Interest of propranolol in the treatment of school refusal anxiety: about three clinical observations

School refusal anxiety is a pathopsychological disorder which touches the young child, between 8 and 13 years. Even if the school refusal is studied for a long time, there is not still consensus as for the specific definition of this disorder or on the best way of treating it. Nevertheless, accountable of long-lasting difficulties in school integration, its short and medium term consequences are serious and well known: school desertion, mood disorder and behavioral problems. Speed and quality of the medico-psychological and educational interventions represent a important factor for evolution and prognosis. Although, psychological interventions remain essential, sometimes the interest of an associated psychotropic medication should be discussed. This one can indeed either improve their results or supporting their installations. Despite more than twenty controlled trials in the pediatric population, no definitive psychopharmacological treatment data exist for anxiety disorder in childhood and especially for school refusal disorder. The majority of the studies stress as well the interest of benzodiazepines as tricyclic antidepressants but without being able to specify the possible superiority of a chemical on the other. On the other hand, the side effects of each one are well-documented, in particular for the benzodiazepines (potential abuse, sedation, potential desinhibition, mnemonic disorder), limiting thus their uses in child. In this work, we would like to emphasize the interest of propranolol in the treatment of somatic symptoms usually met in school refusal anxiety. Although beta-blockers have been used in the treatment of neurovegetative symptoms associated with situational anxiety disorders, there is no controlled data and only some open data to guide pediatric use for anxiety disorders in children. Nevertheless, prescribed with low posology and in substitution of benzodiazepine, this medication enabled us in three severe clinical cases to shorter notably the time of school rehabilitation. Well tolerated on the clinical level, with a greater efficiency on the somatic signs related to anxiety than benzodiazepines and with not having their side effects, this therapeutic can constitute a significant support in the psychological treatment of these children. However, these present results require to be confirm by other observations, which will be lead perhaps to a controlled study.     

Anxiolytics, adrenergic agents, and naltrexone

OBJECTIVE: To review extant data on the efficacy and safety of anxiolytic medications (benzodiazepines, buspirone, and other serotonin 1A agonists), adrenergic agents (beta-blockers and alpha 2-adrenergic agonists clonidine and guanfacine), and the opiate antagonist naltrexone that have been used to treat various psychopathologies in children and adolescents. To identify critical gaps in our current knowledge about these agents and needs for further research. METHOD: All available controlled trials of these medications in children and adolescents published in English through 1997 were reviewed. In addition, selected uncontrolled studies are included. RESULTS: The major finding, that there are virtually no controlled data that support the efficacy of most of these drugs for the treatment of psychiatric disorders in children and adolescents, is both surprising and unfortunate. For some drugs, e.g., buspirone and guanfacine, this is because no controlled studies have been carried out in children and/or adolescents. For other drugs, e.g., clonidine and naltrexone, most of the placebo-controlled studies have failed to demonstrate efficacy. CONCLUSIONS: The strongest recommendations for controlled studies of safety and efficacy in children and adolescents can be given for the following drugs: benzodiazepines for acute anxiety; buspirone (and newer serotonin 1A agonists as they become available) for anxiety and depression; beta-blockers for aggressive dyscontrol; guanfacine for attention-deficit/hyperactivity disorder; and naltrexone for hyperactivity, inattention, and aggression in autistic disorder.     

Advances in pharmacotherapy for pediatric anxiety disorders

Pediatric anxiety disorders are prevalent, chronic, and often lead to significant impaired functioning that impacts both short- and long-term outcomes for children and adolescents. Treatment options include pharmacotherapy and psychosocial interventions. This presentation will review treatment advances specifically for pharmacotherapy. Current research supports serotonin reuptake inhibitors as the medication class to be the first-line treatment option for pediatric anxiety disorders. Available evidence for the efficacy of other classes of medications will be reviewed, along with the available approaches to manage partial responders and nonresponders. The risks and benefits of pharmacotherapy will also be reviewed. In addition, recent research has shown the potential promise of novel agents that act upon other neural systems implicated in the development of pediatric anxiety disorders. Novel compounds that affect the glutamate system will be discussed.     

