Suicidal behavior-advances in clinical and neurobiological research and improvement of prevention strategies.

Suicide is the 14th leading cause of death worldwide. It is responsible for 1%-5% of all mortality. This article highlights the latest developments in universal, selective, and indicated prevention strategies. Concerning universal suicide prevention, current research has shown that strategies such as restricting access to lethal means (e.g., control of analgesics and hot-spots for suicide by jumping) and school-based awareness programs are most efficacious. Regarding selective prevention, substantial progress can be expected in psychological screening methods for suicidal behavior. The measurement of implicit cognition proved to be more valid in predicting future suicide attempts than classic clinical assessment. Latest developments are smartphone-based interventions and real-time monitoring of suicidal behavior. Great effort has been made to establish valid neurobiological screening methods (e.g., genetic and epigenetic risk factors for suicide, hypothalamic-pituitary-adrenal axis) without yielding a major bre-akthrough. Potentially, multiple biomarkers rather than a single one are necessary to identify individuals at risk. With regard to indicated prevention in form of psychopharmacological treatment, recent pharmacoepidemiological studies and meta-analyses have supported a protective role of antidepressants, lithium, and clozapine. However, the data concerning a specific anti-suicidal effect of these drugs are currently not consistent. Promising results exist for ketamine in reducing suicidal ideation, independently of its antidepressant effect. Concerning psychotherapy, recent findings suggest that psychotherapeutic interventions specifically designed to prevent suicide re-attempts are most efficacious. Specifically, cognitive behavioral therapy and psychodynamic therapy approaches proved to decrease the number of suicide re-attempts significantly.

Psychotherapeutic interventions for the prevention of suicide re-attempts: a systematic review.

A history of suicide attempt (SA) is a strong predictor of future suicide re-attempts or suicide. The aim of this systematic review is to evaluate the efficacy of psychotherapeutic interventions specifically designed for the prevention of suicide re-attempts. A systematic search from 1980 to June 2020 was performed via the databases PubMed and Google Scholar. Only randomized controlled trials were included which clearly differentiated suicidal self-harm from non-suicidal self-injury in terms of intent to die. Moreover, psychotherapeutic interventions had to be focused on suicidal behaviour and the numbers of suicide re-attempts had to be used as outcome variables. By this procedure, 18 studies were identified. Statistical comparison of all studies revealed that psychotherapeutic interventions in general were significantly more efficacious than control conditions in reducing the risk of future suicidal behaviour nearly by a third. Separate analyses revealed that cognitive-behavioural therapy as well as two different psychodynamic approaches were significantly more efficacious than control conditions. Dialectical behaviour therapy and elementary problem-solving therapy were not superior to control conditions in reducing the number of SAs. However, methodological reasons may explain to some extent these negative results. Considering the great significance of suicidal behaviour, there is unquestionably an urgent need for further development of psychotherapeutic techniques for the prevention of suicide re-attempts. Based on the encouraging results of this systematic review, it can be assumed that laying the focus on suicidal episodes might be the key intervention for preventing suicide re-attempts and suicides.

Checking and washing rituals are reflected in altered cortical thickness in obsessive-compulsive disorder.

There is growing evidence for structural brain alterations in obsessive-compulsive disorder (OCD). The overall picture is however rather heterogeneous. To detect meaningful associations between clinical symptom profiles and structural alterations, we applied a classification approach, the k-means cluster analysis on clinical data, i.e., the Obsessive Compulsive Inventory-Revised (OCI-R) questionnaire. 73 OCD patients were assigned to three distinct symptom profiles. Using structural MRI and surface-based morphometric analysis (SBM), we compared cortical thickness between all OCD patients and 69 matched healthy subjects as well as among patients according to three symptom profiles. The total sample of OCD patients exhibited a thicker cortex in the pre-supplementary motor cortex (pre-SMA), dorsomedial prefrontal (DMPFC), anterior cingulate cortex and in the right anterior insula. Comparing patients of the three symptom clusters, a subgroup of OCD patients with a specific symptom profile was identified, which showed a thicker cortex in pre-SMA/DMPFC and in the contralateral primary motor cortex. In contrast to both other subgroups, patients in this group were mainly characterized by the predominance of a combination of checking and washing rituals. The other two OCD symptom subgroups showed comparable cortical thickness to healthy controls. Higher cortical thickness in regions of the motor circuitry seems to be related to motor activity-induced neuroplasticity in a specific group of OCD patients. Thicker anterior insular cortex in the total sample of patients points toward a more general pathophysiological process in OCD and potentially indicates abnormal interoceptive processing in OCD.

