Discovery and validation of blood biomarkers for suicidality.

Suicides are a leading cause of death in psychiatric patients, and in society at large. Developing more quantitative and objective ways (biomarkers) for predicting and tracking suicidal states would have immediate practical applications and positive societal implications. We undertook such an endeavor. First, building on our previous blood biomarker work in mood disorders and psychosis, we decided to identify blood gene expression biomarkers for suicidality, looking at differential expression of genes in the blood of subjects with a major mood disorder (bipolar disorder), a high-risk population prone to suicidality. We compared no suicidal ideation (SI) states and high SI states using a powerful intrasubject design, as well as an intersubject case-case design, to generate a list of differentially expressed genes. Second, we used a comprehensive Convergent Functional Genomics (CFG) approach to identify and prioritize from the list of differentially expressed gene biomarkers of relevance to suicidality. CFG integrates multiple independent lines of evidence-genetic and functional genomic data-as a Bayesian strategy for identifying and prioritizing findings, reducing the false-positives and false-negatives inherent in each individual approach. Third, we examined whether expression levels of the blood biomarkers identified by us in the live bipolar subject cohort are actually altered in the blood in an age-matched cohort of suicide completers collected from the coroner's office, and report that 13 out of the 41 top CFG scoring biomarkers (32%) show step-wise significant change from no SI to high SI states, and then to the suicide completers group. Six out of them (15%) remained significant after strict Bonferroni correction for multiple comparisons. Fourth, we show that the blood levels of SAT1 (spermidine/spermine N1-acetyltransferase 1), the top biomarker identified by us, at the time of testing for this study, differentiated future as well as past hospitalizations with suicidality, in a live cohort of bipolar disorder subjects, and exhibited a similar but weaker pattern in a live cohort of psychosis (schizophrenia/schizoaffective disorder) subjects. Three other (phosphatase and tensin homolog (PTEN), myristoylated alanine-rich protein kinase C substrate (MARCKS), and mitogen-activated protein kinase kinase kinase 3 (MAP3K3)) of the six biomarkers that survived Bonferroni correction showed similar but weaker effects. Taken together, the prospective and retrospective hospitalization data suggests SAT1, PTEN, MARCKS and MAP3K3 might be not only state biomarkers but trait biomarkers as well. Fifth, we show how a multi-dimensional approach using SAT1 blood expression levels and two simple visual-analog scales for anxiety and mood enhances predictions of future hospitalizations for suicidality in the bipolar cohort (receiver-operating characteristic curve with area under the curve of 0.813). Of note, this simple approach does not directly ask about SI, which some individuals may deny or choose not to share with clinicians. Lastly, we conducted bioinformatic analyses to identify biological pathways, mechanisms and medication targets. Overall, suicidality may be underlined, at least in part, by biological mechanisms related to stress, inflammation and apoptosis.

Behavioral rehabilitation and the reduction of aggressive and self-injurious behaviors with cognitively impaired, chronic psychiatric inpatients.

Aggressive behavior has been identified as a significant concern and occupational hazard in psychiatric inpatient settings. Several factors, including lax or unclear ward structure, have been identified as contributing to the exhibition of aggressive behavior. Token economies are effective in increasing ward structure and reducing aggressive behavior. This study evaluated the effects of rehabilitation programming, based on Gordon Paul's social learning approach (SLA), on rates of aggressive and self-injurious behaviors in a group of cognitively impaired, chronic psychiatric inpatients, compared to three long-term wards of similar patients. While no differences were found between the two groups prior to implementing SLA procedures, lower rates of aggression and self-injurious behavior were observed at one and two years on the Paul-derived ward. These results support the use of Paul's approach with multiply-impaired psychiatric inpatients in reducing patient aggression.

Improvements in cognitive functioning following intensive behavioural rehabilitation.

Serial evaluation of intelligence tests performed with long-term patients in psychiatric hospitals frequently reveal deterioration in cognitive functioning. Despite early success in the amelioration of cognitive symptoms of schizophrenia, little effort at cognitive remediation is currently directed to long-term psychiatric patients. In contrast, in the brain injury rehabilitation community, cognitive remediation is strongly supported despite mixed results in clinical literature. Within this context, individuals with brain injury in psychiatric hospitals may have little prospect of receiving cognitive remediation services. Utilizing performance on intelligence testing spanning 20 years, the following study evaluates changes in cognitive functioning of a severely brain injured individual, who had been replaced in a long-term psychiatric hospital and treated in an intensive behavioural rehabilitation programme. Results found that the patient demonstrated a significant improvement in overall verbal and nonverbal cognitive functioning during treatment. These improvements were maintained for a 1-year period. It was suggested that the use of 'low tech', small group interventions, within intensive behavioural rehabilitation programmes, may lead to the recovery of cognitive functioning for individuals who are significantly post-injury.

The use of lithium in the treatment of aggressive behaviours with two brain-injured individuals in a state psychiatric hospital.

Brain-injured individuals often experience problems with aggression which can prevent full community reintegration. Two cases involving individuals (one 4 years, one 17 years post-injury) who had been placed in a state psychiatric hospital due to aggressive and/or self-injurious behaviours are discussed. Utilizing medication dosages and behavioural acuity indicators over a 2 year period, the authors demonstrate the efficacy of lithium carbonate in treating aggressive behaviours. Lithium, in concert with other medications, not only led to a decrease in the frequency of aggressive outbursts and in the need for restrictive and costly behaviour control techniques, but also allowed for a significant reduction in the use of neuroleptic medication in one case. The authors conclude that the use of lithium, within the context of an intensive, behavioural rehabilitation programme, may yield positive effects in the control of aggressive behaviour even in long-term post-injury cases.