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Cognitive dysfunction is a core feature of schizophrenia. Although treatment-resistant schizophrenia (TRS) exhibits wide-ranging neuropsychological deficits, factors defining cognitive prognosis in TRS are unclear. We aimed to clarify the association between cognitive dysfunction and factors, such as plasma concentrations of clozapine (CLZ), N-desmethylclozapine (NDMC), and homovanillic acid (HVA), due to differences in antipsychotic responses in patients with schizophrenia. This pilot cross-sectional study included 60 Japanese patients (35 with TRS and 25 with non-CLZ antipsychotic responders (AR)). Cognitive function was evaluated using the Brief Assessment of Cognition Short Form (BAC-SF). Plasma concentrations of HVA, CLZ, and NDMC were analyzed by high-performance liquid chromatography. The cognitive performance of patients with AR was better than that of patients with TRS in all tasks. No significant cognitive differences were detected between the CLZ responders and non-responders. The severity of negative and extrapyramidal symptoms was found to be potentially negatively associated with BAC-SF composite and several subtest scores. In patients with TRS, chlorpromazine equivalents and the CLZ/NDMC ratio were identified as factors negatively associated with Digit Sequencing and the Symbol Coding subtest scores of the BAC-SF, respectively. Our study suggests that patients with TRS experience worse cognitive dysfunction than those with AR, and CLZ responsiveness in TRS may be not associated with cognitive dysfunction. Additionally, higher chlorpromazine equivalents and the CLZ/NDMC ratio may be associated with severity of cognitive dysfunction in patients with TRS. Further studies are required to clarify the relationship between treatment response and cognitive dysfunction in schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Antipsychotic medications offer limited long-term benefit to about 30% of patients with schizophrenia. We aimed to explore the individual-specific imaging markers to predict 1-year treatment response of schizophrenia. Methods: Structural morphology and functional topological features related to treatment response were identified using an individualized parcellation analysis in conjunction with machine learning (ML). We performed dimensionality reductions using the Pearson correlation coefficient and three feature selection analyses and classifications using 10 ML classifiers. The results were assessed through a 5-fold cross-validation (training and validation cohorts, n = 51) and validated using the external test cohort (n = 17). Results: ML algorithms based on individual-specific brain network proved more effective than those based on group-level brain network in predicting outcomes. The most predictive features based on individual-specific parcellation involved the GMV of the default network and the degree of the control, limbic, and default networks. The AUCs for the training, validation, and test cohorts were 0.947, 0.939, and 0.883, respectively. Additionally, the prediction performance of the models constructed by the different feature selection methods and classifiers showed no significant differences. Conclusion: Our study highlighted the potential of individual-specific network parcellation in treatment resistant schizophrenia prediction and underscored the crucial role of feature attributes in predictive model accuracy. [ABSTRACT FROM AUTHOR]

Electroconvulsive therapy (ECT) is one of the most efficacious interventions for treatment-resistant depression. Despite its efficacy, ECTs neural mechanism of action remains unknown. Although ECT has been associated with slowing in the electroencephalogram (EEG), how this change relates to clinical improvement is unresolved. Until now, increases in slow-frequency power have been assumed to indicate increases in slow oscillations, without considering the contribution of aperiodic activity, a process with a different physiological mechanism. In this exploratory study of nine MDD patients, we show that aperiodic activity, indexed by the aperiodic exponent, increases with ECT treatment. This increase better explains EEG slowing when compared to power in oscillatory peaks in the delta (1-3 Hz) range and is correlated to clinical improvement. In accordance with computational models of excitation-inhibition balance, these increases in aperiodic exponent are linked to increasing levels of inhibitory activity, suggesting that ECT might ameliorate depressive symptoms by restoring healthy levels of inhibition in frontal cortices.

Major depressive disorder (MDD) is a leading cause of disability worldwide. One of the most efficacious treatments for treatment-resistant MDD is electroconvulsive therapy (ECT). Recently, magnetic seizure therapy (MST) was developed as an alternative to ECT due to its more favorable side effect profile. While these approaches have been very successful clinically, the neural mechanisms underlying their therapeutic effects are unknown. For example, clinical slowing of the electroencephalogram beginning in the postictal state and extending days to weeks post-treatment has been observed in both treatment modalities. However, a recent longitudinal study of a small cohort of ECT patients revealed that, rather than delta oscillations, clinical slowing was better explained by increases in aperiodic activity, an emerging EEG signal linked to neural inhibition. Here we investigate the role of aperiodic activity in a cohort of patients who received ECT and a cohort of patients who received MST treatment. We find that aperiodic neural activity increases significantly in patients receiving either ECT or MST. Although not directly related to clinical efficacy in this dataset, increased aperiodic activity is linked to greater amounts of neural inhibition, which is suggestive of a potential shared neural mechanism of action across ECT and MST.

Rumination is a maladaptive style of regulating thoughts and emotions. It is a common symptom of Major Depressive Disorder (MDD), and more severe rumination is associated with poorer medication and psychotherapy treatment outcomes, particularly among women. It is unclear to what extent rumination may influence the outcomes of, or be responsive to, repetitive Transcranial Magnetic Stimulation (rTMS) treatment of MDD. We retrospectively examined data collected during rTMS treatment of 155 patients (age 42.52 ± 14.22, 79 female) with moderately severe treatment-resistant MDD. The severity of rumination and depression was assessed before and during a course of 30 sessions of measurement-based rTMS treatment using the Ruminative Responses Scale (RSS) and the Patient Health Questionnaire (PHQ-9), respectively. Relationships among baseline levels of rumination, depression, and treatment outcome were assessed using a series of repeated measures linear mixed effects models. Both depression and rumination symptoms significantly improved after treatment, but improvement in depression was not a significant mediator of rumination improvement. Higher baseline rumination (but not depression severity) was associated with poorer depression outcomes independently of depression severity. Female gender was a significant predictor of worse outcomes for all RRS subscales. Both depressive and ruminative symptoms in MDD improved following rTMS treatment. These improvements were correlated, but improvement in rumination was not fully explained by reduction in depressive symptoms. These findings suggest that while improvement in rumination and depression severity during rTMS treatment are correlated, they are partly independent processes. Future studies should examine whether rumination symptoms should be specifically targeted with different rTMS treatment parameters.

Limited evidence-base on long-term prognosis of treatment-resistant major depression (TRD) is a barrier to clinical decision-making. Therefore, the purpose of this study was to establish cause-specific mortality in TRD compared to non-TRD major depression. We identified all individuals with a diagnosis of major depression (MDD) who were treated with an antidepressant aged 15 to 65 years during 2004–2016 in Finland. Persons with over two treatment trials were defined to have TRD. Data were analysed with Cox proportional hazard models. 176,942 individuals with MDD (63 % women, median age at index diagnosis 40 years), of whom 11 % (n = 19,305) fulfilled the TRD criteria, were followed-up for 1,525,646 person-years (median 8.9 years). There were 959 deaths (6.1 deaths/1000 person-years) in TRD and 7662 deaths (5.6/1000 person-years) in non-TRD. All-cause mortality was 17 % higher (adjusted hazard ratio (aHR), 1.17; 95 % confidence interval (CI), 1.09–1.25) in TRD compared to non-TRD, when sex and age at index antidepressant prescription were controlled for. In TRD, increased mortality was observed for suicides (aHR, 1.90; 95%CI, 1.64–2.20) and for accidental poisonings (aHR, 1.81; 95%CI, 1.48–2.22), but not for natural causes (aHR, 0.98; 95%CI, 0.90–1.07). A higher proportion of accidental drug overdoses was observed in TRD than in non-TRD (62 % vs 42 %, respectively). Definition of TRD lacks consensus. We used routine data to define TRD. The markedly increased mortality due to suicides and accidental overdoses suggests that persons with TRD may experience higher intensity symptoms and more severe suicidal ideation than persons with non-TRD major depression. • Mortality due to suicides was 1.9 times higher in TRD than in non-TRD. • Mortality due to accidental poisonings was 1.8 times higher in TRD than in non-TRD. • Mortality due to natural causes did not differ between TRD and non-TRD in the total population aged 15 to 65 years. • Those aged 15 to 40 years may have increased mortality due to natural causes. [ABSTRACT FROM AUTHOR]

