Biomedical subjects

Zubin Bhagwagar

Publications and source records attributed to Zubin Bhagwagar.

At least 19 recordsLinked to original sources

PubMed2007

Reduction in occipital cortex gamma-aminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects.

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

Adult↗

PubMed2006

The effects of low doses of delta-9 tetrahydrocannabinol on reinforcement processing in the risky decision-making of young healthy adults.

Research suggests that risky decision-making is sensitive to neuromodulatory influences acting upon corticolimbic circuitry. However, while other evidence attests to effects of delta-9 tetrahydrocannabinol (THC) on the activity of reward pathways, relatively little is known about the possible involvement of cannabinoid activity in risky choice. In this experiment, we examined the effects of a single sublingual 5 mg dose of THC on a test of risky decision-making (requiring choices between simultaneously presented gambles differing in their magnitude of gains, magnitude of losses and the probability with which these outcomes were delivered). Tests of non-normative decision-making involving risk-aversion when deciding between gains and risk-seeking choices when deciding between losses were also included. In all, 15 healthy adults were administered 5 mg THC and placebo in a double-blind, placebo-controlled, within-subject, cross-over design. THC had three principal effects relative to placebo: (i) THC reduced choice of gambles with variable gains and losses, but increased choice of gambles with zero-expected value; (ii) THC reduced participants' attention towards losses when the probability of winning was low (and the probability of losing was high); and (iii) THC speeded participants' responses to gambles with large compared to small potential gains. These results suggest that THC mediates specific motivational processes and the processing of reinforcement cues during risky choice, perhaps reflecting altered CB1 receptor or catecholamine activity within corticolimbic pathways.

Adult↗

PubMed2006

Validation of a tracer kinetic model for the quantification of 5-HT(2A) receptors in human brain with [(11)C]MDL 100,907.

The positron emission tomography (PET) ligand [(11)C]MDL 100,907 has previously been introduced to image the serotonin 2A (5-HT(2A)) 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 [(11)C]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-HT(2A) receptor. There did not appear to be radiolabelled metabolites of [(11)C]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-HT(2A) receptor binding with [(11)C]MDL 100,907 and the use of the cerebellum as a reference region for the free and nonspecific binding.

Adult↗

PubMed2006

Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis.

CONTEXT: Selective serotonin reuptake inhibitors (SSRIs) are often described as having a delayed onset of effect in the treatment of depression. However, some trials have reported clinical improvement as early as the first week of treatment. OBJECTIVE: To test the alternative hypotheses of delayed vs early onset of antidepressant action with SSRIs in patients with unipolar depression. DATA SOURCES: Trials identified by searching CENTRAL, The Cochrane Collaboration database of controlled trials (2005), and the reference lists of identified trials and other systematic reviews. STUDY SELECTION: Randomized controlled trials of SSRIs vs placebo for the treatment of unipolar depression in adults that reported outcomes for at least 2 time points in the first 4 weeks of treatment (50 trials from >500 citations identified). Trials were excluded if limited to participants older than 65 years or specific comorbidities. DATA EXTRACTION: Data were extracted on trial design, participant characteristics, and outcomes by a single reviewer. DATA SYNTHESIS: Pooled estimates of treatment effect on depressive symptom rating scales were calculated for weeks 1 through 6 of treatment. In the primary analysis, the pattern of response seen was tested against alternative models of onset of response. The primary analysis incorporated data from 28 randomized controlled trials (n=5872). A model of early treatment response best fit the experimental data. Treatment with SSRIs rather than placebo was associated with clinical improvement by the end of the first week of use. A secondary analysis indicated an increased chance of achieving a 50% reduction in Hamilton Depression Rating Scale scores by 1 week (relative risk, 1.64; 95% confidence interval, 1.2-2.25) with SSRI treatment compared with placebo. CONCLUSIONS: Treatment with SSRIs is associated with symptomatic improvement in depression by the end of the first week of use, and the improvement continues at a decreasing rate for at least 6 weeks.

Adult↗

PubMed2006

Low doses of delta-9 tetrahydrocannabinol (THC) have divergent effects on short-term spatial memory in young, healthy adults.

