Brain-based sex differences in schizophrenia: A systematic review of fMRI studies.

Schizophrenia is a chronic psychiatric disorder with characteristic symptoms of delusions, hallucinations, lack of motivation, and paucity of thought. Recent evidence suggests that the symptoms of schizophrenia, negative symptoms in particular, vary widely between the sexes and that symptom onset is earlier in males. A better understanding of sex-based differences in functional magnetic resonance imaging (fMRI) studies of schizophrenia may provide a key to understanding sex-based symptom differences. This study aimed to summarize sex-based functional magnetic resonance imaging (fMRI) differences in brain activity of patients with schizophrenia. We searched PubMed and Scopus to find fMRI studies that assessed sex-based differences in the brain activity of patients with schizophrenia. We excluded studies that did not evaluate brain activity using fMRI, did not evaluate sex differences, and were nonhuman or in vitro studies. We found 12 studies that met the inclusion criteria for the current systematic review. Compared to females with schizophrenia, males with schizophrenia showed more blood oxygen level-dependent (BOLD) activation in the cerebellum, the temporal gyrus, and the right precuneus cortex. Male patients also had greater occurrence of low-frequency fluctuations in cerebral blood flow in frontal and parietal lobes and the insular cortex, while female patients had greater occurrence of low-frequency fluctuations in the hippocampus, parahippocampus, and lentiform nucleus. The current study summarizes fMRI studies that evaluated sex-based fMRI brain differences in schizophrenia that may help to shed light on the underlying pathophysiology and further understanding of sex-based differences in the clinical presentation and course of the disorder.

National and subnational burden of leukemia and its risk factors, 1990-2019: Results from the Global Burden of Disease study 2019.

BACKGROUND: Hematologic malignancies have a great essential role in cancer global burden. Leukemia which two major subtypes based on the onset, is one of the common subtypes of this malignancy. METHOD: For the GBD 2019 study, cancer registry data and vital registration system were used to estimate leukemia mortality. The Meta-Regression-Bayesian Regularized Trimmed (MR-BRT), Cause of Death Ensemble model (CODEm) and Spatiotemporal Gaussian Process Regression (ST-GPR) were used to model our data and estimate each quantity of interest. Mortality to incidence ratios (MIR) were used to generate incidence and survival from mortality rate. Prevalence and survival were used to generate years lived with disability (YLDs). Age-specific mortality and life expectancy at the same age were used to estimate years of life lost (YLLs). The sum of YLLs and YLDs generates DALYs. RESULTS: The total national incidence of leukemia increased from 6092 (UI 95%: 3803-8507) in 1990 to 6767 (4646-7890) new cases in 2019. However, leukemia age-standardized incidence ratio(ASIR) decreased from 11.6 (8-14.8) to 8.9 (6.2-10.3) new cases per 100,000 in this exact period. At the national level, deaths from leukemia increased 1.5-fold between 1990 and 2019, from 3287 (2284-4201) to 4424 (3137-5030), whereas the age-standardized death rate(ASDR) decreased from 8.3 (6.1-9.8) in 1990 to 6 (4.3-6.8) per 100,000 in 2019. In the study period, total leukemia DALYs decreased 12.2% and reached 162850 (110681-188806), in 2019. The age-standardized DALYs decreased 36.7% from 324.3 (224.8-413.4) in 1990 to 205.3 (140.3-237.8) in 2019. ASDR, DALYs, YLLs, and YLDs rate to high BMI was increasing while smoking and occupational exposure to benzene and formaldehyde were decreasing in the study period. CONCLUSION: This study provided a better understanding of leukemia burden and to reduce controversies of leukemia across Iran. The leukemia status alteration of the country, is trackable.

The impact of circular stapler size on the risk of anastomotic stricture following total mesorectal excision in rectal cancer patients: A retrospective cross-sectional study.

