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Objectives: The ability to identify persons at elevated risk for post-traumatic stress disorder (PTSD) soon after exposure to trauma, could aid clinical decision-making and treatment. In this study, we explored whether cytosine methylation of the 1 F promoter of the NR3C1 (glucocorticoid receptor [GR]) gene obtained immediately following a trauma could predict PTSD., Methods: Our sample comprised 52 trauma survivors (28 women, 24 men), presenting to the Emergency Department (ED) within six hours of a traumatic event and followed for 13 months. Blood samples were taken at intake ( n  = 42) and again at the end of the study (13 months later, n  = 27) to determine NR3C1-1F promoter methylation as well as plasma levels of cortisol, adrenocorticotropic-hormone (ACTH), and neuropeptide-Y (NPY)., Results: At the 13-month follow-up, participants who met the PTSD criteria ( n  = 4) showed significantly lower NR3C1-1F promoter sum percent methylation compared to the non-PTSD group ( n  = 38). Further, NR3C1-1F methylation at ED intake was inversely correlated with PTSD severity 13 months later, indicating that lower NR3C1-1F promoter methylation in the immediate aftermath of trauma was associated with the development of PTSD., Conclusion: To the extent that reduced promoter methylation is associated with greater GR expression and responsivity, this finding is consistent with the hypothalamic-pituitary-adrenal dysregulation previously described for PTSD.

Objectives: This study aimed to identify factors associated with side effects of psychotropic drugs in a real-world setting enriched with treatment-resistant depression (TRD) patients., Methods: A total of 1410 depressed patients were treated in a naturalistic setting. Side effects were measured with the Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU); the total score and UKU subscales were considered. Clinical-demographic variables were tested for association with side effects in univariate and then multivariate analyses., Results: Total, psychic and neurological side effects were associated with depressive symptom severity, while autonomic side effects were higher in those with somatic comorbidities and other side effects were lower in patients receiving trazodone. In multivariate analyses, depressive symptom severity was associated with psychic and total side effects, while generalised anxiety disorder (GAD) with neurological side effects and somatic comorbidities remained associated with autonomic side effects. Trazodone was associated with lower side effects and with augmentation treatments. Augmentation therapies showed opposite effects depending on response status, i.e. increased or decreased the risk of side effects in responders and non-responders/resistant patients, respectively., Conclusions: Psychic side effects may be difficult to distinguish from depressive symptoms and factors associated with different types of side effects are heterogeneous and likely interacting.

Aim: This is the third version of the guideline of the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Posttraumatic Stress Disorders which was published in 2002 and revised in 2008., Method: A consensus panel of 34 international experts representing 22 countries developed recommendations based on efficacy and acceptability of the treatments. In this version, not only medications but also psychotherapies and other non-pharmacological interventions were evaluated, applying the same rigorous methods that are standard for the assessment of medication treatments., Result: The present paper (Part II) contains recommendations based on published randomised controlled trials (RCTs) for the treatment of OCD ( n  = 291) and PTSD ( n  = 234) in children, adolescents, and adults. The accompanying paper (Part I) contains the recommendations for the treatment of anxiety disorders.For OCD, first-line treatments are selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioural therapy (CBT). Internet-CBT was also superior to active controls. Several second-line medications are available, including clomipramine. For treatment-resistant cases, several options are available, including augmentation of SSRI treatment with antipsychotics and other drugs.Other non-pharmacological treatments, including repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS) and others were also evaluated.For PTSD, SSRIs and the SNRI venlafaxine are first-line treatments. CBT is the psychotherapy modality with the best body of evidence. For treatment-unresponsive patients, augmentation of SSRI treatment with antipsychotics may be an option., Conclusion: OCD and PTSD can be effectively treated with CBT and medications.

Aim: This is the third version of the guideline of the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Posttraumatic Stress Disorders (published in 2002, revised in 2008)., Method: A consensus panel of 33 international experts representing 22 countries developed recommendations based on efficacy and acceptability of available treatments. In total, 1007 RCTs for the treatment of these disorders in adults, adolescents, and children with medications, psychotherapy and other non-pharmacological interventions were evaluated, applying the same rigorous methods that are standard for the assessment of medications., Result: This paper, Part I, contains recommendations for the treatment of panic disorder/agoraphobia (PDA), generalised anxiety disorder (GAD), social anxiety disorder (SAD), specific phobias, mixed anxiety disorders in children and adolescents, separation anxiety and selective mutism. Selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line medications. Cognitive behavioural therapy (CBT) is the first-line psychotherapy for anxiety disorders. The expert panel also made recommendations for patients not responding to standard treatments and recommendations against interventions with insufficient evidence., Conclusion: It is the goal of this initiative to provide treatment guidance for these disorders that has validity throughout the world.

