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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.

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., (Published 2016. This article is a U.S. Government work and is in the public domain in the USA.)

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-h 2 =0.35; BD II SNP-h 2 =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.

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.

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., (Published by Elsevier Masson SAS.)

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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., (Copyright 2000 John Wiley & Sons, Ltd.)

Purpose: Tunneled catheters are an alternative means of vascular access for patients in need of hemodialysis who cannot undergo dialysis through a surgical shunt. This study was undertaken to evaluate the performance of the Tesio dialysis catheter., Materials and Methods: A prospective study of the Tesio catheter was performed. Follow-up data regarding catheter function and adequacy of dialysis were obtained from nine hemodialysis facilities., Results: Seventy-nine Tesio catheters were placed in 71 patients. Immediate technical success was 99% (78 of 79 catheters). The procedure complication rate was 9% (seven catheters). Only two complications required intervention: one fatal air embolism and one chest wall hematoma. Sixty-seven catheters in 60 patients were followed up for a total of 4,367 catheter days. Overall, catheter-related infection occurred in 9% (six of 67 catheters). Primary catheter patency was 87% at 1 week, 82% at 1 month, 72% at 3 months, and 66% at 6 months. Mean blood flow was 286 mL/min immediately after insertion, 301 mL/min at 3 months, and 306 mL/min at 6 months. Adequate dialysis dose as reflected by a urea reduction ratio of 60 or more or a urea kinetic modeling, or Kt/V, value of 1.2 or more was observed on at least one occasion for 74% and 76% of catheters, respectively., Conclusion: The Tesio catheter is a reasonable means of vascular access for patients who undergo dialysis but are not candidates for surgical shunt placement.

Objective: The objective of this study was to develop principles of combining pharmacological and psychosocial treatment that can be useful for clinicians who are treating patients with schizophrenia., Method: Research studies in schizophrenia that controlled both pharmacological and psychosocial treatments were reviewed. These included studies using conventional and newer antipsychotics as well as a number of psychosocial methods., Results: The interactions between the forms of treatment appear to be more than merely additive, since each can enhance the effects of the other. Drug and psychosocial treatments may affect different outcome domains, with the former affecting symptoms and the later affecting social outcomes. Recent studies using newer antipsychotics suggest that these agents improve the participation of patients in psychosocial treatments., Conclusion: Understanding the interactions between psychosocial and pharmacological treatments can be useful for clinicians who are developing treatment strategies for patients with schizophrenia. Newer agents with different side-effect profiles and broader effectiveness appear to have improved the outcomes of psychosocial treatments.

The single dose pharmacokinetics of olanzapine in rats, following an oral dose and its distribution in the brain and other tissues after repeated oral and intra-peritoneal (i.p.) administration, were studied. Olanzapine in plasma, brain, liver, lung, kidney, spleen and fat was assayed at predose, 0.25, 0.5, 1, 2, 5, 12, 24, 36, 48 h postoral dose of 6 mg/kg and after daily oral and i.p. doses of 0.25, 1, 3, and 6 mg/kg/day of olanzapine for 15 consecutive days by a sensitive and specific HPLC method with electrochemical detection. Olanzapine was readily absorbed and distributed in plasma and tissues as the peak concentrations were reached within approximately 45 min after the oral dose. The terminal half-life of olanzapine in plasma was 2.5 h and in tissues it ranged from 3 to 5.2 h. The area under the concentration-time curve (AUC(last)) was lowest in plasma and largest in liver and lung. The AUC(last) of olanzapine was eight times larger in brain and three to 32 times larger in other tissues than that in plasma. After repeated oral doses, the plasma and tissue concentrations of olanzapine were generally higher than those after repeated i.p. doses. The liver and spleen had the highest concentrations after oral and i.p doses, respectively. In both cases, the tissue concentrations were four- to 46-fold higher than that in plasma and correlated with administered doses. Likewise, plasma concentrations strongly correlated with the simultaneous brain and tissue concentrations (r(2)>0.908, p<0.0001). On average, the brain levels were 6.3-13.1 and 5.4-17.6 times higher than the corresponding plasma level after oral and i.p. doses, respectively. The tissue to plasma level ratio of olanzapine was higher in other tissues. The data indicated that olanzapine is rapidly absorbed and widely distributed in the tissues of rats after oral and i.p. administration. The plasma concentration appears to predict the simultaneous concentration in brain and other tissues. There was no marked localized accumulation of olanzapine in any of the regions of the rat brain., (Copyright 1999 John Wiley & Sons, Ltd.)

