A systematic review and meta-analysis of the efficacy of ketamine and esketamine on suicidal ideation in treatment-resistant depression.

PURPOSE: To systematically assess the evidence of efficacy and safety of the use of ketamine and esketamine for patients with treatment-resistant depression (TRD) with suicidal ideation (SI). METHODS: We independently searched for clinical trials from inception to January 2023 using electronic databases, e.g., PubMed and EMBASE. A systematic review and meta-analysis were performed to assess SI scores of depression rating scales, which were regarded as the outcomes. RESULTS: A total of five independent double-blind, placebo controlled randomized clinical trials (RCTs) are eligible for inclusion. Four of the studies used ketamine as an intervention and one used esketamine as an intervention. Three hundred ninety-one patients with TRD were included (the intervention group with ketamine or esketamine is 246, and the control group is 145). No statistically significant interaction between the subscales of suicide ideation (SMD = - 0.66, 95% CI (- 1.61, 0.29); Z = 1.36, P = 0.17) and antidepressant effects (SMD = - 0.99, 95% CI (- 2.33, 0.34); Z = 1.46, P = 0.15) based on the results of ketamine and esketamine, compared with placebo groups. CONCLUSION: This meta-analysis suggested that esketamine and ketamine have failed to reduce suicidal ideation in patients with TRD. Further studies are desirable to confirm the effects of ketamine and esketamine in TRD patients.

p-AKT/VPS4B regulates the small extracellular vesicle size in venous malformation endothelial cells.

OBJECTIVE: Small extracellular vesicle (sEV)-mediated intercellular communication is increasingly the key for the understanding of venous malformations (VMs). This study aims to clarify the detailed changes of sEVs in VMs. SUBJECTS AND METHODS: Fifteen VM patients without treatment history and twelve healthy donors were enrolled in the study. sEVs were isolated from both fresh lesions and cell supernatant, and were examined by western blotting, nanoparticle tracking analysis and transmission electron microscopy. Western blot analysis, immunohistochemistry and immunofluorescence were adopted to screening candidate regulator of sEV size. Specific inhibitors and siRNA were employed to validate the role of dysregulated p-AKT/vacuolar protein sorting-associated protein 4B (VPS4B) signaling on the size of sEVs in endothelial cells. RESULTS: The size of sEVs derived from both VM lesion tissues and cell model was significantly increased. VPS4B, whose expression level was mostly significantly downregulated in VM endothelial cells, was responsible for the size change of sEVs. Targeting abnormal AKT activation corrected the size change of sEVs by recovering the expression level of VPS4B. CONCLUSION: Downregulated VPS4B in endothelial cells, resulted from abnormally activated AKT signaling, contributed to the increased size of sEVs in VMs.

m6A transferase METTL3 regulates endothelial-mesenchymal transition in diabetic retinopathy via lncRNA SNHG7/KHSRP/MKL1 axis.

Diabetic retinopathy is one of the microvascular complications in diabetic patients and the leading cause of blindness worldwide. The levels of METTL3, lncRNA SNHG7, KHSRP, MKL1, endothelial and mesenchymal markers were determined by RT-qPCR or western blot assays in vitro and in vivo. H&E staining was used to observe the retinal structure in a mouse model of DR. The expression levels of METTL3 and SNHG7 were significantly downregulated in DR patients, DR mice and high glucose-induced HRMECs cells. Notably, METTL3 installed the m6A modification and enhanced the stability of SNHG7. Besides, METTL3 inhibited HRMECs EndoMT by promoting the expression of SNHG7. Additionally, SNHG7 was found to weaken MKL1 mRNA stability by binding to the RNA-binding protein KHSRP. Furthermore, we verified that METTL3 regulated EndoMT in DR through the SNHG7/MKL1 axis. We conclude that METTL3 regulates endothelial-mesenchymal transition in DR via the SNHG7/KHSRP/MKL1 axis, providing a new target for DR treatment.

[Autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations: a report of 8 cases and literature review]. / SYNGAP1åŸºå› å˜å¼‚ç›¸å ³å¸¸æŸ“è‰²ä½“æ˜¾æ€§æ™ºåŠ›éšœç¢5型8ä¾‹å¹¶æ–‡çŒ®å¤ä¹ .

