Judging a book by its cover: Changing ‘treatment resistant’ to ‘difficult-to-treat’ depression

The recent ‘roadmap’ provided by Rush et al. (2019) takes a critical look at ‘treatment-resistant depression (TRD)’ and recommends ‘difficult to treat depression (DTD)’ as a more appropriate label. The authors suggest that ‘suspected DTD implies a comprehensive search for treatable causes for depression that may have been initially overlooked’. This also implies the need for a realistic appraisal of the balance between symptom control and functional improvement rather than undertaking increasingly adventurous and often futile interventions or saying that ‘nothing more can be done’. The change in labelling from TRD to DTD is equivalent to saying ‘It is difficult ...’ instead of ‘I can’t ...’ in cognitive therapy terms. This change does imply a point at which the question of ‘How much treatment is enough for this person with this depression?’ and ‘What are the pertinent issues still to be addressed at this stage?’

Diagnosis is still an issue in itself and not all depressions are equivalent. Many have argued that the concept of Major Depression has been diluted if not lost altogether by including various depressive subtypes under an umbrella term so that seemingly effective treatments (both pharmacological and psychotherapeutic) have small effect sizes as their possible impact on some depression subtypes may have been lost. This reinforces the importance of identifying melancholic depression as a distinct ‘entity’ with specific psychomotor changes leading to different treatment connotations. If all depressions are seen to be homogeneous, other than in severity, and these treatment implications are unattended, people with this depression type may be unnecessarily relegated to the ‘resistant’ status.

Malhi et al. (2019) recently argued that the typing issues pertinent to depression also apply to TRD and that current definitions of TRD confirm ‘the idea that it is an exceptional form of depression’ and can encourage ‘risky treatment interventions which potentially do more harm than good’. They argued for a longitudinal approach in assessment, which considers the lifespan rather than just the current episode and that ‘sometimes we simply need to alter our approach’.

Rush et al. (2019) advocate more forcefully for a change of approach, where psychiatrists deal with patients with DTD much as cardiologists deal with patients with chronic heart failure, by helping them have the best possible quality of life, rather than oncologists, whose goals are complete remission or cure. Chronic pain provides another good analogy, as management involves identifying triggers for relapse and recurrence, as well as the physiological and psychological adaptations that individuals have made to deal with their pain, their interpersonal context, any medical comorbidities and substance misuse. This approach is more aligned to clinical staging models, which include evaluations of emotional and physical modifications that sufferers have made to their lives over time.

However, there is considerable clinical judgement required in deciding how much treatment is ‘enough’. Rush et al. (2019) point out that it is important to consider treatment equivalence in determining adequacy. They note that courses of antidepressants are not necessarily equivalent to each other and less likely to be equivalent to courses of Electroconvulsive Therapy (ECT), Cognitive Behavioural Therapy (CBT), Interpersonal Therapy (IPT), Dialectical Behaviour Therapy (DBT) or psychoanalytic psychotherapy, all of which have different treatment goals. Incidentally, the burgeoning of manualised psychotherapies enables better comparison of treatments, but this research is mainly undertaken by psychologists using depression severity scales or relapse as outcomes. The psychotherapy literature pays less attention to depression type, lifetime course and comorbidity which are more in psychiatrists’ experience but very applicable to DTD. However, psychiatrists can be criticised for ‘overmedicalising’ and ‘overmedicating’.

There is a balance that needs to be struck between alleviating severity, reversing what is reversible and being prepared to step back and reconsider the clinical situation while maintaining hope and realistic goals. The current RANZCP Mood Disorders Guidelines (Malhi et al., 2015) provide comprehensive approaches to depression subtypes and do suggest a ‘paradigm shift’ when these are not working. Rush et al.’s (2019) paper provides an elegant approach in this complex area which is in accord with the local guidelines. They also note the importance of being aware that recovery is defined not only by caseness or symptom threshold ‘but is rather defined in terms of personally-valued health, promoting hope, self-agency and social inclusion’ and that while, ideally,

depressed patients remain a sustained symptom-free (remitted) state that is associated with the return to the premorbid level of function ... current treatments do not always produce this ideal outcome – even when the diagnosis is correct and the treatments are well-delivered.

