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Treatment resistant depression — Clinical Guidelines

Overview

Treatment-resistant depression (TRD) refers to depression that does not adequately respond to initial antidepressant therapy, posing significant clinical challenges 1.

Diagnosis

Persistent depressive symptoms despite adequate trial of at least two different antidepressants, each for an adequate duration 1.

No specific diagnostic tests; diagnosis based on clinical evaluation and symptom criteria 1.

Management

First-line treatments: Multiple adequate trials of different antidepressants, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants 1.

Adjunctive treatments:

- Lithium: Often recommended as a second-line option 1. - Quetiapine: Used as an atypical antipsychotic adjunct 1. - Esketamine: Shown to be effective as a fast-acting agent, administered via nasal spray 2 6. - Dose: Typically 56.5 mg sublingual or 524 mg intranasal twice weekly 2.

Considerations: Monitor for suicidality and adverse effects, particularly with esketamine 5.

Special Populations

Pediatrics: Limited specific evidence; general principles apply but require careful monitoring 12 14.

Elderly: Increased risk of side effects; individualized treatment plans are crucial 1.

Comorbidities: Tailor treatment considering interactions and specific health conditions 1.

Key Recommendations

Consider esketamine as an adjunctive treatment for TRD due to its rapid efficacy, especially in patients with significant functional impairment 2 6 (Evidence: Strong).

Evaluate the use of lithium or quetiapine for patients not responding to standard antidepressants, balancing efficacy and side effect profiles 1 (Evidence: Moderate).

Closely monitor patients for changes in suicidality when initiating esketamine treatment 5 (Evidence: Moderate).

Individualize treatment plans for elderly patients due to heightened risk of adverse effects 1 (Evidence: Expert opinion).

References

1 Eckert D, Kasper S. Beyond first-line antidepressants: lithium, quetiapine, or esketamine? Integrating meta-analyses and preliminary head-to-head evidence. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 2026. link 2 Ouyang Y, Li J. Efficacy of esketamine nasal spray for treatment-resistant depression: A meta-analysis of randomized controlled studies. Medicine 2025. link 3 Montastruc JL. Drugs and patient's dissatisfaction reporting: From a disproportionality pharmacovigilance analysis to social pharmacology. Therapie 2025. link 4 Wallerstedt SM, Hoffmann M. Quantification of the prevalence of harms in healthcare related to drug treatment: reflections regarding the use of definitions developed for other settings to estimate the magnitude of the problem. European journal of clinical pharmacology 2025. link 5 McIntyre RS, Mansur RB, Rosenblat JD, Teopiz KM, Kwan ATH. The association between ketamine and esketamine and suicidality: reports to the Food And Drug Administration Adverse Event Reporting System (FAERS). Expert opinion on drug safety 2025. link 6 Alnefeesi Y, Chen-Li D, Krane E, Jawad MY, Rodrigues NB, Ceban F et al.. Real-world effectiveness of ketamine in treatment-resistant depression: A systematic review & meta-analysis. Journal of psychiatric research 2022. link 7 Patel P. Cancer Treatment Related Pain. Cancer treatment and research 2021. link 8 Stamp AJ, Dorman ML, Vernazza CR, Deeming G, Reid C, Wilson KE et al.. Can intravenous conscious sedation with midazolam be effective at facilitating surgical dentistry in adolescent orthodontic patients? A service evaluation. British dental journal 2017. link 9 Griffith R. What is Gillick competence?. Human vaccines & immunotherapeutics 2016. link 10 Lister TS, Brewin MP. Variations in laser energy outputs over a series of simulated treatments. The British journal of dermatology 2014. link 11 Chrysikopoulou A, Matheson P, Milles M, Shey Z, Houpt M. Effectiveness of two nitrous oxide scavenging nasal hoods during routine pediatric dental treatment. Pediatric dentistry 2006. link 12 Wilson KE, Welbury RR, Girdler NM. A study of the effectiveness of oral midazolam sedation for orthodontic extraction of permanent teeth in children: a prospective, randomised, controlled, crossover trial. British dental journal 2002. link 13 Mahmood A, Mandall NA, Wright J. The use of general anaesthesia for orthodontic extractions. Community dental health 2001. link 14 Shepherd AR, Hill FJ. An investigation of patient management methods used for orthodontic extractions by general dental practitioners in north west England. British dental journal 2000. link 15 Vanĕk T, Malá J, Saman D, Silhavá I. Production of taxanes in a bioreactor by Taxus baccata cells. Planta medica 1999. link 16 Forshaw S. Treatment without consent. Nursing times 1995. link 17 Gert B, Culver CM. Distinguishing between active and passive euthanasia. Clinics in geriatric medicine 1986. link

Treatment resistant depression