Psychotherapeutic Drugs Research Articles

Upregulating serotonin transporter expression and downregulating monoamine oxidase-A and indoleamine 2, 3-dioxygenase expression involved in the antidepressant effect of sodium valproate in a rat model.

Sodium valproate (VPA) is widely used as an antiepileptic agent and mood stabilizer. In recent years, VPA has been increasingly used as a psychotherapeutic drug to treat depression. In this article, a possible antidepressant mechanism of VPA was investigated by studying the expression and therefore the involvement of tryptophan hydroxylase, serotonin transporter (5-HTT), monoamine oxidase-A (MAO-A), and indoleamine 2, 3-dioxygenase (IDO) in rats exposed to chronic unpredicted stress. Male Sprague-Dawley rats were divided into four groups: the vehicle-treated control group (CG), the VPA-treated control group (VPAC), the vehicle-treated model group (MG), and the VPA-treated model group (VPAM). VPA (300 mg/kg once daily) was administered to VPAC and VPAM rats by means of intragastric gavage while an equivalent volume of vehicle was given to vehicle-treated CG and MG rats. Rat behavior and expression of tryptophan hydroxylase, 5-HTT, MAO-A, and IDO in the hippocampus were determined. A significant reduction in depression-like behaviors was observed with an upregulation of 5-HTT expression and a downregulation of MAO-A and IDO expression in VPAM rats, compared with MG rats. The results may suggest that the antidepressant mechanism of VPA is partly related to elevated serotonin level and its reuse in the vesicles of presynaptic nerve endings.

Future applications of high-resolution MS to meet the demands for pain management drug testing.

Urine specimens submitted for pain management drug testing often contain multiple psychotherapeutic drugs, in addition to opioids. Immunoassay-based screen-and-confirm approaches typically used for clinical drug testing have limited sensitivity to detect therapeutic concentrations of many drugs prescribed in pain management and do not differentiate between drugs in the same class. In addition, screening for all the various illicit and prescription drugs that may be present in the pain management population requires as many as 10-20 individual immunoassays. High-resolution MS approaches have the potential to transform the way clinical drug testing is performed for pain management.

CDC to Clinicians: Be Alert for Children With Poliolike Illness

noncancerpain inolderadults,Solomonsaid. Heledastudythatusedhealthcareutilization dataforMedicarebeneficiariesstartingopioid therapy for noncancer pain to try to help answerthatquestion(SolomonDHetal.ArchInternMed. 2010;170[22]:1979-1986). Thestudy,publishedin2010,wasdevised “somewhat inresponsetotheAGSguideline,” Solomonsaid.Granted,hesaid, researchhad raised concerns about the safety of NSAIDs, butAGS“movedtoofar,perhaps, toembrace thepotential benefits of opioids.” Solomon’s study found that the ratesof adverseeventsvaried,dependingontheopioid and the duration of treatment. For example, the risk of cardiovascular events increased for codeine users after 180 days of use.And the risk of death fromall causes increasedafteronly30daysforusersofoxycodone or codeine. “This study’s findings do not agree with a commonly held belief that all opioids are associated with similar risk,” Solomon and his coauthors wrote. As the baby boomers age—the oldest arenowaged68years, the youngest nearly 50 years—overuse of opioids is expected to increase.With their historyof experimentationwithdrugs, thebabyboomersasagroup may be more likely to seek and abuse opioids thanmembersof their parents’ generation, Trevisan said. WestleyClark,MD, JD,MPH,directorof the Center for Substance Abuse Treatment at the Substance Abuse and Mental Health Services Administration, cited a 2006 report, coauthored by Compton, that projected the number of elderly individuals usingdrugs fornonmedical reasons in2020 (ColliverJDetal.AnnEpidemiol. 2006;16[4]: 257-265). By 2020, the nonmedical use of psychotherapeutic drugs, which includes opioid painkillers, was expected to reach 2.4%, nearly 2.7million, among thepopulation of US individuals 50 years or older, Compton and his coauthors wrote. That compares with 1.2%, or 911 000 people, in that age demographic in 2006. AlthoughtheAHRQstatisticalbriefcan’t prove thatopioidoveruseplayeda substantial role in the increase in US hospitalizations amongolder individuals, Clark said, he views the document as a “cautionary tale.” “I see it as opening the door for greater inquiries,” he said. “It is consistent with a number of other observations being made about the use of prescription opioids.”

