Determinants of treatment response in first-episode psychosis: an 18F-DOPA PET study.

Psychotic illnesses show variable responses to treatment. Determining the neurobiology underlying this is important for precision medicine and the development of better treatments. It has been proposed that dopaminergic differences underlie variation in response, with striatal dopamine synthesis capacity (DSC) elevated in responders and unaltered in non-responders. We therefore aimed to test this in a prospective cohort, with a nested case-control comparison. 40 volunteers (26 patients with first-episode psychosis and 14 controls) received an 18F-DOPA Positron Emission Tomography scan to measure DSC (Kicer) prior to antipsychotic treatment. Clinical assessments (Positive and Negative Syndrome Scale, PANSS, and Global Assessment of Functioning, GAF) occurred at baseline and following antipsychotic treatment for a minimum of 4 weeks. Response was defined using improvement in PANSS Total score of >50%. Patients were followed up for at least 6 months, and remission criteria applied. There was a significant effect of group on Kicer in associative striatum (F(2, 37) = 7.9, p = 0.001). Kicer was significantly higher in responders compared with non-responders (Cohen's d = 1.55, p = 0.01) and controls (Cohen's d = 1.31, p = 0.02). Kicer showed significant positive correlations with improvements in PANSS-positive (r = 0.64, p < 0.01), PANSS negative (rho = 0.51, p = 0.01), and PANSS total (rho = 0.63, p < 0.01) ratings and a negative relationship with change in GAF (r = -0.55, p < 0.01). Clinical response is related to baseline striatal dopaminergic function. Differences in dopaminergic function between responders and non-responders are present at first episode of psychosis, consistent with dopaminergic and non-dopaminergic sub-types in psychosis, and potentially indicating a neurochemical basis to stratify psychosis.

CNVs conferring risk of autism or schizophrenia affect cognition in controls.

In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.

Connectomic correlates of response to treatment in first-episode psychosis.

Connectomic approaches using diffusion tensor imaging have contributed to our understanding of brain changes in psychosis, and could provide further insights into the neural mechanisms underlying response to antipsychotic treatment. We here studied the brain network organization in patients at their first episode of psychosis, evaluating whether connectome-based descriptions of brain networks predict response to treatment, and whether they change after treatment. Seventy-six patients with a first episode of psychosis and 74 healthy controls were included. Thirty-three patients were classified as responders after 12 weeks of antipsychotic treatment. Baseline brain structural networks were built using whole-brain diffusion tensor imaging tractography, and analysed using graph analysis and network-based statistics to explore baseline characteristics of patients who subsequently responded to treatment. A subgroup of 43 patients was rescanned at the 12-week follow-up, to study connectomic changes over time in relation to treatment response. At baseline, those subjects who subsequently responded to treatment, compared to those that did not, showed higher global efficiency in their structural connectomes, a network configuration that theoretically facilitates the flow of information. We did not find specific connectomic changes related to treatment response after 12 weeks of treatment. Our data suggest that patients who have an efficiently-wired connectome at first onset of psychosis show a better subsequent response to antipsychotics. However, response is not accompanied by specific structural changes over time detectable with this method.

Moment-to-moment associations between negative affect, aberrant salience, and paranoia.

INTRODUCTION: There is an ongoing debate about whether negative affect are consequences or triggers of paranoid thinking. It has also been suggested that aberrant salience is central to the development of delusions. This study modelled the moment-to-moment relationships between negative affect, aberrant salience, and paranoia in acute inpatients with psychosis. METHODS: Participants with active paranoid delusions were assessed using clinical rating scales and experience sampling method (ESM) over 14 days. ESM data were analysed using time-lagged multilevel regression modelling. RESULTS: Both negative affect and aberrant salience predicted an increase in paranoia at the next time point. Conversely, the level of paranoia did not predict subsequent changes in negative affect or aberrant salience. Negative affect predicted an increase in aberrant salience at the next time point, and vice versa. CONCLUSIONS: Negative affect and aberrant salience appear to drive and exacerbate paranoia, rather than being merely the sequelae of the symptom. Our results suggest both direct and indirect (via aberrant salience) pathways from negative affect to paranoia.

