Modafinil and cognitive enhancement in schizophrenia and healthy volunteers: the effects of test battery in a randomised controlled trial.

BACKGROUND: Cognitive deficits in schizophrenia have major functional impacts. Modafinil is a cognitive enhancer whose effect in healthy volunteers is well-described, but whose effects on the cognitive deficits of schizophrenia appear to be inconsistent. Two possible reasons for this are that cognitive test batteries vary in their sensitivity, or that the phase of illness may be important, with patients early in their illness responding better. METHODS: A double-blind, randomised, placebo-controlled single-dose crossover study of modafinil 200 mg examined this with two cognitive batteries [MATRICS Consensus Cognitive Battery (MCCB) and Cambridge Neuropsychological Test Automated Battery (CANTAB)] in 46 participants with under 3 years' duration of DSM-IV schizophrenia, on stable antipsychotic medication. In parallel, the same design was used in 28 age-, sex-, and education-matched healthy volunteers. Uncorrected p values were calculated using mixed effects models. RESULTS: In patients, modafinil significantly improved CANTAB Paired Associate Learning, non-significantly improved efficiency and significantly slowed performance of the CANTAB Stockings of Cambridge spatial planning task. There was no significant effect on any MCCB domain. In healthy volunteers, modafinil significantly increased CANTAB Rapid Visual Processing, Intra-Extra Dimensional Set Shifting and verbal recall accuracy, and MCCB social cognition performance. The only significant differences between groups were in MCCB visual learning. CONCLUSIONS: As in earlier chronic schizophrenia studies, modafinil failed to produce changes in cognition in early psychosis as measured by MCCB. CANTAB proved more sensitive to the effects of modafinil in participants with early schizophrenia and in healthy volunteers. This confirms the importance of selecting the appropriate test battery in treatment studies of cognition in schizophrenia.

Fundamental studies of the adhesion of explosives to textile and non-textile surfaces.

This paper describes the use of atomic force microscopy (AFM) to investigate the interactions between explosives crystals and different surfaces. Crystals of TNT, PETN and RDX were mounted onto tipless AFM cantilevers and repeatedly brought into contact with a range of surfaces (n=15), including textile and non-textile surfaces. The adhesion force during each contact was measured, and the results are presented in this work. The results suggest that explosives crystals display a higher adhesion to smoother, non-textile surfaces, particularly glass. This finding may be of use for forensic explosives investigators when deciding the best types of debris to target for explosives recovery.

The stability of TNT, RDX and PETN in simulated post-explosion soils: Implications of sample preparation for analysis.

Explosives residues in soils may be a useful source of evidence following the detonation of an improvised explosive device (IED), such as a vehicle-borne IED. Soil samples collected from the vicinity of an explosion scene will often be stored for some time prior to analysis, yet explosives residues in soil samples are susceptible to rapid degradation or transformation. Although some research has assessed the use of different storage temperatures with a view to reducing explosives' degradation over time, further research examining the degradation of explosives in soil when stored under a variety of storage conditions is crucial to determine the optimal sample collection and storage procedures for soil containing explosives residues. In this work, three different soils were spiked with solutions of TNT, RDX and PETN and stored either at room temperature, refrigerated or frozen. Samples were extracted over 6 weeks, with additional samples gamma-irradiated or nitrogen purged prior to storage. Experimental results indicate that TNT underwent very rapid degradation at room temperature, attributed to microbial action, whereas PETN and RDX proved to be more stable. Gamma irradiation and nitrogen purging proved of some benefit for mitigating TNT degradation, with lower storage temperatures ultimately proving the most effective method of mitigating degradation.

Investigations into the initial composition of latent fingermark lipids by gas chromatography-mass spectrometry.

A more comprehensive understanding of the variability of latent fingermark composition is essential to improving current fingermark detection capabilities in an informed manner. Gas chromatography-mass spectrometry was used to examine the composition of the lipid fraction of latent fingermarks collected from a population of over 100 donors. Variations in the appearances of chromatograms from different donors were apparent in the relative peak sizes of compounds including free fatty acids, squalene, cholesterol and wax esters. Principal component analysis was used as an exploratory tool to explore patterns in this variation, but no correlation to donor traits could be discerned. This study also highlights the practical and inherent difficulties in collecting reproducible samples.

Negative cognition, affect, metacognition and dimensions of paranoia in people at ultra-high risk of psychosis: a multi-level modelling analysis.

