Publications by authors named "Neven Henigsberg"

65 Publications

Choline elevation in amygdala region at recovery indicates longer survival without depressive episode: a magnetic resonance spectroscopy study.

Psychopharmacology (Berl) 2021 May 4;238(5):1303-1314. Epub 2019 Sep 4.

Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Šalata 12, 10000, Zagreb, Croatia.

Rationale: Depression, with variable longitudinal patterns, recurs in one third of patients. We lack useful predictors of its course/outcome, and proton magnetic resonance spectroscopy (1H-MRS) of brain metabolites is an underused research modality in finding outcome correlates.

Objectives: To determine if brain metabolite levels/changes in the amygdala region observed early in the recovery phase indicate depression recurrence risk in patients receiving maintenance therapy.

Methods: Forty-eight patients on stable-dose antidepressant (AD) maintenance therapy were analyzed from recovery onset until (i) recurrence of depression or (ii) start of AD discontinuation. Two 1H-MRS scans (6 months apart) were performed with a focus on amygdala at the beginning of recovery. N-acetylaspartate (NAA), choline-containing metabolites (Cho), and Glx (glutamine/glutamate and GABA) were evaluated with regard to time without recurrence, and risks were assessed by Cox proportional hazard modeling.

Results: Twenty patients had depression recurrence, and 23 patients reached AD discontinuation. General linear model repeated measures analysis displayed three-way interaction of measurement time, metabolite level, and recurrence on maintenance therapy, in a multivariate test, Wilks' lambda = 0.857, F(2,40) = 3.348, p = 0.045. Cho levels at the beginning of recovery and subsequent changes convey the highest risk for earlier recurrence. Patients experiencing higher amygdala Cho after recovery are at a significantly lower risk for depression recurrence (hazard ratio = 0.32; 95% confidence interval 0.13-0.77).

Conclusion: Cho levels/changes in the amygdala early in the recovery phase correlate with clinical outcome. In the absence of major NAA fluctuations, changes in Cho and Glx may suggest a shift towards reduction in (previously increased) glutamatergic neurotransmission. Investigation of a larger sample with greater sampling frequency is needed to confirm the possible predictive role of metabolite changes in the amygdala region early in the recovery phase.
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http://dx.doi.org/10.1007/s00213-019-05303-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062352PMC
May 2021

Choline elevation in amygdala region at recovery indicates longer survival without depressive episode: a magnetic resonance spectroscopy study.

Psychopharmacology (Berl) 2021 May 4;238(5):1303-1314. Epub 2019 Sep 4.

Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Šalata 12, 10000, Zagreb, Croatia.

Rationale: Depression, with variable longitudinal patterns, recurs in one third of patients. We lack useful predictors of its course/outcome, and proton magnetic resonance spectroscopy (1H-MRS) of brain metabolites is an underused research modality in finding outcome correlates.

Objectives: To determine if brain metabolite levels/changes in the amygdala region observed early in the recovery phase indicate depression recurrence risk in patients receiving maintenance therapy.

Methods: Forty-eight patients on stable-dose antidepressant (AD) maintenance therapy were analyzed from recovery onset until (i) recurrence of depression or (ii) start of AD discontinuation. Two 1H-MRS scans (6 months apart) were performed with a focus on amygdala at the beginning of recovery. N-acetylaspartate (NAA), choline-containing metabolites (Cho), and Glx (glutamine/glutamate and GABA) were evaluated with regard to time without recurrence, and risks were assessed by Cox proportional hazard modeling.

Results: Twenty patients had depression recurrence, and 23 patients reached AD discontinuation. General linear model repeated measures analysis displayed three-way interaction of measurement time, metabolite level, and recurrence on maintenance therapy, in a multivariate test, Wilks' lambda = 0.857, F(2,40) = 3.348, p = 0.045. Cho levels at the beginning of recovery and subsequent changes convey the highest risk for earlier recurrence. Patients experiencing higher amygdala Cho after recovery are at a significantly lower risk for depression recurrence (hazard ratio = 0.32; 95% confidence interval 0.13-0.77).

Conclusion: Cho levels/changes in the amygdala early in the recovery phase correlate with clinical outcome. In the absence of major NAA fluctuations, changes in Cho and Glx may suggest a shift towards reduction in (previously increased) glutamatergic neurotransmission. Investigation of a larger sample with greater sampling frequency is needed to confirm the possible predictive role of metabolite changes in the amygdala region early in the recovery phase.
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http://dx.doi.org/10.1007/s00213-019-05303-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062352PMC
May 2021

A functional variant in the serotonin receptor 7 gene (HTR7), rs7905446, is associated with good response to SSRIs in bipolar and unipolar depression.

Mol Psychiatry 2020 06 15;25(6):1312-1322. Epub 2019 Mar 15.

Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA.

Predicting antidepressant response has been a clinical challenge for mood disorder. Although several genome-wide association studies have suggested a number of genetic variants to be associated with antidepressant response, the sample sizes are small and the results are difficult to replicate. Previous animal studies have shown that knockout of the serotonin receptor 7 gene (HTR7) resulted in an antidepressant-like phenotype, suggesting it was important to antidepressant action. In this report, in the first stage, we used a cost-effective pooled-sequencing strategy to sequence the entire HTR7 gene and its regulatory regions to investigate the association of common variants in HTR7 and clinical response to four selective serotonin reuptake inhibitors (SSRIs: citalopram, paroxetine, fluoxetine and sertraline) in a retrospective cohort mainly consisting of subjects with bipolar disorder (n = 359). We found 80 single-nucleotide polymorphisms (SNPs) with false discovery rate < 0.05 associated with response to paroxetine. Among the significant SNPs, rs7905446 (T/G), which is located at the promoter region, also showed nominal significance (P < 0.05) in fluoxetine group. GG/TG genotypes for rs7905446 and female gender were associated with better response to two SSRIs (paroxetine and fluoxetine). In the second stage, we replicated this association in two independent prospective samples of SSRI-treated patients with major depressive disorder: the MARS (n = 253, P = 0.0169) and GENDEP studies (n = 432, P = 0.008). The GG/TG genotypes were consistently associated with response in all three samples. Functional study of rs7905446 showed greater activity of the G allele in regulating expression of HTR7. The G allele displayed higher luciferase activity in two neuronal-related cell lines, and estrogen treatment decreased the activity of only the G allele. Electrophoretic mobility shift assay suggested that the G allele interacted with CCAAT/enhancer-binding protein beta transcription factor (TF), while the T allele did not show any interaction with any TFs. Our results provided novel pharmacogenomic evidence to support the role of HTR7 in association with antidepressant response.
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http://dx.doi.org/10.1038/s41380-019-0397-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745302PMC
June 2020

Neuroimaging research in posttraumatic stress disorder - Focus on amygdala, hippocampus and prefrontal cortex.

