Antipsychotic Efficacy Research Articles

Efficacy and safety profiles of mood stabilizers and antipsychotics for bipolar depression: a systematic review.

The whole picture of psychotropics for bipolar depression (BPD) remains unclear. This review compares the differences in efficacy and safety profiles among common psychotropics for BPD. MEDLINE, EMBASE, and PsycINFO were searched for proper studies. The changes in the depressive rating scale, remission/response rates, nervous system adverse events (NSAEs), gastrointestinal adverse events (GIAEs), metabolic parameters, and prolactin were compared between medication and placebo or among medications with the Cohen's d or number needed to treat/harm. The search provided 10 psychotropics for comparison. Atypical antipsychotics (AAPs) were superior to lithium and lamotrigine at alleviating acute depressive symptoms. Lithium was more likely to induce dry mouth and nausea. Cariprazine and aripiprazole seemed to be associated with an increased risk of akathisia and upper GIAEs. Lurasidone was associated with an increased risk of developing akathisia and hyperprolactinemia. Olanzapine, olanzapine-fluoxetine combination (OFC), and quetiapine were associated with an increased risk of NSAEs, metabolic risk, dry mouth, and constipation. Cariprazine, lurasidone, OFC, or quetiapine was optimal monotherapy for BPD. Further studies are needed to assess the efficacy and safety of lamotrigine for treating BPD. Adverse events varied widely across different drug types due to variations in psychopharmacological mechanisms, dosages, titration, and ethnicities.

Does short-term antipsychotic discontinuation of up to 3 weeks worsen symptoms in acute schizophrenia? A pooled analysis of placebo washout data.

This study aimed to examine symptom changes during short-term discontinuation of antipsychotics up to 3 weeks including the placebo washout phase in acute schizophrenia. The data from three double-blind, randomized, controlled trials comparing lurasidone versus placebo in patients with acute exacerbation of schizophrenia were analyzed. Symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS) total and the Clinical Global Impression-Severity scale (CGI-S) scores. The scores before and after the antipsychotic discontinuation phase were compared, and factors associated with score changes were explored. Among 2154 patients participating in the trials, 600 who received antipsychotic monotherapy and completed the antipsychotic discontinuation phase were included in the analysis. No patients received clozapine. The mean duration of the discontinuation phase was 5.9 ± 2.5 days. The PANSS total and CGI-S scores significantly changed from 94.0 ± 9.5 to 95.4 ± 10.5 (P < 0.001) and from 4.9 ± 0.6 to 4.9 ± 0.7 (P=0.041), respectively, during this phase; however, the absolute difference was minimal. The score changes were not associated with the type or dose of prior antipsychotics, or the duration or strategy (abrupt vs gradual) of antipsychotic discontinuation. Symptoms may not worsen to a clinically meaningful degree after short-term discontinuation of non-clozapine antipsychotics up to 3 weeks in patients with acute exacerbation of schizophrenia, suggesting that antipsychotic efficacy persists at least several days after discontinuation. This finding supports once-daily dosing regimen of antipsychotics and abrupt antipsychotic discontinuation when switching to another antipsychotic.

The Progress and Pitfalls of Pharmacogenetics-Based Precision Medicine in Schizophrenia Spectrum Disorders: A Systematic Review and Meta-Analysis

The inadequate efficacy and adverse effects of antipsychotics severely affect the recovery of patients with schizophrenia spectrum disorders (SSD). We report the evidence for associations between pharmacogenetic (PGx) variants and antipsychotics outcomes, including antipsychotic response, antipsychotic-induced weight/BMI gain, metabolic syndrome, antipsychotic-related prolactin levels, antipsychotic-induced tardive dyskinesia (TD), clozapine-induced agranulocytosis (CLA), and drug concentration level (pharmacokinetics) in SSD patients. Through an in-depth systematic search in 2010-2022, we identified 501 records. We included 29 meta-analyses constituting pooled data from 298 original studies over 69 PGx variants across 39 genes, 4 metabolizing phenotypes of CYP2D9, and 3 of CYP2C19. We observed weak unadjusted nominal significant (p < 0.05) additive effects of PGx variants of DRD1, DRD2, DRD3, HTR1A, HTR2A, HTR3A, and COMT (10 variants) on antipsychotic response; DRD2, HTR2C, BDNF, ADRA2A, ADRB3, GNB3, INSIG2, LEP, MC4R, and SNAP25 (14 variants) on weight gain; HTR2C (one variant) on metabolic syndrome; DRD2 (one variant) on prolactin levels; COMT and BDNF (two variants) on TD; HLA-DRB1 (one variant) on CLA; CYP2D6 (four phenotypes) and CYP2C19 (two phenotypes) on antipsychotics plasma levels. In the future, well-designed longitudinal naturalistic multi-center PGx studies are needed to validate the effectiveness of PGx variants in antipsychotic outcomes before establishing any reproducible PGx passport in clinical practice.

