piperidines and Anxiety-Disorders

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported from China in January, 2020. SARS-CoV-2 is efficiently transmitted from person to person and, in 2 months, has caused more than 82 000 laboratory-confirmed cases of coronavirus disease 2019 (COVID-19) and 2800 deaths in 46 countries. The total number of cases and deaths has surpassed that of the 2003 severe acute respiratory syndrome coronavirus (SARS-CoV). Although both COVID-19 and severe acute respiratory syndrome (SARS) manifest as pneumonia, COVID-19 is associated with apparently more efficient transmission, fewer cases of diarrhoea, increased mental confusion, and a lower crude fatality rate. However, the underlying virus-host interactive characteristics conferring these observations on transmissibility and clinical manifestations of COVID-19 remain unknown.. We systematically investigated the cellular susceptibility, species tropism, replication kinetics, and cell damage of SARS-CoV-2 and compared findings with those for SARS-CoV. We compared SARS-CoV-2 and SARS-CoV replication in different cell lines with one-way ANOVA. For the area under the curve comparison between SARS-CoV-2 and SARS-CoV replication in Calu3 (pulmonary) and Caco2 (intestinal) cells, we used Student's. As far as we know, our study presents the first quantitative data for tropism, replication kinetics, and cell damage of SARS-CoV-2. These data provide novel insights into the lower incidence of diarrhoea, decreased disease severity, and reduced mortality in patients with COVID-19, with respect to the pathogenesis and high transmissibility of SARS-CoV-2 compared with SARS-CoV.. May Tam Mak Mei Yin, The Shaw Foundation Hong Kong, Richard Yu and Carol Yu, Michael Seak-Kan Tong, Respiratory Viral Research Foundation, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, The Hong Kong Hainan Commercial Association South China Microbiology Research Fund, The Jessie & George Ho Charitable Foundation, Perfect Shape Medical, The Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance for the Department of Health of the Hong Kong Special Administrative Region Government, The Theme-Based Research Scheme of the Research Grants Council, Sanming Project of Medicine in Shenzhen, and The High Level-Hospital Program, Health Commission of Guangdong Province, China.. Lower levels of total T3 were strongly correlated with in-hospital mortality in patients with SCMP. A low T3 level might suggest poor prognosis in patients with SCMP.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antibodies, Bacterial; Anxiety Disorders; Arecaceae; Arrhythmias, Cardiac; Autonomic Nervous System; Bacterial Proteins; Behavior Therapy; Burkholderia pseudomallei; Caco-2 Cells; Campylobacter; Campylobacter Infections; Carbazoles; Carcinoma, Non-Small-Cell Lung; Case-Control Studies; Chickens; Computer Simulation; Coumarins; COVID-19; Cross-Sectional Studies; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Diabetes Mellitus, Type 1; Diarrhea; Dietary Supplements; Echocardiography; Educational Measurement; Electrocardiography, Ambulatory; Endoribonucleases; Exercise; Exercise Therapy; Faculty, Dental; Farms; Fear; Female; Flame Retardants; Florida; Gene Expression Regulation, Plant; Halogenated Diphenyl Ethers; Hearing Loss, Sudden; Heart Rate; HIV Infections; Hospital Mortality; Humans; Hypertension; Hypoglycemia; Immunity; In Situ Hybridization; Japan; Kinetics; Kuwait; Lung Neoplasms; Macaca mulatta; Macrophages; Male; Masked Hypertension; Melioidosis; Methyltransferases; Mice; Mice, Inbred BALB C; Middle Aged; Molecular Docking Simulation; Molecular Dynamics Simulation; Myocardium; Oryza; Patient Education as Topic; Peptide Hydrolases; Phosphoric Monoester Hydrolases; Piperidines; Plant Extracts; Plant Proteins; Platelet Count; Poultry Diseases; Prevalence; Protease Inhibitors; Protein Kinase Inhibitors; Protein Kinases; Rabbits; Rats; Rats, Sprague-Dawley; RAW 264.7 Cells; Resistance Training; Retrospective Studies; Risk Factors; SARS-CoV-2; Saudi Arabia; Severe acute respiratory syndrome-related coronavirus; Students; Substance-Related Disorders; Surveys and Questionnaires; Swine; Tachycardia, Ventricular; Takotsubo Cardiomyopathy; Thyroid Gland; Transcriptome; Transfection; Tropism; United Arab Emirates; Virulence; Virulence Factors; Writing

CB(1) receptor antagonists were among the most promising drug targets in the last decade. They have been explored and found to be effective as therapeutic agents for obesity and related cardiometabolic problems; however, use of rimonabant, the first marketed CB(1) receptor antagonist, has been suspended because of its anxiogenic and depressogenic side effects. Because some other antiobesity drugs, like dexfenfluramine or sibutramine, were also suspended, the unmet need for drugs that reduce body weight became enormous. One approach that emerged was the use of CB(1) receptor antagonists that poorly cross the blood brain barrier, the second, the development of neutral antagonists instead of inverse agonists, and the third, use of personalized medicine, namely the selection of the patient population without psychiatric side effects. In this review, we dissect the peripheral and central mechanisms involved in the effects of CB(1) receptor antagonists and argue that central mechanisms are more or less involved in most cardiometabolic therapeutic effects and thus, among patients with unsatisfactory therapeutic response to compounds with peripheral action, centrally acting antagonists may be needed. An analysis of pharmacogenetic factors may help to identify persons who are at no or low risk for psychiatric adverse effects. Here, we present the models and identify molecular mechanisms and receptors involved in the effects of stress-, anxiety- and depression-related neurocircuitries sensitive to CB(1) receptor antagonists, like the serotonergic, noradrenergic and dopaminergic systems, which are not only regulated by CB(1) receptors, but also regulate the synthesis of the endocannabinoid 2-arachidonoyl-glycerol.

