Methodological, Modal, and Cross-Modal Studies of Short Interval Judgements of Duration, with Specific Reference to the Development of a Model of the Internal Clock

A series of experiments was carried out to investigate: (1) the effect of a background sound applied at either the input and/or the output stages on judgements of visual intervals made using the methods of verbal estimation, operative estimation, and reproduction; (2) the effect of lack of knowledge of the method of response during teh input stage of temporal information on the judgement made; (3) the effect of auditory visual cross-modal stimuli on reproductions of intervals; (4) the effect of lack of knowledge of the mode of response during the input of cross-modal temporal stimuli. Analysis of the data revealed: (1) the background sound, when applied in the standard stage of the method of verbal estimation, increased the estimate of the interval; when applied to the judgement stage of the method of operative estimation decreased the production of the interval; when applied to the standard stage of the method of reproduction increased the judgement of the interval; and when applied to the judgement stage of the method of reproduction decreased the reproduction of the interval; (2) that lack of knowledge of the method of response during the standard presentation may decrease the accuracy of the judgement; (3) that the auditory visual cross-modal difference in time estimation was consistent in both the input and output stages of the method of reproduction; (4) that lack of knowledge of teh mode of response during the standard stage of cross-modal temporal processing had no effect on the resulting judgements. The results were discussed in terms of further defining the concept of an ‘internal clock’ hypothesized by Cohen (1965)

Genetic and endocrine correlates of variation in human sociality

Hormones play evolutionarily ancient roles in social behaviour; yet the degree to which hormone systems influence human socio-emotional behaviour remains unclear. It is hypothesized that (i) hormone-associated genes linked to psychiatric conditions contribute to variation in social traits among non-clinical populations, and (ii) changes in endogenous hormone levels coordinate adaptive social behaviour with stimuli in the environment. Consistent with the first hypothesis, a vasopressin receptor polymorphism linked to autism was significantly associated with autistic-like traits in healthy individuals. Consistent with the second hypothesis, an empathy-inducing stimulus was found to mediate a trade-off in hormone levels, with oxytocin increasing and testosterone decreasing. Furthermore, a common polymorphism in the general transcription factor II-I gene, which is linked to Williams syndrome, was associated with oxytocin response to the empathy-inducing stimulus and social anxiety among healthy individuals. Together, these findings highlight the diverse ways through which hormone systems contribute to variation in human sociality

Oxytocin enhances basolateral amygdala activation and functional connectivity while processing emotional faces: preliminary findings in autistic versus non-autistic women

Oxytocin is hypothesized to promote social interactions by enhancing the salience of social stimuli. While previous neuroimaging studies have reported that oxytocin enhances amygdala activation to face stimuli in autistic men, effects in autistic women remain unclear. In this study, the influence of intranasal oxytocin on activation and functional connectivity of the basolateral amygdala – the brain’s “salience detector” – while processing emotional faces vs. shapes was tested in 16 autistic and 21 non-autistic women by fMRI in a placebo-controlled, within-subjects, cross-over design. In the placebo condition, minimal activation differences were observed between autistic and non-autistic women. However, significant drug × group interactions were observed for both basolateral amygdala activation and functional connectivity. Oxytocin increased left basolateral amygdala activation among autistic women (35 voxel cluster, MNI coordinates of peak voxel= -22 -10 -28; mean change=+0.079%, t=3.159, ptukey=0.0166), but not non-autistic women (mean change =+0.003%, t=0.153, ptukey=0.999). Furthermore, oxytocin increased functional connectivity of the right basolateral amygdala with brain regions associated with socio-emotional information processing in autistic women, but not non-autistic women, attenuating group differences in the placebo condition. Taken together, these findings extend evidence of oxytocin’s effects on the amygdala to specifically include autistic women and specify the subregion of the effect.TLP was supported by the Autism Research Trust, Cambridge Trust, and Natural Sciences and Engineering Research Council of Canada. MVL was supported by an ERC Starting Grant (ERC-2017-STG; 755816). MCL was supported by a Canadian Institutes of Health Research (CIHR) Sex and Gender Science Chair (GSB 171373), the O’Brien Scholars Program within the Child and Youth Mental Health Collaborative at the Centre for Addiction and Mental Health (CAMH) and The Hospital for Sick Children, Toronto, the Academic Scholars Award from the Department of Psychiatry, University of Toronto, the CAMH Foundation, and the Ontario Brain Institute. SBC received funding from the Wellcome Trust 214322\Z\18\Z. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. SBC also received funding from the Autism Centre of Excellence, SFARI, the Templeton World Charitable Fund, the MRC, and the National Institute for Health Research (NIHR). Any views expressed are those of the author(s) and not necessarily those of the funder. RB was supported by the MRC UK, Pinsent Darwin Trust and British Academy post-doctoral fellowship

