Childhood adversity and cognitive function in schizophrenia spectrum disorders and healthy controls: evidence for an association between neglect and social cognition.

BACKGROUND: Childhood adversity is associated with cognitive impairments in schizophrenia. However, findings to date are inconsistent and little is known about the relationship between social cognition and childhood trauma. We investigated the relationship between childhood abuse and neglect and cognitive function in patients with a first-episode of schizophrenia or schizophreniform disorder (n = 56) and matched healthy controls (n = 52). To the best of our knowledge, this is the first study assessing this relationship in patients and controls exposed to similarly high levels of trauma. METHODS: Pearson correlational coefficients were used to assess correlations between Childhood Trauma Questionnaire abuse and neglect scores and cognition. For the MCCB domains displaying significant (p < 0.05) correlations, within group hierarchical linear regression, was done to assess whether abuse and neglect were significant predictors of cognition after controlling for the effect of education. RESULTS: Patients and controls reported similarly high levels of abuse and neglect. Cognitive performance was poorer for patients compared with controls for all cognitive domains except working memory and social cognition. After controlling for education, exposure to childhood neglect remained a significant predictor of impairment in social cognition in both patients and controls. Neglect was also a significant predictor of poorer verbal learning in patients and of attention/vigilance in controls. However, childhood abuse did not significantly predict cognitive impairments in either patients or controls. CONCLUSION: These findings are cross sectional and do not infer causality. Nonetheless, they indicate that associations between one type of childhood adversity (i.e. neglect) and social cognition are present and are not illness-specific.

Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder.

We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P=3.28 × 10-8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h2=0.35; BD II SNP-h2=0.25; P=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.

Repurposing Drugs for Cognition in Schizophrenia.

Currently approved treatments for schizophrenia only minimally affect the cognitive features of the illness that are the most closely related to disability. Hence, there is now considerable effort to repurpose drugs for schizophrenia, and to seek agents that can improve cognition by targeting receptor systems other than the dopaminergic system. The results of these studies have been mixed thus far; however, this continues to be a high-priority area of schizophrenia research and an important unmet need.

Efficient light emission from inorganic and organic semiconductor hybrid structures by energy-level tuning.

The fundamental limits of inorganic semiconductors for light emitting applications, such as holographic displays, biomedical imaging and ultrafast data processing and communication, might be overcome by hybridization with their organic counterparts, which feature enhanced frequency response and colour range. Innovative hybrid inorganic/organic structures exploit efficient electrical injection and high excitation density of inorganic semiconductors and subsequent energy transfer to the organic semiconductor, provided that the radiative emission yield is high. An inherent obstacle to that end is the unfavourable energy level offset at hybrid inorganic/organic structures, which rather facilitates charge transfer that quenches light emission. Here, we introduce a technologically relevant method to optimize the hybrid structure's energy levels, here comprising ZnO and a tailored ladder-type oligophenylene. The ZnO work function is substantially lowered with an organometallic donor monolayer, aligning the frontier levels of the inorganic and organic semiconductors. This increases the hybrid structure's radiative emission yield sevenfold, validating the relevance of our approach.

Efficacy of lurasidone across five symptom dimensions of schizophrenia: pooled analysis of short-term, placebo-controlled studies.

OBJECTIVE: To evaluate the efficacy of lurasidone for schizophrenia using an established five-factor model of the Positive and Negative Syndrome Scale (PANSS). METHODS: Patient-level data were pooled from five randomized, double-blind, placebo-controlled, 6-week studies of lurasidone (fixed doses, 40-160mg/d) for patients with an acute exacerbation of schizophrenia. Changes in five established PANSS factors were assessed using mixed-model repeated measures analysis. RESULTS: Compared with placebo (n=496), lurasidone (n=1029, dose groups pooled) significantly improved the PANSS total score at Week 6 (-22.6 vs. -12.8; P<0.001; effect size, 0.45), as well as all factor scores (P<0.001 for each): positive symptoms (-8.4 vs. -6.0; effect size, 0.43), negative symptoms (-5.2 vs. -3.3; effect size, 0.33), disorganized thought (-4.9 vs. -2.8; effect size, 0.42), hostility/excitement (-2.7 vs. -1.6; effect size, 0.31), and depression/anxiety (-3.2 vs. -2.3; effect size, 0.31). Separation from placebo occurred at Week 1 for the positive symptoms, disorganized thought, and hostility/excitement factors and at Week 2 for the other factors. CONCLUSIONS: In this pooled analysis of short-term studies in patients with acute schizophrenia, lurasidone demonstrated significant improvement for each of the five PANSS factor scores, indicating effectiveness across the spectrum of schizophrenia symptoms.

Adsorption studies of a phosphonic acid on ITO: film coverage, purity, and induced electronic structure changes.

