Monoamine Hypothesis Of Depression Research Articles

Simulation of nanocarrier-based targeted delivery of an antidepressant for major depressive disorder

ABSTRACT Although Depression or Major Depressive Disorder (MDD) affects nearly 15% of the adult population, yet, common antidepressants that work through the monoamine hypothesis of depression are not effective against all types of MDD. The other hypothesis, blocking N-methyl D-aspartate (NMDA) receptors (NMDAR) with antagonists to promote antidepressant effects, is not very useful because of the adverse side effects of the NMDA antagonists. In this study, we have proposed a method involving the specific drug delivery of an antidepressant, using nanocarriers. The introduction of nanocarrier encapsulated potent NMDAR antagonist, R-ketamine, in the target neuronal environments of varying membrane potentials of the central nervous system was studied using in-silico coarse grain simulation of hollow spherical polypyrrole nanocarriers or increasing size. The membrane potential ruptures the nanocarrier and releases the drug R-ketamine, which has a high-binding affinity for NMDAR. Such coarse grain simulations are an interesting and emerging field of study and shed preliminary light on the theoretical behaviour of nanopharmaceuticals in vivo. The results of these in silico findings need to be validated with in vivo experimentation to develop an improved antidepressant delivery nanoformulation.

Recent Developments in Pharmacotherapy of Depression: Bench to Bedside.

For the last 70 years, we did not move beyond the monoamine hypothesis of depression until the approval of the S-enantiomer of ketamine, an N-methyl-D-aspartate (NMDA) receptor blocker and the first non-monoaminergic antidepressant characterized by rapid antidepressant and antisuicidal effects. A similar profile has been reported with another NMDA receptor antagonist, dextromethorphan, which has also been approved to manage depression in combination with bupropion. More recently, the approval of a positive allosteric modulator of GABA-A receptors, brexanolone, has added to the list of recent breakthroughs with the relatively rapid onset of antidepressant efficacy. However, multiple factors have compromised the clinical utility of these exciting discoveries in the general population, including high drug acquisition costs, mandatory monitoring requirements, parenteral drug administration, lack of insurance coverage, indirect COVID-19 effects on healthcare systems, and training gaps in psychopharmacology. This narrative review aims to analyze the clinical pharmacology of recently approved antidepressants and discuss potential barriers to the bench-to-bedside transfer of knowledge and clinical application of exciting recent discoveries. Overall, clinically meaningful advances in the treatment of depression have not reached a large proportion of depressed patients, including those with treatment-resistant depression, who might benefit the most from the novel antidepressants.

New antidepressants: monoamines and beyond

The monoamine hypothesis of depression has dominated treatment for decades, but for some with treatment‐resistant depression, alternative approaches are needed. This article discusses some of the other mechanisms involved in depression and how novel treatments could address these.

Mathematical algorithm-based identification of the functional components and mechanisms in depression treatment: An example of Danggui-Shaoyao-San.

Depression, a complex epidemiological mental disorder, affects around 350 million people worldwide. Despite the availability of antidepressants based on monoamine hypothesis of depression, most patients suffer side effects from these drugs, including psychomotor impairment and dependence liability. Traditional Chinese medicine (TCM) is receiving more and more attention due to the advantages of high therapeutic performance and few side effects in depression treatment. However, complex multicomponents and multi-targets in TCM hinder our ability to identify the functional components and molecular mechanisms of its efficacy. In this study, we designed a novel strategy to capture the functional components and mechanisms of TCM based on a mathematical algorithm. To establish proof of principle, the TCM formula Danggui-Shaoyao-San (DSS), which possesses remarkable antidepressant effect but its functional components and mechanisms are unclear, is used as an example. According to the network motif detection algorithm, key core function motifs (CIM) of DSS in treating depression were captured, followed by a functional analysis and verification. The results demonstrated that 198 pathways were enriched by the target genes of the CIM, and 179 coincided with the enriched pathways of pathogenic genes, accounting for 90.40% of the gene enrichment pathway of the C-T network. Then the functional components group (FCG) comprising 40 components was traced from CIM based on the target coverage accumulation algorithm, after which the pathways enriched by the target genes of FCG were selected to elucidate the potential mechanisms of DSS in treating depression. Finally, the pivotal components in FCG of DSS and the related pathways were selected for experimental validation in vitro and in vivo. Our results indicated good accuracy of the proposed mathematical algorithm in sifting the FCG from the TCM formula, which provided a methodological reference for discovering functional components and interpreting molecular mechanisms of the TCM formula in treating complex diseases.

