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Lysergic acid diethylamide (LSD), described as a classical hallucinogen, began its journey from the middle of the last century following an accidental discovery. Since then, it was used as a popular and notorious substance of abuse in various parts of the world. Its beneficial role as an adjunct to psychotherapy was much unknown, until some ‘benevolent’ experiments were carried out over time to explore some of its potential uses. But, many of its effects were unclear and seemed to be a psychedelic enigma. In this review article, we have described the receptor pharmacology, mechanism of action, effects and adverse effects of LSD on the normal body system. We have also highlighted its addictive potentials and the chances of developing tolerance. We have assimilated some of the interesting therapeutic uses of this drug, such as an antianxiety agent, a creativity enhancer, a suggestibility enhancer, and a performance enhancer. We have also described LSD to be successfully used in drug and alcohol dependence, and as a part of psychedelic peak therapy in terminally ill patients. The relevant chronological history and literature in the light of present knowledge and scenarios have been discussed. Based on available evidence, LSD could be tried therapeutically in certain specific conditions under controlled settings. But as we mention, due to all the safety concerns, the use of this nonaddictive ‘entheogen’ in actual practice warrants a lot of expertise, caution, cooperation and ethical considerations.

A ruthenium-catalyzed reductive amination without an external hydrogen source has been developed using carbon monoxide as the reductant and ruthenium(III) chloride (0.008-2 mol %) as the catalyst. The method was applied to the synthesis of antianxiety agent ladasten.

OBJECTIVE To explore the association between the initial 60 days of prescriptions for psychotropic medications and final workers' compensation claim outcomes. METHODS A cohort of 11,394 claimants involved in lost time injuries between 1999 and 2002 were followed through December 31, 2009. Logistic regressions and Cox Proportional Hazard Models were used in the analysis. RESULTS The initial 60 days of prescriptions for psychotropic medications were significantly associated with a final claim cost at least $100,000. Odds ratios were 1.88 for short-acting opioids, 2.14 for hypnotics, antianxiety agents, or antidepressants, and 3.91 for long-acting opioids, respectively. Significant associations were also found between decreased time lost from work and decreased claim closures during the study period. CONCLUSIONS Early prescription of opioids and other psychotropic drugs may be useful predictors of high claim costs and time lost from work.

A ruthenium-catalyzed reductive amination without an external hydrogen source has been developed using carbon monoxide as the reductant and ruthenium(III) chloride (0.008–2 mol %) as the catalyst. The method was applied to the synthesis of antianxiety agent ladasten.

Anxiolytic effects induced by benzalphthalides on mice have been evaluated. The evaluation was based on the spent time and the number of entries of animals into the open arms in the elevated plus maze test. Single administration of benzalphthalides 1 and 11 induced significant increments in both parameters, thus revealing their potentiality as new leads for the development of non-benzodiazepinic and non-nitrogenated antianxiety agents.

In spite of the wide variety of drugs available for treating anxiety, this disorder continues to represent a worldwide health problem that is classified within the first 10 causes of disability. Therefore, the search continues for new antianxiety agents, particularly those not related to benzodiazepines. Even though melatonin has been prescribed as an anxiolytic drug, its use is currently limited due to its short half-life and photo-sensitivity, among other disadvantages. The present study explores the antianxiety properties of a new 1-N substituted melatonin analog, M3C, in pinealectomized rats submitted to two behavioral tests (the cumulative burying behavior paradigm and the elevated plus-maze). Results from both tests show that M3C is effective as an anxiolytic-like agent, at doses lower than any other melatonin analog previously reported. The blocking of these actions by luzindole together with the available data suggests that the anxiolytic properties of M3C are mediated by MT1 and MT2 receptors.

Recent clinical research strongly suggests that there is a period of elevated risk of morbidity in the several months following abrupt discontinuation or reduction of doses in maintenance treatments commonly used in the contemporary management of chronic or recurring major psychiatric disorders. This risk is best quantified for the discontinuation of lithium therapy in bipolar disorders, in which risk of mania, depression, and suicidal behavior may rise. Similar symptomatic risks are well known after stopping antianxiety agents, and probably also follow rapid removal of oral neuroleptics in schizophenia and antidepressants in major depression. Morbid risk probably can be limited by slowing the rate of removal of medication. Such responses probably reflect interactions of individual illness diatheses with physiological adaptations to long-term drug treatments. The findings appear to have broad scientific, clinical, and ethical implications for clinical pharmacology in psychiatry as well as in general medicine.

Lysergic acid diethylamide (LSD), is a classical hallucinogen, discovered accidentally in the middle century. It is a psychedelic drug used to treat drug abuse as it shows limited efficacy, leaving severe and persistent effects in treated patients. Preliminary studies in animals and clinical trials suggest that lysergic acid diethylamide may have anti-depressive, anxiolytic, hallucinogenic and anti-addictive properties. LSD is used as a popular and notorious substance of abuse in various parts of the world. It has an important use as an adjunct to psychotherapy. But, some severe effects were unclear and seemed to be a psychedelic enigma. In this review article, we have focused on the history, receptor pharmacology, chemistry, mechanism of action, pharmacology, applications and adverse effects of LSD on the normal human body system. We have also described its acid trip effect, addictive potentials and the chances of developing its tolerance. LSD is used in many treatments like antianxiety agent, a creativity enhancer, a performance enhancer. It is also used in drug and alcohol dependence, as a part of psychedelic therapy and recently in the therapy of Alzheimer’s disease.

