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Canadian Journal of Psychiatry. Revue... Dec 2021Individuals with intellectual disability (ID) and autism spectrum disorder (ASD) often receive psychotropic medications such as antipsychotics and antidepressants to...
BACKGROUND
Individuals with intellectual disability (ID) and autism spectrum disorder (ASD) often receive psychotropic medications such as antipsychotics and antidepressants to treat aberrant behaviors and mood symptoms, frequently resulting in polypharmacy and drug-related adverse effects. Pharmacogenomic (PGx) studies with ASD and/or ID (ASD/ID) have been scarce despite the promise of optimizing treatment outcomes. We reviewed the literature on PGx studies with antipsychotics and antidepressants (e.g., treatment response and adverse effects) in ASD/ID.
METHODS
We performed a systematic review using MEDLINE, Embase, and PsycINFO, including peer-reviewed original articles in English referring to PGx in the treatment of ASD/ID in any age groups (e.g., treatment response and adverse effects).
RESULTS
A total of 28 PGx studies using mostly candidate gene approaches were identified across age groups. Notably, only 3 studies included adults with ASD/ID while the other 25 studies focused specifically on children/adolescents with ASD/ID. Twelve studies primarily investigated treatment response, of which 5 and 6 studies included patients treated with antipsychotics and antidepressants, respectively. Most interesting results for response were reported for 2 sets of candidate gene studies, namely: (1) The (rs6280) polymorphism was examined in patients treated with risperidone in 3 studies, 2 of which reported an association with risperidone treatment response and (2) the 5-HTTLPR polymorphism and treatment response to antidepressants which was investigated in 4 studies, 3 of which reported significant associations. In regard to side effects, 9 of 15 studies focused on hyperprolactinemia in patients treated with risperidone. Among them, 7 and 5 studies examined the impact of and polymorphisms, respectively, yielding mostly negative study findings.
CONCLUSIONS
There is limited data available on PGx in individuals with ASD/ID and in particular in adults. Given the potential for PGx testing in improving treatment outcomes, additional PGx studies for psychotropic treatment in ASD/ID across age groups are warranted.
Topics: Adolescent; Adult; Antipsychotic Agents; Autism Spectrum Disorder; Child; Humans; Intellectual Disability; Pharmacogenomic Testing; Psychotropic Drugs; Serotonin Plasma Membrane Transport Proteins
PubMed: 33222504
DOI: 10.1177/0706743720971950 -
Lupus Sep 2023Neurological involvement can occur in systemic lupus erythematosus (SLE) due to co-existing neuromyelitis optica spectrum disorder (NMOSD). The symptoms can mimic those...
BACKGROUND
Neurological involvement can occur in systemic lupus erythematosus (SLE) due to co-existing neuromyelitis optica spectrum disorder (NMOSD). The symptoms can mimic those of neuropsychiatric manifestations of SLE. Pathogenic anti-aquaporin-4 (AQP4) antibodies, commonly found in NMOSD, are responsible for the neuroinflammatory response and secondary demyelinating lesions. These anti-AQP4 antibodies can be the drivers of neuroinflammatory process in SLE patients, which is distinct from the immunopathogenesis seen in traditional neuropsychiatric SLE. The clinical course is often a relapsing one and is managed differently. In this review, we describe and outline the clinical course and outcomes of AQP4+ NMOSD/SLE overlap cases.
METHODS
To investigate the co-existence of SLE with AQP4+NMOSD, we conducted a systematic review of individual patient data from case reports and case series reported in major databases. The study extracted clinic-demographic features, imaging and laboratory profiles, treatment approaches, and outcomes of these patients. Inclusion criteria for the review required patients to have positivity for AQP4 or NMO in the blood and/or cerebrospinal fluid (CSF) and exhibit at least one manifestation of both NMOSD and SLE.
RESULTS
In this overlap between SLE and AQP4+NMOSD, a high female preponderance was observed, with 42 out of 46 patients (91.3%) being female. Nearly half of the NMOSD cases (47.8%) had onset after lupus, with a median of 5 years between the two diagnoses. Hematological manifestations were seen in the majority of patients (63%), as well as longitudinally extensive transverse myelitis (87%), and brainstem involvement on imaging (29.6%). Cerebrospinal fluid analysis showed a dominantly lymphocytic pleocytosis, with oligoclonal bands being reported scarcely. Although cyclophosphamide was the most common steroid sparing agent used for maintenance, robust evidence for both efficacy and safety in AQP4+NMOSD is available for mycophenolate mofetil, azathioprine, and rituximab. The majority of reported cases showed a relapsing course, while one patient had a monophasic course.