Injection drug users frequently present to emergency departments with fever. A careful history and physical examination with attention to anatomic localization of symptoms and signs are often necessary to unmask unusual underlying medical conditions. We report a case of a woman with recent injection drug use who presented with fever, a palpable neck mass, and Pancoast's syndrome. She had been seen recently at the ED of another hospital and discharged with oral antibiotics for presumed cellulitis. A mycotic aneurysm of the subclavian artery causing Pancoast's syndrome was later diagnosed by using computed tomography and angiography. A high index of suspicion for anatomically localized infective processes should always be maintained with febrile injection drug users.

Objective: The purpose of this study was to evaluate the clinical safety and efficacy of risperidone compared to haloperidol in patients with treatment-refractory schizophrenia., Method: Sixty-seven medication-unresponsive subjects were randomly assigned to treatment with risperidone (N = 34) or haloperidol (N = 33). After a 3-7 day-placebo washout period, there was a 4-week, double-blind, fixed-dose comparison trial that was followed by a 4-week, flexible-dose phase. Measures of clinical change were quantified by standard psychopathologic and neuromotor instruments., Results: Risperidone demonstrated clinical efficacy superior to that of haloperidol on the total Brief Psychiatric Rating Scale (BPRS) after the first 4 weeks of treatment. Risperidone did not show any advantage over haloperidol after an additional 4 weeks. Overall improvement on the BPRS at 4 weeks was significantly better for the risperidone group (24%) than for the haloperidol group (11%). Risperidone-treated subjects were significantly less likely than haloperidol-treated subjects to require concomitant anticholinergic medication after 4 weeks (20% versus 63%); they also had significantly les observable akathisia (24% versus 53%) and significantly less severe tardive dyskinesia. Baseline characteristics that correlated significantly with risperidone response were positive symptoms, conceptual disorganization, akathisia, and tardive dyskinesia., Conclusions: Risperidone was better tolerated and more effective in a subset of patients with treatment-refractory schizophrenia. Positive psychotic symptoms and extrapyramidal side effects at baseline appear to be powerful predictors of subsequent response to risperidone.

Background: We performed a retrospective analysis of 122 clinical records of 92 male patients with DSM-III-R schizophrenia to examine the relative weight gain liabilities of clozapine, risperidone, olanzapine, and sertindole compared with haloperidol. We hypothesized that the unique pharmacodynamic profiles of these agents would contribute to different amounts and patterns of weight gain., Method: Data were analyzed to determine differences in weight gain during treatment among patients receiving 5 different drug treatments (clozapine [N = 20], olanzapine [N = 13], risperidone [N = 38], haloperidol [N = 43], and sertindole [N = 8]). Measures of maximal weight gain, final weight, and duration to maximal weight gain were calculated., Results: Repeated measures analyses of variance controlling for age, treatment duration, and initial weight revealed statistically significant differences between groups on all 3 measures. Clozapine and olanzapine had the greatest maximal weight gain liability (F = 4.13, df = 4,23; p = .01). Weight gain with clozapine, but not olanzapine or risperidone, appears to persist (as reflected by final weight) despite behavioral interventions (e.g., nutritional consultation, suggested exercise regimen; F = 5.69, df = 4,23; p = .003). Clozapine- and olanzapine-treated subjects appeared to gain weight over a prolonged period of time, whereas risperidone-and sertindole-treated subjects had a more limited period of weight gain (F = 2.95, df = 4,25; p = .04)., Conclusion: Clozapine and olanzapine caused the most weight gain, risperidone was intermediate, and sertindole had less associated weight gain than haloperidol. The relative receptor affinities of the novel antipsychotics for histamine H1 appear to be the most robust correlate of these clinical findings.

