Should rTMS be considered a first-line treatment for major depressive episodes in adults?

Treatment-resistant depression (TRD) is an epidemic with rising social, economic, and political costs. In a patient whose major depressive episode (MDE) persists through an adequate antidepressant trial, insurance companies often cover alternative treatments which may include repetitive transcranial magnetic stimulation (rTMS). RTMS is an FDA-cleared neuromodulation technique for TRD which is safe, efficacious, noninvasive, and well-tolerated. Recent developments in the optimization of rTMS algorithms and targeting have increased the efficacy of rTMS in treating depression, improved the clinical convenience of these treatments, and decreased the cost of a course of rTMS. In this opinion paper, we make a case for why conventional FDA-cleared rTMS should be considered as a first-line treatment for all adult MDEs. RTMS is compared to other first-line treatments including psychotherapy and SSRIs. These observations suggest that rTMS has similar efficacy, fewer side-effects, lower risk of serious adverse events, comparable compliance, the potential for more rapid relief, and cost-effectiveness. This suggestion, however, would be strengthened by further research with an emphasis on treatment-naive subjects in their first depressive episode, and trials directly contrasting rTMS with SSRIs or psychotherapy.

Childhood trauma and treatment resistance in first-episode psychosis: Investigating the role of premorbid adjustment and duration of untreated psychosis.

BACKGROUND: Early identification of treatment non-response in first-episode psychosis (FEP) is essential to outcome. Despite indications that exposure to childhood trauma (CT) can have adverse effects on illness severity, its impact on treatment non-response and the interplay with other pre-treatment characteristics is sparsely investigated. We use a lack of clinical recovery as an early indicator of treatment resistance to investigate the relationship between CT and treatment resistance status at one-year follow-up and the potential mediation of this effect by other pre-treatment characteristics. METHODS: This prospective one-year follow-up study involved 141 participants recruited in their first year of treatment for a schizophrenia-spectrum disorder. We investigated clinical status, childhood trauma (CT), premorbid adjustment (PA), and duration of untreated psychosis (DUP) at baseline and clinical status at one-year follow-up. Ordinal regression analyses were conducted to investigate how PA and DUP affected the relationship between CT and one-year outcome in FEP. RESULTS: 45 % of the FEP sample reported moderate to severe CT, with significantly higher levels of CT in the early treatment resistant group compared to participants with full or partial early recovery. Ordinal regression analysis showed that CT was a significant predictor of being in a more severe outcome group (OR = 4.59). There was a partial mediation effect of PA and a full mediation effect of DUP on the effect of CT on outcome group membership. DISCUSSION: Our findings indicate that reducing treatment delays may mitigate the adverse effects of CT on clinical outcomes and support the inclusion of broad trauma assessment in FEP services.

Microwave ablation of synovial hypertrophy in recurrent monoarthritis: The results of extended cohort and long-term follow-up.

OBJECTIVES: Recurrent monoarthritis (RM) is a major challenge of many rheumatic diseases. Ablation is a well-known technique in the treatment of benign or malign lesions of different etiologies. We aimed to to investigate the success and safety of microwave ablation (MWA) as an adjunctive therapy in a cohort of medical treatment-resistant RM. METHODS: Patients with RM associated with different inflammatory diseases were included. MWA was performed after measuring the size of synovial hypertrophy with 15 or 20-watt power and different durations until microbubbles were shown indicating necrosis. Both clinical and radiologic data were recorded. RESULTS: We applied MWA in total of 24 knee joints of 10 female and 12 male patients aged between 22-71 years. Median intra-articular aspiration (IAA) need in the last 6 months before MWA was 5 (0-15). The median follow-up was 10 (3-16) months. Overall IAA count in the last 6 months before MWA in total of 144 months was 129 and decreased to 7 in post-MWA in total of 226 months (0.89 vs 0.03 per month, p< 0.001). The second MWA session was needed for 3 patients and a third session for 1. Functional disability and pain scores were improved significantly (median score from 9 to 1, p< 0.00001, in both). In magnetic resonance imaging, follow-up significant regression in synovial hypertrophy size was shown especially after 6th month. No complication was observed during the procedure or follow-up. CONCLUSION: As a less invasive technique compared with the surgical approach, MWA of synovial hypertrophy showed significant clinical improvement in RM safely. MWA seems promising as a treatment option candidate in the management of RM.

Overcoming Treatment Resistance in Medulloblastoma: Underlying Mechanisms and Potential Strategies.