Initial depression severity and response to antidepressants v. placebo: patient-level data analysis from 34 randomised controlled trials.

Several often-cited meta-analyses have reported that the efficacy of antidepressant medications depends on the severity of depression. They found that drug-placebo differences increased as a function of initial severity, which was attributed to decreased responsiveness to placebo among patients with severe depression rather than to increased responsiveness to medication. We retested this using patient-level data and also undertaking a meta-analysis of trial-level data from 34 randomised placebo controlled trials (n = 10 737) from the NEWMEDS registry. Although our trial-level data support prevous findings, patient-level data did not show any significant effect of initial depression severity on drug v. placebo difference.

Altered PDE10A expression detectable early before symptomatic onset in Huntington's disease.

There is an urgent need for early biomarkers and novel disease-modifying therapies in Huntington's disease. Huntington's disease pathology involves the toxic effect of mutant huntingtin primarily in striatal medium spiny neurons, which highly express phosphodiesterase 10A (PDE10A). PDE10A hydrolyses cAMP/cGMP signalling cascades, thus having a key role in the regulation of striatal output, and in promoting neuronal survival. PDE10A could be a key therapeutic target in Huntington's disease. Here, we used combined positron emission tomography (PET) and multimodal magnetic resonance imaging to assess PDE10A expression in vivo in a unique cohort of 12 early premanifest Huntington's disease gene carriers with a mean estimated 90% probability of 25 years before the predicted onset of clinical symptoms. We show bidirectional changes in PDE10A expression in premanifest Huntington's disease gene carriers, which are associated with the probability of symptomatic onset. PDE10A expression in early premanifest Huntington's disease was decreased in striatum and pallidum and increased in motor thalamic nuclei, compared to a group of matched healthy controls. Connectivity-based analysis revealed prominent PDE10A decreases confined in the sensorimotor-striatum and in striatonigral and striatopallidal projecting segments. The ratio between higher PDE10A expression in motor thalamic nuclei and lower PDE10A expression in striatopallidal projecting striatum was the strongest correlate with higher probability of symptomatic conversion in early premanifest Huntington's disease gene carriers. Our findings demonstrate in vivo, a novel and earliest pathophysiological mechanism underlying Huntington's disease with direct implications for the development of new pharmacological treatments, which can promote neuronal survival and improve outcome in Huntington's disease gene carriers.

Loss of phosphodiesterase 10A expression is associated with progression and severity in Parkinson's disease.

The mechanisms underlying neurodegeneration and loss of dopaminergic signalling in Parkinson's disease are still only partially understood. Phosphodiesterase 10A (PDE10A) is a basal ganglia expressed dual substrate enzyme, which regulates cAMP and cGMP signalling cascades, thus having a key role in the regulation of dopaminergic signalling in striatal pathways, and in promoting neuronal survival. This study aimed to assess in vivo the availability of PDE10A in patients with Parkinson's disease using positron emission tomography molecular imaging with (11)C-IMA107, a highly selective PDE10A radioligand. We studied 24 patients with levodopa-treated, moderate to advanced Parkinson's disease. Their positron emission tomography imaging data were compared to those from a group of 12 healthy controls. Parametric images of (11)C-IMA107 binding potential relative to non-displaceable binding (BPND) were generated from the dynamic (11)C-IMA107 scans using the simplified reference tissue model with the cerebellum as the reference tissue. Corresponding region of interest analysis showed lower mean (11)C-IMA107 BPND in the caudate (P < 0.001), putamen (P < 0.001) and globus pallidus (P = 0.025) in patients with Parkinson's disease compared to healthy controls, which was confirmed with voxel-based analysis. Longer Parkinson's duration correlated with lower (11)C-IMA107 BPND in the caudate (r = -0.65; P = 0.005), putamen (r = -0.51; P = 0.025), and globus pallidus (r = -0.47; P = 0.030). Higher Unified Parkinson's Disease Rating Scale part-III motor scores correlated with lower (11)C-IMA107 BPND in the caudate (r = -0.54; P = 0.011), putamen (r = -0.48; P = 0.022), and globus pallidus (r = -0.70; P < 0.001). Higher Unified Dyskinesia Rating Scale scores in those Parkinson's disease with levodopa-induced dyskinesias (n = 12), correlated with lower (11)C-IMA107 BPND in the caudate (r = -0.73; P = 0.031) and putamen (r = -0.74; P = 0.031). Our findings demonstrate striatal and pallidal loss of PDE10A expression, which is associated with Parkinson's duration and severity of motor symptoms and complications. PDE10A is an enzyme that could be targeted with novel pharmacotherapy, and this may help improve dopaminergic signalling and striatal output, and therefore alleviate symptoms and complications of Parkinson's disease.

