A prospective international multi-center study on safety and efficacy of deep brain stimulation for resistant obsessive-compulsive disorder.

Deep brain stimulation (DBS) has been proposed for severe, chronic, treatment-refractory obsessive-compulsive disorder (OCD) patients. Although serious adverse events can occur, only a few studies report on the safety profile of DBS for psychiatric disorders. In a prospective, open-label, interventional multi-center study, we examined the safety and efficacy of electrical stimulation in 30 patients with DBS electrodes bilaterally implanted in the anterior limb of the internal capsule. Safety, efficacy, and functionality assessments were performed at 3, 6, and 12 months post implant. An independent Clinical Events Committee classified and coded all adverse events (AEs) according to EN ISO14155:2011. All patients experienced AEs (195 in total), with the majority of these being mild (52% of all AEs) or moderate (37%). Median time to resolution was 22 days for all AEs and the etiology with the highest AE incidence was 'programming/stimulation' (in 26 patients), followed by 'New illness, injury, condition' (13 patients) and 'pre-existing condition, worsening or exacerbation' (11 patients). Sixteen patients reported a total of 36 serious AEs (eight of them in one single patient), mainly transient anxiety and affective symptoms worsening (20 SAEs). Regarding efficacy measures, Y-BOCS reduction was 42% at 12 months and the responder rate was 60%. Improvements in GAF, CGI, and EuroQol-5D index scores were also observed. In sum, although some severe AEs occurred, most AEs were mild or moderate, transient and related to programming/stimulation and tended to resolve by adjustment of stimulation. In a severely treatment-resistant population, this open-label study supports that the potential benefits outweigh the potential risks of DBS.

[Treatment of obsessive-compulsive disorders: recommendations of the revised S3 guidelines on obsessive-compulsive disorders]. / Therapie der Zwangsstörungen: Empfehlungen der revidierten S3-Leitlinie Zwangsstörungen.

In 2022, the first revised version of the S3 guidelines on obsessive-compulsive disorder will be published under the auspices of the German Society for Psychiatry, Psychotherapy and Psychosomatics (DGPPN). This article contains a summary of the most important recommendations for therapy in a condensed form. There were no major changes in the central basic therapy recommendations compared with the first version of the guidelines, as the evidence base has not fundamentally changed since then. Cognitive behavioral therapy (CBT) with exposure and response management is the most effective form of therapy for this clinical picture and therefore the therapy of first choice. Regarding pharmacotherapy, selective serotonin reuptake inhibitors are the first-line medications. They are indicated when CBT with exposure is not available or has not been effective, when CBT is rejected by the patient and in the patient's personal preference for medication, or to increase the readiness for CBT with exposure. New recommendations include, e.g., the use of Internet therapy, and recommendations for the use of CBT and exposure, e.g., also in group format, including video conferencing if appropriate as well as in intensive format.

Interactive impact of childhood maltreatment, depression, and age on cortical brain structure: mega-analytic findings from a large multi-site cohort.

BACKGROUND: Childhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age. METHODS: Within the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer. RESULTS: CM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions. CONCLUSIONS: Severity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.

Massive weight loss following deep brain stimulation of the nucleus accumbens in a depressed woman.

Obese individuals share behavioral characteristics with drug/alcohol addicts as well as obsessive compulsive disease. Deep brain stimulation (DBS) has been used successfully in these disorders, thus warranting an evaluation in obesity. A woman with treatment-resistant depression as well as severe obesity was selected for DBS of the nucleus accumbens (NAcc) bilaterally with depression being the primary and obesity being the secondary target of treatment. Compared to earlier bariatric surgery, the patient showed accelerated weight loss after DBS. Also, depression was significantly reduced. The current case suggests that DBS of the NAcc warrants further evaluation in patients unresponsive to other treatments.

[Psychotherapy of Depression as Neurobiological Process - Evidence from Neuroimaging]. / Psychotherapie depressiver Störungen als neurobiologischer Prozess ­ Erkenntnisse aus der Hirnbildgebung.