Rapid-Acting Antidepressants.

Conventional antidepressants are thought to produce their impact on clinical symptoms by increasing the central availability of biogenic amine neurotransmitters (the monoamine hypothesis of depression). These drugs continue to be the primary medicines used in major depressive disorder. Although they have biological effects after acute dosing, full antidepressant response generally takes weeks of daily administration. Lack of rapid onset is a large limitation in antidepressant therapy (e.g., suicide, lack of medication compliance, difficulty switching medications). The present review of the literature discusses the preclinical and clinical findings on compounds that can produce immediate symptom relief. These compounds include ketamine, scopolamine, and mechanistically-related drugs. Newer additions to the list of potential rapid-acting agents include antagonists of metabotropic (mGlu) 2/3 receptors, negative allosteric modulators of α5-containing GABAA receptors, and psychedelic compounds. An additional benefit of these compounds is that they have demonstrated large effect sizes and, importantly, demonstrated efficacy in patient's refractory to other treatments. A drawback of some of these compounds, to date, is finding ways to expand the duration of clinical efficacy. In addition, for some compounds, the side-effect profile requires management. A primary mechanism by which rapid effects might be produced is through the amplification of excitatory neurotransmission through activation of AMPA receptors. The extracellular efflux of glutamate induced by these drugs has been documented and provides the hypothesized triggering mechanism for AMPA receptor amplification. The preclinical and clinical literature strongly suggests that rapid-acting antidepressants are the current focus of antidepressant drug discovery. Promising clinical findings exist for several compounds including ketamine and other NMDA receptor antagonists, scopolamine, and psilocybin. Two compounds are in late stage clinical development: GLYX-13 (Rapastinel) and eskekamine.

Therapeutic Approaches for NOP Receptor Antagonists in Neurobehavioral Disorders: Clinical Studies in Major Depressive Disorder and Alcohol Use Disorder with BTRX-246040 (LY2940094).

Conventional antidepressants increase the efflux of biogenic amine neurotransmitters (the monoamine hypothesis of depression) in the central nervous system (CNS) and are the principle drugs used to treat major depressive disorder (MDD). However, the lack of efficacy in some patients, the slow onset of action, and the side effect profiles of existing antidepressants necessitate the exploration of additional treatment options. The discovery of the nociceptin/orphanin FQ peptide NOP receptor (N/OFQ-NOP receptor) system and its characterization in preclinical biological and pharmacological stress-related conditions supports the potential antidepressant and anti-stress properties of a NOP receptor antagonist for the treatment of neurobehavioral disorders. BTRX-246040 (formerly LY2940094) was designed to test this hypothesis in the clinic. A small clinical proof of concept study demonstrated efficacy of BTRX-246040 in MDD patients. In this study, BTRX-246040 (40mg, p.o.) significantly reduced negative bias as assessed by the facial recognition test within 1week of treatment and decreased depression symptoms after 8weeks. BTRX-246040 also reduced depression symptoms in a second trial with heavy alcohol drinkers. Given the comorbidity of MDD and alcohol use disorder, a compound with such effects in patients could be a valuable addition to the medications available. A proof of concept study showed efficacy of BTRX-246040 in reducing heavy drinking and increasing the probability of abstinence in individuals diagnosed with alcohol dependence. In addition, plasma levels of gamma-glutamyl transferase were decreased by BTRX-246040 compared to placebo control implying improvement in liver function. Collectively, the clinical data reviewed within this chapter suggest that BTRX-264040 functions to normalize dysfunction in reward circuits. The overall efficacy and safety of this compound with a novel mechanism of action are encouraging of further clinical development. BTRX-246040 is currently under development for MDD by BlackThorn Therapeutics.

Expression of BDNF and trkB in the hippocampus of a rat genetic model of vulnerability (Roman low-avoidance) and resistance (Roman high-avoidance) to stress-induced depression.

