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Background Some antipsychotic drugs elevate prolactin, and hyperprolactinaemia is associated with an increased risk of breast cancer. Women with schizophrenia have an increased incidence of breast cancer, but also multiple risk factors for the condition. Method This paper will critically review recent epidemiological studies concerning antipsychotics and breast cancer from a psychiatric perspective. Results Two recent epidemiological studies have found an association between use of prolactin-elevating antipsychotics and breast cancer in women with schizophrenia and other psychotic disorders. Prolactin-elevating drugs include paliperidone, risperidone, amisulpride and haloperidol, whilst prolactin-sparing antipsychotics included aripiprazole, brexpiprazole, cariprazine and quetiapine. In the two studies, estimated increased risks of breast cancer were disconcertingly high (up to 62%), but a third recent study found only a weak dose-response association. There are extensive methodological complications in this research, including the extent to which studies measure other risk factors for breast cancer and disagreement about the extent of prolactin elevation by some antipsychotics. Conclusion Although causation between prolactin elevating antipsychotics and breast cancer in women has not been demonstrated, recent epidemiological reports are worrying. For women on antipsychotics, informed consent should ideally include discussion of breast cancer concerns within the wider context of treatment benefits and risks.

Current medications for schizophrenia typically modulate dopaminergic neurotransmission. While affecting positive symptoms, antipsychotic drugs have little clinical effect on negative symptoms and cognitive impairment. Moreover, newer 'atypical' antipsychotic drugs also have significant metabolic adverse-effects. The recent positive clinical trial of the novel drug candidate SEP-363856, which targets non-dopamine receptors (trace amine-associated receptor and the 5HT1A receptor), is a potentially promising development for the management of schizophrenia. In this perspective, we briefly overview the role of TAAR1 and the 5HT1A receptor in schizophrenia and explore the specific binding characteristics of SEP-363856 at these receptors. Molecular dynamics simulations (MDS) indicate that SEP-363856 interacts with a small, common set of conserved residues within the TAAR1 and 5HT1A ligand-binding domain. The primary interaction of SEP-363856 involves binding to the negatively charged aspartate residue (Asp1033.32, TAAR1; Asp1163.32, 5HT1A). In general, the binding of SEP-363856 within TAAR1 involves a greater number of aromatic contacts compared to 5HT1A. MDS provides important insights into the molecular basis of binding site interactions of SEP-363856 with TAAR1 and the 5HT1A receptor, which will be beneficial for understanding the pharmacological uniqueness of SEP-363856 and for the design of novel drug candidates for these newly targeted receptors in the treatment of schizophrenia and related disorders.

Aripiprazole, brexpiprazole and cariprazine differ from all other second-generation antipsychotics due to partial agonism at the dopamine D2 and D3 receptors. In contrast to aripiprazole, brexpiprazole has lower intrinsic dopamine D2 activity and higher affinity for the serotonin 5-HT1A and 5-HT2A receptors, while cariprazine has the highest affinity for the dopamine D3 receptor, and the longest half-life. The main adverse effect of dopamine receptor partial agonists (DRPAs) is akathisia of low-to-moderate severity, which occurs in a small proportion of patients, usually in the first few weeks of treatment. While definitive conclusions concerning differences between the DRPAs require head-to-head comparison studies, on the available evidence, akathisia is probably least likely to occur with brexpiprazole and most likely with cariprazine; the risk of akathisia with aripiprazole lies in between. Weight-gain risk is low with aripiprazole and cariprazine, but moderate with brexpiprazole. Risk of sedation is low with DRPAs, as is risk of insomnia and nausea. Partial dopamine agonism leads to a low risk for hyperprolactinaemia (and probably a low risk of sexual dysfunction). Prolactin concentrations fall in some patients (particularly those with elevated levels prior to initiating the drugs). Rates of discontinuation due to adverse effects in pivotal studies were low, and on the whole, DRPAs are well tolerated. Aripiprazole has been implicated in pathological gambling and other impulse control behaviours, likely due to partial dopamine agonist activity (there have been no reports with brexpiprazole and cariprazine). The risks for diabetes and tardive dyskinesia with DRPAs are unknown, but are likely to be low. On the basis of tolerability, DRPAs should be considered as first-line treatment options, particularly in patients with early schizophrenia.

Objective: Milnacipran is a serotonin noradrenaline reuptake inhibitor (SNRI) approved for treatment of fibromyalgia in Australia, but is used for depression in Europe and elsewhere. This paper will briefly review milnacipran and its utility in psychiatry for the treatment of depression. Conclusion: Milnacipran is a dual reuptake inhibitor of noradrenaline and serotonin, with greater effect on noradrenaline than serotonin, in contrast to the related drugs venlafaxine, desvenlafaxine and duloxetine. Rapidly absorbed irrespective of food, milnacipran has a half-life of approximately 8 hours, reaches steady state in 2 days and is excreted renally. Milnacipran helps a minority of patients with fibromyalgia by reducing pain and fatigue. It is also an effective antidepressant with efficacy comparable to venlafaxine and duloxetine, and a side effect profile characteristic of SNRIs. The dose range is 50–200 mg, in divided doses. Milnacipran may be useful for patients with depression and pain, and endogenous depression characterised by anergia, psychomotor retardation and hypersomnia. Caution is necessary in the presence of heart disease, hypertension, renal impairment, epilepsy, glaucoma, bipolar disorder, and bleeding tendency. Milnacipran is likely to be a useful late antidepressant option in treatment-resistant patients, as well as those with chronic pain, anergia and hypersomnia.

