Pharmacogenomic testing and outcome among depressed patients in a tertiary care outpatient psychiatric consultation practice

The authors tested the hypothesis that pharmacogenomic genotype knowledge is associated with better clinical and cost outcomes in depressed patients, after controlling for other factors that might differentiate tested and non-tested patients. Medical records of 251 patients, seen in the Mayo Clinic Rochester outpatient psychiatric practice, who had patient health questionnaire-9 (PHQ-9) scores before and after consultation, were reviewed. Comparisons of differences in pre-consultation and post-consultation depression scores and slopes between tested and non-tested patients and between genotype categories of tested patients, were evaluated, along with healthcare cost and utilization comparisons between tested and non-tested patients, using Kruskal–Wallis tests, Wilcoxon rank-sum tests and group mean comparisons, controlling for significant univariate demographic and clinical differences. Tested patients had significantly higher depression diagnosis frequency, baseline PHQ-9 scores, family history of depression, psychiatric hospitalization history, and higher numbers of antidepressant, mood stabilizer and antipsychotic medication trials. After controlling for these differences, there were no differences between tested and non-tested patients in post-baseline depression scores or slopes for CYP genotype categories. For patients with 5-HTTLPR testing, there was significantly more depression score improvement for patients with the long/long genotype at time 4 (N=55, χ2-value=8.0492, P=0.018) and at time 5 (N=44, χ2-value=6.1492, P=0.046). For a subgroup (n=46) with ⩾two pre- and ⩾two post-baseline PHQ-9 scores, the mean difference between pre-baseline and post-baseline PHQ-9 score slopes for tested patients was −0.08 (median −0.01; range −1.20 to 0.15) compared with 0.13 (median 0.02; range −0.18 to 2.16) for non-tested patients (P=0.03). Among genotype categories, mean differences between pre-consultation and post-consultation slopes were significantly better for poor CYP2D6 metabolizers than intermediate or extensive metabolizers (P=0.04); there was a trend for slope differences to be better for 5-HTTLPR long/long genotype patients (P=0.06). Subsets of local tested and consultant-adjusted non-tested controls (n=19), who had 8 years of longitudinal care within the health system, had similar overall mean healthcare costs before and after testing; however, tested patients on average had significantly fewer time-adjusted post-baseline psychiatric admissions (0.8 vs 3.8, P=0.04) and fewer time-adjusted psychiatric consultations and comprehensive mental health-specialty evaluations (4.2 vs 9.9, P=0.03). Prospective study is indicated as to whether and how pharmacogenomic testing in a psychiatric consultation practice may improve clinical and cost outcomes

Identification of children who may benefit from self-hypnosis at a pediatric pulmonary center

BACKGROUND: Emotional difficulties can trigger respiratory symptoms. Thus, children presenting with respiratory complaints may benefit from a psychological intervention. The purpose of this study was to define the proportion of patients referred to a Pediatric Pulmonary Center who may benefit from instruction in self-hypnosis, as a psychological intervention. METHODS: A retrospective chart review was conducted for all newly referred patients to the SUNY Upstate Medical University Pediatric Pulmonary Center during an 18 month period beginning January 1, 2000. Patients were offered hypnosis if they presented with symptoms or signs suggestive of psychological difficulties. Hypnosis was taught in one or two 15–45 minute sessions by a pediatric pulmonologist. RESULTS: Of 725 new referrals, 424 were 0–5 years old, 193 were 6–11 years old, and 108 were 12–18 years old. Diagnoses of anxiety, habit cough, or vocal cord dysfunction accounted for 1% of the 0–5 year olds, 20% of the 6–11 year olds, and 31% of the 12–18 year olds. Hypnotherapy was offered to 1% of 0–5 year olds, 36% of 6–11 year olds, and 55% of 12–18 year olds. Of 81 patients who received instruction in self-hypnosis for anxiety, cough, chest pain, dyspnea, or inspiratory difficulties, 75% returned for follow-up, and among the returning patients 95% reported improvement or resolution of their symptoms. CONCLUSION: A large number of patients referred to a Pediatric Pulmonary Center appeared to benefit from instruction in self-hypnosis, which can be taught easily as a psychological intervention

Simultaneous genotyping of multiple polymorphisms in human serotonin transporter gene and detection of novel allelic variants

The serotonin transporter, called SLC6A4, SERT or 5-HTT, modulates neurotransmission by removal of serotonin from the synapse of serotonergic neurons, facilitating serotonin reuptake into the presynaptic terminus. Selective serotonin reuptake inhibitors block the action of the serotonin transporter and are used to treat depression and other neuropsychiatric disorders. Three polymorphisms in the 5-HTT gene have been implicated in treatment response and neuropsychiatric disorders. A 44-bp promoter ins/del polymorphism (5-HTTLPR) produces primarily long and/or short alleles due to either 14 (short) or 16 (long) repeats of variably conserved 20–23 bp units. Also implicated, a 17–18 bp variable number tandem repeat found in intron2 (StIn2) is expressed as triallelic content with 9, 10, or 12 repeats (StIn2.9, StIn2.10 or StIn2.12). Finally, a single nucleotide polymorphism rs25531 located within the promoter polymorphic-linked region alters the function of the long promoter allele. We developed a PCR-based fragment analysis assay, which is analyzed on an ABI sequencer, whereby we are able to detect all three genotypes simultaneously. Using this technique, we identified novel sequences, which demonstrate promoter repeat regions containing (1) a 17 repeat with rs25531 A/G polymorphism, (2) two with 18-repeat units, (3) one with 20-repeat units and (4) a 24-repeat sequence. The novel repeats were confirmed by direct sequencing of gel-purified amplicons

