Jeffrey P. Reiss

Atypical Antipsychotic Drugs and the Risk for Acute Kidney Injury and Other Adverse Outcomes in Older Adults: A Population-Based Cohort Study

Context Acute kidney injury (AKI) is reportedly associated with atypical antipsychotic drugs, although the risk has not been quantified. Contribution This population-based cohort study found that persons who had received a prescription for any of 3 atypical antipsychotic drugs in the previous 90 days had an elevated risk for hospitalization with AKI. These drugs were also associated with increased risk for hypotension, acute urinary retention, and death. Caution Only older adults and 3 antipsychotic agents were studied. Implication An association with specific adverse events may explain the increased risk for AKI observed with certain atypical antipsychotic drugs. The Editors Each year, millions of older adults worldwide are prescribed atypical antipsychotic drugs (quetiapine, risperidone, and olanzapine). These drugs are frequently used to manage behavioral symptoms of dementia, which is not an approved indication, and such use has raised safety concerns (1, 2). These drugs antagonize -adrenergic, muscarinic, serotonin, and dopamine receptors (3). Acute kidney injury (AKI) (defined as a sudden loss of kidney function) from atypical antipsychotic drugs is described in several case reports (48). Adverse outcomes potentially attributable to these drugs, such as hypotension, acute urinary retention, and the neuroleptic malignant syndrome or rhabdomyolysis, are known to cause AKI (411). Moreover, pneumonia, acute myocardial infarction, and ventricular arrhythmia have been associated with these drugs in previous population-based studies and AKI may also co-occur with these events (1214). However, no clinical or epidemiologic studies have quantified the risk for AKI from atypical antipsychotic drugs and information on outcomes of hypotension, acute urinary retention, and the neuroleptic malignant syndrome or rhabdomyolysis is limited. Such information would contribute to growing knowledge of potential adverse events from this drug class. The U.S. Food and Drug Administration warns of an increased risk for death in older patients treated with these drugs based on analyses of randomized, placebo-controlled trials (averaging 10 weeks in duration) (1). For these reasons, we did this population-based study of older adults to investigate the 90-day risk for hospitalization with AKI and other adverse outcomes from new use of an oral atypical antipsychotic drug initiated in the nonhospital setting. Methods Design and Setting We conducted this study at the Institute for Clinical Evaluative Sciences according to a prespecified protocol that was approved by the research ethics board at Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. Patient informed consent was not required. We did a population-based, retrospective cohort study of older adults using linked health care databases in Ontario, Canada. Ontario residents have universal access to hospital care and physician services, and those aged 65 years or older have universal prescription drug coverage. The reporting of this study followed guidelines for observational studies (Table 1 of the Supplement) (15). Supplement. Supplementary material Data Sources We ascertained patient characteristics, drug use, covariate information, and outcome data using records from 5 databases. We obtained vital statistics from the Registered Persons Database of Ontario, which contains demographic information on all Ontario residents who have ever been issued a health card. We used the Ontario Drug Benefit database to identify prescription drug use. This database contains highly accurate recordsthe error rate is less than 1%of all outpatient prescriptions dispensed to patients aged 65 years or older (16). We identified diagnostic and procedural information on all hospitalizations from the Canadian Institute for Health Information Discharge Abstract Database. We obtained covariate information from the Ontario Health Insurance Plan database, which includes health claims for inpatient and outpatient physician services. We identified diagnostic information on all admissions to adult mental health beds from the Ontario Mental Health Reporting System. We have used these databases to research adverse drug reactions and health outcomes (including AKI) (1722). The databases were complete for all variables used in this study, except for prescriber information (which was missing for 10.8% of patients in the cohort). Codes from the International Classification of Diseases, Ninth Revision (before 2002), and Tenth Revision (after 2002), were used to assess baseline comorbid conditions in the 5 years before cohort entry (Table 2 of the Supplement). Codes used to ascertain outcomes are detailed in Table 3 of the Supplement, which lists only codes from the Tenth Revision because all events would have occurred after implementation of that coding system. A subpopulation in southwestern Ontario had information on outpatient