IntroductionThe selective breeding of Roman High‐ (RHA) and Low‐Avoidance (RLA) rats for, respectively, rapid versus poor acquisition of the active avoidance response has generated two distinct phenotypes differing in many behavioral traits, including coping strategies to aversive conditions. Thus, RLA rats are considered as a genetic model of vulnerability to stress‐induced depression whereas RHA rats are a model of resilience to that trait. Besides the monoamine hypothesis of depression, there is evidence that alterations in neuronal plasticity in the hippocampus and other brain areas are critically involved in the pathophysiology of mood disorders.Materials and MethodsWestern blot (WB) and immunohistochemistry were used to investigate the basal immunochemical occurrence of brain‐derived neurotrophic factor (BDNF) and its high‐affinity tyrosine‐kinase receptor trkB in the dorsal and ventral hippocampus of adult RHA and RLA rats.Results WB analysis indicated that the optical density of BDNF‐ and trkB‐positive bands in the dorsal hippocampus is, respectively, 48% and 25% lower in RLA versus RHA rats. Densitometric analysis of BDNF‐ and trkB‐like immunoreactivity (LI) in brain sections showed that BDNF‐LI is 24% to 34% lower in the different sectors of the Ammon's horn of RLA versus RHA rats, whereas line‐related differences are observed in the dentate gyrus (DG) only in the ventral hippocampus. As for trkB‐LI, significant differences are observed only in the dorsal hippocampus, where density is 23% lower in the DG of RLA versus RHA rats, while no differences across lines occur in the Ammon's horn.ConclusionThese findings support the hypothesis that a reduced BDNF/trkB signaling in the hippocampus of RLA versus RHA rats may contribute to their more pronounced vulnerability to stress‐induced depression.

A brief history of the development of antidepressant drugs: from monoamines to glutamate.

Major depressive disorder (MDD) is a chronic, recurring, and debilitating mental illness that is the most common mood disorder in the United States. It has been almost 50 years since the monoamine hypothesis of depression was articulated, and just over 50 years since the first pharmacological treatment for MDD was discovered. Several monoamine-based pharmacological drug classes have been developed and approved for the treatment of MDD; however, remission rates are low (often less than 60%) and there is a delayed onset before remission of depressive symptoms is achieved. As a result of a "proof-of-concept" study in 2000 with the noncompetitive NMDA antagonist ketamine, a number of studies have examined the glutamatergic systems as viable targets for the treatment of MDD. This review will provide a brief history on the development of clinically available antidepressant drugs, and then review the possible role of glutamatergic systems in the pathophysiology of MDD. Specifically, the glutamatergic review will focus on the N-methyl-D-aspartate (NMDA) receptor and the efficacy of drugs that target the NMDA receptor for the treatment of MDD. The noncompetitive NMDA receptor antagonist ketamine, which has consistently produced rapid and sustained antidepressant effects in MDD patients in a number of clinical studies, has shown the most promise as a novel glutamatergic-based treatment for MDD. However, compounds that target other glutamatergic mechanisms, such as GLYX-13 (a glycine-site partial agonist at NMDA receptors) appear promising in early clinical trials. Thus, the clinical findings to date are encouraging and support the continued search for and the development of novel compounds that target glutamatergic mechanisms.

Neuropathology of depression in Alzheimer's disease: current knowledge and the potential for new treatments.

Depression is among the most common behavioral and psychological symptoms of dementia, and leads to more rapid decline and higher mortality. Treatment for depression in dementia has centered on conventional antidepressant drug treatment based around the monoamine hypothesis of depression. However, recent major studies have suggested that conventional antidepressant treatments that aim to correct underlying deficits in monoamine neurotransmitters are not effective for depression in dementia. Postmortem studies have also suggested that depression in dementia does not arise from serotonergic or noradrenergic abnormalities, or indeed from the degenerative pathology associated with Alzheimer's disease. In contrast, considerable recent evidence has suggested that alterations in glutamatergic transmission may contribute to the pathophysiology of depression. This supports the view that treatment-resistant depressed patients, such as many dementia patients, may benefit from agents affecting glutamate transmission. This review will thus draw together the wealth of pathological data examining the basis of depression in Alzheimer's disease and relate this to current thinking on treatment, with the aim of generating discussion on potential novel therapeutic strategies.

