Treatment of acute agitation in psychotic disorders

Several psychotic disorders, including schizophrenia, may be associated with symptoms of acute agitation and aggression. While drug treatment of agitation is often essential, non-pharmacological interventions, both environmental and behavioral, also play important roles in the complex management of agitated patients. The most extensively used psychotropic drugs are parenteral formulas of conventional antipsychotics and benzodiazepines. Recently, injection forms of two second generation antipsychotics, olanzapine and ziprasidone, have become available. Both drugs have shown adequate efficacy and tolerability in several double-blind trials of intramuscular administration in acutely agitated psychotic patients. Compared to conventional medication, injection forms of the new antipsychotics may have a faster onset of action and more favorable profile of adverse events. Alternative approaches to injection administration include liquid drug formula, orally disintegrating tablets and wafers, treatment initiation with high doses, or rapid dose escalation. Evidence suggests that second-generation antipsychotics should be among the first-line choices in the treatment of agitation in acute psychosis.     

Temporal lobe volume in disorders with psychotic features

Since early neuropathological findings, temporal lobe has been related to the pathophysiology of some disorders with psychotic features. The aim of this study was to compare temporal lobe volumes and asymmetry differences in patients with schizophrenia, schizoaffective and bipolar disorders, disorders that cover the whole psychotic spectrum. Temporal lobe volumes were estimated using high resolution magnetic resonance imaging in 60 subjects, 15 subjects in each patient and one healthy volunteer (control) group. There are no statistically significant differences in temporal lobe volumes among patient and control groups. Comparison of left and right temporal lobes shows that left temporal lobes are smaller than right temporal lobes, however this difference reaches statistical significance only in groups of patients with schizoaffective and bipolar disorders. Overall temporal lobe volume may be less informative in respect to neuropathology of disorders with psychotic features than volumes of specific temporal lobe structures, in particular medial temporal lobe structures.     

The specificity of platelet glutamate receptor supersensitivity in psychotic disorders

Hypoglutamatergic function is implicated in the pathogenesis of schizophrenia, and supersensitivity of platelet NMDA receptors has been reported in schizophrenia. The aim of this study was to examine the platelet glutamate receptor sensitivity in patients with schizophrenia (n=12), mania with psychotic features (n=10) and depression with psychotic features (n=10) and matched controls (n=12) in order to assess if this is a marker of schizophrenia or occurs in other psychotic conditions. Glutamate receptor sensitivity was assessed using the intracellular calcium response to glutamate measured with spectrofluorometry. The percentage response of the schizophrenic and depressed psychotic subjects to glutamate stimulation was significantly greater than control subjects (p<0.005). The mania with psychotic features group was not significantly different to controls. This data suggests that platelet glutamate receptors may be supersensitive in schizophrenia and depression with psychotic features. Furthermore, the platelet may be a possible peripheral marker of glutamate function in schizophrenia and depression with psychotic features.     

Cognitive impairments in psychotic disorders: common mechanisms and measurement

Decades of research have provided robust evidence of cognitive impairments in psychotic disorders. Individuals with schizophrenia appear to be impaired on the majority of neuropsychological tasks, leading some researchers to argue for a “generalized deficit”, in which the multitude of cognitive impairments are the result of a common neurobiological source. One such common mechanism may be an inability to actively represent goal information in working memory as a means to guide behavior, with the associated neurobiological impairment being a disturbance in the function of the dorsolateral prefrontal cortex. Here, we provide a discussion of the evidence for such impairment in schizophrenia, and how it manifests in domains typically referred to as cognitive control, working memory and episodic memory. We also briefly discuss cognitive impairment in affective psychoses, reporting that the degree of impairment is worse in schizophrenia than in bipolar disorder and psychotic major depression, but the profile of impairment is similar, possibly reflecting common mechanisms at the neural level. Given the recent release of the DSM‐5, we end with a brief discussion on assessing cognition in the context of diagnosis and treatment planning in psychotic disorders.     

Incidence of psychotic disorders among first-generation immigrants and refugees in Ontario

Background:

Evidence suggests that migrant groups have an increased risk of psychotic disorders and that the level of risk varies by country of origin and host country. Canadian evidence is lacking on the incidence of psychotic disorders among migrants. We sought to examine the incidence of schizophrenia and schizoaffective disorders in first-generation immigrants and refugees in the province of Ontario, relative to the general population.