Schizophrenia is believed to arise from an interaction of genetic predisposition and adverse environmental factors, with stress being a primary variable. We propose that alleviating anxiety produced in response to stress during a sensitive developmental period may circumvent the dopamine (DA) system alterations that may correspond to psychosis in adults. This was tested in a developmental rat model of schizophrenia based on prenatal administration of the mitotoxin methyl azoxymethanol acetate (MAM). MAM administration leads to a hyperdopaminergic state consisting of an increase in the number of DA neurons firing spontaneously, which correlates with an increased behavioral response to amphetamine. MAM-treated rats exhibited a heightened level of anxiety during adolescence. Peripubertal administration of the antianxiety agent diazepam was found to prevent the increase in DA neuron activity and blunt the behavioral hyperresponsivity to amphetamine in these rats. These data suggest that the pathophysiological factors leading to the onset of psychosis in early adulthood may be circumvented by controlling the response to stress during the peripubertal period.

The complex title of this chapter reflects several basic points about this important class of medicines. They are now the most widely used psychotropic drugs, and even more in general medicine than in psychiatry [171, 384, 576]. Their origins in the 1950s were aimed specifically at a relatively complex group of depressive disorders prior to consolidation and broad acceptance of the concept “major depressive disorder.” Over the past half-century, indications for the use of these nominally “antidepressant” drugs have broadened extraordinarily. Some agents in this category, old and new, could well have been developed primarily as antianxiety agents. Indeed some that are used internationally as antidepressants are approved by the US FDA only for anxiety disorders (e.g., fluvoxamine and milnacipran). The broad use of such drugs includes various types of clinical depression, anxiety-associated disorders, attention disorders, some pain syndromes, and even urinary incontinence.

The purpose of the grant is to test whether exogenous oxytocin acts as an antianxiety agent and whether social support facilitates its antianxiety effects in a fear-potentiated startle paradigm. Oxytocin given systemically (0.1 micrograms/kg, sc) effectively reduced background anxiety, but not specific cue-potentiated fear. This was found when oxytocin was given either before fear conditioning (acquisition), immediately after fear conditioning (consolidation), or before retrieval/expression of conditioned fear-potentiated startle. Social isolation for 3 weeks potentiated startle; this was reversed by oxytocin. Intracerebroventricular infusion of oxytocin only reduced background anxiety with a very large dose (20 micrograms), suggesting indirect action in brain. It is concluded that oxytocin has unique antianxiety properties that reduce background and social-isolation anxiety -- anxiety states not directly related to cue-specific fear, but are sustained beyond the immediate threat. Oxytocin might be promising as a drug with novel benefits for patients with PTSD.

A scientific information base is developing which focuses on understanding and managing behavior problems in geriatric populations, especially those with dementing illnesses such as Alzheimer's disease. Many of these behavior problems occur in long-term care settings, which have a high prevalence of residents exhibiting emotional and behavioral disorders, often secondary to psychiatric illness. Prior to beginning treatment, behavior disorders must be systematically evaluated and understood to insure optimum care planning. One approach to effectively treating these disorders is to first separate them into two categories: those not amenable to psychotherapeutic medication treatment (nonpsychiatric disorders) and those that are amenable (psychiatric disorders). Specific nonpharmacological treatments may benefit those nonpsychiatric behavioral disorders and include behavioral and environmental paradigms. The psychiatric disorders, especially aggression and assaultive behavior, may be treated beneficially using a variety of psychopharmacological agents, including antianxiety agents, neuroleptics, carbamazapine, ß-blockers, and lithium. The most effective approach toward treating the psychiatric behavior disorders often combines both medication and nonmedication strategies.

SUMMARY Individualization of treatment for patients with IBS is predicated on a thorough analysis of the patient's symptoms, consideration of the reasons for seeking health care, evaluation of symptom-precipitating factors, elimination of confounding features, and the absolute knowledge of the absence of organic illness. Collecting and codifying appropriate historical data allow the physician to educate the patient with respect to the origin of his symptoms, and to enlist the patient as a partner in his future health care. There is no single, universally accepted therapeutic agent available for the treatment of the IBS patient. As a result, treatment is directed at reducing the frequency and intensity of triggering factors as well as ameliorating the symptoms when they arise. Symptoms evoked by psychologic factors may be effectively reduced by psychotherapy or hypnotherapy. Situational anxiety may be treated for brief periods by using antianxiety agents such as diazepam, chlordiazepoxide, buspirone, or similar agents. Depressive reactions may be reduced with suitable doses of antidepressant agents such as amitriptyline. Smooth muscle hyperreactivity may be dulled with small amounts of selected anticholinergics, which are usually most effective in reducing mealinduced discomfort. Peppermint oil may be of additional benefit. Gas-related symptoms require elimination of contributory dietary factors, such as lactose-containing foods, sorbitol, or fructose, as well as certain oligosaccharides. Simethecone, charcoal, or beanase may be helpful. Functional constipation is best treated with graded doses of insoluble or soluble fiber. Diarrheal episodes may be reduced with either loperamide or diphenoxylate. Careful, continued follow-up assessment of therapeutic endeavors, a sincere interest in the patient's concerns, and surveillance for intercurrent organic illness are the cornerstones of complete ongoing care.

The advisability of continuing breastfeeding is an important issue for women with postpartum depression or psychosis. A review of the literature on psychotropic drugs in breast milk is presented. All of the major classes of psychotropic drugs (antidepressants, antipsychotics, antianxiety agents, lithium, hypnotics) have been shown to pass into breast milk following maternal ingestion. Generally, the doses to which children are exposed from breast milk, calculated from measured milk/plasma ratios, are small. Nevertheless most authors err on the side of caution and suggest that breastfeeding be avoided. There is inadequate research on the excretion of drugs into breast milk and the effects on the infant.