Objectives: The therapeutic value of the antidepressant agomelatine in the aftermath of traumatic experience and early post-reminder has been questioned. Herein, agomelatine, its vehicle or melatonin agonist were administered either acutely 1 h post-stressor or repeatedly (7 days) after early post-reminder in a post-traumatic stress rat model (PSS) using the scent of predator urine. Methods: Behavioural responses, and brain molecular and morphological changes were evaluated after each treatment procedure in PSS-exposed and unexposed rats. Results: When administered immediately after PSS, agomelatine induced a significant reduction of anxiety-like behaviour as assessed in the elevated-plus-maze and acoustic startle response at 8 days post-administration. Concomitantly, agomelatine significantly decreased Per1/Per2 expression in the CA1/CA3 areas, suprachiasmatic nucleus and basolateral amygdala, thereby partially restoring genes expression overregulated by PSS. Agomelatine further significantly increased cell growth and facilitated dendritic growth and arbour in dentate gyrus (DG) granule and apical CA1 cells and upregulated brain-derived neurotrophic factor protein in the DG and cortex III versus vehicle. When administered early post-reminder over 7 days before testing, agomelatine was ineffective on behavioural responses pattern, molecular and morphological changes induced by PSS. Conclusions: These findings suggest that agomelatine may be a potential agent in the acute aftermath of traumatic stress exposure.

Objectives: The overview outlines two decades of research from the European Group for the Study of Resistant Depression (GSRD) that fundamentally impacted evidence-based algorithms for diagnostics and psychopharmacotherapy of treatment-resistant depression (TRD). Methods: The GSRD staging model characterising response, non-response and resistance to antidepressant (AD) treatment was applied to 2762 patients in eight European countries. Results: In case of non-response, dose escalation and switching between different AD classes did not show superiority over continuation of original AD treatment. Predictors for TRD were symptom severity, duration of the current major depressive episode (MDE), suicidality, psychotic and melancholic features, comorbid anxiety and personality disorders, add-on treatment, non-response to the first AD, adverse effects, high occupational level, recurrent disease course, previous hospitalisations, positive family history of MDD, early age of onset and novel associations of single nucleoid polymorphisms (SNPs) within the PPP3CC , ST8SIA2 , CHL1 , GAP43 and ITGB3 genes and gene pathways associated with neuroplasticity, intracellular signalling and chromatin silencing. A prediction model reaching accuracy of above 0.7 highlighted symptom severity, suicidality, comorbid anxiety and lifetime MDEs as the most informative predictors for TRD. Applying machine-learning algorithms, a signature of three SNPs of the BDNF , PPP3CC and HTR2A genes and lacking melancholia predicted treatment response. Conclusions: The GSRD findings offer a unique and balanced perspective on TRD representing foundation for further research elaborating on specific clinical and genetic hypotheses and treatment strategies within appropriate study-designs, especially interaction-based models and randomized controlled trials.

This study aimed to determine the prevalence and risk factors of posttraumatic stress disorder (PTSD) in 171 acute optic neuropathy (AON) patients, and to compare the findings to those previously reported on 366 rhegmatogenous retinal detachment (RRD) patients. PTSD positively screened AON patients underwent a structured psychiatric interview and a Visual Function Questionnaire (VFQ). Clinical measures were retrieved from medical records and compared between cohorts. None of the AON patients was diagnosed with PTSD, as opposed to 2.5% of RRD patients (P = 0.063). Of the AON cohort, 34% of patients were administered steroids, compared to none of the RRD patients, whereas all of the RRD patients underwent surgery, compared to none of the AON patients (P < 0.001). Clinical measures and VFQ scores were not found as risk factors for PTSD prediction. Results imply the potential role of surgery and of steroid treatment in developing PTSD in cases of ocular insults.

