Depression is a chronic, recurring and potentially life-threatening illness. Depression is a syndrome notable for heterogeneity of its clinical presentation, treatment responsiveness, neurobiology, and genetics. The highly variable compilation of symptoms that is used to define depression, and the highly variable course of the illness and its response to various treatments, indicate that depression subsumes numerous disease states of distinct etiology, and perhaps distinct pathophysiology. Current understanding of the mechanisms of pharmacotherapy for depression is characterized by the emphasis on increasing synaptic availability of serotonin, noradrenaline, and possibly dopamine, while minimizing side effects. This is unfortunate, because less than half of individuals with depression show full remission in response to these mechanisms. While current pharmacotherapies target monoaminergic systems, distinct neurobiological underpinnings and other systems are likely involved in the pathogenesis of depression. Recently, several promising hypotheses of depression and antidepressant action have been formulated. These hypotheses are largely based on dsyregulation of neural plasticity, CREB, BDNF, corticotropin-releasing factor, glucocorticoid, hypothalamic-pituitary adrenal axis and cytokines. Based on these new theories and hypotheses of depression, a number of new and novel agents show a considerable promise for refining treatment options for depression. In this article, we provide an overview of the mechanisms of action of currently available antidepressant treatments. We then provide a progress report on some of the most promising current strategies.
Axis, Cervical Vertebra ; Brain-Derived Neurotrophic Factor ; Corticotropin-Releasing Hormone ; Cytokines ; Depression ; Dopamine ; Neurobiology ; Norepinephrine ; Plastics ; Population Characteristics ; Research Report ; Serotonin

Serotonin has been implicated in the etiology and pathophysiology of mental illness such as depression, schizophrenia, anxiety disorder, eating disorder, obsessive compulsive disorder, and panic disorder. Many current used treatments of these disorders are thought to act through the modulation of the serotonergic tone. To improve on the efficacy of antipsychotics that are potent D2 receptor blockers, much interest has evolved around complimenting or replacing D2 dopaminergic antagonism by the action on serotonergic transmission. 5-HT2A receptor blockade, under the condition of weaker D2 receptor antagonism, may contribute to the ability of atypical antipsychotics to increase dopamine release in the medical prefrontal cortex while having a smaller effect on mesolimbic dopamine release. These effects may contribute to their advantage for cognition, negative symptoms and psychotic activity. The use of 5-HT1A receptor agonists may substitute for 5-HT2A antagonism and achieve many of the same benefits in combination with weak D2 receptors blockade. Antagonism of 5-HT2C receptors may also useful for improving cortical function. Thus, 5-HT has joined dopamine as a critical target for developing effective antipsychotics in schizophrenia. In the development of new first-line pharmacological treatment for major depressive disorder, 5-HT system will most likely remain important especially if agents can be developed with improved tolerability, faster onset of response or greater efficacy. The promising area for development of serotonergic antidepressants are agents that target the specific 5-HT receptor subtypes, and agents that affect 5-HT plus one or more of the noradrenaline, CRF, dopamine and glucocorticoids systems. Selective targeting of serotonin receptors such as 5-HT1, 5-HT2, or 5-HT7 may have considerable potential in the treatment of depressive disorders. Trophic agents that increased neuroplasticity or neurogenesis via the activation of cyclic AMP-CREB pathway may be beneficial as a target for novel antidepressants.
Antidepressive Agents ; Antipsychotic Agents ; Anxiety Disorders ; Cognition ; Depression* ; Depressive Disorder ; Depressive Disorder, Major ; Dopamine ; Feeding and Eating Disorders ; Glucocorticoids ; Neurogenesis ; Neuronal Plasticity ; Norepinephrine ; Obsessive-Compulsive Disorder ; Panic Disorder ; Prefrontal Cortex ; Receptor, Serotonin, 5-HT1A ; Receptor, Serotonin, 5-HT2A ; Receptor, Serotonin, 5-HT2C ; Receptors, Serotonin ; Schizophrenia* ; Serotonin ; Serotonin Agents*

