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It has been over 50 years since the original serotonin hypothesis was proposed by the British Psychiatrist Alec Coppen. Recently, some authors have questioned the validity of the hypothesis. In this narrative review, we summarise the evidence for the serotonin hypothesis of depression, focusing on psychopharmacology and molecular imaging, as well as systems-level neuroscience. [ABSTRACT FROM AUTHOR]

Depression has a large burden, but the development of new drugs for its treatment has proved difficult. Progresses in neuroscience have highlighted several physiopathological pathways, notably inflammatory and metabolic ones, likely involved in the genesis of depressive symptoms. A novel strategy proposes to repurpose established medical treatments of known safety and to investigate their potential antidepressant activity. Among numerous candidates, growing evidence suggests that statins may have a positive role in the treatment of depressive disorders, although some have raised concerns about possible depressogenic effects of these widely prescribed medications. This narrative review summarises relevant findings from translational studies implicating many interconnected neurobiological and neuropsychological, cardiovascular, endocrine-metabolic, and immunological mechanisms by which statins could influence mood. Also, the most recent clinical investigations on the effects of statins in depression are presented. Overall, the use of statins for the treatment of depressive symptoms cannot be recommended based on the available literature, though this might change as several larger, methodologically robust studies are being conducted. Nevertheless, statins can already be acknowledged as a driver of innovation in mental health, as they provide a novel perspective to the physical health of people with depression and for the development of more precise antidepressant treatments. [ABSTRACT FROM AUTHOR]

Ebselen is an organoselenium compound developed as an antioxidant and subsequently shown to be a glutathione peroxidase (GPx) mimetic. Ebselen shows some efficacy in post-stroke neuroprotection and is currently in trial for the treatment and prevention of hearing loss, Meniere's Disease and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In vitro screening studies show that ebselen is also an effective inhibitor of the enzyme inositol monophosphatase (IMPase), which is a key target of the mood-stabilising drug lithium. Further, in animal experimental studies, ebselen produces effects on the serotonin system very similar to those of lithium and also decreases behavioural impulsivity. The antidepressant effects of lithium in treatment-resistant depression (TRD) have been attributed to its ability to facilitate presynaptic serotonin activity; this suggests that ebselen might also have a therapeutic role in this condition. Human studies utilising magnetic resonance spectroscopy support the notion that ebselen, at therapeutic doses, inhibits IMPase in the human brain. Moreover, neuropsychological studies support an antidepressant profile for ebselen based on positive effects on emotional processing and reward seeking. Ebselen also lowers a human laboratory measure of impulsivity, a property that has been associated with lithium's anti-suicidal effects in patients with mood disorders. Current clinical studies are directed towards assessment of the neuropsychological effects of ebselen in TRD patients. It will also be important to ascertain whether ebselen is able to lower impulsivity and suicidal behaviour in clinical populations. The objective of this review is to summarise the developmental history, pre-clinical and clinical psychopharmacological properties of ebselen in psychiatric disorders and its potential application as a treatment for TRD. [ABSTRACT FROM AUTHOR]

Background: The neurocognitive model of antidepressant treatment in depression states that antidepressants work by producing relatively immediate positive shifts in emotional processing, which translate into clinical improvement with time. St John's Wort has shown antidepressant potential in randomised controlled trials; however, its pharmacological actions are broad and it is unknown whether treatment also produces changes in emotional processing.Aims: We investigated whether short-term treatment with St John's wort has similar effects on emotional processing to those reported with other antidepressants such as selective serotonergic reuptake inhibitors.Methods: Forty-eight healthy participants were given St John's wort or placebo treatment for seven days. On day 7 they completed a battery of tasks to measure emotional processing and other elements of cognition.Results: St John's wort treatment produced similar changes to other antidepressants, for example reducing recognition of disgusted faces and attention to fearful faces, while increasing memory for positive words. We failed to find evidence for an effect of St John's wort on other aspects of cognition including working memory.Conclusions: These findings lend support to the theory that the production of early positive biases in emotional processing may be a common feature of all clinically effective antidepressants with diverse pharmacological mechanisms. [ABSTRACT FROM AUTHOR]

Background: Antidepressants are licensed for use in depressive disorders, but non-response and poor adherence to treatment affect a considerable number of patients. Pre-clinical and clinical evidence suggest that statins can augment the effects of antidepressants. However, the acceptability and tolerability of combining statins with antidepressants are unclear, and their add-on efficacy has only been shown in small, short-term clinical trials. Observational data can provide complementary information about treatment effects on larger samples over longer follow-ups. In this study, we therefore assessed the real-world acceptability, tolerability, and efficacy of concomitant antidepressant and statin treatment in depression. Methods: We conducted a population-based cohort study investigating QResearch primary care research database, which comprises the anonymised electronic healthcare records of 35 + million patients over 1574 English general practices. Patients aged 18–100 years, registered between January 1998 and August 2020, diagnosed with a new episode of depression, and commencing an antidepressant were included. Using a between-subject design, we identified two study groups: antidepressant + statin versus antidepressant-only prescriptions. Outcomes of interest included the following: antidepressant treatment discontinuations due to any cause (acceptability) and due to any adverse event (tolerability) and effects on depressive symptoms (efficacy) measured as response, remission, and change in depression score on the Patient Health Questionnaire-9. All outcomes were assessed at 2, 6, and 12 months using multivariable regression analyses, adjusted for relevant confounders, to calculate adjusted odds ratios (aORs) or mean differences (aMDs) with 99% confidence intervals (99% CIs). Results: Compared to antidepressant-only (N 626,335), antidepressant + statin (N 46,482) was associated with higher antidepressant treatment acceptability (aOR2months 0.88, 99% CI 0.85 to 0.91; aOR6months 0.81, 99% CI 0.79 to 0.84; aOR12months 0.78, 99% CI 0.75 to 0.81) and tolerability (aOR2months 0.92, 99% CI 0.87 to 0.98; aOR6months 0.94, 99% CI 0.89 to 0.99, though not long term aOR12 months 1.02, 99% CI 0.97 to 1.06). Efficacy did not differ between groups (range aOR2-12 months 1.00 and 1.02 for response and remission, range aOR2-12 months − 0.01 and − 0.02 for change in depression score). Conclusions: On real-world data, there is a positive correlation between antidepressant treatment adherence and statin use, partly explained by fewer dropouts due to adverse events. The main limitation of our study is its observational design, which restricts the potential to make causal inferences. [ABSTRACT FROM AUTHOR]

