Metabolic complications of psychotropic medications in psychiatric disorders:Emerging role of de novo lipogenesis and therapeutic consideration

Although significant advances have been made in understanding the pathophysiology of psychiatric disorders(PDs),therapeutic advances have not been very convincing.While psychotropic medications can reduce classical symptoms in patients with PDs,their long-term use has been reported to induce or exaggerate various pre-existing metabolic abnormalities including diabetes,obesity and non-alcoholic fatty liver disease(NAFLD).The mechanism(s)underlying these metabolic abnormalities is not clear;however,lipid/fatty acid accumulation due to enhanced de novo lipogenesis(DNL)has been shown to reduce membrane fluidity,increase oxidative stress and inflammation leading to the development of the aforementioned metabolic abnormalities.Intriguingly,emerging evidence suggest that DNL dysregulation and fatty acid accumulation could be the major mechanisms associated with the development of obesity,diabetes and NAFLD after long-term treatment with psychotropic medications in patients with PDs.In support of this,several adjunctive drugs comprising of anti-oxidants and antiinflammatory agents,that are used in treating PDs in combination with psychotropic medications,have been shown to reduce insulin resistance and development of NAFLD.In conclusion,the above evidence suggests that DNL could be a potential pathological factor associated with various metabolic abnormalities,and a new avenue for translational research and therapeutic drug designing in PDs.

Keep in mind sex differences when prescribing psychotropic drugs

Women represent the majority of patients with psychiatric diagnoses and also the largest users of psychotropic drugs.There are inevitable differences in efficacy,side effects and long-term treatment response between men and women.Psychopharmacological research needs to develop adequately powered animal and human trials aimed to consider pharmacokinetics and pharmacodynamics of central nervous system drugs in both male and female subjects.Healthcare professionals have the responsibility to prescribe sex-specific psychopharmacotherapies with a priority to differentiate between men and women in order to minimize adverse drugs reactions,to maximize therapeutic effectiveness and to provide personalized management of care.

Psychotropic drugs and liver disease:A critical review of pharmacokinetics and liver toxicity

The liver is the organ by which the majority of sub-stances are metabolized, including psychotropic drugs. There are several pharmacokinetic changes in end-stage liver disease that can interfere with the metabolization of psychotropic drugs. This fact is particularly true in drugs with extensive first--pass metabolism, highly protein bound drugs and drugs depending on phase I hepatic metabolic reactions. Psychopharmacological agents are also associated with a risk of hepatotoxicity. The evidence is insufficient for definite conclusions regarding the prevalence and severity of psychiatric drug-induced liver injury. High-risk psychotropics are not advised when there is pre-existing liver disease, and after starting a psychotropic agent in a patient with hepatic impairment, frequent liver function/lesion monitoring is advised. The authors carefully review the pharmacokinetic disturbances induced by end-stage liver disease and the potential of psychopharmacological agents for liver toxicity.

Six psychotropics for pre-symptomatic ＆ early Alzheimer＇s (MCI), Parkinson＇s, and Huntington＇s disease modification

The quest for neuroprotective drugs to slow the progression of neurodegenerative diseases （NDDs）, including Alzheimer＇s disease （AD）, Parkinson＇s disease （PD）, and Huntington＇s disease （HD）, has been largely unrewarding. Preclinical evidence suggests that repurposing quetiapine, lithium, valproate, fluoxetine, donepezil, and memantine for early and pre-symptomatic disease-modification in NDDs may be promising and can spare regulatory barriers. The literature of these psychotropics in early stage and pre-symptomatic AD, PD, and HD is reviewed and propitious findings follow. Mild cognitive impairment （MCI） phase of AD： salutary human randomized controlled trial findings for low-dose lithium and, in selected patients, donepezil await replication. Pre-symptomatic AD： human epidemiological data indicate that lithium reduc- es AD risk. Animal model studies （AMS） reveal encouraging results for quetiapine, lithium, donepezil, and memantine. Early PD： valproate AMS findings show promise. Pre-symptomatic PD： lithium and valproate AMS findings are encouraging. Early HD： uncontrolled clinical data indicate non-progression with lithium, fluoxetine, donepezil, and memantine. Pre-symptomatic HD： lithium and valproate are auspicious in AMS. Many other promising findings awaiting replication （valproate in MCI; lithium, valproate, fluoxetine in pre-symptomatic AD; lithium in early PD; lithium, valproate, fluoxetine in pre-symptomatic PD; donepezil in early HD; lithium, fluoxetine, memantine in pre-symptomatic HD） are reviewed. Dose- and stage-dependent effects are considered. Suggestions for signal-enhancement in human trials are provided for each NDD stage.

