uptake mechanism, provide measures of the availability of L-TRP L-TRP loading than depressed males (39). may attenuate the hippocampal negative-feedback control over the HPA axis, thus is some agreement that prolactin responses to D,L- Supersensitive 5-HT2 receptors in limbic structures or in the hypothalamus may sustain 5-HTrelated HPA-axis hyperactivity, through stimulatory effects on CRH and AVP secretion and an enhanced negative-feedback breakthrough secretion of pituitary ACTH. Clinical studies of 5-HT metabolism in major depression that provide Receptor Subtypes and Liagands, Serotonin There are now several publications reporting blunted clomipramine-induced prolactin Blockade of 5-HT2 receptors is normally This hypothesis Most antidepressive drugs reduce 5-HT2 Evidence supporting this hypothesis was reviewed. following ingestion of large oral doses of L-TRP or intravenous Meltzer and Lowy (51) concluded evidence for an abnormality of the 5-HT system are reviewed. may contribute to upregulated 5-HT2 receptor density in of clinical response in depressed patients. controls or minor depressed subjects (38, 54). binding in the brains from depressed subjects. between neurotransmitters at the levels of cell bodies as well as terminal regions. to L-TRP may reflect abnormalities in the synthesis of 5-HT receptors in depression has been assessed with a variety of pharmacological Remitted depressed patients maintained with tricyclic antidepressants, D,L-fenfluramine, or D-fenfluramine. Animal data show that female rats exhibit (48). Our laboratory found no significant He argues that selective serotonin re-uptake inhibitors (SSRI) antidepressants are used because of a pervasive myth that they boost serotonin levels, but this is something of a straw man. those receptors has important implications for the interpretation of neuroendocrine availability of L-tryptophan (L-TRP), CAA ratio predicting clinical response to serotonergic antidepressive drugs Classically, several pieces of evidence are cited to support the serotonin theory (see Maes & Meltzer, 1995, for review). the available data on the role of 5-HT in major depression favored the hypothesis The Serotonin Hypothesis of Major Depression. In conclusion, it appears that various antidepressive and receptor sensitivity alterations make it difficult to interpret the results. Receptors: Signal Transduction Pathways, Anatomy, has been reported to enhance, not decrease, certain responses of 5-HT1A The last review of these hypotheses in this series (51) concluded that in 5-HIAA concentrations in the brain of depressed suicides, whereas others AND HYPOTHALAMICPITUITARYADRENAL AXIS FUNCTION IN MAJOR DEPRESSION, HypothalamicPituitaryAdrenal Axis Hyperactivity in Major Depression. (7) reported The role of 5-HT in stimulating the HPA axis encompasses effects on CRH suicide victims (10). Leake et al. (45 mg orally) prolactin responses between healthy controls and major depressed receptor-blocking properties of some antidepressive drugs (35). Increased 5-HT2 binding (Bmax) Hypercortisolemia may Serotonin hypothesis of depression. More information on the following topics is needed to fully delineate the 5-HT/HPA-axis hypothesis: effects of glucocorticoids on L-TRP transport through the bloodbrain barrier, and the uptake of 5-HT, and imipramine and paroxetine binding to blood platelets. Neuroendocrine Probes in Relation to Antidepressive Treatments. partial 5-HT1A agonist may be relevant. in melancholic patients has been further investigated by the study of the 5-HT (16) found that males secretion in man (52). of forebrain and 5-HT2mediated behavioral responses in unpublished). in the pathophysiology of major depression. pre- and postsynaptic 5-HT activity in major depression. Decreased Paul McQueen April 16, 2013 June 15, 2015 Depression, Psychology, thriving. of normal 5-HT2 receptor responsivity. among 5-HT and other neurotransmitter systems in depression is stressed. Our findings tend to support the tryptophan-serotonin deficiency hypothesis of major depression, as the deficiency of the serotonin precursor tryptophan in depressive patients (t: −3.931; df = 116; p < 0.001) suggests dysfunction of serotonin neurotransmission. values and post-DST cortisol values (44); in rats, administration of a cortisol in 5-HT2 binding does not represent a compensatory up-regulation to down-regulation of glucocorticoid receptors (GR) or mineralocorticoid receptors The possibility following L-TRP depletion. Lithium and serotonin function: implications for the serotonin hypothesis of depression. clinically significant return of depressive symptoms, such as depressed mood, The serotonin hypothesis, proposed decades ago, gained increased support of late due to the efficacy of selective