serum creatinine levels available before cohort entry; this group was in the catchment area of 12 hospitals in which linked laboratory values were also available (23). Patients We established a cohort of older adults with evidence of a new outpatient prescription for an oral atypical antipsychotic drug (quetiapine, risperidone, or olanzapine) between June 2003 and December 2011. The date of this prescription served as the index date (cohort entry date) for the drug recipients. We matched a group of drug nonrecipients similar in health status to the recipients. We randomly assigned an index date to the entire Ontario population according to the index date of the drug recipients. For example, if more recipients had an index date between 2003 and 2005, a greater proportion of the population would have been randomly assigned an index date between 2003 and 2005. From these adults, after applying our exclusions to both groups, we matched a drug nonrecipient to each recipient on the following 11 characteristics: age (within 2 years); sex; residential status (community-dwelling or long-term care); evidence of comorbid conditions (dementia, schizophrenia or other psychotic disorder, bipolar disorder, major depression or anxiety disorder, Parkinson disease, and chronic kidney disease); constituency in the subpopulation with available information on serum creatinine levels; and the logit of the propensity score for the predicted probability of newly receiving an atypical antipsychotic drug (within a caliper of 0.2 SDs). We derived this propensity score from a logistic regression model and selected 91 variables for inclusion in the score on the basis of their potential association with the study outcomes or atypical antipsychotic drug initiation (variables listed in Table 4 of the Supplement) (24). One of the variables was the Johns Hopkins Adjusted Clinical Group Aggregated Diagnosis Groups (a validated measure of the complexity of comorbid conditions based on groups of diagnoses) (25, 26). Before matching, we excluded the following patients from both groups: those with prescriptions for any antipsychotic drug in the 180 days before their index date to ensure that the drug was newly prescribed (or had the potential to be newly prescribed in the case of the nonrecipients); those who were discharged from a hospital in the 2 days before their index date to ensure that drug use was newly initiated in the nonhospitalized setting (as in Ontario, patients continuing atypical antipsychotic drug treatment initiated in a hospital would have their oral outpatient prescription dispensed the day of or the day after hospital discharge); and those with evidence of end-stage renal disease before their index date (because the development of AKI is no longer relevant). Among the drug recipients, those who received a prescription for more than 1 type of antipsychotic drug (for example, a prescription for quetiapine and olanzapine) on their index date were excluded to compare mutually exclusive groups in subgroup analyses. Among the nonrecipients, those who did not have at least 1 outpatient medication dispensed in the 90 days before their index date were excluded to ensure that such persons were able to receive a prescription. Each drug recipient and nonrecipient could be selected only once for cohort entry. Outcomes We followed patients for 90 days after the index date to assess the prespecified outcomes. We chose 90 days to focus on acute adverse events, avoid potential crossovers between the 2 groups that might occur with longer follow-up, and mimic the duration of follow-up described in clinical trials of atypical antipsychotic drugs in older patients (1, 2, 27). The primary outcome was hospitalization with AKI. The secondary adverse outcomes were known causes of AKI (hospitalization with hypotension, acute urinary retention, the neuroleptic malignant syndrome or rhabdomyolysis, pneumonia, acute myocardial infarction, and ventricular arrhythmia) and all-cause mortality. The diagnosis codes used to identify the outcomes and information on their accuracy are presented in Table 3 of the Supplement (2830). For hospitalization records, up to 25 diagnosis codes can be assigned per hospitalization (for example, codes for AKI or rhabdomyolysis). Therefore, patients with codes for multiple study outcomes were accounted for in the assessment of each outcome. We previously examined the validity of the database code for hospitalization with AKI used in the current study. In this previous validation study (30), the database code for AKI identified a median increase in serum creatinine level of 98 mol/L (1.11 mg/dL) (interquartile range [IQR], 43 to 200 mol/L [0.49 to 2.26 mg/dL]) at the time of hospital presentation from the most recent value before hospitalization. The absence of such a code represented no statistically significant change in serum creatinine level (6 mol/L [0.07 mg/dL]; IQR, 4 to 20 mol/L [0.05 to 0.23 mg/dL]) (30). Although specificity was greater than 95%, the sensitivity of the hospital diagnosis was