Psychotropic effects of aspirin, acetylsalicylate cobalt and acetylsalicylate zinc at various doses

For the first time it is shown that psychotropic action of acetylsalicylates at various doses is manifested as a nonmonotonic dependence having its peaks at therapeutic and ultra-low dose zones. It is discovered that development of effects of aspirin resembles that of acetylsalicylate zinc. Acetylsalicylate cobalt at extremely low doses zone showed the highest antidepressant activity, demonstrating toxicity at high doses. Generally, it is revealed that the use of aspirin and its salts at high doses range causes maximum psychotropic effects development, usually accompanied by side-effects. Therefore, aspirin, acetylsalicylate cobalt and zinc at extremely low doses are recommended for further study as psychotropic medications.

Epidemiological Approach to the Use of Psychotropic Medications at Moulay El Hassan Hospital, in the Gharb Region of Morocco

The use of psychotropic drugs is important in Morocco related to the large amount of sufferers by psychiatric disorders, according to a survey of the Moroccan Ministry of Health (2010). A prevalence of 26.5% of depressive disorders, and 9% for generalized anxiety disorder, and 5.6% of psychotic disorders was recorded within population, hence the importance to describe the use and assess the prevalence of psychotropic and socio-economic factors was associated with their use. Our research is a retrospective study, carried out between February 2010-December 2013, holding a sample of 5618 patients aged between 1 and 90 years old. The study is concerned with drawing social and clinical data from patients’ records. The different classes of psychotropic drugs prescribed to patients in the psychiatric department Moulay El Hassan Hospital, vary between antidepressants (36%), antipsychotics (32%), anxiolytics (10%), anti-epileptics (9%), the class of diverse “sulpiride” (7%), anti-parkinsonian (6%), and hypnotics were prescribed in rare cases. The relationship between socio-economic factors and the take of a psychotropic treatment was very strong in Morocco. In contrast, the patients support showed by close families and the health care staff remain a challenge for Moroccan population.

Effects of Pilocarpine Hydrochloride on the Hyposalivation Induced by Psychotropic Drugs

The aim was to study the secretagogue action of pilocarpine on the murine parotid glands submitted to chronic treatment with psychotropic drugs by salivary flow rate determinations and histological alterations. Fifty four male Wistar rats were equally divided in three groups： C group （control） received saline solution for 30 days; AD group （n = 18） received AmitriptylineR and DiazepamR for 30 days, and ADP group （n = 18） received Amitriptyline R and DiazepamR for 30 days and AmitriptylineR, DiazepamR and pilocarpine for further 30 days, resulting in 60 days of treatment. Saliva samples were collected 30 h after the end of treatment. Parotids were removed and processed for hematoxylin-eosin histological analysis. Dedicated software for image processing allowed the determination of cell number and volume. Significant differences between paired-groups C-AD （P 〈 0.01） and AD-ADP （P 〈 0.01） were observed for glands size and weight. The volume of serous cells was greater in AD, suggesting a hypertrophy of the salivary glands. For salivary flow rate, C group showed the highest average. The number of serous cells was similar between groups ADP and C, with the lowest average being found in AD group （P 〈 0.05）.

A Patient Bill of Rights for Psychotropic Prescription: A Call for a Higher Standard of Care

The pharmaceutical industry has made it very difficult to know what the clinical trial evidence actually is regarding psychotropics. Consequently, primary care physicians and other front-line practitioners are at a disadvantage when attempting to adhere to the ethical and scientific mandates of evidence based prescriptive practice. This article calls for a higher standard of prescriptive care derived from a risk/benefit analysis of clinical trial evidence. The authors assert that current prescribing practices are often empirically unsound and unduly influenced by pharmaceutical company interests, resulting in unnecessary risks to patients. In the spirit of evidenced based medicine’s inclusion of patient values as well as the movement toward health home and integrated care, we present a patient bill of rights for psychotropic prescription. We then offer guidelines to raise the bar of care equal to the available science for all prescribers of psychiatric medications.

