Serotonergic and Noradrenergic Modulation of Emotion Processing by Single Dose Antidepressants 5-HT Modulation of Dopamine Release in Basal Ganglia in Psilocybin-Induced Psychosis in Man—A PET Study with [11C]raclopride Serotonergic psychedelics and personality: A systematic review of contemporary research Effects of dopaminergic and serotonergic manipulation on emotional processing: A pharmacological fMRI study Psilocybin induces schizophrenia‐like psychosis in humans via a serotonin‐2 agonist action Functional serotonin 1A receptor variant influences treatment response to atypical antipsychotics in schizophrenia. Psilocybin Biases Facial Recognition, Goal-Directed Behavior, and Mood State Toward Positive Relative to Negative Emotions Through Different Serotonergic Subreceptors Serotonin Neurotoxicity after (±)3,4-Methylenedioxymethamphetamine (MDMA; “Ecstasy”): A Controlled Study in Humans Influence of 5-HT3 receptor subunit genes HTR3A, HTR3B, HTR3C, HTR3D and HTR3E on treatment response to antipsychotics in schizophrenia Psychopathological, neuroendocrine and autonomic effects of 3,4-methylenedioxyethylamphetamine (MDE), psilocybin and d-methamphetamine in healthy volunteers
Results of an experimental double-blind placebo-controlled study m-Chlorophenylpiperazine effects in neuroleptic-free schizophrenic patients. Evidence implicating serotonergic systems in the positive symptoms of schizophrenia. Different Effects of Typical and Atypical Antipsychotics on Grey Matter in First Episode Psychosis: the ÆSOP Study Five antidepressant treatments in depressed patients. Effects on urinary serotonin and 5-hydroxyindoleacetic acid output. Pharmacological modulation of the neural basis underlying inhibition of return (IOR) in the human 5-HT2A agonist and NMDA antagonist model of psychosis Effects of serotonergic and noradrenergic antidepressants on auditory startle response in patients with major depression Serotonin function in panic disorder: a double blind placebo controlled study with fluvoxamine and ritanserin Differential effects of serotonergic and noradrenergic antidepressants on brain activity during a cognitive control task and neurofunctional prediction of treatment outcome in patients with depression.
Serotonergic and noradrenergic pathways are the main targets of antidepressants . Their differential effects on emotion processing-related brain activation are , however , to be further characterized . We aim ed at elucidating the neural sites of action of an acute differential serotonergic and noradrenergic influence on an emotion-processing task , which was earlier shown to be associated with depressiveness . In a single-blind pseudo-r and omized crossover study , 21 healthy subjects ( 16 subjects finally included in the analysis ) participated to ingest a single dose at three time points of either 40 mg citalopram , a selective serotonin-reuptake inhibitor , 8 mg reboxetine , a selective noradrenaline-reuptake inhibitor , or placebo 2–3 h before functional magnetic resonance imaging ( fMRI ) . During fMRI , subjects performed a task comprising the anticipation and perception of pictures of either ‘ known ’ ( positive , negative , neutral ) or ‘ unknown ’ valence ( r and omly 50 % positive or negative ) . In direct comparison with citalopram and with placebo , reboxetine increased brain activity in the medial thalamus . Citalopram modulated certain prefrontal and insular areas more prominently . Other frontal and parieto-occipital areas were modulated by both drugs . In conclusion , the functional network involved in emotional information processing could be modulated by the acute application of selective noradrenergic and serotonergic drugs revealing a noradrenergic effect in thalamic and frontal areas , and a prefrontal and insular focus of serotonergic modulation . These findings could have implication s for future selection criteria concerning personalized antidepressant medication in depression The modulating effects of serotonin on dopamine neurotransmission are not well understood , particularly in acute psychotic states .  Positron emission tomography was used to examine the effect of psilocybin on the in vivo binding of [11C]raclopride to D2-dopamine receptors in the striatum in healthy volunteers after placebo  and a  psychotomimetic dose of psilocybin ( n = 7 ) .  Psilocybin is a potent indoleamine hallucinogen and a mixed 5-HT2A and 5-HT1A receptor agonist . Psilocybin administration ( 0.25 mg/kg p.o . ) produced changes in mood , disturbances in thinking , illusions , elementary and complex visual hallucinations and impaired ego-functioning .  