Prog Neuropsychopharmacol Biol Psychiatry 2019 03 9;90:37-42. Epub 2018 Nov 9.

Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Croatia; University Hospital Centre, 'Sestre milosrdnice', Zagreb, Croatia. Electronic address:

Neuroimaging research reflects the complexity of post-traumatic stress disorder and shares some common difficulties of post-traumatic stress disorder research, such as the different classifications of the disorder over time, changes in diagnostic criteria, and extensive comorbidities, as well as precisely delineated and prevailing genetic and environmental determinants in the development of the disorder and its clinical manifestations. Synthesis of neuroimaging findings in an effort to clarify causes, clinical manifestations, and consequences of the disorder is complicated by a variety of applied technical approaches in different brain regions, differences in symptom dimensions in a study population, and typically small sample sizes, with the interplay of all of these consequently bringing about divergent results. Furthermore, combinations of the aforementioned issues serve to weaken any comprehensive meta-analytic approach. In this review, we focus on recent neuroimaging studies and those performed on larger samples, with particular emphasis on research concerning the amygdala, hippocampus, and prefrontal cortex, as these are the brain regions postulated by the core research to play a prominent role in the pathophysiology of post-traumatic stress disorder. Additionally, we review the guidelines for future research and list a number of new intersectional and cross-sectional approaches in the area of neuroimaging. We conclude that future neuroimaging research in post-traumatic stress disorder will certainly benefit from a higher integration with genetic research, better profiling of control groups, and a greater involvement of the neuroimaging genetics approach and from larger collaborative studies.
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http://dx.doi.org/10.1016/j.pnpbp.2018.11.003DOI Listing
March 2019

Choline and N-acetyl aspartate levels in the dorsolateral prefrontal cortex at the beginning of the recovery phase as markers of increased risk for depressive episode recurrence under different duration of maintenance therapy and after it: a retrospective cohort study.

Croat Med J 2018 Oct;59(5):244-252

Pero Hrabač, Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10000 Zagreb, Croatia,

Aim: To evaluate the relationship between the dynamics of proton magnetic resonance spectroscopy (1H-MRS) brain metabolite levels at the beginning of the recovery phase of the index depressive episode and the time to the recurrence of depression.

Methods: This retrospective cohort study analyzed the changes in N-acetyl aspartate (NAA), choline (Cho), and glutamate-glutamine in 48 patients with recurrent depression treated with maintenance antidepressant monotherapy at a stable dose. 1H-MRS was performed at the start of the recovery phase and 6 months later. 1H-MRS parameters, index episode descriptors, and depressive disorder course were analyzed by Cox proportional hazards model.

Results: NAA and Cho decrease six months after the beginning of the recovery period were time-independent risk factors for depressive episode recurrence. Hazard ratio associated with NAA decrease was 2.02 (95% confidence interval 1.06-3.84) and that associated with Cho decrease was 2.06 (95% confidence interval 1.02-4.17). These changes were not related to symptoms severity, as Montgomery-Asberg Depression Scale score remained generally unchanged (mean -0.01; standard deviation 1.6) over the first 6 months of recovery.

Conclusion: Patients receiving maintenance antidepressant therapy after recovery who experience a decrease in NAA or Cho levels early in the recovery phase have a double risk of depressive episode recurrence. Sustained NAA and Cho levels at the beginning of the recovery phase may indicate increased brain resilience conferred by antidepressant therapy, while NAA and Cho decrease may indicate only the trait-related temporal effect of therapy in another stratum of patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240822PMC
October 2018

Effect of cytochrome CYP2C19 metabolizing activity on antidepressant response and side effects: Meta-analysis of data from genome-wide association studies.

Eur Neuropsychopharmacol 2018 08 28;28(8):945-954. Epub 2018 Jun 28.

Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, PO80, De De Crespigny Park, Denmark Hill United Kingdom. Electronic address:

Cytochrome (CYP) P450 enzymes have a primary role in antidepressant metabolism and variants in these polymorphic genes are targets for pharmacogenetic investigation. This is the first meta-analysis to investigate how CYP2C19 polymorphisms predict citalopram/escitalopram efficacy and side effects. CYP2C19 metabolic phenotypes comprise poor metabolizers (PM), intermediate and intermediate+ metabolizers (IM; IM+), extensive and extensive+ metabolizers (EM [wild type]; EM+) and ultra-rapid metabolizers (UM) defined by the two most common CYP2C19 functional polymorphisms (rs4244285 and rs12248560) in Caucasians. These polymorphisms were genotyped or imputed from genome-wide data in four samples treated with citalopram or escitalopram (GENDEP, STAR*D, GenPod, PGRN-AMPS). Treatment efficacy was assessed by standardized percentage symptom improvement and by remission. Side effect data were available at weeks 2-4, 6 and 9 in three samples. A fixed-effects meta-analysis was performed using EM as the reference group. Analysis of 2558 patients for efficacy and 2037 patients for side effects showed that PMs had higher symptom improvement (SMD = 0.43, CI = 0.19-0.66) and higher remission rates (OR = 1.55, CI = 1.23-1.96) compared to EMs. At weeks 2-4, PMs showed higher risk of gastro-intestinal (OR = 1.26, CI = 1.08-1.47), neurological (OR = 1.28, CI = 1.07-1.53) and sexual side effects (OR = 1.52, CI = 1.23-1.87; week 6 values were similar). No difference was seen at week 9 or in total side effect burden. PMs did not have higher risk of dropout at week 4 compared to EMs. Antidepressant dose was not different among CYP2C19 groups. CYP2C19 polymorphisms may provide helpful information for guiding citalopram/escitalopram treatment, despite PMs being relatively rare among Caucasians (∼2%).
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http://dx.doi.org/10.1016/j.euroneuro.2018.05.009DOI Listing
August 2018

Genes associated with anhedonia: a new analysis in a large clinical trial (GENDEP).

Transl Psychiatry 2018 08 13;8(1):150. Epub 2018 Aug 13.

