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Background: Major depressive disorder (MDD) affects multiple functional neural networks. Neuroimaging studies using resting-state functional connectivity (FC) have focused on the amygdala but did not assess changes in connectivity between the left and right amygdala. The current study aimed to examine the inter-hemispheric functional connectivity (homotopic FC, HoFC) between different amygdalar sub-regions in patients with MDD compared to healthy controls, and to examine whether amygdalar sub-regions' HoFC also predicts response to Serotonin Selective Reuptake Inhibitors (SSRIs)., Method: Sixty-seven patients with MDD and 64 matched healthy controls were recruited. An MRI scan focusing on resting state fMRI and clinical and cognitive evaluations were performed. An atlas seed-based approach was used to identify the lateral and medial sub-regions of the amygdala. HoFC of these sub-regions was compared between groups and correlated with severity of depression, and emotional processing performance. Baseline HoFC levels were used to predict response to SSRIs after 2 months of treatment., Results: Patients with MDD demonstrated decreased inter-hemispheric FC in the medial (F3,120 = 4.11, p = 0.008, η2 = 0.096) but not in the lateral (F3,119 = 0.29, p = 0.82, η2 = 0.008) amygdala compared with healthy controls. The inter-hemispheric FC of the medial sub-region correlated with symptoms severity (r = -0.33, p < 0.001) and emotional processing performance (r = 0.38, p < 0.001). Moreover, it predicted treatment response to SSRIs 65.4 % of the cases., Limitations: The current study did not address FC changes in MDD biotypes. In addition, structural connectivity was not examined., Conclusions: Using a unique perspective of the amygdalar distinct areas elucidated differential inter-hemispheric FC patterns in MDD patients, emphasizing the role of interhemispheric communication in depression., Competing Interests: Declaration of competing interest No disclosures were noted for this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Some but not other studies on oxytocin for schizophrenia, particularly those using a higher dose, indicate that oxytocin improves negative symptoms of schizophrenia. We performed an add-on randomized controlled trial to examine the effect of high-dose oxytocin, social skills training, and their combination in the treatment of negative symptoms and social dysfunction in schizophrenia. Fifty-one subjects with schizophrenia were randomized, employing a two-by-two design: intranasal oxytocin (24 IU X3/day) or placebo, and social skills training or supportive psychotherapy, for 3 weeks. The primary outcome was the difference in the total score from baseline to end-of-study of a semi-structured interview which assessed patients' social interactions in 3 scenarios: sharing a positive experience, sharing a conflict, and giving support when the experimenter shared a conflict. The interactions were scored using the Coding Interactive Behavior Manual (CIB), clinical symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). No significant difference was found between groups in the total CIB or PANSS scores. The majority of comparisons in the different social interactions between oxytocin and placebo, and between social skills training vs supportive psychotherapy, were also nonsignificant. Social skills training reduced blunted affect and gaze. In post-hoc analyses of the support interaction, oxytocin improved synchrony and decreased tension, while in the positive interaction it improved positive affect and avoidance. None of these findings remained significant when controlling for multiple comparisons. In conclusion, oxytocin did not influence participants' social behavior, and was not effective in improving the symptoms of schizophrenia. Clinicaltrials.gov Identifier: NCT01598623., (© The Author(s) 2024. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.)

