Ricard Navinés

Interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis.

OBJECTIVE To carry out a systematic review of the risk factors for, and incidence of, major depressive episode (MDE) related to antiviral therapy for chronic hepatitis C. DATA SOURCES The MEDLINE, PsycINFO, and Cochrane databases were searched to locate articles published from the earliest available online year until June 2011 using the keywords hepatitis C, interferon-alpha, peginterferon, pegylated interferon, depression, and mood and Boolean operators. Articles written in English, Spanish, and French were included. STUDY SELECTION Prospective studies reporting incidence of interferon-alpha-induced MDE were included. At baseline, patients did not present a DSM-IV/ICD depressive episode, and evaluation was performed by a trained clinician. Twenty-six observational studies met the inclusion criteria. DATA EXTRACTION Extracted data included authors, year of publication, design, characteristics of the population, viral coinfection, adjunctive psychopharmacology, instruments to assess depression, dose and type of interferon-alpha, adjunctive ribavirin treatment, and follow-up time. Outcome of incidence of MDE (primary outcome measure) was abstracted, as were potential predictive variables. DATA SYNTHESIS A full review was performed. Meta-analysis of the cumulative incidence of induced MDE as a function of time was carried out. Odds ratios (ORs) and mean differences were used to estimate the strength of association of variables. RESULTS Overall cumulative incidence of depression was 0.25 (95% CI, 0.16 to 0.35) and 0.28 (95% CI, 0.17 to 0.42) at 24 and 48 weeks of treatment, respectively. According to our analysis, high baseline levels of interleukin 6 (mean difference = 1.81; 95% CI, 1.09 to 2.52), female gender (OR = 1.40; 95% CI, 1.02 to 1.91), history of MDE (OR = 3.96; 95% CI, 2.52 to 6.21), history of psychiatric disorder (OR = 3.18; 95% CI, 1.60 to 6.32), subthreshold depressive symptoms (mean difference = 0.96; 95% CI, 0.31 to 1.61), and low educational level (mean difference = -0.99; 95% CI, -1.59 to -0.39) were predictive variables of MDE during antiviral treatment. CONCLUSIONS One in 4 chronic hepatitis C patients who start interferon and ribavirin treatment will develop an induced major depressive episode. Clinicians should attempt a full evaluation of patients before starting antiviral treatment in order to identify those at risk of developing interferon-induced depression.

Human microRNAs miR-22, miR-138-2, miR-148a, and miR-488 Are Associated with Panic Disorder and Regulate Several Anxiety Candidate Genes and Related Pathways

BACKGROUND The involvement of microRNAs (miRNAs) in neuronal differentiation and synaptic plasticity suggests a role for miRNAs in psychiatric disorders; association analyses and functional approaches were used to evaluate the implication of miRNAs in the susceptibility for panic disorder. METHODS Case-control studies for 712 single-nucleotide polymorphisms (SNPs) tagging 325 human miRNA regions were performed in 203 Spanish patients with panic disorder and 341 control subjects. A sample of 321 anxiety patients and 642 control subjects from Finland and 102 panic disorder patients and 829 control subjects from Estonia was used as a replica. Reporter-gene assays and miRNA overexpression experiments in neuroblastoma cells were used to functionally evaluate the spectrum of genes regulated by the associated miRNAs. RESULTS Two SNPs associated with panic disorder: rs6502892 tagging miR-22 (p < .0002), and rs11763020 tagging miR-339 (p < .00008). Other SNPs tagging miR-138-2, miR-488, miR-491, and miR-148a regions associated with different panic disorder phenotypes. Replication in the north-European sample supported several of these associations, although they did not pass correction for multiple testing. Functional studies revealed that miR-138-2, miR-148a, and miR-488 repress (30%-60%) several candidate genes for panic disorder--GABRA6, CCKBR and POMC, respectively--and that miR-22 regulates four other candidate genes: BDNF, HTR2C, MAOA, and RGS2. Transcriptome analysis of neuroblastoma cells transfected with miR-22 and miR-488 showed altered expression of a subset of predicted target genes for these miRNAs and of genes that might be affecting physiological pathways related to anxiety. CONCLUSIONS This work represents the first report of a possible implication of miRNAs in the etiology of panic disorder.

De novo depression and anxiety disorders and influence on adherence during peginterferon-alpha-2a and ribavirin treatment in patients with hepatitis C

Background  Depression and anxiety have been associated with interferon treatment and low treatment adherence.

Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders

Genetic and functional data indicate that variation in the expression of the neurotrophin‐3 receptor gene (NTRK3) may have an impact on neuronal plasticity, suggesting a role for NTRK3 in the pathophysiology of anxiety disorders. MicroRNA (miRNA) posttranscriptional gene regulators act by base‐pairing to specific sequence sites, usually at the 3′UTR of the target mRNA. Variants at these sites might result in gene expression changes contributing to disease susceptibility. We investigated genetic variation in two different isoforms of NTRK3 as candidate susceptibility factors for anxiety by resequencing their 3′UTRs in patients with panic disorder (PD), obsessive‐compulsive disorder (OCD), and in controls. We have found the C allele of rs28521337, located in a functional target site for miR‐485‐3p in the truncated isoform of NTRK3, to be significantly associated with the hoarding phenotype of OCD. We have also identified two new rare variants in the 3′UTR of NTRK3, ss102661458 and ss102661460, each present only in one chromosome of a patient with PD. The ss102661458 variant is located in a functional target site for miR‐765, and the ss102661460 in functional target sites for two miRNAs, miR‐509 and miR‐128, the latter being a brain‐enriched miRNA involved in neuronal differentiation and synaptic processing. Interestingly, these two variants significantly alter the miRNA‐mediated regulation of NTRK3, resulting in recovery of gene expression. These data implicate miRNAs as key posttranscriptional regulators of NTRK3 and provide a framework for allele‐specific miRNA regulation of NTRK3 in anxiety disorders. Hum Mutat 30:1–10, 2009.

Glucocorticoid Receptors, Brain-Derived Neurotrophic Factor, Serotonin and Dopamine Neurotransmission are Associated with Interferon-Induced Depression.

Background: The role of inflammation in mood disorders has received increased attention. There is substantial evidence that cytokine therapies, such as interferon alpha (IFN-alpha), can induce depressive symptoms. Indeed, proinflammatory cytokines change brain function in several ways, such as altering neurotransmitters, the glucocorticoid axis, and apoptotic mechanisms. This study aimed to evaluate the impact on mood of initiating IFN-alpha and ribavirin treatment in a cohort of patients with chronic hepatitis C. We investigated clinical, personality, and functional genetic variants associated with cytokine-induced depression. Methods: We recruited 344 Caucasian outpatients with chronic hepatitis C, initiating IFN-alpha and ribavirin therapy. All patients were euthymic at baseline according to DSM-IV-R criteria. Patients were assessed at baseline and 4, 12, 24, and 48 weeks after treatment initiation using the Patient Health Questionnaire (PHQ), the Hospital Anxiety and Depression Scale (HADS), and the Temperament and Character Inventory (TCI). We genotyped several functional polymorphisms of interleukin-28 (IL28B), indoleamine 2,3-dioxygenase (IDO-1), serotonin receptor-1A (HTR1A), catechol-O-methyl transferase (COMT), glucocorticoid receptors (GCR1 and GCR2), brain-derived neurotrophic factor (BDNF), and FK506 binding protein 5 (FKBP5) genes. A survival analysis was performed, and the Cox proportional hazards model was used for the multivariate analysis. Results: The cumulative incidence of depression was 0.35 at week 24 and 0.46 at week 48. The genotypic distributions were in Hardy-Weinberg equilibrium. Older age (p = 0.018, hazard ratio [HR] per 5 years = 1.21), presence of depression history (p = 0.0001, HR = 2.38), and subthreshold depressive symptoms at baseline (p = 0.005, HR = 1.13) increased the risk of IFN-induced depression. So too did TCI personality traits, with high scores on fatigability (p = 0.0037, HR = 1.17), impulsiveness (p = 0.0200 HR = 1.14), disorderliness (p = 0.0339, HR = 1.11), and low scores on extravagance (p = 0.0040, HR = 0.85). An interaction between HTR1A and COMT genes was found. Patients carrying the G allele of HTR1A plus the Met substitution of the COMT polymorphism had a greater risk for depression during antiviral treatment (HR = 3.83) than patients with the CC (HTR1A) and Met allele (COMT) genotypes. Patients carrying the HTR1A CC genotype and the COMT Val/Val genotype (HR = 3.25) had a higher risk of depression than patients with the G allele (HTR1A) and the Val/Val genotype. Moreover, functional variants of the GCR1 (GG genotype: p = 0.0436, HR = 1.88) and BDNF genes (Val/Val genotype: p = 0.0453, HR = 0.55) were associated with depression. Conclusions: The results of the study support the theory that IFN-induced depression is associated with a complex pathophysiological background, including serotonergic and dopaminergic neurotransmission as well as glucocorticoid and neurotrophic factors. These findings may help to improve the management of patients on antiviral treatment and broaden our understanding of the pathogenesis of mood disorders.