Beta-adrenoceptor antagonists in neuropsychiatry: an update

Although beta-adrenoceptor antagonists such as propranolol have been used in neuropsychiatry for more than 20 years, their indications, extent of efficacy, and place in therapy remain unclear. In this overview, which concentrates on the recent literature, four indications for use of the drugs are reviewed, with particular reference to efficacy, mode of action, and clinical utility. The indications are anxiety disorders, including performance anxiety; schizophrenia; aggressive behavior; and akathisia. The author concludes that beta-blockers are useful in some forms of anxiety disorder, perhaps those characterized by somatic symptoms and by performance anxiety, and that akathisia seems to be responsive to those drugs. However, the use of high doses of beta-blockers in schizophrenia remains unestablished, and insufficient data are available with respect to their use in aggressive behavior.     

Platelet activity and selective beta-blockade in migraine prophylaxis

Migraine is associated with increased platelet activity and an incidence of cerebrovascular ischemic events. Because cerebrovascular events might result from platelet aggregation, enhancing platelet activity further in the treatment of migraine is not desirable. beta-Adrenoceptor blockers effective in migraine prophylaxis include propranolol (nonselective) and metoprolol (beta 1-selective), but it is uncertain how beta-receptor subtype selectivity might influence platelet behavior in migraine. In 29 patients, comparable clinical responses were obtained with therapeutic doses during 1 month of treatment with propranolol, metoprolol, and the beta 2-selective Li 32-468. Propranolol increased and metoprolol decreased platelet aggregation and ATP release, and the effect of Li 32-468 could be related to that of propranolol. These actions can be largely explained in terms of what is known of platelet beta-receptors and therefore can be generalized to other effective beta-blockers. Since altered platelet activity does not account for the efficacy of these agents in migraine, the actions of beta-blockers on platelets should be considered as side effects. Those beta-blockers inhibiting platelet activity should be preferred in migraine treatment, assuming equal efficacy, which implies the use of beta 1-selective blockers.     

GABAA receptors as targets for novel anxiolytic drugs.

Anxiety disorders are highly prevalent and disabling disorders which are commonly treated with pharmacotherapy and/or psychotherapy. While benzodiazepines are of great value for the treatment of acute anxiety states, their long-term use is hampered by their well-known side effect profile. Meanwhile, antidepressants represent first line treatment options for anxiety disorders. However, their slow onset of action is a disadvantage for their use in these disorders. Therefore, there is need for novel anxiolytics with a rapid onset of action and a favourable side effect profile. Currently, there is a renaissance of gamma-aminobutyric acid type A (GABAA) receptors as targets for the development of novel anxiolytic drugs. While compounds structurally related to GABA, e.g., pregabalin, have already entered large scale clinical development, GABA transporter inhibitors, subtype specific benzodiazepines and GABAA receptor modulating neuroactive steroids are promising new candidates. However, their clinical efficacy has still to be shown in clinical trials.     

Recent advances in the psychopharmacological treatment of anxiety disorders

The authors review recent progress in the pharmacological treatment of anxiety disorders. Most research within the last five years has focused on panic disorder; the findings include support for the usefulness of imipramine and clomipramine and probably other agents; evidence that the benzodiazepines alprazolam, diazepam, lorazepam, and clonazepam are approximately equally effective as antipanic agents; and high variability in relapse rates after discontinuation of drug treatment. Further work is required to determine whether buspirone and other forthcoming serotonin agonist drugs have a role in treating panic disorder and other anxiety disorders. For generalized anxiety disorder, scientific studies do not support the effectiveness of beta blocker; tricyclics may be potentially useful. Psychopharmacological treatments for social phobia, obsessive-compulsive disorder, and posttraumatic stress disorder are also reviewed.     

