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The importance of norepinephrine in depression

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Chantal Moret
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Depression is one of the most common psychological diseases with significant potential morbidity and mortality. Although the underlying pathophysiology of depression has not been clearly defined, preclinical and clinical evidence suggest disturbances in serotonin (5-HT), norepinephrine (NE), and dopamine (DA) neurotransmission in the central nervous system. Virtually all currently available antidepressants act on one or more of the following mechanisms: inhibition of reuptake of 5-HT or NE (and DA), antagonism of inhibitory presynaptic 5-HT or NE receptors, or inhibition of monoamine oxidase. All of these mechanisms result in an enhanced neurotransmission of 5-HT and/or NE. Evidence for the involvement of NE in depression is abundant, and recent studies on neuronal pathways and symptoms highlight the specific role of NE in this disorder. NE plays a determinant role in executive functioning regulating cognition, motivation, and intellect, which are fundamental in social relationships. Social dysfunction is possibly one of the most important factors affecting the quality of life in depressed patients.
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Open Access Full Text Article
DOI: 10.2147/NDT.S19619
The importance of norepinephrine in depression
Chantal Moret
Mike Briley
NeuroBiz Consulting and
Communication, Castres, France
Correspondence: Chantal Moret
NeuroBiz Consulting and Communication,
27 Impasse des Grèses, Castres, France
Tel +33 5 63 71 03 23
Email chantal.moret@neurobiz.com
Abstract: Depression is one of the most common psychological diseases with significant
potential morbidity and mortality. Although the underlying pathophysiology of depression has
not been clearly defined, preclinical and clinical evidence suggest disturbances in serotonin
(5-HT), norepinephrine (NE), and dopamine (DA) neurotransmission in the central nervous
system. Virtually all currently available antidepressants act on one or more of the following
mechanisms: inhibition of reuptake of 5-HT or NE (and DA), antagonism of inhibitory pre-
synaptic 5-HT or NE receptors, or inhibition of monoamine oxidase. All of these mechanisms
result in an enhanced neurotransmission of 5-HT and/or NE. Evidence for the involvement of
NE in depression is abundant, and recent studies on neuronal pathways and symptoms highlight
the specific role of NE in this disorder. NE plays a determinant role in executive functioning
regulating cognition, motivation, and intellect, which are fundamental in social relationships.
Social dysfunction is possibly one of the most important factors affecting the quality of life in
depressed patients.
Keywords: serotonin, antidepressants, neurotransmission, symptoms
Introduction
Depression is associated with significant potential morbidity and mortality contributing
to suicide, medical illness, disruption of interpersonal relationships, lost work time,
and often leading to substance abuse.
1
The underlying pathophysiology of depression
is not clearly understood, but biological, psychological, and social factors all play a
causal role in depression.
2
Imaging studies have shown that patients with depression have smaller hippocam-
pal volume compared with controls,
3
and there may be a link between depression
and hippocampal neurogenesis.
4
Evidence also suggests that major depression may
involve an overactive hypothalamic-pituitary-adrenal axis which results in an effect
similar to the neuroendocrine response to stress.
5
The hormone, estrogen, has also
been implicated in depressive disorders
6–8
and in their treatment.
9
The involvement
of pro-inflammatory cytokines in depression is strongly suggested by meta-analyses
of clinical studies showing higher blood concentrations of interleukin (IL)-6 and
tumor necrosis factor (TNF)-α in depressed patients compared with controls.
10,11
Other possible disease mechanisms that have been suggested include changes in
glutamatergic neurotransmission, reduced neurotransmission of gamma-butyric acid,
abnormal circadian rhythms, deficient neurosteroid synthesis, impaired endogenous
opioid function, acetylcholine imbalance, tyroxine abnormalities, and dysfunction
of specific brain structures and circuits.
12
In spite of these new hypotheses, one of
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Moret and Briley
the oldest, the monoamine hypothesis which postulates a
deficiency of serotonin (5-HT) and/or norepinephrine (NE)
neurotransmission in the brain,
13,14
is still driving clinical
development of new antidepressants. Virtually all currently
available antidepressants act on one or more mechanisms
compatible with the monoamine hypothesis: inhibition
of reuptake of 5-HT or NE; antagonism of presynaptic
inhibitory 5-HT or NE receptors; or inhibition of monoam-
ine oxidase. All of these mechanisms result in an enhanced
neurotransmission of 5-HT and/or NE. The confirmation of
the clinical activity of these antidepressants has done much
to reinforce the monoamine hypothesis.
An association of specific features and symptoms of
depression and a deficiency or dysfunction of certain neu-
rotransmitters has been proposed.
15
Thus, a 5-HT deficiency
is related to anxiety, obsessions, and compulsions; reduced
NE neurotransmission is associated with decreased alertness,
low energy, problems of inattention, concentration, and cog-
nitive ability; while dysfunctional dopamine (DA) activity is
implicated in problems of motivation, pleasure, and reward.
Interestingly, increased 5-HT activity can be associated with
certain symptoms such as fatigue.
