The relationship between negative symptoms and depression in schizophrenia: a systematic review.

OBJECTIVE: To provide an update on the evidence base for the nature of the relationship between negative symptoms and depressive features in people with schizophrenia, and propose new models that reflect their complex relationship. METHOD: A systematic review following PRISMA guidelines. A total of 2210 articles were identified from EMBASE, PsychInfo and MEDLINE, and further two articles were hand-searched from references. Twenty-seven met inclusion criteria and were included in the review. RESULTS: In schizophrenia, primary evidence suggests symptoms of low mood, suicidal ideation and pessimism have more specificity for depression whereas alogia and blunted affect may have more specificity as negative symptoms. Anhedonia, anergia and avolition may be common to both. CONCLUSION: It may be possible to further distinguish depressive features from negative symptoms in schizophrenia when detailed phenomenology is considered. However, in a proposed dimensional model, these two domains continue to share certain phenomena, highlighting their close relationship.

What side effects are problematic for patients prescribed antipsychotic medication? The Maudsley Side Effects (MSE) measure for antipsychotic medication.

BACKGROUND: Capturing service users' perspectives can highlight additional and different concerns to those of clinicians, but there are no up to date, self-report psychometrically sound measures of side effects of antipsychotic medications. Aim To develop a psychometrically sound measure to identify antipsychotic side effects important to service users, the Maudsley Side Effects (MSE) measure. METHOD: An initial item bank was subjected to a Delphi exercise (n = 9) with psychiatrists and pharmacists, followed by service user focus groups and expert panels (n = 15) to determine item relevance and language. Feasibility and comprehensive psychometric properties were established in two samples (N43 and N50). We investigated whether we could predict the three most important side effects for individuals from their frequency, severity and life impact. RESULTS: MSE is a 53-item measure with good reliability and validity. Poorer mental and physical health, but not psychotic symptoms, was related to side-effect burden. Seventy-nine percent of items were chosen as one of the three most important effects. Severity, impact and distress only predicted 'putting on weight' which was more distressing, more severe and had more life impact in those for whom it was most important. CONCLUSIONS: MSE is a self-report questionnaire that identifies reliably the side-effect burden as experienced by patients. Identifying key side effects important to patients can act as a starting point for joint decision making on the type and the dose of medication.

Screening for the metabolic side effects of antipsychotic medication: findings of a 6-year quality improvement programme in the UK.

OBJECTIVES: To increase the frequency and quality of screening for the metabolic syndrome in people prescribed continuing antipsychotic medication. DESIGN: An audit-based, quality improvement programme (QIP) with customised feedback to participating mental health services after each audit, including benchmarked data on their relative and absolute performance against an evidence-based practice standard and the provision of bespoke change interventions. SETTING: Adult, assertive outreach, community psychiatric services in the UK. PARTICIPANTS: 6 audits were conducted between 2006 and 2012. 21 mental health Trusts participated in the baseline audit in 2006, submitting data on screening for 1966 patients, while 32 Trusts participated in the 2012 audit, submitting data on 1591 patients. RESULTS: Over the 6 years of the programme, there was a statistically significant increase in the proportion of patients for whom measures for all 4 aspects of the metabolic syndrome had been documented in the clinical records in the previous year, from just over 1 in 10 patients in 2006 to just over 1 in 3 by 2012. The proportion of patients with no evidence of any screening fell from almost ½ to 1 in 7 patients over the same period. CONCLUSIONS: The findings suggest that audit-based QIPs can help improve clinical practice in relation to physical healthcare screening. Nevertheless, they also reveal that only a minority of community psychiatric patients prescribed antipsychotic medication is screened for the metabolic syndrome in accordance with best practice recommendations, and therefore potentially remediable causes of poor physical health remain undetected and untreated.

A longitudinal study of cortical changes and their cognitive correlates in patients followed up after first-episode psychosis.

