Efficacy Of Antipsychotic Drugs Research Articles

Permissive epigenetic regulatory mechanisms at the histone level are enhanced in postmortem dorsolateral prefrontal cortex of individuals with schizophrenia.

Susceptibility to schizophrenia is determined by interactions between genes and environment, possibly via epigenetic mechanisms. Schizophrenia has been associated with a restrictive epigenome, and histone deacetylase (HDAC) inhibitors have been postulated as coadjuvant agents to potentiate the efficacy of current antipsychotic drugs. We aimed to evaluate global histone posttranslational modifications (HPTMs) and HDAC expression and activity in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia. We used postmortem DLPFC samples of individuals with schizophrenia and controls matched for sex, age, and postmortem interval. Schizophrenia samples were classified into antipsychotic-treated or antipsychotic-free subgroups according to blood toxicology. Expression of HPTMs and HDAC was quantified by Western blot. HDAC activity was measured with a fluorometric assay. H3K9ac, H3K27ac, and H3K4me3 were globally enhanced in the DLPFC of individuals with schizophrenia (+24%-42%, p < 0.05). HDAC activity (-17%, p < 0.01) and HDAC4 protein expression (-20%, p < 0.05) were downregulated in individuals with schizophrenia. Analyses of antipsychotic-free and antipsychotic-treated subgroups revealed enhanced H3K4me3 and H3K27ac (+24%-49%, p < 0.05) and reduced HDAC activity in the antipsychotic-treated, but not in the antipsychotic-free subgroup. Special care was taken to control the effect of confounding factors: age, sex, postmortem interval, and storage time. However, replication studies in bigger cohorts might strengthen the association between permissive HPTMs and schizophrenia. We found global HPTM alterations consistent with an aberrantly permissive epigenome in schizophrenia. Further studies to elucidate the significance of enhanced permissive HPTMs in schizophrenia and its association with the mechanism of action of antipsychotic drugs are encouraged.

Efficacy and Safety Profiles of Antipsychotic Drugs as Viewed by Psychiatrists: A Comparative Analysis of Cariprazine and Risperidone.

Physicians hold the belief that the treatment outcomes and the treatment strategy they eventually adopt is largely determined by the differences in medications. Despite numerous studies focusing on the decision-making processes of psychiatrists, including the choice of antipsychotics when prescribing pharmacotherapy, the impact of therapeutic drug profiling on physicians' decision-making remains poorly comprehended. The aim of this study is to assess the quantitative differences in perceptions of antipsychotics by psychiatrists using cariprazine and risperidone as examples. A total of 79 psychiatrists were interviewed anonymously in St. Petersburg, Russia. The physicians documented the clinical advantages they perceived drugs to possess relative to one another, following a predetermined principle: A B, A=B, A B (2-AC protocol). The comparison is based on eleven parameters that assess the effectiveness and safety of cariprazine or risperidone. It has been hypothesized that the pattern of responses (qualitative difference) and the degree of preference for each drug (quantitative difference) may not align with the data in the original meta-analyses. The perception parameter exhibited a greater difference than anticipated (δ - 0.889), while the threshold for differentiating between the drugs was lower (τ - 1.001). The response pattern only aligned with theory by 44.37%. The dispersion of responses was associated with the length of work experience. The perceived difference between the drugs significantly deviates from the theoretical data, both in terms of strength of perception and pattern (quantitative and qualitative differences).

Association between the rs6313 polymorphism in the 5-HTR2A gene and the efficacy of antipsychotic drugs

BackgroundPrescribing the optimal antipsychotic treatment to schizophrenia is very important as it is well established that patients have different sensitivity to the available antipsychotic drugs. The genotype of the HTR2A T102C (rs6313) polymorphism has been suggested to affect the efficacy of antipsychotic drugs, but the results of different studies have been inconsistentMethodsIn this study, a meta-analysis was used to ascertain the association between allele and genotype polymorphism of rs6313 and the efficacy of antipsychotic drugs. Related studies publicated from January 1995 to December 2021 were retrieved from PubMed, Embase, ScienceDirect, and Web of Science databases. The correlations between allele and genotype polymorphism of rs6313 and the responder rate and scale score reduction rate of antipsychotics were analyzed. In addition, subgroup analyses were performed on time, drug, and ethnicity.ResultsA total of 18 studies were included. The meta-analysis showed that allele and genotype polymorphisms at the rs6313 locus overall were not associated with antipsychotic drug responder rate or scale score reduction rate. Ethnicity subgroup analysis showed that antipsychotic drugs were more effective in patients with allele T in the Caucasian population. Indian patients with the TT genotype had the lowest scale score reduction rate and poor drug treatment effect. East Asian patients with the TC genotype had better treatment effect, whereas in patients with the CC genotype, the treatment was less effective. Drug subgroup analysis showed that patients with the TC genotype treated with clozapine had the highest responder rate and score reduction rate.ConclusionsThe association between rs6313 polymorphism and the efficacy of antipsychotic drugs is mainly influenced by drug and ethnicity. Caucasian patients with the T allele respond better to drug therapy, and Asian patients with TC genotype. The TC genotype was also a good predictor of the efficacy of clozapine treatment.

