MDD

Unmet needs for major depressive disorder

Major depressive disorder (MDD) is a highly prevalent and burdensome condition that is considered to be one of the leading causes of disability¹, affecting more than 264 million people worldwide².

What is major depressive disorder?

Also referred to as clinical depression, major depressive disorder (MDD) has been previously described as more than just a singular disorder, but a spectrum of patient profiles and symptom combinations³. Hypothetically, the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) can describe 227 distinct depression profiles⁴.

According to both the DSM-5 and International Classification of Diseases, 11th Revision (ICD-11), a diagnosis of major depressive disorder requires a presentation of depressed mood and/or anhedonia in addition to five or more key symptoms, almost daily, over a two-week period^4,5:

• Feelings of worthlessness or guilt, hopelessness
• Suicide ideation, plan, or attempt
• Fatigue or loss of energy
• Increased or decreased sleep
• Weight gain or loss
• Diminished ability to think or concentrate, or indecisiveness
• Psychomotor retardation or agitation.

The monitoring and management of these symptoms is essential for the prevention of psychiatric emergency, which can present as suicidal ideation and requires urgent treatment⁶.

What is suicidal ideation?

Suicidal ideation is the act of thinking about, considering or planning suicide⁷. In the worst cases, it can lead to suicidal behaviour and death⁷. Suicide is currently the cause of over 800,000 deaths per year⁸ and is the second leading cause of death in 15–29-year-olds¹.

In the United Kingdom, over 90% of patients who have died from suicide had a previous visit with their GP within weeks to months of their death⁹. Treatments, such as first-line selective serotonin reuptake inhibitors (SSRIs), can however take weeks before seeing improvements in symptoms¹⁰. There is therefore an unmet need for antidepressants that quickly attenuate depressive symptoms, with a faster onset of action than conventional antidepressants, for patients at an increased risk of suicide^10–12.

Therapeutics that antagonise glutaminergic N-methyl-D-aspartate receptors (NMDAR), such as esketamine, have recently drawn attention due to the accumulating evidence of their rapid and sustained antidepressant effects in treatment-resistant patients¹³. Various other NMDAR antagonists and modulators are currently in clinical trials, including arketamine, an optical isomer of esketamine; and rapastinel¹³.

The introduction of rapid acting therapeutics has also produced a need for clinically valid measures that can detect rapid changes in suicidal ideation, such as the Suicide Ideation and Behavior Assessment Tool (SIBAT), which has previously demonstrated validity as an assessment tool for suicide ideation and behaviour¹⁴.

When does major depressive disorder become treatment-resistant depression?

A complex interaction of intrinsic pharmacological properties and extrinsic clinical, environmental, and genetic factors underlies the individual patient response to antidepressant treatment¹⁵.

Response to antidepressant treatment is commonly defined as¹⁶:

1. >50% improvement on a depression rating scale, such as the ‘Hamilton Rating Scale for Depression’.
2. “Much improved” or “very much improved” on the ‘Clinical Global Impressions – Severity of Illness’ and ‘Clinical Global Impressions – Improvement’ scales.

Ultimately, the goal of antidepressant treatment is remission; the absence of depressive symptoms¹⁷. However, this goal is a continual challenge as approximately 50% to 70% of patients do not achieve remission after receiving at least one adequately dosed antidepressant treatment in clinical trials^18–20. This incomplete remission is associated with a range of persistent symptoms (Figure 1)²¹ when compared to patients with full remission of major depressive disorder.

Figure 1: Common residual symptoms of patients who fail to achieve remission (Adapted from Stahl et al21).

The persistent symptoms of incomplete remission can lead to^21–24:

• Higher risk of relapse
• Greater chronicity with smaller durations between episodes
• Impairments in occupational performance and social function
• Increased risk of suicide

A systematic approach to assessing patient responses to treatment is therefore essential for aiding treatment decision-making. A recent report showed that clinically meaningful and substantial changes can be determined in function with the Sheehan Disability Scale (SDS), and in depressive symptoms with the Montgomery-Åsberg Depression Rating Scale (MADRS) and Patient Health Questionnaire-9 (PHQ-9)²⁵.

How prevalent is treatment-resistant depression?

The definition of treatment resistance varies, but a commonly used definition of treatment-resistant depression is the failure of remission following at least two antidepressant treatments from separate pharmacological classes at an appropriate time and dose²⁶.

However, with a large variation of definitions, it is difficult to determine the specific prevalence of treatment-resistant depression. Using the most commonly used definitions, it has been suggested that treatment-resistant depression affects approximately 20% – 30% of people with major depressive disorder²⁷. If defined as an absence of remission, this can rise to as high as 60%²⁷.

