Brendan P. Murphy

Pharmacological treatment of primary negative symptoms in schizophrenia: a systematic review.

BACKGROUND Optimal treatment of primary negative symptoms is important because their presence is associated with poor outcome. AIMS To systematically review all studies dealing with the efficacy of pharmacological agents on primary negative symptoms. METHOD A comprehensive search of the relevant literature was undertaken using electronic database, reference lists and personal contact. RESULTS There is a lack of standardized research designs. Amisulpride is the most extensively studied drug with respect to efficacy against primary negative symptoms. At low doses it demonstrates a consistent, modest effect compared to placebo, though not to conventional antipsychotics and has yet to be tested against other atypicals. Evidence from multiple studies that used simple statistical analyses and inclusion criteria for patients with primary negative symptoms does not support a direct effect for clozapine. Path-analysis studies support the direct effects of risperidone, olanzapine, sertindole and aripiprazole, however, different statistical analyses of the same risperidone study produced conflicting results and the direct effects of olanzapine were not confirmed in selected patients with primary negative symptoms. There are no studies supporting the use of ziprasidone or quetiapine. The effects of typical antipsychotics on primary negative symptoms are inconclusive and likely to depend on drug dosages. Selective serotonin reuptake inhibitors (SSRIs), mirtazepine and NMDA agonists show early promise but require further study. Novel agents such as selegiline, naltrexone, dehydroepiandrosterone, galantamine, Ginkgo, nitric oxide, L-deprenyl and pergolide show positive effects on general negative symptoms but remain untested against primary negative symptoms. CONCLUSIONS Further studies using standardized selective inclusion criteria and controlling for chronicity are needed. Research guidelines are discussed.

Evidence and implications for early intervention in bipolar disorder

Aims: To review the evidence that supports early intervention in the treatment of bipolar disorder. Background: Bipolar disorder is a pleomorphic condition, with varying manifestations that are determined by a number of complex factors including the “stage” of illness. It is consequently a notoriously difficult illness to diagnose and as a corollary is associated with lengthy delays in recognition and the initiation of suitable treatment. Methods: A literature search was conducted using MEDLINE augmented by a manual search. Results: Emerging neuroimaging data suggests that, in contrast to schizophrenia, where at the time of a first-episode of illness there is already discernible volume loss, in bipolar disorder, gross brain structure is relatively preserved, and it is only with recurrences that there is a sequential, but marked loss of brain volume. Recent evidence suggests that both pharmacotherapy and psychotherapy are more effective if instituted early in the course of bipolar disorder, and that with multiple episodes and disease progression there is a noticeable decline in treatment response. Conclusions: Such data supports the notion of clinical staging, and the tailored implementation of treatments according to the stage of illness. The progressive nature of bipolar disorder further supports the concept that the first episode is a period that requires energetic broad-based treatment, with the hope that this could alter the temporal trajectory of the illness. It also raises hope that prompt treatment may be neuroprotective and that this perhaps attenuates or even prevents the neurostructural and neurocognitive changes seen to emerge with chronicity. This highlights the need for early identification at a population level and the necessity of implementing treatments and services at a stage of the illness where prognosis is optimal.

The effects of cannabis and alcohol on simulated arterial driving: Influences of driving experience and task demand

This study compared the effects of three doses of cannabis and alcohol (placebo, low and high doses), both alone and in combination, on the driving performance of young, novice drivers and more experienced drivers. Alcohol was administered as ethanol (95%) mixed with orange juice in doses of approximately 0, 0.4 and 0.6g/kg. Cannabis was administered by inhalation of smoke from pre-rolled cannabis cigarettes (supplied by the National Institute of Drug Abuse, USA). Active cigarettes contained 19 mg delta-9-THC. Using a counterbalanced design, the simulated driving performance of 25 experienced and 22 inexperienced drivers was tested under the nine different drug conditions in an arterial driving environment during which workload was varied through the drive characteristics as well as through the inclusion of a secondary task. High levels of cannabis generally induced greater impairment than lower levels, while alcohol at the doses used had few effects and did not produce synergistic effects when combined with cannabis. Both cannabis and alcohol were associated with increases in speed and lateral position variability, high dose cannabis was associated with decreased mean speed, increased mean and variability in headways, and longer reaction time, while in contrast alcohol was associated with a slight increase in mean speed. Given the limitations of the study, it is of great interest to further explore the qualitative impairments in driving performance associated with cannabis and alcohol separately and how these impairments may manifest in terms of crash characteristics.