CONCLUSION
AQP4+NMOSD in SLE patients is a relapsing and neurologically disabling disorder that can mimic neuropsychiatric manifestations, frequently occurs after the onset of lupus or may predate, responds to immunosuppressants, and necessitates indefinite treatment.
Topics: Humans; Female; Male; Neuromyelitis Optica; Lupus Erythematosus, Systemic; Neoplasm Recurrence, Local; Aquaporin 4; Syndrome; Disease Progression; Autoantibodies
PubMed: 37487596
DOI: 10.1177/09612033231191180 -
Pharmacological Research Feb 2022Antipsychotics represent the mainstay of schizophrenia pharmacological therapy, and their role has been expanded in the last years to mood disorders treatment. Although...
Antipsychotics represent the mainstay of schizophrenia pharmacological therapy, and their role has been expanded in the last years to mood disorders treatment. Although introduced in 1952, many years of research were required before an accurate picture of how antipsychotics work began to emerge. Despite the well-recognized characterization of antipsychotics in typical and atypical based on their liability to induce motor adverse events, their main action at dopamine D2R to elicit the "anti-psychotic" effect, as well as the multimodal action at other classes of receptors, their effects on intracellular mechanisms starting with receptor occupancy is still not completely understood. Significant lines of evidence converge on the impact of these compounds on multiple molecular signaling pathways implicated in the regulation of early genes and growth factors, dendritic spine shape, brain inflammation, and immune response, tuning overall the function and architecture of the synapse. Here we present, based on PRISMA approach, a comprehensive and systematic review of the above mechanisms under a translational perspective to disentangle those intracellular actions and signaling that may underline clinically relevant effects and represent potential targets for further innovative strategies in antipsychotic therapy.
Topics: Animals; Antipsychotic Agents; Brain; Chromatin Assembly and Disassembly; Epigenesis, Genetic; Gene Expression Regulation; Genes, Immediate-Early; Humans; Neuronal Plasticity; Neuroprotective Agents; Neurotransmitter Transport Proteins
PubMed: 35026403
DOI: 10.1016/j.phrs.2022.106078 -
Endocrinology, Diabetes & Metabolism Jan 2022It is uncertain if the combination of sodium-glucose co-transporter 2 inhibitors (SGLT2-Is) and renin-angiotensin-aldosterone system inhibitors (RAAS-Is) provides better... (Meta-Analysis)
Meta-Analysis
Benefits and harms of sodium-glucose co-transporter-2 inhibitors (SGLT2-I) and renin-angiotensin-aldosterone system inhibitors (RAAS-I) versus SGLT2-Is alone in patients with type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials.
INTRODUCTION
It is uncertain if the combination of sodium-glucose co-transporter 2 inhibitors (SGLT2-Is) and renin-angiotensin-aldosterone system inhibitors (RAAS-Is) provides better cardio-renal clinical outcomes in people with type 2 diabetes mellitus (T2DM) compared with SGLT2-Is alone. Using a systematic review and meta-analysis of randomized controlled trials (RCTs), we evaluated the efficacy and safety with respect to cardio-renal outcomes of the combination of SGLT2 and RAAS inhibitors vs SGLT2-Is in patients with T2DM.
METHODS
Studies were identified from MEDLINE, Embase, the Cochrane Library and search of bibliographies to May 2021. The Cochrane risk of bias tool was used to assess the risk of bias of each study. Study-specific risk ratios (RRs) with 95% confidence intervals (CIs) were pooled. Quality of the evidence was assessed using GRADE.
RESULTS
Nine articles comprising 8 RCT evaluations (n = 34,551 participants) that compared SGLT2-Is with placebo in patients with T2DM against a background of standard care and reported subgroup results for those treated with or without RAAS-Is at baseline were included. No RCT specifically investigated the combination of SGLT2 and RAAS inhibitors compared with SGLT2-Is alone. The RRs (95% CIs) for composite cardiovascular outcome and composite CVD death/heart failure hospitalization comparing SGLT2-Is vs placebo in patients on RAAS-Is were 0.93 (0.85-1.01) and 0.88 (0.76-1.02), respectively. The corresponding estimates for patients not on RAAS-Is were 0.78 (0.65-0.93) and 0.73 (0.65-0.82), respectively. There was no evidence of interactions between RAAS-I status and the effects of SGLT2-Is for both outcomes. Single study results showed that SGLT2-Is vs placebo reduced the risk of composite kidney outcome and cardiovascular death in patients with RAAS inhibition. The effect of SGLT2 inhibition vs placebo on kidney parameters, genital infections, volume depletion, hyperkalaemia, hypokalaemia, hypoglycaemia and other adverse events was similar in patients with or without RAAS inhibition. The quality of the evidence ranged from very low to moderate.
