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For many decades, psychiatric treatment has been primarily guided by two major paradigms of psychopathology: a neurochemical paradigm leading to the development of medications and a psychological paradigm resulting in the development of psychotherapies. A third paradigm positing that psychiatric dysfunction results from abnormal communication within a network of brain regions that regulate mood, thought, and behavior has gained increased attention over the past several years and underlies the development of multiple neuromodulation and neurostimulation therapies. This neural circuit paradigm is not new. In the late 19th and early 20th centuries, it was a common way of understanding psychiatric illness and led to several of our earliest somatic therapies. However, with the rise of effective medications and evidence-based psychotherapies, this paradigm went mostly dormant. Its recent reemergence resulted from a growing recognition that medications and psychotherapy leave many patients inadequately treated, along with technological advances that have revolutionized our ability to understand and modulate the neural circuitry involved in psychiatric disorders. In this overview, the authors review the history and current state of neuromodulation for psychiatric illness and specifically focus on these approaches as a treatment for depression, as this has been the primary indication for these interventions over time. [ABSTRACT FROM AUTHOR]

Background: Poor social connection is a central feature of posttraumatic stress disorder (PTSD), but little is known about the neurocognitive processes associated with social difficulties in this population. We examined recruitment of the default network and behavioral responses during social working memory (SWM; i.e., maintaining and manipulating social information on a moment‐to‐moment basis) in relation to PTSD and social connection. Methods: Participants with PTSD (n = 31) and a trauma‐exposed control group (n = 21) underwent functional magnetic resonance imaging while completing a task in which they reasoned about two or four people's relationships in working memory (social condition) and alphabetized two or four people's names in working memory (nonsocial condition). Participants also completed measures of social connection (e.g., loneliness, social network size). Results: Compared to trauma‐exposed controls, individuals with PTSD reported smaller social networks (p =.032) and greater loneliness (p =.038). Individuals with PTSD showed a selective deficit in SWM accuracy (p =.029) and hyperactivation in the default network, particularly in the dorsomedial subsystem, on trials with four relationships to consider. Moreover, default network hyperactivation in the PTSD group (vs. trauma‐exposed group) differentially related to social network size and loneliness (p's <.05). Participants with PTSD also showed less resting state functional connectivity within the dorsomedial subsystem than controls (p =.002), suggesting differences in the functional integrity of a subsystem key to SWM. Conclusions: SWM abnormalities in the default network may be a basic mechanism underlying poorer social connection in PTSD. [ABSTRACT FROM AUTHOR]

Abstract Until recently, therapeutic development in psychiatry was targeted solely toward symptom reduction. While this is a worthwhile goal, it has yielded little progress in improved therapeutics in the last several decades in the field of mood disorders. Recent advancements in our understanding of pathophysiology suggests that an impairment of neuroplasticity may be a critical part of the development of neuropsychiatric disorders. Interventions that enhance or modulate neuroplasticity often reduce depressive symptoms when applied as stand-alone treatments. Unfortunately, when treatments are discontinued, the disease state often returns as patients relapse. However, treatments that enhance or modulate plasticity not only reduce symptom burden, but also may provide an opportune window wherein cognitive or behavioral interventions could be introduced to harness a state of enhanced neuroplasticity and lead to improved longer-term clinical outcomes. Here, we review the potential of synergistically combining plasticity-enhancing and behavioral therapies to develop novel translational treatment approaches for depression. After reviewing relevant neuroplasticity deficits in depression, we survey biological treatments that appear to reverse such deficits in humans, including N- methyl-D-aspartate receptor modulators (ketamine, D-cycloserine), electroconvulsive therapy, and transcranial brain stimulation. We then review evidence that either directly or indirectly supports the hypothesis that a robust enhancement of neuroplasticity through these methods might promote the uptake of cognitive and behavioral interventions to enhance longer-term treatment outcomes through a synergistic effect. We identify key missing pieces of evidence and discuss future directions to enhance this emerging line of research. [ABSTRACT FROM AUTHOR]

Diffusion tensor imaging (DTI) has been used to evaluate white matter (WM) integrity in major depressive disorder (MDD), with several studies reporting differences between depressed patients and controls. However, these findings are variable and taken from relatively small studies often using suboptimal analytic approaches. The presented DTI study examined WM integrity in large samples of medication-free MDD patients (n=134) and healthy controls (n=54) using voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) approaches, and rigorous statistical thresholds. Compared with health control subjects, MDD patients show no significant differences in fractional anisotropy, radial diffusivity, mean diffusivity, and axonal diffusivity with either the VBM or the TBSS approach. Our findings suggest that disrupted WM integrity does not have a major role in the neurobiology of MDD in this relatively large study using optimal imaging acquisition and analysis; however, this does not eliminate the possibility that certain patient subgroups show WM disruption associated with depression. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) of subcallosal cingulate white matter (SCC) may be an effective approach for treatment-resistant depression (TRD) that otherwise fails to respond to more conventional therapies, but DBS is invasive, costly, and has potential for adverse effects. Therefore, it is important to identify potential biomarkers for predicting antidepressant response before intervention. Resting-state EEG was recorded from 12 TRD patients at pre-treatment baseline, after 4 weeks SCC DBS, and after 24 weeks SCC DBS. Lower frontal theta cordance (FTC) at baseline (and higher FTC after 4 weeks) predicted lower depression severity scores after 24 weeks. Greater FTC increases (baseline-4 weeks) predicted greater decreases in depression severity scores subsequently (4-24 weeks) and over the course of the study (baseline-24 weeks). Predictive relationships were topographically specific to theta cordance for frontal electrodes. Thus, results from this pilot study suggest that baseline FTC and changes early in treatment each have utility as biomarkers for predicting 6-month clinical response to SCC DBS for TRD. [ABSTRACT FROM AUTHOR]

