ABSTRACT
The neurotrophic hypothesis of depression suggests an association between effects on neuroplasticity and clinical response to antidepressant drug therapy. We studied individual variability in antidepressant drug effects on cell proliferation in lymphoblastoid cell lines (LCLs) from n=25 therapy-resistant patients versus n=25 first-line therapy responders from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Furthermore, the variability in gene expression of genes associated with cell proliferation was analyzed for tentative candidate genes for prediction of individual LCL donor's treatment response. Cell proliferation was quantified by EdU (5-ethynyl-2'-deoxyuridine) assays after 21-day incubation of LCLs with fluoxetine (0.5 ng µl-1) and citalopram (0.3 ng µl-1) as developed and described earlier. Gene expression of a panel of candidate genes derived from genome-wide expression analyses of antidepressant effects on cell proliferation of LCLs from the Munich Antidepressant Response Signature (MARS) study was analyzed by real-time PCR. Significant differences in in vitro cell proliferation effects were detected between the group of LCLs from first-line therapy responders and LCLs from treatment-resistant patients. Gene expression analysis of the candidate gene panel revealed and confirmed influence of the candidate genes ABCB1, FZD7 and WNT2B on antidepressant drug resistance. The potential of these genes as tentative biomarkers for antidepressant drug resistance was confirmed. In vitro cell proliferation testing may serve as functional biomarker for individual neuroplasticity effects of antidepressants.
Subject(s)
Antidepressive Agents/pharmacology , Cell Proliferation/drug effects , Depressive Disorder, Treatment-Resistant/genetics , Lymphoid Progenitor Cells/drug effects , ATP Binding Cassette Transporter, Subfamily B/drug effects , ATP Binding Cassette Transporter, Subfamily B/genetics , Adult , Antidepressive Agents/therapeutic use , Biomarkers , Cell Line , Cell Proliferation/genetics , Citalopram/pharmacology , Citalopram/therapeutic use , Depressive Disorder, Treatment-Resistant/drug therapy , Female , Fluoxetine/pharmacology , Frizzled Receptors/drug effects , Frizzled Receptors/genetics , Glycoproteins/drug effects , Glycoproteins/genetics , Humans , In Vitro Techniques , Lymphoid Progenitor Cells/metabolism , Male , Middle Aged , Real-Time Polymerase Chain Reaction , Sulfotransferases/drug effects , Sulfotransferases/genetics , Transcription Factor 7-Like 2 Protein/drug effects , Transcription Factor 7-Like 2 Protein/genetics , Transcriptome , Wnt Proteins/drug effects , Wnt Proteins/geneticsABSTRACT
BACKGROUND AND PURPOSE: (R,S)-ketamine produces rapid and significant antidepressant effects in approximately 65% of patients suffering from treatment-resistant bipolar depression (BD). The genetic, pharmacological and biochemical differences between ketamine responders and non-responders have not been identified. The purpose of this study was to employ a metabolomics approach, a global, non-targeted determination of endogenous metabolic patterns, to identify potential markers of ketamine response and non-response. EXPERIMENTAL APPROACH: Plasma samples from 22 BD patients were analyzed to produce metabolomic patterns. The patients had received ketamine in a placebo-controlled crossover study and the samples were obtained 230 min post-administration at which time the patients were categorized as responders or non-responders. Matching plasma samples from the placebo arm of the study were also analysed. During the study, the patients were maintained on either lithium or valproate. KEY RESULTS: The metabolomic patterns were significantly different between the patients maintained on lithium and those maintained on valproate, irrespective of response to ketamine. In the patients maintained on lithium, 18 biomarkers were identified. In responders, lysophosphatidylethanolamines (4) and lysophosphatidylcholines (9) were increased relative to non-responders. CONCLUSIONS AND IMPLICATIONS: The results indicate that the differences between patients who respond to ketamine and those who do not are due to alterations in the mitochondrial ß-oxidation of fatty acids. These differences were not produced by ketamine administration. The data indicate that pretreatment metabolomics screening may be a guide to the prediction of response and a potential approach to the individualization of ketamine therapy.
Subject(s)
Bipolar Disorder/blood , Depressive Disorder, Treatment-Resistant/blood , Ketamine/therapeutic use , Lysophosphatidylcholines/blood , Lysophospholipids/blood , Metabolome/drug effects , Adult , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Biomarkers, Pharmacological/blood , Cross-Over Studies , Depressive Disorder, Treatment-Resistant/drug therapy , Drug Therapy, Combination , Female , Humans , Ketamine/pharmacology , Lithium/therapeutic use , Male , Middle Aged , Pilot Projects , Valproic Acid/therapeutic use , Young AdultABSTRACT
RNA-sequencing (RNA-seq) is a powerful technique to investigate the complexity of gene expression in the human brain. We used RNA-seq to survey the brain transcriptome in high-quality postmortem dorsolateral prefrontal cortex from 11 individuals diagnosed with bipolar disorder (BD) and from 11 age- and gender-matched controls. Deep sequencing was performed, with over 350 million reads per specimen. At a false discovery rate of <5%, we detected five differentially expressed (DE) genes and 12 DE transcripts, most of which have not been previously implicated in BD. Among these, Prominin 1/CD133 and ATP-binding cassette-sub-family G-member2 (ABCG2) have important roles in neuroplasticity. We also show for the first time differential expression of long noncoding RNAs (lncRNAs) in BD. DE transcripts include those of serine/arginine-rich splicing factor 5 (SRSF5) and regulatory factor X4 (RFX4), which along with lncRNAs have a role in mammalian circadian rhythms. The DE genes were significantly enriched for several Gene Ontology categories. Of these, genes involved with GTPase binding were also enriched for BD-associated SNPs from previous genome-wide association studies, suggesting that differential expression of these genes is not simply a consequence of BD or its treatment. Many of these findings were replicated by microarray in an independent sample of 60 cases and controls. These results highlight common pathways for inherited and non-inherited influences on disease risk that may constitute good targets for novel therapies.
