Changes in smoking status, mental state and plasma clozapine concentration: retrospective cohort evaluation

Aims and method. To investigate the percentage of patients who commenced smoking after transferring out of a non-smoking forensic psychiatric unit, the corresponding clozapine dose adjustments, the effects on plasma clozapine/norclozapine concentrations and observed changes in mental state. We reviewed the notes and plasma clozapine/norclozapine concentrations of 46 patients transferred to medium secure units between July 2008 and December 2013. Results. Thirty-five patients commenced smoking. Their median clozapine dose was increased by 50 mg/d. In the non-smokers, the median clozapine dose remained unchanged. Plasma clozapine/norclozapine concentrations were significantly reduced in smokers despite dosage adjustment. Eighteen patients experienced deterioration in mental state after transfer; almost all these patients were smokers. Clinical implications. Approximately three-quarters of patients who were non-smokers by virtue of being in a secure non-smoking environment commenced smoking after transfer. Monitoring of clozapine serum levels and assessment of mental state in the immediate period after a change in smoking status is indicated

Glycopyrrolate in comparison to hyoscine hydrobromide and placebo in the treatment of hypersalivation induced by clozapine (GOTHIC1): a feasibility study

Background: Clozapine-induced hypersalivation (CIH) is a common side effect of clozapine treatment and is disliked by clozapine patients, potentially threatening adherence to clozapine treatment. We proposed a trial of alternative medications, hyoscine and glycopyrrolate, for the treatment of CIH and the primary objective of the feasibility study was to assess the recruitment and retention of community clozapine patients as well as assess the metrics of the primary hypersalivation measure. Methods: This 11-month trial took place in two NHS trusts in northwest UK. Participants were community-dwelling clozapine patients aged 18-65 years who were suffering from CIH, and were recruited from community mental health clinics. They were randomised using a telephone randomisation service to receive either hyoscine (1 week at 0.6mg daily, 3 weeks at 0.9mg daily), glycopyrrolate (1 week at 2mg daily, 3 weeks at 3mg daily) or placebo. Participants and investigators were blinded to which study arm the participants had been randomised to. We collected data on salivation levels and side effects on a weekly basis and also assessed cognition at the beginning and end of the trial. We also interviewed a sample of participants after the trial to gather information on their experience of having taken part. Results: 138 potential participants agreed to being contacted by researchers about participation in the trial and of these, 29 participants were randomised. Of these, four participants exited the trial before taking any trial medication, and two participants left the study owing to concerns of side effects. Data from four participants was missing, and complete data was available for 19 participants who competed the trial. The mean recruitment rate overall was 1.3 participants per site per month, and the overall retention rate was 76%. Interview data suggested that participants’ experiences of trial participation was overwhelmingly positive. Conclusions: The feasibility study demonstrated that a trial of alternative medications in the treatment of CIH is feasible; patients were willing to be randomised to the trial and retention rate was high. Trial registration: ClinicalTrials.gov NCT02613494, registered 24 November 2015. https://clinicaltrials.gov/ct2/show/NCT0261349

Facial emotion recognition and sleep in mentally disordered patients: A natural experiment in a high security hospital

We investigated the relationship between a change in sleep quality and facial emotion recognition accuracy in a group of mentally-disordered inpatients at a secure forensic psychiatric unit. Patients whose sleep improved over time also showed improved facial emotion recognition while patients who showed no sleep improvement showed no change in emotion recognition

The clinical effectiveness and cost effectiveness of clozapine for inpatients with severe borderline personality disorder (CALMED study): A randomised placebo-controlled trial

Background: Data from case series suggest that clozapine may benefit inpatients with borderline personality disorder (BPD), but randomised trials have not been conducted. Methods: Multicentre, double-blind, placebo-controlled trial. We aimed to recruit 222 inpatients with severe BPD aged 18 or over, who had failed to respond to other antipsychotic medications. We randomly allocated participants on a 1:1 ratio to receive up to 400mg of clozapine per day or an inert placebo using a remote web-based randomisation service. The primary outcome was total score on the Zanarini Rating scale for Borderline Personality Disorder (ZAN-BPD) at six months. Secondary outcomes included self-harm, aggression, resource use and costs, side effects and adverse events. We used a modified intention to treat analysis (mITT) restricted to those who took one or more dose of trial medication, using a general linear model fitted at six months adjusted for baseline score, allocation group and site. Results: The study closed early due to poor recruitment and the impact of the COVID-19 pandemic. Of 29 study participants, 24 (83%) were followed up at six months, of whom 21 (72%) were included in the mITT analysis. At six months, 11 (73%) participants assigned to clozapine and 6 (43%) of those assigned to placebo were still taking trial medication. Adjusted difference in mean total ZAN-BPD score at six months was -3.86 (95% Confidence Intervals = -10.04 to 2.32, p=0.22). There were 14 serious adverse events; six in the clozapine arm and eight in the placebo arm of the trial. There was little difference in the cost of care between groups. Interpretation: We recruited insufficient participants to test the primary hypothesis. The study findings highlight problems in conducting placebo-controlled trials of clozapine and in using clozapine for people with BPD, outside specialist inpatient mental health units. Trial registration ISRCTN18352058. https://doi.org/10.1186/ISRCTN1835205

A randomised double-blind placebo-controlled trial of minocycline and/or omega-3 fatty acids added to treatment as usual for at risk Mental States: The NAYAB study.

