Management of treatment-resistant depression requires a comprehensive treatment plan addressing the complex behavioral and emotional needs of the patient. Emphasis is placed on individualized, trauma-informed care that promotes stability, emotional regulation, and improved interpersonal relationships. Through a combination of therapeutic interventions—including individual and group therapy, skill development, family involvement, and ongoing assessment—the treatment approach aims to foster resilience, personal growth, and long-term success. Collaboration among care providers, consistent structure, and adaptive strategies remain central to achieving the desired therapeutic outcomes.
This course is designed for physicians, nurses, physician assistants, social workers, therapists, and counselors involved in the care of patients with depression that is not responding to usual treatment approaches.
The purpose of this course is to equip participants with the knowledge and skills to identify and implement both pharmacologic and nonpharmacologic treatment strategies for managing treatment-resistant depression, with a focus on individualized, trauma-informed care to promote patient stability, emotional regulation, and improved interpersonal relationships.
Upon completion of this course, you should be able to:
- Outline nonpharmacologic options for the management of treatment-resistant depression.
- Compare and contrast pharmacologic options for patients with poorly controlled or treatment-resistant depression.
Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.
Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
John M. Leonard, MD
Mary Franks, MSN, APRN, FNP-C
Alice Yick Flanagan, PhD, MSW
Margaret Donohue, PhD
The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
Sarah Campbell
The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.
Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.
It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.
Supported browsers for Windows include Microsoft Internet Explorer 9.0 and up, Mozilla Firefox 3.0 and up, Opera 9.0 and up, and Google Chrome. Supported browsers for Macintosh include Safari, Mozilla Firefox 3.0 and up, Opera 9.0 and up, and Google Chrome. Other operating systems and browsers that include complete implementations of ECMAScript edition 3 and CSS 2.0 may work, but are not supported. Supported browsers must utilize the TLS encryption protocol v1.1 or v1.2 in order to connect to pages that require a secured HTTPS connection. TLS v1.0 is not supported.
The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.
Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.
#96350: Management of Treatment-Resistant Depression
Treatment-resistant depression is a problem increasingly encountered by primary care and mental health providers. Most definitions of treatment response compare changes in depression rating scale scores between pre-treatment and follow-up. Standardized rating scales such as the MADRS and HAM-D are widely used to quantify treatment response [1]. The definition of antidepressant response falls into four categories [2,3]:
Remission: The absence of depressive symptoms or minimal symptoms (HAM-D score ≤7)
Response: A 50% or greater reduction in symptoms
Partial response: A 25% to 50% reduction in symptoms
Nonresponse: The absence of meaningful response (symptom reduction ≤25%)
Standard antidepressants fail to produce adequate response in 30% to 50% and remission in up to 70% of patients with major depressive disorder (MDD) [4,5,6]. Partial response, instead of full remission, leaves patients with impairing residual symptoms and high risk of relapse. Each relapse increases symptom severity, decreases treatment response, and heightens risk of treatment-resistant MDD [7].
Contributors to treatment-resistant depression include illness severity, medical and psychiatric comorbidity, and the limitations of FDA-approved drug options. The definition of treatment resistance lacks consensus, but the most common definition is inadequate response to two or more antidepressants. This does not consider adjunctive strategies or distinguish patients with partial versus non-response [8,9].
In addition to augmentation strategies, a diverse and growing range of interventions are available as options for treatment-resistant depression. Most engage novel therapeutic targets.
Options for patients lacking benefit from their initial antidepressant include switching antidepressants, switching to or adding psychotherapy, and adjunctive strategies (i.e., adding a second medication). The decisions to switch or add medications should be individualized and based on clinical factors [8]. Clinicians may consider switching to another antidepressant when [8]:
It is the first antidepressant trial.
Side effects are poorly tolerated.
Minimal or no response (i.e., <25% improvement).
There is more time to wait for a response (e.g., less severe, less functional impairment).
Patient prefers switching to another antidepressant.
Lack of response to one first-line antidepressant does not preclude potential benefits from other antidepressants, but the value of switching between classes or within classes of antidepressants is debatable.
An adjunctive medication may be added when [8]:
There have been two or more antidepressant trials.
The initial antidepressant is well tolerated.
There is partial response (i.e., >25% improvement).
There are specific residual symptoms or side effects to the initial antidepressant that can be targeted.
There is less time to wait for a response (e.g., more severe, more functional impairment).
Patient prefers to add on another medication.