Evidence suggests that manipulating spatial information within working memory depends upon a circuitry organized around the prefrontal cortex (PFC) and the activity of the catecholamine systems. Other evidence attests to the effects of Delta-9 tetrahydrocannabinol (THC) on short-term spatial memory function, most probably involving CB(1) receptor activity within hippocampal circuitries. At the current time, there have been no systematic studies of the effects of THC on spatial working memory in human subjects using tasks known to depend upon frontotemporal neural circuitries. We examined the effects of a single sublingual 5 mg dose of THC on a test of spatial working memory (requiring active manipulation of remembered spatial information for the management of future behavior) and a test of spatial span (requiring only the reproduction of sequences of previously presented spatial cues). In all, 19 healthy adults were administered 5 mg THC and placebo in a double-blind, placebo-controlled, within-subject, crossover design. Male participants performed more accurately than female participants. THC significantly enhanced spatial working memory performance of female participants. By contrast, male and female participants produced more intrusion errors during performance of the Spatial Span task. These results suggest that THC has relatively complex effects on spatial memory in human subjects, perhaps reflecting altered CB(1) receptor activity within frontotemporal circuits or altered activity of mesocortical dopaminergic pathways in PFC areas associated with spatial memory.

Adult↗

PubMed2006

Effects of tryptophan depletion on the performance of an iterated Prisoner's Dilemma game in healthy adults.

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. Other research 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 (T-) 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.

Brain↗

PubMed2006

Increased 5-HT(2A) receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [(11)C]MDL 100,907.

OBJECTIVE: A previous positron emission tomography (PET) study reported increased serotonin 5-HT(2A) receptor binding in unmedicated depressed patients with high scores on the Dysfunctional Attitudes Scale. The purpose of the present study was to use the highly selective 5-HT(2A) receptor ligand [(11)C]MDL 100,907 in a PET imaging paradigm to assess 1) 5-HT(2A) receptor binding potential in euthymic subjects with a history of recurrent depression and 2) the relationship between receptor binding and scores on the Dysfunctional Attitudes Scale. METHOD: Cortical 5-HT(2A) receptor binding was measured in 20 unmedicated, fully recovered unipolar depressed patients and 20 age- and gender-matched comparison subjects. Regional estimates of binding potential were obtained using a reversible plasma input function compartmental model and the cerebellum as a reference region to estimate the free and non-specifically bound [(11)C]MDL 100,907 in brain tissue. RESULTS: Relative to the comparison subjects, the recovered depressed patients demonstrated significantly higher 5-HT(2A) receptor binding potential in the frontal cortex (mean increase: 19%), parietal cortex (mean increase: 25%), and occipital cortex (mean increase: 19%). 5-HT(2A) receptor binding potential correlated negatively with age in both patients and comparison subjects and positively with the Dysfunctional Attitudes Scale in the recovered patients. CONCLUSIONS: These findings should be considered preliminary but suggest that recovered subjects with a history of recurrent major depression have elevated binding potential of cortical 5-HT(2A) receptors. The correlation of increased 5-HT(2A) receptor binding potential with increased scores on Dysfunctional Attitudes Scale supports earlier work suggesting that increased 5-HT(2A) receptor availability characterizes a group of depressed patients with high levels of dysfunctional attitudes.

Adult↗

PubMed2006

Potential of levetiracetam in mood disorders: a preliminary review.

Levetiracetam is a newer antiepileptic agent that was first approved by the US FDA in 1999 as an adjunctive therapy for the treatment of refractory partial epilepsy in adults. Since then, it has been approved for a wider patient population, i.e. as adjunctive therapy for partial seizures in patients >4 years of age (worldwide) and as first-line monotherapy for partial seizures in patients >16 years of age (in Europe); and as adjunctive therapy for juvenile myoclonic seizures (in Europe and the US). It has a favourable pharmacokinetic profile and appears to act at a specific site in the CNS. Pharmacodynamic evidence indicates that levetiracetam indirectly facilitates GABAergic function, and an increasing body of evidence suggests an important role for GABA in the pathophysiology of mood disorders. Preclinical studies using animal models of depression, anxiety and mania provide evidence for levetiracetam as a mood stabiliser. Preliminary clinical evidence from case reports and open-label pilot studies indicates that the drug, both as add-on therapy and as monotherapy, has efficacy in a wide range of bipolar spectrum disorders. Most recently, a 31% remission rate was reported in patients with bipolar disorder who were in the depressed phase at baseline and who received levetiracetam as add-on therapy for 8 weeks in an open-label trial. While these results are encouraging, placebo-controlled data are needed to further clarify the role of levetiracetam in the treatment of mood disorders.