BackgroundInflammatory mechanisms are thought to contribute to the onset of psychosis in persons with an at-risk mental state (ARMS). We investigated whether the anti-inflammatory properties of minocycline and omega-3 polyunsaturated fatty acids (omega-3), alone or synergistically, would prevent transition to psychosis in ARMS in a randomised, double-blind, placebo-controlled trial in Pakistan.Methods10,173 help-seeking individuals aged 16-35 years were screened using the Prodromal Questionaire-16. Individuals scoring 6 and over were interviewed using the Comprehensive Assessment of At-Risk Mental States (CAARMS) to confirm ARMS. Participants (n = 326) were randomised to minocycline, omega-3, combined minocycline and omega-3 or to double placebo for 6 months. The primary outcome was transition to psychosis at 12 months.FindingsForty-five (13.8 %) participants transitioned to psychosis. The risk of transition was greater in those randomised to omega-3 alone or in combination with minocycline (17.3.%), compared to 10.4 % in those not exposed to omega-3; a risk-ratio (RR) of 1.67, 95 % CI [0.95, 2.92] p = 0.07. The RR for transitions on minocycline vs. no minocycline was 0.86, 95 % CI [0.50, 1.49] p > 0.10. In participants who did not become psychotic, CAARMS and depression symptom scores were reduced at six and twelve months (mean CAARMS difference = 1.43; 95 % CI [0.33, 1.76] p InterpretationIn keeping with other studies, omega-3 appears to have beneficial effects on ARMS and mood symptom severity but it increased transition to psychosis, which may reflect metabolic or developmental consequences of chronic poor nutrition in the population. Transition to psychosis was too rare to reveal a preventative effect of minocycline but minocycline did not improve symptom severity. ARMS symptom severity and transition to psychosis appear to have distinct pathogeneses which are differentially modulated by omega-3 supplementation.FundingThe study was funded by the Stanley Research Medical Institute

Childhood Trauma and Psychosis: The case for exploring Eye Movement Desensitisation and Reprocessing (EMDR) as an adjunctive treatment for schizophrenia

There is an association between childhood trauma and the development of psychosis in adulthood and a treatment recommended to reduce the symptoms of trauma is Eye Movement Desensitisation and Reprocessing (EMDR). Studies of EMDR in adults with psychotic experiences and a history of trauma have shown encouraging results. As psychosis is a core feature of schizophrenia, and many persons with schizophrenia will have experienced childhood trauma, we review the evidence that EMDR may be a safe and effective adjunctive treatment for schizophrenia. We conclude that the evidence base supports well-designed and adequately powered randomised controlled studies of EMDR in schizophrenia with careful consideration given to inclusion criteria, participant acceptability and selection of clinically relevant outcome measures. Mechanism of action and potential effects on cognitive functioning should also be explored

Effects of a Forest Clearing: Experimentaland Numerical Assessment

There is a renewed interest in the wind estimate over and around forest areas dueto the increasing demand of wind-energy resources. Many researches have been donewith simplied forest models. However, the introduction of a simple two-dimensionalclearing adds further parameters, such as the width of the clearing, which furthercomplicates the analysis. The main purpose of the present experimental and nu-merical efforts is, therefore, to characterize the ow over the forest clearing and tosuggest the suitable location for the wind-power generation over the forest clearing.The experiments were performed in the Minimum Turbulence Level (MTL) windtunnel at KTH in Stockholm, and PIV data evaluation and analysis were carried out.The canopy model consists of several wooden at plates, and to each of the plateswooden cylindrical pins were clamped in a staggered layout to mimic a homogeneoushigh-density forest. The total length of the forest model is 40hc, where hc indicatesthe canopy height. Two cases were experimentally investigated, one with a fullforest conguration and the other with the presence of a clearing that starts fromx=hc = 20 and ends at x=hc = 30, where x is a streamwise coordinate that startsat the forest windward edge. Particle Image Velocimetry (PIV) was performed, andplanar velocity snapshots were taken at the downwind edge of the clearing.Large Eddy Simulations (LES) were also conducted to complement the experi-mental information. The present LES code was developed by modifying the DirectNumerical Simulation (DNS) code of the turbulent boundary layer ow by Kametani& Fukagata (2011), by adding the subgrid scale model part and the empirical canopymodel part into the DNS code.Both the experimental and the numerical results indicate that the clearing is as-sociated to a streamwise velocity defect in the mean prole mainly due to the strongturbulent diffusion into the clearing region. The turbulence is redistributed amongstthe various velocity components so that the streamwise velocity variance is reduced,while the vertical velocity variance is enhanced. The streamwise velocity varianceis in fact damped due to the absence of the canopy drag from x=hc = 20, whileenhanced vertical-velocity uctuations can be observed at the end of the clearing.However, the effects are immediately weakened both by a ow re-acceleration andby a new surface layer development right after passing the downwind clearing edge.The clearing effect seems to be dominant in the roughness sublayer at least for theneutral atmospheric conditions. The clearing perturbation seems to be associatedto turbulent mixing at its initial stage near y hc, followed by a rapid distorsionnear the clearing trailing edge. This phenomenon is highlighted by the low valueof the vertical correlation length scale that, after the clearing trailing edge, risesagain towards to homogenous forest condition. The LES results further show thata suitable area for the wind-turbine operation is close to the upwind clearing edgewhere the energy contents is the highest, while the turbulent intensity is lowestbetween the clearing. They also indicate that wind-speed enhancement can be ex-pected downstream of the short forest edge, implying that the ow can be optimizedfor wind-power generation just by changing the forest conguration

