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The Chemistry of Depression

What Is the Biochemical Basis of Depression?

Verywell / Ellen Lindner

Brain Chemicals and Depression

What are neurotransmitters.

• Key Neurotransmitters
• Chemical Imbalance Causes
• Depression Treatments
• Combatting Stigma

There are several theories about what causes depression . The condition most likely results from a complex interplay of individual factors, but one long-prevalent explanation suggested that abnormal brain chemistry plays a primary role.

More recent findings indicate that depression is likely not the result of chemical imbalances in the brain. However, the belief that chemical imbalances are responsible for causing depression is widely held by the American public. One survey found that nearly 85% of respondents believed that such imbalances were the likely cause of depression.

Sometimes, people with depression relate the condition to a specific factor, such as a traumatic event in their life. However, it's not uncommon for people who are depressed to be confused about the cause. They may even feel they don't have "a reason" to be depressed .

In these cases, learning about the theories of what causes depression can be helpful. Here's an overview of what is known (and not yet known) about how the brain's chemistry may influence depression.

Watch Now: 7 Most Common Types of Depression

Previously, it was suggested that, for some people, having too little of certain substances in the brain (called neurotransmitters) could contribute to the onset or worsening of depression. According to this idea, restoring the balance of brain chemicals could help alleviate symptoms.

This is where the different classes of antidepressant medications may come in. Many antidepressants alter levels of certain neurotransmitters in the brain.

The most commonly prescribed class of antidepressants, known as SSRIs, or selective serotonin reuptake inhibitors , block the reabsorption of serotonin, a neurotransmitter that can affect mood. The "serotonin hypothesis" suggested that low levels of this neurotransmitter were linked to depression. The idea was that increasing serotonin levels could help improve mood and relieve symptoms of depression.

Recent Evidence

The belief that depression is caused by chemical imbalances has been declining in the scientific and medical community for some time. A study published in a 2023 issue of the journal Molecular Psychiatry found further reason to doubt this explanation. The research indicated there is little evidence to suggest that depression is caused by chemical imbalances in the brain.

The belief that chemical balances cause depression is still widely held by the general public. This indicates a need to communicate the more current understanding that depression is a heterogeneous condition that may have many underlying causes. 

While such findings challenge the idea that a serotonin deficiency is responsible for causing depression, it doesn't mean that mental health treatments are ineffective. More research is needed to fully understand what causes depression, how antidepressants affect the condition, and what other treatments may also be effective for managing symptoms of depression.

These findings represent a significant shift in our understanding of depression, but this does not mean people taking antidepressants should stop their medication!

The 2023 study also found a strong connection between traumatic life events and the onset of depression.  This suggests that depression is caused by complex factors, including environmental variables, and cannot be reduced to simply a chemical imbalance in the brain.

Depression Is Complex

Even with the help of medications that affect specific neurotransmitters in the brain, depression is a highly complex condition to treat. What proves to be an effective treatment for one person with depression may not work for someone else. Even something that has worked well for someone in the past may become less effective or  even stop working  for reasons researchers are still trying to understand.

Researchers continue to try to understand the mechanisms of depression, including brain chemicals, in hopes of finding explanations for these complexities and developing more effective treatments.

Depression is a multi-faceted condition. While researchers do not fully understand what causes it, having an awareness of brain chemistry can be useful for medical and mental health professionals, researchers, and many people with depression.

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Put simply, neurotransmitters are chemical messengers in the brain. The nerve cells of the brain use neurotransmitters to communicate with each other , and the messages they send are believed to play a role in mood regulation.

The space between two nerve cells is called the synapse . When cells want to communicate, neurotransmitters can be packaged up and released from the end (axon) of a presynaptic cell. As a packet of neurotransmitters crosses the space, it can be taken up by receptors for a specific chemical on postsynaptic cells (dendrite). For example, serotonin receptors pick up serotonin molecules.

If there are any excess molecules in the space, the presynaptic cell will gather them back up (reuptake) and reprocess them to use in another communication. Each type of neurotransmitter can carry a different message and plays a unique role in creating an individual's brain chemistry.

The chemical theory of depression suggested that imbalances in brain chemistry were a primary cause of depression. However, recent findings found no evidence to support this idea.

It is important to remember that we do not fully understand how imbalances in these chemicals affect mental health conditions such as depression. While research indicates that serotonin levels may not cause depression, other neurotransmitters and interactions may play a part.

The Role of Key Neurotransmitters

The three neurotransmitters that are often implicated in depression are:

Norepinephrine

Other neurotransmitters, including glutamate, GABA, and acetylcholine , can send messages within the brain. Researchers are still learning about the role these brain chemicals play in depression and other conditions, such as Alzheimer's, fibromyalgia, and sleep disorders.

Dopamine creates positive feelings associated with reward or reinforcement that motivate us to continue with a task or activity. Dopamine is believed to play an essential role in a variety of conditions affecting the brain, including Parkinson's and schizophrenia .

There is also evidence that reduced dopamine levels can contribute to depression in some people. When other treatments have failed, medications that affect the dopamine system are often added and can be helpful for some people with depression.

Norepinephrine is both a neurotransmitter and a hormone. It plays a role in the " fight or flight response " along with adrenaline. It helps send messages from one nerve cell to the next.

In the 1960s, Joseph J. Schildkraut suggested norepinephrine was the brain chemical of interest for depression when he presented the "catecholamine" hypothesis of mood disorders.

Schildkraut proposed depression occurs when there is too little norepinephrine in specific brain circuits. Alternatively, mania results when too much of this neurotransmitter is in the brain.

There is evidence that supports the hypothesis; however, it has not gone unchallenged by researchers. For one, changes in norepinephrine levels do not affect mood in every person. Further, medications specifically targeting norepinephrine may alleviate depression in some people but not others.

Another neurotransmitter is serotonin or the "feel good" chemical. In addition to helping regulate your mood, serotonin has a number of different jobs throughout the body from your gut to blood clotting to sexual function.

In relation to its role in depression, serotonin has taken center stage in the past few decades thanks to the advent of antidepressant medications like Prozac (fluoxetine) and other selective serotonin reuptake inhibitors (SSRIs). As their name implies, these medications specifically act on serotonin molecules.

Researchers have looked into serotonin's role in mood disorders for almost 30 years. Arthur J. Prange, Jr. and Alec Coppen's "permissive hypothesis" suggested low serotonin levels allowed norepinephrine to fall as well, but that serotonin could be manipulated to indirectly raise norepinephrine.

Newer antidepressants called serotonin-norepinephrine reuptake inhibitors (SNRIs) like Effexor (venlafaxine) target both serotonin and norepinephrine. Tricyclic antidepressants (TCAs) also affect norepinephrine and serotonin, but they have the added effect of influencing histamine and acetylcholine. These substances produce side effects , such as dry mouth, blurry vision, constipation, and urinary hesitancy.

SSRIs, on the other hand, do not affect histamine and acetylcholine, don't have the same side effects, and are safer from a cardiovascular standpoint. Therefore, doctors, psychiatrists, and people with depression tend to prefer them to older classes of antidepressants like TCAs.

Causes of Low Neurotransmitter Levels

While recent findings found no evidence to support the idea that chemical imbalances are responsible for causing depression, many people do find relief from taking antidepressants that impact neurotransmitter levels. An important question is what might cause the low levels of serotonin, norepinephrine, or dopamine in the first place?

Low levels of neurotransmitters can result when there is a breakdown anywhere in the process. Research has indicated several potential causes of chemical imbalances in the brain, including:

• Molecules that help make neurotransmitters (specific enzymes) are in short supply
• Not enough receptor sites to receive the neurotransmitter
• Presynaptic cells are taking the neurotransmitter back up before it has a chance to reach the receptor cell
• Too few of the molecules that build neurotransmitters (chemical precursors)
• Too little of a specific neurotransmitter (for example, serotonin) is being produced

Several emerging theories are concerned with the factors that promote lowered levels, such as cellular (specifically mitochondrial) stress. However, one of the main challenges for researchers and doctors hoping to connect depression to low levels of specific brain chemicals is that they don't have a way to consistently and accurately measure them.

Current and Future Depression Treatments

Understanding the chemistry of depression may help people better understand the treatments available . Psychotherapy is helpful for some people with depression, but others also find greater relief when these treatments are used alongside medications.

If a person finds that therapy alone is not helping them manage their depression, they may want to try medication. For some people, antidepressants combined with psychotherapy prove especially effective for addressing their symptoms.

To complicate treatment further, medication does not always work for people with depression. One study evaluating the effectiveness of currently available antidepressants found that these medications only work in about 60% of people with depression.

Whatever might be causing your symptoms, depression affects your internal and external life. Therefore, medication alone may not be sufficient to address all the ways in which depression can affect you.

Research suggests that neurotransmitter levels can be affected by factors other than medication and that psychotherapy can help a person learn about them. For example, stress may contribute to low levels of certain neurotransmitters.

While taking an antidepressant medication might help with the symptoms, it doesn't necessarily address the other underlying causes of depression. In this situation, therapy to improve  stress management , heal from emotional wounds , learn to regulate emotions , and improve thinking patterns could potentially be helpful.

If you or a loved one are struggling with depression, contact the Substance Abuse and Mental Health Services Administration (SAMHSA) National Helpline at 1-800-662-4357 for information on support and treatment facilities in your area.

For more mental health resources, see our National Helpline Database .

Depression Treatments on the Horizon

Researchers are studying other molecular pathways in the brain (including the glutaminergic, cholinergic, and opioid systems) to see their role in depression. It may be that rather than a simple deficiency in one specific brain chemical being the causative factor, some depression symptoms could be related to the relative levels of each type of neurotransmitter in different brain regions.

Rather than being a simple equation of some unknown factor causing low levels of one or more neurotransmitters and these low levels creating the symptoms of depression, the actual basis of depression is much more complex.

While this complexity is often evident to people living with depression, medical professionals and researchers are still trying to understand the intricate nature of diagnosing and treating the condition.

For example, in addition to the role of neurotransmitters, we know there are multiple factors involved in causing depression, ranging from genetic factors and childhood experiences to our present day-to-day lives and relationships. Even inflammation is being explored as a potential contributing factor.

Combatting the Chemical Imbalance Stigma

Acknowledging the limitations of our current knowledge of depression and its treatment is important. In recent years, some researchers have expressed concerns that pharmaceutical companies marketing antidepressant medications may have misled consumers by oversimplifying or misrepresenting the research into the brain chemistry of depression.

Sociological research has found that the stigma attached to depression (and taking medication to treat it) is not necessarily lessened by the theory of chemical imbalance.

Several studies have found that when told depression is caused by a chemical imbalance, people tend to feel less confident in their ability to manage the condition. Other studies have found that when depression is framed as a disease of the brain, people are more likely to feel the need to avoid a person with depression (usually out of fear that they are dangerous).

Not all the research has been negative, though. Several studies included in a 2012 meta-analysis indicated that one of the most effective ways to address and challenge social stigma around mental illness is to educate and discuss conditions and treatment—which includes being upfront and honest about what is still unknown or not well understood.

Improving people's understanding of the many factors that can contribute to an increased risk for depression might help people feel more motivated and empowered as they manage their condition.

Final Thoughts

Accepting how little we truly know about the chemistry of depression can help us maintain perspective and expectations for the medications used to treat depression. For people who are trying to find the right treatment, understanding the complex chemistry can be reassuring when a particular drug doesn't work for them or if they need to try more than one antidepressant.

Understanding the complexity of depression can also be helpful for those who have been offered hurtful advice , such as being told to "just snap out of it." It is no easier for someone to forget they are depressed than it would be for someone with diabetes to lower their blood sugar by simply not thinking about it.

Being realistic about the limitations of our knowledge can help us remember that, for the time being, there is no one treatment that will work for everyone with depression. More often than not, an interdisciplinary approach is needed. At the very least, every person dealing with depression needs and deserves a support team.

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By Nancy Schimelpfening Nancy Schimelpfening, MS is the administrator for the non-profit depression support group Depression Sanctuary. Nancy has a lifetime of experience with depression, experiencing firsthand how devastating this illness can be.  

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The Neurobiology of Depression: an Integrated Overview from Biological Theories to Clinical Evidence

• Published: 10 August 2016
• Volume 54 , pages 4847–4865, ( 2017 )

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• F. Ferrari 1 &
• R. F. Villa 1  

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Depressive disorders are heterogeneous diseases, and the complexity of symptoms has led to the formulation of several aethiopathological hypotheses. This heterogeneity may account for the following open issues about antidepressant therapy: (i) antidepressants show a time lag between pharmacological effects, within hours from acute drug administration, and therapeutic effects, within two-four weeks of subchronic treatment; (ii) this latency interval is critical for the patient because of the possible further mood worsening that may result in suicide attempts for the seemingly ineffective therapy and for the apparent adverse effects; (iii) and only 60–70 % of treated patients successfully respond to therapy. In this review, the complexity of the biological theories that try to explain the molecular mechanisms of these diseases is considered, encompassing (i) the classic “monoaminergic hypothesis” alongside the updated hypothesis according to which long-term therapeutical action of antidepressants is mediated by intracellular signal transduction pathways and (ii) the hypothalamic–pituitary-adrenal axis involvement. Although these models have guided research efforts in the field for decades, they have not generated a compelling and conclusive model either for depression pathophysiology or for antidepressant drugs’ action. So, other emerging theories are discussed: (iii) the alterations of neuroplasticity and neurotrophins in selective vulnerable cerebral areas; (iv) the involvement of inflammatory processes; (v) and the alterations in mitochondrial function and neuronal bioenergetics. The focus is put on the molecular and theoretical links between all these hypotheses, which are not mutually exclusive but otherwise tightly correlated, giving an integrated and comprehensive overview of the neurobiology of depressive disorders.

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The study was funded by the Italian Ministry for Education, University and Research (MIUR). Dr. F. Ferrari fellowship award was supported by Premio Anna Licia Giovanetti released for Ph.D. laureate students at the University of Pavia.

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Ferrari, F., Villa, R.F. The Neurobiology of Depression: an Integrated Overview from Biological Theories to Clinical Evidence. Mol Neurobiol 54 , 4847–4865 (2017). https://doi.org/10.1007/s12035-016-0032-y

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Depression research: where are we now?

• Saebom Lee 1 ,
• Jaehoon Jeong 1 ,
• Yongdo Kwak 1 &
• Sang Ki Park 1  

Molecular Brain volume  3 , Article number:  8 ( 2010 ) Cite this article

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Extensive studies have led to a variety of hypotheses for the molecular basis of depression and related mood disorders, but a definite pathogenic mechanism has yet to be defined. The monoamine hypothesis, in conjunction with the efficacy of antidepressants targeting monoamine systems, has long been the central topic of depression research. While it is widely embraced that the initiation of antidepressant efficacy may involve acute changes in monoamine systems, apparently, the focus of current research is moving toward molecular mechanisms that underlie long-lasting downstream changes in the brain after chronic antidepressant treatment, thereby reaching for a detailed view of the pathophysiology of depression and related mood disorders. In this minireview, we briefly summarize major themes in current approaches to understanding mood disorders focusing on molecular views of depression and antidepressant action.

Introduction

Mood disorders such as major depression and bipolar disorders are the most common psychiatric disorders in modern society. About 16% and 1% of the population are estimated to be affected by major depression and bipolar disorder one or more times during their life time, respectively [ 1 ]. The presence of the common symptoms of these disorders are collectively called 'depressive syndrome' and includes a long-lasting depressed mood, feelings of guilt, anxiety, and recurrent thoughts of death and suicide [ 2 ]. The genetic contribution to the manifestation of depression has been estimated as 40-50% [ 3 ]. However, combinations of multiple genetic factors may be involved in the development of depression, because a defect in a single gene usually fails to induce the expression of multifaceted symptoms of depression [ 4 ]. Also, various non-genetic factors such as stress, affective trauma, viral infection, and neurodevelopmental abnormalities increase the complexity of the pathogenesis of the disease. Thus, extensive studies have led to a variety of hypotheses for the molecular mechanism of depression, but a definite pathogenic mechanism has yet to be defined.

