Silvana Riggio

Extrapyramidal side-effects of antipsychotics in a randomised trial

BACKGROUND There are claims that second-generation antipsychotics produce fewer extrapyramidal side-effects (EPS) compared with first-generation drugs. AIMS To compare the incidence of treatment-emergent EPS between second-generation antipsychotics and perphenazine in people with schizophrenia. METHOD Incidence analyses integrated data from standardised rating scales and documented use of concomitant medication or treatment discontinuation for EPS events. Mixed model analyses of change in rating scales from baseline were also conducted. RESULTS There were no significant differences in incidence or change in rating scales for parkinsonism, dystonia, akathisia or tardive dyskinesia when comparing second-generation antipsychotics with perphenazine or comparing between second-generation antipsychotics. Secondary analyses revealed greater rates of concomitant antiparkinsonism medication among individuals on risperidone and lower rates among individuals on quetiapine, and lower rates of discontinuation because of parkinsonism among people on quetiapine and ziprasidone. There was a trend for a greater likelihood of concomitant medication for akathisia among individuals on risperidone and perphenazine. CONCLUSIONS The incidence of treatment-emergent EPS and change in EPS ratings indicated that there are no significant differences between second-generation antipsychotics and perphenazine or between second-generation antipsychotics in people with schizophrenia.

Insulin receptor deficits in schizophrenia and in cellular and animal models of insulin receptor dysfunction

Schizophrenia is associated with abnormalities in glucose metabolism that may lead to insulin resistance and a 3 fold higher incidence of type II diabetes mellitus. The goal of the present studies was to assess the role of insulin-dependent Akt signaling in schizophrenia and in animal and cellular models of insulin resistance. Our studies revealed a functional decrease in insulin receptor (IR)-mediated signal transduction in the dorsolateral prefrontal cortex (BA46) of medicated schizophrenics relative to control patients using post-mortem brain material. We found approximately 50% decreases in the content and autophosphorylation levels of IRbeta and approximately 76-78% decreases in Akt content and activity (pSer(473)-Akt). The inhibition of IRbeta signaling was accompanied by an elevated content of glycogen synthase kinase (GSK)-3 alpha and GSK-3beta without significant changes in phospho-Ser(21/9) GSK-3 alpha/beta levels. A cellular model of insulin resistance was induced by IRbeta knockdown (siRNA). As in schizophrenia, the IRbeta knockdown cells demonstrated a reduction in the Akt content and activity. Total GSK-3 alpha/beta content remained unaltered, but phospho-Ser(21/9) GSK-3 alpha/beta levels were reduced indicating a net increase in the overall enzyme activity similar to that in schizophrenia. Insulin resistance phenotype was induced in mice by treatment with antipsychotic drug, clozapine. Behavioral testing showed decreases in startle response magnitude in animals treated with clozapine for 68 days. The treatment resulted in a functional inhibition of IRbeta but the Akt activation status remained unaltered. Changes in GSK-3 alpha/beta were consistent with a net decrease in the enzyme activity, as opposed to that in schizophrenia. The results suggest that alterations in insulin-dependent Akt signaling in schizophrenia are similar to those observed in our cellular but not animal models of insulin resistance. In animal model, clozapine ameliorates IRbeta deficits at the GSK-3 alpha/beta level, which may justify its role in treatment of schizophrenia. Our studies suggest that aberrant IR function may be important in the pathophysiology of schizophrenia.

Neurobehavioral sequelae of traumatic brain injury

The neurobehavioral sequelae of traumatic brain injury consist of a spectrum of somatic and neuropsychiatric symptoms. The neuropsychiatric symptoms are divided into cognitive and behavioral presentations. In the literature, these neurobehavioral sequelae have been called postconcussive symptoms, postconcussive syndrome, and postconcussive disorder; however, the authors of this review do not use this terminology because the symptoms are not restricted to patients with concussion but instead can be found in all traumatic brain injury patients of all injury severities. The development of neurobehavioral sequelae after traumatic brain injury is a multifactorial process. The patient evaluation requires a multidisciplinary approach in order to delineate physiologic dysfunction and place deficits in the context of the patients preinjury and postinjury psychiatric status. Consequently, the evaluation of the posttraumatic brain injury patient with neurobehavioral sequelae requires a carefully structured history and physical examination with an emphasis on neurological and psychiatric function. Adjunctive evaluations must be tailored to the patient with neuroimaging, neurophysiological, and neuropsychiatric testing. Maximized outcomes may be achieved by the performance of a careful and detailed assessment that places complaints within the context of the individual.

Concussion guidelines step 1: systematic review of prevalent indicators.