Biomarkers for Psychiatry: The Journey from Fantasy to Fact, a Report of the 2013 CINP Think Tank.

BACKGROUND: A think tank sponsored by the Collegium Internationale Neuropsychopharmacologium (CINP) debated the status and prospects of biological markers for psychiatric disorders, focusing on schizophrenia and major depressive disorder. METHODS: Discussions covered markers defining and predicting specific disorders or domains of dysfunction, as well as predicting and monitoring medication efficacy. Deliberations included clinically useful and viable biomarkers, why suitable markers are not available, and the need for tightly-controlled sample collection. RESULTS: Different types of biomarkers, appropriate sensitivity, specificity, and broad-based exploitability were discussed. Whilst a number of candidates are in the discovery phases, all will require replication in larger, real-life cohorts. Clinical cost-effectiveness also needs to be established. CONCLUSIONS: Since a single measure is unlikely to suffice, multi-modal strategies look more promising, although they bring greater technical and implementation complexities. Identifying reproducible, robust biomarkers will probably require pre-competitive consortia to provide the resources needed to identify, validate, and develop the relevant clinical tests.

White matter integrity as a predictor of response to treatment in first episode psychosis.

The integrity of brain white matter connections is central to a patient's ability to respond to pharmacological interventions. This study tested this hypothesis using a specific measure of white matter integrity, and examining its relationship to treatment response using a prospective design in patients within their first episode of psychosis. Diffusion tensor imaging data were acquired in 63 patients with first episode psychosis and 52 healthy control subjects (baseline). Response was assessed after 12 weeks and patients were classified as responders or non-responders according to treatment outcome. At this second time-point, they also underwent a second diffusion tensor imaging scan. Tract-based spatial statistics were used to assess fractional anisotropy as a marker of white matter integrity. At baseline, non-responders showed lower fractional anisotropy than both responders and healthy control subjects (P < 0.05; family-wise error-corrected), mainly in the uncinate, cingulum and corpus callosum, whereas responders were indistinguishable from healthy control subjects. After 12 weeks, there was an increase in fractional anisotropy in both responders and non-responders, positively correlated with antipsychotic exposure. This represents one of the largest, controlled investigations of white matter integrity and response to antipsychotic treatment early in psychosis. These data, together with earlier findings on cortical grey matter, suggest that grey and white matter integrity at the start of treatment is an important moderator of response to antipsychotics. These findings can inform patient stratification to anticipate care needs, and raise the possibility that antipsychotics may restore white matter integrity as part of the therapeutic response.

Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: systematic review and meta-analysis of imaging studies.