BACKGROUND: Paranoia is one of the commonest symptoms of psychosis but has rarely been studied in a population at risk of developing psychosis. Based on existing theoretical models, including the proposed distinction between 'poor me' and 'bad me' paranoia, we aimed to test specific predictions about associations between negative cognition, metacognitive beliefs and negative emotions and paranoid ideation and the belief that persecution is deserved (deservedness). METHOD: We used data from 117 participants from the Early Detection and Intervention Evaluation for people at risk of psychosis (EDIE-2) trial of cognitive­behaviour therapy, comparing them with samples of psychiatric in-patients and healthy students from a previous study. Multi-level modelling was utilized to examine predictors of both paranoia and deservedness, with post-hoc planned comparisons conducted to test whether person-level predictor variables were associated differentially with paranoia or with deservedness. RESULTS: Our sample of at-risk mental state participants was not as paranoid, but reported higher levels of 'bad-me' deservedness, compared with psychiatric in-patients. We found several predictors of paranoia and deservedness. Negative beliefs about self were related to deservedness but not paranoia, whereas negative beliefs about others were positively related to paranoia but negatively with deservedness. Both depression and negative metacognitive beliefs about paranoid thinking were specifically related to paranoia but not deservedness. CONCLUSIONS: This study provides evidence for the role of negative cognition, metacognition and negative affect in the development of paranoid beliefs, which has implications for psychological interventions and our understanding of psychosis.

Psychological treatments for early psychosis can be beneficial or harmful, depending on the therapeutic alliance: an instrumental variable analysis.

BACKGROUND: The quality of the therapeutic alliance (TA) has been invoked to explain the equal effectiveness of different psychotherapies, but prior research is correlational, and does not address the possibility that individuals who form good alliances may have good outcomes without therapy. METHOD: We evaluated the causal effect of TA using instrumental variable (structural equation) modelling on data from a three-arm, randomized controlled trial of 308 people in an acute first or second episode of a non-affective psychosis. The trial compared cognitive behavioural therapy (CBT) over 6 weeks plus routine care (RC) v. supportive counselling (SC) plus RC v. RC alone. We examined the effect of TA, as measured by the client-rated CALPAS, on the primary trial 18-month outcome of symptom severity (PANSS), which was assessed blind to treatment allocation. RESULTS: Both adjunctive CBT and SC improved 18-month outcomes, compared to RC. We showed that, for both psychological treatments, improving TA improves symptomatic outcome. With a good TA, attending more sessions causes a significantly better outcome on PANSS total score [effect size -2.91, 95% confidence interval (CI) -0.90 to -4.91]. With a poor TA, attending more sessions is detrimental (effect size +7.74, 95% CI +1.03 to +14.45). CONCLUSIONS: This is the first ever demonstration that TA has a causal effect on symptomatic outcome of a psychological treatment, and that poor TA is actively detrimental. These effects may extend to other therapeutic modalities and disorders.

Modafinil combined with cognitive training is associated with improved learning in healthy volunteers--a randomised controlled trial.

Improving cognition in people with neuropsychiatric disorders remains a major clinical target. By themselves pharmacological and non-pharmacological approaches have shown only modest effects in improving cognition. In the present study we tested a recently-proposed methodology to combine CT with a 'cognitive-enhancing' drug to improve cognitive test scores and expanded on previous approaches by delivering combination drug and CT, over a long intervention of repeated sessions, and used multiple tasks to reveal the cognitive processes being enhanced. We also aimed to determine whether gains from this combination approach generalised to untrained tests. In this proof of principle randomised-controlled trial thirty-three healthy volunteers were randomised to receive either modafinil or placebo combined with daily cognitive training over two weeks. Volunteers were trained on tasks of new-language learning, working memory and verbal learning following 200 mg modafinil or placebo for ten days. Improvements in trained and untrained tasks were measured. Rate of new-language learning was significantly enhanced with modafinil, and effects were greatest over the first five sessions. Modafinil improved within-day learning rather than between-day retention. No enhancement of gains with modafinil was observed in working memory nor rate of verbal learning. Gains in all tasks were retained post drug-administration, but transfer effects to broad cognitive abilities were not seen. This study shows that combining CT with modafinil specifically elevates learning over early training sessions compared to CT with placebo and provides a proof of principle experimental paradigm for pharmacological enhancement of cognitive remediation.

Improved quality of life over one year is associated with improved adherence in patients with schizophrenia.