Neuroendocrine and neurochemical theories of depression continued to be of importance in understanding pathophysiology and suggesting new kinds of pharmacological intervention. Monoamine theories still dominate the neurochemistry of depression and results from monoamine depletion studies suggest that in certain circumstances lowered activity of serotonin and noradrenaline pathways can indeed lead to clinical depressive symptomatology. More recent developments have implicated changes in the amino acid neurotransmitters, GABA and glutamate, in depressed patients; the ability of the NMDA receptor antagonist, ketamine, rapidly to relieve depressive symptomatology has been a spur to much basic research on the cellular mechanism of glutamatergic antidepressant action. The link between inflammation and depression has led to new kinds of immunological investigations in depressed patients and the possibility of targeted anti-inflammatory treatments. Finally HPA axis abnormalities remain a focus of interest, particularly from the point of view of the many medical co-morbidities which frequently complicate chronic depressive disorders. [ABSTRACT FROM AUTHOR]

Persistent major depression that does not respond to adequate first- or second-line treatment is a common problem in psychiatry. This article updates evidence on recommended treatment strategies and reviews the prospects of more experimental approaches. The main pharmacological development in recent years has been the demonstration that several atypical antipsychotic drugs are effective adjunctive agents in improving symptoms in depression unresponsive to selective serotonin reuptake inhibitors, although their adverse effect burden is high. There is optimism about novel pharmacological strategies based on glutamatergic and anti-inflammatory mechanisms. It is important to combine drug and psychological treatments whenever possible. With persistent therapeutic engagement, the majority of patients remit eventually, but subsequent relapse remains a problem. Clinicians should pursue an active and collaborative treatment plan that makes use of all effective therapeutic modalities and continues into the relapse-prevention phase. LEARNING OBJECTIVES • Be aware of the concept of treatment-resistant depression as a staged condition and of the limitations of this concept • Update knowledge of the efficacy of recommended treatments for resistant depression, including new pharmacological and brain stimulation approaches • Be aware of the need for persistent therapeutic engagement and time-limited treatment trials to achieve remission and prevent relapse DECLARATION OF INTEREST P.J.C. has been a member of a Lundbeck advisory board. I.M.A. has been a member of advisory boards to Lundbeck, Servier and Alkermes. [ABSTRACT FROM AUTHOR]

Clinical depression is a common, debilitating and heterogenous disorder. Existing treatments for depression are inadequate for a significant minority of patients and new approaches are urgently needed. A wealth of evidence implicates the serotonin 1A (5-HT1A) receptor in the pathophysiology of depression. Stimulation of the 5-HT1A receptor is an existing therapeutic target for treating depression and anxiety, using drugs such as buspirone and tandospirone. However, activation of 5-HT1A raphe autoreceptors has also been suggested to be responsible for the delay in the therapeutic action of conventional antidepressants such as selective serotonin reuptake inhibitors (SSRIs). This narrative review provides a brief overview of the 5-HT1A receptor, the evidence implicating it in depression and in the effects of conventional antidepressant treatment. We highlight that pre- and post-synaptic 5-HT1A receptors may have divergent roles in the pathophysiology and treatment of depression. To date, developing this understanding to progress therapeutic discovery has been limited, partly due to a paucity of specific pharmacological probes suitable for use in humans. The development of 5-HT1A 'biased agonism', using compounds such as NLX-101, offers the opportunity to further elucidate the roles of pre- and post-synaptic 5-HT1A receptors. We describe how experimental medicine approaches can be helpful in profiling the effects of 5-HT1A receptor modulation on the different clinical domains of depression, and outline some potential neurocognitive models that could be used to test the effects of 5-HT1A biased agonists. [ABSTRACT FROM AUTHOR]

The fact that selective serotonin reuptake inhibitors (SSRIs) have antidepressant effects in some patients supports the notion that serotonin plays a role in the mode of action of antidepressant drugs. However, neither the way in which serotonin may alleviate depressed mood nor the reason why several weeks needs to elapse before the full antidepressant effect of treatment is expressed is known. Here, we propose a neuropsychological theory of SSRI antidepressant action based on the ability of SSRIs to produce positive biases in the processing of emotional information. Both behavioural and neuroimaging studies show that SSRI administration produces positive biases in attention, appraisal and memory from the earliest stages of treatment, well before the time that clinical improvement in mood becomes apparent. We suggest that the delay in the clinical effect of SSRIs can be explained by the time needed for this positive bias in implicit emotional processing to become apparent at a subjective, conscious level. This process is likely to involve the re-learning of emotional associations in a new, more positive emotional environment. This suggests intriguing links between the effect of SSRIs to promote synaptic plasticity and neurogenesis, and their ability to remediate negative emotional biases in depressed patients. [ABSTRACT FROM AUTHOR]

Current antidepressant agents are similar in efficacy to the original drugs discovered in the 1950s. The development of new treatments for depression is, however, limited by the absence of validated human biomarker models to predict efficacy, clinical profile and dosing. Such models need to meet key criteria for biomarkers including sensitivity, specificity and relevance to depression. Here we review studies exploring whether early changes in emotional processing with antidepressant drug administration meet these criteria. A large body of evidence suggests that changes in emotional memory are particularly relevant to depression and to antidepressant drug action whereas changes in attentional processing are sensitive to anxiolytic drugs. These tasks are not consistently affected by agents which have failed in clinical trials in depression, but do show changes in the predicted direction with agents associated either with amelioration or induction of symptoms. Hence, early assessment of novel drugs on emotional processing may predict likely clinical effects and dosing prior to randomized controlled trials. Greater validation is required to assess whether these effects are an obligatory component of effective treatment of depression and whether use of these models can improve the accuracy of go/no-go decisions in drug development. [ABSTRACT FROM PUBLISHER]

