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Basic & Clinical Pharmacology &... Jan 2019The effect of risperidone treatment in patients with schizophrenia varies according to the dopamine receptor genes. This study aimed to evaluate the relationship between... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The effect of risperidone treatment in patients with schizophrenia varies according to the dopamine receptor genes. This study aimed to evaluate the relationship between genes of the dopamine receptors (D1, D2, and D3) and the effect of risperidone treatment.
METHODS
Three electronic databases (PubMed, Embase, and Cochrane Library) were searched for relevant cohort or case-control studies published before 9 May 2018. A systematic review and meta-analysis was performed for qualitative and quantitative assessment of the relationship between the dopamine receptors D1, D2, and D3 (DRD1, 2, and 3) and the effect of risperidone treatment. The summary odds ratio (OR) and weighted mean difference (WMD) in a random-effects model were used to measure these relationships.
RESULTS
Twelve studies involving 24 SNPs were included. DRD2 (Ser311Cys, rs1801028 Ser/Ser) significantly lowered the improvement rate (determined by the PANSS score) unlike Ser/Cys (WMD: -11.58, 95% CI: -17.35 to -5.18). For Asian patients, A241G (rs1799978) AA carriers showed greater improvement after risperidone therapy (P < 0.05). The polymorphisms of 141C Ins/Del (rs1799732), T939C (rs6275), rs6277, and TaqID (rs1800498) may also influence the treatment effect. TaqIA (rs1800497) and TaqIB (rs17294542) were not associated with the rate of response to risperidone. DRD3 was not associated with an improvement in the PANSS total score; however, Ser9Gly might be related to a change in negative symptoms. No significant effect of DRD1 (rs5326, rs4867798, rs4532, and rs11749676) was found.
CONCLUSIONS
Our result supported the hypothesis that DRD2 affected risperidone treatment. DRD1 had no significant effect on the response to risperidone, whereas DRD3 might be associated with an improvement in negative symptoms. Larger observational studies are warranted to verify these findings and identify other genetic factors involved.
Topics: Antipsychotic Agents; Humans; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; Risperidone; Schizophrenia; Treatment Outcome
PubMed: 30103286
DOI: 10.1111/bcpt.13111 -
The Cochrane Database of Systematic... Jan 2018Tardive dyskinesia (TD) is a disabling movement disorder associated with the prolonged use of antipsychotic medication. Several strategies have been examined in the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Tardive dyskinesia (TD) is a disabling movement disorder associated with the prolonged use of antipsychotic medication. Several strategies have been examined in the treatment of TD. Currently, however, there is no clear evidence of the effectiveness of these drugs in TD and they have been associated with many side effects. One particular strategy would be to use pharmaceutical agents which are known to influence the catecholaminergic system at various junctures.
OBJECTIVES
1. To determine the effects of any of the following drugs for antipsychotic-induced TD in people with schizophrenia or other chronic mental illnesses.i. Drugs which influence the noradrenergic system.ii. Dopamine receptor agonists.iii. Dopamine receptor antagonists.iv. Dopamine-depletor drugs.v. Drugs that increase the production or release of dopamine.2. To examine whether any improvement occurred with short periods of intervention (less than 6 weeks) and, if this did occur, whether this effect was maintained at longer periods of follow-up.3. To examine if there was a differential effect for the various compounds.4. To examine whether the use of non-antipsychotic catecholaminergic drugs are most effective in those with more recent onset TD (less than five years).
SEARCH METHODS
We retrieved 712 references from searching the Cochrane Schizophrenia Group Trials Register (July 2015 and April 2017). We also inspected references of all identified studies for further trials and contacted authors of trials for additional information.
SELECTION CRITERIA
We selected studies if they were randomised controlled trials focusing on people with schizophrenia or other chronic mental illnesses and antipsychotic-induced tardive dyskinesia. We compared the use of catecholaminergic interventions versus placebo, no intervention, or any other intervention for the treatment of antipsychotic-induced tardive dyskinesia.
DATA COLLECTION AND ANALYSIS
We independently extracted data from these trials and we estimated risk ratios (RRs) with 95% confidence intervals (CIs). We assumed that people who left the studies early had no improvement.