Strategies for preventing relapse during the maintenance or stable phase of schizophrenia are discussed for both conventional and newer antipsychotics. For conventional agents, strategies focus on finding dosages that minimize antipsychotic drug side effects and provide adequate protection against psychotic relapse. Although few studies are available to compare older and newer antipsychotics for preventing relapse, there are reasons for proposing that newer drugs will be shown to be superior. Because of their milder side effects, clinicians can choose drug dosages that provide maximum protection against relapse. Further, since patients on the newer drugs are likely to experience fewer discomforting side effects, they may be more likely to take their medications as directed. Other potential advantages of the newer drugs over the older drugs include the likelihood that they are more effective against negative and cognitive symptoms of schizophrenia.

Tissue iron levels in the extrapyramidal system of earlier- and later-onset Parkinson's disease (PD) subjects were evaluated in vivo using a magnetic resonance imaging (MRI) method. The method involves scanning subjects in both high- and low-field MRI instruments, measuring tissue relaxation rate (R2), and calculating the field-dependent R2 increase (FDRI) which is the difference between the R2 measured with the two MRI instruments. In tissue, only ferritin iron is known to increase R2 in a field-dependent manner and the FDRI measure is a specific measure of this tissue iron pool. Two groups of male subjects with PD and two age-matched groups of normal control males were studied. The two groups of six subjects with PD consisted of subjects with earlier- or later-onset (before or after age 60) PD. FDRI was measured in five subcortical structures: the substantia nigra reticulata (SNR), substantia nigra compacta (SNC), globus pallidus, putamen, and caudate nucleus, and in one comparison region; the frontal white matter. Earlier-onset PD subjects had significant (p < 0.05) increases in FDRI in the SNR, SNC, putamen, and globus pallidus, while later-onset PD subjects had significantly decreased FDRI in the SNR when compared to their respective age-matched controls. Controlling for illness duration or structure size did not meaningfully alter the results. Published post-mortem studies on SN iron levels indicate decreased ferritin levels and increased free iron levels in the SN of older PD subjects, consistent with the decreased FDRI observed in our later-onset PD sample, which was closely matched in age to the post-mortem PD samples. The FDRI results suggest that disregulation of iron metabolism occurs in PD and that this disregulation may differ in earlier- versus later-onset PD.

Currently, patients with schizophrenia are usually considered refractory to treatment if they continue to be floridly symptomatic despite receiving treatment with conventional antipsychotic agents. Attempts to improve their response by increasing the dosage, adding supplementary drugs, or switching to agents of another class have not been very successful, and may increase side-effects. Clozapine can be effective, but it is a difficult drug to administer and has therefore been reserved for patients who are doing poorly. With the recent introduction of newer, safer antipsychotic agents, however, even patients who have milder refractory symptoms that persist after treatment with conventional antipsychotics can now be treated.

The introduction of the new generation of antipsychotic medications for the treatment of schizophrenia has been accompanied by a growing interest in the neurocognitive effects of these drugs. The present study compared the effects of risperidone and haloperidol on secondary memory in a group of treatment-resistant schizophrenia patients. The study design included a baseline phase and two double-blind phases in which patients were randomly assigned to medication under two different dose conditions (fixed dose and flexible dose). Secondary memory was assessed at baseline, fixed-dose, and flexible-dose phases, using the California Verbal Learning Test (CVLT). Six measures were selected, which formed three factors (general verbal learning ability, retention, and learning strategy). Risperidone-treated patients showed greater improvement than haloperidol-treated patients in general verbal learning ability, a finding characterized by significant treatment effects on CVLT measures of learning acquisition, recall consistency, and recognition memory. After controlling for benztropine status, differences on the measures of learning acquisition and recall consistency remained significant, and differences in recognition memory weakened slightly (p = 0.07). No significant treatment effects were noted on retention or learning strategy. These findings suggest that risperidone may exert a facilitating effect on the acquisition of new verbal information, an effect that does not appear to be due to the activation of semantic encoding strategies.

