Brain structural and functional abnormalities in patients with tension-type headache: A systematic review of magnetic resonance imaging studies.

Tension-type headache (TTH) stands as the most prevalent form of headache, yet an adequate understanding of its underlying mechanisms remains elusive. This article endeavors to comprehensively review structural and functional magnetic resonance imaging (MRI) studies investigating TTH patients, to gain valuable insights into the pathophysiology of TTH, and to explore new avenues for enhanced treatment strategies. We conducted a systematic search to identify relevant articles examining brain MRI disparities between TTH individuals and headache-free controls (HFC). Fourteen studies, encompassing 312 diagnosed TTH patients, were selected for inclusion. Among these, eight studies utilized conventional MRI, one employed diffusion tensor imaging, and five implemented various functional MRI modalities. Consistent findings across these studies revealed a notable increase in white matter hyperintensity (WMH) in TTH patients. Furthermore, the potential involvement of the specific brain areas recognized to be involved in different dimensions of pain perception including cortical regions (anterior and posterior cingulate cortex, prefrontal cortex, anterior and posterior insular cortex), subcortical regions (thalamus, caudate, putamen, and parahippocampus), cerebellum in TTH pathogenesis was identified. However, no significant association was established between TTH and intracranial abnormalities or total intracranial volume. In conclusion, these findings support the hypotheses regarding the role of central mechanisms in TTH pathophysiology and offer probable brain regions implicated in these mechanisms. Due to the scarce data on the precise role of these regions in the TTH, further preclinical and clinical investigations should be done to advance our knowledge and enhance targeted therapeutic options of TTH.

The clinical utility of diffusion-weighted imaging in diagnosing and predicting treatment response of laryngeal and hypopharyngeal carcinoma: A systematic review and meta-analysis.

PURPOSE: Laryngeal and Hypopharyngeal Carcinomas (LC/HPC) constitute about 24 % of head and neck cancers, causing more than 90,000 annual deaths worldwide. Diffusion-Weighted Imaging (DWI), is currently widely studied in oncologic imaging and can aid in distinguishing cellular tumors from other tissues. Our objective was to review the effectiveness of DWI in three areas: diagnosing, predicting prognosis, and predicting treatment response in patients with LC/HPC. METHODS: A systematic search was conducted in PubMed, Web of Science, and Embase. A meta-analysis by calculating Standardized Mean Difference (SMD) and 95 % Confidence Interval (CI) was conducted on diagnostic studies. RESULTS: A total of 16 studies were included. All diagnostic studies (n = 9) were able to differentiate between the LC/HPC and other benign laryngeal/hypopharyngeal lesions. These studies found that LC/HPC had lower Apparent Diffusion Coefficient (ADC) values than non-cancerous lesions. Our meta-analysis of 7 diagnostic studies, that provided ADC values of malignant and non-malignant tissues, demonstrated significantly lower ADC values in LC/HPC compared to non-malignant lesions (SMD = -1.71, 95 %CI: [-2.00, -1.42], ADC cut-off = 1.2 × 103 mm2/s). Furthermore, among the studies predicting prognosis, 67 % (4/6) accurately predicted outcomes based on pretreatment ADC values. Similarly, among studies predicting treatment response, 50 % (2/4) successfully predicted outcomes based on pretreatment ADC values. Overall, the studies that looked at prognosis or treatment response in LC/HPC found a positive correlation between pretreatment ADC values in larynx/hypopharynx and favorable outcomes. CONCLUSION: DWI aids significantly in the LC/HPC diagnosis. However, further research is needed to establish DWI's reliability in predicting prognosis and treatment response in patients with LC/HPC.

Comparing the effectiveness of letrozole versus methotrexate for treatment of ectopic pregnancy: A randomized controlled trial.

