Current status and future prospects for epigenetic psychopharmacology

Mounting evidence suggest that epigenetic regulation of brain functions is important in the etiology of psychiatric disorders. These epigenetic regulatory mechanisms, such as DNA methylation and histone acetylation, are influenced by many pharmaceutical compounds including psychiatric drugs. It is therefore of interest to investigate how psychiatric drugs are of influence and what the potential is of new epigenetic drugs for psychiatric disorders. With this targeted review we summarize the current state of knowledge in order to provide insight in this developing field. Several traditional psychiatric drugs have been found to alter the epigenome and in a variety of animal studies, experimental compounds with epigenetic targets have been investigated as potential psychiatric drugs. After discussion of the most relevant epigenetic mechanisms we present the evidence for epigenetic effects for the most relevant classes of drugs.     

Target Essentiality and Centrality Characterize Drug Side Effects

To investigate factors contributing to drug side effects, we systematically examine relationships between 4,199 side effects associated with 996 drugs and their 647 human protein targets. We find that it is the number of essential targets, not the number of total targets, that determines the side effects of corresponding drugs. Furthermore, within the context of a three-dimensional interaction network with atomic-resolution interaction interfaces, we find that drugs causing more side effects are also characterized by high degree and betweenness of their targets and highly shared interaction interfaces on these targets. Our findings suggest that both essentiality and centrality of a drug target are key factors contributing to side effects and should be taken into consideration in rational drug design.     

The next generation of PPAR drugs: do we have the tools to find them?

Agonists of PPARalpha and PPARgamma are currently approved for use in treating, respectively, dyslipidemia and type 2 diabetes. Agonists of PPARbeta/delta are currently in development by several pharmaceutical companies. Despite their therapeutic importance, there are dose limiting side effects associated with PPAR drug treatments, thus a new generation of safer PPAR drugs are being actively sought after. In this review we will discuss the side effects associated the PPARs, how the current drugs in clinical development were discovered and new concepts in how to screen for PPAR drugs.     

Correlation of Subjective Side Effects with Plasma Concentrations of Nortriptyline

Plasma levels of tricyclic antidepressant drugs vary considerably between individuals receiving the same amount of drug. The bearing of this variation on the occurrence of subjective side effects was investigated in 40 psychiatric inpatients with depressive disorders. Plasma levels were determined before and during four weeks of treatment with nortriptyline 50 mg. three times a day and patients were rated for subjective side effects, the assessors being unaware of the plasma levels of the drug.Plasma levels varied widely between individual patients, but in any given patient the plasma level tended to be constant over a period of time. The side effects of nortriptyline diminished significantly with time and were in most cases absent during the fourth week of treatment. There was a significant positive correlation between plasma level of nortriptyline and subjective side effects.The steady-state plasma level of a drug which is metabolized is usually a more important determinant for its effect than dosage, since it reflects the amount of drug available for biological action. Very high plasma levels of nortriptyline should presumably be avoided, since there is no evidence that they are needed for therapeutic effect and they are potentially harmful.     

Chirality and Drugs Used in Psychiatry: Nice to Know or Need to Know?

1. Many drugs used to treat psychiatric disorders contain a chiral center or a center of unsaturation and are marketed as a mixture of the resultant enantiomers or geometric isomers, respectively. These enantiomers or geometric isomers may differ markedly with regard to their pharmacodynamic and/or pharmacokinetic properties.2. Examples of the effects of chiral centers or geometric centers on such properties are given for drugs from the following classes: antidepressants (tricyclics, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, viloxazine, bupropion, trazodone, mianserin, venlaflaxine); benzodiazepines, zoplicone, and antipsychotics.3. As described in this review, there are several notable examples of psychiatric drugs currently available where the individual enantiomers or geometric isomers differ considerably with regard to factors such as effects on amine transport systems, interactions with receptors and metabolizing enzymes, and clearance rates from the body. Indeed, relatively recent developments in analytical and preparative resolution of racemic and geometric drug mixtures and increased interest in developing new drugs which interact with specific targets, which have been described in detail at the molecular level, have resulted in increased emphasis on stereochemistry in drug development.     