Scant research attention has been devoted to the phenomenon of multimodal hallucinations, with majority of studies focusing on auditory hallucinations (AH) in psychosis. The current study aimed to explore the frequency and characteristics of these multisensory hallucinations in a primary AH cohort. It was concluded more than half of our sample reported comorbid hallucinations in one or more sensory modes. This conveys significant research and clinical implications, in terms of steps taken for adequate assessment and intervention.

BackgroundThe efficacy of acceptance and commitment therapy (ACT) in psychosis has been reported but not for medication-resistant psychosis.AimsTo test the efficacy of ACT in a sample of community-residing patients with persisting psychotic symptoms. (Australian New Zealand Clinical Trials Registry: ACTRN12608000210370.)MethodThe primary outcome was overall mental state at post-therapy (Positive and Negative Syndrome Scale –total); secondary outcomes were psychotic symptom dimensions and functioning. In total, 96 patients were randomised to ACT (n = 49) or befriending (n = 47). Symptom, functioning and process measures were administered at baseline, post-therapy and 6 months later.ResultsThere was no group difference on overall mental state. In secondary analyses the ACT group showed greater improvement in positive symptoms and hallucination distress at follow-up: Cohen's d = 0.52 (95% CI 0.07–0.98) and 0.65 (95% CI 0.24–1.06), respectively.ConclusionsImprovements reflected the treatment focus on positive symptoms; however, absence of process-measure changes suggests that the ACT intervention used did not manipulate targeted processes beyond befriending. Symptom-specific therapy refinements, improved investigation of process and attention to cognitive functioning and dose are warranted in future research.

Objectives: This paper reviews the major findings of the Victorian Psychiatry Attraction, Recruitment and Retention Needs Analysis Project and considers some of the implications for the psychiatrist workforce working in public sector psychiatry. Conclusions: The report provides a snapshot of the issues that are impairing the ability of Victorian psychiatrists to comprehensively treat those in our community who have severe mental illness. As the report shows, the issues impacting the profession are multi-faceted and complex, yet surmountable.

Central auditory processing has been reported to be impaired in schizophrenia patients who experience auditory hallucinations, and interhemispheric transfer in auditory circuits may be compromised. In this study, we used EEG spectral coherence to examine interhemispheric connectivity between cortical areas known to be important in the processing of auditory information. Coherence was compared across three subject groups: schizophrenia patients with a recent history of auditory hallucinations (AH), schizophrenia patients who did not experience auditory hallucinations (nonAH), and healthy controls (HC). Subjects listened to pure tone and word stimuli while EEG was recorded continuously. Upper alpha and upper beta band coherence was calculated from six pairs of electrodes located over homologous auditory areas in the left and right cerebral hemispheres. Significant between-group differences were found on four electrode pairs (C3-C4, C5-C6, Ft7-Ft8 and Cp5-Cp6) in the upper alpha band. Relative to both the HC and nonAH groups, coherence was lower in the AH patients, consistent with the hypothesis that interhemispheric connectivity is reduced in these patients.

The Melbourne Psychiatric Brain Bank came into existence 25years ago. This review focusses on lines of research that have used tissue from the Brain Bank over periods of time. Hence there is a discussion on the significance of changes in levels of serotonin 2A receptors in the cortex of patients with schizophrenia and the relevance of such changes with regards to the pathophysiology of the disorder. The extensive contribution made by studies using tissue from the Melbourne Psychiatric Brain Bank to understanding the role of muscarinic receptors in the pathophysiology and treatment of schizophrenia is summarised. Finally, findings using brain bank tissue and "omics" technologies are reviewed. In each case, findings using tissue from the Melbourne Psychiatric Brain Bank is placed in context with research carried out on human postmortem CNS in schizophrenia and with findings in other lines of research that can help explain the causes or consequences of changes in CNS molecular cytoarchitecture. This timely review of data from the Melbourne Psychiatric Brain Bank reinforces the challenges faced in trying to increase our understanding of the molecular pathophysiology of schizophrenia. Continuing to increase our understanding of the disorder is important as a precursor to identifying new drug targets that can be exploited to improve the treatment of a disorder where treatment resistance remains a significant problem (Millan et al., 2016).

Central auditory processing in schizophrenia patients with a history of auditory hallucinations has been reported to be impaired, and abnormalities of interhemispheric transfer have been implicated in these patients. This study examined interhemispheric functional connectivity between auditory cortical regions, using temporal information obtained from latency measures of the auditory N1 evoked potential. Interhemispheric Transfer Times (IHTTs) were compared across 3 subject groups: schizophrenia patients who had experienced auditory hallucinations, schizophrenia patients without a history of auditory hallucinations, and normal controls. Pure tones and single-syllable words were presented monaurally to each ear, while EEG was recorded continuously. IHTT was calculated for each stimulus type by comparing the latencies of the auditory N1 evoked potential recorded contralaterally and ipsilaterally to the ear of stimulation. The IHTTs for pure tones did not differ between groups. For word stimuli, the IHTT was significantly different across the 3 groups: the IHTT was close to zero in normal controls, was highest in the AH group, and was negative (shorter latencies ipsilaterally) in the nonAH group. Differences in IHTTs may be attributed to transcallosal dysfunction in the AH group, but altered or reversed cerebral lateralization in nonAH participants is also possible.