CONCLUSIONS
Aggregate published data suggest that the combination of SGLT2 and RAAS inhibitors in the treatment of patients with T2DM may be similar in efficacy and safety if not superior to SGLT2-Is alone. Head-to-head comparisons of the two interventions are warranted to inform T2DM management. The use of SGLT2 inhibition as a first-line therapy in T2DM or its early use in the prevention of renal deterioration and cardiovascular complications in addition to its glycaemic control deserves further study.
Topics: Diabetes Mellitus, Type 2; Glucose; Humans; Hypoglycemic Agents; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Sodium; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 34636161
DOI: 10.1002/edm2.303 -
Cephalalgia : An International Journal... Nov 2010Data on the association between the SLC6A4 5-HTTLPR polymorphism and migraine are conflicting. We performed a systematic review and meta-analysis among studies published... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND METHODS
Data on the association between the SLC6A4 5-HTTLPR polymorphism and migraine are conflicting. We performed a systematic review and meta-analysis among studies published up to September 2009. For each study with genotype information, we calculated odds ratios (OR) and 95% confidence intervals (CI) assuming additive, dominant, and recessive genetic models. We then calculated pooled ORs and 95% CIs.
RESULTS
Among the ten studies identified there was no overall association between the polymorphism and any migraine for Europeans or Asians. However, European women carrying the S allele had an increased risk for any migraine (dominant model: pooled OR=2.02; 95% CI 1.24-3.28). Results among Europeans further suggested an increased risk for migraine with aura among carriers of the S/S genotype (recessive model: pooled OR=1.41; 95% CI 0.83-2.40).
CONCLUSIONS
While our results indicate no overall association between the SLC6A4 5-HTTLPR polymorphism and migraine among Europeans and Asians, gender and migraine aura status may have modifying roles among Europeans.
Topics: Asian People; Female; Genetic Predisposition to Disease; Humans; Male; Migraine Disorders; Odds Ratio; Polymorphism, Single Nucleotide; Serotonin Plasma Membrane Transport Proteins; White People
PubMed: 20959425
DOI: 10.1177/0333102410362929 -
Pharmacological Research Jun 2022The use of sodium-glucose cotransporter-2 inhibitors (SGLT2-Is) has resulted in significant benefits in patients with heart failure irrespective of left ventricular... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
The use of sodium-glucose cotransporter-2 inhibitors (SGLT2-Is) has resulted in significant benefits in patients with heart failure irrespective of left ventricular ejection fraction (LVEF) and the presence of diabetes mellitus. The aim of this systematic review and meta-analysis was to assess the impact of SGLT2-Is on cardiac function indices.
METHODS
We conducted a systematic literature search for studies assessing the changes in LVEF, global longitudinal strain (GLS), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular mass index (LVMi), left atrial volume index (LAVi), and E/e' following the initiation of an SGLT2-I.
RESULTS
A total of 32 studies with 2351 patients were included. SGLT2 inhibition resulted in a significant improvement of LVEF [MD 1.97 (95%CI 0.92, 3.02), p < .01, I:84%] in patients with heart failure, an increase in GLS [MD 1.17 (95% CI 0.25, 2.10), p < .01], a decrease in LVESV [MD: -3.60 (95% CI -7.02, -0.18), p = .04, I:9%] while the effect was neutral concerning LVEDV [MD: -3.10 (95% CI -6.76, 0.56), p = .40, I:4%]. LVMi [MD: -3.99 (95% CI -7.16 to -0.82), p = .01, I:65%], LAVi [MD: -1.77 (95% CI -2.97, -0.57), p < .01, I:0%], and E/e' [MD: -1.39 (95% CI -2.04, -0.73), p < .01, I:55%] were significantly reduced.
CONCLUSIONS
In this systematic review and meta-analysis, the use of SGLT2 inhibitors was associated with an improvement in markers of cardiac function, confirming the importance of SGLT2 inhibition towards the reversal of cardiac remodeling.