Although the Defensive Burying paradigm has been used as a behavioral “model” for the study of anxiety and/or antianxiety agents, the effects of chronic treatment with antidepressant agents (i.e., “antipanic” agents) have not been examined in this paradigm. The present study examined the effects of two antianxiety treatments on this behavior: 1) acute treatment (30-minute pretreatment) with the benzodiazepine anxiolytic chlordiazepoxide and 2) chronic treatment (twice daily for 7–12 weeks) with the antipanic agents imipramine (IMI), desipramine (DMI) or pargyline (PARG). Prior to testing, female Sprague-Dawley rats were placed in a 40 × 30 × 40 cm Plexiglas® chamber containing clay bedding material (5 cm deep) for 30-minute periods on each of four consecutive days. On the fifth day, a wire-wrapped prod was placed at one end of the chamber. Rats were placed in the chamber individually and a 3 mA shock was delivered upon contact with the prod. Defensive Burying behavior (i.e., the moving of bedding material toward or over the prod) was recorded for 15 minutes postshock. In a dose-dependent manner, acute treatment with chlordiazepoxide reduced the frequency of occurrence of burying behavior, increased the latency to initiation of burying, and decreased the duration of burying. In contrast, chronic treatment with IMI, DMI, or PARG failed to exhibit anxiolytic-like effects on any measure of Defensive Burying. These data suggest that the Defensive Burying paradigm may not be an “animal model” for the study of panic disorder and potential antipanic agents.

Previously, with the administration of antidepressant drugs, it has been demonstrated that the rat model of clinical depression, known as the reduction of submissive behavior model (RSBM), has considerable validity. The present study is an attempt to extend the model to mice. Several antidepressant drugs as well as a number of non-antidepressant agents were administered to mice that had been identified as submissive in a behavioral testing situation. Imipramine, desipramine, amoxapine and fluoxetine, representing three different classes of antidepressant drugs, were each able to increase competitive behavior in submissive mice and to decrease the dominance level between dominant and submissive mice in the behavioral tests. The stimulant amphetamine also reduced submissive behavior while yohimbine (also a stimulant), and the antianxiety agent diazepam had no such effect. The neuroleptic drug thiothixen had antidepressant-like effect on submissive C57BL/6J mice behavior. We conclude that like the rat model of depression from which it was developed, the mouse model responds to various antidepressants as predicted and thus may serve as a potential model of clinical depression.

Objective: This study examined the relationship between reduced anxiety level by therapeutic interventions and cell-mediated immunity (CMI) in patients with panic disorder. Methods: The subjects consisted of 42 patients with panic disorder and 42 normal gender- and age-matched controls. Among the patients, 21 were randomly assigned to a combined treatment of cognitive-behavioral therapy and the benzodiazepine antianxiety agent ethyl loflazepate (2 mg daily), and 21 were assigned to the antianxiety agent only. The treatment lasted for 6 weeks. Cell-mediated immune function was measured by the lymphocyte proliferative response to phytohemagglutinin (PHA) and interleukin-2 (IL-2) production. The anxiety level was assessed by the Hamilton Rating Scale for Anxiety and the anxiety subscale of the Symptom Checklist-90 Revised. Results: Prior to treatment, the panic disorder patients had significantly lower IL-2 production and blastogenic response to PHA than the normal controls. However, no significant differences in CMI were found between the pretreatment and posttreatment period in either the patient group receiving medication only or the combined treatment group, though after treatment, patients were significantly less anxious than before treatment in both intervention groups. The delta change (posttreatment value minus pretreatment value) in the self-reported anxiety level was significantly associated with the delta change in the blastogenic response in the combined treatment group. Conclusion: These findings suggest that panic disorder may be associated with decreased CMI, and the reduced level of self-reported anxiety in the patients who underwent combined therapeutic intervention is likely to increase the blastogenic response. Further studies are needed to evaluate the long-term effects of treatment on immune function.

Currently, 28% of U.S. adults smoke, and this percentage is declining by 0.5% per year; however, this rate of decline must double if the goal in Healthy People 2000 (smoking prevalence of no more than 15% among adults) is to be reached. To help decrease physiological barriers to smoking cessation, numerous pharmacological approaches have been used. I review the effec¬tiveness of these approaches, including interventions reported in the relatively older literature as well as more recent approaches, such as nicotine replacement, Clonidine, antianxiety agents, and antidepressants. I also discuss the results and design of clinical trials.

Anxiety disorders are common among patients with bipolar disorder. Bipolar patients with anxiety disorders have poorer treatment outcomes, greater numbers of suicide attempts, higher rates of substance abuse and lower quality of life.1 Complicating treatment, standard antianxiety agents, such as antidepressants, may worsen the course of bipolar disorder, and there is conflicting evidence about antipsychotics. Some data support the use of quetiapine2 or olanzapine for the treatment of bipolar anxiety, while one trial found risperidone to be ineffective.3

A 71-year-old woman with depression had been treated with an antidepressant (maprotiline) and antianxiety agents (clotiazepam and alprazolam). She had previously complained of ocular pain and blurred vision. However, thorough ocular examination was not performed at those times. On examination, visual acuity was no light perception OD and hand motion OS. Intraocular pressures were 33 mm Hg OU. Moderately dilated pupils, atrophic irises, shallow anterior chambers and closed angles were seen in both eyes. Despite treatment, her visual acuity decreased to no light perception bilaterally. Psychiatrists and ophthalmologists should be aware that antidepressants and antianxiety agents can precipitate angle closure glaucoma in susceptible eyes.