BACKGROUND: The hypothesis that cortical dopaminergic alterations underlie aspects of schizophrenia has been highly influential. AIMS: To bring together and evaluate the imaging evidence for dopaminergic alterations in cortical and other extrastriatal regions in schizophrenia. METHOD: Electronic databases were searched for in vivo molecular studies of extrastriatal dopaminergic function in schizophrenia. Twenty-three studies (278 patients and 265 controls) were identified. Clinicodemographic and imaging variables were extracted and effect sizes determined for the dopaminergic measures. There were sufficient data to permit meta-analyses for the temporal cortex, thalamus and substantia nigra but not for other regions. RESULTS: The meta-analysis of dopamine D2/D3 receptor availability found summary effect sizes of d = -0.32 (95% CI -0.68 to 0.03) for the thalamus, d = -0.23 (95% CI -0.54 to 0.07) for the temporal cortex and d = 0.04 (95% CI -0.92 to 0.99) for the substantia nigra. Confidence intervals were wide and all included no difference between groups. Evidence for other measures/regions is limited because of the small number of studies and in some instances inconsistent findings, although significant differences were reported for D2/D3 receptors in the cingulate and uncus, for D1 receptors in the prefrontal cortex and for dopamine transporter availability in the thalamus. CONCLUSIONS: There is a relative paucity of direct evidence for cortical dopaminergic alterations in schizophrenia, and findings are inconclusive. This is surprising given the wide influence of the hypothesis. Large, well-controlled studies in drug-naive patients are warranted to definitively test this hypothesis.

Acute effects of single-dose aripiprazole and haloperidol on resting cerebral blood flow (rCBF) in the human brain.

Antipsychotic drugs act on the dopaminergic system (first-generation antipsychotics, FGA), but some also directly affect serotonergic function (second-generation antipsychotics, SGA) in the brain. Short and long-term effects of these drugs on brain physiology remain poorly understood. Moreover, it remains unclear whether any physiological effect in the brain may be different for FGAs and SGAs. Immediate (+3.30 h) and different effects of single-dose FGA (haloperidol, 3 mg) and a SGA (aripiprazole, 10 mg) on resting cerebral blood flow (rCBF) were explored in the same 20 healthy volunteers using a pulsed continuous arterial spin labeling (pCASL) sequence (1.5T) in a placebo-controlled, repeated measures design. Both antipsychotics increased striatal rCBF but the effect was greater after haloperidol. Both decreased frontal rCBF, and opposite effects of the drugs were observed in the temporal cortex (haloperidol decreased, aripiprazole increased rCBF) and in the posterior cingulate (haloperidol increased, aripiprazole decreased rCBF). Further increases were evident in the insula, hippocampus, and anterior cingulate after both antipsychotics, in the motor cortex following haloperidol and in the occipital lobe the claustrum and the cerebellum after aripiprazole. Further decreases were observed in the parietal and occipital cortices after aripiprazole. This study suggests that early and different rCBF changes are evident following a single-dose of FGA and SGA. The effects occur in healthy volunteers, thus may be independent from any underlying pathology, and in the same regions identified as structurally and functionally altered in schizophrenia, suggesting a possible relationship between antipsychotic-induced rCBF changes and brain alterations in schizophrenia.

Olanzapine: a systematic review and meta-regression of the relationships between dose, plasma concentration, receptor occupancy, and response.

OBJECTIVE: To conduct a systematic review examining the relationships between olanzapine dose, clinical outcome, dopamine occupancy, and plasma concentration; and to evaluate the potential for therapeutic drug monitoring. METHODS: A search using Embase, Medline, and Pubmed was conducted; and the literature was systematically reviewed. Studies meeting inclusion criteria were examined. The relationships between olanzapine dose, response, dopamine occupancy, and concentration were analyzed using statistical regression. RESULTS: Ten studies were included in the analysis for dose-response. The effect size-dose relationship showed a typical dose-response curve with minimal rise in slope for doses higher than 10 mg/d. For the dose-occupancy relationship, 6 studies were included. Doses more than approximately 12 mg/d were sufficient to block 65% of striatal D2 receptors. Doses higher than 20 mg led to minimally higher receptor occupancies. Fifteen studies were included in the meta-regression of olanzapine mean concentrations. A linear relationship between mean plasma concentration and mean dose was observed. CONCLUSIONS: Our review suggests that the likelihood of a favorable response with olanzapine is maximized at doses of 10 to 15 mg/d (perhaps lower in nonsmoking females). Higher doses may be considered if 15 mg is ineffective and if plasma level is less than 20 ng/mL on that dose. There is a direct linear relationship between olanzapine dose and plasma concentration. Therapeutic drug monitoring may be useful in patients who are suspected of nonadherence, where there is potential for a drug interaction, and in patients taking 15 mg/d or more and who have not reached clinical response.

