Recent advances in electroconvulsive therapy in clinical practice and research.

Electroconvulsive therapy (ECT), the oldest somatic therapy still in use in psychiatry today, remains one of the most effective therapeutic interventions for a wide variety of psychiatric disorders. In this article, we review some of the recent advances in ECT that are currently being researched and implemented in clinical practice. We explore recent studies that point to the potential therapeutic benefit and safety of ECT in COVID-19-related neuropsychiatric complications and special populations (such as the elderly and pregnant persons) that are generally at higher risk of having adverse effects from psychotropic medications. We highlight studies that performed a head-to-head comparison of ECT and ketamine, which has shown promise for treatment-resistant depression and acute suicidality. Researchers continue to explore different ways of using ECT by modifying the treatment parameters to maintain efficacy and decrease side effects. Neurocognitive side effects remain one of the major drawbacks to its use and contribute to the negative stigma of this highly effective treatment. In this regard, we describe attempts to improve the safety of ECT by modifying dosing parameters, novel electrode placements, and the addition of augmenting agents with the aim of decreasing side effects and improving efficacy. This review identifies some of the recent advances in the last few years in ECT research while also highlighting areas where further research is needed.

Treatment-Resistant Late-Life Depression: A Review of Clinical Features, Neuropsychology, Neurobiology, and Treatment.

Major depression is common in older adults (≥ 60 years of age), termed late-life depression (LLD). Up to 30% of these patients will have treatment-resistant late-life depression (TRLLD), defined as depression that persists despite two adequate antidepressant trials. TRLLD is challenging for clinicians, given several etiological factors (eg, neurocognitive conditions, medical comorbidities, anxiety, and sleep disruption). Proper assessment and management is critical, as individuals with TRLLD often present in medical settings and suffer from cognitive decline and other marks of accelerated aging. This article serves as an evidence-based guide for medical practitioners who encounter TRLLD in their practice.

A Feasibility Study of LORETA Z-Score Neurofeedback Training in Adults with Schizophrenia-Spectrum Disorder Experiencing Treatment-Resistant Auditory Verbal Hallucinations

Introduction: The incomplete effectiveness of interventions demands new ways to help people diagnosed with schizophrenia who experience auditory verbal hallucinations (SZ-AVH). We aimed to perform a feasibility study of low-resolution electromagnetic tomography analysis (LORETA) neurofeedback with people exhibiting treatment-resistant SZ-AVH. Method(s): We examined changes in resting-state quantitative electroencephalogram (qEEG) in four people with SZ-AVH (three male, one female) after LORETA Z-score neurofeedback training. Result(s): The study design had to be amended due to a national COVID-19 lockdown. Neurofeedback was well tolerated and no participants dropped out. Recruitment was the main feasibility issue. Barriers included a lack of knowledge of neurofeedback by patients and mental health teams, as well as the travel and time commitment involved. For the only patient who completed all 20 sessions, elevated frontal, central, and temporal theta absolute power measured at baseline normalized after treatment, but decreased temporal delta and an increase in coherence for all frequency bands were also found. Conclusion(s): Two key lessons were drawn for the feasibility of trials of EEG neurofeedback in this population. First, significant effort is needed to educate mental health professionals and patients about neurofeedback. Second, the equipment employed for neurofeedback training needs to be physically based at a site where patients routinely attend.Copyright © 2022. Amico et al.

Efficacy of an adjuvant non-face-to-face multimodal lifestyle modification program for patients with treatment-resistant major depression: A randomized controlled trial.