Objectives Bipolar disorder (BD) is intricately associated with chronic clinical conditions. Medical comorbidity is not only more prevalent in mood disorders, but is associated with increased costs, cognitive impairment and, ultimately, premature mortality. Oxidative stress and inflammation may mediate part of this association. To further investigate the association between medical comorbidity status and clinical improvement with adjuvant N acetyl cysteine (NAC) in the context of a placebo-controlled trial. Methods Placebo-controlled randomized clinical trial assessing the effect of NAC over 24 weeks. Symptomatic and functional outcomes were collected over the study period. Medical comorbidities were self-reported, and we took special interest in cardiovascular and endocrine conditions. We evaluated change from baseline to endpoint and the interaction between change and reported medical comorbidities. Results Fifty-one percent of patients reported have a cardiovascular or endocrine comorbidity. Although not found for depressive symptoms or quality of life, a significant interaction between medical comorbidity and change scores was consistently found for all functional outcomes. This indicated an advantage of NAC over placebo in those with a clinical comorbidity. Conclusion Systemic illness moderated only the effect of NAC on functioning, not on depression. Demonstrating an improvement in functional outcomes with an agent that modulates redox and inflammatory pathways, this study lends empirical support to the idea that medical and psychiatric comorbidity are additive in contributing to allostatic states. One intriguing possibility is that comorbid clinical illness could be a marker for more severe oxidative stress states – and thus guide antioxidant use – in BD.

A significant proportion of subjects drop out of medium to long-term clinical studies prior to trial completion. This may bias reported study outcomes and reduce the statistical power of analyses. There is therefore a need for researchers to better understand the characteristics of dropout populations to increase completion rates. Data from a set of participants recruited as part of a 24-week placebo-controlled trial were used to determine the relationship between the five Lindenmayer factors of positive, negative, cognitive, anxiety/depression and excitement symptoms and dropout at trial completion. Results indicated that the rate of trial dropout was significantly predicted by scores on the negative Lindenmayer factor (X² (6, N = 126) = 15.60, p

Oxidative stress has been implicated in several psychiatric illnesses, including schizophrenia. Glutathione is the brain's primary antioxidant and decreased levels of brain glutathione are reported in schizophrenia. Prepulse inhibition (PPI) is a measure of sensory gating, and PPI is reduced in schizophrenia. This study aimed to investigate the effects of brain glutathione depletion on PPI regulation. Rats and mice were treated with the glutathione-depleting agent, 2-cyclohexene-1-one (CHX), and tested for baseline PPI and its disruption by treatment with amphetamine and MK-801. Treatment with CHX caused significant depletion of GSH in frontal cortex and striatum of rats and mice. Baseline PPI and startle were not altered. However, the disruption of PPI after treatment with amphetamine was absent in CHX-treated rats. In contrast, the effect of MK-801 was not altered by CHX-treatment, nor was there any effect of CHX treatment in mice. These data show an interaction of glutathione depletion with the effects of amphetamine treatment on PPI in rats. This effect could reflect loss of plasticity in PPI regulation caused by the additive effects of CHX-induced glutathione depletion and additional oxidative stress caused by amphetamine-induced dopamine release. The significance of these results for schizophrenia is discussed.

OBJECTIVE The pharmacokinetic profile of a drug often gives little indication of its potential therapeutic application with many therapeutic uses of drugs being discovered serendipitously while being studied for different indications. As hypothesis driven quantitative research methodology is exclusively used in early phase trials unexpected but important phenomena may escape detection. In this context this study aimed to examine the potential for integrating qualitative research methods with quantitative methods in early phase drug trials. To our knowledge this mixed methodology has not previously been applied to blinded psychopharmacologic trials. METHOD We undertook qualitative data analysis of clinical observations on the dataset of a randomized double blind placebo controlled trial of N acetylcysteine (NAC) in patients with DSM IV TR diagnosed schizophrenia (N = 140). Textual data on all participants deliberately collected for this purpose were coded using NVivo 2 and emergent themes were analyzed in a blinded manner in the NAC and placebo groups. The trial was conducted from November 2002 to July 2005. RESULTS The principal findings of the published trial could be replicated using a qualitative methodology. In addition significant differences between NAC and placebo treated participants emerged for positive and affective symptoms which had not been captured by the rating scales utilized in the quantitative trial. Qualitative data in this study subsequently led to a positive trial of NAC in bipolar disorder. CONCLUSIONS The use of qualitative methods may yield broader data and has the potential to complement traditional quantitative methods and detect unexpected efficacy and safety signals thereby maximizing the findings of early phase clinical trial research. TRIAL REGISTRATION www.anzctr.org.au Identifier: ACTRN12605000363684.

BackgroundPrevious research has reported auditory processing deficits that are specific to schizophrenia patients with a history of auditory hallucinations (AH). One explanation for these findings is that there are abnormalities in the interhemispheric connectivity of auditory cortex pathways in AH patients; as yet this explanation has not been experimentally investigated. We assessed the interhemispheric connectivity of both primary (A1) and secondary (A2) auditory cortices in n=13 AH patients, n=13 schizophrenia patients without auditory hallucinations (non-AH) and n=16 healthy controls using functional connectivity measures from functional magnetic resonance imaging (fMRI) data.MethodFunctional connectivity was estimated from resting state fMRI data using regions of interest defined for each participant based on functional activation maps in response to passive listening to words. Additionally, stimulus-induced responses were regressed out of the stimulus data and the functional connectivity was estimated for the same regions to investigate the reliability of the estimates.ResultsAH patients had significantly reduced interhemispheric connectivity in both A1 and A2 when compared with non-AH patients and healthy controls. The latter two groups did not show any differences in functional connectivity. Further, this pattern of findings was similar across the two datasets, indicating the reliability of our estimates.ConclusionsThese data have identified a trait deficit specific to AH patients. Since this deficit was characterized within both A1 and A2 it is expected to result in the disruption of multiple auditory functions, for example, the integration of basic auditory information between hemispheres (via A1) and higher-order language processing abilities (via A2).

