piperidines and Phobic-Disorders

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

This article reviews evidence for the utility of antidepressant medications in the treatment of social phobia. Monoamine oxidase inhibitors (MAOIs) were the first antidepressants shown to be effective for social phobia, but dietary restrictions and a relatively high rate of adverse effects often relegate MAOIs to use after other treatments have been found ineffective. Reversible inhibitors of monoamine oxidase (RIMAs) hold promise as safer alternatives to MAOIs, but RIMAs may be less effective and are currently unavailable in the United States. Selective serotonin reuptake inhibitors (SSRIs), of which paroxetine has been the best studied in social phobia to date, have recently emerged as a first-line treatment for the generalized subtype of social phobia. The SSRIs are well tolerated and consistently have been shown to be efficacious in controlled trials.

Topics: Antidepressive Agents; Controlled Clinical Trials as Topic; Drug Approval; Humans; Moclobemide; Monoamine Oxidase Inhibitors; Paroxetine; Phenelzine; Phobic Disorders; Piperidines; Selective Serotonin Reuptake Inhibitors; Treatment Outcome; United States

Social phobia, though the third most common psychiatric disorder in the United States, has received little systematic attention until recently. Chronic and disabling symptoms usually precede other disorders in individuals with comorbidity, including alcohol abuse. Though about 80% of individuals do not seek treatment, controlled trials have demonstrated efficacy for several medications, of which phenelzine (an irreversible monoamine oxidase inhibitor [MAOI]) is the best studied. The benzodiazepines, clonazepam and alprazolam, also hold promise. New reversible MAOIs such as moclobemide and brofaromine are under investigation; fluoxetine and other serotonin selective reuptake inhibitors need further controlled study. The benefits of group cognitive-behavioral therapy also appear substantial. Issues for future investigation include long-term outcome, differential therapeutics, diagnostic subtyping, and combination treatments.

Topics: Benzamides; Benzodiazepines; Clinical Trials as Topic; Cognitive Behavioral Therapy; Combined Modality Therapy; Comorbidity; Fluoxetine; Humans; Moclobemide; Monoamine Oxidase Inhibitors; Phenelzine; Phobic Disorders; Piperidines; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

Animal studies demonstrate that stress and negative affect enhance the release of the neuropeptide substance P (SP), which binds to the neurokinin 1 (NK1) receptor. This positron emission tomography (PET) study evaluated how the activity in the SP-NK1 receptor system in the amygdala was affected by fear provocation in subjects with specific phobia.. Sixteen adult women with DSM-IV-defined specific phobia for either snakes or spiders but not both viewed pictures of feared and non-feared animals while being PET-scanned for 60 min with the highly specific NK1 receptor antagonist [(11)C]GR205171 as the labeled PET tracer.. The uptake of the labeled NK1 receptor antagonist was significantly reduced in the right amygdala during phobic stimulation. In the left amygdala no significant differences were found between phobic and non-phobic conditions. There was a negative correlation in the right, but not left, amygdala between subjective anxiety ratings and NK1 tracer binding.. Fear provocation affects the SP-NK1 receptor system in the right amygdala. This reflects reduced NK1 receptor availability during fear and could mirror an increased release of endogenous substance P.

Topics: Adult; Amygdala; Animals; Antiemetics; Female; Functional Laterality; Humans; Neurokinin-1 Receptor Antagonists; Phobic Disorders; Piperidines; Positron-Emission Tomography; Receptors, Neurokinin-1; Tetrazoles

Evidence is accumulating that pharmacological blockade of the substance P preferring neurokinin-1 (NK1) receptor reduces anxiety. This study compared the effects of an NK1 receptor antagonist, citalopram, and placebo on brain activity and anxiety symptoms in social phobia.. Thirty-six patients diagnosed with social phobia were treated for 6 weeks with the NK1 antagonist GR205171 (5 mg), citalopram (40 mg), or matching placebo under randomized double-blind conditions. GR205171 was administered for 4 weeks preceded by 2 weeks of placebo. Before and after treatment, regional cerebral blood flow (rCBF) during a stressful public speaking task was assessed using oxygen-15 positron emission tomography. Response rate was determined by the Clinical Global Impression Improvement Scale.. Patients improved to a larger extent with the NK1 antagonist (41.7% responders) and citalopram (50% responders), compared with placebo (8.3% responders). Within- and between-group comparisons showed that symptom improvement was paralleled by a significantly reduced rCBF response to public speaking in the rhinal cortex, amygdala, and parahippocampal-hippocampal regions. The rCBF pattern was corroborated in follow-up analyses of responders and subjects showing large state anxiety reduction.. Short-term administration of GR205171 and citalopram alleviated social anxiety. Neurokinin-1 antagonists may act like serotonin reuptake inhibitors by attenuating neural activity in a medial temporal lobe network.