Methods:

We constructed a retrospective cohort that included people aged 14–40 years residing in Ontario as of Apr. 1, 1999. Population-based administrative data from physician billings and hospital admissions were linked to data from Citizenship and Immigration Canada. We used Poisson regression models to calculate age- and sex-adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for immigrant and refugee groups over a 10-year period.

Results:

In our cohort (n = 4 284 694), we found higher rates of psychotic disorders among immigrants from the Caribbean and Bermuda (IRR 1.60, 95% CI 1.29–1.98). Lower rates were found among immigrants from northern Europe (IRR 0.50, 95% CI 0.28–0.91), southern Europe (IRR 0.60, 95% CI 0.41–0.90) and East Asia (IRR 0.56, 95% CI 0.41–0.78). Refugee status was an independent predictor of risk among all migrants (IRR 1.27, 95% CI 1.04–1.56), and higher rates were found specifically for refugees from East Africa (IRR 1.95, 95% CI 1.44–2.65) and South Asia (IRR 1.51, 95% CI 1.08–2.12).

Interpretation:

The differential pattern of risk across ethnic subgroups in Ontario suggests that psychosocial and cultural factors associated with migration may contribute to the risk of psychotic disorders. Some groups may be more at risk, whereas others are protected.Meta-analytic reviews suggest that international migrants have a two- to threefold increased risk of psychosis compared with the host population, and the level of risk varies by country of origin and host country.^1,2 This increased risk may persist into the second and third generations.^2,3 Incidence rates are not typically found to be elevated in the country of origin;^4–7 therefore, it is believed that the migratory or postmigration experience may play a role in the etiology.The migration-related emergence of psychotic disorders is a potential concern in Canada, which receives about 250 000 new immigrants and refugees each year.⁸ However, there is a notable lack of current epidemiological information on the incidence of psychosis among these groups.⁹ Hospital admission data from the early 1900s suggest that European migrants to British Columbia had a higher incidence of schizophrenia than the general population,¹⁰ and more recent data from Ontario suggest higher rates of hospital admission for psychotic disorders in areas with a large proportion of first-generation migrants.¹¹ The fact that a large and increasing proportion of Canada’s population are migrants has been cited as a potential explanation for the higher prevalence of schizophrenia compared with international estimates.¹²The province of Ontario is home to the largest number of migrants in Canada, with first-generation migrants constituting nearly 30% of the population. Canada operates on a human capital model of immigration, using a points-based system that favours younger age, higher education, and proficiency in English or French. Nearly 60% of all newcomers to Canada are economic migrants, 27% are sponsored by a relative living in Canada, and 13% are refugees or temporary workers.⁸ Canada also requires a prearrival medical examination, but less than 0.001% of all applications are denied on the basis of medical grounds, and exemptions may be granted for refugees and some family-reunification applicants.¹³The Canadian migration process differs from that of many countries where the association between migration and psychotic disorders has been previously investigated.^1,2 In most of these countries, migrants generally originate from a smaller number of countries that have historic ties to the host country, and there tends to be a low proportion of refugees, although these processes have changed in recent years. In Canada, migrants come from a wide array of countries, admission policies focus on migrants with professional skills and there is a larger proportion of refugees. Few studies to date have examined the role of refugee status in the risk of psychotic disorders¹⁴ or have assessed all of the migrant groups within a country, because most studies focus on particular groups considered to be at high risk.¹ An examination of migrants to Canada offers a unique opportunity to investigate the risk of psychotic disorders in a group with diverse geographical origins, and the larger proportion of refugees also allows us to investigate their risk separately from immigrant groups. Thus, the breadth, scope and scale of migration to Canada over time offers a diverse and deep population for advancing our understanding of why some groups may have a higher risk of psychotic disorders.Our primary objective was to examine the incidence of schizophrenia and schizoaffective disorders over a 10-year period in first-generation immigrants and refugees in Ontario, relative to the general population. We also compared the incidence among specific migrant groups, stratified by country of birth and refugee status, because research suggests differences in the degree and direction of risk.^1,2 We restricted the sample to first-generation migrants to estimate the extent to which sociodemographic factors had an impact on the risk of schizophrenia and schizoaffective disorders among all migrants.     