Patients with MDD often prefer augmentation (add-on) to switching if partial improvement is achieved with the initial agent [71]. Standard antidepressants are frequently used as add-on therapy to enhance efficacy. For example, combining a TCA and an SSRI may be helpful for some patients, but the TCA dose should be adjusted because SSRIs may increase TCA levels [72,73]. Combining an SSRI, SNRI, or TCA with a presynaptic a2-autoreceptor antagonist (e.g., mirtazapine, trazodone) has shown significantly greater benefit than other combinations, with dosage differences accounting for about 50% of the total difference in treatment effect. Tolerability, as measured in patient dropout, was lower than expected with this combination [74].
Adverse effects are higher in combination pharmacotherapy, and combining antidepressants at treatment initiation is not recommended unless the MDD is characterized as severe (i.e., PHQ-0 >20); chronic (duration longer than two years); and recurrent (three or more episodes) [23].
The optimal duration of add-on therapy is not known, but it seems prudent that patients who are tolerating treatment and achieving therapeutic objectives should continue for at least 6 to 12 months with ongoing reassessment, with indefinite continuation for many [75].
Use of bright-light therapy for treatment of major depression with a seasonal specifier (seasonal affective disorder) is well established [10,11]. There is also evidence supporting its use for additional types of depressive symptom patterns, including non-seasonal depression, milder variations of seasonal depressive patterns, and depression in pregnant and postpartum women [12,13,14]. Bright-light therapy may quicken and enhance the effects of antidepressants [15]. The interaction between light intensity and duration of exposure requires two hours daily with 2,500 lux, one hour with 5,000 lux, and 30 minutes daily with 10,000 lux for efficacy [16]. Light therapy must also use equipment that eliminates ultraviolet frequencies.
The limitations of standard antidepressants, frequent treatment resistance, and the paradigm shift in psychiatry away from specific neurotransmitter focus and toward an integrative neural network perspective has prompted the development of novel depression treatment approaches, such as neurostimulation therapy. Neurostimulation therapies include a range of techniques that deliver electrical or magnetic stimulation to specific brain region targets for the treatment of refractory psychiatric and pain conditions. Neurostimulation efficacy in neurologic disorders led to their introduction in psychiatry. In addition to electroconvulsive therapy (ECT), several others are now FDA-approved for use in MDD and related disorders.
The dorsolateral prefrontal cortex is a common brain stimulation target in patients with MDD. Its normal regulatory function of control over stress and emotion reactivity is thought to be hypoactive in MDD. The dorsolateral prefrontal cortex and rostral anterior cingulate cortex areas are closely inter-connected; decreased activity in these frontal areas accounts for apathy, psychomotor slowness, and impaired executive functioning common in patients with MDD [17,18,19].
ECT remains established as a potent and rapidly acting treatment for severe or refractory MDD and is considered unrivaled among standard options for rapidly inducing antidepressant effects. ECT is effective as acute treatment, but multiple treatments are required and many who respond experience symptoms again within six months [20]. ECT generates electrical stimuli for seizure induction through electrodes applied to the scalp, with the patient under general anesthesia and pre-medicated with a muscle relaxant. Clinical outcomes are highly influenced by electrode placements, electrical intensity, and pulse width [21]. Seizure-induced changes in neurotransmitter activity, neuroplasticity, and functional connectivity account for its effects. ECT also increases brain-derived neurotrophic factor, which may promote neuroplasticity and contribute to the antidepressant effect [21,22].
As first-line treatment, ECT is used for severe melancholic, catatonic, psychotic, or refractory depression and for patients who refuse to eat or drink, have very high suicide risk or severe distress, pregnant women with severe depression, or who have a previous positive ECT response [20,23,24]. A large study reported 95% remission in study completers [25].
Full ECT response requires at least four to six sessions delivered two to three times per week. Twice weekly ECT requires longer treatment duration, but more than three treatments per week is not recommended due to the greater cognitive side effect risk [21]. Relapse rates are greatest in the first six months post-ECT (37.7%). Even patients with maintenance ECT show high relapse rates at one year (51.1%) [26]. Severity of treatment resistance predicts poor ECT response [27,28].
Headaches (45%), muscle soreness (20%), and nausea (1% to 25%) during ECT are transient and treated symptomatically; 7% of patients with MDD switch into a manic or mixed state [21]. Cognitive impairment includes transient post-ECT disorientation, retrograde amnesia (i.e., difficulty recalling information learned pre-ECT), and anterograde amnesia (i.e., difficulty retaining information learned post-ECT). Mild, short-term memory and cognitive impairments are common during, and just after, ECT [24]. Within two to four weeks, impaired anterograde memory usually returns to normal or may improve from pre-ECT levels [29]. Retrograde impairment can persist for prolonged periods [30]. Most distressing to some patients is loss of autobiographic memory recall, infrequently reported to persist beyond six months [24]. ECT lacks absolute contraindication, but increased safety risk is associated with space-occupying cerebral lesion, increased intracranial pressure, recent cerebral hemorrhage, or aneurysm [21,22].