Psilocybin significantly decreased [11C]raclopride receptor binding potential ( BP ) bilaterally in the cau date nucleus ( 19 % ) and putamen ( 20 % ) consistent with an increase in endogenous dopamine . Changes in [11C]raclopride BP in the ventral striatum correlated with depersonalization associated with euphoria . Together with previous reports of 5-HT receptor involvement in striatal dopamine release , it is concluded that stimulation of both 5-HT2A and 5-HT1A receptors may be important for the modulation of striatal dopamine release in acute psychoses . The present results indirectly support the hypothesis of a serotonin-dopamine dysbalance in schizophrenia and suggest that psilocybin is a valuable tool in the analysis of serotonin-dopamine interactions in acute psychotic states HighlightsSerotonergic psychedelics act as agonists at cortical 5‐HT2A receptors.5‐HT2A receptors are expressed in fronto‐temporo‐parieto‐occipital areas .Some personality traits seem to be related to 5‐HT2A receptor expression . Acute and long‐term use of psychedelics is associated with personality changes  . Personality changes induced by psychedelics may have therapeutic effects . & NA ; Serotonergic psychedelics act as agonists at cortical 5‐HT2A receptors and seem to induce personality changes . We conducted a systematic review of studies assessing the effects of these drugs on personality . Papers published from 1985–2016 were included from PubMed , LILACS , and SciELO data bases . Three hundred and sixty‐nine studies were identified , and 18 were included . Specific personality traits , such as Absorption and Self‐Transcendence , seem to influence the effects of psychedelics , and  psychedelic drug users and nonusers appear to differ in some personality traits . Psychedelics administered in controlled setting s may induce personality changes , such as increased Openness and Self‐Transcendence . Increases in global brain entropy induced by acute psychedelic administration predicted changes in Openness , and Self‐Transcendence was negatively correlated with cortical thinning of the posterior cingulate cortex in long‐term religious ayahuasca users . Acute and long‐term use of psychedelics is associated with personality changes that appear to be modulated by 5‐HT2A receptors . These changes seem to induce therapeutic effects that should be further explored in r and omized controlled studies Recent neuroimaging studies have demonstrated abnormal central emotional processing in psychiatric disorders . The dopamine ( DA ) systems and serotonin ( 5-HT ) systems are the main target of psychopharmacotherapy . DA D2 receptor antagonists and selective serotonin reuptake inhibitors ( SSRIs ) are widely used in psychiatric practice . Investigating the effects of these drugs on emotional processing should lead to a better underst and ing of the pathophysiology and pharmacotherapy of neuropsychiatric disorders . We aim ed to examine effects of dopaminergic and serotonergic manipulation on neural responses to unpleasant pictures in healthy volunteers using pharmacological fMRI .  Thirteen healthy male subjects participated in a single-blind , r and omized , placebo-controlled design study . Each subject participated in three fMRI sessions . In each session , participants were orally administered either 25 mg of sultopride or 50 mg of fluvoxamine or placebo prior to scanning , and neural responses to unpleasant and neutral pictures were recorded . Despite no significant differences being found in the subjective ratings of affective pictures across three sessions , compared to placebo , acute treatments of DA D2 receptor antagonists and SSRIs commonly attenuated the amygdala activity , although both treatments had slightly different modulatory effects on other components of the neural circuit of emotional processing . This study has shown that even acute treatment of drugs that manipulate neurotransmitter systems could affect brain activation associated with emotional processing in human brain . At the same time , our findings suggest that pharmacological fMRI could be a powerful tool for investigating the neurophysiological properties of drugs targeting neuropsychiatric disorders PSILOCYBIN , an indoleamine hallucinogen , produces a  psychosis-like syndrome in humans that resembles first episodes of schizophrenia . In healthy human volunteers , the psychotomimetic effects of psilocybin were blocked dose-dependently by the serotonin-2A antagonist ketanserin or the atypical antipsychotic risperidone , but were increased by the dopamine antagonist and typical antipsychotic haloperidol . These data are consistent with animal studies and provide the first evidence in humans that psilocybin-induced psychosis is due to serotonin-2A receptor activation , independently of dopamine stimulation . Thus , serotonin-2A overactivity may be involved in the pathophysiology of schizophrenia and serotonin-2A antagonism may contribute to therapeutic effects of antipsychotics The serotonin ( 5-HT ) 1A receptor has been found to be dysregulated in prefrontal cortex and other brain regions in schizophrenia , and 5-HT1A receptor levels in the amygdala have been related to negative schizophrenia symptoms . We have assessed the impact of the functional C-1019 G variant of the 5-HT1A receptor on the response to risperidone or haloperidol in a prospect i ve , r and omized , double-blind study . Patients were treated for 4 weeks and negative symptoms assessed weekly . The variant influenced the response to  risperidone :  improvement of negative symptoms by 4.38 points for carriers of the C allele , compared with the GG genotype ( 1.22 points , P=0.046 ) . In a second independent study of 130 schizophrenia patients treated with atypical antipsychotics , this effect was confirmed ( P=0.003 ) . The functional variant of the 5-HT1A receptor thus influences the response of schizophrenia patients to atypical antipsychotics and may be useful in the future to predict the pharmacogenetics of negative symptoms BACKGROUND Serotonin ( 5-HT ) 1A and 2A receptors have been associated with dysfunctional emotional processing biases in mood disorders . These receptors further predominantly mediate the subjective and behavioral effects of psilocybin and might be important for its recently suggested antidepressive effects . However , the effect of psilocybin on emotional processing biases and the specific contribution of 5-HT2A receptors across different emotional domains is unknown . METHODS In a r and omized , double-blind study , 17 healthy human subjects received on 4 separate days placebo , psilocybin ( 215 μg/kg ) , the preferential 5-HT2A antagonist ketanserin ( 50 mg ) , or psilocybin plus ketanserin .  Mood states were assessed by self-report ratings , and behavioral and event-related potential measurements were used to quantify facial emotional recognition and goal -directed behavior toward emotional cues . RESULTS Psilocybin enhanced positive mood and attenuated recognition of negative facial expression .  Furthermore , psilocybin increased goal -directed behavior toward positive compared with negative cues , facilitated positive but inhibited negative sequential emotional effects , and valence-dependently attenuated the P300 component . Ketanserin alone had no effects but blocked the psilocybin-induced mood enhancement and decreased recognition of negative facial expression . CONCLUSIONS This study shows that psilocybin shifts the emotional bias across various psychological domains and that activation of 5-HT2A receptors is central in mood regulation and emotional face recognition in healthy subjects . These findings may not only have implication s for the pathophysiology of dysfunctional emotional biases but may also provide a framework to delineate the mechanisms underlying psylocybin 's putative antidepressant effects (±)3,4-Methylenedioxymethamphetamine ( MDMA ; “ Ecstasy ” ) , an increasingly popular recreational drug , is known to damage brain serotonin 5-hydroxytryptamine ( 5-HT ) neurons in experimental animals . Whether MDMA is neurotoxic in humans has not been established . Thirty MDMA users and 28 controls were admitted to a controlled inpatient setting for measurement of biologic and behavioral indexes of central 5-HT function . Outcome measures obtained after at least 2 weeks of drug abstinence included concentrations of monoamine metabolites in cerebrospinal fluid ( CSF ) , prolactin responses to L-tryptophan , nociceptive responses to ischemic pain , and personality characteristics in which 5-HT has been implicated ( i.e. , impulsivity and aggression ) . Subjects with a history of MDMA exposure had lower levels of CSF 5-hydroxyindoleacetic acid ( the major metabolite of 5-HT ) than controls ( p = .002 ) . Although they resembled controls in their prolactin response to L-tryptophan and their response to ischemic pain ,  MDMA  users had lower scores on personality measures of impulsivity ( p = . 004 ) and indirect hostility ( p = .009 ) . The CSF findings suggest that 5-HT neurotoxicity may be a potential complication of MDMA use . Further , differences in personality support the view that 5-HT systems are involved in modulating impulsive and aggressive personality traits . Additional studies of  MDMA-exposed individuals are needed to confirm and extend the present findings . Such studies could help eluci date the role of 5-HT in normal brain function as well as in neuropsychiatric disease states Objectives Among serotonin ( 5-HT ) receptors , the 5-HT3 receptor is the only lig and -gated ion channel . 