Prophylactic treatment with escitalopram of pegylated interferon alfa-2a-induced depression in hepatitis C: a 12-week, randomized, double-blind, placebo-controlled trial.

BACKGROUND Depression is one of the main reasons for treatment withdrawal and failure in chronic hepatitis C patients treated with interferon. Antidepressants are useful for its treatment, but whether they can also be used for prevention has yet to be established. METHOD To evaluate the efficacy and safety of escitalopram for preventing interferon alfa-2a-induced depression, we conducted an investigator-initiated multicenter, randomized, double-blind, placebo-controlled trial in 133 chronic hepatitis C patients without baseline mental disorders who were randomly assigned to receive escitalopram or placebo during the first 12 weeks of treatment. Primary efficacy outcomes were the development of DSM-IV major depression and scores on the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hospital Anxiety and Depression Scale (HADS). Primary safety end points were biochemical and virological responses. Patients were recruited between March 2005 and July 2006. RESULTS Rates of major depression were low (5.4%) and did not differ between placebo (3.2%) and escitalopram (7.6%). MADRS and HADS scores significantly increased during treatment (P < .001 and P = .028, respectively), but there were no differences between treatment groups. Sustained virological response was achieved by 69.2% of patients, 70.4% in the placebo group and 67.9% in the escitalopram group. CONCLUSIONS Findings do not support the use of an antidepressant to prevent interferon-induced depression during the first 12 weeks of treatment in chronic hepatitis C patients at low psychiatric risk. Future studies should be directed to subpopulations of patients at high psychiatric risk. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00166296.

Serotonin and interleukin-6: the role of genetic polymorphisms in IFN-induced neuropsychiatric symptoms.

BACKGROUND Cytokines and serotonin neurotransmission may play an important role on the development of psychopathological symptoms during interferon (IFN) treatment. The aim of the present study was to investigate the association between IFN-induced depression, anxiety and fatigue and functional genetic variants at the interleukin-6 gene (IL-6) and serotonin transporter gene (SERT). METHODS 385 consecutive Caucasian outpatients with chronic hepatitis C initiating treatment with IFN-alpha and ribavirin were included. All patients were interviewed at baseline using the Structured Clinical Interview for DSM-IV (SCID-I) and those with a current major depressive disorder or anxiety disorder before starting treatment were excluded. Depression and anxiety were assessed at baseline during the treatment (at 4, 12, 24 and 48 weeks) using the Hospital Anxiety and Depression Scale and fatigue was evaluated using a visual analogue scale. The 5-HTTLPR region of SERT gene and the functional polymorphism located at the promoter region of IL-6 gene (rs1800795) were genotyped. RESULTS Genotypic distribution was in the Hardy-Weinberg equilibrium for SERT (p=0.41) and for IL-6 (p=0.72) polymorphisms. At baseline we found only a significant effect of IL-6 polymorphism on fatigue symptoms. During antiviral treatment we reported that subjects with CC genotype (IL-6) presented significantly lower changes from baseline in IFN-induced depression (p=0.005) and IFN-induced anxiety (p=0.004). We did not find statistically significant differences on depression (p=0.21) or anxiety (p=0.15) between SS/SL and LL genotypes of SERT. CONCLUSIONS Genetic variations in the IL-6 gene increase the risk of IFN-induced depression and anxiety. The IL-6 polymorphism was associated with fatigue rates in patients with chronic hepatitis C before treatment. Our study confirms the role of inflammatory mechanisms in IFN-induced psychopathological symptoms.

What do all personality disorders have in common? Ineffectiveness and uncooperativeness.