OBJECTIVES: To summarize the clinical phenotype and genetic characteristics of children with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations. METHODS: A retrospective analysis was performed on the medical data of 8 children with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations who were diagnosed and treated in the Department of Pediatrics, Xiangya Hospital of Central South University. RESULTS: The mean age of onset was 9 months for the 8 children. All children had moderate-to-severe developmental delay (especially delayed language development), among whom 7 children also had seizures. Among these 8 children, 7 had novel heterozygous mutations (3 with frameshift mutations, 2 with nonsense mutations, and 2 with missense mutations) and 1 had 6p21.3 microdeletion. According to the literature review, there were 48 Chinese children with mental retardation caused by SYNGAP1 gene mutations (including the children in this study), among whom 40 had seizures, and the mean age of onset of seizures was 31.4 months. Frameshift mutations (15/48, 31%) and nonsense mutations (19/48, 40%) were relatively common in these children. In terms of treatment, among the 33 children with a history of epileptic medication, 28 (28/33, 85%) showed response to valproic acid antiepileptic treatment and 16 (16/33, 48%) achieved complete seizure control after valproic acid monotherapy or combined therapy. CONCLUSIONS: Children with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations tend to have an early age of onset, and most of them are accompanied by seizures. These children mainly have frameshift and nonsense mutations. Valproic acid is effective for the treatment of seizures in most children.

Mitophagy, a Form of Selective Autophagy, Plays an Essential Role in Mitochondrial Dynamics of Parkinson's Disease.

Parkinson's disease (PD) is a severe neurodegenerative disorder caused by the progressive loss of dopaminergic neurons in the substantia nigra and affects millions of people. Currently, mitochondrial dysfunction is considered as a central role in the pathogenesis of both sporadic and familial forms of PD. Mitophagy, a process that selectively targets damaged or redundant mitochondria to the lysosome for elimination via the autophagy devices, is crucial in preserving mitochondrial health. So far, aberrant mitophagy has been observed in the postmortem of PD patients and genetic or toxin-induced models of PD. Except for mitochondrial dysfunction, mitophagy is involved in regulating several other PD-related pathological mechanisms as well, e.g., oxidative stress and calcium imbalance. So far, the mitophagy mechanisms induced by PD-related proteins, PINK1 and Parkin, have been studied widely, and several other PD-associated genes, e.g., DJ-1, LRRK2, and alpha-synuclein, have been discovered to participate in the regulation of mitophagy as well, which further strengthens the link between mitophagy and PD. Thus, in this view, we reviewed mitophagy pathways in belief and discussed the interactions between mitophagy and several PD's pathological mechanisms and how PD-related genes modulate the mitophagy process.

[Application of adeno-associated virus-mediated gene therapy in lysosomal storage diseases]. / è ºç›¸å ³ç— æ¯’ä»‹å¯¼çš„åŸºå› ç–—æ³•åœ¨æº¶é ¶ä½“è´®ç§¯ç—‡ä¸­çš„åº”ç”¨.

Lysosomal storage disorders (LSDs) are a group of single-gene inherited metabolic diseases caused by defects in lysosomal enzymes or function-related proteins. Enzyme replacement therapy is the main treatment method in clinical practice, but it has a poor effect in patients with neurological symptoms. With the rapid development of multi-omics, sequencing technology, and bioengineering, gene therapy has been applied in patients with LSDs. As one of the vectors of gene therapy, adeno-associated virus (AAV) has good prospects in the treatment of genetic and metabolic diseases. More and more studies have shown that AAV-mediated gene therapy is effective in LSDs. This article reviews the application of AAV-mediated gene therapy in LSDs.

Parkin, an E3 Ubiquitin Ligase, Plays an Essential Role in Mitochondrial Quality Control in Parkinson's Disease.

Parkinson's disease (PD), as one of the complex neurodegenerative disorders, affects millions of aged people. Although the precise pathogenesis remains mostly unknown, a significant number of studies have demonstrated that mitochondrial dysfunction acts as a major role in the pathogeny of PD. Both nuclear and mitochondrial DNA mutations can damage mitochondrial integrity. Especially, mutations in several genes that PD-linked have a closed association with mitochondrial dysfunction (e.g., Parkin, PINK1, DJ-1, alpha-synuclein, and LRRK2). Parkin, whose mutation causes autosomal-recessive juvenile parkinsonism, plays an essential role in mitochondrial quality control of mitochondrial biogenesis, mitochondrial dynamics, and mitophagy. Therefore, we summarized the advanced studies of Parkin's role in mitochondrial quality control and hoped it could be studied further as a therapeutic target for PD.