The 'monoamine hypothesis,' which suggests a deficiency or imbalances in the monoamine neurotransmitters, such as serotonin, dopamine and norepinephrine, as the cause of depression has been the central topic of depression research for approximately the last 50 years. This hypothesis has been initiated and supported by the fact that early versions of antidepressants including tricyclics and monoamine oxidase inhibitors have the common effect of acutely enhancing monoamine function [ 5 – 7 ]. Recent development of the selective serotonin reuptake inhibitors (SSRIs) as effective antidepressants has further strengthened the hypothesis [ 6 , 8 ]. However, unresolved complexity of the current antidepressants remains. First, antidepressants are effective in less than 50% of patients, and recently discovered drugs have failed to enlarge the extent of applicable patients [ 2 ]. Second, chronic treatment with antidepressants is required for clinical effects, and the reason for this is unknown [ 9 ]. Third, depression medications as well as mood stabilizers show a wide spectrum of undesired side effects.

In particular, because clinical effects of antidepressants that acutely modify monoamine systems are significantly delayed, it is now believed that an adaptation of downstream events, including lasting changes in gene expression by chronic treatment, underlie the antidepressant efficacy [ 10 ]. This phenomenon suggests that there is probably not a simple relationship between biogenic amines and depression postulated by classical monoamine hypothesis. The complexity may be due to multiple factors, which is likely because depression is a group of disorders with several underlying pathologies. Also, expression of depression symptoms may require disturbances in certain neurotransmitter systems that are functionally interconnected to each other at multiple levels. Taken together, while it still has to be emphasized that the initiation of antidepressant efficacy may be mediated by acute changes in monoamine systems, apparently, the focus of current research is moving toward molecular mechanisms that underlie long-lasting downstream changes in the brain after chronic antidepressant treatment, thereby reaching for a detailed view to the pathophysiology of depression and related mood disorders. In this minireview, we summarize major themes in current approaches to understanding depression and related mood disorders.

Gene-environment interactions

As a way to discovering genes predisposing to depression, geneticists have long been searching for gene variants that play a role in the response to life stresses, a critical environmental factor for the onset of depression, which would be an example of 'gene-environment interaction': whereby an environmental factor is filtered through the activity of a gene to confer differential susceptibility to depression among individuals. To this end, polymorphisms in the serotonin transporter (5-hydroxyltryptamine transporter, 5-HTT) gene have been extensively analyzed. It has been reported that the expression level of 5-HTT from the 5-HTT gene is influenced by polymorphisms in the 5'-flanking region (5-HTT gene-linked polymorphic region, 5-HTTLPR) and in the variable number tandem repeat (VNTR) of the second intron [ 11 , 12 ]. In particular, a short variant of 5-HTTLPR appears to be associated with repressed transcriptional activity of the promoter, decreased 5-HTT expression, and decreased 5-HT uptake when compared with a long variant of 5-HTTLPR [ 13 ]. Significantly, genetic studies have shown that these polymorphisms are associated with major depressive disorder in human [ 14 ]. Moreover, a longitudinal study with 847 New Zealanders has shown that a short allele of 5-HTTLPR variants is associated with an increase in susceptibility to depression in response to life stresses such as job losses or divorces [ 15 ]. Strikingly, in this study, the polymorphism is influential only when the subjects are in significant life stresses, suggesting that 5-HTT may be a connecting point between individual's genetic makeup and environmental triggers of depression. These observations were further strengthened by study showing that increased depression scores in maltreated children without social supports are associated the short allele of 5HTTLPR [ 16 ].

However, the insight from these studies does not appear to be fully supported by other studies. The association of allelic variation in VNTR of 5-HTT gene with the susceptibility to depression was not consistently detected in some analyses [ 17 , 18 ]. A meta-analysis showed that polymorphisms in 5-HTTLPR and the second intron are actually found in depressed patients but the strength of association does not reach a statistical significance [ 19 ]. An extensive study using 1206 twins also failed to find a main effect of 5-HTTLPR, or an interaction between the 5-HTTLPR genotype and stressful life events on major depression [ 20 ]. Moreover, a recent meta-analysis using 14 comparable studies has yielded no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression [ 21 ]. The mixed results from these studies reveal the potential weakness of the 'candidate gene' approach focusing on a specific gene variant to elucidate gene-environment interactions, and thus add importance on unbiased whole-genome scan approach, especially when a disease with polygenic nature, such as depression and related mood disorders, is concerned.

Stress response circuits

Chronic stress is an important component in depression even though it does not seem to function as a necessary or sufficient factor. From this point of view, the hypothalamic-pituitary-adrenal (HPA) axis, a core neuroendocrine circuit for managing stress in the body, has been a topic of interest in depression research [ 22 ]. Corticotrophin-releasing factor (CRF) secreted from the paraventricular nucleus of the hypothalamus enhances secretion of adrenocorticotrophin (ACTH) from the pituitary [ 22 , 23 ], and subsequently, glucocorticoid is secreted from the adrenal cortex, impacting neurobehavioral functions of various brain regions [ 2 ]. The HPA axis forms a feedback loop via certain brain regions such as the hippocampus and amygdala [ 24 ]. It was reported that hypercortisolemia, a persistent upregulation of blood glucocorticoid levels, increases the excitotoxicity of CA3 pyramidal neurons in the hippocampus, resulting in dendritic atrophy, reduction in spinogenesis, apoptosis of neurons, and possibly inhibition of adult neurogenesis [ 25 ]. These functional abnormalities of hippocampal neurons caused by chronic stress can reduce the inhibitory tone on the HPA-axis, which results in hyperactivity of the HPA-axis [ 23 ]. Notably, hyperactivity of HPA-axis is evident in approximately half of depressed patients and chronic treatment with antidepressants often reverses this phenomenon [ 23 , 26 ]. Furthermore, evidence from animal studies suggests that chronic treatment with antidepressants appears to contribute to the recovery of the abnormal function of the hippocampus by increasing neurogenesis [ 27 , 28 ].

In this regard, one research direction is to evaluate the therapeutic potentials of weakening of the functions of the HPA axis. The obvious targets are CRF receptors expressed in the pituitary and glucocorticoid receptors expressed in the hippocampus and other brain regions, because those receptors are core components in the HPA axis and the associated feedback loop [ 24 , 29 – 32 ]. In a similar context, vasopressin receptors have also emerged as alternative targets [ 33 , 34 ]. Vasopressin is a neuropeptide that enhances CRF function and works through vasopressin receptors expressed in the amygdala and other parts of the limbic system. Also, a single nucleotide polymorphism (SNP) of vasopressin 1b (V1b) receptor has protective effects against major depressive disorder [ 35 ]. Intriguingly, antagonism of CRF receptors, glucocorticoid receptors, and vasopressin receptors appear to exhibit antidepressant effects in experimental animals. The applicability to human patients remains to be further refined.

Neurotrophic factors

Long-term stress appears to reduce the expression level of brain derived neurotrophic factor (BDNF) in the hippocampus [ 36 ]. Also, in a post-mortem study of depressed patients, a reduction in BDNF expression was reported [ 37 ]. In addition, polymorphisms of BDNF gene are associated with neuroticism, a personality trait linked to increased susceptibility to depression [ 38 ]. A family-based association study showed that polymorphisms in BDNF genes are related to bipolar disorders [ 39 ]. Conversely, a chronic treatment with antidepressants not only enhances the BDNF level but also increases the stress resistance in animals [ 40 , 41 ]. These observations provided a basis for 'neurotrophism theory' stating that depression is caused by a deficit in neurotrophic factors, and antidepressants neutralize this deficit. This theory may be intimately related to neuronal damages in the hippocampal region caused by hyperactivity of stress response circuits aforementioned. Because BDNF is known to enhance synaptic plasticity in various brain regions [ 42 , 43 ], it is reasonable to postulate that improving BDNF function may be beneficial to the hippocampal neurons that are susceptible to stress-induced damages. Supporting this idea, direct injection of BDNF into the hippocampus of experimental animals induces behavioral changes similar to antidepressant treatment [ 41 ]. Thus, BDNF and its receptor TrkB, have become promising targets of novel-type anti-depression therapies.

Despite these observations, a possible causative relationship between BDNF function and the pathogenesis of depression or antidepressant efficacy requires further clarification. For example, while the antidepressant efficacy is suppressed in experiments using inducible BDNF knock-out mice, depression-related behaviors are only seen in females, showing significant gender differences [ 36 ]. Moreover, forebrain-specific conditional TrkB receptor knockout mice do not exhibit depression-related behaviors such as increased behavioral despair in the forced swim test [ 44 ], whereas it has been demonstrated that activation of TrkB receptor is required for antidepressant-induced behavioral effects [ 45 ]. Thus, the relationship between the loss of BDNF activity and the expression of depressive symptoms is not in a simple correlation. Nevertheless, the potential value of the neurotrophic theory as a basis for the design of new form of anti-depression therapies cannot be excluded by the complexity of the current experimental results.

Histone modifications

One poorly understood characteristic of antidepressants is the long delay before the onset of positive effects in patients [ 10 ]. This phenomenon is often attributed to the slow development of adaptation in the relevant neurons that underlies the beneficial effect of the drugs. The identity of the adaptation is not clear yet, but enduring changes in the state of chromatin are thought to be involved. Chronic electro-convulsive shocks that are effective for some depressed patients also induce changes in wide range of the histone modification patterns in experimental animals [ 46 ]. One locus with prominent changes is BDNF, and in conjunction with the suggestion of BDNF as a potential target for design of new antidepressants, the epigenetic control of BDNF expression has been extensively analyzed in the context of the expression of depression and chronic antidepressant treatments. In the rat hippocampus, chronic electro-convulsive shocks increase acetylated histone H3 at the BDNF promoters 3 and 4, and these modifications appear to be correlated with increased expression of BDNF and CREB [ 46 ]. This upregulation has been linked to the effects of antidepressants in animal studies [ 28 , 47 ]. Moreover, chronic defeat stress, an experimental model for depression, elicits selective downregulation of some BDNF splice variants, in the hippocampus [ 28 ]. This downregulation appears to be due to induction of H3-K27 dimethylation, a histone code for transcriptional repression [ 28 , 48 ]. Conversely, an antidepressant treatment reverses repression of BDNF expression likely by inducing H3 acetylation and H3-K4 methylation, acting as histone codes for transcriptional activation, at the BDNF promoter region [ 49 ]. During this whole process, roles for histone deacetylases (HDACs) seem to be crucial because chronic antidepressant treatment downregulates HDAC5, and overexpression of HDAC5 in the hippocampus prevents its antidepressant effect [ 28 ].

HDAC inhibitors have thus received attention for their potentials as promising therapeutics for depression and related mood disorders. HDAC inhibitors are members of four families: the short chain fatty acids (e.g. sodium butyrate (SB), phenylbutyrate, and valproic acid (VPA)), the hyroxamic acids (e.g. TSA and suberoylanilide hydroxamic acid (SAHA)), the epoxyketones (e.g. trapoxin), and the benzamides. One of the most widely used mood stabilizers is VPA. As VPA is known to have an inhibitory activity on HDAC1 and presumably other HDACs [ 50 ], it has been proposed that its mood stabilizing efficacy may be mediated at least in part by histone modifications. Another study showed that HDAC inhibitors such as VPA, SB, and TSA increase BDNF expression in the brain [ 51 ]. Thus, epigenetic mechanisms, especially histone modification, seem to have the potential to provide new mechanistic insights into the expression of depression and novel treatments for depression and related mood disorders.

Adult hippocampal neurogenesis

Brain imaging studies showing reduced hippocampal volume in depressed patients have provided a platform for investigating adult neurogenesis in the context of the pathogenesis of depression [ 52 ]. The hypothesis states that chronic stresses and other depression-inducing stimuli decrease neurogenesis [ 53 – 55 ], whereas antidepressant efficacy may rely on an increase in neurogenesis [ 54 – 56 ]. Adult neurogenesis is restricted to the subventricular zone and subgranular zone of the hippocampus [ 57 ], and this emphasizes the potential importance of hippocampal neurogenesis during the onset as well as during the treatment of depression. Supporting this idea, various animal models of depression, such as learned helplessness, chronic mild stress, and psychosocial stress, are associated with reductions in hippocampal neurogenesis [ 58 – 60 ]. Conversely, chronic antidepressant treatment not only increases neurogenesis but also supports survival of newborn neurons [ 61 ]. It has also been shown that the antidepressant efficacy of tricyclics, imipramine, and SSRIs requires hippocampal neurogenesis in rodents [ 58 , 62 , 63 ]. Furthermore, chronic fluoxetine treatment appears to increase the number of synapses in the pyramidal cell layers and block the decrease in spine density in the dentate gyrus and other hippocampal cell layers [ 64 ]. Notably, enriched environments, which is known to enhance hippocampal neurogenesis [ 65 ], decrease depression-related behaviors in rodents [ 66 , 67 ].

The expression level of BDNF deserves attention when examining the molecular mechanisms underlying the antidepressant-mediated increase in neurogenesis. As described above, in various animal models of depression, the BDNF level is decreased [ 40 ], whereas chronic antidepressant medication and electro-convulsive shocks increase the levels in the hippocampus [ 28 , 46 ]. A recent study showed that CREB, a transcription factor that regulates expression of CRE-containing target genes including BDNF, is also upregulated and activated in hippocampus by chronic antidepressant treatment [ 2 , 53 , 68 , 69 ]. However, the cause and effect relationship among the induction of CREB and BDNF, the neurogenesis, and behavioral effects of antidepressants remains to be further investigated.

Recent studies demonstrated that long-term administration of mood stabilizers such as lithium, valproic acid, and carbamazepine also enhances adult hippocampal neurogenesis [ 70 – 72 ]. Lithium directly inhibits glycogen synthase kinase-3 (GSK-3) and inositol signaling [ 73 ]. VPA enhances gene expression likely by inhibiting HDACs, indirectly blocks GSK-3 activity, and suppresses inositol signaling [ 71 , 74 – 76 ]. Although it remains unclear whether the GSK-3 and inositol signaling are actually linked with clinical effects of mood stabilizers, the data suggest a common molecular pathway constituting the pathophysiology of depression and related mood disorders that converges on adult hippocampal neurogenesis.

Substance withdrawal

Various drugs such as alcohol, psychostimulants, opiates and N -methyl-D-aspartate (NMDA) receptor antagonists generate a physiological response called withdrawal symptoms during abstinence in humans and experimental animals [ 77 – 80 ]. The characteristics of affective symptoms caused by drug withdrawal and major depressive disorder are strikingly similar [ 80 ]. Depressed mood and anhedonia are commonly present with both drug abstinence and depressive disorders [ 81 ]. Hyperphagia, hypersomnia, feelings of fatigue, and suicidal ideation are also observed in both conditions [ 82 , 83 ]. Disruptions of the HPA axis are also seen during drug withdrawal, and are accompanied by increased levels of cortisol and elevated cerebrospinal levels of CRF [ 84 ]. In addition, elevated levels of cortisol, ACTH and β-endorphin during early cocaine withdrawal resemble those in depressed patients [ 85 ]. Brain-imaging studies using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have revealed that methamphetamine withdrawal induces decreased glucose metabolism in the anterior cingulate cortex and insula, and increased metabolic activity in the amygdala and orbitofrontal cortex, all of which are frequently observed in clinical depression [ 86 ].

Much evidence shows that depression and related mood disorders are accompanied by abnormalities in dopaminergic transmission in the nucleus accumbens (NAc) and ventral tegmental area (VTA), regions that are core parts of the brain reward circuit [ 87 ]. It is well established that depressed patients have difficulties in the expression of pleasure and acquisition of motivation, which are mainly governed by a normal NAc-VTA dopamine circuit [ 88 ]. Consistently, it has been shown that a deregulation of dopamine D2 receptor signaling results in depression-like behaviors in experimental animals [ 89 ], and that neuronal nitric oxide synthase (nNOS) knockout mice with altered dopamine D1 receptor signaling exhibit decreased depression-related behaviors [ 90 ]. Because nearly all drugs of abuse directly or indirectly activate monoaminergic neurotransmission in the limbic system, resulting in reward sensations [ 91 , 92 ], it has been postulated that counter-adaptations may occur in opposition to the reward effects with chronic drug intake, generating cognitive, motivational, and affective impairments, including depression-like symptoms during the drug withdrawal period [ 93 ].