BACKGROUND: The high prevalence of depression is partly attributable to the poor response of patients to first-line antidepressants. Multimodal programs that promote a healthy lifestyle are successful in treating depression when used as a complementary therapy, but their medium- and long-term benefits have not been demonstrated for patients with treatment-resistant depression (TRD). The main aim of this study was to compare the effectiveness of a lifestyle modification program (LMP) with mindfulness-based cognitive therapy (MBCT) and a placebo-control (written suggestions for lifestyle changes) in Spanish patients with TRD. METHODS: This controlled clinical trial randomized 94 patients with TRD into 3 arms. The primary outcome was the Beck Depression Inventory-II (BDI-II) score at baseline, 2, 6 and 12 months. The secondary outcomes were changes in scores that evaluated quality-of-life, adherence to the Mediterranean diet, physical activity, and social support. RESULTS: Relative to the placebo group, the LMP and MBCT groups had significantly better quality of life (p = 0.017; p = 0.027), and the LMP group had significantly better adherence to the Mediterranean diet (p<0.001) and reduced use of antidepressants (p = 0.036). However, the three groups showed no significant differences in BDI-II score. LIMITATIONS: Only about half of the planned 180 patients were recruited, in part due to the COVID-19 pandemic. CONCLUSIONS: There was no evidence that the LMP treatment significantly reduced symptoms of depression relative to the other groups during the COVID-19 lockdown.

A Patient With Schizophrenia in Remission Relapses Following COVID-19: A Case Report.

As managing COVID-19 complications has become more prevalent in psychiatry, its effects can range from provoking new illnesses in previously healthy individuals to inducing relapses in patients in remission. However, an aspect of COVID-19's influence that is not well documented is its effect on medication responsiveness. In this case, we present a 28-year-old male diagnosed with treatment-resistant schizophrenia for eight years. While in remission on a maintenance dose of clozapine, he was admitted to the hospital with signs of severe psychosis after testing positive for COVID-19. On admission, he did not have any other major stressors and no prior comorbidities that could have induced the relapse. Despite being on a higher dose of clozapine for four weeks while hospitalized, the patient's psychosis did not improve. This raises the question if his infection had altered his response to medication that previously brought on remission.

Psychedelic science in post-COVID-19 psychiatry.

The medium- to long-term consequences of COVID-19 are not yet known, though an increase in mental health problems are predicted. Multidisciplinary strategies across socio-economic and psychological levels may be needed to mitigate the mental health burden of COVID-19. Preliminary evidence from the rapidly progressing field of psychedelic science shows that psilocybin therapy offers a promising transdiagnostic treatment strategy for a range of disorders with restricted and maladaptive habitual patterns of cognition and behaviour, notably depression, addiction and obsessive compulsive disorder. The COMPASS Pathways (COMPASS) phase 2b double-blind trial of psilocybin therapy in antidepressant-free, treatment-resistant depression (TRD) is underway to determine the safety, efficacy and optimal dose of psilocybin. Results from the Imperial College London Psilodep-RCT comparing the efficacy and mechanisms of action of psilocybin therapy to the selective serotonin reuptake inhibitor (SSRI) escitalopram will soon be published. However, the efficacy and safety of psilocybin therapy in conjunction with SSRIs in TRD is not yet known. An additional COMPASS study, with a centre in Dublin, will begin to address this question, with potential implications for the future delivery of psilocybin therapy. While at a relatively early stage of clinical development, and notwithstanding the immense challenges of COVID-19, psilocybin therapy has the potential to play an important therapeutic role for various psychiatric disorders in post-COVID-19 clinical psychiatry.

Multi Targeting Deep Brain Stimulation for Treatment-Resistant Depression: A 22 Month Follow up Case Report: Track 2: Brain Stimulation for Treatment Resistant Depression, Pain, and Parkinson's Disease

