Alison Diaper

A validation of the 7.5% CO2 model of GAD using paroxetine and lorazepam in healthy volunteers

The inhalation of 7.5% carbon dioxide (CO2) in healthy subjects produces an increase in blood pressure and heart rate, and increased feelings of anxiety, fear and tension (Bailey et al. 2005). As this state is similar to that of general anxiety rather than panic, we further validated this by examining the effects of anxiolytic medication. Two separate studies in healthy volunteers are described; study one is a double-blind, placebo-controlled study of a single dose of 2mg lorazepam and study two describes the effects of 21 days of treatment with paroxetine. Gas challenges were air and 7.5% CO2 inhaled for 20 minutes, delivered on day 0 (before treatment) and day 21 (after treatment) in the paroxetine study. Subjective effects were measured using visual analogue scales and questionnaires. When compared with placebo, lorazepam 2mg significantly reduced peak CO2-induced subjective fear, feelings of wanting to leave, tension and worry. In the paroxetine study, when compared with day 0, day 21 showed a significantly attenuated peak CO2-induced nervousness and a trend for reduced ratings of anxiety, fear, feel like leaving, tense and worried. In these studies we have shown that this CO2 model of anxiety is sensitive to lorazepam and to a lesser extent paroxetine. This gives support to its utility as an experimental model of general anxiety disorder in healthy volunteers.

Preliminary evidence of anxiolytic effects of the CRF(1) receptor antagonist R317573 in the 7.5% CO(2) proof-of-concept experimental model of human anxiety

We have validated the use of prolonged inhalation of 7.5% carbon dioxide (CO2) as a human model of anxiety and have shown that drugs from two prototypical classes of anxiolytics, benzodiazepines and a serotonin reuptake inhibitor, attenuate CO2-induced symptoms (Bailey et al., 2007a). Preclinical evidence suggests that drugs acting at the corticotropin-releasing factor (CRF) system may be useful for the treatment of depression, anxiety, and other stress-related disorders (Valdez, 2006), hence we have now examined the effects of a CRF1 receptor antagonist in the 7.5% CO2 model. In a randomized double-blind, placebo-controlled, study in 32 healthy participants we examined the effects of 7 days of treatment with the CRF1 receptor antagonist, R317573, at a dose that shows a favourable safety profile and is comparable with those effective in preclinical models (40 mg). On day 8, eight of the placebo-treated group received lorazepam (LZP) 2 mg as a positive control. All participants underwent 20 min inhalation of 7.5% CO2-enriched air. Subjective reports of peak gas effects were assessed using visual analogue scales and questionnaires. The mean age of participants was 26 years, and 13 were male. The peak effects of CO2 were expressed as a difference from baseline scores obtained while breathing air alone. Compared with placebo (PLAC), both drug groups showed a decrease in all subjective symptoms, total score on the panic symptom inventory (CRF 11 [2.6], PLAC 16.4 [3.1], LZP 2.9 [3.0]) and a generalized anxiety disorder symptom scale (CRF 2.2 [1.5], PLAC 8.2 [2.2], LZP 1.1 [1.5]). We have shown that a drug that acts to inhibit the CRF1 receptor shows efficacy in the 7.5% CO2 model of anxiety in healthy participants.

Pharmacological strategies for detoxification.

Detoxification refers to the safe discontinuation from a substance of dependence and is distinct from relapse prevention. Detoxification usually takes between a few days and a few weeks to complete, depending on the substance being misused, the severity of dependence and the support available to the user. Psychosocial therapies alongside pharmacological treatments are essential to improve outcome. The dependencies considered in this overview are detoxification from opioids (with methadone, buprenorphine, α2‐adrenoceptor agonists and adjunct medications), alcohol (with benzodiazepines, anti‐glutamatergics and γ‐aminobutyric acid (GABA)‐ergic drugs), stimulants and cannabis (with no clear recommended pharmacological treatments), benzodiazepines (with dose tapering) and nicotine (with nicotine replacement therapy, antidepressants and partial agonists). Evidence is limited by a lack of controlled trials robust enough for review bodies, and more research is required into optimal treatment doses and regimes, alone and in combination.

Effects of 7.5% CO(2) inhalation on allocation of spatial attention to facial cues of emotional expression

Increased vigilance to threat-related stimuli is thought to be a core cognitive feature of anxiety. We sought to investigate the cognitive impact of experimentally induced anxiety, by means of a 7.5% CO2 challenge, which acts as an unconditioned anxiogenic stimulus, on attentional bias for positive and negative facial cues of emotional expression in the dot-probe task. In two experiments we found robust physiological and subjective effects of the CO2 inhalation consistent with the claim that the procedure reliably induces anxiety. Data from the dot-probe task demonstrated an attentional bias to emotional facial expressions compared with neutral faces regardless of valence (happy, angry, and fearful). These attentional effects, however, were entirely inconsistent in terms of their relationship with induced anxiety. We conclude that the previously reported poor reliability of this task is the most parsimonious explanation for our conflicting findings and that future research should develop a more reliable paradigm for measuring attentional bias in this field.

