A Randomized Controlled Trial of Mindfulness-Based Cognitive Therapy for Treatment-Resistant Depression.

BACKGROUND: Due to the clinical challenges of treatment-resistant depression (TRD), we evaluated the efficacy of mindfulness-based cognitive therapy (MBCT) relative to a structurally equivalent active comparison condition as adjuncts to treatment-as-usual (TAU) pharmacotherapy in TRD. METHODS: This single-site, randomized controlled trial compared 8-week courses of MBCT and the Health Enhancement Program (HEP), comprising physical fitness, music therapy and nutritional education, as adjuncts to TAU pharmacotherapy for outpatient adults with TRD. The primary outcome was change in depression severity, measured by percent reduction in the total score on the 17-item Hamilton Depression Rating Scale (HAM-D17), with secondary depression indicators of treatment response and remission. RESULTS: We enrolled 173 adults; mean length of a current depressive episode was 6.8 years (SD = 8.9). At the end of 8 weeks of treatment, a multivariate analysis showed that relative to the HEP condition, the MBCT condition was associated with a significantly greater mean percent reduction in the HAM-D17 (36.6 vs. 25.3%; p = 0.01) and a significantly higher rate of treatment responders (30.3 vs. 15.3%; p = 0.03). Although numerically superior for MBCT than for HEP, the rates of remission did not significantly differ between treatments (22.4 vs. 13.9%; p = 0.15). In these models, state anxiety, perceived stress and the presence of personality disorder had adverse effects on outcomes. CONCLUSIONS: MBCT significantly decreased depression severity and improved treatment response rates at 8 weeks but not remission rates. MBCT appears to be a viable adjunct in the management of TRD.

Genetic mapping using haplotype, association and linkage methods suggests a locus for severe bipolar disorder (BPI) at 18q22-q23.

Manic depressive illness, or bipolar disorder (BP), is characterized by episodes of elevated mood (mania) and depression. We designed a multistage study in the genetically isolated population of the Central Valley of Costa Rica to identify genes that promote susceptibility to severe BP (termed BPI), and screened the genome ot two Costa Rican BPI pedigrees (McInnes et al., submitted). We considered only individuals who fulfilled very stringent diagnostic criteria for BPI to be affected. The strongest evidence for a BPI locus was observed in 18q22-q23. We tested 16 additional markers in this region and seven yielded peak lod scores over 1.0. These suggestive lod scores were obtained over a far greater chromosomal length (about 40 cM) than in any other genome region. This localization is supported by marker haplotypes shared by 23 of 26 BPI affected individuals studied. Additionally, marker allele frequencies over portions of this region are significantly different in the patient sample from those of the general Costa Rican population. Finally, we performed an analysis which made use of both the evidence for linkage and for association in 18q23, and we observed significant lod scores for two markers in this region.

The effects of ketamine on symptoms of depression and anxiety in real-world care settings: A retrospective controlled analysis.

INTRODUCTION: Ketamine intravenous therapy (KIT) appears effective for treating depression in controlled trials testing a short series of infusions. A rapidly proliferating number of clinics offer KIT for depression and anxiety, using protocols without a strong evidence basis. Controlled comparison of mood and anxiety from real-world KIT clinics, and the stability of outcomes, is lacking. METHODS: We performed a retrospective controlled analysis on patients treated with KIT in ten community clinics across the US, between 08/2017-03/2020. Depression and anxiety symptoms were evaluated using the Quick Inventory of Depressive Symptomatology-Self Report 16-item (QIDS) and the Generalized Anxiety Disorder 7-item (GAD-7) scales, respectively. Comparison data sets from patients who did not undergo KIT were obtained from previously published real-world studies. RESULTS: Of 2758 patients treated, 714 and 836 met criteria for analysis of KIT induction and maintenance outcomes, respectively. Patients exhibited significant and concordant reduction in both anxiety and depression symptoms after induction (Cohen's d = -1.17 and d = -1.56, respectively). Compared to two external datasets of KIT-naive depressed patients or patients starting standard antidepressant therapy, KIT patients experienced a significantly greater reduction in depression symptoms at eight weeks (Cohen's d = -1.03 and d = -0.62 respectively). Furthermore, we identified a subpopulation of late-responders. During maintenance, up to a year post-induction, increases in symptoms were minimal. LIMITATIONS: Due to the retrospective nature of the analyses, interpreting this dataset is limited by incomplete patient information and sample attrition. CONCLUSIONS: KIT treatment elicited robust symptomatic relief that remained stable up to one year of follow-up.

