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Background: The serotonin hypothesis of depression proposes that diminished serotonergic (5-HT) neurotransmission is causal in the pathophysiology of the disorder. Although the hypothesis is over 50 years old, there is no firm in vivo evidence for diminished 5-HT neurotransmission. We recently demonstrated that the 5-HT 2A receptor agonist positron emission tomography (PET) radioligand [ 11 C]Cimbi-36 is sensitive to increases in extracellular 5-HT induced by an acute d-amphetamine challenge. Here we applied [ 11 C]Cimbi-36 PET to compare brain 5-HT release capacity in patients experiencing a major depressive episode (MDE) to that of healthy control subjects (HCs) without depression., Methods: Seventeen antidepressant-free patients with MDE (3 female/14 male, mean age 44 ± 13 years, Hamilton Depression Rating Scale score 21 ± 4 [range 16-30]) and 20 HCs (3 female/17 male, mean age 32 ± 9 years) underwent 90-minute dynamic [ 11 C]Cimbi-36 PET before and 3 hours after a 0.5-mg/kg oral dose of d-amphetamine. Frontal cortex (main region of interest) 5-HT 2A receptor nondisplaceable binding was calculated from kinetic analysis using the multilinear analysis-1 approach with the cerebellum as the reference region., Results: Following d-amphetamine administration, frontal nondisplaceable binding potential (BP ND ) was significantly reduced in the HC group (1.04 ± 0.31 vs. 0.87 ± 0.24, p < .001) but not in the MDE group (0.97 ± 0.25 vs. 0.92 ± 0.22, not significant). ΔBP ND of the MDE group was significantly lower than that of the HC group (HC: 15% ± 14% vs. MDE: 6.5% ± 20%, p = .041)., Conclusions: This first direct assessment of 5-HT release capacity in people with depression provides clear evidence for dysfunctional serotonergic neurotransmission in depression by demonstrating reduced 5-HT release capacity in patients experiencing an MDE., (Copyright © 2022. Published by Elsevier Inc.)

Background: The difficulty in treating mood disorders has brought about clinical interest in alternative treatments, such as transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC). However, the optimal parameters for stimulation and underlying mechanisms of action are unclear. Psychiatric treatments have acute effects on emotional processing that predict later therapeutic action. Such effects have been proposed as cognitive biomarkers for screening novel treatments for depression and anxiety., Methods: This study assessed the effect of tDCS on a battery of emotional processing measures sensitive to antidepressant action. To refine optimal stimulation parameters, DLPFC stimulation using two common electrode montages was compared with sham. Sixty healthy volunteers received 20 minutes of active or sham DLPFC stimulation before completing computerized emotional processing tasks, including a dot-probe measure of vigilance to threat., Results: Relative to sham stimulation, participants receiving simultaneous anodal stimulation of left DLPFC and cathodal stimulation of right DLPFC (bipolar-balanced montage) showed reduced vigilance to threatening stimuli. There was no such significant effect when the cathode was placed on the supraorbital ridge (bipolar-unbalanced montage). There were no effects of tDCS on other measures of emotional processing., Conclusions: Our findings provide the first experimental evidence that modulating activity in the DLPFC reduces vigilance to threatening stimuli. This significant reduction in fear vigilance is similar to that seen with anxiolytic treatments in the same cognitive paradigm. The finding that DLPFC tDCS acutely alters the processing of threatening information suggests a potential cognitive mechanism that could underwrite treatment effects in clinical populations., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The amygdala is a central node in the brain network that processes aversive emotions and is extensively innervated by dorsal raphe nucleus (DRN) serotonin (5-hydroxytryptamine [5-HT]) neurons. Alterations in DRN 5-HT1A receptor availability cause phenotypes characterized by fearful behavior in preclinical models. However, it is unknown whether 5-HT1A receptor availability is linked specifically to the processing of aversive emotions in humans or whether it modulates connectivity in brain networks involved in emotion processing. To answer this question, we investigated the relationship between DRN 5-HT1A receptor availability and amygdala reactivity to aversive emotion and functional connectivity within the amygdala-cortical network., Methods: We studied 15 healthy human participants who underwent positron emission tomography scanning with [(11)C]CUMI-101, a 5-HT1A partial agonist radioligand, and functional magnetic resonance imaging of brain responses during an incidental emotion processing task including happy, fearful, and neutral faces. Regional estimates of 5-HT1A receptor binding potential (nondisplaceable) were obtained by calculating total volumes of distribution for presynaptic DRN and amygdala. Connectivity between the amygdala and corticolimbic areas was assessed using psychophysiologic interaction analysis with the amygdala as the seed region., Results: Analysis of the fear versus neutral contrast revealed a significant negative correlation between amygdala response and DRN binding potential (nondisplaceable) (r = -.87, p < .001). Availability of DRN 5-HT1A receptors positively correlated with amygdala connectivity with middle frontal gyrus, anterior cingulate cortex, bilateral precuneus, and left supramarginal gyrus for fearful (relative to neutral) faces., Conclusions: Our data show that DRN 5-HT1A receptor availability is linked specifically to the processing of aversive emotions in the amygdala and the modulation of amygdala-cortical connectivity., (Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.)

