André Tadić

The catechol-O-methyltransferase Val108/158Met polymorphism affects short-term treatment response to mirtazapine, but not to paroxetine in major depression.

The catechol-O-methyltransferase (COMT) is a major degrading enzyme in the metabolic pathways of catecholaminergic neurotransmitters such as dopamine and norepinephrine. This study investigated whether the functionally relevant Val108/158Met gene variant is associated with differential antidepressant response to mirtazapine and/or paroxetine in 102 patients with major depression (DSM-IV criteria) participating in a randomized clinical trial with both drugs. In patients treated with mirtazapine, but not paroxetine, allelic variations in the COMT gene were associated with differential response. COMTVAL/VAL and COMTVAL/MET genotype carriers showed a better response than COMTMET/MET-bearing patients in the mirtazapine group. Moreover, carriers of the COMTVAL/VAL or COMTVAL/MET genotype had significantly greater HAMD-17 (Hamilton Rating Scale for Depression 17 item version) score reductions than COMTMET/MET homozygotes from week 2 to 6, respectively, in the mirtazapine group. Time course of response and antidepressant efficacy of mirtazapine, but not paroxetine, seem to be influenced in a clinically relevant manner by this allelic variation within the COMT gene.

Association of a MAOA gene variant with generalized anxiety disorder, but not with panic disorder or major depression

This study was conducted to detect a possible association of a T941G single nucleotide polymorphism (SNP) in the monoamine oxidase A (MAOA) gene with generalized anxiety disorder (GAD), panic disorder (PD), or major depression (MD). Fifty GAD patients (34 females and 16 males), 38 PD patients (21 females and 17 males), and 108 MD patients (80 females and 28 males) were included. The comparison group consisted of 276 (132 females and 144 males) unrelated healthy individuals. The 941T allele was over‐represented in patients suffering from GAD (χ2 = 6.757; df = 1; P < 0.01, not corrected for multiple testing) when compared to healthy volunteers. No association was observed in MD or PD. This is the first study specifically analyzing the MAOA G941T polymorphism in GAD and thus needs to be replicated in an independent sample. However, the results are in line with previous data suggesting an association between the MAOA locus and regulation of complex human behavior.

Early improvement is a predictor of treatment outcome in patients with mild major, minor or subsyndromal depression

BACKGROUND There is substantial evidence that early improvement (EI) under antidepressant treatment is a clinically useful predictor of later treatment outcome in patients with major depressive disorders. The aim of this study was to test whether EI can also be used as a predictor for treatment outcome in patients with mild major, minor or subsyndromal depression, i.e. patients, who are typically treated by general practitioners. METHODS Analyses were carried out using data from 223 patients of a 10-weeks randomized, placebo-controlled trial comparing the effectiveness of sertraline and cognitive-behavioural therapy (CBT) in patients with mild major, minor or subsyndromal depression. EI was defined as a reduction of > or =20% on the 17-item Hamilton Rating Scale for Depression (HAMD-17) compared with baseline within the first 2 weeks of treatment. The predictive value of EI for stable response at week 8 and 10 (> or =50% HAMD-17 sum score reduction at weeks 8 and 10) and stable remission (HAMD-17 sum score < or =7 at weeks 8 and 10) was evaluated. RESULTS In both the sertraline- and CBT-treatment group, EI was a highly sensitive predictor for later stable response (76% and 82%, respectively) and stable remission (70% and 75%, respectively). In patients without EI, only a small proportion of sertraline or CBT-treated patients achieved stable response (20.9% and 5.9%, respectively) or stable remission (18.6% and 8.8%, respectively). Patients with EI were by far more likely to achieve stable response or stable remission than patients without as indicated by high odds ratios (95% confidence interval) of 8.1 (3.0-21.8) and 3.8 (1.4-10.1) for sertraline, and 11.1 (2.1-58.4) and 7.2 (1.7-30.8) for CBT-treated patients, respectively. LIMITATIONS Sample sizes were relatively low in different treatment groups. CONCLUSION The identification of early improvement might be useful in clinical decision making in the early course of treatment of patients with mild major, minor and subthreshold depression.

Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study.