There is an increasing demand for effective treatments for depression, particularly for individuals grappling with treatment-resistant depression. Over recent years, a surge of interest has focused on exploring the safety and efficacy of psilocybin as a potential treatment for depression. However, preliminary findings from phase 2 studies have been inconclusive, prompting critical examination of issues such as maintaining blinding and the role of adjunctive psychotherapy. The maintenance of double-blinding and the role of adjunctive psychotherapy introduce biases that complicate the attainment of conclusive results in clinical research. Examining historical data reveals a recurrent pattern linked to the use of psychoactive substances, which starts with an excess of optimism and ends with general addictive behaviors and a heightened risk of serious public health problems. Considering these findings, a cautious and measured approach is imperative, given that the efficacy and safety of psilocybin treatment have yet to be unequivocally established. The potential for excessive optimism among researchers is a notable concern, as unwarranted enthusiasm may inadvertently facilitate the widespread adoption of this treatment without sufficient empirical support. In navigating the complexities of depression treatment, it is necessary to strike a balance between innovation and prudence to ensure evidence-based advancement of therapeutic approaches. [ABSTRACT FROM AUTHOR]

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Introduction: Schizophrenia (SCZ) and autism spectrum disorder (ASD) are neurodevelopmental diseases characterized by different psychopathological manifestations and divergent clinical trajectories. Various alterations at glutamatergic synapses have been reported in both disorders, including abnormal NMDA and metabotropic receptor signaling. Methods: We conducted a bicentric study to assess the blood serum levels of NMDA receptors-related glutamatergic amino acids and their precursors, including L-glutamate, L-glutamine, D-aspartate, L-aspartate, L-asparagine, Dserine, L-serine and glycine, in ASD, SCZ patients and their respective control subjects. Specifically, the SCZ patients were subdivided into treatment-resistant and non-treatment-resistant SCZ patients, based on their responsivity to conventional antipsychotics. Results: D-serine and D-aspartate serum reductions were found in SCZ patients compared to controls. Conversely, no significant differences between cases and controls were found in amino acid concentrations in the two ASD cohorts analyzed. Discussion: This result further encourages future research to evaluate the predictive role of selected D-amino acids as peripheral markers for SCZ pathophysiology and diagnosis. [ABSTRACT FROM AUTHOR]

Background Case Presentation Conclusion In patients with schizophrenia, violent behavior is a clinically important factor that prevents their discharge. Clozapine is an effective antipsychotic medication for treatment‐resistant schizophrenia, and its usefulness for aggressive behavior has also been suggested.We present the case of a 38‐year‐old male patient diagnosed with schizophrenia who was successfully treated with clozapine after recurrent violent behavior. He was diagnosed with schizophrenia during his adolescence. He was hospitalized for treatment in his teens, but his hallucinations and delusions persisted even after discharge. In his 30s, he became noticeably emotionally unstable, and despite being treated for an adequate period with sufficient doses of several antipsychotics, his symptoms did not improve. This led to repeated hospitalizations triggered by violent behavior toward his parents and siblings within the home. During his fourth hospitalization, clozapine was initiated due to multiple incidents of violence toward nursing staff secondary to hallucinations and delusions. As the dose of clozapine was gradually increased with therapeutic drug monitoring, the patient's hostility, uncooperativeness, and suspiciousness markedly improved, and his aggressive behavior disappeared. He was discharged to a facility on day 194 after starting clozapine and has continued outpatient visits.Clozapine was suggested to be effective for aggressive behavior in patients with treatment‐resistant schizophrenia and should be actively considered. In such cases, regular measurement of blood concentration is useful for adjusting the dosage of clozapine. [ABSTRACT FROM AUTHOR]

To investigate whether the association between depression and inflammatory joint disease (IJD; rheumatoid arthritis [RA], psoriatic arthritis [PsA], ankylosing spondylitis/spondyloarthropathies [AS], and juvenile idiopathic arthritis [JIA]) is affected by the severity or treatment-resistance of depression. Parallel cohort studies and case-control studies among 600,404 patients with a depressive episode identified in Swedish nationwide administrative registers. Prospective and retrospective risk for IJD in patients with depression was compared to matched population comparators, and the same associations were investigated in severe or treatment-resistant depression. Analyses were adjusted for comorbidities and sociodemographic covariates. Patients with depression had an increased risk for later IJD compared to population comparators (adjusted hazard ratio (aHR) for any IJD 1.34 [95% CI 1.30–1.39]; for RA 1.27 [1.15–1.41]; PsA 1.45 [1.29–1.63]; AS 1.32 [1.15–1.52]). In case-control studies, patients with depression more frequently had a history of IJD compared to population controls (adjusted odds ratio (aOR) for any IJD 1.43 [1.37–1.50]; RA 1.39 [1.29–1.49]; PsA 1.59 [1.46–1.73]; AS 1.49 [1.36–1.64]; JIA 1.52 [1.35–1.71]). These associations were not significantly different for severe depression or TRD. IJD and depression are bidirectionally associated, but this association does not seem to be influenced by the severity or treatment resistance of depression. [ABSTRACT FROM AUTHOR]

We propose applying the "source control" model of infectious disease treatment to the management of treatment-resistant substance use disorder (SUD). We believe that this conceptual framework complements other models for understanding SUD, fills a gap in our current understanding of treatment-resistant SUD, and advances the destigmatization of SUD by reinforcing SUD as a disease similar to other medical conditions. The model also harmonizes the need for multimodal treatment and novel interventions for both acute supportive care and long-term treatment of SUD. In this manuscript, we discuss the justification for, as well as the strengths and limitations of, the "source control" model for the management of treatment-resistant SUD. We also discuss the model's potential to direct innovative research questions and therapeutic interventions. [ABSTRACT FROM AUTHOR]

Not all patients respond to effective and approved treatment interventions, and there has been growing recognition in the medical field of these "resistant" or refractory illnesses (eg, treatment-resistant depression, resistant hypertension). In the field of substance use disorders, there has not been an explicit acknowledgement of treatmentrefractory addiction (TRA) despite substantial evidence that many patients do not respond to standard-of-care treatment interventions. This article provides a justification for TRA as a critically important condition to recognize and define. TRA is not conceptualized as a diagnosis, but as a signal that a current treatment approach has not worked. The article addresses areas in need of research and consensus in order to ensure the approach to TRA is uniform, thoughtfully addressed, and datadriven. By explicitly acknowledging TRA, clinicians, researchers, and patients and their families can begin to explore the unique features of this population and find ways in which substance use disorders for persons with TRA can be more effectively addressed, which in turn will help to expand remission for persons who suffer from these devastating conditions. [ABSTRACT FROM AUTHOR]

Treatment-resistant depression, defined as a failure of at least two oral antidepressants of adequate dose and duration in the current episode, is a debilitating condition with low rates of response and remission. Intranasal esketamine is the first medication approved by regulatory authorities for difficult to treat depressive episodes that builds directly on the discovery of the rapid antidepressant effects of intravenously administered racemic ketamine. Approved in the United States in 2019, and subsequently, in many countries worldwide, intranasal esketamine is indicated in conjunction with any new or previously taken oral antidepressant medication of the clinician’s choosing for treatment-resistant depression in adults. It is also indicated for the treatment of major depressive disorder in adults with acute suicidal ideation or behavior who may or may not be treatment-naive or have treatment-resistant depression. This article outlines the case for the efficacy, safety profile, and feasibility of acute, short-term intranasal esketamine followed by the long-term continuation of intranasal esketamine versus long-term off-label intravenous ketamine in treatment-resistant depression. The article further suggests biomarkers to predict response that warrant further study.