Introduction: Expert consensus operationalized treatment response and remission in obsessive-compulsive disorder (OCD) as a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) reduction ≥35% and score ≤12 with ≤2 on Clinical Global Impressions Improvement (CGI-I) and Severity (CGI-S) scales, respectively. However, there has been scant empirical evidence supporting these definitions., Methods: We conducted a systematic review and an individual participant data meta-analysis of randomized-controlled trials (RCTs) in adults with OCD to determine optimal Y-BOCS thresholds for response and remission. We estimated pooled sensitivity/specificity for each percent reduction threshold (response) or posttreatment score (remission) to determine response and remission defined by a CGI-I and CGI-S ≤ 2, respectively., Results: Individual participant data from 25 of 94 eligible RCTs (1235 participants) were included. The optimal threshold for response was ≥30% Y-BOCS reduction and for remission was ≤15 posttreatment Y-BOCS. However, differences in sensitivity and specificity between the optimal and nearby thresholds for response and remission were small with some uncertainty demonstrated by the confidence ellipses., Conclusion: While the empirically derived Y-BOCS thresholds in our meta-analysis differ from expert consensus, given the predominance of data from more recent trials of OCD, which involved more refractory participants and novel treatment modalities as opposed to first-line therapies, we recommend the continued use of the consensus definitions., Competing Interests: Declaration of competing interest Abraham Zangen is an inventor of Deep TMS coils developed to study and treat neurological and psychiatric disorders and has financial interest in BrainsWay which produces and markets these coils. Daniel L.C. Costa received honoraria from Janssen, Lundbeck and Schwabe pharmaceuticals. David Mataix-Cols receives royalties for contributing articles to UpToDate, Inc. David Shannahoff-Khalsa reports royalties from two books published by W.W. Norton & Co, Inc. that includes the Kundalini Yoga meditation protocol, personal sales for a DVD for the protocol, and OCD patient fees. Eric A. Storch receives research funding for his institution from the Ream Foundation, International OCD Foundation, and NIH. He is a consultant for Brainsway and Biohaven Pharmaceuticals. He owns stock less than $5000 in NView (for distribution of the Y-BOCS and CY-BOCS) and Limbix. He receives book royalties from Elsevier, Wiley, Oxford, American Psychological Association, Guildford, Springer, Routledge, and Jessica Kingsley. Juliana B. Diniz has received speaker's fees from Lundbeck and Janssen Cilag for lectures. Michael H. Bloch has received grant/research support from Therapix Biosciences, Emalex Biosciences, Janssen Pharmaceuticals, Biohaven Pharmaceuticals, NIH, Lesbian Health Fund, Yale Foundation for Lesbian and Gay Studies (FLAGS), and Patterson Foundation, has served on the advisory board/data monitoring and safety board of Therapix Biosciences, and serves as associate editor of Journal of Child Psychology and Psychiatry and on the editorial boards of Journal of Child and Adolescent Psychopharmacology and Depression & Anxiety. He has received royalties from Wolters Kluwer for Lewis's Child and Adolescent Psychiatry: A Comprehensive Textbook, Fifth Edition and moonlighting pay from the VA. Roseli G. Shavitt has received consultancy honoraria from Lundbeck and research grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) in the past three years. Sabine Wilhelm is a presenter for the Massachusetts General Hospital Psychiatry Academy in educational programs supported through independent medical education grants from pharmaceutical companies. She has received royalties from Elsevier Publications, Guilford Publications, New Harbinger Publications, Springer, and Oxford University Press, speaking honoraria from various academic institutions and foundations, including the International Obsessive Compulsive Disorder Foundation, the Tourette Association of America, and the Centers for Disease Control and Prevention, and payment from the Association for Behavioral and Cognitive Therapies for her role as Associate Editor of the Behavior Therapy journal and John Wiley & Sons, Inc. as Associate Editor of the journal Depression & Anxiety. She has also received honoraria for her role on the Scientific Advisory Board for One-Mind (PsyberGuide), Koa Health, Inc, and Noom, Inc. She has received research and salary support from Koa Health, Inc. None of the remaining co-authors have any conflicts of interest to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

What humans look at strongly determines what they see. We show that individual differences in the tendency to look at positive stimuli are stable across time and across contents, establishing gaze positivity preference as a perceptual trait that determines the amount of positively valence stimuli individuals select for visual processing. Furthermore, we show that patients with major depressive disorder exhibit consistently low positivity preference before treatment. In a subset of patients, we also assessed the positivity preference after two months of treatment in which positivity gaze preference increased to levels similar to healthy individuals. We discuss the possible practical diagnostic applications of these findings, as well as how this general gaze-related trait may influence other behavioral and psychological aspects., (© 2024. The Author(s).)

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants ( n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo ( P < 0.0001, d = 0.91) and to significantly decrease the SDS total score ( P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was -24.4 (s.d. 11.6) in the MDMA group and -13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation. Appeared originally in Nat Med 2021; 27:1025-1033 ., (Copyright © 2023 by the American Psychiatric Association.)