Psychiatry and Medical Genetics, University of Alberta, Edmonton, AB, Canada.

A key feature of major depressive disorder (MDD) is anhedonia, which is a predictor of response to antidepressant treatment. In order to shed light on its genetic underpinnings, we conducted a genome-wide association study (GWAS) followed by investigation of biological pathway enrichment using an anhedonia dimension for 759 patients with MDD in the GENDEP study. The GWAS identified 18 SNPs associated at genome-wide significance with the top one being an intronic SNP (rs9392549) in PRPF4B (pre-mRNA processing factor 4B) located on chromosome 6 (P = 2.07 × 10) while gene-set enrichment analysis returned one gene ontology term, axon cargo transport (GO: 0008088) with a nominally significant P value (1.15 × 10). Furthermore, our exploratory analysis yielded some interesting, albeit not statistically significant genetic correlation with Parkinson's Disease and nucleus accumbens gray matter. In addition, polygenic risk scores (PRSs) generated from our association analysis were found to be able to predict treatment efficacy of the antidepressants in this study. In conclusion, we found some markers significantly associated with anhedonia, and some suggestive findings of related pathways and biological functions, which could be further investigated in other studies.
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http://dx.doi.org/10.1038/s41398-018-0198-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089928PMC
August 2018

Autonomic seizures and déjà vu in a patient with gangliocytoma of the orbitofrontal cortex.

Psychiatr Danub 2018 Jun;30(2):220-222

Department of Neurology, University Hospital Zagreb, HR-Kispaticeva 12, 10000 Zagreb, Croatia,

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http://dx.doi.org/10.24869/psyd.2018.220DOI Listing
June 2018

Antidepressant drug-specific prediction of depression treatment outcomes from genetic and clinical variables.

Sci Rep 2018 04 3;8(1):5530. Epub 2018 Apr 3.

Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, Denmark Hill, London, SE5 8AF, UK.

Individuals with depression differ substantially in their response to treatment with antidepressants. Specific predictors explain only a small proportion of these differences. To meaningfully predict who will respond to which antidepressant, it may be necessary to combine multiple biomarkers and clinical variables. Using statistical learning on common genetic variants and clinical information in a training sample of 280 individuals randomly allocated to 12-week treatment with antidepressants escitalopram or nortriptyline, we derived models to predict remission with each antidepressant drug. We tested the reproducibility of each prediction in a validation set of 150 participants not used in model derivation. An elastic net logistic model based on eleven genetic and six clinical variables predicted remission with escitalopram in the validation dataset with area under the curve 0.77 (95%CI; 0.66-0.88; p = 0.004), explaining approximately 30% of variance in who achieves remission. A model derived from 20 genetic variables predicted remission with nortriptyline in the validation dataset with an area under the curve 0.77 (95%CI; 0.65-0.90; p < 0.001), explaining approximately 36% of variance in who achieves remission. The predictive models were antidepressant drug-specific. Validated drug-specific predictions suggest that a relatively small number of genetic and clinical variables can help select treatment between escitalopram and nortriptyline.
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http://dx.doi.org/10.1038/s41598-018-23584-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882876PMC
April 2018

Lower Choline-Containing Metabolites/Creatine (Cr) Rise and Failure to Sustain NAA/Cr Levels in the Dorsolateral Prefrontal Cortex Are Associated with Depressive Episode Recurrence under Maintenance Therapy: A Proton Magnetic Resonance Spectroscopy Retrospective Cohort Study.

Front Psychiatry 2017 13;8:277. Epub 2017 Dec 13.

Polyclinic Neuron, Zagreb, Croatia.

Background: The aim of this study was to evaluate the relationship between changes in proton magnetic resonance spectroscopy (1H-MRS) parameters at the start of the index episode recovery phase and at recurrence in patients with recurrent depression who were treated with prolonged maintenance therapy.

Methods: 1H-MRS parameters were analyzed in 48 patients with recurrent depression who required maintenance therapy with antidepressant medication prescribed by a psychiatrist and who continued with the same antidepressant during the maintenance phase, either to recurrence of depression, completion of the 10-year observation period, or the start of the withdrawal phase (tapering-off antidepressant). N-acetylaspartate (NAA), choline-containing metabolites (Cho), creatine (Cr), and glutamine/glutamate were measured at the start of the recovery phase and 6 months later.

Results: Recurrent depressive episodes occurred in 20 patients. These individuals had a smaller increase in Cho/Cr after the beginning of the recovery phase compared to the non-recurrent patient group and also exhibited a decreased NAA/Cr ratio.

Conclusion: Sustainable NAA and increased Cho levels at the onset of the recovery phase of the index episode are early markers of antidepressant effectiveness associated with a lower risk of major depressive disorder recurrence. The NAA and Cho changes in the non-recurrent group may be attributable to increased brain resilience, contrary to the transient temporal effect observed in subjects who experienced a depressive episode.
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http://dx.doi.org/10.3389/fpsyt.2017.00277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733547PMC
December 2017

Proton magnetic resonance spectroscopy in Huntington's disease accompanying neuroborreliosis.

Psychiatr Danub 2017 Jun;29(2):226-230

Department of Neurology, University Hospital Zagreb, HR-Kispaticeva 12, 10000 Zagreb, Croatia,

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http://dx.doi.org/10.24869/psyd.2017.226DOI Listing
June 2017

Association between C-reactive protein (CRP) with depression symptom severity and specific depressive symptoms in major depression.

Brain Behav Immun 2017 May 1;62:344-350. Epub 2017 Mar 1.

Aarhus University Hospital, Risskov, Psychosis Research Unit, Aarhus, Denmark; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.

Introduction: Population-based studies have associated inflammation, particularly higher C-reactive protein (CRP), with depressive severity, but clinical trials in major depressive disorder were rather non-specific without examining the role of gender. We aimed to investigate the association between CRP and overall depression severity including specific depressive symptoms and to examine potential gender differences.

Methods: We included 231 individuals with major depressive disorder from the Genome-Based Therapeutics Drugs for Depression (GENDEP) study. At baseline, we assessed high-sensitivity CRP levels and psychopathology with the Montgomery Aasberg Depression Rating Scale (MADRS). We performed linear regression analyses to investigate the association between baseline CRP levels with overall MADRS severity and specific symptoms at baseline and adjusted for age, gender, anti-inflammatory and psychotropic drug treatment, body mass index, smoking, inflammatory diseases, and recruitment center.