Objective:To evaluate the effect of N-acetylcysteine (NAC) on substance use in a double-blind, placebo-controlled trial of NAC in bipolar disorder. It is hypothesised that NAC will be superior to placebo for reducing scores on the Clinical Global Impressions scale for Substance Use (CGI-SU).Methods:Participants were randomised to 6-months of treatment with 2 g/day NAC (n = 38) or placebo (n = 37). Substance use was assessed at baseline using the Habits instrument. Change in substance use was assessed at regular study visits using the CGI-SU.Results:Amongst the 75 participants 78.7% drank alcohol (any frequency), 45.3% smoked tobacco and 92% consumer caffeine. Other substances were used by fewer than six participants. Caffeine use was significantly lower for NAC-treated participants compared with placebo at week 2 of treatment but not at other study visits.Conclusion:NAC appeared to have little effect on substance use in this population. A larger study on a substance using population will be necessary to determine if NAC may be a useful treatment for substance use.

Oxidative stress and reduced brain glutathione (GSH) levels have been reported in psychiatric illnesses including schizophrenia and bipolar disorder. However the role of GSH in cognitive impairment in the illness remains unclear. Treatment of Sprague-Dawley rats and C57Bl/6 mice with 2-cyclohexene-1-one (CHX) dose-dependently reduced striatal and frontal cortical GSH levels similar to those in schizophrenia. In both species, GSH depletion resulted in disruption of short-term spatial recognition memory in a Y-maze test. In conclusion, GSH depletion induces cognitive impairment, which may be relevant to the role of GSH in psychiatric illnesses.

Background Brain glutathione levels are decreased in schizophrenia, a disorder that often is chronic and refractory to treatment. N-acetyl cysteine (NAC) increases brain glutathione in rodents. This study was conducted to evaluate the safety and effectiveness of oral NAC (1 g orally twice daily [b.i.d.]) as an add-on to maintenance medication for the treatment of chronic schizophrenia over a 24-week period. Methods A randomized, multicenter, double-blind, placebo-controlled study. The primary readout was change from baseline on the Positive and Negative Symptoms Scale (PANSS) and its components. Secondary readouts included the Clinical Global Impression (CGI) Severity and Improvement scales, as well as general functioning and extrapyramidal rating scales. Changes following a 4-week treatment discontinuation were evaluated. One hundred forty people with chronic schizophrenia on maintenance antipsychotic medication were randomized; 84 completed treatment. Results Intent-to-treat analysis revealed that subjects treated with NAC improved more than placebo-treated subjects over the study period in PANSS total [−5.97 (−10.44, −1.51), p = .009], PANSS negative [mean difference −1.83 (95% confidence interval: −3.33, −.32), p = .018], and PANSS general [−2.79 (−5.38, −.20), p = .035], CGI-Severity (CGI-S) [−.26 (−.44, −.08), p = .004], and CGI-Improvement (CGI-I) [−.22 (−.41, −.03), p = .025] scores. No significant change on the PANSS positive subscale was seen. N-acetyl cysteine treatment also was associated with an improvement in akathisia ( p = .022). Effect sizes at end point were consistent with moderate benefits. Conclusions These data suggest that adjunctive NAC has potential as a safe and moderately effective augmentation strategy for chronic schizophrenia.

Although harmful command hallucinations have been linked to violent behavior, few studies have examined factors mediating this relationship. The principal aim of this study was to examine a range of factors potentially associated with acting on harmful command hallucinations using a multivariate approach. The sample comprised 75 participants drawn from community and forensic services. Measures assessing characteristics of the command hallucination and the hallucinator, including forensic risk factors, were administered. Using ordinal logistic regression, we found compliance to be associated with increasing age, viewing the command hallucination as positive, congruent delusions, and reporting low maternal control in childhood. Antipsychotic medication was protective while, contrary to expectations, traditional predictors of violence reduced the odds of compliance with command hallucinations viewed as threatening. The findings suggest that compliance with harmful commands is driven by a complex interaction between beliefs related to the command hallucination and personal characteristics, with risk of compliance increasing with age.

There is some evidence for an unusual body odour in schizophrenia that has been linked to a hexenoic acid derivative (trans-3-methyl-2-hexenoic acid; MHA). Poor body odour has been linked to increased negative symptoms and reduced olfactory identification ability. However, the relationship between these findings and MHA, including olfactory sensitivity for MHA, has not been examined. Olfactory sensitivity thresholds were assessed for MHA and n-butyl-alcohol (NBA), in normal controls (CTL; n=24), patients with chronic schizophrenia (CHR; n=32) and a first-episode psychosis cohort (FE; n=31). In addition, forced choice detection of the pheromonal steroids 5-alpha-androst-16-en-3-one, androsterone-sulphate and estrone-3-sulphate was performed along with a measure of olfactory identification. CHR patients had significantly reduced sensitivity to MHA, but not NBA, compared to FE and CTL subjects. While sensitivity to pheromones was not different between the groups, CHR patients who could not detect them also showed poorer sensitivity to MHA. Further, the CHR group showed a significant association between reduced MHA sensitivity and greater levels of disorganised and negative symptoms. No relationships between identification and sensitivity for any substance were found. Our findings are the first to report reduced sensitivity for MHA in chronic schizophrenia patients, in the absence of similar impairment for more traditionally used substances. This may be linked to olfactory habituation effects, abnormal chemical processing or a genetic predisposition.