Medications, psychotherapy, and other treatments are effective for many patients with psychiatric disorders. However, with currently available interventions, a substantial number of patients experience incomplete resolution of symptoms, and relapse rates are high. In the search for better treatments, increasing interest has focused on focal neuromodulation. This focus has been driven by improved neuroanatomical models of mood, thought, and behavior regulation, as well as by more advanced strategies for directly and focally altering neural activity. Deep brain stimulation (DBS) is one of the most invasive focal neuromodulation techniques available; data have supported its safety and efficacy in a number of movement disorders. Investigators have produced preliminary data on the safety and efficacy of DBS for several psychiatric disorders, as well. In this review, we describe the development and justification for testing DBS for various psychiatric disorders, carefully consider the available clinical data, and briefly discuss potential mechanisms of action. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) is currently in pivotal trials as an intervention for treatment-resistant depression (TRD). Although offering hope for TRD, DBS also provokes ethical concerns-particularly about decision-making capacity of people with depression-among bioethicists, investigators, institutional review boards, and the public. Here, we examine this critical issue of informed consent for DBS research using available evidence regarding decision-making capacity and depression. Further, we explore the implications of the nature of TRD as well as that of the intervention (invasive brain surgery) for informed consent. Based on these analyses, we argue that additional safeguards specific to DBS research for TRD, beyond those that might be used in any higher risk study, are not supported by available empirical evidence. We nevertheless underscore the limited data on such invasive procedures in severely ill psychiatric patients and advocate a research agenda for the systematic study of ethical issues raised by these research endeavors. [ABSTRACT FROM AUTHOR]

The current definition of major depressive disorder (MDD) emerged from efforts to create reliable diagnostic criteria for clinical and research use. However, despite decades of research, the neurobiology of MDD is largely unknown, and treatments are no more effective today than they were 50–70 years ago. Here, we propose that the current conception of depression is misguiding basic and clinical research. Redefinition is necessary and could include a focus on a more narrowly defined set of core symptoms. However, we conclude that depression is better defined as the tendency to enter into, and inability to disengage from, a negative mood state rather than the mood state per se. We also discuss the implications of this revised definition for future clinical and basic research. [ABSTRACT FROM AUTHOR]

Background: Repetitive transcranial magnetic stimulation (rTMS) has shown safety and efficacy for treatment-resistant depression, but requires daily treatment for 4-6 weeks. Accelerated TMS, with all treatments delivered over a few days, would have significant advantages in terms of access and patient acceptance. Methods: Open-label accelerated TMS (aTMS), consisting of 15 rTMS sessions administered over 2 days, was tested in 14 depressed patients not responding to at least one antidepressant medication. Effects on depression, anxiety, and cognition were assessed the day following treatment, then after 3 and 6 weeks. Results: No seizure activity was observed and only one patient had a serious adverse event (increased suicidal ideation). Two patients failed to complete a full course of aTMS treatments, and 36% did not complete all study visits. Depression and anxiety significantly decreased following aTMS treatments and improvements persisted 3 and 6 weeks later. Response rates immediately following treatment and at 3 and 6 weeks were 43, 36, and 36%, respectively. Remission rates at the same timepoints were 29, 36, and 29%. Conclusions: Accelerated TMS demonstrated an excellent safety profile with efficacy comparable to that achieved in daily rTMS in other trials. Limitations primarily include open-label treatment and a small sample size. Depression and Anxiety, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Treating acute hepatitis C (HCV) in injection drug users (IDUs) is complicated by a high prevalence of psychiatric comorbidities that may lead to increased risk for depressive complications of interferon treatment. Effective screening strategies are needed to help non-psychiatric clinicians identify depressive disorders. Methods: Thirty IDUs with acute HCV completed the Beck Depression Inventory (BDI), underwent a psychiatric examination, and were randomized to 24 weeks of pegylated interferon treatment (IFA) or observation (OBS). Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of the BDI for diagnosing depression (with a cutoff >10) were calculated. The psychiatrist''s diagnosis was used as the gold standard. Depression severity was assessed over time with the BDI. Results: Forty-seven percent of individuals met criteria for a depressive disorder. Sensitivity (91%) and NPV (92%) were high for the BDI; specificity (58%) and PPV (56%) were low. BDI worsened in 2 patients completing the study (one IFA, one OBS); two IFA patients were discontinued for possible depression-related complications. At baseline, subject-rated fatigue was associated with alanine aminotransferase level. Conclusion: The BDI is an adequate tool for ruling out depressive disorders in active IDUs with acute HCV, but specificity is low. Psychiatric consultation is recommended for all active IDUs being considered for acute HCV treatment. [Copyright &y& Elsevier]

Despite adequate antidepressant monotherapy, the majority of depressed patients do not achieve remission. Even optimal and aggressive therapy leads to a substantial number of patients who show minimal and often only transient improvement. In order to address this substantial problem of treatment-resistant depression, a number of novel targets for antidepressant therapy have emerged as a consequence of major advances in the neurobiology of depression. Three major approaches to uncover novel therapeutic interventions are: first, optimizing the modulation of monoaminergic neurotransmission; second, developing medications that act upon neurotransmitter systems other than monoaminergic circuits; and third, using focal brain stimulation to directly modulate neuronal activity. We review the most recent data on novel therapeutic compounds and their antidepressant potential. These include triple monoamine reuptake inhibitors, atypical antipsychotic augmentation, and dopamine receptor agonists. Compounds affecting extra-monoamine neurotransmitter systems include CRF1 receptor antagonists, glucocorticoid receptor antagonists, substance P receptor antagonists, NMDA receptor antagonists, nemifitide, omega-3 fatty acids, and melatonin receptor agonists. Focal brain stimulation therapies include vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS). [Copyright &y& Elsevier]

Background: Deep brain stimulation (DBS) of the subcallosal cingulate white matter (SCCwm) or anterior limb of the internal capsule (ALIC) may be effective in treating depression. Connectivity patterns of these regions may inform on mechanisms of action for DBS of these targets. Methods: Diffusion tensor imaging (DTI) and probabilistic tractography were performed in 13 nondepressed subjects to determine connectivity patterns of SCCwm and ALIC. Tract maps were generated for each target in each subject, and tract voxels were coded as being unique to either target or shared. Group level tract maps were generated by including only those voxels common to at least 10 of 13 (>75%) subjects. Results: The two targets have distinct patterns of connectivity with regions of overlap. The SCCwm showed consistent ipsilateral connections to the medial frontal cortex, the full extent of the anterior and posterior cingulate, medial temporal lobe, dorsal medial thalamus, hypothalamus, nucleus accumbens, and the dorsal brainstem. The ALIC seed, in contrast, demonstrated widespread projections to frontal pole, medial temporal lobe, cerebellum, nucleus accumbens, thalamus, hypothalamus, and brainstem. Common to both targets, albeit through distinct white matter bundles, were connections to frontal pole, medial temporal lobe, nucleus accumbens, dorsal thalamus, and hypothalamus. Conclusions: Connectivity patterns of these two DBS white matter targets suggest distinct neural networks with areas of overlap in regions implicated in depression and antidepressant response. [Copyright &y& Elsevier]

