Monitoring the Effectiveness of Treatment in Women with Schizophrenia: New Specialized Cooperative Approaches.

Women with schizophrenia have specific health needs that differ from those of men and that change through successive life stages. We aimed to review the biopsychosocial literature on schizophrenia that addresses clinically important questions related to the treatment of women, including somatic morbi-mortality, hyperprolactinemia, comorbid substance use disorders, social risk factors, and medication effectiveness/safety. Data search terms were as follows: (Morbidity AND mortality) OR hyperprolactinemia OR ("substance use disorders" OR addictions) OR ("social risk factors") OR ("drug safety" OR prescription) AND women AND schizophrenia. A secondary aim was to describe a method of monitoring and interdisciplinary staff strategies. Schizophrenia patients show an increased risk of premature death from cardiovascular/respiratory disease and cancer compared to the general population. The literature suggests that close liaisons with primary care and the introduction of physical exercise groups reduce comorbidity. Various strategies for lowering prolactin levels diminish the negative long-term effects of hyperprolactinemia. Abstinence programs reduce the risk of victimization and trauma in women. Stigma associated with women who have serious psychiatric illness is often linked to reproductive functions. The safety and effectiveness of antipsychotic drug choice and dose differ between men and women and change over a woman's life cycle. Monitoring needs to be multidisciplinary, knowledgeable, and regular.

Silencing of SbPPCK1-3 Negatively Affects Development, Stress Responses and Productivity in Sorghum.

Phosphoenolpyruvate carboxylase (PEPC) plays central roles in photosynthesis, respiration, amino acid synthesis, and seed development. PEPC is regulated by different post-translational modifications. Between them, the phosphorylation by PEPC-kinase (PEPCk) is widely documented. In this work, we simultaneously silenced the three sorghum genes encoding PEPCk (SbPPCK1-3) by RNAi interference, obtaining 12 independent transgenic lines (Ppck1-12 lines), showing different degrees of SbPPCK1-3 silencing. Among them, two T2 homozygous lines (Ppck-2 and Ppck-4) were selected for further evaluation. Expression of SbPPCK1 was reduced by 65% and 83% in Ppck-2 and Ppck-4 illuminated leaves, respectively. Expression of SbPPCK2 was higher in roots and decreased by 50% in Ppck-2 and Ppck-4 in this tissue. Expression of SbPPCK3 was low and highly variable. Despite the incomplete gene silencing, it decreased the degree of phosphorylation of PEPC in illuminated leaves, P-deficient plants, and NaCl-treated plants. Both leaves and seeds of Ppck lines had altered metabolic profiles and a general decrease in amino acid content. In addition, Ppck lines showed delayed flowering, and 20% of Ppck-4 plants did not produce flowers at all. The total amount of seeds was lowered by 50% and 36% in Ppck-2 and Ppck-4 lines, respectively. The quality of seeds was lower in Ppck lines: lower amino acid content, including Lys, and higher phytate content. These data confirm the relevance of the phosphorylation of PEPC in sorghum development, stress responses, yield, and quality of seeds.

Critical Issues in the Management of Agitation, Aggression, and End-of-Life in Delusional Disorder: A Mini-Review.

Background: Compared to other psychotic disorders, there is little information about staging care in delusional disorder (DD). Unlike schizophrenia, this is a disorder that begins in middle age, a time at which chronic medical comorbidities have already begun to impact global functioning. With age, the combination of psychological and somatic conditions leads to new behaviours, e.g., agitation, aggression, and behaviours that require specific preventive and interventive measures. With further age, knowledgeable end-of-life care becomes necessary for this population. Aim: The aim of this article was to review existing evidence on the management of these successive phases. Methods: We conducted a narrative review using PubMed and ClinicalTrials.gov and searched for the following terms: (agitation OR aggressivity OR aggression OR palliative OR "end-of-life") AND ("delusional disorder"). Results: We found that the literature was sparse. Existing evidence suggests that medical causes are frequently at the root of agitation and aggression. With respect to management, de-escalation strategies are generally preferred over pharmacotherapy. Specific delusional syndromes, e.g., de Clérambault, Othello, Capgras, Fregoli, as well as folie à deux, are associated with aggression. The somatic subtype of DD is the one most often requiring palliative care at the end of life. Conclusions: We conclude that insufficient attention has been given to the care needs of the accelerated aging process in DD.

Seventy Years of Treating Delusional Disorder with Antipsychotics: A Historical Perspective.