BACKGROUND: Loss of cortical volume in frontotemporal regions occurs in patients with first-episode psychosis (FEP) and longitudinal studies have reported progressive brain volume changes at different stages of the disease, even if cognitive deficits remain stable over time. We investigated cortical changes in patients over the 2 years following their FEP and their associations with clinical and cognitive measures. METHOD: Twenty-seven patients after their FEP (20 with schizophrenia, seven with schizo-affective disorder) and 25 healthy controls matched for age and gender participated in this study. Magnetic resonance imaging (MRI) was performed on a 1.5-T scanner both at baseline and after 2 years. Area and thickness of the cortex were measured using surface-based morphometry (SBM). Patients also underwent neuropsychological testing at these two time points. RESULTS: Progressive cortical thinning in the superior and inferior frontal and, to a lesser extent, superior temporal cortex was observed in patients. Cortical area remained constant. Cortical thinning was associated with duration of treatment at a trend level and was predicted by baseline measures of IQ and working memory. Cortical thinning occurred in the absence of clinical or cognitive deterioration. CONCLUSIONS: The clinical implications of these cortical changes remain uncertain, but patients with less cognitive reserve may be more vulnerable to developing cortical abnormalities when exposed to medication or other disease-related biological factors.

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.

Reflection impulsivity and response inhibition in first-episode psychosis: relationship to cannabis use.

BACKGROUND: People with psychosis demonstrate impaired response inhibition on the Stop Signal Task (SST). It is less clear if this impairment extends to reflection impulsivity, a form of impulsivity that has been linked to substance use in non-psychotic samples. METHOD: We compared 49 patients with first-episode psychosis (FEP) and 30 healthy control participants on two forms of impulsivity measured using the Information Sampling Test (IST) and the SST, along with clinical and IQ assessments. We also compared those patients who used cannabis with those who had either given up or never used. RESULTS: Patients with FEP had significantly greater impairment in response inhibition but not in reflection impulsivity compared with healthy controls. By contrast, patients who reported current cannabis use demonstrated greater reflection impulsivity than those that had either given up or never used, whereas there were no differences in response inhibition. CONCLUSIONS: These data suggest that abnormal reflection impulsivity is associated with substance use in psychosis but not psychosis itself ; the opposite relationship may hold for response inhibition.

Group art therapy as an adjunctive treatment for people with schizophrenia: a randomised controlled trial (MATISSE).

OBJECTIVE: To examine the clinical effectiveness and cost-effectiveness of referral to group art therapy plus standard care, compared with referral to an activity group plus standard care and standard care alone, among people with schizophrenia. DESIGN: A three-arm, parallel group, single-blind, pragmatic, randomised controlled trial. Participants were randomised via an independent and remote telephone randomisation service using permuted blocks, stratified by study centre. SETTING: Study participants were recruited from secondary care mental health and social services in four UK centres. PARTICIPANTS: Potential participants were aged 18 years or over, had a clinical diagnosis of schizophrenia, confirmed by an examination of case notes, and provided written informed consent. We excluded those who were unable to speak sufficient English to complete the baseline assessment, those with severe cognitive impairment and those already receiving arts therapy. INTERVENTIONS: Group art therapy was delivered by registered art therapists according to nationally agreed standards. Groups had up to eight members, lasted for 90 minutes and ran for 12 months. Members were given access to a range of art materials and encouraged to use these to express themselves freely. Activity groups were designed to control for the non-specific effects of group art therapy. Group facilitators offered various activities and encouraged participants to collectively select those they wanted to pursue. Standard care involved follow-up from secondary care mental health services and the option of referral to other services, except arts therapies, as required. MAIN OUTCOME MEASURES: Our co-primary outcomes were global functioning (measured using the Global Assessment of Functioning Scale - GAF) and mental health symptoms (measured using the Positive and Negative Syndrome Scale - PANSS) at 24 months. The main secondary outcomes were level of group attendance, social functioning, well-being, health-related quality of life, service utilisation and other costs measured 12 and 24 months after randomisation. RESULTS: Four hundred and seventeen people were recruited, of whom 355 (85%) were followed up at 2 years. Eighty-six (61%) of those randomised to art therapy and 73 (52%) of those randomised to activity groups attended at least one group. No differences in primary outcomes were found between the three study arms. The adjusted mean difference between art therapy and standard care at 24 months was -0.9 [95% confidence interval (CI) -3.8 to 2.1] on the GAF Scale and 0.7 (95% CI -3.1 to 4.6) on the PANSS Scale. Differences in secondary outcomes were not found, except that those referred to an activity group had fewer positive symptoms of schizophrenia at 24 months than those randomised to art therapy. Secondary analysis indicated that attendance at art therapy groups was not associated with improvements in global functioning or mental health. Although the total cost of the art therapy group was lower than the cost of the two comparison groups, referral to group art therapy did not appear to provide a cost-effective use of resources. CONCLUSIONS: Referring people with established schizophrenia to group art therapy as delivered in this randomised trial does not appear to improve global functioning or mental health of patients or provide a more cost-effective use of resources than standard care alone. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 46150447. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 8. See the HTA programme website for further project information.

