Mapping Systematic Reviews on Forensic Psychiatric Care: A Systematic Review Identifying Knowledge Gaps

Background: Forensic psychiatric care treats mentally disordered offenders who suffer mainly from psychotic disorders, although comorbidities such as personality disorders, neurodevelopmental disorders, and substance abuse are common. A large proportion of these patients have committed violent crimes. Their care is involuntary, and their caregivers' mission is complex: not only to rehabilitate the patient, but also to consider their risk for reoffending and their risk to society. The objective of this overview of systematic reviews is to identify, appraise, and summarize the existing knowledge in forensic psychiatric care and identify knowledge gaps that require further research.Methods: We undertook a systematic literature search for systematic reviews in five defined domains considered important in daily clinical practice within the forensic psychiatric care: (1) diagnostic assessment and risk assessments; (2) pharmacological treatment; (3) psychological interventions; (4) psychosocial interventions, rehabilitation, and habilitation; and (5) restraint interventions. The target population was mentally disordered offenders (forensic psychiatric patients aged >15 years). Each abstract and full text review was assessed by two of the authors. Relevant reviews then were assessed for bias, and those with moderate or low risk of bias were included.Results: Of 38 systematic reviews meeting the inclusion criteria, only four had a moderate risk of bias. Two aimed to incorporate as many aspects of forensic psychiatric care as possible, one investigated non-pharmacological interventions to reduce aggression in forensic psychiatric care, and one focused on women with intellectual disabilities in forensic care. However, most of the primary studies included in these reviews had high risks of bias, and therefore, no conclusions could be drawn. All of our identified domains must be considered knowledge gaps.Conclusion: We could not answer any of our research questions within the five domains because of the high risk of bias in the primary studies in the included systematic reviews. There is an urgent need for more research on forensic psychiatric care since all of our studied domains were considered knowledge gaps

Studies on nuclear receptors involved in drug metabolism

The molecular basis for drug metabolism is starting to emerge as a result of cloning and characterization of a group of nuclear receptors that respond to drugs by transcriptional regulation of key genes encoding enzymes involved in metabolism of commonly used drugs. This thesis describes the identification and functional, as well as the structural, characterization of one of these receptors, the human pregnenolone activated receptor (hPAR, NR1I2) that also has been referred to as the pregnane X receptor (PXR) or the steroid and xenobiotic receptor (SXR) by others. Functional characterization of this, and the closely related, constitutively active receptor CAR (NR1I3) has shown that both PXR and CAR are important for cytochrome P450 gene induction and thus are likely to be important mediators of drug metabolism. PXR was identified by homology searching of human EST databases and two differentially spliced mRNAs were cloned. The expression was high in liver and intestine, and PXR was activated by a large and chemically diverse group of compounds including drugs metabolized by CYP3A4. A transient transfection study using an expression plasmid for PXR together with a luciferase reporter construct, containing a part of the CYP3A4 promoter (- 176 to - 146), showed that PXR induced the expression of this reporter. Based on this study we suggested that PXR was a novel sensor for sterol and xenobiotic metabolism. To further investigate the regulatory role of PXR in CYP3A induction we cloned approximately 10 kb of both the CYP3A7 and the CYP3A4 gene promoters. These two promoters exhibited 90 % sequence identity up to -8,8 kb, indicating a close evolutionary distance between the two genes. A combination of promoter deletion analyses and transient transfections suggests that PYCR and CAR are important for CYP3A4 and CYP3A7 gene induction through a functionally conserved distally located xenobiotic responsive enhancer module. Taken together, we propose that PXR and CAR play important roles in xenobiotic regulation, not only for CYP3A4 regulation in adults, but also for CYP3A7 to protect the embryo against endogenous and exogenous toxins. The chemically broad activation profile of PXR suggested that this receptor could be structurally related to the PPARs (NR1C1-3), another subgroup of orphan nuclear receptors with promiscuous ligand binding proper-ties. We found from the crystal structure of the PPAR gamma ligand binding domain that this receptor has a larger and more accessible ligand binding pocket than other nuclear receptors binding to a structurally more limited set of ligands. We also made a model of the ligand binding domain of PXR based on the available co-crystal structure of VDR (NR1I1), and 1alpha 25-dihydroxyvitamin D3. The model indicated important residues of the ligand binding pocket of PXR. We mutated polar residues from human to mouse and tested them in transient transfection in combination with species specific compounds. The results have increased our understanding for species specific ligand binding to PXR. In addition, we also made a single point mutation in PYR that yielded a constitutive active form of the receptor. PPARgamma agonists belonging to the thiazolidinedione (TZD) class of compounds are currently used for treatment of diabetes type 2. Troglitazone, a TZD, is known to induce CYP3A4 activity. The TZI)s troglitazone, pioglitazone and rosiglitazone were all found to activate PXR on a CYP3A4 promoter. Furthermore an insulin sensitizing non-TZD ligand, JTT-501, did not activate the nuclear receptor PXR but dually activated PPAR alpha and gamma. Therefore JTT is less likely to mediate drug- interactions due to PXR mediated CYP3A4 induction. In conclusion, screening against PXR activation is predicted to be a valuable tool in pre-clinical drug development to obtain better and safer drugs

