Introduction
Major depressive disorder (MDD) is a serious and often chronic disease with a lifetime prevalence estimate ranging between 2% and 21% worldwide.Reference Gutiérrez-Rojas, Porras-Segovia, Dunne, Andrade-González and Cervilla 1 The lifetime prevalence for Canadians is estimated to be 11.3%.Reference Patten, Williams, Lavorato, Wang, McDonald and Bulloch 2 For people with moderate-to-severe MDD, pharmacotherapy is a recommended first-line treatment.Reference Kennedy, Lam and McIntyre 3 –Reference Lam, Kennedy and Adams 5 Despite this, reports from meta-analyses indicate that only 38%–49% of patients with moderate-to-severe MDD who received either a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), or a tricyclic class of agent for MDD in clinical trials achieved remission in clinical trials.Reference Thase, Haight and Richard 6 , Reference Machado, Iskedjian, Ruiz and Einarson 7 The proportion of patients achieving remission in clinical practice is likely lower.Reference Moller 8 Findings from a meta-analysis focused on the recognition of MDD by physicians other than psychiatrists suggest that fewer than half of individuals meeting criteria are identifiedReference Cepoiu, McCusker, Cole, Sewitch, Belzile and Ciampi 9 and, among individuals who received healthcare interventions for a depressive disorder, only 41% received minimally adequate treatment (defined as ≥2 months of pharmacotherapy with ≥4 physician visits or ≥8 psychotherapy sessions within 12 months).Reference Kasteenpohja, Marttunen, Aalto-Setälä, Perälä, Saarni and Suvisaari 10 While we recognize the strong support for evidence-based psychotherapies for the treatment of mild-to-moderate MDD, 4 , Reference Lam, Kennedy and Adams 5 the focus of this review is on optimal pharmacotherapy use.
In the management of chronic diseases, such as hypertension or diabetes, rapidly treating to defined therapeutic targets, sometimes using multiple medications, is a common strategy. 11 , 12 However, when individuals present with symptoms of an episode of MDD (MDE), the traditional approach of “watchful waiting” may be what clinicians do, along with a “start low and go slow” strategy during treatment management.Reference Meredith, Cheng, Hickey and Dwight-Johnson 13 , Reference Schaffer, McIntosh and Goldstein 14 Used more broadly, these approaches can unfortunately contribute to poor outcomes.Reference Habert, Katzman and Oluboka 15 Failure to rapidly address an MDE with a sense of urgency can worsen underlying pathophysiology, increasing symptom severity and reducing the likelihood of treatment success.Reference Oluboka, Katzman and Habert 16 –Reference Ghio, Gotelli, Marcenaro, Amore and Natta 20 In contrast to a “slow and sequential” approach to MDD treatment, early optimized treatment (EOT) requires a measurement-based approach to early diagnosis and assessment of symptom severity, rapid treatment initiation and dose optimization, frequent monitoring, and prompt adjustments to a comprehensive treatment plan (Figure 1 ). Reference Habert, Katzman and Oluboka 15 , Reference Oluboka, Katzman and Habert 16 With an “urgency-to-treat” (UTT) mindset based on an awareness of the risks of delayed treatment, EOT provides a better opportunity for a full, functional recovery (Supplementary Figure S1). Reference Habert, Katzman and Oluboka 15 , Reference Oluboka, Katzman and Habert 16
Early optimized treatment and urgency to treat for MDD: how to implement in clinical practice. aEarly diagnosis followed by rapid, optimal treatment. MDD, major depressive disorder.
The use of measurement-based care (MBC), with initial and repeated assessments using validated scales,Reference Kroenke and Spitzer 21 provides a proxy for diagnosis of MDD and indicates changes during ongoing management.Reference Hong, Murphy and Michalak 22 Regular follow-up appointments (eg, at 2-week intervals) are critical in monitoring clinical status, optimizing medication dosage, and guiding treatment to symptom remission.Reference Kennedy, Lam and McIntyre 3 , Reference Lam, Kennedy and Adams 5 Treatment decisions should be implemented using an integrative process, combining clinical experience in conjunction with guideline-based recommendations, such as those in the Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults.Reference Lam, Kennedy and Adams 5 , Reference McIntyre, Lee and Mansur 23 –Reference Lam, Parikh, Michalak, Dewa and Kennedy 25 Approaching the treatment of an MDE with the mindset of UTT and employing these principles of EOT has been highlighted previously.Reference Habert, Katzman and Oluboka 15 , Reference Oluboka, Katzman and Habert 16 Nonetheless, many healthcare practitioners (HCPs) are not cognizant of the need for urgent treatment of depressive symptoms or encounter other barriers to implementing an EOT approach to treating people with MDD.Reference Nutting, Rost and Dickinson 26 In this review, we highlight the consequences of failing to treat MDD early and urgently, and then consider a range of potential barriers to UTT and EOT in primary care settings and outline how HCPs can navigate these obstacles.
Consequences of delaying optimal treatment for patients with MDD
Failing to effectively treat an MDE prolongs suffering and can result in demoralization, learned helplessness, and feelings of isolation and loneliness. 27 Longer durations of MDEs may worsen the trajectory of MDD, 27 making subsequent episodes more difficult to treat, reducing the chances of achieving remission.Reference Habert, Katzman and Oluboka 15 , Reference Ghio, Gotelli, Marcenaro, Amore and Natta 20 , Reference Hjerrild and Videbech 28 Individuals enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study who required a greater number of treatment steps (thereby needing more time to achieve remission), had, on average, poorer functional outcomes.Reference Trivedi, Morris and Wisniewski 29 Romera and colleagues found that individuals who were switched to an effective treatment after even 8 weeks of ineffective treatment were less likely to return to their baseline level of functioning compared with those who were switched after 4 weeks.Reference Romera, Perez and Menchon 30
End-organ damage
The adage “time is brain” is often applied to the treatment of stroke,Reference von Kummer 31 but it is an equally meaningful principle in the treatment of MDD. Untreated MDD is associated with negative effects in multiple brain areas/structures, particularly within the hippocampusReference Nolan, Roman and Nasa 32 , Reference Zheng, Zhang, Yang, Han and Cheng 33 (Table 1). Compared with healthy individuals, people with MDD are more likely to have reduced gray matter volume,Reference Nolan, Roman and Nasa 32 –Reference Schmaal, Hibar and Samann 36 lower serum levels of nerve growth factor,Reference Chen, Lin, Tu, Cheng, Wu and Tseng 37 and reduced serum brain-derived neurotrophic factor,Reference Tiwari, Qi, Wong and Han 38 a key molecule involved in neurogenesis, neuroplasticity, and synaptogenesis.Reference Colucci-D’Amato, Speranza and Volpicelli 39 , Reference Yang, Nie and Shu 40 There is evidence that these effects may increase with duration or chronicity of MDDReference Schmaal, Veltman and van Erp 35 , Reference Videbech and Ravnkilde 41 –Reference Yucel, McKinnon and Chahal 43 and that they are mitigated by pharmacologic and nonpharmacologic treatment of MDD symptomsReference Nolan, Roman and Nasa 32 , Reference Wilkinson, Sanacora and Bloch 44 –Reference Çakici, Sutterland, Penninx, de Haan and van Beveren 47 (Table 1), suggesting that early and rapid treatment may slow or reverse brain changes associated with MDD.