Vagus nerve stimulation uses an implantable device to provide intermittent stimulation to the left vagus nerve (80% afferent to the central nervous system) [2]. It received FDA approval for treatment-resistant depression in 2005 due to the lack of approved drug treatments and concerns over the long-term efficacy and safety of ECT [31].
Controlled studies with follow-up six months or longer have found significant improvements in depressive symptoms that were often sustained over time, with relapse rates relatively low [32]. Long-term vagus nerve stimulation can lead to significant side effects, including decreases in airway flow and respiratory effort and laryngopharyngeal dysfunction [33]. Given the profound negative impact of treatment-resistant depression and lack of durable response in some patients, vagus nerve stimulation may be a useful option [34]. In a 2017 trial, patients with treatment-resistant MDD and four or more failed depression treatments (including ECT) received vagus nerve stimulation or treatment as usual and were followed five years. Response was a ≥50% decrease in MADRS score at any follow-up visit. Subjects who received vagus nerve stimulation (compared with usual treatment) had more severe treatment-resistant depression on several dimensions [35]. Vagus nerve stimulation led to greater five-year cumulative response (67.6%) and remission (43.3%) rates compared with usual treatment (40.9% and 25.7%, respectively). However, vagus nerve stimulation response often required 12 or more months to appear [35]. Guidelines recommend against the use of vagus nerve stimulation outside a research setting [23].
With deep brain stimulation, an electrode is surgically implanted to stimulate the subgenual cingulate gyrus with high-frequency impulses to reduce depressive symptoms [2]. Deep brain stimulation is invasive and carries the risk of infection, hemorrhage, and other surgical complications. Stimulation-induced adverse effects such as facial contractions, facial paresthesias, olfactory phenomena, anxiety, and mood fluctuations have been reported, particularly at higher levels of stimulation [36].
Most clinical improvement shows delayed onset; one trial in patients with treatment-resistant depression reported remission rates of 27%, 24%, and 37% at three-month, six-month, and two-year follow-up, respectively [37]. Deep brain stimulation can increase the risk of suicide ideation, attempts, and death, strongly indicating that patients should be pre-screened for suicide risk and monitored closely for suicidal behavior pre- and postoperatively [38]. Deep brain stimulation is investigational for treatment-resistant depression and is reserved for use in patients with severe refractory psychiatric, neurologic, or chronic pain conditions [21,36].
For patients who have demonstrated partial or no response to two or more adequate pharmacologic treatment trials, the U.S. Department of Defense/Veterans Affairs (DoD/VA) suggests offering repetitive transcranial magnetic stimulation for treatment.
(https://www.healthquality.va.gov/guidelines/MH/mdd/VADODMDDCPGFinal508.pdf Last Accessed: June 24, 2025)Strength of Recommendation: Weak for
Repetitive transcranial magnetic stimulation delivers high-intensity magnetic pulses to the cortex through a stimulating coil placed to the forehead [39,40]. It is a first-line MDD treatment in patients with one or more failed antidepressant trial [21]. Efficacy in treatment-resistant depression was established using stringent criteria; analysis of 23 trials found significantly greater efficacy and effect size for repetitive transcranial magnetic stimulation over sham [41]. In randomized clinical trials, 20 to 30 sessions over four or more weeks achieved 40% to 55% response and 25% to 35% remission rates [42].
The most frequent side effects are transient scalp pain (40%) and headache (30%). Both diminish with repeated treatment and respond to over-the-counter analgesics. The cognitive safety profile is benign. Seizures are the most serious side effect, but fewer than 25 cases have been reported worldwide [21,43]. Repetitive transcranial magnetic stimulation is contraindicated in patients with any metal or metallic hardware in the head (except the mouth), with a history of seizures, and who take medications that lower seizure threshold [21,44].
A sham-controlled trial randomized patients with MDD to escitalopram (20 mg/day) or prefrontal transcranial direct-current stimulation for 10 weeks. With mean decrease in HAM-D score from baseline, both treatment groups were superior to placebo, but transcranial direct-current stimulation was inferior to escitalopram. New-onset manic switch during transcranial direct-current stimulation therapy is a concerning adverse event; however, the number of reported cases is low [22,45,46].