Network Neighbors of Drug Targets Contribute to Drug Side-Effect Similarity

In pharmacology, it is essential to identify the molecular mechanisms of drug action in order to understand adverse side effects. These adverse side effects have been used to infer whether two drugs share a target protein. However, side-effect similarity of drugs could also be caused by their target proteins being close in a molecular network, which as such could cause similar downstream effects. In this study, we investigated the proportion of side-effect similarities that is due to targets that are close in the network compared to shared drug targets. We found that only a minor fraction of side-effect similarities (5.8 %) are caused by drugs targeting proteins close in the network, compared to side-effect similarities caused by overlapping drug targets (64%). Moreover, these targets that cause similar side effects are more often in a linear part of the network, having two or less interactions, than drug targets in general. Based on the examples, we gained novel insight into the molecular mechanisms of side effects associated with several drug targets. Looking forward, such analyses will be extremely useful in the process of drug development to better understand adverse side effects.     

The Psychotropic Self/Imaginary: Subjectivity and Psychopharmaceutical Use Among Heroin Users with Co-Occurring Mental Illness

Many people diagnosed with mental illnesses struggle with illicit drug addiction. These individuals are often treated with psychiatric medications, yet little is known about how they experience this treatment. Research on the subjective experience of psychiatric medication use highlights the complex, contradictory, and ambiguous feelings often associated with this treatment. However, for those with mental illness and addiction, this experience is complicated by the need to manage both psychiatric medication and illicit drug use. Using ethnographic data from a study of heroin use in Northeast Ohio, we explore this experience by expanding the pharmaceutical self/imaginary (Jenkins, Pharmaceutical Self: The Global Shaping of Experience in an Age of Psychopharmacology, School for Advanced Research Press, Santa Fe, NM, 2010b) to include psychopharmaceuticals and illicit drugs, what we call the psychotropic self/imaginary. Through this lens we explore the ways participants interpret and manage their psychotropic drug use in relation to sociocultural, institutional, and political–economic contexts. This analysis reveals how participants seek desired effects of legally prescribed and illicit drugs to treat mental illness, manage heroin addiction, and maintain a perceived “normal” self. Participants manage their drug use using active strategies, such as selective use of psychiatric medications, in the context of structural constraints, such as restricted access to mental health care, and cultural contexts that blur distinctions between “good” medicines and “bad” drugs.     

Neuroleptic drugs in dementia: benefits and harm

Neuroleptic (antipsychotic) drugs are often used to treat psychiatric symptoms frequently seen in dementia, but their use is controversial. We present a new meta-analysis to assess the efficacy of these drugs for the treatment of psychiatric symptoms in Alzheimer's disease, and discuss the more limited evidence for their potential benefits in other dementias. We recommend that these treatments be limited to the short-term treatment of psychiatric symptoms associated with serious distress or risk.     

Characterizing the Network of Drugs and Their Affected Metabolic Subpathways

A fundamental issue in biology and medicine is illustration of the overall drug impact which is always the consequence of changes in local regions of metabolic pathways (subpathways). To gain insights into the global relationship between drugs and their affected metabolic subpathways, we constructed a drug–metabolic subpathway network (DRSN). This network included 3925 significant drug–metabolic subpathway associations representing drug dual effects. Through analyses based on network biology, we found that if drugs were linked to the same subpathways in the DRSN, they tended to share the same indications and side effects. Furthermore, if drugs shared more subpathways, they tended to share more side effects. We then calculated the association score by integrating drug-affected subpathways and disease-related subpathways to quantify the extent of the associations between each drug class and disease class. The results showed some close drug–disease associations such as sex hormone drugs and cancer suggesting drug dual effects. Surprisingly, most drugs displayed close associations with their side effects rather than their indications. To further investigate the mechanism of drug dual effects, we classified all the subpathways in the DRSN into therapeutic and non-therapeutic subpathways representing drug therapeutic effects and side effects. Compared to drug side effects, the therapeutic effects tended to work through tissue-specific genes and these genes tend to be expressed in the adrenal gland, liver and kidney; while drug side effects always occurred in the liver, bone marrow and trachea. Taken together, the DRSN could provide great insights into understanding the global relationship between drugs and metabolic subpathways.     