16
Evidence for the involvement of 5-HT in depression has
been the subject of numerous studies.
17
The role of NE
15,18
and DA
19,20
has been less extensively studied. This review
briefly summarizes the involvement of NE in depression,
highlighting the importance of the relationship between NE
pathways and specific symptoms.
Evidence for the involvement
of NE in depression
Several lines of evidence suggest that NE is a neurotransmit-
ter of major importance in the pathophysiology and treatment
of depressive disorders.
21
1. NE projections from the locus coeruleus innervate the
limbic system, which is implicated in the regulation of
emotions.
2. Numerous differences have been found in elements of the
NE system in postmortem brains from depressed patients
and healthy controls.
3. Genetic studies show that mice with genetically engi-
neered functional enhancement of the NE system are pro-
tected from stress-induced depression-like behaviors.
4. Experimental depletion of NE in the brain results in a
return of depressive symptoms after successful treatment
with NE antidepressant drugs.
5. Therapeutic agents which specifically increase NE
activity are effective antidepressants.
NE neuroanatomy
Noradrenergic pathways in the brain arise from the cell
bodies in the locus coeruleus and project to different cere-
bral regions and to the spinal cord (Figure 1). In addition to
major projections to the frontal cortex, NE neurons project
to the limbic system, whose various components such as the
amygdala, hippocampus, and hypothalamus are implicated
in emotion and cognition as well as a number of functions
modified in depressed patients such as appetite, response to
pain, levels of pleasure, sexual satisfaction, and aggressive
behavior.
22
Imaging studies indicate that major depression is asso-
ciated with abnormal metabolism in limbic and paralimbic
structures of the prefrontal cortex. This abnormal metabo-
lism is normalized in the amygdala and prefrontal cortex in
patients showing a persistent antidepressant response.
22
Stahl
23
has suggested that it can be instructive to consider
brain neuroanatomy in terms of specific functional centers
(Table 1).
23–26
The “emotional” and “somatic” centers in the
brain receive projections from both NE and 5-HT as well as
DA pathways. The “cognitive” centers, on the other hand,
receive input only from NE as well as DA and histaminergic
projections, but not 5-HT projections.
23–26
Executive function is a complex organization of higher
mental functions that process mental and environmental input
to enable efficient problem-solving capacity in a way that
is acceptable to both the individual and society. It includes
inhibition of irrelevant or unacceptable behavior, the suppres-
sion of nonpertinent information, the regulation of verbal and
nonverbal working memory, self-regulation of affect, motiva-
tion and arousal, planning, decision-making, self-monitoring
of the problem-solving process, and self-evaluation of the
results of the action taken. Anatomically, this occurs in the
prefrontal lobe of the cortex and its afferent and efferent
Cerebral cortex
Fomix
Amygdala
Hypothalamus
Dorsal bundle
Ventral bundle
To spinal
cord
Locus
coeruleus
Cerebellum
Colliculi
Thalamus
Hippocampus
Stria terminalis
Nucleus
accumbens
Figure 1 Sagittal section of the human brain, showing the principal noradrenergic
pathways.
Adapted with permission from Moret C. Understanding neurotransmission in the brain.
Available from: http://www.psy-world.com/unt_noradr.htm.
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Norepinephrine and depression
structures involving the neurotransmitters NE and DA and
to a lesser degree acetylcholine and 5-HT.
27
Executive function is also fundamental to social relationships.
Social dysfunction in depression is possibly one of the most
important factors affecting the quality of life of patients.
Considerable clinical data suggest the importance of NE in the
improvement of clinical dysfunction in depression.
28
Biochemical differences between
depressed patients and healthy controls
An early study
29
found increased β-adrenergic receptor bind-
ing in the frontal cortex of suicide victims. More recently,
post-mortem and functional imaging studies in the prefrontal
cortex of depressed suicide victims have shown altered den-
sity and sensitivity of α
2A
-adrenoceptors which modulate NE
release.
30–32
In addition, decreased NE transporter binding has
been reported in locus coeruleus of postmortem samples from
subjects diagnosed with major depression.
33
Alterations in
putative peripheral markers of central NE function, such as
α
2
-adrenoceptor density in platelets, have also been found in
depressed patients.
34,35
These modifications may all be part of the
primary causal physiopathology of depression. Alternatively,
at least some of them could be the result of compensatory
modifications resulting from changes of NE neurotransmission
in depressed patients. Whatever the interpretation, these data
imply an important role for NE in depression.
Genetic studies of NE function
Genetic studies of NE function have indicated the mul-
tiple roles that NE plays in normal and pathological states.
Functional deletion (knockout) of the NE transporter in mice
results in increased extracellular levels of NE.
36
This model
functionally mimics the therapeutic effects of selective
NE antidepressants. Recently, this model has shown that
NE transporter (NET) knockout mice are resistant to the
stress-induced depressive-like changes in behavior and brain
neurotrophin expression that are seen in wild-type mice.