Objective: The authors designed and evaluated a structured and rigorous informed consent procedure involving subjects with schizophrenia., Method: Informed consent forms were read and explained to 49 schizophrenic patients participating in ongoing clinical treatment research trials. The subjects answered a questionnaire relating to each research protocol. Protocol procedures were reiterated until the patients answered 100% of the questions correctly. Subjects were asked the same questions 7 days later to ascertain how much of the information they had retained., Results: The patients' median score on the first trial of the informed consent questionnaire was 80% correct. To achieve 100% correct responses, 53% of the patients required a second trial of the questionnaire, and 37% of them required three or more trials. Scores improved between the first trial and the trial on day 7. Ninety-six percent of the subjects felt adequately informed, 66% reported participating in the research protocol for personal reasons, and 34% reported participating at the suggestion of others., Conclusions: These findings demonstrate that when adequate informed consent procedures are established, schizophrenic research subjects are able to understand and retain critical components of informed consent information.

Background: The present study compared the effects of risperidone vs. haloperidol on reaction time, manual dexterity, and two types of motor learning in a sample of treatment-resistant schizophrenia patients., Methods: Fifty-six DSM-III-R diagnosed schizophrenia inpatients participated in a randomized, double-blind comparison of risperidone vs. haloperidol. Measures of reaction time, manual dexterity, motor sequence learning, and gross motor learning were administered at baseline, after 4 weeks of fixed-dose medication, and after 4 weeks of flexible-dose medication., Results: The results indicated that patients receiving risperidone showed greater improvement in reaction time and manual dexterity than patients receiving haloperidol. After covarying symptom changes and movement disorder ratings, the results remained significant. The two treatment groups did not differ on either measure of motor learning., Conclusions: The differences in performance in reaction time and manual dexterity may be due to a specific beneficial effect of risperidone, as opposed to a general reduction in extrapyramidal symptom liability, compared to haloperidol.

Background: The new antipsychotics induce minimal extrapyramidal side effects, probably due to their relatively greater affinity for certain nondopaminergic receptors than their older, conventional counterparts; however, this polyreceptor affinity may be responsible for the development of other adverse effects. One serious adverse effect that may be linked to these effects is non-insulin-dependent diabetes mellitus., Methods: We summarize 6 new cases of clozapine- and olanzapine-associated diabetes that we have documented in our clinic. We compare our cases to previous reports and tabulate the pertinent similarities among cases., Results: Two of the cases were olanzapine-associated and 4 were clozapine-associated diabetes. Five of our 6 patients had risk factors for diabetes, as have 7 of the 9 previously reported in the literature. Four of our 6 patients, and 2 of the 4 prior cases in which such data were reported, experienced substantial weight gain after starting their antipsychotics., Conclusions: Novel antipsychotics should be administered with great care to patients with risk factors for diabetes. Although the precise mechanism of the novel antipsychotic-associated diabetes is unclear, we hypothesize that histaminic and possibly serotonergic antagonism induces weight gain, which in turn leads to changes in glucose homeostasis. Additionally, serotonin1A antagonism might decrease pancreatic beta-cell responsiveness, resulting in inappropriately low insulin and hyperglycemia.