Focus on olanzapine

No AccessFocus on olanzapine S Davis S Davis1 Search for more papers by this author Affiliations 1Amayeza Info Services, South Africa Published Online:1 Mar 2023https://doi.org/10.36303/SAGP.0172https://hdl.handle.net/10520/ejc-mp_sagp_v4_n2_a8SectionsPDFView Full Text ToolsAdd to favouritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InRedditGMailOutlookCopy LinkMendeley AboutAbstractOlanzapine is indicated for the management of manifestations of psychotic disorders, acute episodes of moderate to severe mania, and prevention of recurrence of manic or depressive episodes of bipolar disorder.1,21. Rossiter DSouth African Medicines Formulary14thCape TownSouth African Medical Association2022 Google Scholar2. Zyprexa (olanzapine tablets, VELOTAB and Powder for IM injection)Package Insert Eli Lilly (S.A.) (Pty) LimitedBryanston1Dec2006 Google Scholar3. "Olanzapine" MerativeTM Micromedex® DRUGDEX® (electronic version)MerativeAnn Arbor, Michigan, USAAvailable from: https://www.micromedexsolutions.com/Accessed 10 Feb 2023 Google Scholar4. Thomas KSaadabadi A "Olanzapine. Updated 8 Sept 2022" StatPearls [Internet]Treasure Island (FL)StatPearls Publishing2022JanAvailable from: https://www.ncbi.nlm.nih.gov/books/NBK532903/Accessed 10 Feb 2023 Google Scholar5. Bobo WVShelton RC "Bipolar major depression in adults: Efficacy and adverse effects of second-generation antipsychotics. Updated 1 Aug 2022" UpToDateAvailable from: https://www.uptodate.com/contents/bipolar-major-depression-in-adults-efficacy-and-adverse-effects-of-second-generation-antipsychoticsAccessed 10 Feb 2023 Google Scholar6. Zhang JPGallego JARobinson DGet al. "Efficacy and safety of individual second-generation vs first-generation antipsychotics in first episode psychosis: A systematic review and meta-analysis" Int J Neuropsychopharmacol2013 166120518 DOI: https://doi.org/10.1017/S1461145712001277 Google Scholar Previous article Next article FiguresReferencesRelatedDetails None Volume 4, Issue 2 | Mar 2023 Downloaded 6 times LanguagesEnglish InformationCopyright © 2023, Medpharm Publications:All rights reservedPDF download Disclosure The authors confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. The authors confirm that they have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. Ethical conduct of research The authors state that they have obtained appropriate institutional review board outlined in the Declaration of Helsinki for all human or animal experimental investigations. A signed informed consent document has been obtained from all participants included in the study.

Sex differences in antipsychotic efficacy and side effects in psychosis

AbstractThere are a lot of studies investigating gender differences in the side effects of first and second-generation antipsychotic drugs. Even though some side effects are seen at higher rates in women, it is not determined yet the influence of gender on the efficacy and side effects of antipsychotic agents is still not well clear. In this review, we give a brief overview of antipsychotic side effects leading probably to distinguished clinical outcomes in both sexes.Disclosure of InterestNone Declared

The pharmacogenetics of the new-generation antipsychotics - A scoping review focused on patients with severe psychiatric disorders.