A retrospective analysis of ketamine intravenous therapy for depression in real-world care settings.

BACKGROUND: Outcomes of ketamine intravenous therapy (KIT) for depression in real-world care settings have been minimally evaluated. We set out to quantify treatment response to KIT in a large sample of patients from community-based practices. METHODS: We retrospectively analyzed 9016 depression patients who received KIT between 2016 and 2020 at one of 178 community practices across the United States. Depression symptoms were evaluated using the Patient Health Questionnaire-9 (PHQ-9). The induction phase of KIT was defined to be a series of 4-8 infusions administered over 7 to 28 days. RESULTS: Among the 537 patients who underwent induction and had sufficient data, 53.6% of patients showed a response (≥ 50% reduction in PHQ-9 score) at 14-31 days post-induction and 28.9% remitted (PHQ-9 score drop to < 5). The effect size was d = 1.5. Among patients with baseline suicidal ideation (SI), 73.0% exhibited a reduction in SI. A subset (8.4%) of patients experienced an increase in depressive symptoms after induction while 6.0% of patients reported increased SI. The response rate was uniform across 4 levels of baseline depression severity. However, more severe illness was weakly correlated with a greater drop in scores while remission status was weakly inversely correlated with depression severity. Kaplan-Meier analyses showed that a patient who responds to KIT induction has approximately 80% probability of sustaining response at 4 weeks and approximately 60% probability at 8 weeks, even without maintenance infusions. CONCLUSION: KIT can elicit a robust antidepressant response in community clinics; however, a small percentage of patients worsened.

Novel trypanosome Trypanosoma gilletti sp. (Euglenozoa: Trypanosomatidae) and the extension of the host range of Trypanosoma copemani to include the koala ( Phascolarctos cinereus).

Trypanosoma irwini was previously described from koalas and we now report the finding of a second novel species, T. gilletti, as well as the extension of the host range of Trypanosoma copemani to include koalas. Phylogenetic analysis at the 18S rDNA and gGAPDH loci demonstrated that T. gilletti was genetically distinct with a genetic distance (± s.e.) at the 18S rDNA locus of 2.7 ± 0.5% from T. copemani (wombat). At the gGAPDH locus, the genetic distance (± s.e.) of T. gilletti was 8.7 ± 1.1% from T. copemani (wombat). Trypanosoma gilletti was detected using a nested trypanosome 18S rDNA PCR in 3/139 (∼2%) blood samples and in 2/29 (∼7%) spleen tissue samples from koalas whilst T. irwini was detected in 72/139 (∼52%) blood samples and T. copemani in 4/139 (∼3%) blood samples from koalas. In addition, naturally occurring mixed infections were noted in 2/139 (∼1.5%) of the koalas tested.

The potential impact of native Australian trypanosome infections on the health of koalas (Phascolarctos cinereus).

Whole blood collected from koalas admitted to the Australian Zoo Wildlife Hospital (AZWH), Beerwah, QLd, Australia, during late 2006-2009 was tested using trypanosome species-specific 18S rDNA PCRs designed to amplify DNA from Trypanosoma irwini, T. gilletti and T. copemani. Clinical records for each koala sampled were reviewed and age, sex, blood packed cell volume (PCV), body condition, signs of illness, blood loss, trauma, chlamydiosis, bone marrow disease, koala AIDS and hospital admission outcome ('survival'/ 'non-survival') were correlated with PCR results. Overall 73.8% (439/595) of the koalas were infected with at least 1 species of trypanosome. Trypanosoma irwini was detected in 423/595 (71.1%), T. gilletti in 128/595 (21.5%) and T. copemani in 26/595 (4.4%) of koalas. Mixed infections were detected in 125/595 (21%) with co-infections of T. irwini and T. gilletti (101/595, 17%) being most common. There was a statistical association between infection with T. gilletti with lower PCV values and body condition scores in koalas with signs of chlamydiosis, bone marrow disease or koala AIDS. No association between T. gilletti infection and any indicator of health was observed in koalas without signs of concurrent disease. This raises the possibility that T. gilletti may be potentiating other disease syndromes affecting koalas.