Results: Higher CRP levels were significantly associated with greater overall MADRS symptom severity (p=0.02), which was significant among women (p=0.02) but not among men (p=0.68). Among women, higher CRP was associated with increased severity on observed mood, cognitive symptoms, interest-activity, and suicidality, but we found no significant associations among men. Interaction analyses showed no significant gender differences on the overall MADRS score or specific symptoms.

Discussion: Our results support the sickness syndrome theory suggesting that chronic low-grade inflammation may be associated with a subtype of depression. The potential gender differences in psychopathology may be explained by biological and/or psychosocial factors, e.g. differential modulation of immune responses by sex hormones. Clinical studies should investigate symptom-specific and/or gender-specific treatment guided by peripheral inflammatory markers.
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http://dx.doi.org/10.1016/j.bbi.2017.02.020DOI Listing
May 2017

Pharmacogenetics of antidepressant response: A polygenic approach.

Prog Neuropsychopharmacol Biol Psychiatry 2017 04 31;75:128-134. Epub 2017 Jan 31.

Department of Psychiatry, University of Münster, Münster, Germany.

Background: Major depressive disorder (MDD) has a high personal and socio-economic burden and >60% of patients fail to achieve remission with the first antidepressant. The biological mechanisms behind antidepressant response are only partially known but genetic factors play a relevant role. A combined predictor across genetic variants may be useful to investigate this complex trait.

Methods: Polygenic risk scores (PRS) were used to estimate multi-allelic contribution to: 1) antidepressant efficacy; 2) its overlap with MDD and schizophrenia. We constructed PRS and tested whether these predicted symptom improvement or remission from the GENDEP study (n=736) to the STAR*D study (n=1409) and vice-versa, including the whole sample or only patients treated with escitalopram or citalopram. Using summary statistics from Psychiatric Genomics Consortium for MDD and schizophrenia, we tested whether PRS from these disorders predicted symptom improvement in GENDEP, STAR*D, and five further studies (n=3756).

Results: No significant prediction of antidepressant efficacy was obtained from PRS in GENDEP/STAR*D but this analysis might have been underpowered. There was no evidence of overlap in the genetics of antidepressant response with either MDD or schizophrenia, either in individual studies or a meta-analysis. Stratifying by antidepressant did not alter the results.

Discussion: We identified no significant predictive effect using PRS between pharmacogenetic studies. The genetic liability to MDD or schizophrenia did not predict response to antidepressants, suggesting differences between the genetic component of depression and treatment response. Larger or more homogeneous studies will be necessary to obtain a polygenic predictor of antidepressant response.
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http://dx.doi.org/10.1016/j.pnpbp.2017.01.011DOI Listing
April 2017

Combining clinical variables to optimize prediction of antidepressant treatment outcomes.

J Psychiatr Res 2016 07 1;78:94-102. Epub 2016 Apr 1.

Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, Denmark Hill, London, SE5 8AF, UK; Dalhousie University Department of Psychiatry, 5909 Veterans' Memorial Drive, Halifax, B3H 2E2, Nova Scotia, Canada.

The outcome of treatment with antidepressants varies markedly across people with the same diagnosis. A clinically significant prediction of outcomes could spare the frustration of trial and error approach and improve the outcomes of major depressive disorder through individualized treatment selection. It is likely that a combination of multiple predictors is needed to achieve such prediction. We used elastic net regularized regression to optimize prediction of symptom improvement and remission during treatment with escitalopram or nortriptyline and to identify contributing predictors from a range of demographic and clinical variables in 793 adults with major depressive disorder. A combination of demographic and clinical variables, with strong contributions from symptoms of depressed mood, reduced interest, decreased activity, indecisiveness, pessimism and anxiety significantly predicted treatment outcomes, explaining 5-10% of variance in symptom improvement with escitalopram. Similar combinations of variables predicted remission with area under the curve 0.72, explaining approximately 15% of variance (pseudo R(2)) in who achieves remission, with strong contributions from body mass index, appetite, interest-activity symptom dimension and anxious-somatizing depression subtype. Escitalopram-specific outcome prediction was more accurate than generic outcome prediction, and reached effect sizes that were near or above a previously established benchmark for clinical significance. Outcome prediction on the nortriptyline arm did not significantly differ from chance. These results suggest that easily obtained demographic and clinical variables can predict therapeutic response to escitalopram with clinically meaningful accuracy, suggesting a potential for individualized prescription of this antidepressant drug.
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http://dx.doi.org/10.1016/j.jpsychires.2016.03.016DOI Listing
July 2016

Transcriptomics and the mechanisms of antidepressant efficacy.

Eur Neuropsychopharmacol 2016 Jan 12;26(1):105-112. Epub 2015 Nov 12.

King׳s College London, Institute of Psychiatry, King׳s Health Partners Centre for Neurodegeneration Research, London, UK; NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, King׳s College London, London, UK. Electronic address:

The mechanisms by which antidepressants have their effects are not clear and the reasons for variability in treatment outcomes are also unknown. However, there is evidence from candidate gene research that indicates gene expression changes may be involved in antidepressant action. In this study, we examined antidepressant-induced alterations in gene expression on a transcriptome-wide scale, exploring associations with treatment response. Blood samples were taken from a subset of depressed patients from the GENDEP study (n=136) before and after eight weeks of treatment with either escitalopram or nortriptyline. Transcriptomic data were obtained from these samples using Illumina HumanHT-12 v4 Expression BeadChip microarrays. When analysing individual genes, we observed that changes in the expression of two genes (MMP28 and KXD1) were associated with better response to nortriptyline. Considering connectivity between genes, we identified modules of genes that were highly coexpressed. In the whole sample, changes in one of the ten identified coexpression modules showed significant correlation with treatment response (cor=0.27, p=0.0029). Using transcriptomic approaches, we have identified gene expression correlates of the therapeutic effects of antidepressants, highlighting possible molecular pathways involved in efficacious antidepressant treatment.
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http://dx.doi.org/10.1016/j.euroneuro.2015.10.009DOI Listing
January 2016

Clozapine-induced paralytic ileus.

Psychiatr Danub 2015 Sep;27(3):283-4

Department of Neurology, Univesity Hospital Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia,

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September 2015

Exploring the role of drug-metabolising enzymes in antidepressant side effects.

