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Synapse 08/2012; 66(12):1035-9. · 2.94 Impact Factor
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ABSTRACT: Previous studies on the relationship between blood pressure (BP) and psychological morbidity are conflicting. To resolve this confusing picture we examined the hypothesis that there is a non-linear relationship between panic and systolic BP (SBP) and explored the association of generalized anxiety symptoms with SBP. Method We used data from the population-based Nord-Trøndelag health study (HUNT) in which all 92 936 individuals aged ≥20 years residing in one Norwegian county were invited to participate. Panic was assessed using one item from the anxiety subscale of the Hospital Anxiety and Depression Scale (HADS) and generalized anxiety with the remaining six items of this subscale. SBP was the mean of two measurements by an automatic device.
A total of 64 871 respondents had SBP recorded (70%). Both unadjusted (n=61 408) and adjusted analyses provided evidence for a non-linear relationship between panic and SBP, represented by a U-shaped curve with a minimum prevalence of panic at around 140 mmHg. The relationship was strengthened after adjustment for confounders, with the quadratic term significantly associated with panic (p=0.03). Generalized anxiety symptoms were associated only with low SBP.
The U-shaped relationship between SBP and panic provides a unifying explanation for the separate strands of published literature in this area. The results support the hypothesis that high BP and panic disorder could share brainstem autonomic and serotonergic abnormalities. By contrast, generalized anxiety symptoms were more common only at lower BPs, suggesting that any biological link between panic and high BP does not extend to generalized anxiety.
Psychological Medicine 01/2012; 42(9):1969-76. · 6.16 Impact Factor
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ABSTRACT: This study sought to collect information on the former legal-high 'mephedrone' using a web-based survey targeted at mephedrone users.
The survey was advertised on websites frequented by drug users. Individuals were invited to complete the survey if they had taken mephedrone on at least one occasion in the past.
One thousand and six completed forms were received from declared users, making this the largest survey on mephedrone to date.
Results showed that mephedrone users consider its effects to compare best with those of MDMA, and while MDMA was considered marginally safer and its effects more pleasurable, mephedrone's appeal lay in its availability, low price and reliable purity.
Drug and alcohol dependence 03/2011; 118(1):19-22. · 3.60 Impact Factor
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ABSTRACT: Cue-exposure therapy (CET) has been advocated as a potentially effective treatment of addictive behaviours. Strategies that enhance learning may improve the outcome of CET. D-cycloserine (DCS), a partial N-methyl-D-aspartate receptor agonist, has been shown to facilitate extinction of learned fear in rats and augment exposure-based treatment in some anxiety disorders in man.
This double-blind placebo-controlled pilot study used a cue-exposure paradigm, salient for an individual's alcohol drinking, to see if DCS would reduce cue-reactivity compared with placebo.
Sixteen abstinent, alcohol-dependent individuals were randomised to receive either a single-dose (250 mg) DCS or placebo before CET sessions, separated by at least 1 week. Subjective responses were assessed using the Alcohol Urge Questionnaire (AUQ) and visual analogue scales. Cardiovascular responses were assessed using Finapres©.
The cue-exposure paradigm significantly increased craving assessed with the AUQ during the first session. In subsequent sessions, the degree of craving was reduced. However, no significant difference was seen between the DCS and placebo groups in any outcome measure. The variability of responses between individuals was great with more than half the groups reporting no or very small changes in AUQ scores.
This is the first human study to our knowledge to assess the efficacy of DCS in facilitating CET in alcohol dependence. The high proportion of subjects with little or no response to cue-exposure would make any effect of DCS very difficult to detect. It is important that future studies carefully consider the criteria for inclusion.
