Cognitive behavioral therapy following esketamine for major depression and suicidal ideation for relapse prevention: The CBT-ENDURE randomized clinical trial study protocol.

In 2020, esketamine received a supplemental indication as a therapy for major depression with suicidal ideation (MDSI), based on protocols enrolling hospitalized patients. Given the high risk of suicide following hospital discharge and the high relapse rates following discontinuation of esketamine, the optimal long-term treatment approach remains unclear. Cognitive behavioral therapy (CBT) is highly effective in relapse prevention and has been shown to prevent suicide attempts in high-risk populations. Here we describe the study protocol for the CBT-ENDURE trial: Cognitive Behavioral Therapy Following Esketamine for Major Depression and SUicidal Ideation for RElapse Prevention. Patients with depression (N = 100) who are admitted to hospital or are outpatients with clinically significant suicidal ideation will be enrolled in the study. All patients will receive esketamine (twice weekly for four weeks) and will be randomly assigned (1:1 ratio) to receive a 16-week course of CBT plus treatment as usual (CBT group) or treatment as usual only (TAU only group). Patients are followed for a total of 6 months. Supported under a funding announcement from NIMH to conduct safety and feasibility trials for patients at high risk for suicide, the primary outcome of the CBT-ENDURE study is feasibility (as measured by recruitment and retention), with a key secondary outcome being relapse among those who experience substantial benefit following two weeks of esketamine.

The impact of adverse childhood experiences on adult depression severity and treatment outcomes.

BACKGROUND: Past research has established that adverse childhood experiences (ACE) are correlated with depression severity. The purpose of the present study was to examine how the number and nature of ACE exposure is associated with symptomatology and treatment outcomes in adult patients with treatment resistant depression (TRD). METHODS: Participants include 454 patients with a diagnosis of major depression or persistent depressive disorder. A one-way analysis of variance (ANOVA) was used to assess whether number of ACEs was associated with certain outcomes. Linear regression analyses were performed to model the associations between the five ACE subtypes (e.g., sexual abuse, physical violence, injury/illness, childhood grief, and parental upheaval) and symptom severity. Logistic regression analyses were then used to model the association between ACE subtypes and history of lifetime suicide attempt(s) and inpatient admission(s). RESULTS: Greater ACE exposure was associated with more severe symptomatology and treatment outcomes, but these differences were only seen between patients reporting no ACEs versus 3+ ACEs. Only the subtypes of violence and illness/injury were significant predictors of more severe symptomatology. The ACE subtypes of sexual trauma and violence uniquely predicted a lifetime suicide attempt(s), and only the subtype of sexual trauma predicted lifetime inpatient admission(s). LIMITATIONS: Limitations of the present study include retrospective adult assessments of childhood trauma, lack of data on ACE severity and timing, and the cross-sectional reporting of multiple study measures. CONCLUSIONS: Exposure to multiple ACE subtypes, particularly sexual and physical trauma, is associated with depression symptom severity, and history of suicidality, and inpatient admission(s).

Addressing Electroconvulsive Therapy Knowledge Gaps and Stigmatized Views Among Nursing Students Through a Psychiatrist-APRN Didactic Partnership.

BACKGROUND: Knowledge gaps and stigmatized perceptions regarding electroconvulsive therapy (ECT) among patients and health providers contribute to the underutilization of an important therapeutic modality. The proactive education of future advanced practice registered nurses (APRNs) provides an opportunity to optimize the use of this evidence-based clinical practice. AIMS: As part of a general course in psychiatry during the first year of nursing school, we dedicated 1 hour to treatment-refractory depression, including ECT, and a second hour to a summary discussion of mood disorders. We evaluated the efficacy of this didactic offering, which was co-taught by a psychiatrist and a psychiatric APRN. METHOD: At baseline, consenting students (n = 94) provided three words they associated with ECT and then completed three validated instruments: (a) Questionnaire on Attitudes and Knowledge of ECT, (b) Opening Minds Stigma Scale for Health Care Providers, and (c) Self-Stigma of Seeking Help. Among the 67 students who repeated the assessment at endpoint, 39 attended the ECT didactic (Intervention group, 58%) and 28 did not (Control, 42%). RESULTS: After completion of the 3-month course, students showed improvement across all measures (p < .001). The only outcomes that improved differentially between the Intervention and Control groups were the Questionnaire on Attitudes and Knowledge of ECT Attitudes and Knowledge scales (p = .01). Word choice valence associated with ECT shifted favorably by endpoint (p < .001). CONCLUSIONS: An educational intervention co-led by a psychiatric-mental health APRN had a significant impact on nursing students' knowledge and perceptions of ECT. This approach can be readily implemented at other institutions. Future refinements will include the videotaped depiction of a simulated patient undergoing the consent, treatment, and recovery phases of ECT.