Mood disorders such as major depression are common illnesses with considerable morbidity and significant mortality. A long-standing theory is that a breakdown in brain serotonin (5-hydroxytryptamine; 5-HT) signalling is critically involved in the symptoms and drug treatment of clinical depression. However, the nature of this 5-HT defect has proved to be frustratingly elusive, and it remains unclear how the 5-HT signalling effects of antidepressant drugs might alter neuropsychological mechanisms to bring about relief of depressed mood. This article highlights recent discoveries that advance our understanding of how 5-HT-evoked changes at molecular, cellular and neuropsychological levels might interact to alleviate the symptoms of clinical depression. [ABSTRACT FROM AUTHOR]

Anhedonia, a loss of interest and pleasure in normally rewarding stimuli, is a key diagnostic criterion for major depression. It has been suggested that deficits in the processing of reward-relevant stimuli could represent an endophenotype for depression. We hypothesized that people at risk of depression by virtue of a personal history of the illness would show impaired neural responses to a primary rewarding stimulus. Using functional magnetic resonance imaging, we measured the neural response to the sight and flavor of chocolate, and their combination, in 13 unmedicated recovered patients with a history of major depression and 14 healthy controls matched for age and gender. We also examined a control aversive condition consisting of the sight of moldy strawberries and a corresponding unpleasant taste. Participants simultaneously recorded subjective ratings of “pleasantness,” “intensity,” and “wanting.” Despite no differences between the groups in stimulus ratings, patients showed decreased neural responses to the pleasant stimulus in the ventral striatum and increases in the caudate nucleus to the aversive stimulus. Furthermore, patients had a diminished neural supralinearity response (the potentiation produced by simultaneous presentation of the sight and flavor of the stimuli) in the prefrontal cortex for both aversive and pleasant conditions. Patients recovered from depression appear to have deficits in the neural basis of reward and may also have impairments in the cross-modal integration of sensory stimuli. These findings support the view that abnormal neural responses to reward may be an endophenotype for depression and a potential target for intervention and prevention strategies. [ABSTRACT FROM AUTHOR]

Emotional processing measures are sensitive to acute administration of clinically useful antidepressant drugs. We wished to test the hypothesis that these models would also be able to detect agents likely to cause depression as an adverse effect. The anti-obesity drug and cannabinoid type 1 receptor antagonist, rimonabant, is associated with significant rates of depression and anxiety in clinical use. Thirty healthy adult volunteers were randomly assigned to receive a single dose of rimonabant (20 mg) or lactose placebo in a double-blind, between-groups design. Three hours after medication administration, subjects undertook an emotional processing test battery including facial emotion recognition, emotional word attentional dot probe, self-relevant word classification, emotional and declarative memory and the emotion-potentiated acoustic startle response. Subjective state was assessed via self-report measures. A single dose of rimonabant did not alter subjective mood. However, rimonabant selectively reduced incidental recall of positive self-relevant adjectives, an effect contrary to that seen following the administration of antidepressants. There were no effects of rimonabant on the other measures of emotional processing. These results suggest that a single dose of rimonabant decreases positive emotional memory in the absence of changes in subjective state. Further studies are required to examine whether rimonabant might produce a wider range of negative emotional biases with repeated treatment. [ABSTRACT FROM AUTHOR]

The notion that impaired serotonin (5-HT) function can lead to clinical depression has a long history but is still controversial. Some have argued that the 5-HT hypothesis has been misused by the pharmaceutical industry to promote a simplistic biological model of depression to market selective serotonin reuptake inhibitors (SSRIs) to medical practitioners and the public. By contrast, there is now substantial evidence that unmedicated depressed patients have abnormalities in brain 5-HT function; however, the relation of these abnormalities to the clinical syndrome is unclear. The best evidence that 5-HT contributes to the pathophysiology of depression comes from studies of tryptophan depletion, which show that lowering brain 5-HT levels can induce acute symptomatic relapse in recovered depressed patients. Clarification of the mechanism of this effect will enable an understanding of how impaired 5-HT activity contributes to the subjective experience of depression. [Copyright &y& Elsevier]

Rationale. Acute depletion of brain tyrosine using a tyrosine-free amino acid mixture offers a nutritional approach to reduce central catecholamine function. Recent preclinical data suggest that tyrosine-free amino acid mixtures may have region-specific effects through targeting dopamine neurones. Objectives. Here we used fos immunocytochemistry to examine the neuroanatomical sites of action of a tyrosine-free amino acid mixture administered either alone or combined with amphetamine. Methods. Rats (male, Sprague Dawley, 240–260 g) were administered (IP) either a tyrosine-free amino acid mixture (1 g/kg), or the same mixture supplemented with tyrosine and phenylalanine (1 g/kg). Mixtures were injected twice (1 h apart) followed 1 h later by amphetamine (2 mg/kg SC). Two hours later, cardiac perfusion was performed and brains were processed for fos immunocytochemistry. Fos positive cells were counted using computer imaging software. Results. The tyrosine-free amino acid mixture alone did not alter fos expression in ten regions of the rat forebrain compared to saline controls. However, the mixture reduced the increase in fos expression evoked by amphetamine. This effect was region-specific and was greatest in caudate putamen, nucleus accumbens, bed nucleus stria terminalis and lateral habenula, and lacking in other areas including cingulate and insular cortices, lateral septum and central amygdaloid nucleus. Moreover, in most regions the effect of the tyrosine-free mixture was less after tyrosine and phenylalanine supplementation. Conclusions. In summary, a tyrosine-free amino acid mixture reduced amphetamine-induced fos expression but this effect was region-specific and included dopamine-rich regions. These data further support the idea that tyrosine depletion strategies have potential as treatments for mania and other hyperdopaminergic states. [ABSTRACT FROM AUTHOR]