Psychopharmacology (Berl) 2015 Jul 12;232(14):2609-17. Epub 2015 Mar 12.

MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK,

Rationale: Cytochrome P450 enzymes are important in the metabolism of antidepressants. The highly polymorphic nature of these enzymes has been linked to variability in antidepressant metabolism rates, leading to hope regarding the use of P450 genotyping to guide treatment. However, evidence that P450 genotypic differences underlie the variation in treatment outcomes is inconclusive.

Objectives: We explored the links between both P450 genotype and serum concentrations of antidepressant with antidepressant side effects, using data from the Genome-Based Therapeutic Drugs for Depression Project (GENDEP), which is a large (n = 868), pharmacogenetic study of depressed individuals treated with escitalopram or nortriptyline.

Methods: Patients were genotyped for the enzymes CYP2C19 and CYP2D6, and serum concentrations of both antidepressant and primary metabolite were measured after 8 weeks of treatment. Side effects were assessed weekly. We investigated associations between P450 genotypes, serum concentrations of antidepressants and side effects, as well as the relationship between P450 genotype and study discontinuation.

Results: P450 genotype did not predict total side effect burden (nortriptyline: n = 251, p = 0.5638, β = -0.133, standard error (SE) = 0.229; escitalopram: n = 340, p = 0.9627, β = -0.004, SE = 0.085), study discontinuation (nortriptyline n = 284, hazard ratio (HR) = 1.300, p = 0.174; escitalopram n = 376, HR = 0.870, p = 0.118) or specific side effects. Serum concentrations of antidepressant were only related to a minority of the specific side effects measured: dry mouth, dizziness and diarrhoea.

Conclusions: In this sample where antidepressant dosage is titrated using clinical judgement, P450 genotypes do not explain differences between patients in side effects with antidepressants. Serum drug concentrations appear to only explain variability in the occurrence of a minority of specific side effects.
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http://dx.doi.org/10.1007/s00213-015-3898-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480333PMC
July 2015

No change in N-acetyl aspartate in first episode of moderate depression after antidepressant treatment: (1)H magnetic spectroscopy study of left amygdala and left dorsolateral prefrontal cortex.

Neuropsychiatr Dis Treat 2014 17;10:1753-62. Epub 2014 Sep 17.

Polyclinic Neuron, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia ; Psychiatric Clinic Vrapče, Zagreb, Croatia.

Background: The role of brain metabolites as biological correlates of the intensity, symptoms, and course of major depression has not been determined. It has also been inconclusive whether the change in brain metabolites, measured with proton magnetic spectroscopy, could be correlated with the treatment outcome.

Methods: Proton magnetic spectroscopy was performed in 29 participants with a first episode of moderate depression occurring in the left dorsolateral prefrontal cortex and left amygdala at baseline and after 8 weeks of antidepressant treatment with escitalopram. The Montgomery-Asberg Depression Rating Scale, the Hamilton Rating Scale for Depression, and the Beck Depression Inventory were used to assess the intensity of depression at baseline and at the endpoint of the study. At endpoint, the participants were identified as responders (n=17) or nonresponders (n=12) to the antidepressant therapy.

Results: There was no significant change in the N-acetyl aspartate/creatine ratio (NAA/Cr) after treatment with antidepressant medication. The baseline and endpoint NAA/Cr ratios were not significantly different between the responder and nonresponder groups. The correlation between NAA/Cr and changes in the scores of clinical scales were not significant in either group.

Conclusion: This study could not confirm any significant changes in NAA after antidepressant treatment in the first episode of moderate depression, or in regard to therapy response in the left dorsolateral prefrontal cortex or left amygdala. Further research is necessary to conclude whether NAA alterations in the first episode of depression could possibly be different from chronic or late-onset depression, and whether NAA alterations in stress-induced (reactive) depression are different from endogenous depression. The potential role of NAA as a biomarker of a treatment effect has yet to be established.
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http://dx.doi.org/10.2147/NDT.S64702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4179760PMC
October 2014

Predicting symptom clusters of posttraumatic stress disorder (PTSD) in Croatian war veterans: the role of socio-demographics, war experiences and subjective quality of life.

Psychiatr Danub 2014 Sep;26(3):231-8

Department of Psychiatry, University Hospital Centre Zagreb, Kišpatićeva 12, 10000 Zagreb, Croatia,

Background: Previous research has documented multiple chains of risk in the development of PTSD among war veterans. However, existing studies were mostly carried out in the West, while they also did not analyze specific symptom clusters of PTSD. The aim of this study was to examine the role of socio-demographic characteristics, war experiences and subjective quality of life in the prediction of three clusters of PTSD symptoms (i.e., avoidance, intrusion, hyperarousal).

Subjects And Methods: This study comprised 184 male participants who have survived war imprisonment during the Croatian Homeland War in the period from 1991 to 1995. The data was collected through several self-report measuring instruments: questionnaire on socio-demographic data, war experiences (Questionnaire on Traumatic Combat and War Experiences), subjective quality of life (WHO-Five Well-being Index), and PTSD symptoms (Impact of Events Scale - Revised).

Results: The level of three symptom clusters of PTSD was found to be moderate to high, as indicated by the scores on the IES-R. Results of the three hierarchical regression analyses showed the following: traumatic war experiences were significant predictors of avoidance symptoms; traumatic war experiences and subjective quality of life were significant predictors of hyperarousal symptoms; and traumatic war experiences, material status and subjective quality of life were significant predictors of intrusion symptoms.

Conclusions: These findings support the widespread belief that the development of war-related PTSD is accounted for by multiple chains of risk, while traumatic war experiences seem to be the only predictor of all three symptom clusters. Future research should put more emphasis on specific PTSD symptom clusters when investigating the etiopathogenesis of this disorder among war-affected populations.
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September 2014

The effect of atypical antipsychotics on brain N-acetylaspartate levels in antipsychotic-naïve first-episode patients with schizophrenia: a preliminary study.

Neuropsychiatr Dis Treat 2014 7;10:1243-53. Epub 2014 Jul 7.

Polyclinic Neuron, Croatian Institute for Brain Research, University of Zagreb, Zagreb, Croatia ; Vrapče University Hospital, University of Zagreb, Zagreb, Croatia.

Purpose: To investigate the correlates of a clinical therapeutic response by using the parameters measured by proton magnetic resonance spectroscopy after the administration of atypical antipsychotics.