Cognitive Behavioral Therapy to Sustain the Antidepressant Effects of Ketamine in Treatment-Resistant Depression: A Randomized Clinical Trial.

INTRODUCTION: Ketamine has emerged as a rapid-acting antidepressant. While ongoing treatment can prevent relapse, concerns exist regarding long-term exposure. OBJECTIVE: We conducted a randomized trial to examine the feasibility and efficacy of cognitive behavioral therapy (CBT) following intravenous ketamine in treatment-resistant depression (TRD). METHODS: Subjects with TRD were recruited and treated with 6 intravenous infusions of ketamine over 3 weeks. Subjects who experienced a clinical response (≥50% improvement in depression severity) were then randomized to receiving CBT or treatment as usual (TAU) for an additional 14 weeks, using a sequential treatment model. RESULTS: Of the 42 patients who signed consent, 28 patients achieved a response and were randomized to CBT or TAU. When measured using the Montgomery-Asberg Depression Rating Scale (primary outcome measure), the effect size at the end of the study was moderate (Cohen d = 0.65; 95% CI -0.55 to 1.82), though the group-by-time interaction effect was not significant. There was a significant group-by-time interaction as measured by the Quick Inventory of Depressive Symptomatology (F = 4.58; p = 0.033), favoring a greater sustained improvement in the CBT group. This corresponded to a moderate-to-large effect size of the Cohen d = 0.71 (95% CI -0.30 to 1.70) at the end of the study (14 weeks following the last ketamine infusion). In a subset of patients (N = 20) who underwent cognitive testing using the emotional N-back assessments before and after ketamine, ketamine responders showed improvement in the accuracy of emotional N-back (t[8] = 2.33; p < 0.05) whereas nonresponders did not (t[10] <1; p ns). CONCLUSIONS: This proof-of-concept study provides preliminary data indicating that CBT may sustain the antidepressant effects of ketamine in TRD. Further study and optimization of this treatment approach in well-powered clinical trials is recommended.

Barriers to the Implementation of Electroconvulsive Therapy (ECT): Results From a Nationwide Survey of ECT Practitioners.

OBJECTIVE: Electroconvulsive therapy (ECT) is an effective treatment for major depressive disorder; yet, its use is confined to <1% of individuals with this disorder. The authors aimed to examine barriers to ECT from the perspective of the provider. METHODS: Qualitative interviews were conducted with U.S.-based ECT providers to identify potential barriers. A quantitative survey was created asking providers to rank-order barriers to starting a new ECT service or expanding existing services. RESULTS: Survey responses were received from 192 physicians. Respondents were representative of all ECT providers found in the Medicare Provider Utilization and Payment Database with respect to gender and geographic distribution. Approximately one-third (N=58, 30%) of survey respondents graduated from one of 12 residency programs. Programs with dedicated hospital space were more likely to have larger services than those borrowing surgical recovery space (χ2=25.87, df=1, p<0.001). The most prominent provider-reported barriers to expanding an existing ECT service were lack of physical space, stigma on the part of patients, and transportation difficulties. The most prominent barriers to initiating a new service were lack of well-trained colleagues and ECT practitioners, lack of a champion within the institution, and lack of physical space. Wide geographic variation was found in the availability of ECT, with the highest concentration of ECT providers per 1 million individuals found in New England (6.4), and the lowest found in the West South Central (1.1). CONCLUSIONS: Coordinated efforts to overcome identified barriers may allow ECT to be more broadly implemented. Investments in education may increase the number of competent practitioners.

Electroconvulsive Therapy: a Video-Based Educational Resource Using Standardized Patients.

OBJECTIVE: Video-based depictions of electroconvulsive therapy (ECT) can be useful for educational purposes, but many of the readily available resources may worsen already stigmatized views of the procedure. Educators' common reliance on such material highlights the paucity of equipoised depictions of modern ECT well suited for the training of health professionals. The authors developed and tested a new educational module enhanced by videotaped depictions of a simulated patient undergoing the consent, treatment, recovery, and follow-up phases of ECT. METHODS: The didactic intervention interspersed 7 short video clips (totaling 14 min) into a 55-min lecture on treatment-resistant depression. The session, part of an intensive course of preclinical psychiatry, was delivered online through synchronous videoconferencing with Zoom. The primary outcome measure was change in the Questionnaire on Attitudes and Knowledge of ECT (QuAKE). RESULTS: Fifty-three out of 63 (87%) eligible second-year medical students completed assessments at baseline and after exposure to the didactic intervention. QuAKE scores improved between baseline and endpoint: the Attitudes composite increased from 49.4 ± 6.1 to 59.1 ± 5.7 (paired t 10.65, p < 0.001, Cohen's d 0.69), and the Knowledge composite from 13.3 ± 1.2 to 13.9 ± 0.8 (paired t 3.97, p < 0.001, Cohen's d 0.23). CONCLUSIONS: These video-based educational materials proved easy to implement in the virtual classroom, were amenable to adaptation by end-use instructors, were well received by learners, and led to measurable changes in students' knowledge of and attitudes toward ECT.