Topics: Anti-Obesity Agents; Anxiety Disorders; Depressive Disorder; Humans; Obesity; Piperidines; Precision Medicine; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Saredutant (SR48968), a potentially novel treatment option for major depressive disorders (MDD) and generalized anxiety disorder (GAD), is a drug from Sanofi-Aventis currently in phase III clinical trials. MDD is a common mental disorder that affects 121 million people worldwide, nearly 4% of the adult population (www.who.int/mental_health/management/depression/definition/en/). MDD continues to be one of the leading causes of disability with more than three quarters of the diagnosed cases having effective treatments available (www.who.int/mental_health/management/depression/definition/en/). However, even though MDD affects a large portion of the population, effective treatment options with low incidence of adverse events remain a major concern for the pharmaceutical industry. Adverse events (GI side effects1, weight gain, somnolence/insomnia, etc. (Demyttenaere K. (2003) Risk factors and predictors of compliance in depressionEur. Neuropshychopharm.13S69-S75)) from the typical treatments remain the major reason for premature stopping or poor compliance of treatment. New treatments to the market must bear in mind these adverse events, and the pharmaceutical industry is currently looking for drugs with new mechanisms of action and those that are better tolerated.

Topics: Antidepressive Agents; Anxiety Disorders; Benzamides; Clinical Trials, Phase III as Topic; Depressive Disorder, Major; Humans; Neurokinin A; Patient Compliance; Piperidines; Psychiatric Status Rating Scales; Selective Serotonin Reuptake Inhibitors

Both agonists (e.g. Delta(9)-tetrahydrocannabinol, nabilone) and antagonists (e.g. rimonabant, taranabant) of the cannabinoid type-1 (CB(1)) receptor have been explored as therapeutic agents in diverse fields of medicine such as pain management and obesity with associated metabolic dysregulation, respectively. CB(1) receptors are widely distributed in the central nervous system and are involved in the modulation of emotion, stress and habituation responses, behaviours that are thought to be dysregulated in human psychiatric disorders. Accordingly, CB(1) receptor activation may, in some cases, precipitate episodes of psychosis and panic, while its inhibition may lead to behaviours reminiscent of depression and anxiety-related disorders. The present review discusses these side-effects, which have to be taken into account in the therapeutic exploitation of the endocannabinoid system.

Topics: Affect; Animals; Anxiety Disorders; Cannabinoid Receptor Modulators; Depressive Disorder; Dronabinol; Humans; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

Experimental evidence has suggested that drugs that enhance cannabinoid type-1 (CB1) receptor activity may induce anxiolytic and antidepressant effects, whilst the opposite has been reported with antagonists. Thus, the objective of the present review is to discuss the potential psychiatric side-effects of CB1 receptor antagonists, such as rimonabant, which has been recently marketed in several countries for the treatment of smoking cessation, obesity and associated metabolic disorders.. Literature searches were performed in PubMed and SciELO databases up to February 2009. The terms searched were 'obesity', 'rimonabant', 'cannabinoids', 'unwanted effects', 'diabetes', 'smoking cessation' and 'side-effects'.. Clinical trials have revealed that rimonabant may promote weight loss in obese patients, although it may also induce symptoms of anxiety and depression.. Patients taking CB1 receptor antagonists should be carefully investigated for psychiatric side-effects. These drugs should not be prescribed for those already suffering from mental disorders. Nevertheless, the development of new compounds targeting the endocannabinoid system for the treatment of several conditions would be necessary and opportune.

Topics: Anxiety Disorders; Appetite Depressants; Cannabinoid Receptor Modulators; Depressive Disorder; Humans; Metabolic Diseases; Obesity; Piperidines; Placebo Effect; Pyrazoles; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Rimonabant; Smoking; Smoking Cessation

Casopitant, an inhibitor of the neurokinin-1 receptor, and its mesylate salt, are being developed by GlaxoSmithKline plc for the potential treatment of chemotherapy-induced nausea and vomiting (CINV), post-operative nausea and vomiting (PONV), as well as for anxiety, depression and insomnia. Phase II trials are ongoing for anxiety, depression and insomnia, and further results are awaited from phase III trials of CINV and PONV. At the time of publication, it was expected that applications to the FDA for regulatory approval for CINV and PONV would be filed in 2008. Casopitant was previously being developed for the treatment of overactive bladder; however, in September 2007, this indication was no longer listed on the company's product pipeline.

Topics: Animals; Antiemetics; Anxiety Disorders; Clinical Trials as Topic; Contraindications; Depressive Disorder, Major; Drug Evaluation, Preclinical; Female; Fibromyalgia; Humans; Nausea; Neurokinin-1 Receptor Antagonists; Patents as Topic; Piperazines; Piperidines; Postoperative Nausea and Vomiting; Structure-Activity Relationship; Urinary Bladder, Overactive; Vomiting

Since the prevalence of obesity continues to increase, there is a demand for effective and safe anti-obesity agents that can produce and maintain weight loss and improve comorbidity. We did a meta-analysis of all published randomised controlled trials to assess the efficacy and safety of the newly approved anti-obesity agent rimonabant.. We searched The Cochrane database and Controlled Trials Register, Medline via Pubmed, Embase via WebSpirs, Web of Science, Scopus, and reference lists up to July, 2007. We collected data from four double-blind, randomised controlled trials (including 4105 participants) that compared 20 mg per day rimonabant with placebo.. Patients given rimonabant had a 4.7 kg (95% CI 4.1-5.3 kg; p<0.0001) greater weight reduction after 1 year than did those given placebo. Rimonabant caused significantly more adverse events than did placebo (OR=1.4; p=0.0007; number needed to harm=25 individuals [95% CI 17-58]), and 1.4 times more serious adverse events (OR=1.4; p=0.03; number needed to harm=59 [27-830]). Patients given rimonabant were 2.5 times more likely to discontinue the treatment because of depressive mood disorders than were those given placebo (OR=2.5; p=0.01; number needed to harm=49 [19-316]). Furthermore, anxiety caused more patients to discontinue treatment in rimonabant groups than in placebo groups (OR=3.0; p=0.03; number needed to harm=166 [47-3716]).. Our findings suggest that 20 mg per day rimonabant increases the risk of psychiatric adverse events--ie, depressed mood disorders and anxiety-despite depressed mood being an exclusion criterion in these trials. Taken together with the recent US Food and Drug Administration finding of increased risk of suicide during treatment with rimonabant, we recommend increased alertness by physicians to these potentially severe psychiatric adverse reactions.