5-HT3 antagonists such as ondansetron and tropisetron may improve auditory gating and neurocognitive deficits in schizophrenic patients . Moreover , many antipsychotic drugs are antagonists at 5-HT3 receptors . However , the role of 5-HT3 receptor variants on response to antipsychotic drugs in schizophrenic patients is still unclear . Methods In a prospect i ve , r and omized , double-blind study , we have assessed six functional and coding variants of the subunit genes HTR3A , HTR3B as well as the novel HTR3C , HTR3D , and HTR3E subunits in the response to haloperidol or risperidone .  Seventy patients were treated for 4 weeks and positive symptoms , negative symptoms , and general psychopathology were measured by the Positive and Negative Syndrome Scale ( PANSS ) . Results HTR3E had an effect on the speed of response to antipsychotics . GG-allele carriers responded more quickly to treatment on the PANSS negative symptom subscale ( P = 0.03 ) and on the total PANSS score ( P = 0.04 ) irrespective of medication . In a second independent study of 144 schizophrenia patients treated with atypical antipsychotics , this effect could not be confirmed . Conclusion Our findings argue against a major effect of HTR3 variants in response to antipsychotics . Solely , the HTR3E and also the HTR3A variant could exert a weak effect on the speed of response to antipsychotics Abstract The aim of this study was to contribute to the characterization of the entactogen ( ecstasy ) substance group . The psychopathological , neuroendocrine and autonomic effects of common recreational doses of the entactogen 3,4-methylenedioxyethylamphetamine ( MDE ) , the hallucinogen psilocybin , the stimulant d-methamphetamine and placebo were investigated in a double-blind study with healthy volunteers ( n = 32 ) .  Psychological effects of the drugs were assessed by means of st and ardized rating scales , self assessment inventories and free descriptions . The most characteristic effects of MDE were pleasant emotional experiences of relaxation , peacefulness , content and closeness to others . However , significant stimulant and hallucinogen-like effects were also present , although the latter were weaker than the effects of psilocybin . MDE elicited the strongest endocrine and autonomic effects among the three drugs , including robust rises of serum cortisol and prolactin , elevations of blood pressure and heart rate , and a moderate , but significant rise of body temperature . The apparent contrast between psychological and autonomic effects ( subjective relaxation versus physical activation ) was a unique feature of the MDE state . Our findings are in line with both users ’ reports and results from previous experimental studies , and support the view that entactogens constitute a distinct psychoactive substance class taking an intermediate position between hallucinogens and stimulants OBJECTIVE This study evaluated whether alterations in serotonin function in schizophrenic patients could be demonstrated by comparing the reactivity to a serotonin partial agonist , m-chlorophenylpiperazine ( MCPP ) in patients and healthy subjects . This study also assessed whether stimulation of serotonin receptors influenced the symptoms of schizophrenia . DESIGN Double-blind r and omized comparison of MCPP ( 0.1 mg/kg , intravenously , administered over 20 minutes ) and placebo effects in patients and healthy subjects . SETTING Department of Veterans Affairs Medical Center , West Haven , Conn. PATIENTS AND HEALTHY SUBJECTS : Fifteen healthy subjects recruited by public advertisement and 12 schizophrenic in patients who had been neuroleptic free for at least 2 weeks prior to entry into the study . MAIN OUTCOME MEASURES The principal outcome variable was the positive symptoms of schizophrenia operationally defined as the sum of scores on the four key items for schizophrenia on the Brief Psychiatric Rating Scale and the Brief Psychiatric Rating Scale thought disorder factor . Anxiety was assessed with a clinician-rated visual analog scale and plasma hormone levels were measured . RESULTS m-Chlorophenylpiperazine significantly increased the positive symptoms of schizophrenia in patients but not healthy subjects . Patients and healthy subjects exhibited anxiety increases of comparable magnitude following MCPP . However , patients had higher baseline levels of anxiety and exhibited more prolonged anxiogenic responses to MCPP .  