Integrating mobile-phone based assessment for psychosis into people's everyday lives and clinical care: a qualitative study.

BACKGROUND: Over the past decade policy makers have emphasised the importance of healthcare technology in the management of long-term conditions. Mobile-phone based assessment may be one method of facilitating clinically- and cost-effective intervention, and increasing the autonomy and independence of service users. Recently, text-message and smartphone interfaces have been developed for the real-time assessment of symptoms in individuals with schizophrenia. Little is currently understood about patients' perceptions of these systems, and how they might be implemented into their everyday routine and clinical care. METHOD: 24 community based individuals with non-affective psychosis completed a randomised repeated-measure cross-over design study, where they filled in self-report questions about their symptoms via text-messages on their own phone, or via a purpose designed software application for Android smartphones, for six days. Qualitative interviews were conducted in order to explore participants' perceptions and experiences of the devices, and thematic analysis was used to analyse the data. RESULTS: Three themes emerged from the data: i) the appeal of usability and familiarity, ii) acceptability, validity and integration into domestic routines, and iii) perceived impact on clinical care. Although participants generally found the technology non-stigmatising and well integrated into their everyday activities, the repetitiveness of the questions was identified as a likely barrier to long-term adoption. Potential benefits to the quality of care received were seen in terms of assisting clinicians, faster and more efficient data exchange, and aiding patient-clinician communication. However, patients often failed to see the relevance of the systems to their personal situations, and emphasised the threat to the person centred element of their care. CONCLUSIONS: The feedback presented in this paper suggests that patients are conscious of the benefits that mobile-phone based assessment could bring to clinical care, and that the technology can be successfully integrated into everyday routine. However, it also suggests that it is important to demonstrate to patients the personal, as well as theoretical, benefits of the technology. In the future it will be important to establish whether clinical practitioners are able to use this technology as part of a personalised mental health regime.

A comparison of two delivery modalities of a mobile phone-based assessment for serious mental illness: native smartphone application vs text-messaging only implementations.

BACKGROUND: Mobile phone-based assessment may represent a cost-effective and clinically effective method of monitoring psychotic symptoms in real-time. There are several software options, including the use of native smartphone applications and text messages (short message service, SMS). Little is known about the strengths and limitations of these two approaches in monitoring symptoms in individuals with serious mental illness. OBJECTIVE: The objective of this study was to compare two different delivery modalities of the same diagnostic assessment for individuals with non-affective psychosis-a native smartphone application employing a graphical, touch user interface against an SMS text-only implementation. The overall hypothesis of the study was that patient participants with sewrious mental illness would find both delivery modalities feasible and acceptable to use, measured by the quantitative post-assessment feedback questionnaire scores, the number of data points completed, and the time taken to complete the assessment. It was also predicted that a native smartphone application would (1) yield a greater number of data points, (2) take less time, and (3) be more positively appraised by patient participant users than the text-based system. METHODS: A randomized repeated measures crossover design was employed. Participants with currently treated Diagnostic and Statistical Manual (Fourth Edition) schizophrenia or related disorders (n=24) were randomly allocated to completing 6 days of assessment (four sets of questions per day) with a native smartphone application or the SMS text-only implementation. There was then a 1-week break before completing a further 6 days with the alternative delivery modality. Quantitative feedback questionnaires were administered at the end of each period of sampling. RESULTS: A greater proportion of data points were completed with the native smartphone application in comparison to the SMS text-only implementation (ß = -.25, SE=.11, P=.02), which also took significantly less time to complete (ß =.78, SE= .09, P<.001). Although there were no significant differences in participants' quantitative feedback for the two delivery modalities, most participants reported preferring the native smartphone application (67%; n=16) and found it easier to use (71%; n=16). 33% of participants reported that they would be willing to complete mobile phone assessment for 5 weeks or longer. CONCLUSIONS: Native smartphone applications and SMS text are both valuable methods of delivering real-time assessment in individuals with schizophrenia. However, a more streamlined graphical user interface may lead to better compliance and shorter entry times. Further research is needed to test the efficacy of this technology within clinical services, to assess validity over longer periods of time and when delivered on patients' own phones.