Topics: Anti-Obesity Agents; Anxiety Disorders; Depression; Double-Blind Method; Female; Humans; Male; Multicenter Studies as Topic; Obesity; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Weight Loss

Mood and anxiety disorders, the most prevalent of the psychiatric disorders, cause immeasurable suffering worldwide. Despite impressive advances in pharmacological therapies, improvements in efficacy and side-effect profiles are needed. The present literature review examines the role that the endocannabinoid system may play in these disorders and the potential value of targeting this system in the search for novel and improved medications. Cannabis and its major psychoactive component (-)-trans-delta9-tetrahydrocannabinol, have profound effects on mood and can modulate anxiety and mood states. Cannabinoid receptors and other protein targets in the central nervous system (CNS) that modulate endocannabinoid function have been described. The discovery of selective modulators of some of these sites that increase or decrease endocannabinoid neurotransmission, primarily through the most prominent of the cannabinoid receptors in the CNS, the CB1 receptors, combined with transgenic mouse technology, has enabled detailed investigations into the role of these CNS sites in the regulation of mood and anxiety states. Although data point to the involvement of the endocannabinoid system in anxiety states, the pharmacological evidence seems contradictory: both anxiolytic- and anxiogenic-like effects have been reported with both endocannabinoid neurotransmission enhancers and blockers. Due to advances in the development of selective compounds directed at the CB1 receptors, significant progress has been made on this target. Recent biochemical and behavioural findings have demonstrated that blockade of CB1 receptors engenders antidepressant-like neurochemical changes (increases in extracellular levels of monoamines in cortical but not subcortical brain regions) and behavioural effects consistent with antidepressant/antistress activity in rodents.

Topics: Affect; Animals; Anxiety Disorders; Cannabinoid Receptor Modulators; Dronabinol; Humans; Models, Animal; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1

Placebo-controlled trials have evaluated the efficacy of several medications in the treatment of social anxiety disorder but information regarding their relative efficacy is lacking. We compared the efficacy of medications systematically studied for the treatment of social anxiety disorder using meta-analytic techniques. The methodology included a database search of articles published between January 1980 and June 2001 and manual searches of bibliographies in published manuscripts. Trials were included if they reported outcome data on the Liebowitz Social Anxiety Scale (LSAS) or a categorical measure of responder status. Data were extracted independently by two authors. The Q statistic was used to assess homogeneity across trials. All analyses were conducted using intent-to-treat data. There was substantial heterogeneity across trials. The medications with largest effect sizes were phenelzine [effect size, 1.02; 95% Confidence Interval (CI), 0.52-1.52], clonazepam (effect size, 0.97; 95% CI, 0.49-1.45), gabapentin (effect size, 0.78; 95% CI, 0.29-1.27), brofaromine (effect size, 0.66; 95% CI, 0.38-0.94), and the selective serotonin reuptake inhibitors (SSRIs; effect size, 0.65; 95% CI, 0.50-0.81). There were no statistically significant differences between medications or medication groups. However, formal methods of interim monitoring adapted for meta-analyses suggested strongest evidence of efficacy for SSRIs and brofaromine. Several medications are efficacious for the treatment of social anxiety disorder. The stability of the SSRI effect size estimate in conjunction with other evidence for safety and tolerability and their ability to treat comorbid conditions supports the use of SSRIs as the first-line treatment. Direct comparisons of SSRIs vs. other promising medications deserve consideration.

Topics: Acetates; Amines; Anti-Anxiety Agents; Antidepressive Agents; Antimanic Agents; Anxiety Disorders; Calcium Channel Blockers; Clonazepam; Cyclohexanecarboxylic Acids; Excitatory Amino Acid Antagonists; Female; GABA Modulators; Gabapentin; gamma-Aminobutyric Acid; Humans; Male; Monoamine Oxidase Inhibitors; Phenelzine; Phobic Disorders; Piperidines; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

The pharmacological properties of two NK1 antagonists were studied in comparison with a benzodiazepine during a 7% CO2 challenge in a population of healthy volunteers selected for a high sensitivity to the challenge. In total, 19 healthy subjects, pre-screened for their responsiveness to the 7% CO2 test, took part in the randomised, double-blind, cross-over, incomplete block design study. After receiving treatment or placebo, the volunteers were subjected to three 7% CO2 challenges each for a time of 20 min. The treatment consisted of the administration of the following three active drugs: a single dose of benzodiazepine alprazolam (0.75 mg) and a single dose of the NK1 antagonists vestipitant (GW597599) (15 mg) and vofopitant (GR205171) (25 mg). Anxiety during the challenge was evaluated with Visual Analogue Scale-Anxiety (VAS-A) and with Panic Symptom List (PSL III-R). Respiratory parameters, heart rate and skin conductance were also recorded. Compared with placebo, vestipitant showed a significant reduction (p<0.05) in anxiety assessed on the VAS-A scale (ΔVAS-A%) while alprazolam significantly (p<0.01) attenuated the PSL III-R total score. Vofopitant did not show any anxiolytic effect. In the comparison analysis between placebo and drugs, none of the respiratory and other physiological parameters showed a statistically significant difference.

Topics: Adult; Alprazolam; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Benzodiazepines; Carbon Dioxide; Cross-Over Studies; Double-Blind Method; Fluorobenzenes; Heart Rate; Humans; Piperidines; Tetrazoles; Young Adult

Rimonabant is a cannabinoid type 1 receptor (CB1) antagonist formerly used to treat obesity, but which was withdrawn from the market in late 2008 because of its association with psychiatric adverse effects such as depression and anxiety. Previously, we showed that a single dose of rimonabant produced a negative bias on an emotional word memory task, in the absence of subjective mood effects. The present study investigated whether a similar effect on emotional processing could be seen after 7 days' daily treatment with rimonabant 20 mg, using a randomized, placebo-controlled, between-subjects design in healthy volunteers (final n = 21). In comparison with placebo, rimonabant induced a negative bias on a memory recognition task without producing a change in subjective mood. This raises the possibility that the depressogenic effects of rimonabant may be linked to emotional memory biases, and that such biases may be detectable in the absence of subjective mood changes. Investigating such effects could be useful in detecting adverse psychiatric effects of novel treatments.