Psychopharmacologia 02/2011; 216(1):121-9. · 4.08 Impact Factor
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ABSTRACT: The nature of the noradrenergic dysregulation in clinical anxiety disorders remains unclear. In panic disorder, the predominant view has been that central noradrenergic neuronal networks and/or the sympathetic nervous system was normal in patients at rest, but hyper-reactive to specific stimuli, for example carbon dioxide. These ideas have been extended to other anxiety disorders, which share with panic disorder characteristic subjective anxiety and physiological symptoms of excess sympathetic activity. For example, Generalized Anxiety Disorder is characterized by chronic free-floating anxiety, muscle tension, palpitation and insomnia. It has been proposed that there is chronic central hypersecretion of noradrenaline in Generalized Anxiety Disorder, with consequent hyporesponsiveness of central post-synaptic receptors. With regards to other disorders, it has been suggested that there is noradrenergic involvement or derangement, but a more specific hypothesis has not been enunciated. This paper reviews the evidence for noradrenergic dysfunction in anxiety disorders, derived from indirect measures of noradrenergic function in clinical populations.
Journal of Psychopharmacology 01/2011; 25(1):3-16. · 3.04 Impact Factor
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ABSTRACT: Serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressants have evidence of efficacy in the treatment of generalized anxiety disorder (GAD); however, it is not clear whether there is an advantage over selective serotonin reuptake inhibitor (SSRI) medicines and there is limited evidence for noradrenergic dysfunction in GAD. We tested whether a dysfunctional alpha-2 adrenoceptor system is present in patients with GAD and the effects of SNRI treatment on this system. The method used was an infusion of clonidine (a selective alpha-2 adrenergic receptor agonist) on psychological and physiological outcomes in three subject groups: 10 untreated GAD patients, five SNRI-treated GAD patients and seven normal controls. The clonidine challenge elicited sedation, a rise in growth hormone, decrease in blood pressure, decline in saccadic eye movement (SEM) variables, and improvement in verbal fluency as anticipated in the 22 subjects examined. Lower cortisol levels were found in controls and higher blood pressure readings in GAD-treated subjects, as well as evidence that GAD-treated subjects had SEMs that were intermediate between control and GAD subjects' scores and have less clonidine-induced sedation. The implications of these findings with reference to the study hypothesis in this small study are discussed.
Journal of Psychopharmacology 01/2011; 25(1):78-86. · 3.04 Impact Factor
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Journal of Labelled Compounds and Radiopharmaceuticals 01/2011; 54:S304-S304. · 0.91 Impact Factor
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S J Wilson, D J Nutt,
C Alford,
S V Argyropoulos,
D S Baldwin,
A N Bateson,
T C Britton,
C Crowe,
D-J Dijk,
C A Espie,
P Gringras,
G Hajak,
C Idzikowski,
A D Krystal,
J R Nash,
H Selsick,
A L Sharpley,
A G Wade
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ABSTRACT: Sleep disorders are common in the general population and even more so in clinical practice, yet are relatively poorly understood by doctors and other health care practitioners. These British Association for Psychopharmacology guidelines are designed to address this problem by providing an accessible up-to-date and evidence-based outline of the major issues, especially those relating to reliable diagnosis and appropriate treatment. A consensus meeting was held in London in May 2009. Those invited to attend included BAP members, representative clinicians with a strong interest in sleep disorders and recognized experts and advocates in the field, including a representative from mainland Europe and the USA. Presenters were asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic reviews and randomized controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion, aimed to reach consensus where the evidence and/or clinical experience was considered adequate or otherwise to flag the area as a direction for future research. A draft of the proceedings was then circulated to all participants for comment. Key subsequent publications were added by the writer and speakers at draft stage. All comments were incorporated as far as possible in the final document, which represents the views of all participants although the authors take final responsibility for the document.