Background: Up to 34% of patients with schizophrenia are resistant to several treatment trials. Lack of continuous and adequate treatment is associated with relapse, rehospitalization, a lower effect of antipsychotic therapy, and higher risk of side effects. Long-acting injectables antipsychotics (LAI APs) enhance compliance and improve clinical outcomes and quality of life in patients with schizophrenia, and thus it may be advisable to administer two LAI APs at the same time in cases of treatment-resistant schizophrenia. The purpose of this review is to summarize the available literature regarding the combined use of two LAI APs in patients with schizophrenia or other psychotic spectrum disorders. Methods: An extensive literature search for relevant articles regarding any combination of two long-acting injectable antipsychotics has been performed from inception up to 9 February 2024, on PubMed, Scopus and APA PsycInfo, according to the PRISMA statement. Only studies reporting combination of two LAI APs and its clinical outcome in patients with schizophrenia and related disorders were selected. Results: After the selection process, nine case reports, four case series and two observational retrospective studies were included in the final analysis. All patients treated with dual LAI APs reported a good response, and no new or unexpected adverse effects due to the combination of two LAIs were reported. Different drug combinations were used, and the most frequent association resulted in aripiprazole monohydrate + paliperidone palmitate once monthly (32 times). Conclusions: Our review highlights that the treatment regimen with two concurrent LAI APs is already widely used in clinical practice and is recognized as providing a promising, effective, and relatively safe therapeutic strategy for treating the schizophrenia spectrum disorders. [ABSTRACT FROM AUTHOR]

Introduction: Individuals with depression who do not respond to two or more courses of serotonergic antidepressants tend to have greater deficits in reward processing and greater internalizing symptoms, yet there is no validated self-report method to determine the likelihood of treatment resistance based on these symptom dimensions. Methods: This online case-control study leverages machine learning techniques to identify differences in self-reported anhedonia and internalizing symptom profiles of antidepressant non-responders compared to responders and healthy controls, as an initial proof-of-concept for relating these indicators to medication responsiveness. Random forest classifiers were used to identify a subset from a set of 24 reward predictors that distinguished among serotonergic medication resistant, non-resistant, and non-depressed individuals recruited online (N = 393). Feature selection was implemented to refine model prediction and improve interpretability. Results: Accuracies for full predictor models ranged from .54 to .71, while feature selected models retained 3-5 predictors and generated accuracies of .42 to .70. Several models performed significantly above chance. Sensitivity for non- responders was greatest after feature selection when compared to only responders, reaching .82 with 3 predictors. The predictors retained from feature selection were then explored using factor analysis at the item level and cluster analysis of the full data to determine empirically driven data structures. Discussion: Non-responders displayed 3 distinct symptom profiles along internalizing dimensions of anxiety, anhedonia, motivation, and cognitive function. Results should be replicated in a prospective cohort sample for predictive validity; however, this study demonstrates validity for using a limited anhedonia and internalizing self-report instrument for distinguishing between antidepressant resistant and responsive depression profiles. [ABSTRACT FROM AUTHOR]

Approximately 30%-50% of people with schizophrenia worldwide have treatment-resistant schizophrenia (TRS). Currently available standard psychopharmacological and psychological treatments have proven insufficient to achieve full recovery in these patients. Alternative psychological interventions focused on improving emotion regulation, such as the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP), could potentially improve treatment outcomes in this difficult to treat population. The aim of the present case study is to demonstrate how the UP can be adapted for the treatment of TRS. We decided to use UP to treat this particular patient due to the presence of intense unpleasant emotions, aversive reactions, and emotional avoidance strategies. After completing the full treatment protocol, the patient showed significant decreases in scores on the Difficulties in Emotion Regulation Scale (DERS), including total and emotional rejection, life interference, and emotional lack of control. A significant reduction was also observed in anxiety (OASIS) and depressive symptoms (ODSIS). The intervention had a positive impact on auditory hallucinations, with decreased severity, less intense anxiety, and less interference in life. The treatment led to greater control over voices and the patient reported feeling more confident in her relationship with those voices. These results provide preliminary support for the use of UP for the treatment of TRS. [ABSTRACT FROM AUTHOR]

Introduction and purpose: Major depressive disorder (MDD) is the most common psychiatric illness, affecting millions of people worldwide. The first line of pharmacological treatment is usually monoamine reuptake inhibitors. Up to 60% of cases, may be drug-resistant patients, prompting researchers to research substances other than conventional. 1 The purpose of this article was to review recent studies on the use of ketamine in the treatment of drug-resistant depression and present their findings. Brief description of the state of knowledge: Ketamine has been a well-known drug used in anesthesiology and pain management for decades. Because of its multidirectional effects, researchers have become interested in its effects on psychiatric illnesses. Over the past decade or so, there has been a definite increase in research and articles on the use of ketamine in psychiatry. The study has resulted in FDA approval of esketamine for the treatment of treatment-resistant depression in adults in 2019. Material and method: This article is the result of searching keywords on databases such as Google Scholar and Pubmed and collecting scientific literature about depression and ketamine. Articles were preselected by title, number of citations, source, and publication date. Summary: Ketamine has the potential to be a treatment for drug-resistant depression. Its effectiveness varies with the form and dosage, with racemic and higher doses offering greater therapeutic benefits. Ketamine's efficacy is on par with the electroconvulsive therapy. Its onset is faster than traditional antidepressants, significantly reducing suicide risk in a shorter time frame. While the precise mechanisms of its antidepressant effects are not fully understood, it is suggested that its impact on brain neuroplasticity may contribute to the rapid onset of action. Growing evidence supports ketamine's effectiveness in treating TRD, highlighting the need for further research in this area.

IntroductionSchizophrenia (SCZ) and autism spectrum disorder (ASD) are neurodevelopmental diseases characterized by different psychopathological manifestations and divergent clinical trajectories. Various alterations at glutamatergic synapses have been reported in both disorders, including abnormal NMDA and metabotropic receptor signaling.MethodsWe conducted a bicentric study to assess the blood serum levels of NMDA receptors-related glutamatergic amino acids and their precursors, including L-glutamate, L-glutamine, D-aspartate, L-aspartate, L-asparagine, D-serine, L-serine and glycine, in ASD, SCZ patients and their respective control subjects. Specifically, the SCZ patients were subdivided into treatment-resistant and non-treatment-resistant SCZ patients, based on their responsivity to conventional antipsychotics.ResultsD-serine and D-aspartate serum reductions were found in SCZ patients compared to controls. Conversely, no significant differences between cases and controls were found in amino acid concentrations in the two ASD cohorts analyzed.DiscussionThis result further encourages future research to evaluate the predictive role of selected D-amino acids as peripheral markers for SCZ pathophysiology and diagnosis.

The success of deep brain stimulation (DBS) for treating Parkinsons disease has led to its application to several other disorders, including treatment-resistant depression. Results with DBS for treatment-resistant depression have been heterogeneous, with inconsistencies largely driven by incomplete understanding of the brain networks regulating mood, especially on an individual basis. We report results from the first subject treated with DBS for treatment-resistant depression using an approach that incorporates intracranial recordings to personalize understanding of network behavior and its response to stimulation. These recordings enabled calculation of individually optimized DBS stimulation parameters using a novel inverse solution approach. In the ensuing double-blind, randomized phase incorporating these bespoke parameter sets, DBS led to remission of symptoms and dramatic improvement in quality of life. Results from this initial case demonstrate the feasibility of this personalized platform, which may be used to improve surgical neuromodulation for a vast array of neurologic and psychiatric disorders.