The deposition of a prototypical phosphonic acid from an ethanol solution onto indium-tin oxide is studied using XPS to assess the chemisorption kinetics and the purity of the film deposited, and UPS is employed to determine the electronic structure changes induced by the modifier. Room temperature (r.t.) vs. 75 °C depositions are compared, as well as the effect of using air plasma (AP) pretreatment vs. utilizing only detergent-solvent cleaning (DSC) prior to immersion. It is concluded that the order of adsorption kinetics and film purity follows the trend AP 75 °C > DSC 75 °C > AP r.t. > DSC r.t., while the work function obtained for each immersion time depends on whether the substrate is plasma pretreated or not and on the molecular dipole, which saturates at high coverages.

Unconscious emotional reasoning and the therapeutic misconception.

The "therapeutic misconception" describes a process whereby research volunteers misinterpret the intentions of researchers and the nature of clinical research. This misinterpretation leads research volunteers to falsely attribute a therapeutic potential to clinical research, and compromises informed decision making, therefore compromising the ethical integrity of a clinical experiment. We review recent evidence from the neurobiology of social cognition to provide a novel framework for thinking about the therapeutic misconception. We argue that the neurobiology of social cognition should be considered in any ethical analysis of how people make decisions about participating in clinical trials. The neurobiology of social cognition also suggests how the complicated dynamics of the doctor-patient relationship may unavoidably interfere with the process of obtaining informed consent. Following this argument we suggest new ways to prevent or at least mitigate the therapeutic misconception.

Quantum-chemical investigation of second-order nonlinear optical chromophores: comparison of strong nitrile-based acceptor end groups and role of auxiliary donors and acceptors.

We report a detailed quantum-chemical investigation of donor-acceptor substituted dipolar nonlinear optical chromophores incorporating the 4-(dimethylamino)phenyl donor end group and a variety of strong heterocyclic acceptor end groups, including tricyanofurans and tricyanopyrroles. In particular, we study the variation of the molecular second-order polarizability (beta) with the acceptor end group and when inserting auxiliary donors (thiophene) and acceptors (thiazole) into the pi bridge. Both finite-field calculations (in the context of local contributions) and sum-over-states calculations were carried out in order to probe the relationship between beta and the chemical structure of the various chromophores. The trends obtained with these two methods are fully consistent. The large beta values (up to 700 x 10(-30) esu) as well as the observed tunability of the optical absorption maximum (lambda(max)) make the chromophores investigated here interesting candidates for use in electro-optic applications at telecommunications wavelengths.

Subjective experiences on antipsychotic medications: synthesis and conclusions.

OBJECTIVE: This report synthesizes the literature describing the phenomenology, clinical importance and biology of subjective responses to antipsychotic medications in schizophrenia. A patient's experience of an antipsychotic is important because unpleasant or dysphoric responses can impair therapeutic relationships, lead to medication non-adherence, and have direct negative effects on a patient's quality of life. METHOD: The author selectively reviewed early studies of subjective responses to antipsychotics and integrated this literature with the work of the other investigators in this special section. RESULTS: There is substantial evidence that second-generation antipsychotics have advantages in causing fewer dysphoric responses when compared with first-generation agents. Clinical and neuroimaging studies suggest that dopamine blockade is an important determinant of many of these dysphorias. At this point in time it is unclear whether dysphoria results from extrapyramidal symptoms--particularly akathisia and akinesia--or whether they are a direct result of decreased dopamine activity. CONCLUSION: Clinicians and researchers should continue to monitor dysphorias in schizophrenia. Contributions by the authors in this supplement provide new and more refined methods for measuring subjective responses in future studies.

Fluphenazine plasma level monitoring for patients receiving fluphenazine decanoate.

BACKGROUND: Finding a dose of an antipsychotic for maintenance therapy that is both safe and effective can be difficult because clinicians are unable to titrate dose against clinical response in patients who are already stable. Therapeutic monitoring of antipsychotic plasma levels has the potential for helping clinicians in dosage selection. With this in mind, we evaluated the usefulness of monitoring fluphenazine plasma levels for patients with schizophrenia who were receiving maintenance treatment with fluphenazine decanoate. METHOD: Thirty-one patients with schizophrenia were randomly assigned to low, medium, or high (0.1-0.3, 0.3-0.6, 0.6-1.0 ng/ml) plasma levels of fluphenazine. The dose of fluphenazine decanoate was adjusted in order to maintain patients in their assigned range. Side effects, psychopathology, and psychotic exacerbations were measured during the year following randomization. RESULTS: All of the psychotic exacerbations occurred during the first eight weeks following randomization, before patients had adequate time to reach their plasma level assignments. We did not find a relationship between plasma levels of fluphenazine and clinical outcomes or side effects. CONCLUSION: Our results do not provide support for the usefulness of monitoring fluphenazine plasma levels for patients receiving fluphenazine decanoate.