Rats were treated with daily oral doses of 1, 4, and 6 mg/kg risperidone (RSP) and its metabolite, 9-hydroxy-risperidone (9-OH-RSP), for 15 consecutive days. Concentrations of RSP and 9-OH-RSP were measured in plasma, brain, liver, kidney, lungs and fat tissue by high-performance liquid chromatography with electrochemical detection. Non-specific distribution of RSP and 9-OH-RSP in various brain regions was also studied after administration of 6 mg/kg per day oral dose for 15 days. After RSP treatment, concentrations of 9-OH-RSP were higher than those of RSP in plasma and tissues except in brain, where both compounds were present in nearly equal concentrations. Similarly, after 9-OH-RSP treatment, levels of 9-OH-RSP were higher than levels of either RSP or 9-OH-RSP or the sum of RSP and 9-OH-RSP levels measured after treatment with RSP. There was a moderate relationship between RSP dose and tissue levels of RSP and 9-OH-RSP (all rs > or = 0.62, P < 0.01), except in fat. There was also a strong relationship between the dose and tissue levels of 9-OH-RSP (all rs > or = 0.68, P < 0.005). A significant relationship was found between plasma levels of RSP and brain levels of RSP and 9-OH-RSP (all rs > or = 0.57, P < 0.03) after treatment with RSP. After 9-OH-RSP treatment, a much stronger relationship was observed between plasma and brain 9-OH-RSP levels (rs > or = 0.90, P < 0.005). The plasma concentrations of RSP and 9-OH-RSP appear to reflect their concentrations in brain. The tissue-to-plasma ratios of RSP and 9-OH-RSP were relatively low compared to other antipsychotics. In liver, kidney and lung the tissue to plasma ratio for RSP and 9-OH-RSP after treating with RSP ranged from 0.85 to 3.4. The brain to plasma ratio for RSP and 9-OH-RSP was several-fold lower than that in peripheral tissues. After RSP administration, the mean brain to plasma level ratio for RSP was 0.22, and for 9-OH-RSP to it was 0.04. The brain to plasma ratio of 9-OH-RSP after giving 9-OH-RSP was similarly low (0.04). The low brain/plasma ratio of high potency RSP and 9-OH-RSP may in part be due to their low lipophilicity, log P = 3.04 and 2.32, respectively, resulting in limited non-specific accumulation in brain tissue.

Background: This study was undertaken to evaluate whether peripheral (serum) markers of iron status are associated with severity of the choreoathetoid movements seen in tardive dyskinesia (TD)., Methods: Serum iron indices (ferritin, iron, and total iron binding capacity) and fluphenazine levels were measured in a group of 30 male DSM-III diagnosed schizophrenic patients chronically treated with fluphenazine decanoate. The severity of choreoathetoid movements was assessed with the Abnormal Involuntary Movement Scale (AIMS), and akathisia was assessed with the Barnes scale., Results: A significant positive correlation was observed between AIMS scores and serum ferritin. This relationship remained significant after controlling for age and plasma fluphenazine levels. No significant correlations were observed between serum iron or total iron binding capacity and choreoathetoid movement ratings. There were no significant associations between serum iron indices and akathisia ratings., Conclusions: The data suggest that choreoathetoid movements are associated with serum ferritin levels in chronically medicated male schizophrenic patients. This relationship does not seem to be caused by an association of these variable with age or plasma fluphenazine levels. In addition, the relationship seems to be specific, since other iron indices and another extrapyramidal side effect (akathisia) do not demonstrate a similar relationship. In view of reports that antipsychotic medications change normal iron metabolism and increase iron uptake into the brain, the current results could be interpreted to suggest that serum ferritin levels may be a risk factor for TD in patients treated with "classic" antipsychotic medications.

A strategy for the design of molecules with large two-photon absorption cross sections, delta, was developed, on the basis of the concept that symmetric charge transfer, from the ends of a conjugated system to the middle, or vice versa, upon excitation is correlated to enhanced values of delta. Synthesized bis(styryl)benzene derivatives with donor-pi-donor, donor-acceptor-donor, and acceptor-donor-acceptor structural motifs exhibit exceptionally large values of delta, up to about 400 times that of trans-stilbene. Quantum chemical calculations performed on these molecules indicate that substantial symmetric charge redistribution occurs upon excitation and provide delta values in good agreement with experimental values. The combination of large delta and high fluorescence quantum yield or triplet yield exhibited by molecules developed here offers potential for unprecedented brightness in two-photon fluorescent imaging or enhanced photosensitivity in two-photon sensitization, respectively.