• Initial CBD dose was 2 mg/kg/day, which was uptitrated to a median dose of 25 mg/kg/day (range, 2–50). • After a follow-up (6–26 months), 7/28 patients were seizure free and 12/28 had a >50 % seizure decrease. • IESS associated with Down syndrome and cerebral palsy responded especially well. • Adverse effects of CBD were observed in 15 patients (53.5 %) and were mild. The aim of this study was to assess efficacy, safety, and tolerability of highly purified cannabidiol oil (CBD) as add-on therapy for the treatment of a series of patients with infantile epileptic spasms syndrome (IESS) who were resistant to antiseizure medications and ketogenic dietary therapy. We conducted a retrospective analysis of the medical records of 28 infants with treatment-resistant IESS aged 6 to 21 months who received highly purified CBD between July 2021 and June 2023. Data were collected on neurological examinations, EEG, Video-EEG and polygraphic recordings, imaging studies, laboratory testing, and seizure frequency, type, and duration, and adverse effects. As the primary outcome, a reduction of frequency of epileptic spasms (ES) was assessed. ES freedom was considered after a minimal time of 1 month without ES. Sixteen male and 12 female patients, aged 6–21 months, who received CBD for treatment-resistant IESS were included. The etiology was structural in 10, Down syndrome in seven, genetic in nine, and unknown in two. Initial CBD dose was 2 mg/kg/day, which was uptitrated to a median dose of 25 mg/kg/day (range, 2–50). Prior to CBD initiation, patients had a median of 69 ES in clusters per day (range, 41–75) and of 10 focal seizures per week (range, 7–13). After a mean and median follow-up of 15 and 12.5 months (range, 6–26 months), seven patients were ES free and 12 had a >50 % ES reduction. Five of seven patients (71 %) with Down syndrome and 3/5 (60 %) with cerebral palsy responded well. Adverse effects were mild. EEG improvements correlated with ES reductions. In this study evaluating the use of CBD in children with IESS, 19/28 (67.8 %) had a more than 50 % ES reduction with good tolerability. [ABSTRACT FROM AUTHOR]

Introduction Predictors of treatment response to intravenous ketamine remain unclear in patients with treatment-resistant depression (TRD); therefore, this study aimed to clarify these predictors using the US National Institutes of Health database of clinical trials. Methods Data from a placebo-controlled, double-blind, randomized controlled trial were used to assess the efficacy of intravenous ketamine in adult patients with TRD (NCT01920555). For the analysis, data were used from the participants who had received therapeutic doses of intravenous ketamine (i. e., 0.5 and 1.0 mg/kg). Logistic and multivariable regression analyses were conducted to explore the demographic and clinical factors associated with response to treatment or changes in the Hamilton Depression Rating Scale 6 items (HAM-D-6) total score. Results This study included 31 patients with TRD (13 women; mean±standard deviation age, 48.4±10.9 years). Logistic regression analysis showed that the age of onset was positively correlated with treatment response after three days of ketamine administration (β=0.08, p=0.037); however, no association was observed between treatment response and age, sex, baseline HAM-D-6 total score, or dissociative score assessed with the Clinician-Administered Dissociative States Scale 40 min after ketamine infusion. Multiple regression analysis showed that no factors were correlated significantly with the percentage change in the HAM-D-6 total score three days after ketamine administration. Discussion Later disease onset correlates with a better treatment response three days after ketamine infusion in patients with TRD. Glutamatergic signal transmission may be impaired in patients with an earlier onset of depression, resulting in decreased neuroplasticity, which diminishes ketamine response. [ABSTRACT FROM AUTHOR]

Objective: Treatment Resistant Depression (TRD) is commonly defined as the lack of response to two or more antidepressants with different mechanisms of action. Up to 30% of patients diagnosed with major depressive disorder might be considered to present TRD. The objective of this study was to assess the effectiveness and tolerability of esketamine in patients diagnosed with TRD, who were referred to our program after exhausting all available treatments. A secondary objective consisted in researching the relationship between response and previous use of electroconvulsive therapy. Methods: A prospective, observational study was carried out in patients enrolled in the expanded use of esketamine in our center. They received esketamine prior to its marketing authorisation, for therapeutic purposes. Sixteen subjects were analyzed. Effectiveness was assessed with the Montgomery-Asberg depression rating scale (MADRS). Patients were followed up to 4 months after the administration. Results: Esketamine showed a rapid, robust effect in improving depressive symptoms, with no specific correlation between outcome and any demographic or clinical traits evaluated. No differences were found between patients that previously received Electroconvulsive Therapy, and those that didn’t. 10 out of 16 patients responded (＞ 50% change in baseline MADRS scores), but only five achieved remission (＜ 12 points in the global MADRS score). We provide some recommendations, based on clinical experience, to improve tolerability and adherence, and to manage adverse effects. Conclusion: Results suggest that esketamine is a safe, effective and rapid-acting option for TRD. More studies are needed to properly assess predictors of response outcome. [ABSTRACT FROM AUTHOR]

In an article (Asaria in J Eat Disord 11:107, 2023) recently published by the Journal of Eating Disorders, I expressed my lived experience views on the concept of 'terminal anorexia nervosa' (AN), and why I believe that this is a harmful new term. The article was not a response to the original paper in which Gaudiani et al. (J Eat Disord 10:23, 2022) proposed criteria for the label. However, as a result of feedback that my article did not appreciate their criteria, I have written this follow-up paper to build on and reinforce what I previously wrote. This article outlines problems with each criterion in turn, again from my lived experience perspective. It then addresses dangerous ambiguities around how the criteria can be applied safely, and their confusing purpose in the real world. Finally, I discuss the impact of labelling AN sufferers with terms that may suggest their wholehearted allegiance to the illness, in both life and death (or 'till death do us part'). [ABSTRACT FROM AUTHOR]

Intranasal esketamine for treatment-resistant depression has been introduced and approved by the FDA and EMA in 2019 and 2020, respectively. Since then, the administration practices were found different among countries. Major depression has a high impact on many humans lives worldwide and more than a third of treated people are not responding after several treatment attempts. Additional administration with esketamine closed this gap for more than the half of these non-responders. Guidelines for the treatment of major depression recommend starting with add-on esketamine after 2-4 serious attempts of treatment with standard antidepressants (SSRI/SNRI) irrespective of augmentation with others, e.g., second generation antipsychotics or lithium. Thus, intranasal esketamine became an important role in the evidence-based treatment of major depression. The authors review and critically evaluated published articles focusing on preparation, management and observation of intranasal esketamine treatment. There exists a clear recommendation for administrating intranasal esketamine in a medical environment, not limited to a clinical setting for selecting the dose, monitoring the improvements and managing adverse events. The administration of intranasal esketamine is considered as safe during the application itself and long-lasting or severe adverse events during long-term treatment are very rare. Since this is a new approach for treatment application psychiatrists face new different but not difficult treatment procedures compared to prescribing only a medication. [ABSTRACT FROM AUTHOR]