Medication prescribed to people with personality disorder: the influence of patient factors and treatment setting.

OBJECTIVE: To examine the extent of use and clinical rationale for the prescribing of psychotropic drugs for people with personality disorder (PD) who are in contact with mental health services. METHOD: Clinical records of 278 patients with a primary diagnosis of PD were examined. RESULTS: Just over 80% (N = 225) of patients were being prescribed psychotropic medication. One in five was prescribed three or more drugs. People with comorbid mental disorders were more likely to receive psychotropic medication. Half those prescribed antidepressants had no record of depression in their records. While drug treatments were mostly prescribed for depressive and psychotic symptoms, they were also used to try to manage behavioural problems such as self-harm or given in response to patient requests for treatment. People receiving specialist PD services (OR = 0.35, 95% CI = 0.13-0.95) or other specialist services (OR = 0.24, 95% CI = 0.10-0.60) were less likely to be prescribed drug treatments. CONCLUSION: Drug treatments are widely used for people with PD despite the relatively weak evidence base. Both the type of personality problem and the context in which treatment is delivered appear to have an impact on whether drug treatments are prescribed.

Abnormal negative feedback processing in first episode schizophrenia: evidence from an oculomotor rule switching task.

BACKGROUND: Previous studies have shown that patients with schizophrenia are impaired on executive tasks, where positive and negative feedbacks are used to update task rules or switch attention. However, research to date using saccadic tasks has not revealed clear deficits in task switching in these patients. The present study used an oculomotor 'rule switching' task to investigate the use of negative feedback when switching between task rules in people with schizophrenia. METHOD: A total of 50 patients with first episode schizophrenia and 25 healthy controls performed a task in which the association between a centrally presented visual cue and the direction of a saccade could change from trial to trial. Rule changes were heralded by an unexpected negative feedback, indicating that the cue-response mapping had reversed. RESULTS: Schizophrenia patients were found to make increased errors following a rule switch, but these were almost entirely the result of executing saccades away from the location at which the negative feedback had been presented on the preceding trial. This impairment in negative feedback processing was independent of IQ. CONCLUSIONS: The results not only confirm the existence of a basic deficit in stimulus-response rule switching in schizophrenia, but also suggest that this arises from aberrant processing of response outcomes, resulting in a failure to appropriately update rules. The findings are discussed in the context of neurological and pharmacological abnormalities in the conditions that may disrupt prediction error signalling in schizophrenia.

Dissociation of long-term verbal memory and fronto-executive impairment in first-episode psychosis.