Introduction: According to WHO, there are more than 300,000,000 people worldwide suffering from depression. It is the world's leading cause of disability and contributes significantly to the overall global burden of disease. 30% of the patients are refractory, being possible candidates for surgical treatment by means of Deep Brain Stimulation (DBS). We present the follow up at 22 months of a patient with Treatment Refractory Depression (TRD) operated on with a new combination of targets. Materials / Methods: The diagnostic criteria used are those established by Mayberg et al: DSM IV-TR criteria for major depressive disorder with a major depressive episode of at least 1 year duration, with a minimum score of 20 on the 17-item Hamilton Depression Scale (HAM-D). Result(s): 55-year-old male. HAM-D: 26-point. It was decided to simultaneously implant Area 25 (SCG/Cg 25) and the Inferior Thalamic Peduncle (ITP) in order to contemplate the synergistic effect of stimulation of both structures. On December 5, 2018, it was successfully implanted, with previously published techniques, using a deep brain micro register system and stereotactic planning to define the coordinates of each selected target for the implantation of the four tetrapolar electrodes, model 6145 (Abbott) for Area 25 and model 6149 for ITP (Abbott). The electrode implanted in Area 25 was kept lit for 3 months, then only the corresponding to the ITP for an additional 3 months, and finally the four electrodes simultaneously maintaining the stimulation parameters reported in the literature. Post-surgical HAM-D scales were performed, with the following results: * Exclusively Area 25 (21/03/19) = 10 points * Exclusively ITP (13/06/19) = 9 points * Area 25 + ITP (08/08/19) = 14 points. * Area 25 + ITP (19/12/19) = 5 points. * Area 25 + ITP (08/10/20) = 5 points. Discussion(s): The possibility of multiple targets is technically possible and appropriate in very well selected cases. Conclusion(s): The patient showed a statistically significant improvement. Despite maintaining a rating of 5, it is worth mentioning that the patient refers feeling "better" than the previous year considering the time of year (spring), and the burden of the COVID-19 pandemic. This confirms some reports that mention the maintenance of the effect in the long term, even at 8 years, or even an improvement after almost two years can be seen. We consider that the synergism obtained by simultaneous stimulation of both targets could be more effective in terms of control of the depressive state at the long term. Supplemental Data: none. Learning Objectives: 1- To present a new therapeutic modality of multitargeting DBS for major depression. 2- To demonstrate that the combination of surgical targets is a possible option in carefully selected patients. 3- To demonstrate that the therapeutic effect is maintained over the time. Keywords: depression, deep brain stimulation, Area 25, inferior thalamic peduncle, multitargeting Copyright © 2022

Dopamine and Beyond: Implications of Psychophysical Studies of Intracranial Self-Stimulation for the Treatment of Depression.

Major depressive disorder is a leading cause of disability and suicide worldwide. Consecutive rounds of conventional interventions are ineffective in a significant sub-group of patients whose disorder is classified as treatment-resistant depression. Significant progress in managing this severe form of depression has been achieved through the use of deep brain stimulation of the medial forebrain bundle (MFB). The beneficial effect of such stimulation appears strong, safe, and enduring. The proposed neural substrate for this promising clinical finding includes midbrain dopamine neurons and a subset of their cortical afferents. Here, we aim to broaden the discussion of the candidate circuitry by exploring potential implications of a new "convergence" model of brain reward circuitry in rodents. We chart the evolution of the new model from its predecessors, which held that midbrain dopamine neurons constituted an obligatory stage of the final common path for reward seeking. In contrast, the new model includes a directly activated, non-dopaminergic pathway whose output ultimately converges with that of the dopaminergic neurons. On the basis of the new model and the relative ineffectiveness of dopamine agonists in the treatment of depression, we ask whether non-dopaminergic circuitry may contribute to the clinical efficacy of deep brain stimulation of the MFB.

Safety and efficacy of ketamine-augmented electroconvulsive therapy in third trimester pregnancy complicated by COVID-19.

Major depressive disorder during pregnancy can be detrimental to the fetus and patient. Treatments can include electroconvulsive therapy (ECT) for severe cases. The use of ketamine in ECT can provide symptomatic relief as well as induce anesthesia. Here, we describe the case of a 35-year-old gravid woman with a long-standing history of major depressive disorder who presented with treatment-resistant depression with suicidal ideation after an alteration in her antidepressant medication. After psychiatric evaluation, she was deemed to be a good candidate for ECT augmented with ketamine for symptomatic relief. This was complicated by an positive but asymptomatic COVID-19 status. Despite these factors, the patient experienced significant relief after an eight-treatment course of ECT, with a reduction of her PHQ-9 score from 22/27 to 4/27 points.

