Amisulpride Augmentation Therapy Improves Cognitive Performance and Psychopathology in Clozapine-resistant Treatment-refractory Schizophrenia (CTRS): a 12-week Randomized, Double-blind, Placebo-controlled Trial

BackgroundAlthough clozapine is an effective option for treatment-resistant schizophrenia (TRS), there are still 1/3 to 1/2 of TRS patients who do not respond to clozapine. The main purposes of this randomized, double-blind, placebo-controlled trial was to explore the amisulpride augmentation efficacy on the psychopathological symptoms and cognitive function of CTRS patients. MethodsA total of 80 patients were recruited and randomly assigned to receive an initial clozapine plus amisulpride or clozapine plus placebo. Positive and Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), Clinical Global Impression (CGI) scale scores, Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Treatment Emergent Symptom Scale (TESS), laboratory measurements and electrocardiograms (ECG) were performed at baseline, week 6, and week 12. ResultsCompared with clozapine plus placebo group, clozapine plus amisulpride had lower PANSS total score, positive subscore and general psychopathology subscore at week 6 and week 12 (all p Bonferroni< 0.01). Furthermore, compared with clozapine plus placebo group, clozapine plus amisulpride showed improved RBANS language score at week 12 (p Bonferroni< 0.001). Clozapine plus amisulpride group had a higher treatment response rate (p = 0.04), lower scores of CGI severity (CGI-S) and CGI efficacy (CGI-E) at week 6 and week 12 than clozapine plus placebo (all p Bonferroni< 0.05). There were no differences in BMI, QT intervals or laboratory measurements between the groups. Our results demonstrate that amisulpride augmentation therapy can safely improve the psychiatric symptoms and cognitive performance of CTRS patients. ConclusionsOur study indicates that amisulpride augmentation therapy has important clinical significance for the treatment of CTRS to improve clinical symptoms and cognitive function with tolerability and safety.Trial registrationClinicaltrials.gov identifier- NCT03652974. Registered 31 August 2018, https://clinicaltrials.gov/ct2/show/NCT03652974

Prime Editing for Inherited Retinal Diseases

Inherited retinal diseases (IRDs) are chronic, hereditary disorders that lead to progressive degeneration of the retina. Disease etiology originates from a genetic mutation—inherited or de novo—with a majority of IRDs resulting from point mutations. Given the plethora of IRDs, to date, mutations that cause these dystrophies have been found in approximately 280 genes. However, there is currently only one FDA-approved gene augmentation therapy, Luxturna (voretigene neparvovec-rzyl), available to patients with RPE65-mediated retinitis pigmentosa (RP). Although clinical trials for other genes are underway, these techniques typically involve gene augmentation rather than genome surgery. While gene augmentation therapy delivers a healthy copy of DNA to the cells of the retina, genome surgery uses clustered regularly interspaced short palindromic repeats (CRISPR)-based technology to correct a specific genetic mutation within the endogenous genome sequence. A new technique known as prime editing (PE) applies a CRISPR-based technology that possesses the potential to correct all twelve possible transition and transversion mutations as well as small insertions and deletions. EDIT-101, a CRISPR-based therapy that is currently in clinical trials, uses double-strand breaks and nonhomologous end joining to remove the IVS26 mutation in the CEP290 gene. Preferably, PE does not cause double-strand breaks nor does it require any donor DNA repair template, highlighting its unparalleled efficiency. Instead, PE uses reverse transcriptase and Cas9 nickase to repair mutations in the genome. While this technique is still developing, with several challenges yet to be addressed, it offers promising implications for the future of IRD treatment.