Evolutionary Perspectives on Schizophrenia

The theory of evolution may be relevant to psychiatric disorders. Evolution reflects changes in genes throughout time. Thus, evolutionary forces can shape any phenotype that is genetically rooted and that possesses a long history. Schizophrenia is likely an ancient condition with a substantial genetic component. Since the 1960s, several researchers have applied evolutionary principles to the study of schizophrenia. In general, schizophrenia is either viewed as an evolutionary advantageous condition or as a disadvantageous byproduct of normal brain evolution. This paper reviews major evolutionary explanations— historical and current—that speculate on the possible origins of schizophrenia.

Diminished humour perception in schizophrenia: relationship to social and cognitive functioning.

This study attempted to confirm that humour recognition deficits previously found in schizophrenia are specific to the condition and not attributable to other parameters such as depression or anxiety. Secondarily, we explored any possible cognitive or social functioning correlates to humour recognition deficits. A total of 60 participants (20 outpatients with schizophrenia, 20 psychiatric control participants and 20 control participants) underwent a 64-question humour task in addition to a battery of standard cognitive tests and Social Functioning Scales. In order to compare the three groups of participants, we conducted an analysis of variance (ANOVA) and post-hoc t-tests on neuropsychological measures, social functioning measures, and the primary outcome, humour recognition. The schizophrenia group showed significant and substantial deficits in humour recognition compared to the healthy control group, t(38)=5.1, P<0.001, ES=-1.55 and the psychiatric control group, t(38)=3.6, P=0.001. In the schizophrenia group, humour recognition correlated positively with general intellectual functioning (NART) r=.45, P=0.04, social reasoning (WAIS-III Comprehension) r=.54, P=0.01, executive functioning (WCST-CC) r=.69, P=0.001 and social adjustment ratings (SASS scores), r=.54, P=0.02. These findings support the assertion that humour recognition deficits in schizophrenia are specific to the condition and not attributable to other factors such as depression or anxiety. Furthermore, humour recognition deficits in schizophrenia may perhaps be preferentially associated with deficiencies in set shifting and semantic cognition.

Development of a Childhood Attachment and Relational Trauma Screen (CARTS): a relational-socioecological framework for surveying attachment security and childhood trauma history

Background Current psychometric measures of childhood trauma history generally fail to assess the relational-socioecological context within which childhood maltreatment occurs, including the relationship of abusers to abused persons, the emotional availability of caregivers, and the respondents own thoughts, feelings, and actions in response to maltreatment. Objective To evaluate a computerized approach to measuring the relational-socioecological context within which childhood maltreatment occurs. Method The psychometric properties of a Childhood Attachment and Relational Trauma Screen (CARTS) were evaluated as a retrospective survey of childhood maltreatment history designed to be appropriate for completion by adults. Participants were undergraduates (n=222), an internet sample (n=123), and psychiatric outpatients (n=30). Results The internal reliability, convergent, and concurrent validity of the CARTS were supported across samples. Paired differences in means and correlations between rated item-descriptiveness to self, mothers, and fathers also accorded with findings of prior attachment and maltreatment research, illustrating the utility of assessing the occurrence and effects of maltreatment within a relational-socioecological framework. Conclusions Results preliminarily support a new survey methodology for assessing childhood maltreatment within a relational-socioecological framework. Further psychometric evaluation of the CARTS is warranted.

The neural basis of humour comprehension and humour appreciation: The roles of the temporoparietal junction and superior frontal gyrus

Psychological well-being and social acumen benefit from the recognition of humourous intent and its enjoyment. The enjoyment of humour requires recognition, but humour recognition is not necessarily accompanied by humour enjoyment. Humour recognition is crucial during social interactions, while the associated enjoyment is less critical. Few neuroimaging studies have explicitly differentiated between the neural foundations of humour comprehension and humour appreciation. Among such studies, design limitations have obscured the specification of neural correlates to humour comprehension or appreciation. We implemented a trichotomous response option to address these design limitations. Twenty-four participants rated 120 comics (90 unaltered with humourous intent and 30 caption-altered without humourous intent) as either funny jokes (FJ), not funny jokes but intended to be funny (NFJ), or not intended to be funny or non-jokes (NJ). We defined humour comprehension by NFJ minus NJ and humour appreciation by FJ minus NFJ. We measured localized blood oxygen level dependent (BOLD) neural responses with a 3T MRI scanner. We tested for BOLD responses in humour comprehension brain regions of interest (ROIs), humour appreciation ROIs, and across the whole-brain. We found significant NFJ-NJ BOLD responses in our humour comprehension ROIs and significant FJ-NFJ BOLD responses in select humour appreciation ROIs. One key finding is that comprehension accuracy levels correlated with humour-comprehension responses in the left temporo-parietal junction (TPJ). This finding represents a novel and precise neural linkage to humour comprehension. A second key finding is that the superior frontal gyrus (SFG) was uniquely associated with humour-appreciation. The SFG response suggests that complex cognitive processing underlies humour appreciation and that current models of humour appreciation be revised. Finally, our research design provides an operational distinction between humour comprehension and appreciation and a sensitive measure of individual differences in humour comprehension accuracy.