Exploring the possible correlations between gene variations and the clinical effects of the new-generation antipsychotics is considered essential in the framework of personalized medicine. It is expected that pharmacogenetic data will be useful for increasing the treatment efficacy, tolerability, therapeutic adherence, functional recovery, and quality of life in patients with severe psychiatric disorders (SPD). This scoping review investigated the available evidence about the pharmacokinetics, pharmacodynamics, and pharmacogenetics of five new-generation antipsychotics, i.e., cariprazine, brexpiprazole, aripiprazole, lumateperone, and pimavanserin. Based on the analysis of 25 primary and secondary sources and the review of these agents' summaries of product characteristics, aripiprazole benefits from the most relevant data about the impact of gene variability on its pharmacokinetics and pharmacodynamics, with significant consequences on this antipsychotic's efficacy and tolerability. The determination of the CYP2D6 metabolizer status is important when administering aripiprazole, either as monotherapy or associated with other pharmacological agents. Allelic variability in genes encoding dopamine D2, D3, and serotonin, 5HT2A, 5HT2C receptors, COMT, BDNF, and dopamine transporter DAT1 was also associated with different adverse events or variations in the clinical efficacy of aripiprazole. Brexpiprazole also benefits from specific recommendations regarding the CYP2D6 metabolizer status and the risks of associating this antipsychotic with strong/moderate CYP2D6 or CYP3A4 inhibitors. US Food and Drug Administration (FDA) and European Medicines Agency (EMA) recommendations about cariprazine refer to possible pharmacokinetic interactions with strong CYP3A4 inhibitors or inducers. Pharmacogenetic data about cariprazine is sparse, and relevant information regarding gene-drug interactions for lumateperone and pimavanserin is yet lacking. In conclusion, more studies are needed to detect the influence of gene variations on the pharmacokinetics and pharmacodynamics of new-generation antipsychotics. This type of research could increase the ability of clinicians to predict favorable responses to specific antipsychotics and to improve the tolerability of the treatment regimen in patients with SPD.

Comparative Efficacy, Safety, and Acceptability of Pimavanserin and Other Atypical Antipsychotics for Parkinson's Disease Psychosis: Systematic Review and Network Meta-Analysis.

The current comparative efficacy, safety, and acceptability of atypical antipsychotics (AAPs) in treating Parkinson's Disease Psychosis (PDP) are not entirely understood. To evaluate comparative efficacy, safety, and acceptability of AAPs in patients with PDP. We conducted a systematic review and a network meta-analysis to compare the efficacy, safety, and acceptability of pimavanserin, quetiapine, olanzapine, clozapine, ziprasidone, and risperidone. We estimated relative standardized mean differences (SMDs) for continuous outcomes and odds ratios (OR) for binary outcomes, with their respective 95% confidence intervals (CIs). We included 19 unique studies evaluating AAPs in a total of 1,242 persons with PDP. Based on Clinical Global Impression Scale for Severity, pimavanserin (SMD, -4.81; 95% CI, -5.39, -4.24) and clozapine (SMD, -4.25; 95% CI, -5.24, -3.26) significantly improved symptoms compared with placebo. Also, compared to placebo, pimavanserin (OR, 1.16; 95% CI, 1.07, 1.24) significantly improved psychotic symptoms based on Scale for Assessment of Positive Symptoms for Parkinson's Disease Psychosis/Hallucinations and Delusions scores. In comparison to placebo, clozapine (SMD, -0.69; 95% CI, -1.35, -0.02), pimavanserin (SMD, -0.01; 95% CI, -0.56, 0.53), and quetiapine (SMD, 0.00; 95% CI, -0.68, 0.69) did not impair motor function per Unified Parkinson's Disease Rating scale. Based on Mini-Mental State Examination scale, quetiapine (SMD, 0.60; 95% CI, 0.07, 1.14) significantly impaired cognition compared to placebo. In patients with PDP, pimavanserin and clozapine demonstrated significant improvement in psychosis without affecting motor function. With quetiapine being associated with a significant decline in cognition and despite not impairing motor function, our findings suggest that it should be avoided in patients with PDP and reduced cognitive abilities.

Histone deacetylase inhibitors mitigate antipsychotic risperidone-induced motor side effects in aged mice and in a mouse model of Alzheimer's disease.