Patients And Methods: Twenty-five antipsychotic-naïve first-episode patients with schizophrenia were monitored for 12 months. The patients were evaluated using (1)H magnetic resonance spectroscopy in the dorsolateral prefrontal cortex and Positive and Negative Syndrome Scale, Clinical Global Impression Scale of Severity, Tower of London - Drexel University, Letter-Number Span Test, Trail Making Test A, and Personal and Social Performance Scale. They were administered atypical antipsychotics, starting with quetiapine. In the absence of a therapeutic response, another antipsychotic was introduced.

Results: After 12 study months, the N-acetylaspartate/creatine (NAA/Cr) level did not significantly change at the whole-group level. Additional analysis revealed a significant rise in the NAA/Cr level in the study group that stayed on the same antipsychotic throughout the study course (P=0.008) and a significant drop in NAA/Cr in the study group that switched antipsychotics (P=0.005). On the whole-group level, no significant correlations between NAA/Cr values and other scores were found at either baseline or after 12 study months.

Conclusion: One-year treatment with atypical antipsychotics administered to antipsychotic-naïve patients didn't result in a significant rise in the NAA/Cr ratio. However, a significant rise was witnessed in the study group in which a satisfactory therapeutic response had been achieved with a single antipsychotic administration.
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http://dx.doi.org/10.2147/NDT.S61415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094629PMC
July 2014

An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline.

Am J Psychiatry 2014 Dec 31;171(12):1278-86. Epub 2014 Oct 31.

From the Department of Psychiatry, Dalhousie University, Halifax, N.S., Canada; the Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London; the Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, U.K.; the Department of Biochemistry, King's College Hospital, London; the Department of Psychiatry, University of Bonn, Bonn, Germany; the Center for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark; Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland; University Psychiatric Clinic and the Medical Faculty, University of Ljubljana, Slovenia; the Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia; Laboratoire de Psychologie Médicale, Université Libre de Bruxelles and Psy Pluriel, Centre Européen de Psychologie Médicale, Brussels.

Objective: Major depressive disorder has been linked with inflammatory processes, but it is unclear whether individual differences in levels of inflammatory biomarkers could help match patients to treatments that are most likely to be beneficial. The authors tested the hypothesis that C-reactive protein (CRP), a commonly available marker of systemic inflammation, predicts differential response to escitalopram (a serotonin reuptake inhibitor) and nortriptyline (a norepinephrine reuptake inhibitor).

Method: The hypothesis was tested in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study, a multicenter open-label randomized clinical trial. CRP was measured with a high-sensitivity method in serum samples from 241 adult men and women with major depressive disorder randomly allocated to 12-week treatment with escitalopram (N=115) or nortriptyline (N=126). The primary outcome measure was the score on the Montgomery-Åsberg Depression Rating Scale (MADRS), administered weekly.

Results: CRP level at baseline differentially predicted treatment outcome with the two antidepressants (CRP-drug interaction: β=3.27, 95% CI=1.65, 4.89). For patients with low levels of CRP (<1 mg/L), improvement on the MADRS score was 3 points higher with escitalopram than with nortriptyline. For patients with higher CRP levels, improvement on the MADRS score was 3 points higher with nortriptyline than with escitalopram. CRP and its interaction with medication explained more than 10% of individual-level variance in treatment outcome.

Conclusions: An easily accessible peripheral blood biomarker may contribute to improvement in outcomes of major depressive disorder by personalizing treatment choice.
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http://dx.doi.org/10.1176/appi.ajp.2014.14010094DOI Listing
December 2014

Genetic predictors of antidepressant side effects: a grouped candidate gene approach in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study.

J Psychopharmacol 2014 Feb 10;28(2):142-50. Epub 2014 Jan 10.

1Social, Genetic and Developmental Psychiatry Centre, King's College London, London, UK.

Background: The unwanted side effects associated with antidepressants are key determinants of treatment adherence in depression; propensity to experience these adverse drug reactions (ADRs) may be influenced by genetic variation. However, previous work attempting to ascertain the genetic variants involved has had limited success, in part due to the range of ADRs reported with antidepressants.

Method: ADRs reported with antidepressant treatment were categorised using their likely pharmacological basis; adrenergic, cholinergic, serotonergic and histaminergic. To identify genetic predictors of susceptibility to each group of ADRs, a candidate gene analysis was performed with data from 431 depressed patients (from a total sample size of 811 patients) enrolled in the Genome-Based Therapeutic Drugs for Depression (GENDEP) project, who were randomly allocated to receive treatment with escitalopram or nortriptyline. Data from 474 patients treated with citalopram or reboxetine in the GenPod project (total sample of 601 patients) were used for replication of significant findings.

Results: We found no significant predictors of presumed adrenergic, cholinergic and histaminergic ADRs. Putative serotonergic ADRs were significantly associated with variation in the gene encoding the serotonin 2C receptor (HTR2C, rs6644093, odds ratio (OR)=1.72, 95% confidence interval (CI)=1.31-2.25, p=7.43×10(-5)) in GENDEP. However, this finding was not replicated in GenPod.

Conclusions: The association between serotonergic side effects and variation in the HTR2C gene in the GENDEP sample supports the hypothesis that serotonin receptor-mediated mechanisms underlie these adverse reactions, however this finding was not replicated in GenPod.
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http://dx.doi.org/10.1177/0269881113517957DOI Listing
February 2014

Genetic differences in cytochrome P450 enzymes and antidepressant treatment response.

J Psychopharmacol 2014 Feb 20;28(2):133-41. Epub 2013 Nov 20.

1MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.

Aims: Antidepressant response varies between patients, possibly due to differences in the rate cytochrome P450 enzymes metabolise antidepressants into inactive compounds. Drug metabolism rates are influenced by common variants in the genes encoding these enzymes. However, it remains unclear whether treatment outcomes can be predicted by either CYP450 genotype or antidepressant serum concentration.

Methods: In GENDEP (a pharmacogenetic study of depressed individuals treated with either escitalopram or nortriptyline), serum concentrations of antidepressants and their primary metabolite were measured after eight weeks treatment and variants in CYP2D6 and CYP2C19 were genotyped.

