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.

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.

Approaches for optimizing the first electronic hyperpolarizability of conjugated organic molecules.

A two-state, four-orbital, independent electron analysis of the first optical molecular hyperpolarizability, beta, leads to the prediction that |beta| maximizes at a combination of donor and acceptor strengths for a given conjugated bridge. Molecular design strategies that focus on the energetic manipulations of the bridge states are proposed for the optimization of beta. The limitations of molecular classes based on common bridge structures are highlighted and more promising candidates are described. Experimental results supporting the validity of this approach are presented.

Synthesis of organic salts with large second-order optical nonlinearities.

A series of organic salts, in which the cation has been designed to have a large molecular hyperpolarizability, has been prepared. Variation of the counterion (anion) in many cases leads to materials with large powder second harmonic generation efficiencies, the highest of which is roughly 1000 times that of a urea reference.

Relation between bond-length alternation and second electronic hyperpolarizability of conjugated organic molecules.

The solvent dependence of the second hyperpolarizability, gamma, of a variety of unsaturated organic compounds has been measured by third harmonic generation at 1907 nanometers. It is seen that the measured gamma is a function of solvent polarity. These solvent-dependent hyperpolarizabilities are associated with changes in molecular geometry from a highly bond-length alternated, polyene-like structure for a formyl-substituted compound in non-polar solvents, to a cyanine-like structure, with little bond-length alternation, for a dicyanovinyl-substituted compound in polar solvents. By tuning bond-length alternation, gamma can be optimized in either a positive or negative sense for polymethine dyes of a given conjugation length.

A unified description of linear and nonlinear polarization in organic polymethine dyes.

An internal or external electric field F can drive the chemical structure, bond order alternation, and electronic structure of linear polymethine dyes from a neutral, bond-alternated, polyene-like structure, through a cyanine-like structure, and ultimately to a zwitterionic (charge-separated) bond-alternated structure. As the structure evolves under the influence of F, the linear polarizability alpha, the first hyperpolarizability beta, and the second hyperpolarizability gamma are seen to be derivatives, with respect to F, of their next lower order polarization (for alpha) or polarizability (for beta and gamma). These derivative relations provide a unified picture of the dependence of the polarizability and hyperpolarizabilities on the structure in linear polymethine dyes. In addition, they allow for predictions of structure-property relations of higher order hyperpolarizabilities.

Large first hyperpolarizabilities in push-pull polyenes by tuning of the bond length alternation and aromaticity.

Conjugated organic compounds with 3-phenyl-5-isoxazolone or N,N'-diethylthiobarbituric acid acceptors have large first molecular hyperpolarizabilities (beta) in comparison with compounds with 4-nitrophenyl acceptors. For example, julolidinyl-(CH=CH)(3)-CH=N,N'- diethylthiobarbituric acid, which has 12 atoms between the donor and acceptor, has a beta(0) of 911 x 10(-30) electrostatic units, whereas (CH(3))(2)NC(6)H(4),-(CH=CH)(4)-C(6)H(4)NO(2), with 16 atoms between its donor and acceptor, has a beta(0) of 133 x 10(-30) electrostatic units. The design strategies demonstrated here have resulted in chromophores that when incorporated into poled-polymer electrooptic modulators exhibited significant enhancements in electrooptic coefficients relative to polymers containing the commonly used dye Disperse Red-1. Poled polymer devices based on these or related chromophores may ultimately lead to high-speed electrooptic switching elements with low drive-power requirements, suitable for telecommunications applications.

Large molecular third-order optical nonlinearities in polarized carotenoids.

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.

Dopamine-beta-hydroxylase activity and homovanillic acid in spinal fluid of schizophrenics with brain atrophy.

Schizophrenic patients with high ventricle brain ratios and cortical brain atrophy, as shown by computerized tomography, had decreased spinal fluid concentrations of homovanillic acid and dopamine-beta-hydroxylase activity. These decreased cerebral spinal fluid concentrations in patients with brain atrophy support the proposal of disturbed noradrenaline and dopamine neurotransmission in a subgroup of schizophrenic patients.

Infrared photorefractive polymers and their applications for imaging.

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.

Design of organic molecules with large two-photon absorption cross sections.

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.

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.

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.

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.

A controlled dose comparison of haloperidol in newly admitted schizophrenic patients.

Eighty newly admitted or readmitted men with DSM-III schizophrenia were assigned to receive 5, 10, or 20 mg/d of haloperidol for 4 weeks. Staff were not "blind" to dose. By Clinical Global Impression Scale ratings, the 20-mg dose appeared to be superior to both the 5- and 10-mg doses for the first 2 weeks of treatment but not thereafter. On the Brief Psychiatric Rating Scale Schizophrenia factor, the 20-mg dose was superior to the 5-mg dose throughout the trial and tended to be marginally superior to the 10-mg dose after the first 2 weeks of treatment. By the second week of treatment, however, the group receiving the 20-mg dose deteriorated significantly with regard to Brief Psychiatric Rating Scale ratings of Withdrawal-Retardation (blunted affect, motor retardation, and emotional withdrawal) as well as akinesia and akathisia ratings. Furthermore, 35% of patients given 20 mg/d of haloperidol insisted on leaving the hospital against medical advice vs only 4% of those given 5 or 10 mg/d of haloperidol. A 20-mg/d dose of haloperidol, therefore, may have substantial "psychotoxic" effects by the second week of treatment.