The STAR*D trial, the largest open-label trial undertaken to examine the treatment of major depressive disorder (N = 2,876)²⁸, revealed that about one-third of patients who commenced treatment remained depressed²⁹. Enrolled patients began with a selective serotonin reuptake inhibitor (SSRI) treatment and were then managed through an algorithm-guided acute phase treatment over the course of five visits in a 12-week course²⁸.

The wide variety of treatments included, norepinephrine–dopamine reuptake inhibitors (NDRI), serotonin-norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOI), lithium, and thyroxine²⁸.

The results of the seminal STAR*D study show that about one-third of patients who commenced treatment remained depressed even following up to four sequential treatment trials²⁹.

A majority of patients who lack a response to first-line agents also fail to respond to combinations of newer generation antidepressants and adjunctive second generation antipsychotics^30,31.

In addition to a lack of effective treatments, a disproportionate share of personal, medical, and societal burdens is attributable to treatment-resistant depression. There is therefore a great unmet need for newer treatment options that utilise alternative mechanisms of action, such as glutaminergic neurotransmission³², for patients unresponsive to conventional therapies.

Click here to learn more about the biology of treatment-resistant depression

Socioeconomic impact of treatment-resistant depression

As a leading cause of disability¹, major depressive disorder (MDD) is a huge burden that can disrupt the ability to work and can lead to absenteeism and ‘presenteeism’ – decreased productivity at work³³. While specific cognitive impairments associated with major depressive disorder have yet to be causally linked, processing speed, attention, learning, memory, and executive function have been found to be impacted³³.

Treatment-resistant depression (TRD) in particular has a significant socioeconomic impact on healthcare systems, patients, and their families³⁴. The largest driver of this socioeconomic burden is frequent hospitalisation, depression severity that can reduce health-related quality of life (HRQoL), health status, and a reduced ability to work³⁴.

What are the health associated costs of treatment-resistant depression?

Brain disorders pose a serious health challenge to social and healthcare systems in Europe³⁵. It has been estimated that major depressive disorder alone affects 30.3 million people in Europe with an estimated cost of €91.9 billion³⁵. Around 41% of this cost was due to direct healthcare or non-medical related costs and 59% was due to indirect costs, such as absenteeism from work.

A US-based study found that annual direct healthcare costs can be 40% higher for treatment-resistant depression patients³⁶.

The direct costs for treatment-resistant depression are even higher. A US-based retrospective, seven year observational study of patients receiving antidepressant therapy (N = 78,477) found that the annual direct healthcare costs can be 40% higher for treatment-resistant depression patients than non-treatment-resistant depression patients (P <0.001)³⁶. This was due to increased hospitalisations, emergency department visits, outpatient services, outpatient prescription treatments, and adjunctive medications36. Additionally, caring for patients with treatment-resistant depression reduces the economic productivity for caregivers.

Similarly, a later study by Knoth et al. investigated associations between inadequacy of treatment response, determined using the 8-Item Short Form Health Survey (SF-8), and health outcomes. Of the 5,988 patients included in the study, partial response and non-response to treatment was associated with greater emergency department utilisation and hospitalisation (P = 0.05 and P <0.01, respectively)³⁷.

A study across five European countries (France, Germany, Italy, Spain, and the United Kingdom) found that healthcare resource utilisation was higher in the treatment-resistant depressive patients compared to non-treatment-resistant depressive patients and the general population (Figure 2)³⁸.

Figure 2. Healthcare resource utilisation outcomes among TRD and non-TRD respondents compared to general population (Adapted from Jaffe et al³⁸). ER, emergency room; FP, family practitioner; GP, general practitioner; HCP, healthcare professional; nTRD, non-treatment-resistant depression;TRD, treatment-resistant depression.

Overall, the odds of having visited a healthcare professional, general/family practitioner, needing hospitalisation, and visiting an emergency room were significantly higher in the treatment-resistant depression group (P < 0.001)³⁸.

How does treatment-resistant depression impact time at work?

As seen in the Knoth et al. study, partial response and non-response to treatment in patients with major depressive disorder were associated with lower employment (P = 0.01 and P <0.01, respectively) and work productivity loss (P <0.01, for both)³⁷. Among patients in full-time employment with treatment-resistant depression, non-complete responders were 2.37 times more likely to experience absenteeism and 4.17 times more likely to experience presenteeism than responders to treatment (P <0.01)³⁷.