Magnetic seizure therapy uses focused brain stimulation (generally of the right frontal area) to induce a focal seizure. It intends to produce the efficacy of ECT without the cognitive side effects by sparing the hippocampus from seizure activity [2]. A meta-analysis of 1,092 patients with treatment-resistant depression found response and remission rates for active vs. sham magnetic seizure therapy of 25% and 17%, versus 9% and 6%, respectively [47]. A 2016 meta-analysis found that while magnetic seizure therapy had a small short-term effect in improving depression compared with sham, follow-up studies did not demonstrate that the small effect would continue for longer periods [48]. A study of 23 patients with treatment-resistant depression found that 44.4% of the group experienced resolution of suicidal ideation following magnetic seizure therapy [49]. Magnetic seizure therapy add-on to SSRI treatment in treatment-resistant depression improves outcome, but more data are needed before it can be considered a first-line therapy for treatment-resistant depression [47,50].
Ketamine is anN-methyl-D-aspartate receptor (NMDA-R) antagonist that was approved for use as an anesthetic in 1970. Demonstration that a single IV dose in patients with treatment-resistant depression reliably produced rapid, robust antidepressant effects for one week was a breakthrough discovery for research and a turning point for patients for whom all other treatment approaches had failed [51]. The short-term efficacy of ketamine treatment of refractory MDD and bipolar depression is now established; over a dozen placebo-controlled trials have shown that patients with refractory MDD or bipolar depression have significantly greater response, remission, and depressive symptom reduction to single-dose IV ketamine than placebo from 40 minutes through days 10 to 12 post-treatment [52,53]. The approach has become standardized, using a sub-anesthetic dose: 0.5 mg/kg IV over a 40-minute infusion. In a 2015 analysis, ketamine was designated as one of two psychiatric treatments that had the highest potential impact on patient outcomes. This designation was based on the serious unmet need for fast-acting, well-tolerated antidepressants with efficacy in refractory MDD and bipolar depression [54].
The DoD/VA suggests ketamine or esketamine as augmentation for patients with major depressive disorder (MDD) who have not responded to several adequate pharmacologic trials.
(https://www.healthquality.va.gov/guidelines/MH/mdd/VADODMDDCPGFinal508.pdf Last Accessed: June 24, 2025)Strength of Recommendation: Weak for
Substantial interest and optimism among patients, families, patient advocacy groups, and clinicians has been generated by clinical reports of unique antidepressant effects with ketamine and frequent media coverage of potential ketamine treatment benefits. Demand for clinical access to ketamine treatment is rapidly escalating, and a growing number of clinics and practitioners are now offering various forms of ketamine treatment for mood and anxiety disorders throughout the United States [55]. However, many in the field suggest greater caution, and concerns that enthusiasm and desperation of patients and families may be leading to ketamine used in ways that are not yet supported by existing evidence. Others note the lack of large-scale or long-term studies of ketamine treatment in refractory MDD [55].
Use of IV ketamine for treatment-resistant depression is off-label, whereas an intranasal formulation (esketamine) is FDA-approved for treatment-resistant depression and for MDD with suicidality, when used in conjunction with an oral antidepressant [23,56]. A systematic review and meta-analysis of five randomized controlled trials found that twice-weekly dosing of esketamine as augmentation to ongoing oral antidepressant use compared with placebo improved depressive symptoms and remission in patients with MDD at up to 28 days follow-up [57].
Rapastinel is an investigational NMDA-R partial agonist with robust cognitive enhancement and rapid, long-lasting antidepressant effects. This drug comes as a pre-filled IV syringe, administered in less than one minute. After one injection, therapeutic effects appear within two hours and last up to seven days. Rapastinel is well-tolerated, and antidepressant effects last up to 10 weeks with repeat dosing. The drug has no psychotomimetic effects, may be neuroprotective, and may enhance aspects of learning and memory. The long-lasting therapeutic benefits are explained by significant effects on metaplasticity processes in the medial prefrontal cortex and hippocampus [58,59].
Opioids were widely used as depression treatment from roughly 1850 until 1956, when they were replaced by standard antidepressants. Their antidepressant potential has rarely been studied in the past 60 years, but this seems to be changing. The synthetic opioid buprenorphine is a partial mu opioid receptor agonist and kappa opioid receptor antagonist. It is safer in overdose with substantially less euphoria than traditional opioid analgesics such as morphine and oxycodone. A small, open-label study in 1995 hinted that buprenorphine might have benefit in refractory depression [60].
