Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans.

N-methyl-D-aspartate glutamate receptor (NMDA-R) antagonists produce schizophrenia-like positive and negative symptoms in healthy human subjects. Preclinical research suggests that NMDA-R antagonists interfere with the function of gamma-aminobutyric acid (GABA) neurons and alter the brain oscillations. These changes have been hypothesized to contribute to psychosis. In this investigation, we evaluated the hypothesis that the NMDA-R antagonist ketamine produces alterations in cortical functional connectivity during rest that are related to symptoms. We administered ketamine to a primary sample of 22 subjects and to an additional, partially overlapping, sample of 12 subjects. Symptoms before and after the experimental session were rated with the Positive and Negative Syndrome Scale (PANSS). In the primary sample, functional connectivity was measured via functional magnetic resonance imaging almost immediately after infusion began. In the additional sample, this assessment was repeated after 45 min of continuous ketamine infusion. Global, enhanced functional connectivity was observed at both timepoints, and this hyperconnectivity was related to symptoms in a region-specific manner. This study supports the hypothesis that pathological increases in resting brain functional connectivity contribute to the emergence of positive and negative symptoms associated with schizophrenia.

A single-day paradigm of self-regulated human cocaine administration.

UNLABELLED: Prior work by our group has shown the feasibility, safety, and validity of a multi-day, multi-dose paradigm of self-regulated cocaine administration in humans. The current work sought to consolidate these methods in a single-day design focused on reducing logistical complexity, decreasing research burden to human subjects, and increasing suitability for medication development designs. METHODS: Eleven experienced cocaine users participated in a 6-hour, single-day design, consisting of one safety/eligibility and three experimental cocaine periods (during which subjects were allowed to self-administer 8, 16, and 32 mg/70 kg cocaine doses under a fixed-ratio 1:5 minute timeout schedule). Changes in cocaine-induced cardiovascular response, self-administration behavior, and subjective effects were assessed. RESULTS: Procedures were well tolerated by participants, and no significant adverse events were noted. Significant (p < 0.05), changes in measures of cocaine self-administration (e.g., responses, infusions, interinfusion intervals, consumption, and plasma levels), cardiovascular response (HR), and subjective effects ("high") were observed. In contrast, cocaine-induced increases in other vital signs (e.g., SBP, DBP) and subjective effect measures (e.g., paranoia) did not differ between doses. CONCLUSIONS: These data support the safety, tolerability and validity of our single-day design. Depending on the application, such methods may afford advantages for assessing the self-regulation of cocaine administration behavior in humans (e.g., including medication development designs).

Abnormal prefrontal activity subserving attentional control of emotion in remitted depressed patients during a working memory task with emotional distracters.

BACKGROUND: Patients with major depressive disorder (MDD) show deficits in processing of facial emotions that persist beyond recovery and cessation of treatment. Abnormalities in neural areas supporting attentional control and emotion processing in remitted depressed (rMDD) patients suggests that there may be enduring, trait-like abnormalities in key neural circuits at the interface of cognition and emotion, but this issue has not been studied systematically. METHOD: Nineteen euthymic, medication-free rMDD patients (mean age 33.6 years; mean duration of illness 34 months) and 20 age- and gender-matched healthy controls (HC; mean age 35.8 years) performed the Emotional Face N-Back (EFNBACK) task, a working memory task with emotional distracter stimuli. We used blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to measure neural activity in the dorsolateral (DLPFC) and ventrolateral prefrontal cortex (VLPFC), orbitofrontal cortex (OFC), ventral striatum and amygdala, using a region of interest (ROI) approach in SPM2. RESULTS: rMDD patients exhibited significantly greater activity relative to HC in the left DLPFC [Brodmann area (BA) 9/46] in response to negative emotional distracters during high working memory load. By contrast, rMDD patients exhibited significantly lower activity in the right DLPFC and left VLPFC compared to HC in response to positive emotional distracters during high working memory load. These effects occurred during accurate task performance. CONCLUSIONS: Remitted depressed patients may continue to exhibit attentional biases toward negative emotional information, reflected by greater recruitment of prefrontal regions implicated in attentional control in the context of negative emotional information.

Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [11C] DASB binding in the living human brain.