Evaluation of the effects of venlafaxine and pregabalin on the carbon dioxide inhalation models of Generalised Anxiety Disorder and panic

Previous studies have shown that subjective and objective symptoms of anxiety induced by 7.5% CO2 inhalation can be attenuated by anxiolytics such as lorazepam and, to a lesser extent, paroxetine. Venlafaxine and pregabalin, two other licensed treatments for Generalised Anxiety Disorder, were used to further investigate the 7.5% and 35% CO2 models of anxiety in healthy volunteers. Fifty-four participants were randomised to receive either placebo, venlafaxine or pregabalin. Study treatments were dosed incrementally over a three week period, to reach daily doses of 150mg venlafaxine and 200mg pregabalin by the CO2 challenge test day. Participants inhaled air 7.5% CO2 for 20 minutes (single-blind presentation), and a non-blinded single vital capacity of 35% CO2. Subjective ratings were recorded before and after each inhalation. Both 7.5% and 35% CO2 inhalations produced the expected effects of increased ratings of symptoms of panic and anxiety, with increased blood pressure and heart rate. No significant treatment effects were found, although there were trends towards a reduction in feeling tense and nervous by both drugs compared with placebo during the 7.5% CO2 challenge, and a reduction in alertness generally in the venlafaxine group compared with the pregabalin group. In contrast with the clear anxiolytic effects of benzodiazepines reported in several previous CO2 studies, these findings suggest that the anxiogenic effects of CO2 challenges are not significantly influenced by these serotonergic and GABAergic anxiolytics. This may be due to a lack of sensitivity of the CO2 challenges in healthy volunteers to these drug types.

The effects of 7.5% carbon dioxide inhalation on task performance in healthy volunteers

Studies have shown that anxiety can positively or negatively affect performance with respect to focusing of attention or distractibility, subjective workload and effort (Humphreys and Revelle, 1984). The inhalation of carbon dioxide (CO2) is associated with physiological and psychological effects of anxiety (Bailey et al., 2005) but its effects on performance have rarely been reported. The studies reported here looked at the effects of CO2 inhalation on physiological and subjective measures and performance on two tasks. Eight healthy male participants completed a tracking task with a reaction time component, and 12 healthy participants (six male) completed a complex target identification task. Tasks were performed during 20-min inhalations of 7.5% CO2/21% O2/71.5% N2 mixture or medical air. Continuous heart rate and blood pressure measures were taken, in addition to subjective measures of mood and workload. In comparison with air, CO2 increased heart rate and blood pressure, increased subjective scores of panic, anxiety, fear, and tension, and reduced subjective scores of relaxation and happiness. Attention was focussed when inhaling CO2 during the simple task, and central demand was greater when inhaling CO2 during the complex task. Therefore, inhalation of 7.5% CO2 produces effects on task performance which are consistent with anxiety.

A randomised trial of the effect of the glycine reuptake inhibitor Org 25935 on cognitive performance in healthy male volunteers

Cognitive impairment is integral to many neurological illnesses. Specific enhancement of glutamatergic transmission may improve memory and learning. Org 25935 increases the synaptic availability of glycine, an obligate co‐agonist with glutamate at N‐methyl‐d‐aspartate receptors. We hypothesised that Org 25935 would acutely improve the learning and memory of healthy volunteers.

Changes in cardiovascular function after venlafaxine but not pregabalin in healthy volunteers: a double-blind, placebo-controlled study of orthostatic challenge, blood pressure and heart rate

It is generally thought that venlafaxine raises blood pressure at higher doses; however, some studies have found no effect or a decrease in blood pressure. The aim of this study was to evaluate the cardiovascular (CV) effects of 3 weeks of dosing with venlafaxine, pregabalin and placebo on young healthy adults.

The effect of a clinically effective and non-effective dose of lorazepam on 7.5% CO2-induced anxiety

Symptoms of anxiety induced by 7.5% CO2 inhalation can be attenuated by acute administration of GABAA receptor anxiolytics such as lorazepam and alprazolam. This study investigated if these effects are dose‐related, by comparing a 0.5 mg dose (considered non‐clinically effective) and a 2 mg dose of lorazepam (clinically effective) on 7.5% CO2 inhalation.

Buprenorphine/naloxone versus methadone and lofexidine in community stabilisation and detoxification: A randomised controlled trial of low dose short-term opiate-dependent individuals

Buprenorphine/naloxone, methadone and lofexidine are medications with utility in the treatment of opiate withdrawal. We report the first randomised controlled trial to compare the effects of these two medications on withdrawal symptoms and outcome during opiate induction/stabilisation and detoxification. A double-blind randomised controlled trial was conducted in an outpatient satellite clinic of a specialist drug service. Eighty opiate dependent individuals meeting DSM-IV criteria for opiate dependence, using ⩽ ½ g heroin smoked/chased or ¼ g heroin injected or ⩽ 30mg methadone, with ⩽ 3 years of opioid dependency, underwent a short-term opiate treatment programme involving induction/stabilisation on methadone 30mg or buprenorphine/naloxone 4mg/1mg, followed by detoxification (where the methadone group was assisted by lofexidine). The main outcome measures were urine drug screens for opiates and withdrawal and craving questionnaires. There were no overall differences in positive urine drug screens and drop-outs during any phase of the study. During induction/stabilisation, withdrawal symptoms subsided more slowly for buprenorphine/naloxone than for methadone, and craving was significantly higher in the buprenorphine/naloxone group (p<0.05, 95% confidence interval −3.5, −0.38). During detoxification, withdrawal symptoms were significantly greater and the peak of withdrawal was earlier for the methadone/lofexidine group than the buprenorphine/naloxone group (p<0.01, 95% confidence interval 3.0, 8.3). Methadone/lofexidine and buprenorphine/naloxone had comparable outcomes during rapid outpatient stabilisation and detoxification in low dose opiate users.