Medulloblastoma is the most frequently encountered malignant brain tumor in the pediatric population. The standard of care currently consists of surgical resection, craniospinal irradiation, and multi-agent chemotherapy. However, despite this combination of multiple aggressive modalities, recurrence of the disease remains a substantial concern, and treatment resistance is a rising issue. The development of this resistance results from the interplay of a myriad of anatomical properties, cellular processes, molecular pathways, and genetic and epigenetic alterations. In fact, several efforts have been directed towards this domain and characterizing the major contributors to this resistance. Herein, this review highlights the different mechanisms that drive relapse and are implicated in the occurrence of treatment resistance and discusses them in the context of the latest molecular-based classification of medulloblastoma. These mechanisms include the impermeability of the blood-brain barrier to drugs, the overactivation of specific molecular pathways, the resistant and multipotent nature of cancer stem cells, intratumoral and intertumoral heterogeneity, and metabolic plasticity. Subsequently, we build on that to explore potential strategies and targeted agents that can abrogate these mechanisms, undermine the development of treatment resistance, and augment medulloblastoma's response to therapeutic modalities.

Resistance to Targeted Inhibitors of the PI3K/AKT/mTOR Pathway in Advanced Oestrogen-Receptor-Positive Breast Cancer.

The PI3K/AKT/mTOR signalling pathway is one of the most frequently activated pathways in breast cancer and also plays a central role in the regulation of several physiologic functions. There are major efforts ongoing to exploit precision medicine by developing inhibitors that target the three kinases (PI3K, AKT, and mTOR). Although multiple compounds have been developed, at present, there are just three inhibitors approved to target this pathway in patients with advanced ER-positive, HER2-negative breast cancer: everolimus (mTOR inhibitor), alpelisib (PIK3CA inhibitor), and capivasertib (AKT inhibitor). Like most targeted cancer drugs, resistance poses a major problem in the clinical setting and is a factor that has frequently limited the overall efficacy of these agents. Drug resistance can be categorised into intrinsic or acquired resistance depending on the timeframe it has developed within. Whereas intrinsic resistance exists prior to a specific treatment, acquired resistance is induced by a therapy. The majority of patients with ER-positive, HER2-negative advanced breast cancer will likely be offered an inhibitor of the PI3K/AKT/mTOR pathway at some point in their cancer journey, with the options available depending on the approval criteria in place and the cancer's mutation status. Within this large cohort of patients, it is likely that most will develop resistance at some point, which makes this an area of interest and an unmet need at present. Herein, we review the common mechanisms of resistance to agents that target the PI3K/AKT/mTOR signalling pathway, elaborate on current management approaches, and discuss ongoing clinical trials attempting to mitigate this significant issue. We highlight the need for additional studies into AKT1 inhibitor resistance in particular.

A new perspective on hematological malignancies: m6A modification in immune microenvironment.

Immunotherapy for hematological malignancies is a rapidly advancing field that has gained momentum in recent years, primarily encompassing chimeric antigen receptor T-cell (CAR-T) therapies, immune checkpoint inhibitors, and other modalities. However, its clinical efficacy remains limited, and drug resistance poses a significant challenge. Therefore, novel immunotherapeutic targets and agents need to be identified. Recently, N6-methyladenosine (m6A), the most prevalent RNA epitope modification, has emerged as a pivotal factor in various malignancies. Reportedly, m6A mutations influence the immunological microenvironment of hematological malignancies, leading to immune evasion and compromising the anti-tumor immune response in hematological malignancies. In this review, we comprehensively summarize the roles of the currently identified m6A modifications in various hematological malignancies, with a particular focus on their impact on the immune microenvironment. Additionally, we provide an overview of the research progress made in developing m6A-targeted drugs for hematological tumor therapy, to offer novel clinical insights.

Deterioration in cognitive control related mPFC function underlying development of treatment resistance in early psychosis.