Benzodiazepines in clinical practice: consideration of their long-term use and alternative agents

Despite increasing focus on the use of antidepressants and other agents for the treatment of anxiety, benzodiazepines have remained a mainstay of anxiolytic pharmacotherapy due to their robust efficacy, rapid onset of therapeutic effect, and generally favorable side effect profile. In this article, we examine issues related to the long-term use of benzodiazepines, including concerns about the development of therapeutic tolerance, dose escalation, and adverse cognitive effects. We also consider currently available alternatives to benzodiazepines and novel mechanisms of action that may prove fruitful in the development of future generations of anxiolytics.     

Psychopharmacology of anxiety disorders

Exposure of the general population to a 1:4 lifetime risk of disabling anxiety has inspired generations of fundamental and clinical psychopharmacologists, from the era of the earliest benzodiazepines (BZ) to that of the selective serotonin reuptake inhibitors (SSRIs) and related compounds, eg, the serotonin and norepinephrine reuptake inhibitors (SNRIs). This comprehensive practical review summarizes current therapeutic research across the spectrum of individual disorders: generalized anxiety disorder (GAD), panic disorder (PD) and agoraphobia (social anxiety disorder), compulsive disorder (OCD), phobic disorder (including social phobia), and posttraumatic stress disorder (PTSD). Specific diagnosis is a precondition to successful therapy: despite substantial overlap, each disorder responds preferentially to specific pharmacotherapy. Comorbidity with depression is common; hence the success of the SSRIs, which were originally designed to treat depression. Assessment (multidomain measures versus individual end points) remains problematic, as-frequently-do efficacy and tolerability The ideal anxiolytic remains the Holy Grail of worldwide psychopharmacologic research.     

Generalized anxiety disorder in children and adolescents.

Children and adolescents with GAD suffer from excessive, pervasive worries that interfere with social, academic, and family functioning. The comorbidity rate with other anxiety disorders and major depression is high. The course tends to be chronic, and evidence shows continuity between anxiety disorders in youth and adulthood. Individual and group CBT and the incorporation of family anxiety management training have demonstrated efficacy in the treatment of childhood GAD. No double-blind, placebo-controlled, pharmacotherapy trials with adequate sample sizes for children and adolescents with GAD have been published. Preliminary data support the potential efficacy of selective serotonin reuptake inhibitors, buspirone, and high-potency benzodiazepines. Adequately powered, controlled, pharmacologic treatment trials are necessary. Future research should be directed toward comparing the relative efficacy of psychotherapy, pharmacotherapy, and both in the treatment of GAD in youth.     

Propranolol in psychiatry. Therapeutic uses and side effects

There are speculations that beta-adrenergic blocking agents are useful in the treatment of psychiatric disorders. Clinically, propranolol, an agent of this group, has been investigated in the treatment of various clinical disorders including schizophrenia, other psychoses, anxiety disorders, and stress reactions. This paper critically evaluates its efficacy in these disorders and provides a useful clinical perspective. In addition, propranolol produces a number of psychiatric side effects which are due to its central action or due to the peripheral receptor blockade. In addition, idiosyncratic reactions as well as withdrawal effects have also been reported to produce psychiatric side effects. It is important that the physician who wishes to use this drug know the existing knowledge of its usefulness in the treatment of psychiatric disorders as well as its psychiatric side effects.     

Benzodiazepine use, abuse, and dependence

Although benzodiazepines are invaluable in the treatment of anxiety disorders, they have some potential for abuse and may cause dependence or addiction. It is important to distinguish between addiction to and normal physical dependence on benzodiazepines. Intentional abusers of benzodiazepines usually have other substance abuse problems. Benzodiazepines are usually a secondary drug of abuse-used mainly to augment the high received from another drug or to offset the adverse effects of other drugs. Few cases of addiction arise from legitimate use of benzodiazepines. Pharmacologic dependence, a predictable and natural adaptation of a body system long accustomed to the presence of a drug, may occur in patients taking therapeutic doses of benzodiazepines. However, this dependence, which generally manifests itself in withdrawal symptoms upon the abrupt discontinuation of the medication, may be controlled and ended through dose tapering, medication switching, and/or medication augmentation. Due to the chronic nature of anxiety, long-term low-dose benzodiazepine treatment may be necessary for some patients; this continuation of treatment should not be considered abuse or addiction.     