OBJECTIVE: To evaluate the efficacy of two different regimens of Letrozole, an aromatase inhibitor, in the management of ectopic pregnancy compared to methotrexate. STUDY DESIGN: This randomized controlled trial was conducted on 88 women diagnosed with ectopic pregnancy with a baseline level of serum beta-human chorionic gonadotropin under 3000 mIU/mL between June 30, 2023, and December 30, 2023, at the Department of Obstetrics and Gynecology of the Vali-e-Asr Hospital affiliated with Tehran University of Medical Sciences. Participants were allocated into either methotrexate (n = 43), 5-day course Letrozole (n = 24), or 10-day course Letrozole (n = 21) treatments. The methotrexate group received a single dose of 50 mg/m2 dosage intramuscular methotrexate. The 5-day Letrozole group received a 2.5 mg Letrozole tablet three times daily for 5 days, whereas the 10-day Letrozole group received a 2.5 mg Letrozole tablet twice daily for 10 days. The primary outcome was the treatment response, defined as the achievement of a negative serum beta-human chorionic level without the need for additional methotrexate treatment or surgery. The secondary outcomes were the need for additional methotrexate dose or laparoscopic surgery intervention. The trial protocol was prospectively registered in ClinicalTrials.gov with code NCT05918718. RESULTS: The treatment response rates in methotrexate, 5-day Letrozole, and 10-day Letrozole groups were 76.7 %, 75.0 %, and 90.5 %, respectively, with no significant differences between the groups (P-value = 0.358). A total of 10 (23.3 %) patients from the methotrexate group, 3 (12.5 %) from the 5-day Letrozole group, and 2 (9.5 %) from the 10-day Letrozole group required an additional methotrexate dose, with no significant differences between the groups (P-value = 0.307). Furthermore, only 3 (12.5 %) patients, all from the 5-day Letrozole group, were suspected of tubal rupture and underwent surgery (P-value = 0.016). CONCLUSION: Our findings suggest Letrozole as a safe alternative to methotrexate in treating stable ectopic pregnancies, with a favorable treatment response rate. However, there is still a need for future larger studies to determine the applicability of Letrozole in the EP management. Also, the non-significant higher effectiveness of the 10-day Letrozole regimen than the 5-day Letrozole group underscores the need for future research to determine the optimal Letrozole regimen for the management of ectopic pregnancy.

Perioperative esketamine administration for prevention of postpartum depression after the cesarean section: A systematic review and meta-analysis.

BACKGROUND: Postpartum Depression (PPD) exerts a substantial negative effect on maternal well-being post-delivery, particularly among Cesarean Section (C/S) recipients. In this study, we aimed to review the efficacy of perioperative esketamine, the S-enantiomer of ketamine, in preventing PPD incidence and depressive symptoms as measured with the Edinburgh Postnatal Depression Scale (EPDS) after C/S. METHODS: A systematic search for relevant articles was conducted in Scopus, PubMed, Web of Sciences, and PsycINFO until April 6, 2024. Meta-analyses were conducted using random-effect models to compare the PPD incidence and EPDS scores via log odds ratio and Hedge's g, respectively, during the first week post-C/S and at 42 days post-C/S in the esketamine and control group. RESULTS: Fourteen studies, including 12 randomized controlled trials and 2 retrospective cohorts, were reviewed. Our meta-analyses found lower PPD incidence during the first week (log odds ratio: -0.956 [95 % confidence interval: -1.420, -0.491]) and at day 42 post-C/S (log odds ratio: -0.989 [95 % confidence interval: -1.707, -0.272]) among patients administered esketamine compared to controls. Additionally, EPDS scores for the esketamine group were significantly lower than controls during the first week (Hedge's g: -0.682 [95 % confidence interval: -1.088, -0.276]) and at day 42 post-C/S (Hedge's g: -0.614 [95 % confidence interval: -1.098, -0.129]). LIMITATIONS: Presence of various concomitant medications and heterogeneous study designs. CONCLUSION: Our review highlights the potential impact of esketamine in PPD prevention, as well as in alleviating depressive symptoms post-C/S, regardless of PPD occurrence, therefore suggesting the benefits of adding esketamine to peri-C/S analgesic regimen.