Introduction: Several studies have shown an association between panic disorder (PD) and reduced balance abilities, mainly based on functional balance scales. This pilot study aims to demonstrate the feasibility of studying balance abilities of persons with PD (PwPD) using computerized static and, for the first time, dynamic balance measurements in order to characterize balance control strategies employed by PwPD., Methods: Twelve PwPD and 11 healthy controls were recruited. PD diagnosis was confirmed using the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), and the severity of symptoms was evaluated using the Hamilton Anxiety Scale (HAM-A), PD Severity Scales (PDSS), and Panic and Agoraphobia Scale (PAS). Balance was clinically assessed using the Activities-Specific Balance Confidence (ABC) scale and physically by the Mini-Balance Evaluation Systems Test (Mini-BESTest). Dizziness was evaluated using the Dizziness Handicap Inventory (DHI) scale. Postural control was evaluated statically by measuring body sway and dynamically by measuring body responses to rapid unexpected physical perturbations., Results: PwPD had higher scores on the HAM-A (17.6 ± 10.3 vs. 3.0 ± 2.9; p < .001), PDSS (11.3 ± 5.1 vs. 0; p < .001), and PAS (20.3 ± 8.7 vs. 0; p < .001) questionnaires and lower scores on the balance scales compared to the controls (ABC scale: 156.2 ± 5.9 vs. 160 ± 0.0, p = .016; Mini-BESTest: 29.4 ± 2.1 vs. 31.4 ± 0.9, p = .014; DHI: 5.3 ± 4.4 vs. 0.09 ± 0.3, p < .001). In the static balance tests, PwPD showed a not-significantly smaller ellipse area of center of pressure trajectory (p = .36) and higher body sway velocity (p = .46), whereas in the dynamic balance tests, PwPD had shorter recovery time from physical perturbations in comparison to controls (2.1 ± 1.2s vs. 1.6 ± 0.9 s, p = .018)., Conclusion: The computerized balance tests results point to an adoption of a ''postural rigidity'' strategy by the PwPD, that is, reduced dynamic adaptations in the face of postural challenges. This may reflect a nonsecure compensatory behavior. Further research is needed to delineate this strategy., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Purpose: Ketamine, a noncompetitive, high-affinity antagonist of the N-methyl-d-aspartate-type glutamate receptor, has a rapid effect in patients with treatment-resistant disorder, but many patients who respond to intravenous ketamine relapse within several days. The objective of this study was to examine the long-term outcome of patients' mood 5 years after ketamine treatment., Methods: Sixteen electroconvulsive therapy referrals received at least 1 intravenous ketamine treatment in addition to their stable antidepressant medications. Depression was evaluated using the Inventory of Depressive Symptomatology-Clinician-Rated, Hamilton Rating Scales for Depression, and Montgomery-Åsberg Depression Rating Scale. Anxiety was measured using the Hamilton Rating Scale., Results: Of 16 patients treated, 6 achieved complete remission, 3 partially responded, and 7 did not respond. At baseline, all patients were treated with antidepressants, 14 patients were also treated with neuroleptics, of whom 5 patients were treated with quetiapine. The time to relapse in the 5 patients taking quetiapine was significantly longer than in patients who were taking other neuroleptics (965.83 ± 824.68 vs 80.5 ± 114.3, Z = 7.001, P = 0.0001). At the 5-year follow-up, 3 of the patients taking quetiapine maintained their remission. Overall levels of depression and anxiety at all times were improved in comparison to baseline., Conclusions: Our follow-up results suggest that the combination of quetiapine and ketamine can prolong time to relapse after ketamine treatment in patients with treatment-resistant disorder., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was -24.4 (s.d. 11.6) in the MDMA group and -13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation.

Objectives: Despite their impact on daily functioning, we have limited understanding of the executive functioning of older adults with bipolar disorder (OABD). Even less is known about the possible differences in the executive functioning of OABD and older adults with unipolar depression (OADEP)., Methods: After excluding acutely ill patients, the executive functioning of OABD was compared to that of OADEP and healthy controls (n = 22, n = 20, n = 22; respectively). Cognitive insight, a sub-domain of executive functioning, was operationalized as the discrepancy between the participants' self-reported cognitive functioning and appraisals that were made by their care partners. To complement the cognitive profiling, the groups were compared in information processing speed, verbal memory, and visual-spatial memory., Results: OABD were impaired in several cognitive domains compared to healthy controls, most prominently in executive functioning and memory. OABD had poorer executive functioning and visual-spatial memory than OADEP. The findings also tentatively point toward intact cognitive insight among OABD, while OADEP seem to have a heightened level of awareness of their cognitive impairment., Conclusions: OABD have a unique profile of cognitive impairment compared to OADEP. It is characterized by a more severe cognitive impairment, accompanied by relatively intact cognitive insight. The findings may help clarify the cognitive profile of OABD and assist in the development of cognitive rehabilitation programs tailored to their needs. They should, however, be considered preliminary and await further research., (© 2020 John Wiley & Sons Ltd.)

Objective: Major depressive disorder (MDD) is common in anorexia nervosa (AN), associated with worse outcome and greater suicide risk. Electroconvulsive therapy (ECT) is highly effective in the treatment of MDD refractory to antidepressive treatment. We describe a case series of female adolescents with AN receiving ECT for MDD resistant to treatment and/or with severe suicide risk., Method: We retrospectively analyzed the files of all 30 adolescent females hospitalized in our department because of AN between 1998 and 2017 and treated with ECT. Severity of eating disorder (ED) and depressive symptoms was retrospectively assessed using the Clinical Global Impression-Severity Scale., Results: Patients were severely depressed and suicidal on admission. All were resistant to antidepressants. A significant deterioration in depression, with severe suicidality, occurred from admission to pre-ECT, with concomitant improvement in ED symptoms and increase in body mass index (BMI). Significant improvement in depressive and ED symptoms and increase in BMI occurred following ECT, continuing to discharge. Adverse effects were mostly minimal. Fifty-three percentage of the patients were rehospitalized within the first year after ECT, mostly because of deterioration of depression and attempted suicide. Several years after discharge, 46.6% of the patients had no evidence of depression, suicidality, and ED-symptomatology, and another 23% had only evidence of ED symptomatology., Discussion: ECT is safe and well tolerated in AN with severe comorbid treatment resistant MDD and/or with increased suicide risk. Many AN patients undergoing ECT may be remitted at long-term follow-up., (© 2019 Wiley Periodicals, Inc.)