Associations Between Major Depressive Disorder and Brain Structure, Neurotrophins, and Proinflammatory MarkersReference Nolan, Roman and Nasa 32 , Reference Zheng, Zhang, Yang, Han and Cheng 33 , Reference Schmaal, Veltman and van Erp 35 –Reference Tiwari, Qi, Wong and Han 38 , Reference Wilkinson, Sanacora and Bloch 44 -Reference Çakici, Sutterland, Penninx, de Haan and van Beveren 47 , Reference Enache, Pariante and Mondelli 58 –Reference Osimo, Baxter, Lewis, Jones and Khandaker 61
Note. Meta-analytic results are shown in bold.
BDNF, brain-derived neurotrophic factor; CRP, C-reactive protein; CSF, cerebrospinal fluid; DOI, duration of illness; IL, interleukin; NGF, nerve growth factor; TNFα, tumor necrosis factor alpha.
a Pharmacologic or electroconvulsive therapy.
Just as poorly controlled diabetes can damage the heart, kidneys, eyes, and other organs,Reference Cole and Florez 48 , Reference Al-Rubeaan, Al Derwish and Ouizi 49 inadequately treated MDD can cause damage throughout the body. In a systematic review, Arnaud et al. presented evidence that MDD is associated with an increased risk of developing a range of cardiovascular, metabolic, autoimmune, and respiratory conditions, as well as worsening preexisting comorbiditiesReference Arnaud, Brister and Duckworth 50 (Figure 2; Supplementary Table S1). Depression is associated with an increased risk of developing or experiencing cardiac arrest, hypertension, myocardial infarction, heart disease, and stroke, and it may worsen the course of preexisting heart failure, myocardial infarction, and stroke.Reference Arnaud, Brister and Duckworth 50 Depression is also linked to increased risk for or worsening of metabolic conditions (diabetes, obesity, and hyperlipidemia), as well as a range of other conditions including Crohn’s disease, multiple sclerosis, arthritis, asthma, bronchitis, and dementia.Reference Arnaud, Brister and Duckworth 50 However, just as effective treatment of MDD can mitigate its effects on the brain, effective treatment of MDD also may improve outcomes for comorbidities including heart artery disease and myocardial infarction, multiple sclerosis, Alzheimer disease, Parkinson disease, chronic pain, and chronic lung diseaseReference Arnaud, Brister and Duckworth 51 (Figure 2; Supplementary Table S1).
Effects of untreated MDD and of treatment of MDD on brain structure and comorbid conditions. Effects of untreated MDD on somatic conditions are based on Arnaud et al.Reference Arnaud, Brister and Duckworth 50; effects of the treatment of MDD on somatic conditions are based on Arnaud et al.Reference Arnaud, Brister and Duckworth 51 Sources for specific effects on brain structureReference Nolan, Roman and Nasa 32 , Reference Zheng, Zhang, Yang, Han and Cheng 33 , Reference Schmaal, Veltman and van Erp 35 –Reference Tiwari, Qi, Wong and Han 38 , Reference Wilkinson, Sanacora and Bloch 44 –Reference Çakici, Sutterland, Penninx, de Haan and van Beveren 47 , Reference Enache, Pariante and Mondelli 58 –Reference Osimo, Baxter, Lewis, Jones and Khandaker 61 are given in Table 1. BDNF, brain-derived neurotrophic factor; CAD, coronary artery disease; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; DM, diabetes mellitus; GI, gastrointestinal; HF, heart failure; IHD, ischemic heart disease; MI, myocardial infarction; MS, multiple sclerosis.
Inflammation is thought to be an important indirect link between MDD and chronic medical illnesses. For example, findings from numerous studies indicate that an increased risk for coronary heart disease in people with MDDReference Charlson, Moran and Freedman 52 , Reference Goldstein, Carnethon and Matthews 53 may be mediated, at least in part, by proinflammatory pathways.Reference Dhar and Barton 54 , Reference Halaris 55 Circulating inflammatory marker levels are a predictor of coronary heart disease,Reference Danesh, Wheeler and Hirschfield 56 , Reference Kaptoge, Seshasai and Gao 57 and inflammatory cytokine levels are significantly elevated in some people with depression compared with healthy controlsReference Çakici, Sutterland, Penninx, de Haan and van Beveren 47 , Reference Enache, Pariante and Mondelli 58 –Reference Osimo, Baxter, Lewis, Jones and Khandaker 61 (Table 1). Neuroinflammation is positively associated with severity and duration of depression.Reference Setiawan, Wilson and Mizrahi 62 , Reference Setiawan, Attwells and Wilson 63 Conversely, treatment of MDD is associated with a significant decrease in proinflammatory marker levelsReference Çakici, Sutterland, Penninx, de Haan and van Beveren 47 , Reference Köhler, Freitas and Stubbs 60 (Table 1). MDD treatment also significantly reduces neuroinflammation, with larger decreases observed during longer durations of treatment.Reference Setiawan, Attwells and Wilson 63 While a direct causal link has not been demonstrated, the positive effects of antidepressant treatment on inflammatory pathways may underlie, or contribute to, improved comorbidity outcomesReference Arnaud, Brister and Duckworth 51 in patients with MDD.
