Comparing the effect of fluoxetine, escitalopram, and sertraline, on the level of BDNF and depression in preclinical and clinical studies: a systematic review.

Brain-derived neurotrophic factor (BDNF) dysfunction is one of the most important mechanisms underlying depression. It seems that selective serotonin reuptake inhibitors (SSRIs) improve depression via affecting BDNF level. In this systematic review, for the first time, we aimed to review the effect of three SSRIs including fluoxetine, escitalopram, and sertraline, on both depression and BDNF level in preclinical and clinical studies. PubMed electronic database was searched, and 193 articles were included in this study. After reviewing all manuscripts, only one important difference was found: subjects. We found that SSRIs induce different effects in animals vs. humans. Preclinical studies showed many controversial effects, while human studies showed only two effects: improvement of depression, with or without the improvement of BDNF. However, most studies used chronic SSRIs treatment, while acute SSRIs were not effectively used and evaluated. In conclusion, it seems that SSRIs are reliable antidepressants, and the improvement effect of SSRIs on depression is not dependent to BDNF level (at least in human studies).

Sex-controlled differences in sertraline and citalopram efficacies in major depressive disorder: a randomized, double-blind trial.

To investigate the response to antidepressants while controlling for sex, which has been controversial, 92 outpatient males and females with major depressive disorder were assigned to sertraline (100 mg/day) or citalopram (40 mg/day) in two strata and were assessed using Hamilton depression rating scale (HDRS) scores and brain-derived neurotrophic factor (BDNF), interleukin (IL)-6 and cortisol serum levels in this 8-week, randomized, parallel-group, double-blind clinical trial. Data of 40 sertraline and 40 citalopram recipients with equal representation of males and females assigned to each medication were analyzed, while their baseline characteristics were not statistically different (P > 0.05). There were no significant differences between sertraline and citalopram recipients in outcome changes (P > 0.05), all of which indicated improvement, but a significant time-treatment-sex interaction effect in BDNF levels was observed (P = 0.035). Regarding this, subgroup analyses illustrated a significantly greater increase in male BDNF levels following sertraline treatment (P = 0.020) with a moderate to large effect size (Cohen's d = 0.76 and ). Significant associations were observed between percentage changes in IL-6 levels and BDNF levels in sertraline recipients (P = 0.033) and HDRS scores in citalopram recipients (P < 0.001). Sex was an effect modifier in BDNF alterations following sertraline and citalopram administration. Further large-scale, high-quality, long-term studies are recommended.

Emerging drugs for the treatment of irritability associated with autism spectrum disorder.

INTRODUCTION: Autism spectrum disorder (ASD) is an early-onset disorder with a prevalence of 1% among children and reported disability-adjusted life years of 4.31 million. Irritability is a challenging behavior associated with ASD, for which medication development has lagged. More specifically, pharmacotherapy effectiveness may be limited against high adverse effects (considering side effect profiles and patient medication sensitivity); thus, the possible benefits of pharmacological interventions must be balanced against potential adverse events in each patient. AREAS COVERED: After reviewing the neuropathophysiology of ASD-associated irritability, the benefits and tolerability of emerging medications in its treatment based on randomized controlled trials were detailed in light of mechanisms and targets of action. EXPERT OPINION: Succeeding risperidone and aripiprazole, monotherapy with memantine may be beneficial. In addition, N-acetylcysteine, galantamine, sulforaphane, celecoxib, palmitoylethanolamide, pentoxifylline, simvastatin, minocycline, amantadine, pregnenolone, prednisolone, riluzole, propentofylline, pioglitazone, and topiramate, all adjunct to risperidone, and clonidine and methylphenidate outperformed placebo. These effects were through glutamatergic, γ-aminobutyric acidergic, inflammatory, oxidative, cholinergic, dopaminergic, and serotonergic systems. All medications were reported to be safe and tolerable. Considering sample size, follow-up, and effect size, further studies are necessary. Along with drug development, repositioning and combining existing drugs supported by the mechanism of action is recommended.

