Treatment-resistant Symptoms Research Articles

Diagnosis and treatment of patients with gastroesophageal reflux disease - a systematic review of cost-effectiveness and economic burden.

This study aims to review the existing knowledge on the cost-effectiveness and item costs related to the diagnosis and treatment of gastroesophageal reflux disease (GERD) patients at different stages. The study adhered to the PRISMA guidelines. The systematic search involved several steps: finding and identifying relevant articles, filtering them according to the set criteria, and examining the final number of selected articles to obtain the primary information. The number of articles published between 2013 and September 2024 in the Web of Science and PubMed databases was considered. The CHEERS checklist was used for the risk of bias assessment. Ultimately, 36 studies were included. Regarding the cost-effectiveness of GERD treatment, Proton pump inhibitors (PPIs) appeared to be the dominant solution for non-refractory patients. However, this might change with the adoption of the novel drug vonoprazan, which is more effective and cheaper. With advancements in emerging technologies, new diagnostic and screening approaches such as Endosheath, Cytosponge, and combined multichannel intraluminal impedance and pH monitoring catheters should be considered, with potential implications for optimal GERD management strategies. The new diagnostic methods are reliable, safe, and more comfortable than standard procedures. PPIs are commonly used as the first line of treatment for GERD. Surgery, such as magnetic sphincter augmentation or laparoscopic fundoplication, is only recommended for patients with treatment-resistant GERD or severe symptoms. Advances in emerging technologies for diagnostics and screening may lead to a shift in the entire GERD treatment model, offering less invasive options and potentially improving patients' quality of life.

Biomarkers: The Key to Enhancing Deep Brain Stimulation Treatment for Psychiatric Conditions

Background: Deep brain stimulation (DBS) is currently a promising technique for psychiatric patients with severe and treatment-resistant symptoms. However, the results to date have been quite heterogeneous, and the indications for psychosurgery with DBS remain in an experimental phase. One of the major challenges limiting the advancement of DBS in psychiatric disorders is the lack of objective criteria for diagnosing certain conditions, which are often based more on clinical scales rather than measurable biological markers. Additionally, there is a limited capacity to objectively assess treatment outcomes. Methods: This overview examines the literature on the available biomarkers in psychosurgery in relation to DBS, as well as other relevant biomarkers in psychiatry with potential applicability for this treatment modality. Results: There are five types of biomarkers: clinical/behavioral, omic, neuroimaging, electrophysiological, and neurobiochemical. The information provided by each biomarker within these categories is highly variable and may be relevant for diagnosis, response prediction, target selection, program adjustment, etc. Conclusions: A better understanding of biomarkers and their applications would allow DBS in psychosurgery to advance on a more objective basis, guided by the information provided by them and within the context of precision psychiatry.

PANDAS, a series of difficult decisions: a case report

BackgroundPediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS) is a controversial diagnosis with limited evidence-based treatment guidelines available, particularly for severe and treatment-resistant cases.Case presentation: This report describes a 9-year-old male presenting with sudden onset, severe obsessive-compulsive disorder (OCD) symptoms one month following a streptococcus infection. His symptoms included suicidality and recurrent self-injurious behaviors, which led to multiple inpatient hospitalizations. He was diagnosed with PANDAS and was treated with psychotropic medications, antibiotics, immunotherapy, and a tonsillectomy. Over the two years since initial admission, the patient’s condition improved, with a decrease in symptom severity and an increase in adaptive functioning, though symptom remission was slow to occur.ConclusionsThis paper explores the controversies surrounding the PANDAS diagnosis, reviews potential treatments, and discusses the dilemmas of medical decision-making in the setting of severe treatment-resistant symptoms and limited evidence-based guidelines. We hope that this case report will be valuable to healthcare providers facing similar presentations and inspire further investigation into this complex condition.

Rapid and sustained reduction of treatment-resistant PTSD symptoms after intravenous ketamine in a real-world, psychedelic paradigm.