The impact of novel antipsychotic drugs on quality of life among people suffering from schizophrenia

More attention is increasingly being paid to quality of life of people suffering from schizophrenia. The results of numerous clinical trials indicate that novel antipsychotic drugs are as efficient (if not more so) than the conventional drugs. Novel drugs also cause fewer side effects and allow for better quality of life. In order to confirm these thesis we have studied the quality of life of 80 female outpatients in good social remission that have been under psychiatric evaluation for at least six months and were on antipsychotic drugs. Of those 80 outpatients, half were on the conventional medication, while the other half were on the novel antipsychotic drugs. Their life quality was evaluated with the questionnaire "Heinrichs-Hanlon-Carpenter--Quality of life questionnaire", which is one of the most frequently used QL scales. The results demonstrate that the only difference between the two groups lies in the field of social activity. While leaving the question of different influence of novel and conventional drugs open, the authors are trying to find the possible reasons for such results.     

Drug discovery and development focusing on existing medicines: drug re-profiling strategy

As a new strategy for drug discovery and development, I focus on drug re-profiling as a way to identify new treatments for diseases. In this strategy, the actions of existing medicines, whose safety and pharmacokinetic effects in humans have already been confirmed clinically and approved for use, are examined comprehensively at the molecular level and the results used for the development of new medicines. This strategy is based on the fact that we still do not understand the underlying mechanisms of action of many existing medicines, and as such the cellular responses that give rise to their main effects and side effects are yet to be elucidated. To this extent, identification of the mechanisms underlying the side effects of medicines offers a means for us to develop safer drugs. The results can also be used for developing existing drugs for use as medicines for the treatment of other diseases. Promoting this research strategy could provide breakthroughs in drug discovery and development.     

Receptor crosstalk: haloperidol treatment enhances A2A adenosine receptor functioning in a transfected cell model

A(2A) adenosine receptors are considered an excellent target for drug development in several neurological and psychiatric disorders. It is noteworthy that the responses evoked by A(2A) adenosine receptors are regulated by D(2) dopamine receptor ligands. These two receptors are co-expressed at the level of the basal ganglia and interact to form functional heterodimers. In this context, possible changes in A(2A) adenosine receptor functional responses caused by the chronic blockade/activation of D(2) dopamine receptors should be considered to optimise the therapeutic effectiveness of dopaminergic agents and to reduce any possible side effects. In the present paper, we investigated the regulation of A(2A) adenosine receptors induced by antipsychotic drugs, commonly acting as D(2) dopamine receptor antagonists, in a cellular model co-expressing both A(2A) and D(2) receptors. Our data suggest that the treatment of cells with the classical antipsychotic haloperidol increased both the affinity and responsiveness of the A(2A) receptor and also affected the degree of A(2A)-D(2) receptor heterodimerisation. In contrast, an atypical antipsychotic, clozapine, had no effect on A(2A) adenosine receptor parameters, suggesting that the two classes of drugs have different effects on adenosine-dopamine receptor interaction. Modifications to A(2A) adenosine receptors may play a significant role in determining cerebral adenosine effects during the chronic administration of antipsychotics in psychiatric diseases and may account for the efficacy of A(2A) adenosine receptor ligands in pathologies associated with dopaminergic system dysfunction. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11302-010-9201-z) contains supplementary material, which is available to authorized users.     

