Subcortical brain structure and suicidal behaviour in major depressive disorder: a meta-analysis from the ENIGMA-MDD working group.

The aetiology of suicidal behaviour is complex, and knowledge about its neurobiological mechanisms is limited. Neuroimaging methods provide a noninvasive approach to explore the neural correlates of suicide vulnerability in vivo. The ENIGMA-MDD Working Group is an international collaboration evaluating neuroimaging and clinical data from thousands of individuals collected by research groups from around the world. Here we present analyses in a subset sample (n=3097) for whom suicidality data were available. Prevalence of suicidal symptoms among major depressive disorder (MDD) cases ranged between 29 and 69% across cohorts. We compared mean subcortical grey matter volumes, lateral ventricle volumes and total intracranial volume (ICV) in MDD patients with suicidal symptoms (N=451) vs healthy controls (N=1996) or MDD patients with no suicidal symptoms (N=650). MDD patients reporting suicidal plans or attempts showed a smaller ICV (P=4.12 × 10-3) or a 2.87% smaller volume compared with controls (Cohen's d=-0.284). In addition, we observed a nonsignificant trend in which MDD cases with suicidal symptoms had smaller subcortical volumes and larger ventricular volumes compared with controls. Finally, no significant differences (P=0.28-0.97) were found between MDD patients with and those without suicidal symptoms for any of the brain volume measures. This is by far the largest neuroimaging meta-analysis of suicidal behaviour in MDD to date. Our results did not replicate previous reports of association between subcortical brain structure and suicidality and highlight the need for collecting better-powered imaging samples and using improved suicidality assessment instruments.

[Guideline-conform inpatient psychiatric psychotherapeutic treatment of chronic depression: Normative personnel requirements]. / Leitlinienentsprechende stationäre psychiatrisch-psychotherapeutische Behandlung der chronischen Depression : Normative Personalbedarfsermittlung.

BACKGROUND: Chronic depression is a frequent mental disorder representing a significant subjective and economic burden. Effective disorder-specific treatment of chronic depression presupposes sufficient funding of treatment resources. OBJECTIVE: Definition of normative needs of personnel resources for guideline-compliant and evidence-based inpatient treatment of chronic depression based on treatment duration and intensity. The personnel resources determined were compared to the resources provided on the basis of the existing reimbursement system (Psych-PV) in Germany. MATERIAL AND METHODS: Resources determined according to national treatment guidelines and empirical evidence were compared to personnel resources dictated by the German Psych-PV reimbursement algorithm. RESULTS: The current funding algorithm greatly underestimates the resources needed for a guideline-compliant and evidence-based treatment program, even if healthcare providers received 100 % reimbursement of the sum determined by the Psych-PV algorithm. DISCUSSION: The results clearly show that even in the case of a full coverage of the current German reimbursement algorithm, funding allocation for evidence-based inpatient treatment of chronic depression is insufficient. In addition, the difficulties of specific coding of chronic depression in the ICD-10 system generates a major problem in the attempt to measure the current resources needed for sufficient treatment.

European Psychiatric Association Guidance on psychotherapy in chronic depression across Europe.