Topics: Adult; Anxiety Disorders; Depression; Emotions; Female; Humans; Male; Memory, Short-Term; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Recognition, Psychology; Rimonabant; Young Adult

The purpose of this study was to assess the anxiolytic effect of MDL 11,939, a selective 5-HT2 receptor antagonist, in patients with generalized anxiety disorder. After a 1-week placebo lead-in period, 72 healthy male outpatients meeting DSM-III-R criteria for generalized anxiety disorder were randomized to MDL 11,939, 32 mg thrice daily (N = 37), or placebo (N = 35) for 6 weeks. At the end of treatment, MDL 11,939 showed a 7.2-point (30%) decrease in Hamilton Rating Scale for Anxiety scores compared with a 5.7-point (23%) decrease with placebo, but the difference was not significant (p > 0.05). The incidence of adverse events between treatments was similar. MDL 11,939 was well tolerated but did not demonstrate significant anxiolytic effects in this pilot study.

Topics: Adult; Anxiety Disorders; Humans; Male; Piperidines; Serotonin Antagonists; Single-Blind Method

Paroxetine is a selective serotonin reuptake inhibitor which is being developed as an antidepressant. Previous studies suggest it is effective in the treatment of depression and has a low incidence of side effects. The authors report on a 6-week, randomized, prospective trial of paroxetine, imipramine, and placebo in 120 outpatients with major depression. The results showed that paroxetine was significantly superior to placebo in relieving depression. There were no significant differences in antidepressant efficacy between paroxetine and imipramine. However, paroxetine was also significantly superior to placebo on several measures of anxiety. Imipramine either was not superior on these measures or took longer to show a significant difference. Paroxetine lacked the typical anticholinergic side effects that accompanied imipramine therapy. The results show that paroxetine is an effective antidepressant that may have value especially when depression is accompanied by significant anxiety.

Topics: Adult; Antidepressive Agents; Anxiety Disorders; Depressive Disorder; Double-Blind Method; Female; Humans; Imipramine; Male; Neurotransmitter Uptake Inhibitors; Paroxetine; Piperidines; Placebos; Prospective Studies

Serotonin (5-HT) and 5-HT receptors are involved in mood disturbances, such as anxiety and depression. Ritanserin is a new substance with highly selective blocking activity on S2 receptors for 5-HT in the central nervous system. Ritanserin, (20 mg daily) and lorazepam (5 mg daily) were administered to 24 patients suffering from generalized anxiety disorders (DSM III), in a double-blind fashion for six weeks. The results obtained showed comparable improvement in almost all patients with both drugs. Future studies should pay particular attention to psychosomatic disturbances, depressed mood and dysthymic-like disorders, in which ritanserin seems to be more efficacious, according to the best responding items of the general anxiety check list used.

Topics: Adolescent; Adult; Aged; Anxiety Disorders; Double-Blind Method; Female; Humans; Lorazepam; Male; Piperidines; Random Allocation; Receptors, Serotonin; Ritanserin; Serotonin Antagonists

A double-blind study was performed in 83 patients with generalized anxiety disorder comparing daily doses of 5 and 10 mg ritanserin (a selective antagonist of serotonine S2 receptors) versus placebo and 4 mg lorazepam as reference drug. Patients treated with 10 mg ritanserin or 4 mg lorazepam improved significantly better (p less than 0.05) after two weeks than those treated with placebo. On the other hand a daily dose of 5 mg ritanserin appeared to be not superior to placebo. Patients treated with 4 mg lorazepam complained significantly more about sedation and dizziness than patients treated with 10 mg ritanserin (p less than 0.05).

Topics: Adult; Anxiety Disorders; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Lorazepam; Male; Piperidines; Psychological Tests; Ritanserin; Serotonin Antagonists

Topics: Adult; Anxiety Disorders; Clinical Trials as Topic; Dioxoles; Evaluation Studies as Topic; Female; Humans; Indoles; Male; Middle Aged; Piperidines; Spiro Compounds; Time Factors; Tranquilizing Agents

Recent studies have demonstrated anxiolytic potential of pharmacological endocannabinoid (eCB) augmentation approaches in a variety of preclinical models. Pharmacological inhibition of endocannabinoid-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), elicit promising anxiolytic effects in rodent models with limited adverse behavioral effects, however, the efficacy of dual FAAH/MAGL inhibition has not been investigated. In the present study, we compared the effects of FAAH (PF-3845), MAGL (JZL184) and dual FAAH/MAGL (JZL195) inhibitors on (1) anxiety-like behaviors under non-stressed and stressed conditions, (2) locomotor activity and body temperature, (3) lipid levels in the brain and (4) cognitive functions. Behavioral analysis showed that PF-3845 or JZL184, but not JZL195, was able to prevent restraint stress-induced anxiety in the light-dark box assay when administered before stress exposure. Moreover, JZL195 treatment was not able to reverse foot shock-induced anxiety-like behavior in the elevated zero maze or light-dark box. JZL195, but not PF-3845 or JZL184, decreased body temperature and increased anxiety-like behavior in the open-field test. Overall, JZL195 did not show anxiolytic efficacy and the effects of JZL184 were more robust than that of PF-3845 in the models examined. These results showed that increasing either endogenous AEA or 2-AG separately produces anti-anxiety effects under stressful conditions but the same effects are not obtained from simultaneously increasing both AEA and 2-AG.