Research on neurobiological effects of psychotherapy in depression facilitates the improvement of treatment strategies. The cortico-limbic dysregulation model serves as a framework for numerous studies on neurobiological changes in depression. In this model, depression is described as hypoactivation of dorsal cortical brain regions in conjunction with hyperactivation of ventral paralimbic regions. This assumption has been supported by various studies of structural and functional brain abnormalities in depression. However, also regions not included in the original cortico-limbic dysregulation model, such as the dorsomedial prefrontal cortex, seem to play an important role in depression. Functional connectivity studies of depression have revealed an enhanced connectivity within the so-called default mode network which is involved in self-referential thinking. Studies also point to a normalization of limbic and cortical brain activity, especially in the anterior cingulate cortex, during psychotherapy. Some neurobiological markers like the activity of the anterior cingulate cortex, striatum and insula as well as hippocampal volume have been proposed to predict treatment response on a group-level. The activity of the anterior insula appears to be a candidate bio-marker for differential indication for psychotherapy or pharmacotherapy. The cortico-limbic dysregulation model and following research have inspired new forms of treatment for depression like deep brain stimulation of the subgenual anterior cingulate cortex, repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex, neurofeedback and attention training.

[Hoarding as a Disorder of the Obsessive-Compulsive Spectrum]. / Pathologisches Horten und Sammeln als Erkrankung des Zwangsspektrums.

Hoarding often occurs without obsessive-compulsive disorder (OCD), it shows distinguishable neuropsychological and neurobiological correlates and a distinct comorbidity spectrum. Further, it occurs secondarily to other psychiatric and neurobiological disorders. Therefore hoarding disorder has been included as a distinct diagnosis in DSM-5.Neuroimaging studies point to functional and structural abnormalities of networks subserving decision making, attention, action planning and emotional regulation.The cognitive-behavioral model outlines the most important characteristics of pathological hoarding, comprising deficits of information processing, maladaptive beliefs about information processing deficits, maladaptive beliefs about posessions as well as emotional attachment to them accompanied with emotional distress and avoidance.Because of a low willingness for therapy plus a high rate of discontinuation of therapy, a manualized cognitive-behavioral therapy approach for pathological hoarding has been established. It builds on observational learning, cognitive strategies, graduated exposure, response prevention, training/coaching to sort out, and relapse prevention are key components of the treatment. Particularily in case of lacking motivation for any kind of behavioral therapy or other psychological treatments, a pharmacotherapy with SSRIs is recommended.

Decreased limbic and increased fronto-parietal connectivity in unmedicated patients with obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is characterized by recurrent intrusive thoughts and ritualized, repetitive behaviors, or mental acts. Convergent experimental evidence from neuroimaging and neuropsychological studies supports an orbitofronto-striato-thalamo-cortical dysfunction in OCD. Moreover, an over excitability of the amygdala and over monitoring of thoughts and actions involving the anterior cingulate, frontal and parietal cortex has been proposed as aspects of pathophysiology in OCD. We chose a data driven, graph theoretical approach to investigate brain network organization in 17 unmedicated OCD patients and 19 controls using resting-state fMRI. OCD patients showed a decreased connectivity of the limbic network to several other brain networks: the basal ganglia network, the default mode network, and the executive/attention network. The connectivity within the limbic network was also found to be decreased in OCD patients compared to healthy controls. Furthermore, we found a stronger connectivity of brain regions within the executive/attention network in OCD patients. This effect was positively correlated with disease severity. The decreased connectivity of limbic regions (amygdala, hippocampus) may be related to several neurocognitive deficits observed in OCD patients involving implicit learning, emotion processing and expectation, and processing of reward and punishment. Limbic disconnection from fronto-parietal regions relevant for (re)-appraisal may explain why intrusive thoughts become and/or remain threatening to patients but not to healthy subjects. Hyperconnectivity within the executive/attention network might be related to OCD symptoms such as excessive monitoring of thoughts and behavior as a dysfunctional strategy to cope with threat and uncertainty.