Prefrontal cortex-specific Dcc deletion induces schizophrenia-related behavioral phenotypes and fail to be rescued by olanzapine treatment

Multiple genome studies have discovered that variation in deleted in colorectal carcinoma (Dcc) at transcription and translation level were associated with the occurrences of psychiatric disorders. Yet, little is known about the function of Dcc in schizophrenia (SCZ)-related behavioral abnormalities and the efficacy of antipsychotic drugs in vivo. Here, we used an animal model of prefrontal cortex-specific knockdown (KD) of Dcc in adult C57BL/6 mice to study the attention deficits and impaired locomotor activity. Our results supported a critical role of Dcc deletion in SCZ-related behaviors. Notably, olanzapine rescued the SCZ-related behaviors in the MK801-treated mice but not in the cortex-specific Dcc KD mice, indicating that Dcc play a critical in the mechanism of antipsychotic effects of olanzapine. Knockdown of Dcc in prefrontal cortex results in glutamatergic dysfunction, including defects in glutamine synthetase and postsynaptic maturation. As one of the major risk factors of the degree of antipsychotic response, Dcc deletion-induced glutamatergic dysfunction may be involved in the underlying mechanism of treatment resistance of olanzapine. Our findings identified Dcc deletion-mediated SCZ-related behavioral defects, which serve as a valuable animal model for study of SCZ and amenable to targeted investigations in mechanistic hypotheses of the mechanism underlying glutamatergic dysfunction-induced antipsychotic treatment resistance.

Antipsychotic drug efficacy correlates with the modulation of D1 rather than D2 receptor-expressing striatal projection neurons.

Elevated dopamine transmission in psychosis is assumed to unbalance striatal output through D1- and D2-receptor-expressing spiny-projection neurons (SPNs). Antipsychotic drugs are thought to re-balance this output by blocking D2 receptors (D2Rs). In this study, we found that amphetamine-driven dopamine release unbalanced D1-SPN and D2-SPN Ca2+ activity in mice, but that antipsychotic efficacy was associated with the reversal of abnormal D1-SPN, rather than D2-SPN, dynamics, even for drugs that are D2R selective or lacking any dopamine receptor affinity. By contrast, a clinically ineffective drug normalized D2-SPN dynamics but exacerbated D1-SPN dynamics under hyperdopaminergic conditions. Consistent with antipsychotic effect, selective D1-SPN inhibition attenuated amphetamine-driven changes in locomotion, sensorimotor gating and hallucination-like perception. Notably, antipsychotic efficacy correlated with the selective inhibition of D1-SPNs only under hyperdopaminergic conditions-a dopamine-state-dependence exhibited by D1R partial agonism but not non-antipsychotic D1R antagonists. Our findings provide new insights into antipsychotic drug mechanism and reveal an important role for D1-SPN modulation.

Long-term efficacy of antipsychotic drugs in initially acutely ill adults with schizophrenia: systematic review and network meta-analysis.