Developments in treatment of anxiety disorders: psychotherapy, pharmacotherapy, and psychosurgery

A selection of articles that focus on psychosocial treatments, pharmacotherapy, and psychosurgery of anxiety disorders are reviewed. While some medications look clearly beneficial or potentially effective in the treatment of anxiety disorders, other compounds seem less promising or not effective. A combination of proven pharmacotherapies and psychotherapies may be the most clinically prudent approach to the treatment of anxiety disorders. Thermocapsulotomy may be an "extreme" option in selected cases of severe nonobsessive anxiety but may carry a significant risk of adverse effects indicative of frontal lobe functioning impairment. In spite of all the research and progress in studying relatively well-defined therapies, many patients suffering from anxiety and depression still use complementary and alternative therapies. The use of alternative and complementary is likely to increase as insurance coverage expands.     

Efficacy of typical and atypical antipsychotics for primary and comorbid anxiety symptoms or disorders: a review

OBJECTIVE: The efficacy of antipsychotics in the treatment of primary or comorbid anxiety disorders or anxiety symptoms in major depressive disorder or bipolar disorder was reviewed. DATA SOURCES: English-language literature cited in MEDLINE from January 1, 1968, to December 31, 2005, was searched with the keywords anxiety disorder, anxiety symptoms, generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, social phobia, bipolar disorder, major depressive disorder, Hamilton Rating Scale for Anxiety, antipsychotics, typical antipsychotics, atypical antipsychotics, fluphenazine, haloperidol, perphenazine, pimozide, thiothixene, trifluoperazine, loxapine, molindone, chlorpromazine, mesoridazine, thioridazine, fluspirilene, penfluridol, pipothiazine, flupenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, amisulpride, and clinical trial. Randomized, double-blind, placebo-controlled trials and open-label studies with a minimum of 20 subjects with a DSM-III/IV or ICD-10 diagnosis of anxiety disorder and studies without a DSM-III/IV or ICD-10 diagnosis of anxiety disorder but with Hamilton Rating Scale for Anxiety (HAM-A) scores as an outcome were prioritized. Studies on bipolar disorder or major depressive disorder with the analysis of changes in anxiety symptoms were reviewed. Early studies on neurosis/ anxiety or anxious depression without a HAM-A component were also reviewed. DATA SYNTHESIS: Six trials in primary generalized anxiety disorder (GAD), 15 in refractory obsessive-compulsive disorder (OCD), 8 in posttraumatic stress disorder (PTSD), 6 in neurosis with the HAM-A, 1 in social phobia, and 2 in anxiety symptoms in bipolar depression were identified. Low doses of trifluoperazine were superior to placebo in the treatment of GAD. Most of the less well-designed studies showed that other typical antipsychotics might be superior to placebo or as effective as benzodiazepines in the treatment of GAD and other anxiety conditions. In most studies, risperidone, olanzapine, and quetiapine augmentation to antidepressants was superior to placebo in treating refractory OCD and PTSD. Both olanzapine and quetiapine significantly reduced anxiety compared to placebo in studies of bipolar depression. CONCLUSION: Except for trifluoperazine, there is no large, well-designed study of antipsychotics in the treatment of primary or comorbid anxiety symptoms or disorders. The efficacy of these agents in various anxiety conditions needs to be further investigated with large, well-designed comparison studies.     