Buprenorphine/samidorphan combination (BUP/SAM) is an opioid system modulator being investigated as an adjunctive treatment for MDD. It is a fixed-dose combination of buprenorphine and samidorphan (a mu opioid receptor agonist). Samidorphan was added to address the abuse and dependence potential of buprenorphine [61]. A 2019 long-term open-label extension study examined the efficacy and adverse effects of adjunctive BUP/SAM [62]. All patients had confirmed MDD and a current MDE lasting 2 to 24 months. Patients were treated with an established antidepressant therapy for a minimum of 8 weeks before receiving sublingual BUP/SAM (2 mg/2 mg) for up to 52 weeks. Safety was assessed via reported adverse events, the Columbia-Suicide Severity Rating Scale, and the Clinical Opiate Withdrawal Scale. Evaluation of efficacy was achieved using MADRS. Of 1,485 patients, 50% completed the study; 11% withdrew due to adverse events (e.g., nausea, headache, constipation, dizziness, somnolence). Drug withdrawal adverse events were infrequent, and euphoria-related adverse events were uncommon. There was no evidence of increased suicidal ideation or behavior. Improvements in MADRS scores were maintained until the end of the study, suggesting durability of antidepressant effect. BUP/SAM was generally well tolerated, with a low risk of abuse [62].
The cyclooxygenase-2 inhibitor celecoxib has demonstrated significant reductions in depressive symptoms compared to placebo as an SSRI add-on in MDD treatment. The decrease in depressive symptoms begins after the first week. However, celecoxib and all other nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with risk of serious cardiovascular events [63].
Two studies compared statins to placebo as add-on therapy to fluoxetine in the treatment of MDD. In one trial, 30 mg/day lovastatin for six weeks improved antidepressant effects compared to placebo [64]. The other trial found simvastatin 20 mg/day for six weeks significantly decreased depressive symptoms, but remission did not differ from placebo [65].
Statins have relatively few side effects; the most dangerous—rhabdomyolysis—is a very rare event. Statins are primarily used in prevention of cardiovascular events but may have a more favorable benefit/risk balance than other drugs, such as NSAIDs, considering the high cardiovascular comorbidity in persons with depression [66]. Other less common side effects include myopathy, hepatotoxicity, peripheral neuropathy, impaired myocardial contractility, and autoimmune dysfunction.
Silexan is a substance derived from Lavandula angustifolia flowers that increases extracellular serotonin levels. Approved in Germany for the treatment of restlessness related to anxious mood, its antidepressant effects were tested in a randomized controlled trial of 318 patients with mixed anxiety and depressive disorder. Silexan (vs. placebo) significantly reduced MADRS and Hamilton Rating Scale for Anxiety (HAM-A) scores. Antidepressant effects were noted after 2 weeks, became statistically significant at 4 weeks, and remained significant through the 10-week trial [63,67].
Psilocybin is a classical psychedelic and naturally occurring alkaloid found in the Psilocybe genus of mushrooms [68]. Its potential efficacy in the treatment of depression is a recent focus of research interest.
The feasibility, safety, and efficacy of open-label psilocybin were studied in 12 patients with treatment-resistant depression (2 to 13 failed antidepressant trials). All patients received 10-mg (low-dose) oral psilocybin, 25-mg (high-dose) psilocybin one week later, and psychologic support during all sessions. Relative to baseline, depressive symptoms were markedly reduced one week and three months after high-dose treatment. Remission was achieved by 67% at one week and 42% at three months. Marked and sustained improvements in anxiety and anhedonia were also noted. Psilocybin was well tolerated by all patients, without serious or unexpected adverse events [68].
Two psilocybin treatment studies in patients with life-threatening cancer and high levels of depressive and anxious distress were published in 2016. One trial compared low-dose psilocybin (0.3 mg/kg) with niacin placebo, and the other trial compared low-dose (1 or 3 mg/70 kg) and high-dose (22 or 30 mg/70 kg) psilocybin [69,70]. Patients in all sessions were accompanied by trained therapy support. Both studies reported significant improvements in depression and anxiety scores, measures of spiritual well-being, emotional distress related to the cancer, and quality of life. Immediate post-treatment gains were sustained for six-month study durations by 60% to 80% of subjects. These studies confirmed psilocybin could be given safely without significant adverse effects in a controlled environment with trained therapists [69,70].
Management of treatment-resistant depression requires a comprehensive treatment plan addressing the complex behavioral and emotional needs of the patient. Emphasis is placed on individualized, trauma-informed care that promotes stability, emotional regulation, and improved interpersonal relationships. Through a combination of therapeutic interventions—including individual and group therapy, skill development, family involvement, and ongoing assessment—the treatment approach aims to foster resilience, personal growth, and long-term success. Collaboration among care providers, consistent structure, and adaptive strategies remain central to achieving the desired therapeutic outcomes.
2. Trangle M, Gursky TM, Haight R, et al. Institute for Clinical Systems Improvement. Adult Depression in Primary Care. 17th ed. Available at https://www.hpsj.com/wp-content/uploads/2022/02/ICSI-Adult-Depression-in-Primary-Care-2016.pdf. Last accessed June 1, 2025.