BACKGROUND Currently, there is no evidence-based definition for concussion that is being uniformly applied in clinical and research settings. OBJECTIVE To conduct a systematic review of the highest-quality literature about concussion and to assemble evidence about the prevalence and associations of key indicators of concussion. The goal was to establish an evidence-based foundation from which to derive, in future work, a definition, diagnostic criteria, and prognostic indicators for concussion. METHODS Key questions were developed, and an electronic literature search from 1980 to 2012 was conducted to acquire evidence about the prevalence of and associations among signs, symptoms, and neurologic and cognitive deficits in samples of individuals exposed to potential concussive events. Included studies were assessed for potential for bias and confound and rated as high, medium, or low potential for bias and confound. Those rated as high were excluded from the analysis. Studies were further triaged on the basis of whether the definition of a case of concussion was exclusive or inclusive; only those with wide, inclusive case definitions were used in the analysis. Finally, only studies reporting data collected at fixed time points were used. For a study to be included in the conclusions, it was required that the presence of any particular sign, symptom, or deficit be reported in at least 2 independent samples. RESULTS From 5437 abstracts, 1362 full-text publications were reviewed, of which 231 studies were included in the final library. Twenty-six met all criteria required to be used in the analysis, and of those, 11 independent samples from 8 publications directly contributed data to conclusions. Prevalent and consistent indicators of concussion are (1) observed and documented disorientation or confusion immediately after the event, (2) impaired balance within 1 day after injury, (3) slower reaction time within 2 days after injury, and/or (4) impaired verbal learning and memory within 2 days after injury. CONCLUSION The results of this systematic review identify the consistent and prevalent indicators of concussion and their associations, derived from the strongest evidence in the published literature. The product is an evidence-based foundation from which to develop diagnostic criteria and prognostic indicators.

Treatment outcomes of patients with tardive dyskinesia and chronic schizophrenia

OBJECTIVE We compared the response to antipsychotic treatment between patients with and without tardive dyskinesia (TD) and examined the course of TD. METHOD This analysis compared 200 patients with DSM-IV-defined schizophrenia and TD and 997 patients without TD, all of whom were randomly assigned to receive one of 4 second-generation antipsychotics. The primary clinical outcome measure was time to all-cause treatment discontinuation, and the primary measure for evaluating the course of TD was change from baseline in Abnormal Involuntary Movement Scale (AIMS) score. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to compare treatment discontinuation between groups. Changes in Positive and Negative Syndrome Scale (PANSS) and neurocognitive scores were compared using mixed models and analysis of variance. Treatment differences between drugs in AIMS scores and all-cause discontinuation were examined for those with TD at baseline. Percentages of patients meeting criteria for TD postbaseline or showing changes in AIMS scores were evaluated with χ(2) tests. Data were collected from January 2001 to December 2004. RESULTS Time to treatment discontinuation for any cause was not significantly different between the TD and non-TD groups (χ(2)(1) = 0.11, P = .743). Changes in PANSS scores were not significantly different (F(1,974) = 0.82, P = .366), but patients with TD showed less improvement in neurocognitive scores (F(1,359) = 6.53, P = .011). Among patients with TD, there were no significant differences between drugs in the decline in AIMS scores (F(3,151) = 0.32, P = .811); 55% met criteria for TD at 2 consecutive visits postbaseline, 76% met criteria for TD at some or all postbaseline visits, 24% did not meet criteria for TD at any subsequent visit, 32% showed a ≥ 50% decrease in AIMS score, and 7% showed a ≥ 50% increase in AIMS score. CONCLUSIONS Schizophrenia patients with and without TD were similar in time to discontinuation of treatment for any cause and improvement in psychopathology, but differed in neurocognitive response. There were no significant differences between treatments in the course of TD, with most patients showing either persistence of or fluctuation in observable symptoms. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00014001.

Traumatic brain injury and its neurobehavioral sequelae.

The neurobehavioral sequelae of TBI consist of a spectrum of somatic, neurologic, and psychiatric symptoms. The challenge for clinicians lies in understanding the interface of the various symptoms and how they interrelate with other entities. Specifically, the challenge is differentiating post-TBI-related symptoms from preexisting or de novo psychiatric, neurologic, and/or systemic disorders. A comprehensive evaluation and a multidisciplinary approach to evaluating patients are essential to be able to develop the differential diagnosis needed to design a management plan that maximizes recovery.

Traumatic Brain Injury and Its Neurobehavioral Sequelae

The neurobehavioral sequelae (NBS) of traumatic brain injury (TBI) consist of a spectrum of somatic, neurological, and psychiatric symptoms. The challenge for clinicians lies in understanding the interface of the various symptoms and how they interrelate with other entities. Specifically, the challenge is differentiating post-TBI-related symptoms from pre-existing or de novo psychiatric, neurological, and/or systemic disorders. A comprehensive evaluation and a multidisciplinary approach to evaluating patients are essential to be able to develop the differential diagnosis needed to design a management plan that maximizes recovery.

