Introduction

Depressive disorders are a group of conditions characterized by presence of “sad, empty, or irritable mood, accompanied by somatic and cognitive changes” that have a significant impact on one’s ability to function [1]. The most common depressive disorder is major depressive disorder (MDD) [2], commonly referred to simply as depression. In 2019, it was estimated that 2.49% of the world’s population was affected by depression, with the prevalence at that point in time being higher among people aged 20 years or older (3.28%) [2]. The ongoing COVID-19 global pandemic has had a severe toll on mental health and has led to a 27.6% increase in the global prevalence of MDD alone [3].

Treatment options for depression include biomedical approaches (i.e., pharmacotherapy), psychological approaches (i.e., psychotherapy), a combination of the two, or other somatic therapies such as exercise, diet, or light therapy [4, 5]. Antidepressants can be further categorized by generation. First-generation antidepressants (tricyclic antidepressants, TCAs, and monoamine oxidase inhibitors, MAOIs) were the first drugs developed to treat depressive symptoms and are often associated with intolerable side effects [6]. Second-generation antidepressants (selective serotonin reuptake inhibitors, SSRIs, and serotonin and norepinephrine reuptake inhibitors, SNRIs) refer to drugs developed since the 1980s that have improved efficacy and safety, as well as more tolerable side effects compared to first-generation antidepressants [6]. Clinical guidelines recommend most second-generation antidepressants as first-line treatments, which are a set of drugs identified by experts to be the standard initial treatment for patients with moderate-to-severe MDD [7].

After treatment is initiated, patients must be monitored and their response to treatment assessed [4]. Second-line or, subsequently, third-line antidepressants should only be considered in cases where one or more first-line antidepressants have been unsuccessful [7]. The treatment of depression has three main goals: response (i.e., a 50% reduction in symptoms from baseline); remission (i.e., return to a state of normal functioning with minimal symptoms); and recovery (i.e., two months of remission), though recovery is the ultimate aim [4, 8]. There are a number of screening instruments that can be used to assess treatment response, including self-rated scales like the Quick Inventory of Depressive Symptomatology (QIDS-SR) and clinician-administered scales like the Toronto Side Effects Scale that focuses on antidepressant side effects, in addition to clinical assessment and patient’s reported outcome [4]. Once an antidepressant is begun, it may take over eight weeks for patients to see a first response [4].

Approximately 53% of patients with MDD do not exhibit response and 67% do not experience remission in response to first-line antidepressants over the course of 14 weeks [9]. Lack of satisfactory response to antidepressants is referred to as treatment resistance [10], and though definitions of treatment-resistant depression (TRD) vary, a commonly accepted definition is failure to achieve remission after trying at least two antidepressants at an appropriate dose for an adequate length of time [11]. Some jurisdictions have adopted this as the formal definition of TRD, with experts reaching consensus and writing it into their clinical practice guidelines [12].

Studies examining the prevalence of TRD are sparse and vary widely in their estimates. For example, one study published in 2014 found the prevalence of TRD among Canadian primary care patients seeking treatment for depression was approximately 22% [13], while another published in 2021 used two large claims databases in the United States to find that the prevalence of TRD among pharmaceutically-treated patients was approximately 6% [14]. This range reflects not only the lack of consensus on a definition of TRD, but also the variety of challenges that exist in diagnosing this condition. To begin, the diagnosis of TRD is hampered by the phenomenon of pseudo-resistance [15]. This occurs when depression appears to be treatment-resistant, but the lack of response or remission can be attributed to suboptimal doses of antidepressants or discontinuing antidepressants prematurely, whether because of intolerable side effects or patient non-adherence [15]. True resistance to treatment is an issue of medication efficacy, not tolerability. Pseudo-resistance can also be attributed to misdiagnosis, or missing the co-existence of co-morbid conditions which accounts for many cases of depression that is apparently resistant to treatment [16–18]. Moreover, the patient population with TRD tends to be clinically complex, and response to treatment may be challenged by co-morbid conditions such as anxiety, personality, or substance-use disorders [15].