PURPOSE: Patients with chronic depression (CD) by definition respond less well to standard forms of psychotherapy and are more likely to be high utilizers of psychiatric resources. Therefore, the aim of this guidance paper is to provide a comprehensive overview of current psychotherapy for CD. The evidence of efficacy is critically reviewed and recommendations for clinical applications and research are given. METHODS: We performed a systematic literature search to identify studies on psychotherapy in CD, evaluated the retrieved documents and developed evidence tables and recommendations through a consensus process among experts and stakeholders. RESULTS: We developed 5 recommendations which may help providers to select psychotherapeutic treatment options for this patient group. The EPA considers both psychotherapy and pharmacotherapy to be effective in CD and recommends both approaches. The best effect is achieved by combined treatment with psychotherapy and pharmacotherapy, which should therefore be the treatment of choice. The EPA recommends psychotherapy with an interpersonal focus (e.g. the Cognitive Behavioural Analysis System of Psychotherapy [CBASP]) for the treatment of CD and a personalized approach based on the patient's preferences. DISCUSSION: The DSM-5 nomenclature of persistent depressive disorder (PDD), which includes CD subtypes, has been an important step towards a more differentiated treatment and understanding of these complex affective disorders. Apart from dysthymia, ICD-10 still does not provide a separate entity for a chronic course of depression. The differences between patients with acute episodic depression and those with CD need to be considered in the planning of treatment. Specific psychotherapeutic treatment options are recommended for patients with CD. CONCLUSION: Patients with chronic forms of depression should be offered tailored psychotherapeutic treatments that address their specific needs and deficits. Combination treatment with psychotherapy and pharmacotherapy is the first-line treatment recommended for CD. More research is needed to develop more effective treatments for CD, especially in the longer term, and to identify which patients benefit from which treatment algorithm.

Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group.

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

Investigation of decision-making under uncertainty in healthy subjects: a multi-centric fMRI study.

Decision-making is an everyday routine that entails several subprocesses. Decisions under uncertainty occur when either prior information is incomplete or the outcomes of the decision are unclear. The aim of the present study was to disentangle the neural correlates of information gathering as well as reaching a decision and to explore effects of uncertainty acceptance or avoidance in a large sample of healthy subjects. Sixty-four healthy volunteers performed a decision-making under uncertainty task in a multi-center approach while BOLD signal was measured with fMRI. Subjects either had to indicate via button press from which of two bottles red or blue balls were drawn (decision-making under uncertainty condition), or they had to indicate whether 8 red balls had been presented (baseline condition). During the information gathering phase (contrasted against the counting phase) a widespread network was found encompassing (pre-)frontal, inferior temporal and inferior parietal cortices. Reaching a decision was correlated with activations in the medial frontal cortex as well as the posterior cingulate and the precuneus. Effects of uncertainty acceptance were found within a network comprising of the superior frontal cortex as well as the insula and precuneus while uncertainty avoidance was correlated with activations in the right middle frontal cortex. The results depict two distinct networks for information gathering and the indication of having made a decision. While information-gathering networks are modulated by uncertainty avoidance and - acceptance, underlying networks of the decision itself are independent of these factors.

Effects of a genome-wide supported psychosis risk variant on neural activation during a theory-of-mind task.

Schizophrenia is associated with marked deficits in theory of mind (ToM), a higher-order form of social cognition representing the thoughts, emotions and intentions of others. Altered brain activation in the medial prefrontal cortex and temporo-parietal cortex during ToM tasks has been found in patients with schizophrenia, but the relevance of these neuroimaging findings for the heritable risk for schizophrenia is unclear. We tested the hypothesis that activation of the ToM network is altered in healthy risk allele carriers of the single-nucleotide polymorphism rs1344706 in the gene ZNF804A, a recently discovered risk variant for psychosis with genome-wide support. In all, 109 healthy volunteers of both sexes in Hardy-Weinberg equilibrium for rs1344706 were investigated with functional magnetic resonance imaging during a ToM task. As hypothesised, risk carriers exhibited a significant (P<0.05 false discovery rate, corrected for multiple comparisons) risk allele dose effect on neural activity in the medial prefrontal cortex and left temporo-parietal cortex. Moreover, the same effect was found in the left inferior parietal cortex and left inferior frontal cortex, which are part of the human analogue of the mirror neuron system. In addition, in an exploratory analysis (P<0.001 uncorrected), we found evidence for aberrant functional connectivity between the frontal and temporo-parietal regions in risk allele carriers. To conclude, we show that a dysfunction of the ToM network is associated with a genome-wide supported genetic risk variant for schizophrenia and has promise as an intermediate phenotype that can be mined for the development of biological interventions targeted to social dysfunction in psychiatry.

Human amygdala reactivity is diminished by the ß-noradrenergic antagonist propranolol.