Although the neurotransmitter dopamine plays a prominent role in the pathogenesis and treatment of schizophrenia, the dopamine hypothesis of schizophrenia fails to explain all aspects of this disorder. It is increasingly evident that the pathology of schizophrenia also involves other neurotransmitter systems. Data from many streams of research including pre-clinical and clinical pharmacology, treatment studies, post-mortem studies and neuroimaging suggest an important role for the muscarinic cholinergic system in the pathophysiology of schizophrenia. This review will focus on evidence that supports the hypothesis that the muscarinic system is involved in the pathogenesis of schizophrenia and that muscarinic receptors may represent promising novel targets for the treatment of this disorder.

We studied the change in EEG alpha-band average coherence between auditory hallucination (AH) and non-auditory hallucination (non-AH) states in seven auditory hallucinating schizophrenia patients. Four cortical regions were considered based on the existing dominant models for auditory hallucinations, the inner speech model and the central auditory processing deficit (CAPD) model. Coherences between electrodes located over Broca's area (BA 44/45) and Wernicke's area (BA 22/42) and between electrodes located over left-right temporal cortices were examined. There was no significant change observed in the coherence between Broca's and Wernicke's areas, but a significant increase was observed in coherence between the left and right superior temporal cortices during AHs compared with non-AHs, suggesting increased bilateral coherence between auditory cortical areas. Since coherence is a pairwise measure of functional correlation between regions, our findings suggest abnormally increased synchrony between the left and right auditory cortices during AHs in schizophrenia. Further, a significant increase in relative power was observed in the left, but not in the right auditory cortex during AHs. Thus our findings support the CAPD model and are consistent with that which postulate reduced prosodic processing during AHs.

Objective: To analyse the available data regarding the presentation of psychosis in diseases of central nervous system (CNS) white matter.Method: The available neurological and psychiatric literature on developmental, neoplastic, infective, immunological and other white matter diseases was reviewed.Results: A number of diseases of the white matter can present as schizophrenia-like psychoses, including leukodystrophies, neoplasms, velocardiofacial syndrome, callosal anomalies and inflammatory diseases.Conclusions: Production of psychotic symptoms may result from functional asynchrony of interdependent regions, due to alterations in critical circuits as a result of pathology. The nature, location and timing of white matter pathology seem to be the key factors in the development of psychosis, especially during the critical adolescent period of association area myelination. Diseases that disrupt the normal formation of myelin appear to cause psychosis at higher rates than those that disrupt mature myelinated structures. Diffuse rather than discrete lesions, in particular those affecting frontotemporal zones, are also more strongly associated with schizophrenia-like psychosis. These illnesses point to the central role that white matter plays in maintaining CNS connectivity and to how pathology of the white matter may contribute to the neurobiology of psychosis.

Antipsychotic drugs are effective in the treatment of cannabis-induced psychosis, but only clozapine appears effective in the treatment of comorbid schizophrenia and cannabis use. The unique effects of clozapine on cannabis use could, therefore, be due to an as yet unidentified interaction between clozapine and the endogenous cannabinoid system. To address this hypothesis, we used in situ radioligand binding and quantitative autoradiography with the selective cannabinoid CB1 receptor agonist, (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (side chain-2,3,4(N)-3H) ([3H]CP 55940) to measure the density of the CB1 receptor in frontal cortex, hippocampus, nucleus accumbens and striatum from rats treated with a variety of antipsychotic drugs. Clozapine significantly decreased [3H]CP 55940 binding in the nucleus accumbens compared with vehicle after 1 (35.0+/-14.0 vs. 71.2+/-8.5 fmol/mg estimated tissue equivalent (ete); P = 0.03) and 3 months (42.3+/-4.0 vs. 71.1+/-16.3 fmol/mg ete; P0.04) of treatment, an effect not observed with haloperidol, chlorpromazine or olanzapine. In rats treated with clozapine for 3 months and then left for 1 month without treatment, [3H]CP 55940 binding was not different in the nucleus accumbens (100.5+/-22.2 vs. 100.9+/-25.4 fmol/mg ete; P0.10). By contrast, there were significant increases in accumbal [3H]CP 55940 binding in rats treated with haloperidol (136.5+/-14.2 fmol/mg ete; P0.05), chlorpromazine (137.4+/-12.7 fmol/mg ete; P0.05) and olanzapine (144.7+/-10.1 fmol/mg ete; P0.01). These data indicate that in the nucleus accumbens clozapine differs from other antipsychotic drugs in its effects on [3H]CP 55940 binding. If these results can be extrapolated into humans, then this effect of clozapine on the CB1 receptor may be a mechanism that makes it uniquely effective in schizophrenia and comorbid cannabis use.

Traditionally, auditory hallucinations (AHs) heard outside the head have been regarded as more pathological than those heard inside, partly on the basis that internal AHs are conceptually closer to normal thinking than external AHs. Our data show that many patients hear AHs both internally and externally, and there were very few associations between location and demographic and clinical characteristics of the patients or with other characteristics of the AHs themselves. There was evidence that AHs heard internally were associated with better insight than those heard externally. Of those patients whose AHs included commands, greater proportions of those who heard them externally said they could resist than those who heard them internally or in both locations. There appears to be no consistent differential impact and effect of internal and external AHs, and there was no support for the historical view that internal AHs are more benign.