Introduction: Chronic pain is defined as pain lasting longer than 3 months. This often causes persistent emotional distress and functional disability that is refractory to conventional treatments. Emerging evidence suggests that oral Ketamine therapy may have a specific role in managing treatment-resistant chronic pain. This study aimed to assess the effectiveness of oral ketaminewithin a tertiary chronic painmanagement clinic. Methods: This study was a clinic-based retrospective descriptive study of 79 patients with a broad range of chronic pain diagnoses and treated with oral ketamine over a period up to 12 years. Changes in pain, mood and quality of life (QoL) were assessed using a numerical pain severity score, the Brief Pain Inventory (BPI), the Public Health Questionnaire (PHQ-9) and American Chronic Pain Association Quality of Life (QoL) scale. Results: 73 patients were accessible for follow-up (mean daily dose and treatment duration were 193.84 mg and 22.6 months respectively). Pain scores decreased (p < 0.0001) on both numerical scores (41.6% decrease) and BPI scoring (mean decrease 2.61). Mood improved (p < 0.0001) across both PHQ-9 and BPI measurements. Patients also reported less difficulty with daily activities and improved QoL. The most common adverse reaction was drowsiness (21.9%), with 30.1% reporting no adverse reactions from Ketamine. Discussion: This work adds to the growing body of evidence that under the supervision of a pain specialist, oral ketamine therapy may be a safe, tolerable and effective treatment for chronic pain conditions which have not responded to other management options. Further research is required to produce a more accurate understanding of its chronic use. Key message: This real-world study shows that patients being treated with oral ketamine for chronic pain report decreased severity of pain, improved mood and increased quality of life across all conditions. [ABSTRACT FROM AUTHOR]

response to standard first-line treatments. We report a case of treatment-refractory OCD that was successfully treated with the pharmacological strategy of using selective serotonin reuptake inhibitors (SSRIs) in the above-licensed doses. Patient, a 26-year-old male, had failed to respond to multiple trials of SSRIs inside the licensed dose range and augmentation with antipsychotic medication when he was started on high-dose escitalopram(40mg/day). His clinical condition improved greatly after 12 weeks on this regimen, as demonstrated by a significant decrease in the Yale-Brown Obsessive Compulsive Scale (from 33 to 12). This case provides additional support to a small body of evidence that suggests the utility of using higher doses of selective serotonin reuptake inhibitors (SSRIs) in treatment-resistant obsessive-compulsive disorder (OCD).

OBJECTIVE: To investigate the effect of 10 Hz repetitive transcranial magnetic stimulation (rTMS) and intermittent theta-burst stimulation (iTBS) on suicidality in patients with treatment-resistant depression (TRD). METHODS: We used data from a three-site randomized clinical trial comparing 10 Hz rTMS and iTBS applied to the left dorsolateral prefrontal cortex (DLPFC) in patients with TRD. We compared the effect of 10Hz rTMS and iTBS on suicidality as measured by the suicide item of the Hamilton Depression Rating Scale 17-item (HDRS-17). RESULTS: Suicidality remitted in 71 (43.7%) participants randomized to 10Hz stimulation and 91 (49.1%) participants randomized to iTBS, without a significant difference between the proportions in the two groups (Χ2  = 0.674, df = 1, p = 0.4117). There was a significant correlation between change in suicidality and change in depression severity for both modalities (10 Hz, Pearsons r = 0.564; iTBS, Pearsons r = 0.502), with a significantly larger decrease in depression severity for those in whom suicidality remitted compared to those in whom it did not (t = 10.912, df = 276.8, p

BackgroundThe efficacy of psychiatric DBS is thought to be driven by the connectivity of stimulation targets with mood-relevant fronto-temporal networks, which is typically evaluated using diffusion-weighted tractography.ObjectiveLeverage intracranial electrophysiology recordings to better predict the circuit-wide effects of neuromodulation to white matter targets. We hypothesize strong convergence between tractography-predicted structural connectivity and stimulation-induced electrophysiological responses.MethodsEvoked potentials were elicited by single-pulse stimulation to two common DBS targets for treatment-resistant depression - the subcallosal cingulate (SCC) and ventral capsule/ventral striatum (VCVS) - in two patients undergoing DBS with stereo-electroencephalographic (sEEG) monitoring. Evoked potentials were compared with predicted structural connectivity between DBS leads and sEEG contacts using probabilistic, patient-specific diffusion-weighted tractography.ResultsEvoked potentials and tractography showed strong convergence in both patients in orbitofrontal, ventromedial prefrontal, and lateral prefrontal cortices for both SCC and VCVS stimulation targets. Low convergence was found in anterior cingulate (ACC), where tractography predicted structural connectivity from SCC targets but produced no evoked potentials during SCC stimulation. Further, tractography predicted no connectivity to ACC from VCVS targets, but VCVS stimulation produced robust evoked potentials.ConclusionThe two connectivity methods showed significant convergence, but important differences emerged with respect to the ability of tractography to predict electrophysiological connectivity between SCC and VCVS to regions of the mood-related network. This multimodal approach raises intriguing implications for the use of tractography in surgical targeting and provides new data to enhance our understanding of the network-wide effects of neuromodulation.

Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD.

Objectives: To determine the prevalence and correlates of treatment-resistant schizophrenia (TRS) through a systematic review and meta-analysis. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, an electronic search was performed in PubMed and Embase through May 17, 2022. All study designs that assessed a minimum of 20 schizophrenia-spectrum patients and provided data on TRS prevalence or allowed its calculation were included. Estimates were produced using a random-effects model meta-analysis. Results: The TRS prevalence across 50 studies (n = 29,390) was 36.7% (95%CI 33.1-40.5, p < 0.0001). The prevalence ranged from 22% (95%CI 18.4-25.8) in first-episode to 39.5% (95%CI 32.2-47.0) in multiple-episode samples (Q = 18.27, p < 0.0001). Primary treatment resistance, defined as no response from the first episode, was 23.6% (95%CI 20.5-26.8) vs. 9.3% (95%CI 6.8-12.2) for later-onset/secondary (≥ 6 months after initial treatment response). Longer illness duration and recruitment from long-term hospitals or clozapine clinics were associated with higher prevalence estimates. In meta-regression analyses, older age and poor functioning predicted greater TRS. When including only studies with lower bias risk, the TRS prevalence was 28.4%. Conclusion: Different study designs and recruitment strategies accounted for most of the observed heterogeneity in TRS prevalence rates. The results point to early-onset and later-onset TRS as two separate disease pathways requiring clinical attention. Registration number: PROSPERO CRD42018092033.

BackgroundThe efficacy of repetitive transcranial magnetic stimulation (rTMS) for depression may vary depending on the subregion stimulated within the dorsolateral prefrontal cortex (DLPFC). Clinical TMS typically uses scalp-based landmarks for DLPFC targeting, rather than individualized MRI guidance.ObjectiveIn rTMS patients, determine the brain systems targeted by multiple DLPFC stimulation rules by computing several surrogate measures: underlying brain targets labeled with connectivity-based atlases, subgenual cingulate anticorrelation strength, and functionally connected networks.MethodsForty-nine patients in a randomized controlled trial of rTMS therapy for treatment resistant major depression underwent structural and functional MRI. DLPFC rules were applied virtually using MR-image guidance. Underlying cortical regions were labeled, and connectivity with the subgenual cingulate and whole-brain computed.ResultsScalp-targeting rules applied post hoc to these MRIs that adjusted for head size, including Beam F3, were comparably precise, successful in directly targeting classical DLPFC and frontal networks, and anticorrelated with the subgenual cingulate. In contrast, all rules involving fixed distances introduced variability in regions and networks targeted. The 5 cm rule targeted a transitional DLPFC region with a different connectivity profile from the adjusted rules. Seed-based connectivity analyses identified multiple regions, such as posterior cingulate and inferior parietal lobe, that warrant further study in order to understand their potential contribution to clinical response.ConclusionEEG-based rules consistently targeted DLPFC brain regions with resting-state fMRI features known to be associated with depression response. These results provide a bridge from lab to clinic by enabling clinicians to relate scalp-targeting rules to functionally connected brain systems.