Introduction: Colorectal cancer (CRC) surgery complications are a major issue affecting morbidity and mortality rates. Anastomotic stricture, which occurs in almost 30% of patients after surgery for rectal cancer, is one of the most serious but underreported side effects. In this study, we tried to assess the effect of stapler size on anastomotic stricture rate. Materials and Methods: At our facility, all patients underwent low anterior resections (LAR) performed using an open laparotomy technique. A contour-curved stapler and an end-to-end anastomosis (EEA) circular stapler were used in the double stapling technique (DST). All patients also underwent a protective loop ileostomy. Patients who developed stricture following leakage were excluded. Results: This study comprised a total of 173 rectal cancer patients. A 29-mm circle stapler was used to anastomose 77 patients (44.5%), while a 31-mm circular stapler was used to anastomose 96 patients (55.5%). Six individuals experienced strictures; two had a 29 mm stamper and four (4.4%) had a 31 mm one. There was no significant difference between the two groups (p:0.575). On aggregate, 8 patients experienced leakage; 3 (3.8%) of these patients received treatment with a 29 mm stapler, whereas 5 (5.2%) received treatment with a 31 mm stapler. Conclusion: this study found no statistically significant difference in the stricture rates and stapler size. The findings of this study provide credibility to the notion that in rectal cancer patients having LAR, strictures can be safely avoided by performing the anastomoses with both staplers.

Non-alcoholic fatty liver disease and incidence of microvascular complications of diabetes in patients with type 2 diabetes: a prospective cohort study.

Objective: To investigate the association between non-alcoholic fatty liver disease (NAFLD) and liver enzymes with the incidence of microvascular complications (neuropathy, retinopathy, and nephropathy) in a cohort of Iranian patients with type 2 diabetes. Methods: For a total population of 3123 patients with type 2 diabetes, a prospective study was designed for 1215 patients with NAFLD and 1908 gender and age-matched control patients without NAFLD. The two groups were followed for a median duration of 5 years for the incidence of microvascular complications. The association between having NAFLD, the level of liver enzymes, aspartate aminotransferase to platelet ratio index (APRI), Fibrosis-4 (FIB-4) value, and the incidence risk of diabetic retinopathy, neuropathy, and nephropathy were assessed through logistic regression analysis. Results: NAFLD was found to be associated with incidence of diabetic neuropathy and nephropathy (Odds ratio: 1.338 (95% confidence interval: 1.091-1.640) and 1.333 (1.007-1.764), respectively). Alkaline-phosphatase enzyme was found to be associated with higher risks of diabetic neuropathy and nephropathy ((Risk estimate: 1.002 (95% CI: 1.001-1.003) and 1.002 (1.001-1.004), respectively)). Moreover, gamma-glutamyl transferase was associated with a higher risk of diabetic nephropathy (1.006 (1.002-1.009). Aspartate aminotransferase and alanine aminotransferase were inversely associated with the risk of diabetic retinopathy (0.989 (0.979-0.998) and 0.990 (0.983-0.996), respectively). Furthermore, ARPI_T (1), ARPI_T (2), and ARPI_T (3) were shown to be associated with NAFLD (1.440 (1.061-1.954), 1.589 (1.163-2.171), and 2.673 (1.925, 3.710), respectively). However, FIB-4 score was not significantly associated with risk of microvascular complications. Conclusion: Despite the benign nature of NAFLD, patients with type 2 diabetes should be always assessed for NAFLD to ensure early diagnosis and entry into proper medical care. Regular screenings of microvascular complications of diabetes is also suggested for these patients.

Glycemic profile variability: An independent risk factor for diabetic neuropathy in patients with type 2 diabetes.

BACKGROUND: Impaired glycemic control is a potential predictor for macro- and microvascular complications of diabetes, which could be recognized by glycemic variability. The aim of this 10-year prospective cohort study presented here is to gain a better understanding of the correlation between GV and diabetic peripheral neuropathy (DPN) as one of the most common complications of T2DM. METHODS: Since February 2010, 1152 adult patients with T2DM have been followed-up. Baseline features, anthropometric measurements, and laboratory findings were collected and documented during ten years. The association between DPN incidence and glycemic profile variability was evaluated using cox regression analysis. The coefficient of variation of glycemic indices within subjects was calculated and compared using an independent sample t-test. RESULTS: Individuals who developed neuropathy had significantly higher mean levels of glycemic indices (HbA1c, FBS, and 2hpp), urinary albumin excretion, mean creatinine levels, and a longer duration of diabetes. A significant positive correlation between incidence of DPN and glycemic profile variability (cv-FBS10 %, cv-FBS20 %, cv-2hpp20 %, cv-HbA1c5 % and cv-HbA1c10 %) was revealed. Results also showed that higher variability of FBS was associated with the higher risk of neuropathy incidence (HR: 12.29, p-value: 0.045), which indicates that glycemic profile variability is an independent risk factor for DPN in patients with T2DM. CONCLUSION: Variability of glycemic profiles from a visit to visit, regardless of sustained hyperglycemia, was indeed a significant risk factor for DPN in diabetic type 2 patients. CV-FBS was the most critical glycemic variability indices for DPN development.