Traditional treatments for post-traumatic stress disorder (PTSD) often show limited success with high dropout. Ketamine, an N-methyl-D-aspartate antagonist known for rapid antidepressant effects, has decreased PTSD symptoms in some studies but not in others. Administering ketamine in ways that parallel psychedelic-assisted treatments-including preparatory, integration, sensory immersion, and psychotherapy sessions-could decrease PTSD symptoms meaningfully. A retrospective sample of 117 screened outpatients with elevated PTSD Checklist for DSM-5 (PCL-5) scores received intravenous ketamine in supportive environments. The protocol included preparation, intention-setting, and integration sessions accompanying at least six administrations. Administration sessions included eye shades and evocative music paralleling typical psychedelic therapy trials. Mean PCL scores decreased from 52.54 (SD = 12.01) to 28.78 (SD = 16.61), d = 1.64. Patients tolerated treatment well, with no serious adverse events. Covariates, including age, gender, days between PCL assessments, number of psychiatric medications, and suicidal ideation were not significant moderators; concomitant psychotherapy did reach significance, d = 0.51. Of the 117 patients' final PCL scores, 88 (75.21%) measures suggested clinically meaningful improvement and 72 (61.54%) suggested remission of PTSD symptoms. Intravenous ketamine in supportive environments, with hallmarks of psychedelic therapy, preceded large reductions in PTSD symptoms. These results highlight ketamine's potential when delivered in this manner, suggesting environmental factors might account for some variation seen in previous work. Given the molecule's cost, minimal interaction with other psychiatric medications, and legal status, intravenous ketamine in a psychedelic paradigm may be a promising option for PTSD unresponsive to other treatments.

Deep brain stimulation for Tourette's syndrome.

Tourette's syndrome is a neuropsychiatric disorder characterized by formidable motor and vocal tics. Many individuals also present with comorbid neuropsychiatric conditions. Though patients often benefit from pharmacological and behavioral therapies, a subset of individuals develop severe, treatment-resistant symptoms that might necessitate more invasive interventions, such as Deep Brain Stimulation (DBS). DBS, particularly targeting regions like the globus pallidus internus (GPi) and the centromedian-parafascicular complex (CM-Pf) of the thalamus, has demonstrated effectiveness in reducing tic severity and improving quality of life. This review outlines the mechanism, clinical efficacy, and long-term outcome of DBS in TS. Results from clinical studies reveal significant reductions in tics. However, success with DBS is variable depending on a number of factors, including target selection and electrode placement. The use of DBS has ethical considerations, which include risks to the surgical procedure, the need for full and complete informed consent, and questions about the implications of such treatment on cognitive and emotional growth. Long-term follow-up will be required to ensure appropriate patient outcomes and complication management. Additional research and ethical debate will be needed with advancing DBS technology to ensure responsible and equitable treatment. This paper narratively summarizes the surgical options available for TS, with a focus on the current status of DBS in the management of the disease.

Examining relationships among NODDI indices of white matter structure in prefrontal cortical-thalamic-striatal circuitry and OCD symptomatology

Obsessive-compulsive disorder is a psychiatric disorder characterized by intrusive thoughts and repetitive behaviors. There are two prominent features: Harm Avoidance (HA) and Incompleteness (INC). Previous resting-state studies reported abnormally elevated connectivity between prefrontal cortical (PFC) and subcortical regions (thalamus, striatum) in OCD participants. Yet, little is known about the white matter (WM) structural abnormalities in these connections. Using brain parcellation and segmentation, whole brain tractography, and Neurite Orientation Dispersion and Density Imaging (NODDI), we aimed to characterize WM structural abnormalities in OCD vs. healthy controls and determine the extent to which NODDI indices of these connections were associated with subthreshold-threshold HA, INC and overall OCD symptom severity across all participants. Four PFC regions were segmented: ventral medial (vmPFC), ventrolateral (vlPFC), dorsomedial (dmPFC), and dorsolateral (dlPFC). NODDI Neurite Density (NDI) and Orientation Dispersion (ODI) indices of WM structure were extracted from connections between these PFC regions and the thalamus (42 OCD, 44 healthy controls, mean age[SD] = 23.65[4.25]y, 63.9% female) and striatum (38 OCD, 41 healthy controls, mean age[SD] = 23.59[4.27]y, 64.5% female). Multivariate analyses of covariance revealed no between-group differences in these indices. Multivariate regression models revealed that greater NDI in vmPFC-thalamus, greater NDI and ODI in vmPFC-striatum, and greater NDI in dmPFC-thalamus connections were associated with greater INC severity (Q ≤ 0.032). These findings highlight the utility of NODDI in the examination of WM structure in OCD, provide valuable insights into specific WM alterations underlying dimensional INC, and can facilitate the development of customized treatments for OCD individuals with treatment-resistant symptoms.