Different amygdala subregions mediate valence-related and attentional effects of oxytocin in humans.

The neuropeptide oxytocin enhances the processing of positive social stimuli and improves the capacity to effectively attend the eye region of conspecifics. To investigate the neural basis of these effects, we combined intranasal oxytocin administration with high-resolution functional magnetic resonance imaging in a unique emotion classification task. Emotional faces were briefly presented while controlling for the initial fixation, and measuring subsequent eye movements. Oxytocin had differential effects on the activity of specific amygdala subregions. On the one hand, it attenuated activation in lateral and dorsal regions of the anterior amygdala for fearful faces but enhanced activity for happy expressions, thus indicating a shift of the processing focus toward positive social stimuli. On the other hand, oxytocin increased the likelihood of reflexive gaze shifts toward the eye region irrespective of the depicted emotional expression. This gazing pattern was related to an increase of activity in the posterior amygdala and an enhanced functional coupling of this region to the superior colliculi. Thus, different behavioral effects of oxytocin seem to be closely related its specific modulatory influence on subregions within the human amygdala.

Relevance of orbitofrontal neurochemistry for the outcome of cognitive-behavioural therapy in patients with obsessive-compulsive disorder.

Since the advent of non-invasive methods such as proton magnetic resonance spectroscopy ((1)H-MRS), obsessive-compulsive disorder (OCD) has been increasingly associated with an altered composition of neurometabolites and neurotransmitters in several brain areas. Particularly, Inositol has not only been implicated in OCD pathophysiology, but also shown effective in pilot studies in therapy-refractory OCD patients. However, the relevance of regional brain neurochemistry for therapy outcome has not yet been investigated. Whereas numerous neuroimaging findings support a dysfunction of the orbitofrontal cortex (OFC) in OCD, MR-spectroscopic investigations of this region are missing. (1)H-MRS and psychometric measurements were obtained from twenty unmedicated patients with OCD, subsequently enrolled in a 3-month structured inpatient cognitive-behavioural therapy programme, and from eleven matched control subjects. Multiple regression of symptom score changes (Y-BOCS) on (myo-)inositol concentrations in three areas (right orbitofrontal cortex (OFC), right striatum and anterior cingulate cortex) was performed. The concentration of (myo-)inositol in the OFC only predicted the outcome of subsequent CBT regarding Y-BOCS score reduction (Spearman's r(s) = .81, P < 0.003, corrected). The (myo-)inositol concentration did not differ between OCD patients and healthy controls and did not change during therapy. We provide preliminary evidence for a neurochemical marker that may prove informative about a patient's future benefit from behaviour therapy. Inositol, a metabolite involved in cellular signal transduction and a spectroscopic marker of glial activity, predicted the response to CBT selectively in the OFC, adding to the evidence for OFC involvement in OCD and highlighting neurobiological underpinnings of psychotherapy.

Does childhood emotional abuse moderate the effect of cognitive behavioral analysis system of psychotherapy versus meta-cognitive therapy in depression? A propensity score analysis on an observational study.

Background Cognitive Behavioral Analysis System of Psychotherapy (CBASP) and Metacognitive Therapy (MCT) are effective for depression. CBASP might offer most benefit in patients reporting childhood emotional abuse (CEA). This needs to be confirmed in real-world settings and in comparisons with depression-specific psychotherapies. This study examines the moderating influence of CEA on the effectiveness of CBASP versus MCT. Methods In this observational study, we recruited patients treated with either CBASP or MCT in an intensive day treatment program for depression. CEA was assessed using the Childhood Trauma Questionnaire (CTQ). Patients reported symptoms weekly using the Quick Inventory of Depressive Symptoms (QIDS-SR). Mixed model analysis was run on the Intention to Treat dataset (ITT) using propensity matching to overcome baseline imbalances. Results A total of 141 patients were included in the analysis (MCT n = 78, CBASP n = 63). CEA moderated the treatment effect (time x CEA x treatment: ß = 0.03, SE = 0.01, p = 0.014). Post-hoc analyses revealed that CBASP was more effective than MCT in patients without CEA (time x treatment: ß = -0.01, SE = 0.007, p = .045). The difference between CBASP and MCT was not statistically significant for patients with CEA (ß = 0.015, SE = 0.008, p = .11). Limitations Because of non-random treatment allocation the differences between CBASP and MCT can be due to unobserved baseline imbalances. Conclusions Our findings suggest that in patients reporting CEA, CBASP might not offer additional benefits above other depression-specific psychotherapies. Public Health Significance Statements This study shows that, on average, individuals with depression benefit equally from CBASP and MCT under the conditions of routine practice. Yet, CBASP was more effective than MCT for those without childhood emotional abuse. If childhood emotional abuse was present, CBASP and MCT were equally effective.