Background: Abnormalities in the neural representation of rewarding and aversive stimuli have been well-described in patients with acute depression, and we previously found abnormal neural responses to rewarding and aversive sight and taste stimuli in recovered depressed patients. The aim of the present study was to determine whether similar abnormalities might be present in young people at increased familial risk of depression but with no personal history of mood disorder., Methods: We therefore used functional magnetic resonance imaging to examine the neural responses to pleasant and aversive sights and tastes in 25 young people (16-21 years of age) with a biological parent with depression and 25 age- and gender-matched control subjects., Results: We found that, relative to the control subjects, participants with a parental history of depression showed diminished responses in the orbitofrontal cortex to rewarding stimuli, whereas activations to aversive stimuli were increased in the lateral orbitofrontal cortex and insula. In anterior cingulate cortex the at-risk group showed blunted neural responses to both rewarding and aversive stimuli., Conclusions: Our findings suggest that young people at increased familial risk of depression have altered neural representation of reward and punishment, particularly in cortical regions linked to the use of positive and negative feedback to guide adaptive behavior., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Negative attentional biases are thought to increase the risk of recurrence in depression, suggesting that reduction of such biases may be a plausible strategy in the secondary prevention of the illness. However, no previous study has tested whether reducing negative attentional bias causally affects risk factors for depressive recurrence. The current experimental medicine study reports the effects of a computerized attentional bias modification (ABM) procedure on intermediate measures of the risk of depressive recurrence (residual depressive symptoms and the cortisol awakening response) in patients with recurrent depression., Methods: Sixty-one patients with at least two previous episodes of depression who were currently in remission were randomized to receive either an active (positive) or placebo computer-based ABM regime. The ABM regime presented either pictures of faces or words. Residual depressive symptoms, measured using the Beck Depression Inventory and the cortisol awakening response were measured immediately before and after completion of the bias modification and then again after 4 weeks' follow-up., Results: Positive, face-based ABM reduced both measures of recurrence risk (Beck Depression Inventory and cortisol awakening response). This effect occurred during the month following completion of bias modification. Word-based modification did not influence the outcome measures., Conclusions: Positive face-based ABM was able to reduce intermediate measures of recurrence risk in previously depressed patients. These results suggest that ABM may provide a "cognitive vaccine" against depression and offer a useful strategy in the secondary prevention of the illness., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Close supportive relationships protect against psychological disorders and also facilitate recovery. However, little is known about the neurochemical mechanisms that mediate these effects. Variation in serotonin function influences affiliative behavior in humans and nonhuman primates. Here, we used tryptophan depletion in healthy adults to investigate the role of serotonin in the cognitive appraisal of close personal relationships., Methods: Twenty-two healthy adults drank an amino acid drink without tryptophan, and 19 healthy adults drank an amino acid drink containing tryptophan. Participants were presented with color photographs of heterosexual "couples" standing apart or making affiliative touch gestures and rated the couples for descriptors that capture qualities of close personal relationships. Trait attachment style and state affect of participants were also measured., Results: Tryptophan depletion reduced the judged intimacy and romance of photographed couples. Tryptophan-depleted women rated men as more dominant in relationships and touching couples as more able to resolve their conflicts, when compared with nondepleted women. These effects were not due to changes in mood and remained statistically reliable when the marked impact of attachment style upon relationship judgments was statistically controlled., Conclusions: Our results suggest that central serotonin activity influences the appraisal of close intimate partnerships, raising the