Minocycline as an adjunct for treatment-resistant depressive symptoms:study protocol for a pilot randomised controlled trial

BACKGROUND: Depression is one of the leading causes of disability worldwide. A high proportion of patients do not respond to standard drug treatments. Recent evidence has suggested that anti-inflammatory treatment may have beneficial effects in major depression. Minocycline is a tetracycline antibiotic with good CNS penetration that exerts effects on multiple interacting symptoms implicated in the pathophysiology of mood disorders. Open-label studies have suggested that minocycline is effective as an adjunct drug in improving depressive symptoms. METHODS/DESIGN: This is a multi-centre, 3-month, double-blind, placebo-controlled, pilot trial of minocycline added to treatment as usual for patients suffering from DSM-IV major depressive disorder. This will be a double-blind, randomised, controlled, two parallel-arm study with 20 participants in each arm, giving a total of 40 participants. There will be a screening visit, a randomization visit and four follow-up visits. Clinical assessments using the Hamilton Depression Rating Scale (HAM-D), Clinical Global Impression scale (CGI), Patient Health Questionnaire-9 (PHQ −9) and the Generalised Anxiety Disorder scale (GAD-7) will be carried out at every visit. Side effects checklists will also be undertaken at each visit. Biomarkers (inflammatory cytokines and CRP) will be measured at baseline and at the end of the treatment phase. Minocycline will be started at 100 mg once daily (OD) and will be increased to 200 mg at two weeks. DISCUSSION: Anti-inflammatory treatments have been shown to have some beneficial effects in the treatment of major depressive disorder. The aim of this pilot randomised controlled trial is to establish the degree of improvement in depressive symptoms with the addition of minocycline to treatment as usual. TRIAL REGISTRATION: ClinicalTrials.gov NCT02263872 registered 10 October 2014

Glycopyrrolate in comparison to hyoscine hydrobromide and placebo in the treatment of hypersalivation induced by clozapine (GOTHIC1): study protocol for a randomised controlled feasibility study

Abstract Background Clozapine is the only medication licensed for the treatment of resistant schizophrenia in the UK. Although efficacious, a common and unpopular side effect of clozapine treatment is clozapine-induced hypersalivation (CIH), which can contribute to non-adherence. The standard treatment for CIH in the UK is hyoscine hydrobromide but this may aggravate cognitive deficits in patients with schizophrenia while glycopyrrolate may be an effective alternative with a more tolerable side effect profile. There is currently no convincing evidence for hyoscine, or any other medication, as an effective treatment for CIH. Methods/design This is a multicentre randomised, double-blind, placebo-controlled feasibility study of glycopyrronium bromide (glycopyrrolate) and hyoscine hydrobromide (hyoscine) in patients with clozapine-induced hypersalivation. We aim to recruit 42 patients who have been prescribed clozapine and are experiencing hypersalivation, and randomise them to one of three study arms (either hyoscine, glycopyrrolate or placebo). The primary outcome measures will be the participant recruitment and attrition rates, and the secondary outcome will be the metrics of the daytime hypersalivation measure. After a 1-week washout period (discontinuing CIH medication, if any), there will be a 4-week treatment period where participants will be titrated up to the maximum tolerated dose of hyoscine, glycopyrrolate or placebo. Measurements of daytime salivation, nocturnal salivation, cognition and side effects will be taken during home visits in week 2 and week 5. Information on salivation and side effects will also be taken through telephone calls in week 3 and week 4. To gather information on the experience of study participants, exit interviews will also be requested with all participants who drop out of the study and a sample of participants who complete the study. Discussion There is currently no convincing evidence for hyoscine, or any other medication, as an effective treatment for CIH. There is promising evidence that glycopyrrolate may be more successful in the treatment of CIH causing fewer cognitive side effects. We propose to conduct a randomised placebo-controlled feasibility study of glycopyrrolate and hyoscine in the treatment of clozapine-induced hypersalivation to inform the design of a future efficacy trial. Trial registration Clinicaltrials.gov NCT02613494 , 23 November 2015