Developing prediction models for symptom severity around the time of discharge from a tertiary-care program for treatment-resistant psychosis

Antipsychotics are the only therapeutic class indicated in the symptomatic management of psychotic disorders. However, individuals diagnosed with schizophrenia or schizoaffective disorder may not always benefit from these first-line agents. This refractoriness to conventional treatment can be difficult to address in most clinical settings. Therefore, a referral to a tertiary-care program that is better able to deliver specialized care in excess of the needs of most individuals may be necessary. The average outcome following a period of treatment at these programs tends to be one of improvement. Nonetheless, accurate prognostication of individual-level responses may be useful in identifying those who are unlikely to improve despite receiving specialized care. Thus, the main objective of this study was to predict symptom severity around the time of discharge from the Refractory Psychosis Program in British Columbia, Canada using only clinicodemographic information and prescription drug data available at the time of admission. To this end, a different boosted beta regression model was trained to predict the total score on each of the five factors of the Positive and Negative Syndrome Scale (PANSS) using a data set composed of 320 hospital admissions. Internal validation of these prediction models was then accomplished by nested cross-validation. Insofar as it is possible to make comparisons of model performance across different outcomes, the correlation between predictions and observations tended to be higher for the negative and disorganized factors than the positive, excited, and depressed factors on internal validation. Past scores had the greatest effect on the prediction of future scores across all 5 factors. The results of this study serve as a proof of concept for the prediction of symptom severity using this specific approach

White Matter Deficits Assessed by Diffusion Tensor Imaging and Cognitive Dysfunction in Psychostimulant Users With Comorbid Human Immunodeficiency Virus Infection

Background Psychostimulant drug use is commonly associated with drug-related infection, including the human immunodeficiency virus (HIV). Both psychostimulant use and HIV infection are known to damage brain white matter and impair cognition. To date, no study has examined white matter integrity using magnetic resonance imaging (MRI) diffusion tensor imaging (DTI) in chronic psychostimulant users with comorbid HIV infection, and determined the relationship of white matter integrity to cognitive function. Methods Twenty-one subjects (mean age 37.5 ± 9.0 years) with a history of heavy psychostimulant use and HIV infection (8.7 ± 4.3 years) and 22 matched controls were scanned on a 3T MRI. Fractional anisotropy (FA) values were calculated with DTI software. Four regions of interest were manually segmented, including the genu of the corpus callosum, left and right anterior limbs of the internal capsule, and the anterior commissure. Subjects also completed a neurocognitive battery and questionnaires about physical and mental health. Results The psychostimulant using, HIV positive group displayed decreased white matter integrity, with significantly lower FA values for all white matter tracts (p < 0.05). This group also exhibited decreased cognitive performance on tasks that assessed cognitive set-shifting, fine motor speed and verbal memory. FA values for the white matter tracts correlated with cognitive performance on many of the neurocognitive tests. Conclusions White matter integrity was thus impaired in subjects with psychostimulant use and comorbid HIV infection, which predicted worsened cognitive performance on a range of tests. Further study on this medical comorbidity is required

Effects of oxytocin administration on salivary sex hormone levels in autistic and neurotypical women