Treatment of depression may further be challenged by the fact that the aetiology of depression is complex with social, environmental, and genetic factors, as well as neurotransmitters beyond serotonin alone, playing a role [19–24]. Some authors have questioned the serotonin hypothesis of depression in an umbrella review [25], leading to media attention, however others argued that the review had methodological concerns [26]. Despite the challenges with the serotonin hypothesis, studies have consistently shown an improvement in depressive symptoms supported by randomized controlled trials (RCTs) and guidelines continue to provide recommendations for SSRIs as first-line pharmacotherapy [7].

Additionally, the term treatment-resistant depression is contentious because some argue that it implies a sort of therapeutic nihilism [15]. In fact, some clinicians prefer the term “treatment-refractory depression” to avoid instilling a sense of hopelessness in patients because therapeutic options for TRD do exist. One option to address unsatisfactory response to first- or second-line antidepressant treatment is augmentation: adding other medications not typically considered antidepressants [15]. Augmentation may be performed with lithium, triiodothyronine (T3, a thyroid hormone), or second-generation antipsychotics like quetiapine [15]. An alternative course of action is combining or switching classes of antidepressants, for example switching from an SSRI to a tricyclic antidepressant (TCA) [15]. In some cases, the decision may be made to add a different treatment modality altogether, such as psychotherapy, to ongoing pharmacological treatments [15].

Partial or non-response to depression treatment has several negative health, economic, and personal consequences, including greater likelihood of using the emergency department, greater likelihood of hospitalization, lower likelihood of being employed, and, if employed, greater likelihood of decreased work productivity [27]. TRD is also associated with reduced health-related quality of life [28]. However, these associations tell us little about the experiences of patients with TRD. Understanding what it is like to live with, seek care for, and undergo treatment for TRD is important as it can make the condition more understandable to physicians and other mental health professionals, and inform treatment planning [29]. Additionally, it can help incorporate an important patient perspective into health technology assessments (HTAs) used for health policy decision-making about the funding and implementation of depression-related treatments. Accordingly, the objective of this systematic literature review and qualitative meta-synthesis was to characterize and synthesize the state of existing knowledge. This review was guided by the following research question: What are the experiences of and perspectives on TRD of people with this condition, including their experiences of and perspectives on seeking care, and undergoing treatment?

Methods

This systematic review and qualitative meta-synthesis was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement [30] (S1 File). The protocol was registered in PROSPERO prior to the search (record ID: CRD42022356813), and later revised and updated to reflect the addition of the PsycINFO database.

Eligibility criteria and screening

Publications eligible for inclusion were English-language primary empirical qualitative studies examining patients’ experiences with or perspectives on TRD or on specific treatment options for TRD. Eligible study populations were adults aged 18 years or older who had TRD. The qualitative components of mixed method studies were eligible for inclusion. Studies in which participants with TRD also presented with one or more anxiety disorders (eg., panic disorder, specific phobias, generalized anxiety disorder, social anxiety disorder [35]) were included, as depression and anxiety are highly co-morbid and the literature suggests that both are strongly associated with the stable personality trait neuroticism [36, 37].

As there is complexity around defining and diagnosing TRD, at the title and abstract screening stage studies were judged as being about TRD if one or more of the following three criteria were met: (i) the terms “treatment-resistant depression” or “TRD” appeared in the title or abstract; (ii) study participants were described as having undergone at least two adequate but unsuccessful rounds of antidepressants; or (iii) study participants were described as experiencing depressive symptoms for 18 months or longer, despite being on treatment. This third criterion, while not reflective of clinical criteria for TRD, was used as a threshold to alert reviewers to the need for full text screening to ensure all potentially relevant papers were reviewed even if the study authors applied clinical criteria for TRD that differed from ours. As title and abstract screening proceeded, potentially eligible studies were tagged to indicate which of these criteria were met. For potentially eligible studies meeting criteria (i) or (iii), one of the objectives of full text review was to determine the authors’ definition of TRD. Only those papers where TRD was defined as failure of at least two adequate rounds of different antidepressants were eligible for inclusion. For example, some papers described their study sample as patients with TRD, but defined TRD as a failure of at least one adequate round of antidepressants; these papers were excluded. Conversely, if papers did not explicitly describe their study sample as patients with TRD but provided other information that suggested TRD, inclusion/exclusion was determined by applying this definition of failure of at least two adequate rounds of antidepressants.