Efficacy and safety of celecoxib for treatment of mild to moderate postpartum depression: a randomized, double-blind, placebo-controlled trial.

PURPOSE: Evidence has demonstrated the roles of inflammatory processes in pathogenesis of depression. We aim to assess the effects of adjunctive celecoxib with cognitive behavioral therapy (CBT), an anti-inflammatory agent, in treatment of postpartum depression and on levels of Brain-derived neurotrophic factor (BDNF) and inflammatory cytokines. METHODS: This was a randomized, double-blind, placebo-controlled trial to investigate the effects of adjunctive celecoxib with CBT on postpartum depression. Fifty outpatient women with postpartum depression, participated in this study. Patients randomly received either a celecoxib capsule twice a day or a placebo capsule twice a day for 6 weeks. Patients were assessed using the Hamilton Depression Rating Scale (HDRS) and the adverse event checklist at baseline and weeks 2, 4, and 6. RESULTS: Patients in the celecoxib group showed a greater decline in HDRS scores from baseline to all three study time points compared to the placebo group (p = 0.12 for week 2, p = 0.001 for week 4, p < 0.001 for week 6). Rate of response to treatment was significantly higher in the celecoxib group compared to the placebo group at week 4 (60 vs 24%, p = 0.010) and week 6 (96 vs 44%, p < 0.001). Rate of remission was significantly higher in the celecoxib group compared to the placebo group at week 4 (52 vs 20%, p = 0.018) and week 6 (96 vs 36%, p < 0.001). Levels of most inflammatory markers were significantly lower in the celecoxib group compared to the placebo group at week 6. Levels of BDNF were significantly higher in the celecoxib group compared to the placebo group at week 6 (p < 0.001). CONCLUSIONS: Findings suggest adjunctive celecoxib is an effective treatment for the improvement of postpartum depressive symptoms.

Resting-state functional magnetic resonance imaging alterations in borderline personality disorder: A systematic review.

BACKGROUND: Borderline personality disorder (BPD) is a severe psychiatric disorder characterized by emotion dysregulation, impulsivity, and interpersonal disturbances. Several structural and functional neuroimaging abnormalities have been described in BPD. In particular, resting-state functional magnetic resonance imaging (rs-fMRI) studies have recently suggested various connectivity alterations within and between large-scale brain networks in BPD. This review aimed at providing an updated summary of the evidence reported by the available rs-fMRI studies in BPD individuals. METHODS: A search on PubMed, Scopus, and Web of Science was performed to identify rs-fMRI alterations in BPD. A total of 15 studies met our inclusion criteria. RESULTS: Overall, aberrant resting-state functional connectivity (rs-FC) within and between default mode network (DMN), salience network (SN), and central executive network (CEN) were observed in BPD compared to healthy controls, as well as selective functional impairments in bilateral amygdala, anterior and posterior cingulate cortex, hippocampus, and prefrontal cortex. LIMITATIONS: The observational design, small sample size, prevalence of females, high rates of concurrent comorbidities and medications, and heterogeneity across imaging methodologies limit the generalizability of the results. CONCLUSIONS: The identification of altered patterns of rs-FC within and between selective brain networks, including DMN, SN, and CEN, could further our knowledge of the clinical symptoms of BPD, and therefore, future studies with multimodal methodologies and longitudinal designs are warranted to further explore the neural correlates of this disorder.