Animals↗

PubMed2005

Increased salivary cortisol after waking in depression.

RATIONALE: Cortisol hypersecretion is regarded as important in the pathophysiology of major depression. However, recent studies in community-based samples have been inconclusive. OBJECTIVE: To determine whether acutely depressed, medication-free subjects show an exaggerated release of cortisol in saliva in relation to awakening. METHODS: We studied the pattern of waking salivary cortisol in 20 unmedicated acutely depressed subjects and 40 healthy controls. RESULTS: In both groups, salivary cortisol increased rapidly after waking, peaking at 30 min. Overall, patients with acute depression secreted approximately 25% more cortisol than controls, though 60 min after waking, their cortisol levels were similar. CONCLUSIONS: Depressed patients in the community appear to have increased early morning cortisol secretion, but the demonstration of this effect requires control for time of waking.

Adult↗

PubMed2005

Lamotrigine in the treatment of bipolar disorder.

Lamotrigine is a novel anticonvulsant agent that has recently been introduced as a long-term treatment in bipolar disorder. Its role in the treatment of epilepsy is based on its actions to decrease ion channel conductance and antagonise glutamatergic function. Therefore, it has a mode of action unlike other agents used on a long-term basis in mood disorders. The evidence for efficacy is stronger for the prevention of depressive, rather than manic, episodes. The pivotal trials are in bipolar I disorder, but there is interest in its actions in patients with bipolar II and spectrum conditions. Its efficacy in other psychiatric conditions remains to be properly established. It is well tolerated and, with careful prescribing, the incidence of rash occurs no more than with placebo; however this is still a concern. Although usually well tolerated, headache, insomnia and drowsiness are probably the most common side effects.

Bipolar Disorder↗

PubMed2004

Preferential 5-HT1A autoreceptor occupancy by pindolol is attenuated in depressed patients: effect of treatment or an endophenotype of depression?

Using positron emission tomography and the selective 5-HT1A receptor radioligand [11C]WAY100635, we previously demonstrated a preferential occupancy of 5-HT1A autoreceptors, compared to postsynaptic receptors by pindolol in healthy volunteers. We have speculated that preferential occupancy may be clinically important for the purported actions of pindolol in accelerating the antidepressant effects of selective serotonin re-uptake inhibitors (SSRIs). In this study, we have examined the preferential occupancy by pindolol of 5-HT1A autoreceptors, following three different pindolol regimes (10 mg single dose, 2.5 mg t.i.d., and 5 mg t.i.d., in 15 depressed patients on SSRIs. In addition, seven healthy volunteers were examined following a single 10 mg dose of pindolol. We found a preferential occupancy of 22.6+/-7.7% following a single dose of 10 mg of pindolol, in the healthy volunteers, which was attenuated in depressed patients on the same dose of pindolol to 2.9+/-10.8% (Student's t=3.94, df=12, p=0.002). In addition, we found a significant negative correlation between the degree of preferential occupancy and the severity of depression as assessed by the Hamilton depression rating score (HAM-D), Spearman's rho=-0.728, N=14, p=0.003, in the depressed sample. A possible mechanism underlying preferential occupancy and the attenuation of this phenomenon in depressed patients on SSRIs may include changes in the proportion of high affinity 5-HT1A sites in the autoreceptor region of the midbrain raphe. Speculatively, the degree of preferential occupancy may serve as a surrogate marker for depression, or the pharmacological effects of antidepressants.

Adrenergic beta-Antagonists↗

PubMed2004

Normalization of enhanced fear recognition by acute SSRI treatment in subjects with a previous history of depression.

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.

Acute Disease↗

PubMed2004

Increased brain GABA concentrations following acute administration of a selective serotonin reuptake inhibitor.

OBJECTIVE: The authors used magnetic resonance spectroscopy (MRS) to assess the effect of acute administration of the selective serotonin reuptake inhibitor (SSRI) citalopram on cortical levels of gamma-aminobutyric acid (GABA). METHOD: Ten healthy volunteers received either intravenous citalopram (10 mg) or saline in a randomized, double-blind, crossover design. The occipital GABA/creatine ratio was measured with a proton MR spectral editing technique. RESULTS: In comparison with saline, citalopram produced a mean increase of 35% in relative brain GABA concentration in the occipital cortex. CONCLUSIONS: These findings extend previous work showing that SSRI treatment increases cortical GABA in depressed patients and suggest that this results from an action of SSRIs on GABA neurons rather than as a secondary consequence of mood improvement.