Objective: To review the efficacy of anxiolytics (alprazolam and azapirones) in major depressive disorder (MDD) and that of antidepressants in generalized anxiety disorder (GAD), thereby exploring the possible theoretical and clinical implications of this efficacy. Method: A Medline literature search was performed for the period January 1980 to September 1997 of randomized, double-blind comparison studies between anxiolytics and antidepressants in the acute treatment of adult patients with either MDD or GAD. Results: Alprazolam, at doses double those generally recommended for anxiety disorders, appears to be as effective as tricyclic antidepressants (TCAs) in the acute treatment of mild to moderate MDD. Alprazolam was also found to have a more rapid onset of action than do TCAs, particularly for the improvement of anxiety, somatization, and insomnia. Two azapirones (buspirone andgepirone) also have demonstrated a modest acute antidepressant effect in preliminary studies, albeit only in a depressed outpatient sample with considerable anxiety at baseline. Finally, various antidepressant drugs (imipramine, trazodone, paroxetine) were shown to have, at the least, comparable efficacy to benzodiazepines (BZDs) in the acute treatment of GAD. Conclusions: The nonspecificity of treatment response suggests that GAD and MDD are 1) different expressions of a similar disorder with a common neurobiological substrate, 2) discrete diagnostic entities that respond to independent pharmacological effects of the same drugs, or 3) a combination of the two (heterogeneity hypothesis). The most relevant clinical finding is the efficacy of antidepressants in the acute treatment of GAD.

Gender differences in anxiety have long been assumed to exist, but the experimental evidence is contradictory. It has also been suggested that antianxiety agents may have gender-dependent behavioral effects. The present experiment was designed to establish whether or not intact male and female rats behave differently when exposed to a Differential-Reinforcement of Low-Rate 72-s schedule of reinforcement (assumed to assess some of the inhibitory behavioral tendencies associated with anxiety), and whether or not the behavioral effects of acute chlordiazepoxide administration would differ between the sexes. There were no differences between male and female rats in the total number of responses, the total number of obtained reinforcers, or response efficiency in the absence of drug administration. Male and female Wistar rats were then challenged with different doses of chlordiazepoxide (vehicle, 1, 3, 10, 17, and 30 mg/kg). Low doses of chlordiazepoxide (1 and 3 mg/kg) decreased response efficiency, and medium doses (10 and 17 mg/kg) increased response efficiency in male and female rats. The highest dose of CDP (30 mg/kg) further increased response efficiency in male rats, but decreased response efficiency in female rats. These results suggest that the behavioral effects of chlordiazepoxide are dose dependent and that the effects of a large dose of chlordiazepoxide differ between male and female rats. Whether or not gender differences in drug metabolism or whether schedule contingencies played an important role in these observations remains to be determined in future experiments.

This study investigated the role of maternal behavior on the long-term effects of postnatal manipulation (15 min of daily separation from the dam and exposure to clean bedding from Day 1 to Day 14 of postnatal life) on emotionality in the mouse. Mothers were treated with an antianxiety agent (Chlordiazepoxide: 5 mg/kg), daily upon removal of the litter from the nest. Emotionality in adult offspring was tested in the elevated plus maze. Mice manipulated during postnatal development were more explorative and less anxious than unhandled mice, but this effect was not observable in the offspring of Chlordiazepoxide-treated dams. No effect of maternal Chlordiazepoxide was observed in unhandled offspring. The pharmacological treatment of the mother did not affect either pups' ultrasonic calling during separation, or maternal behavior far apart from the daily manipulation sessions. By contrast, Chlordiazepoxide-treated dams were less responsive toward pups upon reunion following daily separation. This alteration of dams' behavior was not related to alterations in the amount of ultrasonic calls emitted by pups during reunion. Finally, when dams were daily injected with Chlordiazepoxide far apart from pups' removal, the pharmacological treatment was devoid of effects. These results support the view that the mother–infant interaction which follows separation plays a major role in determining the effects of postnatal manipulations on adult emotionality. © 1998 John Wiley & Sons, Inc. Dev Psychobiol 32: 225–234, 1998

Anxiety is a prominent feature of human immunodeficiency virus (HIV)-related psychiatric disorders. Psychiatric disorders are associated with poor drug abuse treatment outcome in both healthy and HIV-infected drug users. While it is important to treat anxiety, the use of traditional antianxiety agents such as benzodiazepines can lead to adverse effects such as sedation and misuse, especially in patients with drug abuse problems. A retrospective chart review was employed to examine the use of buspirone in treating anxiety in intravenous drug users with acquired immune deficiency syndrome (AIDS) or AIDS-related complex who were receiving methadone maintenance treatment. All patients were opiate users, and most were also secondary users of other substances, including stimulants and alcohol. Of 17 patients who were started on buspirone, 14 remained on medication for more than 2 weeks. Of this latter group, all showed at least temporary improvement in one or more of the following areas: subjective reduction of anxiety, reduction of prescribed benzodiazepine use, or reduction in the number of urine tests positive for drugs of abuse, particularly morphine. Buspirone was well tolerated by all but three of these patients; there was no evidence of buspirone misuse. Given its favorable adverse effects profile, buspirone may be particularly useful in the treatment of anxiety in HIV-infected drug users.

