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Depression: Neurobiological Basis, Atypical Presentations, and Evidence-Based Treatment

Clinical overview of depression covering neurobiological basis, atypical presentations including flatness, cognitive impairment, irritability, and functioning depression, reasons for consistent underrecognition, and evidence-based treatment including medication, CBT, IPT, and exercise. Neurodivergent-specific presentations addressed.

Melanie Du Preez
MelanieClinical Psychologist
2 min read
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Depression: Neurobiological Basis, Atypical Presentations, and Evidence-Based Treatment

Depression is a neurobiological condition characterised primarily by anhedonia — diminished capacity for positive experience — rather than sadness. The neurobiological basis involves monoaminergic dysfunction (serotonin, dopamine, noradrenaline), HPA axis dysregulation, neuroinflammatory processes, and impaired neuroplasticity in hippocampal and prefrontal regions (Krishnan & Nestler, 2008). It is a whole-brain, whole-body condition with measurable cognitive, somatic, and motivational features.

Atypical presentations covered include: affective flatness and anhedonia presenting as loss of interest rather than sadness; prefrontal cognitive impairment manifesting as concentration difficulties, slowed processing, and indecision (Rogers et al., 2004); fatigue that does not respond to rest; irritability as a primary mood presentation — particularly in men, adolescents, and ADHD presentations; withdrawal presenting as introversion or preference; and functioning depression in which clinical criteria are met alongside maintained occupational and social output.

The article addresses the four most common reasons depression goes unrecognised: incorrect severity benchmarks, attribution of individual symptoms to other causes, motivated resistance to the diagnosis, and the gradual trajectory that removes the person's reference point for their prior baseline.

Evidence-based treatment approaches covered include: antidepressant medication with reference to the Cipriani et al. (2018) Lancet meta-analysis; CBT including behavioural activation as a primary maintenance-disruption mechanism (Beck, 2011); interpersonal therapy for relational presentations (Cuijpers et al., 2011); and exercise, whose evidence base is stronger than is widely appreciated — comparable to antidepressants in mild to moderate presentations (Blumenthal et al., 2007).

Neurodivergent-specific considerations addressed: ADHD-depression overlap in dopaminergic presentations, autistic alexithymia complicating internal identification, and late diagnosis as a depression precipitant.

Dr Melanie du Preez | HPCSA-registered Clinical Psychologist | 26 years clinical experience | Founder, Mindpath Academy | Maudsley/FBT-certified | Specialisations: neurodivergence, trauma, burnout, LGBTQ+ mental health

Tags

depression, major depressive disorder, anhedonia, CBT, behavioural activation, IPT, antidepressants, neurodivergence, ADHD, autism, clinical psychology, therapy

About the Author

Melanie Du Preez

Melanie Du Preez

Clinical Psychologist

Specializations
Stress or AnxietyTrauma or PTSDGrief or Loss
About

I'm a practitioner with a PhD and 26 years of experience — which sounds very official until you factor in that I'm also a late-diagnosed AuDHD adult who spent most of those years wondering why everything felt slightly harder than it seemed to for everyone else. That context matters. It shapes how I work, how I listen, and how I explain things. I'm based in South Africa and work online with clients internationally. I specialise in neurodivergence, eating disorders, trauma, anxiety, and the kind of chronic low-grade overwhelm that doesn't always have a clean diagnostic label. I use evidence-based approaches — primarily BWRT, ACT, DBT, and CBT — but I adapt them to the person in front of me, not the other way around. I'm also a published author and Udemy course creator, because I believe good psychoeducation shouldn't be locked behind a therapy door. Here's the thing: I'm not the practitioner who'll nod politely and hand you a worksheet. I'm the one who'll actually explain what's happening in your brain and help you figure out what to do about it.

Depression: Neurobiological Basis, Atypical Presentations, and Evidence-Based Treatment | Shemesh Health Blog | Shemesh Health