The neural basis of the abnormal self-referential processing and its impact on cognitive control in depressed patients.

Persistent pondering over negative self-related thoughts is a central feature of depressive psychopathology. In this study, we sought to investigate the neural correlates of abnormal negative self-referential processing (SRP) in patients with Major Depressive Disorder and its impact on subsequent cognitive control-related neuronal activation. We hypothesized aberrant activation dynamics during the period of negative and neutral SRP in the rostral anterior cingulate cortex (rACC) and in the amygdala in patients with major depressive disorder. Additionally, we assumed abnormal activation in the fronto-cingulate network during Stroop task execution. 19 depressed patients and 20 healthy controls participated in the study. Using an event-related functional magnetic resonance imaging (fMRI) design, negative, positive and neutral self-referential statements were displayed for 6.5 s and followed by incongruent or congruent Stroop conditions. The data were analyzed with SPM8. In contrast to controls, patients exhibited no significant valence-dependent rACC activation differences during SRP. A novel finding was the significant activation of the amygdala and the reward-processing network during presentation of neutral self-referential stimuli relative to baseline and to affective stimuli in patients. The fMRI analysis of the Stroop task revealed a reduced BOLD activation in the right fronto-parietal network of patients in the incongruent condition after negative SRP only. Thus, the inflexible activation in the rACC may correspond to the inability of depressed patients to shift their attention away from negative self-related stimuli. The accompanying negative affect and task-irrelevant emotional processing may compete for neuronal resources with cognitive control processes and lead thereby to deficient cognitive performance associated with decreased fronto-parietal activation.

Self-referential processing influences functional activation during cognitive control: an fMRI study.

Rostral anterior cingulate cortex (rACC) plays a central role in the pathophysiology of major depressive disorder (MDD). As we reported in our previous study (Wagner et al., 2006), patients with MDD were characterized by an inability to deactivate this region during cognitive processing leading to a compensatory prefrontal hyperactivation. This hyperactivation in rACC may be related to a deficient inhibitory control of negative self-referential processes, which in turn may interfere with cognitive control task execution and the underlying fronto-cingulate network activation. To test this assumption, a functional magnetic resonance imaging study was conducted in 34 healthy subjects. Univariate and functional connectivity analyses in statistical parametric mapping software 8 were used. Self-referential stimuli and the Stroop task were presented in an event-related design. As hypothesized, rACC was specifically engaged during negative self-referential processing (SRP) and was significantly related to the degree of depressive symptoms in participants. BOLD signal in rACC showed increased valence-dependent (negative vs neutral SRP) interaction with BOLD signal in prefrontal and dorsal anterior cingulate regions during Stroop task performance. This result provides strong support for the notion that enhanced rACC interacts with brain regions involved in cognitive control processes and substantiates our previous interpretation of increased rACC and prefrontal activation in patients during Stroop task.

Aberrant anterior cingulate activation in obsessive-compulsive disorder is related to task complexity.

OBJECTIVES: Evidence for working memory (WM) deficits in obsessive-compulsive disorder (OCD) is increasing. However, findings regarding the underlying neural substrates are heterogeneous. Moreover, the influence of cognitive demand on the severity of these deficits and associated activation alterations is a matter of debate. METHODS: To further address this question the present fMRI study examined a sample of 21 predominantly medication-free inpatients with OCD and 21 matched healthy volunteers using a parametric verbal n-back task. RESULTS: In agreement with earlier studies patients exhibited focused activation alterations that could be found to be critically dependent on WM demands: There were no differences in activation between patients and healthy volunteers under low cognitive demands. However, patients exhibited a significantly decreased activation in the dorsal anterior cingulate cortex (dACC) in association with increasing task demands. While dACC activation in controls showed a linear increase with increasing task demands, this linearity was not detectable in patients with OCD. CONCLUSIONS: Present findings provide further support for the relevance of the anterior cingulate in OCD and illustrate that both task demands and task processes are of major influence in this context.