With the widespread use of psychotropics in the elderly, issues related to the availability and appropriate use of psychotropic medications in older patients have become a concern from both therapeutic and economic viewpoints. OBJECTIVE: The purpose of this study was to examine the factors predicting potentially inappropriate psychotropic prescribing for the elderly in office-based practice. METHODS: This study utilized data from the National Ambulatory Medical Care Survey (NAMCS) 1995 to examine psychotropic agents that should be generally avoided in the elderly, based on the criteria previously developed through a consensus process. These included diazepam, chlordiazepoxide, meprobamate, flurazepam, pentobarbital, secobarbital, and amitriptyline. Psychotropic drugs considered inappropriate based on an excessive dosage or excessive duration of therapy were not examined due to the limitations of the data source. National visit estimates were derived based on the patient sampling weight provided for the NAMCS. RESULTS: Approximately 2.03 million (95% CI, 1.70–2.36 million) visits by the elderly involved potentially in appropriate psychotropic medications. Only two potentially inappropriate psychotropic medications, secobarbital and pentobarbital, were not prescribed for the elderly by office-based physicians. The remaining five potentially inappropriate medications accounted for 16.85% of the visits involving psychotropic medications, with amitriptyline alone accounting for over 10%. The most frequently prescribed potentially inappropriate psychotropic classes were antidepressants and antianxiety agents. The logistic analysis results revealed that patient characteristics (injury visit), drug characteristics (number of medications and drug classes), and physician characteristics (specialty and region) predict potentially inappropriate psychotropic prescribing. CONCLUSION: The psychotropic prescribing patterns in ambulatory settings raise concerns regarding the quality of care for the elderly with psychiatric illnesses. The predictive factors may be used to design effective educational and regulatory strategies to improve prescribing for the elderly.

Neurology. 2002;59(5 suppl 2):S8-S13. Chronic daily headache (CDH) affects approximately 4 to 5% of the population and encompasses a number of different diagnoses, including transformed migraine, chronic tension-type headache (TTH), new-onset daily persistent headache, and hemicrania continua. Although the pathophysiology of CDH is still poorly understood, some research has suggested that each of the various subtypes of CDH may have a different pathogenesis. The goals of prophylactic therapy are to reduce the frequency, severity, and duration of headache attacks; to improve responsiveness to treatment of acute attacks; to improve function; and to reduce disability. However, opinions differ as to exactly which are the best and most appropriate outcome measures for prophylaxis. Several pharmacologic treatment options exist, including antidepressants, anticonvulsants, muscle relaxants, serotonin agonists, ergots, serotonin antagonists, antianxiety agents, and other miscellaneous drugs. Tizanidine, an alpha(2)-adrenergic agonist, has recently emerged as a promising prophylactic adjunct for CDH, which implicates a central alpha(2)-adrenergic mechanism as an important factor in the pathophysiology of CDH. Comment: Drs. Lake and Saper provide a superb overview of frequent headache, and taken with Dr. Silberstein's article described above, the two reviews constitute the most up-to-date reviews on the subject. SJT

60 anxious neurotic outpatients completed a double-blind comparative 2 week clinical study of the anxiolytic effect of melperone 10 mg t.i.d. and 25 mg t.i.d. versus placebo. The efficacy was assessed by the Hamilton Anxiety Scale and Clinical Global Impressions. At the end of the 1st and the 2nd week of treatment, the reduction in the Hamilton scores was significantly greater in the melperone groups than in the placebo group, but there was no significant difference in the improvement of the two melperone groups. Similar findings were true for the global assessment. The adverse effects recorded were generally mild and transient, tiredness being the most frequent in both the placebo and melperone groups. No laboratory abnormalities were attributable to melperone. A nonsignificant reduction in systolic blood pressure was observed in the melperone groups, probably due to the antianxiety effect. It is concluded that melperone, in low doses, appears to be both safe and effective as an antianxiety agent. The results indicate that melperone could be a realistic alternative to the benzodiazepines.

The efficacy of chlormezanone, an infrequently prescribed minor tranquilizer, was tested in a six-week double-blind trial involving 154 anxious outpatients. The results showed that chlormezanone (800 mg./day) was significantly more effective than placebo and was equal in effectiveness to chlordiazepoxide (40 mg./day). Chlormezanone produced significantly more sedation and more side effects, but no more attrition, than chlordiazepoxide. Furtherstudies confirming these results could establish chlormezanone as a useful antianxiety agent.

Buspirone, a new nonbenzodiazepine anxiolytic agent, was compared with clorazepate in a double-blind, multicenter trial conducted with 336 outpatients who had moderate to severe anxiety. The two treatments were equally effective for relief of symptoms, including anxiety with associated depression. Although both agents were generally well tolerated, the profile of side effects was dissimilar. Drowsiness and depression occurred significantly (p less than 0.055) more frequently with clorazepate, whereas nausea and headache occurred significantly (p less than 0.055) more frequently with buspirone. Clorazepate-treated patients were significantly (p less than 0.055) more likely to have had an adverse experience that was considered drug related or that interfered with the therapeutic effect. In this study, buspirone was shown to be an effective antianxiety agent, causing significantly less sedation than clorazepate.