For many decades, delusional disorder (DD) has been considered a treatment-resistant disorder, with antipsychotics acknowledged as the best, though imperfect, treatment. It is possible that the discovery of the right drug could turn treatment resistance into treatment response. The goal of this narrative review is to provide a historical perspective of the treatment of DD since the introduction of antipsychotics 70 years ago. The following search terms were used to scan the literature: antipsychotics AND "delusional disorder". Findings were that therapy for DD symptoms has changed over time. Initial reports suggested that the drug of choice was the antipsychotic pimozide, and that this drug was especially effective for the somatic subtype of DD. Subsequent studies demonstrated that other antipsychotics, for instance, risperidone and olanzapine, were also highly effective. Treatment response may vary according to the presence or absence of specific symptoms, such as cognitive defect and depression. Clozapine, partial D2 agonists, and long-acting injectable drugs may be more effective than other drugs, but the evidence is not yet in. Because of the absence of robust evidence, treatment guidelines for the optimal management of DD are not yet available.

The Effect of Menopause on Antipsychotic Response.

Background: It has been hypothesized that, whenever estrogen levels decline, psychosis symptoms in women increase. At menopause, this can happen in two main ways: (a) the loss of estrogen (mainly estradiol) can directly affect central neurotransmission, leading to increase in schizophrenia-related symptoms, and (b) the loss of estrogen can decrease the synthesis of enzymes that metabolize antipsychotic drugs, thus weakening their efficacy. Aims and Methods: The aim of this narrative review was to investigate the second possibility by searching PubMed and ClinicalTrials.gov for studies over the last two decades that investigated the metabolism of antipsychotics and their efficacy before and after menopause in women or that studied systemic and local estrogen level effects on the pharmacokinetics and pharmacodynamics of individual antipsychotic drugs. Results: The evidence suggests that symptom level in women with schizophrenia rises after menopause for many reasons beyond hormones but, importantly, there is an estrogen-dependent loss of efficacy related to antipsychotic treatment. Conclusion: Effective clinical intervention is challenging; nevertheless, several promising routes forward are suggested.

Do Sex/Gender and Menopause Influence the Psychopathology and Comorbidity Observed in Delusional Disorders?

Background: While sex differences and gonadal hormone levels are taken seriously in the understanding and treatment of schizophrenia, their influence in the psychopathology of delusional disorders (DD) remains unknown. Methods: Our strategy was to conduct a narrative review of the effects of (a) sex/gender difference and (b) menopause on delusional content, affective and anxiety-related comorbidity, substance use disorders, cognition, aggressivity, and suicide risk in DD. Results: Because the literature is scarce, our results are tentative. We found that erotomania was more prevalent in women than in men, and especially in women with premenopausal onset. In contrast, jealous and somatic delusions were more commonly seen in DD women with postmenopausal onset. With respect to depressive comorbidity, women with premenopausal onset appear more vulnerable to depression than those with later onset. Age at menopause is reported to correlate positively with intensity of suicidal ideation. Anxiety symptoms may be related to estrogen levels. Men present with higher rates of substance use disorders, particularly alcohol use. Conclusions: Many male/female differences in DD may be attributable to sociocultural factors but menopause, and, therefore, levels of female hormones, influence symptom expression in women and mediate the expression of psychiatric comorbidities. Further research in this area promises to lead to improved individualized treatment.

Delusional Disorder in Old Age: A Hypothesis-Driven Review of Recent Work Focusing on Epidemiology, Clinical Aspects, and Outcomes.

The theme, strength, and duration of a delusion are considered important in distinguishing one psychosis of old age from another. Research results, however, are mostly based on studies conducted on one form of psychosis, namely schizophrenia. The aim of this hypothesis-driven narrative review is to gather clinically important information about the psychosis identified as delusional disorder (DD), as it affects persons of senior age. We hypothesized that DD becomes relatively prevalent in old age, especially in women; and that it is associated with demonstrable brain changes, which, in turn, are associated with cognitive defects and poor pharmacological response, thus increasing the risk of aggression and suicide. Computerized searches in PubMed and ClinicalTrials.gov were conducted using the following search terms: (delusional disorder) AND (elderly OR old OR aged OR psychogeriatrics). A total of 16 recent studies (including case reports) were reviewed. Our hypotheses could not be definitively confirmed because research evidence is lacking. In order to improve eventual outcomes, our literature search demonstrates the need for more targeted, well-designed studies.

Knock-down of phosphoenolpyruvate carboxylase 3 negatively impacts growth, productivity, and responses to salt stress in sorghum (Sorghum bicolor L.).