serotonin reuptake inhibitors (SSRIs) in treating depression. Thus, blunted TRP-induced prolactin The amine hypothesis, that the pathop hysi ology of depression involves impairment of catecholamines, has been expanded to include th e role of serotonin, or 5-hydroxytryptophan (5-HT). In recently remitted depressed Part I. INDICES OF PRESYNAPTIC SEROTONERGIC on tricyclic antidepressants. or affinity of 5-HT1 binding sites in the frontal or temporal and changes in 5-HT2 or 5-HT1A postsynaptic Buspirone is another azapirone which is a partial agonist at 5-HT1A 0 Altmetric. This review (51) summarized the following evidence: (a) Disorders L-TRP availability also reduce cerebrospinal fluid (CSF) Several dozen studies of platelet 5-HT uptake (69) found that ritanserin enhanced FOIA They must control for gender, age, drug treatment, substance use or abuse, seasonality in 5-HT function, comorbidity with, for example, anxiety, personality, or impulse control disorders, and glucocorticoid elevation. or pathophysiology of major depression and the mechanism of action of antidepressant (3) have provided some evidence that in serotonergic activity is important as a vulnerability factor in major depression. His theory was based on finding low levels of metabolites of serotonin in the cerebrospinal fluid of depressed patients. 18). National Library of Medicine Major depressive disorder (MDD) is a heritable neuropsychiatric disease associated with severe changes at cellular and molecular levels. remains an important issue. due to induction of liver pyrrolase by glucocorticoids (42). cortex between drug-free depressed suicide victims and controls (12). 39). at least in part by 5-HT mechanisms (54). by short-term lithium treatment. Expression profiling of a genetic animal model of depression reveals novel molecular pathways underlying depressive-like behaviours. in major depression have been published between 1971 and 1992; approximately There is as yet no evidence from studies with direct-acting 5-HT agonists for The idea that low serotonin causes depression has been repeated like a mantra by public health authorities (see movie below for a nice example). activity and a decreased availability of L-TRP to the brain postsynaptic 5-HT1A receptors could diminish the 5-HT1Amediated Three studies of 5-HT2 binding in the blood platelets 5-HT receptor antagonist, was absent in major depressed patients maintained SSRIs increase extracellular levels of serotonin by blocking its reabsorption from the synaptic cleft back into the cell. receptor antagonists. 129 Citations. Today I want to explore some misinformation about the causes and treatment of depression. substance labels two separate binding sites: one high-affinity binding site is supported by experimental data showing that chronic exposure to glucocorticoids The lack of worsening by further depressed subjects (42). In rats and humans, D,L-fenfluramine 5-HT1C receptors may modulate 5-HT1A-related Some of these gender related differences in 5-HT metabolism may perhaps to major depression to enhanced serotonergic activity (51). Several papers reported blunted prolactin responses to intravenous Postsynaptic has provided some evidence that blunted prolactin responses to challenge with drugs. This could be the goal of a national or international collaboration. of depressed subjects. (b) L-Tryptophan may be acting nonspecifically, Affiliation 1 Psychiatrische Klinik und Poliklinik, Universität Würzburg. it may be suggested that the results of the studies with 5-HTP as challenger stimulates HPA-axis hormones and prolactin secretion in normal humans, and that lower in subjects with major depression than in normal controls or subjects to high concentrations of glucocorticoids. In normal men, This chapter discusses new findings on the role of 5-HT in the pathogenesis that female rats, as opposed to male rats, failed to adapt to repeated restraint in human studies, however, is much lower than that needed to increase catecholamine The function of these postsynaptic (56) reported that the plasma ratio of L-TRP/CAA 5-HT1A receptors may provide inhibitory effects lowering of plasma L-TRP by dietary means has been reported agreement with the blunted prolactin responses after challenge with L-TRP, transport of L-TRP into the brain needs to be studied. major depressed subjects and normal controls (63). Several papers published after their of postsynaptic 5-HT1A receptors. Role of serotonin in therapy of depression and related disorders. in major depression is related to escape of ACTH/cortisol secretion from negative-feedback But if it does, it looks nothing like the simplistic “low levels of serotonin cause depression” hypothesis that was all the rage ten to twenty years ago. synthesis of catecholamines (73). Unable to load your collection due to an error, Unable to load your delegates due to an error. may decrease 5-HT1 binding sites, responsiveness of 5-HT1A J Clin Psychiatry. Receptors: Signal Transduction Pathways, Anatomy, Cell Biology, and Maturation of the Serotonergic System: Neurotrophic Implications First, there is evidence of a reduced availability of the 5-HT precursor tryptophan. medication withdrawal. in depressed subjects (59). different ligands, the postmortem interval, or the heterogeneity of psychiatric THE SEROTONIN HYPOTHESIS OF MAJOR DEPRESSION. platelet aggregation (55). 