3. CareFirst Blue Cross Blue Shield. Clinical Practice Guidelines for Depression in Adults in the Primary Care Setting. Available at https://provider.carefirst.com/carefirst-resources/provider/pdf/depression-guidelines-bok0023.pdf. Last accessed June 1, 2025.
4. Ménard C, Hodes GE, Russo SJ. Pathogenesis of depression: insights from human and rodent studies. Neuroscience. 2016;321:138-162.
5. Mathews DC, Henter ID, Zarate CA. Targeting the glutamatergic system to treat major depressive disorder: rationale and progress to date. Drugs. 2012;72(10):1313-1333.
6. Kaster MP, Moretti M, Cunha MP, Rodrigues AL. Novel approaches for the management of depressive disorders. Eur J Pharmacol. 2016;771:236-240.
7. DeWilde KE, Levitch CF, Murrough JW, Mathew SJ, Iosifescu DV. The promise of ketamine for treatment-resistant depression: current evidence and future directions. Ann N Y Acad Sci. 2015;1345:47-58.
8. Kennedy SH, Lam RW, McIntyre RS, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3. pharmacological treatments. Can J Psychiatry. 2016;61(9):540-560.
9. McIntyre RS, Filteau MJ, Martin L, et al. Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach. J Affect Disord. 2014;156:1-7.
10. Golden RN, Gaynes BN, Ekstrom RD, et al. The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence. Am J Psychiatry. 2005;162(4):656-662.
11. Leppämäki SJ, Partonen TT, Hurme J, Haukka JK, Lönnqvist JK. Randomized trial of the efficacy of bright-light exposure and aerobic exercise on depressive symptoms and serum lipids. J Clin Psychiatry. 2002;63(4):316-321.
12. Jorm AF, Christensen H, Griffiths KM, Rodgers B. Effectiveness of complementary and self-help treatments for depression. Med J Aust. 2002;176(10 Suppl):S84-S95.
13. Prasko J, Horacek J, Klaschka J, Kosova J, Ondrackova I, Sipek J. Bright light therapy and/or imipramine for inpatients with recurrent non-seasonal depression. Neuro Endocrinol Lett. 2002;23(2):109-113.
14. Swanson LM, Burgess HJ, Zollars J, Arnedt JT. An open-label pilot study of a home wearable light therapy device for postpartum depression. Arch Womens Ment Health. 2018;21(5):583-586.
15. Benedetti F, Colombo C, Pontiggia A, Bernasconi A, Florita M, Smeraldi E. Morning light treatment hastens the antidepressant effect of citalopram: a placebo-controlled trial. J Clin Psychiatry. 2003;64(6):648-653.
16. Even C, Schröder CM, Friedman S, Rouillon F. Efficacy of light therapy in nonseasonal depression: a systematic review. J Affect Disord. 2008;108(1-2):11-23.
17. Baeken C, De Raedt R, Bossuyt A, et al. The impact of HF-rTMS treatment on serotonin(2A) receptors in unipolar melancholic depression. Brain Stimul. 2011;4(2):104-111.
18. Mayberg HS. Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment. Br Med Bull. 2003;65:193-207.
19. Davidson RJ, Pizzagalli D, Nitschke JB, Putnam K. Depression: perspectives from affective neuroscience. Annu Rev Psychol. 2002;53:545-574.
20. errin JS, Merz S, Bennett DM, et al. Electroconvulsive therapy reduces frontal cortical connectivity in severe depressive disorder. Proc Natl Acad Sci U S A. 2012;109(14):5464-5468.
21. Milev RV, Giacobbe P, Kennedy SH, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4. neurostimulation treatments. Can J Psychiatry. 2016;61(9):561-575.
22. Brunoni AR, Boggio PS, De Raedt R, et al. Cognitive control therapy and transcranial direct current stimulation for depression: a randomized, double-blinded, controlled trial. J Affect Disord. 2014;162:43-49.
23. U.S. Department of Veterans Affairs. VA/DoD Clinical Practice Guidelines: Management of Major Depressive Disorder (MDD). Available at https://www.healthquality.va.gov/guidelines/MH/mdd. Last accessed June 1, 2025.
24. Malhi GS, Bassett D, Boyce P, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry. 2015;49(12):1087-1206.
25. Petrides G, Fink M, Husain MM, et al. ECT remission rates in psychotic versus nonpsychotic depressed patients: a report from CORE. ECT remission rates in psychotic versus nonpsychotic depressed patients: a report from CORE. J ECT. 2001;17(4):244-253.
26. Jelovac A, Kolshus E, McLoughlin DM. Relapse following successful electroconvulsive therapy for major depression: a meta-analysis. Neuropsychopharmacology. 2013;38(12):2467-2474.