MAIN RESULTS
There are 10 included trials (N = 261) published between 1973 and 2010; eight are new from the 2015 and 2017 update searches. Forty-eight studies are excluded. Participants were mostly chronically mentally ill inpatients in their 50s, and studies were primarily of short (2 to 6 weeks) duration. The overall risk of bias in these studies was unclear, mainly due to poor reporting of allocation concealment and generation of the sequence. Studies were also not clearly blinded and we are unsure if data are incomplete or selectively reported, or if other biases were operating.One small, three-arm trial found that both alpha-methyldopa (N = 20; RR 0.33, 95% CI 0.14 to 0.80; low-quality evidence) and reserpine (N = 20; RR 0.52 95% CI 0.29 to 0.96; low-quality evidence) may lead to a clinically important improvement in tardive dyskinesia symptoms compared with placebo after 2 weeks' treatment, but found no evidence of a difference between alpha-methyldopa and reserpine (N = 20; RR 0.60, 95% CI 0.19 to 1.86; very low quality evidence). Another small trial compared tetrabenazine and haloperidol after 18 weeks' treatment and found no evidence of a difference on clinically important improvement in tardive dyskinesia symptoms (N = 13; RR 0.93, 95% CI 0.45 to 1.95; very low quality evidence). No study reported on adverse events.For remaining outcomes there was no evidence of a difference between any of the interventions: alpha-methyldopa versus placebo for deterioration of tardive dyskinesia symptoms (1 RCT; N = 20; RR 0.33, 95% CI 0.02 to 7.32; very low quality evidence), celiprolol versus placebo for leaving the study early (1 RCT; N = 35; RR 5.28, 95% CI 0.27 to 102.58; very low quality evidence) and quality of life (1 RCT; N = 35; RR 0.87, 95% CI 0.68 to 1.12; very low quality evidence), alpha-methyldopa versus reserpine for deterioration of tardive dyskinesia symptoms (1 RCT; N = 20; not estimable, no reported events; very low quality evidence), reserpine or carbidopa/levodopa versus placebo for deterioration of tardive dyskinesia symptoms (2 RCTs; N = 37; RR 1.18, 95% CI 0.35 to 3.99; very low quality evidence), oxypertine versus placebo for deterioration of mental state (1 RCT; N = 42; RR 2.20, 95% CI 0.22 to 22.45; very low quality evidence), dopaminergic drugs (amantadine, bromocriptine, tiapride, oxypertine, carbidopa/levodopa) versus placebo for leaving the study early (6 RCTs; N = 163; RR 1.29, 95% CI 0.65 to 2.54; very low quality evidence), and tetrabenazine versus haloperidol for deterioration of tardive dyskinesia symptoms (1 RCT; N = 13; RR 1.17, 95% CI 0.09 to 14.92) and leaving the study early (1 RCT; N = 13; RR 0.23, 95% CI 0.01 to 4.00).
AUTHORS' CONCLUSIONS
Although there has been a large amount of research in this area, many studies were excluded due to inherent problems in the nature of their cross-over designs. Usually data are not reported before the cross-over and the nature of TD and its likely response to treatments make it imprudent to use this data. The review provides little usable information for service users or providers and more well-designed and well-reported studies are indicated.
Topics: Adrenergic Uptake Inhibitors; Anti-Dyskinesia Agents; Antipsychotic Agents; Celiprolol; Disease Progression; Dopamine Antagonists; Dyskinesia, Drug-Induced; Haloperidol; Humans; Methyldopa; Randomized Controlled Trials as Topic; Reserpine; Tetrabenazine; Tiapamil Hydrochloride
PubMed: 29342497
DOI: 10.1002/14651858.CD000458.pub3 -
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 -
Behavioral Sciences (Basel, Switzerland) Oct 2021Although blockade of dopamine receptors D2 and D3 appears to be the main mechanism of antipsychotic action, treatment response variability calls for an examination of... (Review)
Review
Dopamine, Serotonin, and Structure/Function Brain Defects as Biological Bases for Treatment Response in Delusional Disorder: A Systematic Review of Cases and Cohort Studies.