Immunochemical detection of trkB receptor in the brain of a rat model of depression

The outbread Roman High- (RHA) and Roman Low-Avoidance (RLA) rat lines were psychogenetically selected for rapid versus poor acquisition of active avoidance, respectively, and differ in many behavioural traits that closely resemble the cardinal symptoms of depression (1). Beyond the monoamine hypothesis of depression, compelling evidence suggests that mood disorders are characterized by reduced neuronal plasticity. Consistently, it has been shown that exposure to stress and antidepressant treatment modulate the expression of neurotrophic molecules and their relevant receptors, and that these changes show an anatomical specificity (2). With the aim to characterize the molecular and neuronal systems involved in the pathogenesis of depression and in the mechanism of action of the antidepressant treatments, here we investigate on the immunochemical occurrence of trkB, the high affinity tyrosinekinase receptor for brain-derived neurotrophic factor (BDNF), in selected areas of the RHA and RLA rat brain by means of western blot (WB) and immunohistochemistry. WB analysis indicates that the relative levels of trkB patently and markedly differed in the prefrontal cortex and the hippocampus, where they were lower in RLA vs RHA rats, and in the caudate-putamen complex proper where, by contrast, they were higher in RLA vs RHA rats. No statistically significant differences were seen in nucleus accumbens and ventral tegmental area. In tissue sections, trkB-like immunoreactive (LI) labelling was mainly localized to neuronal cell bodies and proximal processes, unevenly distributed in the telencephalic cerebral cortex, the hippocampus, and the ventral tegmentum of the midbrain. Densitometric analysis of immunostained brain sections revealed that differences among the two groups are consistent to a good extent with WB data. As a whole, the finding of a different expression of trkB receptor in the RLA vs RHA rat brains implies the occurrence of an altered neuronal responsiveness to BDNF in specific brain regions and may contribute to outline the molecular and morphological basis for the distinct vulnerability to depression in the two rat lines.

Unmet needs in psychiatry and emerging novel pharmacological agents

Despite huge amount of efforts and resources spent to improve the pharmacotherapeutic tools to treat major psychiatric disorders such as depression and schizophrenia, there still exist unmet needs in the field. Treatment resistance, non-adherence, and severe adverse effects such as diabetes mellitus type II, extrapyramidal side effects, etc. are among the unmet needs commonly faced by clinicians, probably due to the fact that the pathophysiology of both schizopherenia and depression have not been fully elucidated. Today, neither the monoamine hypothesis of depression nor the dopamine hypothesis of schizophrenia explains either disorder in full. In spite of its widespread presence throughout the brain, the glutamatergic system has remained almost unexplored with respect to drug discovery for psychiatric illnesses.Recently, the promising outcomes of intravenous use of ketamine to overcome resistance to antidepressant treatment and the administration of a nitroprusside infusion to address resistance to antipsychotics in the treatment of schizophrenia have drawn attention to the glutamatergic system.

Beyond the monoaminergic hypothesis: neuroplasticity and epigenetic changes in a transgenic mouse model of depression

The monoamine hypothesis of depression has dominated our understanding of both the pathophysiology of depression and the action of pharmacological treatments for the last decades, and it has led to the production of several generations of antidepressant agents. However, there are serious limitations to the current monoamine theory, and additional mechanisms, including hypothalamic-pituitary-adrenal (HPA) axis dysfunctions, as well as neurodegenerative and inflammatory alterations, are potentially associated with the pathogenesis of mood disorders. Moreover, new data have recently indicated that epigenetic mechanisms such as histone modifications and DNA methylation could affect diverse pathways leading to depression-like behaviours in animal models. In a transgenic mouse model of depression, in which a downregulation of glucocorticoid receptors (GR) causes a deficit in the HPA axis feedback control, besides alterations in monoamine neurotransmission and neuroplasticity, we found modifications in the expression of many proteins involved in epigenetic regulation, as well as clock genes, in the hippocampus and the frontal cortex, that might be central in the genesis of depressive-like behaviours.

Inflammatory mechanisms in major depressive disorder

As the 'monoamine hypothesis of depression' fails to explain all aspects of major depression, additional causes are being investigated. Several observations suggest that inflammatory mechanisms pay a role in the cause of major depressive disorder (MDD). This article reviews their role in major depression. Recent studies support the concept that inflammatory mechanisms play a crucial role in the pathomechanisms of major depression. Major depression shares similarities with 'sickness behavior', a normal response to inflammatory cytokines. Elevations in proinflammatory cytokines and other inflammation-related proteins in major depression were found in plasma and cerebrospinal fluid (CSF) as well as in postmortem studies. Elevated levels of proinflammatory cytokines persist after clinical symptoms of depression are in remission and can also predict the onset of a depressive episode. Antidepressant treatment can lead to a normalization of elevated cytokine levels in major depression. Finally, we understand how inflammatory mechanisms affect the metabolism of tryptophan and how nonsteroidal antiinflammatory drugs (NSAIDs) can interfere with the effects of antidepressants. Further studies are needed to fully understand the role of inflammatory mechanisms in major depression and the potential treatment implications.