Role of mitophagy in mitochondrial quality control: Mechanisms and potential implications for neurodegenerative diseases.

Neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis) commonly characterized by the gradual loss of neurons have a seriously bad impact on motor and cognitive abilities of affected humans and bring great inconvenience to their lives. Mitochondrial dysfunction has been considered the key and common factor for the pathologies of neurodegenerative diseases for that neurons are extremely energy-intensive due to their unique properties in structures and functions. Thus, mitophagy, as a central role of mitochondrial quality control and currently believed to be the most effective pathway to clear dysfunctional or unwanted mitochondria, is rather crucial in the preservation of neuronal health. In addition, mitophagy establishes an intimated link with several other pathways of mitochondrial quality control (e.g., mitochondrial biogenesis and mitochondrial dynamics), and they work together to preserve mitochondrial health. Therefore, in this review, we summarized the recent process on the mechanisms of mitophagy pathways in mammals, it's linking to mitochondrial quality control, its role in several major neurodegenerative diseases, and possible therapeutic interventions focusing on mitophagy pathways. And we expect that it can provide us with more understanding of the mitophagy pathways and more promising approaches for the treatment of neurodegenerative diseases.

Novel rapid-acting glutamatergic modulators: Targeting the synaptic plasticity in depression.

Major depressive disorder (MDD) is severely prevalent, and conventional monoaminergic antidepressants gradually exhibit low therapeutic efficiency, especially for patients with treatment-resistant depression. A neuroplasticity hypothesis is an emerging advancement in the mechanism of depression, mainly expressed in the glutamate system, e.g., glutamate receptors and signaling. Dysfunctional glutamatergic neurotransmission is currently considered to be closely associated with the pathophysiology of MDD. Biological function, pharmacological action, and signal attributes in the glutamate system both regulate the neural process. Specific functional subunits could be therapeutic targets to explore the novel glutamatergic modulators, which have fast-acting, and relatively sustained antidepressant effects. Here, the present review summarizes the pathophysiology of MDD found in the glutamate system, exploring the role of glutamate receptors and their downstream effects. These convergent mechanisms have prompted the development of other modulators targeting on glutamate system, including N-methyl-d-aspartate receptor antagonists, selective GluN2B-specific antagonists, glycine binding site agents, and regulators of metabotropic glutamate receptors. Relevant researches underly the putative mechanisms of these drugs, which reverse the damage of depression by regulating glutamatergic neurotransmission. It also provides further insight into the mechanism of depression and exploring potential targets for novel agent development.

Dynamin-related protein 1: A protein critical for mitochondrial fission, mitophagy, and neuronal death in Parkinson's disease.

Parkinson's disease (PD) that afflicts millions of individuals worldwide is associated with deposits of aggregate-prone proteins (e.g., α-synuclein) and with mitochondrial dysfunction in neuronal cells. Mitochondria are the main source of reactive oxygen species, provide energy for neuronal cells, and are regarded as dynamic organelles that are determined by mitochondrial fission, fusion, and mitophagy to maintain mitochondrial homeostasis. Growing evidence reveals that several dynamics-related proteins, such as dynamin-related protein 1 (Drp1), mediate mitochondrial fission, fusion, and mitophagy, to protect against neurodegeneration in PD. More importantly, not only is Drp1-mediated fission required for mitophagy that exerts a protective effect on neurons, but abnormal mitochondrial fission and mitophagy can drive neuronal survival or cell death (i.e., autophagy, apoptosis, and necroptosis), suggesting that Drp1 may play a pivotal role in the pathogenesis of PD. Also, PD-related proteins such as α-synuclein, leucine-rich repeat kinase-2, PTEN-induced putative kinase 1, and Parkin have been proven to interact with Drp1, thus contributing to mitochondrial dynamics and clearance, as well as neuronal fate. Here, we review the roles of Drp1 in mitochondrial fission, dynamics, mitophagy, bulk autophagy, apoptosis, and necroptosis for a better understanding of mitochondrial disturbances in PD-associated neurodegeneration and summarize the advances of novel chemical compounds targeting Drp1 to provide new insight into potential PD therapies.

[Etiology and clinical features of epilepsia partialis continua: an analysis of six cases].