Data from six randomised, controlled, comparative studies of risperidone and conventional neuroleptics (haloperidol, zuclopenthixol and perphenazine) in the treatment of 911 patients with chronic schizophrenia were analysed to estimate the benefits and risks of treatment. Efficacy and risk of treatment were assessed by means of the Positive and Negative Syndrome Scale (PANSS) and the Extrapyramidal Symptom Rating Scale (ESRS). An effect size (difference between treatments) was calculated from the PANSS and ESRS scores. The effect size of antipsychotic effect favoured risperidone (sizes ranged from 0.22 to 0.37 on the PANSS subscales), and the effect size of safety also favoured risperidone (sizes ranged from 0.18 to 0.36 on the ESRS). An analysis of the proportions of patients requiring antiparkinsonian medication produced an effect size of 0.37 (20% of risperidone patients and 38% of patients receiving a conventional neuroleptic required antiparkinsonian medication). These data indicate that risperidone is a more effective antipsychotic than the conventional agents and causes less severe extrapyramidal symptoms.

A simple, sensitive and accurate method for the simultaneous determination of risperidone (RSP) and its 9-hydroxy metabolite (9-OH-RSP) in human plasma is described. The relationship between dose of RSP and the plasma concentration of RSP and 9-OH-RSP in a clinical situation is discussed. Both compounds were isolated from plasma by a simple one-step liquid-liquid extraction with 15% methylene chloride in pentane. High-performance liquid chromatography separations were made on a cyano column and the compounds were detected by electrochemical detector. The method had sufficient sensitivity to determine RSP and 9-OH-RSP accurately at concentrations as low as 0.25 ng/ml when 1 ml of plasma is used for the analysis. The assay determinations were accurate, precise and consistent with a coefficient of variation less than 15%. Commonly co-administered drugs and other antipsychotics did not interfere with the analysis of either RSP or 9-OH-RSP There were large variations in inter- and intra-individual values of plasma concentrations of RSP and 9-OH-RSP. The 9-OH-RSP appears to be the major circulating active moiety and its plasma concentrations were, on the average 22 fold higher than that of RSP in schizophrenic patients treated with RSP. The ratio of RSP/9-OH-RSP concentrations suggested that three of the patients may have deficiency in cytochrome P450 enzyme CYP 2D6. The plasma concentrations of RSP showed a weak relationship with the administered daily oral dose (r = 0.4684, p = 0.01, n = 215). However, there was a good relationship between the daily dose of RSP and the plasma concentration of 9-OH-RSP (r = 0.6654, p = 0.01, n = 280) or the total active moiety, sum of RSP and 9-OH-RSP concentrations (r = 0.7041, p = 0.0005, n = 280). The measurement of the total active moiety in plasma of schizophrenic patients may be useful for assessing the relationship between dose and plasma concentration and dose and clinical outcome of patients rather than measuring RSP alone.

We demonstrate the use of a near-infrared-sensitive photorefractive polymer with high efficiency for imaging through scattering media, using an all-optical holographic time gate. Imaging through nine scattering mean free paths is performed at 800nm with a mode-locked continuous-wave Ti:sapphire laser.

Photorefractive polymers with high diffraction efficiency in the visible and near-infrared regions of the electromagnetic spectrum have been developed. These polymers, which have a large dynamic range because of their high orientational birefringence, incorporate a dye designed to have a large dipole moment and a high linear polarizability anisotropy. Such polymers have enabled demonstrations of imaging through scattering media, using a holographic time-gating technique at a wavelength that is compatible with the transparency of biological tissues and with the emission of low-cost semiconductor laser diodes.

