Scientific studies have shown that different brain areas exhibit altered activity in humans suffering from major depressive disorder (MDD), which has encouraged supporters of various theories that try to find a biochemical origin for the disease, as opposed to theories that emphasize psychological or situational causes.
One of these theories is the monoamine hypothesis, which suggests that a deficiency in certain neurotransmitters — serotonin, norepinephrine, and dopamine — is at the root of depression. This hypothesis emerged from observations of how certain drugs affected mood and from the biochemical effects of depression within the brain.
Monoamines
Monoamines are a class of neurotransmitters that includes serotonin, dopamine, norepinephrine, and epinephrine. Many antidepressants raise synaptic levels of serotonin, but they may also boost norepinephrine and dopamine.
The observation of this efficacy gave rise to the monoamine hypothesis of depression, which holds that a lack of certain neurotransmitters is to blame for major depression, and that specific neurotransmitters are associated with specific symptoms.
Normal levels of serotonin have been related to mood and behavior regulation, sleep, and digestion; norepinephrine to the fight-or-flight response; and dopamine to movement, pleasure, and motivation. Some have also postulated a link between monoamines and phenotypes, including serotonin in sleep and suicide, norepinephrine in dysphoria, exhaustion, apathy, cognitive dysfunction, and dopamine in motivation loss and psychomotor symptoms.
The primary weakness of the monoamine hypothesis of depression is the therapeutic lag between the start of antidepressant medication and the observed improvement in symptoms. One explanation for the therapeutic lag is that the initial rise in synaptic serotonin tends to be transient, as serotonergic neurons in the dorsal raphe adapt to 5-HT1A autoreceptor activation. Antidepressants are hypothesized to have a therapeutic impact by gradually desensitizing autoreceptors, finally increasing serotonergic neuron activity.
Serotonin
Most current antidepressants are selective serotonin reuptake inhibitors (SSRIs), which were initially said to act by restoring abnormally low serotonin levels. In 2022, a major review of prior research suggested that depression is not likely caused by a chemical imbalance and called into question what antidepressants do.
“It is always difficult to prove a negative, but I think we can safely say that after a vast amount of research conducted over several decades, there is no convincing evidence that depression is caused by serotonin abnormalities, particularly by lower levels or reduced activity of serotonin,”
lead author Professor Joanna Moncrieff, a Professor of Psychiatry at University College London and a consultant psychiatrist at North East London NHS Foundation Trust, said.
The umbrella review sought to include all relevant studies published in the most prominent disciplines of research on serotonin and depression. The review spanned a sample size of tens of thousands of individuals.
In studies that compared serotonin and its breakdown products in brain fluids or blood with those of healthy control participants, no significant difference was observed between those diagnosed with depression and the control group.
Research on serotonin receptors and the serotonin transporter, the protein targeted by most antidepressants, found weak and inconsistent evidence suggestive of higher levels of serotonin activity in people with depression. However, the researchers say the findings are likely explained by the use of antidepressants among people diagnosed with depression, since such effects were not reliably ruled out.
The authors also examined studies in which hundreds of people’s serotonin levels were artificially reduced by denying their diets of the amino acid essential to produce serotonin. These studies have been presented as evidence that a serotonin deficit is associated with depression.
A meta-analysis conducted in 2007 and a sample of recent studies found that lowering serotonin in this way did not produce depression in hundreds of healthy volunteers, however. There was very weak evidence in a small subgroup of people with a family history of depression, but this only involved 75 participants, and more recent evidence was inconclusive.
Very large studies involving tens of thousands of patients looked at gene variation, including the gene for the serotonin transporter. They found no difference in these genes between people with depression and healthy controls.
These studies also looked at the effects of stressful life events and found that these exerted a strong effect on people’s risk of becoming depressed – the more stressful life events a person had experienced, the more likely they were to be depressed. A famous early study found a relationship between stressful events, the type of serotonin transporter gene a person had and the chance of depression. But larger, more comprehensive studies suggest this was a false finding.
These findings together led the authors to conclude that there is “no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.”
On the other hand, there is evidence from receptor binding studies and pharmacological challenges that suggest serotonin neurotransmission is dysfunctional in depression. Serotonin may indirectly influence mood by modifying emotional processing biases observed at both the cognitive/behavioral and brain levels.
Monoamine Oxidase
An alternative version of the monoamine hypothesis proposes that monoamine oxidase A (MAO-A), an enzyme that metabolizes monoamines, may be overactive in depressed patients. This would lead to reduced levels of monoamines.
This hypothesis received support from a positron emission tomography study, which found significantly elevated activity of MAO-A in the brain of some depressed people. However, in genetic studies, the alterations of MAO-A-related genes have not been consistently associated with depression.
Contrary to the monoamine hypothesis’s assumptions, lowered rather than increased MAO-A activity was associated with symptoms of depression in teenagers. This link was only seen in maltreated adolescents, demonstrating that both biological (MAO genes) and psychological (maltreatment) components contribute to the development of depressive disorders.
Theory Weaknesses
Since the 1990s, research has shown numerous shortcomings to the monoamine hypothesis, and its insufficiency has been critiqued by the psychiatric profession. For starters, depression cannot be caused solely by a defect in the serotonin pathway.
Not all patients treated with antidepressants show improvements despite the usually rapid increase in synaptic serotonin. If significant mood improvements do occur, this is often not for at least two to four weeks. This is inconsistent with the fact that monoamine levels start to increase within hours of using antidepressants.
Intensive investigation has failed to find convincing evidence of a primary dysfunction of a specific monoamine system in people with MDD. Antidepressants that do not work on the monoamine system, such as tianeptine and opipramol, have been known for quite a while.
There have also been contradictory findings about serum 5-HIAA levels, a serotonin metabolite. Experiments with pharmacological agents that cause the depletion of monoamines have shown that this depletion does not cause depression in healthy people.
Another issue is that medications that decrease monoamine levels may also have antidepressant qualities. Furthermore, others claim that depression could be marked by a hyperserotonergic condition.
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