OBJECTIVE: To investigate the etiology and clinical features of epilepsia partialis continua (EPC) in children. METHODS: A retrospective analysis was performed for the clinical features, diagnosis and treatment of six children with EPC, and the clinical and laboratory features and prognosis were compared between the children with different etiologies. RESULTS: There were five girls and one boy, with an onset age ranging from one year and seven months to nine years. Two were diagnosed with Rasmussen encephalitis, one was diagnosed with focal cortical dysplasia, one was diagnosed with Alpers syndrome caused by POLG gene mutation, one was diagnosed with Angelman syndrome, and one was diagnosed with tuberculous meningitis. The latter two children had the predisposing factors for acute encephalopathy induced by status epilepticus and craniocerebral operation during the onset of EPC, while the other four children had natural progression of EPC. All the children had focal seizures except EPC, and symptoms included automatism, bilateral asymmetric tonic seizure, deflection, complex motor, and autonomic symptoms, with disturbance of consciousness in some children. EPC often lasted for several days or even several months. All children had abnormalities on head MRI, including local abnormal signal, cortex swelling, diffusive brain atrophy or brain atrophy at one side, local cortex thickening, and cortical necrosis. Head PET/CT scan was performed for three children and found local hypermetabolism or co-existence of hypermetabolism and hypometabolism. All the children had abnormalities on electroencephalography (EEG), with cerebral, hemispheric, or diffusive distribution of abnormal electrical activities, and during the onset of EPC, some EEG changes were recognizable and some were difficult to identify. All the children with EPC were not sensitive to antiepileptic drugs. EPC was relatively self-limiting in the child with Angelman syndrome. The child with focal cortical dysplasia underwent resection of epileptic foci and had good postoperative control, without neurological dysfunction. The child with Rasmussen encephalitis underwent functional hemispherectomy and had no attack after surgery, with neurological dysfunction. The child with Alpers syndrome had the worst prognosis. CONCLUSIONS: EPC is a special type of epileptic seizures. Immune inflammation and metabolic etiologies are the main causes of EPC in children, and the selection of treatment regimens, treatment outcome, and prognosis depend on etiology.

[Recurrent convulsion and pulmonary infection complicated by psychomotor retardation in an infant].

A 4-month-old girl developed convulsion in the neonatal period, which was focal motor seizures in the initial stage and later became spasm and tonic spasm. And the girl also had psychomotor retardation and recurrent pulmonary infection. Electroencephalography showed hypsarrhythmia, normal results were obtained from cranial magnetic resonance imaging, cerebrospinal fluid examination, and urine organic acid analysis, as well as the spectral analyses of blood ammonia, blood lactic acid, blood amino acids, and acylcarnitines. Gene detection revealed a de novo heterozygous mutation, c.607G>A (p.G203R) , in GNAO1. The girl was then diagnosed with GNAO1-associated early infantile epileptic encephalopathy (EIEE type 17). The seizures were well controlled by topiramate and vigabatrin, but there was no improvement in psychomotor development. She also suffered from recurrent pulmonary infection and died at the age of 12 months due to severe pneumonia. For children with unexplained early infantile epileptic encephalopathy, GNAO1 gene mutations should be considered and genetic tests should be performed as early as possible. Recurrent pulmonary infection should also be taken seriously.

Overexpression of folate biosynthesis genes in rice (Oryza sativa L.) and evaluation of their impact on seed folate content.

Folate (vitamin B9) deficiency is a global health problem especially in developing countries where the major staple foods such as rice contain extremely low folates. Biofortification of rice could be an alternative complement way to fight folate deficiency. In this study, we evaluated the availability of the genes in each step of folate biosynthesis pathway for rice folate enhancement in the japonica variety kitaake genetic background. The first enzymes GTP cyclohydrolase I (GTPCHI) and aminodeoxychorismate synthase (ADCS) in the pterin and para-aminobenzoate branches resulted in significant increase in seed folate content, respectively (P < 0.01). Overexpression of two closely related enzymes dihydrofolate synthase (DHFS) and folypolyglutamate synthase (FPGS), which perform the first and further additions of glutamates, produced slightly increase in seed folate content separately. The GTPCHI transgene was combined with each of the other transgenes except ADCS to investigate the effects of gene stacking on seed folate accumulation. Seed folate contents in the gene-stacked plants were higher than the individual low-folate transgenic parents, but lower than the high-folate GTPCHI transgenic lines, pointing to an inadequate supply of para-aminobenzoic acid (PABA) precursor initiated by ADCS in constraining folate overproduction in gene-stacked plants.