Mobility in Community Dwelling Older Adults: Predicting Successful Mobility Using an Instrumented Battery of Novel Measures.

Mobility in older adults is associated with better quality of life. However, evidence suggests that older people spend less time out-of-home than younger adults. Traditional methods for assessing mobility have serious limitations. Wearable technologies provide the possibility of objectively assessing mobility over extended periods enabling better estimates of levels of mobility to be made and possible predictors to be explored. Eighty-six community dwelling older adults (mean age 79.8 years) had their mobility assessed for one week using GPS, accelerometry and self-report. Outcomes were: number of steps, time spent in dynamic outdoor activity, total distance travelled and total number of journeys made over the week. Assessments were also made of personal, cognitive, psychological, physical and social variables. Four regression models were calculated (one for each outcome). The models predicted 32 to 43% of the variance in levels of mobility. The ability to balance on one leg significantly predicted all four outcomes. In addition, cognitive ability predicted number of journeys made per week and time spent engaged in dynamic outdoor activity, and age significantly predicted total distance travelled. Overall estimates of mobility indicated step counts that were similar to those shown by previous research but distances travelled, measured by GPS, were lower. These findings suggest that mobility in this sample of older adults is predicted by the ability to balance on one leg. Possible interventions to improve out-of-home mobility could target balance. The fact that participants travelled shorter distances than those reported in previous studies is interesting since this high-functioning subgroup would be expected to demonstrate the highest levels.

Trypanosoma irwini n. sp (Sarcomastigophora: Trypanosomatidae) from the koala ( Phascolarctos cinereus).

The morphology and genetic characterization of a new species of trypanosome infecting koalas (Phascolarctos cinereus) are described. Morphological analysis of bloodstream forms and phylogenetic analysis at the 18S rDNA and gGAPDH loci demonstrated this trypanosome species to be genetically distinct and most similar to Trypanosoma bennetti, an avian trypanosome with a genetic distance of 0.9% at the 18S rDNA and 10.7% at the gGAPDH locus. The trypanosome was detected by 18S rDNA PCR in the blood samples of 26 out of 68 (38.2%) koalas studied. The aetiological role of trypanosomes in koala disease is currently poorly defined, although infection with these parasites has been associated with severe clinical signs in a number of koalas. Based on biological and genetic characterization data, this trypanosome species infecting koalas is proposed to be a new species Trypanosome irwini n. sp.

Developmental expression profile of quaking, a candidate gene for schizophrenia, and its target genes in human prefrontal cortex and hippocampus shows regional specificity.

Decreased expression of oligodendrocyte/myelin-related (OMR) genes, including quaking (QKI), is a consistent finding in gene expression studies of post-mortem brain from subjects with schizophrenia, and these changes are most prominent in the hippocampus vs. the prefrontal cortex (PFC). Although expression of QKI and other OMR genes has been examined in rodents, little is known about their developmental trajectory in the human brain. Therefore, we examined expression of QKI and several putative mRNA targets of QKI in human PFC and hippocampus at different ages. The pattern of QKI expression in the PFC resembled that reported in rodents, with high QKI-5 in the fetal brain and an increase in QKI-6 and QKI-7 during the period of active myelination, although QKI-5 expression did not decrease substantially during postnatal development in the PFC in humans as it does in rodent brain. Most of the putative QKI target genes also showed linear increases in expression with increasing age in the PFC. In contrast, expression of these genes showed little evidence of developmental regulation in the hippocampus. Correlations between expression levels of the nuclear vs. cytoplasmic QKI isoforms, and putative splicing targets of the former, also differed between tissues. Thus, we speculate that a robust increase in OMR gene expression normally occurs with age in the PFC, but not in the hippocampus, which may explain why decreases in OMR gene expression in schizophrenia are more pronounced in the latter tissue. We also suggest that OMR transcripts might be processed by different splicing proteins in different tissues.

Mapping genes for psychiatric disorders and behavioral traits.