Most acute phase antipsychotic drug trials in schizophrenia last only a few weeks, but patients must usually take these drugs much longer. We examined the long-term efficacy of antipsychotic drugs in acutely ill patients using network meta-analysis. We searched the Cochrane Schizophrenia Group register up to March 6, 2022 for randomized, blinded trials of at least 6-month duration on all second-generation and 18 first-generation antipsychotics. The primary outcome was change in overall symptoms of schizophrenia; secondary outcomes were all-cause discontinuation; change in positive, negative and depressive symptoms; quality of life, social functioning, weight gain, antiparkinson medication use, akathisia, serum prolactin level, QTc prolongation, and sedation. Confidence in the results was assessed by the CINeMA (Confidence in Network Meta-Analysis) framework. We included 45 studies with 11,238 participants. In terms of overall symptoms, olanzapine was on average more efficacious than ziprasidone (standardized mean difference, SMD=0.37, 95% CI: 0.26-0.49), asenapine (SMD=0.33, 95% CI: 0.21-0.45), iloperidone (SMD=0.32, 95% CI: 0.15-0.49), paliperidone (SMD=0.28, 95% CI: 0.11-0.44), haloperidol (SMD=0.27, 95% CI: 0.14-0.39), quetiapine (SMD=0.25, 95% CI: 0.12-0.38), aripiprazole (SMD=0.16, 95% CI: 0.04-0.28) and risperidone (SMD=0.12, 95% CI: 0.03-0.21). The 95% CIs for olanzapine versus aripiprazole and risperidone included the possibility of trivial effects. The differences between olanzapine and lurasidone, amisulpride, perphenazine, clozapine and zotepine were either small or uncertain. These results were robust in sensitivity analyses and in line with other efficacy outcomes and all-cause discontinuation. Concerning weight gain, the impact of olanzapine was higher than all other antipsychotics, with a mean difference ranging from -4.58 kg (95% CI: -5.33 to -3.83) compared to ziprasidone to -2.30 kg (95% CI: -3.35 to -1.25) compared to amisulpride. Our data suggest that olanzapine is more efficacious than a number of other antipsychotic drugs in the longer term, but its efficacy must be weighed against its side effect profile.

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.

The response of subgroups of patients with schizophrenia to different antipsychotic drugs: a systematic review and meta-analysis

As comparatively few trials in subgroups of patients with schizophrenia have been done, clinicians need to know whether they can rely on the results of randomised controlled trials (RCTs) in the general population of patients with schizophrenia. We aimed to compare the efficacy and side-effects of antipsychotic drugs in different subgroups. In this systematic review and meta-analysis, we searched reference lists of previous systematic reviews and meta-analyses, the Cochrane Schizophrenia Group's Study-Based Register (from database inception to April 27, 2020), and PubMed (from April 1, 2020 to June 14, 2021). We excluded studies in patients with stable schizophrenia (ie, relapse prevention studies), studies with a high risk of bias, and studies from mainland China due to quality concerns concerning allocation and masking methods. We included single-blind RCTs or better that assessed one or more of 16 second-generation and 18 first-generation antipsychotics in the general population of patients with schizophrenia or in one or more of the subgroups: children and adolescents (age range as defined in the original studies), patients with a first episode, patients with predominant or prominent negative symptoms, patients with comorbid substance use, patients with treatment-resistant schizophrenia, or older patients (age range as defined in the original studies). Two authors independently screened the results of the search, retrieved full-text articles, and checked the inclusion criteria. Using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline, all parameters were extracted in duplicate. The primary outcome was change in overall symptoms. We compared drug efficacy between subgroups, by sex, schizoaffective disorder versus schizophrenia, and study origin using random-effects, inverse variance meta-analyses and random-effects subgroup tests, and meta-regression. We included 537 RCTs with 76 382 participants, 26 627 (34·9%) women, 49 755 (65·1%) men, mean age 37·3 years (range of means 7·9-80·2; ethnicity data not available). 412 RCTs included patients in the general population of patients with schizophrenia, 42 included patients with treatment-resistant schizophrenia, 25 included children and adolescents, 20 included patients with their first episode, 20 included patients with predominant or prominent negative symptoms, 13 included patients with comorbid substance use, and 11 included older patients. Of 507 random-effects subgroup tests done, 46 (9%) showed a significant difference (p<0·05) between subgroups, but there was no clear indication as to which drug should be used in which subgroup. The effects of antipsychotics in various patient subgroups were usually similar to those in the general population of patients with schizophrenia, but comparably few studies contributed to the subgroups, in particular in terms of side-effects. If the evidence for treatment in a given subgroup is small, guideline makers and clinicians should consider using the results in the much better studied group of the general population of patients with schizophrenia. German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung; FKZ 01KG1508).