Addressing barriers to UTT and EOT for MDD with practical solutions
Barriers to optimal treatment of MDD can occur at every step of a person’s journey.Reference Nutting, Rost and Dickinson 26 Initial barriers include the continuing shortage of primary care providers in Canada and the United States,Reference Kardas, Lewek and Matyjaszczyk 64 – 67 and individuals’ hesitance to seek treatment even among those with access to services. Barriers to implementation of EOT that HCPs may face in their own practice are summarized in Supplementary Table S2, along with potential strategies for navigating those obstacles. Implementation of the UTT plus EOT approach to treating MDD is illustrated for a hypothetical individual in the Case Scenario (Table 2).
Possible Case Scenario
a PHQ.
b Anxious Distress Specifier Interview, DSM-5-TR.
ADHD, attention-deficit/hyperactivity disorder; ASRS, Adult Self-Report Scale for ADHD; AUDIT, Alcohol Use Disorders Identification Test; DSM-5-TR, Diagnostic and Statistical Manual of Mental Disorders, 5th edition–Text Revision; GAD-7, Generalized Anxiety Disorder 7-Item; MDQ, Mood Disorder Questionnaire; MDD, major depressive disorder; PHQ-9, 9-Item Patient Health Questionnaire; SDS, Sheehan Disability Scale; SNRI, serotonin norepinephrine reuptake inhibitor.
Screening and diagnosis
There are numerous reasons why individuals may not seek treatment for depressive symptoms or may avoid reporting their symptoms.Reference Nutting, Rost and Dickinson 26 Some people are simply unaware that their symptoms are related to MDD. People often emphasize somatic complaints—lethargy, loss of interest, or difficulty sleeping—rather than depressed mood or anhedonia, making it even more difficult for HCPs to ascribe those symptoms to an MDE.Reference Kardas, Lewek and Matyjaszczyk 64 , Reference Goldman, Nielsen and Champion 68 –Reference Stolzenburg, Freitag, Evans-Lacko, Speerforck, Schmidt and Schomerus 71 While the stigma associated with MDD may be declining,Reference Henderson, Robinson and Evans-Lacko 72 , Reference Gronholm, Henderson, Deb and Thornicroft 73 individuals may still experience embarrassment and shame, and be fearful of potential impacts of a diagnosis on their careers. 27 , Reference Wang, Fitzke, Tran, Grell and Pedersen 74 , Reference Coleman, Stevelink, Hatch, Denny and Greenberg 75
Fewer than half of individuals with MDD seen by a physician are recognized as having an MDE.Reference Cepoiu, McCusker, Cole, Sewitch, Belzile and Ciampi 9 HCPs often fail to screen for MDD during clinic visits due to time constraints or a perceived lack of resources to treat the condition.Reference Goldman, Nielsen and Champion 68 , Reference Docherty 76 , Reference Wittchen and Pittrow 77 MDD screening may not even be considered during visits for physical complaints—a consequence of the “one problem, one visit” approach. Other HCPs may not consider MDD screening because they feel they lack the expertise to recognize and treat MDD in its various presentations.Reference Goldman, Nielsen and Champion 68 , Reference Docherty 76 , Reference Wittchen and Pittrow 77 Among HCPs who do screen for an MDE, a meta-analysis of 41 studies assessing diagnostic accuracy found that only 47% of people were properly detected.Reference Mitchell, Vaze and Rao 78 Atypical presentations (eg, somatic complaints) and inability to distinguish symptoms of MDD from other psychiatric conditions may contribute to failure to diagnose and misdiagnosis by HCPs.Reference Robinson 79 –Reference Gates, Petterson, Wingrove, Miller and Klink 81
Clinicians should screen individuals who are at risk for MDD or who present with depressive symptoms.Reference Lam, McIntosh and Wang 24 This does not need to be time consuming or resource intensive, as there are a range of available assessment tools that can be used to rapidly and effectively screen for an MDE.Reference Liu, Hankey, Cao and Chokka 82 , Reference Liu, Hankey, Lou, Chokka and Harley 83 HCPs can start with a simple 2-item questionnaire (Patient Health Questionnaire-2 [PHQ-2]Reference Kroenke, Spitzer and Williams 84), which screens for the presence of the two cardinal symptoms of an MDE, and helps determine if further assessment and monitoring using the more comprehensive scales is needed.Reference Whooley, Avins, Miranda and Browner 85 , Reference Adachi, Aleksic and Nobata 86 Commonly used scales include the 9-Item Patient Health QuestionnaireReference Kroenke and Spitzer 21 (PHQ-9) or the Quick Inventory of Depressive Symptomatology—Self-Report (QIDS-SR).Reference Rush, Trivedi and Ibrahim 87 These and other scales are easy to use and available free online, can be integrated into electronic medical records, and can even be completed prior to an HCP visit.Reference Oluboka, Katzman and Habert 16 , Reference Kroenke and Spitzer 21 , Reference Liu, Hankey, Cao and Chokka 82 , Reference Rush, Trivedi and Ibrahim 87 , Reference Beck, Ward, Mendelson, Mock and Erbaugh 88 Detailed summaries of screening/monitoring tools can be found in Oluboka et al.Reference Oluboka, Katzman and Habert 16 and in the CANMAT 2023 Update.Reference Lam, Kennedy and Adams 5
Alternative diagnoses and comorbidities
The diagnosis of MDD also requires that other conditions that present with depressive symptoms are considered (Supplementary Table S3).Reference Lam, McIntosh and Wang 24 , Reference Robinson 79 , Reference Lyness, Roy-Byrne and Solomon 89 A substantial proportion of people who initially receive a diagnosis of MDD later receive a different or additional diagnosis.Reference Robinson 79 For individuals who have depressive symptoms that are not responding to the current treatment plan, HCPs should continue to explore alternative diagnoses in subsequent visits. The criteria for an MDE occurring in bipolar disorder (bipolar depression) are identical to those required to diagnose an episode in MDD. 90 Therefore, it is crucial to consider this as a potential diagnosis, and screen for the presence of bipolar disorder. This can be done with the Mood Disorder Questionnaire (MDQ),Reference Hirschfeld, Williams and Spitzer 91 Rapid Mood Screener,Reference McIntyre, Patel and Masand 92 or Bipolarity Index.Reference Aiken, Weisler and Sachs 93