BACKGROUND: Animal models of anxiety disorders emphasize the crucial role of locus ceruleus-noradrenergic (norepinephrine, NE) signaling, the basolateral amygdala (BLA) and their interactions in the expression of anxiety-like behavioral responses to stress. Despite clinical evidence for the efficacy of a ß-noradrenergic receptor blockade with propranolol in the alleviation of anxiety symptoms and the secondary prevention of post traumatic stress disorder, preclinical evidence for a ß-noradrenergic modulation of BLA activity in humans is missing. METHOD: We combined functional magnetic resonance imaging in healthy volunteers with probabilistic mapping of intra-amygdalar responses to fearful, neutral and happy facial expressions to test the hypothesis that a ß-noradrenergic receptor blockade with propranolol would inactivate the BLA. RESULTS: Consistent with our a priori hypothesis, propranolol diminished BLA responses to facial expressions, independent of their emotional valence. The absence of activity changes in probabilistically defined visual control regions underscores the specific action of propranolol in the BLA. CONCLUSIONS: Our findings provide the missing link between the anxiolytic potential of propranolol and the biological basis of ß-noradrenergic activation in the human BLA as a key target for the pharmacological inhibition of anxiety neurocircuitry. Moreover, our findings add to emerging evidence that NE modulates both the reactivity (sensitivity) and the operating characteristics (specificity) of the BLA via ß-noradrenergic receptors.

Processing of autobiographical memory retrieval cues in borderline personality disorder.

BACKGROUND: Affective dysregulation in borderline personality disorder (BPD) in response to both external stimuli and memories has been shown to be associated with functional alterations of limbic and prefrontal brain areas. This study aimed to examine neuronal networks involved in autobiographical memory retrieval using standardized stimuli that gain autobiographical significance by illustrating marked solitary and social situations of human life. METHODS: Using event-related functional Magnetic Resonance Imaging (fMRI), we examined the processing of pictures from the Thematic Apperception Test (TAT) in 14 BPD patients and 14 controls. RESULTS: In both groups, TAT stimuli activated brain areas known to be involved in autobiographical memory retrieval. BPD subjects lacked differential amygdala, orbitofrontal and cingulate activations for TAT versus neutral stimuli. In the TAT condition, compared to controls, BPD subjects displayed increased BOLD responses in the bilateral orbitofrontal and insular regions, in the left anterior cingulate and medial prefrontal cortex, as well as in the parietal and parahippocampal areas, consistent with a more aversive and arousing experience assessed by self-reports. CONCLUSIONS: Increased BOLD responses during TAT processing in BPD subjects were in line with previously reported changes in anterior cingulate and orbitofrontal cortices, which are known to be involved in memory retrieval. However, BPD subjects displayed hyperactivation in these areas for both TAT and neutral stimuli. The deficit of selective activation of areas involved in autobiographical memory retrieval suggests a general tendency towards a self-referential mode of information processing in BPD, or a failure to switch between emotionally salient and neutral stimuli.

[Life threatening menorrhagia in thrombasthenia. (Glanzmann-Naegeli) thrombasthenia]. / Lebensbedrohliche Menorrhagie bei Thrombasthenie. (Thrombasthenia Glanzmann-Naegeli).

Glanzmann's Thrombasthenia is a rare inherited disorder of platelet aggregation with normal platelet count and humoral coagulation. It is caused by the deficiency or functional disorder of platelet membrane glycoproteins IIb und IIIa. This complex is considered to be a receptor for fibrinogen. Menorrhagia often occurs as a clinical manifestation of affected females. We report a case of severe menorrhagia in a 13-year-old girl during her third menstrual cycle. She needed several red blood cell transfusions. The bleeding could only be stopped by administration of Lynestrenol.

Inhibition of the phosphate self-exchange flux in human erythrocytes and erythrocyte ghosts.