Medication Safety

Medication Safety

Inhibition of P‐glycoprotein by psychotherapeutic drugs in a canine cell model

Drug-drug interactions related to long-term therapies are of increasing concern. Psychotherapeutic drugs, licensed for the use in dogs for the management of separation anxiety and other behavioural disorders, are examples of drugs used in long-term therapies. In an in vitro system with canine P-glycoprotein (P-gp) expressing cell lines, three psychotherapeutic drugs with a different mode of action were tested for their ability to inhibit the canine multidrug transporter P-gp. At 10μm, the selective serotonin reuptake inhibitor fluoxetine and the tricyclic antidepressant clomipramine inhibited P-gp for 41% and 59%, respectively. In contrast, selegeline did not inhibit the function of the canine P-gp.

Sigma-1 Receptor Enhances Neurite Elongation of Cerebellar Granule Neurons via TrkB Signaling

Sigma-1 receptor (Sig-1R) is an integral membrane protein predominantly expressed in the endoplasmic reticulum. Sig-1R demonstrates a high affinity to various synthetic compounds including well-known psychotherapeutic drugs in the central nervous system (CNS). For that, it is considered as an alternative target for psychotherapeutic drugs. On the cellular level, when Sig-1R is activated, it is known to play a role in neuroprotection and neurite elongation. These effects are suggested to be mediated by its ligand-operated molecular chaperone activity, and/or upregulation of various Ca2+ signaling. In addition, recent studies show that Sig-1R activation induces neurite outgrowth via neurotrophin signaling. Here, we tested the hypothesis that Sig-1R activation promotes neurite elongation through activation of tropomyosin receptor kinase (Trk), a family of neurotrophin receptors. We found that 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate (PRE-084), a selective Sig-1R agonist, significantly promoted neurite outgrowth, and K252a, a Trk inhibitor, attenuated Sig-1R-mediated neurite elongation in cerebellar granule neurons (CGNs). Moreover, we revealed that Sig-1R interacts with TrkB, and PRE-084 treatment enhances phosphorylation of Y515, but not Y706. Thus, our results indicate that Sig-1R activation promotes neurite outgrowth in CGNs through Y515 phosphorylation of TrkB.

The Relationship between Perceived Discrimination and Psychotherapeutic and Illicit Drug Misuse in Chicago, IL, USA

Based on several stress-coping frameworks, recent studies have suggested that perceived experiences of discrimination, a psychosocial stressor, may be associated with various risky health behaviors. The 2001 Chicago Community Adult Health Study (n = 3,101), a face-to-face representative probability sample of adults in Chicago, IL, USA, was used to examine the relationship among lifetime everyday discrimination, major discrimination, and the use of illicit and psychotherapeutic drugs for nonmedical reasons. We used negative binomial logistic and multinomial regression analyses controlling for potential confounders. Approximately 17% of the respondents reported using one or more illicit drugs and/or misusing one or more psychotherapeutic drug. Adjusting for socio-demographic characteristics, other stressors and various personality-related characteristics, results from negative binomial regression suggest that respondents who experienced moderate to high levels of everyday discrimination misused on average 1.5 different kinds of drugs more than respondents that experienced relatively low levels of everyday discrimination (p < 0.05). Similarly, an increase in one lifetime major discrimination event was associated with an increase of misusing 1.3 different drugs on average regardless of experiences of everyday discrimination (p < 0.001). When examining the types of drugs misused, results from multinomial logistic regression suggest that everyday discrimination was only associated with illicit drug use alone; however, lifetime major discrimination was associated with increased odds of using any illicit and both illicit/psychotherapeutic drugs. Mental health and substance use clinical providers should be aware of these potential relationships and consider addressing the harmful effects of perceived discrimination, in all patients not only among racial/ethnic minority patients.