Objective: Many studies suggest that age at onset (AAO) is an important factor for clinically differentiating patients with juvenile and adult onset of obsessive-compulsive disorder (OCD). The present international study aimed to assess the prevalence of different AAO groups and compare related socio-demographic and clinical features in a large sample of OCD patients., Methods: A total of 431 OCD outpatients, participating in the ICOCS network, were first categorised in groups with childhood (≤12 years), adolescent (13-17 years) and adult-onset (≥18 years), then in pre-adult and adult onset (≥18 years) and their socio-demographic and clinical features compared., Results: Twenty-one percent (n = 92) of the sample reported childhood onset, 36% (n = 155) adolescent onset, and 43% (n = 184) adult onset. Patients with adult onset showed a significantly higher proportion of females compared with the other subgroups (χ(2 )=( )10.9, p< 0.05). Childhood- and adolescent-onset patients had been more frequently treated with cognitive behavioural therapy (CBT), compared to adult-onset patients (χ(2 )=( )11.5; p < 0.05). The pre-adult- versus adult-onset analysis did not show any additional significant difference., Conclusions: The present international multicentre study confirms that OCD onset occurs more frequently before adult age, with approximately one out of five patients showing childhood onset. Pre-adult onset was associated with higher rate of CBT, while adult onset was more prevalent in females.

In recent years, many assessment and care units for obsessive-compulsive disorder (OCD) have been set up in order to detect, diagnose and to properly manage this complex disorder, but there is no consensus regarding the key functions that these units should perform. The International College of Obsessive-Compulsive Spectrum Disorders (ICOCS) together with the Obsessive Compulsive and Related Disorders Network (OCRN) of the European College of Neuropsychopharmacology (ECNP) and the Anxiety and Obsessive Compulsive Disorders Section of the World Psychiaric Association (WPA) has developed a standards of care programme for OCD centres. The goals of this collaborative initiative are promoting basic standards, improving the quality of clinical care and enhance the validity and reliability of research results provided by different facilities and countries.

Objectives: Only few studies investigated treatment strategies for treatment resistant depression (TRD). The objective of this multicentre study was to evaluate TRD patients who did not respond to at least two antidepressants., Methods: A total of 417 patients, who failed to respond to a previous retrospectively assessed antidepressant (AD1), were firstly included in a 6-week venlafaxine treatment (AD2); secondly, those who failed to respond were treated for further 6 weeks with escitalopram (AD3)., Results: Out of 417 patients who had failed to respond to previous treatment (AD1), 334 completed treatment with venlafaxine to prospectively define TRD. In the intent to treat (ITT) population in the first phase of the trial (AD2), responders to venlafaxine were 151 (36.21%) out of which remitters were 83 (19.90%). After phase one, 170 non-responders, defined as TRD, were included in the second phase and 157 completed the course. Of the 170 ITT entering the second phase (AD3), responders to escitalopram were 71 (41.76%) out of which remitters were 39 (22.94%). After the third treatment, patients showed a dropout rate of 7.65% and a rate of presence of at least one serious adverse event of 19.18%., Conclusions: Relevant rates of response and remission may be observed after a third line treatment in patients resistant to two previous treatments. A relevant limitation of this study was represented by the design: naturalistic, non-randomized, open-label, without a control sample and with unblinded raters.

Purpose: Mood disorders are present in more than 90% of suicides, and a genetic vulnerability to suicidality is well established. Numerous lines of evidence relate the transcription factor Cyclic adenosine monophosphate Response Element Binding protein (CREB1) to suicide, and to the aetiology of major depressive disorder (MDD). Our aim was to test for association between CREB1 single nucleotide polymorphisms (SNPs) and both suicide risk (SR) and a personal history of suicide attempt (SA) in MDD patients., Materials and Methods: A sample of 250 MDD patients collected in the context of a European multicenter resistant depression study and treated with antidepressants over a period of at least 4 weeks were genotyped for five CREB1 SNPs (rs2709376, rs2253206, rs7569963, rs7594560, and rs4675690). To assess suicidality, the Mini International Neuropsychiatric Interview (MINI) and the Hamilton Rating Scale for Depression (HAM-D) were applied., Results: Neither single-marker nor haplotypic association were found between SR and/or a personal history of SA with any of the investigated SNPs after multiple testing correction. For females, an association between rs2709376 and a personal history of SA was found (p = 0.016), however not resisting multiple testing correction., Conclusions: Although we found significant CREB1 single marker association with a personal history of SA in female MDD patients, this finding could not be confirmed in haplotypic analyses after multiple testing correction. Larger well-defined cohorts are required to confirm or refute a possible association of CREB1 and SA in female MDD patients.