This can further exacerbate mental health issues, as employment is known to have a beneficial effect on various aspects of mental health, including symptoms, self-esteem, social ability, and quality of life³⁹. Similarly, the Jaffe et al. study that revealed a higher level of healthcare resource utilisation (HRU) also found a significantly higher relative risk of absenteeism, presenteeism, overall work impairment, and activity impairment in patients with treatment-resistant depression than in the non-treatment-resistant depressive population (Figure 3) (P < 0.001)³⁸.

Figure 3. Work productivity and activity impairment-general health outcomes among TRD and non-TRD respondents (Adapted from Jaffe et al³⁸). nTRD, non-treatment-resistant depression; TRD, treatment-resistant depression.

In the United Kingdom, the need for improved treatments is becoming ever more important as mental disorders have become the most common reason to receive state-funded benefits, comprising approximately 46.5% of all claims³⁹. Of these, 44.2% were classified as having a depressive disorder³⁹.

The global impact of the coronavirus disease 2019 (COVID-19) pandemic has also had a huge effect on mental health and employment.

Fears associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak and mass lockdowns impacting employment are predicted to lead to increases in mental disorders and suicide⁴⁰.

Higher rates of depression (14.6% to 48.3%), and psychological distress (34.43% to 38%), have been seen during the COVID-19 pandemic in populations from China, Spain, Italy, Iran, the United States, Turkey, Nepal, and Denmark⁴⁰. Prevention and treatment strategies of mental disorders, such as major depressive disorder, are therefore urgently needed in addition to the need to reduce viral transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)⁴¹.

Patient and carer burden for treatment-resistant depression

The burden of major depressive disorder (MDD) and treatment-resistant depression (TRD) goes beyond the economic impact and is considerable for carers, patients, and their families. While patients can experience many impactful symptoms, including suicide ideation, carers are also at risk of developing mental health issues and exhaustion.

How does treatment-resistant depression influence suicide risk?

While increased mortality in depression can result from physical illnesses, it is often associated with suicide. In patients with treatment-resistant depression, risk of suicide has been shown to be elevated, especially among patients with previous suicide attempts²⁴. However, the exact relation between treatment-resistant depression and suicide-related outcomes is not yet completely understood⁴².

Olin et al. however showed that a partial response to a treatment can still have a beneficial impact on suicide risk in patients with treatment-resistant depression⁴³. Their results highlighted that a response to a treatment (with a >50% reduction in MADRS score) and a partial clinical response to a treatment (with a MADRS score reduction between 25–29%) reduces the risk of suicidal behaviour⁴³.

When the burden of treatment-resistant depression becomes great enough, some patients consider assisted dying where available^43,44

Some countries in Europe, particularly Belgium and The Netherlands, allow assisted dying for non-terminal illness, including mental disorders, under strict conditions⁴⁴.The United States also now allows assisted dying in four states, however it is restricted to terminal physical illness⁴⁵.

What is the impact on quality of life for people with treatment-resistant depression?

In a study by Lex et al., the impact on quality of life was found to be high in people with treatment-resistant depression, with 81% of participants describing their quality of life as “poor” or “very poor” (N = 79)⁴⁶. A further 70% reported themselves as being “dissatisfied” or “very dissatisfied” with their health⁴⁶. Based on international normative data, Figure 4 shows the distributions of the standardised z-scores and highlights how physical, psychological, and social quality of life are particularly impacted⁴⁶.

Figure 4. Distributions of World Health Organization quality of life scale scores across physical, psychological, emotional, and environmental domains among people with treatment-resistant depression (Adapted from Lex et al⁴⁶). WHOQOL-BREF, World Health Organization Quality Of Life scale.

The average physical and psychological quality of life scores were two standard deviations below the international norm and social quality of life scores were one standard deviation below⁴⁶. The impact on environmental quality of life was however consistent with international norms⁴⁶.

This highlights the need to target quality of life as a clinical outcome when developing treatments as well as the need to assess quality of life when caring for patients.

Does the burden of treatment-resistant depression affect carers?

Caregivers also face significant burdens when caring for patients of treatment-resistant depression, such as dependence and fear of suicide, that stem from the emotional, physical, social, and financial problems associated with caring for a depressed patient^47,48.

Rane et al. reported high levels of psychiatric caseness among informal caregivers of treatment-resistant depressive patients compared to controls (34% vs 4%, P = 0.009)⁴⁹. This may be further worsened by the stigma associated with mental illness. This perceived stigma has been shown in a previous study that found 43% of caregivers (N = 481) of people with mental illness felt they were devalued⁵⁰. This stigma has been found to increase depressive symptoms in caregivers⁵¹, leading to complications for the patient in their care.

Click here to learn more about the biology of treatment-resistant depression

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