An automatic recording system for the study of escape from fear in rats

Escape from fear (EFF) is an active response to a conditioned stimulus (CS) previously paired with an unconditioned fearful stimulus (US), which typically leads to the termination of the CS. In this paradigm, animals acquire two distinct associations: S–S [CS–US] and R–O [response–outcome] through Pavlovian and instrumental conditioning, respectively. The present study describes a computer controlled automatic recording system that captures the development of EFF and allows the determination of the respective roles of S–S and R–O associations in this process. We validated this system by showing that only rats subjected to a simultaneous CS–US conditioning (i.e., CS and US occur together at the beginning of each trial) acquired EFF, not those subjected to an unpaired CS–US conditioning. Paired rats had a progressively increased number of EFF and significantly shorter escape latencies than unpaired rats across the 5-trial blocks on the test day. However, during the conditioning phase, the unpaired rats emitted more 22kHz ultrasonic vocalizations, a validated measure of conditioned reactive fear responses. Our results demonstrate that the acquisition of EFF is contingent upon pairing of the CS with the US, not simply the consequence of a high level of generalized fear. Because this commercially available system is capable of examining both conditioned active and reactive fear responses in a single setup, it could be used to determine the relative roles of S–S and R–O associations in EFF, the neurobiology of conditioned active fear response and neuropharmacology of psychotherapeutic drugs.

PMH12 - Impact of polydrug use on prescription drug abuse

Prescription drug abuse has emerged as a major public health threat over the past decade. The role of polydrug use (PDU) of psychotherapeutic drugs is currently not well understood in prescription drug abuse (defined as nonmedical use of prescription drugs-NMUPD). This study aims to characterize NMUPD and examine the role of PDU in contributing to prescription drug abuse. The National Survey of Drug Use and Health (NSDUH-2010) was utilized to study a population of noninstitutionalized, civilian Americans, aged 12 years and over for NMUPD. NMUPD was defined as the act of consuming a drug from any of the four drug classes (pain relievers, stimulants, tranquilizers and sedatives) without a valid prescription or with a prescription for the experience or feeling it caused. PDU was defined as the use of two or more prescription psychotherapeutic drugs within the past one year. Associations between PDU and NMUPD were tested with respect to demographic and socio-economic factors. Out of a sample of 5166 individuals who were taking psychotherapeutic drugs, about 29% (n=1493) were engaged in PDU. About 4.47% (n=231) of the sample fit the criteria for NMUPD. About 6.50% (n=97) of the PDU sample (n=1493) were engaged in NMUPD. NMUPD was found to be more common among polydrug-users than monodrug-users (6.5% vs. 3.65%). A Chi-Square test for independence showed a significant association between PDU and NMUPD (χ2=20.167, p<0.0001). Demographically, a majority of the polydrug-users with NMUPD were in the age-group 18-25 years (55%), female (54.64%), single (83.51%), nonhispanic white (77.32%), with high school graduation (60.82%) and income less than $10,000 annually (68.04%). PDU is a notable and legitimate risk factor for NMUPD. NMUPD among polydrug-users appears to be more prevalent in a population that is young, mostly female, nonhispanic white, with limited income and education.

Phenotyping and Genotyping of Drug Metabolism to Guide Pharmacotherapy in Psychiatry

In psychiatry, around 130 drugs are available which have been detected and developed during the last 60 years. These drugs are effective and essential for the treatment of many psychiatric disorders and symptoms. Therapeutic outcomes, however, are still far from satisfactory for many patients. One major reason underlying insufficient response or problems of tolerability or toxicity is considerable interindividual variability in the pharmacokinetic properties of the patients. At the exact same dose, a more than 20-fold interindividual variation in steady state concentrations of the drugs in the body may result. Patients differ in their ability to absorb, distribute, metabolize and excrete drugs due to concurrent disease, age, concomitant medication or genetic peculiarities. A valuable tool for tailoring the dosage of the prescribed medication(s) to the individual characteristics of a patient is therapeutic drug monitoring (TDM). For a considerable number of psychopharmacologic compounds, TDM has become a clinical routine for dose adjustment. The benefits of TDM regarding optimization of psychopharmacotherapy can be further enhanced by genotyping of cytochrome P450 enzymes (CYP). These enzymes are highly polymorphic and involved in the metabolism of most psychotherapeutic drugs. Genotyping related information may be supportive especially for drugs that are predominantly metabolized by CYP2C19 or CYP2D6. The in vivo activity of CYP isoenzymes can be determined using probe drug assays. When used appropriately, phenotyping and genotyping methods are most helpful for problem solving and improvement of the outcomes of psychopharmacotherapy for many patients.