Psychotropic drug abuse in pregnancy and its impact on child neurodevelopment:A review

Substance abuse by women of child-bearing age and fetal in utero drug exposure has increased in the number of infants born with health issues.Prenatal exposure to psychoactive substances can lead to neurological and neurodevelopmental deficits later in life.Useful data concerning the effects of psychoactive drugs on fetal neurodevelopmental status are sparse.Understanding the neurodevelopmental consequences of prenatally drug-exposed children has become a pressing global concern.The aim of this review is to gather current evidence and information on neurodevelopmental outcomes of in utero drug exposure.A literature search was performed on the PubMed,Scopus,and Google Scholar databases using the terms“psychotropic drugs”,“neurodevelopmental consequences”,“prenatal drug exposure”,and“pregnancy”.Available studies on in utero drug exposure were reviewed and found to support the idea that some degree of health issues are present in fetuses and children.Different psychoactive substances have profound neurodevelopmental consequences,such as structural brain changes,poor attention span,Down syndrome,attention deficit hyperactivity disorder,autism spectrum disorder,imbalances in neurotransmitter levels,and many structural deficits.The pervasive use of psychoactive drugs in women of child-bearing age is an important health concern.Further scientific efforts are needed to investigate the effect of prenatal exposure to psychoactive drugs on children.

An overview of management of narcotics and psychotropic drugs in China

Narcotics and psychotropic drugs are known as controlled drugs with special management and super vision due to their psychic and physiological dependence. Based on the literature review, experts interview and policy comparative analysis, our study summarized and reviewed the status of related legislation and regulations since the enactment of the Narcotics and Psychotropic Drugs Regulations in 2005. We found the problems of legal loopholes, the complexity of supervision system and the irrational use of narcotics in the treatment of chronic non-cancer. Our analysis suggested that China should reinforce legislation, strengthen the cooperation among departments, establish the information network and improve the guideline of narcotics and psychotropic drugs for clinical treatment as quickly as possible.

Pediatric off-label use of psychotropic drugs approved for adult use in Japan in the light of approval information regarding pediatric patients in the United States: a study of a pharmacy prescription database

Background Off-label use of psychotropic prescriptions for pediatric patients has been increasing in Japan.This study sought to clarify pediatric patients' off-label use of psychotropics approved only for adults in Japan.Methods This retrospective study on psychotropic utilization employed a pharmaceutical health insurance claims database supplied by a pharmacy for the fiscal year 2016.Seven psychotropic drugs were examined.For each drug,we calculated the proportion of patients aged < 16 years or who were under the approved age limit set in the United States out of all patients.The maximum daily dose of each drug within the study period was plotted by age.Results Data of 45,715 patients (female:26,799,male:18,916) with 331,920 prescriptions were examined in this study.For each drug,the proportion of pediatric patients aged < 16 years ranged from 0.15 to 1.1%,while the proportion of those under the approved age limit in the United States ranged from 0 to 0.27%.Olanzapine had the highest reported proportion.No drugs other than olanzapine were taken under the approved age limit in the United States.Conclusions We identified the pediatric off-label use of psychotropics that were limited to adult use in Japan.The results indicated the possibility of referring to international guidelines or evidence in clinical practice,but these factors do not discount the existing problems with off-label use.More clinical trials within the pediatric population in Japan are needed to address the issue of off-label use and obtain useful and reliable information in the package inserts for rational use in future pediatric patients.

Metabolic syndrome:a psychiatric outlook

A metabolic syndrome is a cluster of clinical signs that are risk factors for the development of type 2 diabetes mellitus,and cardiovascular disease.This cluster includes obesity,elevated blood sugar,high blood pressure,and high cholesterol.Atypical antipsychotics that are associated with a group of signs and symptoms have resulted in an increased focus on this syndrome.This review included accessible literature,such as review articles and original research articles.It provides useful guidelines for psychiatrists and gives them psycho-education so that they can identify and monitor patients who may have the syndrome and properly manage it.

Relationship of functional gastrointestinal disorders and psychiatric disorders: Implications for treatment

This article revisits the links between psychopathology and functional gastrointestinal disorders such as irritable bowel syndrome （IBS）, discusses the rational use of antidepressants as well as non-pharmacological approaches to the management of IBS, and suggests guidelines for the treatment of IBS based on an interdisciplinary perspective from the present state of knowledge. Relevant published literature on psychiatric disorders, especially somatization disorder, in the context of [BS, and literature providing direction for management is reviewed, and new directions are provided from findings in the literature. IBS is a heterogeneous syndrome with various potential mechanisms responsible for its clinical presentations. IBS is typically complicated with psychiatric issues, unexplained symptoms, and functional syndromes in other organ systems. Most IBS patients have multiple complaints without demonstrated cause, and that these symptoms can involve systems other than the intestine, e.g. bones and joints （fibromyalgia, temporomandibular joint syndrome）, heart （non-cardiac chest pain）, vascular （post-menopausal syndrome）, and brain （anxiety, depression）. Host IBS patients do not have psychiatric illness per se, but a range of psychoform （psychological complaints in the absence of psychiatric disorder） symptoms that accompany their somatoform （physical symptoms in the absence of medical disorder） complaints. It is not correct to label IBS patients as psychiatric patients （except those more difficult patients with true somatization disorder）. One mode of treatment is unlikely to be universally effective or to resolve most symptoms. The techniques of psychotherapy or cognitive-behavioral therapy can allow IBS patients to cope more readily with their illness. Specific episodes of depressive or anxiety disorders can be managed as appropriate for those conditions. Medications designed to improve anxiety or depression are not uniformly useful for psychiatric complaints in IBS, because the psychoform symptoms that sound similar to those seen in psychiatric disorders may not have the same significance in patients with IBS.