Noncompliance with medication is common among patients who have schizophrenia and is a leading cause of rehospitalization in this population. Both standard and subjective risk-factor assessments have been used to identify patients who are likely to refuse or discontinue treatment. Noncompliant patients who have schizophrenia commonly have been treated with potent D2 dopamine-receptor antagonists and therefore may have experienced extrapyramidal side effects. The newer antipsychotics (i.e., serotonin-dopamine antagonists) are efficacious in reducing the symptoms of schizophrenia without associated dysphoria and motor side effects. Clozapine and other newer antipsychotics may improve certain aspects of cognition. The improved psychiatric state and cognitive function may facilitate "involved compliance" as a result of increased insight, awareness, and judgment. These cognitive faculties allow patients to appreciate their improved state and take steps to maintain it. The periodic visits for blood monitoring mandated for clozapine therapy also facilitate the formation of a therapeutic alliance that allows the clinician to monitor compliance. Facilitating involved compliance this way among patients who have schizophrenia may reduce the cost of this disorder to society.

Large two-photon absorptivities are reported for symmetrical bis-donor stilbene derivatives with dialkylamino or diphenylamino groups. These molecules exhibit strong optical limiting of nanosecond pulses over a broad spectral range in the visible. Relative to bis(di-n-butylamino)stilbene, bis(diphenylamino)stilbene exhibits a 90-nm red shift of its optical limiting band but only a minimal shift of ~13 nm of its lowest one-photon electronic absorption band. Mixtures of these compounds offer an unprecedented combination of broad optical limiting bandwidth and high linear transparency.

Background: In two double-blind trials conducted in North America, 513 patients with chronic schizophrenia received risperidone, haloperidol, or placebo. In the present study, combined data from the two trials were analyzed., Method: Patients were randomly assigned to receive placebo, fixed doses of risperidone (2, 6, 10, and 16 mg/day) or 20 mg/day of haloperidol for 8 weeks. Factor analysis of scores on the Positive and Negative Syndrome Scale (PANSS) produced five dimensions (negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, and anxiety/depression), similar to the five dimensions of previous factor-analytic studies of PANSS data., Results: Mean changes (symptom reductions) in PANSS factor scores from baseline to treatment Weeks 6 and 8 were significantly greater in patients receiving 6-16 mg/day of risperidone than in patients receiving placebo or haloperidol. The advantages of risperidone were greatest for negative symptoms, uncontrolled hostility/excitement, and anxiety/depression. Even at the lowest dose, 2 mg/day, risperidone was significantly (p < or = .05) superior to haloperidol in reducing negative symptoms. The differences in outcomes between risperidone and haloperidol on PANSS scores were not related to extrapyramidal symptoms., Conclusion: Risperidone produced significantly (p < or = .05) greater improvements than haloperidol on all five dimensions. The large between-group differences on negative symptoms, hostility/excitement, and anxiety/depression suggest that risperidone and other serotonin/dopamine antagonists have qualitatively different effects from those of conventional antipsychotic agents.

The management of acute extrapyramidal effects (EPEs) induced by antipsychotic drugs is reviewed. EPEs associated with antipsychotics include acute dystonias, pseudoparkinsonism, and akathisia. Acute dystonias consist of abnormal muscle spasms and postures and usually occur three to five days after antipsychotic therapy begins or the dosage is increased. Acute dystonias should be treated with anticholinergic medications or benzodiazepines. Antipsychotic-induced pseudoparkinsonism has the same clinical appearance as idiopathic parkinsonism. Symptoms generally appear within the first three months. Pseudoparkinsonism is managed by lowering the anti-psychotic dosage or by adding an anticholinergic agent or a mantadine; switching to a low-potency agent or an atypical antipsychotic may also help. Akathisia is characterized by subjective feelings of restlessness and anxiety and objective signs of motor activity, such as inability to sit still. This EPE appears days to weeks after antipsychotic exposure begins and can be difficult to manage. If reduction of the antipsychotic dosage or a switch to a less potent antipsychotic is not practical or effective, an anticholinergic, beta-blocker, or benzodiazepine may be added. Lipophilic beta-blockers, especially propranolol and metoprolol, appear to be the most effective treatments. Anticholinergic agents are commonly given to prevent acute dystonias, especially in high-risk patients, but long-term prophylaxis is controversial. Atypical antipsychotics may have less potential to induce EPEs. Options in the management of antipsychotic-associated EPEs include using the lowest effective dosage of antipsychotic, treating the reactions with medications, and changing the antipsychotic to one with less potential for inducing EPEs.

