Antidepressants (alongside psychotherapies) are the first-line treatment for people with major depression (NICE, 2022). While antidepressants work for some, not everyone responds. This response is called ‘treatment-resistant’ depression (TRD) and affects up to 55% of British primary care users with depression (Thomas et al., 2013).

Evidence suggests that many GPs manage people with TRD via recurrent antidepressants (Talbot et al., 2022). However, this approach is not evidence-based, as demonstrated by a 2011 systematic review of the evidence for antidepressant augmentation (Connolly et al., 2011). This review showed that evidence does not support switching antidepressants following an insufficient treatment response. This approach has also confused some patients due to their lack of response (Talbot et al., 2023).

A recent qualitative systematic review exploring individuals’ experiences of antidepressants found that many are unaware of alternative treatments for depression and that antidepressants masked, rather than solved, their problems (Crowe et al., 2023a). This, combined with debates about whether this population are treatment-resistant or antidepressant-resistant, led to the conclusion that we need to better understand the lived experience of those diagnosed with TRD. The study by Crowe and colleagues (2023b) summarised in this blog aimed to add to this knowledge gap by conducting a qualitative meta-synthesis.

Methods

The authors searched six databases in September 2022, followed by manual searches of the reference lists of identified papers. The search strategy included qualitative studies in adults with TRD. Non-English language studies, systematic reviews, and mixed methods studies where qualitative findings were not reported separately were excluded. and then all authors screened studies and decided on eligibility.

Eligible studies were quality assessed using the Critical Appraisal Skills Programme (Long et al., 2020). The results sections of the included studies were then analysed using Thomas and Harden’s (2007) thematic synthesis. This method aims to discern themes and patterns across the data of included studies. Themes went beyond existing findings in the included studies to develop novel interpretations.

Results

Nine studies were included in the analysis, with the majority being conducted in the United Kingdom (n = 4). There were 140 participants in the overall sample (60% female), with ages ranging from 18 to 75 years. Most participants were of a White ethnicity. Participants in the sample lived with depression for 18 months to 50 years.

Four themes were developed: feeling trapped (identified from 6 studies); loss of self (identified from 5 studies); disconnection (identified from 3 studies); and questioning (identified from 2 studies).

Theme 1: Feeling trapped

The first theme described the pervasive sense of hopelessness associated with living with treatment resistant depression (TRD), where most participants believed that no treatment could alleviate their depression. One participant described their depression as being like cancer, seeing it as a terminal condition that could not be cured or managed:

I felt really, really low and for some reason, I felt like people come in this world and something just got stuck in there for no reason… mine is like a cancer now, you can’t get rid of it.

Many participants expressed that this ‘terminal’ depression left them feeling as though suicide was their only option:

Well, when I’m in it [depression], I think it’ll never stop. I mean, intellectually, you know it will, but sort of emotionally, you think, “This is it for life, I better start making plans [suicide].

Theme 2: Loss of self

The second theme described how participants’ experiences of TRD resulted in a perceived loss of self. This loss of self included a loss of control, personality, emotions, values, and thoughts, and was intertwined with feelings of shame, self-hate, and self-punishment. Depression became their sense of self.

You’re just, blank, there is no you, you just exist, you don’t live. Ah, breathe, ‘cos that’s the only thing about life you do, you know, but there is no emotions, no thoughts, no nothing.

Theme 3: Disconnection

The third theme described participants’ perceived sense of isolation from others. They articulated a contradictory experience of disengaging and excluding themselves from others while also yearning for connection.

You take offence to whatever people say. You interpret how others think you’re awful. When I enter the coach of the subway, I’m standing pressed against the door and can hear people whispering and talking about me, saying what a horrible person I am.

I felt isolated. I was never part of any groups, and I didn’t really have any close friends. I couldn’t relate to my peers. I was almost agoraphobic. I craved emotional company.

Theme 4: Questioning

In the final theme, participants described feeling frustrated at not receiving an explanation from their GPs about their recurrent depression. Many participants also described overthinking, thinking something was very wrong, difficulty understanding, and feeling a lack of clarity around their recurrent depression.

The lack of a framework has a very negative impact: what are you working on, where are you headed, how long will it take?

In addition, some participants described feeling sceptical about the effectiveness and long-term effects of antidepressants.

I’d rather not take any medications. Today, I don’t feel as good as I did ten years ago. I don’t think it’s from age. I think it’s from mixing all those drugs together. Maybe the long-term effects aren’t so good.

Conclusions

The authors concluded:

While antidepressants may help treat some people with depression, there is a need for more innovative approaches to the treatment of depression.

In summary, this study underscores the lack of perceived effective treatment for treatment resistant depression (TRD), which was described as further perpetuating feelings of despair and confusion for many people with TRD.