Precuneus connectivity and symptom severity in chronic depression✰.

Although abnormal resting state connectivity within several brain networks has been repeatedly reported in depression, little is known about connectivity in patients with early onset chronic depression. We compared resting state connectivity in a homogenous sample of 32 unmedicated patients with early onset chronic depression and 40 healthy control participants in a seed-to-voxel-analysis. According to previous meta-analyses on resting state connectivity in depression, 12 regions implicated in default mode, limbic, frontoparietal and ventral attention networks were chosen as seeds. We also investigated associations between connectivity values and severity of depression. Patients with chronic depression exhibited stronger connectivity between precuneus and right pre-supplementary motor area than healthy control participants, possibly reflecting aberrant information processing and emotion regulation deficits in depression. Higher depression severity scores (Hamilton Rating Scale for Depression) were strongly and selectively associated with weaker connectivity between the precuneus and the subcallosal anterior cingulate. Our findings correspond to results obtained in studies including both episodic and chronic depression. This suggests that there may be no strong differences between subtypes of depression regarding the seeds analyzed here. To further clarify this issue, future studies should directly compare patients with different courses of depression.

Long-Term Follow-up of Cognitive-Behavioral Therapy for Obsessive-Compulsive Disorder: Symptom Severity and the Role of Exposure 8-10 Years After Inpatient Treatment.

Obsessive-compulsive disorder (OCD) can be effectively treated by cognitive behavioral therapy (CBT) with exposure and response prevention (ERP). Yet, little is known about the long-term effects of inpatient CBT up to one decade after treatment. Thirty patients who had been treated with 12 weeks of intensive inpatient CBT with ERP were examined 8-10 years after their stay in hospital with regard to obsessive-compulsive symptoms, secondary outcomes, and use of healthcare services. Significant (p < .001) improvements in OC symptoms with medium and large effects compared to baseline on the Yale-Brown-Obsessive-Compulsive Scale (Y-BOCS) and on the Obsessive-Compulsive Inventory (OCI-R) could still be observed, with 20% of the patients reaching remission status. Continuation of exposure exercises after the inpatient stay was the sole significant factor for improved scores at follow-up. The results suggest that OCD does not necessarily take a chronic course. However, maintenance of exposure training seems to be crucial for sustained improvement.

The Role of Parvalbumin-positive Interneurons in Auditory Steady-State Response Deficits in Schizophrenia.

Despite an increasing body of evidence demonstrating subcellular alterations in parvalbumin-positive (PV+) interneurons in schizophrenia, their functional consequences remain elusive. Since PV+ interneurons are involved in the generation of fast cortical rhythms, these changes have been hypothesized to contribute to well-established alterations of beta and gamma range oscillations in patients suffering from schizophrenia. However, the precise role of these alterations and the role of different subtypes of PV+ interneurons is still unclear. Here we used a computational model of auditory steady-state response (ASSR) deficits in schizophrenia. We investigated the differential effects of decelerated synaptic dynamics, caused by subcellular alterations at two subtypes of PV+ interneurons: basket cells and chandelier cells. Our simulations suggest that subcellular alterations at basket cell synapses rather than chandelier cell synapses are the main contributor to these deficits. Particularly, basket cells might serve as target for innovative therapeutic interventions aiming at reversing the oscillatory deficits.