Efficacy and safety of celecoxib monotherapy for treatment of moderate depressive symptoms following COVID-19 infection: A randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Celecoxib, a nonsteroidal anti-inflammatory agent, was found to be an effective add-on treatment for unipolar and bipolar depression. We investigated the potential beneficial effect of celecoxib monotherapy on depressive symptoms after Coronavirus disease (COVID-19). METHODS: This was a randomized, double-blind, placebo-controlled clinical trial investigating the therapeutic effects of celecoxib monotherapy in patients with moderate depressive symptoms following COVID-19 infection. Patients were randomized to receive either a celecoxib capsule (100 mg) twice daily or a placebo capsule twice daily for 6 weeks. Participants were assessed with the Hamilton Depression Rating Scale (HDRS) and the side effect checklist at baseline and weeks 3 and 6. RESULTS: A total of 62 patients were included. GLM repeated-measures showed a significant effect of time × treatment (F = 12.95, df = 1.98, p < 0.001) for celecoxib, suggesting superior improvement of depressive symptoms in celecoxib compared to placebo from baseline to the study endpoint. HDRS scores in the celecoxib group showed a greater decline from baseline to both week 3 (t = 4.12, p < 0.001, Cohen's d = 1.10) and week 6 (t = 4.76, p < 0.001, Cohen's d = 1.27), compared to the placebo group. Rate of response to treatment (70% vs 9%, p < 0.001) and remission (67% vs 0%, p < 0.001) was significantly higher in celecoxib compared to the placebo group at week 6. Adverse event frequencies were not significantly different between the two groups. CONCLUSION: We demonstrated that treatment with celecoxib significantly improved depression scores of patients with depressive symptoms following COVID-19 infection. Further trials with larger sample sizes and longer study periods should assess our findings before any suggestion for clinical use. The trial was prospectively registered at the Iranian registry of clinical trials (www.irct.ir; registration number: IRCT20090117001556N142).

Reboxetine Combination Therapy With Fluoxetine in Moderate to Severe Obsessive-Compulsive Disorder: A Placebo-Controlled, Double-Blind, Randomized Trial.

OBJECTIVES: Reboxetine is a potent and selective norepinephrine reuptake inhibitor that was effective in combination with citalopram for resistant obsessive-compulsive disorder (OCD). This study aims to assess its effectiveness and tolerability in combination with fluoxetine in treating OCD. METHODS: In this 2-center, placebo-controlled, and double-blind, randomized clinical trial, 76 patients with OCD were assigned into 2 parallel groups to receive fluoxetine (up to 80 mg/d) plus placebo (F + P) or fluoxetine (up to 80 mg/d) plus reboxetine (F + R) (10 mg twice daily) for 10 weeks. Participants were assessed with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline and weeks 5 and 10. RESULTS: A total of 76 patients completed the trial. There was no significant difference between the 2 groups in baseline Y-BOCS scores. General linear model repeated-measures showed significant effects on time × treatment interaction on total Y-BOCS ( F = 6.33, df = 1.42, P = 0.006) and obsession subscale scores ( F = 10.39, df = 1.48, P < 0.001), and insignificance on compulsion subscale scores ( F = 1.86, df = 1.24, P = 0.173). Reboxetine combination therapy demonstrated a higher partial and complete treatment response rate ( P < 0.01) according to the Y-BOCS total scores. There was no significant difference between the 2 groups in the frequency of adverse effects. CONCLUSIONS: Reboxetine combination therapy with fluoxetine can effectively improve symptoms in patients with OCD in a short period of treatment. However, further studies with larger sample sizes and longer follow-up periods are needed to confirm these findings.This trial was registered with the Iranian Registry of Clinical Trials ( www.irct.ir ; No IRCT20090117001556N129).

L-Theanine adjunct to risperidone in the treatment of chronic schizophrenia inpatients: a randomized, double-blind, placebo-controlled clinical trial.