Journal of Psychopharmacology 11/2010; 24(11):1577-601. · 3.04 Impact Factor
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ABSTRACT: This study used a web-based questionnaire to investigate user perceptions of the benefits and harms of hallucinogenic drug use. Over 600 forms were submitted. Users were asked to comment on the acute and prolonged effects of different drugs and to provide more specific information on how particular drugs have harmed and/or helped them. Subjects reported relatively less harm associated with the classic hallucinogens, LSD and psilocybin, than other drugs specifically focused on in the questionnaire (MDMA, cannabis, ketamine and alcohol). A wide-range of benefits was reported, including: help with mood disorders, addictions and migraine as well as more general long-term improvements in wellbeing. Symptoms of hallucinogen persisting perceptual disorder were reported by a number of subjects and these were most closely associated with use of LSD; however, few users regarded these effects as troubling. Eighty-one per cent of users reported having had a ‘spiritual experience’ on a hallucinogenic drug and over 90% considered ‘access to the unconscious mind’ to be a specific property of the classic hallucinogens. With caution, these findings support recent calls for a systematic investigation of the therapeutic potential of the classic hallucinogens and highlight the scope for empirical investigations of spiritual and psychodynamic phenomena.
07/2010; 15(4):283-300.
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NeuroImage 01/2010; 52:S127-S128. · 5.89 Impact Factor
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ABSTRACT: The aims of this study were, firstly to use receptor autoradiography to investigate the effect of antisense oligonucleotides to the α2D-adrenoceptor on receptor binding and, secondly to measure behavioural and physiological parameters to determine whether the chronic antisense infusion had any effect on α2-adrenoceptor function in vivo.A 3 day infusion of antisense to the α2D-adrenoceptor significantly reduced specific [3H]-RX821002 binding in the septum (20–30%) and anterior hypothalamic area (20–30%). β-Adrenoceptor expression was unaffected in those brain areas examined, indicating the antisense knockdown was specific to the α2-adrenoceptors.On the second day of the infusion, the hypothermic response to UK 14,304 was significantly attenuated in the antisense-treated group compared with both vehicle and mismatch controls. The effect was fully reversible and a similar decrease in body temperature was observed in all the treatment groups 4 days after the end of infusion.During the second day of the infusion, the effects of UK 14,304 on behaviour were reduced in the antisense-treated rats, but were not significantly lower than those of the vehicle and mismatch, UK 14,304 controls. These trends were not observed 4 days after the end of the infusion.In conclusion, antisense has been shown to selectively knockdown α2-adrenoceptor expression in specific brain areas. The consequence of this knockdown is a significant attenuation of UK 14,304-induced hypothermia and a reduction in its sedative actions. These changes were fully reversed 4 days after the end of the infusion.British Journal of Pharmacology (1999) 128, 515–522; doi:10.1038/sj.bjp.0702823
British Journal of Pharmacology 01/2009; 128(3):515 - 522. · 4.41 Impact Factor
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ABSTRACT: Studies in human volunteers that can demonstrate proof of concept are attractive in that possible mechanisms and potential new drug treatments can be examined. We have been developing models of anxiety disorders using the inhalation of 7.5% CO(2) for 20 min to model generalised anxiety disorder, as well as using the previously reported 35% CO(2) as a model for panic anxiety. In a double-blind, placebo-controlled, three-way crossover study in 12 healthy volunteer subjects, we compared a full agonist at the benzodiazepine receptor that binds to four alpha-subtypes of the receptor (alpha-1,-2,-3,-5) (alprazolam 1 mg), with zolpidem (5 mg), an agonist selective for the alpha-1 subtype of the gamma amino butyric acid-receptor subtype A (GABA-A) receptor, which is a widely used hypnotic drug. Compared with placebo, both drugs significantly attenuated peak CO(2)-induced changes in subjective feelings after the inhalation of 7.5% CO(2) for 20 min. However, there were fewer significant differences after a single vital capacity inhalation of 35% CO(2), where zolpidem was less efficacious than alprazolam at reducing CO(2)-induced symptoms. In conclusion, our results show that zolpidem shows some anxiolytic efficacy in the 7.5% CO(2) model, similar to alprazolam, and this is the first report of such an effect of zolpidem in a model of anxiety. These and other studies of benzodiazepines in clinical and volunteer studies suggest a definite role of the GABA-A receptor in CO(2)-induced anxiety, and it would be of interest to examine other GABA-A receptor subtype selective drugs, which are now in early phase clinical studies and are showing selective efficacy in pharmacodynamic studies.