37
Human genetic studies have shown that variations in the
gene coding for NET which alter neurotransmitter release
are related to individual differences in behavior and suscep-
tibility to depression.
38
The polymorphism, NET-T182C,
for example, is associated with an increased susceptibility
to depression.
39
Catechol-O-methyltransferase (COMT) 158Val/Met
is a polymorphism of a major enzyme in catecholamine
inactivation. The alleles encoding Val and Met are associ-
ated with relatively high and relatively low COMT activity,
respectively. The Val/Val genotype, a high-activity COMT
genotype, was significantly less frequent in male suicide com-
pleters than in male controls.
40
An association of 158Val/Met
polymorphism with major depression is still unclear, since some
studies have found the Met allele (low COMT activity) to be
associated with major depression
41
while others have not.
42,43
NE depletion studies
Studies in depressed patients in remission and no longer
taking medication have shown that a drastic reduction of NE
levels (by inhibition of the key synthetic enzyme, tyrosine
hydroxylase, with α-methyl-p-tyrosine) results in a rapid
reappearance of depressive symptoms. Interestingly, how-
ever, catecholamine depletion in healthy control volunteers
does not result in depressed mood.
18,44,45
Clinical activity of noradrenergic
antidepressants
A considerable proportion of patients fail to respond ade-
quately to selective serotonin reuptake inhibitors (SSRIs).
Analysis of the unresolved symptoms suggests that a specific
set of symptoms related to decreased positive affect respond
poorly to serotonergic antidepressants, namely loss of plea-
sure, loss of interest, fatigue, and loss of energy.
46
There is
evidence to suggest that antidepressants that enhance NE
and DA activity offer a therapeutic advantage over 5-HT
antidepressants in the treatment of symptoms associated with
reduced positive affect.
Table 1 Neuronal projections to different brain “centers”
Emotional centers
NE projections from the locus coeruleus to the hypothalamus
NE projections from the locus coeruleus to the amygdala and
prefrontal cortex
5-HT projections from the midbrain raphe to the hypothalamus
5-HT projections from the midbrain raphe to the amygdala and prefrontal
cortex
DA projections from the ventral tegmentum to the nucleus accumbens
Somatic centers
NE projections from the locus coeruleus to the hypothalamus
NE projections from the locus coeruleus to the cerebellum
NE projections from the locus coeruleus to the spinal cord
5-HT projections from the midbrain raphe to the hypothalamus
5-HT projections from the midbrain raphe to the striatum
5-HT projections from the midbrain raphe to the spinal cord
DA projections from the substantia nigra to the striatum
Cognitive centers
NE projections from the locus coeruleus to the dorsolateral
prefrontal cortex
DA projections from the ventral tegmentum to the dorsolateral
prefrontal cortex
Histamine projections from the hypothalamus to the dorsolateral
prefrontal cortex
Source: Summarized from references 23–26.
Abbreviations: 5-HT, serotonin; DA, dopamine; NE, norepinephrine.
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Moret and Briley
The undisputed antidepressant action of NE-selective
tricyclic antidepressants such as desipramine and nortrip-
tyline suggests a major involvement of NE neurotransmission
in depression, although these compounds or their metabolites
also have some action on the 5-HT system. The selective NE
reuptake inhibitor, reboxetine, has demonstrated equivalent
efficacy to the TCA (tricyclic antidepressants) in some
studies
47,48
and is approved as an antidepressant in Europe
but not in the USA. A recent publication
49
suggests, however,
that there may be considerable publication bias and that if
unpublished studies are also considered, the antidepressant
activity is unclear.
The SNRIs (serotonin and norepinephrine reuptake
inhibitors) venlafaxine, milnacipran, and duloxetine show
at least equivalent antidepressant efficacy to the SSRIs, and
there is evidence that they may be more effective than the
SSRIs in achieving remission.
50
Conclusion
Although 5-HT has been the most studied neurotransmitter
in depression, converging lines of evidence suggest that NE
is of major importance in the pathophysiology and treatment
of depressive disorder. NE projections from the locus ceo-
ruleus innervate the limbic system, which is implicated in the
regulation of emotions and cognition. Substantial functional
biochemical differences exist in the NE system in postmortem
brains from depressed patients and healthy controls. Genetic
manipulation of the NE system that increases NE neurotrans-
mission protects animals from stress-induced depressive
behavior, while chemical manipulation that depletes the brain
of NE increases the susceptibility of recovered depressed
patients to a depressive relapse. Therapeutic agents which
specifically increase NE activity are effective antidepressants,
and there is evidence that those acting simultaneously on
5-HT and NE neurotransmission may have an antidepressant
action superior to SSRIs.
50
Disclosure
Dr Chantal Moret has no potential conflict of interest.
Dr Mike Briley is a consultant for Pierre Fabre Médicament,
Asahi Kasei Pharma, Germania Pharmaceutica, Janssen
Pharmaceutica, and Cypress BioScience.