As described above, in many ways, depressive mood subsequent to drug withdrawal shares common characteristics, such as neuro-hormonal changes, regional brain activity, and pharmacological responses, with clinical depression. However, it needs to be emphasized that the onset, course, duration, and other factors such as involvement of substances diagnostically distinguishes substance-induced mood disorders from major depressive disorders [ 94 , 95 ]. Some experimental data also hint at differences between these conditions at the molecular level, demanding cautions when interpreting the related observations. For example, dopamine transporter densities are increased in the striatum in both cases [ 96 ], but serotonin transporter densities are elevated in the brainstem during the early stage of cocaine abstinence [ 97 ], but not in clinical depression [ 98 ]. Also, some abstinent drug addicts have been treated with antidepressant drugs to reduce drug craving, but the positive effect of these drugs needs further validation [ 99 ]. Nonetheless, insights from these views not only tell us that brain reward circuits composed of the mesolimbic system are potentially important in understanding depression, but also provide a useful behavioral readout for depressive mood in experimental animals.

Circadian rhythms

Circadian rhythm is a roughly 24-hour cycle of biochemical, physiological, and behavioral processes under control of internal clock [ 100 – 102 ]. From the clinical point of view, a potential link between circadian rhythms and depression or related mood disorders has long been postulated. For example, it is relatively well known that insufficient length of light phase to entrain the circadian rhythm can be causative for the development of seasonal affective disorders [ 103 , 104 ]. Also, abnormal regulation of sleep/wake cycles, body temperature, blood pressure, and various endocrine functions under the control of circadian clock are prominent symptoms of mood disorders [ 102 , 105 – 110 ]. However, molecular mechanisms underlying the link are still largely unknown.

Recently, interesting observations have been made in the mutant mouse that has a deletion of 19th exon of Clock gene, a core component of molecular clock. The mouse exhibits hyperactive VTA dopaminergic neurons and behavioral phenotypes that are reminiscence of mania seen in bipolar disorder patients [ 111 , 112 ]. Moreover, lithium, a mood stabilizer for bipolar depression patients, effectively inhibits GSK3β, a core regulatory component in the molecular clock. Lithium also has an effect on the nuclear entry of Period-Cryptochrome heterodimers, a key process to form a negative loop in the molecular clock, likely through an inhibition of GSK3β activity. Furthermore, lithium appears to regulate activity of Rev-erb α that links the negative loop to the positive loop in the biological clock [ 113 – 116 ].

Potential links between circadian rhythm and the monoamine system are also reported. The synthesis and/or secretion of monoamine neurotransmitters and the function of their receptors are under influence of circadian rhythms. The circadian rhythmicity of dopamine transporter and tyrosine hydroxylase expression in dopaminergic neurons is also disrupted when the suprachiasmatic nucleus of the hypothalamus, the central part of endogenous clock, is damaged [ 117 ]. Moreover, monoamine oxidase-A (MAO-A) expression is regulated by dimer formation of Clock and Bmal1, and MAO-A activity accordingly shows a circadian rhythmicity [ 118 ]. Conversely, the expression of circadian genes such as Clock, Per1 , and Bmal1 is stimulated when dopamine D1 receptor is activated, and suppressed when dopamine D2 receptor is activated in the limbic area [ 119 ]. Collectively, the molecular clock appears to be tightly interconnected with monoamine systems, which might explain symptomatic correlation between circadian rhythm and depression at the molecular level.

Although the relationship among the daily variations of mood, endogenous molecular clock, and the expression of depressive symptoms is complicated, normalization of the biological rhythms of a depressive individual could have a beneficial effect. In this regard, the recent development of agomelatine as an antidepressant is of great interest. Agomelatine is a potent agonist for melatonin receptors and has capacity to reset the internal circadian clock [ 120 , 121 ]. Intriguingly, it also exhibits antagonistic activity on 5-HT 2 C receptor, thereby indirectly enhancing the dopamine and norepinephrine neurotransmission [ 122 – 124 ]. Moreover, agomelatine affects differentially various stages of neurogenesis in the dorsal and ventral hippocampus [ 125 ]. Further understanding of the molecular basis of agomelatine action and its efficacy may provide interesting insight into the interface between circadian rhythm and pathophysiology of depression.

Functional anatomy

Information on brain regions and neural circuitry responsible for the expression and progression of a disease is an important platform to better diagnose the disease and to properly interpret the observations obtained from molecular, cellular, and tissue experiments in the clinically relevant context. While various brain regions are known to be involved in regulation of mood or emotion, definite information on central neural circuits responsible for mood disorders is still incomplete, mainly because anatomical lesions in patients have been less consistently found relative to other various neurological disorders such as some neurodegenerative diseases. However, there are neuropathological and neuroradiological studies that have established interesting associations between mood disorders and structural abnormalities in the brain. For example, glial reduction was observed in anterior cingulate gyrus and neuronal abnormalities were detected in the dorsolateral prefrontal cortex in post-mortem neuropathological studies of mood disorder patients [ 126 , 127 ]. Radiological studies using MRI also revealed reduced volumes of orbitofrontal and subgenual anterior cingulate cortex [ 128 – 130 ], electrical stimulation of which correlatively elicits an antidepressant effect [ 131 ]. Most notably, reductions in hippocampal volume in depressed elderly patients were reported [ 132 , 133 ].

Recent brain imaging studies mainly using fMRI are adding information on brain regions that play important roles in depressive symptoms at the functional level [ 134 ]. Functional changes in brain regions such as prefrontal/cingulate cortex, hippocampus, striatum, amygdala, and thalamus are correlated with depression [ 52 ]. The neocortex and hippocampus also appear to play critical roles in the symptoms related to the cognitive deficits that are prevalent in depressed patients [ 55 ], and the nucleus accumbens and amygdala seem to be core regions for anhedonia and emotional memory-related symptoms [ 135 , 136 ]. The functional changes in the hypothalamus are also linked to sleep- and appetite-associated symptoms [ 137 ]. Research on these topics is now being accelerated by fast advances in brain imaging technologies, and the outcome, in combination with the information from the conventional anatomical studies, is driving the generation of a higher-resolution picture of the neural circuitry relevant to depression.

A prerequisite for effective control of depression and related mood disorders is to understand their detailed molecular pathways. Although the classical stress model of depression and current understanding of antidepressant action appears to be partially linked via epigenetic mechanisms and hippocampal neurogenesis (Figure 1 ), obviously, the current picture of the pathophysiology of depression is largely incomplete, and thus many potential hypotheses are being generated and tested, forming fragmented neurobiological views of depression and related mood disorders. One major task in the field must be to integrate the relevant hypotheses to formulate a bigger picture of the pathophysiology of depression and related disorders. A key step may be to define the high-resolution neural circuitry of depression, which will provide a platform to better interpret the observations obtained from molecular, cellular, and tissue experiments at the organism level. Another critical step will be to identify 'depression genes' that are causative for depression. This will help us generate genetic animal models that may not only be critical for clarifying many issues in depression research using experimental animals, but may also be useful for assessing the potential efficacy of candidate antidepressants. Finally, the most challenging task in the field is to overcome the limitations of current therapies, which are only effective in a fraction of patients. It has long been expected that novel antidepressants targeting non-monoamine systems would enlarge the extent of treatable patients (Figure 1 ), but the progress still falls short of expectations, thereby leaving it as a pressing task in the field.

Approaches to the development of antidepressants targeting non-monoaminergic components . Chronic stress can cause hypercortisolemia which results in neuronal damages in the hippocampus, thereby weakening the feedback inhibition on HPA axis. Chronic stress also can inhibit the expression of neurotrophic factors through epigenetic mechanisms. On the other hand, chronic treatment of antidepressants and mood stabilizers can establish epigenomic environments that favor the expression of anti-depression genes. The targets may include genes for neurotrophic factors which prevent neuronal damages and enhance hippocampal neurogenesis. Some of approaches to the development of antidepressants targeting non-monoaminergic components are also shown.

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This work was supported by a grant (2009K001271) from Brain Research Center of the 21st Century Frontier Research Program and by grants, 331-2007-1-C00213, 3-200900000001605, and 20090076351, funded by the Ministry of Education, Science, and Technology, the Republic of Korea.

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Lee, S., Jeong, J., Kwak, Y. et al. Depression research: where are we now?. Mol Brain 3 , 8 (2010). https://doi.org/10.1186/1756-6606-3-8

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Inside the Brain: Depression Neurotransmitters

Reviewed by Heather Cashell, LCSW · November 02, 2020 ·

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Humans have studied the brain for thousands of years, and while we’ve learned so much about how it works, there’s still so much left to understand. Since the brain controls nearly everything we do, it’s only right that we look to the brain when our bodies feel out-of-whack.

Things are no different when talking about depression. With what we know today, the symptoms of depression are heavily linked to deficiencies in the brain and other parts of the body. In terms of brain activity, the deficiencies are generally linked to neurotransmitters in the brain.

These neurotransmitters are the real ‘bread and butter’ when it comes to an understanding of how the brain works, how it communicates with itself, and how it communicates with the rest of the body. A deeper understanding of neurotransmitters is essential when understanding the brain.

So, what is a neurotransmitter? And Depression Neurotransmitters? And Depression Neurotransmitters?

Neurotransmitters are the chemical messengers inside the brain that allow neurons to communicate with one another. This communication is one reason we feel pleasure, pain, confusion, a loss of memory, a loss of motor skills, and so much more.

There are really three things in play here -- the neuron, the neurotransmitter, and the synapse. The neuron, also known as the nerve cell, is what the chemicals use as a transport system from one end of a neuron to the other end of the neuron, and eventually to an entirely different neuron.

There are nearly 90 billion neurons located inside the brain, and they’re all important to the brain's function. The neurons are connected to one another through synapses, which are the spaces in-between each neuron.

The neurotransmitter (chemical) travels through the neuron until it arrives at the axon, which is the end of the neuron with the synapse. As the neurotransmitter is released through the synapse, binding receptors are located on the dendrite, the neuron's end with the receptors.

Of course, there is a wide range of things that can go wrong. Since we don’t live in a perfect world, we need to understand how things can go wrong and how it might affect the individual experiencing the imbalance.

Depression Neurotransmitters

Since over 100 different neurotransmitters are found in the brain, they each have their own binding receptors responsible for taking up the neurotransmitters. For example, adrenaline is a neurotransmitter (that also acts as a hormone) with adrenaline receptors.

Unfortunately, many people either have an excess supply of neurotransmitters, a deficient supply of neurotransmitters, an excess of enzymes that break down neurotransmitters, or even a deficient supply of binding receptors.

Any of these situations could affect how we think, behave, act, speak, move, and much more. That’s where we start to see the link between depression and neurotransmitters .

Although most of the neurotransmitters found in the brain can have an indirect effect on depression, three neurotransmitters are receiving the most attention -- dopamine, serotonin, and norepinephrine. Don’t worry, we’ll discuss them in more detail below!

1.    Dopamine And Depression Neurotransmitter

Dopamine is a neurotransmitter in the brain that many people refer to as the ‘pleasure neurotransmitter.’ It’s produced in the body when L-Tyrosine (amino acid) is converted into L-DOPA, the precursor to dopamine. Dopamine also acts as a hormone in the blood.

In the brain, dopamine is responsible for that sense of accomplishment we get when we achieve something and the motivation that keeps us going. It’s not only linked to pleasure but to reward and reinforcement -- such as that feeling we get when someone complements our outfit.

Most people living with depression are also experiencing low dopamine levels, especially when serotonin-related antidepressants aren’t working (also known as selective serotonin reuptake inhibitors or SSRIs). That’s why dopamine medication is often used in addition to serotonin medication.

2.    Serotonin And Depression Neurotransmitter

Serotonin is a neurotransmitter often confused with dopamine. It’s commonly referred to as the ‘happy neurotransmitter’ and is produced in the body when L-Tryptophan is converted into L-5OH-tryptophan, the precursor to serotonin. It also acts as a hormone in the blood.

In terms of depression, serotonin is the most-studied neurotransmitter in the brain. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressant in the United States and often help reduce the symptoms of depression.

Several issues can occur with serotonin levels inside the brain. Depression symptoms can occur when not enough serotonin is produced, a lack of binding receptors to receive the serotonin, inability of serotonin to reach serotonin receptors, and even a deficient supply of tryptophan -- since it’s needed to produce serotonin.

3.    Norepinephrine And Depression Neurotransmitter

Norepinephrine is a neurotransmitter often referred to as noradrenaline. It plays a major role in the body’s fight-or-flight response and affects everything from memory to attention, stress, energy, and emotional regulation.

In fact, norepinephrine was once believed to be the primary neurotransmitter involved in a depression instead of serotonin. It was also believed that an increase in norepinephrine caused mania. While certain studies do prove these hypotheses, it doesn’t seem to occur with everyone.

That’s why many people believe norepinephrine is certainly part of the problem, but it isn’t the entire problem. As a result, you often see serotonin-norepinephrine reuptake inhibitors (SNRIs) prescribed instead of SSRIs; that way, the imbalance of norepinephrine is satisfied as well.

4.    Other Depression Neurotransmitters To Consider

There are over 100 neurotransmitters in the brain, and while the three listed above are the main ones involved in depression, there are certainly others worth considering. The three we’re going to add to this list are glutamate, GABA, and acetylcholine.

Acetylcholine is one of the major neurotransmitters linked to memory, attention, focus, and more. Choline is the main precursor to acetylcholine, and it’s largely linked to Alzheimer’s and fibromyalgia.

Glutamate is also involved in learning and memory, but it’s involved in every excitatory brain function. On the other hand, GABA is largely linked to sleep, stress, anxiety, and other mood-related symptoms. Any deficiency could lead to depression-like symptoms.

While GABA is the most intriguing, researchers are still trying to see whether acetylcholine and glutamate have any direct effects on depression.

What Causes Depression Neurotransmitters To Drop ?

When talking about depression, most patients experience a decrease in either one, multiple, or all of the neurotransmitters listed above -- especially dopamine, serotonin, and norepinephrine. The decrease is attributed to several  factors , and it’s different in each individual.

Let’s take a look at the most common factors that lead to a decrease in neurotransmitters in the brain:

• A lack of neurotransmitter production inside the brain. For example, the brain isn’t producing enough serotonin.
• An inefficient supply of precursors to the specific neurotransmitter. For example, not enough tryptophan to convert to serotonin or enough tyrosine to convert to dopamine.
• An issue with the presynaptic cell causes the neurotransmitter to be taken away before binding to a receptor.
• An inefficient supply of binding receptor sites would mean there’s no home for the neurotransmitter once released into the synapse.
• A lack of specific enzymes responsible for helping convert the precursor into the neurotransmitter. This usually means there’s enough of the precursor but not enough enzymes to synthesize the neurotransmitter.

When any of the above three situations occur, there’s a chance you experience a change in behavior due to the lack of neurotransmitter activity in the brain. The longer this problem persists, the higher chance it will affect the rest of the body’s processes.

Finding The Help You Need

Depression is one of the most common mental disorders experienced in the United States today and is often met with various other illnesses, disorders, and behavioral issues. That’s why it’s so important to find the help you need immediately to ensure the problem doesn’t persist or worsen.

That’s where a therapist or psychologist comes in handy. They know how to properly diagnose you with depression and how to treat your type of depression. Since treatment is different in each individual, they take the time to understand your symptoms, current lifestyle, and past experiences.

Of course, you need to understand a problem before you can start to seek the help needed. That’s where Mind Diagnostics comes in to save the day. We’ve created a comprehensive, online depression test to see whether or not you might be experiencing depression.

The test is designed to warn the patient to seek help early on in the process. Don’t worry, we won’t forget about you once you’ve completed the test. Instead, we’ll stick around to ensure you’re matched with the right therapist and ensure you receive the type of care you need.

Together, we can start to build a brighter future for you and your loved ones. Since depression affects more than just the patient, it’s important to take these moments in life seriously. The sooner you receive the help you need, the sooner you can return to the quality life you always imagined for yourself.