27. Heijnen WT, Birkenhäger TK, Wierdsma AI, van den Broek WW. Antidepressant pharmacotherapy failure and response to subsequent electroconvulsive therapy: a meta-analysis. J Clin Psychopharmacol. 2010;30(5):616-619.
28. Haq AU, Sitzmann AF, Goldman ML, Maixner DF, Mickey BJ. Response of depression to electroconvulsive therapy: a meta-analysis of clinical predictors. J Clin Psychiatry. 2015;76(10):1374-1384.
29. Semkovska M, McLoughlin DM. Objective cognitive performance associated with electroconvulsive therapy for depression: a systematic review and meta-analysis. Biol Psychiatry. 2010;68(6):568-577.
30. Sackeim HA, Prudic J, Fuller R, Keilp J, Lavori PW, Olfson M. The cognitive effects of electroconvulsive therapy in community settings. Neuropsychopharmacology. 2007;32(1):244-254.
31. Nemeroff CB, Mayberg HS, Krahl SE, et al. VNS therapy in treatment-resistant depression: clinical evidence and putative neurobiological mechanisms. Neuropsychopharmacology. 2006;31(7):1345-1355.
32. Nahas Z, Teneback C, Chae JH, et al. Serial vagus nerve stimulation functional MRI in treatment-resistant depression. Neuropsychopharmacology. 2007;32(8):1649-1660.
33. Hatton KW, McLarney JT, Pittman T, Fahy BG. Vagal nerve stimulation: overview and implications for anesthesiologists. Anesth Analg. 2006;103(5):1241-1249.
34. Rush AJ, Siefert SE. Clinical issues in considering vagus nerve stimulation for treatment-resistant depression. Exp Neurol. 2009;219(1):36-43.
35. Aaronson ST, Sears P, Ruvuna F, et al. A 5-year observational study of patients with treatment-resistant depression treated with vagus nerve stimulation or treatment as usual: comparison of response, remission, and suicidality. Am J Psychiatry. 2017;174(7):640-648.
36. Rabins P, Appleby BS, Brandt J, et al. Scientific and ethical issues related to deep brain stimulation for disorders of mood, behavior, and thought. Arch Gen Psychiatry. 2009;66(9):931-937.
37. Malone DA Jr, Dougherty DD, Rezai AR, et al. Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry. 2009;65(4):267-275.
38. Appleby BS, Duggan PS, Regenberg A, Rabins PV. Psychiatric and neuropsychiatric adverse events associated with deep brain stimulation: a meta-analysis of ten years' experience. Mov Disord. 2007;22(12):1722-1728.
39. Wassermann EM, Lisanby SH. Therapeutic application of repetitive transcranial magnetic stimulation: a review. Clin Neurophysiol. 2001;112(8):1367-1377.
40. Schutter DJLG, van Honk J. A framework for targeting alternative brain regions with repetitive transcranial magnetic stimulation in the treatment of depression. J Psychiatry Neurosci. 2005;30(2):91-97.
41. Health Quality Ontario. Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression. Available at https://www.hqontario.ca/Evidence-to-Improve-Care/Health-Technology-Assessment/Reviews-And-Recommendations/Repetitive-Transcranial-Magnetic-Stimulation-for-Treatment-Resistant-Depression. Last accessed June 1, 2025.
42. Carpenter LL, Janicak PG, Aaronson ST, et al. Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice. Depress Anxiety. 2012;29(7):587-596.
43. Serafini G, Pompili M, Belvederi Murri M, et al. The effects of repetitive transcranial magnetic stimulation on cognitive performance in treatment-resistant depression: a systematic review. Neuropsychobiology. 2015;71(3):125-139.
44. Klein MM, Treister R, Raij T, et al. Transcranial magnetic stimulation of the brain: guidelines for pain treatment research. Pain. 2015;156(9):1601-1614.
45. Dondé C, Neufeld NH, Geoffroy PA. The impact of transcranial direct current stimulation (tDCS) on bipolar depression, mania, and euthymia: a systematic review of preliminary data. Psychiatr Q. 2018;89(4):855-867.
46. Sampaio B Jr, Tortella G, Borrione L. et al. Efficacy and safety of transcranial direct current stimulation as an add-on treatment for bipolar depression: a randomized clinical trial. JAMA Psychiatry. 2018;75(2):158-166.
47. Lam RW, Chan P, Wilkins-Ho M, Yatham LN. Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and meta-analysis. Can J Psychiatry. 2008;53(9):621-631.
48. Health Quality Ontario. Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and meta-analysis of randomized controlled trials. Ont Health Technol Assess Ser. 2016;16(5):1-66.
49. Sun Y, Blumberger DM, Mulsant BH, et al. Magnetic seizure therapy reduces suicidal ideation and produces neuroplasticity in treatment-resistant depression. Transl Psychiatry. 2018;8(1):253.