One third of people with psychosis become antipsychotic treatment-resistant and the underlying mechanisms remain unclear. We investigated whether altered cognitive control function is a factor underlying development of treatment resistance. We studied 50 people with early psychosis at a baseline visit (mean < 2 years illness duration) and follow-up visit (1 year later), when 35 were categorized at treatment-responsive and 15 as treatment-resistant. Participants completed an emotion-yoked reward learning task that requires cognitive control whilst undergoing fMRI and MR spectroscopy to measure glutamate levels from Anterior Cingulate Cortex (ACC). Changes in cognitive control related activity (in prefrontal cortex and ACC) over time were compared between treatment-resistant and treatment-responsive groups and related to glutamate. Compared to treatment-responsive, treatment-resistant participants showed blunted activity in right amygdala (decision phase) and left pallidum (feedback phase) at baseline which increased over time and was accompanied by a decrease in medial Prefrontal Cortex (mPFC) activity (feedback phase) over time. Treatment-responsive participants showed a negative relationship between mPFC activity and glutamate levels at follow-up, no such relationship existed in treatment-resistant participants. Reduced activity in right amygdala and left pallidum at baseline was predictive of treatment resistance at follow-up (67% sensitivity, 94% specificity). The findings suggest that deterioration in mPFC function over time, a key cognitive control region needed to compensate for an initial dysfunction within a social-emotional network, is a factor underlying development of treatment resistance in early psychosis. An uncoupling between glutamate and cognitive control related mPFC function requires further investigation that may present a future target for interventions.

Targeting Neoantigens in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is currently the third leading cause of cancer-related death in the United States after lung and colon cancer. PDAC is estimated to be the second leading cause of cancer-related death by 2030. The diagnosis at a late stage is the underlying cause for higher mortality and poor prognosis after surgery. Treatment resistance to chemotherapy and immunotherapy results in recurrence after surgery and poor prognosis. Neoantigen burden and CD8+ T-cell infiltration are associated with clinical outcomes in PDAC and paucity of neoantigen-reactive tumor-infiltrating lymphocytes may be the underlying cause for treatment resistance for immunotherapy. This suggests a need to identify additional neoantigens and therapies targeting these neoantigens to improve clinical outcomes in PDAC. In this review, we focus on describing the pathophysiology, current treatment strategies, and treatment resistance in PDAC followed by the need to target neoantigens in PDAC.

Homologous recombination proficient subtypes of high-grade serous ovarian cancer: treatment options for a poor prognosis group.

Approximately 50% of tubo-ovarian high-grade serous carcinomas (HGSCs) have functional homologous recombination-mediated (HR) DNA repair, so-called HR-proficient tumors, which are often associated with primary platinum resistance (relapse within six months after completion of first-line therapy), minimal benefit from poly(ADP-ribose) polymerase (PARP) inhibitors, and shorter survival. HR-proficient tumors comprise multiple molecular subtypes including cases with CCNE1 amplification, AKT2 amplification or CDK12 alteration, and are often characterized as "cold" tumors with fewer infiltrating lymphocytes and decreased expression of PD-1/PD-L1. Several new treatment approaches aim to manipulate these negative prognostic features and render HR-proficient tumors more susceptible to treatment. Alterations in multiple different molecules and pathways in the DNA damage response are driving new drug development to target HR-proficient cancer cells, such as inhibitors of the CDK or P13K/AKT pathways, as well as ATR inhibitors. Treatment combinations with chemotherapy or PARP inhibitors and agents targeting DNA replication stress have shown promising preclinical and clinical results. New approaches in immunotherapy are also being explored, including vaccines or antibody drug conjugates. Many approaches are still in the early stages of development and further clinical trials will determine their clinical relevance. There is a need to include HR-proficient tumors in ovarian cancer trials and to analyze them in a more targeted manner to provide further evidence for their specific therapy, as this will be crucial in improving the overall prognosis of HGSC and ovarian cancer in general.

A Review: Genetic Mutations as a Key to Unlocking Drug Resistance in Cervical Cancer.

Cervical cancer is the fourth most common cancer in women. Advanced stage and metastatic disease are often associated with poor clinical outcomes. This substantiates the absolute necessity for high-throughput diagnostic and treatment platforms that are patient and tumour specific. Cervical cancer treatment constitutes multimodal intervention. Systemic treatments such as chemotherapy and/or focal radiotherapy are typically applied as neoadjuvant and/or adjuvant strategies. Cisplatin constitutes an integral part of standard cervical cancer treatment approaches. However, despite initial patient response, de novo or delayed/acquired treatment resistance is often reported, and toxicity is of concern. Chemotherapy resistance is associated with major alterations in genomic, metabolomic, epigenetic and proteomic landscapes. This results in imbalanced homeostasis associated with pro-oncogenic and proliferative survival, anti-apoptotic benefits, and enhanced DNA damage repair processes. Although significant developments in cancer diagnoses and treatment have been made over the last two decades, drug resistance remains a major obstacle to overcome.