Photorefractive polymers sensitized by two-photon absorption.

We demonstrate the recording of holograms and their nondestructive readout in a photorefractive polymer, using two-photon absorption. Sensitivity is provided by the excitation of the electroactive chromophore with femtosecond pulses, followed by charge injection into the photoconducting poly(N -vinylcarbazole) matrix. The holograms can be fully erased with a pulsed laser source but are insensitive to cw laser beams with the same wavelength. Studies of the field and intensity dependence of the diffraction efficiency indicate that the holograms are formed through the photorefractive effect.

A compensatory mirror cortical mechanism for facial affect processing in schizophrenia.

When primates passively observe other subjects perform specific gestures or actions, premotor and motor cortical areas involved in the internal representation and actual execution of those actions exhibit neuronal activation. This mirror mechanism matches observation, representation, and execution, facilitating internal motor rehearsal, imitation, recognition of actions by others and their meanings, and social learning. Schizophrenic patients have deficits in processing affect displayed by other people's faces, which likely relates to the poor social adaptation and functioning seen in the condition. We hypothesized that, when correctly performing working-memory tasks requiring facial affect processing, schizophrenic patients would show relative increased activity in brain areas involved in social learning and in the internal representation of facial expressions when compared to controls. We used functional magnetic resonance imaging in schizophrenic patients and normal controls to detect relative changes of blood flow in cortical areas related to the representation of facial expressions while the subjects performed simple working-memory tasks with facial emotion diagrams or color circles as cues. We found that, when the task cues were facial expressions in contrast to color circles, the schizophrenic group exhibited increased activation of the face movement areas in motor and pre-motor cortex.

Clozapine and haloperidol in moderately refractory schizophrenia: a 6-month randomized and double-blind comparison.

BACKGROUND: Despite the demonstrated efficacy of clozapine in severely refractory schizophrenia, questions remain regarding its efficacy for primary negative symptoms, comparison with a moderate dose of a first-generation antipsychotic, and adverse effects during a longer-term trial. This study examined its efficacy in partially responsive, community-based patients, compared clozapine with moderate-dose haloperidol, and extended treatment to 6 months. METHODS: Randomized, double-blind, 29-week trial comparing clozapine (n = 37) with haloperidol (n = 34). Subjects with schizophrenia who were being treated in community settings at 3 collaborating clinical facilities were enrolled. RESULTS: Subjects treated with haloperidol were significantly more likely to discontinue treatment for lack of efficacy (51%) than were those treated with clozapine (12%). A higher proportion of clozapine-treated subjects met an a priori criterion of improvement (57%) compared with haloperidol-treated subjects (25%). Significantly greater improvement was seen in symptoms of psychosis, hostile-suspiciousness, anxiety-depression, thought disturbance, and total score measured on the Brief Psychiatric Rating Scale. No differences were detected in negative symptoms using the Brief Psychiatric Rating Scale or the Schedule for Assessment of Negative Symptoms. Subjects treated with clozapine experienced more excess salivation, dizziness, and sweating and less dry mouth and decreased appetite than those treated with haloperidol. CONCLUSIONS: Compared with a first-generation antipsychotic given in a moderate dose, clozapine offers substantial clinical benefits to treatment-refractory subjects who can be treated in the community. Advantages are seen in a broad range of symptoms but do not extend to negative symptoms.

Treatment with atypical antipsychotics: new indications and new populations.

Atypical antipsychotics have revolutionized the treatment of schizophrenia, becoming the treatment of choice for patients not only during their first episode, but also throughout their life course. Of note, as of 1999 more than 70% of prescriptions for these drugs are being prescribed for conditions other than schizophrenia, such as bipolar disorder and geriatric agitation. While there have been very few controlled trials that have established the efficacy of the atypical antipsychotics for these "off-label" uses, there have been a large number of open trials and case reports. The few controlled trials suggest that the atypical antipsychotics may be useful for affective disorders (both mania and depression), geriatric conditions such as senile dementia and aggression, as well as a variety of other disorders. Atypical agents may be particularly helpful for elderly, child, or adolescent patients who are especially susceptible to the side effects of medications and whose risk of tardive dyskinesia is high but further controlled studies are necessary.

Simultaneous determination of clozapine and its N-desmethyl and N-oxide metabolites in plasma by liquid chromatography/electrospray tandem mass spectrometry and its application to plasma level monitoring in schizophrenic patients.