Depression is a heterogeneous group of syndromes comprised of numerous diseases of distinct causes and pathophysiologies. Recently, several promising hypotheses of depression and antidepressant action have been formulated. These hypotheses are largely based on dysregulation of neural plasticity, CREB, BDNF, corticotropin-releasing factor, glucocorticoid, hypothalamicpituitary adrenal axis and cytokines. Recent work has revealed that several brain regions such as hippocampus, prefrontal cortex, amygdala, nucleus accumbens, and other hypothalamic nuclei are involved in the neural circuit of depression. The brain regions are critical in regulating memory, mood, motivation, sleep, eating, circadian rhythm and responses to rewarding and adverse stimuli, which are all abnormal in depressed patients. The neurobiological understanding of depression will fundamentally improve the treatment and prevention of that illness.
Amygdala ; Axis, Cervical Vertebra ; Brain ; Brain-Derived Neurotrophic Factor ; Circadian Rhythm ; Corticotropin-Releasing Hormone ; Cytokines ; Depression* ; Eating ; Hippocampus ; Humans ; Memory ; Motivation ; Neurobiology* ; Nucleus Accumbens ; Plastics ; Prefrontal Cortex ; Reward

Neurotrophic factors are critical regulators of the formation and plasticity of neuronal networks. Brain-derived neurotrophic factor (BDNF) is abundant in the brain and periphery, and is found in both human serum and plasma. Animal studies have demonstrated that stress reduces BDNF expression or activity in the hippocampus and that this reduction can be prevented by treatment with antidepressant drugs. A similar change in BDNF activity occurs in the brain of patients with major depression disorder (MDD). Recently, clinical studies have indicated that serum or plasma BDNF levels are decreased in untreated MDD patients. Antidepressant treatment for at least four weeks can restore the decreased BDNF function up to the normal value. Therefore, MDD is associated with impaired neuronal plasticity. Suicidal behavior can be a consequence of severe impaired neuronal plasticity in the brain. Antidepressant treatment promotes increased BDNF activity as well as several forms of neuronal plasticity, including neurogenesis, synaptogenesis and neuronal maturation. BDNF could also play an important role in the modulation of neuronal networks. Such a neuronal plastic change can positively influence mood or recover depressed mood. These alterations of BDNF levels or neuronal plasticity in MDD patients before and after antidepressant treatment can be measured through the examination of serum or plasma BDNF concentrations. BDNF levels can therefore be useful markers for clinical response or improvement of depressive symptoms, but they are not diagnostic markers of major depression.
Animals ; Antidepressive Agents ; Brain ; Brain-Derived Neurotrophic Factor ; Depression ; Hippocampus ; Humans ; Nerve Growth Factors ; Neurogenesis ; Neuronal Plasticity ; Neurons ; Plasma ; Plastics ; Reference Values

Major depressive disorder (MDD) is a common disorder, widely distributed in the population, and usually associated with substantial symptom severity and role impairment. MDD is also a complex and heterogeneous disorder, at etiological, phenotypical, and biological levels. The gene or series of genes, which cause MDD, have so far not been identified. However, certain genetic variations, called polymorphisms, may increase the risk of MDD in a susceptible person. In addition, environmental stress also is a common precipitating factor of MDD. Various stressful life-experiences-prenatal stress, aversive early life experiences, ongoing or recent psychosocial stress-are important environmental factors contributing to the development of MDD. Nevertheless, not all persons exposed to these stresses become depressed. Environmental stress interacts with a person's genetic makeup to influence his or her risk for developing MDD. It is the combination of genes, early life stress, and ongoing stress, which may ultimately determine an individual's responsiveness to stress and vulnerability to MDD. Consequently, the gene and environment interactions may impact multiple neurobiological systems implicated in MDD. The gene-environment interaction in the pa-thophysiology of MDD leads to advances in personalized medicine by means of genotyping for inter-individual variability in drug action and metabolism. Such concept may explain why some subjects become depressed while others remain unaffected.
Depression ; Depressive Disorder, Major ; Gene-Environment Interaction ; Genetic Variation ; Humans ; Precision Medicine ; Life Change Events ; Precipitating Factors ; Serotonin ; Stress, Psychological