Microstructural white matter alterations associated with social anxiety disorders: A systematic review.

BACKGROUND: Social anxiety disorder (SAD) is a psychiatric condition characterized by impaired social functioning that negatively impacts individuals' quality of life. Previous neuroimaging studies have revealed morphological and functional changes in various brain regions associated with SAD. Recent advances in diffusion tensor imaging (DTI) and diffusion-weighted imaging (DWI) have enabled the investigation of microstructural white matter (WM) alterations in SAD. This study aims to provide an overview of DTI/DWI studies exploring WM microstructure changes in SAD. METHODS: A systematic search on PubMed, Scopus, Web of Science, and PsycINFO was conducted for relevant records on July 8, 2023. An exploratory meta-analysis was also performed. RESULTS: Eight studies were reviewed. Consistent findings indicated reduced fractional anisotropy and increased diffusivity measures in different WM tracts in SAD patients compared to healthy controls. These alterations were mostly observed within regions of the fronto-limbic network, like uncinate fasciculus (UF) and superior and inferior longitudinal fasciculi (SLF and ILF). Finally, our exploratory meta-analysis on four studies utilizing a voxel-wise analytic approach yielded no significant differences between SAD patients and controls. LIMITATIONS: Limited number of studies, small sample sizes, and heterogeneity in analysis methods. CONCLUSIONS: Patients with SAD exhibited altered WM integrity, particularly in the UF, SLF, and ILF, compared to healthy controls. However, due to the limited number of included studies, our meta-analysis yielded no significant differences between SAD patients and controls. Therefore, future research is crucial to unravel the link between altered WM structure and the involvement of other limbic and cortical structures in SAD pathogenesis.

White matter alterations in affective and non-affective early psychosis: A diffusion MRI study.

BACKGROUND: The early years after the onset of psychotic disorders, known as "early psychosis" (EP) are critical to determining the path of psychosis trajectory. We used a Diffusion Magnetic Resonance Imaging (DMRI) connectometry approach to assess the microstructural changes of white matter (WM) associated with EP. METHODS: We used the Human Connectome Project in Early Psychosis (HCP-EP) dataset to collect DMRI data from patients with EP. The imaging data were processed in the Montreal Neuroimaging Initiative space and transformed into quantitative anisotropy (QA). The QA value was translated into the WM connectivity of each tract and used in the subsequent analysis. RESULTS: 121 patients with EP (94 non-affective/27 affective) and 56 healthy controls were recruited. EP was associated with increased QA in the body and tapetum of corpus callosum (CC) and decreased QA in the bilateral cerebellum, and middle cerebellar peduncle. Compared to non-affective psychosis, affective psychosis showed increased QA in the bilateral cerebellum and vermis and decreased QA in the forceps minor, body of CC, right cingulum, and bilateral inferior fronto-occipital fasciculus. Furthermore, QA changes in several WM tracts were correlated with positive and negative symptom scale scores. LIMITATIONS: DMRI intrinsic limitations, limited sample size, and neurobiological effects of psychotropic treatment. CONCLUSIONS: EP is associated with alterations in WM connectivity primarily in the CC and cerebellar regions. Also, affective and non-affective psychosis have distinct alterations in WM connectivity. These results can be used for the early diagnosis and differentiation of psychotic disorders.

Methotrexate as the first-line treatment of unruptured tubular ectopic pregnancies with high initial human chorionic gonadotropin levels: A retrospective cohort.