White matter structure and symptom dimensions in obsessive-compulsive disorder.

There is evidence that the different symptom dimensions in obsessive-compulsive disorder (OCD) may be mediated by partially distinct neural systems. This DTI study investigated the relationship between symptom dimensions and white matter microstructure. Fractional anisotropy (FA), axial and radial diffusivity was analyzed in relation to the main OCD symptom dimensions. Symptom severity on the obsessing dimension was negatively correlated with FA in the corpus callosum and the cingulate bundle. Severity on the ordering dimension was negatively correlated with FA in, amongst others, the right inferior fronto-occipital fasciculus and the right optic radiation. All correlations were ascribable to alterations in radial diffusivity while there was no association between symptoms and axial diffusivity. Present results illustrate an association between alterations in visual processing tracts and ordering symptoms which are characterized by altered visual processing and increased attention towards irrelevant detail. They also indicate an association between obsessive thoughts and alterations in structures known to be relevant for cognitive control and inhibition. Hence, different symptom dimensions must be taken into account in order to disentangle the neurobiological underpinnings of OCD.

Fronto-cingulate effective connectivity in obsessive compulsive disorder: a study with fMRI and dynamic causal modeling.

Evidence suggests that obsessive compulsive disorder (OCD) is associated with an overactive error control system. A key role in error detection and control has been ascribed to the fronto-cingulate system. However, the exact functional interplay between the single components of this network in OCD is largely unknown. Therefore, the present study combined a univariate data analysis and effective connectivity analysis using dynamic causal modeling (DCM) to examine error control in 21 patients with OCD and 21 matched healthy controls. All subjects performed an adapted version of the Stroop color-word task while undergoing fMRI scans. Enhanced activation in the fronto-cingulate system could be detected in OCD patients during the incongruent task condition. Additionally, task-related modulation of effective connectivity from the dorsal ACC to left DLPFC was significantly stronger in OCD patients. These findings are consistent with an overactive error control system in OCD subserving suppression of prepotent responses during decision-making.

The novel brain-specific tryptophan hydroxylase-2 gene in panic disorder.

Panic disorder is a common psychiatric disorder characterized by recurrent anxiety attacks and anticipatory anxiety. Due to the severity of the symptoms of the panic attacks and the frequent additional occurrence of agoraphobia, panic disorder is an often debilitating disease. Elevation of central serotonin levels by drugs such as clomipramine represents one of the most effective treatment options for panic disorder. This points to an important role of dysregulation of the serotonergic system in the genetic etiology of panic disorder. The novel brain-specific 5-HT synthesizing enzyme, tryptophan hydroxylase-2 (TPH2), which represents the rate-limiting enzyme of 5-HT production in the brain, may therefore be of particular importance in panic disorder. We focused on the putative transcriptional control region of TPH2 and identified two novel common single nucleotide polymorphisms (SNPs) of TPH2 in and close to this region. Moreover, a recently described loss-of-function mutation of TPH2 which results in an 80% reduction of serotonin production, was assessed. In an analysis of the putative transcriptional control region SNPs in a sample of panic disorder patients and controls no association of the disorder with the TPH2 SNPs or haplotypes was found. Moreover, the loss-of-function R441H mutation of TPH2 was not present in the panic disorder patients. The results of this first study of TPH2 in panic disorder argue against an importance of allelic variation of TPH2 in the pathogenesis of panic disorder with or without agoraphobia.

Association of a functional 1019C>G 5-HT1A receptor gene polymorphism with panic disorder with agoraphobia.

Panic disorder is a common anxiety disorder which frequently co-occurs with agoraphobia. A functional promoter polymorphism in the serotonin receptor 1A (5-HT1A) gene has been found to be associated with major depression as well as anxiety- and depression-related personality traits. We investigated a possible association between this 5-HT1A gene promoter polymorphism and panic disorder by genotyping the 1019C>G single nucleotide polymorphism in 134 panic-disorder patients with and without agoraphobia and matched 134 controls. In our sample no significant evidence of allelic association in the combined panic-disorder group was found. However, our results show a significant association with the G allele in patients with panic disorder with agoraphobia (p=0.03, n=101). In conclusion, our findings do not support a major contribution of this polymorphism to the pathogenesis of panic disorder, but provide evidence for a possible role in the subgroup with agoraphobia.