An important contributing factor in dry eye disease: somatization.

Somatization is an important mental process that may causes medically unexplained and treatment-resistant somatic symptoms. The aim of the study is assess the presence of somatization in patients with dry eye disease (DED). Eighty-eight patients with no objective DED finding and ongoing DED treatment were included in this prospective and observational study. Patients with subjective symptoms formed the symptom group and patients without subjective symptoms formed the control group. All patients were scored with the Turkish version of the Ocular Surface Disease Index (OSDI), Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), Symptom Checklist-90-R (SCL-90R) somatization subscale, Toronto Alexithymia Scale (TAS), Pain Catastrophizing Scale (PCS), and Symptom Interpretation Questionnaire (SIQ). Mean OSDI score was significantly higher in the symptom group than in the control group. The mean HAM-D and HAM-A outcomes did not differ between the groups. The mean SCL-90R somatization subscale, TAS, and PCS scores were significantly higher in the symptom group than in the control group. In the SIQ, somatic attributional style score was significantly higher in the symptom group than in the control group. The SCL-90R somatization subscale, PCS, and somatic attributional style scores had positive and mild-moderate correlation with OSDI scores in the symptom group. The TAS score had positive and moderate correlation with OSDI scores in all sample analyses. Somatization should be considered in patients with DED with chronic ocular surface symptoms. Presence of subjective symptoms resistant to treatment may be an indicator of somatization.

Unraveling the Enigma: Huntington’s Disease Masquerading as Treatment-Resistant Psychosis - A Case Study

IntroductionThis unusual case report unfolds a complex and emblematic scenario involving the diagnosis and management of a 46-year-old patient with treatment-resistant psychiatric symptoms, eventually revealing a significant association with Huntington’s Disease (HD). The initial presentation at Obregia Hospital featured early signs of psychosis, such as mood swings, social withdrawal, and mild cognitive impairment. Despite predominant treatment with atypical antipsychotics, significant improvements remained elusive.ObjectivesOur primary objectives were to document the intricate diagnostic journey, the challenges faced in managing the patient’s psychiatric symptoms, and the eventual revelation of an underlying neurological disorder, Huntington’s Disease. We aimed to emphasize the importance of a multidisciplinary approach to such complex cases.MethodsThe patient’s clinical course was closely monitored, and the Positive and Negative Syndrome Scale (PANSS) was used to assess the severity of symptoms upon admission. The patient’s severe psychotic state led to involuntary hospitalization. Clinical observations pointing to an underlying neurological disorder prompted a neurology consultation and further investigations, including brain CT and MRI scans, but also genetic testing.ResultsThe CT scan revealed potential Huntington’s Disease evolution, while genetic testing confirmed the presence of the specific HTT mutation. Brain MRI with contrast substance highlighted characteristic Huntington’s Disease changes, such as cortical atrophy, necrosis, and substantial loss of brain tissue, particularly in the basal ganglia, cortical regions, and thalamic nuclei. The patient was hospitalized for nearly seven weeks, during which various psychiatric medications were trialed with limited success. However, a gradual increase of Trihexyphenidyl dosage, as well as a wash-up with saline solution and vitamin supplements (B1, B6, and C), was initiated. Subsequently, the introduction of oral haloperidol in gradually increasing doses led to significant improvements in psychiatric symptoms, dyskinesia, and overall functionality.ConclusionsThis complex case underscores the paramount importance of a multidisciplinary approach in diagnosing and managing patients with Huntington’s Disease and concurrent psychiatric symptoms. The revelation of a confirmed Huntington’s Disease diagnosis also necessitated genetic testing for the patient’s two adult children, with the son testing positive. This case illustrates the challenges of adapting treatment strategies continuously in such multifaceted scenarios and highlights the compelling need for a collaborative and integrative approach.Disclosure of InterestNone Declared

Factors associated with self-perceived treatment-resistance in bipolar disorder.