DRD3 Ser9Gly polymorphism and treatment response to antipsychotics in schizophrenia: A meta-analysis

The association between dopamine D3 receptor (DRD3) Ser9Gly polymorphism and treatment response to antipsychotic drugs (APDs) in schizophrenia (SCZ) has been widely reported with inconsistent results, thus we performed an updated meta-analysis to derive a more precise estimation of the relationship. PubMed, Cochrane Library, Medline, Embase, CNKI, Weipu and Wanfang databases were searched for eligible studies published until March 2022. Odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of the associations in four genetic models. A total of 13 studies with 1769 patients were included in this meta-analysis. Our findings suggested that Ser9Gly polymorphism was significantly associated with treatment response to APDs in SCZ in allele model (Ser vs Gly, OR = 0.72, 95 % CI = 0.58–0.89, P = 0.002), recessive model (Ser/Ser vs Ser/Gly + Gly/Gly, OR = 0.55, 95 % CI = 0.36–0.86, P = 0.008) and co-dominant model (Ser/Ser vs Gly/Gly, OR = 0.57, 95 % CI = 0.33–0.99, P = 0.045) in Caucasians, but not in Asians. meta-regression revealed that the associations were not confounded by mean age, male ratio and treatment duration (P > 0.05). In summary, our results indicated the DRD3 Ser9Gly may influence the efficacy of APDs in specific genetic models, of which Ser allele and Ser/Ser genotype contributed to poor treatment response in Caucasians.

Demystifying Morgellons Disease

Morgellons disease is an understudied complex of physical and psychological symptoms that requires further research because medical authorities have diagnosed and treated patients’ symptoms as delusional. In contrast, other studies have demonstrated a connection between the hallmark subcutaneous fibers and spirochetal infection. The literature includes case reports of Morgellons treated as delusional infestation with antipsychotic drugs to a certain degree of success, reinforcing the thesis of Morgellons as a purely psychological disease but not addressing the etiology of the somatic symptoms. An under-designed CDC study has similarly concluded that no single joint infectious agent exists in Morgellons disease patients. However, other small sample size case reports identified a common microorganism, Borrelia, and concluded it could cause symptoms as a single species of a more extensive polymicrobial infection. Much literature exists discussing the difficulty in diagnosing polymicrobial infections and the role that they may play in neurodegenerative diseases. This literature review aims to find common ground between these seemingly opposing schools of thought by demonstrating that their findings are not mutually exclusive. The efficacy of antipsychotic drugs does not exclude the possibility of Morgellons having organic pathophysiology. Similarly, studies demonstrating a lack of a single common microorganism in Morgellons patients do not prove that Morgellons disease is not infectious in origin. Establishing that these theories coexist is the aim of this review and demonstrating that further studies, case reports, and clinical trials are necessary to develop a common diagnosis and effective treatments.

Maintenance Treatment With Antipsychotic Drugs in Schizophrenia: A Cochrane Systematic Review and Meta-analysis.

Antipsychotic drugs are the mainstay of treatment of schizophrenia, and are known to reduce acute symptoms of the disorder. An original version of the current review, published in 2012, examined whether antipsychotics are effective for relapse prevention, compared to withdrawing these agents for people with schizophrenia or schizophrenia-like psychoses, based on evidence from randomized trials. The current report of the update of the review is focused on some newly investigated outcomes: rates of remission and recovery, change in social functioning and in quality of life. The updated review included 75 randomized controlled trials (RCTs) published from 1959 to 2017, involving 9145 participants. Although some potential sources of bias limited the overall quality, the efficacy of antipsychotic drugs for maintenance treatment in schizophrenia was clear and robust to a series of sensitivity analyses. Antipsychotic drugs were more effective than placebo in preventing relapse at 1 year (drug 24% versus placebo 61%, 30 RCTs, n = 4249, RR = 0.38, 95% CI = 0.32 to 0.45) and in reducing hospitalization (drug 7% versus placebo 18%, 21 RCTs, n = 3558, RR = 0.43, 95% CI = 0.32 to 0.57). Quality of life appeared to be better in drug-treated participants (7 RCTs, n = 1573, SMD = -0.32, 95% CI = -0.57 to -0.07); the same for social functioning (15 RCTs, n = 3588, SMD = -0.43, 95% CI = -0.53 to -0.34). Although based on data from fewer studies, maintenance treatment apparently increased the possibility to achieve remission of symptoms (drug 53%, placebo 31%; 7 RCTs, 867 participants; RR = 1.73, 95% CI = 1.20 to 2.48) and to sustain it over 6 months (drug 36%, placebo 26%; 8 RCTs, 1807 participants; RR = 1.67, 95% CI = 1.28 to 2.19). There were no data on recovery. Antipsychotic drugs as a group were associated with more participants experiencing side effects such as movement disorders (e.g., at least one movement disorder: drug 14% versus placebo 8%, 29 RCTs, n = 5276, RR 1.52, 95% CI = 1.25 to 1.85) and weight gain (drug 9% versus placebo 6%, 19 RCTs, n = 4767, RR = 1.69, 95% CI = 1.21 to 2.35, NNTH = 25, 95% CI = 20 to 50). For people with schizophrenia, the evidence suggests that maintenance on antipsychotic drugs does not only prevent relapses and rehospitalizations, but that patients also benefit in terms of quality of life, functioning and sustained remission. These positive effects must be weighed against the backdrop of the adverse effects of antipsychotics.