Results: Amongst patients taking escitalopram (n=223), the genotype CYP2C19 was significantly associated with escitalopram serum concentrations and desmethylescitalopram:escitalopram ratio. For those taking nortriptyline (n=161), the CYP2D6 genotype was significantly associated with nortriptyline and 10-hydroxynortriptyline serum concentrations and 10-hydroxynortriptyline:nortrip-tyline ratio. CYP450 genotypes conferring greater enzyme activity were linked to lower drug serum concentrations and higher metabolite:drug ratios. Nonetheless, no significant association was found between either CYP450 genotype or antidepressant serum concentration and treatment response.

Conclusions: While there is a significant relationship between the CYP450 genotype and serum concentrations of escitalopram and nortriptyline, the genotypes are not predictive of differences in treatment response for either drug. Furthermore, differences in antidepressant serum concentrations are not associated with variability in treatment response.
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http://dx.doi.org/10.1177/0269881113512041DOI Listing
February 2014

Genome-wide association study of co-occurring anxiety in major depression.

World J Biol Psychiatry 2013 Dec 19;14(8):611-21. Epub 2013 Sep 19.

MRC SGDP Centre, Institute of Psychiatry, King's College London , London , UK.

Objectives: Co-morbidity between depression and anxiety disorders is common. In this study we define a quantitative measure of anxiety by summating four anxiety items from the SCAN interview in a large collection of major depression (MDD) cases to identify genes contributing to this complex phenotype.

Methods: A total of 1522 MDD cases dichotomised according to those with at least one anxiety item scored (n = 1080) and those without anxiety (n = 442) were analysed, and also compared to 1588 healthy controls at a genome-wide level, to identify genes that may contribute to anxiety in MDD.

Results: For the quantitative trait, suggestive evidence of association was detected for two SNPs, and for the dichotomous anxiety present/absent ratings for three SNPs at genome-wide level. In the genome-wide analysis of MDD cases with co-morbid anxiety and healthy controls, two SNPs attained P values of < 5 × 10⁻⁶. Analysing candidate genes, P values ≤ 0.0005 were found with three SNPs for the quantitative trait and three SNPs for the dichotomous trait.

Conclusions: This study provides an initial genome-wide assessment of possible genetic contribution to anxiety in MDD. Although suggestive evidence of association was found for several SNPs, our findings suggest that there are no common variants strongly associated with anxious depression.
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http://dx.doi.org/10.3109/15622975.2013.782107DOI Listing
December 2013

Genetic predictors of response to serotonergic and noradrenergic antidepressants in major depressive disorder: a genome-wide analysis of individual-level data and a meta-analysis.

PLoS Med 2012 16;9(10):e1001326. Epub 2012 Oct 16.

Institute of Psychiatry, King's College London, London, UK.

Background: It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way.

Methods And Findings: The NEWMEDS consortium, an academia-industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies (three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study). After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants (genome-wide significance p<5×10(-8)). No biological pathways were significantly overrepresented in the results. No significant associations (genome-wide significance p<5×10(-8)) were detected in a meta-analysis of NEWMEDS and another large sample (STAR*D), with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D.

Conclusions: No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study. Please see later in the article for the Editors' Summary.
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http://dx.doi.org/10.1371/journal.pmed.1001326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3472989PMC
March 2013

Self-report and clinician-rated measures of depression severity: can one replace the other?

Depress Anxiety 2012 Dec 29;29(12):1043-9. Epub 2012 Aug 29.

Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.

Background: It has been suggested that clinician-rated scales and self-report questionnaires may be interchangeable in the measurement of depression severity, but it has not been tested whether clinically significant information is lost when assessment is restricted to either clinician-rated or self-report instruments. The aim of this study is to test whether self-report provides information relevant to short-term treatment outcomes that is not captured by clinician-rating and vice versa.

Methods: In genome-based drugs for depression (GENDEP), 811 patients with major depressive disorder treated with escitalopram or nortriptyline were assessed with the clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS), Hamilton Rating Scale for Depression (HRSD), and the self-report Beck Depression Inventory (BDI). In sequenced treatment alternatives to relieve depression (STAR*D), 4,041 patients treated with citalopram were assessed with the clinician-rated and self-report versions of the Quick Inventory of Depressive Symptomatology (QIDS-C and QIDS-SR) in addition to HRSD.

Results: In GENDEP, baseline BDI significantly predicted outcome on MADRS/HRSD after adjusting for baseline MADRS/HRSD, explaining additional 3 to 4% of variation in the clinician-rated outcomes (both P < .001). Likewise, each clinician-rated scale significantly predicted outcome on BDI after adjusting for baseline BDI and explained additional 1% of variance in the self-reported outcome (both P < .001). The results were confirmed in STAR*D, where self-report and clinician-rated versions of the same instrument each uniquely contributed to the prediction of treatment outcome.

Conclusions: Complete assessment of depression should include both clinician-rated scales and self-reported measures.
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http://dx.doi.org/10.1002/da.21993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750710PMC
December 2012

Dissecting the genetic heterogeneity of depression through age at onset.

Am J Med Genet B Neuropsychiatr Genet 2012 Oct 22;159B(7):859-68. Epub 2012 Aug 22.

MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, United Kingdom.

Genome-wide studies in major depression have identified few replicated associations, potentially due to heterogeneity within the disorder. Several studies have suggested that age at onset (AAO) can distinguish sub-types of depression with specific heritable components. This paper investigates the role of AAO in the genetic susceptibility for depression using genome-wide association data on 2,746 cases and 1,594 screened controls from the RADIANT studies, with replication performed in 1,471 cases and 1,403 controls from two Munich studies. Three methods were used to analyze AAO: First a time-to-event analysis with controls censored, secondly comparing controls to case-subsets defined using AAO cut-offs, and lastly analyzing AAO as a quantitative trait. In the time-to-event analysis three SNPs reached suggestive significance (P < 5E-06), overlapping with the original case-control analysis of this study. In a case-control analysis using AAO thresholds, SNPs in 10 genomic regions showed suggestive association though again none reached genome-wide significance. Lastly, case-only analysis of AAO as a quantitative trait resulted in 5 SNPs reaching suggestive significance. Sex specific analysis was performed as a secondary analysis, yielding one SNP reaching genome-wide significance in early-onset males. No SNPs achieved significance in the replication study after correction for multiple testing. Analysis of AAO as a quantitative trait did suggest that, across all SNPs, common genetic variants explained a large proportion of the variance (51%, P = 0.04). This study provides the first focussed analysis of the genetic contribution to AAO in depression, and establishes a statistical framework that can be applied to a quantitative trait underlying any disorder.
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http://dx.doi.org/10.1002/ajmg.b.32093DOI Listing
October 2012

A randomized, double-blind, placebo-controlled 8-week trial of the efficacy and tolerability of multiple doses of Lu AA21004 in adults with major depressive disorder.