Journal of Psychopharmacology 07/2008; 23(2):117-22. · 3.04 Impact Factor
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ABSTRACT: This study sought to test the association between ecstasy-use and abnormal sleep. An anonymous web-based questionnaire containing questions on drug use and sleep was completed by 1035 individuals. From this large sample, a group of 89 ecstasy users were found who reported very little use of other drugs. This "ecstasy-only" group was further divided into two groups of 31 current users and 58 abstinent users. The subjective sleep of current and former ecstasy-only users was compared with that of matched controls. Patients were asked to rate their sleep according to: 1) sleep quality, 2) sleep latency, 3) night time awakenings and 4) total sleep time. Current ecstasy-only users reported significantly worse sleep quality (P < 0.05) and a greater total sleep time (P < 0.001) than controls. It was inferred that these differences might be due to recovery from the acute effects of the drug. Abstinent ecstasy-only users reported significantly more nighttime awakenings than controls (P < 0.01). These subjective findings are in agreement with the objective findings of previous studies showing persistent sleep abnormalities in ecstasy users.
Journal of Psychopharmacology 06/2008; 23(3):249-57. · 3.04 Impact Factor
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D.A. Hince,
S.D Hood,
H. Robinson,
A. Rich,
J. Potokar,
S.J. Davies,
S.V. Argyropoulos,
J. Nash,
K. Morris,
J. Potter,
S. Forward,
L. Morris, D.J. Nutt
Journal of Psychopharmacology. 01/2008; 22.
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10/2007: pages 181 - 199; , ISBN: 9780470986844
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ABSTRACT: There is interest in the development of augmentation therapy in the treatment of anxiety disorders. Recent publications have shown that D-cycloserine can benefit exposure therapy in a group of acrophobic (height phobic) subjects and in patients with social anxiety disorder. These studies were based on the animal data suggesting that drugs acting to enhance glutamate function may be developed to accelerate the behavioural treatment of anxiety disorders. Perhaps by enhancing glutamate/N-methyl-D-aspartate receptor function, learning is thus enhanced. This study examines the effects of D-cycloserine 50 mg on a task that involves learning. We manipulated anxiety levels to model the effects of high anxiety.
To evaluate performance and learning, we used the Manikin task. Two groups of 24 healthy volunteers participated in a double-blind, placebo-controlled study. One group received the inhalation of CO(2) 7.5% to model high anxiety, and the second group received air to represent lower anxiety. Subjects received D-cycloserine 50 mg or placebo, and the Manikin task was performed during the gas inhalation.
There were significant differences in the group inhaling air, but not CO(2), with the D-cycloserine group showing an increase in correct responses. This difference was apparent at several time blocks during the 20-min task. These findings were supported by subjective measures in that participants who received D-cycloserine reported that the task was easier.
We have shown that at lower anxiety levels, D-cycloserine 50 mg improved the performance of this challenging visuospatial cognitive task. This increase in performance was not seen when anxiety was higher, and D-cycloserine did not appear to increase subjective anxiety. These data lend support to the use of D-cycloserine and related glutamate enhancers as cognitive modulators and suggest that the actions of D-cycloserine are not simply related to increased arousal or anxiety.
Psychopharmacologia 10/2007; 193(4):579-85. · 4.08 Impact Factor
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ABSTRACT: The pharmacological treatment of anxiety has a long and chequered history, and recent years have seen a rich development in
the options available to prescribers. Most of the currently used anxiolytic agents act via monoaminergic (chiefly serotonin)
or amino acid (GABA or glutamate) neurotransmitters, and this chapter describes the pharmacology of the major drug groups.
Clinical applications are discussed with respect to the five major anxiety disorders, as well as simple phobia and depression
with concomitant anxiety. Prospective future developments in the field are considered.
