They might not always be easily identifiable, but millions of people across the globe are living with the debilitating symptoms of depression.
This common mental disorder is thought to affect around 5% of the world’s adult population, with the pandemic responsible for a sharp rise in cases of major depressive disorder (MDD), particularly among younger populations and females.[1],[2]
While sometimes inaccurately characterised as ‘a case of the blues’, depression is a complex illness that can present in a variety of psychological and physical ways. The internationally recognised Diagnostic and Statistical Manual of Mental Disorders (DSM-5) defines a Major Depressive episode as “a period of at least two weeks when a person experienced a depressed mood or loss of interest or pleasure in daily activities, and had a majority of specified symptoms, such as problems with sleep, eating, energy, concentration, or self-worth.”[3]
It can make the lives of sufferers incredibly difficult; in some cases, even the most straightforward of tasks present themselves as insurmountable challenges. In more serious cases, depression can lead to suicide, and with more than 700,000 lives lost this way each year, there is a clear imperative to develop effective treatments and drug therapies that support patients in managing their illness.
The progression of novel drugs to clinical trial represents promise in this area, but the nature of depression brings particular challenges for trial co-ordinators. Adherence, for example, is a particular problem. Research using electronic monitoring in clinical trials shows that adherence levels are poorest for antidepressive medications, with notably low levels of initiation at the outset and subsequent rapid abandonment of adherence to the treatment protocol. Indeed, the analysis revealed that 50% of trial participants had discontinued treatment after just three months.[4]
Within any trial environment, adherence can be compromised by universal issues, such as participants experiencing adverse side effects. However, in trials for anti-depressant therapies, many of the reasons behind poor adherence are inherent in the nature of the illness itself. For example, depressive patients frequently experience cognitive impairment, struggling with clarity of thought, concentration and decision making. Others might lack sufficient motivation to repeatedly follow the treatment schedule as instructed. Others still might experience difficulties with recalling the required information.
There is also potential for patients with MDD to intensively reflect and ruminate on whether they are feeling any benefit from the treatment. This questioning can prevent good adherence habits from forming in the crucial early stages of the trial or, later, might trigger inaccurate negative subjective judgements over efficacy that weaken adherence to the protocol or lead the participant to decide they will abandon the trial completely.
The challenges associated with establishing a strong pattern of adherence in depressive patients is underlined by research from medical practice. Here, one study’s findings showed that more than a quarter (27.9%) of patients who had been prescribed antidepressants were found either to have only filled a single prescription or to not have started taking their medicine at all.[5]
With an understanding of the specific difficulties associated with adherence in depressive patients, the spotlight then turns on how such issues can be better managed. Interventions have been shown to be effective, with one systematic review highlighting the positive influence of measures aimed at tackling short and medium-term adherence to medication among adults with depressive disorders.[6]
The impact of any intervention, however, is dependent on the level of information available. Those who are better equipped with robust, reliable detail on the individual circumstances of poorly adherent patients will be better informed on how to manage any form of intervention in the most appropriate way. This applies equally to clinicians who are looking to intervene in the recovery of a patient on a prescribed course of antidepressants as it does to trial co-ordinators looking to ensure they gain full understanding of a candidate’s exposure to a treatment in order to gauge levels of efficacy and safety.
Within a clinical trial then, good adherence data can be seen as critical to guiding efforts to safeguard the power of the study through effective interventions. However, commonly employed methods of in-trial adherence measurement are beset by problems when it comes to patients with MDD. Self-reporting, for example, assumes that the input from a candidate is reliably accurate, but, in fact, the high level of stigma that is still associated with mental disorders such as depression can lead to high levels of variability between the given data and the objective truth of the situation.
The placebo response is also a recognised point of friction in trials for MDD treatments.[7] Placebo responses with a particularly strong magnitude and/or the presence of high levels of variability can represent an unhelpful layer of noise, making it more complicated to decipher the authentic signals on efficacy coming out of the study. This, again, underlines the need to monitor, measure and account for adherence comprehensively in order to generate stronger data to inform the complex process of decoding and evaluating trial output.
Taken together, the factors described above provide clear indication of the need to consider the specific challenges inherent when conducting clinical trials of antidepressant treatments with patients diagnosed with depressive disorders. But, in fact, these implications have far wider reach, given the fact that depression is among the most common comorbidities of many chronic medical diseases, from cancer and cardiovascular disease to inflammatory and neurological disorders.[8]
In trials for therapies tackling these disease areas, the prevalence of comorbidity means there is an increased risk of the cohort including a higher proportion of candidates with depression than would be the case among the general population. As such, there is an increased likelihood that adherence levels will be diminished and, if poor monitoring techniques are employed, this will not be actively managed during the trial or accurately accommodated in the data.
In this context, screening patients for a diagnosis of MDD provides valuable additional information to trial co-ordinators. However, in cases of comorbidity, symptomatic overlap can make the diagnosis of depression difficult for medical practitioners, leaving many patients undiagnosed. This is highlighted in one study looking at psychiatric comorbidity in immune-mediated diseases, which found that two-fifths (40.1%) of the cohort met the criteria for depression but that a third of those were undiagnosed.[9]
Whether depression is the subject of a clinical trial or a hidden risk, its presence further underlines the importance of adopting the most robust possible position on adherence in order to elicit the levels of data quality necessary for critical judgements on efficacy and safety of emerging treatments. And given the inherent weaknesses in patient self-reporting methods of adherence monitoring, this data quality can only truly be addressed through more reliable digital technologies.
At Aardex, the challenges associated with adherence in MDD and conditions affecting the Central Nervous System (CNS) are areas that we understand at great depth, having published 69 peer-reviewed papers on the use of our Medication Event Monitoring System (MEMS) in depression. This integrated suite of medication adherence solutions – which incorporates software, app, smart packaging and devices – provides a complete set of tools for addressing adherence challenges and elevating the integrity of trials.
The adoption of such ‘best practice’ measures brings clear value to adherence in trials that incorporate participants with depression, whether they are the subject of the trial itself or hidden among the cohort in plain sight. And with better trials, the pharmaceutical industry’s leaders stand a better chance of uncovering more effective treatments for the millions more across the world who are wrestling with the darkness of this disease.
[1] https://www.who.int/news-room/fact-sheets/detail/depression
[2] https://www.healthdata.org/news-events/insights-blog/acting-data/new-global-burden-disease-analyses-show-depression-and
[3] https://www.nimh.nih.gov/health/statistics/major-depression
[4] https://pubmed.ncbi.nlm.nih.gov/21942628/
[5] https://pmc.ncbi.nlm.nih.gov/articles/PMC2629822/
[6] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9301839/pdf/12888_2022_Article_4120.pdf
[7] https://pmc.ncbi.nlm.nih.gov/articles/PMC3628961/
