10 Biological Causes of Depression: A Complete Guide
Depression arises from a web of biological causes—genetic predisposition, monoamine and glutamate/GABA imbalance, chronic inflammation, HPA axis dysregulation, BDNF reduction, impaired neurogenesis, mitochondrial dysfunction, and gut-brain miscommunication—all contributing to mood, cognition, and brain structure changes. This guide explores the top 10 biological causes of depression driving depressive disorders.
Top 10 Biological Causes of Depression
- Genetic Vulnerability
Family and twin studies reveal that 40–50% of depression risk is heritable. Variants in genes like 5-HTTLPR (serotonin transporter), BDNF, CRHR1, and FKBP5 are implicated, especially when combined with life stress.
- Monoamine Neurotransmitter Deficits
Historically, depression has been linked to low serotonin, norepinephrine, and dopamine. Notably, cerebrospinal analyses show reduced dopamine metabolite levels in depressed patients . These deficits underlie mechanisms of antidepressants and dopamine-boosting therapies.
- HPA Axis Dysregulation & Cortisol
Chronic stress over activates the hypothalamic-pituitary-adrenal (HPA) axis, elevating cortisol. High cortisol disrupts the hippocampus, impairs neurogenesis, and fuels inflammation.
- Chronic Inflammation & Immune Dysregulation
Elevated proinflammatory cytokines—IL‑6, IL‑1β, TNF‑α—are consistently found in depressed individuals . These cytokines disrupt neurotransmission, activate the kynurenine pathway, and promote neurotoxicity via metabolites like quinolinic acid.
- Microglial Activation & Neuroinflammation
Brain immune cells, microglia, release cytokines that reduce BDNF and foster neuroinflammatory processes. This contributes to impaired neuronal growth and depression-related brain changes.
- BDNF Reduction & Impaired Neuroplasticity
Brain-Derived Neurotrophic Factor (BDNF) is critical for neural plasticity. Chronic stress lowers BDNF levels in the hippocampus and prefrontal cortex, correlating with depressive symptoms. Antidepressants often reverse this by increasing BDNF.
- Reduced Neurogenesis in the Hippocampus
Persistent stress and decreased BDNF stifle hippocampal neurogenesis. The neurogenesis hypothesis posits that insufficient production of new neurons contributes to depression—supported by structural MRI findings.
- Mitochondrial Dysfunction & Oxidative Stress
Markers like 8-oxo-dG and F2-isoprostanes signal increased oxidative damage in depression. Dysfunctional mitochondria impair brain energy metabolism and neuroplasticity.
- Gut–Brain Axis & Microbiome Imbalance
The gut microbiome communicates with the brain via immune signals, neurotransmitters, and the vagus nerve . Dysbiosis may elevate inflammation, alter serotonin production, and disturb the tryptophan–kynurenine pathway, linking gut health to mood disorders.
- Glutamate–GABA Dysregulation & Kynurenine Toxicity
Inflammation elevates neurotoxic quinolinic acid (QUIN), activating NMDA receptors and triggering glutamatergic excitotoxicity. Simultaneously, anti-inflammatory kynurenine metabolites decline. Disruption in GABA/glutamate balance impairs mood regulation.
Treatment Options: Best Anti-Depression Medicines
While biological causes of depression are complex, effective treatment is possible through a combination of lifestyle changes, psychotherapy, and prescription medications. When depression has a biological basis—such as chemical imbalances, inflammation, or structural changes in the brain—antidepressant medications play a central role in recovery.
Below are two commonly prescribed and medically approved treatments that target biological pathways linked to depression:
1. Duloxetine 30mg Tablet (Brand name: Cymbalta)
Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI) used to treat major depressive disorder (MDD), generalized anxiety disorder, and chronic pain conditions often linked with depression.
How It Works:
- Increases levels of serotonin and norepinephrine in the brain by preventing their reabsorption.
- Helps regulate mood, pain perception, and stress response—key biological areas often impaired in depression.
Benefits:
- Especially useful for patients with both depression and physical symptoms like fatigue or body pain.
- Fewer sedative effects than some other antidepressants.
- Often considered among the best anti-depression medicines for individuals with mixed emotional and somatic symptoms.
“Duloxetine helps patients who struggle with the emotional and physical burden of depression. Its dual action on neurotransmitters provides comprehensive relief,” says Dr. Jennifer Frank, Psychiatrist at the American Psychiatric Association.
(Source: Mayo Clinic – Duloxetine)
2. Seroquel 100mg Tablet (Generic: Quetiapine)
Seroquel is an atypical antipsychotic commonly used in lower doses as an adjunct treatment for depression, especially treatment-resistant depression (TRD) and bipolar depression.
How It Works:
- Alters the activity of dopamine and serotonin in key brain circuits involved in mood regulation.
- At lower doses (50–300mg), Seroquel exerts antidepressant and anti-anxiety effects without strong antipsychotic action.
Benefits:
- Helps individuals who haven’t responded well to standard SSRIs or SNRIs.
- Reduces symptoms of insomnia, anxiety, and emotional instability often co-occurring with depression.
- Often used as part of combination therapy with traditional antidepressants.
Frequently Asked Questions
1. What are the main biological factors of depression?
Depression is caused by a combination of biological factors including genetics, low serotonin or dopamine levels, chronic inflammation, hormonal imbalances, and changes in brain structure.
2. Can inflammation cause depression?
Yes. Studies show that elevated levels of inflammatory cytokines like IL‑6 and TNF‑α can affect brain chemistry and mood, contributing to symptoms of depression.
3. How does the gut-brain axis affect depression?
The gut and brain communicate via hormones and nerves. Imbalances in gut bacteria (dysbiosis) can increase inflammation, reduce serotonin production, and worsen depression.