Prescription opioid mortality trends in New York City, 1990–2006: Examining the emergence of an epidemic

Background: The drug overdose mortality rate tripled between 1990 and 2006; prescription opioids have driven this epidemic. We examined the period 1990–2006 to inform our understanding of how the current prescription opioid overdose epidemic emerged in urban areas. Methods: We used data from the Office of the Chief Medical Examiner to examine changes in demographic and spatial patterns in overdose fatalities induced by prescription opioids (i.e., analgesics and methadone) in New York City (NYC) in 1990–2006, and what factors were associated with death from prescription opioids vs. heroin, historically the most prevalent form of opioid overdose in urban areas. Results: Analgesic-induced overdose fatalities were the only types of overdose fatalities to increase in 1990–2006 in NYC; the fatality rate increased sevenfold from 0.39 in 1990 to 2.7 per 100,000 persons in 2006. Whites and Latinos were the only racial/ethnic groups to exhibit an increase in overdose-related mortality. Relative to heroin overdose decedents, analgesic and methadone overdose decedents were more likely to be female and to concurrently use psychotherapeutic drugs, but less likely to concurrently use alcohol or cocaine. Analgesic overdose decedents were less likely to be Black or Hispanic, while methadone overdose decedents were more likely to be Black or Hispanic in contrast to heroin overdose decedents. Conclusions: The distinct epidemiologic profiles exhibited by analgesic and methadone overdose fatalities highlight the need to define drug-specific public health prevention efforts.

A Prospective Evaluation of Psychotherapeutic and Illicit Drug Use in Patients Presenting with Chronic Pain at the Time of Initial Evaluation

Background: Reports of chronic pain and associated opioid use, abuse, and fatalities continue to increase at an alarming rate, not only in the United States but also across the globe. In light of the many resultant fatalities, multiple authors and authorities have cautioned against the excessive use of opioids. Consequently, the Food and Drug Administration, Drug Enforcement Administration, and multiple state authorities have been proposing and implementing a plethora of regulations to curb opioid overuse and abuse. In the majority of cases, pain physicians have been portrayed as the perpetrators responsible for escalating use and abuse and resultant fatalities. Objectives: To assess the patterns of psychotherapeutic drug use and illicit drug use at the time of initial evaluation. Study Design: A prospective evaluation. Setting: A private, specialty referral interventional pain management clinic in the United States. Methods: Participants were all new patients presenting to interventional pain management evaluated by one physician. Inclusion criteria was patients over 18 years of age with chronic spinal pain of at least one year duration. Results: The results of this evaluation indicate that 94% of patients were on long-term opioids prior to presenting to interventional pain management. Illicit drug use is also common, although it has declined significantly. While a large proportion of individuals (45.7%) have used illicit drugs at some point in the past, current illicit drug use is present in only 7.9% of patients, both past and current use are similar to that of the general population. More importantly, a significant proportion of patients have been on opioids (high doses of more than 40 mg equivalents of morphine 48.8%) on a long-term basis, initiated and maintained by primary care physicians, prior to presenting to interventional pain management. Further, 35% were on benzodiazepines, and 9.2% on carisoprodol prior to presenting to interventional pain management. Limitations: The limitations of this evaluation include that it is a prospective, single center evaluation by one physician that is partially dependent on subjective recall of the patient. Conclusion: This study shows an overwhelming majority of patients were initiated and maintained with opioids in managing chronic noncancer pain. They were frequently on high doses over a long period of time with multiple drug combinations prescribed by primary care physicians. Key Words: Chronic pain, persistent pain, noncancer pain, controlled substances, substance abuse, prescription drug abuse, opioids, prescriptions, urine drug testing, fatalities, regulations