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Post-stroke depression (PSD) is the most frequent and important neuropsychiatric consequence of stroke. It is strongly associated with exacerbated deterioration of functional recovery, physical and cognitive recoveries, and quality of life. However, its mechanism is remarkably complicated, including the neurotransmitters hypothesis (which consists of a monoaminergic hypothesis and glutamate-mediated excitotoxicity hypothesis), inflammation hypothesis, dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, and neurotrophic hypothesis and neuroplasticity. So far, the underlying pathogenesis of PSD has not been clearly defined yet. At present, selective serotonin reuptake inhibitors (SSRIs) have been used as the first-line drugs to treat patients with PSD. Additionally, more than SSRIs, a majority of the current antidepressants complied with multiple side effects, which limits their clinical application. Currently, a wide variety of studies revealed the therapeutic potential of natural products in the management of several diseases, especially PSD, with minor side effects. Accordingly, in our present review, we aim to summarize the therapeutic targets of these compounds and their potential role in-clinic therapy for patients with PSD.
... Noradrenergic (NE) neurons project to the limbic system, the functions of which are associated with emotion and cognition. 48,49 Stahl 50 suggested that, in neuroanatomical terms, emotional functional centers in the brain receive input from both NE and 5-HT neuronal projections, while cognitive functional centers receive direct projections from NE, dopaminergic, and histaminergic but not 5-HT neurons. Since desvenlafaxine presented a significant favorable treatment response in ameliorating depressive symptoms and has direct effects on NE neurotransmission, NE transmission might have contributed to the better treatment responses in improving depressive symptoms. ...
Acute Efficacy and Safety of Escitalopram Versus Desvenlafaxine and Vortioxetine in the Treatment of Depression With Cognitive Complaint: A Rater-Blinded Randomized Comparative Study
Article
Objective This study aimed to compare the efficacy and safety of escitalopram, vortioxetine, and desvenlafaxine for acute treatment of major depressive disorder (MDD) with cognitive complaint (CC). Methods A total of 129 patients with MDD who also complained of CC were randomized evenly to either escitalopram, vortioxetine, or desvenlafaxine group and underwent a multi-center, six-week, rater-blinded, and head-to-head comparative trial. Differences in depressive symptoms following treatment were measured using the Hamilton Depression Rating Scale (HAMD) and the Montgomery-Åsberg Depression Rating Scale (MADRS). Subjective cognitive function and the presence of adverse events were assessed. Results The three antidepressant treatment groups did not show significant differences in the improvement of depressive symptoms as measured by HAMD and MADRS. Desvenlafaxine treatment was associated with a superior treatment response rate in depressive symptoms compared to vortioxetine or escitalopram treatment. However, no significant differences were found in the remission rate of depressive symptoms. The three antidepressant treatment groups did not show significant differences in the improvement of CC. Adverse profiles of each treatment group were tolerable, with no significant differences. Conclusion In acute antidepressant treatment for MDD with CC, escitalopram, vortioxetine, and desvenlafaxine presented similar efficacy in relief of depressive symptoms; however, desvenlafaxine was associated with a superior treatment. Further studies are needed to confirm these results by investigating the therapeutic efficacy and safety profile of long-term antidepressant treatment of MDD with CC (Clinical Trial Registry, http://cris.nih.go.kr/cris/en/: KCT0002173).
... During "fight-or-flight" situations, the sympathetic nervous system becomes highly active, resulting in enhanced norepinephrine release from sympathetic nerve endings and epinephrine secretion from the adrenal gland medulla [10]. The limbic system, which is involved in the regulation of emotions and cognition, is innervated by norepinephrine projections from the locus coeruleus [11]. ...
Emotion Regulation, the Function of Stress Hormones & Digital Technologies
Article
Full-text available
  • Apr 2022
Emotion control in stressful situations is an important aspect of mental health. On the other hand, acute stress, affects the prefrontal cortex control, probably resulting in a loss of emotion regulation abilities. To lessen the threat, the stress response activates a number of defensive systems, including hormone messenger communication. In this article we are going to examine the present literature in relation to emotion control via understanding the function of the primary stress hormone, cortisol, and that of the catecholamines, epinephrine and norepinephrine. We have also presented and underlined the role of ICTs, web and mobile applications, AI & STEM tools, serious games, e-learning, tele-education services, etc., in the support and improvement procedures for achieving emotional self-control and regulation of the stress hormones.
... The limited efficacy of drug treatments acting on the dopaminergic and noradrenergic systems, and the gaps in our knowledge of the aetiology of ADHD, introduces the possibility that other neurotransmitter systems might be involved. One such neurotransmitter is serotonin (5-HT), which is linked to a range of cognitive and emotional functions (Moret and Briley 2011). Critically, it can be linked to the core symptoms of ADHD. ...