Anxiety elevations did not correlate with increases in the four key symptoms in patients . Patients exhibited lower baseline prolactin levels compared with healthy subjects , but the two groups did not differ in their prolactin , growth hormone , and cortisol responses to MCPP . CONCLUSIONS Schizophrenics , the only psychotic patient group studied to date , are the first patient group to exhibit propsychotic responses to MCPP . These data provide further evidence that serotonin systems modulate positive symptoms in some schizophrenic patients Typical antipsychotic drugs act on the dopaminergic system , blocking the dopamine type 2 ( D2 ) receptors . Atypical antipsychotics have lower affinity and occupancy for the dopaminergic receptors , and a high degree of occupancy of the serotoninergic receptors 5-HT2A . Whether these different pharmacological actions produce different effects on brain structure remains unclear . We explored the effects of different types of antipsychotic treatment on brain structure in an epidemiologically based , nonr and omized sample of patients at the first psychotic episode . Subjects were recruited as part of a large epidemiological study ( ÆSOP : aetiology and ethnicity in schizophrenia and other psychoses ) . We evaluated 22 drug-free patients , 32 on treatment with typical antipsychotics and 30 with atypical antipsychotics .  We used high-resolution MRI and voxel-based methods of image analysis . The MRI analysis suggested that both typical and atypical antipsychotics are associated with brain changes . However , typicals seem to affect more extensively the basal ganglia ( enlargement of the putamen ) and cortical areas ( reductions of lobulus para central is , anterior cingulate gyrus , superior and medial frontal gyri , superior and middle temporal gyri , insula , and precuneus ) , while atypical antipsychotics seem particularly associated with enlargement of the thalami . These changes are likely to reflect the effect of antipsychotics on the brain , as there were no differences in duration of illness , total symptoms scores , and length of treatment among the groups . In conclusion , we would like to suggest that even after short-term treatment , typical and atypical antipsychotics may affect brain structure differently The 24-hour urinary serotonin ( 5-HT ) and 5-hydroxyindoleacetic acid ( 5-HIAA ) outputs were repeatedly measured in 21 patients with major affective disorders after a minimum of three weeks free of drug treatments and at steady state during subsequent antidepressant treatments or during the second week after a series of electroconvulsive treatments ( ECTs ) .  The 5-HIAA outputs were more variable over time than the outputs of major catecholamine metabolites , previously studied by us . Patients with rapid mood cycles excreted large amounts of 5-HT .  Lithium carbonate and ECTs  reduced the outputs of 5-HT and 5-HIAA , respectively . Lithium carbonate also stabilized the output of 5-HT . No common effect of different antidepressant treatments on indole outputs was found Rationale Attentional deficits are common symptoms in schizophrenia . Recent evidence suggests that schizophrenic patients show abnormalities in spatial orienting of attention , particularly a deficit of inhibition of return ( IOR ) . IOR is mostly thought to reflect an automatic , inhibitory mechanism protecting the organism from redirecting attention to previously scanned , insignificant locations . Pharmacologic challenges with hallucinogens have been used as models for psychosis . Objectives The aim of this study was to investigate the neural correlates underlying orienting of attention in the human N-methyl-d-aspartic acid antagonist and 5-HT2A agonist models of psychosis . Material s and methods Fourteen healthy volunteers participated in a r and omized , double-blind , cross-over event-related functional magnetic resonance imaging ( fMRI ) study with dimethyltryptamine ( DMT ) and S-ketamine . We administered a covert orienting of attention task with nonpredictive peripheral cues , and we scanned the subjects on two separate days at least 14 days apart with a placebo and a verum condition on each day . Results DMT , but not S-ketamine , slowed down reaction times significantly . IOR was blunted after DMT , but not after S-ketamine . Relative to placebo , S-ketamine increased activation in the IOR condition in the right superior frontal gyrus , left superior temporal gyrus , and right midfrontal frontal gyrus . Conclusions The discrepancy between the behavioral and functional imaging outcome indicates that pharmacological fMRI might be a sensitive tool to detect drug-modulated blood oxygenation level-dependent signal changes in the absence of behavioral abnormalities . Our findings might help to further clarify the contradictory findings of IOR in schizophrenic patients and might , thus , shed more light on possible differential pathomechanisms of schizophrenic symptoms Rationale Amplitude , habituation and prepulse inhibition ( PPI ) of the acoustic startle response ( ASR ) in rodents and humans are sensitive to psychotropic drugs . Studies with rodents suggest that an increase or decrease in serotonin level in the brain alters several modalities of the ASR . So far , little is known about serotonergic and noradrenergic startle modulation in humans . Objective This study was design ed to investigate the effects of the selective serotonin uptake inhibitor sertraline versus the selective noradrenalin uptake inhibitor reboxetine on magnitude , habituation and PPI of ASR in patients with major depression . Methods We studied ASR in 23 patients with the diagnosis of major depression according to DSM-IV who were r and omly treated either with sertraline or with reboxetine .  