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Depression: Managing Resistance and Partial Response to Treatment

Heidi L. Gaddey, MD
Brandyn Mason, DO
Amol Naik, MD

American Family Physician. 2024;109(5):410-416.

Author disclosure: No relevant financial relationships.

Treatment-resistant depression is defined as absence of remission despite trials of two or more antidepressant medications and can occur in up to 31% of patients with major depressive disorder. Partial response to treatment is defined as less than 50% reduction in depression-rating scores. Before diagnosing treatment-resistant depression or partial response to treatment, adherence to adequate doses and duration of medications should be confirmed. Management strategies include adding psychotherapy, switching antidepressant medication class, or augmenting with additional medications. Current guidelines recommend augmentation with a second-generation antidepressant, an atypical antipsychotic, tricyclic antidepressants, lithium, or a triiodothyronine medication as pharmacologic options. Ketamine and esketamine can also be used as augmentation for treatment-resistant depression and may help reduce suicidal ideation. Electroconvulsive therapy and repetitive transcranial magnetic stimulation may be effective. Pharmacogenetic testing has limited evidence and is not recommended. Nonpharmacologic therapies include psychotherapy, exercise, and focused dietary changes.

Epidemiology

Depression is among the most common psychiatric disorders in the United States. Major depressive disorder has a 12-month prevalence of 10% and a lifetime prevalence of 21%, with an average onset at 30 years of age.1 Only about one-third of patients respond to an initial trial of a first-line antidepressant medication, and a significant proportion of patients will not respond despite multiple interventions.2 Although it lacks a universal definition, treatment-resistant depression is most commonly defined as absence of remission using validated scoring tools despite trials of two or more antidepressant medications at adequate dose, duration, and adherence.3,4 This definition, however, does not account for partial response to treatment, which is defined as less than 50% reduction in depression-rating scores. When applied to treatment, these often overlapping criteria can make comparing and synthesizing studies difficult.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating Comments
Switching to or augmenting with another antidepressant class or adding psychotherapy is recommended for patients who have depression with partial response to optimized initial treatment.8–11 C Clinical practice guidelines
Augmentation with a second-generation antipsychotic is an effective option for treatment-resistant depression.9,11,23,24,26 A Clinical practice guidelines, Cochrane review, and randomized controlled trials and meta-analyses
Ketamine and esketamine (available as brand Spravato) can be considered for treatment-resistant depression when other medications have been ineffective.11,29 B Clinical practice guidelines, Cochrane review, and randomized controlled trials and meta-analyses
Electroconvulsive therapy can be considered for treatment-resistant depression with associated suicidality, psychosis, or catatonia.9,11,46 C Clinical practice guidelines, expert opinion

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

Before diagnosing treatment-resistant depression or partial response to treatment, patients should be assessed to verify the accuracy of the depression diagnosis and evaluated for comorbid or exacerbating medical or psychiatric conditions. Adherence to medications should also be confirmed. Diagnosis of bipolar disorder should specifically be considered; patients should be screened for symptoms of mania or hypomania because up to 25% of patients presenting with depression or anxiety in a primary care setting are diagnosed with bipolar disorder.5 Particular attention should be paid to medication adherence because nonadherence rates for antidepressant medications has been estimated to be 46%.6 The prevalence of treatment-resistant depression among patients with major depressive disorder is 31%.7 The general approach to treatment-resistant depression and partial response to treatment includes adding psychotherapy, switching antidepressant medication class, or augmenting with additional medications.8–11

HEIDI L. GADDEY, MD, is program director of the Carle Foundation Hospital Family Medicine Residency, Urbana, Ill.

BRANDYN MASON, DO, is associate program director of the Carle Foundation Hospital Family Medicine Residency.

AMOL NAIK, MD, is core faculty for the Carle Foundation Hospital Family Medicine Residency.

Address correspondence to Heidi L. Gaddey, MD, 611 W. Park St., Urbana, IL 61801 (heidi.gaddey@carle.com). Reprints are not available from the authors.

Author disclosure: No relevant financial relationships.

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