Clinscience
What are the new possibilities to help patients with MDD?

Major depressive disorder (MDD) in adolescents is a commonly occurring seriously impairing and often undertreated disorder. It is a heterogeneous disorder with many contributing etiological pathways. MDD usually occurs in the context of a remarkably high prevalence of depressed mood and a high prevalence of subsyndromal depressive episodes. This disorder is very often recurrent and typically comorbid with other mental disorders. MDD is quite a common psychiatric disorder in older adults and occurs in 2% of adults aged 55 years and older.

One of the well-known models to explain the development of  major depressive disorder is the stress-vulnerability model. This model postulates that the likelihood for depression increases due to the interaction between intrinsic vulnerability (i.e. heritability) and risk factors. The past 40 years of research have identified most consistently, the following depression risk factors: cognition and cognitive processes, stressors, certain sociodemographic factors such as being female, parental depression and certain traits, behaviour patterns and dispositions.

Most risk factors can occur at any point throughout life and the likelihood of their occurrence (constituting absolute risk) differs throughout the lifespan. Major depressive disorder and the neuroticism personality trait have overlapping genetic susceptibilities and may also possibly have a genetic basis. Most genetic studies of MDD have considered a small set of functional polymorphisms relevant to monoaminergic neurotransmission. Meta-analyses of clinical trials suggest small positive associations between the polymorphism in the serotonin transporter promoter region (5-HTTLPR) and bipolar disorder, suicidal behaviour and depression-related personality traits, but not yet to MDD itself.

Treatment

All major guidelines for the treatment of depression agree upon the need for a biopsychosocial assessment of stressors, patient’s overall health issues, and any risk of harm that patients may pose to themselves or to others. Other universal recommendations include individualizing treatment according to patients’ profiles and needs using standardized measurement tools to track symptomatology, prescribing an appropriate dosage of a medication for an adequate duration and treating patients to remission.

Although all major international guidelines for the treatment of major depressive disorder are evidence-based, treatment recommendations may occasionally be influenced by factors such as the personal experience of authors.

Mild depression

Depending on the guidelines, treatment recommendations for mild cases of MDD range from antidepressant pharmacotherapy or psychotherapy (usually in combination) to active monitoring of if a possibility exists that the episode might resolve itself. The National Institute of Clinical Excellence (NICE) guideline for mild disorders also includes the options of self-help as well as sleep hygiene education.

The general idea of mild depression treatment is that low-intensity treatments should be tried first. Only in cases of chronic depression or if a patient has had a previously severe episode, antidepressants or evidence-based psychotherapies are appropriate.

Moderate depression

The treatment of moderate depression is concerned with antidepressant monotherapy, some form of psychotherapy as a monotherapy or a combination of the two, especially when the patient has significant psychosocial problems or a comorbidity.

Commonly recommended first-line pharmacotherapeutic options include SSRIs, SNRIs, bupropion and mirtazapine. Psychotherapeutic methods include cognitive-behavioural therapy (CBT), cognitive therapy and behaviour therapy with activity scheduling.

Severe depression

For severe depression, the recommendations suggest a combination of an antidepressants and psychotherapy, or, if the patient has psychotic features, a combination of antidepressants and antipsychotic medications.

New possibilities to treat MDD

SPRAVATO™ by Janssen Pharmaceutical Companies of Johnson & Johnson

SPRAVATO™ (esketamine) is a nasal spray for adults with treatment-resistant depression (TRD) who have cycled through multiple treatments without relief. It uses the first new mechanism of action to treat MDD. In short and long-term clinical trials, those who received SPRAVATO™ and a newly initiated oral antidepressant achieved a superior improvement of depression symptoms and sustained improvement of their symptoms over time, compared to adults who received placebo and an oral antidepressant.

In recent days the U.S. Food and Drug Administration (FDA)  has approved SPRAVATO™ CIII nasal spray for use in conjunction with an oral antidepressant in adults with treatment-resistant depression. People who are currently struggling with MDD are considered to have TRD if they have not responded adequately to at least two different antidepressants of adequate dose and duration in the current depressive episode. SPRAVATO™ was studied in a robust Phase III clinical trial program with more than 1,700 adults with TRD.

In the short-term study, those who took it and an oral antidepressant experienced superior improvement in depression symptoms at four weeks, compared to those who received placebo and an oral antidepressant. In the long-term study, patients in stable remission taking SPRAVATO™ who continued treatment with the medicine were 51% less likely to relapse versus those who received placebo and an oral antidepressant.

DiSK by Celon Pharma

DiSK is the new form of esketamine in a Dry Powder Inhaler, whose efficacy, pharmacokinetics and safety were determined in clinical trials in subjects with TRD in the course of MDD.  Scientists compared DiSK with placebo and assessed the results using the Montgomery-Asberg Depression Rating Scale (MADRS) total score at Day 14 of the treatment phase. The results are very promising.

Summary

Major depressive disorder has a significant impact on an individual’s everyday life as well as society, with the majority of the costs being generated outside of the healthcare system. Several cost-of-illness studies on MDD focus on the direct, medical and in some cases direct non-medical costs.

Indirect costs are not frequently assessed even if they impose a significant burden on society, particularly during the acute phases of the disease. Pharmacological treatment is an important component of direct medical costs, which are estimated to account for between 6% and 29% of total direct health care costs. The Longitudinal Investigation of Depression Outcomes (LIDO) study was an international, cross-sectional, observational study that involved primary care patients with MDD from six countries: Israel, Brazil, Australia, Spain, Russia, and the United States.

Results confirmed that the economic burden of the disease can vary depending on the severity of MDD and are incredibly significant. For Spain (Barcelona), the mean annual health care costs for patients in remission were lower compared with the costs for patients who were partially in remission or who experienced persistent depression. The new therapies like SPRAVATO™ or DiSK for MDD will probably  be able to lower the indirect costs of MDD.

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References

1. Kessler, R. C., de Jonge, P., Shahly, V., van Loo, H. M., Wang, P. S.-E., & Wilcox, M. A. (2014). Epidemiology of depression. In I. H. Gotlib & C. L. Hammen (Eds.), Handbook of depression (p. 7–24). Guilford Press.

2. Schaakxs, Roxanne, et al. “Risk Factors for Depression: Differential Across Age?” The American Journal of Geriatric Psychiatry, vol. 25, no. 9, 2017, pp. 966–977., doi:10.1016/j.jagp.2017.04.004.

3. Kok, Rob M., and Charles F. Reynolds. “Management of Depression in Older Adults.” Jama, vol. 317, no. 20, 2017, p. 2114., doi:10.1001/jama.2017.5706.

4. Levinson, Douglas F. “The Genetics of Depression: A Review.” Biological Psychiatry, vol. 60, no. 2, 2006, pp. 84–92., doi:10.1016/j.biopsych.2005.08.024.

5. Hammen, Constance. “Risk Factors for Depression: An Autobiographical Review.” Annual Review of Clinical Psychology, U.S. National Library of Medicine, 7 May 2018, www.ncbi.nlm.nih.gov/pubmed/29328780.

6. https://www.cmeinstitute.com/Psychlopedia/Pages/depression/12iod/sec1/section.aspx

7. https://www.medicographia.com/2011/10/economic-burden-of-depression-on-society/

8. https://celonpharma.com/pipeline/neurology-2/a-new-form-of-s-ketamine-in-treatment-of-depression/

9. https://www.janssen.com/janssen-announces-us-fda-approval-spravato-esketamine-ciii-nasal-spray-adults-treatment-resistant

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