Phosphoenolpyruvate carboxylase (PEPC) is a carboxylating enzyme with important roles in plant metabolism. Most studies in C4 plants have focused on photosynthetic PEPC, but less is known about non-photosynthetic PEPC isozymes, especially with respect to their physiological functions. In this work, we analyzed the precise roles of the sorghum (Sorghum bicolor) PPC3 isozyme by the use of knock-down lines with the SbPPC3 gene silenced (Ppc3 lines). Ppc3 plants showed reduced stomatal conductance and plant size, a delay in flowering time, and reduced seed production. In addition, silenced plants accumulated stress indicators such as Asn, citrate, malate, and sucrose in roots and showed higher citrate synthase activity, even in control conditions. Salinity further affected stomatal conductance and yield and had a deeper impact on central metabolism in silenced plants compared to wild type, more notably in roots, with Ppc3 plants showing higher nitrate reductase and NADH-glutamate synthase activity in roots and the accumulation of molecules with a higher N/C ratio. Taken together, our results show that although SbPPC3 is predominantly a root protein, its absence causes deep changes in plant physiology and metabolism in roots and leaves, negatively affecting maximal stomatal opening, growth, productivity, and stress responses in sorghum plants. The consequences of SbPPC3 silencing suggest that this protein, and maybe orthologs in other plants, could be an important target to improve plant growth, productivity, and resistance to salt stress and other stresses where non-photosynthetic PEPCs may be implicated.

Factors Influencing Adherence to Antipsychotic Medications in Women with Delusional Disorder: A Narrative Review.

BACKGROUND: Adherence to medication regimens is of great importance in psychiatry because drugs sometimes need to be taken for long durations in order to maintain health and function. OBJECTIVE: This study aimed to review influences on adherence to antipsychotic medications, the treatment of choice for the delusional disorder (DD), and to focus on adherence in women with DD. METHODS: This is a non-systematic narrative review of papers published since 2000 using PubMed and Google Scholar, focusing on women with DD and medication adherence. RESULTS: Several factors have been identified as exerting influence on adherence in women with persistent delusional symptoms who are treated with antipsychotics. Personality features, intensity of delusion, perception of adverse effects, and cognitive impairment are patient factors. Clinical time spent with the patient, clarity of communication, and regular drug monitoring are responsibilities of the health provider. Factors that neither patient nor clinician can control are the social determinants of health, such as poverty, easy access to healthcare, and cultural variables. CONCLUSION: There has been little investigation of factors that influence adherence in the target population, e.g., women with DD. Preliminary results of this literature search indicate that solutions from outside the field of DD may apply to this population. Overall, a solid therapeutic alliance appears to be the best hedge against nonadherence.

Hormone Targets for the Treatment of Sleep Disorders in Postmenopausal Women with Schizophrenia: A Narrative Review.

While the early identification of insomnia in patients with schizophrenia is of clinical relevance, the use of specific compounds to treat insomnia has been studied less in postmenopausal women with schizophrenia. We aimed to explore the effects of melatonin, sex hormones, and raloxifene for the treatment of insomnia in these populations. Although melatonin treatment improved the quality and efficiency of the sleep of patients with schizophrenia, few studies have explored its use in postmenopausal women with schizophrenia. The estrogen and progesterone pathways are dysregulated in major psychiatric disorders, such as in schizophrenia. While, in the context of menopause, a high testosterone-to-estradiol ratio is associated with higher frequencies of depressive symptoms, the effects of estradiol and other sex hormones on sleep disorders in postmenopausal women with schizophrenia has not been sufficiently investigated. Raloxifene, a selective estrogen receptor modulator, has shown positive effects on sleep disorders in postmenopausal women. Future studies should investigate the effectiveness of hormonal compounds on insomnia in postmenopausal women with schizophrenia.

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.

Genetic and Pharmacological Inhibition of Autophagy increases the Monoubiquitination of Non-Photosynthetic Phosphoenolpyruvate Carboxylase.