Topics: Amidohydrolases; Animals; Anti-Anxiety Agents; Anxiety Disorders; Behavior, Animal; Benzodioxoles; Body Temperature; Brain; Carbamates; Endocannabinoids; Female; Locomotion; Male; Maze Learning; Mice, Inbred C57BL; Mice, Inbred ICR; Monoacylglycerol Lipases; Piperazines; Piperidines; Pyridines; Stress, Psychological

Social withdrawal should not be considered a direct measure of the negative symptoms of schizophrenia as it may result not only from asociality (primary negative symptom) but also from other altered processes such as anxiety. To understand the contribution of these two factors to social deficit, we investigated whether the social withdrawal observed in the subchronic phencyclidine (PCP) rat model of schizophrenia could be attributed to increased anxiety. Compared to saline controls, PCP-treated rats (5 mg/kg, twice daily for 7 days, followed by a washout period) spent significantly less time in social interaction, but did not show anxiety-like behaviors in different relevant behavioral paradigms. In addition, their social deficit was not affected by a behavioral procedure known to reduce anxiety-like behavior (repeated exposure to the same partner) nor by systemic administration of the classical anxiolytic diazepam. In contrast, PCP-induced social withdrawal was reversed by the cannabinoid agonist CP55,940, a drug with known anxiogenic properties. Furthermore, when using the social approach task, PCP-treated animals performed similarly to control animals treated with diazepam, but not to those treated with the anxiogenic compound pentylenetetrazole. Taken together, our results indicate that PCP-induced social withdrawal cannot be attributed to increased anxiety. These data are discussed in the context of primary versus secondary negative symptoms and the deficit syndrome of schizophrenia.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Behavior, Animal; Cannabinoids; Carbamates; Disease Models, Animal; Exploratory Behavior; Interpersonal Relations; Male; Phencyclidine; Piperidines; Rats; Rats, Wistar; Schizophrenia; Schizophrenic Psychology; Social Behavior

The brain serotonergic system is colocalized and interacts with the neuropeptidergic substance P/neurokinin-1 (SP/NK1) system. Both these neurochemical systems have independently been implicated in stress and anxiety, but interactions between them might be crucial for human anxiety conditions. Here, we examined the serotonin and substance P/neurokinin-1 (SP/NK1) systems individually as well as their overlapping expression in 16 patients with posttraumatic stress disorder (PTSD) and 16 healthy controls. Participants were imaged with the highly selective radiotracers [(11)C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) and [(11)C]GR205171 assessing serotonin transporter (SERT) and NK1 receptor availability, respectively. Voxel-wise analyses in the amygdala, our a priori-defined region of interest, revealed increased number of NK1 receptors, but not SERT in the PTSD group. Symptom severity, as indexed by the Clinician-administered PTSD Scale, was negatively related to SERT availability in the amygdala, and NK1 receptor levels moderated this relationship. Exploratory, voxel-wise whole-brain analyses revealed increased SERT availability in the precentral gyrus and posterior cingulate cortex of PTSD patients. Patients, relative to controls, displayed lower degree of overlapping expression between SERT and NK1 receptors in the putamen, thalamus, insula and lateral orbitofrontal gyrus, lower overlap being associated with higher PTSD symptom severity. Expression overlap also explained more of the symptomatology than did either system individually, underscoring the importance of taking interactions between the neurochemical systems into account. Thus, our results suggest that aberrant serotonergic-SP/NK1 couplings contribute to the pathophysiology of PTSD and, consequently, that normalization of these couplings may be therapeutically important.

Topics: Adult; Amygdala; Aniline Compounds; Anxiety Disorders; Brain; Case-Control Studies; Cerebral Cortex; Female; Humans; Male; Piperidines; Positron-Emission Tomography; Receptors, Neurokinin-1; Serotonin; Serotonin Plasma Membrane Transport Proteins; Stress Disorders, Post-Traumatic; Substance P; Sulfides; Tetrazoles; Transcriptome

Epidemiological data suggest women are at increased risk for developing anxiety and depression, although the mechanisms for this sex/gender difference remain incompletely understood. Pre-clinical studies have begun to investigate sex-dependent emotional learning and behavior in rodents, particularly as it relates to psychopathology; however, information about how gonadal hormones interact with the central nervous system is limited. We observe greater anxiety-like behavior in male mice with global knockout of the cannabinoid 1 receptor (Cnr1) compared to male, wild-type controls as measured by percent open arm entries on an elevated plus maze test. A similar increase in anxiety-like behavior, however, is not observed when comparing female Cnr1 knockouts to female wild-type subjects. Although, ovariectomy in female mice did not reverse this effect, both male and female adult mice with normative development were sensitive to Cnr1 antagonist-mediated increases in anxiety-like behavior. Together, these data support an interaction between sex, potentially mediated by gonadal hormones, and the endocannabinoid system at an early stage of development that is critical for establishing adult anxiety-like behavior.

Topics: Animals; Anxiety Disorders; Cannabinoid Receptor Antagonists; Exploratory Behavior; Female; Male; Mice, Inbred C57BL; Mice, Knockout; Ovariectomy; Piperidines; Psychotropic Drugs; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Sex Characteristics

Excessive fear is a hallmark of several emotional and mental disorders such as phobias and panic disorders. Considerable attention is focused on defining the neurobiological mechanisms of the extinction of conditioned fear memory in an effort to identify mechanisms that may hold clinical significance for remediating aberrant fear memory. Serotonin modulates the acquisition and retention of conditioned emotional memory, and the serotonin 2A receptor (5HT2AR) may be one of the postsynaptic targets mediating such effects. Here we tested the hypothesis that the 5HT2AR regulates the consolidation and extinction of fear memory in male C57BL/6J mice. The influence of 5HT2ARs on memory consolidation was further confirmed with a novel object recognition task. With a trace fear conditioning paradigm, administration of the 5HT2AR agonist TCB-2 (1.0 mg/kg, i.p.) before the extinction test facilitated the acquisition of extinction of fear memory as compared to vehicle treatment. In contrast, administration of the 5HT2AR antagonist MDL 11,939 (0.5 mg/kg, i.p.) delayed the acquisition of extinction of fear memory. Further, the post-conditioning administration of TCB-2 enhanced contextual and cued fear memory, possibly by facilitating the consolidation of fear memory. Administration of TCB-2 also facilitated the acquisition of extinction of fear memory in delay fear conditioned mice. Stimulation or blockade of 5HT2ARs did not affect the encoding or retrieval of conditioned fear memory. Finally, administration of TCB-2 right after training in an object recognition task enhanced the consolidation of object memory. These results suggest that stimulation of 5HT2ARs facilitates the consolidation and extinction of trace and delay cued fear memory and the consolidation of object memory. Blocking the 5HT2AR impairs the acquisition of fear memory extinction. The results support the view that serotonergic activation of the 5HT2AR provides an important modulatory influence on circuits engaged during extinction learning. Taken together these results suggest that the 5HT2AR may be a potential therapeutic target for enhancing hippocampal and amygdala-dependent memory. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Bridged Bicyclo Compounds; Cues; Extinction, Psychological; Fear; Male; Memory; Memory, Episodic; Methylamines; Mice; Mice, Inbred C57BL; Molecular Targeted Therapy; Nerve Tissue Proteins; Nootropic Agents; Piperidines; Receptor, Serotonin, 5-HT2A; Recognition, Psychology; Reinforcement, Psychology; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists

Cannabinoids have long been shown to have a range of potential therapeutic effects, including antiemetic actions, analgesia, and anxiolysis. However, psychomimetic and memory disruptive side effects, as well as the potential for abuse and dependence, have restricted their clinical development. Endogenous cannabinoids (i.e., endocannabinoids; eCBs), such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are produced throughout the limbic system and other brain regions associated with emotionality and are believed to modulate behavioral responses to stress-related conditions. AEA and 2-AG are rapidly metabolized by the respective enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Accordingly, inhibition of each enzyme increases brain levels of the appropriate eCB. Although FAAH inhibition has been established to decrease anxiety-like behavior, the role of 2-AG has been difficult to ascertain until the recent synthesis of JZL184, a potent and selective MAGL inhibitor. In the present study, we investigated the effects of inhibiting FAAH or MAGL on anxiety-like behavior in marble burying, a model of repetitive, compulsive behaviors germane to anxiety disorders such as obsessive-compulsive disorder. The FAAH inhibitor PF-3845, the MAGL inhibitor JZL184, and the benzodiazepine diazepam decreased marble burying at doses that did not affect locomotor activity. In contrast, Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of marijuana, did not consistently reduce marble burying without also eliciting profound decreases in locomotor behavior. The CB1 cannabinoid receptor antagonist rimonabant blocked the reduction in marble burying caused by FAAH and MAGL inhibitors, but not by diazepam, indicating a CB1 receptor mechanism of action. These data indicate that elevation of AEA or 2-AG reduces marble burying behavior and suggest that their catabolic enzymes represent potential targets for the development of new classes of pharmacotherapeutics to treat anxiety-related disorders.

Topics: Amidohydrolases; Animals; Anti-Anxiety Agents; Anxiety Disorders; Benzodioxoles; Cannabinoid Receptor Modulators; Diazepam; Disease Models, Animal; Dronabinol; Endocannabinoids; Enzyme Inhibitors; Male; Mice; Mice, Inbred C57BL; Monoacylglycerol Lipases; Obsessive-Compulsive Disorder; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

The propensity to develop an anxiety disorder is thought to be determined by genetic and environmental factors. Here we investigated the relationship between a genetic predisposition to trait anxiety and experience-based learned fear in a psychopathological mouse model. Male CD-1 mice selectively bred for either high (HAB), or normal (NAB) anxiety-related behaviour on the elevated plus maze were subjected to classical fear conditioning. During conditioning both mouse lines showed increased fear responses as assessed by freezing behaviour. However, 24 h later, HAB mice displayed more pronounced conditioned responses to both a contextual or cued stimulus when compared with NAB mice. Interestingly, 6 h and already 1 h after fear conditioning, freezing levels were high in HAB mice but not in NAB mice. These results suggest that trait anxiety determines stronger fear memory and/or a weaker ability to inhibit fear responses in the HAB line. The enhanced fear response of HAB mice was attenuated by treatment with either the α(2,3,5)-subunit selective benzodiazepine partial agonist L-838,417, corticosterone or the selective neurokinin-1 receptor antagonist L-822,429. Overall, the HAB mouse line may represent an interesting model (i) for identifying biological factors underlying misguided conditioned fear responses and (ii) for studying novel anxiolytic pharmacotherapies for patients with fear-associated disorders, including post-traumatic stress disorder and phobias.

Topics: Animals; Anti-Anxiety Agents; Anxiety Disorders; Behavior, Animal; Corticosterone; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Expressed Emotion; Fear; Fluorobenzenes; Male; Mice; Neurokinin-1 Receptor Antagonists; Phobic Disorders; Physical Conditioning, Animal; Piperidines; Psychopathology; Triazoles; Up-Regulation

The amino-terminal pro-brain natriuretic peptide (NT-proBNP) is released into the plasma predominantly from ventricular cardiomyocytes, particularly in patients with chronic cardiac diseases, although small amounts are detectable in the plasma of healthy subjects. While NT-proBNP has been widely exploited in human medicine, limited literature is available related to its characterization in veterinary medicine (e.g., correlation with damage and specificity) and, particularly, in the context of preclinical drug safety assessment. This paper describes the analytical performance characteristics and the biological variability of NT-proBNP in male beagle dogs by using a commercially available enzyme-linked immunosorbent assay. Male beagle dogs were treated with Casopitant, an NK1 receptor antagonist under development for depression and anxiety, which, when administered chronically to dogs, caused cardiac toxicity. Heart weight increase, myocardial necrosis, degeneration, and inflammation associated with high serum levels of cardiac troponin I characterized the end stage pathology observed in dogs treated orally at 40 mg/kg for 39 weeks. Based on these data, ad hoc studies were designed in order to evaluate the possible relationship between NT-proBNP serum levels and both standard toxicology endpoints, such as the organ weight and histology, as well as nonstandard endpoints such as macroscopic morphometry and echocardiography. Early changes of NT-proBNP serum levels were observed following 2 weeks of treatment onward, preceding most, if not all of the anatomical and functional changes. The results obtained demonstrate that NT-proBNP acts as an early biomarker of cardiac changes, representing a sensitive and predictive marker of drug-induced cardiac liability.