Command hallucinations (CHs) are hallucinations that direct the patient to perform an action. Beyond issues related to the danger that some CHs may pose, comparatively little is known about the broader clinical context of CHs. To investigate this, 199 patients were interviewed using the Mental Health Research Institute Unusual Perceptions Scale. More than two thirds of the sample reported hearing CHs. A quarter of these patients felt unable to resist them. Patients with CHs reported their voices more negatively than those who did not hear commands. More of those unable to resist CHs rated their hallucinations as intrusive, they had fewer coping strategies than those able to resist, and they were prescribed higher dosages of medication. CHs are associated with a greater degree of adverse hallucinatory and illness experience. Patients who experience CHs may have a more malignant form of the underlying disorder. Thus, CHs warrant special therapeutic attention for reasons beyond any harm that their commands pose to themselves or others.

Australia is a diverse country comprising people from many different backgrounds, races and ethnic groups including immigrant and indigenous cultures. The mental health needs of Australian society reflect the composition of the Australian population and the particular issues faced by the various sectors of the society. In conjunction with greater understanding of the significant burdens that illnesses such as dementia, depression, schizophrenia, suicide and anxiety disorders place on all levels of Australian society, there is a changing view of the priorities for mental health research. In this article we summarize current, emerging and future mental health challenges confronting Australia and review the efforts that Australian researchers are making to meet these challenges.Declaration of interest: The first author (S.L.C.) is a consultant for Cogtest Ltd, London and the second author (D.L.C.) has received Research funding from Eli Lilly and is a consultant for Novartis and Bristol-Myers Squibb.

Evidence now suggests that compromised prenatal brain development may increase the risk for the manifestation of neurological disorders such as schizophrenia. We present a guinea-pig model which mimics a condition of human pregnancy, namely, chronic placental insufficiency. Previously we reported that at term there are changes in the brains of these offspring which are relevant to changes in patients with schizophrenia. The aim of this study was to examine whether deficits in brain structure persist to adolescence and young adulthood (8-12 weeks) and have implications for behavioral function. Reduced uteroplacental blood flow was induced via unilateral ligation of the uterine artery at mid-gestation. The brain was examined in control and prenatally compromised (PC) animals 8 weeks after birth using morphometric and immunohistochemical markers. In a separate cohort of animals, prepulse inhibition (PPI) of the acoustic startle response was assessed at 4, 8 and 12 weeks of age. Brain neurochemistry was examined by determining the concentrations of dopamine and its metabolite, dihydroxyphenylacetic acid (DOPAC), at 12 weeks using high performance liquid chromatography. In PC animals compared with controls there was a reduction in brain weight, persistent enlargement of the lateral ventricles, a reduction in the volume of the basal ganglia and septal region and no evidence of gliosis. No differences were observed in concentration of catecholamines in any brain region examined. At 12, but not 4 or 8, weeks of age, PPI was reduced in PC animals compared with controls. The findings of reduced brain weight, ventriculomegaly, reduced basal ganglia volume and absence of astrogliosis in the PC guinea-pig brain at adolescence parallel some of the changes observed in patients with schizophrenia. The impairment of PPI is comparable to sensorimotor gating deficits observed in patients with schizophrenia. These results indicate that adverse prenatal conditions lead to long-term alterations in brain structure and function which resemble alterations seen in patients with schizophrenia and therefore support the early neurodevelopmental hypothesis of schizophrenia.

While many who hear auditory hallucinations (AHs) experience them as unpleasant, some do not. Little is known about the correlates of AHs that are not unpleasant, or of the characteristics of those who hear them. To better understand this symptom, we used a comprehensive structured interview schedule to study 199 subjects who had experienced AHs. Subjects' responses to AHs were combined into two indexes: one assessing total affective impact and the other assessing the affective direction (positive or negative). Subjects who had grandiose delusions experienced their AHs more positively. AHs that were more frequent, lasted longer, and were louder were experienced more negatively. AHs heard in the second person and those related to people with whom the subjects had personal relationships were more positive than those heard in the third person. Many other aspects of AHs were unrelated to total affective impact or direction. It is argued that the positive evaluation of voices by subjects requires greater attention than it has received previously. Implications for assessment, clinical practice, and research are discussed.

OBJECTIVE: Previous investigation has revealed stable olfactory identification deficits in neuroleptic-naive patients experiencing a first episode of psychosis, but it is unknown if these deficits predate illness onset. METHOD: The olfactory identification ability of 81 patients at ultra-high risk for psychosis was examined in relation to that of 31 healthy comparison subjects. Twenty-two of the ultra-high-risk patients (27.2%) later became psychotic, and 12 of these were diagnosed with a schizophrenia spectrum disorder. RESULTS: There was a significant impairment in olfactory identification ability in the ultra-high-risk group that later developed a schizophrenia spectrum disorder but not in any other group. CONCLUSIONS: These findings suggest that impairment of olfactory identification is a premorbid marker of transition to schizophrenia, but it is not predictive of psychotic illness more generally.

Apolipoprotein D (apoD) is an atypical plasma apolipoprotein and, based on its primary structure, it is a member of the lipocalin protein superfamily. Lipocalins have been extensively used as disease markers and, accordingly, apoD has become increasingly recognized as an important factor in the pathology of human neurodegenerative and neuropsychiatric disorders. ApoD expression is increased in the plasma and brains of subjects with schizophrenia and bipolar disorder, suggesting that it acts as a marker for disease pathology. ApoD also exhibits complex regulation by antipsychotic drug treatment and may represent a distinguishing mechanism of typical versus atypical drugs. The precise role of apoD in the CNS and disease remains to be elucidated, but recent findings have suggested that it plays an important role in the regulation of arachidonic acid signaling and metabolism providing further support for phospholipid membrane pathology in schizophrenia.