Untreated and unrecognized psychiatric comorbidities can affect the treatment and prognosis of MDD and, therefore, identifying these conditions at the earliest possible point is critical for treatment planning. It has been estimated that 46% of people with MDD have a comorbid anxiety disorder,Reference Kessler, Sampson and Berglund 94 and anxious distress occurs in up to 78% of people with MDD.Reference Gaspersz, Nawijn, Lamers and Penninx 95 The co-occurrence of an anxiety disorder during an MDE is associated with significantly reduced quality of life, increased suicidal ideation, greater healthcare resource utilization, and greater medical expenditures compared with an MDE without comorbid anxiety.Reference Armbrecht, Shah and Poorman 18 , Reference Kessler, Sampson and Berglund 94 , Reference Rao and Zisook 96 , Reference Zhou, Cao and Yang 97 Individuals with more severe baseline anxiety may be less responsive to MDD treatment.Reference Hicks, Sevilimedu and Johnson 98 When diagnosed, comorbid anxiety and anxious distress may be treated effectively with first-line medications indicated for MDD,Reference Lam, Kennedy and Adams 5 , Reference Schaffer, McIntosh and Goldstein 14 , Reference Fagiolini, Cardoner and Pirildar 99 potentially with the use of adjunctive therapy.Reference Trivedi, Thase and Fava 100 Attention-deficit/hyperactivity disorder (ADHD) is also a common comorbidity,Reference Kato, Tsuda, Chen, Tsuji and Nishigaki 101 occurring in an estimated 7% (95% CI, 4%–11%) of adults with MDD.Reference Sandstrom, Perroud, Alda, Uher and Pavlova 102 MDD with comorbid ADHD is associated with more severe and chronic depressive symptoms, poorer functional outcomes, and an increased risk of suicide compared with MDD alone.Reference Kato, Tsuda, Chen, Tsuji and Nishigaki 101 , Reference Chen, Pan and Hsu 103 –Reference Baldessarini, Tondo, Pinna, Nuñez and Vázquez 106 Individuals who receive active ADHD treatment, however, are no more likely to be resistant to MDD treatment than those without ADHD.Reference Chen, Pan and Hsu 103 Psychiatric comorbidities commonly encountered in people with MDD for which CANMAT has provided treatment recommendations include anxiety disorders, substance use disorders, ADHD, and personality disorders.Reference McIntyre, Rosenbluth and Ramasubbu 107
Nonpsychiatric comorbidities also can complicate the course and treatment of MDD. As an example, sleep fragmentation associated with obstructive sleep apnea, which occurs in more than 30% of individuals diagnosed with MDD,Reference Stubbs, Vancampfort and Veronese 108 can lead to daytime sleepiness, fatigue, and impaired memory and cognition.Reference Aftab, Anthony, Rahmat, Sangle and Khan 109 People with MDD have longer obstructive apneic episodes compared with nondepressed individuals, resulting in substantially greater hypoxiaReference Carney, Freedland, Duntley and Rich 110 and neuronal damage.Reference Cross, Kumar and Macey 111 However, detecting comorbid obstructive sleep apnea and treating it with continuous positive airway pressure therapy can significantly reduce symptoms of depression in people with MDD.Reference Habukawa, Uchimura and Kakuma 112 CANMAT treatment recommendations for other common metabolic and medical comorbidities in people with MDD are available.Reference McIntyre, Rosenbluth and Ramasubbu 107
Increasing awareness and reducing stigma
Public awareness and mental health literacy are keys to reducing stigma associated with MDD and hesitancy to seek treatment. 27 , Reference Burns and Birrell 113 , Reference Brijnath, Protheroe, Mahtani and Antoniades 114 Internet-based programs have the potential to increase mental health literacy and may encourage users of online materials to seek appropriate treatment.Reference Burns and Birrell 113 An assessment of web-based interventions revealed that those based on structured programs that target specific populations and include evidence-based information can improve mental health literacy, reduce stigma, and increase healthcare seeking.Reference Brijnath, Protheroe, Mahtani and Antoniades 114 Exposure to such interventions may open individuals to recognizing their own symptoms and discussing them with their HCPs. Clinicians can also help increase understanding and reduce stigma associated with an MDD diagnosis by directing people to a peer support group (eg, Hope+Me, Mood Disorders Association of Ontario, Peer Support Canada) or interactive web resources (eg, MoodFX 115), and providing patient education regarding the nature of MDD and its treatment. 27 The CANMAT Health Options for Integrated Care and Empowerment in Depression (CHOICE-D) Patient and Family Guide to Depression Treatment,Reference Parikh, Kcomt, Fonseka and Pong 116 a plain-language guide to depression treatment based on the CANMAT clinical treatment guidelinesReference Kennedy, Lam and McIntyre 3 , Reference Lam, McIntosh and Wang 24 , Reference Lam, Kennedy, Parikh, MacQueen, Milev and Ravindran 117 –Reference Ravindran, Balneaves and Faulkner 121 and written by patients and families, is another important tool for improving understanding of MDD treatment options and encouraging greater patient involvement in healthcare decision-making.Reference Parikh, Kcomt, Fonseka and Pong 116 , Reference Fonseka, Pong, Kcomt, Kennedy and Parikh 122 The CANMAT Depression GuidelinesReference Lam, Kennedy and Adams 5 provide a comprehensive guide to managing persons with MDD at all stages.
Employing UTT + EOT for MDD
Prescribing medication
The traditional “watchful waiting” approach is a critical barrier to EOT.Reference Habert, Katzman and Oluboka 15 When moderate-to-severe MDD is diagnosed, the EOT approach involves the rapid initiation of an antidepressant medication that carries a first-line recommendation (which is generally a monoamine reuptake inhibitor).Reference Kennedy, Lam and McIntyre 3 , Reference Lam, Kennedy and Adams 5 A combination of pharmacotherapy and evidence-based psychotherapy may be considered.Reference Lam, Kennedy and Adams 5 The initial medication choice ideally considers factors that impact long-term tolerability, such as the likelihood of sexual dysfunction, sedation, and potential for weight gain.Reference Ashton, Jamerson, W and Wagoner 123 The individual’s symptoms and comorbidities also impact medication choices that ideally increase the likelihood of early response.Reference Lam, Kennedy and Adams 5 For example, a person struggling with MDD with anxious distress and/or a comorbid anxiety disorder could benefit from a prescription that has a higher likelihood of addressing these symptoms.Reference Kennedy, Lam and McIntyre 3 , Reference Schaffer, McIntosh and Goldstein 14 HCPs should consider any history of response or nonresponse to previous medicationsReference Kennedy, Lam and McIntyre 3 and discuss options with their patients, addressing the acceptability, or lack thereof, of potential adverse effects.