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How Depression Affects the Brain

June 17, 2021

When we think about depression, what comes to mind are feelings and emotions – or, for some, the absence of feelings and emotions. In order to really understand depression, however, it’s important to be aware that the condition has physical aspects as well. Most people understand what depression looks like on the outside, in terms of a person’s behavior, but our medical understanding of the actual progression of the disease and its treatments continues to evolve.  

What we know right now is that, on a chemical level, depression involves neurotransmitters, which can be thought of as the messengers that carry signals between brain cells, or neurons.  

“The current standard of care for the treatment of depression is based on what we call the ‘monoamine deficiency hypothesis,’ essentially presuming that one of three neurotransmitters in the brain is deficient or underactive,” says Rachel Katz, MD , a Yale Assistant Professor of Clinical Psychiatry.  

But according to Dr. Katz, this is only part of the story. There are about 100 types of neurotransmitters overall, and billions of connections between neurons in each person’s brain.  

There remains much to learn.

A long road to understanding depression

For years and years, doctors and researchers assumed that depression stemmed from an abnormality within these neurotransmitters, particularly serotonin or norepinephrine. But over time, these two neurotransmitters did not seem to account for the symptoms associated with major depression. As a result, doctors began to look elsewhere.  

The search proved fruitful.  “There are chemical messengers, which include glutamate and GABA, between the nerve cells in the higher centers of the brain involved in regulating mood and emotion,”  says John Krystal, MD , chair of Yale’s Department of Psychiatry, noting that these may be alternative causes for the symptoms of depression. 

These two are the brain’s most common neurotransmitters. They regulate how the brain changes and develops over a lifetime. When a person experiences chronic stress and anxiety, some of these connections between nerve cells break apart. As a result, communication between the affected cells becomes “noisy,” according to Dr. Krystal. And it’s this noise, along with the overall loss of connections, that many believe contribute to the biology of depression.  

This “neurobiology of depression” is important to understand. First, it helps doctors understand how the disease develops and evolves. Also important, though, is that those same doctors can then use their new understanding of depression’s mechanisms to build targeted treatment plans. And, since depression is often a long-term disease, people needs long-term treatments for it.  

“There are clear differences between a healthy brain and a depressed brain,” Dr. Katz says. “And the exciting thing is, when you treat that depression effectively, the brain goes back to looking like a healthy brain.”  

We have entered a new era of psychiatry, Dr. Katz adds. As we shift away from a single hypothesis about what causes depression, we are also learning more about the brain as a whole, in all of its complexities.  

In this video, Drs. Katz and Krystal explain how depression affects the brain.

More news from Yale Medicine

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Overview: toward a dysregulation hypothesis of depression

• PMID: 2862799
• DOI: 10.1176/ajp.142.9.1017

The authors suggest that the activity of neurotransmitter systems in the affective disorders and related psychiatric syndromes may be better understood as a reflection of a relative failure in their regulation, rather than as simple increases or decreases in their activity. A model organized around the concept of "dysregulation" posits that persistent impairment in one or more neurotransmitter homeostatic regulatory mechanisms confers a trait vulnerability to unstable or erratic neurotransmitter output. Evidence from clinical and animal model studies for dysregulation of the noradrenergic system in depression is examined with respect to criteria generated by such a general model, and a specific configuration of noradrenergic dysregulation in some forms of depression is proposed.

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Assessing the peripheral levels of the neurotransmitters noradrenaline, dopamine and serotonin and the oxidant/antioxidant equilibrium in circus horses.

Simple Summary

1. introduction, 2. materials and methods, 2.1. animals and study design, 2.2. blood sampling and analysis, 2.3. statistical analysis, 4. discussion, 5. conclusions, author contributions, institutional review board statement, informed consent statement, data availability statement, conflicts of interest.

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Cocco, R.; Sechi, S.; Rizzo, M.; Arrigo, F.; Giannetto, C.; Piccione, G.; Arfuso, F. Assessing the Peripheral Levels of the Neurotransmitters Noradrenaline, Dopamine and Serotonin and the Oxidant/Antioxidant Equilibrium in Circus Horses. Animals 2024 , 14 , 2354. https://doi.org/10.3390/ani14162354

Cocco R, Sechi S, Rizzo M, Arrigo F, Giannetto C, Piccione G, Arfuso F. Assessing the Peripheral Levels of the Neurotransmitters Noradrenaline, Dopamine and Serotonin and the Oxidant/Antioxidant Equilibrium in Circus Horses. Animals . 2024; 14(16):2354. https://doi.org/10.3390/ani14162354

Cocco, Raffaella, Sara Sechi, Maria Rizzo, Federica Arrigo, Claudia Giannetto, Giuseppe Piccione, and Francesca Arfuso. 2024. "Assessing the Peripheral Levels of the Neurotransmitters Noradrenaline, Dopamine and Serotonin and the Oxidant/Antioxidant Equilibrium in Circus Horses" Animals 14, no. 16: 2354. https://doi.org/10.3390/ani14162354

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• Published: 12 October 2018

Glutamatergic neurometabolite levels in major depressive disorder: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies

• Sho Moriguchi 1 , 2   na1 ,
• Akihiro Takamiya 1   na1 ,
• Yoshihiro Noda 1 ,
• Nobuyuki Horita 3 ,
• Masataka Wada 1 ,
• Sakiko Tsugawa 1 ,
• Eric Plitman 2 ,
• Yasunori Sano 1 ,
• Ryosuke Tarumi 1 ,
• Muhammad ElSalhy 1 ,
• Nariko Katayama 1 ,
• Kamiyu Ogyu 1 ,
• Takahiro Miyazaki 1 ,
• Taishiro Kishimoto 1 ,
• Ariel Graff-Guerrero 2 ,
• Jeffrey H. Meyer 2 ,
• Daniel M. Blumberger 4 ,
• Zafiris J. Daskalakis 4 ,
• Masaru Mimura 1 &
• Shinichiro Nakajima 1 , 2  

Molecular Psychiatry volume  24 ,  pages 952–964 ( 2019 ) Cite this article

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Alterations in glutamatergic neurotransmission are implicated in the pathophysiology of depression, and the glutamatergic system represents a treatment target for depression. To summarize the nature of glutamatergic alterations in patients with depression, we conducted a meta-analysis of proton magnetic resonance ( 1 H-MRS) spectroscopy studies examining levels of glutamate. We used the search terms: depress* AND ( MRS OR “ magnetic resonance spectroscopy ”). The search was performed with MEDLINE, Embase, and PsycINFO. The inclusion criteria were 1 H-MRS studies comparing levels of glutamate + glutamine (Glx), glutamate, or glutamine between patients with depression and healthy controls. Standardized mean differences (SMD) were calculated to assess group differences in the levels of glutamatergic neurometabolites. Forty-nine studies met the eligibility criteria, which included 1180 patients and 1066 healthy controls. There were significant decreases in Glx within the medial frontal cortex (SMD = −0.38; 95% CI, −0.69 to −0.07) in patients with depression compared with controls. Subanalyses revealed that there was a significant decrease in Glx in the medial frontal cortex in medicated patients with depression (SMD = −0.50; 95% CI, −0.80 to −0.20), but not in unmedicated patients (SMD = −0.27; 95% CI, −0.76 to 0.21) compared with controls. Overall, decreased levels of glutamatergic metabolites in the medial frontal cortex are linked with the pathophysiology of depression. These findings are in line with the hypothesis that depression may be associated with abnormal glutamatergic neurotransmission.

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Introduction.

The heterogeneity of the illness features that characterize depression makes it difficult to elucidate the underlying pathology of the illness and its treatment. The glutamate hypothesis of depression was proposed in the 1990s, when antagonists of the N -methyl- d -aspartate (NMDA) receptor, an ionotropic glutamate receptor, were found to possess antidepressant-like mechanisms of action in mice [ 1 ]. Furthermore, infusion of low-dose ketamine, which is an NMDA receptor antagonist, is associated with robust decreases in depressive symptoms in depressed patients [ 2 ].

Recent data suggest that glutamatergic dysfunction is involved in the biological mechanisms underlying depression [ 3 ]. For example, positron emission tomography (PET) studies have reported reduced metabotropic glutamate receptor subtype 5 density in patients with depression, which was further substantiated by a post-mortem study [ 4 ]. In addition, animal model studies have also demonstrated that depressive-like behaviors are associated with alterations in cortical glutamate [ 5 , 6 , 7 ]. Furthermore, a recent meta-analysis showed that ketamine has rapid antidepressant effects in depressed patients compared with placebo [ 8 ]. As a result, glutamatergic neurometabolites have garnered increasing interest in terms of their role in the underlying pathophysiology of depression.

To date, several proton magnetic resonance spectroscopy ( 1 H-MRS) studies have examined regional levels of glutamatergic metabolites in patients with depression compared with controls. However, findings are inconsistent across studies, which report increases [ 8 ], no differences [ 9 , 10 ], or decreases [ 11 , 12 , 13 ] in glutamatergic neurometabolite levels in patients with depression across a variety of brain regions. These differences may be due to differences in regions of interest (ROIs), MRS methodologies, stages or severities of illness, or medications (e.g., antidepressant treatments). A recent meta-analysis noted that glutamate levels were lower within the anterior cingulate cortex (ACC) of patients with depression compared with controls [ 14 ]; of note, this meta-analysis included 16 studies published until 2010 and consisted of 281 patients and 301 controls. There were some limitations in this meta-analysis, as several of the included studies had all of the ROIs merged into one [ 14 ]. Furthermore, another recent meta-analysis reported that glutamine + glutamate (Glx) levels were decreased in the prefrontal cortex (PFC) in patients with depression compared with controls, whereas no significant difference was found in terms of glutamate levels between the two groups [ 15 ]. This meta-analysis also noted that reductions in Glx levels within the PFC were related to the number of failed antidepressant treatment trials. Specifically, this meta-analysis focused exclusively on glutamate and Glx in the PFC, and included 17 studies published until 2014, totaling 363 patients and 306 controls [ 15 ]. Notably, the inclusion of more recent reports would allow the meta-analysis of data from specific brain regions in patients with depression. Importantly, 22 papers, which is more than double the number of studies included in past meta-analyses, have been published since these meta-analyses.

Therefore, we conducted a systematic review and meta-analysis to compare the levels of specific regional glutamatergic neurometabolites; we aimed to do so in a comprehensive fashion, including the most recent studies on the topic. Based on previous meta-analyses, we hypothesized that Glx levels in the medial PFC (mPFC) would be decreased in patients with depression compared with controls [ 14 , 15 ]. We also explored the influences of age, sex, symptom severity, and antidepressant treatment on group differences in the levels of regional glutamatergic neurometabolites.

Protocol registration

The full protocol was uploaded to the International Prospective Register of Systematic Reviews website (CRD42017079668). We have followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [ 16 ].

Study search

We used the search terms: depress* AND ( MRS OR “ magnetic resonance spectroscopy ”). The search was performed with MEDLINE (1946 to October 2017), Embase (1947 to October 2017), and PsycINFO (1806 to October 2017). The searches were rerun just before the final analyses and further studies were retrieved for inclusion in March 2018.

A hand search was conducted by SM, AT, and SN. Candidate articles were independently screened and scrutinized by these authors. Discrepancies in study selection were resolved by discussion among the three authors.

Data extraction

Any data concerning a fundamental description of each study and data related to the outcomes described below were independently extracted by SM and AT. We have extracted any data regardless of the definitions of the primary/secondary endpoints of each original study. The extracted data were cross-checked and discrepancies were resolved by discussion between the two authors. If different publications reported data from the same population, we included data from the publication with the larger sample size. When studies did not report data, we e-mailed the authors to obtain the data.

Inclusion criteria

Publication type.

Any English, full-length, or short articles were included, whereas non-English articles and conference abstracts were excluded.

Study design

We included cross-sectional studies and randomized control studies with MRS data in both patients with depression and healthy controls.

Studies were included if: (1) patients met the Diagnostic and Statistical Manual of Mental Disorders (DSM), 3rd, 4th, or 5th edition criteria for major depressive disorder without bipolar disorder, the International Classification of Disease diagnostic (ICD) criteria for major depressive disorder without bipolar disorder, or consensus expert evaluation confirmed the diagnosis of depression without bipolar disorder; (2) we included all age range from pediatric to senior subjects; (3) authors compared glutamate, glutamine, or glutamine + glutamate (Glx) levels in the brains of patients with depression and subjects without depression using 1 H-MRS; (4) authors included at least three subjects in each group; and (5) data were sufficient and appropriate to obtain mean differences between groups. In contrast, studies were excluded if they did not present data exclusively from patients with depression.

Quality assessment

The quality of the original studies was assessed using the Newcastle-Ottawa Quality Assessment Scale after arranging it for a cross-sectional study design [ 17 ]. This scale assigns four and two points for patient selection and comparability, respectively. Six points indicated the highest quality, whereas zero points indicates the lowest quality.

Primary outcomes

The primary outcome was Glx levels. The secondary outcomes were glutamate and glutamine levels. The ROIs were as follows: (1) the mPFC, including both the mPFC and ACC since their ROIs often overlap; (2) the dorsolateral PFC (DLPFC); (3) the thalamus; (4) the medial temporal lobe (mTemp), including the hippocampus and para hippocampus; and (5) the occipital cortex. When data from bilateral lobes were reported separately, the left lobe was used because the left lobe was examined in most studies.

Statistical analyses

All continuous primary and secondary outcomes were compared between patients and controls using the standardized mean difference (SMD). SMD and two-sided 95% confidence intervals (CIs) were chosen as the summary statistic for the meta-analysis. Interpretation of the magnitude of the SMD was as follows: small, SMD = 0.2; medium, SMD = 0.5; and large, SMD = 0.8. The calculation of SMD was conducted using Review Manager ver. 5.3 (Cochrane Collaboration, Oxford, UK). We conducted a meta-analysis for each metabolite in each ROI that included four studies or more. The heterogeneity among original studies and subgroups was evaluated using the I 2 statistic, whereby I 2  = 0% indicated no heterogeneity, 0% <  I 2  < 30% indicated the least heterogeneity, 30% ≤  I 2  < 50% indicated moderate heterogeneity, 50% ≤  I 2  < 75% indicated substantial heterogeneity, and 75% ≤  I 2 indicated considerable heterogeneity. Publication bias was evaluated using a funnel plot and Begg–Kendall test. Subgroup analyses based on medication status (i.e., unmedicated, medicated) were performed for levels of glutamatergic neurometabolites. To make these subgroups, a clear cut-off year for the unmedicated period was not set. If there were four or less studies on one ROI, the ROI was not included in the analysis. We used a meta-regression in mixed-effects model to assess the relationship between moderators and the effect size of glutamatergic neurometabolites between patients and controls as a dependent variable. For the meta-regression, we used “average age among subjects”, “female ratios among subjects”, or “depression severity with 17 items Hamilton Depression Rating Scale (HAMD-17)” as independent variables, because the HAMD-17 was examined in most studies as the severity scale. A mixed-model meta-regression was performed using the Comprehensive Meta-Analysis version 3. The variables for each study included: (1) clinico-demographic characteristics of the subjects (i.e., age, sex, medication status, and symptom severity, as measured by the HAMD, Beck’s Depression Inventory (BDI), or the Montgomery–Asberg Depression Rating Scale (MADRS)); (2) MRS scan methods; (3) neurometabolite quantification methods; and (4) ROIs. Given our initial assumption that Glx levels in the mPFC would be decreased in patients with depression compared with controls, the significance level for all tests was set at a p -value of 0.05 (two tailed).

Characteristics of included studies

The search identified 49 studies, which included a total of 1180 patients and 1066 healthy controls. A total of 49 articles were ultimately included into our analysis (Fig.  1 ). Characteristics of the studies are described in Table  1 . Thirty-six studies (73%) examined Glx, 27 studies (55%) examined glutamate, and 11 studies (22%) examined glutamine. Twenty-nine studies (59%) and 19 studies (39%) reported on unmedicated and medicated patients, respectively. Three studies measured glutamine levels in the DLPFC. Two studies measured Glx levels in the occipital cortex and thalamus, glutamate levels in the occipital cortex, and glutamine levels in the mTemp. One study measured glutamate levels in the thalamus and glutamine levels in the occipital cortex and thalamus. The sample sizes ranged from 9 to 63 for patients with depression and 10 to 50 for healthy controls. The average ages of each study ranged from 13.3 to 72.1 years for patients with depression and 13.6 to 72.7 years for healthy controls. Thirty-two (65%) and 12 (24%) studies were performed at a magnetic field strength of 3T and 1.5T, respectively. Magnetic resonance imaging (MRI) protocols and methodological information, including measurement technique and parameters, for each study are described in Table  1 . The Newcastle-Ottawa Scale score ranged from 2 to 6 and the average was 5.1 (Supplementary Table  1 ), which suggests that the quality of the included studies was good on average.

