Neuroscience Breakthroughs Since Graduate School - Part 5: Depression

Since major depressive disorder (MDD) is a heterogeneous disorder, researchers study its diverse phenotypes. Heritability ranges from 26% to 39% in twins (van Calker et al., 2021). Traditional antidepressants (ADs) exhibit a delayed onset of effect. For example, serotonin-selective reuptake inhibitors (SSRIs) are associated with clinical improvement in the first week, with decreasing gains over 6 weeks (Taylor et al., 2005). About 30-40% of patients respond to their first antidepressant trial with reduced symptom severity but not remission. The monoamine deficiency hypothesis is poorly supported by research findings, especially for serotonin. Current research has targeted seven key areas: the interaction of multiple neurotransmitter (NT) systems, decreased neurogenesis and repair, structural abnormalities, functional abnormalities, inflammation, hypothalamic-pituitary-adrenal (HPA) axis dysfunction, and reduced heart rate variability (HRV). This installment concludes with a summary of biofeedback and neurofeedback efficacy in MDD.

Click on our narrator icon to listen to this post.

Neurotransmitters in Major Depressive Disorder

Neuroscientists are increasingly adopting a systems approach, studying how NTs interact in MDD. They have mainly focused on dopamine, endocannabinoids, GABA, glutamate, norepinephrine, and serotonin. These NTs operate in concert, not in isolation (El Mansari et al., 2010).

The monoaminergic deficiency hypothesis has been poorly supported by research findings.

Advokat and colleagues (2019) provided a valuable overview in Julien's Primer of Drug Action (14th ed.):

Historically, depression was conceptualized as a deficiency in the levels of various neurotransmitters, particularly the monoamines serotonin, norepinephrine, and dopamine. It was thought that restoring the levels of these neurotransmitters to 'normal,' usually by sustaining their presence in the synaptic cleft by blocking their degradation and/or presynaptic reuptake, was responsible for their efficacy in restoring a normal mood state. These proposed physiological theories of depression and the proposed effects of various antidepressants on these transmitter systems have not held up and have been largely discarded (p. 435).

Stahl (2021) reinforced this conclusion in Stahl's Essential Psychopharmacology (5th ed.):

Thus, there is no clear and convincing evidence that monoamine deficiency accounts for depression: i.e., there is no 'real' monoamine deficit. Likewise, there is no clear and convincing evidence that abnormalities in monoamine receptors account for depression even though all the classic drugs to treat depression raise monoamine levels (p. 264).

Moncrieff and colleagues' (2022) systematic umbrella review of serotonin's role in depression likewise found:

The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.

Erittzoe and colleagues' (2020) finding of reduced serotonin release in response to a d-amphetamine challenge was not direct evidence of a monoamine deficit and requires replication.

Glutamate's Role in Depression

Jaso and colleagues (2017) emphasized the importance of glutamate in CNS communication and MDD pathophysiology:

It should be noted that glutamate is the major excitatory neurotransmitter in the central nervous system (CNS); it is estimated that up to 50% of CNS neurons use glutamate as their primary neurotransmitter in contrast to only 10-20% of monoaminergic neurons. In addition, both clinical and preclinical studies support the notion that glutamatergic dysfunction plays a key role in the pathophysiology of MDD, suggesting that a subsidiary role for glutamate in ketamine’s antidepressant response is unlikely.

The rapid response of treatment-resistant patients to ketamine infusion (Ketalar) and nasal spray (esketamine, Spravato) has intensified research into glutamate's role in MDD.

AMPA and NMDA receptors are two types of fast excitatory glutamate receptors. Illustration 193046428 © Juan Gaertner | Dreamstime.com

Modified caption: From left to right: the NMDA and AMPA receptors transport calcium cations into neurons after being activated by the neurotransmitter glutamate, and the GABA receptor right transports chloride anions after the activation by gamma-aminobutyric acid.

Glutamate binding to NMDA receptors on GABA interneurons increases GABA release and inhibits glutamate release by neurons projecting to the medial prefrontal cortex (mPFC). van Noordt and Segalowitz mPFC graphic © Frontiers in Human Neuroscience.