Pimavanserin augments the efficacy of atypical antipsychotic drugs in a mouse model of treatment-refractory negative symptoms of schizophrenia

Negative symptoms are a core, pervasive, and often treatment-refractory phenotype of schizophrenia, one which contributes to poor functional outcome, ability to work, pursue educational goals, and quality of life, as well as caretaker burden. Improvement of negative symptoms in some patients with schizophrenia has been reported with some atypical antipsychotic drugs [AAPDs], but improvement is absent in many patients and partial in others. Therefore, more effective treatments are needed, and better preclinical models of negative symptoms are needed to identify them. Sub-chronic [sc] treatment of rodents with phencyclidine [PCP], a noncompetitive N-methyl-d-aspartate [NMDAR] antagonist, produces deficits in social interactions [SI] that have been widely studied as a model of negative symptoms in schizophrenia. Acute restraint stress [ARS] also provides a model of treatment-refractory negative symptoms [TRS] to AAPDs. By themselves, in sc-PCP mice, the AAPDs, risperidone, olanzapine, and aripiprazole, but not the selective 5-HT2AR inverse agonist, pimavanserin [PIM], rescued the SI deficit in sc-PCP mice, as did the combination of PIM with sub-effective doses of each of these AAPDs. These three AAPDs alone did not rescue SI deficit in sc-PCP+ 2 h-ARS mice, indicating these mice were treatment refractory. However, co-administration of PIM with any of the AAPDs significantly restored SI in these mice. PIM may be an effective adjunctive therapy for treating negative symptoms of schizophrenia in some patients who have failed to respond to AAPDs, but further studies are needed.

Antipsychotic medication for women with schizophrenia spectrum disorders.

There are significant differences between men and women in the efficacy and tolerability of antipsychotic drugs. Here, we provide a comprehensive overview of what is currently known about the pharmacokinetics and pharmacodynamics of antipsychotics in women with schizophrenia spectrum disorders (SSDs) and translate these insights into considerations for clinical practice. Slower drug absorption, metabolism and excretion in women all lead to higher plasma levels, which increase the risk for side-effects. Moreover, women reach higher dopamine receptor occupancy compared to men at similar serum levels, since oestrogens increase dopamine sensitivity. As current treatment guidelines are based on studies predominantly conducted in men, women are likely to be overmedicated by default. The risk of overmedicating generally increases when sex hormone levels are high (e.g. during ovulation and gestation), whereas higher doses may be required during low-hormonal phases (e.g. during menstruation and menopause). For premenopausal women, with the exceptions of quetiapine and lurasidone, doses of antipsychotics should be lower with largest adjustments required for olanzapine. Clinicians should be wary of side-effects that are particularly harmful in women, such as hyperprolactinaemia which can cause oestrogen deficiency and metabolic symptoms that may cause cardiovascular diseases. Given the protective effects of oestrogens on the course of SSD, oestrogen replacement therapy should be considered for postmenopausal patients, who are more vulnerable to side-effects and yet require higher dosages of most antipsychotics to reach similar efficacy. In conclusion, there is a need for tailored, female-specific prescription guidelines, which take into account adjustments required across different phases of life.

Response efficacy and heterogeneity of antipsychotic drugs in schizophrenia: Systemic review and meta-analysis.