Excluded from this review were: primary quantitative studies (n = 9); reviews; editorials, opinion or perspective pieces, or commentaries (n = 3); protocols or papers reporting preliminary findings without including sufficient empirical data (n = 1); conference abstracts, posters, or presentations; clinical practice guidelines; and grey literature including articles published in the News section of scientific journals. Unpublished works such as theses or pre-prints were also excluded (n = 1). Studies that exclusively used a quantitative scale to evaluate patient experiences were excluded as they are closed-ended and necessarily predefine aspects of patient experience. Studies that did not focus on patient perspectives were excluded (n = 5).

Studies were excluded on the basis of their included patient population (n = 88). In particular, studies that incorporated any pediatric participants were excluded, as were studies that focused on depression not described as treatment-resistant or those in which participants’ primary diagnosis was unclear. Studies about chronic, persistent, or recurrent depression were also excluded if there was no indication that participants experienced failure of at least two adequate antidepressant rounds, as these are forms of depression distinct from TRD. Studies were also excluded if they focused on depression or TRD in pregnant people or those with postpartum depression, as these periods are commonly marked by a variety of drastic physiological and lifestyle changes that may result in causal attribution. Studies in which the majority of participants had Alzheimer’s disease or dementia, bipolar disorder, borderline personality disorder, post-traumatic stress disorder (PTSD), or psychotic illnesses (eg., schizophrenia, schizoaffective disorder, depression with psychotic features, drug-induced psychosis, or delusional disorder [38]) were also excluded. We also identified studies about circumstantial or situational TRD, such as that which occurred in relation to illness (eg., cancer, HIV), divorce, or death of a loved one. These papers about situational depression were excluded on the principle that it would not have been possible to untangle the experience of these illnesses or significant life events from the experience of depression. Studies about a different topic altogether were excluded (n = 1). Studies examining the clinical or cost-effectiveness of antidepressants or other treatment options for TRD were excluded. To ensure comparable health resources were available to participants in included studies, study locations were limited to high-income member countries of the Organization for Economic Co-operation and Development (OECD) or European Economic Area (EEA) (n = 1).

Titles and abstracts were screened by two independent reviewers (AC and one of MP, DH, or KS). Where we conflicted, we arrived at a final decision through discussion. Full texts were obtained for those references that met eligibility criteria, as well as for references where the title and abstract alone were insufficient to determine eligibility. The same reviewers screened the full texts, and once again, conflicts were resolved through discussion and consensus. All screening was performed in Covidence [39]. A PRISMA flow diagram was constructed to depict the flow of information through the review. A summary of the inclusion and exclusion criteria are shown in Table 1.

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Table 1. Review inclusion and exclusion criteria.

https://doi.org/10.1371/journal.pmen.0000128.t001

Results

A total of 18,568 references (duplicates removed) were retrieved using the electronic database search strategy. Of those, 125 were deemed potentially eligible for inclusion and proceeded to full-text review. We were unable to access the full texts of three references, so only 122 full texts were assessed for eligibility. An additional five papers were identified through hand-searching and citation-chaining, of which two were excluded in title and abstract screening and two were deemed ineligible in full-text review. One additional record was found through Connected Papers but was excluded. The search is depicted in the PRISMA flow diagram shown in Fig 1. In total, 16 primary qualitative studies were included [46–61]. A list of the full texts that were reviewed but ultimately excluded is provided in S3 File with the reason for exclusion for each paper. A list of all references retrieved but screened as irrelevant is provided in S4 File. Eighty-four out of the 125 full texts we reviewed (retrieved through the electronic search, hand-searching, and citation-chaining) were excluded because participants had MDD but not TRD, or there was insufficient information to determine whether participants had a treatment-resistant form of MDD.