Sex hormones have biological effects on inflammation, and these might contribute to the sex-specific features of depression. C-reactive protein (CRP) is the most widely used inflammatory biomarker and consistent evidence shows a significant proportion (20–30 %) of patients with major depressive disorder (MDD) have CRP levels above 3 mg/L, a threshold indicating at least low-grade inflammation. Here, we investigate the interplay between sex hormones and CRP in the cross-sectional, observational Biomarkers in Depression Study. We measured serum high-sensitivity (hs-)CRP, in 64 healthy controls and 178 MDD patients, subdivided into those with hs-CRP below 3 mg/L (low-CRP; 53 males, 72 females) and with hs-CRP above 3 mg/L (high-CRP; 19 males, 34 females). We also measured interleukin-6, testosterone, 17-β-estradiol (E2), progesterone, sex-hormone binding globulin (SHBG), follicle-stimulating and luteinising hormones, and calculated testosterone-to-E2 ratio (T/E2), free androgen and estradiol indexes (FAI, FEI), and testosterone secretion index. In males, high-CRP patients had lower testosterone than controls (p = 0.001), and lower testosterone (p = 0.013), T/E2 (p < 0.001), and higher FEI (p = 0.015) than low-CRP patients. In females, high-CRP patients showed lower SHGB levels than controls (p = 0.033) and low-CRP patients (p = 0.034). The differences in testosterone, T/E2 ratio, and FEI levels in males survived the Benjamini-Hochberg FDR correction. In linear regression analyses, testosterone (β = −1.069 p = 0.033) predicted CRP concentrations (R2 = 0.252 p = 0.002) in male patients, and SHBG predicted CRP levels (β = −0.628 p = 0.009, R2 = 0.172 p = 0.003) in female patients. These findings may guide future research investigating interactions between gonadal and immune systems in depression, and the potential of hormonal therapies in MDD with inflammation. • Males with MDD show decreased levels of testosterone and TSI. • Females with MDD and healthy controls have similar sex hormone levels. • Males with MDD with high-CRP have decreased levels of testosterone. • Females with MDD and high-CRP have decreased levels of SHBG. • In MDD, CRP levels are predicted by testosterone in males and by SHBG in females. [ABSTRACT FROM AUTHOR]

Abstract We report the effects of a tyrosine (and phenylalanine)-free amino acid mixture on tyrosine levels, ex vivo catecholamine synthesis and in vivo catecholamine release in brain regions of the rat. Administration of a tyrosine-free amino acid load reduced tissue levels of tyrosine (-50% after 2 h) in all brain regions examined (frontal cortex, hippocampus, striatum). The tyrosine-free amino acid mixture also reduced DOPA accumulation: this effect was most marked in striatum (-44%) and nucleus accumbens (-34%), areas with a predominantly dopaminergic innervation. Smaller decreases (-20-24%) were detected in other areas (cortex, hippocampus and hypothalamus). The effect on DOPA accumulation was prevented by supplementing the mixture with tyrosine/phenylalanine. The tyrosine-free amino acid mixture did not alter 5-HTP accumulation in any region. In microdialysis experiments, the tyrosine-free amino acid mixture did not consistently alter striatal extracellular dopamine under basal conditions but markedly, and dose-dependently, reduced the release of dopamine induced by amphetamine. In contrast, the tyrosine-free amino acid mixture did not alter either basal or amphetamine-evoked release of noradrenaline in hippocampus. Overall, these studies indicate that administration of a tyrosine-free amino acid mixture to rats depletes brain tyrosine to cause a decrease in regional brain catecholamine synthesis and release. Dopaminergic neurones appear to be more vulnerable to tyrosine depletion than noradrenergic neurones. [ABSTRACT FROM AUTHOR]

Objective: The present study aimed to 1) assess facial expression recognition in subjects with a previous history of major depressive disorder relative to subjects with no history of depression and 2) characterize the effects of acute citalopram infusion on recognition performance for both groups. Method: Unmedicated euthymic women with a history of major depression and matched comparison subjects with no history of depression were given a facial expression recognition task following intravenous infusion of saline or citalopram (10 mg) in a double-blind, between-group design. Results: Following saline infusion, subjects with a previous history of depression showed a selectively greater recognition of fear relative to the subjects with no history of depression. The abnormal fear processing observed in the subjects with a previous history of depression was normalized following citalopram infusion, an effect that was opposite to that seen with the subjects with no history of depression. Conclusions: These results suggest that increased recognition of fear is a trait vulnerability marker for depression and that this is normalized following a single dose of citalopram. [ABSTRACT FROM AUTHOR]

Background: Studies suggest that d-cycloserine (DCS) may have antidepressant potential through its interaction with the glycine site of the N-methyl-D-aspartate receptor; however, clinical evidence of DCS's efficacy as a treatment for depression is limited. Other evidence suggests that DCS affects emotional learning which may also be relevant for the treatment of depression and anxiety. The aim of the present investigation was to assess the effect of DCS on emotional processing in healthy volunteers and to further characterise its effects on emotional and autobiographical memory. Methods: Forty healthy volunteers were randomly allocated to a single dose of 250 mg DCS or placebo in a double-blind design. Three hours later, participants performed an Emotional Test Battery [including Facial Expression Recognition Task (FERT), Emotional Categorisation Task (ECAT), Emotional Recall Task (EREC), Facial Dot-Probe Task (FDOT) and Emotional Recognition Memory Task (EMEM)] and an Autobiographical Memory Test (AMT). Also, participants performed the FERT, EREC and AMT tasks again after 24 h in order to assess longer lasting effects of a single dose of DCS. Results: DCS did not significantly affect the FERT, EMEM and FDOT performance but significantly increased emotional memory and classification for positive words v. negative words. Also, DCS enhanced the retrieval of more specific autobiographical memories, and this effect persisted at 24 h. Conclusions: These findings support the suggestion that low-dose DCS increases specific autobiographical memory retrieval and positive emotional memory. Such effects make it an intriguing agent for further investigation in clinical depression, which is characterised by decreased autobiographical memory specificity and increased negative bias in memory recall. It also underscores the potential role of DCS as an adjunct to cognitive behavioural therapy in depression. [ABSTRACT FROM AUTHOR]