Topics: Administration, Oral; Animals; Antidepressive Agents; Anxiety Disorders; Biomarkers; Depression; Dogs; Drug Administration Schedule; Echocardiography; Enzyme-Linked Immunosorbent Assay; Heart Diseases; Humans; Male; Natriuretic Peptide, Brain; Neurokinin-1 Receptor Antagonists; Organ Size; Peptide Fragments; Piperazines; Piperidines; Predictive Value of Tests; Risk Factors; Troponin I

Chronic stress is the primary environmental risk factor for the development and exacerbation of affective disorders, thus understanding the neuroadaptations that occur in response to stress is a critical step in the development of novel therapeutics for depressive and anxiety disorders. Brain endocannabinoid (eCB) signaling is known to modulate emotional behavior and stress responses, and levels of the eCB 2-arachidonoylglycerol (2-AG) are elevated in response to chronic homotypic stress exposure. However, the role of 2-AG in the synaptic and behavioral adaptations to chronic stress is poorly understood. Here, we show that stress-induced development of anxiety-like behavior is paralleled by a transient appearance of low-frequency stimulation-induced, 2-AG-mediated long-term depression at GABAergic synapses in the basolateral amygdala, a key region involved in motivation, affective regulation, and emotional learning. This enhancement of 2-AG signaling is mediated, in part, via downregulation of the primary 2-AG-degrading enzyme monoacylglycerol lipase (MAGL). Acute in vivo inhibition of MAGL had little effect on anxiety-related behaviors. However, chronic stress-induced anxiety-like behavior and emergence of long-term depression of GABAergic transmission was prevented by chronic MAGL inhibition, likely via an occlusive mechanism. These data indicate that chronic stress reversibly gates eCB synaptic plasticity at inhibitory synapses in the amygdala, and in vivo augmentation of 2-AG levels prevents both behavioral and synaptic adaptations to chronic stress.

Topics: Adaptation, Psychological; Amygdala; Animals; Anxiety Disorders; Arachidonic Acids; Benzodioxoles; Cannabinoid Receptor Modulators; Chronic Disease; Disease Models, Animal; Endocannabinoids; Glycerides; Male; Mice; Mice, Inbred ICR; Monoacylglycerol Lipases; Organ Culture Techniques; Piperidines; Stress, Psychological

We investigated the mechanism underlying the anxiolytic actions of the neuropeptide nociceptin/orphanin FQ (N/OFQ) using the elevated plus-maze test and T-maze test. Microinfusions of N/OFQ (10 or 32pmol) into the central amygdala (ACE) increased the time spent in the open arms of the elevated plus-maze (anxiolytic-like effects), whereas microinfusions of N/OFQ (10, 32 or 100 pmol) into the basolateral amygdala (ABL) did not affect the time spent in the open arms. Moreover, microinfusions of N/OFQ (32 pmol) into the ACE impaired escape performance from the open arms of the elevated T-maze (anxiolytic-like effects), but did not change inhibitory avoidance of the open arms. A non-peptidyl N/OFQ receptor (NOP) antagonist, J-113397(1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one) (10 mg/kg, s.c.), blocked the anxiolytic-like effects induced by N/OFQ. These results indicate that the anxiolytic-like effects of N/OFQ might be due to impaired escape performance from the open arms and it implicates the N/OFQ system within the ACE in the mediation of panic action.

Topics: Amygdala; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Benzimidazoles; Male; Maze Learning; Microinjections; Nociceptin; Opioid Peptides; Piperidines; Rats; Rats, Sprague-Dawley; Vasodilator Agents

Preclinical and clinical research shows that the cannabinoid brain receptor type 1 (CB(1)) modulates alcohol- and nicotine-related behaviors. Throughout the nicotine-induced relapse to alcohol, the rats were pre-treated for 10 days with the CB(1) cannabinoid receptor antagonist rimonabant (0, 0.03, 0.3 and 3.0 mg/kg i.p.). In this condition, a long-lasting nicotine-induced relapse to alcohol was observed, and this effect was reversed in a dose-dependent manner with rimonabant. Surprisingly, rats that were not exposed to nicotine developed tolerance to the effects of rimonabant from the sixth day. Also, 3.0 mg/kg of rimonabant reduced the responses for sucrose. Evaluation in the Elevated Plus-Maze after nicotine treatment did not reveal anxiogenic effects. Finally, at the conclusion of rimonabant treatment, a rapid reinstatement of alcohol consumption was detected. These results suggest that rimonabant can prevent the relapse to alcohol, even when an interaction with nicotine exists-the most frequent situation in human alcohol abuse.

Topics: Alcohol-Induced Disorders, Nervous System; Alcoholism; Animals; Anxiety Disorders; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Synergism; Male; Maze Learning; Nicotine; Nicotinic Agonists; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Reinforcement, Psychology; Rimonabant; Secondary Prevention; Substance Withdrawal Syndrome; Sucrose

Preclinically, the combination of an SSRI and 5-HT autoreceptor antagonist has been shown to reduce the time to onset of anxiolytic activity compared to an SSRI alone. In accordance with this, clinical data suggest the coadministration of an SSRI and (+/-) pindolol can decrease the time to onset of anxiolytic/antidepressant activity. Thus, the dual-acting novel SSRI and 5-HT(1A/B) receptor antagonist, SB-649915-B, has been assessed in acute and chronic preclinical models of anxiolysis. SB-649915-B (0.1-1.0 mg/kg, i.p.) significantly reduced ultrasonic vocalization in male rat pups separated from their mothers (ED(50) of 0.17 mg/kg). In the marmoset human threat test SB-649915-B (3.0 and 10 mg/kg, s.c.) significantly reduced the number of postures with no effect on locomotion. In the rat high light social interaction (SI), SB-649915-B (1.0-7.5 mg/kg, t.i.d.) and paroxetine (3.0 mg/kg, once daily) were orally administered for 4, 7, and 21 days. Ex vivo inhibition of [(3)H]5-HT uptake was also measured following SI. SB-649915-B and paroxetine had no effect on SI after 4 days. In contrast to paroxetine, SB-649915-B (1.0 and 3.0 mg/kg, p.o., t.i.d.) significantly (p<0.05) increased SI time with no effect on locomotion, indicative of an anxiolytic-like profile on day 7. Anxiolysis was maintained after chronic (21 days) administration by which time paroxetine also increased SI significantly. 5-HT uptake was inhibited by SB-649915-B at all time points to a similar magnitude as that seen with paroxetine. In conclusion, SB-649915-B is acutely anxiolytic and reduces the latency to onset of anxiolytic behavior compared to paroxetine in the SI model.

