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.
•Response to ketamine induction in the community is ∼ 50%; remission rate is 30%.•8% of patients worsen during ketamine induction for depression.•Ketamine induction reduces suicidal ideation in a ...majority of patients.•Durability of antidepressant response after ketamine induction is ∼ 60% at 8 weeks.
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.
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.
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.
KIT can elicit a robust antidepressant response in community clinics; however, a small percentage of patients worsened.
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.
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.
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.
Due to the retrospective nature of the analyses, interpreting this dataset is limited by incomplete patient information and sample attrition.
KIT treatment elicited robust symptomatic relief that remained stable up to one year of follow-up.
•Depression and anxiety outcomes data for KIT are highly concordant and stable over time.•Eighty percent of the patients had SI pretreatment and 50% had no SI at all after KIT induction.
Identifying genes involved in social behavior is important for autism research. Williams–Beuren syndrome (WBS) is a developmental syndrome with unique neurocognitive features, including low IQ, ...deficits in visuospatial and visual‐motor abilities, hypersensitivity to sounds, hypersociability, and increased general anxiety. The syndrome is caused by a recurrent hemizygous deletion of the 7q11.23 region, containing about 28 genes. One of genes in the region, GTF2I, has been implicated in the hypersociability and visuospatial deficits of WBS based on genotype–phenotype correlation studies of patients with atypical deletions. In order to clarify the involvement of GTF2I in neurocognitive function, especially social behavior, we have developed and characterized Gtf2i‐deficient mice. We found that homozygous deletion of Gtf2i causes lethality during embryonic development with neural tube closure defects and exencephaly, consistent with other reports. Gtf2i heterozygous animals show no gross changes in brain structure or development. Furthermore, heterozygous animals show no alterations in learning and memory, including spatial memory as assessed by the Morris water maze, but show alterations in the recognition of novel objects. Interestingly, they show increased social interaction with unfamiliar mice and do not show typical social habituation processes, reminiscent of the hypersociability observed in WBS patients. The mice do not appear to show increased anxiety, supporting a specific effect of Gtf2i on defined domains of the WBS phenotype. These data indicate that Gtf2i is involved in several aspects of embryonic development and the development of social neurocircuitry and that GTF2I haploinsufficiency could be a contributor to the hypersociability in WBS patients.
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 ∼1.5 Mb WBS deletion, and GTF2IRD2, deleted in carriers of the rare ∼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.
RNA metabolism and dysmyelination in schizophrenia McInnes, L. Alison; Lauriat, Tara L.
Neuroscience and biobehavioral reviews,
2006, 2006-00-00, 2006-1-00, 20060101, Volume:
30, Issue:
4
Journal Article
Peer reviewed
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.
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 ∼11
kb 3′ UTR extending through intron 9, exon 10 and approximately 5
kb 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.
KIAA0513 was previously identified as upregulated in the dorsolateral prefrontal cortex of subjects with schizophrenia by microarray analysis. In the present study, the differential expression in the ...schizophrenic subjects was confirmed by quantitative RT-PCR. The limited homology to proteins of known function and lack of functional domains in the encoded protein have made it difficult to predict a function for KIAA0513. We used in situ hybridization, RNA blots, western blots, and immunocytochemistry to examine KIAA0513 expression in normal brain and peripheral tissues. The gene is ubiquitously expressed but is enriched in the brain, particularly in the cerebellum. Finally, interacting proteins were identified using a yeast two-hybrid screen to functionally characterize the protein. KIAA0513 interacts with KIBRA, HAX-1, and INTS4, which also interact with proteins involved in neuroplasticity, apoptosis, and cytoskeletal regulation. Therefore, KIAA0513 is likely to be involved in signaling pathways related to these processes.
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