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According to the cognitive neuropsychological model, antidepressants reduce symptoms of depression and anxiety by increasing positive relative to negative information processing. Most studies of whether antidepressants alter emotional processing use small samples of healthy individuals, which lead to low statistical power and selection bias and are difficult to generalise to clinical practice. We tested whether the selective serotonin reuptake inhibitor (SSRI) sertraline altered recall of positive and negative information in a large randomised controlled trial (RCT) of patients with depressive symptoms recruited from primary care.
The PANDA trial was a pragmatic multicentre double-blind RCT comparing sertraline with placebo. Memory for personality descriptors was tested at baseline and 2 and 6 weeks after randomisation using a computerised emotional categorisation task followed by a free recall. We measured the number of positive and negative words correctly recalled (hits). Poisson mixed models were used to analyse longitudinal associations between treatment allocation and hits.
A total of 576 participants (88% of those randomised) completed the recall task at 2 and 6 weeks. We found no evidence that positive or negative hits differed according to treatment allocation at 2 or 6 weeks (adjusted positive hits ratio = 0.97, 95% CI 0.90–1.05, p = 0.52; adjusted negative hits ratio = 0.99, 95% CI 0.90–1.08, p = 0.76).
In the largest individual placebo-controlled trial of an antidepressant not funded by the pharmaceutical industry, we found no evidence that sertraline altered positive or negative recall early in treatment. These findings challenge some assumptions of the cognitive neuropsychological model of antidepressant action.
Treatment resistance causes significant burden in psychosis. Clozapine is the only evidence-based pharmacologic intervention available for people with treatment-resistant schizophrenia; current guidelines recommend commencement after two unsuccessful trials of standard antipsychotics.
This paper aims to explore the prevalence of treatment resistance and pathways to commencement of clozapine in UK early intervention in psychosis (EIP) services.
Data were taken from the National Evaluation of the Development and Impact of Early Intervention Services study (N = 1027) and included demographics, medication history and psychosis symptoms measured by the Positive and Negative Syndrome Scale (PANSS) at baseline, 6 months and 12 months. Prescribing patterns and pathways to clozapine were examined. We adopted a strict criterion for treatment resistance, defined as persistent elevated positive symptoms (a PANSS positive score ≥16, equating to at least two items of at least moderate severity), across three time points.
A total of 143 (18.1%) participants met the definition of treatment resistance of having continuous positive symptoms over 12 months, despite treatment in EIP services. Sixty-one (7.7%) participants were treatment resistant and eligible for clozapine, having had two trials of standard antipsychotics; however, only 25 (2.4%) were prescribed clozapine over the 12-month study period. Treatment-resistant participants were more likely to be prescribed additional antipsychotic medication and polypharmacy, instead of clozapine.
Prevalent treatment resistance was observed in UK EIP services, but prescription of polypharmacy was much more common than clozapine. Significant delays in the commencement of clozapine may reflect a missed opportunity to promote recovery in this critical period.
Generalised anxiety disorder and symptoms are associated with poor physical, emotional and social functioning and frequent primary and acute care visits. We investigated recent temporal trends in anxiety and related mental illness in UK general practice.
The aims of this analysis are to examine temporal changes in recording of generalised anxiety in primary care and initial pharmacologic treatments.
Annual incidence rates of generalised anxiety diagnoses and symptoms were calculated from 795 UK general practices contributing to The Health Improvement Network (THIN) database between 1998 and 2018. Poisson mixed regression was used to account for age, gender and general practitioner practice. Subsequent pharmacologic treatment was examined.
Generalised anxiety recording rates increased in both genders aged 18–24 between 2014 and 2018. For women, the increase was from 17.06 to 23.33/1000 person years at risk (PYAR); for men, 8.59 to 11.65/1000 PYAR. Increases persisted for a composite of anxiety and depression (49.74 to 57.81/1000 PYAR for women; 25.41 to 31.45/1000 PYAR for men). Smaller increases in anxiety were seen in both genders age 25–34 and 35–44. Anxiety rates among older patients remained stable, although a composite of anxiety and depression decreased for older women. About half of drug-naïve patients were prescribed anxiety drugs within 1 year following diagnosis. The most common choice was a selective serotonin reuptake inhibitor. Benzodiazepine prescription rate has fallen steadily.
We observed a substantial increase in general practitioner consulting for generalised anxiety and depression recently, concentrated within younger people and in particular women.
Movement disorders associated with exposure to antipsychotic drugs are common and stigmatising but underdiagnosed.
To develop and evaluate a new clinical procedure, the ScanMove instrument, for the screening of antipsychotic-associated movement disorders for use by mental health nurses.
Item selection and content validity assessment for the ScanMove instrument were conducted by a panel of neurologists, psychiatrists and a mental health nurse, who operationalised a 31-item screening procedure. Interrater reliability was measured on ratings for 30 patients with psychosis from ten mental health nurses evaluating video recordings of the procedure. Criterion and concurrent validity were tested comparing the ScanMove instrument-based rating of 13 mental health nurses for 635 community patients from mental health services with diagnostic judgement of a movement disorder neurologist based on the ScanMove instrument and a reference procedure comprising a selection of commonly used rating scales.
Interreliability analysis showed no systematic difference between raters in their prediction of any antipsychotic-associated movement disorders category. On criterion validity testing, the ScanMove instrument showed good sensitivity for parkinsonism (90%) and hyperkinesia (89%), but not for akathisia (38%), whereas specificity was low for parkinsonism and hyperkinesia, and moderate for akathisia.
The ScanMove instrument demonstrated good feasibility and interrater reliability, and acceptable sensitivity as a mental health nurse-administered screening tool for parkinsonism and hyperkinesia.
Social disability is a hallmark of severe mental illness yet individual
differences and factors predicting outcome are largely unknown.