Initially , ASR assessment was carried out when patients were drug-free for at least 2 weeks and again after 14 days of treatment . Results The habituation of ASR was strongly attenuated by sertraline and not significantly altered by reboxetine . None of the substances altered the startle reactivity . In addition , PPI was not altered by sertraline , but reboxetine tended to decrease PPI . The startle reactivity at baseline was correlated with improvement of depressive symptoms at the end of the study . Conclusion These results provide the first evidence for different effects of noradrenergic and serotonergic antidepressants on the startle response in depressed patients In order to evaluate serotonin ( 5-HT ) function in panic disorder , a double blind placebo controlled study was conducted with ritanserin , a specific 5-HT2 receptor antagonist , and fluvoxamine , a selective 5-HT reuptake inhibitor , in 60 patients with panic disorder . Patients were treated for 8 weeks with 150 mg fluvoxamine , 20 mg ritanserin or placebo ; these dose levels were reached after 1 week . In addition , as an index of 5-HT function in panic disorder , plasma concentration of β-endorphin , cortisol and 5-hydroxyindolacetic-acid ( 5-HIAA ) were measured . Furthermore , 5-HT uptake in blood platelets was assessed . Noradrenergic function was assessed by measuring plasma MHPG concentration . In addition , plasma melatonin concentration was measured . Treatment with fluvoxamine result ed in a profound reduction in the number of panic attacks , followed by a decrease in avoidance behavior . Treatment with ritanserin appeared to be ineffective . During treatment no significant changes were observed in plasma concentrations of β-endorphin , cortisol , 5-HIAA and MHPG . With respect to 5-HT kinetics in blood platelets , a substantial increase in Km was observed after treatment with fluvoxamine , whereas Vmax decreased . After treatment with fluvoxamine , plasma concentration of melatonin was significantly increased , which suggests that melatonin synthesis is in part under serotonergic control . The findings of the present study do not support the hypothesis that 5-HT2 receptors are supersensitive in patients suffering from panic disorder , but allow no conclusions about the involvement of other 5-HT receptor subtypes BACKGROUND We investigated the differential effects of serotonergic and noradrenergic antidepressants on brain activation in patients with major depressive disorder during a Stroop task . We predicted that pretreatment hyperactivity in the rostral anterior cingulate cortex would predict better treatment outcomes . METHODS In total , 20 patients underwent naturalistic open-label clinical treatment with citalopram ( n = 12 ) or reboxetine ( n = 8) . We performed functional magnetic resonance imaging at baseline and after 6 weeks of treatment . RESULTS There were no significant group differences in clinical characteristics , treatment outcomes or baseline fMRI activations . The group by time interaction revealed significant voxels in the right amygdala-hippocampus complex ( p < 0.05 , family-wise error corrected by use of the bilateral amygdala and hippocampus mask image as a small volume ) , indicating a posttreatment blood oxygen level- dependent signal decrease in the citalopram group . Pretreatment hyperactivity in the rostral anterior cingulate cortex was not related to symptom improvement . LIMITATIONS Our study was a nonr and omized clinical trial . CONCLUSION These results indicate that serotonergic and noradrenergic antidepressants have a differential effect on brain activity , especially in the amygdala and hippocampus
Long-term use was associated with thinning of the posterior cingulate cortex , thickening of the anterior cingulate cortex , and decreased neocortical 5-HT2A receptor binding .
Despite the high method ological heterogeneity and the small sample sizes , the results suggest that hallucinogens increase introspection and positive mood by modulating brain activity in the fronto-temporo-parieto-occipital cortex
Serotonergic hallucinogens produce alterations of perceptions , mood , and cognition , and have anxiolytic , antidepressant , and antiaddictive properties .
These drugs act as agonists of frontocortical 5-HT2A receptors , but the neural basis of their effects are not well understood .
Thus , we conducted a systematic review of neuroimaging studies analyzing the effects of serotonergic hallucinogens in man .