BackgroundElectroconvulsive therapy (ECT) is the most effective treatment for treatment-resistant depression (TRD), especially for acute suicidal ideation, but the associated cognitive adverse effects and negative stigma limit its use. Another seizure therapy under development is magnetic seizure therapy (MST), which could potentially overcome the restrictions associated with ECT with similar efficacy. The neurophysiological targets and mechanisms of seizure therapy, however, remain poorly understood.Methods/designThis neurophysiological study protocol is published as a companion to the overall Confirmatory Efficacy and Safety Trial of Magnetic Seizure Therapy for Depression (CREST-MST) protocol that describes our two-site, double-blind, randomized, non-inferiority clinical trial to develop MST as an effective and safe treatment for TRD. Our aim for the neurophysiological component of the study is to evaluate two biomarkers, one to predict remission of suicidal ideation (primary outcome) and the other to predict cognitive impairment (secondary outcome). Suicidal ideation will be assessed through cortical inhibition, which according to our preliminary studies, correlates with remission of suicidal ideation. Cortical inhibition will be measured with simultaneous transcranial magnetic stimulation (TMS) and electroencephalography (EEG), TMS-EEG, which measures TMS-evoked EEG activity. Cognitive adverse effects associated with seizure therapy, on the contrary, will be evaluated via multiscale entropy analysis reflecting the complexity of ongoing resting-state EEG activity.DiscussionECT and MST are known to influence cortical inhibition associated with depression, suicidal ideation severity, and clinical outcome. Therefore, evaluating cortical inhibition and brain temporal dynamics will help understand the pathophysiology of depression and suicidal ideation and define new biological targets that could aid clinicians in diagnosing and selecting treatments. Resting-state EEG complexity was previously associated with the degree of cognitive side effects after a seizure therapy. This neurophysiological metric may help clinicians assess the risk for adverse effects caused by these useful and effective treatments.Trial registrationClinicalTrials.gov NCT03191058 . Registered on June 19, 2017.

Ryan B Rush1– 3 1Panhandle Eye Group, Amarillo, TX, USA; 2Southwest Retina Specialists, Amarillo, TX, USA; 3Department of Surgery, Texas Tech University Health Science Center, Amarillo, TX, USACorrespondence: Ryan B Rush, Southwest Retina Specialists, 7411 Wallace Blvd, Amarillo, TX, 79106, USA, Tel +1 806 351-1870, Email ryan.rush.md@gmail.comPurpose: To assess the 12 month outcomes of intravitreal faricimab (IVF) in treatment-resistant diabetic macular edema (DME) recalcitrant to intravitreal aflibercept (IVA).Methods: This study was undertaken as a retrospective interventional case series of DME subjects receiving care at a single private practice facility. Subjects at baseline had undergone ≥ 8 IVA injections over the previous 12 months, ≥ 4 IVA injections over the previous 6 months, had an optical coherence tomography (OCT)-measured central macular thickness (CMT) of ≥ 320 microns, and had observable edema on OCT. The baseline visit for this study’s purpose was considered the examination in which the subject was changed from IVA to IVF. Subjects were managed with a treat-and-extend (TAE) protocol and followed over 12 months from baseline.Results: A total of 51 eyes of 51 subjects were analyzed. There were 39.2% (20/51) of patients who reached a treatment interval of ≥ 8 weeks and had a fluid-free macula on OCT at 12 months. The CMT on OCT of the patient population reduced from 400.2 (385.3– 415.3) microns at baseline to 340.6 (324.3– 356.9) microns at 12 months (p< 0.01). There were 21.6% (11/51) of patients who improved ≥ 3 lines of Snellen visual acuity at 12 months. The visual acuity of the overall study population improved from 0.60 (0.54– 0.66) logMAR (Snellen 20/80) at baseline to 0.47 (0.41– 0.53) logMAR (Snellen 20/59) at 12 months (p< 0.01).Conclusion: A longer treatment interval and improved functional and anatomical outcomes at 12 months may be attained in a clinically significant minority of aflibercept-resistant DME patients after changing to IVF when a TAE protocol is employed. Specialists may consider IVF whenever resistance to IVA is experienced in this patient population.Keywords: faricimab, treatment-resistant, diabetic macular edema, recalcitrance

Ryan B Rush1– 3 1Department of Ophthalmology, Panhandle Eye Group, Amarillo, TX, USA; 2Department of Ophthalmology, Southwest Retina Specialists, Amarillo, TX, USA; 3Department of Surgery, Texas Tech University Health Science Center, Amarillo, TX, USACorrespondence: Ryan B Rush, Southwest Retina Specialists, 7411 Wallace Blvd, Amarillo, TX, 79106, USA, Tel +1 806 351-1870, Email ryan.rush.md@gmail.comPurpose: To assess the 12-month outcomes of intravitreal faricimab (IVF) in treatment-resistant neovascular age-related macular degeneration (nAMD) subjects recalcitrant to intravitreal aflibercept (IVA).Methods: This study was conducted as a retrospective interventional case series of nAMD patients receiving treatment at a single private practice institution. All included patients at baseline had undergone six or more IVA injections over the previous 12 months, four or more IVA injections over the previous 6 months, had a central macular thickness (CMT) ≥ 320 μm on optical coherence tomography (OCT), and were observed to have intraretinal and/or subretinal fluid on OCT assessment. The baseline exam for the purpose of this study was considered the visit in which the patient was switched from IVA to IVF. Patients were managed with a real-world treat-and-extend protocol and followed over a 12-month study period.Results: A total of 54 eyes of 54 subjects were analyzed. Overall, 31.5% (17/54) of subjects attained a treatment interval ≥ 8 weeks and had a fluid-free macula on OCT at 12 months. The CMT on OCT decreased from 395.4 (383.5– 407.3) μm at baseline to 350.0 (335.1– 364.8) μm at the end of the 12-month study interval (p< 0.01). There were 16.7% (9/54) of subjects who gained three or more lines of Snellen visual acuity at the end of the study. Visual acuity improved from 0.72 (0.67– 0.77) logMAR (Snellen 20/105) at baseline to 0.59 (0.55– 0.64) logMAR (Snellen 20/78) at the end of the study (p< 0.01).Conclusion: A clinically significant minority of aflibercept-resistant nAMD subjects may attain longer treatment intervals and improved outcomes at 12 months after switching to IVF when a treat-and-extend treatment protocol is utilized. IVF use may be considered whenever resistance to IVA is encountered in this patient population.Keywords: faricimab, treatment-resistant, neovascular age-related macular degeneration, recalcitrance

Abstract This report highlights a rare single-gene cause of early-onset, treatment-resistant schizophrenia, and its unique responsiveness to clozapine therapy. This case describes a pediatric female who was diagnosed with early-onset schizophrenia and catatonia in her early adolescence, and was later found to have DLG4-related synaptopathy, also known as SHINE syndrome. SHINE syndrome is a rare neurodevelopmental disorder caused by dysfunction of the postsynaptic density protein-95 (PSD-95), encoded by the DLG4 gene. After failing three antipsychotic drug treatments, the patient was started on clozapine, which resulted in significant improvements in positive and negative symptoms. This case illustrates the impact of clozapine in treatment-resistant early-onset psychosis and exemplifies practical implications for genetic testing in early-onset schizophrenia.

Antipsychotic medications are increasingly used for difficult-to-treat depression in young people. However, the evidence-base for this is unclear. Our aim was to assess the evidence for the efficacy of atypical antipsychotics in treating unipolar and bipolar depression in adolescents and young adults. We conducted a comprehensive systematic review and meta-analysis of randomized-control-trial studies (RCTs) of antipsychotic medications for 10- to 25-year-olds with unipolar and bipolar depression. The primary outcome of interest was change in depressive symptoms from baseline to trial endpoint. No studies were identified that evaluated the use of antipsychotics in the treatment of unipolar depression. However, we identified four studies, of quetiapine, lurasidone and olanzapine/fluoxetine combination, comprising a total of 866 randomized patients, that evaluated treatment of bipolar depression. All studies used the Children's Depression Rating Scale-Revised (CDRS-R). Our meta-analysis revealed the weighted mean difference (WMD) was −4.58 (95 % CI, −6.59 to −2.57) between antipsychotic and placebo-treated groups. Response and remission rates were also significantly in favor of antipsychotic treatment. There were few studies, several did not address risk-of-bias domains and there was a lack of non-industry sponsored studies. There is an absence of evidence for the use of antipsychotic medications in treatment of youth unipolar depression, and no recommendations can be made. There is some evidence for the efficacy of antipsychotics, specifically lurasidone and olanzapine/fluoxetine combination, in the treatment of young people with bipolar depression. However, this evidence is limited and more studies investigating the use of these medications in young people are needed. • Absence of trials for use of antipsychotics to treat youth unipolar depression • Limited evidence for use of atypical antipsychotics in youth bipolar depression • Quetiapine not shown to be effective • Lurasidone and Olanzapine/fluoxetine combination some evidence for efficacy • More studies required on a wider range of antipsychotics [ABSTRACT FROM AUTHOR]