Early follow-up and medication optimization
Older, now outdated guidelines supported extended medication trials in MDD, advocating up to 8 weeks of antidepressant treatment before any dose optimization, medication augmentation, or switch options were considered. 124 –Reference Gelenberg, Freeman and Markowitz 126 However, most people will require an earlier adjustment to their medication,Reference Robinson 79 and overly long trials of a particular agent without timely follow-up is inconsistent with optimal MDD treatment. HCPs may hesitate to optimize medication doses rapidly, instead making incremental changes after each failed trial.Reference Habert, Katzman and Oluboka 15 , Reference Oluboka, Katzman and Habert 16 This “go-slow” approach may increase the time to remission and reduces the likelihood of full, functional recovery.Reference Habert, Katzman and Oluboka 15 Consequently, a much earlier reassessment of symptoms (eg, 1–4 weeks after initiation of pharmacotherapyReference Kennedy, Lam and McIntyre 3 , Reference Lam, Kennedy and Adams 5) using MBCReference Kennedy, Lam and McIntyre 3 , Reference Lam, Kennedy and Adams 5 is a critical part of UTT + EOT (Figure 1).
Applying MBC ensures a systematic approach to symptom assessment at baseline and in measuring response to treatment. Although clinicians may have concerns about adequate time and resources for monitoring symptoms, MBC actually helps streamline/organize care to make it more efficient and effective. Together with MDD symptom assessment scales (eg, the PHQ-9 or QIDS-SR), other subjective scales are available that assess the degree of functional impairment (eg, the Lam Employment Absence and Productivity Scale,Reference Lam, Michalak and Yatham 127 Sheehan Disability Scale [SDS]Reference Sheehan, Harnett-Sheehan and Raj 128 or the World Health Organization Disability Assessment Scale, self-ratedReference Ustün, Chatterji and Kostanjsek 129), which helps set treatment goals beyond symptom remission.Reference Lam, Parikh, Michalak, Dewa and Kennedy 25
In clinical trials, a lack of improvement in symptoms or functioning in the first 2 weeks after treatment initiation is predictive of later treatment failure.Reference Habert, Katzman and Oluboka 15 In line with these findings, clinical guidelines now recommend reassessing individuals within 2 weeks of starting medication to look for early symptom reduction and improved functional capabilities, to monitor adverse effects, and to address dosage optimization.Reference Kennedy, Lam and McIntyre 3 , Reference Lam, Kennedy and Adams 5 Repeated follow-up every 2 to 4 weeks thereafter is recommended to assess the need for further refining of the treatment plan, based on the HCP’s clinical judgment (with the assistance of assessment scores).
For HCPs who find the process of rapid treatment optimization daunting, clinical practice guidelines and algorithms are valuable resources to guide subsequent treatment adjustment decisions during follow-up appointments.Reference Kennedy, Lam and McIntyre 3 , Reference Lam, Kennedy and Adams 5 , Reference Lam, McIntosh and Wang 24 , Reference Katzman, Anand, Furtado and Chokka 130 An algorithm developed by the authors (Figure 3) and generally based on the updated CANMAT guidelines may support HCP decision-making for treatment optimization. The first step at the (EOT recommended) 2-week follow-up is to increase medication dosage until either no further clinical benefit has been realized, or side effects have become unacceptable.Reference Kennedy, Lam and McIntyre 3 If insufficient improvement has occurred, (ie, <25% reduction in scale scores), an add-on/adjunctive medication may be neededReference Blier, Ward, Tremblay, Laberge, Hébert and Bergeron 131 (Supplementary Table S4). Alternatively, a medication switch can be considered, particularly when tolerability is a problem, although in some cases, the addition of an adjunctive medication can minimize or reverse adverse effects.Reference Lam, Kennedy and Adams 5 Strategies for addressing “difficult-to-treat depression”Reference Lam, Kennedy and Adams 5 , Reference Rush, Aaronson and Demyttenaere 132 , Reference McAllister-Williams, Arango and Blier 133 are discussed below.
An algorithm for guiding treatment steps in the management of MDD, based in part on the 2023 update on CANMAT clinical guidelines. Adapted with permission from Lam et al.Reference Lam, Kennedy and Adams 5 CANMAT, Canadian Network for Mood and Anxiety Treatments; PHQ-9, 9-Item Patient Health Questionnaire.