Objective: Anxiety disorders are frequently under-diagnosed conditions in primary care, although they can be managed effectively by general practitioners., Methods: This paper is a short and practical summary of the World Federation of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety disorders, obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD) for the treatment in primary care. The recommendations were developed by a task force of 30 international experts in the field and are based on randomized controlled studies., Results: First-line pharmacological treatments for these disorders are selective serotonin reuptake inhibitors (for all disorders), serotonin-norepinephrine reuptake inhibitors (for some) and pregabalin (for generalized anxiety disorder only). A combination of medication and cognitive behavior/exposure therapy was shown to be a clinically desired treatment strategy., Conclusions: This short version of an evidence-based guideline may improve treatment of anxiety disorders, OCD, and PTSD in primary care.

Objectives: Posttraumatic obsessions have been reported in a few studies and case series. However, as the patients described were chronic, and the onset of their posttraumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD) symptoms was dated some time previously, this hampers interpretation of the temporal, biological and psychological relationship of OCD following traumatic events. In the current paper we describe the emergence of posttraumatic obsessions a short time following the exposure to a traumatic event., Methods: The emergence of posttraumatic obsessions, a few months after exposure to trauma, is described for five veterans. All the veterans participated in combat during the summer of 2006 (in the Second Lebanon War)., Results: For all cases, OCD symptoms were initially related to the trauma but later became generalized and independent., Conclusions: The course of the symptoms suggests a potential environmental role in the development of OCD following an exposure to a traumatic event. These observations suggest a biological linkage between exposure to trauma and OCD.

OBJECTIVES. Evidence in favour of switching between selective serotonin reuptake inhibitor (SSRI) and tricyclic (TCA) antidepressants in treatment resistant depression has been tested in a few studies only, consequently a prospective study was undertaken to evaluate the impact of switching strategies. METHODS. One hundred eighty-nine patients who failed to respond to a previous antidepressant were randomised to four arms: firstly they received citalopram or desipramine for a 4-week period; secondly, those who failed to respond were treated for a further 4-week period with the same antidepressant (citalopram-citalopram and desipramine-desipramine arms) or switched to the alternate one (citalopram-desipramine and desipramine-citalopram arms). RESULTS. There was no difference in the first 4-week phase between patients receiving citalopram versus desipramine in Hamilton Rating Scale for Depression (HRSD), Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Impression (CGI) scores. In the second 4-week phase remitter rates were higher among non-switched patients (P = 0.04). Moreover, considering HRSD and MADRS, switched patients reported significantly higher scores (P ≤ 0.02 for both scales at each time-point). CONCLUSIONS. This study supports the thesis that switching from an SSRI to a TCA (and vice versa) in non-responders to a 4-week trial of an SSRI/TCA is not associated with improved response. The result goes in the opposite direction to that predicted by current guidelines.

Objectives: Dystrobrevin binding protein 1 (Dysbindin) is a plausible candidate gene for major depressive disorders (MDD) due to its involvement in synaptic signaling, plasticity and localization in the brain., Methods: Two intronic SNPs of DTNBP1; rs760761 (P1320) and rs2619522 (P1763) were analyzed in 206 patients with DSM-IV MDD to investigate the functional impact of genotypes on susceptibility for depression and some clinical phenotypes. The Sequenom iPLEX assay (Sequenom, Cambridge, MA) was used for genotyping., Results and Conclusions: Despite the limited power of analysis, our results showed that these two SNPs in DTNPB1 gene were not related to clinical phenotypes such as melancholia, age at onset, suicidality and co-morbid anxiety disorders, as well as to treatment response phenotypes.

Background: Most epidemiological studies report higher prevalence rates of stress-related disorders such as acute stress disorder, post-traumatic stress disorder (PTSD) and major depressive disorder in women than in men. Few animal models of PTSD have taken gender differences into account and have typically used male subjects. In order to explore gender-related PTSD-like stress-responses more thoroughly, we applied an animal model that focuses selectively on individual patterns of behavioural responses., Methods: Prevalence rates of individual behavioural response to a single exposure to predator scent stress (PSS) were assessed by both elevated plus-maze and startle response paradigms. Prevalence rates of extreme behavioural disruption (EBR) on both tests were assessed, correlated to corticosterone levels, and compared to global population response data. In addition, we assessed learning and memory in the Morris water-maze (MWM)., Results: There were no significant differences between the behavioural responses related to oestrous cycle phase in terms of global data for the groups or in terms of prevalence rates of EBR. The overall patterns of response of males and females were affected, yet females demonstrated greater levels of baseline anxiety-like behaviour and lower peak levels of post-exposure anxiety-like behaviour than males. However, the prevalence rates of individual subjects who responded with PTSD-like behaviour were equal for female and male subjects. PSS-exposed female subjects demonstrated significantly compromised performance in the MWM compared to males., Conclusions: In this animal model, the results clarified that the assumption that females are more vulnerable is true for the magnitude of the response, but not for the prevalence of pathological response patterns in rat populations.