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Expression and Processing of a Small Nucleolar RNA from the Epstein-Barr Virus Genome

Small nucleolar RNAs (snoRNAs) are localized within the nucleolus, a sub-nuclear compartment, in which they guide ribosomal or spliceosomal RNA modifications, respectively. Up until now, snoRNAs have only been identified in eukaryal and archaeal genomes, but are notably absent in bacteria. By screening B lymphocytes for expression of non-coding RNAs (ncRNAs) induced by the Epstein-Barr virus (EBV), we here report, for the first time, the identification of a snoRNA gene within a viral genome, designated as v-snoRNA1. This genetic element displays all hallmark sequence motifs of a canonical C/D box snoRNA, namely C/C′- as well as D/D′-boxes. The nucleolar localization of v-snoRNA1 was verified by in situ hybridisation of EBV-infected cells. We also confirmed binding of the three canonical snoRNA proteins, fibrillarin, Nop56 and Nop58, to v-snoRNA1. The C-box motif of v-snoRNA1 was shown to be crucial for the stability of the viral snoRNA; its selective deletion in the viral genome led to a complete down-regulation of v-snoRNA1 expression levels within EBV-infected B cells. We further provide evidence that v-snoRNA1 might serve as a miRNA-like precursor, which is processed into 24 nt sized RNA species, designated as v-snoRNA124pp. A potential target site of v-snoRNA124pp was identified within the 3′-UTR of BALF5 mRNA which encodes the viral DNA polymerase. V-snoRNA1 was found to be expressed in all investigated EBV-positive cell lines, including lymphoblastoid cell lines (LCL). Interestingly, induction of the lytic cycle markedly up-regulated expression levels of v-snoRNA1 up to 30-fold. By a computational approach, we identified a v-snoRNA1 homolog in the rhesus lymphocryptovirus genome. This evolutionary conservation suggests an important role of v-snoRNA1 during γ-herpesvirus infection

Mood instability and irritability as core symptoms of major depression : an exploration using Rasch analysis

Background: Mood instability (MI) and irritability are related to depression but are not considered core symptoms. Instruments typically code clusters of symptoms that are used to define syndromic depression, but the place of MI and irritability has been under-investigated. Whether they are core symptoms can be examined using Rasch analysis. Method: We used the UK Psychiatric Morbidity Survey 2000 data (n = 8,338) to determine whether the nine ICD/DSM symptoms, plus MI and irritability, constitute a valid depression scale. Rasch analysis was used, a method concerned with ensuring that items constitute a robust scale and tests whether the count of symptoms reflects an underlying interval-level measure. Two random samples of 500 were drawn, serving as calibration and validation samples. As part of the analysis, we examined whether the candidate symptoms were unidimensional, followed a Guttman pattern, were locally independent, invariant with respect to age and sex, and reliably distinguished different levels of depression severity. Results: A subset of five symptoms (sad, no interest, sleep, cognition, suicidal ideas) together with mood instability and irritability satisfactorily fits the Rasch model. However, these seven symptoms do not separate clinically depressed persons from the rest of the population with adequate reliability (Cronbach α = 0.58; Person Separation Index = 0.35), but could serve as a basis for scale development. Likewise, the original nine DSM depression symptoms failed to achieve satisfactory reliability (Cronbach α = 0.67; Person Separation Index = 0.51). Limitations: The time frame over which symptoms were experienced varied, and some required recall over the last year. Symptoms other than those examined here might also be core depression symptoms. Conclusion: Mood instability and irritability are candidate core symptoms of the depressive syndrome and should be part of its clinical assessment

5-HTTLPR Polymorphism Impacts Task-Evoked and Resting-State Activities of the Amygdala in Han Chinese

Background: Prior research has shown that the amygdala of carriers of the short allele (s) of the serotonin transporter (5-HTT) gene (5-HTTLPR) have a larger response to negative emotional stimuli and higher spontaneous activity during the resting state than non-carriers. However, recent studies have suggested that the effects of 5-HTTLPR may be specific to different ethnic groups. Few studies have been conducted to address this issue. Methodology/Principal Findings: Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) was conducted on thirty-eight healthy Han Chinese subjects (l/l group, n = 19; s/s group, n = 19) during the resting state and during an emotional processing task. Compared with the s/s group, the l/l group showed significantly increased regional homogeneity or local synchronization in the right amygdala during the resting state (|t|.2.028, p,0.05, corrected), but no significant difference was found in the bilateral amygdala in response to negative stimuli in the emotional processing task. Conclusions/Significance: 5-HTTLPR can alter the spontaneous activity of the amygdala in Han Chinese. However, the effect of 5-HTTLPR on the amygdala both in task state and resting state in Asian population was no similar with Caucasians. The