The phosphate self-exchange flux in resealed erythrocyte ghosts and in amphotericin B (5.5 microM) permeabilized erythrocytes has been studied. The phosphate self-exchange flux exhibits an S-shaped concentration dependence and a self-inhibition in permeabilized red cells while in erythrocyte ghosts no self-inhibition of the phosphate flux has been observed. The apparent half-saturation constants and the apparent Hill coefficients were assessed by the double reciprocal Hill plots of 1/JP versus 1/[P]n. The phosphate half-saturation constants amount to approx. 125 mM in ghosts and to about 75 mM in permeabilized cells while the apparent Hill coefficients amount to 1.15 and to 1.65 (pH 7.2, 25 degrees C), respectively. Both chloride and sulfate elicit a mixed-type inhibition of the phosphate self-exchange flux. In permeabilized cells, chloride and sulfate shift the flux optimum towards higher phosphate concentrations and reduce the apparent Hill coefficients. In erythrocyte ghosts, the apparent Hill coefficients are insensitive to these anions. The double reciprocal Hill plots indicate a mixed-type inhibition of the phosphate self-exchange flux by DNDS, salicylate and dipyridamole and a noncompetitive inhibition of the phosphate self-exchange flux by phlorhizin. By contrast, the Hill-Dixon plots for chloride and sulfate indicate a competitive inhibition of the phosphate self-exchange flux in erythrocyte ghosts and a mixed-type inhibition in permeabilized cells and provide Hill coefficients of greater than unity for chloride and sulfate. The Dixon plots for DNDS, salicylate, phlorhizin and dipyridamole show a noncompetitive inhibition of the phosphate flux and provide apparent Hill coefficients of 0.95-1.0 for inhibitor binding. Using the Debye-Hückel theory, the effects of ionic strength upon phosphate transport and inhibitor binding can be eliminated. The results of our studies provide strong evidence for the assumption that electrostatic forces are involved in phosphate transport and in inhibitor binding.

[Frequency spectrum and integral value of electromyographic recordings of the masseter and temporal muscles in correlation with muscle length]. / Elektromyogramme von Mm. masseter und temporalis in Abhängigkeit zur Muskellänge.

In 15 children and 15 adults the influence of muscle length on the EMG-recordings of the anterior temporal and superficial masseter muscles was investigated. Myoelectric activity was measured by surface electromyography during maximal clenching in habitual occlusion. The quantitative EMG analysis was performed by means of a computer program which allowed calculation of a) the integrated value and b) the mean frequency of the power spectrum (MPF) from the raw signal after Fourier transformation. Muscle length was determined with the aid of lateral cephalometric films. Using a correlation analysis this investigation revealed the following results: Under standardized functional conditions short muscles work with a higher activity and a higher MPF than long muscles. In children as well as in adults muscle activity and MPF show close negative correlations with the parameter "muscle length". These relations are directly proportional.

Chloride mediated inhibition of the phosphate and the sulfate transport by dipyridamole in human erythrocyte ghosts.

The inhibition of the unidirectional phosphate and sulfate flux in human erythrocyte ghosts by dipyridamole has been investigated. The inhibition of the phosphate and the sulfate flux is mediated by chloride. At zero chloride, dipyridamole was found to be completely ineffective. At 10 mM chloride, dipyridamole acts as a noncompetitive inhibitor of the phosphate and the sulfate flux and elicits an up to 95% inhibition of the phosphate and the sulfate transport. The results of our studies provide strong evidence for a cooperative binding of chloride and of dipyridamole to the non-protonated form of the band 3 membrane domain.

Ca2+ uptake and IP3-induced Ca2+ release in permeabilized human lymphocytes.

The 45Ca2+ uptake and 45Ca2+ release in saponin-permeabilized human lymphocytes were studied. An ATP-dependent Ca2+ uptake into a nonmitochondrial, intracellular Ca2+ store is observed which is approx. 2 orders of magnitude greater than the ATP-independent Ca2+ uptake. The Ca2+ uptake is inhibited by vanadate, but it is insensitive to oligomycin and ruthenium red. IP3 induces dose-dependent 45Ca2+ release. For half-maximum Ca2+ release 0.25-0.5 microM IP3 is required. The results of our studies suggest that 45Ca2+ is predominantly stored within the endoplasmic reticulum of the lymphocytes.