Objective: Evidence both from animal and human studies suggests a role for dopaminergic pathways in the treatment of depression. Ropinirole, a selective agonist of dopamine D2/D3, is in use for the treatment of parkinsonism. Preliminary evidence suggests that such agonists might be useful as antidepressants. We tested whether an add-on ropinirole is an effective in depressed patients., Methods: We conducted a double-blind, randomized, placebo-controlled trial of add-on ropinirole in depressed patients unresponsive to at least one antidepressant. We recruited 32 unipolar and bipolar patients who remained depressed (modified 21-item Hamilton Depression Rating Scale) despite at least 4 weeks of treatment with an adequate dose of antidepressant medication. Patients received either 2 mg of oral ropinirole or placebo twice daily added on to their current medication and were evaluated weekly for 7 weeks using the Hamilton Depression Rating Scale and Montgomery-Asberg Depression Rating Scale., Results: No difference in primary or secondary outcome measures was detected between the treatment and control groups., Discussion: These results differ from previous studies and are unexpected in light of theoretical considerations. This may indicate that there are differences in pharmacological activity between ropinirole and other dopaminergic agents such as pramipexole.

Prototype matching, which involves comparing a patient clinical presentation with a prototype description of the disorder, addresses some of the clinical limitations of categorical approaches. Most research to-date on prototype matching has been conducted with personality disorders. Here, we examined the validity and clinical utility of prototype diagnosis for mood and anxiety disorders. We compared clinicians prototype diagnosis (based on DSM IV and empirically derived) to categorical diagnosis (based on independent SCID interview) in predicting patient global adaptive functioning rated across the clinician, patient and independent interviewer among N = 80 clinicians and N = 170 patients. Our findings show that prototype diagnosis (both one that is based on DSM criteria and empirically derived) demonstrates some incremental validity over and above the categorical DSM IV, in predicting patient's global adaptive functioning. This is particularly pronounced for mood disorders (MDD and dysthymia) as well as several anxiety disorders (OCD, social phobia) across a range of experience level of diagnosticians. Furthermore, clinicians rated the prototype matching approach as more useful in clinical practice compared with the binary categorical system. Using a dimensional approach, which is based on prototype matching that also preserves the advantages of categorical system offers a valid and efficient approach to psychiatric assessment., (Copyright © 2018. Published by Elsevier B.V.)

Objective: Implantable Cardioverter Defibrillators (ICDs), have previously been associated with the onset of depression and anxiety. The aim of this one-year prospective study was to evaluate the rate of new onset psychopathological symptoms after elective ICD implantation., Methods: A total of 158 consecutive outpatients who were scheduled for an elective ICD implantation were diagnosed and screened based on the Mini International Neuropsychiatric Interview (MINI). Depression and anxiety were evaluated using the Hamilton Rating Scales for Depression (HAM-D) and Anxiety (HAM-A). Patient's attitude toward the ICD device was evaluated using a Visual Analog Scale (VAS)., Results: Patients' mean age was 64±12.4years; 134 (85%) were men, with the majority of patients performing the procedure for reasons of 'primary prevention'. According to the MINI diagnosis at baseline, three (2%) patients suffered from major depressive disorder and ten (6%) from dysthymia. Significant improvement in HAM-D mean scores was found between baseline, three months and one year after implantation (6.50±6.4; 4.10±5.3 and 2.7±4.6, respectively F(2100)=16.42; p<0.001). There was a significantly more positive attitude toward the device over time based on the VAS score [F(2122)=53.31, p<0.001]., Conclusions: ICD implantation significantly contributes to the reduction of depressive symptoms, while the overall mindset toward the ICD device was positive and improved during the one-year follow-up., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Body image disturbances are a prominent feature of eating disorders (EDs). Our aim was to test and evaluate a computerized assessment of body image (CABI), to compare the body image disturbances in different ED types, and to assess the factors affecting body image. The body image of 22 individuals undergoing inpatient treatment with restricting anorexia nervosa (AN-R), 22 with binge/purge AN (AN-B/P), 20 with bulimia nervosa (BN), and 41 healthy controls was assessed using the Contour Drawing Rating Scale (CDRS), the CABI, which simulated the participants' self-image in different levels of weight changes, and the Eating Disorder Inventory-2-Body Dissatisfaction (EDI-2-BD) scale. Severity of depression and anxiety was also assessed. Significant differences were found among the three scales assessing body image, although most of their dimensions differentiated between patients with EDs and controls. Our findings support the use of the CABI in the comparison of body image disturbances in patients with EDs vs., Controls: Moreover, the use of different assessment tools allows for a better understanding of the differences in body image disturbances in different ED types.