Subject(s)
Bipolar Disorder/metabolism , Circadian Rhythm/physiology , GTP Phosphohydrolases/metabolism , Neuronal Plasticity/physiology , Prefrontal Cortex/metabolism , Transcriptome , Adult , Aged , Bipolar Disorder/genetics , Circadian Rhythm/genetics , Female , GTP Phosphohydrolases/genetics , Genome-Wide Association Study , Humans , Male , Meta-Analysis as Topic , Microarray Analysis , Middle Aged , Neuronal Plasticity/genetics , Polymerase Chain Reaction , Principal Component Analysis , Sequence Analysis, RNA/methods , Young AdultSubject(s)
Carbohydrate Epimerases/genetics , Polymorphism, Single Nucleotide/genetics , Serotonin Plasma Membrane Transport Proteins/metabolism , Thalamus/metabolism , Adolescent , Adult , Benzylamines/pharmacokinetics , Bipolar Disorder/genetics , Brain Mapping , Carbon Isotopes/pharmacokinetics , Depressive Disorder, Major/genetics , Female , Genome-Wide Association Study , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Positron-Emission Tomography , Protein Binding/drug effects , Protein Binding/genetics , Serotonin Plasma Membrane Transport Proteins/genetics , Thalamus/diagnostic imaging , Young AdultABSTRACT
The brain serotonergic system has an essential role in the physiological functions of the central nervous system and dysregulation of serotonin (5-HT) homeostasis has been implicated in many neuropsychiatric disorders. The tryptophan hydroxylase-2 (TPH2) gene is the rate-limiting enzyme in brain 5-HT synthesis, and thus is an ideal candidate gene for understanding the role of dysregulation of brain serotonergic homeostasis. Here, we characterized a common, but functional single-nucleotide polymorphism (SNP rs1386493) in the TPH2 gene, which decreases efficiency of normal RNA splicing, resulting in a truncated TPH2 protein (TPH2-TR) by alternative splicing. TPH2-TR, which lacks TPH2 enzyme activity, dominant-negatively affects full-length TPH2 function, causing reduced 5-HT production. The predicted mRNA for TPH2-TR is present in postmortem brain of rs1386493 carriers. The rs13864923 variant does not appear to be overrepresented in either global or multiplex depression cohorts. However, in combination with other gene variants linked to 5-HT homeostasis, this variant may exhibit important epistatic influences.
Subject(s)
Alternative Splicing , Depression/genetics , Genetic Predisposition to Disease/genetics , Serotonin/biosynthesis , Tryptophan Hydroxylase/genetics , Animals , Brain Stem/metabolism , Cell Line, Transformed , Female , Genetic Predisposition to Disease/psychology , Genotype , Humans , Male , PC12 Cells , Pedigree , Polymorphism, Single Nucleotide/genetics , RatsSubject(s)
Geriatrics , Quality of Health Care , Quality of Life , Activities of Daily Living , Aged , Cognition Disorders , Health Status , Humans , Mental Health , United StatesABSTRACT
Hypochondriasis is a heterogeneous disorder. This was well demonstrated in the study by Kellner et al, which showed that patients with high levels of disease fear tended to be more anxious or phobic, whereas patients with high levels of disease conviction tended to have more and more severe somatic symptoms. Little comorbidity exists to support the statement that hypochondriasis is an obsessive-compulsive spectrum disorder. Although patients exist whose hypochondriac concerns are identical in quality to the intrusive thoughts of patients with OCD, as a group, patients with hypochondriasis do not share a comorbidity profile comparable with that of patients with OCD. The data support a closer relationship between hypochondriasis and somatization disorder than between hypochondriasis and OCD. The family history data is limited by the lack of adequate studies. Using comparable methods of the family history approach, Black's study reported a higher frequency of GAD but not OCD among the relatives of OCD patients--a finding similar to what Noyes found among the relatives of hypochondriac patients; however, using the direct interview method, somatization disorder was the only statistically more common disorder, among relatives of female hypochondriac patients. Therefore, although the parallel in overlap with GAD is suggestive of a commonality between OCD, GAD, and hypochondriasis, the finding of a greater frequency of somatization disorder leans against the hypothesis that hypochondriasis is best considered an OCD spectrum disorder. The pharmacologic treatment data are the one type of biologic evidence that supports a bridge to OCD. The pharmacologic studies suggest that for patients with general hypochondriasis, TCAs are not effective and that higher dosages and longer trials of the SRIs are needed. These pharmacologic observations are comparable with the ones made for patients with OCD but dissimilar to the observations made for depression. The benefit of imipramine among patients with illness phobia must be assessed in placebo-controlled trials among illness phobics and among hypochondriacs. Even more valuable would be a direct comparison of a TCA (e.g., imipramine or desipramine) and a selective SRI (e.g., fluoxetine) to determine whether the response to selective SRIs is greater. Although the pharmacologic data are compelling in supporting the hypothesis that hypochondriasis is an obsessive-compulsive spectrum disorder, the comorbidity data are equally compelling in dispelling that hypothesis. Perhaps future studies clarify the subtypes of hypochondriasis, be they "phobic, obsessive, and depressive," "chronic and episodic," "early onset versus late onset" or some other as yet undetermined subtype. Such clarification may be aided by better instruments to assess the obsessive-compulsive and hypochondria spectrums within individuals and families and by neuropsychological or pharmacologic challenge and neuroimaging studies.