Pharmacological management of behavioral symptoms associated with dementia

Dementia is a clinical syndrome with features of neurocognitive decline. Subtypes of dementia include Alzheimer's, frontotemporal, Parkinson's, Lewy body disease, and vascular type. Dementia is associated with a variety of neuropsychiatric symptoms that may include agitation, psychosis, depression, and apathy. These symptoms can lead to dangerousness to self or others and are the main source for caregiver burnout. Treatment of these symptoms consists of nonpharmacological and pharmacological interventions. However, there are no Food and Drug Administration-approved medications for the treatment of behavioral and psychological symptoms of dementia. Pharmacological interventions are used off-label. This article reviews the current evidence supporting or negating the use of psychotropic medications along with safety concerns, monitoring, regulations, and recommendations.

Aging effects on QT interval： Implications for cardiac safety of antipsychotic drugs

Objectives To explore the effect of aging on cardiac toxicity specifically the interaction of age and antipsychotic drugs to alter the QT interval. Methods The Medline databases were searched using the OvidSP platforms with the search strategy： ＂QT interval＂ or ＂QT＂ and ＂age＂ or ＂aging＂. The entry criteria were： over 10,000 apparently healthy individuals with data on both sexes; QT interval corrected for heart rate （QTc） and an expression of its variance for multiple age decades extending into the older ages. Results QTc increased in duration with increasing age. Considering a modest one SD increment in QTc in the normal population, the addition of Chlorpromazine produced a QTc on average greater than 450 ms for ages 70 years and older. Risperidone, that did not on average alter QTc, would be expected to produce a QTc of 450 ms in persons in their mid 70 years under some circumstances. QTc prolongation 〉 500 ms with antipsychotic drugs is more likely for persons with QTc initially at the 99th percentile. It may occur with Haloperidol which does not on average alter QTc. Conclusions The range of values for the QT interval in apparently normal older men or women, when combined with the range of expected QT interval changes induced by antipsychotic drugs, can readily be associated with prolonged QTc. Individuals with QTc at the 99th percentile may have serious QTc prolongation with antipsychotic drugs even those that are not usually associated with QTc prolongation.

Role of antipsychotics for treating behavioral and psychological symptoms of dementia

Over the past three decades, concerns about the high prevalence of antipsychotic use in the nursing homes （NHs） for the management of behavioral and psychological symptoms of dementia continue to be emphasized and intervened by many. However, despite the numerous side effects and the recent blackbox warning by the United States Food and Drug Administration about the increased risks for stroke and sudden death associated with the use of antipsychotics in dementia, the preva-lence of antipsychotic use in NHs remains high. While the use of antipsychotics appeared to have modest effcacy in reducing symptoms of aggression and psychosis in dementia, there is insuffcient evidence to routinely rec-ommend the use of alternative psychopharmacological treatments for these symptoms. Hence, clinicians have to balance the safety warnings against the need to treat these symptoms in order to prevent harm to the resident that may result from his/her dangerous behaviors. Although the use of antipsychotics may be warranted in some cases, organizational, resource and training support should be provided to encourage and equip NH staff to participate in interventions so as to minimize inappropriate use of these medicines in NHs. This review will discuss the place in therapy, the trend and appropriateness of antipsychotic use in NHs, as well as the effectiveness of current and future strategies for reducing antipsychotic use in the NHs.