DMO-transport in human red blood cells.

The DMO (5,5-dimethyloxazolidine-2,4-dione) transport was studied in human red blood cells by measuring the 14C-DMO back exchange under self exchange conditions from 14C-DMO labeled cells at 0 degrees C. the unidirectional DMO-flux was linearly related to the DMO concentration up to approx. 100 mM. The unidirectional DMO-flux increases as pH is reduced. The DMO transport is not inhibited by anion transport inhibitors like DIDS, SITS, dipyridamole, phlorhizin, salicylate or butanol. A close correlation between the unidirectional DMO-flux and DMOH, the unionized form of DMO, has been observed suggesting that DMO is transported predominantly by nonionic diffusion. the permeability of DMOH is 9.5 X 10(-6) cm/s (0 degrees C) while the permeability of DMO- cannot be assessed from our data.

Characterization of the Band 3 substrate site in human red cell ghosts by NDS-TEMPO, a disulfonatostilbene spin probe: the function of protons in NDS-TEMPO and substrate-anion binding in relation to anion transport.

NDS-TEMPO is a specific disulfonatostilbene spin label for the Band 3 substrate site (K.F. Schnell, W. Elbe, J. Käsbauer & E. Kaufmann, Biochim. Biophys. Acta 732:266-275, 1983). The pH dependence of NDS-TEMPO binding and of chloride and sulfate binding was studied in resealed human erythrocyte ghosts. pH was varied from 6.0 to 9.0. The ESR spectra from NDS-TEMPO-labeled red cell ghosts exhibited a strong immobilization of membrane-bound NDS-TEMPO. Changes of pH had no effect upon the mobility of membrane-bound NDS-TEMPO. A mutual competition between NDS-TEMPO binding and the binding of the substrate-anions, chloride and sulfate, was observed throughout the entire pH range. The maximal number of NDS-TEMPO binding sites per cell was in the range of 9.0 X 10(5) to 1.10 X 10(6) and was found to be insusceptible to changes of pH. The NDS-TEMPO/substrate-site and the chloride/substrate-site dissociation constants amounted to 1.25 microM and to 17 mM and were independent of pH from pH 6.0 to 8.0, while the sulfate/substrate-site dissociation constant displayed a strong pH dependency with a maximum of approximately 50 mM at about pH 7.0. The NDS-TEMPO inhibition constants from the chloride and the sulfate flux experiments were 0.5 microM (0 degree C) and 1.8 microM (25 degrees C), respectively, and are in close accordance with the NDS-TEMPO/substrate-site dissociation constants. Our studies provide strong evidence for the assumption that NDS-TEMPO binds in fact to the substrate site of Band 3. They show that the strong pH dependence of the chloride and of the sulfate transport cannot result from the pH dependency of substrate-anion binding, but point to the participation of ionizable regulator sites in transport catalysis. These regulator sites seem to be positioned outside the substrate site of the Band 3 transport domain.

Concentration dependence of the chloride selfexchange and homoexchange fluxes in human red cell ghosts.