烯二炔类抗肿瘤抗生素及其靶向药物研究近况

烯二炔类抗生素是一种结构新颖、作用机制独特的新型抗肿瘤抗生素,烯二炔结构是其活性中心。该类抗生素具有极强的抗肿瘤活性,却因毒性较大难以直接用于临床。近年来,研究人员展开了烯二炔类抗生素靶向药物的研发工作,以提高其肿瘤靶向性并减少药物毒副作用。归纳总结了已报道的天然来源的烯二炔类抗肿瘤抗生素及其活性代谢物,并重点介绍烯二炔类抗生素相关靶向药物的研究进展,旨在为其深度开发提供参考。     

3D-QSAR study indicates an enhancing effect of membrane ions on psychiatric drugs targeting serotonin receptor 5-HT1A

Antidepressants and antipsychotics are psychiatric agents used for the treatment of various types of psychiatric diseases. Although currently among the most commonly prescribed drugs, their effectiveness and adverse effects are the topic of many studies and controversial claims. Here we generate QSAR models based on compounds series including 20 drugs recommended for two critical psychiatric diseases: depression and schizophrenia and we use these QSAR models to predict the biological activity of these 20 antidepressants and antipsychotics. We establish the membrane ions' contributions (sodium, potassium, calcium and iron) mediated by water to the antagonism of these drugs at the 5-HT1A receptor. The reliability of our QSAR models in predicting compounds activity is indicated by significant values for cross-validated correlation q2 (0.60-0.76) and fitted correlation r2 (0.96-0.98) coefficients. Our results indicate that potassium, calcium and iron play a key role for the antagonistic activity of drugs at the 5-HT1A receptor. Moreover, based on the established QSAR equations, we analysed 24 new escitalopram derivatives as possibly improved antidepressants targeting the 5-HT1A receptor. We identified that the presence of methyl groups and hydrogen atoms improves antidepressant activity while the simultaneous presence of ethyl, propyl or halogens decreased drastically antidepressant activity at the 5-HT1A site.     

Mathematical modeling of multi-drugs therapy: a challenge for determining the optimal combinations of antiviral drugs

In the current era of antiviral drug therapy, combining multiple drugs is a primary approach for improving antiviral effects, reducing the doses of individual drugs, relieving the side effects of strong antiviral drugs, and preventing the emergence of drug-resistant viruses. Although a variety of new drugs have been developed for HIV, HCV and influenza virus, the optimal combinations of multiple drugs are incompletely understood. To optimize the benefits of multi-drugs combinations, we must investigate the interactions between the combined drugs and their target viruses. Mathematical models of viral infection dynamics provide an ideal tool for this purpose. Additionally, whether drug combinations computed by these models are synergistic can be assessed by two prominent drug combination theories, Loewe additivity and Bliss independence. By combining the mathematical modeling of virus dynamics with drug combination theories, we could show the principles by which drug combinations yield a synergistic effect. Here, we describe the theoretical aspects of multi-drugs therapy and discuss their application to antiviral research.     

Lithium attenuates dopamine depleting effects of reserpine and tetrabenazine but not that of alpha methyl-p-tyrosine

Concurrent administration of lithium (Li) significantly attenuates the dopamine (DA) depleting effects of reserpine and tetrabenazine, but does not change alpha-methyl-p-tyrosine (AMPT) induced DA depletion in rat brain. This effect of Li is probably mediated, in part, by inhibiting the magnesium-dependent binding of both reserpine and tetrabenazine to their specific receptor sites. Such interaction between these drugs may attenuate the beneficial effects of tetrabenazine and reserpine on patients with tardive dyskinesia or tardive dystonia who are treated concurrently with lithium for their psychiatric disorder.     

The safety of psychotropic drug use during pregnancy: a review

A substantial number of women of childbearing age are prescribed psychotropic drugs, and because nearly 50% of pregnancies are unplanned, many women are still taking them upon becoming pregnant. This article reviews the various classes of psychotropic drugs that are commonly used to treat psychiatric disorders--antidepressants, benzodiazepines, antipsychotics, antiepileptics, lithium and monoamine oxidase (MAO) inhibitors--in terms of their safety during pregnancy. Evidence-based information from epidemiologic studies indicates that most psychotropic drugs are relatively safe for use during pregnancy. There is also an increasingly large body of evidence-based information in the literature indicating that it may be more harmful to both the mother and her baby if she is not treated appropriately when suffering from a severe psychiatric disorder. Therefore, it is important for women with psychiatric disorders and their healthcare providers to have access to evidenced-based information about the safety of these drugs when taken during pregnancy to ensure that women make an informed decision as to whether they should continue with the pharmacotherapy they have been using to treat their condition.