BACKGROUND The purpose of this study was to assess the efficacy and safety and to explore the dose response of esketamine intravenous (IV) infusion in patients with treatment-resistant depression (TRD). METHODS This multicenter, randomized, placebo-controlled trial was conducted in 30 patients with TRD. Patients were randomly assigned 1:1:1 to receive an IV infusion of .20 mg/kg or .40 mg/kg esketamine or placebo over 40 minutes on day 1. The primary end point was change in Montgomery-Åsberg Depression Rating Scale total score from day 1 (baseline) to day 2. Nonresponders who received placebo on day 1 were randomly assigned again 1:1 to IV esketamine .20 mg/kg or .40 mg/kg on day 4. Secondary efficacy and safety measures were also evaluated. RESULTS Of the enrolled patients, 97% (29 of 30) completed the study. The least squares mean changes (SE) from baseline to day 2 in Montgomery-Åsberg Depression Rating Scale total score for the esketamine .20 mg/kg and .40 mg/kg dose groups were -16.8 (3.00) and -16.9 (2.61), respectively, and showed significant improvement (one-sided p = .001 for both groups) compared with placebo (-3.8 [2.97]). Esketamine showed a rapid (within 2 hours) and robust antidepressant effect. Treatment-emergent adverse events were dose dependent. The most common treatment-emergent adverse events were headache, nausea, and dissociation; the last-mentioned was transient and did not persist beyond 4 hours from the start of the esketamine infusion. CONCLUSIONS A rapid onset of robust antidepressant effects was observed in patients with TRD after a 40-minute IV infusion of either .20 mg/kg or .40 mg/kg of esketamine. The lower dose may allow for better tolerability while maintaining efficacy.

Gender Differences in Axis I and Axis II Comorbidity in Patients with Borderline Personality Disorder

Background/Aims: Differences in the clinical presentation of men and women with borderline personality disorder (BPD) are of potential interest for investigations into the neurobiology, genetics, natural history, and treatment response of BPD. The purpose of this study was to investigate gender differences in axis I and axis II comorbidity and in diagnostic criteria in BPD patients. Methods: 110 women and 49 men with BPD were assessed with the computer-based version of the Munich-Composite International Diagnostic Interview and the Structured Clinical Interview for DSM-IV Personality Disorders. Gender differences were investigated for the following outcomes: (a) lifetime, 12-month and 4-week prevalence of axis I disorders; (b) axis II disorders, and (c) DSM-IV BPD diagnostic criteria. Results: With regard to lifetime prevalence of axis I disorders, men more often displayed a substance use disorder, in particular alcohol dependency (65 vs. 43%); on the other hand, women more frequently had an affective (94 vs. 82%), anxiety (92 vs. 80%) or eating disorder (35 vs. 18%), in particular anorexia nervosa (21 vs. 4%). Regarding the 12-month prevalence, we found significantly more women suffering from anorexia nervosa (13 vs. 0%). Considering the 4-week prevalence, there were no significant gender differences. With regard to axis II disorders, men had a higher frequency of antisocial personality disorder (57 vs. 26%). Regarding the BPD diagnostic criteria, men more often displayed ‘intensive anger’ (74 vs. 49%), whereas women more frequently showed ‘affective instability’ (94 vs. 82%). Conclusion: In this German study, we could replicate and extend the findings from previous US studies, where men and women with BPD showed important differences in their pattern of psychiatric comorbidity. The implications for clinicians and researchers are discussed.

A coordinate-based ALE functional MRI meta-analysis of brain activation during verbal fluency tasks in healthy control subjects

BackgroundThe processing of verbal fluency tasks relies on the coordinated activity of a number of brain areas, particularly in the frontal and temporal lobes of the left hemisphere. Recent studies using functional magnetic resonance imaging (fMRI) to study the neural networks subserving verbal fluency functions have yielded divergent results especially with respect to a parcellation of the inferior frontal gyrus for phonemic and semantic verbal fluency. We conducted a coordinate-based activation likelihood estimation (ALE) meta-analysis on brain activation during the processing of phonemic and semantic verbal fluency tasks involving 28 individual studies with 490 healthy volunteers.ResultsFor phonemic as well as for semantic verbal fluency, the most prominent clusters of brain activation were found in the left inferior/middle frontal gyrus (LIFG/MIFG) and the anterior cingulate gyrus. BA 44 was only involved in the processing of phonemic verbal fluency tasks, BA 45 and 47 in the processing of phonemic and semantic fluency tasks.ConclusionsOur comparison of brain activation during the execution of either phonemic or semantic verbal fluency tasks revealed evidence for spatially different activation in BA 44, but not other regions of the LIFG/LMFG (BA 9, 45, 47) during phonemic and semantic verbal fluency processing.

The MAOA T941G polymorphism and short-term treatment response to mirtazapine and paroxetine in major depression.