Genetic predictors of response to serotonergic and noradrenergic antidepressants in major depressive disorder: a genome-wide analysis of individual-level data and a meta-analysis.

BACKGROUND: It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way. METHODS AND FINDINGS: The NEWMEDS consortium, an academia-industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies (three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study). After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants (genome-wide significance p<5×10(-8)). No biological pathways were significantly overrepresented in the results. No significant associations (genome-wide significance p<5×10(-8)) were detected in a meta-analysis of NEWMEDS and another large sample (STAR*D), with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D. CONCLUSIONS: No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study. Please see later in the article for the Editors' Summary.

Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation.

BACKGROUND: Clozapine is the only antipsychotic drug licensed for treatment-resistant schizophrenia but its use is often delayed. Since previous studies, national guidelines on the use of clozapine and other antipsychotics have been disseminated to clinicians. AIMS: To determine the theoretical delay to clozapine initiation and to quantify the prior use of antipsychotic polypharmacy and high-dose antipsychotic treatment. METHOD: Clinico-demographic data were extracted from the treatment records of all patients commencing clozapine in our centre between 2006 and 2010. RESULTS: Complete records were available for 149 patients. The mean theoretical delay in initiating clozapine was 47.7 months (s.d. = 49.7). Before commencing clozapine, antipsychotic polypharmacy and high-dose treatment was evident in 36.2 and 34.2% of patients respectively. Theoretical delay was related to illness duration (ß = 0.7, P<0.001) but did not differ by gender or ethnicity. CONCLUSIONS: Substantial delays to clozapine initiation remain and antipsychotic polypharmacy and high doses are commonly used prior to clozapine, despite treatment guidelines.

Tetrabenazine augmentation in treatment-resistant schizophrenia: a 12-week, double-blind, placebo-controlled trial.

Evidence linking schizophrenia to alterations in presynaptic dopamine (DA) grows, although treatments to date have largely focused on postsynaptic D2 receptor blockade. This study examined augmenting response in treatment-resistant schizophrenia through the addition of tetrabenazine (TBZ), a presynaptic vesicular monoamine transporter (VMAT2) inhibitor. Participants included 41 outpatients (mean age, 43.5 years) with treatment-refractory schizophrenia, stabilized on their present antipsychotic treatment (clozapine, 73%) for more than 3 months. Individuals were randomly assigned to TBZ augmentation (12.5-75 mg/d), titrated according to a fixed, flexible schedule, or placebo over 12 weeks. Twenty subjects received TBZ, and 21 received placebo; doses of 18 of the 20 TBZ-treated individuals were titrated up to the maximum of 75 mg/d, and 16 (80%) of them completed the trial. Tetrabenazine was well tolerated and not linked to increased adverse effects, including those that have been reported more frequently (eg, parkinsonism, depression, and sedation) with higher doses (>100 mg/d) used in the treatment of hyperkinetic movement disorders. However, there was no indication of clinical improvement as measured using the Brief Psychiatric Rating Scale, the Clinical Global Impression scale, and the Global Assessment of Functioning scale. In examining those receiving TBZ-clozapine specifically, there was no indication of drug-drug interactions or difference in response compared to the overall sample. Tetrabenazine was not effective, as used here, in augmenting clinical response in treatment-resistant schizophrenia. It may be premature, however, to discount the potential benefits of VMAT2 inhibitors in treating psychosis in light of what is presently understood regarding presynaptic DA's role and evidence that "endogenous sensitization" may occur over the course of the illness.