Mislocalization of neuronal mitochondria reveals regulation of Wallerian degeneration and NMNAT/WLD(S)-mediated axon protection independent of axonal mitochondria.

Axon degeneration is a common and often early feature of neurodegeneration that correlates with the clinical manifestations and progression of neurological disease. Nicotinamide mononucleotide adenylytransferase (NMNAT) is a neuroprotective factor that delays axon degeneration following injury and in models of neurodegenerative diseases suggesting a converging molecular pathway of axon self-destruction. The underlying mechanisms have been under intense investigation and recent reports suggest a central role for axonal mitochondria in both degeneration and NMNAT/WLD(S) (Wallerian degeneration slow)-mediated protection. We used dorsal root ganglia (DRG) explants and Drosophila larval motor neurons (MNs) as models to address the role of mitochondria in Wallerian degeneration (WD). We find that expression of Drosophila NMNAT delays WD in human DRG neurons demonstrating evolutionary conservation of NMNAT function. Morphological comparison of mitochondria from WLD(S)-protected axons demonstrates that mitochondria shrink post-axotomy, though analysis of complex IV activity suggests that they retain their functional capacity despite this morphological change. To determine whether mitochondria are a critical site of regulation for WD, we genetically ablated mitochondria from Drosophila MN axons via the mitochondria trafficking protein milton. Milton loss-of-function did not induce axon degeneration in Drosophila larval MNs, and when axotomized WD proceeded stereotypically in milton distal axons although with a mild, but significant delay. Remarkably, the protective effects of NMNAT/WLD(S) were also maintained in axons devoid of mitochondria. These experiments unveil an axon self-destruction cascade governing WD that is not initiated by axonal mitochondria and for the first time illuminate a mitochondria-independent mechanism(s) regulating WD and NMNAT/WLD(S)-mediated axon protection.

Dealing with misfolded proteins: examining the neuroprotective role of molecular chaperones in neurodegeneration.

Human neurodegenerative diseases arise from a wide array of genetic and environmental factors. Despite the diversity in etiology, many of these diseases are considered "conformational" in nature, characterized by the accumulation of pathological, misfolded proteins. These misfolded proteins can induce cellular stress by overloading the proteolytic machinery, ultimately resulting in the accumulation and deposition of aggregated protein species that are cytotoxic. Misfolded proteins may also form aberrant, non-physiological protein-protein interactions leading to the sequestration of other normal proteins essential for cellular functions. The progression of such disease may therefore be viewed as a failure of normal protein homeostasis, a process that involves a network of molecules regulating the synthesis, folding, translocation and clearance of proteins. Molecular chaperones are highly conserved proteins involved in the folding of nascent proteins, and the repair of proteins that have lost their typical conformations. These functions have therefore made molecular chaperones an active area of investigation within the field of conformational diseases. This review will discuss the role of molecular chaperones in neurodegenerative diseases, highlighting their functional classification, regulation, and therapeutic potential for such diseases.

Intramuscular AAV delivery of NT-3 alters synaptic transmission to motoneurons in adult rats.