This meta-analysis aimed to assess antipsychotic and placebo effects in patients with schizophrenia at the level of symptom factors. A systematic literature search up to June 2020 was undertaken and 62 studies were included, with 23,478 patients with schizophrenia at the study baseline point. We calculated mean differences with 95% confidence intervals. The comparison was made according to the study content using a continuous method with a random-effects model. Patients with schizophrenia treated by antipsychotic drugs had a significantly lower psychiatric rating scale total score; lower clinical global impression of severity; lower positive and negative syndrome scale; and lower assessment of negative symptoms total score, when compared to placebo treated patients. Patients with schizophrenia treated with an antipsychotic drug show a much greater improvement and lower inconsistency in the level of symptom factors when compared to the effects of placebo. Our findings evidence for a comparatively homogeneous outcome of the antipsychotic-treatment in improving schizophrenia symptoms. This opposes the notion of the presence of patient sub-groups with treatment non-responsive schizophrenia.

Interaction of clozapine with metformin in a schizophrenia rat model

The low efficacy of antipsychotic drugs (e.g., clozapine) for negative symptoms and cognitive impairment has led to the introduction of adjuvant therapies. Because previous data suggest the procognitive potential of the antidiabetic drug metformin, this study aimed to assess the effects of chronic clozapine and metformin oral administration (alone and in combination) on locomotor and exploratory activities and cognitive function in a reward-based test in control and a schizophrenia-like animal model (Wisket rats). As impaired dopamine D1 receptor (D1R) function might play a role in the cognitive dysfunctions observed in patients with schizophrenia, the second goal of this study was to determine the brain-region-specific D1R-mediated signaling, ligand binding, and mRNA expression. None of the treatments affected the behavior of the control animals significantly; however, the combination treatment enhanced D1R binding and activation in the cerebral cortex. The Wisket rats exhibited impaired motivation, attention, and cognitive function, as well as a lower level of cortical D1R binding, signaling, and gene expression. Clozapine caused further deterioration of the behavioral parameters, without a significant effect on the D1R system. Metformin blunted the clozapine-induced impairments, and, similarly to that observed in the control animals, increased the functional activity of D1R. This study highlights the beneficial effects of metformin (at the behavioral and cellular levels) in blunting clozapine-induced adverse effects.

Antipsychotic Drugs or Benzodiazepines for Rapid Tranquilization in Mental Health Facilities or Emergency Department Settings

&#x0D; Evidence from 5 systematic reviews, 3 randomized controlled trials, and 4 observational studies provide inconsistent evidence regarding the comparative efficacy and safety of antipsychotic drugs and benzodiazepines for adults with acute aggression or agitation requiring rapid tranquilization in emergency department or mental health inpatient settings.&#x0D; Overall, the evidence came from low- to moderate-quality studies. Some studies suggested different antipsychotic drugs and benzodiazepines, alone or in combination, have similar efficacy, whereas others favoured one treatment over another.&#x0D; No studies differentiated between adults aged 18 to 64 years and those older than 65 years. Most studies included mixed ages or excluded patients older than 75 years.&#x0D; No studies differentiated between aggression or agitation associated with psychiatric illness and other etiologies such as alcohol intoxication.&#x0D; One guideline suggests initial treatment with intramuscular lorazepam, promethazine, or 1 of aripiprazole, droperidol, or olanzapine. If the desired outcome is not achieved with monotherapy, the guideline recommends an intramuscular combination of either promethazine plus haloperidol or lorazepam plus haloperidol.&#x0D;

Pharmacotherapy for borderline personality disorder: A review

IntroductionBorderline personality disorder (BPD) is characterized by instability of interpersonal relationships, self-image, and emotions, and by impulsivity. Although patients with BPD are misdiagnosed, some of them receive mental health treatment. Even if the first-line treatment of this disorder is psycotherapy, the patients with BPD may be highly symptomatic and are often prescribed multiple medications in a manner unsupported by evidence.ObjectivesThe aim of this study is to study the available evidence about the pharmacotherapy for borderline personality disorder.MethodsA review of the available literature about the management of borderline personality disorder and de pharmacotherapy for personality disorders was performed.ResultsFirst-line treatment of the personality disorders is psycotherapy. The treatment plan for BPD may include individual and group therapy, medication, self-education, specialized substance use disorder treatment, partial hospitalization, or brief hospitalization during times of crises. Medications are generaly used only as adjuncts to psychotherapy and the adjunctive use of symptom targeted medications has been found to be useful. There is limited information to guide pharmacotherapy; preliminary evidence limits the practice of polypharmacy. Sympton-domain focused medication treatment is recommeded by some guidelines: cognitive-perceptual symtoms (low-dose antipsychotic drugs), impulsive-behavioral dyscontrol (mood stabilizers), affective dysregulation (mood stabilizers and low-dose antipsychotic drugs) and self-harm (omega-3 fatty acids).ConclusionsBPD cause significant distress and impariment of social, occupational and role functioning. The first-line treatment for BPD is psychotherapy; however symptom-focused, medication treatment of BPD is generally considered to be an adjunct to psychotherapy. The data support the efficacy of low dose antipsychotic drugs and mood stabilizers.