Second-Generation Antidepressants and Hyponatremia Risk: A Population-Based Cohort Study of Older Adults

BACKGROUND Hyponatremia may occur after initiation of a second-generation antidepressant drug. However, the magnitude of this risk among older adults in routine care is not well characterized. STUDY DESIGN Retrospective, population-based, matched-cohort study. SETTING & PARTICIPANTS In Ontario, Canada, 2003 to 2012, we compared older adults with a mood or anxiety disorder who were dispensed 1 of 9 second-generation antidepressant drugs with matched adults with comparable indicators of baseline health who were not dispensed an antidepressant drug (n=138,246 per group). A similar comparison was made in a subpopulation with available laboratory data (n=4,186 per group). PREDICTOR Second-generation antidepressant prescription versus no antidepressant prescription. OUTCOMES The primary outcome was hospitalization with hyponatremia. A secondary outcome was hospitalization with both hyponatremia and delirium. MEASUREMENTS We assessed hospitalization with hyponatremia using a diagnosis code and, in the subpopulation, serum sodium values. We assessed hospitalization with hyponatremia and delirium using a combination of diagnosis codes. RESULTS Second-generation antidepressant use versus nonuse was associated with higher 30-day risk for hospitalization with hyponatremia (450/138,246 [0.33%] vs 84/138,246 [0.06%]; relative risk [RR], 5.46 [95% CI, 4.32-6.91]). This association was consistent in the subpopulation with serum sodium values (73/4,186 [1.74%] vs 18/4,186 [0.43%]; RR, 4.23 [95% CI, 2.50-7.19]; absolute risk increase, 1.31% [95% CI, 0.87%-1.75%]). Second-generation antidepressant use versus nonuse was also associated with higher 30-day risk for hospitalization with both hyponatremia and delirium (28/138,246 [0.02%] vs 7/138,246 [0.005%]; RR, 4.00 [95% CI, 1.75-9.16]). LIMITATIONS Measures of serum sodium could be ascertained in only a subpopulation. CONCLUSIONS Use of a second-generation antidepressant in routine care by older adults is associated with an approximate 5-fold increase in 30-day risk for hospitalization with hyponatremia compared to nonuse. However, the absolute increase in 30-day incidence is low.

Homelessness and housing crises among individuals accessing services within a Canadian emergency department

ACCESSIBLE SUMMARY Studies have indicated that individuals who are homeless access hospital emergency departments more frequently and may have different needs than individuals who are housed. Successful interventions have been developed and tested to reduce discharge to homelessness for psychiatric inpatients but have not been similarly tested for discharge from emergency departments. This study was developed to provide baseline data on this issue to inform future emergency department interventions. Findings from the current study suggest that discharge from emergency departments to homelessness happens frequently in London, Canada. Participants are unlikely to spontaneously disclose their housing/homelessness issue when first entering the emergency department, which may result in services that do not adequately meet their complex needs. Screening for housing issues is necessary within emergency departments and psychiatric crisis teams as housing issues may be a reason for accessing care or contribute to the presenting condition. Nurses are in an ideal position to evaluate housing needs among emergency department patients. Services outside of the emergency department are also needed to address housing issues, particularly outside of regular office hours. ABSTRACT Individuals who have mental health issues and are homeless or in housing crisis have been found to access emergency departments more frequently than individuals with stable housing. While emergency departments primarily focus on medical issues, homeless individuals may require psychosocial support as well. This study examined issues around housing crises and emergency department use for individuals with mental illness in Canada. Collecting baseline data about these issues is important to inform subsequent interventions. Administrative data from a hospital emergency department and psychiatric crisis service were collected, and five individuals accessing the emergency department for psychiatric reasons were interviewed. Results indicated that individuals with an identified housing crisis accessed the emergency department 930 times in 6 months. None of the interview participants identified housing as the primary reason for accessing the emergency department, but all noted that housing was a contributing stressor. Future research is needed to examine ways in which discharge to homelessness from emergency departments can be avoided and identify alternative services to address housing concerns, particularly for individuals with mental illness. Crisis service and emergency department staff, especially nurses, can play an important role in screening for housing issues and connecting individuals to outside services.Accessible summary Studies have indicated that individuals who are homeless access hospital emergency departments more frequently and may have different needs than individuals who are housed. Successful interventions have been developed and tested to reduce discharge to homelessness for psychiatric inpatients but have not been similarly tested for discharge from emergency departments. This study was developed to provide baseline data on this issue to inform future emergency department interventions. Findings from the current study suggest that discharge from emergency departments to homelessness happens frequently in London, Canada. Participants are unlikely to spontaneously disclose their housing/homelessness issue when first entering the emergency department, which may result in services that do not adequately meet their complex needs. Screening for housing issues is necessary within emergency departments and psychiatric crisis teams as housing issues may be a reason for accessing care or contribute to the presenting condition. Nurses are in an ideal position to evaluate housing needs among emergency department patients. Services outside of the emergency department are also needed to address housing issues, particularly outside of regular office hours. Abstract Individuals who have mental health issues and are homeless or in housing crisis have been found to access emergency departments more frequently than individuals with stable housing. While emergency departments primarily focus on medical issues, homeless individuals may require psychosocial support as well. This study examined issues around housing crises and emergency department use for individuals with mental illness in Canada. Collecting baseline data about these issues is important to inform subsequent interventions. Administrative data from a hospital emergency department and psychiatric crisis service were collected, and five individuals accessing the emergency department for psychiatric reasons were interviewed. Results indicated that individuals with an identified housing crisis accessed the emergency department 930 times in 6 months. None of the interview participants identified housing as the primary reason for accessing the emergency department, but all noted that housing was a contributing stressor. Future research is needed to examine ways in which discharge to homelessness from emergency departments can be avoided and identify alternative services to address housing concerns, particularly for individuals with mental illness. Crisis service and emergency department staff, especially nurses, can play an important role in screening for housing issues and connecting individuals to outside services.