Tryptophan modulation in individuals with attention deficit hyperactivity disorder: a systematic review
Article
Full-text available
The serotonergic system is implicated in ADHD, but the impact of serotonin’s precursor molecule, tryptophan, on ADHD symptomology remains unclear. Systematic searches of randomised controlled trials with an experimental tryptophan intervention in children and adults with ADHD identified 14 studies measuring core and related symptoms of the condition. Risk of bias was assessed using the Cochrane Risk of Bias tool. The 14 studies all used acute tryptophan depletion procedures, and most did not investigate core ADHD symptoms (inattention, impulsivity, hyperactivity) as primary outcome measures. Only two studies examined attention and revealed mixed effects of tryptophan. Similar effects were found for impulsivity in a small number of studies. No studies investigated hyperactivity. Most studies focused on reactive aggression, but samples were heterogenous and small, rendering potential meta-analyses inconclusive or misleading. However, the narrative analysis indicates tryptophan interventions may impact reactive aggression. More research is needed on the effect of tryptophan modulation on core ADHD symptoms, especially in adults, using more diverse samples to determine potential as an intervention. From current data, tryptophan modulation appears to alter aggressive behaviour in ADHD; however, the available studies were insufficient for the planned meta-analysis.
... The main function of noradrenaline is associated with the fight-or-flight response where the body is ready to react to an emergency. Depletion of norepinephrine resulted in depression, which is contributing to significant potential morbidity, mortality, suicide, medical illness, etc. (Moret and Briley 2011). Noradrenaline belongs to the catecholamine class is derived from phenylalanine and tyrosine. ...
Utilization of Agro Waste for Beneficial Product Formulation
Article
  • Feb 2022
In the past few years, we have been very familiar with the waste hierarchy concept of the 3 R’s, Reduce, Reuse and Recycle. This review article aims to suggest a possible way to reuse the agro-waste sector. It will focus on the zero waste food industry. While consuming our day-to-day food unknowingly we throw away some of the important portions of fruits and vegetables which can help us fight diseases and stay healthy. Therefore, we need proper management to utilize these beneficial components present in those fruit scrapes. An abundant amount of food waste is been produced during the processing of food from the different food industries. In addition to this, agro wastes like peels, seeds, etc. are also generated from fruit and vegetable agriculture. This paper mainly focuses on the agro-waste of the food industry, which can be consumed when the bioactive compound is extracted and is available as a functional food. The bioactive compounds have the potential to control blood pressure, diabetes, inflammation, etc. Thus, by incorporating these bioactive compounds we can enhance the quality of food. Recently functional food is consumed by a large population for its beneficial effect on our body.
... This means that the differentiation between major mental disorders, such as mood and psychotic disorders, relies primarily on symptom presentation [14]. Given the rapidly growing evidence base for the gut microbiota's influence on multiple systems and pathways that are known to be commonly dysregulated across these mental disorders, including inflammation [15,16] and oxidative stress [17]; tryptophan metabolism and the kynurenine pathway [18,19]; mitochondrial dysfunction [20]; neurotransmitters [21][22][23][24][25]; brain plasticity and neurotrophic factors [26] and metabolic processes [27,28], the gut and its resident bacteria are increasingly recognised as important research targets. Critically, the functional potential of different bacteria is increasingly understood [29,30], meaning that identification of key taxa that are differentially abundant in people with mental disorders and that influence these commonly dysregulated systems is an imperative. ...
A systematic review of gut microbiota composition in observational studies of major depressive disorder, bipolar disorder and schizophrenia
Article
Full-text available
The emerging understanding of gut microbiota as ‘metabolic machinery’ influencing many aspects of physiology has gained substantial attention in the field of psychiatry. This is largely due to the many overlapping pathophysiological mechanisms associated with both the potential functionality of the gut microbiota and the biological mechanisms thought to be underpinning mental disorders. In this systematic review, we synthesised the current literature investigating differences in gut microbiota composition in people with the major psychiatric disorders, major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ), compared to ‘healthy’ controls. We also explored gut microbiota composition across disorders in an attempt to elucidate potential commonalities in the microbial signatures associated with these mental disorders. Following the PRISMA guidelines, databases were searched from inception through to December 2021. We identified 44 studies (including a total of 2510 psychiatric cases and 2407 controls) that met inclusion criteria, of which 24 investigated gut microbiota composition in MDD, seven investigated gut microbiota composition in BD, and 15 investigated gut microbiota composition in SZ. Our syntheses provide no strong evidence for a difference in the number or distribution (α-diversity) of bacteria in those with a mental disorder compared to controls. However, studies were relatively consistent in reporting differences in overall community composition (β-diversity) in people with and without mental disorders. Our syntheses also identified specific bacterial taxa commonly associated with mental disorders, including lower levels of bacterial genera that produce short-chain fatty acids (e.g. butyrate), higher levels of lactic acid-producing bacteria, and higher levels of bacteria associated with glutamate and GABA metabolism. We also observed substantial heterogeneity across studies with regards to methodologies and reporting. Further prospective and experimental research using new tools and robust guidelines hold promise for improving our understanding of the role of the gut microbiota in mental and brain health and the development of interventions based on modification of gut microbiota.