Psychological Treatment of Depression in People Aged 65 Years and Over : A Systematic Review of Efficacy, Safety, and Cost-Effectiveness.

OBJECTIVES: Depression in elderly people is a major public health concern. As response to antidepressants is often unsatisfactory in this age group, there is a need for evidence-based non-pharmacological treatment options. Our objectives were twofold: firstly, to synthesize published trials evaluating efficacy, safety and cost-effectiveness of psychological treatment of depression in the elderly and secondly, to assess the quality of evidence. METHOD: The electronic databases PubMed, EMBASE, Cochrane Library, CINAL, Scopus, and PsycINFO were searched up to 23 May 2016 for randomized controlled trials (RCTs) of psychological treatment for depressive disorders or depressive symptoms in people aged 65 years and over. Two reviewers independently assessed relevant studies for risk of bias. Where appropriate, the results were synthesized in meta-analyses. The quality of the evidence was graded according to GRADE (Grading of Recommendations Assessment, Development and Evaluation). RESULTS: Twenty-two relevant RCTs were identified, eight of which were excluded from the synthesis due to a high risk of bias. Of the remaining trials, six evaluated problem-solving therapy (PST), five evaluated other forms of cognitive behavioural therapy (CBT), and three evaluated life review/reminiscence therapy. In frail elderly with depressive symptoms, the evidence supported the efficacy of PST, with large but heterogeneous effect sizes compared with treatment as usual. The results for life-review/reminiscence therapy and CBT were also promising, but because of the limited number of trials the quality of evidence was rated as very low. Safety data were not reported in any included trial. The only identified cost-effectiveness study estimated an incremental cost per additional point reduction in Beck Depression Inventory II score for CBT compared with talking control and treatment as usual. CONCLUSION: Psychological treatment is a feasible option for frail elderly with depressive symptoms. However, important questions about efficacy, generalizability, safety and cost-effectiveness remain.Funding agencies: Swedish Agency for Health Technology Assessment and Assessment of Social Services, SBU; Swedish Agency for Health Technology Assessment and Assessment of Social Services</p

Oral Microbiota Development in Early Childhood

Early life determinants of the oral microbiota have not been thoroughly elucidated. We studied the association of birth and early childhood characteristics with oral microbiota composition using 16 S ribosomal RNA (rRNA) gene sequencing in a population-based Swedish cohort of 59 children sampled at 6, 12 and 24 months of age. Repeated-measurement regression models adjusted for potential confounders confirmed and expanded previous knowledge about the profound shift of oral microbiota composition in early life. These alterations included increased alpha diversity, decreased beta diversity and alteration of bacterial composition with changes in relative abundance of 14 of the 20 most common operational taxonomic units (OTUs). We also found that birth characteristics, breastfeeding and antibiotic use were associated with overall phyla distribution and/or with the relative abundance of specific OTUs. Further, we detected a novel link between morning salivary cortisol level, a physiological marker of neuroendocrine activity and stress, and overall phyla distribution as well as with decreased abundance of the most common OTU mapped to the Streptococcaceae family. In conclusion, a major part of the maturation of the oral microbiome occurs during the first two years of life, and this development may be influenced by early life circumstances

Meta-analysis of randomized controlled trials of problem-solving therapy (PST) vs. supportive therapy (ST) for elderly with a depressive disorder.

<p>Meta-analysis of randomized controlled trials of problem-solving therapy (PST) vs. supportive therapy (ST) for elderly with a depressive disorder.</p