AIM: Quality of life (QoL) is increasingly considered an important outcome in health research. We wished to explore the determinants of change in QoL in patients with schizophrenia over the course of a one-year RCT. METHODS: Predictors of change in observer-rated QoL (Quality of Life Scale: QLS) were assessed in 363 patients with schizophrenia during the CUtLASS clinical trial. RESULTS: Change in QLS score over the course of a year correlated with change in psychotic and depressive symptoms and treatment adherence. Linear regression showed that improvement in QoL was predicted by reduction in negative and depressive symptoms and improvement in adherence rating. These three change scores together explained 38% of the variance in QLS change. Exploration of the direction of any possible causal effect, using TETRAD, indicated that improved adherence leads to improved QoL, and that change in depression also leads to QoL change. The relationship between QoL and negative symptoms suggests that greater social activity (reflected as better QoL scores) improves negative symptoms. Such a direct relationship between treatment adherence and QoL has not been reported before. CONCLUSION: Improving adherence to medication would appear to be a key approach to improving measured quality of life in people with schizophrenia.

Affective instability prior to and after thoughts about self-injury in individuals with and at-risk of psychosis: a mobile phone based study.

It has been proposed that affective instability may be associated with thoughts about self-injury. The aim of this study was to test the hypotheses that instability in feelings of depression, but not anxiety, guilt, or hostility, would predict greater concurrent and subsequent thoughts about self-injury. Thirty-six individuals with psychosis completed questions on touch-screen mobile phones at semi-random times each day for one week. The instability of depression predicted greater concurrent and subsequent levels of thoughts about self-injury, even when controlling for depression level. Conversely, self-injurious thoughts predicted more stable depression. The instability of guilt, anxiety, and hostility did not significantly predict levels of thoughts about self-injury. Results indicate that a variable depressive state may trigger the onset of thoughts about self-injury, which increases the risk of its subsequent recurrence. The onset of self-injurious thoughts may, however, have a stabilizing effect on subsequent depression.

Cognitive-self consciousness and metacognitive beliefs: Stress sensitization in individuals at ultra-high risk of developing psychosis.

OBJECTIVE: Metacognitive beliefs (MCB) may guide information and attention processes, increasing affective and symptomatic reactions to stressful events. Cognitive self-consciousness (CSC; i.e., a preoccupation with one's thoughts) may increase awareness of MCB, potentially triggering the onset of psychotic symptoms. This study tested the hypotheses that (1), MCB would moderate affective and symptomatic reactions to stress in individuals at ultra-high risk (UHR) of developing psychosis, and (2), greater CSC would precede worsening in psychotic symptoms in individuals with strong MCB. METHOD: Twenty-seven individuals at UHR of developing psychosis completed a self-report diary when prompted by an electronic wristwatch several times each day for 6 days (experience sampling). RESULTS: MCB moderated the association between affective, but not symptomatic, responses to social stress. CSC preceded the subsequent occurrence of hallucinations in individuals who reported strong beliefs about the need to control their thoughts. CONCLUSIONS: The data suggest that MCB sensitize an individual to social stressors. CSC may represent times where an individual is aware that their thoughts are uncontrollable, and therefore contradicting their MCB, motivating them to make an external attribution. The findings have implications for improving the effectiveness of interventions for people experiencing hallucinations.

Affective variability predicts suicidal ideation in individuals at ultra-high risk of developing psychosis: an experience sampling study.

OBJECTIVE: There is a suggestion in the literature that more variable affect increases suicidal ideation through the repeated re-activation of latent suicidal cognitions. The hypothesis that affective variability would be a better predictor of suicidal ideation and related behaviour than affect level was tested in individuals at ultra-high risk of developing psychosis. This study also examined the prediction that affective variability is a suicide-specific mechanism and would not predict levels of attenuated psychotic phenomena. METHOD: Twenty-seven ultra-high risk individuals were required to complete ambulant ratings of their affect when prompted by an electronic wristwatch for six days (the experience sampling method). In the debriefing session, participants were assessed with a semi-structured interview (the Comprehensive Assessment of At-Risk Mental State), which assessed the severity and frequency of suicidality and psychosis-related phenomena. RESULTS: The variability of negative and positive affect was predictive of the frequency of suicidal thoughts and behaviour. More variable negative, but not positive affect, was also associated with more severe suicidal ideation and related behaviour. Affect variability was not significantly related to the severity of attenuated psychotic phenomena. CONCLUSION: Affective variability appears to be a specific risk factor for suicidal ideation in individuals at ultra-high risk of developing psychosis. Early intervention should focus on providing individuals with skills for regulating their own affect.