The feasibility and validity of ambulatory self-report of psychotic symptoms using a smartphone software application.

BACKGROUND: Semi-structured interview scales for psychosis are the gold standard approach to assessing psychotic and other symptoms. However, such assessments have limitations such as recall bias, averaging, insensitivity to change and variable interrater reliability. Ambulant, real-time self-report assessment devices may hold advantages over interview measures, but it needs to be shown that the data thus collected are valid, and the collection method is acceptable, feasible and safe. We report on a monitoring system for the assessment of psychosis using smartphone technology. The primary aims were to: i) assess validity through correlations of item responses with those on widely accepted interview assessments of psychosis, and ii) examine compliance to the procedure in individuals with psychosis of varying severity. METHODS: A total of 44 participants (acute or remitted DSM-4 schizophrenia and related disorders, and prodromal) completed 14 branching self-report items concerning key psychotic symptoms on a touch-screen mobile phone when prompted by an alarm at six pseudo-random times, each day, for one week. Face to face PANSS and CDS interviews were conducted before and after the assessment period blind to the ambulant data. RESULTS: Compliance as defined by completion of at least 33% of all possible data-points over seven days was 82%. In the 36 compliant participants, 5 items (delusions, hallucinations, suspiciousness, anxiety, hopelessness) showed moderate to strong (rho 0.6-0.8) associations with corresponding items from interview rating scales. Four items showed no significant correlation with rating scales: each was an item based on observable behaviour. Ambulant ratings showed excellent test-retest reliability and sensitivity to change. CONCLUSIONS: Ambulatory monitoring of symptoms several times daily using smartphone software applications represents a feasible and valid way of assessing psychotic phenomena for research and clinical management purposes. Further evaluation required over longer assessment periods, in clinical trials and service settings.

Role of dopamine D(2) receptors for antipsychotic activity.

This review summarizes the current state of knowledge regarding the proposed mechanisms by which antipsychotic agents reduce the symptoms of schizophrenia while giving rise to adverse side effects. The first part summarizes the contribution of neuroimaging studies to our understanding of the neurochemical substrates of schizophrenia, putting emphasis on direct evidence suggestive of a presynaptic rather than a postsynaptic dysregulation of dopaminergic neurotransmission in this disorder. The second part addresses the role of D(2) and non-D(2) receptor blockade in the treatment of schizophrenia and highlights a preponderant role of D(2) receptors in the mechanism of antipsychotic action. Neuroimaging studies have defined a narrow, but optimal, therapeutic window of 65-78 % D(2) receptor blockade within which most antipsychotics achieve optimal clinical efficacy with minimal side effects. Some antipsychotics though do not conform to that therapeutic window, notably clozapine. The reasons for its unexcelled clinical efficacy despite subthreshold levels of D(2) blockade are unclear and current theories on clozapine's mechanisms of action are discussed, including transiency of its D(2) receptor blocking effects or preferential blockade of limbic D(2) receptors. Evidence is also highlighted to consider the use of extended antipsychotic dosing to achieve transiency of D(2) blockade as a way to optimize functional outcomes in patients. We also present some critical clinical considerations regarding the mechanisms linking dopamine disturbance to the expression of psychosis and its blockade to the progressive resolution of psychosis, keeping in perspective the speed and onset of antipsychotic action. Finally, we discuss potential novel therapeutic strategies for schizophrenia.