Antipsychotic drugs are still widely prescribed to control various severe neuropsychiatric symptoms in the elderly and dementia patients although they are off-label use in the United States. However, clinical practice shows greater side effects and lower efficacy of antipsychotics for this vulnerable population and the mechanisms surrounding this aged-related sensitivity are not well understood. Our previous studies have shown that aging-induced epigenetic alterations may be involved in the increasing severity of typical antipsychotic haloperidol induced side effects in aged mice. Still, it is unknown if similar epigenetic mechanisms extend to atypical antipsychotics, which are most often prescribed to dementia patients combined with severe neuropsychiatric symptoms. In this study, we report that atypical antipsychotic risperidone also causes increased motor side effect behaviors in aged mice and 5xFAD mice. Histone deacetylase (HDAC) inhibitor Valproic Acid and Entinostat can mitigate the risperidone induced motor side effects. We further showed besides D2R, reduced expression of 5-HT2A, one of the primary atypical antipsychotic targets in the striatum of aged mice that are also mitigated by HDAC inhibitors. Finally, we demonstrate that specific histone acetylation mark H3K27 is hypoacetylated at the 5htr2a and Drd2 promoters in aged mice and can be reversed with HDAC inhibitors. Our work here establishes evidence for a mechanism where aging reduces expression of 5-HT2A and D2R, the key atypical antipsychotic drug targets through epigenetic alteration. HDAC inhibitors can restore 5-HT2A and D2R expression in aged mice and decrease the motor side effects in aged and 5xFAD mice.

Impact of membrane lipid polyunsaturation on dopamine D2 receptor ligand binding and signaling.

Increasing evidence supports a relationship between lipid metabolism and mental health. In particular, the biostatus of polyunsaturated fatty acids (PUFAs) correlates with some symptoms of psychiatric disorders, as well as the efficacy of pharmacological treatments. Recent findings highlight a direct association between brain PUFA levels and dopamine transmission, a major neuromodulatory system implicated in the etiology of psychiatric symptoms. However, the mechanisms underlying this relationship are still unknown. Here we demonstrate that membrane enrichment in the n-3 PUFA docosahexaenoic acid (DHA), potentiates ligand binding to the dopamine D2 receptor (D2R), suggesting that DHA acts as an allosteric modulator of this receptor. Molecular dynamics simulations confirm that DHA has a high preference for interaction with the D2R and show that membrane unsaturation selectively enhances the conformational dynamics of the receptor around its second intracellular loop. We find that membrane unsaturation spares G protein activity but potentiates the recruitment of β-arrestin in cells. Furthermore, in vivo n-3 PUFA deficiency blunts the behavioral effects of two D2R ligands, quinpirole and aripiprazole. These results highlight the importance of membrane unsaturation for D2R activity and provide a putative mechanism for the ability of PUFAs to enhance antipsychotic efficacy.

Antipsychotic Drugs Efficacy in Dextromethorphan-Induced Psychosis.

Psychosis is known as a broad term of symptoms that cause serious disorganization of behavior, thinking, and perception of reality. One of the medicines that recently gained much attention in terms of its psychotic potential is dextromethorphan (DXM). DXM, a widely used antitussive drug, is a commonly abused drug because of its euphoric, hallucinogenic, and dissociative properties. To date, DXM is a legally marketed cough suppressant that is neither a controlled substance nor a regulated chemical under the Controlled Substances Act. The management of DXM-related psychosis is dependent on the type of psychotic symptoms. Atypical neuroleptics (i.e., olanzapine, risperidone, quetiapine) and typical haloperidol have been used in symptomatic treatment due to their efficacy, especially in positive symptoms (hallucinations and delusions). These agents are also recognized as the preferred option in the symptomatic treatment of DXM-related psychosis due to their better efficacy and safety profile than typical haloperidol in the short-term course. The focus of the present review concerns the current stage of knowledge about DXM psychotic potency as well as the management of DXM-related psychoses with a special emphasis on atypical antipsychotic drugs (i.e., olanzapine, risperidone, quetiapine, and haloperidol).

Identification and Characterization of ML321: A Novel and Highly Selective D2 Dopamine Receptor Antagonist with Efficacy in Animal Models That Predict Atypical Antipsychotic Activity.