In the past year, some of the most exciting findings in the genetic investigation of mammalian behavior have been obtained through mapping and through gene manipulation studies in the mouse system. These include the localization of a gene for circadian periodicity in the mouse, gene knockouts of serotonin receptors, and the development of a transgenic model of Alzheimer's disease. The recent development of genetic maps covering the entire human genome and the implementation of new approaches to genetic analysis may now facilitate elucidation of complex behaviors in humans, particularly psychiatric disorders.

Mapping genes for psychiatric disorders and behavioral traits.

In the past year, findings from genetic studies in non-human organisms have yielded a number of exciting insights regarding the genetic basis of complex behaviors. Although there were encouraging developments in the genetic study of human behavioral traits, particularly those involved with cognitive function, there was relatively little progress in genetic mapping of the most common psychiatric phenotypes.

Duplication of 17(p11.2p11.2) in a male child with autism and severe language delay.

Duplications of 17(p11.2p11.2) have been associated with various behavioral manifestations including attention deficits, obsessive-compulsive symptoms, autistic traits, and language delay. We are conducting a genetic study of autism and are screening all cases for submicroscopic chromosomal abnormalities, in addition to standard karyotyping, and fragile X testing. Using array-based comparative genomic hybridization analysis of data from the Affymetrix GeneChip(R) Human Mapping Array set, we detected a duplication of approximately 3.3 Mb on chromosome 17p11.2 in a male child with autism and severe expressive language delay. The duplication was confirmed by measuring the copy number of genomic DNA using quantitative polymerase chain reaction. Gene expression analyses revealed increased expression of three candidate genes for the Smith-Magenis neurobehavioral phenotype, RAI1, DRG2, and RASD1, in transformed lymphocytes from Case 81A, suggesting gene dosage effects. Our results add to a growing body of evidence suggesting that duplications of 17(p11.2p11.2) result in language delay as well as autism and related phenotypes. As Smith-Magenis syndrome is also associated with language delay, a gene involved in acquisition of language may lie within this interval. Whether a parent of origin effect, gender of the case, the presence of allelic variation, or changes in expression of genes outside the breakpoints influence the resultant phenotype remains to be determined.

An atypical deletion of the Williams-Beuren syndrome interval implicates genes associated with defective visuospatial processing and autism.

BACKGROUND: During a genetic study of autism, a female child who met diagnostic criteria for autism spectrum disorder, but also exhibited the cognitive-behavioural profile (CBP) associated with Williams-Beuren syndrome (WBS) was examined. The WBS CBP includes impaired visuospatial ability, an overly friendly personality, excessive non-social anxiety and language delay. METHODS: Using array-based comparative genomic hybridisation (aCGH), a deletion corresponding to BAC RP11-89A20 in the distal end of the WBS deletion interval was detected. Hemizygosity was confirmed using fluorescence in situ hybridisation and fine mapping was performed by measuring the copy number of genomic DNA using quantitative polymerase chain reaction. RESULTS: The proximal breakpoint was mapped to intron 1 of GTF2IRD1 and the distal breakpoint lies 2.4-3.1 Mb towards the telomere. The subject was completely hemizygous for GTF2I, commonly deleted in carriers of the classic approximately 1.5 Mb WBS deletion, and GTF2IRD2, deleted in carriers of the rare approximately 1.84 Mb WBS deletion. CONCLUSION: Hemizygosity of the GTF2 family of transcription factors is sufficient to produce many aspects of the WBS CBP, and particularly implicate the GTF2 transcription factors in the visuospatial construction deficit. Symptoms of autism in this case may be due to deletion of additional genes outside the typical WBS interval or remote effects on gene expression at other loci.

Molecular characterization of Babesia kiwiensis from the brown kiwi (Apteryx mantelli).

To further investigate the recently described avian piroplasm, Babesia kiwiensis, blood samples were collected from 13 wild-caught and 8 zoo-captive brown kiwi (Apteryx mantelli) and screened for the presence of piroplasm DNA using a nested-polymerase chain reaction (PCR) targeting the 18S rRNA gene of most members of Piroplasmida. All captive birds gave a negative PCR result, while 12 wild-caught birds were PCR positive. The nearly full-length 18S rRNA gene for B. kiwiensis was sequenced. Upon phylogenetic analysis, it was found to belong to the babesid group of piroplasms and was ancestral, yet genetically similar, to the Babesia canis-related species. An insight into the current taxonomy of the avian piroplasms is also given. An Ixodes anatis tick collected from 1 of the North Island brown kiwi was also screened using PCR and was found to be positive for B. kiwiensis DNA.