Objectives: To determine the prevalence and correlates of treatment-resistant schizophrenia (TRS) through a systematic review and meta-analysis. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, an electronic search was performed in PubMed and Embase through May 17, 2022. All study designs that assessed a minimum of 20 schizophrenia-spectrum patients and provided data on TRS prevalence or allowed its calculation were included. Estimates were produced using a random-effects model meta-analysis. Results: The TRS prevalence across 50 studies (n = 29,390) was 36.7% (95%CI 33.1-40.5, p < 0.0001). The prevalence ranged from 22% (95%CI 18.4-25.8) in first-episode to 39.5% (95%CI 32.2-47.0) in multiple-episode samples (Q 18.27, p < 0.0001). Primary treatment resistance, defined as no response from the first episode, was 23.6% (95%CI 20.5-26.8) vs. 9.3% (95%CI 6.8-12.2) for later- onset/secondary (≥ 6 months after initial treatment response). Longer illness duration and recruitment from long-term hospitals or clozapine clinics were associated with higher prevalence estimates. In meta-regression analyses, older age and poor functioning predicted greater TRS. When including only studies with lower bias risk, the TRS prevalence was 28.4%. Conclusion: Different study designs and recruitment strategies accounted for most of the observed heterogeneity in TRS prevalence rates. The results point to early-onset and later-onset TRS as two separate disease pathways requiring clinical attention. [ABSTRACT FROM AUTHOR]

IntroductionIn cross-sectional studies of depressed patients, relationships between depression and levels of IL-8 are inconsistent, and have not been examined in relation to sex. Given identified sex differences in longitudinal data, it is important to evaluate sex-specific cross-sectional relationships between IL-8 and depressive symptoms, which may explain some inconsistency in the extant literature. It is further unknown whether IL-8 levels may relate to specific symptom profiles among depressed patients, with or without regard to sex.MethodsAmong 108 patients with treatment resistant depression (50 females), we evaluated cross-sectional relationships between IL-8 and depression severity, as measured by the Hamilton Depression Rating Scale [HAM-D] Score, and examined sex-specific relationships, as well as relationships with depressive symptom profiles. Other inflammatory markers (IL-6, IL-10, TNF-α, CRP) were also explored in relation to HAM-D.ResultsHigher IL-8 was associated with lower total HAM-D score (standardized β = -0.19, p = 0.049). Sex-specific effects were identified (IL-8 x sex interaction: p = 0.03), in which higher IL-8 related to lower HAM-D score in females (standardized β = -0.41, p = 0.004, effect size (sr2) = 0.17), but not males (standardized β = 0.02, p = 0.91). Among a subset of 94 patients (41 females) who had individual HAM-D items available, we evaluated relationships between IL-8 and HAM-D factor subscores. Across sexes, higher IL-8 was associated with lower anxiety/hypochondriasis subscores (standardized β = -0.31, p = 0.002; sex interaction: p = 0.99). Sex differences were identified for relationships between IL-8 and two other HAM-D factor subscores.ConclusionsIL-8 may be related to anxiety symptoms across sexes, but may have a sex-specific relationship with other depressive symptoms. Further evaluation of sex-specific relationships between IL-8, depression symptom profiles, treatment response, and potential neurobiological correlates, may inform mechanisms of depression pathophysiology and aid in development of precision medicine strategies.

The effects of common antidepressants on suicidal ideation (SI) is unclear. In the landmark STAR*D trial antidepressants were effective for Major Depressive Disorder (MDD) in early treatment phases, but less effective in later phases. The effects of antidepressants on SI across the entire sample of the STAR*D trial has never been investigated. We performed a secondary analysis of the STAR*D data with the primary outcome of change in score on the suicide item (item three) of the Hamilton Rating Scale for Depression (HRSD17) across all four study levels. We used descriptive statistics and logistic regression analyses. Pearson correlation was used for change in SI versus change in depression (HRSD16). Reduction in mean (SD) SI was greater in levels one: 0.29 (±0.78) (p

BackgroundPrecise targeting of brain functional networks is believed critical for treatment efficacy of rTMS (repetitive pulse transcranial magnetic stimulation) in treatment resistant major depression.ObjectiveTo use imaging data from a "failed" clinical trial of rTMS in Veterans to test whether treatment response was associated with rTMS coil location in active but not sham stimulation, and compare fMRI functional connectivity between those stimulation locations.MethodsAn imaging substudy of 49 Veterans (mean age, 56 years; range, 27-78 years; 39 male) from a randomized, sham-controlled, double-blinded clinical trial of rTMS treatment, grouping participants by clinical response, followed by group comparisons of treatment locations identified by individualized fiducial markers on structural MRI and resting state fMRI derived networks.ResultsThe average stimulation location for responders versus nonresponders differed in the active but not in the sham condition (P = .02). The average responder location derived from the active condition showed significant negative functional connectivity with the subgenual cingulate (P

Patients with major depressive disorder (MDD) may be refractory to or have contraindications that preclude treatment with antidepressant pharmacotherapies. Alternative therapies such as repetitive transcranial magnetic stimulation (rTMS) continue to evolve, and include theta burst stimulation (TBS), which has advantages over conventional rTMS. The aim of this study was to identify and meta-analyze efficacy data from all randomized controlled trials (RCTs) investigating TBS as a treatment for MDD. Published reports of RCTs (January 1, 2010 to October 23, 2020) were identified via systematic searches in computerized databases, followed by review of individual reports for inclusion. Inclusion criteria included primary diagnosis of MDD ≥ 1 week duration of therapy with ≥10 sessions, and treatment with any form of TBS. The Cochrane GRADE methodology and PRISMA criteria were used for evaluation of individual trials. Data from ten RCTs were included, representing 667 patients. Of these, 8 RCTs compared TBS to sham treatment and one compared TBS to standard rTMS (i.e., high frequency stimulation over left dorsolateral prefrontal cortex [HFL]). Quality of evidence assessment yielded high confidence in the finding of TBS being superior to sham on response measured by the Hamilton Depression Rating Scale (HRSD) (RR = 2.4; 95% CI: 1.27 to 4.55; P = 0.007; I2 = 40%). Comparison of HRSD response rates for TBS versus rTMS produced no statistically significant difference (RR = 1.02; 95% CI: 0.85 to 1.23; P = 0.80; I2 = 0%). The incidence of adverse events between TBS and rTMS was not statistically different. The findings of a positive effect of TBS vs. sham, and noninferiority of TBS vs. standard HFL rTMS support the continued development of TBS to treat depression.

BackgroundRepetitive Transcranial Magnetic Stimulation (rTMS) is an effective intervention for treatment-resistant Major Depressive Disorder (MDD). Early improvement during high-frequency left-sided (HFL) stimulation of the dorsolateral prefrontal cortex (DLPFC) is an important predictor of longer-term outcome, but most patients benefit later in their treatment course. We examined patients without early improvement with HFL to determine whether augmentation with additional stimulation approaches improved treatment outcome.Methods139 participants received HFL in a measurement-based care paradigm. Participants who achieved < 20% improvement by treatment 10 could continue with HFL (N = 17) or receive one of two augmentation strategies: bilateral stimulation (BL; HFL followed by low-frequency stimulation of right DLPFC) (N = 69) or intermittent theta-burst priming of left DLPFC (iTBS-P) (N = 17) for their remaining treatment sessions. The primary outcome was the percent reduction in depressive symptoms at treatment 30.ResultsParticipants who achieved < 20% improvement by treatment 10 and continued with HFL showed limited benefit. iTBS-P participants had significantly greater improvement, while those receiving BL trended toward improved outcomes. Ten sessions of either augmentation strategy appeared necessary to determine the likelihood of benefit.ConclusionsAugmentation of early non-response to HFL appears to improve rTMS outcomes, with a novel iTBS-P strategy surpassing both continued HFL or BL treatment in participants with < 20% improvement after 10 treatments. These findings suggest that measurement-based care with addition of augmented stimulation for those not showing early improvement may yield superior rTMS treatment outcomes.

