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Biomedical subjects

Philip J Cowen

Publications and source records attributed to Philip J Cowen.

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

Emotional bias and waking salivary cortisol in relatives of patients with major depression.

BACKGROUND: Biases in the processing of emotional information have been shown to be abnormal in subjects with major depression, both during an episode and after full recovery. However, it is unclear whether these biases are a cause or an effect of the depression. This study set out to explore whether such biases represent a vulnerability factor for depression by looking at unaffected first-degree relatives of those with major depressive disorder. We also measured waking salivary cortisol, as the regulation of the hypothalamo-pituitary-adrenal (HPA) axis is thought to be impaired in depressive disorder. METHOD: Twenty-five female relatives and 21 age-matched controls completed a facial expression recognition task, an emotional categorization task with positive and negative personality characteristics, and had their waking salivary cortisol measured on a work day and a non-work day. RESULTS: The depressed relative group was significantly faster to recognize facial expressions of fear than controls. The depressed relative group also showed significantly increased reaction time to recognize positive versus negative personality characteristics in the categorization task. There was no difference in waking salivary cortisol between groups, although there was an effect of work day versus non-work day. CONCLUSIONS: Subtle biases in the processing of emotional information may exist in the unaffected first-degree relatives of those with depression. As such, this may represent a familial vulnerability factor to developing a depressive illness.

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

Tryptophan supplementation induces a positive bias in the processing of emotional material in healthy female volunteers.

RATIONALE: The serotonin precursor L-tryptophan (TRP) is available as a nutritional supplement and is licensed as an antidepressant in a number of countries. However, evidence of its efficacy as the primary treatment for depression is limited, and the direct action of TRP on the symptoms of depression and anxiety has not been well-characterised. OBJECTIVES: The present study assessed whether TRP induces cognitive changes opposite to the negative biases found in depression and characteristic of those induced by serotonergic antidepressants in healthy volunteers. MATERIALS AND METHODS: Thirty eight healthy volunteers were randomised to receive 14 days double-blind intervention with TRP (1 g 3x a day) or placebo. On the final day, emotional processing was assessed using four tasks: facial expression recognition, emotion-potentiated startle, attentional probe and emotional categorisation and memory. RESULTS: TRP increased the recognition of happy facial expressions and decreased the recognition of disgusted facial expressions in female, but not male, volunteers. TRP also reduced attentional vigilance towards negative words and decreased baseline startle responsivity in the females. CONCLUSIONS: These findings provide evidence that TRP supplementation in women induces a positive bias in the processing of emotional material that is reminiscent of the actions of serotonergic antidepressants. This highlights a key role for serotonin in emotional processing and lends support to the use of TRP as a nutritional supplement in people with mild depression or for prevention in those at risk. Future studies are needed to clarify the effect of tryptophan on these measures in men.

Adolescent↗
PubMed2006

5HT(3) antagonism abolishes the emotion potentiated startle effect in humans.

RATIONALE: The serotonergic system has been implicated in emotional processing in animals and humans. Although the contribution of different receptor subtypes has been hypothesised, there have been few direct tests of this in human subjects. OBJECTIVES: The current study aimed to explore the involvement of the serotonin type 3 (5HT3) receptor subtype in a battery of emotional processing tasks previously found to be sensitive to SSRI administration. MATERIALS AND METHODS: Healthy volunteers were randomised to receive the 5HT3 antagonist, ondansetron (12 mg, oral), or placebo in a double blind between groups design. Emotional processing was assessed using three tasks: affective modulation of the startle reflex, emotional categorisation and memory and facial expression recognition. Subjective state ratings, blood pressure and pulse were also collected before and after ondansetron and placebo. RESULTS: Ondansetron was well tolerated and did not affect subjective measures of mood, anxiety or well-being in these healthy volunteers. However, the emotion potentiated effect was abolished in the volunteers receiving ondansetron. Facial expression recognition and emotional memory were not significantly affected. CONCLUSIONS: These results suggest an involvement of 5HT3 receptors in certain aspects of fear processing in humans. These effects are consistent with anxiolytic actions of 5HT3 antagonism in animal models and suggest that the 5HT3 receptor may play a role in the effects of serotonergic manipulations on fear and anxiety.

Adult↗
PubMed2006

Antidepressant drug treatment modifies the neural processing of nonconscious threat cues.