Antidepressant effect of prolonged twice-weekly intranasal esketamine treatments after nonresponse to electroconvulsive therapy in a patient with treatment-resistant depression

Presents a case report of a woman with depressive episodes, which began in early 2019 and was worsened by the change of her long-standing antidepressant regimen of fluoxetine to mirtazapine. Subsequently, she received 12 right unilateral ultrabrief pulse electroconvulsive therapy (ECT) treatments without any benefit. She experienced no benefit from 4 additional trials of antidepressants and during our evaluations over several weeks, her mood remained severely depressed. After 6 treatments, she experienced >50% reduction in her depression. However, her esketamine treatments were paused for 8 weeks due to COVID-19. Her depression worsened and a 4-week-long course of twice-weekly treatments was initiated, which resulted in a >50% reduction in her depression. After switching to weekly maintenance treatments, her symptoms of low mood, anhedonia, and suicidal ideation returned to her pre-treatment baseline. As she had responded well to twice-weekly treatments, the frequency of treatments was increased. In summary, this patient responded to twice-weekly esketamine treatments, experienced symptomatic worsening after switching to weekly treatments, but was able to attain remission with prolonged twice-weekly treatments. (PsycInfo Database Record (c) 2022 APA, all rights reserved)

The Influence of Research Follow-Up during COVID-19 Pandemic on Mental Distress and Resilience: A Multicenter Cohort Study of Treatment-Resistant Depression.

BACKGROUND: During the COVID-19 outbreak, patients with mental disorders have faced more negative psychological consequences than the public. For people with treatment-resistant depression (TRD), it is unclear whether research engagement would protect them from the deterioration of their symptoms. The study aimed to examine if chronic depressive patients would have improved resilience and mental distress levels after follow-up interviews during an observation period under COVID-19. METHODS: The study was nested within a three-year prospective cohort study. A two-group comparison design was conducted, i.e., the follow-up group with regular research interviews every three months after baseline assessment and the control group with one assessment-only interview. The two groups were compared with demographics, psychosocial, and suicide information. RESULTS: Baseline assessments were not significantly different in sociodemographic variables, suicide risks, mental distress, and resilience between groups. Significant differences were detected in resilient coping and mental distress levels (p < 0.05). The follow-up group (n = 46) experienced a higher level of resilient coping (37% vs. 25%) and lower level of mental distress (47.8% vs. 64.7%) than the control group (n = 68). CONCLUSIONS: Findings highlight under universal government strategy against COVID-19, TRD patients receiving regular research follow-ups exhibited better resilience and less mental distress than those without regular support from healthcare providers.

P.0729 Highlights of psychedelic history and current research on psilocybin application for treatment of depression – a comprehensive literature review

Introduction: Psychedelics have seen various labels: mystical sacrament aids, potential interrogation tools for the Cold War, agents for social change in the Hippie counter movement, a panacea for various mental disorders, and a tool to “hack” of the psyche. This has led to their reputation as both societal threat and a psychopharmacological breakthrough. After the loss of data on over 1000 clinical papers spanning 40000 study subjects in the 60′s, a 40-year hiatus, and a few very determined researchers, new insights of increasingly quality have been emerging from research on the potential benefits of the use of psilocybin in depression. We aim to review available data on psilocybin for treating depression, providing a bird's-eye view on the literature (historical and current), while reporting potential neurobiological, psychological and cognitive mechanisms involved, safety and methodological concerns (as well as recent advancements), emerging modalities of treatment, with a commentary on social and cultural movements occurring in parallel to the scientific endeavor to create regulated and scientifically approved treatments. Methods: Eligible studies will be identified through an electronic search of Medline and clinicaltrials.gov from inception to the date of submission. The search strategy will combine relevant standardized subject terms and text words for psychedelics, psilocybin, and depression, with relevant Boolean operators implemented. Only articles written in the English language will be included. Reference lists from eligible studies will be cross-checked to identify potential additional studies. For data synthesis, results and outcomes will be explored narratively, along reporting and critical analysis of relevant statistical data. Results: Psilocybin emulates serotonin, with special affinity for the 5-HT2A receptor. Neuroimaging studies suggest an attenuation of the default mode network and an overall increase in multiple brain area connectivity [1]. Current treatment models involve previous psychological profiling and preparation, followed by one to two sessions where administration of 25 mg of psilocybin under supervision and support from the researcher, a physician, and a therapist, with post-treatment integration. Since 2011, five clinical studies, evaluated psilocybin treatment efficacy on patients suffering from clinical depression [2,3,4]. Limited by small samples, variability of setting, timeline, and methodology, they combined number of 139 patients. Despite these limitations, 60% of patients reported significant symptom reduction (58-83%) providing promising preliminary evidence for further investment. A recent trial found no significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients, further contributing to this trend of research [5]. Over 50 studies addressing effects of psilocybin in depression have been approved on clinicaltrials.gov. One of these [6] is a phase 2 multicentered clinical trial, aiming to further evaluate the safety and efficacy of psilocybin in treatment resistant depression in a variable dose range. Conclusion: Psilocybin might become a promising approach to depression. These therapies have been (re)gaining social and cultural support, with parallel “off label” use in various spiritual and psychotherapeutic settings. There is a need for the upmost rigor in designing future research. Psilocybin might emerge as an important therapeutic tool for current and upcoming global mental health challenges in a post-COVID-19 world. No conflict of interest