Patients with bipolar disorder often report self-perceived treatment resistance. However, it is not known to what extent it is due to actual treatment resistance. The Juntendo University provides "Bipolar Disorder Treatment Rebuilding Program," in which patients with self-reported treatment resistant bipolar disorder are hospitalized for 2 weeks and undergo detailed examinations. In this study, we report our experience with the initial 43 patients hospitalized during the one and half years after the launch of the program. Among the patients who underwent full assessment, only one was regarded as having genuine treatment-resistant bipolar disorder without comorbidity. In other cases, ten were not diagnosed with bipolar disorder, 3 had organic brain diseases, 12 had comorbid mental disorders and its symptoms were regarded as treatment-resistant bipolar symptoms by the patients, and 18 did not receive adequate treatment because attendant physicians did not adhere to the treatment guidelines or patients did not adhere to the treatment because of lack of insight. The number of participants was not large, and selection bias hampered the generalization of the findings. Insight and adherence were assessed without the use of validated tools. We could not verify recovery after adequate treatment because of the limited hospitalization period. The findings suggest that most patients with self-perceived treatment-resistant bipolar disorder may not have genuine treatment-resistant bipolar disorder. These results shed light on the difficulties of public education of bipolar disorder and importance of providing appropriate services for diagnosis and treatment of bipolar disorder in the community.

Treatment resistance NMDA receptor pathway polygenic score is associated with brain glutamate in schizophrenia.

Dysfunction of glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia and may be particularly relevant in severe, treatment-resistant symptoms. The underlying mechanism may involve hypofunction of the NMDA receptor. We investigated whether schizophrenia-related pathway polygenic scores, composed of genetic variants within NMDA receptor encoding genes, are associated with cortical glutamate in schizophrenia. Anterior cingulate cortex (ACC) glutamate was measured in 70 participants across 4 research sites using Proton Magnetic Resonance Spectroscopy (1H-MRS). Two NMDA receptor gene sets were sourced from the Molecular Signatories Database and NMDA receptor pathway polygenic scores were constructed using PRSet. The NMDA receptor pathway polygenic scores were weighted by single nucleotide polymorphism (SNP) associations with treatment-resistant schizophrenia, and associations with ACC glutamate were tested. We then tested whether NMDA receptor pathway polygenic scores with SNPs weighted by associations with non-treatment-resistant schizophrenia were associated with ACC glutamate. A higher NMDA receptor complex pathway polygenic score was significantly associated with lower ACC glutamate (β=-0.25, 95% CI=-0.49, -0.02, competitive p=0.03). When SNPs were weighted by associations with non-treatment-resistant schizophrenia, there was no association between the NMDA receptor complex pathway polygenic score and ACC glutamate (β=0.05, 95% CI=-0.18, 0.27, competitive p=0.79). These results provide initial evidence of an association between common genetic variation implicated in NMDA receptor function and ACC glutamate levels in schizophrenia. This association was specific to when the NMDA receptor complex pathway polygenic score was weighted by SNP associations with treatment-resistant schizophrenia.

Gluten Sensitivity Underlying Resistant “Laryngopharyngeal Reflux” Symptoms and Signs