Objectives: To evaluate the effectiveness of the first-line medical management with Methotrexate (MTX) in the treatment of patients with stable tubal Ectopic Pregnancies (EPs) and varying ranges of Beta-Human Chorionic Gonadotropin (ß-HCG) levels. Materials and methods: In this retrospective cohort study, we reviewed the medical records of a total of 184 patients with the diagnosis of tubal EP, who received MTX as their first-line treatment. Patients with a baseline ß-HCG< 4800 mIU/mL received single-dose MTX (n = 136) and those with an initial ß-HCG≥ 4800 mIU/mL underwent the double-dose MTX regimen (n = 48). The treatment success was determined by evaluating the reported weekly ß-HCG levels of the patients. Results: Baseline ß-HCG and mass size in the single-dose group were 1895.1 ± 1463.4 mIU/mL and 2.2 ± 1.1 cm, respectively, compared to 17,867.6 ± 31,870.5 mIU/mL and 2.3 ± 1.1 cm in the double-dose group. Treatment duration was 30.6 ± 16.9 days for single dose and 41.0 ± 27.0 days for double dose, with additional MTX in 27.2% and 12.5% in respective groups. Single dose achieved a 92.6% success rate, and double dose, 81.3%, without serious adverse effects. No significant effects were seen for either baseline ß-HCG and mass size on the treatment success rates of both groups (p-value>0.05). However, the presence of Fetal Heart Rate (FHR) was associated with poorer responses only in the single-dose group (p-value=0.034). Conclusions: Medical management with MTX shows promise as a first-line treatment for tubal EPs with ß-HCG> 2000, suggesting a potential reassessment of existing guidelines in light of this emerging evidence. However, further research seems crucial in this field.

Effects of non-pharmacological interventions on gait and balance of persons with Multiple Sclerosis: A narrative review.

BACKGROUND: Multiple Sclerosis (MS) is among the most common reasons for disability in young adults. Mobility impairment, primarily related to gait and balance, is ranked as the preeminent concern among persons with MS (PwMS). Gait and balance dysfunction can directly affect the quality of life and activities of daily life in PwMS, hence the importance of effective treatment strategies. Previous studies have demonstrated the positive effect of various non-pharmacological rehabilitation methods, including physiotherapy and electrical stimulation, on gait and mobility in PwMS. Non-pharmacological methods can be tailored to the individual needs and abilities of each patient, allowing healthcare providers to create personalized training programs. Furthermore, these methods typically result in minimal or no side effects. PURPOSE: This review provides a comprehensive overview of an array of non-pharmacological treatment approaches aimed at enhancing ambulatory performance in PwMS. METHODS: We performed a narrative review of the original papers available in PubMed, investigating the effects of different nonmedical approaches on the gait and balance performance of the PwMS. Reviewed treatment approaches include "exercise, physical rehabilitation, dual-task (DT) rehabilitation, robot-assisted rehabilitation, virtual reality-assisted rehabilitation, game training, electrical stimulation devices, auditory stimulation, visual feedback, and shoe insoles". RESULTS AND CONCLUSIONS: Eighty articles were meticulously reviewed. Our study highlights the positive effects of non-pharmacological interventions on patients' quality of life, reducing disability, fatigue, and muscle spasticity. While some methods, including exercise and physiotherapy, showed substantial promise, further research is needed to evaluate whether visual biofeedback and auditory stimulation are preferable over conventional approaches. Additionally, approaches such as functional electrical stimulation, non-invasive brain stimulation, and shoe insoles demonstrate substantial short-term benefits, prompting further investigation into their long-term effects. Non-pharmacological interventions can serve as a valuable complement to medication-based approaches.

Effects of routine repetitive transcranial magnetic stimulation on the sleep duration of patients with treatment-resistant depression: A prospective cohort study.