Despite advances in treatment, the disease's advanced stages and spread to other parts of the body often lead to poor outcomes. This highlights the urgent need for better diagnostic and treatment methods tailored to each patient and their specific tumour. Treatment for cervical cancer usually involves a combination of therapies. Chemotherapy and focused radiation therapy are commonly used before or after surgery to improve outcomes. However, some patients develop resistance to these treatments, either from the start or after initially responding to therapy. This resistance can make treatment less effective and increase the risk of side effects. Chemotherapy resistance is often linked to changes in the genes and proteins of cancer cells. These changes disrupt the normal balance within the cells, making them more prone to grow and survive, resist cell death, and repair DNA damage caused by treatment. Despite progress in cancer research and treatment, drug resistance remains a significant challenge. This review aims to explore how acquired genetic mutations contribute to drug resistance in cervical cancer. By understanding these mutations better, researchers and clinicians in low- to middle-income countries can develop more effective treatment strategies to improve outcomes for patients.

Clozapine treatment and astrocyte activity in treatment resistant schizophrenia: A proton magnetic resonance spectroscopy study.

Clozapine is the only antipsychotic approved for treating treatment-resistant schizophrenia (TRS), characterized by persistent positive symptoms despite adequate antipsychotic treatment. Unfortunately, clozapine demonstrates clinical efficacy in only ~30-60 % of patients with TRS (clozapine-responders; ClzR+), while the remaining ~40-70 % are left with no pharmacological recourse for improvement (clozapine-resistant; ClzR-). Mechanism(s) underlying clozapine's superior efficacy remain unclear. However, in vitro evidence suggests clozapine may mitigate glutamatergic dysregulations observed in TRS, by modulating astrocyte activity in ClzR+, but not ClzR-. A factor that if proven correct, may help the assessment of treatment response and development of more effective antipsychotics. To explore the presence of clozapine-astrocyte interaction and clinical improvement, we used 3 T proton-magnetic resonance spectroscopy to quantify levels of myo-Inositol, surrogate biomarker of astrocyte activity, in regions related to schizophrenia neurobiology: Dorsal-anterior-cingulate-cortex (dACC), left-dorsolateral-prefrontal-cortex (left-DLPFC), and left-striatum (left-striatum) of 157 participants (ClzR- = 30; ClzR+ = 37; responders = 38; controls = 52). Clozapine treatment was assessed using clozapine to norclozapine plasma levels, 11-12 h after last clozapine dose. Measures for symptom severity (i.e., Positive and Negative Symptoms Scale) and cognition (i.e., Mini-Mental State Examination) were also recorded. Higher levels of myo-Inositol were observed in TRS groups versus responders and controls (dACC (p < 0.001); left-striatum (p = 0.036); left-DLPFC (p = 0.023)). In ClzR+, but not ClzR-, clozapine to norclozapine ratios were positively associated with myo-Inositol levels (dACC (p = 0.004); left-DLPFC (p < 0.001)), and lower positive symptom severity (p < 0.001). Our results support growing in vitro evidence of clozapine-astrocyte interaction in clozapine-responders. Further research may determine the viability of clozapine-astrocyte interactions as an early marker of clozapine response.

Clozapine use in the first two years after first-episode psychosis in a real-world clinical sample.

BACKGROUND: Approximately 20-30% of patients with schizophrenia fail to respond to antipsychotic treatment and are considered treatment resistant (TR). Although clozapine is the treatment of choice in these patients, in real-world clinical settings, clinicians often delay clozapine initiation, especially in first-episode psychosis (FEP). AIM: The main aim of this study was to describe prescription patterns for clozapine in a sample of patients diagnosed with FEP and receiving specialized treatment at a university hospital. More specifically, we aimed to determine the following: (1) the proportion of patients who received clozapine within two years of disease onset, (2) baseline predictors of clozapine use, (3) time from starting the first antipsychotic to clozapine initiation, (4) concomitant medications, and (5) clozapine-related adverse effects. METHODS: All patients admitted to a specialized FEP treatment unit at our hospital between April 2013 and July 2020 were included and followed for two years. The following variables were assessed: baseline sociodemographic characteristics; medications prescribed during follow-up; clozapine-related adverse effects; and baseline predictors of clozapine use. We classified the sample into three groups: clozapine users, clozapine-eligible, and non-treatment resistant (TR). RESULTS: A total of 255 patients were consecutively included. Of these, 20 (7.8%) received clozapine, 57 (22.4%) were clozapine-eligible, and 178 (69.8%) were non-TR. The only significant variable associated with clozapine use at baseline was the Global Assessment of Functioning (GAF) score (R2=0.09, B=-0.07; OR=0.94; 95% CI: 0.88-0.99; p=0.019). The median time to clozapine initiation was 55.0 (93.3) days. The most common side effect was sedation. CONCLUSIONS: A significant proportion (30.2%) of patients in this cohort were treatment resistant and eligible for clozapine. However, only 7.8% of the sample received clozapine, indicating that this medication was underprescribed. A lower baseline GAF score was associated with clozapine use within two years, suggesting that it could be used to facilitate the early identification of patients who will need treatment with clozapine, which could in turn improve treatment outcomes.