We still lack operative and theoretically founded definitions of what a personality disorder (PD) is, as well as empirically validated and feasible instruments to measure the disorder construct. The Temperament and Character Inventory (TCI) is the only personality instrument that explicitly distinguishes personality style and disordered functioning. Here, we seek to (1) confirm in a clinical sample that the character dimensions of the TCI capture a general construct of PD across all specific PD subtypes, (2) determine whether such core features can be used to detect the presence of PD, and (3) analyze whether such detection is affected by the presence and severity of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Axis I symptoms. Two hundred five anxious/depressed outpatients were evaluated with the Structural Clinical Interview for DSM-IV Axis I and II Disorders. Assessment also included the TCI, the Hamilton rating scales for depression and anxiety, and the Panic and Agoraphobia Scale. Sixty-one patients (29.8%) were diagnosed as having a DSM-IV PD. Self-directedness and Cooperativeness, but no other TCI dimensions, predicted the presence of PD (Nagelkerke R(2) = 0.35-0.45) and had a moderate diagnostic utility (kappa = 0.47-0.58) when Axis I symptoms were absent or mild. However, accuracy decreased in anxious or depressed patients. Our study supports the hypothesis of a disorder construct that is not related to the intensity of any specific PD subtype but which is common to all PDs. This construct relies largely on internal representations of the self revealing ineffectiveness and uncooperativeness.

Perfectionism dimensions in major postpartum depression

BACKGROUND Although perfectionism from a multidimensional perspective has generally been associated with depressive illness, there are not many studies on its role in major depression in the postnatal period. The aim of the present study was to explore the relationship between perfectionism dimensions using the Frost Multidimensional Perfectionism Scale (FMPS) and major postpartum depression. METHODS One-hundred-twenty-two women with major postpartum depression (SCID-I; DSM-IV) and 115 healthy postpartum women were evaluated using the FMPS, an instrument for the assessment of six perfectionism dimensions: concern over mistakes, personal standards, parental expectations, parental criticism, doubt about actions and organisation. Other variables were also considered: neuroticism, psychiatric history, social support, life events and genotype combinations according to serotonin transporter expression (5-HTTLPR and Stin2 VNTR polymorphisms). RESULTS The prevalence of high-perfectionism was higher in major postpartum depression group than in control group (34% vs. 11%; p<0.001). Multivariate models confirmed high-perfectionism as an independent factor associated with major postpartum depression. Specifically, the high-concern over mistakes dimension increased over four-fold the odds of major depression in postpartum period. (OR=4.14; 95% CI=1.24-13.81) Neuroticism, personal psychiatric history and 5-HTT low-expressing genotypes at one of the loci were also identified as independent factors. CONCLUSIONS High-perfectionism, and particularly high-concern over mistakes is a personality dimension associated with major postpartum depression. The inclusion of perfectionism assessment, together with others factors, may be considered in order to improve the detection of women at risk of postpartum depression, in whom early intervention may be of benefit.

A multidisciplinary support programme increases the efficiency of pegylated interferon alfa-2a and ribavirin in hepatitis C

BACKGROUND & AIMS Adherence to antiviral treatment is important to achieve sustained virological response (SVR) in chronic hepatitis C (CHC). We evaluated the efficiency of a multidisciplinary support programme (MSP), based on published HIV treatment experience, to increase patient adherence and the efficacy of pegylated interferon alfa-2a and ribavirin in CHC. METHODS 447 patients receiving antiviral treatment were distributed into 3 groups: control group (2003-2004, n=147), MSP group (2005-2006, n=131), and MSP-validation group (2007-2009, n=169). The MSP group included two hepatologists, two nurses, one pharmacist, one psychologist, one administrative assistant, and one psychiatrist. Cost-effectiveness analysis was performed using a Markov model. RESULTS Adherence and SVR rates were higher in the MSP (94.6% and 77.1%) and MSP-validation (91.7% and 74.6%) groups compared to controls (78.9% and 61.9%) (p<0.05 in all cases). SVR was higher in genotypes 1 or 4 followed by the MSP group vs. controls (67.7% vs. 48.9%, p=0.02) compared with genotypes 2 or 3 (87.7% vs. 81.4%, p=n.s.). The MSP was the main predictive factor of SVR in patients with genotype 1. The rate of adherence in patients with psychiatric disorders was higher in the MSP groups (n=95, 90.5%) compared to controls (n=28, 75.7%) (p=0.02). The cost per patient was € 13,319 in the MSP group and € 16,184 in the control group. The MSP group achieved more quality-adjusted life years (QALYs) (16.317 QALYs) than controls (15.814 QALYs) and was dominant in all genotypes. CONCLUSIONS MSP improves patient compliance and increases the efficiency of antiviral treatment in CHC, being cost-effective.