Although blockade of dopamine receptors D2 and D3 appears to be the main mechanism of antipsychotic action, treatment response variability calls for an examination of other biological systems. Our aim is to systematically review reports of treatment response in delusional disorder (DD) in order to help determine its biological bases. Computerized searches of ClinicalTrials.gov, PubMed, and Scopus databases (from 1999 to September 2021) were systematically reviewed, in keeping with PRISMA directives. We used the search terms: (treat * OR therap * AND (delusional disorder)). We included all studies that explored the biological mechanisms of treatment response in DD, as diagnosed by ICD or DSM criteria. A total of 4344 records were initially retrieved, from which 14 papers were included: case reports, case series, and cohort studies. Findings point to (1) dopaminergic dysfunction (based on biochemical and genetic studies), (2) serotonergic dysfunction (based on partial agonism/antagonism of drugs), and (3) brain structure/function impairment, especially in the temporal and parietal lobes, as crucial factors in treatment response. Further studies with higher levels of evidence are needed to help clinicians determine treatment.
PubMed: 34677234
DOI: 10.3390/bs11100141 -
Journal of Clinical Psychopharmacology Feb 2016In the last 10 years, dopamine replacement therapy (DRT) has become a well-known risk factor for developing an impulse control disorder, such as gambling disorder (GD).... (Review)
Review
BACKGROUND
In the last 10 years, dopamine replacement therapy (DRT) has become a well-known risk factor for developing an impulse control disorder, such as gambling disorder (GD). Another medication, aripiprazole (ARI), has been more recently identified as another risk factor. Dopamine replacement therapy and ARI share a dopamine agonist action. Our work aimed at comparing patients with PG according to their treatment with DRT or ARI.
METHODS
Two methods were combined-a systematic review concentrated on case reports and the analysis of a French disordered gamblers cohort focused on patients using ARI or DRT at inclusion.
RESULTS
We reported 48 cases of GD possibly due to DRT and 17 cases of GD possibly due to ARI. Because of their standardized assessment, only the EVALJEU patients could be compared. Two clinical patterns emerged. Patients in the ARI group were young, impulsive, and high novelty seekers and had a history of substance misuse. Their first gambling experience occurred during adolescence. Conversely, patients in the DRT group were old, and they began gambling late in life. They showed low levels of gambling-related cognition.
CONCLUSIONS
Patients in the ARI group seemed to be more severe pathological gamblers than patients in the DRT group. Aripiprazole is a partial D2 receptor agonist, whereas DRT includes full D2 receptor agonist. The trigger mechanism of PG development is complex and cannot only be attributed only to the pharmacodynamic effects of dopaminergic drugs. Indeed, individual vulnerability factors and environmental factors need to be considered.
Topics: Adolescent; Aripiprazole; Disruptive, Impulse Control, and Conduct Disorders; Dopamine Agonists; Gambling; Humans; Receptors, Dopamine D2; Risk Factors
PubMed: 26658263
DOI: 10.1097/JCP.0000000000000444 -
Translational Psychiatry Jun 2024Excessive and persistent aggressiveness is the most common behavioral problem that leads to psychiatric referrals among children. While half of the variance in childhood...
Excessive and persistent aggressiveness is the most common behavioral problem that leads to psychiatric referrals among children. While half of the variance in childhood aggression is attributed to genetic factors, the biological mechanism and the interplay between genes and environment that results in aggression remains elusive. The purpose of this systematic review is to provide an overview of studies examining the genetics of childhood aggression irrespective of psychiatric diagnosis. PubMed, PsycINFO, and MEDLINE databases were searched using predefined search terms for aggression, genes and the specific age group. From the 652 initially yielded studies, eighty-seven studies were systematically extracted for full-text review and for further quality assessment analyses. Findings show that (i) investigation of candidate genes, especially of MAOA (17 studies), DRD4 (13 studies), and COMT (12 studies) continue to dominate the field, although studies using other research designs and methods including genome-wide association and epigenetic studies are increasing, (ii) the published articles tend to be moderate in sizes, with variable methods of assessing aggressive behavior and inconsistent categorizations of tandem repeat variants, resulting in inconclusive findings of genetic main effects, gene-gene, and gene-environment interactions, (iii) the majority of studies are conducted on European, male-only or male-female mixed, participants. To our knowledge, this is the first study to systematically review the effects of genes on youth aggression. To understand the genetic underpinnings of childhood aggression, more research is required with larger, more diverse sample sets, consistent and reliable assessments and standardized definition of the aggression phenotypes. The search for the biological mechanisms underlying child aggression will also benefit from more varied research methods, including epigenetic studies, transcriptomic studies, gene system and genome-wide studies, longitudinal studies that track changes in risk/ameliorating factors and aggression-related outcomes, and studies examining causal mechanisms.