03/2006: pages 469-501;
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A. L. HUDSON,
R. GOUGH,
R. TYACKE,
L. LIONE,
M. LALIES,
J. LEWIS,
S. HUSBANDS,
P. KNIGHT,
F. MURRAY,
P. HUTSON, D. J. NUTT
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ABSTRACT: Over several years our group has sought to synthesize and identify selective ligands for imidazoline (I) receptors, in particular the I2 binding site. As a consequence, [3H]2-(2-benzofuranyl)-2-imidazoline (2BFI) has proved extremely useful for binding and autoradiographic studies. More recently we have synthesized a BU series of compounds and examined these for their affinities for both I1 and I2 binding sites. BU224 (2-(4,5-dihydroimidaz-2-yl)-quinoline) shows high affinity for I2 receptors with a Ki of 2.1 nM. BU226 (2-(4,5-dihydroimidaz-2-yl)-isoquinoline) demonstrated slightly higher affinity (Ki 1.4 nM) for I2 receptors, but overall BU224 displayed greater selectivity for I2 over I1 receptors (832-fold) than BU226 (380-fold). Both compounds showed low (μM) affinity for 2-adrenoceptors. Given BU224's ability to cross the blood brain barrier, we predict that its in vivo effects are likely to be mediated via I2 receptors. Brain dialysis revealed BU224 to dose dependently (0–20 mg/kg ip) elevate basal noradrenaline in rat frontal cortex and basal dopamine in striatum. In a rat model of opiate withdrawal, behavioral studies showed that BU224 (10 mg/kg, sc) was able to reduce acute weight loss and diarrhea, but not the number of wet dog shakes associated with the withdrawal syndrome.
Annals of the New York Academy of Sciences 02/2006; 881(1):81 - 91. · 3.15 Impact Factor
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ABSTRACT: Citation: European NeuropsychopharmacologyThe Journal of the European College of Neuropsychopharmacology,Volume 16, Supplement 4, Page S186S.V. Argyropoulos, S.D. Hood, S.J.C. Davies, D.A. Hince, K. Morris, D.J. Nutt, J.P. PotokarPsychopharmacology Unit, University of Bristol, Bristol, United KingdomIntroduction and Methods: Research evidence has suggested that the dopaminergic system may be functioning abnormally in social anxiety disorder (Tiihonen et al, 1997; Schneier et al, 2000). The aim of our study was to assess the effect of the acute administration of a single dose of a dopamine agonist (pramipexole 0.5 mg) and an antagonist (sulpiride 400 mg) on social anxiety symptoms, following anxiogenic challenges (verbal tasks and autobiographical scripts), in patients with DSM-IV social anxiety disorder. This included groups of untreated (n = 10) and treated/remitted (n = 11) subjects on selective serotonin reuptake inhibitors (SSRIs). Each participant was studied in a double-blind crossover design, the two test days being one week apart. Our working hypothesis was that the dopamine antagonist would exacerbate social anxiety in comparison with the dopamine agonist challenge.Results: Untreated patients proved vulnerable to significant increases in anxiety measures following both behavioural challenges on both medications, as measured with a series of visual analogue scales relevant to symptoms of social anxiety (all p < 0.05). The effect of the two drugs was indistinguishable. Following remission with SSRIs, the anxiogenic effect of pramipexole was significantly reduced while that of sulpiride remained largely unaffected.Conclusion: There appears to be an instability of the dopamine system under stress in social anxiety and this is only partly rectified by successful treatment. These results should be seen in the context of the putative mode of action of SSRIs in this condition, and the development of future treatments that may impact directly on the dopamine system.References:1. Schneier, F.R., Liebowitz, M.R., Abi-Dargham, A., et al, 2000. Low dopamine D2 receptor binding potential in social phobia. Am. J. Psychiatry; 157; 457-4592. Tiihonen, J., Kuikka, J., Bergstrom, K., et al, 1997. Dopamine reuptake site densities in patients with social phobia. Am. J. Psychiatry; 154: 239-242 Key-words:ANTIDEPRESSANTS: CLINICALANXIETY DISORDERSDOPAMINE
European Neuropsychopharmacology. 01/2006; 16(4):S186-.
