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Increased levels of inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-6 (IL-6) may play a role in depression. Mild depressive-like symptoms can be induced in humans through activation of the innate immune system with endotoxin. Whether preventive treatment with antidepressants can reduce endotoxin-induced symptoms has never been tested. In a doubleblind, randomized, placebo-controlled, cross-over study, we administered intravenous low-dose endotoxin (0.8 ng/kg) ordoi:10.1016/j.bbi.2010.10.013 pmid:20955776 pmcid:PMC3025065 fatcat:xzvhirrduvgijlcedjcenzaagu
more »... o to 11 healthy subjects who had received oral pre-treatment with citalopram (10 mg twice a day) or placebo for five days. The Montgomery-Åsberg Depression Rating Scale, the State and Trait Anxiety Inventory, and a visual analog scale were used to measure depressive and anxiety symptoms and social anhedonia. Serum levels of TNF and IL-6 were measured with immunoassays. Compared to placebo, endotoxin administration increased serum levels of TNF and IL-6, and caused mild depressive-like symptoms, in particular lassitude and social anhedonia. While citalopram pre-treatment had no effect on the innate immune response to endotoxin, it reduced the endotoxin-induced MADRS total score by 50%, with a moderate effect size (Cohen's d=0.5). Most of the MADRS total score was due to the Lassitude item, and citalopram pre-treatment specifically reduced endotoxin-induced lassitude with a large effect size (Cohen's d=0.9). These results suggest that subchronic pre-treatment with the serotonin-reuptake inhibitor citalopram blunts mood symptoms induced by acute immune system activation with endotoxin without inhibiting the peripheral immune response.
This version: [PrePrint] URL identifying the publication in the King's Portal: [https://kclpure.kcl.ac.uk/portal/en/publications/antidepressant-responseand-the-serotonin-transporter-genelinked-polymorphic-region(1c110784-d687-45e4-85fc-46ccf1c9229d).html] Antidepressant response and the serotonin transporter gene-linked polymorphic region (5-HTTLPR)doi:10.1016/j.biopsych.2010.04.034 pmid:20615496 pmcid:PMC2929304 fatcat:x5typedxlrfuhpcaotyqupn34y
ZUBIN College's reply: Dr Bhagwagar is angry because, through no fault of his own, he was unable to pass Part I of the MRCPsych in time to move onto the (old) registrar pay scale when the specialist ... Dr Bhagwagar and other readers may also be interested to know that the Court of Electors recently agreed to reduce the length of time candidates for Part II of the MRCPsych must have spent in approved ...doi:10.1192/pb.21.12.784-b fatcat:md6i3wn6mjasthzs3jr4xkfp7q
Objectives: Decreasing serotonergic neurotransmission in humans has been found to impair memory consolidation. Such effects may be relevant to the memory deficits seen in major depression and the cognitive actions of antidepressant drugs used to treat them. However, the improvement in cognitive function often found following successful pharmacological treatment in depression may be confounded by symptom improvement. Rationale: The present study assessed the effects of an acute challenge withdoi:10.1007/s00213-002-1151-x pmid:12185407 fatcat:radh7xktj5cqvjv3sf5735g4mu
more »... selective serotonergic re-uptake inhibitor citalopram in healthy (nondepressed) females. Methods: Immediate and delayed recall/recognition was assessed using the auditory verbal learning test following 10 mg (intravenous) citalopram or placebo in a double-blind between groups design. Results: Immediate recall on the verbal memory test was unaffected by citalopram administration. However, volunteers receiving citalopram showed enhanced longterm memory performance in terms of delayed recall and recognition relative to those receiving placebo. Sustained attention performance was also comparable in the two groups of subjects suggesting that non-specific increases in information processing are not responsible for this effect. Conclusions: These results indicate that augmentation of serotonergic neurotransmission is associated with increased memory consolidation, which may be relevant to its therapeutic and cognitive actions in acutely depressed patients.
Dr Bhagwagar is on the speaker's panel for Bristol-Myers Squibb and As-traZeneca USA; has been on advisory boards for Bristol-Myers Squibb, Janssen, and Lilly; and has also received funding from the Medical ...doi:10.1001/archpsyc.63.11.1217 pmid:17088502 pmcid:PMC2211759 fatcat:vihvhstt35dnzggythx33ao2oq
Neuroendocrine studies of brain serotonin (5-HT) function in depression generally show evidence of impaired 5-HT function but it is disputed whether or not this impairment resolves with clinical recovery. Aims To use the endocrine response to the selective 5-HTreuptake inhibitor, citalopram, to study brain 5-HT function in acute and recovered depressed subjects relative to healthy controls. Method We used a double-blind, placebo-controlled design to measure the prolactin and cortisol responsesdoi:10.1192/bjp.180.1.24 pmid:11772847 fatcat:c2q2twbberdgpkdsfp34bd2vh4
more »... o citalopram (10 mg intravenously) in patients with major depression, in unmedicated subjects recovered from depression and in healthy controls. Results The prolactin responses to citalopram were blunted similarly in both acutely depressed and recovered subjects. The cortisol responses were blunted in the acutely depressed patients but not in the recovered subjects. Conclusions Our data support the proposal that some aspects of impaired 5-HT neurotransmission may be trait markers of vulnerability to depression. The recovery of the cortisol response to citalopram may indicate resolution of hypothalamic – pituitary-adrenal axis dysfunction.