Background: Up to 34% of patients with schizophrenia are resistant to several treatment trials. Lack of continuous and adequate treatment is associated with relapse, rehospitalization, a lower effect of antipsychotic therapy, and higher risk of side effects. Long-acting injectables antipsychotics (LAI APs) enhance compliance and improve clinical outcomes and quality of life in patients with schizophrenia, and thus it may be advisable to administer two LAI APs at the same time in cases of treatment-resistant schizophrenia. The purpose of this review is to summarize the available literature regarding the combined use of two LAI APs in patients with schizophrenia or other psychotic spectrum disorders. Methods: An extensive literature search for relevant articles regarding any combination of two long-acting injectable antipsychotics has been performed from inception up to 9 February 2024, on PubMed, Scopus and APA PsycInfo, according to the PRISMA statement. Only studies reporting combination of two LAI APs and its clinical outcome in patients with schizophrenia and related disorders were selected. Results: After the selection process, nine case reports, four case series and two observational retrospective studies were included in the final analysis. All patients treated with dual LAI APs reported a good response, and no new or unexpected adverse effects due to the combination of two LAIs were reported. Different drug combinations were used, and the most frequent association resulted in aripiprazole monohydrate + paliperidone palmitate once monthly (32 times). Conclusions: Our review highlights that the treatment regimen with two concurrent LAI APs is already widely used in clinical practice and is recognized as providing a promising, effective, and relatively safe therapeutic strategy for treating the schizophrenia spectrum disorders.

We report the case of a Chinese male with schizoaffective disorder, an active smoker and a nonresponder to clozapine (600 mg daily). Therapeutic clozapine monitoring was analyzed, revealing a low concentration‐dose ratio. A pharmacogenetic test showed that the patient had the CYP1A2*1F/*1F genotype, indicating an ultra‐rapid clozapine metabolizer. In combination with fluvoxamine, a CYP1A2 enzyme inhibitor, clozapine plasma concentrations approached the reference range and achieved clinical improvement. This case demonstrates how pharmacogenetics can help understand the value of therapeutic drug monitoring to enhance the treatment of refractory schizoaffective disorder. [ABSTRACT FROM AUTHOR]

Intranasal esketamine for treatment-resistant depression has been introduced and approved by the FDA and EMA in 2019 and 2020, respectively. Since then, the administration practices were found different among countries. Major depression has a high impact on many humans lives worldwide and more than a third of treated people are not responding after several treatment attempts. Additional administration with esketamine closed this gap for more than the half of these non-responders. Guidelines for the treatment of major depression recommend starting with add-on esketamine after 2–4 serious attempts of treatment with standard antidepressants (SSRI/SNRI) irrespective of augmentation with others, e.g., second generation antipsychotics or lithium. Thus, intranasal esketamine became an important role in the evidence-based treatment of major depression. The authors review and critically evaluated published articles focusing on preparation, management and observation of intranasal esketamine treatment. There exists a clear recommendation for administrating intranasal esketamine in a medical environment, not limited to a clinical setting for selecting the dose, monitoring the improvements and managing adverse events. The administration of intranasal esketamine is considered as safe during the application itself and long-lasting or severe adverse events during long-term treatment are very rare. Since this is a new approach for treatment application psychiatrists face new different but not difficult treatment procedures compared to prescribing only a medication.

IntroductionChronic pain is defined as pain lasting longer than 3 months. This often causes persistent emotional distress and functional disability that is refractory to conventional treatments. Emerging evidence suggests that oral Ketamine therapy may have a specific role in managing treatment-resistant chronic pain. This study aimed to assess the effectiveness of oral ketamine within a tertiary chronic pain management clinic.MethodsThis study was a clinic-based retrospective descriptive study of 79 patients with a broad range of chronic pain diagnoses and treated with oral ketamine over a period up to 12 years. Changes in pain, mood and quality of life (QoL) were assessed using a numerical pain severity score, the Brief Pain Inventory (BPI), the Public Health Questionnaire (PHQ-9) and American Chronic Pain Association Quality of Life (QoL) scale.Results73 patients were accessible for follow-up (mean daily dose and treatment duration were 193.84 mg and 22.6 months respectively). Pain scores decreased (p

Objective: In the general population, repeated cognitive testing produces learning effects with potential for improved test performance. It is currently unclear whether the same effect of repeated cognitive testing on cognition pertains to people living with schizophrenia, a condition often associated with significant cognitive impairments. This study aims to evaluate learning ability in people with schizophrenia and—considering the evidence that antipsychotic medication can additionally impair cognitive performance—explore the potential impact of anticholinergic burden on verbal and visual learning. Method: The study included 86 patients with schizophrenia, treated with clozapine, who had persisting negative symptoms. They were assessed at baseline, weeks 8, 24 and 52 using Positive and Negative Syndrome Scale, Hopkins Verbal Learning Test–Revised (HVLT-R) and Brief Visuospatial Memory Test-R (BVMT-R). Results: There were no significant improvements in verbal or visual learning across all measurements. Neither the clozapine/norclozapine ratio nor anticholinergic cognitive burden significantly predicted participants' total learning. Premorbid IQ was significantly associated with verbal learning on the HVLT-R. Conclusions: These findings advance our understanding of cognitive performance in people with schizophrenia and demonstrate limited learning performance in individuals with treatment-refractory schizophrenia.

This report highlights a rare single-gene cause of early-onset, treatment-resistant schizophrenia, and its unique responsiveness to clozapine therapy. This case describes a pediatric female who was diagnosed with early-onset schizophrenia and catatonia in her early adolescence, and was later found to have DLG4-related synaptopathy, also known as SHINE syndrome. SHINE syndrome is a rare neurodevelopmental disorder caused by dysfunction of the postsynaptic density protein-95 (PSD-95), encoded by the DLG4 gene. After failing three antipsychotic drug treatments, the patient was started on clozapine, which resulted in significant improvements in positive and negative symptoms. This case illustrates the impact of clozapine in treatment-resistant early-onset psychosis and exemplifies practical implications for genetic testing in early-onset schizophrenia. [ABSTRACT FROM AUTHOR]

BackgroundNovel technologies make it possible to incorporate pharmacogenetic testing into the medical management of depression. However, previous studies indicate that there may be a subset of subjects who have concerns about genetic testing and may be psychologically vulnerable. If so, pharmacogenetic testing in depressed subjects could negatively impact their mental health and undermine treatment goals.MethodsIn this study, we developed a standardized instrument to assess motivations and attitudes around pharmacogenetic testing in a cohort of 170 depressed Veterans participating in a multi-center clinic trial.ResultsTesting reveals that subjects were largely positive about the use of genetic testing to guide pharmacological treatment and help plan their future. Most subjects showed only modest concerns about the impact on family, inability to cope with the results, and fear of discrimination. The severity of depression did not predict the concern expressed about negative outcomes. However, non-Caucasian subjects were more likely on average to endorse concerns about poor coping and fear of discrimination.ConclusionsThese data indicate that while the overall risk is modest, some patients with depression may face psychosocial challenges in the context of pharmacogenetic testing. Future work should identify factors that predict distress and aim to tailor test results to different populations.