Are antipsychotic prescribing patterns different in older and younger adults? : a survey of 1357 psychiatric inpatients in Toronto

Objective: To compare antipsychotic prescribing patterns in younger (aged 59 years or younger) and older (aged 60 years or older) patients with psychotic or mood disorders. Method: Pharmacy records of all patients discharged from the Centre for Addiction and Mental Health over a 21-month period were reviewed. A total of 1357 patients who were prescribed an antipsychotic at the time of their discharge were included in the analysis (956 with a primary psychotic disorder and 401 with a primary mood disorder). World Health Organization-defined daily doses were used as the standardized dosing unit. Results: Both in patients with a primary psychotic disorder and in patients with a primary mood disorder, the prescribing patterns were similar in older and younger patients, with no statistical difference in the proportions receiving first-generation antipsychotics, second-generation antipsychotics (SGAs), multiple antipsychotics, or long-acting (depot) antipsychotics. Overall, the mean daily antipsychotic doses were lower only in the older group of patients with a primary mood disorder. However, the mean dose of SGAs was about 30% lower in older patients in both diagnostic groups. Regardless of age, patients with a mood disorder were prescribed lower doses of antipsychotics than those with a psychotic disorder. Conclusions: Our data suggest that older patients are prescribed lower antipsychotic dosages primarily when using SGAs. This finding emphasizes the need for dose-finding studies assessing both the efficacy and the safety of antipsychotics in older patients with a psychotic or mood disorder.peer-reviewe

The role of untreated psychosis in neurodegeneration: A review of hypothesized mechanisms of neurotoxicity in first-episode psychosis

For over 20 years, studies have tried to measure the association between the duration of untreated psychosis (DUP) and changes in brain morphology. A hypothesis that untreated psychosis is neurotoxic has been postulated, but the mechanisms of that toxicity have not been described. We re-analyzed papers collected for a systematic review to extract data on the hypotheses that have been generated on the potential mechanisms by which DUP could impact brain morphology in first-episode psychosis. Dopaminergic hyperactivity, prolonged hypothalamic-pituitary-adrenal activation, and persistent activity of catecholamines have been hypothesized as mechanisms to explain these associations. However, the question remains as to whether the observed structural changes are permanent or may be reversed via antipsychotic treatment

Coping, fostering resilience, and driving care innovation for autistic people and their families during the COVID-19 pandemic and beyond

Abstract: The new coronavirus disease (COVID-19) pandemic is changing how society operates. Environmental changes, disrupted routines, and reduced access to services and social networks will have a unique impact on autistic individuals and their families and will contribute to significant deterioration in some. Access to support is crucial to address vulnerability factors, guide adjustments in home environments, and apply mitigation strategies to improve coping. The current crisis highlights that our regular care systems are not sufficient to meet the needs of the autism communities. In many parts of the world, people have shifted to online school and increased use of remote delivery of healthcare and autism supports. Access to these services needs to be increased to mitigate the negative impact of COVID-19 and future epidemics/pandemics. The rapid expansion in the use of telehealth platforms can have a positive impact on both care and research. It can help to address key priorities for the autism communities including long waitlists for assessment and care, access to services in remote locations, and restricted hours of service. However, system-level changes are urgently needed to ensure equitable access and flexible care models, especially for families and individuals who are socioeconomically disadvantaged. COVID-19 mandates the use of technology to support a broader range of care options and better meet the diverse needs of autistic people and their families. It behooves us to use this crisis as an opportunity to foster resilience not only for a given individual or their family, but also the system: to drive enduring and autism-friendly changes in healthcare, social systems, and the broader socio-ecological contexts

Neurobiology of delusions in Alzheimer’s disease

Alzheimer’s disease (AD) is associated with cognitive and functional impairment as well as neuropsychiatric sequelae, including psychotic symptoms such as delusions and hallucinations. Strong evidence supports the need to study delusions separate from hallucinations. Integrating the epidemiology, clinical correlates, and neuropathological and genetic literature for delusions in AD allows us to speculate on etiology and mechanisms. Plaque and tangle deposition in individuals with susceptible alleles of serotonergic, muscarinic, nicotinic, or Apoε4 genes appears to result in disruption of cortical circuitry, culminating in delusions. While delusions in AD correspond to a phenotype distinct from AD without delusions, subtypes of delusions may also define further distinct clinical entities. Persecutory delusions may occur earlier in the illness and have a more significant genetic component than misidentification delusions, which are associated with increased cognitive impairment and advanced dementia. Clearly distinguishing between these two syndromes is essential to making progress in the area of delusions in AD.peer-reviewe

Economic inequalities in the effectiveness of a primary care intervention for depression and suicidal ideation.