Background: Adolescent major depressive disorder (MDD) is associated with disrupted processing of emotional stimuli and difficulties in cognitive reappraisal. Little is known however about how current pharmacotherapies act to modulate the neural mechanisms underlying these key processes. The current study therefore investigated the neural effects of fluoxetine on emotional reactivity and cognitive reappraisal in adolescent depression. Methods: Thirty-one adolescents with MDD were randomised to acute fluoxetine (10 mg) or placebo. Seventeen healthy adolescents were also recruited but did not receive any treatment for ethical reasons. During functional magnetic resonance imaging (fMRI), participants viewed aversive images and were asked to either experience naturally the emotional state elicited ('Maintain') or to reinterpret the content of the pictures to reduce negative affect ('Reappraise'). Significant activations were identified using whole-brain analysis. Results: No significant group differences were seen when comparing Reappraise and Maintain conditions. However, when compared to healthy controls, depressed adolescents on placebo showed reduced visual activation to aversive pictures irrespective of the condition. The depressed adolescent group on fluoxetine showed the opposite pattern, i.e. increased visuo-cerebellar activity in response to aversive pictures, when compared to depressed adolescents on placebo. Conclusions: These data suggest that depression in adolescence may be associated with reduced visual processing of aversive imagery and that fluoxetine may act to reduce avoidance of such cues. This could reflect a key mechanism whereby depressed adolescents engage with negative cues previously avoided. Future research combining fMRI with eye-tracking is nonetheless needed to further clarify these effects. [ABSTRACT FROM AUTHOR]

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 [11C]Cimbi-36 is sensitive to increases in extracellular 5-HT induced by an acute d-amphetamine challenge. Here we applied [11C]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. 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 [11C]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. 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). 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. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Serotonin and Depression," by D. Healy in the April 21, 2015 issue.

The feasibility of using saliva samples as diagnostic for health status is assessed. Although blood is regularly used for this purpose, an alternative non-invasive route which yields equivalent clinical information is desirable. The non-invasive saliva testing is validated by comparing its result to that of blood examination. In this investigation, we used glutathione as a paradigmatic example of a biomarker and diagnostic auxiliary. Correlation between the levels of total unbound glutathione, reduced and oxidized, in saliva and whole blood samples from healthy individuals is evaluated. Both salivary and blood glutathione were measured using an enzymatic kinetic assay which was improved to eliminate measurement errors arising from the variation in the enzyme activity from different batches. [ABSTRACT FROM AUTHOR]

There has been increasing interest in the antidepressant effects of the muscarinic cholinergic receptor antagonist scopolamine. Here we assess, for the first time, whether a transdermal scopolamine patch is sufficient to induce changes in cognition that are consistent with the reported cognitive and antidepressant effects of scopolamine. A scopolamine or placebo patch was administered to healthy volunteers ( n=33) for 17 h in a double-blind, between-subject procedure. There was no clear effect of scopolamine patch on emotional cognition, verbal or working memory, suggesting that the effective dose of scopolamine available through the patch is too low to represent a viable antidepressant mechanism. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article on the relationship between modern psychiatry and bipolar II disorder that was published in a previous issue.

The article presents information on the effect of fluoxetene on minor depressive disorders. Fluoxetine significantly reduced depression compared with placebo at 12 weeks. Fluoxetine is effective and safe for the treatment of minor depressive disorder. There has been longstanding uncertainty about the value of antidepressant treatment in milder depressive states-that is, depressive conditions not possessing the required number of symptoms to meet DSM-IV criteria for major depressive episode. In DSM-IV, such conditions can be classified as minor depressive disorder, while in lCD-10 the term mild depressive episode is used.

Introduction: Statins have been proposed as a strategy for treating depression, but their benefit in the absence of concurrent antidepressant treatment is unclear. This meta-analysis investigated the antidepressant effects of statin monotherapy in the general population.Methods: We conducted a literature search of randomised controlled trials using any statin monotherapy versus any control condition for depressive symptoms. Our primary efficacy outcome was the mean value on any standardised scale for depression at study endpoint. We also measured efficacy at three further timepoints (<6 months, 6-12 months, >12 months), as well as acceptability, tolerability, and safety. Respectively, continuous and dichotomous outcomes were computed using standardised mean difference (SMD) or relative risk (RR) with 95% confidence intervals (CI) using a random-effect model.Results: Pooled analyses did not show that statin monotherapy improves depressive symptoms at endpoint (N = 2712 SMD = -0.18; 95% CI = -0.41 to 0.04), nor at any other specific timepoint. No difference between statins and control was identified for any of the other outcome measures.Discussion: These results differ from those of previous meta-analyses and, compounded by more recently available evidence, suggest that statins may not have intrinsic antidepressant properties, but may be useful for the management of depression in add-on to antidepressants.Limitations: Data from heterogeneous populations and using different statins were pooled, though several sensitivity and subgroup analyses were performed to account for that. PROSPERO registration: CRD42022306653. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=306653. [ABSTRACT FROM AUTHOR]

Rationale: Clinical studies suggest that the highly lipophilic, anti-inflammatory molecule, simvastatin, might be an ideal candidate for drug repurposing in the treatment of depression. The neuropsychological effects of simvastatin are not known, but their ascertainment would have significant translational value about simvastatin's influence on mood and cognition. Objectives: We aimed to investigate the effects of simvastatin on a battery of psychological tests and inflammatory markers in healthy volunteers. Methods: Fifty-three healthy subjects were randomly assigned to 7 days of either simvastatin (N = 27) or sucrose-based placebo (N = 26) given in a double-blind fashion. Then, participants were administered questionnaires measuring subjective rates of mood and anxiety, and a battery of tasks assessing emotional processing, reward learning, and verbal memory. Blood samples for C-reactive protein were also collected. Results: Compared to placebo, participants on simvastatin showed a higher number of positively valenced intrusions in the emotional recall task (F1,51 = 4.99, p = 0.03), but also an increase in anxiety scores (F1,51 = 5.37, p = 0.02). An exploratory analysis of the females' subgroup (N = 27) showed lower number of misclassifications as sad facial expression in the simvastatin arm (F1,25 = 6.60, p = 0.02). No further statistically significant changes could be observed on any of the other outcomes measured. Conclusions: We found limited evidence that 7-day simvastatin use in healthy volunteer induces a positive emotional bias while also being associated with an increase in anxiety, potentially reflecting the early effects of antidepressants in clinical practice. Such effect might be more evident in female subjects. Different drug dosages, treatment lengths, and sample selection need consideration in further experimental medicine and clinical studies. Trial registration: Clinicaltrials.gov: NCT04652089. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Changes in emotional processing have been shown following acute administration of a range of monoaminergic antidepressants, and may represent an important common neuropsychological mechanism underpinning their therapeutic effects. Tianeptine is an agent that challenges the traditional monoaminergic hypothesis of antidepressant action, though its exact mode of action remains controversial. Healthy volunteers were randomised to receive a single dose of tianeptine (12.5 mg) or placebo, and subsequently completed a battery of tasks measuring emotional processing, including facial expression recognition, emotional memory and attentional vigilance, as well as working and verbal memory. Tianeptine-treated subjects were less accurate at identifying facial expressions, though this was not valence specific. The tianeptine group also showed reduced positive affective memory and reduced attentional vigilance to positive stimuli. There were no effects on emotional categorization or non-emotional cognition. The negative biases in aspects of emotional processing observed following acute tianeptine administration are at variance with the positive biases generally seen after acute administration of conventional antidepressant drugs, despite tianeptine’s putative antidepressant efficacy. This is an intriguing finding in the context of the lack of consensus regarding tianeptine’s mechanism of action; however, it may be consistent with the reported ability of acute tianeptine to increase the re-uptake of serotonin. [ABSTRACT FROM AUTHOR]

