Pathogenesis: Biochemical Hypotheses

The main hypotheses regarding the pathogenesis of depressive disorders suggest that a fundamental deficit may lie in the destabilization of central neurotransmitter systems. Over time, however, it has become clear that depression cannot be reduced to a simple monoaminergic deficiency, but rather represents the result of a complex interaction between genetic vulnerabilities, stressful events, neuroendocrine dysfunctions, inflammatory mechanisms, and impaired neuroplasticity.

The Catecholaminergic and Serotonergic Theory

The earliest pathogenetic theories date back to the 1960s and are based on the observation that antidepressants work by enhancing the activity of cerebral monoaminergic systems, particularly through inhibition of synaptic reuptake or enzymatic degradation of norepinephrine (NE), serotonin (5-HT), and dopamine (DA). According to this view, depression corresponds to a functional deficit of monoaminergic neurotransmitters, while mania is linked to their excess.

Schildkraut observed that, during depressive episodes, patients showed increased urinary metabolites of norepinephrine, especially vanillylmandelic acid (VMA) and normetanephrine (NM). This increase diminished with the administration of tricyclic antidepressants or monoamine oxidase inhibitors (MAOIs), suggesting excessive intracellular deamination of NE, reducing its availability for synaptic transmission.

Supporting this theory, studies on plasma renin activity (PRA) in upright posture, a marker of peripheral adrenergic activity, showed significantly attenuated responses in patients with major depression compared to controls. Thus, sympathetic activation, mediated by hypothalamic stimulation, appears impaired or dysfunctional in depressed subjects.

Regarding serotonin, numerous studies have documented reduced levels of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) of depressed individuals, indicating decreased central serotonergic activity. 5-HT deficit has also been linked to impulsivity and increased suicide risk. Additionally, low urinary levels of N-1-methylnicotinamide have further supported impaired serotonin metabolism.

Despite early support, the monoaminergic theory was later revised. First, the therapeutic effects of antidepressants take weeks to emerge, even though neurochemical changes occur within hours. Second, substances like cocaine and amphetamines, which strongly increase synaptic monoamines, do not produce lasting antidepressant effects, while newer antidepressants do not necessarily act on monoamine reuptake.

This led to the concept of receptor down-regulation: tricyclics and other antidepressants reduce expression of postsynaptic beta-adrenergic and 5-HT2 receptors, a change that develops over weeks and correlates with clinical improvement. Beta-adrenergic down-regulation requires serotonergic input, and vice versa, demonstrating close functional interaction between these systems.

The Dopaminergic Theory

Alongside norepinephrine and serotonin, the dopaminergic system has gained attention, especially to explain symptoms like anhedonia, low motivation, and psychomotor slowing—often resistant to traditional drugs. Initially secondary, the dopaminergic hypothesis became central as many depressed patients showed dysfunctions in the mesolimbic dopaminergic pathway, involved in reward, interest, and activation.

Depression may involve reduced activation of D2 receptors, both presynaptic (autoreceptors that inhibit DA release) and postsynaptic. Clinical studies showed that apomorphine, a dopamine agonist, can induce depressive symptoms via presynaptic D2 receptor activation. Conversely, dopaminergic antidepressants reduce receptor sensitivity and enhance dopamine release.

Clinical and experimental data also link increased severity of extrapyramidal symptoms (a marker of hypodopaminergia) with worse depression. Patients with parkinsonism or on dopamine-blocking neuroleptics more often develop depressive symptoms, reinforcing the hypothesis of dopaminergic involvement.

Pharmacological studies by Altamura, Corsini, and others confirmed that apomorphine induces depression via D2 receptor activation, while chronic antidepressant use reduces receptor sensitivity. Dopaminergic agents like L-DOPA have shown efficacy in unipolar depression with psychomotor slowing, though effects are often short-lived.

Additional dopamine receptor subtypes (D3, D4, D5) have been identified, whose role in depression remains under investigation. Some may become targets for novel treatments.

Measurement of Homovanillic Acid (HVA)

Further support for the dopaminergic hypothesis comes from CSF studies on monoamine metabolites. Specifically, homovanillic acid (HVA), the primary DA metabolite, is reduced in some depression subtypes. Kasa and Lakshmi Reddy found significantly lower HVA levels in depressed patients, though Post et al. reported less conclusive findings.