Perceptual closure ability is postulated to depend upon rapid transmission of magnocellular information to prefrontal cortex via the dorsal stream. In contrast, illusory contour processing requires only local interactions within primary and ventral stream visual regions, such as lateral occipital complex. Schizophrenia is associated with deficits in perceptual closure versus illusory contours processing that is hypothesized to reflect impaired magnocellular/dorsal stream. Perceptual closure and illusory contours performance was evaluated in separate groups of 12 healthy volunteers during no TMS, and during repetitive 10 Hz rTMS stimulation over dorsal stream or vertex (TMS-vertex). Perceptual closure and illusory contours were performed in 11 schizophrenia patients, no TMS was applied in these patients. TMS effects were evaluated with repeated measures ANOVA across treatments. rTMS significantly increased perceptual closure identification thresholds, with significant difference between TMS-dorsal stream and no TMS. TMS-dorsal stream also significantly reduced perceptual closure but not illusory contours accuracy. Schizophrenia patients showed increased perceptual closure identification thresholds relative to controls in the no TMS condition, but similar to controls in the TMS-dorsal stream condition. Conclusions of this study are that magnocellular/dorsal stream input is critical for perceptual closure but not illusory contours performance, supporting both trickledown theories of normal perceptual closure function, and magnocellular/dorsal stream theories of visual dysfunction in schizophrenia.

Background: Fear of flying (FoF), a common phobia in the developed world, is usually treated with cognitive behavioral therapy, most efficiently when combined with exposure methods, e.g., virtual reality exposure therapy (VRET). We evaluated FoF treatment using VRET in a large motion-based VR system. The treated subjects were seated on a moving platform. The virtual scenery included the interior of an aircraft and a window view to the outside world accompanied by platform movements simulating, e.g., takeoff, landing, and air turbulence. Relevant auditory stimuli were also incorporated., Case Report: Three male patients with FoF underwent a clinical interview followed by three VRETs in the presence and with the guidance of a therapist. Scores on the Flight Anxiety Situation (FAS) and Flight Anxiety Modality (FAM) questionnaires were obtained on the first and fourth visits. Anxiety levels were assessed using the subjective units of distress (SUDs) scale during the exposure. All three subjects expressed satisfaction regarding the procedure and did not skip or avoid any of its stages. Consistent improvement was seen in the SUDs throughout the VRET session and across sessions, while patients' scores on the FAS and FAM showed inconsistent trends. Two patients participated in actual flights in the months following the treatment, bringing 12 and 16 yr of avoidance to an end., Discussion: This VR-based treatment includes critical elements for exposure of flying experience beyond visual and auditory stimuli. The current case reports suggest VRET sessions may have a meaningful impact on anxiety levels, yet additional research seems warranted.

Unlabelled: Schizophrenic patients have a high rate of smoking and cognitive deficits which may be related to a decreased number or responsiveness of nicotinic receptors in their brains. Varenicline is a partial nicotinic agonist which is effective as an antismoking drug in cigarette smokers, although concerns have been raised about potential psychiatric side-effects. We conducted a double-blind placebo controlled study in 87 schizophrenic smokers to evaluate the effects of varenicline (2 mg/day) on measures of smoking, cognition, psychiatric symptoms, and side-effects in schizophrenic patients who were cigarette smokers. Varenicline significantly decreased cotinine levels (P<0.001), and other objective and subjective measures of smoking (P < .01), and responses on a smoking urges scale (P = .02), more than placebo. Varenicline did not improve scores on a cognitive battery designed to test the effect of drugs on cognitive performance in schizophrenia (the MATRICS battery), either in overall MATRICS battery Composite or individual Domain scores, more than placebo. There were no significant differences between varenicline vs. placebo effects on total symptom scores on psychiatric rating scales, PANSS, SANS, or Calgary Depression scales, and there were no significant drug effects in any of these scales sub-scores when we used Benjamin-Hochberg corrected significance levels (α = .05). Varenicline patients did not show greater side-effects than placebo treated patients at any time point when controlled for baseline side-effect scores. Our study supports the use of varenicline as a safe drug for smoking reduction in schizophrenia but not as a cognitive enhancer., Trial Registration: ClinicalTrials.gov 00802919.

Objective: In this retrospective cross-sectional study, we evaluated the existence of psychiatric symptoms which appeared after implantation of an implantable cardioverter defibrillator (ICD)., Methods: Patients with ICDs were diagnosed using the Mini International Neuropsychiatric Interview (MINI) and were excluded if they had any psychiatric diagnosis prior to ICD implantation. Depression and anxiety were evaluated using the HAM-D and HAM-A rating scales and their attitude towards the ICD using a visual analog scale (VAS). Ninety five ICD patients with mean age of 66 years (±11.5) were recruited, 80 (84%) were men., Results: Four (4%) patients were diagnosed with new-onset MDD and one patient (1%) with anxiety. Twenty seven (28%) were found to have significant depressive symptoms (HAM-D >8), without MDD diagnosis; half of them attributing these symptoms to the device. Seven (8%) patients experienced phantom shocks and had relatively higher depressive scores (HAM-D 10.3 vs. 5.8; F = 3.696; p = 0.058). The MDD rates in our study were rather consistent with those reported for cardiac patients., Conclusions: We suggest that ICD contributed little, if any, additional depressive or anxiety symptoms after implantation. We found that the overall attitude towards the device was positive and that shocks and phantom shocks were related to depressive symptoms.