A sensitive high-performance liquid chromatography method with electrochemical detection for the determination of olanzapine in human plasma is described. Olanzapine from plasma samples was isolated by a simple one-step liquid--liquid extraction with 15% methylene chloride in pentane with an extraction recovery of approximately 94% of the total olanzapine in plasma. The compound was separated on a cyano column. Under the conditions described, commonly coadministered drugs and other common antipsychotic drugs did not interfere with the analysis of olanzapine. The lower limit of determination of the assay was 0.25 ng of olanzapine per ml when 1 ml of plasma was used for the analysis. The interaassay and intraassay variance was (CV%) less than 10%. The standard curve was linear within the range of 0.25 to 50 ng/ml of olanzapine. This method has been used for the determination of plasma levels of olanzapine in patients with schizophrenia who were treated with daily oral doses of 10, 15, and 20 mg of olanzapine. The results indicate that the plasma level of olanzapine increases linearly with the administered daily oral dose (r = 0.6889, p = 0.01).

Objective: Treatment efficacy in schizophrenia is typically defined in terms of symptom reduction. However, new antipsychotic medications could potentially have an impact on aspects of disability, such as neurocognitive deficits. The authors evaluated the effects of risperidone on verbal working memory, a memory component of theoretical interest because of its link to prefrontal activity and of practical interest because of its link to psychosocial rehabilitation., Method: Verbal working memory of 59 treatment-resistant schizophrenic patients was assessed as part of a randomized, double-blind comparison of treatment with risperidone and haloperidol. Verbal working memory was measured under both distracting and nondistracting conditions at baseline and after 4 weeks of both fixed- and flexible-dose pharmacotherapy., Results: Risperidone treatment had a greater beneficial effect on verbal working memory than haloperidol treatment across testing conditions (with and without distraction) and study phases (fixed and flexible dose). The treatment effect remained significant after the effects of benztropine cotreatment, change in psychotic symptoms, and change in negative symptoms were controlled. Neither benztropine status nor symptom changes were significantly related to memory performance., Conclusions: Treatment with risperidone appears to exert a more favorable effect on verbal working memory than treatment with a conventional neuroleptic. The beneficial effect appears to be due, at least partially, to a direct effect of the drug, possibly through antagonism of the 5-HT2A receptor. Results from this study suggest that pharmacotherapeutic efficacy in schizophrenia treatment could be broadened to include impact on neurocognitive abilities.

Garito and co-workers have suggested a mechanism to dramatically increase the second hyperpolarizability, gamma, in linear pi-electron-conjugated molecules. Polarization is introduced that leads to a difference between the dipole moments of the molecule's ground state and excited state. Here a series of carotenoids was examined that had increasing intramolecular charge transfer (ICT) from the polyenic chain to the acceptor moiety in the ground state, and gamma was measured for these compounds as a function of wavelength by third-harmonic generation. The compound with the greatest ICT exhibited a 35-fold enhancement of gammamax (the gamma measured at the peak of the three-photon resonance) relative to the symmetric molecule beta-carotene, which itself has one of the largest third-order nonlinearities known. Stark spectroscopic measurements revealed the existence of a large difference dipole moment, Delta mu, between the ground and excited state. Quantum-chemical calculations underline the importance of interactions involving states with large Delta mu.