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Fig 1. PRISMA flow diagram.

https://doi.org/10.1371/journal.pmen.0000128.g001

The 16 included papers included a total of 242 participants, of whom 201 (83.1%) had unipolar TRD. The forty-one individuals across all studies who did not have TRD had MDD but not TRD (12) [50], bipolar disorder (11) [46, 47, 49, 53, 54, 56], and emotionally unstable personality disorder (2) [53]. Eleven participants had been diagnosed with bipolar disorder but met criteria for TRD and had been experiencing depressive symptoms continuously for at least one year [55], and five participants were caregivers [59, 60]. Wherever possible, data attributed to participants who did not fulfil the TRD criteria were separated and excluded from this review. Participant sex or gender was reported for 216 of 242 individuals; 114 (52.8%) were described as female/women and 102 (47.2%) were described as male/men. Participant ages ranged from 18 years [51] to 77 years [55], though not all studies [56, 58] provided an age range. Six studies reported the race or ethnicity of their participants [49, 52, 53, 55, 57, 61]. Across those six papers, there were 102 participants, of whom 59 were white, eight were Black, one was Asian, one was Hispanic, nine were described as New Zealand European, and one was described as “other” meaning not white British. Lawrence et al. [55] only reported the race or ethnicity of five of their 24 participants, stating that five participants were non-white and that zero participants were Hispanic or Latino. Watts and colleagues [61] reported the race or ethnicity of 20 individuals although only 19 ultimately participated in qualitative interviews. With a few exceptions (for example [55, 59]), studies did not report further demographic information such as participants’ average income, education level, or employment status. While sexual orientation has been found to be associated with depression [62], none of the included studies reported information about participants’ sexual orientation.

Few studies reported the length of time since the onset of participants’ depression [51, 54, 58–60] or the number of antidepressants tried by their participants [47, 58]. Some participants reported decades-long experience with depression [51, 54]. Table 2 describes the studies captured in this review, including the study design, main purpose or research question addressed, geographic location, and participant characteristics.

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Table 2. Summary of included studies.

https://doi.org/10.1371/journal.pmen.0000128.t002

The results of the critical appraisal are presented in S5 File. Studies were considered of acceptable quality. In all studies, the main findings were described in great detail with links to empirical data such as participant quotes. In addition, all studies integrated their main results with prior work and described the implications of their findings. Limitations were identified in all 16 included papers. Data collection methods were described in adequate detail in the majority of studies and data collection instruments (i.e., the interview guide) were well-described in 15 of the 16 included papers ([57] being the exception). All papers except [48, 51] provided adequate detail with respect to data analysis methods. However, only seven studies [46–49, 52, 56, 61] identified a specific qualitative approach. Only one paper made mention of reflexivity [52] but none included any formal reflexivity statement. The sampling strategy was not described in eight of the included papers [51–54, 56–58, 61], and only one study provided sufficient detail when describing their participants [47].

Of the included papers, only two focused on the overall experience of TRD [50, 52], while 14 examined experiences of specific treatments (ketamine/esketamine, deep brain stimulation (DBS), psilocybin, and wake and light therapy) [46–49, 51, 53–61]. In the therapy-specific papers, nearly all participants were naïve to the treatment in question. In most cases, the participants were enrolled in a trial examining the efficacy of the intervention [48, 51, 56–61]. In the sections below, when we refer to a “new therapy,” we mean the treatment that participants were trying for the first time in the therapy-specific studies, rather than a novel treatment.

Although these papers had heterogeneous aims, there were commonalities in the descriptions of experiences of TRD and new therapies that enabled us to identify themes or categories of findings belonging to three main groups: i) symptoms of depression; ii) response to past treatment failures; iii) experiences with a new therapy.