Adult↗

PubMed2003

Lack of effect of a single dose of hydrocortisone on serotonin(1A) receptors in recovered depressed patients measured by positron emission tomography with [11C]WAY-100635.

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

Adult↗

PubMed2003

Tryptophan depletion alters the decision-making of healthy volunteers through altered processing of reward cues.

While accumulating evidence suggests that effective real-life decision-making depends upon the functioning of the orbitofrontal cortex, much less is known about the involvement of the monoamine neurotransmitter systems and, in particular, serotonin. In the present study, we explored the impact of depleting the serotonin precursor, tryptophan, on human decision-making. Eighteen healthy volunteers consumed an amino-acid drink containing tryptophan and 18 healthy volunteers consumed an amino-acid drink without tryptophan, before choosing between simultaneously presented gambles, differing in the magnitude of expected gains (ie reward), the magnitude of expected losses (ie punishment), and the probabilities with which these outcomes were delivered. Volunteers also chose between gambles probing identified non-nomative biases in human decision-making, namely, risk-aversion when choosing between gains and risk-seeking when choosing between losses. Tryptophan-depleted volunteers showed reduced discrimination between magnitudes of expected gains associated with different choices. There was little evidence that tryptophan depletion was associated with altered discrimination between the magnitudes of expected losses, or altered discrimination between the relative probabilities with which these positive or negative outcomes were delivered. Risk-averse and risk-seeking biases were also unchanged. These results suggest that serotonin mediates decision-making in healthy volunteers by modulating the processing of reward cues, perhaps represented within the orbitofrontal cortex. It is possible that such a change in the cognition mediating human choice is one mechanism associated with the onset and maintenance of anhedonia and lowered mood in psychiatric illness.

Adult↗

PubMed2003

Increase in concentration of waking salivary cortisol in recovered patients with depression.

OBJECTIVE: Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis with elevated plasma cortisol levels is characteristic of acute major depression. However, it is unclear whether HPA axis abnormalities are present in fully recovered patients. An increase in salivary cortisol levels after waking provides a simple, dynamic measure of HPA axis activity. The authors measured this increase in recovered depressed patients and in a healthy comparison group. METHOD: Salivary cortisol levels were measured upon waking and at 15-minute intervals for the next hour in 31 medication-free, recovered depressed patients and in 31 matched healthy comparison subjects. RESULTS: The increase in salivary cortisol levels that followed waking was significantly higher in the patients. CONCLUSIONS: Greater secretion of cortisol may be present in depressed subjects after clinical recovery and withdrawal of medication. This may put patients at risk of further episodes of depression as well as comorbid medical conditions, such as coronary heart disease.

Adult↗

PubMed2003

Risperidone augmentation decreases rapid eye movement sleep and decreases wake in treatment-resistant depressed patients.

BACKGROUND: The atypical antipsychotic agent risperidone has beneficial effects on mood in patients with schizophrenia. This study aimed to assess whether risperidone produced typical antidepressant-like effects in the polysomnogram of healthy subjects and in depressed patients unresponsive to antidepressant medication. METHOD: We measured the effect of a single dose of risperidone (1 mg) on the polysomnogram of 8 healthy volunteers in a placebo-controlled, double-blind, crossover design. We also measured the effects of open-label risperidone treatment (0.5-1.0 mg daily) on the polysomnogram of 8 patients meeting DSM-IV criteria for major depressive disorder who had received therapeutic doses of an antidepressant with an unsatisfactory response. Sleep was recorded at baseline and following 2 weeks of risperidone addition. RESULTS: In the healthy volunteers, risperidone significantly decreased rapid eye movement (REM) sleep (p =.04). After 2 weeks of risperidone treatment, depressed patients had significantly less wake (p =.02) and REM sleep (p =.02). Scores on depression rating scales for the depressed patients showed a significant decline (p <.05). CONCLUSION: Risperidone administration decreases REM sleep in both healthy volunteers and medication-resistant depressed patients, an action characteristic of conventional antidepressant medication. In depressed patients, risperidone also decreased wake. The utility of risperidone as an augmentation agent in depressed patients merits controlled study.

Administration, Oral↗

PubMed2002

Acute administration of citalopram facilitates memory consolidation in healthy volunteers.

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 with the selective serotonergic re-uptake inhibitor citalopram in healthy (non-depressed) 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 long-term 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.

Adult↗