A randomized controlled trial of bibliotherapy for carers of young people with first-episode psychosis

Caring for young people with first-episode psychosis (FEP) is challenging and can adversely affect carer well-being, with limited evidence-based support materials available. We aimed to examine whether completion of a self-directed problem-solving bibliotherapy among carers of young people with FEP led to a better experience of caring, less distress and expressed emotion, and better general health than carers who only received treatment as usual (TAU). A randomized controlled trial was conducted across two early-intervention psychosis services in Melbourne, Australia. A total of 124 carers were randomized to problem-solving bibliotherapy intervention (PSBI) or TAU and assessed at baseline, 6-week and 16-week follow-up. Intent-to-treat analyses were carried out and indicated that recipients of PSBI had a more favorable experience of caring than those receiving TAU, and these effects were sustained at both follow-up time points. Across the other measures, both groups demonstrated improvements by week 16, although the PBSI group tended to improve earlier. The PSBI group experienced a greater reduction in negative emotional evaluations of the need to provide additional support to young people with FEP than the TAU group by week 6, while the level of psychological distress decreased at a greater rate from baseline to 6 weeks in the PSBI compared with the TAU group. These findings support the use of problem-solving bibliotherapy for first-time carers, particularly as a cost-effective adjunct to TAU.

Intensive case management for high-risk patients with first-episode psychosis: Service model and outcomes

BACKGROUND The first episode of psychosis is a crucial period when early intervention can alter the trajectory of the young persons ongoing mental health and general functioning. After an investigation into completed suicides in the Early Psychosis Prevention and Intervention Centre (EPPIC) programme, the intensive case management subprogramme was developed in 2003 to provide assertive outreach to young people having a first episode of psychosis who are at high risk owing to risk to self or others, disengagement, or suboptimal recovery. We report intensive case management model development, characterise the target cohort, and report on outcomes compared with EPPIC treatment as usual. METHODS Inclusion criteria, staff support, referral pathways, clinical review processes, models of engagement and care, and risk management protocols are described. We compared 120 consecutive referrals with 50 EPPIC treatment as usual patients (age 15-24 years) in a naturalistic stratified quasi-experimental real-world design. Key performance indicators of service use plus engagement and suicide attempts were compared between EPPIC treatment as usual and intensive case management, and psychosocial and clinical measures were compared between intensive case management referral and discharge. FINDINGS Referrals were predominately unemployed males with low levels of functioning and educational attainment. They were characterised by a family history of mental illness, migration and early separation, with substantial trauma, history of violence, and forensic attention. Intensive case management improved psychopathology and psychosocial outcomes in high-risk patients and reduced risk ratings, admissions, bed days, and crisis contacts. INTERPRETATION Characterisation of intensive case management patients validated the clinical research focus and identified a first episode of psychosis high-risk subgroup. In a real-world study, implementation of an intensive case management stream within a well-established first episode of psychosis service showed significant improvement in key service outcomes. Further analysis is needed to determine cost savings and effects on psychosocial outcomes. Targeting intensive case management services to high-risk patients with unmet needs should reduce the distress associated with pathways to care for patients, their families, and the community. FUNDING National Health & Medical Research Council and the Colonial Foundation.

Vascular Endothelial Growth Factor and Brain-Derived Neurotrophic Factor in Quetiapine Treated First-Episode Psychosis

Objective. It has been suggested that atypical antipsychotics confer their effects via brain-derived neurotrophic factor (BDNF). We investigated the effect of quetiapine on serum levels of BDNF and vascular endothelial growth factor (VEGF) in drug-naive first-episode psychosis subjects. Methods. Fifteen patients drawn from a larger study received quetiapine treatment for twelve weeks. Baseline levels of serum BDNF and VEGF were compared to age- and sex-matched healthy controls and to levels following treatment. Linear regression analyses were performed to determine the relationship of BDNF and VEGF levels with outcome measures at baseline and week 12. Results. The mean serum BDNF level was significantly higher at week 12 compared to baseline and correlated with reductions in Brief Psychiatric Rating Scale (BPRS) and general psychopathology scores. Changes in serum VEGF levels also correlated significantly with a reduction in BPRS scores, a significant improvement in PANNS positive symptoms scores, and displayed a positive relationship with changes in BDNF levels. Conclusions. Our findings suggest that BDNF and VEGF are potential biomarkers for gauging improvement of psychotic symptoms. This suggests a novel neurotrophic-based mechanism of the drug effects of quetiapine on psychosis. This is the first report of VEGF perturbation in psychosis.