BACKGROUND: Various studies suggest the hippocampus and serotonergic systems are important in the pathology of bipolar disorder (BD). We therefore measured hippocampal serotonergic markers in post-mortem tissue from BD and control subjects. METHODS: The density and affinity of [3H]citalopram binding to the serotonin transporter (SERT), as well as the density of the 5HT(2A), 5HT(1A), 5HT(1D) and 5HT(1F) receptors were measured. RESULTS: The density of SERT and 5HT receptors was no different in BD. There was a significant decrease in the affinity of [3H]citalopram binding to SERT in the stratum lacunosum-moleculare (S(lac)) in BD (K(d) mean+/-S.E.M.=4.3+/-0.8 vs. 1.9+/-0.3 nM). LIMITATIONS: This study was completed using relatively small cohorts. CONCLUSIONS: There are no generalised changes in hippocampal serotonergic markers in the hippocampus from subjects with BD. There is a decreased affinity of radioligand binding to S(lac) SERT in subjects with BD.

Over the last decade there has been escalating debate regarding the competency of patients with psychoses to give informed consent to participate in research. This debate has been made evermore complex by variations in the definition and evaluation of competency. Importantly, competency must meet both medical and legal standards, although the criteria for each of these are not always consistent and may be mediated by contextual factors. The matter of competency to give informed consent is further complicated in the case of patients with psychoses. As a result of their disorder, patients with psychoses develop a mental state where there is impairment of reality appreciation. The impact on competency however, is highly variable and can frequently be accommodated in the consent process. Establishing associations between particular psychotic symptoms and their severity, with competency to consent at different levels of risk is the central theme of research currently being conducted.

A [H(2)(15)O] PET correlation analysis technique was employed to correlate brain activations associated with self-reports of auditory hallucinations in hallucinating patients (n=8) and perception of transient, random human speech in non-hallucinating (n=7) patients and normal control subjects (n=8). Perception of externally generated human speech amongst the non-hallucinating and normal control participants was associated with a consistent pattern of extensive bilateral auditory cortex activation (Brodmann areas 40/41/42/22). Hallucinating participants demonstrated a network of cortical activations including bilateral auditory cortex, left limbic regions, right medial frontal and right prefrontal regions. The observed pattern of activation is consistent with models of auditory hallucinations as mis-remembered episodic memories of speech.

This study investigated the suitability of high-resolution storage phosphor imaging for the quantitative analysis of radioligand binding to human brain tissue. Hence, the binding of [(3)H]mazindol to the dopamine transporter in caudate-putamen tissue homogenates or frozen tissue sections apposed to either autoradiographic film or phosphor imaging plates was measured. Estimates of binding affinity were similar for homogenate studies and phosphor imaging plates (Kd=6.44+/-0.14 and 6.91+/-0.47 nM, respectively), but higher values were obtained with film autoradiography (Kd=11.31+/-0.82 nM). The density of binding was similar for both autoradiographic techniques (Bmax=371.9+/-30.8 fmol/mg estimated tissue equivalent, ETE (imaging plate) and 425+/-13.77 fmol/mg ETE (film)), although lower values were obtained from tissue homogenates (Bmax=64.27+/-6.74 fmol/mg wet weight). These results suggest that high resolution phosphor imaging can be used to analyse radioligand binding parameters in human brain tissue. Moreover, the reduced exposure time of phosphor imaging plates (e.g. 7 days vs 5 weeks) allows results to be obtained more rapidly than with conventional film autoradiography.

The pharmacological characterisation of the benzodiazepine binding site associated with the gamma-aminobutyric acid (GABA(A)) receptor in human brain has been demonstrated using in situ radioligand binding and autoradiography. The use of high-resolution phosphorimaging has allowed both the affinity (K(d)) and density (B(max)) of [(3)H]flumazenil binding to be measured within regions of the hippocampal formation as well as the cerebellum and frontal cortex. The Scatchard plots of data from all brain regions were linear with Hill coefficients close to unity consistent with the presence of a single binding site for [(3)H]flumazenil. The affinities of [(3)H]flumazenil binding within all the brain regions were similar (K(d) 1.57+/-0.20-3.08+/-0.01 nM), while the density of [(3)H]flumazenil binding varied significantly between the brain regions analysed (B(max) 182.7+/-7.3-596.7+/-34.0 fmol/mg ETE; P0.0001). In conclusion, the present results indicate that in situ radioligand binding and high-resolution phosphorimaging techniques can be utilized to measure the distribution, density and affinity of [(3)H]flumazenil to the GABA(A) receptor within the human frontal cortex, cerebellum and hippocampal formation.

Cognitive behavior therapy for psychosis has been a prominent intervention in the psychological treatment of psychosis. It is, however, a challenging therapy to deliver and, in the context of increasingly rigorous trials, recent reviews have tempered initial enthusiasm about its effectiveness in improving clinical outcomes. Acceptance and commitment therapy shows promise as a briefer, more easily implemented therapy but has not yet been rigorously evaluated in the context of psychosis. The purpose of this trial is to evaluate whether Acceptance and Commitment Therapy could reduce the distress and disability associated with psychotic symptoms in a sample of community-residing patients with chronic medication-resistant symptoms. This is a single (rater)-blind multi-centre randomised controlled trial comparing Acceptance and Commitment Therapy with an active comparison condition, Befriending. Eligible participants have current residual hallucinations or delusions with associated distress or disability which have been present continuously over the past six months despite therapeutic doses of antipsychotic medication. Following baseline assessment, participants are randomly allocated to treatment condition with blinded, post-treatment assessments conducted at the end of treatment and at 6 months follow-up. The primary outcome is overall mental state as measured using the Positive and Negative Syndrome Scale. Secondary outcomes include preoccupation, conviction, distress and disruption to life associated with symptoms as measured by the Psychotic Symptom Rating Scales, as well as social functioning and service utilisation. The main analyses will be by intention-to-treat using mixed-model repeated measures with non-parametric methods employed if required. The model of change underpinning ACT will be tested using mediation analyses. This protocol describes the first randomised controlled trial of Acceptance and commitment therapy in chronic medication-resistant psychosis with an active comparison condition. The rigor of the design will provide an important test of its action and efficacy in this population. Australian New Zealand Clinical Trials Registry: ACTRN12608000210370 . Date registered: 18 April 2008