The concentration dependence of the unidirectional chloride flux in human red cell ghosts was studied under selfexchange and under homoexchange conditions. Under selfexchange conditions the intracellular concentration of chloride [Cl]in is equal to the extracellular concentration [Cl]ex and [Cl]in and [Cl]ex are raised concomitantly. Under homoexchange conditions [Cl]in or [Cl]ex were varied separately at a fixed trans-concentration of chloride. The chloride fluxes were calculated from the rate of the tracer efflux and the intracellular chloride. All experiments were executed in isotonic (330 mosM) KCl/K-citrate/sorbitol solutions containing 0-100 mM KCl, 40 mM K-citrate and different concentrations of sorbitol for isoosmotic substitution. The chloride selfexchange and the chloride homoexchange fluxes exhibit a pure saturation kinetics. The halfsaturation constant for the chloride selfexchange was approximately 20 mM, the maximal flux was approx. 3.5 X 10(-4) mol/(min . g cells). The apparent chloride halfsaturation constants from the homoexchange experiments were in the range of 0.9-4.5 mM for the outer and of 5.5-14.5 mM (0 degree C, pH 7.3) for the inner membrane surface, both halfsaturation constants increase with increasing trans-concentrations. At infinite trans-concentrations of chloride, the halfsaturation constant for the outer and the inner membrane surface amounts to approximately 5 mM and approximately 15 mM, respectively. The slope of the double reciprocal plots of flux versus cis-chloride concentration decreases with increasing trans-concentration of chloride. The kinetics of the chloride transport provides evidence for a carrier mediated transport mechanism with a single reciprocating transport site. The translocation of the loaded carrier appears to be much faster than the translocation of the unloaded carrier.(ABSTRACT TRUNCATED AT 250 WORDS)

Concentration dependence of the unidirectional sulfate and phosphate flux in human red cell ghosts under selfexchange and under homoexchange conditions.

The concentration dependence of the sulfate and the phosphate selfexchange and homoexchange fluxes was studied in resealed red cell ghosts (25 degrees C, pH 7.3). The selfexchange fluxes were calculated from the rate constant of the tracer back-exchange and from the intracellular substrate anion content. The homoexchange fluxes were determined from the initial cis-to-trans tracer fluxes and the initial specific substrate anion activities at the cis-membrane side. Sulfate and phosphate concentrations ranging from approx. 2-100 mM were employed. The selfexchange fluxes of sulfate and of phosphate exhibit sigmoidal flux/concentration curves. The apparent Hill coefficients were in the range of 1.2-1.4 indicating a type of positive cooperativity. Under homoexchange conditions the positive cooperativity of the flux/concentration curves disappears. The outward homoexchange fluxes of sulfate and phosphate display a saturation kinetics with Hill coefficients close to 1.0. The inward homoexchange fluxes exhibit a negative type of cooperativity with Hill coefficients smaller than 1.0. The sulfate and the phosphate half-saturation concentrations for the outer and the inner membrane surface are equal in size and amount to approx. 35 mM for sulfate and to approx. 110 mM for phosphate, respectively. The positive cooperativity of the unidirectional sulfate and phosphate fluxes under selfexchange conditions and the disappearance of the positive cooperativity under homoexchange conditions indicate a cooperativity of the translocation process. The saturation of the outward homoexchange flux and the negative cooperativity of the inward homoexchange flux suggest a substrate anion binding according to the law of mass action at the inner and a negative cooperativity of substrate anion binding at the outer membrane surface.

Electron spin resonance studies on the inorganic-anion-transport system of the human red blood cell. Binding of a disulfonatostilbene spin label (NDS-TEMPO) and inhibition of anion transport.

The disulfonatostilbene spin label, NDS-TEMPO, was synthesized (purity over 96%) and the binding of the spin label to human red-cell ghosts was studied. NDS-TEMPO is readily absorbed to the membrane surface. Both pretreatment of the ghosts with FDNB and DIDS and the presence of DNDS completely prevent the binding of NDS-TEMPO to red-cell ghosts. Chloride and sulfate competitively inhibit the binding of NDS-TEMPO. Conversely, NDS-TEMPO is a strong, competitive inhibitor of chloride and of sulfate transport. The dissociation constants of NDS-TEMPO from the ESR studies were in the range 1.0-2.0 microM (pH 7.6, 20 degrees C). The inhibition constants of NDS-TEMPO as obtained from the flux experiments were in the range 0.5-2.5 microM (pH 7.3, 25 degrees C). The close accordance of the NDS-TEMPO dissociation constants from the ESR studies with the NDS-TEMPO inhibition constants from the flux measurements indicate a specific labeling of the inorganic-anion-transport system.