Laryngopharyngeal reflux (LPR) is one of the most common conditions encountered in otolaryngology. Gluten sensitivity may mimic the signs and symptoms of LPR or act as an aggravating cofactor with LPR. Gluten sensitivity and food intolerance also have been implicated as conditions that may be associated specifically with LPR symptoms and signs resistant to traditional medical treatment. Medical management of LPR may be insufficient to control symptoms and laryngeal signs of reflux, constituting resistant LPR. Eliminating gluten from the diet could provide symptomatic relief to patients with gluten sensitivity and LPR that is not controlled adequately by current regimens. The purpose of our study was to investigate the relationship between gluten sensitivity and LPR. We aimed to evaluate reflux finding score (RFS) improvement following elimination of gluten from the diet in patients with resistant LPR who had positive blood tests associated with gluten sensitivity. Symptom improvement was also assessed following dietary gluten elimination. Lastly, we aimed to identify predictors for a positive response to a gluten-free diet. Adult patients who underwent gluten sensitivity testing for treatment-resistant LPR symptoms and/or signs were included. Patients with ≥1 positive test were advised to begin a therapeutic trial of a gluten-free diet. Subjects who chose not to trial a gluten-free diet or tested negative for gluten sensitivity markers served as controls. RFS was the primary outcome measure. One hundred ninety-seven patients were included; 81 trialed a gluten-free diet. Subjects who trialed the gluten-free diet were significantly more likely to demonstrate objective improvement in RFS (77.14% vs 43.88%), and report subjective improvement (55.41% vs 25.77%) than those who did not. RFS had decreased significantly from baseline at 1-3, 3-6, 6-12, and >12-month interval follow-up examinations in subjects who trialed a gluten-free diet. Comparison between subjects who trialed the gluten-free diet, tested positive for a gluten sensitivity marker but did not trial the gluten-free diet, and subjects who were negative for all gluten sensitivity markers revealed that a gluten-free diet was associated with a significantly greater percent improvement in RFS compared to controls at 1-3, 6-12, and >12-months. Gluten sensitivity can mimic or aggravate LPR. A gluten-free diet should be considered for patients with resistant LPR, especially if blood test abnormalities that suggest gluten sensitivity are identified. The diet should be maintained for a minimum of three months to demonstrate objective improvement using RFS.

Pharmacokinetics of Nasal Esketamine in Patients with Allergic Rhinitis with and Without Nasal Decongestant Pretreatment and in Healthy Subjects with and Without Nasal Corticosteroid Pretreatment.

Nasal esketamine is indicated for the treatment of adults with treatment-resistant depression and depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. Primary objectives of this study were to evaluate the effect of nasal decongestant pretreatment in patients with allergic rhinitis and the impact of daily nasal corticosteroid administration by healthy subjects on nasal esketamine pharmacokinetics. Patients with allergic rhinitis self-administered 56 mg of nasal esketamine after pretreatment with nasal oxymetazoline (0.05%) at 1h before esketamine and without oxymetazoline pretreatment. They were exposed to grass pollen in an allergen challenge chamber to induce allergic rhinitis symptoms at approximately 2 h before each esketamine administration until 1 h after. Healthy subjects self-administered esketamine (56mg) before and after administration for 16consecutive days of mometasone (200µg), with the second esketamine dose administered 1h after the last mometasone dose. The plasma pharmacokinetics of esketamine and noresketamine were assessed after each esketamine administration. The tolerability of esketamine, including effects on dissociative and potential psychotomimetic symptoms and level of sedation and suicidal ideation and behavior, was evaluated. The rate of esketamine absorption was slightly greater in patients exhibiting symptoms of allergic rhinitis (decrease in median tmax from 32min to 22min). Increases in esketamine Cmax and AUC were also small (mean, ≤ 21%). The pharmacokinetics of esketamine was not affected by oxymetazoline or mometasone pretreatment. Esketamine was well tolerated when it was administered with or without pretreatment of oxymetazoline or mometasone. Patients exhibiting symptoms of rhinitis may receive nasal esketamine spray without dose adjustment. In addition, esketamine may be administered 1 h after using a nasal decongestant or corticosteroid. The study was registered in the Clinical Trials (NCT02154334) and EudraCT (2014-000534-38) registries.

The multimodal Munich Clinical Deep Phenotyping study to bridge the translational gap in severe mental illness treatment research.