Rationale: Bright light treatment (BLT) is an efficacious antidepressant intervention, but its mechanism of action is not well understood. Antidepressant drugs acutely affect how emotional information is processed, pushing the brain to prioritise positive relative to negative input. Whether BLT could have a similar effect is not known to date. Objective: To test whether BLT acutely influences emotional information processing similar to antidepressant drugs, using an established healthy volunteer assay. Methods: Following a double-blind, parallel-group design, 49 healthy volunteers (18–65 years, 26 females) were randomly allocated to 60-min BLT (≥ 10,000 lux) or sham-placebo treatment early in the morning in autumn/winter. Immediately after treatment, emotional information processing was assessed using the Oxford Emotional Test Battery, a validated set of behavioural tasks tapping into emotional information processing in different cognitive domains. Participants also completed questionnaires before and after treatment to assess changes in subjective state. Results: The BLT group did not show significantly more positively biased emotional information processing compared to the placebo group (p > 0.05 for all measures). After adjustment for pre-treatment scores, there were also no significant post-treatment differences between groups in subjective state (p > 0.05 for all measures). Conclusions: BLT did not show immediate effects on emotional information processing in an established healthy volunteer assay. Thus, BLT might exert its clinical effects through a different (cognitive) mechanism than other antidepressant interventions. Future studies should corroborate this finding including clinical populations and more intensive treatment regimes, and control for potential chronobiological effects. [ABSTRACT FROM AUTHOR]

Rationale: Chronic fatigue syndrome (CFS) is a common and burdensome illness with a poorly understood pathophysiology, though many of the characteristic symptoms are likely to be of brain origin. The use of high-field proton magnetic resonance spectroscopy (MRS) enables the detection of a range of brain neurochemicals relevant to aetiological processes that have been linked to CFS, for example, oxidative stress and mitochondrial dysfunction. Methods: We studied 22 CFS patients and 13 healthy controls who underwent MRS scanning at 7 T with a voxel placed in the anterior cingulate cortex. Neurometabolite concentrations were calculated using the unsuppressed water signal as a reference. Results: Compared to controls, CFS patients had lowered levels of glutathione, total creatine and myo-inositol in anterior cingulate cortex. However, when using N-acetylaspartate as a reference metabolite, only myo-inositol levels continued to be significantly lower in CFS participants. Conclusions: The changes in glutathione and creatine are consistent with the presence of oxidative and energetic stress in CFS patients and are potentially remediable by nutritional intervention. A reduction in myo-inositol would be consistent with glial dysfunction. However, the relationship of the neurochemical abnormalities to the causation of CFS remains to be established, and the current findings require prospective replication in a larger sample. [ABSTRACT FROM AUTHOR]

Background: Growing evidence from clinical trials and epidemiological studies suggests that statins can have clinically significant antidepressant effects, potentially related to anti-inflammatory action on several neurobiological structures. However, the underlying neuropsychological mechanisms of these effects remain unexplored. Aims: In this experimental medicine trial, we investigated the 7-day effects of the lipophilic statin, atorvastatin on a battery of neuropsychological tests and inflammation in healthy volunteers. Methods: Fifty healthy volunteers were randomised to either 7 days of atorvastatin 20 mg or placebo in a double-blind design. Participants were assessed with psychological questionnaires and a battery of well-validated behavioural tasks assessing emotional processing, which is sensitive to putative antidepressant effects, reward learning and verbal memory, as well as the inflammatory marker, C-reactive protein. Results: Compared to placebo, 7-day atorvastatin increased the recognition (p = 0.006), discriminability (p = 0.03) and misclassifications (p = 0.04) of fearful facial expression, independently from subjective states of mood and anxiety, and C-reactive protein levels. Otherwise, atorvastatin did not significantly affect any other psychological and behavioural measure, nor peripheral C-reactive protein. Conclusions: Our results reveal for the first time the early influence of atorvastatin on emotional cognition by increasing the processing of anxiety-related stimuli (i.e. increased recognition, discriminability and misclassifications of fearful facial expression) in healthy volunteers, in the absence of more general effects on negative affective bias. Further studies exploring the effects of statins in depressed patients, especially with raised inflammatory markers, may clarify this finding and inform future clinical trials. [ABSTRACT FROM AUTHOR]

Helping other people can entail risks for the helper. For example, when treating infectious patients, medical volunteers risk their own health. In such situations, decisions to help should depend on the individual's valuation of others' well-being (social preferences) and the degree of personal risk the individual finds acceptable (risk preferences). We investigated how these distinct preferences are psychologically and neurobiologically integrated when helping is risky. We used incentivized decision-making tasks (Study 1; N = 292 adults) and manipulated dopamine and norepinephrine levels in the brain by administering methylphenidate, atomoxetine, or a placebo (Study 2; N = 154 adults). We found that social and risk preferences are independent drivers of risky helping. Methylphenidate increased risky helping by selectively altering risk preferences rather than social preferences. Atomoxetine influenced neither risk preferences nor social preferences and did not affect risky helping. This suggests that methylphenidate-altered dopamine concentrations affect helping decisions that entail a risk to the helper. [ABSTRACT FROM AUTHOR]