Studies in vitro suggest that the expression of the serotonin transporter (5-HTT) is regulated by polymorphic variation in the promoter region of the 5-HTT gene (5-HTTLPR); however, results from human brain imaging studies examining the relation between 5-HTT genotype and 5-HTT radioligand binding in vivo have been inconsistent. This inconsistency could reflect small participant numbers or the use of sub-optimal radiotracer for measuring the 5-HTT. We used positron emission tomography in conjunction with the selective 5-HTT ligand [(11)C] DASB to examine the availability of the 5-HTT in seven brain regions in 63 healthy European caucasian volunteers who were genotyped for short (S) and long (L) variants (SLC6A4 and rs25531) of the 5-HTTLPR. [(11)C] DASB binding potential was not influenced by the allelic status of participants whether classified on a biallelic or triallelic basis in any of the regions studied. Our PET findings, in a relatively large sample with a near optimal radiotracer, suggest that 5-HTTLPR polymorphic variation does not affect the availability of 5-HTT to [(11)C] DASB binding in adult human brain. The reported impact of 5-HTTLPR polymorphic variation on emotional processing and vulnerability to depression are more likely therefore to be expressed through effects exerted during neurodevelopment.

The 5-HT1B receptor: a novel target for the pathophysiology of depression.

The serotonergic (5-HT) system has been widely implicated in the pathophysiology of Major Depressive Disorder (MDD). Although the 5-HT system is a popular target for drug therapy in MDD the role that serotonin plays in MDD is not clearly understood. An abundance of research suggests that several 5-HT receptor subtypes may be dysfunctional in patients with MDD including the 5-HT(1B) receptor. Evidence implicating 5-HT(1B) receptors in the pathophysiology of depression comes from a number of converging lines of research. Two common genetic polymorphisms of 5-HT(1B) receptors, G861C and C129T, have been implicated in affective disorders. Rats predisposed to learned helplessness have exhibited downregulation of 5-HT(1B) receptor messenger ribonucleic acid (mRNA) in dorsal raphe nucleus (DRN). Pharmacological studies have demonstrated augmentation of extracellular 5-HT levels and antidepressant effects following administration of selective serotonin reuptake inhibitors (SSRIs) in the absence or blockade of 5-HT(1B) receptors. 5-HT(1B) receptor agonists administered alone or with antidepressants have been shown to be effective in preclinical models of depression. Recent interest has focused on p11, an s100 EF-hand protein family protein which colocalizes with 5-HT(1B) receptors. P11 plays a central role in the modulation of 5-HT(1B) receptor function and is dysregulated in preclinical models of depression and postmortem MDD samples. A review of the literature provides strong evidence that 5-HT(1B) receptors and related factors such as p11 are involved in the pathophysiology of depression. The following explores possible factors which may render the 5-HT(1B) receptor dysfunctional, resulting in susceptibility to depression. Implications of using the 5-HT(1B) receptor as a biomarker for vulnerability to MDD are discussed.

'It's not over when it's over': persistent neurobiological abnormalities in recovered depressed patients.

The tendency of major depression to recur is a leading problem in clinical management and is responsible for much of the illness burden. Until recently, biological studies of depression have focused on the mechanisms involved in acute illness but there are now many data to suggest that neurobiological abnormalities persist when depressed patients are clinically recovered and withdrawn from medication. These abnormalities encompass a number of neurochemical and neuropsychological mechanisms that could be relevant to recurrence, including changes in the availability of serotonin (5-hydroxytryptamine, 5-HT) receptor subtypes, decreases in cortical gamma-aminobutyric acid (GABA), increases in cortisol secretion and negative biases in the processing of emotional information. Studies of groups at high risk of depression before illness onset will help to clarify which biological abnormalities precede the development of depression and which are the product of recurrent illness. Ultimately this work should lead to a better understanding of the neurobiology of vulnerability to depression and more innovative approaches to primary and secondary prevention.

Inositol for depressive disorders.