Treatment of severe mental illness (SMI) symptoms, especially negative symptoms and cognitive dysfunction in schizophrenia, remains a major unmet need. There is good evidence that SMIs have a strong genetic background and are characterized by multiple biological alterations, including disturbed brain circuits and connectivity, dysregulated neuronal excitation-inhibition, disturbed dopaminergic and glutamatergic pathways, and partially dysregulated inflammatory processes. The ways in which the dysregulated signaling pathways are interconnected remains largely unknown, in part because well-characterized clinical studies on comprehensive biomaterial are lacking. Furthermore, the development of drugs to treat SMIs such as schizophrenia is limited by the use of operationalized symptom-based clusters for diagnosis. In line with the Research Domain Criteria initiative, the Clinical Deep Phenotyping (CDP) study is using a multimodal approach to reveal the neurobiological underpinnings of clinically relevant schizophrenia subgroups by performing broad transdiagnostic clinical characterization with standardized neurocognitive assessments, multimodal neuroimaging, electrophysiological assessments, retinal investigations, and omics-based analyzes of blood and cerebrospinal fluid. Moreover, to bridge the translational gap in biological psychiatry the study includes in vitro investigations on human-induced pluripotent stem cells, which are available from a subset of participants. Here, we report on the feasibility of this multimodal approach, which has been successfully initiated in the first participants in the CDP cohort; to date, the cohort comprises over 194 individuals with SMI and 187 age and gender matched healthy controls. In addition, we describe the applied research modalities and study objectives. The identification of cross-diagnostic and diagnosis-specific biotype-informed subgroups of patients and the translational dissection of those subgroups may help to pave the way toward precision medicine with artificial intelligence-supported tailored interventions and treatment. This aim is particularly important in psychiatry, a field where innovation is urgently needed because specific symptom domains, such as negative symptoms and cognitive dysfunction, and treatment-resistant symptoms in general are still difficult to treat.

Successful Treatment with High-Dose Immunoglobulin of a Complicated Patient with Catatonia and Central Nervous System Autoantibodies

Ms. X is a 52-year-old Filipino female with no prior psychiatric or medical history who initially presented to an outside hospital for new onset headache, neck pain, and altered mental status. She was admitted inpatient medicine service and was found to have HIV/AIDs and cryptococcal meningoencephalitis. Ms. X had a good response to appropriate antifungal therapies and was able to discharge home with full resolution of symptoms on high dose fluconozaole. Unfortunately, Ms. X developed transaminitis on high dose fluconazole, the dose was reduced and she presented to our institution with recurrent cryptococcal meningoencephalitis as evidenced by elevated titers of cryptococcal antigen in CSF and MRI studies showing T2 and FLAIR hyperintensities in bilateral basal ganglia, thalamus and medial temporal lobes and evidence of intracranial hypertension. Consequently, Ms. X developed prominent neuropsychiatric symptoms including agitation, cognitive impairment, paranoia, visual hallucinations and symptoms of catatonia. Despite adequate treatment of the cryptococcal infection evidenced by decreasing cryptococcal antigen titers in CSF, and appropriate psychiatric treatment, her neuropsychiatric symptoms persisted and her MRI studies continued to show signs of neuroinflammation in the aforementioned areas. Antibody testing for basal ganglia targets was completed to investigate a possible non-infectious cause of neuroinflammation and neuropsychiatric symptoms. Ms. X was found to have elevated titers of anti-D1, anti-GM1 and anti-tubulin receptor antibodies in her CSF. Due to the severity and treatment resistant nature of her neuropsychiatric symptoms, she was treated with 2 g/kg/day IVIG for 4 days. She showed significant improvement in her neuropsychiatric symptoms after 3 days and full resolution of her neuropsychiatric symptoms 1 week following IVIG. Given remarkable clinical response to IVIG a second round of IVIG was administered 2 weeks later in order to sustain the response. After several months of prolonged hospitalization, Ms X was able to discharge to the care of her family and to date her neuropsychiatric symptoms remain in remission. We propose Ms. X’s persistent, treatment resistant neuropsychiatric symptoms were related to a post-infectious inflammatory encephalopathy that responded robustly to IVIG.