BACKGROUND: Verbal memory is frequently and severely affected in schizophrenia and has been implicated as a mediator of poor clinical outcome. Whereas encoding deficits are well demonstrated, it is unclear whether retention is impaired. This distinction is important because accelerated forgetting implies impaired consolidation attributable to medial temporal lobe (MTL) dysfunction whereas impaired encoding and retrieval implicates involvement of prefrontal cortex. METHOD: We assessed a group of healthy volunteers (n=97) and pre-morbid IQ- and sex-matched first-episode psychosis patients (n=97), the majority of whom developed schizophrenia. We compared performance of verbal learning and recall with measures of visuospatial working memory, planning and attentional set-shifting, and also current IQ. RESULTS: All measures of performance, including verbal memory retention, a memory savings score that accounted for learning impairments, were significantly impaired in the schizophrenia group. The difference between groups for delayed recall remained even after the influence of learning and recall was accounted for. Factor analyses showed that, in patients, all variables except verbal memory retention loaded on a single factor, whereas in controls verbal memory and fronto-executive measures were separable. CONCLUSIONS: The results suggest that IQ, executive function and verbal learning deficits in schizophrenia may reflect a common abnormality of information processing in prefrontal cortex rather than specific impairments in different cognitive domains. Verbal memory retention impairments, however, may have a different aetiology.

Analysis of gene expression in two large schizophrenia cohorts identifies multiple changes associated with nerve terminal function.

Schizophrenia is a severe psychiatric disorder with a world-wide prevalence of 1%. The pathophysiology of the illness is not understood, but is thought to have a strong genetic component with some environmental influences on aetiology. To gain further insight into disease mechanism, we used microarray technology to determine the expression of over 30 000 mRNA transcripts in post-mortem tissue from a brain region associated with the pathophysiology of the disease (Brodmann area 10: anterior prefrontal cortex) in 28 schizophrenic and 23 control patients. We then compared our study (Charing Cross Hospital prospective collection) with that of an independent prefrontal cortex dataset from the Harvard Brain Bank. We report the first direct comparison between two independent studies. A total of 51 gene expression changes have been identified that are common between the schizophrenia cohorts, and 49 show the same direction of disease-associated regulation. In particular, changes were observed in gene sets associated with synaptic vesicle recycling, transmitter release and cytoskeletal dynamics. This strongly suggests multiple, small but synergistic changes in gene expression that affect nerve terminal function.

Do patients with schizophrenia exhibit aberrant salience?

BACKGROUND: It has been suggested that some psychotic symptoms reflect 'aberrant salience', related to dysfunctional reward learning. To test this hypothesis we investigated whether patients with schizophrenia showed impaired learning of task-relevant stimulus-reinforcement associations in the presence of distracting task-irrelevant cues. METHOD: We tested 20 medicated patients with schizophrenia and 17 controls on a reaction time game, the Salience Attribution Test. In this game, participants made a speeded response to earn money in the presence of conditioned stimuli (CSs). Each CS comprised two visual dimensions, colour and form. Probability of reinforcement varied over one of these dimensions (task-relevant), but not the other (task-irrelevant). Measures of adaptive and aberrant motivational salience were calculated on the basis of latency and subjective reinforcement probability rating differences over the task-relevant and task-irrelevant dimensions respectively. RESULTS: Participants rated reinforcement significantly more likely and responded significantly faster on high-probability-reinforced relative to low-probability-reinforced trials, representing adaptive motivational salience. Patients exhibited reduced adaptive salience relative to controls, but the two groups did not differ in terms of aberrant salience. Patients with delusions exhibited significantly greater aberrant salience than those without delusions, and aberrant salience also correlated with negative symptoms. In the controls, aberrant salience correlated significantly with 'introvertive anhedonia' schizotypy. CONCLUSIONS: These data support the hypothesis that aberrant salience is related to the presence of delusions in medicated patients with schizophrenia, but are also suggestive of a link with negative symptoms. The relationship between aberrant salience and psychotic symptoms warrants further investigation in unmedicated patients.

Impaired conscious and preserved unconscious inhibitory processing in recent onset schizophrenia.