Efficacy of Chinese herbal formula Kai-Xin-San on rodent models of depression: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Kai-Xin-San (KXS, or Happy Feeling Powder), a typical Chinese herbal prescription, is frequently used for treating depression by the multi-level and multi-target mechanism. AIM OF THE STUDY: To systematically investigate the efficacy and safety of KXS on depression in preclinic trials. MATERIALS AND METHODS: We independently searched for preclinical animal studies of KXS on depression from inception to June 28, 2022, using electronic databases, e.g., PUBMED. The measurements were performed to assess the outcomes of behavioral tests. RESULTS: This systematic review and meta-analysis included twenty-four studies and 608 animals. A remarkable effect of KXS in depression behavioral tests, including sucrose consumption test (SMD: 2.36, 95% CI: (1.81, 2.90); Z = 8.49, P < 0.00001)., forced swimming test (MD = -60.52, 95% CI: (-89.04, -31.99); Z = 4.16, P < 0.0001), rearing times (MD=4.48, 95% CI: (3.39, 5.57); Z = 8.05, P < 0.00001) and crossing times (MD = -33.7, 95% CI: (25.74, 41.67); Z = 8.29, P < 0.00001) in the open field test, showing KXS's excellent efficiency in improving depressive-like symptoms of animals. CONCLUSIONS: Our meta-analysis showed KXS remarkably relieved animals' depressive-like symptoms, providing evidence that KXS can be a promising drug candidate for depression treatment.

Langmuir and Langmuir-Blodgett films of hybrid amphiphiles with a polyoxometalate headgroup.

A hybrid was at first synthesized by a postfunctionalization of an aminomethane trisalkoxo-functionalized Anderson-type polyoxometalate (POM) encapsulated by three tetrabutylammonium ions using a 3,5-bis(tetradecyloxy)benzoic acid by amidation. Then the three TBA(+) counter cations were programmatically replaced by protons (H(+)) following a molecule-to-amphiphile conversion. In this way one hybrid and three POM-containing hybrid amphiphiles (PCHAs) were acquired by adjusting the number (n) of TBA(+) ions and number (3 - n) of H(+) ions (n = 3, 2, 1, and 0). These compounds can be spread onto a water surface to form a Langmuir monolayer film at the air-water interface. Surface pressure-molecular area measurements exhibit the TBA(+) (H(+)) number playing an important role in the forming ability and stability of Langmuir monolayer films. Also, the Langmuir-Blodgett (LB) technique has been used to transfer the monolayer film onto solid supports to fabricate solid multilayer films. It was found that the PCHA with three H(+) ions had the best Langmuir film-forming ability and thus formed stable LB films with a two-dimensional ordered structure. Our findings are instructive in fabricating and using solid films of the amphiphiles with POM headgroups.

Antidepressant effects of the traditional Chinese herbal formula Xiao-Yao-San and its bioactive ingredients.

BACKGROUND: Depression is one of the most debilitating and severe psychiatric disorders and a serious public health concern. Currently, many treatments are indicated for depression, including traditional Chinese medicinal formulae such as Xiao-Yao-San (XYS), which has effective antidepressant effects in clinical and animal studies. PURPOSE: To summarize current evidence of XYS in terms of the preclinical and clinical studies and to identify the multi-level, multi-approach, and multi-target potential antidepressant mechanisms of XYS and active components of XYS by a comprehensive search of the related electronic databases. METHODS: The following electronic databases were searched from the beginning to April 2022: PubMed, MEDLINE, Web of Science, Google Scholar, and China National Knowledge Infrastructure. RESULTS: This review summarizes the antidepressant mechanisms of XYS and its active ingredients, which are reportedly correlated with monoamine neurotransmitter regulation, synaptic plasticity, and hypothalamic-pituitary-adrenal axis, etc. CONCLUSION: XYS plays a critical role in the treatment of depression by the regulation of several factors, including the monoaminergic systems, hypothalamic-pituitary-adrenal axis, synaptic plasticity, inflammation, brain-derived neurotrophic factor levels, brain-gut axis, and other pathways. However, more clinical and animal studies should be conducted to further investigate the antidepressant function of XYS and provide more evidence and recommendations for its clinical application. Our review provides an overview of XYS and guidance for future research direction.