Quetiapine v. lithium in the maintenance phase following a first episode of mania: randomised controlled trial

BackgroundLithium and quetiapine are considered standard maintenance agents for bipolar disorder yet it is unclear how their efficacy compares with each other.AimsTo investigate the differential effect of lithium and quetiapine on symptoms of depression, mania, general functioning, global illness severity and quality of life in patients with recently stabilised first-episode mania.MethodMaintenance trial of patients with first-episode mania stabilised on a combination of lithium and quetiapine, subsequently randomised to lithium or quetiapine monotherapy (up to 800 mg/day) and followed up for 1 year. (Trial registration: Australian and New Zealand Clinical Trials Registry - ACTRN12607000639426.)ResultsIn total, 61 individuals were randomised. Within mixed-model repeated measures analyses, significant omnibus treatment × visit interactions were observed for measures of overall psychopathology, psychotic symptoms and functioning. Planned and post hoc comparisons further demonstrated the superiority of lithium treatment over quetiapine.ConclusionsIn people with first-episode mania treated with a combination of lithium and quetiapine, continuation treatment with lithium rather than quetiapine is superior in terms of mean levels of symptoms during a 1-year evolution.

Duration of untreated negative symptoms and duration of active negative symptoms: proof of concepts

Aim: Negative symptoms are responsible for enormous burden in schizophrenia; yet they remain under‐recognized and under‐treated. There is mounting evidence that early intervention is crucial and that response to treatment falls away with chronicity. Current measures of illness duration fail to adequately capture the true time course of negative symptoms and new concepts are required to correct this and to focus clinical attention. The aim of this paper is to introduce accurate measures of negative symptom duration.

Olanzapine or chlorpromazine plus lithium in first episode psychotic mania: An 8-week randomised controlled trial

BACKGROUND Treatment strategies for mental disorders may vary according to illness stage. However no data currently exist to guide treatment in first episode psychotic mania. The aim of this study was to compare the safety and efficacy profile of chlorpromazine and olanzapine, as add-on to lithium, in patients with a first episode of psychotic mania, expecting better safety profile and adherence to olanzapine but similar efficacy for both treatments. METHODS Data from 83 patients were collected in an 8-week randomised controlled trial on clinical variables, side effects, vital signs, and weight. Analyses of treatment differences over time were based on intent-to-treat principles. Kaplan-Meier estimated survival curves were used to analyse time-to-event data and mixed effects models repeated measures analysis of variance were used to determine treatment group differences over time on safety and efficacy measures. RESULTS Ethics committee approval to delay informed consent procedure until recovery from the acute episode allowed the inclusion of 83 patients highly representative of those treated in the public sector. Contrary to our hypotheses, safety profile of both medications was similar. A signal for higher rate (P=.032) and earlier occurrence (P=.043) of mania remission was observed in the olanzapine group which did not survive correction for multiple comparisons. CONCLUSIONS Olanzapine and chlorpromazine have a similar safety profile in a uniquely representative cohort of patients with first episode psychotic mania. The possibility for a greater impact of olanzapine on manic symptoms leading to earlier remission of the episode needs exploration in a large sample.

Randomized Controlled Trial of Clozapine and CBT for First-Episode Psychosis with Enduring Positive Symptoms: A Pilot Study

Here we report the results of a pilot study investigating the relative and combined effects of a 12 week course of clozapine and CBT in first-episode psychosis patients with prominent ongoing positive symptoms following their initial treatment. Patients from our early psychosis service who met the inclusion criteria (n = 48) were randomized to one of four treatment groups: clozapine, clozapine plus CBT, thioridazine, or thioridazine plus CBT. The degree of psychopathology and functionality of all participants was measured at baseline then again at 6, 12 and 24 weeks, and the treatment outcomes for each group determined by statistical analysis. A substantial proportion (52%) of those treated with clozapine achieved symptomatic remission, as compared to 35% of those who were treated with thioridazine. Overall, those who received clozapine responded more rapidly to treatment than those receiving the alternative treatments. Interestingly, during the early treatment phase CBT appeared to reduce the intensity of both positive and negative symptoms and thus the time taken to respond to treatment, as well having as a stabilizing effect over time.