They outline some potential roadblocks to recovery, including medical conditions that were previously unidentified or have emerged in the course of the depression and areas including undeclared eating disorder, substance use, conflicts over sexuality or other secrets. In my experience, these are issues that some patients had avoided addressing, hoping that ‘the right antidepressant’ would fix the problem and obviate the need for them to address such personally challenging topics.

As with chronic pain, it is important to consider the emotional and physical modifications that patients have made to their lives over time: some have become accustomed to being depressed and find it difficult to give up chronic depression for a variety of reasons, usually related to not having a meaningful life to return to. In these situations, CBT can prompt changes to more hopeful, empowering cognitions; IPT is very useful to address the ‘role transition’ (to reconcile their situation if recovery is limited, or also [ironically] to transitioning back to recovery); and mindfulness-based interventions and DBT can promote acceptance and emotional regulation and improve suicidality.

However, some recent innovations may open promising possibilities for maximising treatments. First, clinical genomics can provide advice on how to tailor the best doses and types of antidepressants and other medications for individuals; in the future, brain imaging may assist with guiding treatments, and e-health programmes and other technologies such as virtual reality and avatars may play a role. There is now a range of potentially useful structured evidence-based psychotherapies, some of which can also be delivered online, where appropriate.

On a less technological front, there is increasing emphasis on the impact that strategies to improve lifestyle behaviours such as prescribing exercise and dietary changes, advocating ceasing substance use, including smoking can have on improving mood and overall health. Berk et al. (2013) have stated that

a range of factors appear to increase the risk for the development of depression, and seem to be associated with systemic inflammation; these include psychosocial stressors, poor diet, physical inactivity, obesity, smoking, altered gut permeability, atopy, dental caries, sleep and vitamin D deficiency.

These are mainly reversible but likely to have more of a part to play as depression becomes more chronic and the sufferer, more disempowered. These issues are pertinent to other chronic conditions with which depression is frequently comorbid (including diabetes, cardiac and cerebrovascular disease and pain).

Over 30 years ago, in New South Wales (NSW), a publicly funded Mood Disorders Unit (MDU; Brodaty et al., 1993) dealt with DTD by undertaking a comprehensive assessment of the individual, their family and social situation, followed by a multidisciplinary review with the patient, with an emphasis on depression typing and holistic treatment planning. In the case of long-term depression with multiple trials of medication, patients were generally taken off all/most medication and a small but significant number improved after this. As well as reintroducing antidepressants, other medications and ECT if deemed appropriate (particularly for bipolar, psychotic and melancholic depressions), they were introduced to a psychotherapeutic approach, usually a group CBT course and, where appropriate, systemic family therapy. This situation is again very analogous to chronic pain, where medications were initially useful, become less so over time. This compounded by months or years of adding other medications can lead to flatness of affect and symptoms induced by the medications themselves. The accompanying search for ‘finding the right medication(s)’ is not the whole answer.

Rush et al. (2019) also mention the costs of DTD, which is extremely relevant in terms of the current discussion of the burden of disease related to depression, both emotionally and financially. Our public mental health services have also tended to become more ‘crisis-based’ and concerned with determining risk as opposed to taking a longer term view on assessment and management. This is related, at least in part, to decreased funding so that they do not consider they have the resources to provide ‘enough’ treatment, including proactively approaching the very problems in terms of increased disability that may lead to DTD.

Finally, should we be championing a series of public multidisciplinary DTD Clinics that have more in common with Chronic Pain Clinics or Heart Failure Clinics? Would this be cost-effective? Certainly, the MDU as an inpatient and outpatient facility provided a comprehensive service and also a significant amount of ongoing clinical research. Should this type of resource be more available in the public sector?

Addressing precipitating, maintaining and protective factors for each individual, with consideration of their values and realistic goals for what recovery means to them may provide true precision medicine for DTD and further research possibilities. Rush et al.’s (2019) approach is a good blueprint, with the College Guidelines providing more local context. The paper is a useful impetus for further meaningful discussion.