Abstract: Background: Oxytocin administration, which may be of therapeutic value for individuals with social difficulties, is likely to affect endogenous levels of other socially relevant hormones. However, to date, the effects of oxytocin administration on endogenous hormones have only been examined in neurotypical individuals. The need to consider multi-hormone interactions is particularly warranted in oxytocin trials for autism due to evidence of irregularities in both oxytocin and sex steroid systems. Methods: In this double-blind cross-over study, saliva samples were collected from 16 autistic and 29 neurotypical women before and after intranasal administration of 24 IU oxytocin or placebo. Oestradiol, testosterone, and oxytocin levels were quantified in saliva samples. Participants also completed the Autism-Spectrum Quotient (AQ) and Empathy Quotient (EQ) questionnaires. Results: Distinct patterns of change in testosterone and oestradiol levels pre- to-post-administration were observed in autistic relative to neurotypical women (ANCOVA, p < 0.05 main effect of Group), controlling for sample collection time. The mean percent change oestradiol was + 8.8% for the autism group and − 13.0% for the neurotypical group (t = 1.81, p = 0.08), while the mean percent change testosterone was + 1.1% in the autism group and − 12.6% in the neurotypical group (t = 1.26, p = 0.22). In the oxytocin condition, the mean percent change oestradiol was + 12.6% in the autism group and − 6.9% in the neurotypical group (t = 1.78, p = 0.08), while the mean percent change testosterone was + 14.4% in the autism group and − 15.2% in the neurotypical group (t = 3.00, p = 0.006). Robust regression confirmed that group differences in percent change hormone levels were not driven by a small number of influential individuals. Baseline hormone levels did not differ between groups when considered individually. However, baseline testosterone relative to oestradiol (T:E2 ratio) was higher in autistic women (p = 0.023, Cohen’s d = 0.63), and this ratio correlated positively and negatively with AQ and EQ scores, respectively, in the combined sample. Limitations: Further studies with larger and more diverse autistic sample are warranted to confirm these effects. Conclusions: This study provides the first evidence that oxytocin influences endogenous testosterone levels in autistic individuals, with autistic women showing increases similar to previous reports of neurotypical men. These findings highlight the need to consider sex steroid hormones as a variable in future oxytocin trials

Cost of antipsychotic polypharmacy in the treatment of schizophrenia

<p>Abstract</p> <p>Background</p> <p>This study compared the costs of antipsychotic polypharmacy for patients who initiated on 1 of the 3 most commonly prescribed atypical antipsychotics – olanzapine, quetiapine, or risperidone.</p> <p>Methods</p> <p>Data were drawn from a large, prospective, naturalistic, multi-site, nonrandomized study of treatment for schizophrenia in the United States conducted between July 1997 and September 2003. Participants who were initiated on olanzapine (N = 405), quetiapine (N = 115), or risperidone (N = 276) were followed for 1 year post initiation and compared on: (a) average daily cost of the index antipsychotic while on the index antipsychotic, (b) average daily cost of the coprescribed antipsychotics while on the index antipsychotic, (c) average daily cost of the index antipsychotic and the coprescribed antipsychotics while on the index antipsychotic, (d) total annual cost of antipsychotic medications prescribed in the year following initiation on the index antipsychotic, using propensity score-adjusted bootstrap resampling method. Average daily antipsychotic costs and total annual antipsychotic costs were also estimated using more recent (2004) antipsychotic drug prices.</p> <p>Results</p> <p>During the 1 year following initiation on the index antipsychotic, the total average daily cost of the index antipsychotic was higher for quetiapine ($15.33) than olanzapine ($13.90, p < .05) and risperidone ($11.04, p < .01), although the average daily cost of the index antipsychotic was higher for olanzapine ($10.08) than risperidone ($6.74, p < .01) or quetiapine ($6.63, p < .01). Lower total average daily costs were observed in risperidone than olanzapine or quetiapine. Significantly lower average daily cost of concomitant antipsychotic medications for olanzapine ($3.82) compared to quetiapine ($8.70, p < .01) or risperidone-initiated patients ($4.30, p < .01) contributed to the lower average daily cost of all antipsychotic medication for olanzapine-initiated patients. Each dollar spent on the index antipsychotic was accompanied by spending an additional$1.31 on concomitant antipsychotics for quetiapine compared to $0.64 for risperidone and$0.38 for olanzapine-initiated patients. A separate intent-to-treat analysis of the total annual antipsychotic cost found a significantly higher total annual antipsychotic cost for quetiapine-initiated patients ($5320) compared to olanzapine ($4536, p < .01) or risperidone ($3813, p < .01).</p> <p>Conclusion</p> <p>Prevalent antipsychotic polypharmacy adds substantial cost to the treatment of schizophrenia. Comparison of medication costs need to address the costs of all antipsychotics. A better understanding of concomitant antipsychotic costs provides a more accurate portrayal of antipsychotic medication costs in the treatment of schizophrenia.</p