Real-world effectiveness of repeated ketamine infusions for treatment resistant depression during the COVID-19 pandemic.

Herein we evaluate the impact of COVID-19 restrictions on antidepressant effectiveness of intravenous (IV) ketamine in adults with treatment-resistant depression (TRD). We conducted a case series analysis of adults with TRD (n = 267) who received four ketamine infusions at an outpatient clinic in Ontario, Canada, during COVID-19 restrictions (from March 2020 - February 2021; n = 107), compared to patients who received treatment in the previous year (March 2019 - February 2020; n = 160). Both groups experienced significant and comparable improvements in depressive symptoms, suicidal ideation, and anxiety with repeated ketamine infusions. Effectiveness of IV ketamine was not attenuated during the COVID-19 period.

Study protocol for a randomised placebo-controlled trial of pramipexole in addition to mood stabilisers for patients with treatment resistant bipolar depression (the PAX-BD study).

BACKGROUND: Treatment Resistant Bipolar Depression (TRBD) is a major contributor to the burden of disease associated with Bipolar Disorder (BD). Treatment options for people experiencing bipolar depression are limited to three interventions listed by National Institute for Health and Care: lamotrigine, quetiapine and olanzapine, of which the latter two are often not well tolerated. The majority of depressed people with BD are therefore prescribed antidepressants despite limited efficacy. This demonstrates an unmet need for additional interventions. Pramipexole has been shown to improve mood symptoms in animal models of depression, in people with Parkinson's Disease and two proof of principle trials of pramipexole for people with BD who are currently depressed. METHODS: The PAX-BD study, funded by the United Kingdom (UK) National Institute for Health Research, aims to extend previous findings by assessing the efficacy, safety and health economic impact of pramipexole in addition to mood stabilisers for patients with TRBD. A randomised, double-blind, placebo controlled design is conducted in a naturalistic UK National Health Service setting. An internal pilot study to examine feasibility and acceptability of the study design is included. Participants with TRBD are screened from National Health Service secondary care services in up to 40 mental health trusts in the UK, with the aim of recruiting approximately 414 participants into a pre-randomisation phase to achieve a target of 290 randomised participants. Primary safety and efficacy measures are at 12 weeks following randomisation, with follow up of participants to 52 weeks. The primary outcome is depressive symptoms as measured by Quick Inventory for Depressive Symptomatology - Self Report. Secondary outcomes include changes in anxiety, manic symptoms, tolerability, acceptability, quality of life and cost-effectiveness. Outcome measures are collected remotely using self-report tools implemented online, and observer-rated assessments conducted via telephone. ANCOVA will be used to examine the difference in rating scale scores between treatment arms, and dependent on compliance in completion of weekly self-report measures. A mixed effects linear regression model may also be used to account for repeated measures. TRIAL REGISTRATION: ISRCTN72151939. Registered on 28 August 2019, http://www.isrctn.com/ISRCTN72151939 Protocol Version: 04-FEB-2021, Version 9.0.