Opioid Epidemic in the United States

Over the past two decades, as the prevalence of chronic pain and health care costs have exploded, an opioid epidemic with adverse consequences has escalated. Efforts to increase opioid use and a campaign touting the alleged undertreatment of pain continue to be significant factors in the escalation. Many arguments in favor of opioids are based solely on traditions, expert opinion, practical experience and uncontrolled anecdotal observations. Over the past 20 years, the liberalization of laws governing the prescribing of opioids for the treatment of chronic non-cancer pain by the state medical boards has led to dramatic increases in opioid use. This has evolved into the present stage, with the introduction of new pain management standards by the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) in 2000, an increased awareness of the right to pain relief, the support of various organizations supporting the use of opioids in large doses, and finally, aggressive marketing by the pharmaceutical industry. These positions are based on unsound science and blatant misinformation, and accompanied by the dangerous assumptions that opioids are highly effective and safe, and devoid of adverse events when prescribed by physicians. Results of the 2010 National Survey on Drug Use and Health (NSDUH) showed that an estimated 22.6 million, or 8.9% of Americans, aged 12 or older, were current or past month illicit drug users, The survey showed that just behind the 7 million people who had used marijuana, 5.1 million had used pain relievers. It has also been shown that only one in 6 or 17.3% of users of non-therapeutic opioids indicated that they received the drugs through a prescription from one doctor. The escalating use of therapeutic opioids shows hydrocodone topping all prescriptions with 136.7 million prescriptions in 2011, with all narcotic analgesics exceeding 238 million prescriptions. It has also been illustrated that opioid analgesics are now responsible for more deaths than the number of deaths from both suicide and motor vehicle crashes, or deaths from cocaine and heroin combined. A significant relationship exists between sales of opioid pain relievers and deaths. The majority of deaths (60%) occur in patients when they are given prescriptions based on prescribing guidelines by medical boards, with 20% of deaths in low dose opioid therapy of 100 mg of morphine equivalent dose or less per day and 40% in those receiving morphine of over 100 mg per day. In comparison, 40% of deaths occur in individuals abusing the drugs obtained through multiple prescriptions, doctor shopping, and drug diversion. The purpose of this comprehensive review is to describe various aspects of crisis of opioid use in the United States. The obstacles that must be surmounted are primarily inappropriate prescribing patterns, which are largely based on a lack of knowledge, perceived safety, and inaccurate belief of undertreatment of pain. Key words: Opioid abuse, opioid misuse, nonmedical use of psychotherapeutic drugs, nonmedical use of opioids, National Survey on Drug Use and Health, opioid guidelines.

Hormone therapy after endometrial cancer.

Endometrial carcinoma is one of the absolute contraindications of hormone therapy (HT). After all the existing opinions so far, HT after Stage I or II is still thought of as a possibility and up to now, the continuously combined estrogen (CAS 53-16-7) / progestogen (CAS 57-83-0) replacement therapy (CCEPT) has been recommended. However, only observational studies have been conducted as yet. Although no study established an increased rate of recurrence or mortality, alternatives such as phyto-preparations, tibolone, or particular psychotherapeutic drugs such as venlafaxine should be considered for the relief of climacteric complaints. In particular considered is progestogen-only therapy. However, the currently discussed possible progestogen effects regarding the risk of breast cancer have to be taken into account. Generally after hysterectomy, at least for patients with cardiovascular risk factors, the preference today is to use low-dose estrogen therapy (patches, gels) instead of CCEPT, and this also is now recommended for patients after endometrial cancer. This is important because of the risk factors for endometrial carcinoma, such as hypertension, obesity, polycystic ovary syndrome, diabetes mellitus etc. However, each form of HT should only be exceptionally recommended, and the patients must be informed about the risks that exist and the use of alternatives.