BACKGROUND: Impairments in inhibitory function have been found in studies of cognition in schizophrenia. These have been linked to a failure to adequately maintain the task demands in working memory. As response inhibition is known to occur in both voluntary and involuntary processes, an important question is whether both aspects of response inhibition are specifically impaired in people with schizophrenia. METHOD: The subjects were 33 patients presenting with a first episode of psychosis (27 with schizophrenia and six with schizo-affective disorder) and 24 healthy controls. We administered two motor response tasks: voluntary response inhibition was indexed by the stop-signal task and involuntary response inhibition by the masked priming task. We also administered neuropsychological measures of IQ and executive function to explore their associations with response inhibition. RESULTS: Patients with schizophrenia compared to healthy controls showed significantly increased duration of the voluntary response inhibition process, as indexed by the stop-signal reaction time (SSRT). By contrast, there were no group differences on the pattern of priming on the masked priming task, indicative of intact involuntary response inhibition. Neuropsychological measures revealed that voluntary response inhibition is not necessarily dependent on working memory. CONCLUSIONS: These data provide evidence for a specific impairment of voluntary response inhibition in schizophrenia.

Interrater reliability of the Antipsychotic Non-Neurological Side-Effects Rating Scale measured in patients treated with clozapine.

The Antipsychotic Non-Neurological Side-Effects Rating Scale (ANNSERS) was developed to provide a comprehensive measure for rating non-neurological adverse drug reactions (ADRs) to antipsychotics. Although there were already available measures that adequately rated specific non-neurological ADRs, such as sexual side effects, a need was identified for a scale that comprehensively rated the full range of non-neurological ADRs commonly seen across the spectrum of first and second generation antipsychotic drugs, including metabolic and autonomic ADRs. This article reports on work to establish the interrater reliability of an early version and a later, more comprehensive version of the ANNSERS (versions 1 and 2, v1 and v2, respectively). The measures were administered in London centres to patients treated with clozapine. Trained clinicians rated the patients simultaneously and independently. Interrater reliability on the scores was calculated using the kappa coefficient method. The results (mean kappa coefficients of 0.77 and 0.72, respectively) indicate that substantial interrater reliability was achieved for both versions. Items for which the main basis for rating was laboratory investigations rather than patient interview were largely excluded from this study, and kappas were also not calculated for items with a low frequency (less than 10%) of endorsement. Samples of patients on other antipsychotics would be required to reliably calculate kappa coefficients for these items. In conclusion, the ANNSERS represents a clinically applicable research innovation, with good interrater reliability on clinician judged items, which is now available for the comprehensive assessment of non-neurological ADRs to antipsychotics, to aid the processes of clinical audit, research and drug discovery.

Screening for the metabolic syndrome in community psychiatric patients prescribed antipsychotics: a quality improvement programme.

OBJECTIVE: The aim was to evaluate a quality improvement programme designed to increase screening for the metabolic syndrome in community psychiatric patients prescribed antipsychotics. METHOD: Baseline audit against evidence-based standards, followed by provision of benchmarked data and a range of change interventions, with re-audit 1 year later. RESULTS: At baseline, 48 assertive outreach teams across the UK submitted data on screening over the previous year for 1966 patients. At re-audit, 35 of the teams submitted data for 1516 patients. Screening for all four aspects of the metabolic syndrome (measuring blood pressure, obesity, blood glucose and plasma lipids) had increased significantly by re-audit. Clinical variables increasing the likelihood of full screening were clozapine treatment and a known diagnosis of diabetes or dyslipidaemia. CONCLUSION: The programme's success may be partly attributed to the use of a widely-accepted audit standard, and bespoke change interventions that directly addressed barriers to screening identified by the participating clinical teams.

Naturalistic follow-up of co-morbid substance use in schizophrenia: the West London first-episode study.