RATIONALE: Inadequate responses to current schizophrenia treatments have accelerated research into novel therapeutic approaches. OBJECTIVES: This study investigated the efficacy and tolerability of adjunctive L-theanine, an ingredient with neuroimmunomodulatory and neuroprotective properties, for chronic schizophrenia. METHODS: Eighty chronic schizophrenia inpatients were equally assigned to receive risperidone (6 mg/day) plus either L-theanine (400 mg/day) or matched placebo in this 8-week, randomized, parallel-group, double-blind, placebo-controlled trial. The participants were assessed using the Positive and Negative Syndrome Scale (PANSS) by recording the results of subscales at baseline and weeks 4 and 8 to measure treatment efficacy. Additionally, the participants were assessed for the Hamilton Depression Rating Scale (HDRS) and adverse events, including the Extrapyramidal Symptom Rating Scale (ESRS). RESULTS: Sixty patients, 30 in each group, were included in the analyses. All baseline demographic and clinical characteristics were comparable between the groups (p-values > 0.05). The reduction rates from baseline to endpoint in negative, general psychopathology, and total scores of PANSS were greater in the L-theanine group (p-values = 0.03, 0.01, and 0.04, respectively). Regarding general psychopathology scores, the reduction in the L-theanine group was also greater until week 4 (p-value < 0.01). The time × treatment interaction effect was significant on negative (p-value = 0.03), general psychopathology (p-value < 0.01), and total (p-value = 0.04) scores of PANSS, indicating additional improvements in the L-theanine group. The HDRS and side effects were comparable between the groups (p-values > 0.05). CONCLUSIONS: L-Theanine adjunct to risperidone safely and tolerably outperformed adjunctive placebo for schizophrenia, and promising evidence indicated its effects on primary negative symptoms, which need to be scrutinized in further studies. TRIAL REGISTRATION: The study protocol was registered and published prospectively in the Iranian Registry of Clinical Trials ( http://www.irct.ir ; registration number: IRCT20090117001556N133) on 2020-12-12.

Effects of Antidepressant Medication on Brain-derived Neurotrophic Factor Concentration and Neuroplasticity in Depression: A Review of Preclinical and Clinical Studies.

Depression is the most prevalent and debilitating disease with great impact on societies. Evidence suggests Brain-Derived Neurotrophic Factor (BDNF) plays an important role in pathophysiology of depression. Depression is associated with altered synaptic plasticity and neurogenesis. BDNF is the main regulatory protein that affects neuronal plasticity in the hippocampus. A wealth of evidence shows decreased levels of BDNF in depressed patients. Important literature demonstrated that BDNF-TrkB signaling plays a key role in therapeutic action of antidepressants. Numerous studies have reported anti-depressant effects on serum/plasma levels of BDNF and neuroplasticity which may be related to improvement of depressive symptoms. Most of the evidence suggested increased levels of BDNF after antidepressant treatment. This review will summarize recent findings on the association between BDNF, neuroplasticity, and antidepressant response in depression. Also, we will review recent studies that evaluate the association between postpartum depression as a subtype of depression and BDNF levels in postpartum women.

l-carnitine adjunct to risperidone for treatment of autism spectrum disorder-associated behaviors: a randomized, double-blind clinical trial.

Present study was designed to evaluate the efficacy and safety of l-carnitine as an adjuvant agent to risperidone in the treatment of autism spectrum disorder (ASD)-associated behaviors. In this study, 68 children with confirmed ASD were randomly allocated to receive either l-carnitine (150 mg/day) or matched placebo in addition to risperidone. We utilized the Aberrant Behavior Checklist-Community Edition scale (ABC-C) and a checklist of potential adverse effects to assess changes in behavioral status and safety profile at weeks 0, 5 and 10 of the trial. The primary outcome was defined as a change in the irritability subscale score. Sixty patients with similar baseline characteristics completed the trial period. Although scores of ABC-C subscales significantly decreased in both groups over the trial period, the combination of l-carnitine and risperidone resulted in more reduction on the irritability and hyperactivity subscales compared to the combination of risperidone and placebo (P = 0.033 and P < 0.001, respectively). However, changes in lethargy, stereotypic behavior and inappropriate speech subscales were similar between groups. In conclusion, l-carnitine adjuvant to risperidone could improve irritability and hyperactivity features in children with ASD. Results of this study should be considered preliminary and further clinical trials with larger sample sizes and longer follow-up periods are warranted.

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.

Effect of famotidine on cognitive and behavioral dysfunctions induced in post-COVID-19 infection: A randomized, double-blind, and placebo-controlled study.