possibility that serotonergic dysfunction contributes to altered cognitions about relationships in psychiatric illnesses., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Selective serotonin reuptake inhibitors (SSRIs) are popular medications for anxiety and depression, but their effectiveness, particularly in patients with prominent symptoms of loss of motivation and pleasure, has been questioned. There are few studies of the effect of SSRIs on neural reward mechanisms in humans., Methods: We studied 45 healthy participants who were randomly allocated to receive the SSRI citalopram, the noradrenaline reuptake inhibitor reboxetine, or placebo for 7 days in a double-blind, parallel group design. We used functional magnetic resonance imaging to measure the neural response to rewarding (sight and/or flavor of chocolate) and aversive stimuli (sight of moldy strawberries and/or an unpleasant strawberry taste) on the final day of drug treatment., Results: Citalopram reduced activation to the chocolate stimuli in the ventral striatum and the ventral medial/orbitofrontal cortex. In contrast, reboxetine did not suppress ventral striatal activity and in fact increased neural responses within medial orbitofrontal cortex to reward. Citalopram also decreased neural responses to the aversive stimuli conditions in key "punishment" areas such as the lateral orbitofrontal cortex. Reboxetine produced a similar, although weaker effect., Conclusions: Our findings are the first to show that treatment with SSRIs can diminish the neural processing of both rewarding and aversive stimuli. The ability of SSRIs to decrease neural responses to reward might underlie the questioned efficacy of SSRIs in depressive conditions characterized by decreased motivation and anhedonia and could also account for the experience of emotional blunting described by some patients during SSRI treatment., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Patients with depression show abnormalities in the neural circuitry supporting working memory. These abnormalities apparently persist into clinical remission, raising the possibility that they might be trait markers indicating vulnerability to depression., Methods: We studied 17 young people who had a depressed parent but no personal history of depressive illness (FH) and 15 healthy control subjects with no family history of depression. Participants performed a verbal working memory task of varying cognitive load (n-back) while undergoing functional magnetic resonance imaging scanning. We used multiple regression analyses to assess overall capacity (1-, 2-, 3-back vs. 0-back) as well as linear and quadratic modulation of cognitive demand., Results: Performance accuracy and response latency did not differ between groups, and overall capacity was similar. However, for both linear and quadratic load response activity, FH participants showed greater activation in lateral occipital cortex, superior temporal cortex, and superior parietal cortex., Conclusions: Our data suggest that, as in depressed patients, maintenance of task performance in FH participants is associated with a significant increase in the load-response activity of the cortical regions involved in working memory. This neural abnormality could form part of the predisposition to develop depressive disorders., (Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Studies using proton magnetic resonance spectroscopy (MRS) have indicated that unmedicated, acutely depressed patients have decreased levels of gamma-aminobutyric acid (GABA) in occipital cortex. Cortical levels of glutamate (Glu) may be increased, although these data are less consistent. The aim of this study was to use MRS to determine whether changes in GABA and Glu levels were present in patients with mood disorders who had recovered and were no longer taking medication., Methods: An [1H]-MRS was used to measure levels of GABA, of the combined concentration of Glu and glutamine (Gln), and of N-acetylaspartate (NAA) in occipital cortex in medication-free, fully recovered subjects with a history of recurrent unipolar depression (n = 15), bipolar disorder (n = 16), and a group of healthy controls (n = 18)., Results: Occipital levels of GABA and NAA were significantly lower in recovered depressed and bipolar subjects than in healthy controls, whereas Glu +Gln concentrations were higher., Conclusions: Our data suggest that recovered unmedicated subjects with a history of mood disorder have changes in cortical concentrations of GABA, NAA, and Glu +Gln. These biochemical abnormalities may be markers of a trait vulnerability to mood disorder, rather than neurochemical correlates of an abnormal mood state.