Quality and temporal properties of premonitory urges in patients with skin picking disorder.

Skin picking is a newly recognized obsessive-compulsive spectrum disorder in DSM-5. Similar to some repetitive behaviors in Gilles de la Tourette syndrome (GTS) and obsessive-compulsive disorder (OCD), premonitory urges are assumed to play a critical role in maintaining skin picking behavior, by creating a vicious cycle. The present study is the first to investigate the quality of premonitory urges, as well as the temporal relationship between urges and skin picking behavior in individuals with skin picking disorder. Quality and intensity of premonitory urges was assessed in 15 individuals with skin picking. Urge quality was assessed with the translated University of São Paulo Sensory Phenomena Scale (USP-SPS). Urge intensity was assessed continuously over 20 min using a computer-based tool. Participants were instructed either a) to pick freely or b) to suppress their skin picking behavior. Skin picking events during the free and suppression condition were recorded on video and coded manually. Regarding the types of urges, individuals with skin picking reported mainly physical urge sensations (80%), visual "just-right" feelings (80%), and urge-only sensations (80%) similar to urges reported by GTS and OCD patients. Moreover, the data showed a strong temporal relationship between the intensity of premonitory urges and the emergence of skin picking behavior (R2 = .23) that was weakened when skin picking was suppressed (R2 = .06). The results suggest that skin picking behavior is maintained by premonitory urges and that this vicious cycle of negative reinforcement can be, at least partially, broken by suppressing skin picking behavior.

Quetiapine addition to serotonin reuptake inhibitors in patients with severe obsessive-compulsive disorder: a double-blind, randomized, placebo-controlled study.

OBJECTIVE: Although many patients with obsessive-compulsive disorder (OCD) benefit from treatment with serotonin reuptake inhibitors (SRIs), it is estimated that 40% to 60% of them do not respond. The objective of the present study was to evaluate the efficacy of quetiapine added to baseline treatment with SRIs for the treatment of OCD in severely ill adult subjects. METHOD: Forty patients (21 men, 19 women) with primary OCD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria participated in a 12-week, double-blind, placebo-controlled trial. They were randomly assigned to dosages of quetiapine titrated up to 400 mg/d (n = 20) or to placebo (n = 20) in addition to their SRI treatment. During the continuation phase (weeks 6-12), subjects received different dosages between 400 and 600 mg/d depending on clinical response. At entry, all patients were unresponsive to at least 1 course of at least 12 weeks of treatment with SRIs at defined doses. The total Yale-Brown Obsessive-Compulsive Scale score was the primary efficacy parameter. RESULTS: Intention-to-treat, last-observation-carried-forward analysis demonstrated a mean +/- SD decrease in Yale-Brown Obsessive-Compulsive Scale score of 5.2 +/- 5.4 in the quetiapine group and 3.9 +/- 4.9 in the placebo group. The analysis of treatment effects between the 2 groups showed no significant difference. There were no significant group differences in any of the other self-rating scales or clinician-administered rating scales. CONCLUSIONS: In this study, augmentation of SRI treatment with quetiapine in severe OCD had no additional effect.

The temporal relationship between premonitory urges and covert compulsions in patients with obsessive-compulsive disorder.

Recent studies in patients with obsessive-compulsive disorder (OCD) have shown that many compulsions are associated with urges rather than obsessions. Premonitory urges are uncomfortable sensory feelings or a rising inner tension, often likened to the urge to scratch, yawn or blink. We studied premonitory urges preceding mental compulsions in 19 patients with OCD and preceding eye blinks in 16 healthy controls. Urge intensity was assessed continuously over 20 min using a real-time urge intensity monitor; compulsions and blinks were measured as discrete events in a free compulsion/blinking and a compulsion/blink suppression condition. Urge intensity showed an inverted U-shaped relationship (increase then decrease) around compulsions within a time-window of approximately 60 s in patients with OCD and within 13 s around blinks in healthy controls. Urge intensity was higher during compulsion / blink suppression and varied more independently of compulsion execution in patients with OCD. There is a close temporal relationship between premonitory sensations and compulsion execution that changes when compulsions are suppressed, indicating that urge intensity might drive the execution of and is then alleviated by compulsions. Suppression weakens the association between urge intensity and compulsion execution.