Topics: Biomarkers; Diabetes Mellitus, Type 2; Heart Failure; Humans; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume; Ventricular Function, Left
PubMed: 35523389
DOI: 10.1016/j.phrs.2022.106243 -
Current Pharmaceutical Design 2018New Oral Anticoagulants (NOACs) are effective and widely used to prevent and treat thromboembolic diseases, but the response to NOACs differs according to ABCB1... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
New Oral Anticoagulants (NOACs) are effective and widely used to prevent and treat thromboembolic diseases, but the response to NOACs differs according to ABCB1 genotypes.
OBJECTIVE
We investigated the effects of ABCB1 genotypes on the pharmacokinetics and clinical outcomes of NOACs.
METHODS
We searched PubMed, Embase, and the Cochrane Library for studies on ABCB1 genotypes published from the inception of these databases until May 23, 2018. The Weighted Mean Difference (WMD) and Odds Ratio (OR) with 95% Confidence Interval (CI) were calculated for continuous and dichotomous data, respectively. Summary results were calculated using a random effects model.
RESULTS
Ten studies involving 2609 individuals were included in the systematic review, and three studies involving 535 individuals were included in the meta-analysis. Overall, four ABCB1 single-nucleotide polymorphisms were identified in the review. Carriers of the ABCB1 rs1045642 CC genotype had lower maximum plasma concentration (Cmax) than those of TT (WMD = -16.99 ng/mL; 95% CI = -33.39 to -0.59; P = 0.04), and carriers of the rs2032582 GG genotype showed lower Cmax than those of the A/T allele (WMD = -19.21 ng/mL; 95% CI = -36.62 to -1.80; P = 0.03). Carriers of the rs1045642 CC genotype showed lower area under the curve from time 0 to infinity (AUC0-∞) than those of the T allele (WMD = -78.58 ng·h/mL; 95% CI = -151.14 to -6.01; P = 0.03). ABCB1 rs4148738 genotypes did not affect the risks of ischemic stroke or systemic embolism (OR = 0.88), ischemic events (OR = 0.98), bleeding (OR = 0.94), major bleeding (OR = 1.14), or minor bleeding (OR = 0.94) in patients treated with dabigatran.
CONCLUSION
Cmax was lower in carriers of ABCB1 rs1045642 CC than in those of TT and in carriers of rs2032582 GG than in those of the A/T allele, and AUC0-∞ was lower in carriers of rs1045642 CC than in those of TT. Conversely, ABCB1 rs4148738 genotypes did not affect primary clinical endpoints in dabigatran-administered patients. Future studies should analyze the relationships of ABCB1 genotypes with the pharmacokinetics and clinical outcomes of specific NOACs.
Topics: ATP Binding Cassette Transporter, Subfamily B; Administration, Oral; Anticoagulants; Genotype; Humans; Treatment Outcome
PubMed: 30338730
DOI: 10.2174/1381612824666181018153641 -
Pharmacogenomics Jul 2016Chemotherapeutic agents have been shown to increase lung patient survival, however their use may be limited by their serious adverse effects. We aimed to assess int... (Meta-Analysis)
Meta-Analysis Review
AIM
Chemotherapeutic agents have been shown to increase lung patient survival, however their use may be limited by their serious adverse effects. We aimed to assess int impact of pharmacogenetic variation of influx transporters on inter-individual patient variation in adverse drug reactions.
PATIENTS & METHODS
We conducted a meta-analysis and systemic review and identified 16 publications, totaling 1510 patients, to be eligible for review.
RESULTS
Meta-analysis showed east-Asian patients expressing SLCO1B1 521T>C or 1118G>A to have a two- to fourfold increased risk of irinotecan-induced neutropenia but not diarrhea. American patients, expressing SLC19A1 IVS2(4935) G>A, were further associated with pemetrexed/gemcitabine-induced grade 3+ leukopenia.