Mental Health Engagement Network: Innovating Community-Based Mental Healthcare

Background: Canadian mental health care reform calls for new service delivery models that capitalize on health promotion, support and early intervention as patients and services are transitioning from institutions to communities. The Mental Health Engagement Network (MHEN) intervention is a smart technology enabled service delivery model that electronically links individuals to their health care professionals, promoting information sharing between individuals and their health care professionals, and promoting access to mental health care services. This project, funded by Canada Health Infoway, began in September 2011 and will complete in March 2013. Methods: The MHEN project is a longitudinal, mixed qualitative and quantitative research study which has recruited 400 (245 men and 155 women) research participants diagnosed with a mood or a psychotic disorder who are currently working with community based mental health care professionals (54 mental health care professionals across 4 agencies in the London and surrounding area). Each participant has been randomly assigned into Group 1 (early intervention) or Group 2 (later intervention). Group 1 participants received an iPhone 4S, a TELUS health space™ account, and version 1.0 of the Lawson SMART record (a web-based application that provides individuals with a personal health record and tools to help them manage their health) in July, 2012. Participants in Group 2 initially acted as a control group, and received the version 2 intervention in March, 2013. Results: Participants felt the Lawson SMART record was quite (33.1%) or extremely (29.2%) helpful, and gave participants quite a bit more (26.8%) and an extreme amount more (21%) independence. Web analytics demonstrated that participants visited the Lawson SMART record mobile and desktop home page a total of 16, 928 times. Conclusion: This new service delivery model has the potential to provide quality care to those living in the community with mental illness, enhance health status and quality of life, and reduce the burden of mental illness on the healthcare system by decreasing more costly service uses.

Quality Review in Psychiatry

This position paper has been substantially revised by the Canadian Psychiatric Association’s Professional Standards and Practice Committee and approved for republication by the CPA’s Board of Directors on August 31, 2016. The original position paper1 was developed by the Professional Standards and Practice Council and approved by the Board of Directors on April 9, 1994.

Intrinsic connectivity network dynamics in PTSD during amygdala downregulation using real-time fMRI neurofeedback: A preliminary analysis

Posttraumatic stress disorder (PTSD) has been associated with a disturbance in neural intrinsic connectivity networks (ICN), including the central executive network (CEN), default mode network (DMN), and salience network (SN). Here, we conducted a preliminary investigation examining potential changes in ICN recruitment as a function of real‐time fMRI neurofeedback (rt‐fMRI‐NFB) during symptom provocation where we targeted the downregulation of neural response within the amygdala—a key region‐of‐interest in PTSD neuropathophysiology. Patients with PTSD (n = 14) completed three sessions of rt‐fMRI‐NFB with the following conditions: (a) regulate: decrease activation in the amygdala while processing personalized trauma words; (b) view: process trauma words while not attempting to regulate the amygdala; and (c) neutral: process neutral words. We found that recruitment of the left CEN increased over neurofeedback runs during the regulate condition, a finding supported by increased dlPFC activation during the regulate as compared to the view condition. In contrast, DMN task‐negative recruitment was stable during neurofeedback runs, albeit was the highest during view conditions and increased (normalized) during rest periods. Critically, SN recruitment was high for both the regulate and the view conditions, a finding potentially indicative of CEN modality switching, adaptive learning, and increasing threat/defense processing in PTSD. In conclusion, this study provides provocative, preliminary evidence that downregulation of the amygdala using rt‐fMRI‐NFB in PTSD is associated with dynamic changes in ICN, an effect similar to those observed using EEG modalities of neurofeedback.