BACKGROUND: Economic disadvantage is associated with depression and suicide. We sought to determine whether economic disadvantage reduces the effectiveness of depression treatments received in primary care. METHODS: We conducted differential-effects analyses of the Prevention of Suicide in Primary Care Elderly: Collaborative Trial, a primary-care-based randomized, controlled trial for late-life depression and suicidal ideation conducted between 1999 and 2001, which included 514 patients with major depression or clinically significant minor depression. RESULTS: The intervention effect, defined as change in depressive symptoms from baseline, was stronger among persons reporting financial strain at baseline (differential effect size = -4.5 Hamilton Depression Rating Scale points across the study period [95% confidence interval = -8.6 to -0.3]). We found similar evidence for effect modification by neighborhood poverty, although the intervention effect weakened after the initial 4 months of the trial for participants residing in poor neighborhoods. There was no evidence of substantial differences in the effectiveness of the intervention on suicidal ideation and depression remission by economic disadvantage. CONCLUSIONS: Economic conditions moderated the effectiveness of primary-care-based treatment for late-life depression. Financially strained individuals benefited more from the intervention; we speculate this was because of the enhanced treatment management protocol, which led to a greater improvement in the care received by these persons. People living in poor neighborhoods experienced only temporary benefit from the intervention. Thus, multiple aspects of economic disadvantage affect depression treatment outcomes; additional work is needed to understand the underlying mechanisms

Towards the development of new subtype-specific muscarinic receptor radiopharmaceuticals-radiosynthesis and ex vivo biodistribution of [18F] 3-(4-(2-(2-(2-fluoroethoxy) ethoxy) ethylthio)-1, 2, 5-thiadiazol-3-yl)-1-methyl-1, 2, 5, 6-tetrahydropyridine

Muscarinic receptors have been implicated in neurological disorders including Alzheimer’s disease, Parkinson’s disease, and schizophrenia. Nineteen derivatives of thiadiazolyltetrahydropyridine (TZTP), a core that has previously shown high affinities towards muscarinic receptor subtypes, were synthesized and evaluated via in vitro binding assays. The title compound, a fluoro-polyethyleneglycol analog of TZTP (4c), was subsequently labelled with fluorine-18. Fluorine-18-labelled 4c was produced, via an automated synthesis, in an average radiochemical yield of 36% (uncorrected for decay), with high radiochemical purity (>99%) and high specific activity (326 GBq/µmol; end-of-bombardment), within 40 min (n = 3). Ex vivo biodistribution studies following tail-vein injection of [18F]4c in conscious rats displayed sufficient brain uptake (0.4%–0.7% injected dose / gram of wet tissue in all brain regions at 5 min post injection); however, there were substantial polar metabolites present in the brain, thereby precluding future use of [18F]4c for imaging in the central nervous system.peer-reviewe

Differentiating the Cognitive Profile of Schizophrenia from That of Alzheimer Disease and Depression in Late Life

To compare the cognitive profile of older patients with schizophrenia to those with other neuropsychiatric disorders assessed in a hospital-based memory clinic.Demographic, clinical, and cognitive data of all patients referred to the memory clinic at the Centre for Addiction and Mental Health between April 1, 2006 and August 15, 2008 were reviewed. We then identified four groups of older patients with: (1) late-life schizophrenia (LLS) and no dementia or depression (DEP); (2) Alzheimer's disease (AD); (3) DEP and no dementia or LLS; (4) normal cognition (NC) and no DEP or LLS.The four groups did not differ in demographic data except that patients with AD were about 12 years older than those with LLS. However, they differed on cognitive tests even after controlling for age. Patients with LLS were impaired on most cognitive tests in comparison with patients with NC but not on recalling newly learned verbal information at a short delay. They experienced equivalent performance on learning new verbal information in comparison with patients with AD, but better performance on all other tests of memory, including the ability to recall newly learned verbal information. Finally, they were more impaired than patients with DEP in overall memory.Patients with LLS have a different cognitive profile than patients with AD or DEP. Particularly, memory impairment in LLS seems to be more pronounced in learning than recall. These findings suggest that cognitive and psychosocial interventions designed to compensate for learning deficits may be beneficial in LLS

Prediction of brain clozapine and norclozapine concentrations in humans from a scaled pharmacokinetic model for rat brain and plasma pharmacokinetics