Objectives: Repetitive transcranial magnetic stimulation (rTMS), using standard coils, provided modest symptomatic benefits in patients with Parkinson's disease (PD). In our previous exploratory studies, using the newly developed Hesed coil (providing deeper rTMS; rDTMS) high frequency (HF), excitatory rDTMS over the primary motor cortex (M1), did not achieve sufficient beneficial effect for PD symptoms, while low frequency (LF) inhibitory stimulation, was mildly beneficial. To further investigate the optimal rDTMS stimulation parameters for PD patients, and to assess whether there is an added value for dual stimulation, consisting of HF rDTMS over the prefrontal cortex (PFC) along with LF M1 rDTMS. The rational for the selection of the current stimulation parameters and sites lies on the previous studies that demonstrated an inhibitory effect of 1Hz rTMS on the increased cortical activity in PD as well as dopamine release by PFC stimulation., Patients and Methods: An open comparative active study of one month duration (12 sessions) of LF rDTMS over M1 alone (n=9) or combined with HF PFC rDTMS (M1-PFC, n=10). Outcome measures included the total and motor Unified Parkinson's Disease Rating Scale scores (T-UPDRS and M-UPDRS) and other variables, were collected at baseline and on days 30 and 60., Results: For the M1+PFC group, T-UPDRS score improved from baseline to day 30, by 15% (median: 52 points, decreased to 44, p=0.02, effect size: 0.51) and M-UPDRS score improved by 24% (median: 37 points decreased to 28, p=0.04, effect size: 0.47). The corresponding results for the M1 group were insignificant. Additionally, the between groups comparison, was insignificant., Conclusion: rDTMS, consisting of M1 excitation with PFC inhibition improved PD motor symptoms but was not significantly superior to M1 rDTMS alone. rDTMS stimulation protocols for M1 should be further evaluated in larger scale controlled studies., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Schizophrenia is characterized by cognitive deficits which persist after acute symptoms have been treated or resolved. Transcranial direct current stimulation (tDCS) has been reported to improve cognition and reduce smoking craving in healthy subjects but has not been as carefully evaluated in a randomized controlled study for these effects in schizophrenia. We conducted a randomized double-blind, sham-controlled study of the effects of 5 sessions of tDCS (2 milliamps for 20minutes) on cognition, psychiatric symptoms, and smoking and cigarette craving in 37 outpatients with schizophrenia or schizoaffective disorder who were current smokers. Thirty subjects provided evaluable data on the MATRICS Consensus Cognitive Battery (MCCB), with the primary outcome measure, the MCCB Composite score. Active compared to sham tDCS subjects showed significant improvements after the fifth tDCS session in MCCB Composite score (p=0.008) and on the MCCB Working Memory (p=0.002) and Attention-Vigilance (p=0.027) domain scores, with large effect sizes. MCCB Composite and Working Memory domain scores remained significant at Benjamini-Hochberg corrected significance levels (α=0.05). There were no statistically significant effects on secondary outcome measures of psychiatric symptoms (PANSS scores), hallucinations, cigarette craving, or cigarettes smoked. The positive effects of tDCS on cognitive performance suggest a potential efficacious treatment for cognitive deficits in partially recovered chronic schizophrenia outpatients that should be further investigated., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Hypofunction of NMDA receptor-mediated neurotransmission might play a critical role in schizophrenia. Sarcosine, N- methylglycine and inhibitor of the glycine transporter-1 (Gly-T1), has been suggested as a novel treatment for schizophrenia., Methods: Open label sarcosine was added to 22 stabilized patients: 5 patients received 2 gm/d, and 17 received 4gm/d. Pharmacokinetics samples, clinical and cognitive parameters using PANSS, CGI and MCCB were collected for all patients., Results: Significant improvement was observed after one week of treatment on PANSS sub-scale of 'positive symptoms' (Z= -2.68; P=0.007) and 'general psychopathology' (Z= -3.02; P=0.003), an improvement in PANSS total score and CGI-S showed a trend (Z= -2.72; P=0.06; Z=-2.69; P=0.08). Speed of processing (MCCB subscale) improved significantly (Z=-2.13; P=0.03). Sarcosine exhibited linear kinetics, with a Tmax and t½ of ~1½- 2½ hr and ~1hr, respectively., Limitations: This was a short period, open label pilot study with small sample size per dosage group., Conclusions: Sarcosine is a safe compound and might be efficacious in the treatment of schizophrenia.

