Updated: Jan 25
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.
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.
Note. Red denotes the dorsal, and yellow the ventral mPFC.
Ketamine and esketamine interfere with GABA interneuron NMDA receptors. Das (2020) NMDA receptor graphic © ACS Publications.
Note. Calcium and sodium ions cannot enter the NMDA receptor and depolarize the neuron when esketamine or ketamine blocks their channel.
This reduces GABA release and increases glutamate availability in the mPFC. Researchers theorize that increased glutamate binding at mPFC AMPA receptors may mediate rapid improvement in about 70% of treatment-resistant MDD patients. ID 181293078 © Juan Gaertner | Dreamstime.com.
Modified note. Glutamate receptors are located on the membranes of neurons. The neurotransmitter glutamate (orange) activates the receptor to transport cations (red) into the neuron. This postsynaptic excitation is important for neural communication, memory formation, learning, and regulation.
Increased glutamate binding at hippocampal AMPA receptors is theorized to increase BDNF expression, promote neurogenesis, and activate newly created hippocampal neurons. Rawat and colleagues (2022) reported that ketamine activates adult-born immature granule neurons (ABINs) in mice.
Decreased Neurogenesis and Repair
Advokat et al. (2019) explained how the failure of the monoamine deficiency hypothesis led to the neurogenic theory of depression:
Another weakness of this model is that the neurotransmitter changes occur soon after drug administration, but the clinical antidepressant effect develops more slowly, often during several weeks of continuous treatment. This delay was hypothesized to be due to changes in receptor sensitivity caused by the chronic increase in synaptic levels of neurotransmitter. In the past few years, however, this view has broadened, and attention has shifted to the study of the long-term actions of antidepressant treatments on intracellular processes, such as second messengers, and their functions in the neuron.
Two of these second-messenger functions are (1) to protect neurons from damage due to injury or trauma; and (2) to promote and maintain the health and stability of newly formed neurons. Research into these processes has led to a new way of thinking about depression (and the effect of antidepressant treatment) called the neurogenic theory of depression.
Neurogenic Theory of Depression
The neurogenic theory of depression proposes that damaged neurons can repair themselves and the adult brain creates new functional neurons in the hippocampus and frontal cortex. The hippocampus participates in functions like attention, concentration, and memory, which are often compromised in depression (Advokat et al., 2019).
When depression, hypoglycemia, infection, and stress damage adult neurons in the hippocampus, neurotrophins like brain-derived neurotrophic factor (BDNF) participate in their repair (Advokat et al., 2019; Miranda et al., 2019). Hippocampus graphic © SciePro/Shutterstock.com.
We summarized the evidence for neurogenesis in Neuroscience Breakthroughs Since Graduate School - Part 4: Neurons. For a refresher, although there is a consensus on adult human hippocampal neurogenesis (Eriksson et al., 1998; Jurkowski et al., 2020; Planchez et al., 2020), cortical neurogenesis remains controversial.
In the graphic below, the neuron on the left has been tagged with a green dye to document that it was created in adulthood (Simon Braun, HiFo/UZH). The graphic below was retrieved from sci.news.
Note. Neural stem cells giving rise to neurons are green, and an adult hippocampal neuron is red.
Advokat and colleagues (2019) view depression as a neurodegenerative disorder. They observed that 50% of depressed patients exhibit abnormal physiological stress responses. Hippocampal neurons are highly vulnerable to changes like chronically elevated glucocorticoid levels due to their high density of cortisol receptors (Kim et al., 2015). BDNF levels are depressed in depressed patients (Neto et al., 2011).
Note. The figure shows a normal brain cell in the hippocampus on the left panel. In the middle panel, stress or other neuronal insults like hypoxia-ischemia, hypoglycemia, neurotoxins, and viruses can cause an increase in glucocorticoids and a decrease in the expression of BDNF. This combination causes atrophy of the brain cells in the hippocampus, leading to hippocampal shrinkage.
Antidepressants appear to increase serotonin and norepinephrine levels, increasing BDNF expression (Launay et al., 2011; Molteni et al., 2006; Neto et al., 2011). There is evidence that SSRIs bind to specialized BDNF (TRK) receptors that promote BDNF signaling. Graphic © psych scene.
Stress reduction can reduce glucocorticoids, increasing the growth of neurites (e.g., dendrites and axons), cell survival, and hippocampal volumes (Advokat et al., 2019).
There is neuroimaging and postmortem evidence of neuron and glial volume reductions in the cingulate cortex, hippocampus, and prefrontal cortex (Durman et al., 2016; Elbejjani et al., 2015; Sarawagi et al., 2021). Shrinkage may be due to neuronal insults, elevated cortisol, decreased BDNF, and reduced neurogenesis in the hippocampus.
Sarawagi et al. (2021) graphic © Frontiers in Psychiatry.
Note. Schematic of glutamatergic and GABAergic projections involved in mood regulation and reward pathway. A subset of several known interconnections among different brain regions is shown. Major glutamatergic projections (red color) arise from the frontal cortex to the anterior cingulate cortex (ACC), thalamus (TH), ventral tegmental area (VTA), hippocampus (HPC), and nucleus accumbens (NAc). Additionally, glutamatergic neurons originate from the hippocampus and innervate into the hypothalamus (HT), VTA, NAc, and PFC, and from the amygdala to HT, ACC, and NAc. The GABAergic projections (green color) are widely distributed throughout the brain. The major projections relevant to this review are from HT to the occipital and parietal cortex, HPC to PFC, and NAc to the thalamus and VTA. The structural changes observed in the brain regions of depressed subjects are shown in the respective boxes.
The right prefrontal cortex is more activated than the left in MDD (Kaya & McCabe, 2019). Studies of amygdala blood flow have been inconclusive (Peluso et al., 2009).