Anxiety and depressive disorders in 4,425 long term benzodiazepine users in general practice

Consumption rates of anxiolytic drugs, and especially of benzodiazepines, remain very high in France compared to other Western countries, whereas clinical guidelines limit their indications to short term treatments and only for some precise anxiety disorders. Recent epidemiologic surveys in the community indicated that more than 15% of people used once or more an anxiolytic drug in the past year. The issue of chronic treatments is particularly crucial because of their poor benefit/risk ratio in most anxiety disorders (limited efficacy, cognitive side effects, withdrawal and dependence problems). To address this important public health issue, and knowing that, in France, benzodiazepines are prescribed mainly by general physicians, our aims were to explore psychiatric diagnoses in GP's patients with chronic use of anxiolytic benzodiazepines. We included 4 425 patients consuming such drugs regularly for six months or more, and assessed their anxiety and depression symptoms through various clinical scales (Hospital Anxiety and Depressive scale - HAD, Clinical Global Impression scale - CGI, Sheehan Disability Scale - SDS, Cognitive Dependence to Benzodiazepines scale - CDB) and with the Mini International Neuropsychiatric Interview for DSM IV criteria. Only 2.2% of the subjects had neither anxious nor depressive symptoms as indicated by low scores on both subscores (less than 8) of the HAD scale, used as a screener. Nearly three quarters of the 4,257 subjects (73.2%), had CGI scores of at least 5 (markedly ill to extremely ill). Social and familial disability was also high in more than 40% of the sample (marked to extreme disruption according to SDS scores). About half of the sample had CDB scores suggesting a benzodiazepine dependence. According to the MINI, 85.1% of the patients had at least one current DSM IV diagnosis of affective disorder. The most frequent diagnoses were major depressive episode (60%), generalized anxiety disorder (61.2%), and panic disorder (22.5%). An anxiety and depressive comorbidity wad found in 41.9% of the subjects. Some methodological limitations must be taken into account in the discussion of our results, and especially the fact that the included patients were not supposed to be totally representative of all patients consuming anxiolytic benzodiazepines in general practice. However, the size of our sample is sufficiently large to limit possible biases in patient selection. The main result of this study is that a great majority of the patients had significant symptomatology, in particular major depressive episodes and generalized anxiety disorder, often with marked severity and disability. These data are in line with the knowledge of a lack of efficacy of benzodiazepines in depressive and most anxiety disorders, despite long term treatment. They also confirm the current guidelines which recommend prescribing serotoninergic antidepressants, and not benzodiazepines, when long term treatments are needed for severe and chronic affective disorders. This epidemiologic study leads to the conclusion that a specific and attentive diagnostic assessment should be done in all patients receiving benzodiazepines for more than three months, in order to purpose in many cases other long term therapeutic strategies.     

Antidepressants and somatic symptoms: therapeutic actions are expanding beyond affective spectrum disorders to functional somatic syndromes

Having expanded their original role as primary treatment for depression to preferred treatment for anxiety disorders, antidepressants are now emerging as potential therapeutic agents for many other disorders characterized by distressing or even painful somatic symptoms.     

Non-benzodiazepines for the treatment of insomnia

Benzodiazepine hypnotics, the mainstay of pharmacological treatment for insomnia, have been associated with altered sleep architecture, psychomotor and memory impairment, rebound insomnia, withdrawal effects, tolerance, dependence, abuse potential and respiratory depression. Non-benzodiazepines, such as zolpidem, zopiclone and zaleplon, demonstrate hypnotic efficacy similar to that of benzodiazepines along with excellent safety profiles. Non-benzodiazepines generally cause less disruption of normal sleep architecture than benzodiazepines. Psychomotor and memory impairment may be less problematic with non-benzodiazepines, especially when compared to longer-acting benzodiazepines. Rebound insomnia and withdrawal symptoms occur infrequently upon discontinuation of non-benzodiazepines and may be less common and milder than those seen upon discontinuation of some benzodiazepines. For the long-term treatment of insomnia, which is generally not recommended, zolpidem and zopiclone are particularly good options because they do not develop tolerance rapidly and have a low abuse potential. Limited data indicate that zaleplon has low tolerance and abuse potential, although further experience is needed to determine its long-term efficacy and safety profile. Since non-benzodiazepines produce minimal respiratory depression, they may be safer than benzodiazepines in patients with respiratory disorders. The choice of which hypnotic to use should be based on the patient's primary sleep complaint, health history, adverse effects and cost.     