Depression in Parkinson's disease (dPD) is difficult to diagnose because depressive symptoms can overlap with symptoms of Parkinson's disease (PD). Subject-rated scales such as the 30-item Geriatric Depression Scale (GDS) may be useful in screening for dPD. There were 57 patients (33 men, 24 women; mean age, 58.6 years [SD ± 8.4]) enrolled in a study of pallidotomy for intractable PD who were evaluated for depression before and after surgery. Subjects were evaluated using the 17-item Hamilton Depression Rating Scale (HDRS), Structured Clinical Interview for Diagnostic and Statistical Manual-III (SCID), and the GDS. SCID was used to diagnose major depression with confirmation by an expert geropsychiatrist. Receiver-operating curves (ROC) were used to identify cutoff points with maximal discriminant validity for diagnosing dPD. A total of 213 evaluation time points were included for the 52 patients with time points that included a valid SCID diagnosis, GDS, and HDRS. A ROC established points of maximum specificity/sensitivity for the GDS at a cutoff of 9/10 (sensitivity = 0.809, specificity = 0.837, positive predictive value [PPV] = 0.584, negative predictive value [NPV] = 0.939) and for the HDRS at a cutoff of 12/13 (sensitivity = 0.810, specificity = 0.821, PPV = 0.580, NPV = 0.934). The GDS was moderately correlated with the HDRS (Pearson's r = 0.54; P < 0.001). The GDS is useful in screening for dPD. A cutoff score of 9/10 has acceptable discriminant validity for dPD, and the GDS has a moderate correlation with the HDRS in PD patients. © 2005 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Repetitive transcranial magnetic stimulation (TMS) as a treatment for depression has shown statistically significant effects, but the clinical significance of these effects has been questioned. Methods: Patients with medication-resistant depression were randomized to receive 15 sessions of active or sham repetitive TMS delivered to the left dorsolateral prefrontal cortex at 110% the estimated prefrontal cortex threshold. Each session consisted of 32 trains of 10 Hz repetitive TMS delivered in 5-second trains. The primary end point was treatment response defined as a ≥50% decrease in Hamilton Depression Rating Scale (HDRS) score at both 1 and 2 weeks following the final repetitive TMS treatment. Remission was defined as a HDRS score <8. Results: The response rate for the TMS group was 30.6% (11/35), significantly (p = .008) greater than the 6.1% (2/33) rate in the sham group. The remission rate for the TMS group was 20% (7/35), significantly (p = .033) greater than the 3% (1/33) rate in the sham group. The HDRS scores showed a significantly (p < .002) greater decrease over time in the TMS group compared with the sham group. Conclusions: Transcranial magnetic stimulation can produce statistically and clinically significant antidepressant effects in patients with medication-resistant major depression. [Copyright &y& Elsevier]

This article summarizes updates from the 2023 U.S. Department of Veterans Affairs and Department of Defense guideline for the management of posttraumatic stress disorder (PTSD) and acute stress disorder. It summarizes changes from the 2017 guideline and describes 34 recommendations in 5 topic areas—assessment and diagnosis, prevention, treatment, treatment of nightmares, and treatment of PTSD with co-occurring conditions—while highlighting 6 recommendations rated as strong. Description: The U.S. Department of Veterans Affairs (VA) and Department of Defense (DoD) worked together to revise the 2017 VA/DoD Clinical Practice Guideline for the Management of Posttraumatic Stress Disorder and Acute Stress Disorder. This article summarizes the 2023 clinical practice guideline (CPG) and its development process, focusing on assessments and treatments for which evidence was sufficient to support a recommendation for or against. Methods: Subject experts from both departments developed 12 key questions and reviewed the published literature after a systematic search using the PICOTS (population, intervention, comparator, outcomes, timing of outcomes measurement, and setting) method. The evidence was then evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method. Recommendations were made after consensus was reached; they were based on quality and strength of evidence and informed by other factors, including feasibility and patient perspectives. Once the draft was peer reviewed by an external group of experts and their inputs were incorporated, the final document was completed. Recommendations: The revised CPG includes 34 recommendations in the following 5 topic areas: assessment and diagnosis, prevention, treatment, treatment of nightmares, and treatment of posttraumatic stress disorder (PTSD) with co-occurring conditions. Six recommendations on PTSD treatment were rated as strong. The CPG recommends use of specific manualized psychotherapies over pharmacotherapy; prolonged exposure, cognitive processing therapy, or eye movement desensitization and reprocessing psychotherapy; paroxetine, sertraline, or venlafaxine; and secure video teleconferencing to deliver recommended psychotherapy when that therapy has been validated for use with video teleconferencing or when other options are unavailable. The CPG also recommends against use of benzodiazepines, cannabis, or cannabis-derived products. Providers are encouraged to use this guideline to support evidence-based, patient-centered care and shared decision making to optimize individuals' health outcomes and quality of life. [ABSTRACT FROM AUTHOR]

Objective: Deep brain stimulation of the subcallosal cingulate (SCC DBS) has been studied as a potential treatment for severe and refractory major depressive disorder since 2005. The authors used an open-label, long-term follow-up design to examine participants enrolled in a clinical trial of SCC DBS for treatment-resistant depression.Methods: Long-term outcome data were collected for 28 patients (20 with major depressive disorder and seven with bipolar II disorder; one patient in the major depression subgroup was later reclassified as having bipolar II disorder) receiving SCC DBS for 4-8 years.Results: Response and remission rates were maintained at ≥50% and ≥30%, respectively, through years 2-8 of the follow-up period. Three-quarters of all participants met the treatment-response criterion for more than half of their duration of participation in the study, with 21% of all patients demonstrating continuous response to treatment from the first year onward. Of 28 participants, 14 completed ≥8 years of follow-up, 11 completed ≥4 years, and three dropped out before 8 years. The procedure itself was generally safe and well tolerated, and there were no side effects of acute or chronic stimulation. The rate of medical or surgical complications was consistent with the rate observed in studies of DBS for other indications. There were no suicides.Conclusions: In >8 years of observation, most participants experienced a robust and sustained antidepressant response to SCC DBS. [ABSTRACT FROM AUTHOR]

