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When nothing else is working

Alternative approaches to treating depression

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Ben Van Leeuwen MD

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This presentation has no ineligible company content, promotes no ineligible company, and is not supported financially by any ineligible company. I receive no financial remuneration from any ineligible company related to this presentation.  

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Financial Disclosure

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Why This Matters

  • Approximately 30–40% of patients with major depressive disorder do not remit with standard antidepressants/psychotherapy
  • Treatment resistance is associated with:
    • Increased cardiovascular disease, diabetes, chronic pain
    • Poor medication adherence and more difficult post-operative recovery
  • Poor treatment adherence leads to higher healthcare utilization
  • Treatment resistant depression (TRD) = system-wide morbidity multiplier

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What Is Treatment-Resistant Depression?

  • Failure of ≥2 adequate antidepressant trials from different classes
    • Adequate dose and duration required
  • Often ambulatory but persistently impaired
  • Represents a plateau of standard care rather than disease severity

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Why Interventional Treatments Exist

  • Monoamine-based treatments → indirect neuroplastic effects
  • Limited impact on:
    • Network dysfunction
    • Synaptic connectivity
  • TRD reflects impaired neuroplasticity
  • Interventional treatments:
    • Directly modulate circuits
    • Accelerate synaptic change

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Depression as a Circuit-Based Disorder

  • Prefrontal–limbic dysregulation
    • Reduced top-down emotional control (hypoactive prefrontal cortex)
    • Hyperactivity in limbic and default mode networks
  • Chronic stress associated with impaired synaptic plasticity/dendritic atrophy
  • Targeting circuits ≠ adding more medications

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What Is TMS?

  • Repetitive magnetic stimulation → cortical depolarization
  • Targets left DLPFC
  • Induces:
    • Long-term potentiation (LTP)-like effects
    • Network-level modulation
  • No systemic medication exposure, sedation, or anesthesia
  • FDA-cleared for major depressive disorder (age 15+), OCD

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TMS: Outcomes & Safety

  • Response rates 60–70%
  • Remission rates 30–40%
  • Benefits often durable over months to years
  • Minimal side effects: scalp discomfort or headache
  • No cognitive impairment; extremely low seizure risk (<0.1%)

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Who Is TMS Best For?

  • Major depressive disorder with inadequate medication response
  • History of medication intolerance or sensitivity
  • Preference to avoid systemic therapies
  • Stable patients without urgent symptom escalation (no acute suicidality)

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Ketamine: Paradigm Shift

  • Rapid antidepressant effects (hours–days)
  • Effective in treatment-resistant depression
  • Changed assumptions about antidepressant onset
  • Useful when rapid clinical response is needed

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Ketamine: Mechanism

NMDA receptor antagonism

Glutamate surge → AMPA receptor activation

Increased BDNF, mTOR signaling

Rapid synaptogenesis

Restores network connectivity

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Ketamine: Clinical Use & Safety

  • Generally is administered IV or IM in monitored setting
  • Induction series can be followed by individualized maintenance
  • Side effects
    • Transient dissociation expected
    • Transient blood pressure elevation possible
  • No evidence of neurotoxicity at clinical doses
  • Controlled setting mitigates misuse risk

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Esketamine (Spravato)

  • S-enantiomer of ketamine
  • FDA-approved for treatment-resistant depression
    • Also approved for depression with acute suicidal ideation
  • Intranasal administration
  • REMS-regulated monitoring program
    • Requires in-clinic dosing and monitoring

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Comparing the Modalities

  • TMS
    • Gradual onset, no systemic exposure, best for stable but chronic non-responders
  • Ketamine
    • Rapid onset, IV or IM administration
    • Useful in severe/urgent cases
  • Esketamine
    • Rapid onset, structured protocol, intranasal FDA-approved option

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Clinical Application: what would you do next?

A 52-year-old woman presents with a long-standing history of major depressive disorder. Over the past several years, she has completed four adequate antidepressant trials across different classes, each at therapeutic dose and duration, with only partial or transient benefit. She remains adherent to treatment and has engaged intermittently in psychotherapy.

Despite these efforts, she continues to experience persistent fatigue, anhedonia, low motivation, and cognitive slowing. She is still working but with increasing difficulty, describing that “everything feels harder than it should.” She denies active suicidal ideation but reports a sense of emotional flatness and diminished quality of life.

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When to Refer

  • Failure of ≥2 antidepressants
  • Persistent functional impairment
  • Medication intolerance or adverse effects
  • Depression interfering with medical recovery
  • Earlier referral associated with better outcomes

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Key Takeaways

  • TRD is common and under-recognized
  • Depression is a circuit disorder
  • TMS and ketamine target neuroplasticity
  • These treatments complement standard care
  • Timing of referral matters

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Questions?

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Sources

  • Rush AJ et al. Am J Psychiatry, 2006 (STAR*D)
  • Duman RS et al. Neuron, 2016
  • Berlim MT et al. Br J Psychiatry, 2014
  • Wilkinson ST et al. Am J Psychiatry, 2018
  • Daly EJ et al. Am J Psychiatry, 2018
  • Sanacora G et al. JAMA Psychiatry, 2017
  • APA Practice Guideline for Major Depressive Disorder (2023)
  • VA/DoD Clinical Practice Guideline for MDD (2022)

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