Stuttering is a speech impediment that has characteristically been resistant to permanent change by means of the usual modes of speech therapy or psychotherapy. The specific etiology of stuttering is unknown, but current theoretical formulations are in terms of learning theory or of an alteration in the auditory feedback system. Previous research has indicated that antianxiety agents and phenothiazines have had no significant benefit for the treatment of stuttering.1,2 Several recent reports, however, suggest that haloperidol, a butyrophenone, may bring about a reduction in the number of dysfluencies. Tapia in 1969 suggested that since haloperidol had proved to be an effective treatment for the Gilles de la Tourette syndrome, which includes both motor tics and an explosive-like speech pattern, it might also be effective in treatment of motor tics alone and stuttering. He obtained good results with patients who had motor tics, but only 2 of his 11 adolescent stutterers improved significantly.3 These results differed considerably from those of an earlier Italian study that did not involve control groups and reported significant results with child stutterers.4 Malcolm and Wells noted the similarities between motor tics and stuttering (both starting in early childhood, pre-dominantly in males, and intensifying under stress) and pointed to their own success in treating patients with motor tics by use of haloperidol. They, too, considered the possible effectiveness of haloperidol for the threatment of stuttering, and their results were quite encouraging.5 This paper reports a double-blind placebo study of the usefulness of haloperidol as a treatment for adult stuttering.

SUMMARY To evaluate the clinical effects of lorazepam on neurosis, a double-blind controlled trial by group comparison procedure was carried out using diazepam and placebo as control drugs. The clinical improvement and aggravation rates by means of a variety of assessment of change were compared between each of the two active drugs and placebo. The superiority, characteristics of therapeutic effects and minor side effects of lorazepam which is similar to those of diazepam, a standard benzodiazepine anxiolytie for the treatment of neurosis, were demonstrated. From this study, many important problems which might be influenced upon the outcome of the pharmacotherapy on neurotics, such as positive and negative placebo effects, aggravation and drop-out during the trial, were also evaluated.

1 A new sensitive, specific and rapid radioimmunoassay procedure for the determination of plasma concentrations of the neuroleptic drug perphenazine is described. 2 The antiserum developed for perphenazine did not cross-react with most of the major metabolites of perphenazine nor the tricyclic antidepressants and antianxiety agents commonly co-administered with the drug. 3 The assay, based on the above antiserum, enabled the quantitation of 50 pg of the drug in 200 microliters of plasma with a coefficient of variation of about 8% and therefore should be applicable for single dose pharmacokinetic studies, as well as therapeutic monitoring of the drug in patients.

The pharmacotherapy of minimal brain dysfunction (MBD) is reviewed. Studies using central nervous system (CNS) stimulants (amphetamines and methylphenidate, deanol, pemoline, caffeine), antidepressants (imipramine and desipramine), anticonvulsants (phenytoin and primidone), antianxiety agents (chlordiazepoxide, hydroxyzine, meprobamate), antipsychotic agents (phenothiazines, thioxanthenes, butyrophenones) and miscellaneous agents (benztropine, thyrotropin-releasing hormone, megavitamins) are discussed. When drugs are indicated, the CNS stimulants are the agents of choice in the treatment of MBD. The use of tricyclic antidepressants in MBD is regarded as investigational and warrants careful monitoring to minimize toxicities. Anticonvulsants have been ineffective in controlling behavior problems; however, phenytoin may be helpful in auditory perception problems. Anti-anxiety and antipsychotic agents are not as desirable as the CNS stimulants for treatment since they do not decrease distractibility or increase attention spans.

Two groups of anxious patients were treated with either clorazepate (n = 27, 15 mg at night), or diazepam (n = 27, 5 mg three times a day), and the anxiolytic effects of the treatments compared during a 22 day period. Both drugs were effective antianxiety agents (as assessed by the Hamilton Anxiety Scale, Analogue and Rapid Symptom Check List scales). The response to drug treatment did not differ according to the type of anxiety--psychological or somatic. No significant difference was observed between the two drug treatments. Separation of patients according to their anxiety type did not change this finding. Clorazepate, when administered as a single dose at night, is an effective short term anxiolytic.

With appropriate precautions, psychotropic agents can be used in the considerable number of patients requiring concurrent treatment for peptic ulcer, and especially its primary form, duodenal ulcer. After discussing the recent advances in the treatment of ulcers, particularly the striking gains achieved with the H 2 receptor blockers, the authors examine the coordination of that treatment with the administration of antianxiety agents, antidepressants, neuroleptics, and lithium. They also assess the extent to which certain psychotropics themselves have a favorable effect on the evolution of ulcers.

1. 1. Chlordiazepoxide (10 mg/kg) failed to reduce the conditioned acceleration of a free operant avoidance task to a conditioned stimulus for fear and an unconditioned loud noise stimulus. 2. 2. These results, in conjunction with previous findings, were interpreted to suggest that antianxiety agents do not directly inhibit mechanisms that produce emotional reactions such as fear or anxiety.

1. 1. AHR-3219 blocked tonic seizures induced by maximal electroshock or pentylenetetrazol in mice in doses comparable to those of diazepam. 2. 2. The drug produced muscle relaxation in mice or cats in doses comparable to or less than those of diazepam, respectively. 3. 3. The antianxiety activity of AHR-3219, as determined in rats by blockade of natural aversion (disinhibition) or of conditioned suppression (conflict behavior), was similar to that seen after diazepam. 4. 4. Lethality studies suggested that AHR-3219 and diazepam were equally toxic after intraperitoneal administration while AHR-3219 was less toxic after oral administration.