Posttraumatic stress disorder (PTSD) negatively impacts military veterans and their intimate partners. Cognitive-Behavioral Conjoint Therapy (CBCT) was developed to address both PTSD and relationship satisfaction among couples. Although efficacious in improving PTSD, the effects of CBCT and the 8-session brief CBCT (bCBCT) on relationship satisfaction among veteran patients with PTSD are modest. Pharmacological augmentation with the neuropeptide oxytocin is promising for enhancing bCBCT's potency due to its effects on mechanisms of trauma recovery (e.g., extinction learning) and relationship functioning (e.g., trust, communication). The goal of this pilot uncontrolled clinical trial was to examine the feasibility and preliminary efficacy of bCBCT augmented with intranasal oxytocin for improving PTSD and relationship satisfaction among 10 U.S. veterans with PTSD and their intimate partners. Veterans self-administered 40 international units of intranasal oxytocin 30 min before each bCBCT session delivered to the couple via telehealth. Both partners completed pre-assessment, weekly, post, and 3-month follow-up assessments of PTSD symptoms and relationship satisfaction. Couples also provided qualitative feedback related to feasibility and engagement. Nine dyads completed the treatment. There were no serious adverse events. Veterans and partners reported moderate to large effect size improvements in relationship satisfaction (Hedge's g = 0.55 and 1.01, respectively). Veterans reported large effect size reductions in PTSD severity (Hedge's g = 1.87). These results suggest that virtual oxytocin-assisted bCBCT is feasible, scalable, potentially efficacious, and should be tested with a placebo-controlled randomized controlled trial. • Intranasal oxytocin could boost effects of couples therapy for PTSD. • This open trial is the first to augment couples therapy for PTSD with oxytocin. • 9 of 10 couples completed the treatment with no serious adverse events. • Veterans self-reported large improvements in PTSD symptoms. • Dyads reported moderate-to-large improvements in relationship satisfaction. [ABSTRACT FROM AUTHOR]

Background: Deep brain stimulation has been investigated in the past decade as a viable intervention for treatment-resistant depression. Methods: Several anatomic targets have been tested, with the most extensive published experience found for the subcallosal cingulate (SCC) white matter. Results: This article reviews the current state of clinical research of SCC deep brain stimulation for treatment-resistant depression, including an overview of the rationale for targeting SCC, practical considerations for subject recruitment and evaluation, surgical planning, and stimulation parameters. Conclusion: Clinical management of patients in the initial and long-term naturalistic phases of treatment, including the potential role for psychotherapeutic rehabilitation, is discussed. [Copyright &y& Elsevier]

Leveraging military veterans' intimate relationships during treatment has the potential to concurrently improve posttraumatic stress disorder (PTSD) symptoms and relationship quality. Cognitive-Behavioral Conjoint Therapy (CBCT) and an 8-session Brief Cognitive-Behavioral Conjoint Therapy (bCBCT) are manualized treatments designed to simultaneously improve PTSD and relationship functioning for couples in which one partner has PTSD. Although efficacious in improving PTSD, the effects of CBCT on relationship satisfaction are small, especially among veterans. Intranasal oxytocin, which targets mechanisms of PTSD and relationship quality, may enhance the efficacy of bCBCT. The purpose of this 4-year clinical trial is to compare the outcomes of bCBCT augmented with intranasal oxytocin versus bCBCT plus placebo. We will also explore potential mechanisms of action: self-reported communication skills, empathy, and trust. We will recruit 120 dyads (i.e., veteran with PTSD and their intimate partner) from the VA San Diego Healthcare System. Veterans will be administered 40 international units of oxytocin (n = 60) or placebo (n = 60) 30 min before each of 8 bCBCT sessions delivered via telehealth. Clinical and functioning outcomes will be assessed at five timepoints (baseline, mid-treatment, post-treatment, and 3- and 6-month follow-up). Study findings will reveal the efficacy of oxytocin-assisted brief couple therapy for PTSD, which could serve as highly scalable option for couples coping with PTSD, as well as provide preliminary evidence of interpersonal mechanisms of change. ClinicalTrials.gov Identifier: NCT06194851 [ABSTRACT FROM AUTHOR]

Background Subcallosal cingulate white matter (SCC) deep brain stimulation (DBS) is an evolving investigational treatment for depression. Mechanisms of action are hypothesized to involve modulation of activity within a structurally defined network of brain regions involved in mood regulation. Diffusion tensor imaging was used to model white matter connections within this network to identify those critical for successful antidepressant response. Methods Preoperative high-resolution magnetic resonance imaging data, including diffusion tensor imaging, were acquired in 16 patients with treatment-resistant depression, who then received SCC DBS. Computerized tomography was used postoperatively to locate DBS contacts. The activation volume around the contacts used for chronic stimulation was modeled for each patient retrospectively. Probabilistic tractography was used to delineate the white matter tracts traveling through each activation volume. Patient-specific tract maps were calculated using whole-brain analysis. Clinical evaluations of therapeutic outcome from SCC DBS were defined at 6 months and 2 years. Results Whole-brain activation volume tractography demonstrated that all DBS responders at 6 months ( n = 6) and 2 years ( n = 12) shared bilateral pathways from their activation volumes to 1) medial frontal cortex via forceps minor and uncinate fasciculus; 2) rostral and dorsal cingulate cortex via the cingulum bundle; and 3) subcortical nuclei. Nonresponders did not consistently show these connections. Specific anatomical coordinates of the active contacts did not discriminate responders from nonresponders. Conclusions Patient-specific activation volume tractography modeling may identify critical tracts that mediate SCC DBS antidepressant response. This suggests a novel method for patient-specific target and stimulation parameter selection. [ABSTRACT FROM AUTHOR]

• Posttraumatic stress disorder is related to aberrant threat and reward processing. • Intranasal oxytocin impacts brain systems that mediate threat and reward. • We examined oxytocin effects on brain connectivity in a childhood-trauma exposed sample. • Oxytocin impacted amygdala-anterior insula connectivity to fearful faces. • Results varied by gender and hemisphere, but not posttraumatic stress disorder. Novel treatments that target neurobiological alterations associated with childhood trauma, particularly among those with posttraumatic stress disorder (PTSD), could mitigate negative outcomes for these at-risk individuals. PTSD is characterized by abnormalities within the brain's salience network and reward circuitry, which are modulated by intranasal oxytocin. Using a double-blind, randomized, placebo-controlled crossover design, we tested whether intranasal oxytocin (24 international units) influenced functional coupling of the amygdala with the anterior insula (AI), dorsal anterior cingulate cortex, and nucleus accumbens in response to implicitly presented fearful, angry, and happy faces among childhood trauma-exposed individuals with (n = 16, 9 women) and without PTSD (n = 18, 12 women). Psychophysiological interaction analyses revealed that oxytocin effects were limited to amygdala-AI connectivity in the fear condition, distinct for men and women, and not impacted by PTSD diagnosis. In response to fear faces, oxytocin reduced left amygdala-left AI connectivity for women but not men; reduced left amygdala-right AI connectivity among women, but increased this connectivity in men; and reduced right amygdala-right anterior insula connectivity for men, but increased it for women. Results suggest that intranasal oxytocin modulates threat salience among childhood trauma-exposed individuals and that these effects vary as a function of gender and hemisphere. [ABSTRACT FROM AUTHOR]

