Meeting the challenges of managing major depressive disorder

What is TRD?

Ana Gonzalez-Pinto (University of the Basque Country, Spain) introduced the topic of TRD as ‘an insufficient response to two antidepressants at adequate dose and duration’². This could be as monotherapy, or in combination or augmentation therapy³, although no universally accepted definition exists². The alternative description ‘difficult-to-treat depression’ has been suggested⁴, to avoid stigma associated with the term ‘resistant’.

Clinical factors predicting TRD include anxiety disorder, symptom severity, suicidal risk, and number of depressive episodes⁵. Non-response to antidepressant treatment is common, with remission rates dropping from 37% initially to 13% by the 4^th treatment step in the STAR*D study⁶.

Consequences of TRD include increased risks of hospitalization, suicide attempt and treatment non-adherence

Consequences of TRD include increased risks of hospitalization⁷, suicide attempt⁸ and treatment non-adherence⁹. Neurobiological sequelae involve progressive alterations in brain morphometry and circuit function and increased neuroinflammation^10-12.

Improving management of TRD

Key principles for managing TRD are⁴:

• Achieve optimal symptom control
• Target symptoms associated with poor outcomes (e.g. anxiety)
• Target symptoms to maximize function and quality of life (e.g. cognitive dysfunction)
• Manage comorbidities to reduce overall symptom burden (e.g. physical health problems)
• Optimize long-term outcomes by ensuring adequate prophylaxis

Using a highly structured treatment algorithm led to shorter time and fewer medication changes to achieve remission

Enabling clinicians to make earlier treatment decisions is important^3,13, including predicting treatment response. Using a highly structured treatment algorithm led to shorter time and fewer medication changes to achieve remission¹³. Early detection and optimized treatment is critical for patients to achieve full symptomatic and functional recovery, using a combination of pharmacotherapy and psychotherapy.

Underlying neurobiology

Evidence is growing that the glutamate system and neuroinflammation also have roles in MDD

Most antidepressants target the monoamine system, but Maurizio Pompili (Sapienza University of Rome, Italy) presented evidence that the glutamate system and neuroinflammation also have roles in MDD. Glutamate may be involved in regulation of monoaminergic neurons¹⁴ and neuroplasticity¹⁵. Abnormal cytokine levels may have a role in the pathogenesis of MDD and TRD¹⁶, and there is an association between neuroinflammation and suicidal behavior¹⁷.

Treating suicidal behavior

Suicidal behavior is a significant challenge in managing patients with MDD said Philippe Courtet (University of Montpellier, France). One proposal is that suicidal behavior should be considered as a distinct mental disorder rather than a complication of the associated psychiatric illness¹⁸. Assessment and risk stratification are important so level of intervention can be determined.

Suicidal behavior should be considered as a distinct mental disorder

Management usually consists of treating the underlying psychiatric condition as there have been no specific treatment options. Epidemiological studies have shown an inverse correlation between suicide rate and use of antidepressants but evidence is not conclusive¹⁹. Suicidal depressed patients respond less well to antidepressants in the short term²⁰.

There is a need for specific anti-suicidal drugs, but this patient group is often excluded from clinical trials. A recent review²¹ highlighted potential benefit from agents including lithium, clozapine, ketamine, selective serotonin reuptake inhibitors and buprenorphine. These can be used alongside psychosocial interventions which may be brief (eg. crisis response planning) or longer-term (eg. cognitive behavioral therapy)²¹.

Educational financial support for this Satellite symposium was provided by Janssen Pharmaceutica NV.