Preferred reporting items for systematic reviews and meta-analyses (PRISMA) diagram for study search

Meta-analysis

Glx levels in the mPFC were measured in 502 patients and 408 controls. There were significantly lower levels of Glx within the medial frontal cortex in patients with depression compared with controls (SMD = −0.38; 95% CI, −0.69 to −0.07; I 2  = 81%; p  = 0.2) (Table  2 , Fig.  2 ). There were no identified differences in glutamate or glutamine levels in any regions (Table  2 , Fig.  3 and Supplementary Figure  2 ).

Study effect sizes of Glx differences between depression and controls in the medial prefrontal cortex. Each data marker represents a study, and the size of the data marker is proportional to the total number of individuals in that study. The summary effect size for each brain region is denoted by a diamond

Study effect sizes of glutamate differences between depression and controls in the medial prefrontal cortex. Each data marker represents a study, and the size of the data marker is proportional to the total number of individuals in that study. The summary effect size for each brain region is denoted by a diamond

Moderator analyses

Subgroup analyses and sensitivity analysis.

Levels of Glx ( I 2  = 81%), glutamate ( I 2  = 85%), and glutamine ( I 2  = 95%) in the mPFC showed considerable heterogeneity. In addition, the leave-1-out sensitivity analysis showed that the results of Glx in the mPFC were robust. Subgroup analyses of Glx levels in the mPFC revealed that there was a significant decrease in medicated patients with depression (SMD = −0.50; 95% CI, −0.80 to −0.20; I 2  = 52%; p  = 0.001), but not in unmedicated patients (SMD = −0.27; 95% CI, −0.76 to 0.21; I 2  = 87%; p  = 0.27). The leave-1-out sensitivity analysis showed that the SMD of one study in the unmedicated depression group was high; after removing the study, there was a significant decrease in unmedicated patients with depression [ 18 ]. We also conducted subgroup analyses on mPFC Glx levels for varying reference methods. mPFC Glx levels corrected for CSF were significantly lower in patients with depression compared with controls (SMD = −0.60; 95% CI, −0.93 to −0.27; I 2  = 71%; p  < 0.001), whereas there was no significant difference in mPFC Glx levels between groups when Glx levels were referenced to creatine levels (SMD = −0.05; 95% CI, −0.63 to 0.53; I2 = 86%; p  = 0.87).

Meta-regression analyses

There were no associations between subject age (coefficient: −0.0082; 95% CI: (−0.036, 0.020); p  = 0.56), female ratio (coefficient: −0.26; 95% CI: (−2.0, 1.5); p  = 0.77), or clinical severity of HAMD 17 (coefficient: −0.0082; 95% CI: (−0.070, 0.042); p  = 0.62) and Glx levels in the mPFC.

Publication bias

The Begg–Kendall test did not indicate any publication bias for mPFC Glx or mPFC glutamate, respectively (tau = −0.18, p  = 0.21; tau = −0.19, p  = 0.27, respectively) (Supplementary Figure  1 ).

This was the first study to compare glutamatergic neurometabolites, such as glutamate, glutamine, and Glx in broad brain regions between patients with depression and healthy controls, while also considering factors that can affect glutamatergic levels, such as medication status. We conducted a meta-analysis to compare levels of glutamatergic neurometabolites between patients with depression and controls. Our main findings are fourfold: (1) with a small effect size, Glx levels were decreased within the mPFC in patients with depression compared with controls; (2) no significant differences were found in glutamate or glutamine levels between the two groups; (3) Glx levels were lower within the mPFC in medicated patients with depression compared with controls, whereas no differences were found between unmedicated patients with depression and controls; and (4) no relationships were found between the effect sizes of mPFC Glx levels and any clinical variables in patients with depression.

Main findings

Both animal and clinical studies have proposed that glutamatergic dysfunction is implicated in the pathophysiology of depression. Animal studies have demonstrated that stress causes depressive states that are accompanied by glutamatergic system alterations [ 19 ]. Chronic mild stress decreases the expression of NMDA receptor subunits in the frontal cortex [ 20 , 21 ]. Repeated stress also decreases the expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits in the PFC [ 22 ]. Exposure to chronic stress decreases the number of mPFC neurons in rats [ 23 , 24 ]. Thus, an extensive body of evidence has strongly indicated that the depressive state is related to abnormalities in the glutamatergic system.

Clinical studies have also suggested that the glutamatergic system plays an important role in the pathophysiology of depression. Some studies have reported that glutamate levels in plasma and cerebrospinal fluid (CSF) are higher in patients with depression than in controls [ 25 , 26 , 27 , 28 ], whereas others have indicated that there are no difference between the two groups [ 29 , 30 ]. In addition, post-mortem studies have found higher glutamate levels in the mPFC of patients with depression than in that of controls [ 31 ]. However, in contrast, another study showed that there was a reduction of CSF glutamate levels in patients with treatment-resistant depression compared with controls [ 32 ]. Thus, the existing findings that have assessed glutamate levels in depression are inconsistent and seem to depend on the studies and sample source. These inconsistent findings may be due to the clinical and biological heterogeneity of depression. On the other hand, post-mortem studies have also noted glutamatergic dysfunction within the frontal cortex of patients with depression. There were observed reductions in the density of glutamatergic neurons in the orbitofrontal cortex of patients with depression [ 33 ]. In addition, reductions in the protein expression of NMDA receptor subunits (NR2A and NR2B) were observed in the PFC of patients with depression [ 20 ]. A PET study using 11 C-ABP688 revealed lower mGluR5 availability in the PFC, cingulate cortex, insula, thalamus, and hippocampus in the depression group compared with the controls [ 4 ]. In another study, a lower mGluR5 availability with 11 C-ABP688 was also detected in patients with depression compared with controls in many cortical areas [ 34 ]. These findings are corroborated by preclinical studies, suggesting that depressive symptoms may be associated with reductions in the mGluR5 protein [ 35 , 36 ]. Collectively, these findings suggest that glutamatergic mGluR dysfunction might contribute to the pathophysiology of depression. However, the physiological implications of mGluR5 disturbances in depression still remain unclear [ 37 , 38 , 39 ]. Again, these observations from animal and clinical studies support the hypothesis that disruption of the glutamatergic system is associated with the pathophysiology of depression, and they further suggest that modulation of the glutamatergic system may lead to a novel therapeutic approach to depression. Our main finding of Glx reduction within the mPFC in patients with depression warrants further studies to fully elucidate the underlying mechanism of depression and the therapeutic implications of modulating the glutamatergic system.

It has been reported that a variety of depression treatments increase Glx levels in the mPFC. For example, antidepressants and electroconvulsive therapy (ECT) increase Glx levels in the mPFC in patients with depression [ 11 , 13 , 40 ]. In addition, several lines of investigation have shown that ketamine, an NMDA receptor antagonist, has antidepressant effects and increases glutamate levels in the PFC in patients with depression through NMDAreceptor inhibition and subsequent AMPAR activation [ 41 , 42 ]. The NMDAreceptor inhibition and subsequent AMPAreceptor stimulation leads to inhibition of eukaryotic elongation factor 2 kinase, as well as activation of brain-derived neurotrophic factor, tropomyosin-related kinase B, and mammalian target of rapamycin signaling, thereby increasing levels of synaptic proteins in the PFC [ 43 , 44 , 45 ]. Overall, these results support hypo-glutamatergic function in depression and are in line with our finding of decreased levels of Glx within the mPFC in patients with depression.

Findings of moderator analyses

The main finding should be confirmed in further studies because the heterogeneity of the included studies was high. Our subanalyses found that Glx levels were lower in the mPFC of medicated patients with depression than those of controls, whereas there were no differences between unmedicated patients with depression and controls. However, one study reported high Glx levels in unmedicated patients compared with controls [ 18 ]. After removing this study, we found that there was also a significant decrease of Glx levels in unmedicated patients with depression in comparison with controls. In addition, effects sizes were similar between unmedicated and medicated patients compared with controls. However, as described above, it has previously been reported that treatment of depression is associated with Glx elevations within the mPFC in patients with depression; this has been shown with antidepressant treatment, ECT, and ketamine administration [ 11 , 13 , 40 , 42 ]. It is difficult to accurately assess the difference between the treatment group and the untreated group due to the high heterogeneity of the included studies in both groups. Furthermore, medication information other than antidepressants, such as benzodiazepines, mood stabilizers, and antipsychotics, was not sufficient to perform the meta-regression analyses. Thus, further research is clearly needed to elucidate the effects of various depression treatments on glutamatergic neurometabolites.

Notably, the present meta-regression did not find that glutamatergic neurometabolite concentrations in patients vary in association with symptom severity. Thus, the group difference in mPFC Glx levels between patients with depression and controls could not be explained by symptom severity. Of note, the symptomatology of depression, including psychotic symptoms or melancholic types, represents a clinically important factor that might also contribute to the heterogeneity. However, information concerning symptoms was insufficient in the included studies for further analyses. Thus, further studies will be required to investigate specific subtypes of depression.

Our subgroup analyses found that mPFC Glx levels corrected for CSF were lower in patients with depression compared with controls, whereas there were no group differences in mPFC Glx levels referenced to creatine levels. Given that creatine levels are lower in patients with depression compared with controls (Supplementary Figure  3 ), Glx levels referenced to creatine could be overestimated in patients with depression. Taken together, these findings again suggested that mPFC Glx levels may be decreased in patients with depression in comparison with controls.

Limitations

This meta-analysis has some limitations. First, although the meta-analysis analyzed data region by region, both voxel sizes and ROIs were different among the included studies. The quality control procedure also varied among studies. These differences might skew the results of ROI analyses. Second, the field strength of most studies was 3T or lower, which precluded the accurate division of glutamate and glutamine. We could not specify which glutamatergic metabolites in which cell types are affected in depression. Glx is made up of both glutamate and glutamine but glutamate accounts for about 80% of Glx levels at 1.5T or 3T [ 46 ]. 1 H MRS also does not provide information regarding cell types. Future studies should include studies with increased field strength to improve separation of individual signal spectra. Third, the present study did not consider confounders such as food or smoking status. The majority of studies included in the meta-analysis did not include meal or smoking information. Food intake can influence Glx levels in the brain, with Glx decreasing by as much as 17% in the PFC after fasting [ 47 ]. Smoking also interferes with the glutamate levels in the mPFC [ 48 ]. Thus, studies that report food or smoking condition should be included in future meta-analyses. Fourth, the number of included subjects in studies was relatively small. The sample sizes ranged from 9 to 63 for depression and 10–50 for healthy controls. Further studies with larger sample sizes should be conducted. Fourth, we could not analyze specific age groups even though we included studies with no exclusion in age. Indeed, a few studies investigated pediatric subjects. Thus, future studies are warranted to investigate a wide range of age groups in an effort to confirm whether the results would be consistent in both pediatric and adult patients with depression. Finally, statistical heterogeneity is high in terms of Glx in the mPFC. In the past meta-analysis, mPFC Glx levels in patients with depression were associated with symptom severity in meta-regression analyses, although such a relationship was not identified in our analysis [ 15 ]. This is likely attributable to the clinical heterogeneity caused by differences in patient characteristics [ 49 ] or the influence of other methodological factors such as neurometabolite reference method (i.e., Cr versus water).

The results of this meta-analysis suggest that depression is associated with decreased levels of Glx in the mPFC. This further substantiates the development of novel treatment interventions that seek to modulate the glutamatergic system in patients with depression.

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These authors contributed equally: Sho Moriguchi, Akihiro Takamiya

Authors and Affiliations

Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan

Sho Moriguchi, Akihiro Takamiya, Yoshihiro Noda, Masataka Wada, Sakiko Tsugawa, Yasunori Sano, Ryosuke Tarumi, Muhammad ElSalhy, Nariko Katayama, Kamiyu Ogyu, Takahiro Miyazaki, Taishiro Kishimoto, Masaru Mimura & Shinichiro Nakajima

Research Imaging Centre, Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada

Sho Moriguchi, Eric Plitman, Ariel Graff-Guerrero, Jeffrey H. Meyer & Shinichiro Nakajima

Department of Pulmonology, Yokohama City University Graduate School of Medicine, Yokohama, Japan

Nobuyuki Horita

Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Canada

Daniel M. Blumberger & Zafiris J. Daskalakis

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Conflict of interest.

DMB receives research support from the Canadian Institutes of Health Research (CIHR), National Institutes of Health – US (NIH), Weston Brain Institute, Brain Canada and the Temerty Family through the CAMH Foundation and the Campbell Research Institute. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd. and he is the site principal investigator for three sponsor-initiated studies for Brainsway Ltd. He received in-kind equipment support from Magventure for an investigator-initiated study. He received medication supplies for an investigator-initiated trial from Indivior. He has participated in an advisory board for Janssen.

MM has received grants and/or speaker’s honoraria from Asahi Kasei Pharma, Astellas Pharmaceutical, Daiichi Sankyo, Dainippon-Sumitomo Pharma, Eisai, Eli Lilly, Fuji Film RI Pharma, Janssen Pharmaceutical, Kracie, Meiji-Seika Pharma, Mochida Pharmaceutical, MSD, Novartis Pharma, Ono Yakuhin, Otsuka Pharmaceutical, Pfizer, Shionogi, Takeda Yakuhin, Tanabe Mitsubishi Pharma, and Yoshitomi Yakuhin within the past three years.

YN receives research grants from Japan Health Foundation, Meiji Yasuda Mental Health Foundation, Mitsui Life Social Welfare Foundation, Takeda Science Foundation, SENSHIN Medical Research Foundation, Health Science Center Foundation, and Daiichi Sankyo Scholarship Donation Program. He receives equipment-in-kind support for an investigator-initiated study from Magventure Inc.

ZJD has received within the last 3 years both research and equipment in-kind support for an investigator-initiated study through Brainsway Ltd. and Magventure.

EP has received funding from the Vanier Canada Graduate Scholarship, the Ontario Graduate Scholarship, and the Canada Graduate Scholarship—Master’s.

AG has received support from the United States National Institute of Health, CIHR, OMHF, Consejo Nacional de Ciencia y Tecnología, the Instituto de Ciencia y Tecnología del DF, the Brain & Behavior Research Foundation (Formerly NARSAD), the Ontario Ministry of Health and Long-Term Care, the Ontario Ministry of Research and Innovation Early Research Award, and Janssen.

NS has received fellowship grants from CIHR, research support from Japan Society for the Promotion of Science, Japan Research Foundation for Clinical Pharmacology, Naito Foundation, Uehara Memorial Foundation, Takeda Science Foundation, Daiichi Sankyo, and MSD, manuscript fees or speaker’s honoraria from Dainippon Sumitomo Pharma and Yoshitomi Yakuhin within the past three years. Other authors have no financial or other relationship relevant to the subject of this manuscript.

TK has received consultant fees from Dainippon Sumitomo, Novartis, Otsuka and speaker’s honoraria from Banyu, Eli Lilly, Dainippon Sumitomo, Janssen, Novartis, Otsuka and Pfizer. He has received grant support from the Pfizer Health Research, Takeda, Tanabe-Mitsubishi, Dainippon-Sumitomo, Otsuka and Mochida.

JHM have received operating grant funds for other studies from Janssen in the past 5 years. JHM has been a consultant to Mylan, Lundbeck, Takeda, Teva, and Trius in the past 5 years. JHM is an inventor on five patents of blood markers to predict brain inflammation or to diagnose affective disorders, and a dietary supplement to reduce depressed mood postpartum.