HRS Regulates Small Extracellular Vesicle PD-L1 Secretion and Is Associated with Anti-PD-1 Treatment Efficacy.

PD-L1 localized to immunosuppressive small extracellular vesicles (sEV PD-L1) contributes to tumor progression and is associated with resistance to immune-checkpoint blockade (ICB) therapy. Here, by establishing a screening strategy with a combination of tissue microarray (TMA), IHC staining, and measurement of circulating sEV PD-L1, we found that the endosomal sorting complex required for transport (ESCRT) member protein hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) was the key regulator of circulating sEV PD-L1 in head and neck squamous cell carcinoma (HNSCC) patients. Increased HRS expression was found in tumor tissues and positively correlated with elevated circulating sEV PD-L1 in patients with HNSCC. The expression of HRS was also negatively correlated to the infiltration of CD8+ T cells. Knockdown of HRS markedly reduced PD-L1 expression in HNSCC cell-derived sEVs, and these sEVs from HRS knockdown cells showed decreased immunosuppressive effects on CD8+ T cells. Knockout of HRS inhibited tumor growth in immunocompetent mice together with PD-1 blockade. Moreover, a higher HRS expression was associated with a lower response rate to anti-PD-1 therapy in patients with HNSCC. In summary, our study reveals HRS, the core component of ESCRT-0, regulates sEV PD-L1 secretion, and is associated with the response to ICB therapy in patients with HNSCC, suggesting HRS is a promising target to improve cancer immunotherapy.

Efficacy and safety of istradefylline for Parkinson's disease: A systematic review and meta-analysis.

As an adenosine receptor A2A antagonist, istradefylline is used as an adjunctive agent of levodopa to improve motor symptoms in advanced Parkinson's disease (PD) patients. In this study, we re-evaluated the effects of istradefylline on treating the motor symptoms of PD patients. We performed a literature search up to November 2021 from electronic databases. Eligible studies were synthesized for efficacy, tolerability, OFF time, Unified Parkinson's Disease Rating Scale part III score, ON state with dyskinesia, and the incidence of treatment-emergent adverse events. As a result, nine clinical studies with 2727 subjects on istradefylline treatment for PD patients were included. Our results showed that compared to placebo, istradefylline exhibited a statically significant difference in efficacy (1.39 [1.15 to 1.69]; p = 0.001), decreasing OFF time (-0.58 [-1.01 to - 0.16]; p = 0.007), and improving ON state with dyskinesia (0.69 [0.02 to 1.37]; p = 0.043). For tolerability, UPDRS III, and adverse effects, there was no significant difference between istradefylline and placebo. In conclusion, the results suggest that istradefylline exhibits an efficient and well-tolerated role in treating PD patients. Randomized controlled trials and long-term studies are still required to investigate the effects of istradefylline on motor and non-motor symptoms of PD in future research.

Comparative efficacy and acceptability of drug treatments for Parkinson's disease with depression: A systematic review with network meta-analysis.

Depressive symptom is the prevailing non-motor symptom of Parkinson's disease (PD). Drug treatments for depressed PD (dPD) can mitigate the symptoms of patients. However, the results are discordant and need further analysis. This systematic review with network meta-analysis aims to evaluate the drug treatments for dPD. We included double-blind, randomized controlled trials to compare antidepressants with placebo or other antidepressants in dPD. We performed traditional pairwise analysis and network meta-analysis concerning the efficacy, acceptability, depression score, and adverse effect. The surface under the cumulative ranking curve was to assess the ranking probabilities of the enrolled agents. We enrolled 62 studies, including 12,353 subjects, to analyze these estimates. For the traditional pairwise meta-analysis, dopamine agonist (DOP; OR = 2.20 [95% CI, 1.46 to 3.33]) and selective serotonin reuptake inhibitor (SSRI; OR = 2.30 [95% CI, 1.15 to 4.60]) were observed to improve the efficacy compared with placebo. For network meta-analysis, DOP was observed to improve the efficacy compared with placebo (OR = -0.84 [95% CI, -1.20 to -0.48]). Both direct and indirect evidence showed that several treatments, e.g., DOP, monoamine-oxidase inhibitor, serotonin-norepinephrine reuptake inhibitors, SSRI, and tricyclic antidepressants, significantly improved depressive symptoms. DOP and SSRI had good efficacy and improved symptoms considerably in dPD, but the adverse effect of these agents was needed to follow closely.