J Clin Psychiatry 2012 Jul;73(7):953-9

Poliklinika Neuron, Croatian Institute for Brain Research, Medical School, University of Zagreb, Zagreb, Croatia.

Objective: Lu AA21004 is an investigational multimodal antidepressant. This randomized controlled trial evaluated the efficacy and tolerability of multiple doses of Lu AA21004 versus placebo in adults with major depressive disorder (MDD).

Method: Adults diagnosed with MDD (based on DSM-IV-TR criteria) with a Montgomery-Asberg Depression Rating Scale (MADRS) score ≥ 26 were randomly assigned (1:1:1:1) to receive Lu AA21004 1 mg, 5 mg, or 10 mg or placebo for 8 weeks (between August 2008 and August 2009). The primary endpoint was reduction in 24-Item Hamilton Depression Rating Scale (HDRS-24) total score after 8 weeks of treatment compared with placebo for Lu AA21004 10 mg. Additional outcomes included response and remission rates, Sheehan Disability Scale (SDS), Clinical Global Impressions-Global Improvement scale (CGI-I), MADRS total score, and HDRS-24 total score in subjects with baseline Hamilton Anxiety Rating Scale (HARS) score ≥ 20. Adverse events were assessed throughout the study.

Results: A total of 560 subjects (mean age = 46.4 years) were randomized. There was a statistically significant reduction from baseline in HDRS-24 total score at week 8 for Lu AA21004 10 mg vs placebo (P < .001). There were improvements (nominal P values < .05 with no adjustment for multiplicity) in HDRS-24 total score, response and remission rates, CGI-I score, MADRS total score, and HDRS-24 total score in subjects with baseline HARS score ≥ 20 at week 8 for all Lu AA21004 treatment groups vs placebo. No significant differences were seen in SDS scores between any dose of Lu AA21004 and placebo. The most common adverse events were nausea, headache, and dizziness.

Conclusions: After 8 weeks of treatment with Lu AA21004 10 mg, there was a significant reduction in HDRS-24 total score compared with placebo in adults with MDD. Lu AA21004 was well tolerated in this study.

Trial Registration: ClinicalTrials.gov identifier: NCT00735709.
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http://dx.doi.org/10.4088/JCP.11m07470DOI Listing
July 2012

Non-random dropout and the relative efficacy of escitalopram and nortriptyline in treating major depressive disorder.

J Psychiatr Res 2012 Oct 6;46(10):1333-8. Epub 2012 Jul 6.

Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, London, United Kingdom.

Most comparisons of the efficacy of antidepressants have relied on the assumption that missing data are randomly distributed. Dropout rates differ between drugs, suggesting this assumption may not hold true. This paper examines the effect of non-random dropout on a comparison of two antidepressant drugs, escitalopram and nortriptyline, in the treatment of major depressive disorder. The GENDEP study followed adult patients with major depressive disorder over 12 weeks of treatment, and the primary analysis found no difference in efficacy of the two antidepressants under missing at random assumption. By applying the recently developed Muthén-Roy model, we compared the relative efficacy of these two antidepressants taking into account non-random distribution of missing outcomes (NMAR). Individuals who dropped out of the study were those who were not responding to treatment. Based on the best fitting NMAR model, it was found that escitalopram reduced symptom scores by an additional 1.4 points on the Montgomery-Åsberg Depression Rating Scale (p = 0.02), equivalent to 5% of baseline depression severity, compared to nortriptyline. We conclude that association between dropout and worsening symptoms led to an overestimate of the effectiveness of treatment, especially with nortriptyline, in the primary analysis. These findings review the primary analysis of GENDEP and suggest that, when non-random dropout is accounted for, escitalopram is more effective than nortriptyline in reducing symptoms of major depression.
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http://dx.doi.org/10.1016/j.jpsychires.2012.06.014DOI Listing
October 2012

Early and delayed onset of response to antidepressants in individual trajectories of change during treatment of major depression: a secondary analysis of data from the Genome-Based Therapeutic Drugs for Depression (GENDEP) study.

J Clin Psychiatry 2011 Nov;72(11):1478-84

MRC Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King’s College London, United Kingdom, London, UK.

Objective: The timing and rate of improvement after the initiation of an antidepressant has implications for establishing the mechanism of antidepressant action and for answering the clinically relevant question of how long an appropriate trial of antidepressant medication should be. We explore the individual trajectories of relative change in depression severity to establish what proportion of individuals experience early and late onset of improvement.

Method: Longitudinal latent class analysis was applied in a secondary analysis of data obtained from the Genome-Based Therapeutic Drugs for Depression (GENDEP) study. In the GENDEP trial, conducted in 9 European academic psychiatry centers from July 2004 to June 2008, 811 treatment-seeking adult subjects with DSM-IV major depression received escitalopram or nortriptyline for 12 weeks. Montgomery-Asberg Depression Rating Scale measurements were taken weekly. The secondary analysis reported in this article was conducted in 2010.

Results: A model with 9 latent classes provided a good description of the individual trajectories of symptom change over time. These classes included 3 nonresponder classes, 3 classes with varying degrees of improvement concentrated in the first 3 weeks (early improvement), and 3 classes with varying degrees of improvement that was more prominent in the second 3 weeks than in the first 3 weeks (delayed improvement). More than half of the subjects who eventually reached remission showed a pattern of delayed improvement, and their eventual outcome could not be predicted from early time points. Early marked response occurred more frequently in subjects treated with nortriptyline than in those treated with escitalopram (12.9% vs 7.5%, χ² = 6.29, P = .01). Delayed complete remission occurred more frequently in subjects treated with escitalopram than in those treated with nortriptyline (13.6% vs 6.1%, χ² = 11.52, P = .0007).

Conclusions: Both early and delayed improvement are common. Although early changes are maintained, the eventual outcome of 12-week antidepressant treatment can be accurately predicted only after 8 weeks.

Trial Registration: http://www.controlled-trials.com Identifier: ISRCTN03693000.
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http://dx.doi.org/10.4088/JCP.10m06419DOI Listing
November 2011
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