Background: Repetitive transcranial magnetic stimulation (TMS) is an evidence-based treatment for pharmacoresistant major depressive disorder (MDD), however, the evidence in veterans has been mixed. To this end, VA implemented a nationwide TMS program that included evaluating clinical outcomes within a naturalistic design. TMS was hypothesized to be safe and provide clinically meaningful reductions in MDD and posttraumatic stress disorder (PTSD) symptoms.Methods: Inclusion criteria were MDD diagnosis and standard clinical TMS eligibility. Of the 770 patients enrolled between October 2017 and March 2020, 68.4% (n = 521) met threshold-level PTSD symptom criteria. Treatments generally used standard parameters (e.g., left dorsolateral prefrontal cortex, 120% motor threshold, 10 Hz, 3000 pulses/treatment). Adequate dose was operationally defined as 30 sessions. MDD and PTSD symptoms were measured using the 9-item patient health questionnaire (PHQ-9) and PTSD checklist for DSM-5 (PCL-5), respectively.Results: Of the 770 who received at least one session, TMS was associated with clinically meaningful (Cohen's d>1.0) and statistically significant (all p<.001) reductions in MDD and PTSD. Of the 340 veterans who received an adequate dose, MDD response and remission rates were 41.4% and 20%, respectively. In veterans with comorbid PTSD, 65.3% demonstrated clinically meaningful reduction and 46.1% no longer met PTSD threshold criteria after TMS. Side effects were consistent with the known safety profile of TMS.Limitations: Include those inherent to retrospective observational cohort study in Veterans.Conclusions: These multisite, large-scale data supports the effectiveness and safety of TMS for veterans with MDD and PTSD using standard clinical approaches. [ABSTRACT FROM AUTHOR]

Objectives: Musculoskeletal disorders often lead to chronic pain in Veterans. Chronic pain puts sufferers at risk for substance misuse, and early intervention is needed for both conditions. This pilot study tested the feasibility and acceptability of a Screening, Brief Intervention, and Referral to Treatment for Pain Management intervention (SBIRT‐PM) to help engage Veterans seeking disability compensation for painful musculoskeletal disorders in multimodal pain treatment and to reduce risky substance use, when indicated. Methods: This pilot study enrolled 40 Veterans from 8 medical centers across New England in up to 4 sessions of telephone‐based counseling using a motivational interviewing framework. Counseling provided education about, and facilitated engagement in, multimodal pain treatments. Study eligibility required Veterans be engaged in no more than 2 Veteran Affairs (VA) pain treatment modalities, and study participation involved a 12‐week postassessment and semistructured interview about the counseling process. Results: Majorities of enrolled Veterans screened positive for comorbid depression and problematic substance use. Regarding the offered counseling, 80% of participants engaged in at least one session, with a mean of 3 sessions completed. Ninety percent of participants completed the postassessment. Numerically, most measures improved slightly from baseline to week 12. In semistructured interviews, participants described satisfaction with learning about new pain care services, obtaining assistance connecting to services, and receiving support from their counselors. Discussion: It was feasible to deliver SBIRT‐PM to Veterans across New England to promote engagement in multimodal pain treatment and to track study outcomes over 12 weeks. Preliminary results suggest SBIRT‐PM was well‐received and has promise for the targeted outcomes. [ABSTRACT FROM AUTHOR]

Connectivity analyses and computational modeling of human brain function from fMRI data frequently require the specification of regions of interests (ROIs). Several analyses have relied on atlases derived from anatomical or cyto-architectonic boundaries to specify these ROIs, yet the suitability of atlases for resting state functional connectivity (FC) studies has yet to be established. This article introduces a data-driven method for generating an ROI atlas by parcellating whole brain resting-state fMRI data into spatially coherent regions of homogeneous FC. Several clustering statistics are used to compare methodological trade-offs as well as determine an adequate number of clusters. Additionally, we evaluate the suitability of the parcellation atlas against four ROI atlases (Talairach and Tournoux, Harvard-Oxford, Eickoff-Zilles, and Automatic Anatomical Labeling) and a random parcellation approach. The evaluated anatomical atlases exhibit poor ROI homogeneity and do not accurately reproduce FC patterns present at the voxel scale. In general, the proposed functional and random parcellations perform equivalently for most of the metrics evaluated. ROI size and hence the number of ROIs in a parcellation had the greatest impact on their suitability for FC analysis. With 200 or fewer ROIs, the resulting parcellations consist of ROIs with anatomic homology, and thus offer increased interpretability. Parcellation results containing higher numbers of ROIs (600 or 1,000) most accurately represent FC patterns present at the voxel scale and are preferable when interpretability can be sacrificed for accuracy. The resulting atlases and clustering software have been made publicly available at: . Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc [ABSTRACT FROM AUTHOR]

Background: Deep brain stimulation (DBS) for treatment-resistant depression (TRD) is the focus of great interest and numerous studies. Given the state of this research, the risks of DBS, the uncertainty of direct benefits, and the potential for therapeutic misconception (TM), examination of research participants' perspectives is critical to addressing concerns about the adequacy of consent among people with TRD. Methods: Among 31 participants considering DBS studies at two sites, self-report questionnaires were used to examine three dimensions of TM (eight true/false items). Additional Likert-scale items assessed perceptions of risks, potential benefits, and altruistic motivations. Results: Participants correctly identified the surgery itself as the riskiest study procedure, although only four participants rated the surgery as 'high risk.' Most participants rated the entire DBS study as 'moderate' or lower risk. Participants rated the likelihood of others benefiting in the future more strongly than they did the likelihood of personal benefit. Participants held positive attitudes toward research, and were moderately altruistic. Nearly two-thirds of the 31 participants (64.5%) answered at least one of the true/false TM items incorrectly. Conclusions: Individuals considering DBS studies for TRD demonstrated reasonable perceptions of risks and benefits, distinguished among procedural risks, and expressed hopes for personal benefit as well as altruism. Findings related to TM were mixed: Participants understood the experimental stage of DBS for depression and endorsed the possibility of no personal benefit, yet there was some evidence for TM. Although these findings are reassuring, investigators must nevertheless remain vigilant about identifying and addressing potential misconceptions. [ABSTRACT FROM AUTHOR]