Therapeutic alliance and adherence
HCPs may find that a lack of therapeutic alliance hinders their ability to engage people in the development of a treatment plan and ensure their adherence once developed.Reference Bobes, Saiz-Ruiz and Pérez 134 The maxim, “drugs don’t work in people who don’t take them,” credited to former US Surgeon General C. Everett Koop,Reference Lindenfeld and Jessup 135 aptly sums up the consequences of nonadherence, which can have many underlying causes. Some individuals may simply lack insight into their symptoms and/or feel that they do not need medication. Others may fail to fill prescriptions if they cannot afford them. Patients may have concerns about adverse effects that were not adequately addressed or may overestimate the risks or severity of such adverse effects. Still others may believe that there is a stigma regarding taking a medication for mental health conditions.Reference Kardas, Lewek and Matyjaszczyk 64 , Reference Sirey, Bruce, Alexopoulos, Perlick, Friedman and Meyers 136 –Reference Townsend, Pareja and Buchanan-Hughes 138
Fewer than half of individuals prescribed a medication for MDD remain adherent (defined as taking the medication on ≥80% of days covered) after 3 months, and only a quarter are adherent at 1 year.Reference Keyloun, Hansen, Hepp, Gillard, Thase and Devine 139 Sexual dysfunction and weight gain are among the most common reasons for stopping antidepressant medication because these adverse effects are described as “extremely difficult to live with,”Reference Ashton, Jamerson, W and Wagoner 123 although people are often hesitant to discuss these issues. Some individuals stop their medication due to a perceived lack of improvement, while others stop once their symptoms improve, believing that they no longer need the medication.Reference Kardas, Lewek and Matyjaszczyk 64 , Reference Bobes, Saiz-Ruiz and Pérez 134 , Reference Fortney, Pyne and Edlund 137 Lack of trust in the HCP and/or poor patient–HCP communication can also contribute to poor adherence to the treatment plan.Reference Kardas, Lewek and Matyjaszczyk 64
While MBC is central to the UTT + EOT approach, successful treatment also hinges on an open and supportive relationship with the patient.Reference Kroenke and Spitzer 21 , Reference Kardas, Lewek and Matyjaszczyk 64 When people with an MDE were asked what they valued in their care, the most highly ranked items included having trust in the HCP’s goals for their care and having a feeling that their HCP was listening to and supporting their own goals and concerns.Reference Cooper, Brown and Vu 140 People also regarded receiving information about their treatment and knowing what to expect as important aspects of their depression care.Reference Cooper, Brown and Vu 140
To ensure individuals’ confidence in the treatment plan and support their adherence to treatment, HCPs can spend a few minutes at the time of the initial prescription and at subsequent treatment steps educating their patients. They should let them know what to expect from the medication, including any potential early (and usually transient) side effects, and emphasize the importance of adherence.Reference Lin, Von Korff and Katon 141 , Reference Masand 142 HCPs should routinely inquire about adherence and tolerability, proactively discussing issues such as sexual dysfunction, risk of sedation, and weight gain.Reference Ashton, Jamerson, W and Wagoner 123 They should encourage patients to continue taking medication regularly to increase the likelihood that symptoms will continue to improve over time.
Providing treatment that persists to symptomatic remission and full functional recovery
When a person with type 2 diabetes or hypertension initiates treatment, HCPs will continue to optimize their regimen to reach defined treatment targets 11 , 12 Analogously, treatment goals for MDD should aim beyond improvement of the presenting symptoms to include a full symptomatic remission and return to full functioning.Reference McIntyre, Lee and Mansur 23 , Reference Rosenblat, Simon and Sachs 143 –Reference Weiss, Meehan and Brown 145 Some patients may become nonadherent to MDD treatment after symptoms have partially improved. Likewise, HCPs may stop optimizing treatment after a partial response.
Many of the same barriers that hinder the UTT + EOT approach in the treatment of acute MDD also impede the continuation of treatment to full functional recovery. Ongoing symptoms of unaddressed psychiatric or somatic comorbidities, lack of social or psychological support outside of the clinic (which may include treatment stigmatization), and challenges with returning to work or lack of employment can limit a person’s commitment to continued treatment.Reference Kardas, Lewek and Matyjaszczyk 64 , Reference Bobes, Saiz-Ruiz and Pérez 134 Costs and limited coverage for both pharmacologic and psychological treatments can also be barriers to continuing MDD treatment.Reference Kardas, Lewek and Matyjaszczyk 64 For HCPs, barriers to continued treatment to full functional recovery may include limited awareness of available counseling resources.
Continuing measurement-based care
Persistence in treating to full functional recovery requires the HCP to continue treatment and monitor progress using MBC until that target is achieved.Reference Habert, Katzman and Oluboka 15 , Reference Oluboka, Katzman and Habert 16 For an MDE, the treatment target is a PHQ-9 score target of <5 for symptom remissionReference Kroenke and Spitzer 21 and an SDS total score of ≤6 for functional recovery.Reference Sheehan and Sheehan 146 If an individual has more than 50% improvement from treatment initiation, but still has a PHQ-9 score of 6 to 8, the HCP should continue to target the remaining symptoms and functional deficits that remain.Reference Sheehan and Sheehan 146 Patient-reported outcome scales (eg, the 12-Item Short-Form Health SurveyReference Ware, Kosinski and Keller 147) may also be used to assess specific aspects of well-being that the individual feels are important measures of their own treatment success.Reference Demyttenaere, Donneau, Albert, Ansseau, Constant and van Heeringen 144 , Reference Weiss, Meehan and Brown 145 , Reference McIntyre, Ismail and Watling 148 Because functional recovery can lag behind symptomatic remission,Reference Sheehan, Harnett-Sheehan, Spann, Thompson and Prakash 149 –Reference van der Voort, Seldenrijk and van 151 the clinician should continue to monitor function and subjective outcomes after the symptom reduction target is met.Reference McIntyre, Lee and Mansur 23 , Reference Lam, McIntosh and Wang 24 , Reference Zajecka 152 Continuing measurement-based treatment of comorbid conditions is also critical for achieving full functional recovery.