BACKGROUND: The impact of co-morbid substance use in first-episode schizophrenia has not been fully explored. METHOD: This naturalistic follow-up of a cohort of 152 people with first-episode schizophrenia examined substance use and clinical outcome in terms of symptoms and social and neuropsychological function. RESULTS: Data were collected on 85 (56%) of the patient cohort after a median period of 14 months. Over the follow-up period, the proportion of smokers rose from 60% at baseline to 64%. While 30% reported lifetime problem drinking of alcohol at baseline, only 15% had problem drinking at follow-up. Furthermore, while at baseline 63% reported lifetime cannabis use and 32% were currently using the drug, by the follow-up assessment the latter figure had fallen to 18.5%. At follow-up, persistent substance users had significantly more severe positive and depressive symptoms and greater overall severity of illness. A report of no lifetime substance use at baseline was associated with greater improvement in spatial working memory (SWM) at follow-up. CONCLUSIONS: Past substance use may impede recovery of SWM performance in people with schizophrenia in the year or so following first presentation to psychiatric services. The prevalence of substance use other than tobacco tends to diminish over this period, in the absence of specific interventions. Persistent substance use in first-episode schizophrenia is associated with more severe positive and depressive symptoms but not negative symptoms, and should be a target for specific treatment intervention.

Cost-effectiveness of first- v. second-generation antipsychotic drugs: results from a randomised controlled trial in schizophrenia responding poorly to previous therapy.

BACKGROUND: There are claims that the extra costs of atypical (second-generation) antipsychotic drugs over conventional (first-generation) drugs are offset by improved health-related quality of life. AIMS: To determine the relative costs and value of treatment with conventional or atypical antipsychotics in people with schizophrenia. METHOD: Cost-effectiveness acceptability analysis integrated clinical and economic randomised controlled trial data of conventional and atypical antipsychotics in routine practice. RESULTS: Conventional antipsychotics had lower costs and higher quality-adjusted life-years (QALYs) than atypical antipsychotics and were more than 50% likely to be cost-effective. CONCLUSIONS: The primary and sensitivity analyses indicated that conventional antipsychotics may be cost-saving and associated with a gain in QALYs compared with atypical antipsychotics.

Pharmacological management of acute mania: does current prescribing practice reflect treatment guidelines?

The records of 70 inpatients with an acute manic episode were audited, to examine the relationship between current prescribing practice, the recommendations of recent clinical guidance and short-term clinical outcomes. Overall, 38 combinations of medication were prescribed. Within the first 24 hours of treatment, monotherapy with a second generation antipsychotic was favoured. At discharge, combination treatment (a mood stabilizer and a second generation antipsychotic) predominated. Early initiation of medication was significantly associated with an earlier clinical decision to discharge. Prescribing was generally in accord with published guidelines. The findings reinforce the value of prescribing surveys in mental health and the need to share understanding of the constraints that may lead to deviation from prescribing guidelines.

Befriending patients with medication-resistant schizophrenia: can psychotic symptoms predict treatment response?

OBJECTIVES: Supportive interventions are used in schizophrenia, but little research has been conducted into whether any baseline variable predicts treatment response. The aim of this study was to establish if baseline delusions or hallucinations are associated with changes in overall symptoms in patients who received a befriending intervention. DESIGN: The sample consisted of 44 patients with schizophrenia. These patients comprised the befriending arm of a multicentre randomized controlled trial which compared the efficacy of using CBT against befriending as an adjunct to routine care for patients with medication-resistant schizophrenia. METHODS: Scores for auditory hallucinations and delusions relating to persecution or control were entered into two regression models. The dependent variables were change in overall symptoms (1) between baseline and end of the intervention, and (2) between baseline and 9 months post-intervention. RESULTS: Baseline delusions predicted a good response and auditory hallucinations predicted a poor response at 9 months. CONCLUSIONS: Baseline psychotic symptoms strongly predicted outcome in this sample. The finding that hallucinations predicted a poor outcome is consistent with previous research. These results may help to determine which patients would benefit from supportive interventions.