Executive summary of Concussion guidelines step 1: systematic review of prevalent indicators.

BACKGROUND: Currently, there is no evidence-based definition for concussion that is being uniformly applied in clinical and research settings. OBJECTIVE: To conduct a systematic review of the highest-quality literature about concussion and to assemble evidence about the prevalence and associations of key indicators of concussion. The goal was to establish an evidence-based foundation from which to derive, in future work, a definition, diagnostic criteria, and prognostic indicators for concussion. METHODS: Key questions were developed, and an electronic literature search from 1980 to 2012 was conducted to acquire evidence about the prevalence of and associations among signs, symptoms, and neurologic and cognitive deficits in samples of individuals exposed to potential concussive events. Included studies were assessed for potential for bias and confound and rated as high, medium, or low potential for bias and confound. Those rated as high were excluded from the analysis. Studies were further triaged on the basis of whether the definition of a case of concussion was exclusive or inclusive; only those with wide, inclusive case definitions were used in the analysis. Finally, only studies reporting data collected at fixed time points were used. For a study to be included in the conclusions, it was required that the presence of any particular sign, symptom, or deficit be reported in at least 2 independent samples. RESULTS: From 5437 abstracts, 1362 full-text publications were reviewed, of which 231 studies were included in the final library. Twenty-six met all criteria required to be used in the analysis, and of those, 11 independent samples from 8 publications directly contributed data to conclusions. Prevalent and consistent indicators of concussion are (1) observed and documented disorientation or confusion immediately after the event, (2) impaired balance within 1 day after injury, (3) slower reaction time within 2 days after injury, and/or (4) impaired verbal learning and memory within 2 days after injury. CONCLUSION: The results of this systematic review identify the consistent and prevalent indicators of concussion and their associations, derived from the strongest evidence in the published literature. The product is an evidence-based foundation from which to develop diagnostic criteria and prognostic indicators.

Disulfiram—Ethanol Induced Delirium

OBJECTIVE: To report a case of delirium, without major autonomic symptoms, as the primary manifestation of concomitant use of alcohol while taking disulfiram. CASE SUMMARY: A 50-year-old white woman with a history of bipolar disorder, type I, and alcohol dependence being treated with disulfiram was admitted to an inpatient psychiatric unit with a three- to four-day history of a change in mental status, including deficits in orientation, concentration, and visual hallucinations. Significant finding on review of systems included the spurious report of a 9.1kg weight loss. Tachycardia and nonfocal neurologic signs on physical examination were also noted. Extensive metabolic, infectious, and neurologic work-up revealed no abnormalities that alone could explain the patients acute confusional state. It was subsequently discovered that the patient had imbibed alcohol on at least two separate occasions while taking disulfiram prior to her change in mental status and that a similar, although shorter, experience had occurred previously. DISCUSSION: This is the first case, to the authors knowledge, that describes an acute confusional state as the primary manifestation of a patient taking alcohol while being prescribed disulfiram as aversive therapy for alcohol abuse. Possible pathophysiologic mechanisms for delirium as a complication of alcohol ingestion while taking disulfiram include disturbances in various neuroendocrine axes, neurotransmitter systems, and metabolic derangements. Other reports of possible neuropsychiatric complications of disulfiram therapy are also reviewed. CONCLUSIONS: The differential diagnosis for the presentation of delirium in a patient known to be undergoing aversive therapy for alcohol dependence with disulfiram should include nonadherence to alcohol abstinence.

Concussion and its neurobehavioural sequelae

Abstract A concussion results from a force to the brain that results in a transient loss of connectivity within the brain. Sport psychiatrists are increasingly called to be part of the concussion team and need to be prepared to manage issues related to concussion and its behavioural sequelae. Objectively, the best evidence available suggests that deficits in attention and/or in balance are the most reliable objective findings that a concussion has occurred. Prognosis after a concussion is generally very good, although a sub-set of patients that are yet well defined seem pre-disposed to delayed recovery. Neither head CT nor MRI are sufficiently sensitive to diagnose the type of injuries that pre-dispose patients to the neurobehavioural sequelae that have been associated with a concussion; confounding this is the finding that many of these signs and symptoms associated with concussion occur in other types of non-head injuries. Brain biomarkers and functional MRI (fMRI) hold promise in both diagnosis and prognosis of concussion, but are still research tools without validated clinical utility at this time. Finally, neurocognitive testing holds promise as a diagnostic criterion to demonstrate injury but, unfortunately, these tests are also limited in their prognostic utility and are of limited value.