Topics: Animals; Anti-Anxiety Agents; Anxiety Disorders; Behavior, Animal; Benzoxazines; Brain; Callithrix; Drug Synergism; Male; Motor Activity; Paroxetine; Piperidines; Quinolines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptor, Serotonin, 5-HT1A; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin Antagonists; Social Behavior; Vocalization, Animal

The endocannabinoids anandamide and 2-arachidonoyglycerol (2-AG) may contribute to the regulation of mood and emotion. In this study, we investigated the impact of the endocannabinoid transport inhibitor AM404 on three rat models of anxiety: elevated plus maze, defensive withdrawal and separation-induced ultrasonic vocalizations. AM404 (1-5 mg kg(-1), intraperitoneal (i.p.)) exerted dose-dependent anxiolytic-like effects in the three models. These behavioral effects were associated with increased levels of anandamide, but not 2-AG, in the prefrontal cortex and were prevented by the CB(1) cannabinoid antagonist rimonabant (SR141716A), suggesting that they were dependent on anandamide-mediated activation of CB(1) cannabinoid receptors. We also evaluated whether AM404 might influence motivation (in the conditioned place preference (CPP) test), sensory reactivity (acoustic startle reflex) and sensorimotor gating (prepulse inhibition (PPI) of the startle reflex). In the CPP test, AM404 (1.25-10 mg kg(-1), i.p.) elicited rewarding effects in rats housed under enriched conditions, but not in rats kept in standard cages. Moreover, AM404 did not alter reactivity to sensory stimuli or cause overt perceptual distortion, as suggested by its lack of effect on startle or PPI of startle. These results support a role of anandamide in the regulation of emotion and point to the anandamide transport system as a potential target for anxiolytic drugs.

Topics: Animals; Animals, Newborn; Anti-Anxiety Agents; Anxiety Disorders; Anxiety, Separation; Arachidonic Acids; Behavior, Animal; Brain; Cannabinoid Receptor Modulators; Carrier Proteins; Disease Models, Animal; Endocannabinoids; Male; Maze Learning; Neural Inhibition; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Cannabinoid, CB1; Reflex, Startle; Rimonabant

We present a case of anesthesia for electroconvulsive (ECT) therapy that was complicated by emetic sensitivity to etomidate, fragile ictal threshold, and mild pseudocholinesterase deficiency. The anesthetic was designed in this patient taking all his issues in consideration. The mild pseudocholinesterase deficiency necessitated a (50-75%) reduction in succinylcholine dosage, careful monitoring of the train of four, and postictal amnestic coverage to prevent paralysis upon waking. The significant emetic response to etomidate prompted substitution to propofol and preemptive ondansetron. Propofol significantly raised the ictal threshold but significantly reduced the postprocedural emesis. Eventually, this clinical challenge was resolved with adjunctive use of low-dose etomidate and remifentanil. This combination preserved the ictal parameters, providing patient comfort, good clinical response, and therapeutic efficacy. Although seizure duration and quality often are restored with hyperventilation and caffeine, this case necessitated a return to etomidate for the restoration of satisfactory ictal parameters. Although this effect of remifentanil has been described with methohexital, and etomidate with alfentanil, to the best of our knowledge, this is the first reported case of adjunctive remifentanil with etomidate for preserving ictal threshold. The outpatient course of ECT was thus completed with all psychiatric and anesthetic goals satisfied: adequate seizure quality and duration, no paralysis upon waking, no post-ECT nausea and vomiting, and patient satisfaction. Anesthesiologists should be aware of factors influencing the seizure duration and, keeping in mind the coexisting medical conditions of the patient, adjustments should be made to get the best possible outcome.

Topics: Adult; Alcoholism; Anesthesia; Anesthetics, Intravenous; Anxiety Disorders; Bipolar Disorder; Differential Threshold; Electroconvulsive Therapy; Etomidate; Humans; Male; Piperidines; Remifentanil

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Anxiety Disorders; Butyrophenones; Female; Humans; Male; Middle Aged; Piperidines; Psychotic Disorders; Schizophrenia

Topics: 1-Propanol; Adjustment Disorders; Adult; Aged; Antidepressive Agents; Antiparkinson Agents; Anxiety Disorders; Basal Ganglia Diseases; Biperiden; Bipolar Disorder; Delayed-Action Preparations; Depression; Depressive Disorder, Major; Female; Humans; Mental Disorders; Middle Aged; Paranoid Disorders; Piperidines; Schizophrenia, Disorganized; Tranquilizing Agents; Tremor

Topics: Adolescent; Adult; Aged; Anxiety Disorders; Female; Humans; Middle Aged; Phenothiazines; Piperidines; Psychotic Disorders; Tranquilizing Agents

Topics: Adult; Aged; Anxiety Disorders; Biliary Tract Diseases; Cardiovascular Diseases; Depression; Dysautonomia, Familial; Female; Gastrointestinal Diseases; Humans; Hypertension; Lung Diseases; Male; Middle Aged; Neoplasms; Piperidines; Tranquilizing Agents

Topics: Antisocial Personality Disorder; Anxiety; Anxiety Disorders; Atropine; Bipolar Disorder; Depression; Drug Combinations; Drug Therapy; Electroencephalography; Glycolates; Hallucinogens; Mental Disorders; Piperidines; Psychoses, Alcoholic; Psychotic Disorders; Pyrrolidines; Schizophrenia; Toxicology

Topics: Aged; Anxiety; Anxiety Disorders; Disease; Humans; Piperidines; Psychomotor Agitation; Reserpine