Estrogens in schizophrenia: progress, current challenges and opportunities.

Purpose of reviewSchizophrenia is a heterogeneous psychiatric disorder with a different, but not necessarily milder clinical presentation in women as compared to men. These sex differences have largely been attributed to the protective role of estrogens. This article reviews the current state of estrogen research in schizophrenia.Recent findingsEstrogens regulate important pathophysiological pathways in schizophrenia, including dopamine activity, mitochondrial function, and the stress system. Estrogen deficiency is common in both sexes and is associated with increases in psychotic symptoms. Hyperprolactinemia causes secondary estrogen deficiency and can be a reaction to stress, or secondary to prolactin-raising antipsychotics. Therefore, prolactin-sparing antipsychotics should be preferred especially in premenopausal women, who are more prone to hyperprolactinemia. Premenopausal women furthermore require lower doses of antipsychotics than men, since estrogens raise the availability and efficacy of antipsychotics.SummaryThe past years have established the importance of estrogens in the pathophysiology of schizophrenia and have shown its relevance to clinical practice through its influence on antipsychotic drug efficacy. Future research should focus on the neurobiological and clinical effect of contraceptives in premenopausal women with schizophrenia. Furthermore, the potential of estrogen-like augmentation with raloxifene and phytoestrogens in schizophrenia should be established in the coming years.

Treating Schizophrenia Thinking beyond the Choice of Antipsychotic

The treatment of schizophrenia has evolved over the past half century primarily in the context of antipsychotic drug development. Although there has been significant progress resulting in the availability and use of numerous medications, these reflect three basic classes of medications (conventional (typical), atypical and dopamine partial agonist antipsychotics) all of which, despite working by varying mechanisms of actions, act principally on dopamine systems. Many of the second-generation (atypical and dopamine partial agonist) antipsychotics are believed to offer advantages over first-generation agents in the treatment for schizophrenia. However, the pharmacological properties that confer the different therapeutic effects of the new generation of antipsychotic drugs have remained elusive, and certain side effects can still impact patient health and quality of life. Moreover, the efficacy of antipsychotic drugs is limited prompting the clinical use of adjunctive pharmacy to augment the effects of treatment. In addition, the search for novel and non-dopaminergic antipsychotic drugs has not been successful to date, though numerous development strategies continue to be pursued, guided by various pathophysiologic hypotheses. This article provides a brief review and critique of the current therapeutic armamentarium for treating schizophrenia and drug development strategies and theories of mechanisms of action of antipsychotics, and focuses on novel targets for therapeutic agents for future drug development.

ANTIPSYCHOTICS: FROM THE FIRST TO THE THIRD GENERATION

The review is devoted to comparative analysis of antipsychotics of three generations. When writing the review, a systematic search in the databases PubMed, Medline, Elsevier was carried out, a simple filter for keywords was used. Pharmacological and clinical issues of antipsychotic therapy were considered, the mechanisms of action of antipsychotics of different generations were revealed. Current trends in the development of approaches to the therapy of schizophrenia and the concept of atypicality of antipsychotics were discussed. A comparative analysis of indications for use, tolerance (safety of use) and efficacy of various antipsychotic drugs with an emphasis on the effect on negative (primary, persistent) symptoms has been conducted. The hypothesis underlying new approaches to the therapy of schizophrenia, based on the effect on dopamine autoreceptors, consisting of a high density of D2 and low density of D3 receptors, has been presented. It has been shown that antipsychotics of the third generation open up new possibilities in the therapy of psychosis within the framework of a personalized approach in psychiatry with the achievement of functional recovery of patients. The characteristics of the drugs representatives of the third generation of antipsychotics aripiprazole and cariprazine were given. The uniqueness of cariprazine as the only drug that inhibits D3 receptors in vitro, as well as in vivo in patients with schizophrenia was emphasized. The data of evidence-based studies of the effectiveness of cariprazine in the treatment of negative, including predominant negative symptoms were presented.