Emotional and symptomatic reactivity to stress in individuals at ultra-high risk of developing psychosis.

BACKGROUND: The stress-vulnerability model of psychosis continues to be influential. The aim of this study was to compare emotional and symptomatic responses to stress in individuals at ultra-high risk (UHR) of developing psychosis, in age- and gender-matched healthy controls, and in patients with non-affective psychosis. METHOD: A total of 27 UHR, 27 psychotic and 27 healthy individuals completed the experience sampling method, an ambulant diary technique, where they were required to fill in self-assessment questions about their emotions, symptoms and perceived stress at semi-random times of the day for 6 days. Quesionnaire and interview assessments were also completed. RESULTS: Multilevel regression analyses showed that individuals at UHR of developing psychosis reported greater negative emotions in response to stress than the healthy individuals. Against the initial hypotheses, the UHR individuals also experienced greater emotional reactivity to stress when compared with the patient group. No significant differences were observed between the patients and the non-clinical sample. Stress measures significantly predicted the intensity of psychotic symptoms in UHR individuals and patients, but the extent of this did not significantly differ between the groups. CONCLUSIONS: Individuals at UHR of developing psychosis may be particularly sensitive to everyday stressors. This effect may diminish after transition to psychosis is made and in periods of stability. Subtle increases in psychotic phenomena occur in response to stressful events across the continuum of psychosis.

The role of metacognitive beliefs in stress sensitisation, self-esteem variability, and the generation of paranoia.

INTRODUCTION. Stress sensitisation may play a key role in the formation of psychosis. The authors examined whether metacognitive beliefs and self-esteem moderate affective response to stress, and whether subtle fluctuations in self-esteem act as a mediator between stress and attenuated psychotic phenomena. METHOD. 70 healthy volunteers completed two conditions of the same experimental tasks, which were designed to be either neutral or stress inducing. Ambulant assessments of negative affect, self-esteem, and suspicious thoughts were taken before and after each task, and standardised questionnaires were completed at the beginning or end of each session. RESULTS. Metacognitive belief subscales, but not self-esteem, moderated the association between stress and resultant negative affect, and negative affect and suspicious thinking. Individuals who placed greater emphasis on controlling their thoughts had greater variability in their self-esteem during the stress condition, which in turn predicted the severity of their attenuated psychotic phenomena. DISCUSSION. Metacognitive beliefs may sensitise an individual to minor stressors, by increasing affective reactivity and causing subtle shifts in appraisals of self-worth. Psychosocial intervention may wish to target these beliefs in order to desensitise an individual to negative events.

Experience sampling research in individuals with mental illness: reflections and guidance.

OBJECTIVE: The experience sampling method (ESM) represents a valuable way of assessing clinical phenomena in real world settings and across time. Despite its theoretical advantages, using this methodology in psychiatric populations is challenging. This paper acts as a guide to researchers wishing to employ this approach when investigating mental illness. METHOD: The contents represent the opinions of researchers around the United Kingdom and the Netherlands who are experienced at using the ESM. RESULTS: In ESM studies, participants are required to fill in questions about their current thoughts, feelings and experiences when prompted by an electronic device (e.g. a wristwatch, PDA). Entries are typically made at fixed or random intervals over 6 days. This article outlines how to design and validate an ESM diary. We then discuss which sampling procedure to use and how to increase compliance through effective briefing and telephone sessions. Debriefing, data management and analytical issues are considered, before suggestions for future clinical uses of the ESM are made. CONCLUSION: The last decade has seen an increase in the number of studies employing the ESM in clinical research. Further research is needed to examine the optimal equipment and procedure for different clinical groups.

Analytical separations of mammalian decomposition products for forensic science: a review.

The study of mammalian soft tissue decomposition is an emerging area in forensic science, with a major focus of the research being the use of various chemical and biological methods to study the fate of human remains in the environment. Decomposition of mammalian soft tissue is a postmortem process that, depending on environmental conditions and physiological factors, will proceed until complete disintegration of the tissue. The major stages of decomposition involve complex reactions which result in the chemical breakdown of the body's main constituents; lipids, proteins, and carbohydrates. The first step to understanding this chemistry is identifying the compounds present in decomposition fluids and determining when they are produced. This paper provides an overview of decomposition chemistry and reviews recent advances in this area utilising analytical separation science.

Substituted naphthoquinones as novel amino acid sensitive reagents for the detection of latent fingermarks on paper surfaces.