A review of the literature of drug interactions of the antianxiety agents yields little of clinical significance. Recorded drug interactions of this group involve primarily meprobamate, chlordiazepoxide, and diazepam. The only interaction of note with meprobamate is the development of tolerance partially as a result of microsomal enzyme induction by meprobamate, chronic alcohol ingestion, and possibly some other agents. Of the benzodiazepine interactions, the one of most serious note is the incidence of respiratory depression and/or hypotension which occurs when diazepam is given intravenously for convulsions after prior parenteral administration of a barbiturate. The benzodiazepine derivatives may inhibit diphenylhydantoin metabolism. Hence, patients on diphenylhydantoin therapy should be closely monitored when the benzodiazepine anti-anxiety agents are introduced to or deleted from the therapeutic regimen.

Diazepam is frequently the subject of review by various agencies and institutions charged with determining whether or not to substitute another, more economical drug--in most instances, chlordiazepoxide. A review of the comparative literature has shown that, on clinical and pharmacokinetic grounds, chlordiazepoxide is not the drug of choice for all clinical indications recommended for the benzodiazepines as a class, particularly for use as an antianxiety agent. There is evidence that the antianxiety effect of chlordiazepoxide is related to the appearance of its two active metabolites, which may explain the observed delay in its onset of action. When chlordiazepoxide's reduced clearance in the elderly and in patients with liver disease is considered along with its limited range of indications, substitution of diazepam with chlordiazepoxide is clearly not reasonable. Diazepam and lorazepam are preferred choices in acute anxiety because they are themselves active anxiolytics. Oxazepam is recommended in alcoholic cirrhotics because its plasma clearance does not seem to be significantly affected by liver disease. Diazepam is recommended for chronic anxiety because of the rapid onset of action of diazepam itself and the smooth transition to the nondrug state via its longer-acting active metabolite.

The literature comparing meprobamate and the barbiturates is extensively reviewed, and the differences between these agents are found to be significant, from both pharmacological and clinical standpoints. These include major differences in site and mode of action, effects on conditioned responses and other animal behavior, primary indications for use in human beings, and effects on normal human behavior. The barbiturates are shown to be useful primarily as hypnotics which, in clinical doses, produce motor and intellectual impairment. Meprobamate is shown to be a specific antianxiety agent which produces no significant behavioral impairment at clinical dosage. A critique of this review follows.

A double blind controlled study was carried out in 20 patients with essential hypertension to evaluate an effect of medazepam on blood pressures during mirror drawing test performance. Patients were administered orally a tablet of medazepam (5mg) or placebo three times a day for one week. The results were obtained in the following way by the method of analysis of variance for blood pressures.1) Increasing in blood pressure was significantly alleviated after administration of medazepam in both systolic and diastolic, when compared with that of pre-administration. On the other hand, placebo showed little alleviation.2) Some differences were found between the two groups in the pattern of fluctuations in diastolic blood pressures during mirror drawing test performance.

The traditional use of essential oils in aromatherapy has offered numerous health benefits. However, few scientific studies have been conducted with these oils to confirm their therapeutic efficacy. (+)-Limonene is a chemical constituent of various bioactive essential oils. The present study reports on the anxiolytic-like effects of (+)-limonene in an elevated maze model of anxiety in mice. At concentrations of 0.5% and 1.0%, (+)-limonene, administered to mice by inhalation, significantly modified all the parameters evaluated in the elevated plus maze test. The pharmacological effect of inhaled (+)-limonene (1%) was not blocked by flumazenil. Analysis of (+)-limonene using gas chromatography–mass spectrometry (GC–MS) showed its volatility to be high. These data suggest possible connections between the volatility of (+)-limonene and its anxiolytic-like effect on the parameters evaluated in the elevated plus maze test. The data indicate that (+)-limonene could be used in aromatherapy as an antianxiety agent.

Antianxiety agents' effects on the reported frequency of fainting, dizziness, loss of consciousness, and bone fractures were studied in a large ambulatory elderly population. The frequency of these symptoms in participants using seven different antianxiety drugs and that of a control group were compared. Dizziness and episodes of loss of consciousness and falls were reported more frequently in women using these drugs compared with controls (p

Forty derivatives (1-40) of pyrazolo[1,5-a]pyrimidine were synthesized and evaluated for antianxiety properties via gross behavioral observations in rats. Five of these compounds, including 5,7-dimethylpyrazolo[1,5-a]pyrimidine (6) and the 3-fluoro (7), 3-chloro (8), 3-bromo (9), and 3-iodo (10) derivatives, were selected for advanced evaluation. Although 6 and 7 had marginal activity, 8-10 had an anxiolytic effect in animals comparable to the clinically useful benzodiazepines, diazepam, and chlorodiazepoxide. Comparison with chlorpromazine indicated that 6-10 are probably not antipsychotic agents. These compounds also lacked activity in anticonvulsant and analgesic tests. Acute toxicity data (mouse, ip and po) indicated that 8-10 had excellent therapeutic ratios, although 10 was more poorly absorbed than 8 and 9. Further demonstration of anxiolytic efficacy was obtained by comparing the effects of 8 and 9 with the benzodiazepines in modifying provoked aggression in monkeys, rats (muricide), and fighting mice. The most remarkable observation, however, was that 8 and 9 had no effect, at the anxiolytic threshold, in potentiating the CNS depressant effects of ethanol or sodium barbital (po) in treated mice. In contrast, diazepam and chlorodiazepoxide potentiated this drug interaction effect at minimal anxiolytic doses.