In this report, which is an update of a guideline published in 2002 (Bandelow et al. 2002, World J Biol Psychiatry 3:171), recommendations for the pharmacological treatment of anxiety disorder, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD) are presented. Since the publication of the first version of this guideline, a substantial number of new randomized controlled studies of anxiolytics have been published. In particular, more relapse prevention studies are now available that show sustained efficacy of anxiolytic drugs. The recommendations, developed by the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-traumatic Stress Disorders, a consensus panel of 30 international experts, are now based on 510 published randomized, placebo- or comparator-controlled clinical studies (RCTs) and 130 open studies and case reports. First-line treatments for these disorders are selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) and the calcium channel modulator pregabalin. Tricyclic antidepressants (TCAs) are equally effective for some disorders, but many are less well tolerated than the SSRIs/SNRIs. In treatment-resistant cases, benzodiazepines may be used when the patient does not have a history of substance abuse disorders. Potential treatment options for patients unresponsive to standard treatments are described in this overview. Although these guidelines focus on medications, non-pharmacological were also considered. Cognitive behavioural therapy (CBT) and other variants of behaviour therapy have been sufficiently investigated in controlled studies in patients with anxiety disorders, OCD, and PTSD to support them being recommended either alone or in combination with the above medicines.

Four major brain regions have been repeatedly implicated in the pathophysiology of obsessive compulsive disorder (OCD) in in vivo neuroimaging studies: the caudate nucleus, the orbitofrontal cortex, the anterior cingulate gyrus and the mediodorsal thalamic nucleus. The present review describes the neuroimaging studies on schizophrenia, pertaining to these brain regions. Our working hypothesis is that such common brain regions, if dysfunctional in schizophrenic patients, would be candidates for a neural network subserving the newly emerging syndrome of schizo-obsessive disorder. Findings, though, are controversial. We conclude that further studies, aimed at specific monitoring of these brain regions, in patients suffering from the schizo-obsessive syndrome are warranted.

In this report, recommendations for the pharmacological treatment of anxiety and obsessive-compulsive disorders are presented, based on available randomized, placebo- or comparator-controlled clinical studies. Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for panic disorder. Tri2-cyclic antidepressants (TCAs) are equally effective, but they are less well tolerated than the SSRIs. In treatment-resistant cases, benzodiazepines like alprazolam may be used when the patient does not have a history of dependency and tolerance. Due to possible serious side effects and interactions with other drugs and food components, the irreversible monamine oxidase inhibitor (MAOI) phenelzine should be used only when first-line drugs have failed. In generalised anxiety disorder, venlafaxine and SSRIs can be recommended, while buspirone and imipramine may be alternatives. For social phobia, SSRIs are recommended for the first line, and MAOIs, moclobemide and benzodiazepines as second line. Obsessive-compulsive disorder is best treated with SSRIs or clomipramine.

OCD was considered a rare, treatment refractory disorder of psychological origin, up until 20 years ago. Research in the last two decades has altered the perspectives regarding OCD. It is now clear that OCD is a prevalent disorder--about 2% of the population suffer from OCD--and that it is amenable both to psychological (cognitive-behavioural approach) and pharmacological intervention (with serotonergic medication). The biochemical and neuroanatomical (the frontal basal-thalamo cortical circuit) pathophysiology of OCD is also beginning to emerge. OCD is unique with regards to its specific response to serotonergic medication that blocks reuptake. Clomiprimine, fluoxetine, fluvoxemine, paroxetine, sertraline and citalopram were all found to be effective treatments for OCD based on large, multicentre, double-blind, placebo-controlled studies. As only serotonergic medications appear to be effective in OCD, the serotonergic hypothesis has been formulated and tested. Indeed, pharmacological challenges with specific serotonin agonists such as mCPP and sumatriptan, which were associated with transient exacerbation of OCD symptoms, are in line with the specific role of 5HT in the pathogenesis of OCD. However, this serotonergic hypothesis, while necessary, is not sufficient. It is clear that the dopaminergic and autoimmune mechanism are also implicated in the pathogenesis of OCD. Further studies are required to understand the relevance of the serotonergic and non-serotonergic systems in OCD, and to highlight the various possible subtypes of this intriguing disorder.