Background: Deep brain stimulation (DBS) for treatment-resistant depression (TRD) is the focus of great interest and numerous studies. Given the state of this research, the risks of DBS, the uncertainty of direct benefits, and the potential for therapeutic misconception (TM), examination of research participants’ perspectives is critical to addressing concerns about the adequacy of consent among people with TRD. Methods: Among 31 participants considering DBS studies at two sites, self-report questionnaires were used to examine three dimensions of TM (eight true/false items). Additional Likert-scale items assessed perceptions of risks, potential benefits, and altruistic motivations. Results: Participants correctly identified the surgery itself as the riskiest study procedure, although only four participants rated the surgery as “high risk.” Most participants rated the entire DBS study as “moderate” or lower risk. Participants rated the likelihood of others benefiting in the future more strongly than they did the likelihood of personal benefit. Participants held positive attitudes toward research, and were moderately altruistic. Nearly two-thirds of the 31 participants (64.5%) answered at least one of the true/false TM items incorrectly. Conclusions: Individuals considering DBS studies for TRD demonstrated reasonable perceptions of risks and benefits, distinguished among procedural risks, and expressed hopes for personal benefit as well as altruism. Findings related to TM were mixed: Participants understood the experimental stage of DBS for depression and endorsed the possibility of no personal benefit, yet there was some evidence for TM. Although these findings are reassuring, investigators must nevertheless remain vigilant about identifying and addressing potential misconceptions. [ABSTRACT FROM PUBLISHER]

Wingo AP, Baldessarini RJ, Holtzheimer PE, Harvey PD. Factors associated with functional recovery in bipolar disorder patients. Bipolar Disord 2010: 12: 319–326. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Among bipolar disorder (BPD) patients, functional recovery, defined as regaining individual premorbid residential and vocational status, is far less common than symptomatic recovery. As several factors have tentatively been implicated in outcomes in BPD, we investigated predictors of functional recovery among BPD patients, including demographic, clinical, and neurocognitive factors. Methods: We assessed functional recovery status with standardized residential and occupational indices, assessed neurocognitive functioning with performance-based neuropsychological tests, and collected demographic and clinical information for 65 euthymic or residually depressed Structured Clinical Interview for DSM-IV-defined type I or II BPD patients. We examined predictors of functional recovery with multiple logistic regression modeling. Results: More education (p = 0.006), fewer years of illness (p = 0.037), and being married (p = 0.045) were associated independently with functional recovery, even after controlling for residual depressive symptoms, diagnostic type (I versus II), and psychiatric comorbidity. Functionally unrecovered BPD patients performed less well than recovered patients on verbal fluency (effect size = 0.54, p = 0.03), a measure of executive functioning, but this difference was not significant when adjusted for residual mood symptoms and education. Conclusions: Among euthymic or mildly depressed BPD patients, functional recovery was associated with more education, being married, and fewer years of illness. [ABSTRACT FROM AUTHOR]

Introduction: Focal brain stimulation has potential as a treatment for posttraumatic stress disorder (PTSD). In this review, we aim to inform selection of focal brain stimulation targets for treating PTSD by examining studies of the functional neuroanatomy of PTSD and treatment response. We first briefly review data on brain stimulation interventions for PTSD. Although published data suggest good efficacy overall, the neurobiological rationale for each stimulation target is not always clear. Methods: Therefore, we assess pre‐ and post‐treatment (predominantly psychotherapy) functional neuroimaging studies in PTSD to determine which brain changes seem critical to treatment response. Results of these studies are presented within a previously proposed functional neural systems model of PTSD. Results: While not completely consistent, research suggests that downregulating the fear learning and threat and salience detection circuits (i.e., amygdala, dorsal anterior cingulate cortex and insula) and upregulating the emotion regulation and executive function and contextual processing circuits (i.e., prefrontal cortical regions and hippocampus) may mediate PTSD treatment response. Conclusion: This literature review provides some justification for current focal brain stimulation targets. However, the examination of treatment effects on neural networks is limited, and studies that include the stimulation targets are lacking. Further, additional targets, such as the cingulate, medial prefrontal cortex, and inferior parietal lobe, may also be worth investigation, especially when considering how to achieve network level changes. Additional research combining PTSD treatment with functional neuroimaging will help move the field forward by identifying and validating novel targets, providing better rationale for specific treatment parameters and personalizing treatment for PTSD. [ABSTRACT FROM AUTHOR]

Background: Although repetitive transcranial magnetic stimulation ('TMS') is becoming a gold standard treatment for pharmacoresistant depression, we lack neural target biomarkers for identifying who is most likely to respond to TMS and why. To address this gap in knowledge we evaluate neural targets defined by activation and functional connectivity of the dorsolateral prefrontal cortex-anchored cognitive control circuit, regions of the default mode network and attention circuit, and interactions with the subgenual anterior cingulate. We evaluate whether these targets and interactions between them change in a dose-dependent manner, whether changes in these neural targets correspond to changes in cognitive behavioral performance, and whether baseline and early change in neural target and cognitive behavioral performance predict subsequent symptom severity, suicidality, and quality of life outcomes. This study is designed as a pragmatic, mechanistic trial partnering with the National Clinical TMS Program of the Veteran's Health Administration. Methods: Target enrollment consists of 100 veterans with pharmacoresistant Major Depressive Disorder (MDD). All veterans will receive a clinical course of TMS and will be assessed at 'baseline' pre-TMS commencement, 'first week' after initiation of TMS (targeting five sessions) and 'post-treatment' at the completion of TMS (targeting 30 sessions). Veterans will be assessed using functional magnetic resonance imaging (fMRI), a cognitive behavioral performance battery, and established questionnaires. Multivariate linear mixed models will be used to assess whether neural targets change with TMS as a function of dose (Aim 1), whether extent and change of neural target relates to and predicts extent of behavioral performance (Aim 3), and whether extent of neural target change predicts improvement in symptom severity, suicidality, and quality of life (Aim 3). For all three aims, we will also assess the contribution of baseline moderators such as biological sex and age. Discussion: To our knowledge, our study will be the first pragmatic, mechanistic observational trial to use fMRI imaging and cognitive-behavioral performance as biomarkers of TMS treatment response in pharmacoresistant MDD. The results of this trial will allow providers to select suitable candidates for TMS treatment and better predict treatment response by assessing circuit connectivity and cognitive-behavioral performance at baseline and during early treatment. Trial registration: ClinicalTrials.gov NCT04663481, December 5th, 2020, retrospectively registered. The first veteran was enrolled October 30th, 2020. [ABSTRACT FROM AUTHOR]