CLIFF ORD, ZUBIN BHAGWAGAR RICHARD WHALE, ELIZABETH M. CLIFFORD, ZUBIN BHAGWAGAR and PHILIP J. COWEN and PHILIP J. ...doi:10.1192/bjp.178.5.454 pmid:11331562 fatcat:scp6a3tzcbd7zbyqrqpfwpsx6y
Cl ozapine, a second-generation antipsychotic, is the treatment of choice in refractory schizophrenia because of its proven efficacy over typical antipsychotics as well as other atypical antipsychotics (1). However, a major drawback to clozapine therapy is the increased risk of neutropenia and agranulocytosis (2). In patients who develop either of these serious side effects, clozapine is immediately discontinued. Unfortunately, trials of other antipsychotics often prove ineffective, anddoi:10.1176/appi.ajp.2008.07111823 pmid:18593787 fatcat:kbgdxhrohvappmng57hpb3psqm
more »... ns find themselves faced with the difficult decision of whether to rechallenge those patients with clozapine (3). Even more concerning for the clinician is the relative absence of any controlled data to suggest treatment options when clozapine cannot be used because of serious side effects, such as neutropenia or agranulocytosis. This case review highlights this particular aspect and provides some useful thinking points for clinicians and patients in this situation. Efforts at rechallenge with clozapine have met with some success (4-9). In a retrospective review of 53 cases of clozapine rechallenge in the United Kingdom and Ireland, 62% of the patients did not develop a blood dyscrasia on rechallenge (8). Of course, clozapine rechallenge is not without its risks. In the same retrospective review, it was found that among the 38% of cases who did develop a blood dyscrasia on rechallenge, in 85% of the cases, the blood dyscrasia occurred more quickly and was more severe than with the initial trial of clozapine. In addition, in 65% of the cases in which patients developed a blood dyscrasia on rechallenge, the blood dyscrasia lasted longer after discontinuation of clozapine following rechallenge than when clozapine was first discontinued. Thus, when deciding whether to rechallenge a patient with clozapine, the clinician must carefully weigh the risks and benefits of a clozapine rechallenge. Here we present a patient with refractory schizophrenia who successfully tolerated a clozapine challenge 2 years after developing clozapine-induced neutropenia and failing to respond to a subsequent clozapine rechallenge. We propose that polypharmacy may have contributed to the initial episode of neutropenia as well as the failed clozapine rechallenge in our patient. We also discuss logical issues in medical decision making before considering clozapine rechallenges in patients. Case Presentation "S.P." was a 55-year-old divorced African American man with a 30-year history of paranoid schizophrenia who was referred to our unit for medication adjustment after a 2-year gradual worsening of psychotic symptoms characterized by thought disturbance and behavioral disorganization. As a result of his worsening symptoms, 3 months before admission, S.P. went from living independently in a supervised care setting to requiring close supervision and help with activities of daily living. Two months before admission, he stopped bathing and washing his clothes and refused to socialize. S.P.'s relationship with his case manager, which had previously been good, deteriorated, and he began to refuse to let the case manager into his home. His neighbors complained of loud noises, objects being thrown on the floor; also, S.P. could be heard conversing with himself. S.P. was hospitalized voluntarily; written consent was obtained before admission. Upon admission, he reported auditory hallucinations but no command auditory hallucinations or ever acting on the voice's instructions. S.P. also possessed multiple well-organized and developed delusions, including persecutory delusions and delusions of grandeur, as well as some ideas of reference.