Background: The hippocampus is implicated in the pathophysiology of schizophrenia; however, volumetric changes are subtle and have limited diagnostic specificity. It is possible that the shape of the hippocampus may be more characteristic of schizophrenia. Methods: Forty-five patients with chronic schizophrenia and 139 healthy control subjects were scanned using magnetic resonance imaging. Hippocampi were traced manually, and two-dimensional shape information was analyzed. Results: Two shape factors were found to be adequate to represent variance in the shape of the hippocampus. One of these factors, representing volume loss behind the head of the hippocampus, provided a degree of discrimination between patients with chronic schizophrenia and healthy control subjects; however, overall hippocampal volume following appropriate adjustment for brain volume showed a similar level of discrimination. Patients with chronic schizophrenia were best characterized using these two measures together, but diagnostic specificity was only moderate. Conclusions: This study identified that less of the hippocampus was distributed in its posterior two-thirds in patients with chronic schizophrenia, and specifically in the region just posterior to the hippocampal head. Group discrimination on the basis of hippocampal volume and shape measures was moderately good. A full three-dimensional analysis of hippocampal shape, based on large samples, would be a useful extension of the study.

Aberrant cholinergic inputs and synaptic neurotransmission in the prefrontal cortex induce cognitive impairment, which is a central feature of schizophrenia. Postsynaptic excitatory muscarinic cholinergic M(1) and M(4) receptors are the major cholinoceptive targets in the prefrontal cortex and hence may be involved in the pathology and/or pharmacotherapeutics of schizophrenia.Using quantitative autoradiography, the authors analyzed the binding of the M(1)/M(4) receptor selective antagonist [(3)H]pirenzepine in prefrontal cortex (Brodmann's areas 8, 9, 10, and 46) from schizophrenia patients who had (N=6) or had not (N=11) been treated with the anticholinergic agent benztropine mesylate and from normal comparison subjects (N=20). Moreover, preliminary studies of [(3)H]pirenzepine binding in rat frontal cortex following administration of antipsychotic drugs or benztropine mesylate were performed.Relative to those of comparison subjects, the mean levels of [(3)H]pirenzepine binding were significantly lower in Brodmann's areas 9 and 46 of the schizophrenia patients not treated with benztropine mesylate (18% lower in Brodmann's area 9 and 21% lower in Brodmann's area 46) and in all four examined regions of the patients who had received benztropine (51%-64% lower). Antipsychotic or anticholinergic drugs tended to increase or have no effect on the density of [(3)H]pirenzepine-labeled receptors in rat frontal cortex.Because M(1) and M(4) receptors are critical to the functions of prefrontal cortical acetylcholine, the present findings suggest a functional impairment in cholinergic neurotransmission in schizophrenia and the possibility that muscarinic receptors are involved in the pharmacotherapeutics of the disorder.

A number of studies suggested that cannabis use can cause or exacerbate psychoses and may increase the risk of developing schizophrenia. These findings suggest that changes in the cannabinoid system of the brain may be involved in the pathology of schizophrenia. To determine whether changes in the cannabinoid system were present in the brains of subjects with schizophrenia, we used in situ radioligand binding and autoradiography to measure the binding of [3H]CP-55940 to the cannabinoid-1 receptor in the dorsolateral prefrontal cortex (Brodmann's area 9), caudate-putamen and areas of the temporal lobe from schizophrenic and control subjects, some of whom had ingested cannabis close to death. There was an increase in the density of [3H]CP-55940 binding to cannabinoid-1 receptors in the dorsolateral prefrontal cortex from subjects with schizophrenia (mean+/-S.E.M.: 142+/-9.9 vs 119+/-6.6fmol/mg estimated tissue equivalents; P

SUMMARY 1. The hippocampal formation plays an important role in the normal functioning of the brain, being implicated in cognition and sensory gating, both of which are affected in schizophrenia. The hippocampal formation receives information from the association cortices, which is processed by glutamatergic transmission within the hippocampus. Dopamine, noradrenaline, 5-hydroxytryptamine (5-HT), acetylcholine and GABA, all of which have been proposed to play a role in the neurobiology of schizophrenia, can affect this transmission. 2. The advent of the ‘atypical’ antipsychotics, with their broad pharmacological spectra and improved therapeutic outcome, has revitalized research into neurotransmitter dysfunction other than that of dopamine. In particular, there has been interest in the serotonergic and cholinergic systems within the hippocampal formation because these are two of the transmitter systems targeted by clozapine and olanzapine. 3. From the study of these systems, using tissue obtained post-mortem from subjects with schizophrenia, we propose that there is a hyperserotonergic state in the hippocampal formation of some subjects with schizophrenia caused by a conformational change in the 5-HT transporter. The model we propose allows us to construct further studies that will test the consequences of such a hyperserotonergic state in the hippocampal formation. This model has the potential to open new avenues in schizophrenia research.