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Moriguchi, S., Takamiya, A., Noda, Y. et al. Glutamatergic neurometabolite levels in major depressive disorder: a systematic review and meta-analysis of proton magnetic resonance spectroscopy studies. Mol Psychiatry 24 , 952–964 (2019). https://doi.org/10.1038/s41380-018-0252-9

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Accepted : 10 August 2018

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DOI : https://doi.org/10.1038/s41380-018-0252-9

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Depression as a Neuroendocrine Disorder: Emerging Neuropsychopharmacological Approaches beyond Monoamines

Mervin chávez-castillo.

1 Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo, Venezuela

2 Psychiatric Hospital of Maracaibo, Maracaibo, Venezuela

Victoria Núñez

Manuel nava, Ángel ortega, milagros rojas, valmore bermúdez.

3 Universidad Simón Bolívar, Departamento de Ciencias Sociales y Humanas, Cúcuta, Colombia

Joselyn Rojas-Quintero

4 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA

Depression is currently recognized as a crucial problem in everyday clinical practice, in light of ever-increasing rates of prevalence, as well as disability, morbidity, and mortality related to this disorder. Currently available antidepressant drugs are notoriously problematic, with suboptimal remission rates and troubling side-effect profiles. Their mechanisms of action focus on the monoamine hypothesis for depression, which centers on the disruption of serotonergic, noradrenergic, and dopaminergic neurotransmission in the brain. Nevertheless, views on the pathophysiology of depression have evolved notably, and the comprehension of depression as a complex neuroendocrine disorder with important systemic implications has sparked interest in a myriad of novel neuropsychopharmacological approaches. Innovative pharmacological targets beyond monoamines include glutamatergic and GABAergic neurotransmission, brain-derived neurotrophic factor, various endocrine axes, as well as several neurosteroids, neuropeptides, opioids, endocannabinoids and endovanilloids. This review summarizes current knowledge on these pharmacological targets and their potential utility in the clinical management of depression.

1. Introduction

Depression is one of the most frequent mental disorders in everyday clinical practice and is currently regarded as the leading cause of disability worldwide [ 1 ]. In addition to the profoundly debilitating condition of this disorder, major depressive disorder (MDD) entails an increased risk of medical comorbidities [ 2 ] and very high direct and indirect financial costs [ 3 ]; profiling this disorder as an important problem for public health.

In spite of this outlook, pharmacotherapy alternatives for MDD remain insufficient: Currently available antidepressant drugs (AD) have only been shown to achieve remission rates around 56% after four successive treatment stages [ 4 ]. Moreover, a majority of the available AD at present display problematic side-effect profiles and a delayed onset of action, further complicating the management of this disorder [ 5 ]. The development of newer, more effective, and tolerable agents is a pressing matter in neuropsychopharmacology, yet relatively few new drugs have been approved for MDD in recent decades [ 6 ].

Both the limited effectivity of existing AD and the scarcity of novel options may stem from a once revolutionary, yet—in retrospect—excessive and misguided focus on the monoamine hypothesis for the pathophysiology of depression, which centers on defective neurotransmission of serotonin (5-hydroxytriptamine, 5HT), noradrenaline (NA), and dopamine (DA) in the brain [ 7 ]. Indeed, the serendipitous discovery of tricyclic AD drove the “reverse engineering” of this hypothesis, which in turn has guided much of the development of all AD throughout history [ 8 ]. Nevertheless, the monoamine hypothesis has been heavily contested regarding its validity and the relative importance of its components [ 9 , 10 ]. At present, advances in molecular psychiatry have reframed neuronal monoamine dysregulation to be the end state of a complex interplay among pathophysiologic pathways involving several nonmonoamine neurotransmitters, as well as several endocrine-metabolic components [ 11 ].

This more holistic understanding of the pathophysiology of MDD has allowed for the design and investigation of novel and promising AD candidates, with activity outside the monoamine dysregulation end state, thus providing provocative windows for intervention [ 12 ]. As preclinical and clinical studies progress at various rates for these molecules, this review aims to summarize current views on the neurobiology of depression, with an emphasis on emerging pharmacological targets beyond monoamine neurotransmission.

2. Expanding Views on the Neurobiology of Depression

The understanding of depression as a clinical entity has evolved radically, from the early descriptions of Hippocrates' melancholia and other primitive pre-Kraepelinian conceptualizations to the rich variety of descriptions derived from various psychological currents during the 20th century, to the revolutionizing contributions of psychopharmacology and neurobiology in more recent history [ 13 ]. Research advances in the latter fields have particularly propelled medical models for depression and mental disorders in general, marking a transition in the understanding of these diagnoses from rather intangible, elusive concepts, to more concrete biological terms, especially centering on the monoamine hypothesis [ 14 ]. However, novel approaches exceed and intertwine with this central dysfunction in monoamine neurotransmission, by involving other neural, endocrine and metabolic pathophysiologic components ( Figure 1 ). Firstly, neurotransmitters beyond the three classic monoamines will be discussed in the following paragraphs.

Expanding views on the neurobiology of depression. GABA: γ -aminobutyric acid; BDNF: brain-derived neurotrophic factor. Current neuropsychopharmacological approaches to depression are centered on the monoamine hypothesis. Nevertheless, the imperfect results obtained in clinical practice with currently available antidepressant drugs have propelled the discovery of various potential pharmacological targets beyond noradrenaline, dopamine, and serotonin.

2.1. Glutamate: A Versatile Regulator

Glutamate (Glu) is the major excitatory neurotransmitter in the mammalian brain [ 15 ]. In normal circumstances, Glu plays a prominent role in synaptic plasticity, learning, and memory. However, in pathological conditions, it is known to be a potent trigger for rapid or delayed neurotoxicity [ 16 ]. With emerging findings of antidepressant effects for glutamatergic drugs, speculation has arisen about the role of Glu in the pathophysiology of mood disorders [ 17 ]. In particular, depressed patients appear to have increased basal glutamatergic activity. As a result, preclinical and clinical studies with drugs directly targeting glutamatergic neurotransmission present new and provocative opportunities for antidepressant treatment [ 18 ].

Glu receptors are divided into two major families: ionotropic and metabotropic glutamate receptors (mGluRs). The ionotropic group includes NMDA, AMPA, and kainate receptors [ 19 ]. In resting conditions, NMDA receptors are blocked by magnesium until membrane depolarization, when the combined binding of two Glu molecules and two molecules of glycine or D-serine allows the influx of calcium, serving as a functional marker of converging excitatory input and ultimately producing excitation over longer periods of time [ 20 ]. AMPA receptors mediate the fast rapidly desensitizing excitations at most synapses and are responsible for the initial reaction to Glu in the synapse. Their activation permits the influx of sodium resulting in the depolarization of the neuronal membrane. Like AMPA receptors, kainate receptors are associated with voltage-dependent channels that primarily allow for the influx of sodium ions that mediate fast excitatory neurotransmission, but they appear to be less widespread and have a distinct distribution [ 21 ]. On the other hand, the metabotropic family consists of group I receptors (mGluR1 and mGluR5), which potentiate both presynaptic glutamate release and postsynaptic NMDA currents, and group II (mGluR2 and mGluR3), and group III receptors (mGluR4, mGluR6, mGluR7, and mGluR8), which tend to suppress glutamate function [ 19 , 22 ].

To date, evidence has emerged indicating that NMDA receptor antagonists, group I metabotropic glutamate receptor (mGluR1 and mGluR5) antagonists, and positive modulators of AMPA receptors have antidepressant-like activity in a variety of preclinical models [ 23 ]. Historically, the preclinical antidepressant-like effects of the NMDA receptor antagonists AP-7 and MK-801 first suggested Glu signaling to be a potential therapeutic approach [ 24 ].

This research led to the experimental use of ketamine a noncompetitive NMDA receptor antagonist, which was profiled as a reasonable candidate for psychiatry given the previous years of safe and well-tolerated use in the fields of anesthesia and neurology [ 25 ]. Ketamine has been shown to induce rapid antidepressant effects within 24 hours of use at subanesthetic doses, lasting for at least several days after a single infusion in various blind pilot clinical trials, which has led to the coining of the term “rapid-acting antidepressants” (RAA) [ 26 – 28 ]. This effect has been reported to begin after the initial psychotomimetic, dissociative, and euphoric effects have subsided, suggesting that the antidepressant effects are not just a result of acute elevated mood [ 29 ]. Nonintravenous ketamine preparations, such as oral and intramuscular forms, have also shown antidepressant efficacy [ 30 , 31 ]. Intranasal ketamine appears most promising, owing to its high penetrance into the central nervous system and ease of administration [ 32 ]. This rapid action has prompted speculation posting glutamatergic neurotransmission as the key pharmacological target to bypass the delay in the onset of action of classic monoaminergic drugs. Nonetheless, concerns remain surrounding the use of ketamine as an antidepressant due to its pharmacological similarity to the potent psychotomimetic drug, phencyclidine (PCP), and its abuse liability as a hallucinogenic club drug [ 33 ].

Ketamine displays an interesting pharmacologic profile, as it is a µ -opioid receptor agonist with superior affinity for NMDA receptors [ 33 ]. Ketamine antagonizes NMDA receptors on GABAergic interneurons and on postsynaptic neurons, resulting in disinhibition of cortical glutamatergic neurons through the former [ 34 ] and increased synthesis of intracellular growth factors through the latter [ 22 ]. In addition, ketamine promotes inhibition of spontaneous NMDA receptor-mediated excitatory postsynaptic currents. In turn, this leads to suppression of elongation factor 2 kinase activity (eEF2K), permitting a rapid increase in the translation of brain-derived neurotrophic factor (BDNF), an important mediator for neuroplasticity and neuroprotection [ 35 ]. Ketamine has also been noted to inhibit signaling by nitric oxide, which allows for the stabilization of nitrergic Rheb, a small G protein that enhances intracellular signaling [ 36 ]. Indeed, ketamine seems to activate many intracellular cascades, including the mammalian target of rapamycin (mTOR) pathway, which has been observed to lead to an increased number and function of new synapses in the prefrontal cortex (PFC) of rats, reverting the synaptic deficits that result from exposure to stress [ 22 , 37 ]. Furthermore, ketamine appears to increase p70 s6 kinase (p70s6K) and 4E-binding protein phosphorylation, both involved in the modulation of synaptogenesis ( Figure 2 ) [ 37 ].

Effects of ketamine on the glutamatergic synapse. Ketamine acts as an NMDA antagonist on GABAergic interneurons, as well as on postsynaptic glutamatergic neurons. Antagonism in the former results in disinhibition of presynaptic glutamatergic neurons, thus favoring activation of AMPAR in postsynaptic glutamatergic neurons. This, along with activation of voltage-dependent calcium channels, results in activation of the PI3K pathway which leads to increased mTOR activity. Furthermore, antagonism of NMDAR leads to inhibition of the nitric oxide pathway, which in turn leads to Rheb stabilization and mTOR pathway potentiation. mTOR increases p70s6K activity, which promotes BDNF signaling. BDNF activity is also favored by the inactivation of eEf2K secondary to NMDAR antagonism.

The promising results with ketamine have ignited considerable research on other rapid-acting antidepressant molecules [ 38 ]. Esketamine and arketamine—the (S) and (R) isomers of ketamine—have also been evaluated in both preclinical and clinical studies. In particular, in animal models, arketamine appears to induce more potent and longer-lasting antidepressant effects than esketamine without psychotomimetic effects [ 39 ]. Nevertheless, clinical research on arketamine is scarce to date, while esketamine appears to be effective for the acute improvement of depressive symptoms, yet less potent than ketamine, and with a similar side-effect profile [ 40 ]. Finally, (S) -norketamine, another ketamine derivate, has been reported to induce rapid and long-lasting antidepressant effects in rodent models with lower potency than esketamine, yet without psychotomimetic and other detrimental biochemical and neurophysiologic effects [ 41 ]. Indeed, with further investigation, ketamine-related molecules could strike a balance between clinical effectivity and tolerability in the relatively near future.

Repastinel is another RAA unrelated to ketamine, a tetrapeptide derived from the light chain of the B6B21 monoclonal antibody which acts as a NMDA receptor modulator and glycine-site partial agonist [ 41 ]. In animal models, repastinel appears to promote long-term potentiation of electrophysiological activity in the hippocampus and PFC by enhancing NMDA receptor-dependent signaling [ 42 ]. Although clinical research on repastinel is only in its early stages, repastinel appears to induce rapid and sustained antidepressant effects and be well-tolerated with no psychotomimetic effects [ 43 ].

In contrast with these rather selective glutamatergic agents, scopolamine, a nonselective muscarinic receptor antagonist, also displays Glu-modulating activity, which may correlate with antidepressant effects [ 44 ]. Animal models show that, like ketamine, scopolamine is a RAA, increasing glutamatergic neurotransmission and activation of mTORC1 signaling in the PFC [ 22 , 45 ]. This enhancement is thought to occur via blockade of muscarinic receptors located on GABAergic interneurons in the medial PFC, similar to the initial cellular target underlying the actions of ketamine [ 46 ]. Several clinical studies have reported rapid antidepressant effects following intravenous infusion of low doses of scopolamine, and repeated doses (3 doses over 5–7 days) produced long-lasting improvements in mood for up to two weeks [ 47 , 48 ]. In this scenario, scopolamine has shown more efficacy in treatment-naïve patients, although treatment-resistant patients still show significant reductions in depressive symptoms [ 49 ].

Because of the current limitations of ketamine, its derivatives, and other emerging RAA, such as psilocybin, which is unrelated to ketamine and its associated mechanisms of action, yet also presents the clinical dilemma of rapid clinical effectivity vs tolerability and psychotomimetic effects [ 50 – 52 ], research has been conducted to seek more tolerable NMDA receptor antagonists that could replicate its antidepressant effect with less adverse effects. Memantine, a NMDA receptor antagonist currently approved for the management of Alzheimer's disease, has been studied in mood disorders. Preclinical reports in rodent models of depression have noted antidepressant-like effects [ 53 ]. However, currently available clinical placebo-controlled trials have failed to demonstrate efficacy on depressive symptoms in humans [ 54 , 55 ].

Riluzole, an FDA-approved medication for the treatment of amyotrophic lateral sclerosis, has also been used in some ketamine extension studies [ 56 , 57 ]. It is a Glu receptor modulator [ 58 ] with apparent efficacy as both monotherapy [ 52 ] and adjunctive therapy in patients with treatment-resistant major depressive disorder (MDD) [ 59 ]. Research has found this antidepressant effect to be especially notable at 4 weeks in treatment-resistant populations, although placebo-controlled studies tend to deny any significant differences [ 60 ]. Therefore, further investigation is required to better characterize the clinical efficacy of riluzole in this context. Pharmacodynamic studies suggest riluzole is not an open-channel antagonist of the NMDA receptor and rather acts by enhancing the surface expression of AMPA receptor subunits in cultured hippocampal neurons, resembling the activity of lamotrigine in this aspect [ 61 ]. Riluzole has also been reported to stimulate BDNF expression [ 62 ] and accelerate Glu clearance from the synaptic cleft by facilitating Glu reuptake by astrocytes [ 63 ]. Both of these effects have been associated with antidepressant-like effects in preclinical rodent models [ 64 ].

There are currently several other Glu-modulating molecules under early experimental study for depression. Ro(25)-6981, an NMDA receptor antagonist with selectivity for the NR2B subunit has shown antidepressant-like effects, possibly mediated by increased expression of postsynaptic cascades such as the mTOR pathway [ 21 ]. A similar candidate, MK-801 (dizocilpine), is a high-affinity, noncompetitive antagonist of NMDA receptors with comparatively inconsistent antidepressant effects [ 65 ]. Although both appear to have significant antidepressant effects in the short term, neither appear to be as long-acting as ketamine [ 21 , 66 ].

Metabotropic Glu receptors have also been examined as potential therapeutic targets in depression [ 67 ]. {"type":"entrez-nucleotide","attrs":{"text":"LY341495","term_id":"1257705759","term_text":"LY341495"}} LY341495 , an mGlu2/3 receptor antagonist, and not {"type":"entrez-nucleotide","attrs":{"text":"LY379268","term_id":"1257807854","term_text":"LY379268"}} LY379268 , an agonist for this receptor group, has been associated with an antidepressant effect [ 68 , 69 ]. This appears to involve activation of the mTORC1 pathway, in a similar fashion to MGS0039, another mGlu2/3 receptor antagonist, as well as ketamine. {"type":"entrez-nucleotide","attrs":{"text":"LY341495","term_id":"1257705759","term_text":"LY341495"}} LY341495 also rapidly reverses anhedonia caused by chronic stress exposure in animal models, a rigorous rodent test of rapid antidepressant actions [ 70 ].