S12-05 Cytokines-mediated Inflammation and Decreased Neurogenesis in Animal Models of Depression

The monoamine hypothesis of depression is increasingly called into question by newer theories that revolve around changes in neuronal plasticity, primarily in the hippocampus, at both the structural and the functional levels. Chronic stress negatively regulates hippocampal function while antidepressants ameliorate the effects of stress on neuronal morphology and activity. Both stress and antidepressants have been shown to affect levels of brain-derived neurotrophic factor (BDNF) whose transcription is dependent on cAMP response element binding protein (CREB). BDNF itself has antidepressant-like actions and can induce transcription of a number of molecules. One class of genes regulated by both BDNF and serotonin (5-HT) are neuropeptides including VGF (non-acryonimic) which has a novel role in depression. Neuropeptides are important modulators of neuronal function but their role in affective disorders is just emerging. Recent studies demonstrate that VGF, which is also a CREB-dependent gene, is upregulated by antidepressant drugs and voluntary exercise and is reduced in animal models of depression. VGF enhances hippocampal synaptic plasticity as well as neurogenesis in the dentate gyrus but the mechanisms of antidepressant-like actions of VGF in behavioral paradigms are not known. We summarize experimental data describing the roles of BDNF, VGF and other neuropeptides in depression and how they may be acting through the generation of new neurons and altered synaptic activity. Understanding the molecular and cellular changes that underlie the actions of neuropeptides and how these adaptations result in antidepressant-like effects will aid in developing drugs that target novel pathways for major depressive disorders.

SS05-01 - The place of agomelatine in the antidepressant armamentarium

The choice of an antidepressant is tailored according to patient factors (age, sex, severity, diagnostic subtype, comorbid disorders, past response) and to drug characteristics (efficacy, tolerability, safety, simplicity of use, discontinuation syndrome).A wide range of antidepressants are available nowadays, with mode of action mainly based on the monoamine hypothesis of depression, but all have limitations: still too many nonresponding patients, late onset of action, and poor tolerability profile, resulting in low adherence. The challenges for a new antidepressant are first to provide all patients with rapid and sustained antidepressant efficacy in relieving all symptoms, second to lead patients out of depression by achieving complete remission, and third to ensure that patients are compliant throughout treatment.Agomelatine is a new antidepressant with an innovative mode of action acting as an agonist of melatonergic MT1 and MT2 receptors as well as an antagonist of serotonergic 5-HT2C receptors. These receptors play a major role in circadian rhythms, which are dysregulated in depression. Recent data suggest that the distinctive antidepressant efficacy of agomelatine results from the potential synergy between these receptors.Agomelatine rapidly improves depressive symptoms in most subtypes of depression, particularly in patients with anxiety symptoms, known as factor of resistance. Moreover, agomelatine shows greater antidepressant efficacy than fluoxetine in severely depressed patients (HAM-D total score difference over 8 weeks: 1.49; P = 0.024).Thanks to its unique impact on mechanisms at the core of depressive dysregulation, agomelatine provides doctors and patients with an innovative approach to depression treatment.

The Future of Depression Psychopharmacology

Along with the development of selective serotonin reuptake inhibitors there has been a tremendous widening of the definition of depression and an impressive decrease in the placebo-drug difference in controlled studies. In the early 1960s, about one third of depressed patients improved with placebo and two thirds with active compounds. Current controlled studies suggest that the situation has certainly not improved. The Sequenced Treatment Alternatives to Relieve Depression Study found that response rates to new compounds after the failure of the first antidepressant are low. The monoamine hypothesis of depression was formulated in the mid 1960s based on the antidepressant efficacy of the monoamine reuptake inhibitors, monoamine oxidase inhibitors, and the depressogenic effects of reserpine as a monoamine depleter. However, no monoamine-related finding has been found that is diagnostic for depression. A second major hypothesis regarding depression has been the stress cortisol hypothesis. However, blood cortisol levels are not diagnostic of depression. Psychiatric clinicians are convinced that there are patients for whom antidepressants have made the difference between life and death. However, physicians may generalize unjustifiably based on single dramatic cases to a much larger diagnostic group. Perhaps there are many causes of different types of human sadness, and perhaps only some of these involve mechanisms related to monoamines. Thus, perhaps only some kinds of depression are responsive to monoamine affecting antidepressants..