Optimal dose of aripiprazole for augmentation therapy of antidepressant-refractory depression: preliminary findings based on a systematic review and dose–effect meta-analysis

Background Aripiprazole augmentation is proven effective for antidepressant-refractory depression, but its licensed dose range is wide and optimal dosage remains unclear. Aims To find the optimal dosage of aripiprazole augmentation. Method Multiple electronic databases were searched (from inception to 16 February 2021) to identify all assessor-masked randomised controlled trials evaluating aripiprazole augmentation therapy in adults (≥18 years old, both genders) with major depressive disorder showing inadequate response to at least one antidepressant treatment. A random-effects, one-stage dose–effect meta-analysis with restricted cubic splines was conducted. Outcomes were efficacy (treatment response: ≥50% reduction in depression severity), tolerability (drop-out due to adverse effects) and acceptability (drop-out for any reason) after 8 weeks of treatment (range 4–12 weeks). Results Ten studies met the inclusion criteria. All were individually randomised, placebo-controlled, multi-centre, parallel studies including 2625 participants in total. The maximum target dose–efficacy curve showed an increase up to doses between 2 mg (odds ratio OR = 1.46, 95% CI 1.15–1.85) and 5 mg (OR = 1.93, 95% CI 1.33–2.81), and then a non-increasing trend through the higher licensed doses up to 20 mg (OR = 1.90, 95% CI 1.52–2.37). Tolerability showed a similar trend with greater uncertainty. Acceptability showed no significant difference through the examined dose range. Certainty of evidence was low to moderate. Conclusions Low-dose aripiprazole as augmentation treatment might achieve the optimal balance between efficacy, tolerability and acceptability in the acute treatment of antidepressant-refractory depression. However, the small number of included studies and the overall moderate to high risk of bias seriously compromise the reliability of the results. Further research is required to investigate the benefits of low versus high dose.

Correlation between α1-Antitrypsin Deficiency and SARS-CoV-2 Infection: Epidemiological Data and Pathogenetic Hypotheses

The most common hereditary disorder in adults, α1-antitrypsin deficiency (AATD), is characterized by reduced plasma levels or the abnormal functioning of α1-antitrypsin (AAT), a major human blood serine protease inhibitor, which is encoded by the SERine Protein INhibitor-A1 (SERPINA1) gene and produced in the liver. Recently, it has been hypothesized that the geographic differences in COVID-19 infection and fatality rates may be partially explained by ethnic differences in SERPINA1 allele frequencies. In our review, we examined epidemiological data on the correlation between the distribution of AATD, SARS-CoV-2 infection, and COVID-19 mortality rates. Moreover, we described shared pathogenetic pathways that may provide a theoretical basis for our epidemiological findings. We also considered the potential use of AAT augmentation therapy in patients with COVID-19.

Evaluation of Clonidine Augmentation Therapy for Obsessive-Compulsive Disorder Treatment; a Randomized Clinical Trial

Background: Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disorder worldwide. Inadequate response of OCD patients to a usual agent makes this disorder a great challenge, and recent studies have recommended augmentation therapy as a new choice. Objectives: As traces of noradrenergic dysfunction have been noted in OCD pathophysiology, the current study aimed to assess the efficacy of clonidine augmentation therapy for treating OCD. Methods: This was a randomized clinical trial conducted on 57 OCD patients divided into the two groups of 1-mg clonidine augmentation therapy (n = 28) and placebo group (n = 29). The medication was administered for 12 weeks. Patients’ primary treatment, including SSRIs or clomipramine, continued by receiving the same dose used before participation in this study. The Yale-Brown Obsessive-Compulsive scale (Y-BOCS) and Clinical Global Impression-Severity scale (CGI-S) were used to assess the patients at the start of the study and then at four-week intervals. Drug-related adverse effects and global improvement were assessed and compared between the two groups. Results: The initial CGI scores were 3.89 ± 1.57 and 4.10 ± 1.61 at the baseline and 2.29 ± 1.18 and 3.07 ± 1.51 at the end of the study in the intervention and control groups, respectively. Both groups revealed a significant improvement (P-value = 0.001) with no significant difference between them (P-value = 0.22). The primary Y-BOCS score in the clonidine-treated group was 27.61 ± 8.08 versus 28.69 ± 7.44 in the control group at the baseline, which declined to 20.25 ± 6.08 versus 25.45 ± 7.35 at the end of the study, respectively. Both groups revealed a significant improvement (P-value = 0.001), but there was no statistically significant difference between them (P-value = 0.06). Drug-related complications were not statistically different between the two groups (P-value > 0.05); however, the clonidine-treated patients presented more adverse effects than control subjects. Conclusions: Although the use of clonidine posed no remarkable drug-related adverse effects, it was not superior to placebo considering symptom relief.