A quantitative regional expression profile of EAAT2 known and novel splice variants reopens the question of aberrant EAAT2 splicing in disease.

The glutamate transporter 1 (GLT1) in rodents, or EAAT2 in humans, is alternatively spliced in a complex manner including the use of multiple 5' and 3' untranslated regions and several coding variants. We used quantitative RT-PCR to profile these splice variants in human and rat brain. We also used RT-PCR and Northern blotting to demonstrate that a novel isoform of GLT1b has an approximately 11kb 3' UTR extending through intron 9, exon 10 and approximately 5kb into the 3' untranslated region of GLT1. However, our most important finding concerns an aberrant transcript lacking exon 9, which contains a motif permitting translocation from the endoplasmic reticulum. This variant had previously been associated with amyotrophic lateral sclerosis until several groups reported high levels in normal brain tissue. In contrast, our data shows that this aberrant transcript is present at 0.1-0.2% of the major EAAT2 isoforms.

Early rapid rise in EAAT2 expression follows the period of maximal seizure susceptibility in human brain.

Seizures are relatively common in the first weeks of life and can have lasting effects on brain development due to glutamate excitotoxicity. The excitatory amino acid transporter 2 (EAAT2) is responsible for the majority of glutamate uptake in the brain and mice with this gene deleted die from seizures. Therefore, we reasoned that developmental changes in the expression of EAAT2 might correlate with the period of increased susceptibility to seizures in humans, reflecting a changing vulnerability to excitotoxic insults. Expression levels of eight splice forms of EAAT2 were measured using quantitative RT-PCR from human prefrontal cortex and hippocampus at 1-2 months, 1-2 years, 8 years, 15-16 years, and 18-22 years of age. There was a significant increase in expression of most isoforms between 1-2 months and 1-2 years with isoform-specific patterns after that period. The increase in EAAT2 expression during the first 2 years of life corresponds to a period of maximal synapse formation and other changes in the glutamatergic system such as increased NMDA receptor expression. Moreover, the low expression of EAAT2 in the first months of life corresponds to the period of maximum susceptibility to seizures.

RNA metabolism and dysmyelination in schizophrenia.

Decreased expression of a subset of oligodendrocyte and myelin-related genes is the most consistent finding among gene expression studies of postmortem brain tissue from subjects with schizophrenia (SCZ), although heritable variants have yet to be found that can explain the bulk of this data. However, expression of the glial gene Quaking (QKI), encoding an RNA binding (RBP) essential for myelination, was recently found to be decreased in SCZ brain. Both oligodendrocyte/myelin related genes, and other RBPs that are known or predicted to be targets of QKI, are also decreased in SCZ. Two different quaking mutant mice share some pathological features in common with SCZ, including decreased expression of myelin-related genes and dysmyelination, without gross destruction of white matter. Therefore, although these mice are not a model of SCZ per se, understanding the similarities and differences in gene expression between brains from these mice and subjects with SCZ could help parse out distinct genetic pathways underlying SCZ.

Quantitative analysis of glutamate transporter mRNA expression in prefrontal and primary visual cortex in normal and schizophrenic brain.

Abnormalities of the glutamatergic system in schizophrenia have been identified in numerous studies, but little is known about the role of glutamate transporters and their messenger RNA (mRNA) expression. In addition, the abundances of the two major isoforms of human excitatory amino acid transporter 2 (EAAT2) or its rat ortholog, glutamate transporter 1, have never been compared in a quantitative manner. Using quantitative reverse transcription-polymerase chain reaction, we established that the expression of the EAAT1, EAAT2a, EAAT2b, and EAAT3 transcripts was not different in the dorsolateral prefrontal and primary visual cortices of persons with schizophrenia relative to matched controls. EAAT2a expression was about 25-fold and 10-fold higher than EAAT2b in human and rat brain, respectively. The data provided no evidence of an effect of antipsychotic medications on the mRNA expression of the glutamate transporters. However, because most of the schizophrenic subjects in the cohort had been treated with antipsychotics for many years, it is still possible that changes in transporter expression were masked by medication effects.