Abstract: Background: [11C]MDL100,907 is a promising positron emission tomography (PET) ligand for 5-HT2A receptor quantification in vivo. Studies suggest that [11C]MDL100,907 PET may be quantified by non-invasive reference tissue analyses using cerebellum as reference region. We systematically investigated the validity of such analyses. Methods: Five healthy volunteers underwent [11C]MDL100,907 PET at baseline and after mirtazapine pre-treatment. Regional time–activity curves of 10 regions of interest (ROI) were analyzed for binding potential (BP ND) and mirtazapine receptor occupancy (Occ) using: simplified reference tissue model (SRTM), multi-linear reference tissue model (MRTM), their two-parameter versions (SRTM2/MRTM2), non-invasive graphical analysis (NIGA) and a tissue activity concentration ratio. NIGA was also applied voxel-wise to generate BP ND maps. These methods were compared with a two-tissue compartment model with arterial input function (2TCM) Results: SRTM and MRTM frequently failed to yield reliable results. SRTM2 and MRTM2 gave virtually identical estimates of BP ND, which were highly correlated with 2TCM analyses (R 2 ≥0.86) although with negative bias (−29±27% at baseline across all ROI). NIGA was less biased (−19±16%) and better correlated with 2TCM (R 2 ≥0.93). Regarding Occ, NIGA and SRTM2/MRTM2 showed comparable mean biases (−11±27% vs. −7±47%) but correlation with 2TCM was higher for NIGA (R 2 =0.90 vs. 0.77). NIGA parametric maps (analysed using identical ROI) resulted in moderate bias in BP ND (−26±22%; R 2 ≥0.88) and Occ (−17±36%; R 2 =0.78). Estimates obtained from tissue ratios performed least favourably. Conclusions: NIGA is well suited for analysis of [11C]MDL100,907 PET studies, yielding estimates of 5-HT2A receptor availability and changes that are highly correlated with results from invasive 2TCM analyses. This should greatly enhance the applicability of 5-HT2A receptor PET studies. [Copyright &y& Elsevier]

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 &y& Elsevier]

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 &y& Elsevier]

We investigated the impact of the administration of a tyrosine-depleting amino acid mixture compared to a balanced mixture on measures of mood, craving and selective processing of smoking-related cues in healthy cigarette smokers instructed to abstain from smoking for 12 h prior to, and during, the experiment. A modified Stroop task was used to index selective processing of smoking-related cues. We observed evidence for an increase in subjective craving among mates, and an attenuation of the selective processing of smoking-related cues compared to control cues among females, in the tyrosine-depleting condition compared to the balanced condition. No effects of mixture were observed on measures of subjective mood. These results tentatively support for the rote of dopaminergic neurotransmission in mediating the response of cigarette smokers to smoking-related cues. In addition, these results also provide further evidence for sex differences in the factors that maintain cigarette smoking, in particular with respect to conditioned reinforcement of smoking behaviour, and suggest that the relationship between subjective craving and selective processing of smoking-related cues may differ in mates and females. [ABSTRACT FROM AUTHOR]

Abstract: Drugs which inhibit the re-uptake of monoamines in the brain are effective in the treatment of depression; however, the neuropsychological mechanisms which lead to the resolution of depressive symptomatology are unclear. Behavioral studies in healthy volunteers suggest that acute administration of the selective norepinephrine reuptake inhibitor reboxetine modulates emotional processing. The current study therefore explored the neural basis of this effect. A single dose of reboxetine (4 mg) or placebo was administered to 24 healthy volunteers in a double-blind between-group design. Neural responses during categorisation and recognition of self-referent personality trait words were assessed using event-related functional Magnetic Resonance Imaging (fMRI). Reboxetine had no effect on neuronal response during self-referent categorisation of positive or negative personality trait words. However, in a subsequent memory test, reboxetine reduced neuronal activation in a fronto-parietal network during correct recognition of positive target words vs. matched distractors. This was combined with increased speed to recognize positive vs. negative words compared to control subjects and suggests facilitated memory for positive self-referent material. These results support the hypothesis that antidepressants have early effects on the neural processing of emotional material which may be important in their therapeutic actions. [Copyright &y& Elsevier]

The synthesis of serotonin (5-HT) in the central nervous system is dependent on the availability to the brain of its precursor amino acid, tryptophan (TRP). Recent studies suggest that alpha-lactalbumin, a whey-derived protein with a relatively high TRP content, increases plasma TRP and produces endocrine and cognitive changes consistent with facilitation of brain 5-HT function. In the present study we assessed the biochemical and cognitive effects of alpha-lactalbumin (40 g) in 28 healthy female subjects in a parallel group, placebo-controlled design. Relative to a casein-derived control protein, alpha-lactalbumin increased plasma TRP and the ratio of TRP to neutral amino acids. However, there was no effect on salivary cortisol secretion or tasks of emotional processing shown previously to be sensitive to pharmacological manipulation of 5-HT in healthy volunteers. The results suggest that alpha-lactalbumin produces a relatively modest increase in TRP availability which may not be sufficient to produce the changes in emotional processing seen with administration of pure TRP in healthy subjects. Further studies in subjects more vulnerable to stress are needed to assess the potential therapeutic effects of alpha-lactalbumin in clinical populations. [ABSTRACT FROM AUTHOR]

The synthesis of serotonin (5-HT) in the central nervous system is dependent on the availability to the brain of its precursor amino acid, tryptophan (TRP). Recent studies suggest that α-lactalbumin, a whey derived protein with a relatively high TRP content, increases plasma TRP and produces endocrine and cognitive changes consistent with facilitation of brain 5-HT function. In the present study we assessed the biochemical and cognitive effects of α-lactalbumin (40g) in 28 healthy female subjects in a parallel group, placebo-controlled design. Relative to a casein-derived control protein, α-lactalbumin increased plasma TRP and the ratio of TRP to neutral amino acids. However, there was no effect on salivary cortisol secretion or tasks of emotional processing shown previously to be sensitive to pharmacological manipulation of 5-HT in healthy volunteers. The results suggest that α-lactalbumin produces a relatively modest increase in TRP availability which may not be sufficient to produce the changes in emotional processing seen with administration of pure TRP in healthy subjects. Further studies in subjects more vulnerable to stress are needed to assess the potential therapeutic effects of α-lactalbumin in clinical populations. [ABSTRACT FROM AUTHOR]