Topics: Child; Female; Humans; Male; Aggression; Catechol O-Methyltransferase; Gene-Environment Interaction; Genome-Wide Association Study; Monoamine Oxidase; Receptors, Dopamine D4
PubMed: 38862490
DOI: 10.1038/s41398-024-02870-7 -
The Cochrane Database of Systematic... Nov 2017Uterine fibroids occur in up to 40% of women aged over 35 years. Some are asymptomatic, but up to 50% cause symptoms that warrant therapy. Symptoms include anaemia... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Uterine fibroids occur in up to 40% of women aged over 35 years. Some are asymptomatic, but up to 50% cause symptoms that warrant therapy. Symptoms include anaemia caused by heavy menstrual bleeding, pelvic pain, dysmenorrhoea, infertility and low quality of life. Surgery is the first choice of treatment. In recent years, medical therapies have been used before surgery to improve intraoperative and postoperative outcomes. However, such therapies tend to be expensive.Fibroid growth is stimulated by oestrogen. Gonadotropin-hormone releasing analogues (GnRHa) induce a state of hypo-oestrogenism that shrinks fibroids , but has unacceptable side effects if used long-term. Other potential hormonal treatments, include progestins and selective progesterone-receptor modulators (SPRMs).This is an update of a Cochrane Review published in 2000 and 2001; the scope has been broadened to include all preoperative medical treatments.
OBJECTIVES
To assess the effectiveness and safety of medical treatments prior to surgery for uterine fibroids.
SEARCH METHODS
We searched the Cochrane Gynaecology and Fertility Group specialised register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL in June 2017. We also searched trials registers (ClinicalTrials.com; WHO ICTRP), theses and dissertations and the grey literature, handsearched reference lists of retrieved articles and contacted pharmaceutical companies for additional trials.
SELECTION CRITERIA
We included randomised comparisons of medical therapy versus placebo, no treatment, or other medical therapy before surgery, myomectomy, hysterectomy or endometrial resection, for uterine fibroids.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by The Cochrane Collaboration.
MAIN RESULTS
We included a total of 38 RCTs (3623 women); 19 studies compared GnRHa to no pretreatment (n = 19), placebo (n = 8), other medical pretreatments (progestin, SPRMs, selective oestrogen receptor modulators (SERMs), dopamine agonists, oestrogen receptor antagonists) (n = 7), and four compared SPRMs with placebo. Most results provided low-quality evidence due to limitations in study design (poor reporting of randomisation procedures, lack of blinding), imprecision and inconsistency. GnRHa versus no treatment or placebo GnRHa treatments were associated with reductions in both uterine (MD -175 mL, 95% CI -219.0 to -131.7; 13 studies; 858 participants; I² = 67%; low-quality evidence) and fibroid volume (heterogeneous studies, MD 5.7 mL to 155.4 mL), and increased preoperative haemoglobin (MD 0.88 g/dL, 95% CI 0.7 to 1.1; 10 studies; 834 participants; I² = 0%; moderate-quality evidence), at the expense of a greater likelihood of adverse events, particularly hot flushes (OR 7.68, 95% CI 4.6 to 13.0; 6 studies; 877 participants; I² = 46%; moderate-quality evidence).Duration of hysterectomy surgery was reduced among women who received GnRHa treatment (-9.59 minutes, 95% CI 15.9 to -3.28; 6 studies; 617 participants; I² = 57%; low-quality evidence) and there was less blood loss (heterogeneous studies, MD 25 mL to 148 mL), fewer blood transfusions (OR 0.54, 95% CI 0.3 to 1.0; 6 studies; 601 participants; I² = 0%; moderate-quality evidence), and fewer postoperative complications (OR 0.54, 95% CI 0.3 to 0.9; 7 studies; 772 participants; I² = 28%; low-quality evidence).GnRHa appeared to reduce intraoperative blood loss during myomectomy (MD 22 mL to 157 mL). There was no clear evidence of a difference among groups for other primary outcomes after myomectomy: duration of surgery (studies too heterogeneous for pooling), blood transfusions (OR 0.85, 95% CI 0.3 to 2.8; 4 studies; 121 participants; I² = 0%; low-quality evidence) or postoperative complications (OR 1.07, 95% CI 0.43 to 2.64; I² = 0%; 5 studies; 190 participants; low-quality evidence). No suitable data were available for analysis of preoperative bleeding. GnRHa versus other medical therapies GnRHa was associated with a greater reduction in uterine volume (-47% with GnRHa compared to -20% and -22% with 5 mg and 10 mg ulipristal acetate) but was more likely to cause hot flushes (OR 12.3, 95% CI 4.04 to 37.48; 5 studies; 183 participants; I² = 61%; low-quality evidence) compared with ulipristal acetate. There was no clear evidence of a difference in bleeding reduction (ulipristal acetate 5 mg: OR 0.71, 95% CI 0.3 to 1.7; 1 study; 199 participants; moderate-quality evidence; ulipristal acetate 10 mg: OR 0.39, 95% CI 0.1 to 1.1; 1 study; 203 participants; moderate-quality evidence) or haemoglobin levels (MD -0.2, 95% CI -0.6 to 0.2; 188 participants; moderate-quality evidence).There was no clear evidence of a difference in fibroid volume between GnRHa and cabergoline (MD 12.71 mL, 95% CI -5.9 to 31.3; 2 studies; 110 participants; I² = 0%; low-quality evidence).The included studies did not report usable data for any other primary outcomes. SPRMs versus placebo SPRMs (mifepristone, CDB-2914, ulipristal acetate and asoprisnil) were associated with greater reductions in uterine or fibroid volume than placebo (studies too heterogeneous to pool) and increased preoperative haemoglobin levels (MD 0.93 g/dL, 0.5 to 1.4; 2 studies; 173 participants; I² = 0%; high-quality evidence). Ulipristal acetate and asoprisnil were also associated with greater reductions in bleeding before surgery (ulipristal acetate 5 mg: OR 41.41, 95% CI 15.3 to 112.4; 1 study; 143 participants; low-quality evidence; ulipristal acetate 10 mg: OR 78.83, 95% CI 24.0 to 258.7; 1 study; 146 participants; low-quality evidence; asoprisnil: MD -166.9 mL; 95% CI -277.6 to -56.2; 1 study; 22 participants; low-quality evidence). There was no evidence of differences in preoperative complications. No other primary outcomes were measured.
AUTHORS' CONCLUSIONS
A rationale for the use of preoperative medical therapy before surgery for fibroids is to make surgery easier. There is clear evidence that preoperative GnRHa reduces uterine and fibroid volume, and increases preoperative haemoglobin levels, although GnRHa increases the incidence of hot flushes. During hysterectomy, blood loss, operation time and complication rates were also reduced. Evidence suggests that ulipristal acetate may offer similar advantages (reduced fibroid volume and fibroid-related bleeding and increased haemoglobin levels) although replication of these studies is advised before firm conclusions can be made. Future research should focus on cost-effectiveness and distinguish between groups of women with fibroids who would most benefit.
Topics: Antineoplastic Agents, Hormonal; Blood Loss, Surgical; Chemotherapy, Adjuvant; Dopamine Agonists; Estrogen Antagonists; Female; Gonadotropin-Releasing Hormone; Humans; Hysterectomy; Leiomyoma; Myometrium; Operative Time; Preoperative Care; Progestins; Randomized Controlled Trials as Topic; Uterine Neoplasms
PubMed: 29139105
DOI: 10.1002/14651858.CD000547.pub2 -
International Journal of Clinical... Sep 2015To describe the efficacy, tolerability and safety of brexpiprazole for the treatment of schizophrenia and as adjunct for major depressive disorder (MDD). (Review)
Review
Brexpiprazole for schizophrenia and as adjunct for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antipsychotic - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed?