Antipsychotic monotherapy and polypharmacy in the naturalistic treatment of schizophrenia with atypical antipsychotics

BACKGROUND: Antipsychotic monotherapy is recognized as the treatment of choice for patients with schizophrenia. Simultaneous treatment with multiple antipsychotics (polypharmacy) is suggested by some expert consensus guidelines as the last resort after exhausting monotherapy alternatives. This study assessed the annual rate and duration of antipsychotic monotherapy and its inverse, antipsychotic polypharmacy, among schizophrenia patients initiated on commonly used atypical antipsychotic medications. METHODS: Data were drawn from a large prospective naturalistic study of patients treated for schizophrenia-spectrum disorders, conducted 7/1997–9/2003. Analyses focused on patients (N = 796) who were initiated during the study on olanzapine (N = 405), quetiapine (N = 115), or risperidone (N = 276). The percentage of patients with monotherapy on the index antipsychotic over the 1-year post initiation, and the cumulative number of days on monotherapy were calculated for all patients and for each of the 3 atypical antipsychotic treatment groups. Analyses employed repeated measures generalized linear models and non-parametric bootstrap re-sampling, controlling for patient characteristics. RESULTS: During the 1-year period, only a third (35.7%) of the patients were treated predominately with monotherapy (>300 days). Most patients (57.7%) had at least one prolonged period of antipsychotic polypharmacy (>60 consecutive days). Patients averaged 195.5 days on monotherapy, 155.7 days on polypharmacy, and 13.9 days without antipsychotic therapy. Olanzapine-initiated patients were significantly more likely to be on monotherapy with the initiating antipsychotic during the 1-year post initiation compared to risperidone (p = .043) or quetiapine (p = .002). The number of monotherapy days was significantly greater for olanzapine than quetiapine (p < .001), but not for olanzapine versus risperidone, or for risperidone versus quetiapine-initiated patients. CONCLUSION: Despite guidelines recommending the use of polypharmacy only as a last resort, the use of antipsychotic polypharmacy for prolonged periods is very common during the treatment of schizophrenia patients in usual care settings. In addition, in this non-randomized naturalistic observational study, the most commonly used atypical antipsychotics significantly differed on the rate and duration of antipsychotic monotherapy. Reasons for and the impact of the predominant use of polypharmacy will require further study

Pharmacotherapy of Schizophrenic Patients: Preponderance of Off-Label Drug Use

Multiple drug class combinations are often prescribed for the treatment of schizophrenia, although antipsychotic monotherapy reflects FDA labeling and scientific justification for combinations is highly variable. This study was performed to gain current data regarding drug treatment of schizophrenia as practiced in the community and to assess the frequencies of off-label drug class combinations. 200 DSM IV-diagnosed schizophrenic patients recruited from community treatment sources participated in this cross-sectional study of community based schizophrenic patients. Drug class categories include First and Second Generation Antipsychotic drugs (FGA and SGA, respectively), mood stabilizers, antidepressants and anti-anxiety drugs. 25.5% of patients received antipsychotic monotherapy; 70% of patients received an antipsychotic and another drug class. A total of 42.5% of patients received more than one antipsychotic drug. The most common drug class combination was antipsychotic and a mood stabilizer. Stepwise linear discriminant function analysis identified the diagnosis of schizoaffective schizophrenia, history of having physically hurt someone and high scores on the General Portion of the PANSS rating scale predicted the combined use of an antipsychotic drug and a mood stabilizer. “Real world” pharmacotherapy of schizophrenia has developed its own established practice that is predominantly off-label and may have outstripped current data support. The economic implications for public sector payers are substantial as well as for the revenue of the pharmaceutical industry, whose promotion of off-label drug use is an increasingly problematic. These data are consistent with the recognition of the therapeutic limitations of both first and second generation antipsychotic drugs