Molecular Mechanism of Psychosis
Article
Full-text available
  • Oct 2021
Biomedical research in line with most baseline studies, has proven biological alterations due to exposure to some heavy metals such as lead, mercury, cadmium, and arsenic have been implicated in patients with neurochemical imbalance, pharmacological viewpoint, and brain imaging as part of psychotic prognosis. Some of the most prevailing psychological conditions with notable tendencies of downheartedness and transience are depression and schizophrenia. However, the basal pathophysiology of these conditions from the pre symptomatic and diagnosed point of view, implicates dopamine, norepinephrine, and 5-HT neurotransmitters. Maternal Immune Activation (MIA) triggered by immunological changes from external factors mutating against the immune cells from predisposition to heavy metals leads to priming of the Central Nervous System (CNS) microglia cells which can create a pathway to expose offspring to psychosis. Based on this information, psychosis has been framed due to deficiency in neural signaling in homeostatic imbalance from oxidative stress, metabolic cascades, influenza, and inflammatory response. This review gives details of the role played by neurotransmitters and heavy metals, their toxicity mechanisms, along with the health effect leading to mental disorders like psychosis, depression, bipolar disorder, schizophrenia etc. Hence, the need for more research in this budding field and the challenges of identifying and developing new treatments for persons predisposed to lengthened risk of neurological autoimmune disorders should be considered.
A Bioluminescent Probe for Detecting Norepinephrine in Vivo
Article
  • Apr 2022
As a neurotransmitter, norepinephrine (NE) is critical for psychiatric conditions, neurodegenerative diseases, and pheochromocytoma. A real-time and noninvasive method for the detection of NE as a tracer to investigate the NE-relevant disease treatment process is urgently desirable. Herein, we successfully developed a turn-on NE bioluminescent probe (NBP), which was grounded on p-toluenethiol deprotectrf by nucleophilic substitution. Compared with other analytes, the NBP exhibited high sensitivity and selectivity in vitro. More importantly, the NBP provides a promising strategy for in vivo imaging of NE in living animals with noninvasive visualization and real-time features.
Molecular Mechanism of Psychosis
Article
Full-text available
  • Oct 2021
Biomedical research in line with most baseline studies has proven biological alterations due to exposure to some heavy metals such as lead, mercury, cadmium, and arsenic have been implicated in patients with neurochemical imbalance, pharmacological viewpoint, and brain imaging as part of psychotic prognosis. Some of the most prevailing psychological conditions with notable tendencies of downheartedness and transience are depression and schizophrenia. However, the basal pathophysiology of these conditions from the pre-symptomatic and diagnosed point of view, implicates dopamine, norepinephrine, and 5-HT neurotransmitters. Maternal Immune Activation (MIA) triggered by immunological changes from external factors mutating against the immune cells from predisposition to heavy metals leads to priming of the Central Nervous System (CNS) microglia cells which can create a pathway to expose offspring to psychosis. Based on this information, psychosis has been framed due to deficiency in neural signalling in homeostatic imbalance from oxidative stress, metabolic cascades, influenza, and inflammatory response. This review gives details of the role played by neurotransmitters and heavy metals, their toxicity mechanisms, along with the health effect leading to mental disorders like psychosis, depression, bipolar disorder, schizophrenia etc. Hence, the need for more research in this budding field and the challenges of identifying and developing new treatments for persons predisposed to the lengthened risk of neurological autoimmune disorders should be considered.
Major Depressive Disorder
Article
Full-text available
  • Aug 2013
The treatment guideline draws on several international guidelines: ( i ) Practice Guidelines of the American Psychiatric Association (APA) for the Treatment of Patients with Major Depressive Disorder, Second Edition; [1] ( ii ) Clinical Guidelines for the Treatment of Depressive Disorders by the Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatments (CANMAT); [2] ( iii ) National Institute for Clinical Excellence (NICE) guidelines; [3] ( iv ) Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for Depression (RANZCAP); [4] ( v ) Texas Medication Algorithm Project (TMAP) Guidelines; [5] ( vi ) World Federation of Societies of Biological Psychiatry (WFSBP) Treatment Guideline for Unipolar Depressive Disorder; [6] and ( vii ) British Association for Psychopharmacology Guidelines. [7
Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: A meta-analysis of monoamine depletion studies
Article
Full-text available
Dysfunction in the monoamine systems of serotonin (5-HT), norepinephrine (NE) and dopamine (DA) may causally be related to major depressive disorder (MDD). Monoamine depletion studies investigate the direct effects of monoamines on mood. Acute tryptophan depletion (ATD) or para-chlorophenylalanine (PCPA) deplete 5-HT, acute phenylalanine/tyrosine depletion (APTD) or alpha-methyl-para-tyrosine (AMPT) deplete NE/DA. Available depletion studies found conflicting results in heterogeneous populations: healthy controls, patients with previous MDD in remission and patients suffering from MDD. The decrease in mood after 5-HT and NE/DA depletion in humans is reviewed and quantified. Systematic search of MEDLINE and EMBASE (1966-October 2006) and cross-references was carried out. Randomized studies applying ATD, PCPA, APTD or AMPT vs control depletion were included. Pooling of results by meta-analyses was stratified for studied population and design of the study (within or between subjects). Seventy-three ATD, 2 PCPA, 10 APTD and 8 AMPT studies were identified of which 45 ATD and 8 APTD studies could be meta-analyzed. 5-HT or NE/DA depletion did not decrease mood in healthy controls. 5-HT or NE/DA depletion slightly lowered mood in healthy controls with a family history of MDD. In drug-free patients with MDD in remission, a moderate mood decrease was found for ATD, without an effect of APTD. ATD induced relapse in patients with MDD in remission who used serotonergic antidepressants. In conclusion, monoamine depletion studies demonstrate decreased mood in subjects with a family history of MDD and in drug-free patients with MDD in remission, but do not decrease mood in healthy humans. Although depletion studies usefully investigate the etiological link of 5-HT and NE with MDD, they fail to demonstrate a causal relation. They presumably clarify a vulnerability trait to become depressed. Directions for further investigation of this vulnerability trait are proposed.