Background Treatment-resistant depression (TRD) is a pervasive and difficult to treat condition for which deep brain stimulation (DBS) of the subcallosal cingulate white matter (SCCwm) is an emerging therapeutic option. However, neuropsychological safety data for this novel treatment have only been published for a small number of subjects. Moreover, little is known regarding the neuropsychological profile present in TRD patients at baseline, prior to initiation of DBS therapy. This report describes the neuropsychological effects of TRD and acute and chronic DBS of the SCCwm in patients with unipolar and bipolar TRD. Methods Patients with TRD (N = 17) were compared to a healthy control group (N = 15) on subtests from the Cambridge Neuropsychological Test Automated Battery and the Stroop Task. Patients were then tested again at subsequent time points of 1 and 6 months following the initiation of chronic DBS of the SCCwm. Results Patients with TRD showed similar levels of performance to healthy controls on most neuropsychological measures, with the exception that the TRD group had slower processing speed. Patients with bipolar TRD, relative to those with unipolar TRD, obtained lower scores on measures of executive function and memory only at baseline. With acute and chronic SCCwm DBS, neuropsychological function improved in multiple domains including processing speed and executive function (planning, set shifting, response inhibition), and memory remained stable. Conclusions Patients with TRD show slowed processing speed but otherwise largely preserved neuropsychological functioning. DBS of the SCCwm does not result in worsening of any aspect of neuropsychological function and may improve certain domains. Future research is warranted to better understand the effects of TRD and DBS on neuropsychological function. [ABSTRACT FROM AUTHOR]

Background: A few studies have examined the durability of transcranial magnetic stimulation (TMS) antidepressant benefit once patients remitted. This study examined the long-term durability of clinical benefit from TMS using a protocol-specified TMS taper and either continuation pharmacotherapy or naturalistic follow-up.Methods: Patients were remitters from an acute double-blind sham-controlled trial of TMS (n = 18), or from an open-label extension in patients who did not respond to the acute trial (n = 43). Long-term durability of TMS acute effect was examined in remitters over a 12-week follow-up. Relapse, defined as 24-item Hamilton Depression Rating Scale (HDRS-24) ≥20, was the primary outcome.Results: Of 61 remitters in the acute trial, five entered naturalistic follow-up and 50 entered the TMS taper. Thirty-two patients completed TMS taper and 1-, 2-, and 3-month follow-up. At 3-month visit, 29 of 50 (58%) were classified as in remission (HDRS-24 ≤10), two of 50 (4%) as partial responders (30%≤ HDRS-24 reduction <50% from baseline), and one of 50 (2%) met criteria for relapse. During the entire 3-month follow-up, five of the 37 patients relapsed (relapse rate = 13.5%), but four of them regained remission by the end of the study. The average time to relapse in these five patients was 7.2 ± 3.3 weeks. Patients who relapsed had higher depression scores at 1 month.Conclusions: While one third of the sample was lost to follow-up, our results demonstrate that most patients contributing to observations experienced persistence of benefit from TMS followed by pharmacotherapy or no medication. Longer follow-up and more rigorous studies are needed to explore the true long-term durability of remission produced by TMS. [ABSTRACT FROM AUTHOR]

Background A few studies have examined the durability of transcranial magnetic stimulation ( TMS) antidepressant benefit once patients remitted. This study examined the long-term durability of clinical benefit from TMS using a protocol-specified TMS taper and either continuation pharmacotherapy or naturalistic follow-up. Methods Patients were remitters from an acute double-blind sham-controlled trial of TMS (n = 18), or from an open-label extension in patients who did not respond to the acute trial (n = 43). Long-term durability of TMS acute effect was examined in remitters over a 12-week follow-up. Relapse, defined as 24-item Hamilton Depression Rating Scale (HDRS-24) ≥20, was the primary outcome. Results Of 61 remitters in the acute trial, five entered naturalistic follow-up and 50 entered the TMS taper. Thirty-two patients completed TMS taper and 1-, 2-, and 3-month follow-up. At 3-month visit, 29 of 50 (58%) were classified as in remission ( HDRS-24 ≤10), two of 50 (4%) as partial responders (30%≤ HDRS-24 reduction <50% from baseline), and one of 50 (2%) met criteria for relapse. During the entire 3-month follow-up, five of the 37 patients relapsed (relapse rate = 13.5%), but four of them regained remission by the end of the study. The average time to relapse in these five patients was 7.2 ± 3.3 weeks. Patients who relapsed had higher depression scores at 1 month. Conclusions While one third of the sample was lost to follow-up, our results demonstrate that most patients contributing to observations experienced persistence of benefit from TMS followed by pharmacotherapy or no medication. Longer follow-up and more rigorous studies are needed to explore the true long-term durability of remission produced by TMS. [ABSTRACT FROM AUTHOR]

Research on deep brain stimulation (DBS) for treatment-resistant depression appears promising, but concerns have been raised about the decisional capacity of severely depressed patients and their potential misconceptions about the research. We assessed 31 DBS research participants with the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR), a well-validated capacity measure, and with a scale to measure therapeutic misconception, which occurs when subjects do not recognize key differences between treatment and clinical research. Correlations with baseline depressive symptoms were explored. Subjects' performance on the MacCAT-CR was excellent, but therapeutic misconception was still apparent. A trend toward significance was found in the correlation between baseline depression ratings and total therapeutic misconception score. Responses to open-ended prompts revealed both reassuring and concerning statements related to expectations of risk, benefit, and individualization. Even severely depressed patients did not manifest impairments in their capacity to consent to DBS research. Therapeutic misconception, however, remained prevalent. [ABSTRACT FROM AUTHOR]