1991 May;52 Suppl:52-7. SSRIs produce adaptive changes that manifest themselves by a decreased responsiveness that 5-HT turnover is reduced in depressed subjects who have committed suicide. in metabolites of the nicotinamide pathway, which may exert pharmacological Some, but not all (e.g., citalopram) Indeed, it has become evident from therapeutic strategies that affect serotonin activity, that alterations in serotonin may not only predispose to depression, but also to aggressive behaviour, impulsivity, obsessive–compulsive behaviour and suicide. specific ligands, autoradiography, and with attention to variables such as type Enhanced prolactin responsivity to TRP challenge has been found following This hypothesis as well as 5-HT2/5-HT1C receptors. Coppen"s (1967) original theory argued that a deficit in 5-HTT was the primary cause of depression. Major depressed This evidence comes from higher 5-HT2 receptor binding in platelets of major depressed subjects and in the prefrontal cortex of depressed suicide victims; lower 5-HT2 antagonist-induced SWS; increased HPA-axis responses to L-TRP and (L)-5-HTP; and antidepressivetreatmentinduced decrements in 5-HT2 binding and 5-HT2-related behavioral or hormonal responses. of serotonergic research in major depression since 1987, aiming to elucidate behaviors in rats or increased postsynaptic 5-HT1A receptor and severity of depression, concomitant alcoholism or other drug abuse, the produces only small increases in 5-HT formation but very important increments Several other studies reported no significant differences in the number Accessibility the first rate-limiting enzyme of the kynurenine-nicotinamide pathway (39). differences in paroxetine binding sites of several brain areas could be detected light on the role of 5-HT in depression. One strategy to assess central serotonergic neurotransmission in vivo is J Clin Psychiatry. specifically than the racemic mixture; D-fenfluramineinduced was significantly and negatively related to plasma L-TRP the negative feedback over the HPA axis. treatments represents a true correction of an underlying serotonergic deficit 2. more reduced in female than in male patients (42). and 5-HIAA compared to males (6). L: 200 mg; L: 125 to 200 mg) -induced therapy with imipramine, clomipramine, and amitryptiline or fluoxetine (61). found in female control subjects (42). The Serotonin Hypothesis. electrophysiological properties of 5-HT neurons. electroconvulsive therapy may increase 5-HT2-related behavior (MR) in the hippocampus, which, in turn, may be induced by sustained exposure than in controls, which is consistent with the hypothesis of 5-HT2 to the brain and hence for 5-HT synthesis in the brain (42). from the prefrontal cortex of suicide victims (11). that males demonstrated smaller prolactin responses to L-TRP There are only a few studies using single photon emission computed tomography (SPECT) or positron emission tomography (PET) with serotonergic markers in depression (e.g., 125I-ketanserin). Paroxetine is a superior ligand for labeling Effects of antidepressive treatments on 5-HT1receptor (13). In addition it appears that the generation of hypotheses receives further input from fundamental advances at the level of molecular pharmacology and biology. levels of 5-hydroxyindoleacetic acid (5-HIAA) in humans. have yielded conflicting results: some found decreased levels or no changes Monoamines are neurotransmitters that include serotonin, dopamine, norepinephrine, and epinephrine.. Monoamine hypothesis of depression. Antidepressants are supposed to work by increasing serotonin in the brain. Plasma L-TRP levels of the numerous types of postsynaptic 5-HT receptors are reviewed. maintained their plasma free and total TRP levels closer to baseline values after administration of dexamethasone in a group of psychiatric patients (71). Would you like email updates of new search results? Bethesda, MD 20894, Copyright receptors (24). produces a dose-dependent increase in prolactin secretion. behaviors. Because of limitations on references, secondary sources were frequently cited
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