OBJECTIVE
To describe the efficacy, tolerability and safety of brexpiprazole for the treatment of schizophrenia and as adjunct for major depressive disorder (MDD).
DATA SOURCES
The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov, for the search terms 'brexpiprazole' OR 'OPC-34712', and by also querying the EMBASE (Elsevier) commercial database for clinical poster abstracts, and by asking the manufacturer for copies of posters presented at congresses. Product labelling provided additional information.
STUDY SELECTION
All available clinical reports of studies were identified.
DATA EXTRACTION
Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the available study reports and other sources of information.
DATA SYNTHESIS
Brexpiprazole is a new dopamine D2 receptor partial agonist that received approval for the treatment of schizophrenia and for adjunctive use for the treatment of MDD based on a clinical trial development programme that included two pivotal Phase III trials of brexpiprazole monotherapy in acute schizophrenia, and two pivotal Phase III trials of adjunctive brexpiprazole in acute MDD in patients who demonstrated inadequate response to standard antidepressant therapy. In addition, results from a 52-week relapse prevention/maintenance randomised placebo-controlled withdrawal study in patients with schizophrenia are available. In these trials, brexpiprazole was administered once daily and titrated to target doses. The recommended dose for the treatment of schizophrenia is 2-4 mg/day and that for MDD, 2 mg/day. Pooling together all the available data for the recommended target dose of brexpiprazole for acute schizophrenia from the above studies, the percentage of responders is 45.5% vs. 31.0% for placebo, yielding a NNT of 7 (95% CI 5-12). In the relapse prevention/maintenance trial, significantly fewer patients relapsed in the brexpiprazole group compared with placebo (13.5% vs. 38.5%), resulting in a NNT of 4 (95% CI 3-8). When the results for brexpiprazole 1, 2 and 3 mg from the two Phase III MDD trials are pooled together, 23.2% of the patients receiving brexpiprazole were responders, vs. 14.5% for placebo, yielding a NNT of 12 (95% CI 8-26). Brexpiprazole was well tolerated - for schizophrenia, discontinuation rates because of an adverse event (AE) were overall lower for patients receiving brexpiprazole vs. placebo, and for MDD a total of 3% of brexpiprazole-treated patients and 1% of placebo-treated patients discontinued because of AEs, resulting in a NNH of 53 (95% CI 30-235). Although the most commonly encountered AE noted in product labelling was akathisia (5.5% in the acute schizophrenia trials and 8.6% in the MDD trials), differences from placebo were small, generating a non-significant NNH of 112 for patients with schizophrenia and a modest NNH of 15 (95% CI 11-23) for patients with MDD. Short-term weight gain appears modest; however, more outliers with an increase of ≥ 7% of body weight were evident in open-label 52-week safety studies. Effects on glucose and lipids were small. Minimal effects on prolactin were observed, and no clinically relevant effects on the ECG QT interval were evident.
CONCLUSIONS
Clinical trials of brexpiprazole support its efficacy at the recommended target dose of 2-4 mg/day for the treatment of schizophrenia, and at the recommended target dose of 2 mg/day as adjunct to antidepressant medication for the treatment of MDD. Head-to-head comparisons with other available agents among patients with schizophrenia and MDD in the 'real world' are needed.
Topics: Antidepressive Agents; Antipsychotic Agents; Chemotherapy, Adjuvant; Clinical Trials as Topic; Depressive Disorder, Major; Dopamine Agonists; Humans; Quinolones; Schizophrenia; Thiophenes
PubMed: 26250067
DOI: 10.1111/ijcp.12714 -
The International Journal of... Jul 2021Hyponatremia associated with antipsychotic drugs is a rare but potentially life-threatening adverse drug reaction; the underlying pharmacological mechanism has not yet...
Hyponatremia Following Antipsychotic Treatment: In Silico Pharmacodynamics Analysis of Spontaneous Reports From the US Food and Drug Administration Adverse Event Reporting System Database and an Updated Systematic Review.