Aim: The aim of this study was to evaluate the short-term and long-term effects of routine repetitive transcranial magnetic stimulation (rTMS) on the sleep duration, depressive symptoms, and quality of life of patients with treatment-resistant depression (TRD). Methods: In this prospective cohort study, 25 participants with TRD were assessed using the Insomnia Severity Index (ISI) and four sleep duration components of the Pittsburgh Sleep Quality Index (PSQI). Depression severity was measured with Hamilton's Depression Rating Scale (HDRS) and Beck's Depression Inventory (BDI-II), and patient-perceived quality of life with the 36-Item Short-Form Survey (SF-36). All of these measures were evaluated at baseline (T0), and immediately (T1), 6 weeks (T2), and 12 weeks (T3) after the end of intervention. Results: At T1 endpoint, HDRS, BDI, SF-36, ISI, and three PSQI items (time to wake up, time taken to fall asleep, and Real Sleep Time) significantly improved, though these gains were reduced at follow-up endpoints (T2 and T3). Adjusting for confounders (age, sex, occupational status, BMI, and hypnotic medication) revealed that only improvements in HDRS, BDI, and time taken to fall asleep at T1 remained statistically significant. Linear regression analyses showed no significant association between reduced time taken to fall asleep and depression symptoms, suggesting rTMS can independently enhance this parameter, irrespective of depression resolution. Conclusion: Routine rTMS therapy can potentially enhance sleep duration in TRD individuals, alongside improved depressive symptoms and quality of life. However, these benefits tend to decrease over long-term follow-up, emphasizing a more pronounced short-term efficacy of rTMS.

Diffusion magnetic resonance imaging for treatment response prediction in schizophrenia spectrum disorders: A systematic review.

A substantial portion of schizophrenia spectrum disorder (SSD) patients exhibit resistance to antipsychotic treatments, emphasizing the need for reliable treatment response biomarkers. Previous magnetic resonance imaging (MRI) studies have identified various imaging predictors in SSD. This study focuses on evaluating the effectiveness of diffusion MRI sequences, diffusion tensor imaging (DTI) and diffusion-weighted imaging (DWI), in predicting antipsychotic response in SSD patients. A systematic search for relevant articles was conducted in PubMed, Embase, Scopus, and Web of Science on February 11, 2024. Twelve studies involving a total of 742 patients were systematically reviewed. The baseline DTI/DWI biomarkers revealed significant associations with antipsychotic treatment response. Notably a consistent negative link was found between response and baseline fractional anisotropy (FA) in fronto-temporo-limbic white matter tracts, specifically the superior longitudinal fasciculus, providing moderate-level evidence. In addition, weak-level evidence was found for the negative association between the treatment response and baseline FA in the corpus callosum, internal, and external capsule tracts. Collectively, this review demonstrated that obtaining pre-treatment brain diffusion MRI scans, particularly from white matter tracts of fronto-temporo-limbic network, can assist in delineating the treatment response trajectory in patients with SSD. However, additional larger randomized controlled trials are required to further substantiate these findings.

Comparison of laparoscopic and hysteroscopic surgical treatments for isthmocele: A prospective cohort.

Objective: To evaluate the clinical outcomes of laparoscopic and hysteroscopic surgical approaches for treating symptomatic isthmocele and identify their associated factors. Materials and Methods: Forty-six patients with symptomatic isthmocele diagnosed using transvaginal saline infusion sonohysterography were enrolled in this prospective cohort study. Patients underwent either laparoscopic or hysteroscopic isthmoplasty based on their residual myometrial thicknesses and fertility desires and were subsequently followed by clinical and ultrasonographic examinations. Results: Twenty-two patients underwent laparoscopy and 24 underwent hysteroscopic surgery. At baseline, there was no significant difference in the mean age and years since the last cesarean section between the two groups. However, the hysteroscopy group had a higher mean parity and previous cesarean sections (p=0.00, 0.03). The most common symptoms were abnormal uterine bleeding, infertility, and dysmenorrhea. The mean baseline residual myometrial thickness was significantly higher in the laparoscopy group (p=0.00), and only laparoscopic surgery led to a significant increase in residual myometrial thickness in patients (p=0.00). Both procedures significantly reduced abnormal uterine bleeding (p=0.00), but only laparoscopy reduced infertility (p=0.00) and hysteroscopy reduced dysmenorrhea (p=0.03). Hysteroscopy showed better symptom resolution in younger patients (p=0.01), whereas age did not affect laparoscopy outcomes. Conclusion: Both approaches showed similar effectiveness in resolving abnormal uterine bleeding, with laparoscopy excelling in infertility resolution and hysteroscopy excelling in dysmenorrhea resolution.