Recent developments in the psychopharmacology of social phobia

The past 2 decades have witnessed an upsurge in the interest in anxiety disorders. Much research effort has been dedicated to panic disorder and obsessive — compulsive disorder. However, it is only very recently that we have begun to understand some of the basic principles about the psychopharmacology of social phobia. Drug classes thus far studied include beta-blockers, nonselective and irreversible monoamine oxidase inhibitors (MAOIs), and benzodiazepines. Beta blockers appear to be of use in specific social phobias, such as public speaking, whereas they are of little use in generalized social phobia. There is considerable evidence suggesting that MAOIs are effective in reducing both social anxiety as well as social avoidance in generalized social phobia. A disadvantage of the conventional irreversible MAOIs is their risk for hypertensive crises when combined with dietary tyramine. Thus far only a small number of studies with selective MAO-A inhibitors, such as moclobemide and brofaromine, have been conducted in social phobia, and the results indicate that both compounds are effective. Drugs exerting selective and specific actions on certain components of, for example, the serotonergic system, can now be studied, and it is hoped that the role of 5-hydroxytryptamine) and other neuronal systems in social phobia can be elucidated. In order to gain more information about selective serotonergic drugs, the first double-blind placebo-controlled study with fluvoxamine was recently published. Preliminary results indicate a reduction in social anxiety after a prolonged treatment period. Finally, the role of peptides in the treatment of social phobia is critically reviewed. The MSH/ACTH analog Org 2766 was investigated in patients suffering from social phobia. No anxiolytic effects of this peptide were observed.     

Predictors of pharmacotherapy response in anxiety disorders

Although treatment with different compounds such as tricyclic antidepressants, selective serotonin reuptake inhibitors, high-potency benzodiazepines, and monoamine oxidase inhibitors has been proven effective in anxiety disorders, 20% to 40% of patients are nonresponders. Given the limited efficacy, the delayed onset of response (it takes several weeks before a clinical effect can be seen for most of these drugs), and the occurrence of side effects associated with pharmacotherapy, predicting response in anxiety disorders would be immensely valuable. This review surveys the literature over the past years on predictors of response to pharmacotherapy in obsessivecompulsive disorder, social anxiety disorder, panic disorder, and posttraumatic stress disorder. Prediction of treatment response may be founded on demographic and clinical variables, neurochemical and electrophysiologic parameters, imaging studies, and genetic markers.     

Benzodiazepine use, cognitive impairment, and cognitive-behavioral therapy for anxiety disorders: issues in the treatment of a patient in need

Cognitive-behavioral therapy (CBT) is effective in the treatment of anxiety disorders when used in conjunction with benzodiazepine pharmacotherapy and when used as a monotherapy. Patients using CBT alone have dropout rates similar to or lower than those patients undergoing other forms of therapy, including benzodiazepines. CBT also works well with patients who do not respond adequately to pharmacotherapy. Combined CBT and benzodiazepine treatment has additive effects when compared with benzodiazepine monotherapy; however, patients receiving combined therapy who subsequently discontinue benzodiazepine treatment experience a loss of efficacy compared with CBT and placebo, perhaps due to fear extinction being context dependent. To avoid this loss of efficacy, CBT may be administered alone or as a bridge between benzodiazepine use and discontinuation during a medication taper. The case report upon which this supplement is based questions the value of CBT for patients experiencing cognitive impairment due to an anxiety disorder, benzodiazepine medication, substance abuse, or a combination of these factors. This article addresses this concern and asserts that CBT is a valuable treatment option in these cases.