To explore trajectories and predictors of social recovery following a
first episode of psychosis (FEP).
A sample of 764 individuals with FEP were assessed on entry into early
intervention in psychosis (EIP) services and followed up over 12 months.
Social recovery profiles were examined using latent class growth
Three types of social recovery profile were identified: Low Stable (66%),
Moderate-Increasing (27%), and High-Decreasing (7%). Poor social recovery
was predicted by male gender, ethnic minority status, younger age at
onset of psychosis, increased negative symptoms, and poor premorbid
Social disability is prevalent in FEP, although distinct recovery
profiles are evident. Where social disability is present on entry into
EIP services it can remain stable, highlighting a need for targeted
Interventions to reduce treatment delay in first-episode psychosis have met with mixed results. Systematic reviews highlight the need for greater understanding of delays within the care pathway if successful strategies are to be developed.
To document the care-pathway components of duration of untreated psychosis (DUP) and their link with delays in accessing specialised early intervention services (EIS). To model the likely impact on efforts to reduce DUP of targeted changes in the care pathway.
Data for 343 individuals from the Birmingham, UK, lead site of the National EDEN cohort study were analysed.
A third of the cohort had a DUP exceeding 6 months. The greatest contribution to DUP for the whole cohort came from delays within mental health services, followed by help-seeking delays. It was found that delay in reaching EIS was strongly correlated with longer DUP.
Community education and awareness campaigns to reduce DUP may be constrained by later delays within mental health services, especially access to EIS. Our methodology, based on analysis of care pathways, will have international application when devising strategies to reduce DUP.
The objective of health technology assessment (HTA) is to support decision making in health care. HTA does not claim to provide a definite solution to a health care problem, but to assist decision makers with evidence-based information about the clinical, ethical, social, and economic implications of the development, diffusion, and use of health care technology.
This descriptive analysis examines prescribing trends of antidepressants in English primary care, providing analysis of NHS reimbursement data for groups of antidepressants between 1989 and 1994. Prescribing trends seem unaffected by the release of information on the effectiveness and costeffectiveness of antidepressant drugs. We found that simple distribution of the results of health technology assessments may not be sufficient to influence practice.
The possibility of restoring fertility among some infertile couples through assisted reproductive technology has led to questions about the terms under which such treatments should be made available. Although there is now evidence on their effectiveness, there is considerable variation in the availability of these treatments under the U.K. National Health Service.
In individual studies and limited meta-analyses venlafaxine has been reported to be more effective than comparator antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs).
To perform a systematic review of all such studies.
We conducted a systematic review of double-blind, randomised trials comparing venlafaxine with alternative antidepressants in the treatment of depression. The primary outcome was the difference in final depression rating scale value, expressed as a standardised effect size. Secondary outcomes were response rate, remission rate and tolerability.
A total of 32 randomised trials were included. Venlafaxine was more effective than other antidepressants (standardised effect size was −0.14, 95% Cl −0.07 to −0.22). A similar significant advantage was found against SSRIs (20 studies) but nottricyclic antidepressants (7 studies).
Venlafaxine has greater efficacy than SSRIs although there is uncertainty in comparison with other antidepressants. Further studies are required to determine the clinical importance of this finding.
Meta-analysis is commonly used in reviews of the effectiveness of medical
technologies, but this approach has not been used in direct support of
guidelines development groups. This paper describes the approach of the North
of England Guidelines Development Project in describing the evidence using
meta-analyses that were conducted explicitly to address questions on the
choice of therapy raised by the guidelines development groups. Particular
emphasis is placed on the context within which the contributing trials were
conducted and the extent to which systematic differences between trials
(heterogeneity) was observed, described, and explained. There is a trade-off
between internal and external validity for different metrics when presenting
the results of trials. More interpretable metrics, such as risk differences or
weighted mean differences, are confounded by study design issues and strong
assumptions. More robust measures such as odds ratios or standardized weighted
mean differences are difficult to interpret physically. Individual patient
data may prove particularly helpful in addressing pivotal questions on the
magnitude of effects of interventions, though accessing and reanalyzing these
data requires a substantial investment in time and other resources.
Meta-analysis is the quantitative synthesis of the results of a systematic overview of previous studies. Systematic overviews are a method of collating and synthesising all the available evidence on a particular scientific question. For example, in making decisions about the most effective and efficient treatment for a condition, it is important to review all the previously generated evidence. On occasions it is appropriate to calculate some overall estimate of the effectiveness of the treatment. This can be done fairly simply by performing a stratified analysis of the available results, weighting the studies so that the larger, more statistically powerful studies are given more weight. However, the validity of such a quantitative approach will rest upon the method with which the studies have been selected and the completeness of the evidence collected in the systematic review.
It should be emphasised that the principles of the sytematic overview apply to many, perhaps all, areas of medical research. However, in the context of this book we shall concentrate almost exclusively on evaluations of the effectiveness of treatments, in particular using randomised controlled trials (RCTs). This is because the RCT is the most powerful research design available to assess the effects of health care, because of the random allocation of confounding variables between the groups to be compared (Altman, 1991).
Systematic reviews versus subjective reviews
The principle of systematic reviews is that the process of the review should be as scientific and systematic as the process of carrying out new research studies. Systematic reviews and meta-analyses are a scientific endeavour, and to accomplish them properly requires considerable effort and attention to detail. One can reasonably enlarge this argument and claim that the design of new studies and the interpretation of results can only be done sensibly in the context of a comprehensive and systematic review of the literature. It seems that the medical profession has been rather late in accepting this principle and reviewing literature is often seen as a secondary process, in many ways qualitatively different from generating the research evidence itself. Systematic reviews have a key place in efforts to draw conclusions from research and thus influence clinical practice.
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