Videbech P, Ravnkilde B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry 161: 1957-1966
Article
Full-text available
  • Nov 2004
Several studies have found reduced hippocampal volume in patients with unipolar depression, but discrepancies exist. The authors performed a systematic review and meta-analysis of volumetric studies of the hippocampus in patients with mood disorders. Studies of hippocampal volume in unipolar and bipolar patients were identified. A meta-analysis of the 12 studies of unipolar depression fulfilling specific criteria was performed. The sample comprised 351 patients and 279 healthy subjects. The studies were highly heterogeneous regarding age and gender distribution, age at onset of the disorder, average number of episodes, and responsiveness to treatment, but the pooled effect size of depression was significant in both hemispheres for the unipolar patients. The weighted average showed a reduction of hippocampal volume of 8% on the left side and 10% on the right side. The causes of the heterogeneity were analyzed, and a meta-regression showed that the total number of depressive episodes was significantly correlated to right but not left hippocampal volume reduction. Hippocampal volume is reduced in patients with unipolar depression, maybe as a consequence of repeated periods of major depressive disorder. Bipolar patients did not seem to show a reduction in hippocampal volume, but this has been much less investigated.
Improvement of social adaptation in depression with serotonin and norepinephrine reuptake inhibitors
Article
Full-text available
  • Oct 2010
Depression is a disabling condition resulting in significant impairment in social functioning, involving the patient's family, friends, work colleagues, and society at large. Although both psychologic and pharmacologic treatments generally improve many depressive symptoms, they do not always result in significant improvement in social functioning. The importance of recovery of social functioning in depressed patients is now widely appreciated, and studies are beginning to include it in evaluations of therapeutic efficacy. Among the various social adjustment evaluation rating scales, the Social Adaptation Self-Evaluation Scale, a social motivation and behavior scale, has been found to be simple to use and sensitive to change. Using this scale, the selective norepinephrine reuptake inhibitor, reboxetine, has been shown to be significantly more effective in improving social functioning than the selective serotonin reuptake inhibitor, fluoxetine. These findings are consistent with the notion that improvement in social adaptation involves functions depending primarily on noradrenergic neurotransmission. This hypothesis suggests that the serotonin and norepinephrine reuptake inhibitors, venlafaxine, duloxetine, and milnacipran, could be particularly helpful in improving social functioning. Preliminary studies with the serotonin and norepinephrine reuptake inhibitors suggest that they significantly improve social functioning. Comparative studies with selective serotonin reuptake inhibitors on the effects on social functioning should be encouraged.
Reboxetine for acute treatment of major depression: Systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials
Article
Full-text available
To assess the benefits and harms of reboxetine versus placebo or selective serotonin reuptake inhibitors (SSRIs) in the acute treatment of depression, and to measure the impact of potential publication bias in trials of reboxetine. Systematic review and meta-analysis including unpublished data. Bibliographic databases (Medline, Embase, PsycINFO, BIOSIS, and Cochrane Library), clinical trial registries, trial results databases, and regulatory authority websites up until February 2009, as well as unpublished data from the manufacturer of reboxetine (Pfizer, Berlin). ELIGIBILITY CRITERIA: Double blind, randomised, controlled trials of acute treatment (six weeks or more) with reboxetine versus placebo or SSRIs in adults with major depression. Remission and response rates (benefit outcomes), as well as rates of patients with at least one adverse event and withdrawals owing to adverse events (harm outcomes). The procedures for data extraction and assessment of risk of bias were always conducted by one person and checked by another. If feasible, data were pooled by meta-analyses (random effects model). Publication bias was measured by comparing results of published and unpublished trials. We analysed 13 acute treatment trials that were placebo controlled, SSRI controlled, or both, which included 4098 patients. Data on 74% (3033/4098) of these patients were unpublished. In the reboxetine versus placebo comparison, no significant differences in remission rates were shown (odds ratio 1.17, 95% confidence interval 0.91 to 1.51; P=0.216). Substantial heterogeneity (I(2)=67.3%) was shown in the meta-analysis of the eight trials that investigated response rates for reboxetine versus placebo. A sensitivity analysis that excluded a small inpatient trial showed no significant difference in response rates between patients receiving reboxetine and those receiving placebo (OR 1.24, 95% CI 0.98 to 1.56; P=0.071; I(2)=42.1%). Reboxetine was inferior to SSRIs (fluoxetine, paroxetine, and citalopram) for remission rates (OR 0.80, 95% CI 0.67 to 0.96; P=0.015) and response rates (OR 0.80, 95% CI 0.67 to 0.95; P=0.01). Reboxetine was inferior to placebo for both harm outcomes (P<0.001 for both), and to fluoxetine for withdrawals owing to adverse events (OR 1.79, 95% CI 1.06 to 3.05; P=0.031). Published data overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also underestimated harm. Reboxetine is, overall, an ineffective and potentially harmful antidepressant. Published evidence is affected by publication bias, underlining the urgent need for mandatory publication of trial data.
