From the Guidelines
For patients with treatment-resistant depression, I strongly recommend a multi-faceted approach starting with medication optimization, including the use of ketamine or esketamine as a treatment option, as suggested by the 2022 U.S. Department of Veterans Affairs and U.S. Department of Defense clinical practice guideline 1.
Key Recommendations
- Consider switching to a different class of antidepressants (from an SSRI to an SNRI like venlafaxine 75-225mg daily or duloxetine 30-120mg daily) or augmenting current treatment with medications like aripiprazole (2-15mg daily), quetiapine (150-300mg daily), or lithium (600-900mg daily with blood level monitoring).
- Esketamine nasal spray (56-84mg twice weekly initially, then weekly to monthly) has shown efficacy for TRD, as supported by a meta-analysis of 5 RCTs examining esketamine as augmentation therapy 1.
- Non-medication approaches include electroconvulsive therapy (ECT), which remains highly effective, or transcranial magnetic stimulation (TMS), typically administered in daily sessions over 4-6 weeks.
- Psychotherapy, particularly cognitive behavioral therapy or interpersonal therapy, should be integrated with medication management.
- Lifestyle modifications including regular exercise, improved sleep hygiene, and stress reduction techniques are important complementary strategies.
Definition of Treatment-Resistant Depression
- TRD should be defined after a minimum of two failed treatments with <25% of improvement with adequate dosing and duration, as recommended by a Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials 1.
- Partial response to at least one treatment within the current episode should be considered for the definition of partially responsive depression (PRD).
Importance of Early Intervention
- Early intervention is crucial, as higher rates of suicide and lower life expectancy are strongly correlated with severity and treatment resistance in depression, as highlighted by a systematic review and meta-analysis of registry-based studies 1.
- Optimizing pharmacological treatment for patients with TRD by using evidence-based algorithms and guidelines is recommended to promote response and remission and reduce severity of symptoms commonly associated with risky behaviors.
From the FDA Drug Label
SPRAVATO is indicated for the treatment of: Treatment-resistant depression (TRD) in adults as monotherapy or in conjunction with an oral antidepressant Depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior in conjunction with an oral antidepressant
The treatment of treatment-resistant depression (TRD) in adults can be done using SPRAVATO as monotherapy or in conjunction with an oral antidepressant.
- The recommended dosage of SPRAVATO for the treatment of TRD in adults is shown in Table 1, with dosage adjustments made based on efficacy and tolerability.
- Evidence of therapeutic benefit should be evaluated at the end of the induction phase to determine the need for continued treatment.
- The recommended dosage is:
- Induction Phase (Weeks 1 to 4): Administer twice per week, 56 mg or 84 mg
- Maintenance Phase (Weeks 5 to 8): Administer once weekly, 56 mg or 84 mg
- Week 9 and after: Administer every 2 weeks or once weekly, 56 mg or 84 mg 2
From the Research
Definition and Prevalence of Treatment-Resistant Depression
- Treatment-resistant depression (TRD) is defined as the absence of remission despite trials of two or more antidepressant medications, affecting up to 31% of patients with major depressive disorder 3.
- TRD can occur in patients who do not respond to first-line antidepressant treatments, resulting in a more severe course of illness and increased risk of suicide 4.
Management Strategies for Treatment-Resistant Depression
- Management strategies for TRD include adding psychotherapy, switching antidepressant medication class, or augmenting with additional medications 3.
- Current guidelines recommend augmentation with a second-generation antidepressant, an atypical antipsychotic, tricyclic antidepressants, lithium, or a triiodothyronine medication as pharmacologic options 3.
- Ketamine and esketamine can also be used as augmentation for treatment-resistant depression and may help reduce suicidal ideation 4, 3.
Pharmacological Interventions for Treatment-Resistant Depression
- Augmenting current antidepressant treatment with mianserin or an antipsychotic (cariprazine, olanzapine, quetiapine, or ziprasidone) improves depressive symptoms over the short-term (8 to 12 weeks) 5.
- However, this evidence is mostly of low or moderate quality due to imprecision of the estimates of effects, and improvements with antipsychotics need to be balanced against the increased likelihood of dropping out of treatment or experiencing an adverse event 5.
- Augmentation with lithium, triiodothyronine, and second-generation antipsychotics are also reviewed as potential strategies for managing TRD 6.
Non-Pharmacological Interventions for Treatment-Resistant Depression
- Non-pharmacologic therapies, including psychotherapy, exercise, and focused dietary changes, can be effective in managing TRD 3.
- Somatic therapies, such as electroconvulsive therapy, repetitive transcranial magnetic stimulation, magnetic seizure therapy, and deep brain stimulation, are also detailed as potential treatment options 6.
- Novel therapeutics, including ketamine, psilocybin, anti-inflammatories, and new directions, are reviewed as potential strategies for managing TRD 6.