Recapturing meaning in life has been described as an essential element in the process of recovery from severe mental illness (SMI), but limited quantitative research still restricts our understanding of this phenomenon. The purpose of the current study was to explore the meaning in life among people with SMI and variables that may influence it such as internalized stigma and insight into the mental illness. We expected a significant negative correlation between internalized stigma and meaning in life, and that internalized stigma would moderate the relationship between insight and meaning in life. To explore these assumptions, 60 persons with SMI completed questionnaires that assessed their meaning in life, insight into their mental illness and internalized stigma, after which the data were analyzed using correlation and cluster analysis. Both hypotheses were confirmed. The mechanism behind the relationship between self-stigma and meaning in life and the theoretical and clinical implications of the moderation model are discussed., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Insight into mental illness and self-stigma among persons with serious mental illness (SMI) have been found to be related, but the process behind this relation is still unclear. The current study examined whether shame and guilt proneness mediates or moderates the relation between insight into mental illness and self-stigma among persons with SMI. Sixty persons with SMI completed questionnaires that assessed their insight, shame, guilt proneness, and self-stigma. Results reveal that shame proneness but not guilt proneness mediates the relation between insight and self-stigma. The theoretical and clinical implications of the differences between shame and guilt and their relation to the development of self-stigma are discussed., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Collinear flankers increase the reports of the target present, an effect attributed to excitatory activation induced by the flankers on the target location, which consequently induces the filling-in effect (Polat & Sagi, 2007). Repetitive transcranial magnetic stimulation (rTMS) is a powerful tool for non-invasive investigation of neural processing in the human brain. We explored how rTMS over the left dorsolateral prefrontal cortex (LDLPFC) affects filling-in perception in normal controls. Active and Sham rTMS were used over the DLPFC (90% of the subjects' motor threshold (MT)) using 10-Hz pulses for 5- and 20-s intertrain intervals. We used the filling-in paradigm to probe hit rates (pHit) and false-positive reports (false alarm, pFA). We found that the changes in the filling-in effect (pHit, pFA) were not significantly different between the groups. However, the reaction time (RT) was significantly reduced in the rTMS group but not in the Sham group. Our results suggest that neural processing in this area is not critical in the processing of the filling-in effect, probably because this process is mediated by lower-level visual processing., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Exogenous testosterone therapy has psychotropic effects and has been proposed as an antidepressant augmentation strategy for depressed men. We sought to assess the antidepressant effects of testosterone augmentation of a serotonergic antidepressant in depressed, hypogonadal men. For this study, we recruited 100 medically healthy adult men with major depressive disorder showing partial response or no response to an adequate serotonergic antidepressant trial during the current episode and a screening total testosterone level of 350 ng/dL or lower. We randomized these men to receive testosterone gel or placebo gel in addition to their existing antidepressant regimen. The primary outcome measure was the Hamilton Depression Rating Scale (HDRS) score. Secondary measures included the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impression Scale, and the Quality of Life Scale. Our primary analysis, using a mixed effects linear regression model to compare rate of change of scores between groups on the outcome measures, failed to show a significant difference between groups (mean [95% confidence interval] 6-week change in HDRS for testosterone vs placebo, -0.4 [-2.6 to 1.8]). However, in one exploratory analysis of treatment responders, we found a possible trend in favor of testosterone on the HDRS. Our findings, combined with the conflicting data from earlier smaller studies, suggest that testosterone is not generally effective for depressed men. The possibility remains that testosterone might benefit a particular subgroup of depressed men, but if so, the characteristics of this subgroup would still need to be established.

Mid-life onset male dysthymic disorder (DD) seems to be a distinct clinical condition with limited therapeutic options. Testosterone replacement is mood-enhancing and has been proposed as an antidepressant therapy, though this strategy has received limited systematic study. We therefore conducted a six-week double-blind placebo-controlled clinical trial in 23 men with DD and with low or low-normal testosterone (T) level (i.e, screening total serum testosterone <350 ng/dL). Enrolled men were randomized to receive intramuscular injections of 200 mg of testosterone cypionate or placebo every 10 days. The primary outcome measures were the Clinical Global Impression (CGI) improvement score and the 21-item Hamilton Depression Rating Scale (HDRS) score.Twenty-three patients were randomized. The mean (SD) age of the enrolled patients was 50.6 (7.0) years and that of total testosterone level was 339 (93) ng/dL. The median duration of the current dysthymic episode was 3.6 (2.3) years, and the mean (SD) HDRS was 14.0 (2.9). After the intervention, the mean HDRS score decreased significantly more in the testosterone group (7.46 [4.56]) than in the placebo group (1.8 [4.13], t21 = -3.07, P = 0.006). Remission, defined as a CGI improvement score of 1 or 2 and a final HDRS score lower than 8, was achieved by 7 (53.8%) of 13 in the testosterone group and 1 (10%) of 10 in the placebo group (P = 0.03). Testosterone replacement may be an effective antidepressant strategy for late-onset male dysthymia.