Background: The amygdala is believed to play a key role in processing emotionally salient, threat-relevant, events that require further online processing by cortical regions. Emotional disorders such as depression and anxiety have been associated with hyperactivity of the amygdala, but it is unknown whether antidepressant treatment directly affects amygdala responses to emotionally significant information., Methods: The current study assessed the effects of 7 days administration of the selective serotonin reuptake inhibitor (SSRI), citalopram, on amygdala responses to masked presentations of fearful and happy facial expressions in never-depressed volunteers using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging. A double-blind, between-groups design was used with volunteers randomized to 20 mg/day citalopram versus placebo., Results: Volunteers receiving citalopram showed decreased amygdala responses to masked presentations of threat compared with those receiving placebo. Citalopram also reduced responses within the hippocampus and medial prefrontal cortex (mPFC) specifically during the fear-relevant stimuli. These neural differences were accompanied by decreased recognition of fearful facial expressions assessed after the scan. By contrast, there was no effect of citalopram on the neural or behavioral response to the happy facial expressions., Conclusions: These results suggest a direct effect of serotonin potentiation on amygdala response to threat-relevant stimuli in humans. Such effects may be important in the therapeutic actions of antidepressants in depression and anxiety.

Background: Acute tryptophan depletion can induce a transient reappearance of depressive symptoms in recovered depressed patients. The neurochemical mechanism is thought to be impairment of brain serotonin neurotransmission, but the neuropsychologic mechanisms underlying the effect are unclear., Methods: To assess whether low-dose tryptophan depletion can tease out the psychological mechanisms sensitive to substrate depletion in vulnerable subjects without inducing mood changes, a between-subjects randomized design was used. Recovered depressed patients (n = 24) and healthy volunteers (n = 24) were administered while fasting either a tryptophan-free or a control mixture, containing 31.2 and 33.2 g of amino acids, respectively. Objective and subjective ratings of mood were made before and 5 hours after ingestion; at the latter time point, cognitive and emotional processing were also assessed., Results: Low-dose tryptophan depletion did not affect mood. Significant changes in emotional and cognitive processing occurred in the recovered depressed group, however, and to a lesser extent in the healthy volunteers. The profile of effects seen in the recovered patients suggested a return of the impairments seen in acute depression., Conclusions: Our data suggest that low-dose tryptophan depletion permits investigation of the cognitive correlates of acute reductions in brain serotonin in populations vulnerable to depression and in healthy volunteers, without causing depressive symptoms.

Background: Elevated cortisol levels might account for the reduction in central serotonin 1A (5-hydroxytryptamine [5-HT](1A)) receptor binding and function observed in patients with major depression. We tested this hypothesis by studying the effect of acute administration of hydrocortisone on 5-HT(1A) receptor binding potential (BP) in subjects recovered from depression., Methods: We studied 14 subjects (8 male, 6 female) who had recovered from at least two episodes of major depression and had been euthymic and drug free for at least 6 months. Serotonin 1A receptor BP was measured by [(11)C]WAY-100635 in conjunction with positron emission tomography. Subjects were tested on two occasions in a double-blind, random-order, crossover design after administration of either hydrocortisone (100 mg orally) or placebo 12 hours previously. Positron emission tomography scans were analyzed with a region of interest analysis., Results: Hydrocortisone treatment did not decrease 5-HT(1A) receptor BP either in the hippocampus, which was our a priori hypothesis, or in other cortical 5-HT(1A) regions; however, female subjects had a higher 5-HT(1A) receptor BP in certain brain areas compared with male subjects., Conclusions: These data are consistent with an earlier study in healthy volunteers and do not support the proposal that decreased 5-HT(1A) receptor BP in patients with acute major depression is a consequence of cortisol hypersecretion.

Background: The study aimed to determine the effects of the atypical antipsychotic agent, olanzapine, on the polysomnogram in healthy subjects. We predicted that olanzapine, via serotonin(2C) (5-HT(2C)) receptor blockade, would increase slow-wave sleep (SWS)., Methods: We studied the effects of single evening doses of olanzapine (5 mg and 10 mg orally) on the polysomnogram of 9 healthy male volunteers, using a placebo-controlled, double-blind, cross-over design., Results: Compared to placebo, the 5-mg and 10-mg doses of olanzapine significantly increased SWS, sleep continuity measures, and subjective sleep quality. In addition, 10 mg of olanzapine suppressed rapid eye movement (REM) sleep and increased REM sleep latency., Conclusions: Olanzapine (5 mg and 10 mg) produced substantial (59.1% and 83.3%) and highly significant dose-related increases in SWS in humans probably via blockade of brain 5-HT(2C) receptors. 5-HT(2C) receptor antagonism may account for some of the therapeutic and adverse effects of olanzapine therapy.

Background: We studied the effect of a single dose of a formulation of a methanolic extract of Hypericum perforatum (HP), also known as St. John's wort, on plasma concentrations of growth hormone (GH), prolactin (PRL), and cortisol (CORT) in 12 healthy male volunteers., Methods: Subjects received 9 tablets of the finished product Jarsin 300 and placebo in a double-blind, balanced-order, cross-over design., Results: Following HP relative to placebo, there was a significant increase in plasma GH and a significant decrease in plasma PRL. Plasma CORT levels were unchanged., Conclusions: Taken together with data from animal experimental studies, the findings suggest that this dose of HP may increase some aspects of brain dopamine function in humans.

Background: Impairments in both basal activity and activation of the hypothalamic-pituitary-adrenal axis (HPA) have been reported in chronic fatigue syndrome (CFS; neurasthenia). We sought to replicate these findings and examined basal activity of the HPA in a carefully selected sample of patients with CFS., Methods: Basal activity of the HPA was assessed using salivary and urinary cortisol collection over a 24-hour period in 22 (12 male; 10 female) patients meeting criteria for CFS and appropriate controls., Results: Salivary and urinary cortisol measures did not differ between CFS patients and controls., Conclusions: Basal activity of the HPA was not reduced in CFS patients. Reasons for the failure to replicate previous findings are discussed.

