Which neurotransmitter is primarily implicated in the monoamine hypothesis of depression?

Monoamine Hypothesis of Depression: Primary Neurotransmitters

Serotonin, norepinephrine, and dopamine are the three monoamine neurotransmitters primarily implicated in the monoamine hypothesis of depression, with serotonin historically receiving the most attention due to the selective efficacy of serotonin reuptake inhibitors. 1

The Core Monoamine Hypothesis

The monoamine hypothesis predicts that depression results from depletion of serotonin, norepinephrine, and/or dopamine in the central nervous system 1. This theory emerged from observations that:

• Antidepressants that elevate levels of these neurotransmitters effectively alleviate depressive symptoms 1
• The mechanism of action of early antidepressants (MAO inhibitors and tricyclics) pointed to monoamine involvement 2
• Type A monoamine oxidase (MAOA), which catabolizes all three monoamines, shows increased expression in depression alongside decreased brain levels of serotonin and norepinephrine 3

Individual Neurotransmitter Roles

Serotonin (5-HT)

• The serotonin transporter gene (SLC6A4/5-HTT) shows the most extensively studied associations with depression, particularly the 5-HTTLPR polymorphism affecting serotonin expression 4
• Patients responding to selective serotonin reuptake inhibitors (SSRIs) relapse more frequently following serotonin depletion than catecholamine depletion 5

Norepinephrine (NE)

• Patients responding to selective catecholamine reuptake inhibitors relapse more frequently following catecholamine depletion than serotonin depletion 5
• The COMT Val158Met polymorphism affects noradrenaline metabolism, with the low-activity Met/Met genotype consistently associated with increased depression risk 4

Dopamine (DA)

• Dopamine is involved in reward processing, motivation, and mood regulation—all domains affected in depression 6
• Specific symptoms of depression can be assigned to specific neurotransmitter mechanisms, with dopamine particularly associated with loss of positive affect 7

Critical Revision of the Hypothesis

The original hypothesis has undergone major revision based on monoamine depletion studies showing that the monoamine systems likely play a modulatory rather than primary causal role. 5

Key findings that forced this revision:

• Monoamine depletion does not worsen symptoms in depressed patients off medication 1, 5
• Monoamine depletion does not cause depression in healthy volunteers with no depressive illness 1, 5
• Intensive investigation has failed to find convincing evidence of a primary dysfunction of a specific monoamine system in patients with major depressive disorders 1
• Relapse during treatment is specific to the type of antidepressant and type of depletion, suggesting monoamines modulate "other" brain neurobiologic systems that have a more primary role in depression 5

Clinical Implications

Antidepressant agents require intact monoamine systems for their therapeutic effect, even though monoamine deficiency may not be the primary cause of depression itself. 1

• The modulatory function of monoamine systems appears necessary during drug-induced recovery and maintenance of recovery after a prior episode 5
• Recovered patients with prior depression history do relapse with serotonin depletion, indicating vulnerability persists even after clinical recovery 5
• Current treatments can be targeted toward patients' specific symptoms based on which neurotransmitter systems are most affected 7