A liquid chromatography tandem mass spectrometry (LC-MS-MS) assay method for the simultaneous determination of clozapine and its N-desmethyl (norclozapine) and N-oxide metabolites in human plasma is described. The compounds were extracted from plasma by a single step liquid-liquid extraction procedure and analyzed using a high performance liquid chromatography electrospray tandem mass spectrometer system. The compounds were eluted isocratically on a C-18 column, ionized using positive ion atmospheric pressure electrospray ionization method by a TurboIonspray source and analyzed using multiple reaction monitoring mode. The ion transitions monitored were m/z 327 --> m/z 270 for clozapine, m/z 313 --> m/z 192 for norclozapine, m/z 343 --> m/z 256 for clozapine-N-oxide and m/z 421--> m/z 201 for internal standard. The standard curves of clozapine, norclozapine and clozapine-N-oxide were linear over the range of 1 ng/ml to 1000 ng/ml when 0.5 ml of plasma was used for the analysis (r(2) >0.998). Three pooled plasma samples collected from patients who were treated with clozapine were used as long-term quality control samples to check the validity of spiked standard curve samples made at various times. The intra- and inter-assay variations for the spiked standard curve and quality control samples were less than 14%. These variations for the long-term patient quality control samples were less than 11%. The LC-MS-MS assay for simultaneous determination of clozapine, norclozapine and clozapine-N-oxide reported here is highly specific, sensitive, accurate and rapid. This method is currently being used for the plasma level monitoring of clozapine and its N-desmethyl and N-oxide metabolites in patients treated with clozapine. The plasma levels of clozapine, norclozapine and clozapine-N-oxide varied widely within and among patients. The data revealed that the norclozapine and clozapine N-oxide metabolites were present at about 58%+/-14% and 17%+/-6% of clozapine concentrations in plasma, respectively.

Evidence-based pharmacologic treatment for people with severe mental illness: a focus on guidelines and algorithms.

Medication treatment of severe mental illness has been advanced and complicated by the introduction of numerous therapeutic agents. Practice guidelines based on research evidence have been developed to help clinicians make complex decisions. Studies of usual care suggest an important potential role for guidelines in improving the quality of medication treatment for people with severe mental illness. The authors review current evidence-based guidelines for medication treatment of persons with severe mental illness. Four categories of guidelines are described: recommendations, comprehensive treatment options, medication algorithms, and expert consensus. The authors note that more research is needed on optimal next-step strategies and the treatment of patients with comorbidity and other complicating problems. They discuss barriers to the implementation of guidelines, and they observe that the potential of guidelines and algorithms to promote evidence-based medication treatment for persons with severe mental illness depends on refinement of tools, progress in research, and cooperation of physicians, nonphysician clinicians, administrators, and consumers and family members.

Quality Enhancement Research Initiative in Mental Health.

The Veterans Administration (VA) recently introduced its Quality Enhancement Research Initiative (QUERI) to facilitate the translation of best practices into usual clinical care. The Mental Health QUERI (MHQ) was charged with developing strategic plans for major depressive disorder (MDD) and schizophrenia. Twenty percent or more of VA service users are affected by 1 of these 2 disorders, disorders that often have a devastating impact on affected individuals. Despite the increasing availability of efficacious treatments for each disorder, substantial gaps remain between best practices and routine care. In this context, the MHQ identified steps critical to the success of a sustained process of rapid-cycle health care improvement for MDD and schizophrenia, including research initiatives to close gaps in knowledge of best treatment practices, demonstration projects to close gaps in practice and to expand understanding of effective strategies for implementing clinical guidelines, targeted enhancements of the VA information system, and research and dissemination initiatives to increase the availability of resources to support the accelerated incorporation of best practices into routine care. This article presents an overview of the elements in the initial MHQ strategic plans and the rationale behind them.

Simultaneous determination of risperidone and 9-hydroxyrisperidone in plasma by liquid chromatography/electrospray tandem mass spectrometry.

A simple and highly sensitive liquid chromatographic/electrospray tandem mass spectrometric (LC/MS/MS) assay was developed for the simultaneous determination of risperidone (RSP) and its major circulating metabolite 9-hydroxyrisperidone (9-OH-RSP) in the plasma of humans and rats. A simple one-step solvent extraction with 15% methylene chloride in pentane was used to isolate the compounds from plasma. The compounds were eluted from a phenyl-hexyl column and detected with a Perkin-Elmer SCIEX API2000 triple-quadrupole mass spectrometer using positive ion atmospheric pressure electrospray ionization and multiple reaction monitoring. The assay was linear over the range 0.1-100 ng ml(-1) when 0.5 ml of plasma was used in the extraction. The overall intra- (within-day) and inter- (between days) assay variations were < 11%. The variations in the concentrations of two long-term quality control samples from pooled patient plasma samples analyzed over a period of 6 months were approximately 10%. The analysis time for each sample was 4 min and more than 100 samples could be analyzed in one day by running the system overnight. The assay is simple, highly sensitive, selective, precise and fast. This method is being used for the therapeutic drug monitoring of schizophrenic patients treated with RSP and to study the pharmacokinetics and tissue distribution of RSP and 9-OH-RSP in rats.