Indeed, stimulation of the mTOR cascade, as well as concurrent activation of AMPA receptors in the PFC may be essential for the antidepressant effect linked to Glu modulators [ 71 ]. The importance of AMPA receptors as mediators of antidepressant effects has been highlighted by Alt et al. [ 72 ]: Certain structural variants of AMPA receptors may be associated with modulation of AMPA receptor-mediated currents. In turn, this appears to facilitate monoaminergic neurotransmission by promoting BDNF signaling.

On the other hand, a study by Palucha-Poniewiera et al. in rats reported short-lived antidepressant effects for both MTEP, an mGlu5 receptor antagonist, and AMN802, an mGlu7 receptor agonist. Their onset of action began within 60 minutes of administration and disappeared at around 23 hours after. Results showed MTEP did not promote mTORC1 signaling; whereas AMN802 stimulated this pathway, yet failed to concurrently activate AMPA receptors [ 66 ]. Insights into this class of molecules are still in early experimental phases and further research is required.

Lastly, both zinc and magnesium have shown antidepressant activity in preclinical [ 73 – 75 ] and clinical studies [ 76 – 78 ] and may be valuable adjunctive agents in the pharmacotherapy of depression. Zinc and magnesium appear to decrease the activity of NMDA receptors, in association with increased BDNF and glycogen synthase kinase-3 (GSK-3) signaling.

2.2. GABA: From Anticonvulsants to Mood Stabilizers to Antidepressants?

γ -Aminobutyric acid (GABA) is the main inhibitory neurotransmitter on the mammalian brain, and its various receptors are widespread in the central nervous system [ 79 ]. Two general classes of GABA receptors are known: in the GABA-A family, the receptor is part of a ligand-gated ion channel complex where each isoform consists of five homologous or identical subunits surrounding a central chloride ion-selective channel gated by GABA. They are located in the postsynaptic membrane and drive immediate neuronal inhibition, while those located in extrasynaptic membranes respond to ambient GABA conferring long-term inhibition [ 80 ]. In contrast, the GABA-B family includes metabotropic G protein-coupled receptors that open or close ion channels via a second messenger system [ 81 ]. GABA-modulating agents, such as anticonvulsant drugs (ACD), are widely known to be effective in the management of depression [ 82 ]. This effect has been proposed to be due to a more favorable Glu-GABA balance driven by ACD. However, the distinct mood-regulating pattern of each ACD, as well as the absence of mood regulation by some ACD, suggests the antidepressant pharmacodynamics of GABAergic drugs to be more complex than solely a shift in the Glu-GABA equilibrium [ 83 ].

Reports have demonstrated increased GABA-B receptor binding in rodent brains after chronic administration of several antidepressant drugs [ 84 ], supporting a GABAergic hypothesis of antidepressant drug action. Nevertheless, further research has been inconsistent regarding the purported antidepressant effect of GABA-B receptor binding [ 85 ]. Currently, the proven clinical efficacy of ACD in mood disorders continues to fuel the study of GABAergic modulation in this context [ 86 ].

Virtually, all of the known molecular components of the GABA and Glu systems have been considered as potential therapeutic targets [ 87 ]. In particular, negative allosteric modulators of GABA-A receptors containing α 5 subunits ( α 5 GABA-NAMs) have been proposed as a novel class of rapid-acting antidepressants. These produce a similar net effect to that of ketamine in the forebrain, yet with reduced side effects due to the comparatively lower expression of α 5 subunits in this region. In a study on male mice, MRK-016, a α 5 GABA-NAM, was associated with an antidepressant-like response, without changes in side effect-monitoring parameters, such as rota-rod performance, conditioned-place preference, and locomotion [ 88 ]. Further research is required to better characterize the usefulness and suitability of this promising molecule in humans.

2.3. Brain-Derived Neurotrophic Factor

Decreased hippocampal expression of BDNF is a well-recognized component of the neurobiology of depression, anxiety, and stress, and antidepressant treatment has been observed to increase levels of this messenger [ 89 ]. By activating signaling mediated by tropomyosin-related kinase receptor (TrkB), BDNF plays a central role in neurogenesis and neuronal survival and growth [ 90 , 91 ]. Although BDNF was initially proposed as a therapeutic alternative for depression, clinical trials with recombinant BDNF have failed to achieve significant antidepressant efficacy [ 92 , 93 ].

Recent efforts have been directed to find other ways to exploit the beneficial effects of BDNF signaling, specifically through the study of TrkB ligands [ 94 ]. In particular, the use of 7,8-dihydroxyflavone, a TrkB agonist, has shown antidepressant activity in mice models [ 95 , 96 ], along with promotion of neurogenesis [ 97 , 98 ]. On the other hand, ANA-12 is a selective TrkB antagonist that can inhibit its neurotrophic activity in the nucleus accumbens without compromising neuronal survival. Paradoxically, this antagonist has also been linked with antidepressant and anxiolytic activity in mice models [ 99 , 100 ]. Therefore, further research is needed to clarify the pharmacology and clinical correlates of the use of TrkB ligands for depression.

3. Endocrine Pharmacotherapeutic Targets in Depression

The fields of psychiatry and endocrinology have long been known to be largely interrelated with various mental and endocrine disorders often displaying bidirectional relationships [ 101 ]. Depressive and anxious symptoms are common in subjects with hormonal disturbances and may represent a challenge for clinicians [ 102 ]. Although patients with depression do not always have overt or severe endocrine disease, hormonal changes are frequent in this population, with accumulating evidence supporting a pathophysiologic role in the context of depression, and by extension, endocrine disturbances may be a therapeutic target in this disorder [ 103 ].

Thyroid hormone is notoriously involved in brain development and function, and neuropsychiatric manifestations are hallmarks of thyroid disease [ 104 ]. Conversely, psychiatric disorders often feature disruptions of the hypothalamus-pituitary-thyroid axis (HPTA): Patients with depression have been found to show abnormal responses to thyroid-stimulating hormone (TSH) and thyrotropin-releasing hormone (TRH), as well as elevated TRH concentrations in cerebrospinal fluid and increased prevalence of antithyroid antibodies [ 105 ]. Available data to date indicates overt thyroid pathology is rare in subjects with depression [ 106 ]. On the contrary, subclinical thyroid pathology appears to be a significant risk factor for psychiatric disorders [ 105 ], with multiple studies demonstrating depressive symptoms to be significantly more frequent or severe in patients with subclinical hypothyroidism than in age- and sex-matched controls [ 107 – 109 ]. This outlook outlines the complexity of the involvement of the HPTA in the pathophysiology of depression.

Indeed, the role of the HPTA in depression may be subtler than gross thyroid disease, articulated by the ubiquity of thyroid hormone receptors in all tissues, and the susceptibility of this system to stress. Dynamic adjustments of the HPTA represent a physiological response in stress conditions, such as intense physical activity and pregnancy [ 110 ]. However, in depression, a chronic state of low-grade systemic inflammation appears to disrupt the HPTA and many other endocrine and immune axes [ 111 ]. In vitro and in vivo studies have shown T3 to stimulate microglial migration and activation, a prominent phenomenon seen in depression, schizophrenia, and autism spectrum disorders [ 112 , 113 ]. In this context, T3 signaling appears to result in disruptions in the PI3K, and MAPK/ERK cascades, as well as potentiated nitric oxide-mediated microglial migration and activation [ 114 – 116 ]. These events could contribute to the dysfunctions in neurotrophism, neuroplasticity, and neurotransmission seen in depression [ 117 ].

Administration of thyroid hormone is a well-supported augmenting strategy in the management of refractory depression, even in euthyroid patients [ 118 – 120 ]. However, hormone replacement alone may be insufficient to treat depression in hypothyroid patients, and further research is needed to better characterize the profile of patients who would benefit most from this intervention [ 121 ].

Corticosteroids have also been widely recognized to play a role in the neuroendocrine disturbances found in depression. Cortisol, the final product of the hypothalamus-pituitary-adrenal axis (HPAA), is broadly regarded as the “stress hormone,” mediating a myriad of essential functions across all organ systems under acute and chronic stress conditions [ 122 ]. However, cortisol is also a notorious participant in the pathophysiology of chronic stress-related illnesses, as seen in depression [ 123 ]. Central corticotropin-releasing hormone (CRH) hyperstimulation appears to be a key perpetuating factor of chronic stress and depression, and it has been suggested that suppression of CRH activity might be the final and common step of antidepressant action that is necessary for the stable remission of MDD [ 124 ]. Two primary CRH receptor subtypes—CRHR1 and CRHR2—have been described in the central nervous system (CNS) according to their neuroanatomical expression patterns; with CRHR1 appearing to play a key role in mediating the CRH-elicited effects in depression and anxiety [ 125 ]. Specific CRHR1 haplotypes have been linked with the development of MDD [ 126 ]. Therefore, the CRHR1 gene may be considered a candidate gene for antidepressant pharmacogenetics [ 127 ].

Evidence over the years for increased CRH activity initially led to the development of CRH receptor antagonists as putative treatments for depression [ 123 ]. A prominent member of this group is R121919, which has been shown to alleviate anxiety in rats and primates, as well as reduce depression scores with good tolerability in a small study with 20 subjects diagnosed with MDD [ 128 ]. NBI-30775/R121919, another CRH1 receptor antagonist, has been reported to have a clinical profile and efficacy comparable to paroxetine [ 129 ]. In contrast, CP-316,311, a selective nonpeptide CHRH1 antagonist, has failed to show efficacy in the treatment of MDD, despite being well-tolerated [ 130 ]. NBI-34041, another CRH1 receptor antagonist, has been reported to reduce stress-related secretion of cortisol upon administration, without systemic adverse effects [ 131 ]. Thus, CRH1 receptor antagonists may be promising novel therapeutic options for depression and anxiety in the future. These advancements will need to circumvent certain currently recognized difficulties regarding the pharmaceutic formulations and pharmacokinetics of these compounds, in order to assure sufficient bioavailability and penetration of the blood-brain barrier [ 132 ].

Sexual hormones have also been implicated in the neurobiology of depression, particularly regarding their very characteristic fluctuations throughout the life cycle and their correlation with mood disorders, in both sexes [ 133 ]. Episodes of mood disorders have been found to be more prevalent during key life periods with important hormonal changes, such as puberty, menopause, and the postpartum period [ 133 – 135 ]. Indeed, females are subject to a wider array of fluctuations with more dramatic consequences, in consonance with a more than doubled risk of mood disorders, in comparison to men [ 136 , 137 ]. This disparity highlights a potential role for gonadal hormones in the etiology of mood disorders. Estrogen receptors are thoroughly distributed in the brain [ 138 ], with these hormones participating in the organization of developing neurons, and the activation of mature neurons. Estrogens drive neurite growth and synaptogenesis, augment BDNF activity, and modulate neurotransmission of 5HT, NA, DA, Glu and Ach [ 139 ]. In particular, estrogens increase serotonergic activity by regulating 5HT metabolism and 5HT receptor expression, as well as modulating the spontaneous firing of the serotonergic neurons in the raphe nuclei [ 139 ].

In a clinical context, the role of estrogens in depression has been more thoroughly studied during the perimenopausal period. Several studies have focused on estrogen replacement therapy (ERT) as a way to alleviate depression, with interesting results. In a placebo-controlled trial on perimenopausal women by Schmidt et al. [ 140 ], ERT was linked with partial or full remission of depressive symptoms as early as 3 weeks after initiating treatment, while Klaiber et al. [ 141 ] reported similar benefits for high-dose ERT in perimenopausal women with MDD over 3 months. A larger study included 661 perimenopausal women who were divided into various groups: receiving oral estrogens and progesterone, receiving transdermal estradiol and progesterone, and a placebo group. After a 48-month follow-up, women who received oral ERT showed significant relief of depressive symptoms in comparison to the placebo group [ 142 ].

Nevertheless, a meta-analysis of 10 studies with 1,208 perimenopausal women ascertained supplementation with bioidentical estrogens to have no significant effects on depressive symptoms, even with adjunctive progestogens, despite being effective in the management of vasomotor symptoms [ 143 ]. Furthermore, the KNHANES study determined prolonged oral contraceptive use and ERT usage to be linked with a significantly higher risk of depression [ 144 ]. Therefore, the clinical use of estrogens for depression remains controversial and requires further research.

Similar to what occurs in menopause, the sudden drop in estradiol levels seen after delivery has been hypothesized to contribute prominently to postpartum depression (PPD) [ 138 ]. Moreover, fluctuations in progestogen levels may also intervene significantly: Progesterone and other progestogens have been related to negative mood states, possibly by disrupting GABAergic neurotransmission [ 145 ]. In postmenopausal women treated with progesterone and animals treated with allopregnanolone (APG), there is a bimodal association between serum APG concentration and adverse mood, resembling an inverted U-shaped curve. Moreover, in humans, the maximal effective concentration of APG for producing negative mood is within the range of physiological luteal-phase serum concentrations [ 146 ].

Clinical data on the use of estrogens or progestogens in PPD is currently scarce, although available results suggest treatment with sublingual estradiol to be linked with rapid reduction of depressive symptoms [ 147 ]. Administration of transdermal E2 has also been considered as a possible therapeutic pathway, considering that in this way, hepatic metabolism is by-passed and risk for venous thromboembolism decreases. However, recent pilot studies have been unsuccessful as of yet [ 148 ]. What has been considered a promising target in postpartum depression has been the aforementioned APG. In a randomized controlled trial, Kanes et al. researched the use of an intravenous dose of APG, finding scarce adverse events and significant improvement of the symptoms [ 149 ]. Further studies are required to elucidate the role of hormone therapy in PPD, as this entity continues to be recognized as remarkably difficult to treat.

Finally, androgens of both adrenal and gonadal origin can cross the blood-brain barrier, with multiple effects on the brain, and various androgens, including testosterone, can be synthesized de novo in the brain [ 150 , 151 ]. Androgens act as allosteric modulators of GABA-A receptors, increasing the duration and frequency of the opening of their associated chloride channel [ 152 ], modulating various neurotransmitter systems and neuronal excitability, with important implications in the neurobiology of mood disorders [ 152 – 155 ]. This profile appears to have significant clinical correlations: Testosterone levels decline progressively with age, in association with symptoms intriguingly similar to those seen in depression, including negative mood, fatigue, irritability, and low libido [ 156 ]. In addition, men treated with antiandrogen drugs have shown greater risk of developing MDD [ 157 ].

Interestingly, clinical studies have failed to show effectiveness for testosterone administration as an augmentation strategy in the management of depression in men [ 158 ], whereas administration of low-dose testosterone in women with treatment-resistant MDD has been observed to significantly improve depressive symptoms in comparison to placebo [ 159 ]. These paradoxical findings are consistent with the higher sensitivity of females to androgens, as higher androgen exposure has been noted to exert a definite negative influence in mood in females [ 160 , 161 ]. Future studies should address these differences between gender and their clinical relevance.

4. Neurosteroid Pharmacotherapeutic Targets in Depression

Many neuron types—especially glutamatergic and GABAergic neurons—have shown de novo synthesis of steroidal messengers, termed neurosteroids, which have been observed to modulate neuronal excitability [ 162 ]. Allopregnanolone is the most well described of these molecules at present, which has been noted to have sedative and anesthetic effects as well as an impact in mood regulation [ 163 ]. As with all steroids, synthesis of APG requires the expression of several CYP enzymes in neurons [ 164 ].

APG appears to act as an allosteric modulator of the GABA-A receptor, as well as a negative feedback signal for the HPAA: In chronic stress conditions, lower APG levels have been linked with greater activation of the HPAA and a slower recovery towards homeostasis [ 165 ]. This in turn may be influenced by decreased basal activation of GABA-A receptors, a hypothesis consistent with the lower levels of APG found in the cerebrospinal fluid (CSF) and peripheral blood found in patients with various affective disorders, including MDD [ 166 ]. Selective serotonin reuptake inhibitors, tricyclic antidepressants, and mirtazapine have been observed to elevate APG levels, whereas electroconvulsive therapy, repeated transcranial magnetic stimulation, and sleep deprivation appear to have no such effect [ 167 ]. SAGE-217, a synthetic derivate of APG, is currently undergoing phase 2 clinical trials, with preliminary findings showing modest improvements in clinical scores for depression after short-term use [ 168 ]. Further studies are needed to explore the use of APG or its synthetic analogues in MDD.