We have developed and characterized a novel D2R antagonist with exceptional GPCR selectivity - ML321. In functional profiling screens of 168 different GPCRs, ML321 showed little activity beyond potent inhibition of the D2R and to a lesser extent the D3R, demonstrating excellent receptor selectivity. The D2R selectivity of ML321 may be related to the fact that, unlike other monoaminergic ligands, ML321 lacks a positively charged amine group and adopts a unique binding pose within the orthosteric binding site of the D2R. PET imaging studies in non-human primates demonstrated that ML321 penetrates the CNS and occupies the D2R in a dose-dependent manner. Behavioral paradigms in rats demonstrate that ML321 can selectively antagonize a D2R-mediated response (hypothermia) while not affecting a D3R-mediated response (yawning) using the same dose of drug, thus indicating exceptional in vivo selectivity. We also investigated the effects of ML321 in animal models that are predictive of antipsychotic efficacy in humans. We found that ML321 attenuates both amphetamine- and phencyclidine-induced locomotor activity and restored pre-pulse inhibition (PPI) of acoustic startle in a dose-dependent manner. Surprisingly, using doses that were maximally effective in both the locomotor and PPI studies, ML321 was relatively ineffective in promoting catalepsy. Kinetic studies revealed that ML321 exhibits slow-on and fast-off receptor binding rates, similar to those observed with atypical antipsychotics with reduced extrapyramidal side effects. Taken together, these observations suggest that ML321, or a derivative thereof, may exhibit ″atypical″ antipsychotic activity in humans with significantly fewer side effects than observed with the currently FDA-approved D2R antagonists.

Efficacy and Safety of Second-generation Antipsychotics in Schizophrenia Pharmacotherapy: A Comparative Narrative Review

Antipsychotic medications are essential in schizophrenia pharmacotherapy, with notable differences in efficacy and safety. This review aims to discuss and compare the differences in efficacy and safety among various second-generation antipsychotic drugs (SGAs). A narrative review was conducted involving the English-based published literature in three scientific databases between 2000 and January 2021: Google Scholar, Scopus, and PubMed. Clozapine is widely considered an effective therapy option in cases of resistance. Maintenance of schizophrenia treatment with paliperidone palmitate was effective and resulted in a longer duration between relapses. The risk of weight gain and diabetes mellitus was increased significantly with clozapine and olanzapine. Risperidone caused neuroleptic malignant syndrome (NMS) and significantly elevated prolactin levels. The extent of safety concerns reported varied by study design. While there were minor differences in the dose-dependent role of SGAs in acute episode treatment, there were significant differences in the type and intensity of side effects, and hence adherence determinants.

Ulotaront: a TAAR1/5-HT1A agonist in clinical development for the treatment of schizophrenia

ABSTRACT Introduction Current antipsychotics are postsynaptic dopamine-2(D2) receptor blockers, which often, but not always, effectively improve acute psychotic symptoms and prevent relapse in schizophrenia and other severe mental disorders, but are associated with various side effects, including parkinsonism, akathisia, sedation/somnolence, and cardiometabolic alterations. Furthermore, the efficacy of current antipsychotics for negative and cognitive symptoms in schizophrenia is limited. Ulotaront is a novel trace-amine-associated receptor-1(TAAR1) agonist with serotonin-1A receptor agonist activity, and without postsynaptic D2-receptor antagonism. Phase 2 clinical data for ulotaront in patients with acutely exacerbated schizophrenia are promising regarding the potential improvement in positive, negative, and depressive symptoms. Areas covered An overview of the pharmacokinetic and pharmacodynamic properties of ulotaront is given. Summary of clinical efficacy and safety/tolerability from Phase 1/2-trials, and of ongoing Phase 3-trials, is also given. Expert opinion Ulotaront is a promising agent for the treatment of schizophrenia with an apparent benign safety profile, which might provide a much-needed new and different treatment option for various domains of schizophrenia. Data from larger Phase 3-trials, including for relapse prevention, schizophrenia subdomains, and in adolescents, are awaited. If ongoing Phase 3-trials in adults are successful, further research on combination regimens with existing antipsychotics, and in treatment-resistant schizophrenia as well as in mood disorders would be desirable.

Application of Antipsychotic Medication: Gender Differences in Tolerance and Medication Response

This paper covers the role of gender factor in the efficacy and tolerance of antipsychotic therapy in patients with schizophrenic spectrum disorders. The author describes phenomenology of definitions that characterizes differences between male and female sexes. The authors give the data on biological basis of gender differences, frequency of occurrence and clinical features of neuroendocrine dysfunctions (NED) in patients with schizophrenic spectrum disorders during the therapy by first and second generations antipsychotics. It is shown that female patients are more “vulnerable” for some NED. It is emphasized that the problem of tolerance is now more relevant and significant in comparison with the efficacy of antipsychotics, because intolerance or poor tolerance are one of the most common reasons for non-adherence to therapy up to the complete abandonment of it.

