvements:
   • Goals include re-engagement, vitality, motivation, and cognitive function.
   • Persistent issues like anhedonia, low energy, or poor sleep affect life satisfaction.
2. Functional Recovery:
   • Key domains include family, work, self-care, and community participation.
   • Functional recovery requires addressing core symptoms and fostering a sense of personal agency.

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Role of Atypical Antipsychotics in Adjunctive Therapy​

Overview by Dr. Leslie Citrome​

I’m Dr. Leslie Citrome, Clinical Professor of Psychiatry at New York Medical College. Here, I’ll discuss FDA-approved atypical antipsychotics for adjunctive treatment in MDD:

Approved Agents​

1. Aripiprazole (Abilify): Partial agonist at dopamine D2 and serotonin 5-HT1A receptors; initial dose 2-5 mg/day, up to 15 mg/day.
2. Quetiapine Extended Release (Seroquel XR): Antagonist at D2 and 5-HT2A receptors; starting dose 50 mg/day, target 150-300 mg/day.
3. Olanzapine-Fluoxetine Combination (Symbyax): Effective in treatment-resistant cases. Initial dose 6 mg/25 mg, up to 12 mg/50 mg.
4. Brexpiprazole (Rexulti): Similar to aripiprazole but with a gentler side effect profile; initial dose 0.5-1 mg/day, max 3 mg/day.
5. Cariprazine (Vraylar): Partial agonist at D2, D3 (high affinity), and 5-HT1A receptors; starting dose 1.5 mg/day, max 3 mg/day.

Considerations for Use​

• Effectiveness: Enhances response rates compared to antidepressants alone.
• Side Effects: Sedation, weight gain, restlessness, and metabolic concerns vary across agents.

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Emerging Treatments: Lumateperone​

Lumateperone (Caplyta), a novel adjunctive treatment, has shown promise in late-stage trials:

• Potent 5-HT2A antagonist with indirect modulation of AMPA and NMDA pathways.
• Exhibits significant early symptom improvement with minimal metabolic side effects.

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Individualizing Adjunctive Therapies​

Insights by Dr. Greg Mattingly​

I’m Dr. Greg Mattingly, Associate Clinical Professor at Washington University School of Medicine. Let’s explore strategies for tailoring adjunctive treatment:

1. Retaining Benefits: Maintain gains from the primary antidepressant while boosting effectiveness.
2. Avoiding Withdrawal Symptoms: Gradual adjustments to minimize discontinuation effects.
3. Patient-Centric Approach: Address residual symptoms (e.g., anhedonia, agitation) with evidence-based multimodal treatments.

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Measurement-Based Care: A Critical Component​

Utilizing tools like the PHQ-9, GAD-7, and quality-of-life scales ensures:

• Better Symptom Tracking: Early detection of residual issues.
• Improved Adherence: Patients feel engaged in their treatment.
• Higher Remission Rates: Measured outcomes inform precise therapeutic adjustments.

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Conclusion​

Adjunctive therapies play a vital role in improving outcomes for patients with MDD. By leveraging evidence-based strategies, measuring patient outcomes, and considering individual preferences, clinicians can optimize treatments for better symptom control, quality of life, and functional recovery. Thank you for joining this discussion.