The role of other neurosteroids in depression remains less clearly understood. Androstenedione may be particularly relevant as a regulator of the HPAA and androgen metabolism, but current findings are contradictory: Both direct and inverse relationships have been described between androstenedione and depressive symptoms [ 169 , 170 ]. Future research may clear these discrepancies and present further potential therapeutic strategies involving neurosteroids.

5. Neuropeptide Pharmacotherapeutic Targets in Depression

5.1. oxytocin and arginine vasopressin.

In parallel to the study of neurosteroids, modern psychiatric research for future therapies has shown prominent interest in neuropeptides ( Figure 3 ), especially oxytocin (OXT) and arginine vasopressin (AVP) [ 171 ]. Central oxytocin signaling exerts anxiolytic and antidepressant effects, whereas vasopressin tends to promote anxious and depressive behaviors. These opposing effects may underline the importance of the balanced activity of these neuropeptides regarding emotional regulation. Shifting this equilibrium towards oxytocin through positive social stimuli and psychopharmacotherapy may aid in the management of depression [ 172 ].

Neuropeptide pharmacotherapeutic targets in depression. OXT: oxytocin; LHA: lateral nucleus; PVH: paraventricular nucleus; DMH: dorsomedial nucleus; VMH: ventromedial nucleus; ARC: arcuate nucleus; AVPR1B: arginine vasopressin receptor 1B; NK1: neurokinin 1. Key findings regarding the current knowledge on neuropeptides in the neuropsychopharmacology of depression include the following: (1) Abundant preclinical and clinical evidence suggests oxytocin may significantly contribute to the improvement of depression-related symptoms such as sexual dysfunction, anhedonia, and sleep disturbances. (2) AVPR1B antagonists appear to reduce symptoms of anxiety and depression in both animal and human models. (3) Several modulators of neuropeptide signaling have shown antidepressant activity; however, further research is required to characterize their significance and utility.

Indeed, in rodent studies, OXT has been clearly associated with positive social interaction [ 173 , 174 ], and synthetic OXT has been shown to shift stress responses in rodents towards a more active coping style, after both central and peripheral administration [ 172 ]. Furthermore, OXT but not AVP, was recently shown to stimulate neuronal growth and to rescue glucocorticoid- or stress-induced suppression of neurogenesis in the hippocampus of adult rats [ 175 ]. In humans, OXT levels have been observed to be significantly lower in both psychotic and nonpsychotic depression [ 176 ], as well as bipolar depression [ 177 ]. Moreover, OXT appears to be particularly lower in subjects with the melancholic phenotype of depression, as ascertained in an mRNA expression study by Meynen et al. [ 178 ].

In addition, there is preclinical and clinical evidence that OXT may also contribute to the improvement of other depression-related symptoms, including sexual dysfunction: a study with ventral injections of OXT in male rats showed that stimulation of paraventricular DA receptors not only induces penile erection but also increases mesolimbic DA neurotransmission by activating oxytocin neurons. These findings suggest these mediators can powerfully influence both the consummatory and motivational/rewarding aspects of sexual behavior [ 179 ], anhedonia. [ 180 ], and possibly, sleep disturbances [ 181 ]. Furthermore, OXT but not AVP, was recently shown to stimulate neuronal growth and to rescue glucocorticoid- or stress-induced suppression of neurogenesis in the hippocampus of adult rats [ 175 ].

On the other hand, AVP appears to be an anxiogenic mediator [ 182 ]. AVP receptors have been long identified—AVPR1A, AVPR1B and AVPR2 [ 183 ]—though AVP can also bind to the structurally related OXT receptor (OXTR) with high affinity. AVR1A receptors are widely distributed on blood vessels and have also been found in the CNS, including the paraventricular nucleus, whereas AVPR2 receptors are predominantly located in the principal cells of the renal collecting system [ 172 ]. The AVP receptor family is G protein-coupled receptors: AVPR1A and AVPR1B are both coupled to Gq/11 and signal via phospholipase C [ 184 , 185 ]. AVPR2 is coupled to Gs which, when activated, elevates cAMP levels by recruiting adenylate cyclase [ 186 ].

Studies on AVPR1B antagonists have yielded favorable results such as alleviation of anxiety and depression in animal and human models [ 187 , 188 ]. In rat models, the AVP gene has been strongly correlated with trait anxiety [ 189 ]. Furthermore, clinical trials have associated the use of AVPR1B antagonists to HPAA modulation in subjects with MDD, along with amelioration of clinical symptoms [ 190 ].

5.2. Other Neuropeptides

Neurokinin 1 (NK1) antagonists were some of the earliest alternatives proposed for nonmonoamine-related biologic treatments for depression, following findings that linked chronic administration of MK-869, one of these molecules, with improvement of depressive symptoms [ 91 , 191 ]. This led to the clinical study of aprepitant, another NK1 antagonist. Although initial reports were favorable, it failed to demonstrate efficacy in phase III clinical trials, discouraging further scientific interest in this matter [ 192 ].

However, more recent research suggests almost full central blockade of NK1 receptors is required for efficacy in the treatment of depression [ 193 , 194 ]. Casopitant and orvepitant, two NK1 antagonists capable of much greater blockade have shown antidepressant efficacy in various isolated randomized trials [ 193 – 195 ]. This promising data have renewed interest in NK1 antagonists and other neuropeptide-related alternatives for depression.

Neuropeptide Y (NPY) is a very widespread neurotransmitter in the CNS, acting through a wide array of receptors [ 196 – 198 ]. In recent years, NPY has been reported to be decreased in depression, anxiety, and stress, in both plasma [ 199 ] and CSF [ 200 ]. Conversely, antidepressant treatment has been linked with increased NPY levels [ 201 ].

NPY-related therapeutic interventions have gained attention I light of these findings. Data from mice models are abundant: central administration of NPY has been associated with reduced immobility and longer swimming times in forced swim tests [ 202 ], along with other similar correlates [ 203 – 205 ], while Y1 receptor knockout mice tend to show opposite results [ 206 ]. In contrast, Y2 and Y4 receptor knockout mice have shown more resilient phenotypes in these tests [ 206 , 207 ], and the infusion of Y2 antagonists—as well as Y1 agonists—has been related with antidepressant effects [ 202 ]. This would suggest a differential role for distinct NPY receptor types, a promising hypothesis for future research.

Galanin has also been proposed to intervene in the neurobiology of depression [ 208 , 209 ]. The galanin system includes three major G protein-coupled receptors (GALR1, GALR2, and GALR3), all which are widespread in the CNS and tend to colocalize with monoamine receptors, forming heteroreceptor complexes [ 210 ]. Thus, galanin signaling is an important modulator of neurotransmission. Galanin overexpression has been described in depression and stress [ 211 ], and serum galanin levels have been suggested as a biomarker for depression [ 212 ]. In a siRNA GALR1 and GALR2 knockdown rat model, coadministration of fluoxetine with the Gal (1–16) fragment obtained greater antidepressant effects [ 213 ]. Several other studies have found similar results with various galanin ligands [ 214 – 217 ]. Nevertheless, understanding of the neurobiology of galanin is still incipient, in particular regarding mood regulation.

6. Pharmacotherapeutic Targets for Depression in Reward Neurocircuits

The reward system encompasses various neurocircuits which mediate motivational behavior and learning in response to external and internal stimuli [ 218 ]. Anatomically, this system originates in the ventral tegmental area (VTA) and projects to the nucleus accumbens (NAcc), lateral hypothalamus, lateral septum, hippocampus, amygdala, PFC, and anterior cingulate cortex (ACC) [ 219 ]. Preclinical and clinical findings in neuroimaging have demonstrated that the anhedonia and loss of motivation found in depression is closely linked with decreased size and functionality of several of the nuclei in the reward system, in particular the NAcc and ACC [ 220 , 221 ], along with reduced dopaminergic neurotransmission, one of the pillars of the monoamine hypothesis [ 222 , 223 ].

Functionally, reward processing involves two interrelated components: motivational processing, which centers attention and behavior on rewarding stimuli and fundamentally involves dopaminergic neurotransmission; and hedonic processing, which mediates the pleasurable reaction to these stimuli, and involves GABAergic, opioid, endocannabinoid (EC), and endovanilloid (EV) signaling throughout the NAcc, ventral pallidum, insular cortex, and orbitofrontal cortex [ 224 , 225 ]. The crosstalk among these systems is complex and remains to be fully elucidated [ 226 , 227 ]. However, specific components in these circuits have already emerged as potential targets in the neuropsychopharmacological approach to depression ( Figure 4 ).

Pharmacotherapeutic targets for depression in reward neurocircuits. ∗ Agonist. ∗ ∗ Antagonist. ∗ ∗ ∗ Modulator. μ : µ -opioid receptor. δ : δ -opioid receptor. κ: κ-opioid receptor. CB1: cannabinoid receptor 1. CB2: cannabinoid receptor 2. TRPV1: transient receptor potential cation channel V1. Research on pharmacotherapeutic targets for depression in the reward system remains principally preclinical. Currently available results presume some potential clinical utility for these substances for the treatment of depression, with varying degrees of efficacy and differing pharmacological profiles.

Dysregulation of opioid signaling has long been associated with depression, as indeed, opioids were historically trialed in the management of this disorder long before the introduction of modern AD [ 228 – 230 ]. Opioid receptors are in the G protein-coupled receptor superfamily, including three distinct types—mu ( µ ), delta ( δ ), and kappa (κ)—with different physiologic roles. Endogenous opioids are their native ligands, a group of peptides characterized by sharing a specific NH-terminal sequence (Tyr-Gly-Gly-Phe). Endogenous opioids have been classified as enkephalins, dynorphins, and β -endorphin according to their structure and their affinity for different receptor types [ 231 ].

Opioid peptides and their receptors are amply distributed in the central and peripheral nervous systems, intervening in nociception, analgesia, endocrine, and immunologic regulation, mood regulation, as well as hedonic and motivational processing, and modulation of addictive behavior [ 229 ]. In the CNS, opioid receptors are predominantly expressed in the brainstem, limbic nuclei, and cortex; the latter two being particularly relevant to mood disorders [ 232 ]. Indeed, neuroimaging and pathology studies—both in living subjects and postmortem —in subjects with depression and suicidal behavior, have shown structural and functional alterations in opioid signaling, especially in the PFC, NAcc, and ACC [ 233 – 237 ].

Although both misuse and chronic, high-dose treatment with opioids have been consistently linked increased incidence, relapse, and recurrence of depression [ 238 – 241 ], more nuanced used may be beneficial in this regard. In preclinical research, various opioid agonists such as morphine, codeine, levorphanol, methadone, and tramadol have been observed to yield better outcomes than commonly available antidepressants in mice models evaluating depressive behavior, with these effects being reversible by naloxone, an opioid antagonist [ 242 ]. The antidepressant efficacy of opioids may depend specifically on δ-receptor agonism, as observed in mice and rats treated with intracerebroventricular and intraperitoneal UFP-512, a δ -selective opioid agonist [ 243 ]. Because of the tolerance, dependence and abuse potential associated with unopposed and selective δ agonism [ 244 ], interest for the use of opioids in this situation has shifted to combined opioid agonists/antagonists. In particular, the coadministration of buprenorphine, a δ -receptor partial agonist and antagonist of δ and κ receptors, along with samidorfan, a δ -selective antagonist, has been associated with rapid antidepressant effects [ 245 ].

Another opioid-related potential pharmacological target for depression has been found in opiorphin, an inhibitor of Zn-ectopeptidase, neutral endopeptidase, and aminopeptidase N, all of which intervene in the rapid inactivation of enkephalins [ 246 ]. In preclinical models, opioid administration has been linked with attenuated depressive responses, with this effect being reversible by the administration of naldrindole, a δ -selective antagonist [ 247 ], or naloxone [ 248 ]. Despite these promising results, research in humans remains scarce, and further study is required to assuage concerns related to misuse of these substances.

The endocannabinoid system also has an important role in mood regulation, and levels of EC metabolites in CSF have been correlated with severity of depression [ 237 ]. EC are lipophilic substances synthesized on demand in various nuclei within the reward circuits, the principal molecules being anandamide, which also shows affinity for vanilloid receptors, and 2-arachidonoylglycerol [ 249 , 250 ]. Cannabinoid receptor 1 is localized in glutamatergic and GABAergic synapses throughout basal nuclei, while cannabinoid receptor 2 can be found both in the CNS and in immune cells, posing a provocative link between depression and systemic health [ 251 ]. Polymorphisms in the genes encoding these receptors have been correlated with specific treatment resistance [ 252 ], severe depression symptoms, [ 253 ] anxiety, and suicidal behavior [ 254 ]. Furthermore, levels of cannabinoid receptor ligands in CSF have been determined to be increased in subjects with depression after undergoing electroconvulsive therapy [ 255 ].

Although clinical research remains scarce regarding EC modulation in depression, preclinical findings appear promising. Recently, Xiaolie et al. investigated the role of curcumin, a cannabinoid receptor modulator, and dexanabinol-loaded solid lipid nanoparticles in depression treatment in mice and cultured cells. Their findings showed this compound increased EC expression and potentiated cannabinoid receptor activation, with increased activity in the ERK1/2 pathway, a key cascade in the activity of many AD [ 256 ].

Finally, endovanilloids are endogenous substances which possess a vanillyl group and show affinity for the TRPV1 receptor, the main molecules in this category being anandamide, n- acylethanolamines, n -acyldopamines, n -oleoyl-dopamine, and n -arachidonoyl-dopamine, as well as some lipoxygenase derivatives of arachidonic acid like 12-hydroperoxyeicosatetraenoic acid [ 257 ]. Though their physiology remains obscure, endovanilloids have been implicated in locomotion, pain modulation, and regulation of emotion, cognition, and behavior; pharmacological modulation of TRPV1 receptors has been speculated to be useful in the treatment of pain, anxiety, depression, and various neurological disorders [ 258 ]. TRPV1 receptors have been shown to modulate input to the locus coeruleus, a key area implicated in the regulation of mood, the stress response, and memory processing [ 259 ].

In preclinical studies, TRPV1 knockout mice tend to exhibit reduced immobility time and reduced latency times in the novelty-suppressed feeding paradigm, consistent with a decreased depressive response [ 260 ]. TRPV1 receptor modulation has been observed to boost the effect of AD [ 261 ], and arvanil, a synthetic agonist ofTRPV1 and cannabinoidreceptors, appears to induce significant antidepressant effects in mice [ 262 ]. Future research in humans in this field should clear the significance and utility of the neuropsychopharmacological modulation of the reward system in depression.

7. Conclusions

Expanding comprehension of depression as a neuroendocrine disorder has injected much-needed hope into the landscape of neuropsychopharmacology. In particular, glutamate-based alternatives may be the most feasible in the near future, with promising and active clinical trials at the moment evaluating the use of both intravenous and oral ketamine, along with several other related molecules [ 263 , 264 ]. Likewise, nonpharmacological interventions, both well-established—including lifestyle modifications and electroconvulsive therapy—and more novel, such as deep brain stimulation, transcranial magnetic stimulation, and psychosurgery, should not be discounted, as their place in the treatment of depression has become better characterized in recent years.

Furthermore, evolving views on the pathophysiology of depression suggest pharmacological and nonpharmacological interventions centered on the immunologic, metabolic, and cardiovascular aspects of this disorder may break new ground in the field of psychiatric therapeutics in the future. Therefore, although present therapeutic outcomes require urgent improvement, there may be enough forthcoming innovation to remain optimistic regarding the conundrum of treatment alternatives in depression.

Acknowledgments

This work was supported by research grant no. CC-0437-10-21-09-10 from the Technological, Humanistic, and Scientific Development Council (CONDES), University of Zulia, and research grant no. FZ-0058-2007 from Fundacite-Zulia.

Conflicts of Interest

The authors declare that they have no conflicts of interest.