Even with the vigorous application of the UTT + EOT approach, some people will have suboptimal outcomes and will be unable to achieve sustained remission, despite multiple treatment steps.Reference Rush, Aaronson and Demyttenaere 132 , Reference McAllister-Williams, Arango and Blier 133 In these individuals with “difficult-to-treat depression,” treatment goals may be revised to controlling symptoms and maximizing function, as in the management of other chronic diseases (Supplementary Table S5).Reference Lam, Kennedy and Adams 5 , Reference Rush, Aaronson and Demyttenaere 132 , Reference McAllister-Williams, Arango and Blier 133
Medication combinations
Some HCPs may be hesitant to combine medications in the treatment of an MDE, but for individuals with an inadequate response to antidepressant treatment and for those with psychotic symptoms, psychomotor agitation, or hostility, medication combinations may be necessary.Reference McIntyre and Weiller 153 , Reference Chen 154 The use of combination pharmacotherapiesReference Blier, Ward, Tremblay, Laberge, Hébert and Bergeron 131 , Reference Blier, Gobbi and Turcotte 155 , Reference Kruizinga, Liemburg and Burger 156 including augmentation with low-dose adjunctive medications initially indicated for psychosis (ie, serotonin-dopamine modulators [SDMs]),Reference Zhou, Keitner and Qin 157 , Reference Mishra, Sarangi, Maiti, Sood and Reeta 158 have shown efficacy for treating people with MDD,Reference Lam, Kennedy and Adams 5 with or without psychotic features.Reference Lam, Kennedy and Adams 5 , Reference Nelson, Thase and Bellocchio 159 Aripiprazole and brexpiprazole are first-line adjunctive agents recommended in the CANMAT 2023 UpdateReference Lam, Kennedy and Adams 5 (Supplementary Table S4). Clinicians should consider these options early in treatment, using medications with different receptor affinities to target specific symptoms.Reference Kennedy, Lam and McIntyre 3 , Reference McIntyre and Weiller 153 , Reference Blier 160 –Reference Cleare, Pariante and Young 162 Adjunctive treatment with an SDM is associated with significant reductions in healthcare resource utilization,Reference Seetasith, Greene, Hartry and Burudpakdee 163 and earlier initiation of the SDM after beginning antidepressant treatment (mean of 3.9 monthsReference Seetasith, Greene, Hartry and Burudpakdee 163 or 0–6 monthsReference Yermilov, Greene, Chang, Hartry, Yan and Broder 164) results in greater reductions in healthcare costs and resource utilization compared with later initiation. Adjunctive agents that also have approved indications for psychotic disorders are generally prescribed at lower doses for the treatment of mood disorders. When considering the addition of an adjunctive agent, clinicians must use caution and discuss with their patients the potential benefits versus adverse effects of these options, which also includes addressing the potential stigma that these medications might carry.Reference Townsend, Pareja and Buchanan-Hughes 138 , Reference Mattingly, Matthews-Hayes, Patel, Kramer and Stahl 165
Nonpharmacologic strategies
This discussion of strategies for the UTT + EOT approach has focused on pharmacologic treatment of MDD. However, many people will not attain remission and a functional recovery with pharmacologic treatment alone. Nonpharmacologic strategiesReference Lam, Kennedy and Adams 5 are an essential component of treatment planning, and should be implemented with the initiation of pharmacotherapy. MDD drastically affects all areas of a person’s life, and patients should be encouraged to take an active part in their recovery while pharmacotherapy is being optimized. For example, gentle behavioral activation gained from activities such as attending to personal hygiene, taking short walks, or brief periods of socialization can provide a sense of autonomy and control, as opposed to solely taking medication and passively waiting for it to work.
Evidence-based guidelines recommend the use of nonpharmacologic strategies for mild-to-moderate MDD and combined pharmacologic and nonpharmacologic strategies for other individuals, particularly those with moderate-to-severe MDD.Reference Lam, McIntosh and Wang 24 , Reference Cleare, Pariante and Young 162 Cognitive behavioral therapy (CBT), interpersonal therapy (IPT), and behavioral activation (BA) are first-line recommended psychological therapies for the acute treatment of MDD. CBT and mindfulness-based cognitive therapy are first-line recommendations for maintenance treatment.Reference Parikh, Quilty and Ravitz 120 In addition to psychotherapies, repetitive transcranial magnetic stimulation (rTMS) has shown efficacy when combined with antidepressant pharmacotherapy.Reference Lam, Kennedy and Adams 5 , Reference Hassanzadeh, Moradi, Arasteh and Moradi 166
Emerging technologies can play an important role in reducing the burden on time and resources for patients and HCPs in MDD care.Reference Pratap, Renn and Volponi 167 The CANMAT GuidelinesReference Lam, Kennedy and Adams 5 provide an overview of guided and unguided apps to provide CBT and other therapies as adjuncts to standard care. A 39-study meta-analysis indicated that internet-based programs can personalize CBT and reduce depressive symptoms (based on PHQ-9 score) versus merely being placed on a wait list.Reference Karyotaki, Efthimiou and Miguel 168 Other applications (eg, Text4Mood) can provide supportive CBT-based messaging to people with MDD,Reference Agyapong, Mrklas and Juhás 169 or may be valuable in addressing specific symptoms or comorbidities. As an example, MoodGYM has been shown to provide substantial improvement in anxious symptoms in people with MDD.Reference Twomey and O’Reilly 170 Cognitive behavioral therapy for insomnia (CBTi), which reduces Insomnia Severity Index scores compared with hypnotics or no treatment in people with an MDE,Reference Feng, Han, Li, Geng and Miao 171 also can be delivered effectively via the Internet.Reference Zachariae, Lyby, Ritterband and O’Toole 172 The 2016 CANMAT guidelines section on disease burden and principles of care provides additional examples of internet-based resources.Reference Lam, McIntosh and Wang 24 HCPs are cautioned that online applications may not be evidence-based or may fail to ensure data security or patient privacy and safety.Reference Torous, Nicholas, Larsen, Firth and Christensen 173 , Reference Oti and Pitt 174 When recommending an online program, HCPs should ask at subsequent visits if the program was adopted and whether the patient found it useful.
Additional recommended nonpharmacologic approaches that can be used in conjunction with pharmacotherapy, include lifestyle interventions such as exercise and light therapy.Reference Lam, Kennedy and Adams 5 , Reference Ravindran, Balneaves and Faulkner 121 Exercise is clearly associated with substantial symptom reduction in people diagnosed with MDD.Reference Schuch, Vancampfort, Richards, Rosenbaum, Ward and Stubbs 175 It is recommended as first-line therapy for mild-to-moderate MDD and as a second-line adjunctive treatment option for moderate-to-severe MDD.Reference Ravindran, Balneaves and Faulkner 121 In meta-analyses, exercise effectively reduced symptoms of depression in people with MDD compared with physically inactive controlsReference Heissel, Heinen and Brokmeier 176 and, when used adjunctively, was significantly more effective than pharmacotherapy alone.Reference Lee, Gierc, Vila-Rodriguez, Puterman and Faulkner 177 Evidence suggests that just 90 minutes a week of physical activity is enough to have a positive impact on mood symptoms and cognition in individuals with serious mental illness, and time exercising was significantly associated with brain-derived neurotrophic factor expression in study participants.Reference Aas, Djurovic and Ueland 178 Light therapy was associated with statistically significant mild-to-moderate reduction in symptoms of nonseasonal depression in a meta-analysis of 23 randomized controlled trials.Reference Tao, Jiang and Zhang 179 It is recommended as a second-line lifestyle intervention for mild severity nonseasonal MDE.Reference Lam, Kennedy and Adams 5 Finally, clinicians can provide information to support their patients with MDD within the community, including resources for accessing social support agencies (eg, for food, housing, or domestic violence issues) and faith communities, where appropriate. Even among people who are not socially isolated, loneliness can have long-lasting, negative effects on depressive symptom severity and the risk of a subsequent MDE.Reference Lee, Pearce and Ajnakina 180 Therefore, providing support for reducing social isolation can be an important component of care for people with MDD.