Medicaid Cost Control Measures Aimed At Second-Generation Antipsychotics Led To Less Use Of All Antipsychotics

"Atypical" or second-generation antipsychotics are a class of drug introduced in the 1990 s for the treatment of schizophrenia. Given their growing use and rising cost, these and other psychotherapeutic drugs are increasingly subject to prior authorization and other restrictions in state Medicaid programs. To evaluate the effects of these policies, we collected drug-level information on their use and on utilization management strategies--for example, requirements for prior authorization, quantity limits, and so-called step therapy--in thirty state Medicaid programs between 1999 and 2008. In the eleven states that instituted prior authorization during that period, use of atypicals per enrollee rose by 14 percent, versus 19 percent in the other nineteen states. Prior authorization also had spillover effects, in that reduced use of drugs subject to this requirement was not fully offset by the substitution of other atypicals or of typical antipsychotics. To understand the impact on patients and the resulting use of health services, studies should be undertaken of a large, national sample of Medicaid enrollees being treated with atypical antipsychotics. Comparative effectiveness research should guide physicians and health plans on appropriate first treatments, while prior authorization policies should focus on moving patients to appropriate second-line therapies when necessary.

Joseph Vincent Brady

Joseph Vincent Brady

C-B1-01: Psychotherapeutic Prescription Patterns Across Health Plans in the Mental Health Research Network

Background The need for effectiveness and dissemination research is at least as great in mental health as in other areas of health care. The Mental Health Research Network aims to use the VDW for multi-site studies of mental disorder epidemiology, treatment patterns, or treatment effectiveness. We expect that the existing infrastructure is satisfactory in some areas, while others will need improvement or expansion. We present early results from validation studies of enrollment and pharmacy data on patterns of psychotherapeutic drug use.

Theater Troupe Dramatizes Addicts' Long, Painful Journey

NIDA estimates that 7 million people used prescription psychotherapeutic drugs nonmedically in the past month and that more than 3 million used an illicit drug for the first time in the past 12 months.

Serious Behavioral Disorders in Children and Adolescents

This issue of Pediatric Annals is devoted to the worrisome disorders of depression and other serious mental health conditions in children and adolescents. All practitioners are aware that these are common disorders in this age group, with estimates of 2% to 6% being affected at any point in time and an overall prevalence of 20% by the late adolescent period. Many or most families (including my own) have one or more members with depression or a related condition. Unfortunately, many pediatric practitioners must assume primary management of some of these patients because of the unavailability or inaccessibility of psychiatrists or psychologists in some geographic areas. In addition, a depressed child may present with symptoms to the primary care provider before they reach out to a mental health professional. Knowing the most current treatment options supported by literature can aid in providing proper patient referrals. The articles in this issue provide considerable practical management assistance and summarize the available data regarding treatment with psychotherapeutic drugs and other potential therapeutic modalities. Emslie and colleagues (see page 300) review three studies of antideCanada issued the orange, yellow, and green stamp in 2010 to raise money for mental health (Sante Mentale) activities. From the collection of ST Shulman with permission.

Targeting ligand-operated chaperone sigma-1 receptors in the treatment of neuropsychiatric disorders

Introduction: Current drugs for the treatment of psychiatric or neurodegenerative disorders have limitations. Psychotherapeutic drugs such as typical and atypical antipsychotics, tricyclic antidepressants and selective monoamine reuptake inhibitors, aim to normalize the hyper- or hypo-neurotransmission of monoaminergic systems. Despite their contribution to the outcomes of psychiatric patients, these agents often exert severe side effects and require chronic treatments to promote amelioration of symptoms. Drugs available for the treatment of neurodegenerative disorders are severely limited.Areas covered: Recent evidence that has shed light on sigma-1 receptor ligands, which may serve as a new class of antidepressants or neuroprotective agents. Sigma-1 receptors are novel ligand-operated molecular chaperones regulating signal transduction, ER stress, cellular redox, cellular survival and synaptogenesis. Selective sigma-1 receptor ligands exert rapid antidepressant-like, anxiolytic, antinociceptive and robust neuroprotective actions in preclinical studies. Recent studies that suggest that reactive oxygen species might play a role as signal integrators downstream of Sig-1Rs are also covered.Expert opinion: The advances in sigma receptor research in the last decade have begun to elucidate the intracellular signal cascades upstream and downstream of sigma-1 receptors. The novel ligand-operated properties of the sigma-1 receptor chaperone may enable interventions by which stress-related cellular systems can be pharmacologically controlled.