Common changes in rat cortical gene expression after chronic treatment with chlorpromazine and haloperidol may be related to their antipsychotic efficacy

It has been postulated that common molecular changes resulting from treatment with antipsychotic drugs are involved in their therapeutic mechanisms of action. There are studies showing antipsychotic drug treatment causes changes in rat cortical gene expression. Hence, in this study, we sort to identify common changes in gene expression caused by two antipsychotic drugs because such changes could be related to their therapeutic mechanisms of action. In this study, RNA levels in rat cortex was measured using Affymetrix GeneChip® Rat Genome 230 2.0 Arrays after treatment with vehicle, haloperidol or chlorpromazine in drinking water for 28 days (n ​= ​10 per group). Panther Gene Ontology Classification System was used to identify biological consequences of changes in gene expression after drug treatment. Using criteria for differential gene expression established using our current data sets, compared to vehicle, chlorpromazine and haloperidol treatment changed levels of cortical RNA for 454 and 102 genes, respectively. Moreover, at the level of significance of p ​< ​0.05 treatment with both drugs cause highly correlated fold changes in the expression of 154 genes that includes enzymes and regulators of their activity, receptors and receptor signalling pathways, regulators of gene translation and transcription, components of the cytoskeleton, molecular transporters and regulators of protein trafficking across membranes. We conclude that changing gene expression is an important mechanism of action of antipsychotic drugs and some of these changes may be involved in the therapeutic benefits of those drugs.

In vivo Characterization of the Opioid Receptor-Binding Profiles of Samidorphan and Naltrexone in Rats: Comparisons at Clinically Relevant Concentrations.

The atypical antipsychotic olanzapine is approved for the treatment of schizophrenia and bipolar I disorder; however, weight gain and metabolic dysregulation associated with olanzapine therapy have limited its clinical utility. In clinical studies, treatment with the combination of olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM) mitigated olanzapine-associated weight gain while providing antipsychotic efficacy similar to that of olanzapine. Although samidorphan is structurally similar to the opioid receptor antagonist naltrexone, the two differ in their pharmacokinetics and in vitro binding affinities to mu, delta, and kappa opioid receptors (MOR, DOR, and KOR, respectively). The objective of this series of nonclinical studies was to compare the in vivo binding profiles of samidorphan and naltrexone and their receptor occupancies at MOR, DOR, and KOR in rat brains. Male rats were injected with samidorphan or naltrexone to obtain total and unbound plasma and brain concentrations representing levels observed in humans at clinically relevant oral doses. Subsequently, samidorphan and naltrexone brain receptor occupancy at MOR, DOR, and KOR was measured using ultra-performance liquid chromatography and high-resolution accurate-mass mass spectrometry. A dose-dependent increase in samidorphan occupancy was observed at MOR, DOR, and KOR (EC50: 5.1, 54.7, and 42.9 nM, respectively). Occupancy of naltrexone at MOR (EC50: 15.5 nM) and KOR was dose dependent; minimal DOR occupancy was detected. At the clinically relevant unbound brain concentration of 23.1nM, samidorphan bound to MOR, DOR, and KOR with 93.2%, 36.1%, and 41.9% occupancy, respectively. At 33.5 nM, naltrexone bound to MOR and KOR with 79.4% and 9.4% occupancy, respectively, with no binding at DOR. At clinically relevant concentrations, samidorphan occupied MOR, DOR, and KOR, whereas naltrexone occupied only MOR and KOR. The binding profile of samidorphan differs from that of naltrexone, with potential clinical implications.

Association between neuropeptide Y gene polymorphism and antipsychotics effect.