Conclusions
The consequences of delaying effective treatment for an MDE are grave. People with MDD and their HCPs encounter numerous obstacles to the urgent and optimal treatment of MDD. A lack of awareness of an UTT + EOT approach is the first of these obstacles, and we hope that this article addresses that educational need. Suboptimal treatment of MDD can worsen illness trajectory, as well as negatively impact physical health and alter brain structure and function. HCPs who implement strategies to overcome barriers to the UTT + EOT approach of using early diagnosis, rapid treatment initiation, frequent measurement-based monitoring, prompt adjustment of treatment, and timely medication combination, may improve patient outcomes.
Supplementary material
The supplementary material for this article can be found at http://doi.org/10.1017/S1092852925000276.
Data availability statement
Data contained in this review article are available from the cited sources.
Acknowledgments
Medical writing and editorial support were provided by Kathleen M. Dorries, PhD, and John H. Simmons, MD, of Peloton Advantage, LLC, an OPEN Health company, and funded by Otsuka Pharmaceutical Development & Commercialization, Inc.
Author contribution
All authors contributed to the drafting, critical review, and revision of this manuscript, with the support of medical writers provided by Otsuka Canada Pharmaceutical Inc. and Lundbeck Canada Inc. All authors granted approval of the final manuscript for submission.
Financial support
This research and manuscript were funded by an unrestricted grant from Otsuka Pharmaceutical Development & Commercialization, Inc.
Disclosure
Oloruntoba Oluboka has received honoraria for serving as a consultant, advisory committee member, and/or as a speaker for Allergan/AbbVie, CPD Network, HLS Therapeutics, Janssen, Lundbeck, Otsuka, Pfizer, and Sunovion; and received grants or research support from Lundbeck-Otsuka Alliance. Jeffrey Habert has received honoraria for serving as a consultant, advisory committee member, and/or speaker for AbbVie, Elvium, Eisai, Idorsia, Lundbeck, Otsuka, Pfizer, and Takeda. Atul Khullar has received speaker honoraria from AbbVie, Axsome, Eisai, Elvis Pharmaceuticals, Idorsia, Jazz Pharmaceuticals, Lundbeck, Otsuka, Pfizer, Sunovion, and Takeda; and served as a consultant for the Canadian Collaborative Research Network, the American Association of Critical-Care Nurses, and the International Centre for Professional Development in Health and Medicine. David J. Robinson has participated in advisory board and/or consultancy meetings for AbbVie, Boehringer Ingelheim, Eisai, Janssen, and Otsuka; served as a speaker for AbbVie, the Canadian Collaborative Research Network, the Canadian Psychiatric Association, Diabetes Canada, Eisai, Janssen, Lundbeck, and Otsuka; and served as Chair and founding member of Master Clinician Alliance (a not-for-profit physician organization). Martin A. Katzman is a speaker and/or advisor for AbbVie, Aleafia Cannabis, Allergan/AbbVie, Bausch Health, Biron, Canopy Biosciences, Eisai, Elvium, Empower Cannabis, Janssen, Lilly, Lundbeck, Merck, Novartis, Otsuka, Pfizer, Purdue, Sante Cannabis, Shire, Sunovion, Takeda, and Tilray. He has also supported clinical trials and/or research studies for AbbVie, Aleafia Cannabis, Biron, Canopy Biosciences, Janssen, Lilly, Lundbeck, Pfizer, and Takeda. Larry J. Klassen has served as a consultant and served on advisory boards for and received honoraria from AbbVie, Bausch, Biron, BMS, Eisai, Elvium, Idorsia, Janssen, Lundbeck, Otsuka, Pfizer, Sunovion and Takeda. Claudio N. Soares has received honoraria for his participation as a consultant and/or advisory committee member for Bayer, Diamond Therapeutics, Eisai, Lundbeck, Otsuka, and Pfizer; and grants/research support from Clairvoyant Therapeutics, Eisai, Ontario Brain Institute, and Otsuka. Pratap R. Chokka has served as a consultant, served on advisory boards, and received honoraria from AbbVie, Eisai, Elvium, Idorsia, Janssen, Lundbeck, and Otsuka; and received research grants from AbbVie, Lundbeck, and Otsuka. Margaret A. Oakander has received honoraria for participation in advisory boards, for program development, and for serving as a speaker from AbbVie, Bausch, Biron, Elvium, Eisai, Idorsia, Janssen, Lundbeck, Otsuka, Pfizer, Sunovion, and Takeda. Roger S. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; has received speaker/consultation fees from AbbVie, Alkermes, Atai Life Sciences, Axsome, Bausch Health, Biogen, Boehringer Eisai, Ingelheim, Intra-Cellular, Janssen, Kris, Lundbeck, Mitsubishi Tanabe, Neumora Therapeutics, Neurocrine, NewBridge Pharmaceuticals, Novo Nordisk, Otsuka, Pfizer, Purdue, Sage, Sanofi, Sunovion, Takeda, and Viatris; and is a CEO of Braxia Scientific Corp. Diane McIntosh has received honoraria for serving as a consultant, advisory committee/board member, and/or speaker for AbbVie, Eisai, Janssen-Ortho, Lundbeck, Otsuka, Sunovion, and Takeda. Pierre Blier has received honoraria from AbbVie, Janssen, Lundbeck, Otsuka, and Pfizer for participation in advisory boards and as a speaker; research grants from Allergan/AbbVie, Canadian Institutes of Health Research, Janssen, Ontario Brain Institute, and Otsuka; and honoraria for expert testimony from Merck. Sidney H. Kennedy has received funding for consulting or speaking engagements from AbbVie, Boehringer-Ingelheim, Brain Canada, Janssen, Lundbeck, Otsuka, Pfizer, Sanofi, Servier, and Sunovion; and received research support from Brain Canada, CIHR, Janssen, Lundbeck, Neurocrine, Ontario Brain Institute, Otsuka, and SPOR. Matthieu Boucher is an employee of Otsuka Canada Pharmaceuticals Inc.
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