Symptoms and Circuits, Part 2 Anxiety Disorders
Article
  • Dec 2003
P.2.b.004 Functional activity of α2-adrenoceptors in postmortem frontal cortex of depressed suicide victims
Article
Endocrine disturbances and psychiatric disorders
Article
  • Nov 2001
The possibility of a cause and effect link between endocrinopathies and mental disorders was suggested at the beginning of the last century, but was never demonstrated because of a lack of adequate methodology. Therefore, in the 1960s, psychoneuroendocrinology developed as a methodological approach to assess brain neurotransmitter function indirectly in psychiatric disorders. In the past two decades, however, the initial aetiopathogenetic connection between endocrine disturbances and mental disorders has been re-proposed with new and stronger experimental evidence. The aim of this article is to review the most recent advances suggesting a causative role of endocrinopathies in some psychiatric disorders, especially major depression, post-traumatic stress disorder and eating disorders.
Neutrophil β2-adrenoceptor function in major depression: Gs coupling, effects of imipramine and relationship to treatment outcome
Article
Abnormal beta(2)-adrenoceptor density and beta(2)-adrenoceptor-mediated cyclic adenosine monophosphate (cAMP) responses were inconsistently reported in major depressive disorder. Tricyclic antidepressants downregulate beta-adrenoceptor density and decrease coupling to G(s) protein. Abnormal beta-adrenoceptor coupling may exist in major depressive disorder and may relate to treatment response. We investigated beta(2)-adrenoceptor coupling to G(s) protein in 25 controls, 23 major depressive disorder drug-free patients and 16 major depressive disorder patients after chronic imipramine treatment using agonist displacement experiments. Pretreatment beta(2)-adrenoceptor coupling and density were normal in patients as a whole. Chronic imipramine induced beta(2)-adrenoceptor uncoupling. This effect was observed in treatment responders who had increased beta(2)-adrenoceptor density in the high-conformational state and supercoupling prior to treatment. Beta(2)-adrenoceptor density decreased after imipramine treatment. Treatment non-responders had seemingly normal pretreatment beta(2)-adrenoceptor function, which was not changed by imipramine. Differences in beta(2)-adrenoceptor regulation in major depressive disorder may underlie treatment response. The results indirectly implicate abnormal agonist-mediated beta(2)-adrenoceptor gene expression, protein kinase A, and protein kinase C in major depressive disorder.
α2-Adrenoceptor Functionality in Postmortem Frontal Cortex of Depressed Suicide Victims
Article
  • Nov 2010
Alterations in brain density and signaling associated with monoamine receptors are believed to play a role in depressive disorders. This study evaluates the functional status of α₂(A)-adrenoceptors in postmortem frontal cortex of depressed subjects. G-protein activation and inhibition of adenylyl cyclase (AC) activity induced by the α₂-adrenoceptor agonist UK14304 were measured in triplicate in samples from 15 suicide victims with an antemortem diagnosis of major depression and 15 matched control subjects. Basal [³⁵S] guanosine γ thio-phosphate (GTPγS) binding and cyclic adenosine monophosphate accumulation did not differ between groups. In depressed victims, an increase in [³⁵S] GTPγS binding potency (EC₅₀ = .58 μmol/L vs. EC₅₀ = 3.31 μmol/L; p < .01; depressed vs. control) and a significant reduction in the maximal inhibition of AC activity (I(max) = 27 ± 4% vs. I(max) = 47 ± 5%; p < .01) were observed after incubation with the α(2)-adrenoceptor agonist UK14304. No differences were found between antidepressant-free and antidepressant-treated subjects. A significant relationship between EC₅₀ values for [³⁵S] GTPγS and I(max) values for AC assay was found (n = 30; r = -.43; p < .05). The dual regulation of α(2A)-adrenoceptor signaling pathways raises the possibility that factors affecting the G-protein cycle and/or selective access of Gα(i/o)-protein to AC might be relevant to receptor abnormalities in depression, providing further support for the involvement of α₂(A)-adrenoceptors in the pathogenesis of depression.