The pathogenesis of schizophrenia is associated with neuropeptide Y (NPY) gene polymorphism to explore the relationship between rs16141, rs16145, and rs5573 polymorphisms in the NPY gene and antipsychotics response in the Chinese population. The unrelated 228 Chinese Han patients with schizophrenia were enrolled in the present study. Genotypisation within NPY gene was performed using the KASP genotyping assays. Before treatment and on the weekends of the 2nd, 4th, and 8th weeks after treatment, the medication status of the patients was recorded and the positive and negative syndrome scale (PANSS) was used to evaluate the clinical effect. A reduction in total PANSS scores ≥50% were classified as good responders, while others were poor responders. We evaluated the association between NPY gene and antipsychotic efficacy by comparing allele and genotype distribution, correlation analysis, linkage imbalance, and five genetic models between the two groups. No significant associations were found in the rs16141, rs16145, and rs5573 of NPY and antipsychotic treatment response (all p > 0.05). There was no significant relationship between the three SNPs polymorphisms in the NPY gene and the changes of positive, negative and general psychopathology subscales scores at each stage (all p > 0.05). The distribution of genotype and allele frequencies of locus rs16141 was not statistically difference between good responders and poor responders (genotype: χ2 =4.088, p=0.043, p-correction = 0.129; allele: χ2 = 4.088, p = 0.027, p-correction = 0.081). The allele distribution of rs5573 was significantly different between groups, yet the difference was disappeared after correcting (χ2 = 4.136, p = 0.042, p-correction =0.126). The distribution frequencies of TA/TG and GG haplotypes constituted by rs16141 and rs5573 showed no statistical difference between the two groups (p > 0.05). In recessive inheritance mode, NPYrs5573 was found to be associated with antipsychotic drug response (G/G vs. A/A +A/G: p = 0.028, AIC = 197.2, BIC = 210.9). This study didn't found association between polymorphisms in the NPY gene locus (rs16141, rs16145, and rs5573) and the response to antipsychotics after Bonferroni correction. The polymorphism of NPY gene and the efficacy of antipsychotic drugs in patients with schizophrenia need further study.

11.4 Extrapolation of Atypical Antipsychotics for the Treatment of Schizophrenia From Adults to Adolescents

Antipsychotic drug development in pediatric patients is often challenged by disease heterogeneity, patient recruitment, clinical trial attrition, and ethical concerns. Regulatory agencies have explored various pathways to expedite pediatric drug development over the last decade. Extrapolation-based drug development strategies rely on leveraging prior data to reduce evidentiary requirements for newer data in establishing drug efficacy. On January 13, 2020, the FDA released a general advice letter to sponsors highlighting the acceptance of extrapolating the efficacy of atypical antipsychotics to pediatric patients.

Smoking in Schizophrenia: Dependancy Assessment, Neurobiological Aspects and Management Difficulties

Tobacco is the leading cause of preventable death worldwide. Numerous studies have shown that the frequency of smoking in schizophrenic patients is significantly higher than in the general population or in other psychiatric disorders, which hinders both treatment strategies and the efficacy of antipsychotics. The objectives of our study are: to highlight the prevalence of smoking in this population, to assess its dependence on nicotine, as well as to support the difficulties of its management. We conducted a cross-sectional study of 186 patients, hospitalized at Ar-razi Hospital in Salé, using the Fagerström scale, associated with a questionnaire that included age, marital status, educational level, occupation, duration of psychiatric follow-up, somatic comorbidities, current treatment, other substances used, withdrawal attempts, age of first cigarette, family history of smoking, and finally, number of cigarettes per day before and then after psychiatric diagnosis. The frequency of tobacco use in our schizophrenic patients was high. Unfortunately, these patients remain poorly aware of the harms of tobacco, hence the need to integrate a tobacco control strategy into the hospital management of schizophrenia.

Efficacy difference of antipsychotics in Alzheimer's disease and schizophrenia: explained with network efficiency and pathway analysis methods.

Approximately 50% of Alzheimer's disease (AD) patients will develop psychotic symptoms and these patients will experience severe rapid cognitive decline compared with those without psychosis (AD-P). Currently, no medication has been approved by the Food and Drug Administration for AD with psychosis (AD+P) specifically, although atypical antipsychotics are widely used in clinical practice. These drugs have demonstrated modest efficacy in managing psychosis in individuals with AD, with an increased frequency of adverse events, including excess mortality. We compared the differences between the genetic variations/genes associated with AD+P and schizophrenia from existing Genome-Wide Association Study and differentially expressed genes (DEGs). We also constructed disease-specific protein-protein interaction networks for AD+P and schizophrenia. Network efficiency was then calculated to characterize the topological structures of these two networks. The efficiency of antipsychotics in these two networks was calculated. A weight adjustment based on binding affinity to drug targets was later applied to refine our results, and 2013 and 2123 genes were identified as related to AD+P and schizophrenia, respectively, with only 115 genes shared. Antipsychotics showed a significantly lower efficiency in the AD+P network than in the schizophrenia network (P< 0.001) indicating that antipsychotics may have less impact in AD+P than in schizophrenia. AD+P may be caused by mechanisms distinct from those in schizophrenia which result in a decreased efficacy of antipsychotics in AD+P. In addition, the network analysis methods provided quantitative explanations of the lower efficacy of antipsychotics in AD+P.