We studied the effects of haloperidol (0.5 mg, intravenously) on latent inhibition in an auditory paradigm and two visual paradigms in healthy subjects. Haloperidol increased latent inhibition in one visual paradigm and tended to increase latent inhibition in an auditory task, compared to saline-injected controls. These results indicate that haloperidol can enhance the selectivity of attention. In contrast, previous studies have reported that acute schizophrenics show reduced latent inhibition.

Brain serotonin (5-HT) neuroendocrine function, plasma tryptophan, and platelet 5-HT content were examined in 20 patients treated in a lipid clinic for hypercholesterolaemia with combined drug and diet therapy and in 20 healthy matched controls. Treatment had produced a substantial decrease in total cholesterol concentrations in the patients, but they still had higher cholesterol and triglyceride levels than control subjects. The patients were somewhat more depressed than controls but did not differ from them in degree of hostility, free or total plasma tryptophan, or prolactin response to 30 mg of d-fenfluramine. This study does not reveal evidence of abnormal brain 5-HT neuroendocrine function in hypercholesterolaemic patients receiving cholesterol-lowering medications and diet.

Antidepressant drugs produce striking effects on sleep architecture that are best understood in terms of their interactions with the monoamine pathways controlling sleep and wakefulness. Many different antidepressant drugs, including tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and selective 5-hydroxytryptamine (5-HT; serotonin) reuptake inhibitors (SSRIs), decrease rapid eye movement (REM) sleep. The reduction in REM sleep produced by antidepressants may be an important part of their mechanism of action; however, the ability of new antidepressant compounds, such as nefazodone and moclobemide, to increase REM sleep throws doubt on this suggestion. The effects of antidepressants on slow-wave sleep (SWS) are quite diverse; in general, antidepressants having significant 5-HT2A/2C receptor antagonist properties increase SWS, whereas other drugs, such as SSRIs or MAOIs, either lower SWS or produce no change. Sleep continuity is improved acutely following administration of antidepressants with sedating properties such as certain TCAs, trazodone, and mianserin. Some nonsedating drugs (ritanserin and nefazodone) also improve sleep continuity measures, possibly through 5-HT2A/2C receptor blockade.

Results from animal studies have suggested that serotonin (5-HT) antagonists acting on the 5-HT3 receptor may have anxiolytic properties. We have assessed whether pretreatment with the 5-HT3 receptor antagonist BRL 46470 (1 mg orally) attenuates the increase in anxiety induced in healthy volunteers by intravenous infusion of m-chlorophenylpiperazine (mCPP: 0.08 mg/kg over 2 min). In this double-blind placebo-controlled crossover study in 12 healthy men who were volunteers, infusion of mCPP caused significant increases in self-ratings for the psychological and physical symptoms of anxiety, for the symptoms of panic attack, and in the plasma levels of cortisol and prolactin, with four subjects (33%) experiencing an mCPP-induced "panic attack." Pretreatment with BRL 46470 did not attenuate any of these mCPP-induced changes. These results do not support suggestions from animal studies that 5-HT3 receptor antagonists can attenuate mCPP-induced anxiety, although it is conceivable that a different dose of BRL 46470 may have been effective.

We assessed the effect of two regimens of lithium treatment (3 days and 2 weeks) on brain serotonin (5-HT) function in healthy subjects by measuring the prolactin (PRL) responses to the 5-HT releasing agent, d-fenfluramine (30 mg) before and after lithium administration. Neither regime of lithium treatment altered d-fenfluramine-induced PRL release. These results are in contrast to the facilitation produced by lithium of the PRL responses to the 5-HT precursor L-tryptophan. The data suggest that the ability of lithium to increase brain 5-HT neurotransmission in humans may depend on interactions with particular 5-HT receptor subtypes or specific mechanisms of 5-HT release.

The effects of a novel antidepressant, nefazodone (50 mg, 100 mg, and 200 mg orally) on neuroendocrine function and temperature were assessed using a single-blind, crossover design in eight healthy male volunteers. Nefazodone significantly increased plasma levels of prolactin (PRL) and raised oral temperature. There was also a trend towards an increase in plasma cortisol. These results are consistent with an acute facilitatory effect of some aspects of 5-HT neurotransmission, perhaps mediated through nefazodone's metabolism to its major metabolite, m-chlorophenylpiperazine (mCPP).