BACKGROUND: There are a number of effective interventions for the treatment of depression. It is possible that the efficacy of these treatments will be improved further by the use of adjunctive therapies such as inositol. OBJECTIVES: 1. To determine the effectiveness of inositol in the treatment of depression.2. To determine the adverse effects and acceptability of treatment with inositol. SEARCH STRATEGY: The Cochrane Controlled Trials Register (CCTR), The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR) incorporating results of group searches of EMBASE, MEDLINE, LILACS, CINAHL, PSYNDEX and PsycLIT were searched. Reference lists of relevant papers and major textbooks of affective disorder were checked. Experts in the field and pharmaceutical companies were contacted regarding unpublished material. SELECTION CRITERIA: All randomised controlled trials that compare treatment with inositol, whether as monotherapy or adjunctive therapy, to an alternative treatment, whether another antidepressant medication or placebo, for patients with a diagnosis of depressive disorder (diagnosed according to explicit criteria). DATA COLLECTION AND ANALYSIS: Data were independently extracted from the original reports by two reviewers. Statistical analysis was conducted using Review Manager version 4.2.1. MAIN RESULTS: Four trials were identified, with a total of 141 participants. These were short term trials of double-blind design. The trials did not show clear evidence of a therapeutic benefit, nor any evidence of poor acceptability. REVIEWERS' CONCLUSIONS: It is currently unclear whether or not inositol is of benefit in the treatment of depression. Ongoing studies should reduce this uncertainty.

Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635.

Positron emission tomography (PET) studies with the selective 5-HT(1A) receptor ligand, [(11)C]WAY-100635, have indicated that the binding potential (BP) of brain 5-HT(1A) receptors is lowered in unmedicated subjects with acute major depression. However, it is unclear if these changes persist after recovery from depression. To resolve this issue, we used [(11)C]WAY-100635 in conjunction with PET imaging to compare 5-HT(1A) BP in 18 healthy controls and 14 male subjects with recurrent major depression who were clinically recovered and free of antidepressant medication. BP values, derived from a reference tissue model, were analysed by region of interest and statistical parametric mapping. Both analyses showed a widespread and substantial (17%) decrease in 5-HT(1A) receptor BP in cortical areas in the recovered depressed subjects. In contrast, 5-HT(1A) BP in the raphe nuclei did not distinguish depressed subjects from controls. Our results suggest a persistent dysfunction in cortical 5-HT(1A) BP as measured by [(11)C]WAY-100635 in recovered depressed men. Lowered 5-HT(1A) receptor binding availability could represent a trait abnormality that confers vulnerability to recurrent major depression.

Effects of beta-adrenoceptor blockade on components of human decision-making.

RATIONALE: Converging evidence from studies with neurological patients and brain imaging studies with healthy volunteers suggests that the capacity to make choices between actions associated with probabilistic rewards and punishments depends upon a network of cortico-limbic systems including the orbitofrontal cortex, cingulate cortex, amygdala and striatum. The involvement of such structures highlights the emotional aspects of decision-making and suggests that decision-making may be sensitive to manipulations of the catecholamine systems that innervate these structures. In this study, we investigated the possible role of noradrenaline (NA). OBJECTIVE: We examined the effects of a single oral 80 mg dose of the beta-adrenoceptor blocker, propranolol, on the decision-making of healthy volunteers in a double-blind, placebo-controlled, between-subjects design. METHODS: Seventeen volunteers ingested a placebo while 15 volunteers ingested propranolol. Visual analogue scales, and self-reported positive and negative ratings, were used to assess subjective changes and mood. Vital signs were also monitored. Seventy-five minutes after treatment, volunteers were asked to make a series of choices between two simultaneously presented gambles, differing in the magnitude of possible gains (i.e. reward), the magnitude of possible losses (i.e. punishment), and the probabilities with which these outcomes were delivered. Volunteers also chose between gambles probing identified non-cognitive biases in human decision-making, namely, risk-aversion when choosing between gains and risk-seeking when choosing between losses. RESULTS: Propranolol treatment did not result in gross changes in subjective state or mood in comparison to placebo, but did slow heart rate significantly. Propranolol produced a selective change in volunteers' decision-making; namely, it significantly reduced the discrimination between large and small possible losses when the probability of winning was relatively low and the probability of losing was high. CONCLUSIONS: These results suggest that NA modulates the processing of punishment signals when choosing between probabilistic rewards and punishments under conditions of increased arousal.

Contrasting effects of citalopram and reboxetine on waking salivary cortisol.