Predicting treatment resistance in schizophrenia patients: Machine learning highlights the role of early pathophysiologic features.

Detecting patients with a high-risk profile for treatment-resistant schizophrenia (TRS) can be beneficial for implementing individually adapted therapeutic strategies and better understanding the TRS etiology. The aim of this study was to explore, with machine learning methods, the impact of demographic and clinical patient characteristics on TRS prediction, for already established risk factors and unexplored ones. This was a retrospective study of 500 patients admitted during 2020 to the University Hospital Group for Paris Psychiatry. We hypothesized potential TRS risk factors. The selected features were coded into structured variables in a new dataset, by processing patients discharge summaries and medical narratives with natural-language processing methods. We compared three machine learning models (XGBoost, logistic elastic net regression, logistic regression without regularization) for predicting TRS outcome. We analysed feature impact on the models, suggesting the following factors as markers of a high-risk TRS profile: early age at first contact with psychiatry, antipsychotic treatment interruptions due to non-adherence, absence of positive symptoms at baseline, educational problems and adolescence mental disorders in the personal psychiatric history. Specifically, we found a significant association with TRS outcome for age at first contact with psychiatry and medication non-adherence. Our findings on TRS risk factors are consistent with the review of the literature and suggest potential in using early pathophysiologic features for TRS prediction. Results were encouraging with the use of natural-langage processing techniques to leverage raw data provided by discharge summaries, combined with machine leaning models. These findings are a promising step for helping clinicians adapt their guidelines to early detection of TRS.

Evasion of apoptosis and treatment resistance in squamous cell carcinoma of the head and neck.

Combinations of surgery, radiotherapy and chemotherapy can eradicate tumors in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN), but a significant proportion of tumors progress, recur, or do not respond to therapy due to treatment resistance. The prognosis for these patients is poor, thus new approaches are needed to improve outcomes. Key resistance mechanisms to chemoradiotherapy (CRT) in patients with LA SCCHN are alterations to the pathways that mediate apoptosis, a form of programmed cell death. Targeting dysregulation of apoptotic pathways represents a rational therapeutic strategy in many types of cancer, with a number of proteins, including the pro-survival B-cell lymphoma 2 family and inhibitors of apoptosis proteins (IAPs), having been identified as druggable targets. This review discusses the mechanisms by which apoptosis occurs under physiological conditions, and how this process is abnormally restrained in LA SCCHN tumor cells, with treatment strategies aimed at re-enabling apoptosis in LA SCCHN also considered. In particular, the development of, and future opportunities for, IAP inhibitors in LA SCCHN are discussed, in light of recent encouraging proof-of-concept clinical trial data.

Long road towards effective HER3 targeting in breast cancer.

Breast cancer is a heterogeneous disease, encompassing multiple different subtypes. Thanks to the increasing knowledge of the diverse biological features of each subtype, most patients receive personalized treatment based on known biomarkers. However, the role of some biomarkers in breast cancer evolution is still unknown, and their potential use as a therapeutic target is still underexplored. HER3 is a member of the human epidermal growth factors receptor family, overexpressed in 50%-70% of breast cancers. HER3 plays a key role in cancer progression, metastasis development, and drug resistance across all the breast cancer subtypes. Owing to its critical role in cancer progression, many HER3-targeting therapies have been developed over the past decade with conflicting findings. Next-generation antibody-drug conjugates have recently shown promising results in solid tumors expressing HER3, including breast cancer. In this review, we discuss the HER3 role in the pathogenesis of breast cancer and its relevance across all subtypes. We also explore the new anti-HER3 treatment strategies, calling into question the significance of HER3 detection as crucial information in breast cancer treatment.

Non-invasive brain stimulation for treatment-resistant schizophrenia: protocol of a systematic review and network meta-analysis.