Prospects for the Treatment of Depression

Antidepressant drugs represent the principal form of treatment for major depressive disorder. While there are a plethora of medications available for this task, current drugs have many shortcomings. In the face of these deficiencies there is an ongoing search for new agents. The search has been guided, in part, by drug design based on existing agents and their putative mechanism of action. This has been less than fruitful in addressing inadequacies of existing medications as it has not produced compounds which are novel in terms of pharmacological mechanisms. Recent insights from molecular biological approaches hold promise for the discovery of novel compounds, in particular the so-called neurogenesis hypothesis suggests novel therapeutic approaches. Although significantly modified over the years, the monoamine hypothesis of depression and antidepressant drug action still remains an important driving force behind the development of new compounds. Several recently marketed agents and some in early-phase development tend to conform to these existing mechanistic hypotheses. Clearly the place of these agents in the treatment of depression is dependent on issues such as short- and long-term safety and efficacy. Duloxetine has been developed as a dual monoamine re-uptake inhibitor. Agomelatine is a compound with major effects on the circadian system as well as effects on subtypes of the serotonin receptor system. While the mechanism of action of this compound is not certain, recent evidence would suggest that the drug exerts its effects through antagonist actions at serotonin receptors. Compounds based on the hypothalamic pituitary adrenal axis, substance P antagonism and other neuropeptides have potential application for the treatment of depression but require further development before that potential is realized.

Antidepressant research in the era of functional genomics: Farewell to the monoamine hypothesis

Although blockade by antidepressants of monoamine uptake into nerve endings is one of the cornerstones of the monoamine hypothesis of depression, there is a clear discrepancy between the rapid effects of antidepressants in increasing synaptic concentrations of monoamine and the lack of immediate clinical efficiency of antidepressant treatment. Novel biological approaches beyond the 'monoamine hypothesis' are definitely expected to cause paradigm shifts in depression research. Functional genomics are powerful tools that can be used to identify genes affected by antidepressants or by other effective therapeutic manipulations. Using RNA fingerprinting technique, we have previously identified several cDNA fragments as antidepressant related genes and from these, original cDNA microarrays were developed. Some of these candidate genes may encode common functional molecules induced by chronic antidepressant treatment. Defining the roles of these genes in drug-induced neural plasticity is likely to transform the course of research on the biological basis of depression. Such detailed knowledge will have profound effects on the diagnosis, prevention, and treatment of depression.

383. Differential cloning and DNA microarrays in depression research

Depression is one of the major psychiatric diseases. Although blockade by antidepressants of monoamine uptake into nerve endings is one of the cornerstones of the monoamine hypothesis of depression, there is a clear discrepancy between the rapid effects of antidepressants in increasing synaptic concentrations of monoamine and the lack of immediate clinical efficiency of antidepressant treatment. It is known that antidepressant effect is generally observed after repeated administration for several weeks. This delay could be explained at the molecular level by an action on gene transcription. Recently introduced technique, DNA microarray, enabled us to perform large-scale coordinate monitoring of gene expression during different functional states in normal and diseased samples, or in control and treated animals. This method of large-scale gene expression analysis creates a bridge between the molecular pharmacological approach and study at the systems level to understand the pathophysiology of depression and the mechanisms of action of the treatment. In addition to the gene expression monitoring, cDNA microarray can be used for gene discovery by probing enriched libraries derived from the experiments with differential cloning techniques, which includes Differential Display PCR, RNA fingerprinting, Suppressive Subtractive Hybridization, and Representational Difference Analysis. While screening of the common biochemical changes induced after antidepressant treatment in rat brain with these genome-pharmacological approach, we identified several interesting candidate genes and expressed sequence tags, ESTs. We believe that these molecules would be attractive target molecules for future antidepressant development with a new class of action in the brain.

Blue genes and the monoamine hypothesis of depression.

Article AbstractAlthough the monoaminehypothesis of depressionproposes that depressionis due to a deficiency inmonoaminergic neurotransmission,no deficiencies in the levels or receptorsfor serotonin, dopamine, and/ornorepinephrine have been consistentlyreported. Currently, the evolvingmonoamine hypothesis considersthe possibility that depression may belinked to a deficiency in signal transductionfrom the monoamine neurotransmitterto its postsynaptic neuronin the presence of normal amounts ofneurotransmitter and receptor. Such adeficiency in the molecular eventsthat cascade from receptor occupancyby neurotransmitter to transcription ofgenes could lead to a deficient responseof target neurons to neurotransmissionand thus, depression.