BACKGROUND: Clozapine is highly effective in treatment-resistant schizophrenia, although, there remains significant variability in the response to this drug. To better understand this variability, the objective of this study was to predict brain extracellular fluid (ECF) concentrations and receptor occupancy of clozapine and norclozapine in human central nervous system by translating plasma and brain ECF pharmacokinetic (PK) relationships in the rat and coupling these with known human disposition of clozapine in the plasma. METHODS: Unbound concentrations of clozapine and norclozapine were measured in rat brain ECF using quantitative microdialysis after subcutaneous administration of a 10 mg/kg single dose of clozapine or norclozapine. These data were linked with plasma concentrations obtained in the same rats to develop a plasma-brain ECF compartmental model. Parameters describing brain ECF disposition were then allometrically scaled and linked with published human plasma PK to predict human ECF concentrations. Subsequently, prediction of human receptor occupancy at several CNS receptors was based on an effect model that related the predicted ECF concentrations to published concentration-driven receptor occupancy parameters. RESULTS: A one compartment model with first order absorption and elimination best described clozapine and norclozapine plasma concentrations in rats. A delay in the transfer of clozapine and norclozapine from plasma to the brain ECF compartment was captured using a transit compartment model approach. Human clozapine and norclozapine concentrations in brain ECF were simulated, and from these the median percentage of receptor occupancy of dopamine-2, serotonin-2A, muscarinic-1, alpha-1 adrenergic, alpha-2 adrenergic and histamine-1 for clozapine, and dopamine-2 for norclozapine were consistent with values reported in the literature. CONCLUSIONS: A PK model that relates clozapine and norclozapine disposition in rat plasma and brain, including blood-brain barrier transport, was developed. Using allometry and published human plasma PK, the model was successfully translated to predict clozapine and norclozapine concentrations and accordant receptor occupancy of both agents in human brain. These predicted exposure and occupancy measures at several receptors that bind clozapine may be employed to extend our understanding of clozapine's complex behavioral effects in humans

Physician-based availability of psychotherapy in Ontario : a population-based retrospective cohort study

BACKGROUND: Psychotherapy is recommended as a first-line treatment for the management of common psychiatric disorders. The objective of this study was to evaluate the availability of publicly funded psychotherapy provided by physicians in Ontario by describing primary care physicians (PCPs) and psychiatrists whose practices focus on psychotherapy and comparing them to PCPs and psychiatrists whose practices do not. METHODS: This was a population-based retrospective cohort study. We included all PCPs and psychiatrists in Ontario who submitted at least 1 billing claim to the Ontario Health Insurance Plan between Apr. 1, 2015, and Mar. 31, 2016, and categorized them as psychotherapists if at least 50% of their outpatient billings were related to the provision of psychotherapy. We measured practice characteristics such as total number of patients and new patients, and average visit frequency for 4 physician categories: PCP nonpsychotherapists, PCP psychotherapists, psychiatrist nonpsychotherapists and psychiatrist psychotherapists. We also measured access to care for people with urgent need for mental health services. RESULTS: Of 12 772 PCPs, 404 (3.2%) were PCP psychotherapists; of 2150 psychiatrists, 586 (27.3%) were psychotherapists. Primary care physician nonpsychotherapists had the highest number of patients and number of new patients, followed by psychiatrist nonpsychotherapists, PCP psychotherapists and psychiatrist psychotherapists. Primary care physician nonpsychotherapists had the lowest average annual number of visits per patient, whereas both types of psychotherapists had a much greater number of visits per patient. Primary care physician and psychiatrist nonpsychotherapists saw about 25% of patients with urgent needs for mental health services, whereas PCP and psychiatrist psychotherapists saw 1%-3% of these patients. INTERPRETATION: Physicians who provide publicly funded psychotherapy in Ontario see a small number of patients, and they see few of those with urgent need for mental health services. Our findings suggest that improving access to psychotherapy will require the development of alternative strategies

Myelin-Associated Glycoprotein Gene and Brain Morphometry in Schizophrenia

Myelin and oligodendrocyte disruption may be a core feature of schizophrenia pathophysiology. The purpose of the present study was to localize the effects of previously identified risk variants in the myelin-associated glycoprotein (MAG) gene on brain morphometry in schizophrenia patients and healthy controls. Forty-five schizophrenia patients and 47 matched healthy controls underwent clinical, structural magnetic resonance imaging, and genetics procedures. Gray and white matter cortical lobe volumes along with hippocampal volumes were calculated from T1-weighted MRI scans. Each subject was also genotyped for the two disease-associated MAG single nucleotide polymorphisms (rs720308 and rs720309). Repeated measures general linear model (GLM) analysis found significant region by genotype and region by genotype by diagnosis interactions for the effects of MAG risk variants on lobar gray matter volumes. No significant associations were found with lobar white matter volumes or hippocampal volumes. Follow-up univariate GLMs found the AA genotype of rs720308 predisposed schizophrenia patients to left temporal and parietal gray matter volume deficits. These results suggest that the effects of the MAG gene on cortical gray matter volume in schizophrenia patients can be localized to temporal and parietal cortices. Our results support a role for MAG gene variation in brain morphometry in schizophrenia, align with other lines of evidence implicating MAG in schizophrenia, and provide genetically based insight into the heterogeneity of brain imaging findings in this disorder