What are the determinants of parametrial invasion in patients with early stage cervical cancer: A cross sectional study.

Introduction: There was an increase in number of patients presented with early-stage cervical cancer (CC). Tumors with favorable pathological features might be candidates for less radical surgery. Methods: We retrospectively reviewed 700 patients with histologically confirmed CC between January 2011 and March 2020. Chi-square, Fisher's exact tests and multivariate logistic regression analysis were used to assess relations between parametrial involvement (PI) and clinic-pathological variables. Results: Total number of 132 patients with stage IA to IIA were eligible to participate. Squamous cell carcinoma was reported in 100 (75.8%) patients, adenocarcinoma and other tumor pathologies were found in 24(18.2%) and 8(6.1%), respectively. Considering the 2018 FIGO stage, 11 (8.4%) patients had IA, 111 (83%%) IB and 10 (7.6%) IIA. Nine patients (6.8%) had PI on permanent pathologic report. Univariate analysis demonstrated that following variables were statistically different between patients with and without PI: age ≥50, tumor size ≥ 3 cm, lower segment involvement, poorly differentiated pathology, deep stromal invasion, pelvic lymph node, lympho-vascular involvement and positive surgical margin (all p values < 0.05). Among these variables only tumor size ≥3 cm (OR: 2.1, 95% CI: 1.11-4.16, p value: 0.02), deep stromal invasion (OR: 2.2, 95% CI: 1.9-7.43, p value: 0.02) and positive surgical margin (OR: 5.1, 95% CI: 3.97-11.15, p value: 0.008) were independent risk factor of PI in multivariate analysis. Conclusions: Early stage CC might be surgically approached in a more conservative manner if patients have tumor size <3 cm and do not have deep stromal invasion in conization.

Paroxysmal nocturnal haemoglobinuria, diagnosis and haematological findings, first report from Iran, model for developing countries.

Since paroxysmal nocturnal haemoglobinuria (PNH) was first described in 1881, the diagnosis and follow-up patients diagnosed with the illness has remained an area of concern, with several different techniques of varying sensitivity having been described in the literature for both the diagnosis and monitoring treatment of the disease. PNH is a rare and life-threatening disease that manifests symptoms of haemolytic anaemia. Hence, a quick and reliable technique for precise diagnosis would be crucial. PNH patients who have previously been diagnosed with aplastic anaemia or myelodysplastic syndrome carry small PNH clones and for more than a century traditional method with low sensitivity was used for such patients. In 2010, the International Clinical Cytometry Society described a highly sensitive method for detection and quantification of different types of PNH clones using multi-colour flow cytometry. In this method, a three-colour flow cytometer is essential to detect PNH affected cells amongst monocytes and granulocytes. This started a new era in the diagnosis of patients who carry small clones of PNH cells. Before this, flow cytometric analysis was used only for detection of PNH cells amongst erythrocytes. By using flow cytometry instruments with more light sources, the sensitivity of detection and quantification of PNH clones would be augmented. However, standardisation and crosstalk compensation would be the most concerning issue. For the first time in Iran, we set up and standardised multi-colour flow cytometry technique to detect PNH cells in erythrocytes and leukocytes at Payvand medical laboratory.

Implementation of supervised physical training to reduce vasovagal syncope recurrence: A randomized controlled trial.

INTRODUCTION: Physical techniques used for the prevention of vasovagal syncope have limited evidence for efficacy. We aimed to evaluate multimodal supervised physical training as a treatment approach. METHODS: In this 1:1 randomized trial, patients with ≥2 episodes of clinically diagnosed vasovagal syncope were included. On top of standard care, the intervention arm performed supervised tilt training and aerobic exercise in six sessions at a cardiac rehabilitation center (three sessions during the first month, and then at 3-month intervals), plus home tilt training. The control arm received standard care with a similar protocol of home tilt training. The primary outcome was time to first syncopal recurrence during 1 year of follow-up. RESULTS: Fifty participants were randomized (mean age: 34.5 ± 14.8 years; 64% female). The rate of syncopal recurrence was 28% and 64% within the intervention and control arms, respectively, with significantly higher syncope-free survival at 1 year in the intervention arm (Log-rank p = .003). The frequency of recurrent syncopal events was significantly lower with physical training (p = .017). Participants in the intervention arm reported significantly higher adherence to the home tilt training program (80% vs. 52%; p = .037). CONCLUSION: Among patients with recurrent vasovagal syncope, a supervised program of tilt training and aerobic exercise reduced syncopal recurrence. Future trials are warranted to further investigate multimodal supervised physical techniques as a therapeutic approach in treating vasovagal syncope.