Objective: Cortisol hypersecretion is one of the most reliable biological abnormalities in major depression, but it is uncertain if it represents an illness marker or a trait vulnerability to mood disorder. The present study sought to answer this question by measuring waking salivary cortisol levels in young people at familial risk of depression but with no personal history of mood disorder. Method: The authors studied 49 young people who had not been depressed themselves but who had a parent with a history of major depression (FH+) and a comparison group of 55 participants who had no personal history of depression and no reported depression in a first-degree relative. The authors measured the amount of cortisol secreted in saliva during the first 30 minutes after awakening on a workday and on a nonworkday. Results: The amount of cortisol secreted by the FH+ subjects was greater than that of the comparison subjects n both work- days (mean=698 nmolxminutes/liter, SD= 243, versus mean=550, SD=225) and non-workdays (mean=633 nmolxminutes/liter, SD=216, versus mean=492, SD=166). The increase in cortisol secretion was not accounted for by differences in parental attachment, life events, personality, or current mental state. Conclusions: Hypersecretion of cortisol can be detected in asymptomatic individuals at genetic risk of depression and may represent an illness endophenotype. Further studies will be needed to find out if increased waking salivary cortisol levels can predict individual risk of illness and whether the increased cortisol secretion has implications for general health and cognitive function. [ABSTRACT FROM AUTHOR]

The positron emission tomography (PET) ligand [11C]MDL 100,907 has previously been introduced to image the serotonin 2A (5-HT2A) receptor in human brain. The aim of this work was to contribute to the verification of the tracer kinetic modelling in human studies. Five healthy volunteers were scanned twice after intravenous bolus injection of approximately 370 MBq [11C]MDL 100,907 using dynamic PET. One scan was performed under baseline condition, the other scan commenced 90 mins after a single oral dose of 30 mg of the antidepressant mirtazapine, which binds to the 5-HT2A receptor. There did not appear to be radiolabelled metabolites of [11C]MDL 100,907 in human plasma, which are likely to cross the blood–brain barrier. Total volumes of distribution VD in 11 different brain regions were estimated using a reversible, two tissue, four rate constants compartment model with a variable fractional blood volume term and the metabolite-corrected plasma input function. There were no significant changes of the VD in the cerebellum between the baseline and the blocked scans confirming the cerebellum as a region devoid of displaceable binding. Regional estimates of binding potential were then obtained indirectly using the cerebellar VD and occupancies calculated. The mean occupancy with this clinically effective dose of mirtazapine was 60% without significant regional differences. This study confirmed the use of an arterial input kinetic model for the quantification of 5-HT2A receptor binding with [11C]MDL 100,907 and the use of the cerebellum as a reference region for the free and nonspecific binding.Journal of Cerebral Blood Flow & Metabolism (2007) 27, 161–172. doi:10.1038/sj.jcbfm.9600323; published online 10 May 2006 [ABSTRACT FROM AUTHOR]

Amphetamines are highly addictive drugs that have pronounced effects on emotional and cognitive behavior in humans. These effects are mediated through their potent dopaminergic agonistic properties. Dopamine has also been implicated in the modulation of responses of the ‘reward circuit’ in animal and human studies. In this study we use functional magnetic resonance imaging (fMRI) to identify the brain circuitry involved in the psychostimulant effect of methamphetamine in psychostimulant-naïve human subjects. Seven healthy volunteers were scanned in a 3T MR imaging system. They received single-blind intravenous infusions of methamphetamine (0.15 mg/kg), and rated their experience of ‘mind-racing’ on a button press throughout the experiment. Data were analyzed with statistical parametric mapping methods. Amphetamine administration activated the medial orbitofrontal cortex, the rostral part of the anterior cingulate cortex, and the ventral striatum. Ratings of ‘mind-racing’ after methamphetamine infusion correlated with activations in the rostral part of the anterior cingulate cortex and in the ventral striatum. In addition, activations in the medial orbitofrontal cortex were independent of motor and related responses involved in making the ratings. These findings indicate that the first administration of a psychostimulant to human subjects activates classical reward circuitry. Our data also support recent hypotheses suggesting a central role for the orbitofrontal cortex in drug reinforcement and the development of addiction. [ABSTRACT FROM AUTHOR]

Objective: Antidepressants that inhibit the reuptake of serotonin (SSRI5) or nor- epinephrine (SNRIs) are effective in the treatment of disorders such as depression and anxiety. Cognitive psychological theories emphasize the importance of correcting negative biases of information processing in the nonpharmacological treatment of these disorders, but it is not known whether antidepressant drugs can directly modulate the neural processing of affective information. The present study therefore assessed the actions of repeated antidepressant administration on perception and memory for positive and negative emotional information in healthy volunteers. Method: Forty-two male and female volunteers were randomly assigned to 7 days of double-blind intervention with the SSRI citalopram (20 mg/day), the SNRI reboxetine (8 mg/day), or placebo. On the final day, facial expression recognition, emotion-potentiated startle response, and memory for affect-laden words were assessed. Questionnaires monitoring mood, hostility, and anxiety were given before and after treatment. Results: In the facial expression recognition task, citalopram and reboxetine reduced the identification of the negative facial expressions of anger and fear. Citalopram also abolished the increased startle response found in the context of negative affective images. Both antidepressants increased the relative recall of positive (versus negative) emotional material. These changes in emotional processing occurred in the absence of significant differences in ratings of mood and anxiety. However, reboxetine decreased subjective ratings of hostility and elevated energy Conclusions: Short-term administration of two different antidepressant types had similar effects on emotion-related tasks in healthy volunteers, reducing the processing of negative relative to positive emotional material. Such effects of antidepresants may ameliorate the negative biases in information processing that characterize mood and anxiety disorders. They also suggest a mechanism of action potentially compatible with cognitive theories of anxiety and depression. [ABSTRACT FROM AUTHOR]