We examined whether elevating levels of neurotrophin-3 (NT-3) in the spinal cord and dorsal root ganglion (DRG) would alter connections made by muscle spindle afferent fibers on motoneurons. Adeno-associated virus (AAV) serotypes AAV1, AAV2 and AAV5, selected for their tropism profile, were engineered with the NT-3 gene and administered to the medial gastrocnemius muscle in adult rats. ELISA studies in muscle, DRG and spinal cord revealed that NT-3 concentration in all tissues peaked about 3 months after a single viral injection; after 6 months NT-3 concentration returned to normal values. Intracellular recording in triceps surae motoneurons revealed complex electrophysiological changes. Moderate elevation in cord NT-3 resulted in diminished segmental excitatory postsynaptic potential (EPSP) amplitude, perhaps as a result of the observed decrease in motoneuron input resistance. With further elevation in NT-3 expression, the decline in EPSP amplitude was reversed, indicating that NT-3 at higher concentration could increase EPSP amplitude. No correlation was observed between EPSP amplitude and NT-3 concentration in the DRG. Treatment with control viruses could elevate NT-3 levels minimally resulting in measurable electrophysiological effects, perhaps as a result of inflammation associated with injection. EPSPs elicited by stimulation of the ventrolateral funiculus underwent a consistent decline in amplitude independent of NT-3 level. These novel correlations between modified NT-3 expression and single-cell electrophysiological parameters indicate that intramuscular administration of AAV(NT-3) can exert long-lasting effects on synaptic transmission to motoneurons. This approach to neurotrophin delivery could be useful in modifying spinal function after injury.

Transplantation of Schwann cells and/or olfactory ensheathing glia into the contused spinal cord: Survival, migration, axon association, and functional recovery.

Schwann cells (SCs) and olfactory ensheathing glia (OEG) have shown promise for spinal cord injury repair. We sought their in vivo identification following transplantation into the contused adult rat spinal cord at 1 week post-injury by: (i) DNA in situ hybridization (ISH) with a Y-chromosome specific probe to identify male transplants in female rats and (ii) lentiviral vector-mediated expression of EGFP. Survival, migration, and axon-glia association were quantified from 3 days to 9 weeks post-transplantation. At 3 weeks after transplantation into the lesion, a 60-90% loss of grafted cells was observed. OEG-only grafts survived very poorly within the lesion (<5%); injection outside the lesion led to a 60% survival rate, implying that the injury milieu was hostile to transplanted cells and or prevented their proliferation. At later times post-grafting, p75(+)/EGFP(-) cells in the lesion outnumbered EGFP(+) cells in all paradigms, evidence of significant host SC infiltration. SCs and OEG injected into the injury failed to migrate from the lesion. Injection of OEG outside of the injury resulted in their migration into the SC-injected injury site, not via normal-appearing host tissue but along the pia or via the central canal. In all paradigms, host axons were seen in association with or ensheathed by transplanted glia. Numerous myelinated axons were found within regions of grafted SCs but not OEG. The current study details the temporal survival, migration, axon association of SCs and OEG, and functional recovery after grafting into the contused spinal cord, research previously complicated due to a lack of quality, long-term markers for cell tracking in vivo.

Lentiviral vector-mediated transduction of neural progenitor cells before implantation into injured spinal cord and brain to detect their migration, deliver neurotrophic factors and repair tissue.

PURPOSE: Stem cells represent an attractive source for cell replacement therapy in neurological disorders due to their self-renewal and multi-potency. Genetic manipulation of these cells may allow controlled release of therapeutic proteins, suppress immune rejection, or produce essential neurotransmitters. Furthermore, when the expression cassette is incorporated into the host genome ex vivo, this technique also may be used as a method to trace cells following implantation into tissues of interest. METHODS: We explored the possibility of transducing pluripotent fetal rat cortical neural progenitor cells (NPCs) using lentiviral vectors encoding the green fluorescent protein (GFP) or neurotrophic factors (BDNF, CNTF, D15A, GDNF, MNT and NT-3) prior to implanting these cells into the contused spinal cord or injured brain. RESULTS: In vitro staining of these cells for neural markers (such as nestin, GFAP, Tuj-1 and RIP) after transduction did not reveal any significant difference from non-transduced cells. When they were transduced with a vector encoding CNTF or MNT, however, cells started expressing GFAP in vitro. Following delayed (1 week) implantation into the lesion site of the moderately contused rat spinal cord or the injured brain, transduced cells survived up to 12 weeks post-implantation (the longest time point examined) and most of the NPCs turned into an astrocytic phenotype in the spinal cord, but not in the brain. Nestin and GFP positive cells were detected in the brain, but not in the spinal cord lesion. GFP positive cells in the spinal cord migrated rostrally and caudally from the lesion/implantation site towards uninjured tissue. CONCLUSIONS: Novel findings in this study are the longterm expression of a foreign gene in NPCs using lentiviral vectors; this enabled tracking of the cells following implantation. This expression also allowed the observation that NPCs developed differently in the injured spinal cord and brain. Moreover, NPCs could be transduced to overexpress neurotrophic factors. In sum, NPC survival and the long-term transgene expression that allows easy tracking of migrating cells make NPCs promising candidates for implantation into the injured spinal cord or brain and a potentially powerful tool to enhance regeneration when transduced ex vivo to produce therapeutic molecules.