CONCLUSION
Future studies should look to robust validation of SLCO1B1 and SLC19A1 as prognostic markers in the management of lung cancer patients.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Case-Control Studies; Humans; Liver-Specific Organic Anion Transporter 1; Neutropenia; Pharmacogenomic Testing; Pharmacogenomic Variants; Predictive Value of Tests; Reduced Folate Carrier Protein
PubMed: 27380948
DOI: 10.2217/pgs-2015-0005 -
Multiple Sclerosis and Related Disorders May 2024Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disorder characterized by relapses of inflammation and demyelination primarily affecting the optic nerve... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disorder characterized by relapses of inflammation and demyelination primarily affecting the optic nerve and the spinal cord. C5 complement inhibition is an effective therapeutic approach in the treatment of NMOSD. In this systematic review and meta-analysis, we aimed to determine the role of C5 inhibitors in the treatment of patients with seropositive anti-aquaporin-4 antibody (AQP4+IgG) NMOSD.
METHODS
This systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Relevant articles were systematically searched through Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science databases until October 6th, 2023. We included randomized clinical trials (RCTs) that investigated the treatment with C5 inhibitors compared to placebo in patients with seropositive NMOSD. The primary endpoint was the rates of first adjudicated relapse. Secondary endpoints included different disability and quality of life measures. The random-effects model was used for all statistical analyses.
RESULTS
Two RCTs with a total of 201 patients were included. C5 inhibitors demonstrated significant reduction of first adjudicated relapse (risk ratio (RR) = 0.05, 95 % CI 0.01-0.15) and Hauser Ambulation Index (HAI) (mean difference (MD): -0.79, 95 % CI -1.27 to -0.31). There was no significant difference between the two groups in Expanded Disability Status Scale (EDSS) (MD -0.23, 95 % CI -0.54-0.08). C5 inhibitors significantly improved the mean change in EQ-5D index (MD 0.08, 95 % CI 0.01-0.14; P = 0.02); however, no significant difference was shown in the mean change in EQ-5D VAS (MD 3.79, 95 % CI -1.61 to 9.19; P = 0.17). Safety measures were comparable between C5 inhibitors and placebo.
CONCLUSION
NMOSD Patients with AQP4+IgG receiving C5 inhibitors have lower rate of relapses and improved levels of disability and quality of life. Real-world studies are warranted to establish the long-term safety of C5 inhibitors.
Topics: Neuromyelitis Optica; Humans; Aquaporin 4; Autoantibodies; Complement C5; Randomized Controlled Trials as Topic
PubMed: 38479045
DOI: 10.1016/j.msard.2024.105524 -
Tremor and Other Hyperkinetic Movements... 2024Tardive Dyskinesia (TD) is a neurological disorder characterized by involuntary movements, often caused by dopamine receptor antagonists. Vesicular Monoamine Transporter... (Comparative Study)
Comparative Study Review
BACKGROUND
Tardive Dyskinesia (TD) is a neurological disorder characterized by involuntary movements, often caused by dopamine receptor antagonists. Vesicular Monoamine Transporter 2 (VMAT2) inhibitors, such as valbenazine and deutetrabenazine, have emerged as promising therapies for TD and several clinical trials have shown their efficacy. This study aims to compare the efficacy and safety profile of VMAT2 inhibitors, focusing on a recent trial conducted in the Asian population.
METHODS
We reviewed the PubMed, Cochrane Library, Embase database, and clinicaltrials.gov between January 2017 and October 2023, using the keywords "tardive dyskinesia" AND ("valbenazine" [all fields] OR " deutetrabenazine " [all fields]) AND "clinical trial". The reviewed articles were studied for efficacy and side effects.
RESULTS
An initial search yielded 230 articles, of which 104 were duplicates. Following the title and abstract screening, 25 additional articles were excluded. A full-text review resulted in the exclusion of 96 more articles. Ultimately, four double-blind clinical trials met the inclusion criteria. The deutetrabenazine studies demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores compared to placebo, with no difference in adverse events. The valbenazine studies showed favorable results in reducing TD symptoms and were well-tolerated.
DISCUSSION
The studies reviewed in this analysis underscore the potential of deutetrabenazine and valbenazine as valuable treatment options for TD in diverse populations. Both medications demonstrated significant improvements in AIMS scores, suggesting their effectiveness in managing TD symptoms. Additionally, they exhibited favorable safety profiles, with low rates of serious adverse events and no significant increase in QT prolongation, parkinsonism, suicidal ideation, or mortality.
CONCLUSION
The studies reviewed highlight the promising efficacy and tolerability of deutetrabenazine and valbenazine as treatments for Tardive Dyskinesia, providing new hope for individuals affected by this challenging condition.
Topics: Humans; Randomized Controlled Trials as Topic; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins
PubMed: 38497033
DOI: 10.5334/tohm.842