BACKGROUND: The amygdala is believed to play a key role in processing emotionally salient, threat-relevant, events that require further online processing by cortical regions. Emotional disorders such as depression and anxiety have been associated with hyperactivity of the amygdala, but it is unknown whether antidepressant treatment directly affects amygdala responses to emotionally significant information. METHODS: The current study assessed the effects of 7 days administration of the selective serotonin reuptake inhibitor (SSRI), citalopram, on amygdala responses to masked presentations of fearful and happy facial expressions in never-depressed volunteers using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging. A double-blind, between-groups design was used with volunteers randomized to 20 mg/day citalopram versus placebo. RESULTS: Volunteers receiving citalopram showed decreased amygdala responses to masked presentations of threat compared with those receiving placebo. Citalopram also reduced responses within the hippocampus and medial prefrontal cortex (mPFC) specifically during the fear-relevant stimuli. These neural differences were accompanied by decreased recognition of fearful facial expressions assessed after the scan. By contrast, there was no effect of citalopram on the neural or behavioral response to the happy facial expressions. CONCLUSIONS: These results suggest a direct effect of serotonin potentiation on amygdala response to threat-relevant stimuli in humans. Such effects may be important in the therapeutic actions of antidepressants in depression and anxiety.

Adolescent↗
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

Lack of effect of tyrosine depletion on mood in recovered depressed women.

The role of dopamine (DA) pathways in the pathophysiology of depressive disorder is poorly understood. However, because DA plays a key role in motivational behavior, it is important to study in a disorder characterized by anhedonia, lack of energy and psychomotor retardation. A recently developed dietary manipulation ('tyrosine (TYR) depletion') offers a novel method to assess the role of DA in major depression. We studied 15 euthymic women with a past history of recurrent depression, who received a 74 g amino-acid drink lacking TYR and phenylalanine (PHE) (TYR-free) and a balanced (BAL) amino acid drink on two separate occasions in a double-blind, random-order, crossover design. Plasma prolactin levels rose following the TYR-free drink relative to the balanced mixture, while performance on a spatial recognition memory task was impaired. However, relative to the BAL drink, the TYR-free drink did not lower objective or subjective measures of mood. We conclude that as in healthy volunteers, TYR depletion in euthymic subjects, with a past history of major depression, attenuated DA function, as reflected in increased plasma prolactin levels and decreased spatial memory performance. However ratings of depression were unaffected, suggesting that disruption of dopaminergic function by this manipulation does not induce a lowering of mood in individuals vulnerable to depression.

Adult↗
PubMed2005

The effect of bosentan on matrix metalloproteinase-9 levels in patients with systemic sclerosis-induced pulmonary hypertension.

OBJECTIVE: Systemic sclerosis (SSc) is an autoimmune disease that can potentially involve all tissues and organs of the human body. Based on the extent of the disease and organ involvement, different subsets of patients and organ involvement, different subsets of patients have been identified and several classifications proposed have been identified and several classifications proposed aiming to better stratify affected patients. The occurrence aiming to better stratify affected patients. The occurrence of pulmonary arterial hypertension (PAH), characterized of pulmonary arterial hypertension (PAH), characterized by altered tissue remodelling of the entire vessel wall, is the most severe complication that influences prognosis and survival. The molecular basis underlying the vascular damage is not yet known, but a family of enzymes named matrix metalloproteinases (MMPs), with a proteolytic activity towards several extra-cellular matrix (ECM) components, is likely to be involved. Recently, a dual inhibitor of endothelin-1, bosentan, has been successfully evaluated in clinical trials in PAH patients. RESEARCH DESIGN AND METHOD: The aim of this study is to investigate the expression of MMP-2 and MMP-9 in the serum of different subsets of SSc patients, and in patients treated with bosentan. Thirty-five Caucasian patients with SSc were enrolled in the study, 12 of whom were found to have isolated PAH assessed by Doppler echocardiography. Eight patients fully met the inclusion criteria and were eligible for therapy with bosentan given at the dosage of 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily for 50 weeks(15). The remaining patients (4/12) initiated bosentan therapy for a few weeks and, therefore, were considered at the baseline level only. Serum samples were analysed by gelatine zymography. RESULTS: The results suggest that MMP-9 but not MMP-2 is differently expressed according to the degree of organ involvement. In particular, MMP-9 serum levels are significantly decreased in PAH with respect to other subsets of SSc patients. Moreover, in bosentan-treated patients, after 12 months of therapy MMP-9 significantly (p < 0.05) increased and correlated with an improved clinical outcome, as measured by the '6-minutes walking' test. CONCLUSIONS: This is the first time that MMP-9 serum levels are reported to be down-regulated in PAH patients and up-regulated following bosentan treatment. Whether MMP-9 has a pathogenetic role in the vascular damage observed in PAH patients or it is a marker of bosentan effectiveness is not yet known. However, MMP-9 may be an important molecule that needs further investigation in SSc patients to better define its role.