OBJECTIVES: This is an investigation of the efficacy and safety of famotidine, a selective histamine H2 receptor antagonist, on improvement of cognitive impairment, depression and anxiety symptoms developing post-COVID-19, in a 12-week, randomized controlled trial. METHODS: A total of 50 patients with a confirmed diagnosis of COVID-19 and a score ≤ 23 on the Mini-Mental State Examination (MMSE) test or a score ≤ 22 on the Montreal Cognitive Assessment (MoCA) were randomly assigned to either the famotidine (40 mg twice daily) or the placebo group. Changes in MMSE scores at weeks 6 and 12 were the primary outcome, while changes in other scales were the secondary outcomes. Participants and evaluators were blinded. RESULTS: At weeks 6 and 12, patients in the famotidine group had significantly higher MMSE scores (p = 0.014, p < 0.001, respectively). Regarding the MoCA scale, the famotidine group had a significantly higher score at weeks 6 and 12 (p = 0.001, p < 0.001, respectively). Considering the HAM-D scale (Hamilton Depression Rating Scale), at weeks 6 and 12, the famotidine group experienced a larger reduction (p = 0.009, p = 0.02, respectively). Additionally, comparison of the HAM-A scale scores (Hamilton Anxiety Rating Scale) at weeks 6 and 12 showed a statistically significant larger reduction in the famotidine group (p = 0.04, p = 0.02, respectively). The two groups did not differ in the frequency of adverse effects. CONCLUSION: Our study supports safety and efficacy of famotidine in treating cognitive impairment, depression and anxiety symptoms induced by COVID-19. TRIAL REGISTRATION: This trial was registered at the Iranian registry of clinical trials (IRCT: www.irct.ir; registration number: IRCT20090117001556N138).

Parkinson's Disease: A Narrative Review on Potential Molecular Mechanisms of Sleep Disturbances, REM Behavior Disorder, and Melatonin.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. There is a wide range of sleep disturbances in patients with PD, such as insomnia and rapid eye movement (REM) sleep behavior disorder (or REM behavior disorder (RBD)). RBD is a sleep disorder in which a patient acts out his/her dreams and includes abnormal behaviors during the REM phase of sleep. On the other hand, melatonin is the principal hormone that is secreted by the pineal gland and significantly modulates the circadian clock and mood state. Furthermore, melatonin has a wide range of regulatory effects and is a safe treatment for sleep disturbances such as RBD in PD. However, the molecular mechanisms of melatonin involved in the treatment or control of RBD are unknown. In this study, we reviewed the pathophysiology of PD and sleep disturbances, including RBD. We also discussed the potential molecular mechanisms of melatonin involved in its therapeutic effect. It was concluded that disruption of crucial neurotransmitter systems that mediate sleep, including norepinephrine, serotonin, dopamine, and GABA, and important neurotransmitter systems that mediate the REM phase, including acetylcholine, serotonin, and norepinephrine, are significantly involved in the induction of sleep disturbances, including RBD in PD. It was also concluded that accumulation of α-synuclein in sleep-related brain regions can disrupt sleep processes and the circadian rhythm. We suggested that new treatment strategies for sleep disturbances in PD may focus on the modulation of α-synuclein aggregation or expression.

L-theanine combination therapy with fluvoxamine in moderate-to-severe obsessive-compulsive disorder: A placebo-controlled, double-blind, randomized trial.