Phosphoenolpyruvate carboxylase (PEPC) is an enzyme with key roles in carbon and nitrogen metabolisms. The mechanisms that control enzyme stability and turnover are not well known. This paper investigates the degradation of PEPC via selective autophagy, including the role of the monoubiquitination of the enzyme in this process. In Arabidopsis, the genetic inhibition of autophagy increases the amount of monoubiquitinated PEPC in the atg2, atg5, and atg18a lines. The same is observed in nbr1, which is deficient in a protein that recruits monoubiquitinated substrates for selective autophagy. In cultured tobacco cells, the chemical inhibition of the degradation of autophagic substrates increases the quantity of PEPC proteins. When the formation of the autophagosome is blocked with 3-methyladenine (3-MA), monoubiquitinated PEPC accumulates as a result. Finally, pull-down experiments with a truncated version of NBR1 demonstrate the recovery of intact and/or fragmented PEPC in Arabidopsis leaves and roots, as well as cultured tobacco cells. Taken together, the results show that a fraction of PEPC is cleaved via selective autophagy and that the monoubiquitination of the enzyme has a role in its recruitment towards this pathway. Although autophagy seems to be a minor pathway, the results presented here increase the knowledge about the role of monoubiquitination and the regulation of PEPC degradation.

Hypothalamic-pituitary-adrenal axis-related genes and cognition in major mood disorders and schizophrenia: a systematic review.

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation and cognitive deficits are two well-characterized endophenotypes present in different serious mental illnesses (SMIs), including major depressive disorder, bipolar disorder and schizophrenia. Our aim was to study the influence of genetic and epigenetic variations in HPA axis-related genes on cognitive performance in clinical samples, including patients with major mood disorders and schizophrenia. A systematic search was performed using PubMed (Medline), PsycINFO and Scopus databases. The systematic review identified 12 studies dealing with HPA-related genes and cognition in samples including patients with SMIs, focusing on single nucleotide polymorphism (SNP) variants, while no studies analysing epigenetic variations were found. The results suggest different and specific effects on the cognitive performance of SNP variants in the HPA axis-related genes studied, as well as interactions with traumatic experiences. There was high heterogeneity in the studied samples, genes analysed, and cognitive tasks evaluated. The relationship between HPA-related genes and cognition in SMIs is still largely unknown, and further studies including larger samples and epigenetic variations are needed.

A systematic review of the operational definitions for antipsychotic response in delusional disorder.

This review aimed to examine and analyse the definitions used for antipsychotic response in delusional disorder (DD) and to provide a discussion of the methodology used. A systematic review was performed using the PubMed, Scopus and PsycINFO databases (1990-October 2017) according to the PRISMA statement. In addition, reference searches were performed manually through identified studies to obtain other relevant articles. The search terms included 'antipsychotic response', 'antipsychotics', 'treatment response' and 'delusional disorder'. After the screening and selection processes, 11 studies fulfilled our inclusion criteria using different methods to define antipsychotic response in DD. Studies included chart reviews (n=5) and observer-rated scales (n=6), in which two studies used the Clinical Global Impression-Improvement scale, two studies evaluated antipsychotic response by mean changes from the baseline to endpoint scores [Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale], one study combined the Clinical Global Impression-Improvement scale and mean changes from baseline scores (PANSS) and one study reported responder rates on the basis of a scale-derived cut-off (PANSS). A lack of consensus in the definitions of antipsychotic response in DD and a high degree of heterogeneity of the methods used are reflected. Recent proposals on the use of scale-derived cut-offs to evaluate antipsychotic response in schizophrenia would be highly recommended for DD research.

Salinity promotes opposite patterns of carbonylation and nitrosylation of C4 phosphoenolpyruvate carboxylase in sorghum leaves.

MAIN CONCLUSION: Carbonylation inactivates sorghum C 4 PEPCase while nitrosylation has little impact on its activity but holds back carbonylation. This interplay could be important to preserve photosynthetic C4 PEPCase activity in salinity. Previous work had shown that nitric acid (NO) increased phosphoenolpyruvate carboxylase kinase (PEPCase-k) activity, promoting the phosphorylation of phosphoenolpyruvate carboxylase (PEPCase) in sorghum leaves (Monreal et al. in Planta 238:859-869, 2013b). The present work investigates the effect of NO on C4 PEPCase in sorghum leaves and its interplay with carbonylation, an oxidative modification frequently observed under salt stress. The PEPCase of sorghum leaves could be carbonylated in vitro and in vivo, and this post-translational modification (PTM) was accompanied by a loss of its activity. Similarly, PEPCase could be S-nitrosylated in vitro and in vivo, and this PTM had little impact on its activity. The S-nitrosylated PEPCase showed increased resistance towards subsequent carbonylation, both in vitro and in vivo. Under salt shock, carbonylation of PEPCase increased in parallel with decreased S-nitrosylation of the enzyme. Subsequent increase of S-nitrosylation was accompanied by decreased carbonylation. Taken together, the results suggest that S-nitrosylation could contribute to maintain C4 PEPCase activity in stressed sorghum plants. Thus, salt-induced NO synthesis would be protecting photosynthetic PEPCase activity from oxidative inactivation while promoting its phosphorylation, which will guarantee its optimal functioning in suboptimal conditions.