Effect of joint immobilization using extension splint immediately after total knee arthroplasty on post-operative knee function and pain: a randomized clinical trial.

PURPOSE: Investigate the effect of semirigid extension bracing after total knee arthroplasty (TKA) on articular pain and function. METHODS: The present randomized clinical trial included 72 patients undergoing unilateral primary TKA. Patients in the case group received eight days of post-operative semirigid extension-locked knee bracing, whereas controls did not. The outcomes assessed preoperatively and on the first, ninth, 30th day, and one year post-operatively included the knee society score (KSS), functional KSS (FKSS), VAS pain score, amount of postoperative opiate painkiller usage (tablet oxycodone 5mg), and knee ROM. RESULTS: The case group had a significantly lower flexion ROM on postoperative day nine compared to the control group (95.3° vs. 100.8°, p=0.03), while it became significantly higher 1 month (114.1° vs. 104.7°, p=0.03) and one year post-operative (128.0° vs. 120.5°, p=0.002). Also, FKSS was significantly higher in the case group than in the controls in the one month post-operative assessment (37.0 vs. 32.6, p=0.009) but not in the one year post-operative assessment. The case group patients had a significantly lower pain than the controls on days one (5.8 vs. 7.2, p=0.02) and nine post-operative (4.1 vs. 5.2, p=0.048), but not at later assessments. The amount of one month post-operative opium (oxycodone) consumption was significantly lower in the brace group (12.4 vs. 14.1 tablets, p=0.03). The KSS were not significantly different between the groups after the surgery. CONCLUSION: Extension-locked splinting immediately after TKA is a noninvasive, non-pharmacological, and inexpensive intervention with possible promising effects on knee ROM, short-term functional improvement, and acute post-operative pain management.

Obesity and Diabetic Complications: A Study from the Nationwide Diabetes Report of the National Program for Prevention and Control of Diabetes (NPPCD-2021) Implications for Action on Multiple Scales.

BACKGROUND: Obesity plays a major role in the pathogenesis and development of macro- and microvascular complications of type 2 diabetes (T2D) and type 1 diabetes (T1D). We aimed to assess the association between obesity and macrovascular and microvascular complications of diabetes. METHODS: This study consisted of 111,830 patients (age range: 1-106) with diabetes including 10,641 T1D (3187 obese [38.2% men] and 7454 non-obese [45.5% men]) and 101,189 T2D (51,873 obese [27.5% men] and 49,316 non-obese [33.4% men]) from the National Program for Prevention and Control of Diabetes (NPPCD-2021) in Iran, who attended academic tertiary care outpatient clinics from February 2016 to April 2021. A pooled logistic regression model was used to examine the association between obesity and diabetic complications. RESULTS: Among patients with T1D, a significant association was found between obesity and cardiovascular disease (CVD), neuropathy, nephropathy and retinopathy (OR= 1.75, 1.56, 1.80 and 1.92, P-value= 0.001, 0.004, 0.001 and <0.001, respectively). In T2D, a statistically significant association was found between obesity and CVD, neuropathy and nephropathy (OR= 1.63, 1.98, 1.21, respectively, P-values <0.001). CONCLUSION: Obesity was independently associated with CVD, neuropathy and nephropathy in patients with T1D and T2D and with retinopathy only in T1D, to different degrees. The association between obesity and retinopathy and neuropathy was the strongest among T1D and T2D, respectively. Findings from this study suggest that obesity affects diabetic complications differently among the two types of diabetes, in terms of epidemiology and pathophysiology. This signifies the importance of different preventive and therapeutic approaches to obesity in T1D compared to T2D, on a national and global scale.

Compression stockings for treating vasovagal syncope (COMFORTS-II) trial: Rationale and design of a triple-blind, multi-center, randomized controlled trial.