Akathisia with haloperidol and thiothixene.

We studied the incidence of akathisia in two populations of newly admitted schizophrenic patients: one group was treated with haloperidol and the other group was treated with thiothixene hydrochloride. Within six hours after taking a 5-mg test dose of haloperidol, 40% of the patients experienced akathisia; during maintenance treatment with 10 mg of haloperidol taken at bedtime, 75% of the patients experienced akathisia by the seventh day. With thiothixene hydrochloride (0.22-mg/kg test dose; 0.44-mg/kg maintenance dose), the respective percentages were 20% and 46%. The akathisia experienced after administration of the test of haloperidol dose was not mild or inconsequential; 28% of the patients experienced moderate, 17% of the patients experienced severe, and 22% of the patients experienced very severe akathisia. Akathisia with haloperidol could not be suppressed completely in half of the patients. Treatment-resistant akathisia was experienced as anxiety and depression. We believe these tallies to be important because akathisia causes much misery and often goes undiagnosed.

Low- and conventional-dose maintenance therapy with fluphenazine decanoate. Two-year outcome.

We evaluated the effectiveness and the side effects of what we defined as low (5-mg) and conventional (25-mg) doses of fluphenazine decanoate administered every two weeks in a double-blind comparison. Subjects were 66 patients who fulfilled DSM-III criteria for schizophrenic disorder. Evaluation of the survival with each dose revealed no significant difference at one year, but significantly better survival was seen with the 25-mg dose (64%) than the 5-mg dose (31%) at two years. There was no significant difference in survival when the clinician was permitted to make a dosage adjustment up to 10 mg in the low-dose group and 50 mg in the higher-dose group when the patient demonstrated evidence of a symptomatic exacerbation. Patients assigned to the higher dose appeared to feel more uncomfortable during the early months of the study, as indicated by significantly higher scores on subscales of the Hopkins Symptom Checklist-90R and higher side effect scores for retardation and akathisia. Implications for clinical practice are discussed.

Differential effect of low and conventional doses of fluphenazine on schizophrenic outpatients with good or poor information-processing abilities.

Thirty-six stabilized schizophrenic outpatients were randomly assigned to receive either 5 or 25 mg of fluphenazine decanoate biweekly and were followed up for two years. The best and worst outcomes were found in groups with good or poor information-processing abilities (as measured by a partial-report span-of-apprehension task) given the same 25-mg dose of fluphenazine decanoate. The 86% two-year survival rate of the patients with poor span performance was considerably better, while the 44% one-year and the 21% two-year survival rates of patients with good span performance were considerably lower than previously reported survival rates for schizophrenic patients receiving a conventional dose of fluphenazine. The significant correlations in a patient's span performance for periods up to one year were consistent with the hypothesis that this task taps processes associated with vulnerability to schizophrenic disorder.

Predicting drug-free improvement in schizophrenic psychosis.

In a sample of 22 psychotic schizophrenic patients, eight improved substantially during a 30-day drug-free period. The drug-free improver group differed from the nonimprover group in demonstrating a later age of onset, briefer psychotic episodes, shorter hospitalizations, and better prognostic scores on the Phillips Scale, Strauss-Carpenter Modified Prognostic Scale, and the Vaillant Scale. After drug withdrawal, drug-free improvers frequently demonstrated further improvement when treated with doses of neuroleptic drugs that were substantially lower than the clinically recommended doses. The authors raise the question as to whether the drug-free improvers may represent a subgroup of schizophrenic patients who are being overtreated presently by standard neuroleptic practice.

Lack of behavioral supersensitivity to d-amphetamine after pimozide withdrawal. A trial with schizophrenic patients.

The dopamine hypothesis of schizophrenia claims that increased dopamine activity underlies psychotic behavior. This hypothesis gets major support from the reported d-amphetamine-induced worsening of psychosis, because amphetamine increases dopamine activity in the brain. Dopamine receptor supersensitivity has been shown to be present in animals during the postneuroleptic period. In this study the postulated relationships between psychotic decompensation as observed after d-amphetamine infusion and the dopamine receptor supersensitivity expected to be present during the neuroleptic withdrawal period were examined. Twenty milligrams of d-amphetamine administered intravenously did not cause a stronger psychotogenic effect in 12 schizophrenic patients. One week after discontinuation of pimozide treatment, the d-amphetamine-induced change as indicated by the Brief Psychiatric Rating Scale (BPRS) paranoid disturbance cluster score, was not significantly different from the response to a similar infusion during the drug-free state. Unexpectedly, the increase in the BPRS mannerisms and posturing item and in the pulse rate response to d-amphetamine were decreased. These results raise questions about the role of dopamine in d-amphetamine effects and suggest postneuroleptic dopamine receptor subsensitivity. They challenge a simple dopamine hypothesis of schizophrenia.