This study investigated the possible association of the MAOA T941G gene variant with differential antidepressant response to mirtazapine and/or paroxetine in 102 patients with major depression (DSM‐IV criteria) participating in a randomized double‐blind controlled clinical trial. Female mirtazapine‐treated patients homozygous for the T‐allele had a significantly faster and better treatment response than TG/GG‐patients. In males, we failed to show an association between MAOA T941G gene variant and mirtazapine response. In the paroxetine‐treated group, there were no significant differences in treatment response between MAOA T941G genotype groups. Time course of response and antidepressant efficacy of mirtazapine, but not paroxetine, seem to be influenced in a clinically relevant manner by this allelic variation within the MAOA gene, at least in female patients. An independent replication of our finding is needed. If replicated, genotyping of this locus could become a promising tool to predict response to mirtazapine treatment in females suffering from major depression.

The 5-HTTLPR Polymorphism modulates the association of serious life events (SLE) and impulsivity in patients with Borderline Personality Disorder

BACKGROUND Impulsivity belongs to the key features of Borderline Personality Disorder (BPD). It has been linked to altered serotoninergic neurotransmission and, genetically, to an over-representation of the short (S) allele of the serotonin transporter promoter-linked polymorphic region polymorphism (5-HTTLPR). On the other hand, serious life events (SLE) are of major importance in the development of BPD. However, the inter-relations between SLEs, impulsivity, and 5-HTTLPR are not understood. METHOD 159 BPD patients from Germany were included in this study. Impulsivity was assessed by the Barratt Impulsiveness Scale (BIS). We analysed (1) the effects of SLEs on impulsivity; and (2) modulating effects of the 5-HTTLPR polymorphism on the effects of SLEs on impulsivity. RESULTS Regression analyses confirmed a decreasing effect of childhood sexual abuse, the cumulative SLE-related reactions and the impairment by SLEs on BIS sum score. Regarding BIS sum score, all SLEs except for rape were associated with a decrease of impulsivity in SS/SL carriers and an increase of BIS sum score in LL carriers. CONCLUSIONS This study analyzing a specific gene x environment interaction in BPD patients suggests an interaction between SLEs and the 5-HTTLPR S/L polymorphism in the development of impulsivity in BPD patients. Clinical and research implications are discussed.

Reliability of three alternate forms of the trail making tests a and B.

The majority of patients with Major Depressive Disorder (MDD) suffer from significant executive dysfunctions. To investigate the time course of executive functions during antidepressant treatment, repeated measures of executive functions are necessary. In order to avoid practice effects, the assessment of alternate forms is suggested. The aim of this study was to compare the processing times of four alternate versions of the Trail Making Test (TMT) A and B in patients with MDD. Fifty-five subjects with DSM-IV MDD were included in the study. We analyzed mean processing times and retest reliability of the four versions of TMT A and B. Mean processing times did not differ between the four tested versions of TMT A and B. Retest reliability of TMT A and B was between 0.76 and 0.89 and between 0.86 and 0.94, respectively. Because of their identical difficulty and high reliability, the herein described versions of the TMT A and B are suitable for sequential testing of executive functioning.

Interaction between gene variants of the serotonin transporter promoter region (5-HTTLPR) and catechol O-methyltransferase (COMT) in borderline personality disorder.

Borderline personality disorder (BPD) is characterized by a heterogeneous symptomatology with instability in impulse control, interpersonal relationships and self‐image. BPD patients display repeated self‐injury, chronic suicidal tendencies and emotional dysregulation, mainly dysregulation of negative affect. In its etiology, genetic and environmental factors have been suggested. Recently, an investigation in male healthy volunteers found gene–gene effects of the catechol‐O‐methyl‐transferase (COMT) low‐activity (Met158) and the low‐expression allele of the deletion/insertion (short/long or S/L, respectively) polymorphism in the serotonin transporter‐linked promoter region (5‐HTTLPR) on the central processing of aversive stimuli. The purpose of the present study was to test for association between BPD and the COMT Val158Met single nucleotide polymorphism (SNP), the 5‐HTTLPR S/L variant and the interaction of these two gene variants. One hundred sixty one well‐defined Caucasian BPD patients and 156 healthy controls were recruited from central Germany. In BPD patients, the genotype COMT Met158Met was over‐represented compared to healthy controls (P = 0.0085; adjusted P = 0.034). We observed no differences in 5‐HTTLPR genotypes between BPD and controls (P = 0.286). Additionally, the COMT Met158Met genotype was significantly over‐represented in BPD patients carrying at least one 5‐HTTLPR S allele (P = 0.0007; adjusted P = 0.028). Logistic regression analysis confirmed an interaction of the COMT Met158 and the 5‐HTTLPR S allele (P = 0.001). These data suggest an involvement of altered dopaminergic and/or noradrenergic neurotransmission as well as an interactive effect of COMT and 5‐HTTLPR gene variants in the etiology of BPD, and underline the usefulness of analyses of gene–gene effects in diseases of complex inheritance with multiple genes involved.