Neuropsychopharmacological profile of Astragalus membranaceous var.mongholicus

Objective:To clarify the neuropharmacological profile of the Mongolian vetch,Astragalus mongholicus(Astragalus membranaceous var.mongholicus;synonym:A.mongholicus),extracts were evaluated for behavioral effects in rats and mice.Methods:An aqueous extract of A.mongholicus was made by boiling roots from freshlycollected plants in 2.5 volumes(w/v)of water for 60 minutes.An ethanol extract was made by incubating in 70%ethanol for 5 days at 25
C.Effects of the aqueous extracts were evaluated in a forced swimming assessment of antidepressant effects,a hole-board test of exploratory behavior,an analysis of inhibition of aggression following electrical stimulation and influences on amnesia resulting from electroshock.Furthermore,effects of ethanol extracts of A.mongholicus were assessed on L-tryptophan induced twitches(indicating serotonin-mediated effects)and on hypothermia induced by apomorphine(indicating dopamine-mediated interactions)in mice.Results:Per os(PO)administration of the aqueous decoction of the vetch to rats increased the response in a forced swimming test as reflected in wheel rotations.However,the decoction had no significant effect on the exploratory behavior of rats in the hole-board test.Acute PO administration of the aqueous extract of A.mongholicus decreased the threshold for aggressive behavior and this effect persisted with subchronic administration.Chronic administration of the plant extract suppressed aggression of rats.An ethanol extract of A.mongholicus showed an antiserotoninergic action and had a significant influence on the hypothermia induced by apomorphine.Conclusion:A.mongholicus has a variety of potent psychotropic actions,suggesting influences on diverse neurotransmitter systems.

Drug-induced stuttering:A comprehensive literature review

Drug-induced stuttering(DIS)is a type of neurogenic stuttering(NS).Although DIS has not been reported as frequently as other cases of NS in the literature,it is not a negligible adverse drug reaction(ADR)which can significantly affect the quality of life if not treated.This literature review aims to evaluate the epidemiological and clinical characteristics of DIS and suggests some pathophysiological mechanisms for this ADR.Relevant English-language reports in Google Scholar,PubMed,Web of Science,and Scopus were identified and assessed without time restriction.Finally,a total of 62 reports were included.Twenty-seven drugs caused 86 episodes of stuttering in 82 cases.The most episodes of DIS were related to antipsychotic drugs(57%),mostly including clozapine,followed by central nervous system agents(11.6%)and anticonvulsant drugs(9.3%).The majority of the cases were male and between the ages of 31 and 40 years.Repetitions were the most frequent core manifestations of DIS.In 55.8%of the episodes of DIS,the offending drug was withdrawn to manage stuttering,which resulted in significant improvement or complete relief of stuttering in all cases.Based on the suggested pathophysiological mechanisms for developmental stuttering and neurotransmitters dysfunctions involved in speech dysfluency,it seems that the abnormalities of several neurotransmitters,especially dopamine and glutamate,in different circuits and areas of the brain,including cortico-basal ganglia-thalamocortical loop and white matter fiber tracts,may be engaged in the pathogenesis of DIS.

Management guidelines for behavioural and psychotic symptoms in persons with dementia—A review article

This paper is a review article which has systematically gathered contemporary evidence, the best practice guidelines for the management, treatment of behavioural and psychological symptoms of dementia and the various approaches including pharmacological and non-pharmacological approaches. It sets out to outline the various types of behaviour in different subtypes of dementia and a practical approach for clinicians in managing these behaviours.

More than Half of Patients with Schizophrenia Are Receiving Polypharmacy and Co-Prescription of Anxiolytics in Pakistan —Findings from Research on Asian Prescription Pattern in 2016

Objective: Little is known about the prescription pattern of psychotropic drugs for patients with schizophrenia in Pakistan. The purpose of this study was to evaluate the characteristic features of psychotropic drug prescriptions for patients with schizophrenia in Pakistan. Methods: Three centers in Pakistan participated in a large scale collaborative study known as Research on Asian Prescription Pattern (REAP). The 2016 REAP survey included centers from 15 countries in Asia and used a unified research protocol. The design of the study was quantitative and of descriptive epidemiology. Analysis was made on the data collected from three centers i.e., Lahore, Karachi and Islamabad. The data collected in Pakistan were compared with those from other Asian countries. The details of REAP were presented on the homepage of REAP (http://www.REAP.Asia). Results: From Pakistan, 298 patients were included. Patients with schizophrenia in Pakistan received higher rate of antipsychotic polypharmacy and a higher rate of co-prescription of mood stabilizers and anxiolytics when compared with participants from other South Asian countries (India and Bangladesh). Conclusion: The main findings of the study were that a majority of the patients were prescribed antipsychotic polypharmacy drugs in Pakistan. Insufficient training on the use of psychotropic drugs and a lack of treatment guideline are considered to be the major contributing factors. Further education and training on the proper use of psychotropic drugs are recommended to psychiatrists in Pakistan. The guidelines on pharmacotherapy for patients with schizophrenia should also be developed and promoted in Pakistan.