Background Ethical concerns regarding early-phase clinical trials of DBS for treatment-resistant depression (TRD) include the possibility that participants' decisions to enroll might be motivated by unrealistic expectations of personal benefit or minimization of risks. Methods Thematic analyses were conducted on a sample of 26 adults considering participation in two DBS trials. Influences on the decision making of these potential DBS trial participants were derived from responses to questions posed in the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR), a semi-structured interview designed to evaluate decisional capacity to consent to research. Results Participants cited numerous factors as influential in their enrollment decisions, including perceived lack of other treatment options, desire to take initiative, beliefs about DBS as a novel treatment, possibility of DBS efficacy, hoped-for improvements, potential risks and disadvantages of DBS or clinical trial participation, and altruism. No individual expressed a set of motivations or influencing factors that suggested compromised decision-making capacity or diminished voluntariness of decision making. Conclusions These results suggest that individuals make the decision to enroll in early-phase trials of DBS for TRD based on a number of complex and sometimes idiosyncratic considerations, and that the trials that were studied utilized sufficiently robust informed consent processes. These findings offer evidence that the emerging research area of DBS can be advanced in an ethically sound manner, provided that safeguards and processes for discussing trials with participants are carefully and proactively enacted. [ABSTRACT FROM AUTHOR]

Abstract: The experience of self is unique and pivotal to clinically relevant cognitive and emotional functions. However, well-controlled data on specialized brain regions and functional networks underlying the experience of self remain limited. This functional magnetic resonance imaging study investigated neural activity and connectivity specific to processing one''s own face in healthy women by examining neural responses to the pictures of the subjects'' own faces in contrast to faces of their own mothers, female friends and strangers during passive viewing, emotional and self-relevance evaluations. The processing of one''s own face in comparison to processing of familiar faces revealed significant activity in right anterior insula (AI) and left inferior parietal lobule (IPL), and less activity in right posterior cingulate/precuneus (PCC/PCu) across all tasks. Further, the seed-based correlation analysis of right AI, and left IPL, showed differential functional networks in self and familiar faces contrasts. There were no differences in valence and saliency ratings between self and familiar others. Our preliminary results suggest that the self-experience cued by self-face is processed predominantly by brain regions and related networks that link interoceptive feelings and sense of body ownership to self-awareness and less by regions of higher order functioning such as autobiographical memories. [Copyright &y& Elsevier]

Abstract: The extension of group-level connectivity methods to individual subjects remains a hurdle for statistical analyses of neuroimaging data. Previous group analyses of positron emission tomography data in clinically depressed patients, for example, have shown that resting-state connectivity prior to therapy predicts how patients eventually respond to pharmacological and cognitive–behavioral therapy. Such applications would be considerably more informative for clinical decision making if these connectivity methods could be extended into the individual subject domain. To test such an extension, 46 treatment-naïve depressed patients were enrolled in an fMRI study to model baseline resting-state functional connectivity. Resting-state fMRI scans were acquired and submitted to exploratory structural equation modeling (SEM) to derive the optimal group connectivity model. Jackknife and split sample tests confirm that group model was highly reproducible, and path weights were consistent across the best five group models. When this model was applied to data from individual subjects, 85% of patients fit the group model. Histogram analysis of individual subjects'' paths indicate that some paths are better representative of group membership. These results suggest that exploratory SEM is a viable technique for neuroimaging connectivity analyses of individual subjects'' resting-state fMRI data. [Copyright &y& Elsevier]

Objective: The mother-child relationship may have important implications for emotional development and adult psychopathology. The objective of this study was to examine brain responses to processing maternal faces in healthy adult women.Methods: Ten healthy adult female volunteers with adequate early-life maternal care and a normal relationship with their living mothers participated in the study. Functional magnetic resonance imaging was used to examine brain responses to pictures of the subject's mother, a close female friend, and 2 age-matched female strangers during passive viewing, valence (emotional), and salience (self-relevance) evaluations.Results: The main contrast of mother, compared with all others (that is, friend and older and younger strangers), demonstrated the following: first, significant activation in the left posterior cingulate cortex-precuneus (PCC-Pcu), collapsed across all tasks; second, right ventromedial prefrontal cortex-anterior cingulate cortex (VMPFC-ACC) activation during the valence condition; and third, left dorsolateral prefrontal cortex (DLPFC) activation during the salience condition. In the region-of-interest analyses, the VMPFC-ACC and DLPFC showed significant activations in response to mothers' faces and deactivation in response to control faces. Among the 3 regions, only VMPFC-ACC activity distinguished the unique processing of one's own mother's face from that of a close friend. PCC-Pcu activations demonstrate a graded response (mother > friend > strangers) and, further, demonstrated differential response with respect to mothering style.Conclusions: The activation in prefrontal and cingulate cortices related to maternal face processing is consistent with their implicated roles in mother-infant interactions, personal familiarity, and emotional and self-relevant processing. These findings suggest a neural basis for maternal attachment and propose a focus for future studies aimed at investigating the impact of disrupted maternal attachment on emotional development. [ABSTRACT FROM AUTHOR]

Objective: To assess the efficacy of increasing the number of fast left repetitive transcranial magnetic stimulations (rTMS) (10 Hz @ 120% of motor threshold (MT) over the left dorsolateral prefrontal cortex (DLPFC)) needed to achieve remission in treatment-resistant depression (TRD). And, to determine if patients who do not remit to fast left will remit using slow right rTMS (1 Hz @ 120% MT over the right DLPFC). Method: Patients were part of a multicenter sham-controlled trial investigating the efficacy of fast left rTMS. Patients who failed to meet minimal response criteria in the sham-controlled study could enroll in this open fast left rTMS study for an additional 3-6 weeks. Patients who failed to remit to fast left could switch to slow right rTMS for up to 4 additional weeks. The final outcome measure was remission, defined as a HAM-D score of <3 or 2 consecutive HAM-D scores less than 10. Results: Forty-three of 141 (30.5%) patients who enrolled in the open phase study eventually met criteria for remission. Patients who remitted during fast left treatment received a mean of 26 active treatments (90,000 pulses). Twenty-six percent of patients who failed fast left remitted during slow right treatment. Conclusion: The total number of rTMS stimulations needed to achieve remission in TRD may be higher than is used in most studies. TRD patients who do not respond to fast left rTMS may remit to slow right rTMS or additional rTMS stimulations. Depression and Anxiety, 2011. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]