In this paper, we present our preliminary studies into naphthoquinones as novel reagents for the detection of latent fingermarks on paper. Latent fingermarks deposited on paper substrates were treated with solutions of selected naphthoquinones in ethyl acetate/HFE-7100, with subsequent heating. The selected compounds were 1,4-dihydroxy-2-naphthoic acid, 1,2-naphthoquinone-4-sulfonate, 2-methoxy-1,4-naphthoquinone and 2-methyl-1,4-naphthoquinone. All of the tested compounds yielded purple-brown visible fingermarks, which also exhibited photoluminescence when illuminated with a high intensity filtered light source at 555 nm and viewed through red goggles. Indirect heat using an oven at 150°C for 1h was found to be superior to direct heat with an iron, which while providing faster development lead to increased levels of background colouration. Luminescence spectrophotometry revealed differences in photoluminescence characteristics for fingermarks developed with the different naphthoquinones, with excitation over the range 530-590 nm. Luminescence spectrophotometry of developed lysine, glycine and serine spots on paper was used to confirm that the naphthoquinones were reacting with amino acids in the latent fingermark.

A capillary electrophoresis method for the determination of selected biogenic amines and amino acids in mammalian decomposition fluid.

A simple capillary zone electrophoresis method for the determination of selected biogenic amines (tyramine and tryptamine) and amino acids (tryptophan, phenylalanine and tyrosine) in mammalian decomposition fluids is presented. Separations were carried out in a fused silica capillary (75microm i.d., total length 65cm, effective length 56cm) with detection by ultraviolet absorbance spectrophotometry at 200nm. In order to improve resolution and total analysis time, the method was subjected to optimisation utilising a chemometric approach. A screening design was carried out followed by a central composite design (CCD), using peak resolution and total analysis time as response factors. The influences of four experimental variables (pH, background electrolyte concentration, percentage of organic modifier (methanol) and applied voltage) were investigated. Optimum separation conditions were determined to be; a background electrolyte of boric acid (70mM) adjusted to pH 9.5 with 0.1M sodium hydroxide with 32% methanol (v/v). Applied voltage was 30kV, with the resulting current being less than 26microA. Under these conditions the analytes were separated within 12min. Tryptamine, tyramine, tryptophan, tyrosine and phenylalanine were identified by migration time and spiking in porcine decomposition fluids.

Patient factors associated with receipt of combination antipsychotic drug therapy in the treatment of schizophrenia.

Although discouraged in available treatment guidelines, combination antipsychotic prescribing (CAP) is a common practice in the treatment of schizophrenia. Patient characteristics may be associated with this type of treatment. A dataset (N = 363) derived from parallel randomised controlled trials was interrogated to identify factors associated with the receipt of CAP, and a logistic regression analysis was used to predict the occurrence of CAP. Significant predictors of CAP were longer illness, low global functioning score and high treatment adherence rating. Co-prescribed patients received a higher combined dose.

Effects of cognitive therapy on the longitudinal development of psychotic experiences in people at high risk of developing psychosis.

BACKGROUND: There have been recent advances in the identification of people at high risk of psychosis and psychological treatments have shown promise for prevention. AIMS: To compare the longitudinal course of psychotic experiences and emotional dysfunction in high-risk participants receiving cognitive therapy with those receiving treatment as usual. METHOD: Data from a recent randomised controlled trial of cognitive therapy for people at risk of developing psychosis were utilised to examine three different statistical models that were based on 432 measurements of psychotic experiences and 421 of emotional dysfunction (anxiety-depression) contributed by 57 participants across the 13 measurement occasions (monthly monitoring for a year). RESULTS: Psychotic experiences and emotional dysfunction were correlated and decreased significantly over the course of the study, with most improvement in the early months. The reduction in positive symptoms, but not emotional dysfunction, was enhanced by allocation to cognitive therapy. CONCLUSIONS: Psychotic experiences and emotional dysfunction appear to interact in people at risk of developing psychosis. There appears to be a specific benefit of cognitive therapy.

Investigation into the temporal stability of aqueous standard solutions of psilocin and psilocybin using high performance liquid chromatography.

This paper reports an investigation into the temporal stability of aqueous solutions of psilocin and psilocybin reference drug standards over a period of fourteen days. This study was performed using high performance liquid chromatography utilising a (95:5% v/v) methanol: 10 mM ammonium formate, pH 3.5 mobile phase and absorption detection at 269 nm. It was found that the exclusion of light significantly prolonged the useful life of standards, with aqueous solutions of both psilocin and psilocybin being stable over a period of seven days.