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ABSTRACT: Citation: European NeuropsychopharmacologyThe Journal of the European College of Neuropsychopharmacology,Volume 16, Supplement 4, Page S458S.J.C. Davies1, S.D. Hood2, S.V. Argyropoulos1, D.A. Hince1, K. Morris1, D.J. Nutt1, J. Potokar11University of Bristol, Psychopharmacology Unit, Bristol, United Kingdom2University of Western Australia, School of Psychiatry/Clinical Neurosciences (M521), Perth, AustraliaIntroduction: In a previous study we reported that depletion of serotonin through rapid tryptophan depletion techniques impairs the ability of SSRI or cognitive therapy treated patients with panic disorder or social anxiety disorder to buffer the blood pressure response to stressors (Davies 2005). Compared with the non-tryptophan depletion (normal serotonin) condition, the blood pressure response to stress was an average of 9.0 mmHg systolic/5.7 mmHg diastolic greater under tryptophan depletion (low serotonin) conditions (p = 0.007 for systolic, p = 0.032 for diastolic). There is evidence that the neurotransmitter dopamine, in addition to serotonin, may be implicated in the aetiology of social anxiety disorder (Schneier 2000). In this study we investigate the impact of two conditions which influence dopamine receptor binding, administration of the D2/D3 receptor antagonist sulpiride and the D2/D3 agonist pramipexole, in both untreated patients and patients who had responded to treatment with serotonin promoting drugs.Methods: We studied 21 patients with a DSM-IV diagnosis of generalized social anxiety disorder, 10 symptomatic and untreated, and 11 recovered after treatment with SSRIs. Sixteen were males (76%) and the mean age was 37 years. Using a double-blind randomized crossover design, we compared the mean blood pressure response to public speaking challenges validated in social anxiety disorder (verbal task and autobiographical script) between the two conditions influencing dopamine D2 and D3 receptor binding. The challenges were performed 3 hours after single doses of (a) sulpiride (400 mg) or (b) pramipexole (0.5 mg) given on two separate study days in random order. Blood pressures were measured using standardized methods before and immediately after both stress challenges and the mean change from baseline calculated.Results: Considering all 21 patients, mean diastolic blood pressure response to public speaking challenges were significantly greater under conditions of D2/D3 agonism (pramipexole) than D2/D3 antagonism (sulpiride) (8.5 v 4.5 mmHg, p = 0.024). For the mean systolic blood pressure response there was a non-significant trend in the same direction, the corresponding figures were 9.5 v 7.0 mmHg. In both cases the differences were accounted for by a strikingly lower blood pressure response to stress in the SSRI treated patients under the sulpiride condition compared with both the same patients under the pramipexole condition and with the untreated patients under sulpiride and pramipexole conditions. Mean diastolic blood pressure responses to the stress challenges were 1.6 mmHg in treated patients on sulpiride, 7.6 mmHg in treated patients on pramipexole (p = 0.044 for comparison with sulpiride) and 9.6 and 7.8 mmHg for the untreated patients on sulpiride and pramipexole respectively. Mean systolic blood pressure responses to the challenges were 4.3 mmHg on sulpiride in treated patients compared with 9.0 mmHg on pramipexole, and 10.0 mmHg on each drug in the untreated patients.Conclusions: These data suggest that, in social anxiety disorder dopamine receptor activation, in addition to serotonin throughput, is implicated in control of cardiovascular aspects of the acute stress response. Only under conditions both of optimised serotonin throughput and D2/D3 antagonism are patients with social anxiety disorder able to achieve a significant reduction in the blood pressure response to stress.References:1. Davies S.J.C., Hood S.D., et al., 2005, Depleting brain 5HT enhances both cardiovascular and psychological stress reactivity in humans, J Psychopharm, 19, suppl. 5, A20.2. Schneier F.R., Liebowitz M.R., et al., 2000, Low dopamine D(2) receptor binding potential in social phobia, Am J Psychiatry, 157, 457-459. Key-words:ANXIETY DISORDERSDOPAMINESTRESS
European Neuropsychopharmacology. 01/2006; 16.