Forty derivatives (1-40) of pyrazolo[1,5-a]pyrimidine were synthesized and evaluated for antianxiety properties via gross behavioral observations in rats. Five of these compounds, including 5,7-dimethylpyrazolo[1,5-a]pyrimidine (6) and the 3-fluoro (7), 3-chloro (8), 3-bromo (9), and 3-iodo (10) derivatives, were selected for advanced evaluation. Although 6 and 7 had marginal activity, 8-10 had an anxiolytic effect in animals comparable to the clinically useful benzodiazepines, diazepam, and chlorodiazepoxide. Comparison with chlorpromazine indicated that 6-10 are probably not antipsychotic agents. These compounds also lacked activity in anticonvulsant and analgesic tests. Acute toxicity data (mouse, ip and po) indicated that 8-10 had excellent therapeutic ratios, although 10 was more poorly absorbed than 8 and 9. Further demonstration of anxiolytic efficacy was obtained by comparing the effects of 8 and 9 with the benzodiazepines in modifying provoked aggression in monkeys, rats (muricide), and fighting mice. The most remarkable observation, however, was that 8 and 9 had no effect, at the anxiolytic threshold, in potentiating the CNS depressant effects of ethanol or sodium barbital (po) in treated mice. In contrast, diazepam and chlorodiazepoxide potentiated this drug interaction effect at minimal anxiolytic doses.

In a sample of middle class individuals seeking marital and sexual counseling, 30% had diagnosable psychiatric illness, including 14% who had depressions at the time of interview. Those with psychiatric syndromes were significantly more likely to have been prescribed psychoactive drugs than those without these syndromes. Those with depression were more likely to have received diazepam and similar drugs than antidepressants. The same was true for those with other syndromes but in many of these cases, diazepam or other antianxiety agents seemed more appropriate. Thus, affective disorder might well be the psychiatric syndrome for which these drugs are most often inappropriately prescribed. Inappropriate treatment is a matter of concern in an illness which is potentially fatal.

Buspirone is an antianxiety compound that has been extensively evaluated in clinical trials: it has proved superior to placebo and comparable to diazepam in the treatment of patients with generalized anxiety disorder. In this study, 33 outpatients with generalized anxiety disorder were entered into a crossover study of 3 weeks each of placebo, buspirone 10 to 30 mg daily, and diazepam 10 to 30 mg daily. Psychiatrist and patient ratings were made, together with psychological tests and EEG and skin conductance measures before and after each treatment. Of the nine dropouts, six were on buspirone at the time of dropout. For the remaining 24 patients, the mean daily doses attained of buspirone and diazepam were both 20 mg. On most clinical ratings diazepam was superior to buspirone and placebo, which did not differ. Diazepam produced minor psychomotor changes and the expected major effects on the EEG. Buspirone was without effect. Side effects on buspirone were mainly nausea and giddiness and on diazepam, drowsiness. The lack of efficacy of buspirone is discussed in terms of the previous benzodiazepine exposure--23/24 patients had had previous exposure and only 10 were able to tolerate a pretrial placebo washout period. The implications are considerable for the introduction of any new antianxiety agent not cross-tolerant with the benzodiazepines into a chronically anxious group of patients with previous long-term benzodiazepine therapy.

Anxiolytic drugs are adjuncts to non-pharmacological treatments for anxiety. Alcohol and tobacco remain the major psychoactive agents that are used in our community. Benzodiazepine drugs are the agents of choice if an acute reduction in anxiety or intermittent therapy is needed and are helpful for long-term use in a few patients. For panic disorders, alprazolam is effective for short- and long-term treatment, although it needs a slow reduction in dosage and carries a risk of withdrawal reactions in about 30% of sufferers. Clonazepam also may help panic attacks and possibly other benzodiazepine agents would show similar effects at equivalent doses. Antidepressant drugs, including monoamine-oxidase inhibitor agents, although more toxic and sometimes less tolerated than is alprazolam, have antipanic effects in high doses and are of use for prolonged therapy for panic disorders. Neuroleptic agents' general usefulness as anxiolytic drugs is restricted because of their acute and long-term toxicity. There is no place for the use of antidepressant or neuroleptic drugs as treatments of first choice in uncomplicated generalized anxiety. beta-blocking agents have limited adjunctive use for performance anxiety and social phobias. Buspirone heralds a new class of anxiolytic agents. Buspirone has advantages in patients who can tolerate its slow onset of action, with reduced psychomotor effects, lower interactive effects with cortical depressant substances and a seeming lack of dependency or any withdrawal syndrome.

Benzodiazepine anxiolytics are known to pose risks associated with drug dependence, abuse, and withdrawal symptoms. Recently, a new antianxiety agent, buspirone, was introduced in the United States. Buspirone appears to lack abuse liability and does not lead to drug dependence or withdrawal symptoms. This article reviews the results of animal and clinical studies in which the potential for buspirone dependence or abuse and the effects of its withdrawal were assessed.

Over the past five years, the mechanisms of action of several classes of antianxiety drugs have been clarified. Benzodiazepines, triazolopyridazines, and barbiturates seem to produce their anxiolytic effects by interacting with a specific high affinity receptor (viz. benzodiazepine receptor) in the brain. The benzodiazepine receptor is functionally and perhaps structurally coupled to a receptor for the major inhibitory neurotransmitter GABA as well as a chloride channel or ionophore. Taken together, this receptor “complex” may mediate the behavioral effects of a number of chemically diverse antianxiety agents. Evidence for the role of the benzodiazepine-GABA receptor-chloride ionophore complex in the mechanism of action of minor tranquilizers and a possible interaction with the novel anxiolytic buspirone is discussed.