AIM: The main aim of this study was to investigate the additional effects of L-theanine, an amino acid in tea and an analog of glutamate with neuroprotective and anti-depressant properties, on obsessive-compulsive disorder (OCD) symptoms in combination with fluvoxamine. METHODS: Patients from either sex aged between 18 and 60 years diagnosed with OCD, based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), who had a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of more than 21 were enrolled in a double-blinded, parallel-group, placebo-controlled, clinical trial of 10 weeks to receive either L-theanine (100 mg twice daily) and fluvoxamine (100 mg daily initially followed by 200 mg daily after week 5) or placebo and fluvoxamine. The primary outcome of interest in this study was the Y-BOCS total score decrease from baseline. RESULTS: From a total of 95 evaluated patients, 50 completed our study; 30 were randomly assigned to each group. Multivariate analysis (ANOVA) showed a significant effect of time × $$ \times $$ treatment for L-theanine in obsession subscale (F = 5.51, P = 0.008) of the Y-BOCS score but not in the total and compulsion scores. Our results showed significantly more improvement in obsession subscale scores in L-theanine compared to placebo group (P = 0.007, Cohen's d = 0.82). Also, total Y-BOCS scores were lower in L-theanine compared to placebo group at week 5 (P = 0.039, Cohen's d = 0.60) and 10 (P = 0.008, Cohen's d = 0.80). However, there was no significant between-group differences in compulsion subscale scores. Complete response was also more frequent in the L-theanine group (P = 0.0001). CONCLUSION: Findings in this study suggest L-theanine as a relatively safe and effective adjuvant therapy for moderate to severe OCD.

Neuroimaging Correlates of Treatment Response to Transcranial Magnetic Stimulation in Bipolar Depression: A Systematic Review.

Transcranial magnetic stimulation (TMS) has become a promising strategy for bipolar disorder (BD). This study reviews neuroimaging findings, indicating functional, structural, and metabolic brain changes associated with TMS in BD. Web of Science, Embase, Medline, and Google Scholar were searched without any restrictions for studies investigating neuroimaging biomarkers, through structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), functional MRI (fMRI), magnetic resonance spectroscopy (MRS), positron emission tomography (PET), and single photon emission computed tomography (SPECT), in association with response to TMS in patients with BD. Eleven studies were included (fMRI = 4, MRI = 1, PET = 3, SPECT = 2, and MRS = 1). Important fMRI predictors of response to repetitive TMS (rTMS) included higher connectivity of emotion regulation and executive control regions. Prominent MRI predictors included lower ventromedial prefrontal cortex connectivity and lower superior frontal and caudal middle frontal volumes. SPECT studies found hypoconnectivity of the uncus/parahippocampal cortex and right thalamus in non-responders. The post-rTMS changes using fMRI mostly showed increased connectivity among the areas neighboring the coil. Increased blood perfusion was reported post-rTMS in PET and SPECT studies. Treatment response comparison between unipolar depression and BD revealed almost equal responses. Neuroimaging evidence suggests various correlates of response to rTMS in BD, which needs to be further replicated in future studies.

l-theanine adjunct to sertraline for major depressive disorder: A randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Unsatisfactory responses to major depressive disorder (MDD) therapeutics available necessitated up-to-date treatment approaches. This study sought to investigate the efficacy and tolerability of adjunctive l-theanine, a green tea constituent with neuropsychotropic effects, for MDD. METHODS: Sixty MDD (DSM-5) patients were equally assigned to receive sertraline (100 mg/d) plus either l-theanine (200 mg/d) or matched placebo in a six-week randomized, parallel-group, double-blind, placebo-controlled study. The participants were assessed using the Hamilton depression rating scale (HDRS) at baseline and weeks 2, 4, and 6. Changes in scores, early improvement, response and remission rates, and adverse events were compared between the groups. RESULTS: Twenty-five participants in each group, a total of 50 patients, completed the study. All baseline characteristics were similar between the groups. The general linear model repeated-measures analysis demonstrated a significant time-treatment interaction effect for HDRS during the trial (p-value = 0.014), indicating more remarkable symptom improvement in the l-theanine group. A greater reduction in HDRS scores was observed in the l-theanine group from baseline to weeks 2, 4, and 6 (p-values = 0.02, 0.03, and 0.01, respectively). All patients responded to sertraline plus l-theanine until week 6. l-theanine was superior to placebo regarding response to treatment and remission rates at week 6 (p-values = 0.05 and 0.02, respectively). The frequency of side effects was comparable between the groups. LIMITATIONS: The small sample size and short study period were the limitations. CONCLUSIONS: l-theanine adjunct to sertraline outperforms placebo in treating MDD in a safe manner. Further long-term, large-scale studies are recommended to confirm this evidence.