Discussion

Patients with TRD described their depressive symptoms, and emphasized how these symptoms contributed to experiences of isolation [47, 49–51, 61], hopelessness [47], and self-blame [54, 58]. Patients reported believing they will never recover from depression, as well as being desperate to find an effective treatment, which impacted their experiences with new, sometimes experimental, therapies. Patients often approached new therapies with “cautious optimism” [51, 56], lowering their expectations in an attempt to avoid disappointment if the new therapy proved to be yet another ineffective treatment [50, 51, 54, 58, 61]. Some participants likened depression to a “prison” [61] of the mind, a term that has previously been used in the literature to describe the experience of this condition [63]. These findings share similarities with the experiences of people who have depression not classified as resistant to treatment. For instance, patients with treatment-responsive MDD felt hopeless while in the middle of a depressive episode, were unsatisfied with their antidepressant treatment and reported trying multiple medications before finding one that worked well, and described feeling frustrated or desperate if their antidepressant did not adequately relieve their symptoms [64–66]. However, the experiences of people with TRD and those of people with MDD are also different in several important respects. To begin, the hopelessness felt by patients with MDD was described as a “bothersome symptom” [64] experienced when feeling depressed, as opposed to a general state of being that persisted even outside of depressive episodes in people with TRD. Furthermore, unlike participants with TRD, the majority of patients with MDD did consider their antidepressants to be effective, particularly in reducing their anxiety, making them feel less overwhelmed, increasing their motivation and optimism, making them feel better able to socialize, and overall helping them maintain a normal life [64, 66]. Their dissatisfaction stemmed instead from the experience of side effects, perception that their antidepressants did not take effect quickly enough, lack of desire to be on long-term medication, and, in some cases, a lack of relief from the symptom of fatigue specifically [64, 66].

This work has implications for health technology assessment (HTA) and policy-making as patient experiences, perspectives, attitudes, beliefs, values, and preferences are increasingly being incorporated into decisions about the development, implementation, and funding of drugs and health technologies. HTA bodies, both in Canada and internationally, recognize the importance of this type of evidence [67, 68]. For instance, a recent HTA of pharmacogenomic (PGx) testing in depression care included direct engagement with patients with depression, speaking to both medication-naïve individuals, as well as to people who did not adequately respond or were unable to tolerate at least one drug [69]. Findings from that exercise affirm findings of futility and desperation in the present review, underscoring the importance of engaging with this patient population when prioritizing and assessing depression-related services and technologies [70–72]. Understanding the feelings of desperation experienced by patients who have exhausted all traditional therapies may influence the policy consideration of “atypical” or less “traditional” therapies for this population.

Furthermore, these findings may also have implications for clinical practice and research relating to new interventions, particularly those which may be considered “extreme” [59] or of “last resort” [46, 49, 56, 59]. Existing literature highlights ethical challenges associated with offering or withholding such treatments for patients with TRD [70–73]. For patients and families who are desperate to achieve remission after exhausting numerous treatment options, being offered the opportunity to try an alternative therapy or intervention (eg., hospital admission, psychotherapy, medication, neurostimulation), even one with limited expected benefit, may foster hope, though only about one-fifth of psychiatrists report they would provide additional neurostimulation specifically (i.e., transcranial magnetic stimulation, electroconvulsive therapy, etc.) to patients with depression if they believed this type of treatment would ultimately be unhelpful [70]. At the same time, others have argued that applying the label of “medical futility” without having explored the full range of available treatments can have negative consequences for patients [71]. In the research context, concerns have been raised about informed decision making with respect to deep brain stimulation (DBS) for depression [73, 74]. These stem both from patients’ desperation and vulnerability, and the fact that depression itself may impact one’s cognitive abilities [74], as well as several important differences between DBS studies and more typical research with depressed patients [73]. The procedure to implant the DBS system is an invasive brain surgery that carries risk in-and-of itself, and more than that, such research studies may be longer and more complex than trials involving pharmacotherapy due to a need for appropriate follow-up care and monitoring [73]. Consequently, there has been discussion in the literature as to whether additional safeguards are required to ensure that informed consent processes in DBS studies with patients with TRD are ethically sound [73]. Dunn and colleagues [73] have argued that additional safeguards beyond what would typically be needed in any high-risk research study are not necessarily required, though they highlight a paucity of empirical evidence about inherently relevant topics such as decision-making capacity among patients with TRD who are severely ill, or the effects of depression on decision-making. In any case, transparency, the setting of realistic expectations, and engaging in a robust conversation with patients and research participants about what a procedure entails, potential benefits, and potential risks are critical prior to exposing them to interventions that may cause unnecessary harm while offering unclear or limited clinical effectiveness [70, 72].