Machine Learning for prediction of violent behaviors in schizophrenia spectrum disorders: a systematic review.

Background: Schizophrenia spectrum disorders (SSD) can be associated with an increased risk of violent behavior (VB), which can harm patients, others, and properties. Prediction of VB could help reduce the SSD burden on patients and healthcare systems. Some recent studies have used machine learning (ML) algorithms to identify SSD patients at risk of VB. In this article, we aimed to review studies that used ML to predict VB in SSD patients and discuss the most successful ML methods and predictors of VB. Methods: We performed a systematic search in PubMed, Web of Sciences, Embase, and PsycINFO on September 30, 2023, to identify studies on the application of ML in predicting VB in SSD patients. Results: We included 18 studies with data from 11,733 patients diagnosed with SSD. Different ML models demonstrated mixed performance with an area under the receiver operating characteristic curve of 0.56-0.95 and an accuracy of 50.27-90.67% in predicting violence among SSD patients. Our comparative analysis demonstrated a superior performance for the gradient boosting model, compared to other ML models in predicting VB among SSD patients. Various sociodemographic, clinical, metabolic, and neuroimaging features were associated with VB, with age and olanzapine equivalent dose at the time of discharge being the most frequently identified factors. Conclusion: ML models demonstrated varied VB prediction performance in SSD patients, with gradient boosting outperforming. Further research is warranted for clinical applications of ML methods in this field.

Potential efficacy of caffeine ingestion on balance and mobility in patients with multiple sclerosis: Preliminary evidence from a single-arm pilot clinical trial.

OBJECTIVES: Caffeine's potential benefits on multiple sclerosis (MS), as well as on the ambulatory performance of non-MS populations, prompted us to evaluate its potential effects on balance, mobility, and health-related quality of life (HR-QoL) of persons with MS (PwMS). METHODS: This single-arm pilot clinical trial consisted of a 2-week placebo run-in and a 12-week caffeine treatment (200 mg/day) stage. The changes in outcome measures during the study period (weeks 0, 2, 4, 8, and 12) were evaluated using the Generalized Estimation Equation (GEE). The outcome measures were the 12-item Multiple Sclerosis Walking Scale (MSWS-12) for self-reported ambulatory disability, Berg Balance Scale (BBS) for static and dynamic balance, Timed Up and Go (TUG) for dynamic balance and functional mobility, Multiple Sclerosis Impact Scale (MSIS-29) for patient's perspective on MS-related QoL (MS-QoL), and Patients' Global Impression of Change (PGIC) for subjective assessment of treatment efficacy. GEE was also used to evaluate age and sex effect on the outcome measures over time. (Iranian Registry of Clinical Trials, IRCT2017012332142N1). RESULTS: Thirty PwMS were included (age: 38.89 ± 9.85, female: 76.7%). Daily caffeine consumption significantly improved the objective measures of balance and functional mobility (BBS; P-value<0.001, and TUG; P-value = 0.002) at each study time point, and the subjective measure of MS-related QoL (MSIS-29; P-value = 0.005) two weeks after the intervention. Subjective measures of ambulatory disability (MSWS-12) and treatment efficacy (PGIC) did not significantly change. The effect of age and sex on the outcome measures were also assessed; significant sex-time interaction effects were found for MSWS-12 (P-value = 0.001) and PGIC (P-value<0.001). The impact of age on BBS scores increased as time progressed (P-value = 0.006). CONCLUSIONS: Caffeine may enhance balance, functional mobility, and QoL in PwMS. Being male was associated with a sharper increase in self-reported ambulatory disability over time. The effects of aging on balance get more pronounced over time. TRIAL REGISTRATION: This study was registered with the Iranian Registry of Clinical Trials (Registration number: IRCT2017012332142N1), a Primary Registry in the WHO Registry Network.