Aims: To evaluate the effect of repeated high-frequency transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC), combined with either smoking or neutral cues, on cigarette consumption, dependence and craving., Design: Participants were divided randomly to real and sham stimulation groups. Each group was subdivided randomly into two subgroups presented with either smoking-related or neutral pictures just before the daily TMS intervention. Ten daily rTMS sessions were applied every week-day and then a maintenance phase was conducted in which rTMS sessions were less frequent., Setting: Single-site, out-patient, randomized, double-blind, sham-controlled., Participants: Forty-eight chronic smokers who smoked at least 20 cigarettes per day and were motivated to quit smoking. Healthy males and females were recruited from the general population using advertisements in newspapers and on internet websites., Intervention: Ten daily rTMS sessions were administered using a standard figure-8 coil over the DLPFC. Stimulation included 20 trains/day at 100% of motor threshold. Each train consisted of 50 pulses at 10 Hz with an inter-train interval of 15 seconds., Measurements: Cigarette consumption was evaluated objectively by measuring cotinine levels in urine samples and subjectively by participants' self-reports. Dependence and craving were evaluated by standard questionnaires., Findings: Ten daily rTMS sessions over the DLPFC reduced cigarette consumption and nicotine dependence. Furthermore, treatment blocked the craving induced by daily presentation of smoking-related pictures. However, these effects tended to dissipate over time., Conclusions: Multiple high-frequency rTMS of the DLPFC can attenuate nicotine craving.

Background: Major depression disorder is a syndrome that involves impairment of cognitive functions such as memory, attention, and plasticity. In this study, we explored whether depression affects perception as well., Methods: We used a recently developed paradigm that assesses the filling-in process by probing false-positive reports (false alarm [FA]), hit rates (pHit), sensitivity (d'), and decision criteria (Cr). We used a Yes-No paradigm in a low-level detection task involving a Gabor target, in the presence of collinear flankers, inducing filling-in, with differing target-flanker separations of 3-15 lambda(wavelength). The depressive state of patients was assessed using the Hamilton Depression Rating Scale. Two groups were tested: an experimental group with major depression (n = 27) and a control group (n = 32)., Results: The performances of the control and the experimental groups were not significantly different regarding d'. In contrast, a specific pattern of significant differences between the control group and the hospitalized group was found for the decision criterion, pHit, and pFA, but only for target-flanker separations of 3 lambda, whereas the results for the other separations were insignificant. The differences between the control and the depressed groups are not due to a global cognitive dysfunction in depression., Conclusions: The results suggest that the filling-in process is deficient, probably because of reduced excitation among neurons. Neural excitation is a key factor in the neural processing involved in memory and decision making. In addition, it is still possible that the patients may be unable to match their internal representation to the changing sensory information.

Current treatments for Obsessive Compulsive Disorder (OCD) rely primarily on serotonergic mechanisms. However, approximately 30% of patients do not respond to serotonin reuptake inhibitors and remain chronically ill. Given the behavioral similarities between some of the compulsive behaviors in OCD and addiction, we hypothesized that the opioid antagonist naltrexone might attenuate compulsions in OCD as well. The effect of naltrexone augmentation to SRI was compared to placebo in 10 OCD outpatients who had not responded to an adequate dose of SSRI or clomipramine for at least 2 months. Participants underwent 5 weeks of treatment with naltrexone or placebo (and 1 week of tapering) in a randomized, double-blind, cross-over design. Patients were evaluated weekly using the Y-BOCS, CGI, HAM-A, and MADRS scales. A two-way repeated measures MANOVA revealed no significant effect for Y-BOCS. However, while receiving naltrexone, patients had significantly higher scores on CGI, MADRS and HAM-A as compared to placebo. The lack of significant findings on OC symptoms could be due to either ceiling effect or alternatively, due to a non-specific exacerbation on anxiety and depression but not on OC symptoms.

Purpose of Review: The purpose of the review is to update the current literature regarding the role, if any, that testosterone plays in depressive illness. We have considered the influences on depression of endogenous testosterone, that is, hypogonadism and depression; and exogenous testosterone, that is, as a potential antidepressant., Recent Findings: Studies do not support a consistent relationship between testosterone level and mood. There may be vulnerable subpopulations in whom hypogonadism contributes to depression; and chronic depressive illness may lead to hypogonadism in some men. Results from multiple randomized, controlled clinical trials are conflicting. Most do not support testosterone as a broadly effective antidepressant, but it may be effective in carefully selected populations, such as hypogonadal men, antidepressant-resistant men, men with early onset depression, and/or HIV-infected men., Summary: There is little support for a pervasive influence of testosterone on mood.