One of the main findings of this review is that there are few studies examining the experiences of patients with TRD, with this information typically included in studies focused on the experiences of particular interventions for TRD. This likely reflects clinical difficulty identifying members of this patient population. One major challenge is that the proportion of patients diagnosed with MDD who have true resistance to treatment is likely much smaller than what current estimates [13, 14] suggest because misdiagnosis is common. There is strong evidence from several countries that patients with bipolar disorder are often misdiagnosed as having MDD [75–77], and this group contributes to the phenomenon of pseudo-resistance because antidepressants for treatment of bipolar disorder tend to be ineffective and can in some cases exacerbate bipolar disorder symptoms [78]. Similarly, some patients labeled as having TRD may have unrecognized depressive subtypes such as unipolar MDD with psychotic features, for which antidepressants alone would be ineffective [7].

Beyond misdiagnosis, the identification of patients with TRD is complex due to the co-occurrence of MDD with co-morbidities such as anxiety disorder, substance abuse, personality disorders, and non-psychiatric chronic and organ disease—all of which are predictive of resistance to depression treatment [12]. Pseudo-resistance may also arise when patients are co-prescribed medications for their psychiatric or physical health that act as CYP450 (a group of enzymes associated with liver drug metabolism) inducers, as these may reduce plasma levels of some antidepressants [79]. Smoking can also influence medication metabolism, and reductions in the serum levels of fluvoxamine, duloxetine, trazadone, and mirtazapine in particular have been observed in smokers compared to non-smokers [80]. As over half of patients with MDD are lifetime smokers [81], this may be a contributing factor to treatment effectiveness and addressing the smoking status of patients with TRD could potentially enhance treatment response.

Beyond challenges identifying patients with TRD, the clinical complexity of TRD patients may also impede their participation in research. This may happen explicitly, such as when studies exclude patients with co-morbidities, and implicitly, related to the energy, organization, and effort required to offer consent and complete the required research activities. Even in cases where the presence of co-morbidities does not render patients ineligible for participation in primary empirical work, secondary work may exclude papers with clinically complex patient populations, much like we have done in the present review. Finally, it may be difficult to recruit patients with TRD as study participants: some clinicians may avoid using the term “treatment-resistant” in favour of terms such as “treatment-refractory depression” or “difficult-to-treat depression” to avoid introducing therapeutic nihilism [82], and as such some patients may not identify themselves as having TRD.

These challenges notwithstanding, it is clear there is also an issue of research reporting, particularly in qualitative research of patient experience. During the screening process of this review, we identified over 100 studies that were potentially relevant and required full text assessment to determine inclusion. Of those, the majority (84) were excluded because their participants consisted of people with MDD but not TRD, or because it was not possible to determine whether the participant population had TRD defined as failure of at least two adequate rounds of antidepressants (S3 File). For example, one paper’s study population consisted of patients who had been diagnosed with depression between 18 months and 44 years prior to study initiation, but their diagnoses were all listed as simply “depression” with no further specification and no antidepressant history described [83]. It is conceivable that at least some of these participants had TRD, but we felt it necessary to exclude it because we could not confirm that this paper met our inclusion criterion of participants having failed at least two adequate rounds of antidepressants.

The issue of inadequate or incomplete research reporting indicates there may be a need to standardize the type of information presented about research participants with heterogeneous conditions like depression, much the way certain demographic information (eg., sex or gender; race or ethnicity) is almost always presented. Information relevant to depression that authors should consider including includes the time since onset of participants’ depression, the length of the current depressive episode or average length of participants’ depressive episodes, frequency of episodes, and the number of antidepressants that participants have tried but found to be ineffective. This information might help identify participants as having a specific type of depression regardless of how authors choose to describe their study population. Of course, caution is needed to ensure that none of this information is presented in a way that could identify participants or jeopardize their privacy.

Conclusions

This review synthesized existing qualitative research about patients’ perspectives of and experiences with TRD. Sixteen papers were included, of which 14 focused on experiences of specific therapies. Patients described depression as a state of disconnection and felt an overall sense of futility and hopelessness that they would ever fully recover. At the same time, they were desperate to get better and were hopeful that new treatments may provide relief, though this hope was tempered by their history of recurrent depressive symptoms. Greater examination of the overall experience of TRD is required, particularly if evidence about patient perspectives, experiences, attitudes, values, and beliefs is to be used to inform clinical practice and policy decision-making, particularly with respect to administrative/implementation and funding decisions.

Supporting information