Altered impulse control is associated with substance use disorders, including cocaine dependence. We sought to identify the neural correlates of impulse control in abstinent male patients with cocaine dependence (PCD). Functional magnetic resonance imaging (fMRI) was conducted during a stop signal task that allowed trial-by-trial evaluation of response inhibition. Fifteen male PCD and 15 healthy control (HC) subjects, matched in age and years of education, were compared. Stop signal reactiondoi:10.1038/sj.npp.1301568 pmid:17895916 pmcid:PMC2731999 fatcat:xun7f3vxhzc2pmt25w3shrnaie
more »... e (SSRT) was derived on the basis of a horse race model. By comparing PCD and HC co-varied for stop success rate, task-related frustration rating, and post-error slowing, we isolated the neural substrates of response inhibition, independent of attentional monitoring (of the stop signal) and post-response processes including affective responses and error monitoring. Using region of interest analysis, we found no differences between HC and PCD who were matched in stop signal performance in the pre-supplementary motor area (pre-SMA) previously shown to be associated with SSRT. However, compared with HC, PCD demonstrated less activation of the rostral anterior cingulate cortex (rACC), an area thought to be involved in the control of stop signal inhibition. The magnitude of rACC activation also correlated negatively with the total score and the impulse control subscore of the Difficulty in Emotion Regulation Scale in PCD. The current study thus identified the neural correlates of altered impulse control in PCD independent of other cognitive processes that may influence stop signal performance. Relative hypoactivation of the rACC during response inhibition may represent a useful neural marker of difficulties in impulse control in abstinent cocaine-dependent men who are at risk of relapse.
Todd Constable, Zubin Bhagwagar and Michelle Hampson Background The pathophysiology of auditory verbal hallucinations remains poorly understood. ...doi:10.1192/bjp.bp.110.086835 pmid:21972276 pmcid:PMC3065772 fatcat:3yhnnm6f75b5nck7z7vkpo6lgy
Background-Treatments for obsessive-compulsive disorder (OCD) usually lead to incomplete symptom relief and take a long-time to reach full effect. Convergent evidence suggests that glutamate abnormalities contribute to the pathogenesis of OCD. Ketamine is a potent noncompetitive antagonist of the N-methyl-D-aspartate glutamate receptor. Trials have reported rapid antidepressant effects after low-dose ketamine infusion. Methods- We conducted an open-label trial of ketamine (0.5mg/kg IV over 40doi:10.1016/j.biopsych.2012.05.028 pmid:22784486 pmcid:PMC3667652 fatcat:d27euh6yabdhlbsntqbihikxta
more »... nutes) in 10 subjects with treatment-refractory OCD. Response was defined as a greater than 35% improvement in OCD symptoms and greater than a 50% improvement in depression symptoms from baseline at any time between 1-3 days following infusion. Results-None of 10 subjects experienced a response in OCD symptoms in the first 3 days following ketamine. Four of 7 patients with comorbid depression experienced an antidepressant response to ketamine in the first 3 days following infusion. Both OCD and depression symptoms demonstrated a statistically significant improvement in the first 3 days following infusion compared to baseline, but the OCD response was <12%. The percentage reduction in depressive symptoms in the first 3 days following ketamine infusion was significantly greater than the reduction in OCD symptoms. Discussion-Ketamine effects on OCD symptoms, in contrast to depressive symptoms, did not appear to persist or progress after the acute effects of ketamine had dissipated.
Adaptive social behavior often necessitates choosing to cooperate with others for long-term gains at the expense of noncooperative behaviors giving larger immediate gains. Although little is know about the neural substrates that support cooperative over noncooperative behaviors, recent research has shown that mutually cooperative behavior in the context of a mixed-motive game, the Prisoner's Dilemma (PD), is associated with increased neural activity within reinforcement circuitry. Otherdoi:10.1038/sj.npp.1300932 pmid:16407905 fatcat:ca3smjry2bebzagerivcldqq5i
more »... attests to a role for serotonin in the modulation of social behavior and in reward processing. In this study, we used a within-subject, crossover, double-blind design to investigate performance of an iterated, sequential PD game for monetary reward by healthy human adult participants following ingestion of an amino-acid drink that either did (T + ) or did not (TÀ) contain l-tryptophan. Tryptophan depletion produced significant reductions in the level of cooperation shown by participants when playing the game on the first, but not the second, study days. This effect was accompanied by a significantly diminished probability of cooperative responding given previous mutually cooperative behavior. These data suggest that serotonin plays a significant role in the acquisition of socially cooperative behavior in human adult participants, and suggest novel hypotheses concerning the serotonergic modulation of reward information in socially cooperative behavior in both health and psychiatric illness.
Zubin Bhagwagar is funded by an MRC Clinical Training Fellowship. ...doi:10.1038/sj.npp.1300001 pmid:12496952 fatcat:5rpferfelrdebevea77efoxqfm
. , Rosa Hoshi, Zubin Bhagwagar, Naga Venkatesha Murthy, Rainer Hinz, Philip Cowen, H. ...doi:10.1192/bjp.bp.108.050344 pmid:19336788 fatcat:ml4lzlxebbamflj3odrcyh52ny
Serotonin and the 5-HT 1B receptor in particular are involved in a variety of physiological functions including food intake, sexual activity, and locomotion (Ruf and Bhagwagar, 2009; Sari, 2004) all ...doi:10.1002/syn.20942 pmid:21484884 pmcid:PMC3149753 fatcat:kj3lfidzwnfw3cchkdyuzo6b4q
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