A growing body of evidence suggests that major depression is associated with increased productions of pro-inflammatory cytokines such as IL-1, IL-6, IL-12 or TNF-alpha and increased concentrations of prostaglandin E2 and negative-regulatory cytokines such as IL-4 or IL-10. In major depression, interactions among brain 5-HT levels, the activity of its autoreceptors, and that of postsynaptic receptors play a critical role in mood changes and depression. Recently, the link between cytokines and serotonergic turnover has been explored. Cytokines such as IL-1, IL-2 and IFN-gamma reduce the production of 5-HT by stimulating the activity of indoleamine-2,3 dioxygenase (IDO), an enzyme which convert tryptophan, the precursor of 5-HT to kynurenine. The kynurenine is metabolized into quinolinic acid (quinolinate) and kynurenic acid (kynurenate), an excitotoxic NMDA receptor agonist and the antagonist of three ionotropic excitotatory aminoacid receptors, respectively. The cytokineserotonin interaction through IDO that leads to the challenge between quinolinate and kynurenate in the brain may finally induce the neurodegeneration in depression. The neurodegeneration hypothesis of depression can explain how people cope with psychological or physical stress at different stages according to severity and duration of stress and why major depression develops.
Autoreceptors ; Brain ; Cytokines ; Depression* ; Dinoprostone ; Interleukin-1 ; Interleukin-10 ; Interleukin-12 ; Interleukin-2 ; Interleukin-4 ; Interleukin-6 ; Kynurenic Acid ; Kynurenine ; N-Methylaspartate ; Neurogenesis ; Quinolinic Acid ; Serotonin ; Tryptophan ; Tumor Necrosis Factor-alpha

The current understanding of the mechanisms of pharmacotherapy for depression is characterized by an emphasis on increasing synaptic availability of serotonin, noradrenaline, and possibly dopamine, while minimizing side effects. The acute effects of current available effective antidepressants include blocking selective serotonin or noradrenaline reuptake, alpha2 autoreceptors or monoamine oxidase. Although efficacious, current treatments often produce partial or limited symptomatic improvement rather than remission. While current pharmacotherapies target monoaminergic systems, distinct neurobiological underpinnings and other systems are likely involved in the pathogenesis of depression. Recently, several promising hypotheses of depression and antidepressant action have been formulated. These hypotheses are largely based on dsyregulation of neural plasticity, CREB, BDNF, corticotropin-releasing factor, glucocorticoid, hypothalamic-pituitary adrenal axis and cytokines. Based on these new theories and hypotheses of depression, a number of new and novel agents, including corticotropin-releasing factor antagonists, antiglucocorticoids, and substance P antagonists show a considerable promise for refining treatment options for depression. In this article, the current available pharmacotherapies, current understanding of neurobiology and pathogenesis of depression and new and promising directions in pharmacological research on depression will be discussed.
Antidepressive Agents* ; Autoreceptors ; Axis, Cervical Vertebra ; Brain-Derived Neurotrophic Factor ; Corticotropin-Releasing Hormone ; Cytokines ; Depression ; Dopamine ; Drug Therapy ; Monoamine Oxidase ; Neurobiology ; Neuropeptides ; Norepinephrine ; Plastics ; Serotonin ; Substance P