Classification of suicidality by training supervised machine learning models with brain MRI findings: A systematic review.

BACKGROUND: Suicide is a global public health issue causing around 700,000 deaths worldwide each year. Therefore, identifying suicidal thoughts and behaviors in patients can help lower the suicide-related mortality rate. This review aimed to investigate the feasibility of suicidality identification by applying supervised Machine Learning (ML) methods to Magnetic Resonance Imaging (MRI) data. METHODS: We conducted a systematic search on PubMed, Scopus, and Web of Science to identify studies examining suicidality by applying ML methods to MRI features. Also, the Prediction Model Risk of Bias Assessment Tool (PROBAST) was employed for the quality assessment. RESULTS: 23 studies met the inclusion criteria. Of these, 20 developed prediction models without external validation and 3 developed prediction models with external validation. The performance of ML models varied among the reviewed studies, with the highest reported values of accuracies and Area Under the Curve (AUC) ranging from 51.7 % to 100 % and 0.52 to 1, respectively. Over half of the studies that reported accuracy (12/21) or AUC (13/16) achieved values of ≥0.8. Our comparative analysis indicated that deep learning exhibited the highest predictive performance compared to other ML models. The most commonly identified discriminative imaging features were resting-state functional connectivity and grey matter volume within prefrontal-limbic structures. LIMITATIONS: Small sample sizes, lack of external validation, heterogeneous study designs, and ML model development. CONCLUSIONS: Most of the studies developed ML models capable of ML-based suicide identification, although ML models' predictive performance varied across the reviewed studies. Thus, further well-designed is necessary to uncover the true potential of different ML models in this field.

Efficacy and safety of adjunctive therapy with fingolimod in patients with schizophrenia: A randomized, double-blind, placebo-controlled clinical trial.

OBJECTIVES: Studies have suggested that fingolimod, a sphingosine-1-phosphate receptor modulator, exerts neuroprotective and anti-inflammatory effects. Although fingolimod is approved for the treatment of relapsing-remitting multiple sclerosis, limited studies have investigated its effects in patients with schizophrenia. This study investigated the efficacy and safety of fingolimod adjuvant to risperidone in schizophrenia treatment. METHODS: This eight-week, randomized, double-blinded, placebo-controlled trial included 80 (clinical trials registry code: IRCT20090117001556N137) patients with chronic schizophrenia. Participants were assigned to two equal arms and received risperidone plus either fingolimod (0.5 mg/day) or a matched placebo. The positive and negative symptom scale (PANSS) was used to measure and compare the effectiveness of treatment strategies at baseline and weeks 2, 4, 6, and 8. Treatment side effects were also compared. RESULTS: Seventy participants completed the trial (35 in each arm). The baseline characteristics of the groups were comparable (P-value > 0.05). There were significant time-treatment interaction effects on negative symptoms (P-value = 0.003), general symptoms (P-value = 0.037), and the PANSS total score (P-value = 0.035), suggesting greater improvement in symptoms following the fingolimod adjuvant therapy. In contrast, the longitudinal changes in positive and depressive symptoms were similar between the groups (P-values > 0.05). Regarding the safety of treatments, there were no differences in extrapyramidal symptoms [assessed by the extrapyramidal symptom rating scale (ESRS)] or frequency of other complications between the fingolimod and the placebo groups (P-values > 0.05). CONCLUSIONS: This study indicated that fingolimod is a safe and effective adjuvant agent for schizophrenia treatment. However, further clinical trials are required to suggest extensive clinical application.