50. Bretlau LG, Lunde M, Lindberg L, Undén M, Dissing S, Bech P. Repetitive transcranial magnetic stimulation (rTMS) in combination with escitalopram in patients with treatment-resistant major depression: a double-blind, randomised, sham-controlled trial. Pharmacopsychiatry. 2008;41(2):41-47.
51. Garay RP, Zarate CA Jr, Charpeaud T, et al. Investigational drugs in recent clinical trials for treatment-resistant depression. Expert Rev Neurother. 2017;17(6):593-609.
52. Jaso BA, Niciu MJ, Iadarola ND, et al. Therapeutic modulation of glutamate receptors in major depressive disorder. Curr Neuropharmacol. 2017;15(1):57-70.
53. Kishimoto T, Chawla JM, Hagi K, et al. Single-dose infusion ketamine and non-ketamine N-methyl-D-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med. 2016;46(7):1459-1472.
54. Agency for Healthcare Research and Quality. Healthcare Horizon Scanning System Potential High-Impact Interventions: Priority Area 05: Depression and Other Mental Health Disorders. Rockville, MD: Agency for Healthcare Research and Quality; 2015.
55. Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 2017;74(4):399-405.
56. LexiDrug. Available at https://online.lexi.com. Last accessed June 1, 2025.
57. Papakostas GI, Salloum NC, Hock RS, et al. Efficacy of esketamine augmentation in major depressive disorder: a meta-analysis. J Clin Psychiatry. 2020;81(4):19r12889.
58. Moskal JR. Glutamatergic-based rapid acting antidepressants: the link to synaptic plasticity. Curr Neuropharmacol. 2017;15(1):2.
59. Burgdorf J, Zhang XL, Weiss C, et al. The long-lasting antidepressant effects of rapastinel (GLYX-13) are associated with a metaplasticity process in the medial prefrontal cortex and hippocampus. Neuroscience. 2015;308:202-211.
60. Bodkin JA, Zornberg GL, Lukas SE, Cole JO. Buprenorphine treatment of refractory depression. J Clin Psychopharmacol. 1995;15(1): 49-57.
61. Pathak S, Vince B, Kelsh DK, et al. Abuse potential of buprenorphine/samidorphan combination compared to buprenorphine and placebo: a phase 1 randomized controlled trial. J Clin Pharmacol. 2019;59(2):206-217.
62. Thase ME, Stanford AD, Memisoglu A, et al. Results from a long-term open-label extension study of adjunctive buprenorphine/samidorphan combination in patients with major depressive disorder. Neuropsychopharmacology. 2019;44(13):2268-2276.
63. Henter ID, de Sousa RT, Gold PW, Brunoni AR, Zarate CA Jr, Machado-Vieira M. Mood therapeutics: novel pharmacological approaches for treating depression. Expert Rev Clin Pharmacol. 2017;10(2):153-166.
64. Ghanizadeh A, Hedayati A. Augmentation of fluoxetine with lovastatin for treating major depressive disorder, a randomized double-blind placebo controlled-clinical trial. Depress Anxiety. 2013;30(11):1084-1088.
65. Gougol A, Zareh-Mohammadi N, Raheb S, et al. Simvastatin as an adjuvant therapy to fluoxetine in patients with moderate to severe major depression: a double-blind placebo-controlled trial. J Psychopharmacol. 2015;29(5):575-581.
66. Schjerning Olsen AM, Fosbøl EL, Lindhardsen J, et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation. 2011;123(20):2226-2235.
67. Nemeroff CB, Heim CM, Thase ME, et al. Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma. Proc Natl Acad Sci U S A. 2003;100(24):14293-14296.
68. Carhart-Harris RL, Bolstridge M, Rucker J, et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 2016;3(7):619-627.
69. Ross S, Bossis A, Guss J, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016;30(12):1165-1180.
70. Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J Psychopharmacol. 2016;30(12):1181-1197.
71. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.
72. Nelson JC, Mazure CM, Bowers MB Jr, Jatlow PI. A preliminary, open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Arch Gen Psychiatry. 1991;48(4):303-307.
73. Preskorn SH, Beber JH, Faul JC, Hirschfeld R. Serious adverse effects of combining fluoxetine and tricyclic antidepressants. Am J Psychiatry. 1990;147(4):532.
1. U.S. Department of Defense/Veterans Affairs. The Management of Major Depressive Disorder. Washington, DC: U.S. Government Printing Office; 2022. Available at https://www.healthquality.va.gov/guidelines/MH/mdd/VADODMDDCPGFinal508.pdf. Last accessed June 24, 2025.
Mention of commercial products does not indicate endorsement.