BACKGROUND: Reduced venous return is an important trigger of vasovagal syncope (VVS). Elastic compression stockings (ECS) can modify venous return and be of therapeutic interest; however, evidence for ECS efficacy in VVS is scarce. This randomized controlled trial was designed to address the issue. METHODS: COMFORTS-II is a multicenter, triple-blind, parallel design, randomized controlled trial aimed to assess the efficacy of ECS in preventing VVS recurrences. Using central online randomization, 268 participants will be allocated to 2 arms (1:1 ratio), wearing intervention ECS (25-30 mm Hg pressure) or sham ECS (≤10 mm Hg pressure). All participants will receive standard VVS treatment in the form of education, and lifestyle modification recommendations (drinking 2-3 l/d of fluids and consuming 10 g/d-roughly half a tablespoon-of table salt). Adherence to ECS treatment will be evaluated through diary sheets, and compared between study arms. Follow-up continues for 1 year, and is conducted via a 24/7 phone line available to patients and trimonthly visits. The co-primary outcomes are proportion of participants with any syncopal recurrence and time to first syncopal episode. Secondary outcomes include frequency of VVS spells, time intervals between recurrences, and incidence of any patient-reported adverse effects. CONCLUSION: To the best of our knowledge, COMFORTS-II is the first clinical trial to assess ECS efficacy among patients with VVS, addressing an important gap in evidence for VVS treatments.

Incidence of symptomatic COVID-19 in close contacts of patients after discharge from hospital.

BACKGROUND: There is a little evidence about the infectiousness of recovered COVID-19 patients. Considering that the circumstance of the isolation of the COVID-19 patients after-discharge is not always optimal, it is not very unlikely that viral transmission still occurs after hospital discharge. This study aims to investigate the incidence of symptomatic COVID-19 in close contacts of recovered patients after discharge from hospital. METHODS: Four hundred fifty discharged COVID-19 patients discharged from the largest public treatment center in Tehran, capital city of Iran, were followed up. Demographic and clinical data of participants were collected from medical records. Follow-up data were acquired via telephone call interviews with patients or their main caregivers at home. RESULTS: The study's response rate was 93.77% (422 participated in the study). 60.90% patients were male and 39.10% were female (sex ratio = 1.55 male). The most prevalent comorbidities in these patients were hypertension (29.68%) and diabetes (24.80%). The mean of home isolation after discharge was 25.85. Forty-one (9.71%) patients had at least one new case in their close contacts, up to 3 weeks after they were discharged. There was a significant association between having at least a comorbidity with the odds of getting infected in close contacts [OR (CI) 2.22 (1.05-4.68)]. Density of inhabitant per room in a house' and the quality of isolation had significant associations with observing new cases in the patients' close contacts [high to moderate; OR (CI) 2.44 (1.06-5.61], [bad to good; OR (CI) 2.31 (1.17-4.59)], respectively. CONCLUSION: After hospital discharge, COVID-19 transmission can still occur, when a large number of people lives together in a single house. Another explanation can be that the less precaution measures are taken by recovered patients' cohabitants. Such conditions are also likely to happen when the recovered patient has other chronic diseases and requires additional care.

Cerebellar Microstructural Abnormalities in Parkinson's Disease: a Systematic Review of Diffusion Tensor Imaging Studies.

Diffusion tensor imaging (DTI) is now having a strong momentum in research to evaluate the neural fibers of the CNS. This technique can study white matter (WM) microstructure in neurodegenerative disorders, including Parkinson's disease (PD). Previous neuroimaging studies have suggested cerebellar involvement in the pathogenesis of PD, and these cerebellum alterations can correlate with PD symptoms and stages. Using the PRISMA 2020 framework, PubMed and EMBASE were searched to retrieve relevant articles. Our search revealed 472 articles. After screening titles and abstracts, and full-text review, and implementing the inclusion criteria, 68 papers were selected for synthesis. Reviewing the selected studies revealed that the patterns of reduction in cerebellum WM integrity, assessed by fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity measures can differ symptoms and stages of PD. Cerebellar diffusion tensor imaging (DTI) changes in PD patients with "postural instability and gait difficulty" are significantly different from "tremor dominant" PD patients. Freezing of the gate is strongly related to cerebellar involvement depicted by DTI. The "reduced cognition," "visual disturbances," "sleep disorders," "depression," and "olfactory dysfunction" are not related to cerebellum microstructural changes on DTI, while "impulsive-compulsive behavior" can be linked to cerebellar WM alteration. Finally, higher PD stages and longer disease duration are associated with cerebellum white matter alteration depicted by DTI. Depiction of cerebellar white matter involvement in PD is feasible by DTI. There is an association with disease duration and severity and several clinical presentations with DTI findings. This clinical-imaging association may eventually improve disease management.

