Which two neurotransmitters have been found to be implicated in depression?

Inhibitory and excitatory neurotransmitter systems in depressed and healthy: A positron emission tomography and magnetic resonance spectroscopy study

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https://doi.org/10.1016/j.pscychresns.2021.111327Get rights and content

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Highlights

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Medial prefrontal GABA and glutamate concentrations were assessed in 42 patients and 45 healthy controls.

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[11C]Flumazenil PET was used to assess GABA-A receptor availability in a subsample of 28 patients and 15 healthy controls.

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High levels of GABA in the prefrontal cortex was associated with low availability of GABA-A receptors in the same region, in depressed patients and healthy controls.

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Prior findings of reduced GABA and glutamate in depression was not replicated in this relatively large sample.

Abstract

The Gamma-aminobutyric acid (GABA) and glutamate (Glu) neurotransmitter systems are implicated in depression. While previous studies found reduced GABA levels, and a tendency towards reduced Glu, using proton (1H) magnetic resonance spectroscopy (1H-MRS), little is known about GABAA receptor availability in depression. Here, the aim was to characterize GABA and Glu-levels in dorsal anterior cingulate cortex (dACC), whole-brain GABAA availability, and their relationship in patients with depression compared to healthy controls. Forty-two patients and 45 controls underwent 1H-MRS using a MEGA-PRESS sequence to quantify dACC GABA+ and Glu (contrasted against creatine [Cr]). Immediately preceding the 1H-MRS, a subsample of 28 patients and 15 controls underwent positron emission tomography (PET) with [11C]Flumazenil to assess whole-brain GABAA receptor availability. There were no differences in dACC GABA+/Cr or Glu/Cr ratios between patients and controls. The same was true for whole-brain GABAA receptor availability. However, there was a significant negative relationship between GABA+/Cr ratio and receptor availability in ACC, in a whole-brain voxel-wise analysis across patients and controls, controlling for group or depressive symptoms. This relatively large study did not support the GABA-deficit hypothesis in depression, but shed light on GABA-system functioning, suggesting a balance between neurotransmitter concentration and receptor availability in dACC.

Depression is a serious condition that negatively affects how a person thinks, feels, and behaves. According to a recent study (Nature, 2014) more than 350 million people are affected by depression, making it one of the most frequent causes of disability and common disorders that affect humans worldwide.

What causes depression?

During the last decade, increased access to brain imaging technology has allowed neuroscientists and hospital clinicians to view the brain in detail, measure neural activity, and quantify neurotransmitter levels. Such studies have revealed many clues regarding the underlying contributing factors of depression and the pathophysiology of this disease.

Serotonin: the happy neurotransmitter

Various animal models have demonstrated that chronic stress causes low serotonin levels in the brain. In patients, low brain serotonin activity correlates with a higher risk for more violent attempted and successful suicides.  Serotonin levels have also been implicated in seasonal affective disorder (SAD). 

According to a recent study, sunlight keeps serotonin levels high by decreasing serotonin transporter (SERT) activity.  Because serotonin-releasing neurons use SERT to recapture released serotonin, limiting SERT activity increases serotonin-dependent activity and downstream neuronal signaling. For this reason, patients afflicted with SAD experience increased SERT levels as nights lengthen, thereby diminishing active serotonin levels while increasing the risk of depression.

Figure 1. The role of serotonin in normal and depressed people with or without SSRIs treatment.

Currently, the most widely prescribed antidepressants are selective serotonin reuptake inhibitors (SSRIs), which include brand names such as Prozac, Zoloft, Paxil and Celexa. These drugs block the uptake of serotonin (via SERT) by the neurons that produced it, making this neurochemical more available to neighboring postsynaptic neurons.

Dopamine: a chemical for motivation

Reduced dopamine levels, too, may contribute to depression. Although dopamine was thought initially to be crucial to the “reward” system in the brain and the neurons that control feelings related to pleasure, it more directly impacts the neurons that underlie motivation and habit formation. Dopamine motivates people to take action toward goals, desires, and needs, and issues a surge of reinforcing pleasure once they’ve been accomplished. Low dopamine levels make people and animal models less likely to work toward achieving a goal.

People with clinical depression often have increased levels of monoamine oxidase A (MAO-A), an enzyme that breaks down key neurotransmitters, resulting in very low levels of serotonin, dopamine and norepinephrine.  In 2013, a team from Stanford using optogenetic mouse models showed that inhibiting midbrain dopamine-releasing neurons induced depression-like behaviors caused by chronic stress, reinforcing the link between low dopamine and depression in patients.

Therapies for patients that don’t respond to standard treatments

Notions that the brain is a chemical soup in which not enough dopamine or too little serotonin contribute to severe depression helped pharmacologists design a series of antidepressants that work –although only in some cases. For too long, however, this view has limited advances in the field, including the delay to develop treatments for the 30% to 40% of depressed patients who, according to the National Institute of Mental Health, generally don’t respond to standard antidepressant treatments.

Ketamine: A promising quick fix

One of the most exciting, recent findings related to treatments for depression was the discovery that ketamine, a glutamate NMDA receptor antagonist and a FDA approved anesthetic, appears to counteract depression in a matter of hours.  Although ketamine may be an alternative treatment for many patients with major depressive disorder who don’t get better with standard antidepressant drugs, it hasn't been thoroughly studied for long-term safety and effectiveness, and the FDA hasn't approved it to specifically treat mood disorders. Nevertheless, some clinics are providing “off-label” treatments. In the meantime, pharmaceutical companies are spending millions to develop patentable derivatives and ketamine analogues.

Depressive environmental factors

The biomedical community has come a long way towards understanding what causes depression and how best to treat some individuals- but they still don’t have answers for the most effective ways to treat all of the different disease subtypes. We cannot ignore the fact, too, that trauma early in life, hormonal changes, sustained stress, or sudden, emotional losses can push some people over the edge. 

Interestingly, alterations in brain wave electrical patterns during sleep (for example, reduced deep sleep and time spent dreaming) and changes in the cerebral blood flow, also have been linked with depression.

Figure 2.  National Institute of Health funding awarded for cancer research, mental illness and depression research in 2013.

Depression: A public health problem flying under the radar

Despite indications that depression is a predictor of aggressive behavior towards oneself or towards others, many people seem to ignore this, and prefer to sweep this problem under the rug.  Why? One of the reasons may be that for many years, scientists couldn’t explain the physiological basis of the disease (like the brain lesions and plaque deposits that, for example, are commonly observed in patients with advanced Alzheimer’s disease).  Although depression is thought to affect nearly 10% of the US population, and as many as two thirds of those who commit suicide exhibit some symptoms of depression, society has thus far been slow to react to this public health concern. 

New hope to treat mood disorders

Given the complex and variable nature of mood disorders, outcomes likely will be better with treatments that are individualized and multi-faceted. After a period of belt tightening, last week Congress overwhelmingly approved a 2016 spending package that includes a $2 billion increase for the NIH.

There is hope that in the near future some of the grant funding practices that have advanced our better understand or and treatments for cancer can be applied toward an effort to better understand and treat depression. Within the last decade, NIH funds have supported incredible strides forward in oncology, including the widespread adoption of tumor marker biology in assessing an individual’s risk for developing cancer and advances in personalized medicine for treating patients (Figure 2). Investing more resources in laboratories and hospitals that study and treat mental illness will transform our understanding of depression and lead the way toward new strategies that support the prevention and recovery of this disease.

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