Enzymatic activity, gene expression and posttranslational modifications of photosynthetic and non-photosynthetic phosphoenolpyruvate carboxylase in ammonium-stressed sorghum plants.

Sorghum plants grown with 5mM (NH4)2SO4 showed symptoms of stress, such as reduced growth and photosynthesis, leaf chlorosis, and reddish roots. Phosphoenolpyruvate carboxylase (PEPC) activity, by supplying carbon skeletons for ammonium assimilation, plays a pivotal role in tolerance to ammonium stress. This work investigated the effect of ammonium nutrition on PPC and PPCK gene expression, on PEPC activity, and on post-translational modifications (PTMs) of PEPC in leaves and roots of sorghum plants. Ammonium increased PEPC kinase (PEPCk) activity and the phosphorylation state of PEPC in leaves, both in light and in the dark, due to increased PPCK1 expression in leaves. This result resembled the effect of salinity on sorghum leaf PEPC and PEPCk, which is thought to allow a better functioning of PEPC in conditions that limit the income of reduced C. In roots, ammonium increased PEPC activity and the amount of monoubiquitinated PEPC. The first effect was related to increased PPC3 expression in roots. These results highlight the relevance of this specific isoenzyme (PPC3) in sorghum responses to ammonium stress. Although the role of monoubiquitination is not fully understood, it also increased in germinating seeds along with massive mobilization of reserves, a process in which the anaplerotic function of PEPC is of major importance.

Proline synthesis in barley under iron deficiency and salinity.

This work investigates proline synthesis in six barley varieties subjected to iron deficiency, salinity or both stresses. The highest growth under Fe sufficiency corresponded to Belgrano and Shakira. A moderate augment of leaf phosphoenolpyruvate carboxylase (PEPC) activity was observed in all six varieties in response to Fe deficiency, consistently in leaves and sporadically in roots. All six varieties accumulated proline under Fe deficiency, to a higher extent in leaves than in roots. The decrease of Fe supply from 100 µM NaFe(III)-EDTA to 0.5 µM NaFe(III)-EDTA reduced growth and photosynthetic pigments similarly in the six barley varieties. On the contrary, differences between varieties could be observed with respect to increased or, conversely, decreased proline content as a function of the amount of NaFe(III)-EDTA supplied. These two opposite types were represented by Belgrano (higher proline under Fe deficiency) and Shakira (higher proline under Fe sufficiency). Time-course experiments suggested that leaf PEPC activity was not directly responsible for supplying C for proline synthesis under Fe deficiency. High proline levels in the leaves of Fe-deficient Belgrano plants in salinity were associated to a better performance of this variety under these combined stresses.

Nitric oxide regulation of leaf phosphoenolpyruvate carboxylase-kinase activity: implication in sorghum responses to salinity.

Nitric oxide (NO) is a signaling molecule that mediates many plant responses to biotic and abiotic stresses, including salt stress. Interestingly, salinity increases NO production selectively in mesophyll cells of sorghum leaves, where photosynthetic C4 phosphoenolpyruvate carboxylase (C4 PEPCase) is located. PEPCase is regulated by a phosphoenolpyruvate carboxylase-kinase (PEPCase-k), which levels are greatly enhanced by salinity in sorghum. This work investigated whether NO is involved in this effect. NO donors (SNP, SNAP), the inhibitor of NO synthesis NNA, and the NO scavenger cPTIO were used for long- and short-term treatments. Long-term treatments had multifaceted consequences on both PPCK gene expression and PEPCase-k activity, and they also decreased photosynthetic gas-exchange parameters and plant growth. Nonetheless, it could be observed that SNP increased PEPCase-k activity, resembling salinity effect. Short-term treatments with NO donors, which did not change photosynthetic gas-exchange parameters and PPCK gene expression, increased PEPCase-k activity both in illuminated leaves and in leaves kept at dark. At least in part, these effects were independent on protein synthesis. PEPCase-k activity was not decreased by short-term treatment with cycloheximide in NaCl-treated plants; on the contrary, it was decreased by cPTIO. In summary, NO donors mimicked salt effect on PEPCase-k activity, and scavenging of NO abolished it. Collectively, these results indicate that NO is involved in the complex control of PEPCase-k activity, and it may mediate some of the plant responses to salinity.