Repeated oral esketamine in patients with treatment resistant depression and comorbid posttraumatic stress disorder

IntroductionKetamine and its S-enantiomer esketamine are novel pharmacotherapeutic options for treatment resistant depression (TRD). There is growing evidence on the efficacy for other psychiatric disorders, including posttraumatic stress disorder (PTSD). It is hypothesized that psychotherapy may further potentiate the effects of (es)ketamine in psychiatric disorders. MethodsRepeated oral esketamine was prescribed once or twice weekly in five patients suffering from TRD and comorbid PTSD. We describe the clinical effects of esketamine and report data from psychometric instruments and patients’ perspectives. ResultsEsketamine treatment duration ranged from six weeks to a year. In four patients, we observed improvement in depressive symptoms, increased resilience and more receptiveness to psychotherapy. One patient experienced symptom worsening in response to a threatening situation during esketamine treatment, highlighting the need for a safe setting. Discussion(Es)ketamine treatment within a psychotherapeutic framework appears promising in patients with treatment resistant symptoms of depression and PTSD. Controlled trials are warranted to validate these results and to elucidate the optimal treatment methods.

Early progression of a pancreatic metastasis of synovial sarcoma after pancreatectomy

BackgroundSynovial sarcoma is a malignant tumor that constitutes up to 10% of all soft-tissue sarcomas. The most frequent metastatic sites of synovial sarcoma are the lungs, lymph nodes, and bone, whereas pancreatic metastasis is extremely rare. Here, we report a case of pancreatic metastasis of synovial sarcoma.Case presentationNine years before presentation, a 31-year-old woman underwent extensive resection of the primary tumor after chemotherapy for left upper extremity synovial sarcoma. Six months before presentation, interscapulothoracic amputation was performed for an enlarged mass in the left upper extremity; the patient was treated with pazopanib. Three months before presentation, chest computed tomography showed multiple lung metastases; during subsequent follow-up, abdominal computed tomography revealed a pancreatic metastasis of synovial sarcoma. The doubling time of the pancreatic tumor was 14 days, and it grew rapidly. Furthermore, treatment-resistant pancreatitis symptoms were detected; thus, we performed distal pancreatectomy and administered one course of a 70% dose of trabectedin. However, the patient died of rapid progression of lung metastasis and respiratory failure within 2 months after surgery.ConclusionsPancreatectomy may be carefully performed in cases of isolated pancreatic metastasis. However, the presence of other distant extrapancreatic metastases (e.g., uncontrolled lung metastases) may rule out pancreatectomy treatment.

Pharmacokinetics and pharmacogenomics of clozapine in an ancestrally diverse sample: a longitudinal analysis and genome-wide association study using UK clinical monitoring data

The antipsychotic, clozapine, is the only licensed drug against the treatment-resistant symptoms that affect 20-30% of people with schizophrenia. Clozapine is markedly underprescribed, partly because of concerns about its narrow therapeutic range and adverse drug reaction profile. Both concerns are linked to drug metabolism, which varies across populations globally and is partly genetically determined. Our study aimed to use a cross-ancestry genome-wide association study (GWAS) design to investigate variations in clozapine metabolism within and between genetically inferred ancestral backgrounds, to discover genomic associations to clozapine plasma concentrations, and to assess the effects of pharmacogenomic predictors across different ancestries. In this GWAS, we analysed data from the UK Zaponex Treatment Access System clozapine monitoring service as part of the CLOZUK study. We included all available individuals with clozapine pharmacokinetic assays requested by their clinicians. We excluded people younger than 18 years, or whose records contained clerical errors, or with blood drawn 6-24 h after dose, a clozapine or norclozapine concentration less than 50 ng/mL, a clozapine concentration of more than 2000 ng/mL, a clozapine-to-norclozapine ratio outside of the 0·5-3·0 interval, or a clozapine dose of more than 900 mg/day. Using genomic information, we identified five biogeographical ancestries: European, sub-Saharan African, north African, southwest Asian, and east Asian. We did pharmacokinetic modelling, a GWAS, and a polygenic risk score association analysis using longitudinal regression analysis with three primary outcome variables: two metabolite plasma concentrations (clozapine and norclozapine) and the clozapine-to-norclozapine ratio. 19 096 pharmacokinetic assays were available for 4760 individuals in the CLOZUK study. After data quality control, 4495 individuals (3268 [72·7%] male and 1227 [27·3%] female; mean age 42·19 years [range 18-85]) linked to 16 068 assays were included in this study. We found a faster average clozapine metabolism in people of sub-Saharan African ancestry than in those of European ancestry. By contrast, individuals with east Asian or southwest Asian ancestry were more likely to be slow clozapine metabolisers than those with European ancestry. Eight pharmacogenomic loci were identified in the GWAS, seven with significant effects in non-European groups. Polygenic scores generated from these loci were associated with clozapine outcome variables in the whole sample and within individual ancestries; the maximum variance explained was 7·26% for the metabolic ratio. Longitudinal cross-ancestry GWAS can discover pharmacogenomic markers of clozapine metabolism that, individually or as polygenic scores, have consistent effects across ancestries. Our findings suggest that ancestral differences in clozapine metabolism could be considered for optimising clozapine prescription protocols for diverse populations. UK Academy of Medical Sciences, UK Medical Research Council, and European Commission.