A meta-analysis by Banki indicated that reduced HVA is particularly marked in depression with dominant psychomotor slowing. Ray et al. also found a link between low HVA and suicide risk, supporting hypodopaminergia’s central role in severe depressive forms.

HPA Axis and Stress

Among modern pathogenetic models, the neuroendocrine hypothesis is one of the most robust. In chronic stress, the hypothalamic-pituitary-adrenal (HPA) axis—key mediator of stress response—can become dysregulated, leading to cortisol hypersecretion by the adrenal cortex.

This persistent hypercortisolism has neurotoxic effects on the hippocampus, a brain region critical for mood regulation and negative feedback on the HPA axis. Excess cortisol reduces neurogenesis, promotes apoptosis, and causes hippocampal atrophy, as confirmed by imaging studies—possibly explaining cognitive deficits in depression.

The dexamethasone suppression test (DST) evaluates negative feedback via glucocorticoid receptors and is often abnormal in depression. In affected patients, dexamethasone fails to adequately suppress cortisol production, suggesting hypothalamic receptor resistance.

Besides affecting vulnerable brain areas, cortisol alters monoaminergic transmission and inhibits brain-derived neurotrophic factor (BDNF) synthesis, thus impairing structural and functional brain networks involved in affect regulation.

Inflammatory and Immune Hypotheses

Depression is increasingly recognized as a syndrome with inflammatory and immune components. Emerging evidence shows elevated levels of proinflammatory cytokines—IL-6, IL-1β, and TNF-α—in depressed individuals. These cytokines can cross the blood-brain barrier or stimulate afferent neuronal pathways (e.g., vagus nerve), disrupting brain physiology.

One mechanism involves indoleamine-2,3-dioxygenase (IDO) activation by cytokines, diverting tryptophan metabolism away from serotonin toward kynurenine and neurotoxic metabolites (e.g., quinolinic acid), reducing 5-HT availability and potentially promoting neurodegeneration.

Neuroinflammation also impairs glial cell function. Activated microglia release nitric oxide, prostaglandins, and free radicals with cytotoxic effects. Astrocytes—crucial for metabolic and synaptic support—are reduced in number and function in cortical areas of depressed patients, compromising synaptic homeostasis and neuroplasticity.

Neurotrophic Factors and Neuroplasticity

An additional key hypothesis in modern depression research involves impaired neuroplasticity. Depressed brains show disrupted synaptic remodeling and reduced neurogenesis, especially in the hippocampus, prefrontal cortex, and amygdala—regions central to mood and stress regulation.

Brain-derived neurotrophic factor (BDNF) is essential for neuronal survival, synaptogenesis, and synaptic plasticity. Animal and human studies show BDNF levels are reduced in major depression, particularly in the hippocampus and serum. Chronic stress, via HPA axis activation and cortisol overproduction, suppresses BDNF gene transcription and synthesis.

Antidepressants not only affect monoaminergic systems but also increase BDNF synthesis and promote hippocampal neurogenesis. These effects emerge after 2–3 weeks of treatment, matching clinical response latency, and support the “neuroplasticity hypothesis,” where functional neural recovery—not just neurotransmitter restoration—is key to antidepressant action.

Genetic variants of BDNF, like the Val66Met polymorphism, have been linked to higher depression vulnerability, poorer treatment outcomes, and brain structural changes. The interaction between genetics, chronic inflammation, prolonged stress, and reduced BDNF creates a favorable terrain for depression development and chronicity.

Conclusions

The pathogenesis of depression represents an integrated and multidimensional model. The original monoaminergic theory provided a useful foundation, but it is now evident that altered serotonin, norepinephrine, and dopamine transmission alone cannot explain the full spectrum of depressive pathology.

Current evidence highlights a complex network involving neurotransmitter systems, neuroendocrine pathways (especially the HPA axis), systemic and local inflammatory processes, neurotrophic factors, and brain plasticity mechanisms. Even partial disruption of one system—particularly in genetically predisposed individuals or under chronic stress—can trigger a cascade leading to depression onset.

Modern therapeutic approaches should aim not only to restore monoaminergic transmission but also to normalize HPA activity, modulate neuroimmune inflammation, and recover neuroplasticity. Future strategies may include neuroendocrine modulators, anti-inflammatories, neurotrophic agents, and personalized treatments based on individual biological profiles.

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