BACKGROUND
Hyponatremia associated with antipsychotic drugs is a rare but potentially life-threatening adverse drug reaction; the underlying pharmacological mechanism has not yet been explained.
METHODS
We investigated the relationship between pharmacological targets of antipsychotic drugs and the occurrence of hyponatremia by conducting a nested case-control study using the Food and Drug Administration Adverse Event Reporting System database. Multiple logistic regression was used to determine the associations between antipsychotics receptor occupancy and hyponatremia. We also performed a systematic review of clinical studies on this association.
RESULTS
Of 139 816 reports involving at least 1 antipsychotic, 1.1% reported hyponatremia. Olanzapine was the most frequently suspected drug (27%). A significant positive association was found between dopamine D3, D4, and hyponatremia, while adrenergic α 1, serotonin 5-HT1A, and 5-HT2A receptor occupancies were negatively associated. A multivariable stepwise regression model showed that dopamine D3 (adj. odds ratio = 1.21; 95% CI = 1.09-1.34; P < .05) predicted the risk for hyponatremia (P < .05), while serotonin 5-HT2A occupancy (Adj. odds ratio = 0.78; 95% CI = 0.68-0.90; P < .01) exhibited a protective effect against hyponatremia. Among the 11 studies included in the systematic review, incidence rates of hyponatremia diverged between 0.003% and 86%, whereas the odds of developing hyponatremia from effect studies ranged between 0.83 and 3.47.
CONCLUSIONS
Antipsychotic drugs having a combined modest occupancy for D3 and 5-HT2A receptors and higher levels of D3 receptor occupancy correspond to different degrees of risk for hyponatremia. Based on the few, relatively large-scale available studies, atypical antipsychotics have a more attenuated risk profile for hyponatremia.
Topics: Antipsychotic Agents; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Hyponatremia; Pharmacovigilance; United States; United States Food and Drug Administration
PubMed: 33575781
DOI: 10.1093/ijnp/pyab005 -
Frontiers in Behavioral Neuroscience 2020The role of glucagon-like peptide 1 (GLP-1) in insulin-dependent signaling is well-known; GLP-1 enhances glucose-dependent insulin secretion and lowers blood glucose in...
Can GLP-1 Be a Target for Reward System Related Disorders? A Qualitative Synthesis and Systematic Review Analysis of Studies on Palatable Food, Drugs of Abuse, and Alcohol.
The role of glucagon-like peptide 1 (GLP-1) in insulin-dependent signaling is well-known; GLP-1 enhances glucose-dependent insulin secretion and lowers blood glucose in diabetes. GLP-1 receptors (GLP-1R) are also widely expressed in the brain, and in addition to its role in neuroprotection, it affects reward pathways. This systematic review aimed to analyze the studies on GLP-1 and reward pathways and its currently identified mechanisms. "Web of Science" and "Pubmed" were searched to identify relevant studies using GLP-1 as the keyword. Among the identified 26,539 studies, 30 clinical, and 71 preclinical studies were included. Data is presented by grouping rodent studies on palatable food intake, drugs of abuse, and studies on humans focusing on GLP-1 and reward systems. GLP-1Rs are located in reward-related areas, and GLP-1, its agonists, and DPP-IV inhibitors are effective in decreasing palatable food intake, along with reducing cocaine, amphetamine, alcohol, and nicotine use in animals. GLP-1 modulates dopamine levels and glutamatergic neurotransmission, which results in observed behavioral changes. In humans, GLP-1 alters palatable food intake and improves activity deficits in the insula, hypothalamus, and orbitofrontal cortex (OFC). GLP-1 reduces food cravings partially by decreasing activity to the anticipation of food in the left insula of obese patients with diabetes and may inhibit overeating by increasing activity to the consumption of food in the right OFC of obese and left insula of obese with diabetes. Current preclinical studies support the view that GLP-1 can be a target for reward system related disorders. More translational research is needed to evaluate its efficacy on human reward system related disorders.
PubMed: 33536884
DOI: 10.3389/fnbeh.2020.614884