Adult↗
PubMed2005

Olanzapine increases slow wave sleep and sleep continuity in SSRI-resistant depressed patients.

OBJECTIVE: The atypical antipsychotic drug olanzapine has been employed as an augmentation treatment in depressed patients unresponsive to treatment with selective serotonin reuptake inhibitors (SSRIs). In healthy subjects, acute olanzapine administration increases sleep continuity and enhances slow wave sleep (SWS). The aim of the present study was to determine if the addition of olanzapine to SSRI treatment in depressed patients produced similar effects on sleep. METHOD: We measured the effect of open-label olanzapine addition (2.5 mg/day initially) on the polysomnograms of 12 patients referred from primary care sources who met DSM-IV criteria for major depressive disorder and who had had an unsatisfactory response to therapeutic doses of an SSRI. Patients were first enrolled in November 2001; final assessment occurred in November 2003. Sleep polysomnogram recordings were made on 3 occasions: before olanzapine addition, on the first night of olanzapine treatment, and after 3 weeks of olanzapine treatment. RESULTS: After the first night of olanzapine treatment and during the third week, subjects showed improvements in sleep efficiency (p < .001), subjective sleep quality (p < .05), and SWS (p < .01). Scores on the Hamilton Rating Scale for Depression fell significantly (p = .001), with the majority of the decrease being apparent after the first week of treatment. CONCLUSION: Olanzapine improves sleep continuity and increases SWS in patients receiving SSRI treatment. These effects are apparent after the first dose of olanzapine and are maintained for the next 3 weeks. The ability of olanzapine to increase SWS is probably attributable to 5-HT(2A/2C) receptor blockade, which has been identified as a relevant mechanism in the therapeutic effect of olanzapine in SSRI-resistant depressed patients.

Adult↗
PubMed2004

A 5-HT2C receptor promoter polymorphism (HTR2C - 759C/T) is associated with obesity in women, and with resistance to weight loss in heterozygotes.

The serotonin 5-HT(2C) receptor (HTR2C) helps regulate appetite and body weight. An HTR2C promoter polymorphism (-759C/T) has been associated with obesity and with weight gain in response to antipsychotic (neuroleptic) drugs. We studied this polymorphism in 120 obese women (BMI > or = 30) and 104 non-obese (BMI < or = 25) women. The C allele was commoner in the obese group (OR = 1.72 [95% CI, 1.13-2.64], P = 0.008). Ninety-five of the obese women participated in a randomized trial of psychological treatments for weight loss. Among these women, heterozygotes lost less weight during the trial than did homozygotes (6.8 vs. 9.7 kg; P = 0.047) and weighed more 6 months (90.1 vs. 83.6 kg; P = 0.006) and 12 months (91.8 vs. 84.6 kg; P = 0.009) later. Heterozygotes also had higher triglyceride levels than homozygotes. C/C subjects in the obesity trial did not differ from T/T subjects in terms of weight loss or triglycerides. In a separate RT-PCR study of 43 subjects, we found that HTR2C mRNA abundance in frontal cortex was unaffected by -759C/T status. Our data extend the evidence that HTR2C promoter variation may be a risk factor for obesity and, perhaps through heterosis, influences weight loss by obese women. Pharmacogenetic testing of HTR2C promoter variants may be valuable when evaluating anti-obesity drugs which act directly or indirectly on the receptor.

Adult↗
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

Comparison of the effects of citalopram and escitalopram on 5-Ht-mediated neuroendocrine responses.

Acute oral administration of selective serotonin re-uptake inhibitors (SSRIs) increases plasma cortisol by facilitating brain serotonin activity. Recently, salivary cortisol sampling has grown in popularity as a noninvasive means of assessing HPA axis activity. The aim of the present study was to find out whether acute oral administration of the SSRI, citalopram, increases salivary cortisol in healthy volunteers and whether the increase produced by an equivalent dose of its active isomer, escitalopram, is greater. A total of 15 healthy subjects were tested on three occasions receiving either oral citalopram (20 mg), escitalopram (10 mg), or placebo in a double-blind, randomized, crossover design. Salivary cortisol and plasma cortisol and prolactin were measured for 240 min after each treatment. Relative to placebo, both citalopram and escitalopram increased salivary and plasma cortisol levels with no evidence of consistent differences between them. Plasma prolactin concentration was not altered by either active treatment. Plasma and salivary cortisol responses after citalopram but not escitalopram correlated significantly. The present study does not support an enhanced effect of escitalopram on 5-HT-mediated neuroendocrine responses.

Adult↗
PubMed2004

Methamphetamine activates reward circuitry in drug naïve human subjects.

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.

Adult↗
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↗