Analysis of TBX1 variation in patients with psychotic and affective disorders

A significant portion of patients with 22q11 deletion syndrome (22q11DS) develop psychiatric disorders, including schizophrenia and other psychotic and affective symptoms, and the responsible gene/s are assumed to also play a significant role in the etiology of nonsyndromic psychiatric disease. The most common psychiatric diagnosis among patients with 22q11DS is schizophrenia, thought to result from neurotransmitter imbalances and also from disturbed brain development. Several genes in the 22q11 region with known or suspected roles in neurotransmitter metabolism have been analyzed in patients with isolated schizophrenia; however, their contribution to the disease remains controversial. Haploinsufficiency of the TBX1 gene has been shown to be sufficient to cause the core physical malformations associated with 22q11DS in mice and humans and via abnormal brain development could contribute to 22q11DS-related and isolated psychiatric disease. 22q11DS populations also have increased rates of psychiatric conditions other than schizophrenia, including mood disorders. We therefore analyzed variations at the TBX1 locus in a cohort of 446 white patients with psychiatric disorders relevant to 22q11DS and 436 ethnically matched controls. The main diagnoses included schizophrenia (n = 226), schizoaffective disorder (n = 67), bipolar disorder (n = 82), and major depressive disorder (n = 29). We genotyped nine tag SNPs in this sample but did not observe significant differences in allele or haplotype frequencies in any of the analyzed groups (all affected, schizophrenia and schizoaffective disorder, schizophrenia alone, and bipolar disorder and major depressive disorder) compared with the control group. Based on these results we conclude that TBX1 variation does not make a strong contribution to the genetic etiology of nonsyndromic forms of psychiatric disorders commonly seen in patients with 22q11DS.     

Obesity and psychotic disorders: uncovering common mechanisms through metabolomics

Primary obesity and psychotic disorders are similar with respect to the associated changes in energy balance and co-morbidities, including metabolic syndrome. Such similarities do not necessarily demonstrate causal links, but instead suggest that specific causes of and metabolic disturbances associated with obesity play a pathogenic role in the development of co-morbid disorders, potentially even before obesity develops. Metabolomics – the systematic study of metabolites, which are small molecules generated by the process of metabolism – has been important in elucidating the pathways underlying obesity-associated co-morbidities. This review covers how recent metabolomic studies have advanced biomarker discovery and the elucidation of mechanisms underlying obesity and its co-morbidities, with a specific focus on metabolic syndrome and psychotic disorders. The importance of identifying metabolic markers of disease-associated intermediate phenotypes – traits modulated but not encoded by the DNA sequence – is emphasized. Such markers would be applicable as diagnostic tools in a personalized healthcare setting and might also open up novel therapeutic avenues.     

The development of psychotic disorders in adolescence: A potential role for hormones

This article is part of a Special Issue “Puberty and Adolescence”.     

Stigmatization of patients suffering from schizophrenia

For the general public, but also for healthcare professionals, schizophrenia is still one of those areas of medicine connected with feelings of unease, fear and prejudice. These feelings lead to stigmatization and discrimination which are unjust processes which put patients suffering from mental illnesses into undesirable and unequal positions. Aim of this research was to establish the extent of stigmatization of mentally ill patients among the population of healthcare professionals and future healthcare professionals and if they differ from general population. Results show that stigmatization of schizophrenic patients is high among all included populations. Although there were no statistical differences between groups regarding the assessment of schizophrenic patients, nurses employed in psychiatric wards exhibited a tendency towards higher acceptance of schizophrenic patients, as well as better understanding of that illness. This data emphasizes a growing need for continuous education of general population but also of healthcare professionals.     

The Coevolution of Secrecy and Stigmatization

We propose a coevolutionary model of secrecy and stigmatization. According to this model, secrecy functions to conceal potential fitness costs detected in oneself or one’s genetic kin. In three studies, we found that the content of participants’ distressing secrets overlapped significantly with three domains of social information that were important for inclusive fitness and served as cues for discriminating between rewarding and unrewarding interaction partners: health, mating, and social-exchange behavior. These findings support the notion that secrecy functions primarily as a defense against stigmatization by suppressing information about oneself or one’s kin that evolutionarily has been devalued in mating and social exchange.     

Discovery and biological profile of isoindolinone derivatives as novel metabotropic glutamate receptor 1 antagonists: A potential treatment for psychotic disorders

We describe here the discovery and biological profile of a series of isoindolinone derivatives as developed mGluR1 antagonists. Our combined strategy of rapid parallel synthesis and conventional medicinal optimization successfully led to N-cyclopropyl 22 and N-isopropyl isoindolinone analogs 21 and 23 with improved in vivo DMPK profiles. Moreover the most advanced analog 23 showed an oral antipsychotic-like effect at a dose of 1 mg/kg in an animal model.