BACKGROUND: Non-invasive brain stimulation (NIBS) is a promising intervention for treatment-resistant schizophrenia. However, there are multiple available techniques and a comprehensive synthesis of evidence is lacking. Thus, we will conduct a systematic review and network meta-analysis to investigate the comparative efficacy and safety of NIBS techniques as an add-on to antipsychotics for treatment-resistant schizophrenia. METHODS: We will include single- and double-blind randomized-controlled trials (RCT) comparing any NIBS technique with each other or with a control intervention as an add-on to antipsychotics in adult patients with treatment-resistant schizophrenia. We will exclude studies focusing on predominant negative symptoms, maintenance treatment, and single sessions. The primary outcome will be a change in overall symptoms, and secondary outcomes will be a change in symptom domains, cognitive performance, quality of life, functioning, response, dropouts, and side effects. We will search for eligible studies in previous reviews, multiple electronic databases and clinical trial registries from inception onwards. At least two independent reviewers will perform the study selection, data extraction, and risk of bias assessment. We will measure the treatment differences using standardized mean difference (SMD) and odds ratio (OR) for continuous and dichotomous outcomes, respectively. We will conduct pairwise and network meta-analysis within a frequentist framework using a random-effects model, except for rare event outcomes where we will use a fixed-effects Mantel-Haenszel method. We will investigate potential sources of heterogeneity in subgroup analyses. Reporting bias will be assessed with funnel plots and the Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) tool. The certainty in the evidence will be evaluated using the Confidence in Network Meta-analysis (CINeMA) approach. DISCUSSION: Our network meta-analysis would provide an up-to-date synthesis of the evidence from all available RCTs on the comparative efficacy and safety of NIBS for treatment-resistant schizophrenia. This information could guide evidence-based clinical practice and improve the outcomes of patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO-ID CRD42023410645.

Update on the assessment of resistance to antidepressant treatment: Rationale for the Antidepressant Treatment History Form: Short Form-2 (ATHF-SF2).

All definitions of treatment-resistant depression (TRD) require that patients have experienced insufficient benefit from one or more adequate antidepressant trials. Thus, identifying "failed, adequate trials" is key to the assessment of TRD. The Antidepressant Treatment History Form (ATHF) was one of the first and most widely used instruments that provided objective criteria in making these assessments. The original ATHF was updated in 2018 to the ATHF-SF, changing to a checklist format for scoring, and including specific pharmacotherapy, brain stimulation, and psychotherapy interventions as potentially adequate antidepressant treatments. The ATHF-SF2, presented here, is based on the consensus of the ATHF workgroup about the novel interventions introduced since the last revision and which should/should not be considered effective treatments for major depressive episodes. This document describes the rationale for these choices and, for each intervention, the minimal criteria for determining the adequacy of treatment administration. The Supplementary Material that accompanies this article provide the Scoring Checklist, Data Collection Forms (current episode and composite of previous episodes), and Instruction Manual for the ATHF-SF2.

Identifying and managing treatment resistance early with the integration of a clozapine clinic within an early intervention for psychosis service.

BACKGROUND: Despite being the most effective antipsychotic medication for treatment-resistant psychosis, clozapine is often under-utilized with long delays to initiation. AIMS: This study aimed to determine whether the integration of a clozapine clinic within an early intervention for psychosis service resulted in a change in the rate and time to initiation of clozapine, the number of trials of different antipsychotic medications prior to clozapine, community initiation and discontinuation rates. METHODS: A clozapine clinic was established in the Early Psychosis Prevention and Intervention Centre in Melbourne. This was a pre- and post-evaluation study design. The 'clozapine clinic' cohort included those who commenced on clozapine from 01 January 2016 to 30 June 2018. RESULTS: Prior to the clozapine clinic, 24 young people commenced clozapine over the 30-month period compared to 36 in the clozapine clinic cohort (RR = 1.30, 95% CI: 0.75-2.28, p = .32). In the pre-clozapine clinic cohort, 4.6% of all those with a first episode of psychosis were commenced on clozapine compared to 6% in the clozapine clinic cohort. Prior to the clozapine clinic, the median time to the commencement of clozapine was 72 weeks (IQR: 38, 87), compared to 53.5 weeks (IQR: 38, 81.5) in the clozapine clinic (Z = -0.86, p = .393). The mean number of different antipsychotic medications prior to commencing clozapine remained stable at 3.2 (SD ± 1.1) in both cohorts (t = -0.20, p = .841). There was a lower rate of discontinuation in the clozapine clinic (43.5% vs. 14.7%, HR = 0.30, 95% CI: 0.09-0.98, p = .046). CONCLUSIONS: While this study was underpowered and there are limitations to the naturalistic study design, the findings lend support to the integration of a clozapine clinic within early intervention for psychosis services.