RATIONALE: Acute administration of antidepressants which potentiate serotonin (5-HT) and noradrenaline (NA) function stimulates the hypothalamic-pituitary-adrenal (HPA) axis and increases salivary free cortisol in healthy subjects. The effects of repeated antidepressant administration have been less studied, but the ability of such treatment to modulate HPA axis activity may be relevant to therapeutic effects. OBJECTIVE: The objective of the study was to assess the effect of short-term treatment with two different antidepressant medications on HPA axis activity. METHODS: We studied the effect of 6-day treatment with the selective serotonin re-uptake inhibitor (SSRI) citalopram (20 mg daily) and the selective noradrenaline re-uptake inhibitor, reboxetine (8 mg daily), on diurnal salivary cortisol in a parallel group, placebo-controlled, double-blind design. RESULTS: Citalopram significantly enhanced the increase in salivary cortisol produced by waking, while the effect of reboxetine treatment was indistinguishable from placebo. There was no change in basal salivary cortisol levels sampled in a standard pattern throughout the day. CONCLUSIONS: Short-term treatment with citalopram and reboxetine produced strikingly different effects on waking salivary cortisol, arguing against a common effect of antidepressant drugs on HPA axis function. Waking salivary cortisol may be a more reliable means of assessing the effects of antidepressant treatment on the HPA axis than a standard regime of basal salivary sampling.

Acute SSRI administration affects the processing of social cues in healthy volunteers.

Enhancement of serotonin neurotransmission plays an important role in the antidepressant response to agents presently available to treat depression. This response forms the major evidence for the role of serotonin in affective and social behaviour in humans. The present study investigated the effects of acute administration of the selective serotonin reuptake inhibitor (SSR1), citalopram (10 mg, i.v.) upon a measure of emotional processing in healthy female volunteers. Subjects completed a facial expression recognition task following infusion of citalopram or saline (between-subjects design, double-blind). Facial expressions associated with five basic emotions--happiness, sadness, fearfulness, anger and disgust--were displayed. Each face had been 'morphed' between neutral (0%) and each emotional standard (100%) in 10% steps, leading to a range of emotional intensities. Mood and subjective experience were also monitored throughout the testing session. Volunteers receiving citalopram detected a higher number of facial expressions of fear and happiness, with reduced response times, relative to those given the placebo. By contrast, changes in the recognition of other basic emotions were not observed following citalopram. Notable differences in mood were also not apparent in these volunteers. These results suggest that acute administration of antidepressant drugs may affect neural processes involved in the processing of social information. This effect may represent an early acute effect of SSRIs on social and emotional processing that is relevant to their therapeutic actions.

Acute citalopram administration produces correlated increases in plasma and salivary cortisol.

RATIONALE: Intravenous administration of the selective serotonin (5-HT) re-uptake inhibitor, citalopram, increases plasma cortisol. This would be expected to produce a parallel increase in salivary cortisol concentration. OBJECTIVE: To find out whether IV citalopram produces correlated increases in plasma and salivary cortisol levels. METHODS: Twelve healthy volunteers were tested on two occasions receiving either citalopram (10 mg IV) or saline in a double-blind, randomised, cross-over design. Plasma and salivary cortisol levels were measured before and for 150 min after each infusion. RESULTS: Relative to placebo, citalopram significantly increased cortisol levels in both plasma and saliva. The size of the increases in plasma and saliva cortisol correlated significantly with each other. CONCLUSIONS: Monitoring changes in salivary cortisol might be a valid and acceptable means of measuring 5-HT-mediated cortisol release.

Pindolol augmentation of selective serotonin reuptake inhibitors: PET evidence that the dose used in clinical trials is too low.

OBJECTIVE: Positron emission tomography (PET) was used to examine whether the dose of pindolol used to augment antidepressant medication achieves a significant occupancy of the serotonin type 1A (5-HT(1A)) autoreceptor in depressed patients receiving medication. METHOD: The authors examined eight depressed patients on one of two regimes of pindolol (2.5 mg t.i.d. and 5.0 mg t.i.d.) with PET and [11C]WAY-100635. RESULTS: The 5-mg t.i.d. regime achieved a modest (19%) but significant occupancy of the 5-HT(1A) autoreceptor, while the regime used in the vast majority of clinical trials (2.5 mg t.i.d.) did not achieve a significant occupancy. CONCLUSIONS: The dose of pindolol used in clinical trials is suboptimal and may explain the inconsistent results. Therefore, a thorough test of pindolol's efficacy will necessitate doses higher than those used in present clinical trials.