Strengths and limitations

This study includes intriguing quotes about people’s experiences of living with treatment resistant depression (TRD). This study also contributes to an under-researched area and systematically collated existing studies to direct future research. However, it is unclear what practical significance lies in understanding these experiences. There is already a lot of research into the daily realities of living with depression (e.g., Achterbergh et al., 2020), and it seems from this study that there is limited difference in how people experience TRD.

I believe this limitation relates to the author’s claim that they followed Thomas and Harden’s thematic synthesis, which emphasises ‘going beyond’ the included studies’ findings to generate new concepts and understandings. ‘Going beyond’ description may have been an advantage and supported a more nuanced exploration of the social processes underlying people’s experiences.

There are also additional limitations to the study, like:

• The search strategy was not based on a framework like PICO (population, intervention/issue, comparison/context, outcomes) and only one author initially screened studies, which raises concerns about rigour and trustworthiness.
• The final theme (questioning) was developed from two out of nine studies. While it is important to point out nuances in the data, I question whether this could be perceived as a theme across the entire data set if it was only present in a small minority of the data.
• Relatedly, no theme was reported across the entire data set. There was no mention of or consideration for why this lack of consistency exists in the discussion.
• The limitation that most studies included White participants was not discussed. This heterogeneous sample raises questions about the transferability of results to people with Black and Asian ethnicities.

Implications for practice

This qualitative systematic review shows that antidepressants might not always help depression. For this patient population, it may be important for health professionals to work with patients to explore other treatments for managing their depression. Treatment could include cognitive behavioural therapy, which was shown in a systematic review to be an effective intervention for TRD at short-term, mid-term, and long-term follow-up (Li et al., 2018).

In addition, my research shows that people with TRD value having community and people around them who understand antidepressant non-response (Talbot et al., 2023). With this in mind, I suggest GPs more actively recommend to people with potential TRD that they get involved in local support groups, to access this peer support and community.

This meta-synthesis only included 140 participants across nine studies. This limited amount of evidence shows how little we know about TRD, and suggests that there is a large number of people living with TRD who are underserved in research. Future research is clearly needed to improve treatment pathways for people with TRD, and should be a priority for clinical research going forward.

Statement of interests

I am completing a DPhil and have published on people’s experiences with GP care for ‘treatment resistant depression’ (TRD) at the University of Oxford. I had TRD but was then diagnosed with bipolar.

Links

Primary paper

Crowe, M., Manuel, J., Carlyle, D., Thwaites, B., & Lacey, C. (2023b). The experience of ‘treatment‐resistant’ depression: A qualitative meta‐synthesis. International Journal of Mental Health Nursing, 32(3), 662-672.

Other references

Achterbergh, L., Pitman, A., Birken, M., Pearce, E., Sno, H., & Johnson, S. (2020). The experience of loneliness among young people with depression: a qualitative meta-synthesis of the literature. BMC Psychiatry, 20(1), 1-23.

Connolly, K. R., & Thase, M. E. (2011). If at first you don’t succeed: a review of the evidence for antidepressant augmentation, combination and switching strategies. Drugs, 71, 43-64.

Crowe, M., Inder, M., & McCall, C. (2023a). Experience of antidepressant use and discontinuation: A qualitative synthesis of the evidence. Journal of Psychiatric and Mental Health Nursing, 30(1), 21-34.

Li, J. M., Zhang, Y., Su, W. J., Liu, L. L., Gong, H., Peng, W., & Jiang, C. L. (2018). Cognitive behavioral therapy for treatment-resistant depression: A systematic review and meta-analysis. Psychiatry Research, 268, 243-250.

Long, H. A., French, D. P., & Brooks, J. M. (2020). Optimising the value of the critical appraisal skills programme (CASP) tool for quality appraisal in qualitative evidence synthesis. Research Methods in Medicine & Health Sciences, 1(1), 31-42.

NICE (2022). Depression in adults: treatment and management [Online]. Available: https://www.nice.org.uk/guidance/ng222

Talbot, A., Ford, T., Ryan, S., Mahtani, K. R., & Albury, C. (2023). #TreatmentResistantDepression: A qualitative content analysis of Tweets about difficult‐to‐treat depression. Health Expectations.

Talbot, A., Lee, C., Ryan, S., Roberts, N., Mahtani, K. R., & Albury, C. (2022). Experiences of treatment-resistant mental health conditions in primary care: a systematic review and thematic synthesis. BMC Primary Care, 23(1), 1-17.

Thomas, J., & Harden, A. (2008). Methods for the thematic synthesis of qualitative research in systematic reviews. BMC Medical Research Methodology, 8(1), 1-10.

Thomas, L., Kessler, D., Campbell, J., Morrison, J., Peters, T. J., Williams, C., … & Wiles, N. (2013). Prevalence of treatment-resistant depression in primary care: cross-sectional data. British Journal of General Practice, 63(617), e852-e858.

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