Accumulating evidence has suggested the existence of reciprocal communication between immune, endocrine, and neurotransmitter system. Cytokine hypothesis of depression implies that increased pro-inflammatory cytokine such as -1, IL-6, IL-12, TNF-alpha, and IFN-gamma in major depression, acting neuromodulators, play a key role in the mediation of behavioral, neuroendocrine, and neurochemical disturbances in depression. Concerning the relation between cytokines and serotonin metabolism, pro-inflammatory cytokines have profound effects on the metabolism of brain serotonin through the enzyme indoleamine-2,3-dioxygenase(IDO) that metabolizes tryptophan, the precursor of 5-HT to neurodegenerative quinolinate and neuroprotective kynurenate. The neurodegeneration process is reinforced by the neurotoxic effect of the hypercortisolemia during depression. From this perspective, it is possible that efficacy of antidepressants in the treatment of depression may, at least in part, rely on downregulation of pro-inflammatory cytokine synthesis. So, the use of cytokine synthesis inhibitors or cytokine antagonists may be a new treatment approach in depression. However, at present the question whether cytokines play a causal role in the onset of depression or are mere epiphenomena sustaining depressive symptoms remains to be elucidated. Nevertheless, cytokine hypothesis has created new perspectives in the study of psychological and pathophysiological mechanism that are associated with major depression, as well as the prospect for developing a new generation antidepressants.
Antidepressive Agents ; Brain ; Cytokines ; Depression ; Down-Regulation ; Interleukin-12 ; Interleukin-6 ; Kynurenic Acid ; Negotiating ; Neurotransmitter Agents ; Psychoneuroimmunology ; Quinolinic Acid ; Serotonin ; Tryptophan ; Tumor Necrosis Factor-alpha

OBJECTIVES: The purpose of this study was to investigate 1) the neuropsychological deficits with major depressive disorder(MDD) in depressed state and 2) the changes of neuropsychological dysfunctions during depressed episodes and remitted periods in the MDD group. METHODS: 12 patients with MDD and 70 normal controls who were diagnosed and classified by DSM-IV and SCID-IV interview participated in this study. The psychopathology was measured using the Hamilton rating scale for depression(HAM-D) and Brief Psychiatric Rating Scale(BPRS). The memory function, executive function, and sustained attention were measured by a trained psychologist using the Korean version of Memory Assessment Scale(K-MAS), Wisconsin Card Sorting Test(WCST), and Vigilance(VIG) and Cognitrone (COG) in Vienna Test System. After 6 weeks of treatment, we retested the cognitive tests in order to measure the cognitive functions in remitted states. RESULTS: Patients with MDD achieved significantly lower score in sentence immediately recall, verbal memory score and total memory score of the K-MAS, total errors of the WCST, response time of Vigilance and response time at "Yes" response of Cognitrone than normal controls at baseline. After 6 weeks of medication, the psychiatric symptoms in the patient group were attenuated, and most of the neuropsychological functions including attention, memory, and frontal/executive function were improved except for response time of Cognitrone. CONCLUSIONS: This study provides evidence for distinct neuropsychological deficits in patients with MDD on their depressed states and remitted periods. The impairment on response time remains after remission, and this would be a trait marker of major depressive disorder.
Depressive Disorder, Major ; Diagnostic and Statistical Manual of Mental Disorders ; Executive Function ; Humans ; Memory ; Psychopathology ; Reaction Time ; Wisconsin

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation method that delivers 1–2 mA of current to the scalp. Several clinical studies have been conducted to confirm the therapeutic effect of major depressive disorder (MDD) patients with tDCS. Some studies have shown tDCS's antidepressant effect, while the others showed conflicting results in antidepressant effects. Our aim of this review is to understand the biological bases of tDCS's antidepressant effect and review the results of studies on tDCS's antidepressant effect. For the review and search process of MDD treatment using tDCS, the US National Library of Medicine search engine PubMed was used. In this review, we discuss the biological mechanism of tDCS's antidepressant effect and the existing published literature including meta-analysis, systematic review, control trial, open studies, and case reports of antidepressant effects and cognitive function improvement in patients with MDD are reviewed. We also discuss the appropriate tDCS protocol for MDD patients, factors predictive of response to tDCS treatment, the disadvantages of tDCS in MDD treatment, and side effects.
Brain ; Cognition ; Depressive Disorder, Major* ; Humans ; Methods ; National Library of Medicine (U.S.) ; Scalp ; Search Engine ; Transcranial Direct Current Stimulation*