Effects of a Mediterranean diet on the development of diabetic complications: A longitudinal study from the nationwide diabetes report of the National Program for Prevention and Control of Diabetes (NPPCD 2016-2020).

OBJECTIVE: To evaluate the effectiveness of a Mediterranean dietary pattern on the incidence of macrovascular and microvascular complications of diabetes, namely cardiovascular disease (CVD), diabetic foot disorders, diabetic retinopathy, nephropathy, and neuropathy. METHODS: This longitudinal study was conducted among 71392 adults with diabetes who attended academic tertiary-care outpatient clinics from February 2016 to March 2020 across Iran using the National Program for Prevention and Control of Diabetes database. Among them, 22187 patients with diabetes (type 1 and type 2) completed 2-11 follow-up visits after baseline registration. The association between adherence to a Mediterranean diet and diabetic complications was assessed using pooled logistic regression models. This association was adjusted for potential confounders. The effect of time was assessed using fractional polynomials. RESULTS: A total of 22187 participants were included in the analysis (30.22% men and 69.78% women) with either type 1 (mean age 50.7 years) or type 2 (mean age 59.9 years) diabetes. After adjustment for confounding variables, there was a negative correlation between adherence to a Mediterranean diet and the incidence of CVD among patients with type 1 diabetes (T1D) and 2 diabetes (T2D) (OR= 0.53, 95% CI: 0.37 - 0.75, p-value <0.001 and OR= 0.61, 95% CI: 0.57 - 0.89, p-value <0.001, respectively). Also, the diet had a statistically significant protective effect against incident symptomatic neuropathy (OR= 0.32, 95% CI: 0.23 - 0.43, p-value <0.001, and OR= 0.68, 95% CI: 0.64 - 0.72, p-value <0.001, respectively), nephropathy (OR= 0.42, 95% CI: 0.30 - 0.58, p-value <0.001, and OR= 0.88, 95% CI: 0.80 - 0.96, p-value= 0.007, respectively), and retinopathy (OR= 0.32, 95% CI: 0.24 - 0.44, p-value <0.001, and OR= 0.68, 95% CI: 0.61 - 0.71, p-value <0.001, respectively) in T1D and T2D. CONCLUSION: The Mediterranean dietary pattern is associated with a lower incidence of CVD and microvascular complications (i.e. diabetic retinopathy, nephropathy, and neuropathy) among a cohort of patients with T1D and T2D in Iran.

Efficacy and safety of tipepidine as adjunctive therapy in major depressive disorder: A randomized, double-blind, placebo-controlled clinical trial.

AIM: Tipepidine, a synthetic, non-opioid expectorant, has been shown to improve depressive-like behavior in animal models of depression. In this study, we assessed the efficacy and tolerability of tipepidine combination therapy with citalopram in treatment of major depressive disorder (MDD). METHODS: In a randomized, double-blinded, placebo-controlled clinical trial, 62 patients with MDD were assigned into two parallel groups to receive citalopram (up to 40 mg/day) plus placebo or citalopram plus tipepidine (30 mg twice daily) for 6 weeks. Participants were assessed with the Hamilton Rating Scale for Depression (HAM-D) at baseline and Weeks 2, 4, and 6. RESULTS: Fifty-six patients completed the trial. The tipepidine group showed greater improvement in HAM-D scores from baseline to all three study time points (P = 0.048 for all). The remission and response-to-treatment rates were significantly higher in the tipepidine group (53.6% and 100%) compared to the placebo group (25.0% and 75%) at the study end-point (P = 0.029 and 0.005, respectively). The remission and response times in patients in the tipepidine group were also shorter compared with the placebo group (log-rank P = 0.020 and 0.004). There was no significant difference between the two groups in baseline parameters or frequency of side-effects. CONCLUSION: Tipepidine combination therapy with citalopram can effectively improve symptoms of patients with MDD in a shorter period of treatment. However, further studies with larger sample sizes and longer follow-up treatment are needed to confirm our findings.