PET measurement of the influence of corticosteroids on serotonin-1A receptor number.

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis and serotonergic system interact functionally. The modulatory effect of corticosteroids on 5-HT(1A) receptor number and function has been repeatedly demonstrated in preclinical studies suggesting that raised corticosteroid levels decrease 5-HT(1A) receptor number and function in the hippocampus. METHODS: We used positron emission tomography (PET) to quantify the number of 5-HT(1A) receptors in two studies, the first in normal subjects given a single dose of hydrocortisone using a random-order, double-blind, placebo-controlled design and second in patients treated long-term with corticosteroids. RESULTS: We did not find that exposure to elevated levels of corticosteroids in either the short or long term alters 5-HT(1A) receptor binding in the hippocampus or other brain regions examined. CONCLUSIONS: This study does not support the hypothesis that corticosteroids exert a major inhibitory regulatory control over the 5-HT(1A) receptor binding in the human brain.

Decreased sensitivity of 5-HT(1D) receptors in melancholic depression.

BACKGROUND: Brain serotonin (5-HT) function is abnormal in major depression, but the involvement of different 5-HT receptor subtypes has been little studied. The availability of selective ligands now makes it possible to test the sensitivity of 5-HT(1D) receptors in patients with depression. AIMS: The aim of the study was to use the 5-HT(1D) receptor agonist, zolmitriptan, to test the sensitivity of 5-HT(1D) receptors in patients with depression before and after treatment with selective serotonin reuptake inhibitors (SSRIs). METHOD: We measured the growth hormone response to zolmitriptan (5 mg orally) in patients with major depression before and after SSRI treatment. A matched sample of healthy subjects acted as a control group. RESULTS: The growth hormone response to zolmitriptan was blunted in patients with a melancholic depressive syndrome. SSRI treatment produced a marked reduction in zolmitriptan-induced growth hormone release. CONCLUSIONS: Patients with melancholic depression have impaired sensitivity of the post-synaptic 5-HT(1D) receptors that mediate growth hormone release. The reduction in 5-HT(1D) receptor sensitivity following SSRI treatment is probably an adaptive response to increased levels of synaptic 5-HT.

Modelling a loss event: effect of imagined bereavement on the hypothalamic-pituitary-adrenal axis.

BACKGROUND: Loss events are the stressors most closely associated with the onset of depressive illnesses. The acute cortisol response to loss has been little studied although it could be an important mediator of the effects of environmental stress on psychological state. METHODS: The salivary cortisol response to an established negative mood induction procedure involving music and an imagined bereavement was measured in 30 healthy volunteers. RESULTS: Considerable but transient mood lowering in response to the negative mood induction was associated with a small increase in cortisol output over 30 min. CONCLUSIONS: This procedure has some potential as a tool to investigate individual differences in the neuroendocrine response to loss events, but this is limited. There remains a need for laboratory models of relevant psychosocial stressors in mood disorders research.

Zolmitriptan-induced growth hormone release in humans: mediation by 5-HT1D receptors?

RATIONALE: Effective neuroendocrine probes of 5-HT1B and 5-HT1D receptor function may facilitate investigation of the role of these receptor subtypes in the pathophysiology of depression and the mode of action of antidepressant medication. OBJECTIVE: To investigate the neuroendocrine profile of the 5-HT1B/1D receptor agonist, zolmitriptan, in healthy volunteers. METHODS: Twelve subjects entered a double-blind, placebo-controlled, cross-over design study of zolmitriptan (5 mg orally). Blood samples were taken at 15-min intervals for assay of prolactin and growth hormone. A further six healthy men were recruited to an equivalent study to examine the effect of ketanserin (a 5-HT receptor antagonist with some preference for 5-HT1D over 5-HT1B receptors) on the growth hormone response to zolmitriptan. RESULTS: Zolmitriptan significantly increased plasma growth hormone but had no effect on plasma prolactin or oral temperature. The increase in growth hormone produced by zolmitriptan was significantly attenuated by ketanserin. CONCLUSIONS: We suggest that the ability of triptans such as zolmitriptan, sumatriptan and rizatriptan to increase plasma growth hormone is mediated by their common agonist activity at postsynaptic 5-HT1D receptors.