[Arterial Hyper- and Hypotension associated with psychiatric medications: a risk assessment based on the summaries of product characteristics (SmPCs)]. / Arterielle Hyper- und Hypotonie assoziiert mit Psychopharmaka: eine Risikobewertung basierend auf den Fachinformationen.

Introduction Psychiatric medications are well-known triggers of clinically relevant blood pressure changes. Therefore, we aimed at creating ranking lists for their risk of causing arterial hyper- or hypotension. Methods We analyzed 784 Summaries of Product characteristics (SmPCs, available online from "Rote Liste" or "Gelbe Liste" websites) from 105 psychiatric medications registered in adult psychiatry in Germany and extracted the standardized reported risks of increasing or decreasing arterial blood pressure. Results According to the SmPCs, atomoxetine had the highest risk of arterial hypertension ("very frequent", > 10 %), and another 15 substances followed in the category "frequent" (> 1 %): duloxetine, milnacipran, venlafaxine, bupropion, citalopram, tranylcypromine (particularly with certain diets), reboxetine, methylphenidate, clozapine, paliperidone, risperidone, buprenorphine+naloxone, memantine, galantamine, and rivastigmine. Conversely, 7 substances, namely amitriptyline, tranylcypromine, chlorprothixen, flupentixol, levomepromazine, olanzapine and trimipramine had the highest reported risk of low blood pressure ("very frequent"), and another 25 substances had the risk "frequent". No risk of hypertension or hypotension was documented for many other substances. Incidentally, we observed that the reported effects on blood pressure for single substances (e. g. citalopram) markedly differed between the SmPCs from different manufacturers, rendering a clear risk assessment impossible for many medications. Discussion According to the German SmPc, many psychiatric medications are associated with the risk of arterial hypertension and, even more so, hypotension. We hardly observed substance group effects, such as high blood pressure with noradrenergic antidepressants. Commonly used tables summarising secondary causes of arterial hypertension should be revised in terms of psychiatric medications. Our rank orders of risk may aid choosing the best psychiatric medications in patients with known hypertension or at risk for syncope, as well as when blood pressure changes occur under psychiatric pharmacotherapy. A definitive risk assessment however requires controlled studies.

Childhood adversity impacts on brain subcortical structures relevant to depression.

Childhood adversity plays an important role for development of major depressive disorder (MDD). There are differences in subcortical brain structures between patients with MDD and healthy controls, but the specific impact of childhood adversity on such structures in MDD remains unclear. Thus, aim of the present study was to investigate whether childhood adversity is associated with subcortical volumes and how it interacts with a diagnosis of MDD and sex. Within the ENIGMA-MDD network, nine university partner sites, which assessed childhood adversity and magnetic resonance imaging in patients with MDD and controls, took part in the current joint mega-analysis. In this largest effort world-wide to identify subcortical brain structure differences related to childhood adversity, 3036 participants were analyzed for subcortical brain volumes using FreeSurfer. A significant interaction was evident between childhood adversity, MDD diagnosis, sex, and region. Increased exposure to childhood adversity was associated with smaller caudate volumes in females independent of MDD. All subcategories of childhood adversity were negatively associated with caudate volumes in females - in particular emotional neglect and physical neglect (independently from age, ICV, imaging site and MDD diagnosis). There was no interaction effect between childhood adversity and MDD diagnosis on subcortical brain volumes. Childhood adversity is one of the contributors to brain structural abnormalities. It is associated with subcortical brain abnormalities that are relevant to psychiatric disorders such as depression.