Clinical Practice Guidelines for the Use of Transcranial Direct Current Stimulation in Psychiatry.

Clinical Practice Guidelines for the Use of Transcranial Direct Current Stimulation in Psychiatry.

Electroconvulsive therapy or clozapine for adolescents with treatment-resistant schizophrenia: an explorative analysis on symptom dimensions

Objective This study sought to compare pre-intervention patient characteristics and post-intervention outcomes in a naturalistic sample of adolescent inpatients with treatment-resistant psychotic symptoms who received either electroconvulsive therapy (ECT) or clozapine. Methods Data of adolescents with schizophrenia/schizoaffective disorder receiving ECT or clozapine were retrospectively collected from two tertiary-care psychiatry-teaching university hospitals. Subscale scores of the Positive and Negative Symptom Scale (PANSS) factors were calculated according to the five-factor solution. Baseline demographics, illness characteristics, and post-intervention outcomes were compared. Results There was no significant difference between patients receiving ECT (n = 13) and clozapine (n = 66) in terms of age, sex, and the duration of hospital stay. The ECT group more commonly had higher overall illness and aggression severity. Smoking was less frequent in the clozapine group. Baseline resistance/excitement symptom severity was significantly higher in the ECT group, while positive, negative, affect, disorganisation, and total symptom scores were not. Both interventions provided a significant reduction in PANSS scores with large effect sizes. Conclusion Both ECT and clozapine yielded high effectiveness rates in adolescents with treatment-resistant schizophrenia/schizoaffective disorder. Youth receiving ECT were generally more activated than those who received clozapine.

Increased Prevalence of Rare Copy Number Variants in Treatment-Resistant Psychosis.

It remains unknown why ~30% of patients with psychotic disorders fail to respond to treatment. Previous genomic investigations of treatment-resistant psychosis have been inconclusive, but some evidence suggests a possible link between rare disease-associated copy number variants (CNVs) and worse clinical outcomes in schizophrenia. Here, we identified schizophrenia-associated CNVs in patients with treatment-resistant psychotic symptoms and then compared the prevalence of these CNVs to previously published schizophrenia cases not selected for treatment resistance. CNVs were identified using chromosomal microarray (CMA) and whole exome sequencing (WES) in 509 patients with treatment-resistant psychosis (a lack of clinical response to ≥3 adequate antipsychotic medication trials over at least 5 years of psychiatric hospitalization). Prevalence of schizophrenia-associated CNVs in this sample was compared to that in a previously published large schizophrenia cohort study. Integrating CMA and WES data, we identified 47 cases (9.2%) with at least one CNV of known or possible neuropsychiatric risk. 4.7% (n = 24) carried a known neurodevelopmental risk CNV. The prevalence of well-replicated schizophrenia-associated CNVs was 4.1%, with duplications of the 16p11.2 and 15q11.2-q13.1 regions, and deletions of the 22q11.2 chromosomal region as the most frequent CNVs. Pairwise loci-based analysis identified duplications of 15q11.2-q13.1 to be independently associated with treatment resistance. These findings suggest that CNVs may uniquely impact clinical phenotypes beyond increasing risk for schizophrenia and may potentially serve as biological entry points for studying treatment resistance. Further investigation will be necessary to elucidate the spectrum of phenotypic characteristics observed in adult psychiatric patients with disease-associated CNVs.