Depression, often considered a monolithic clinical diagnosis, is seen to have varying clinical presentations. These polymorphic presentations make the clinicians job of identifying, diagnosing, and treating inherently challenging. Compounding this problem, approximately a third of patients with major depressive disorder (MDD) do not respond to treatment, with only half achieving remission. This treatment resistance results in high morbidity and makes MDD one of the leading causes of disability in the world per the World Health Organisation.

Early intervention, intensive and multimodal treatment are key to improving outcomes in this patient population. Challenges inherent to treatment include polymorphism in clinical presentation, multifactorial aetiology and complex pathophysiology. Modern research has enabled us to identify distinct pathophysiological processes underlying a depressive syndrome, increasing our ability to better understand this complex entity.

In this presentation, we will discuss the different pathophysiological processes underlying depression. We will review current evidence for approaching patients with difficult to treat presentations using conventional and complementary medicine modalities. In addition, we will discuss the latest developments in conceptualizing treatment resistance and novel, experimental treatments that are under investigation.

Learning Objectives:

1. Define depression and treatment resistant depression.
2. Discuss pathophysiological processes implicated in the clinical presentation of depression.
3. Describe evidence-based conventional and integrative treatments for depressive disorders.
4. Review novel and experimental approaches for difficult to treat depression.

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