Topics: Adult; Anxiety; Cerebrovascular Circulation; Citalopram; Double-Blind Method; Female; Humans; Male; Neurokinin-1 Receptor Antagonists; Phobic Disorders; Piperidines; Positron-Emission Tomography; Selective Serotonin Reuptake Inhibitors; Temporal Lobe; Tetrazoles

Differences between responders and non-responders to drug therapy were investigated in social phobia. Two previously published studies were pooled to obtain data of 30 patients who were treated for 12 weeks with brofaromine or fluvoxamine. Four criterion variables were used to divide patients in responders and non-responders. Depending on the criterion variable up to 72% of the patients were regarded as responders. Non-responders differed from responders in that they had a higher heart rate and a higher blood pressure. They were also characterized by higher scores on several psychometric scales, indicative of illness severity.

Topics: Adult; Arousal; Blood Pressure; Double-Blind Method; Female; Fluvoxamine; Heart Rate; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Personality Inventory; Phobic Disorders; Piperidines; Prognosis; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

Factors that predict nonresponse to drug therapy (brofaromine or fluvoxamine) were investigated in a sample of 44 panic disorder patients. We used a strict definition of nonresponse to find patients who did not respond at all after 12 weeks of treatment. Using this definition, 15 patients (32.6%) were considered nonresponders. Nonresponders had a higher score on the Blood-Injury subscore of the Fear Questionnaire (FQ) and more often had high scores on several FQ subscores, indicative of comorbid phobic symptoms. These variables were subsequently used to predict nonresponse.

Topics: Adult; Agoraphobia; Double-Blind Method; Female; Fluvoxamine; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Panic; Panic Disorder; Personality Inventory; Phobic Disorders; Piperidines; Prognosis; Treatment Outcome

Patients with social phobia often describe personality traits characterized by avoidant social behavior and more general depressive-anxious features. There is only sparse knowledge about the effects of drug treatment on these traits.. Fifty-seven patients with social phobia completed a 12-week double-blind, placebo-controlled trial with the reversible and selective monoamine oxidase A inhibitor brofaromine 150 mg/day. The Clinical Global Impressions-Improvement scale, Liebowitz Social Anxiety Scale, a questionnaire with 140 items regarding personality traits, and ratings on the presence or absence of diagnostic criteria for the DSM-III-R avoidant and dependent personality disorders were used for assessments at baseline and endpoint. Comparisons were made with a group of 58 healthy controls.. Before treatment, there were no significant differences between the brofaromine and placebo groups in their ratings on situationally bound social anxiety or on personality traits that differed significantly from those of the controls. At endpoint, a marked normalization was noted in the brofaromine group. The changes that had occurred differed significantly from those in the placebo group. The normalization of traits seemed more marked than the normalization of anxiety in more specific social phobic situations. The number of brofaromine patients who fulfilled the criteria for avoidant personality disorder had diminished from 15 (60%) to 5 (20%).. The results support the conclusion that the maladaptive personality traits characteristic of social phobia are at least as responsive to the monoamine oxidase inhibitor brofaromine as are the more circumscribed social anxiety responses.

Topics: Adult; Comorbidity; Double-Blind Method; Female; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Mood Disorders; Personality Disorders; Phobic Disorders; Piperidines; Placebos; Self Concept; Treatment Outcome

Seventy-seven patients with a primary diagnosis of social phobia (DSM-III-R) were randomized to treatment with the reversible and selective monoamine oxidase type A inhibitor brofaromine (n = 37) or placebo (n = 40) for 12 weeks in a double-blind trial. A fixed dose of 150 mg/day or a matching placebo was given after a 2-week dose titration phase. Patients with additional diagnoses of simple phobia, generalized anxiety disorder, dysthymia or major depressive disorder currently in remission were accepted. Patients with other Axis I mental disorders were excluded. In the brofaromine group, 78% of the patients scored much or very much improved on the Clinical Global Impression scale compared with 23% in the placebo group. The anxiety and avoidance scores on the Liebowitz Social Anxiety Scale (LSAS) were significantly reduced in favor of brofaromine. The clinical effects were not significantly correlated with the plasma concentration of brofaromine. After 12 weeks the brofaromine group scored significantly lower than the placebo group on a core depression part of the Montgomery-Asberg Depression Rating Scale. After 12 weeks of treatment the brofaromine group had significantly higher total scores on the LSAS than an age- and gender-matched group of healthy controls. The brofaromine group improved further during 9-month follow-up treatment period, whereas 60% of the placebo responders who continued long-term treatment relapsed. The most common side effects in the brofaromine group were sleep disturbances, dry mouth and nausea.

Topics: Adult; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Personality Inventory; Phobic Disorders; Piperidines; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

Topics: Adult; Agoraphobia; Humans; Male; Monoamine Oxidase Inhibitors; Panic Disorder; Phobic Disorders; Piperidines

There is circumstantial evidence that antidepressants, particularly monoamine oxidase inhibitors (MAOIs) and beta-blockers, may have some beneficial effects in social phobia. In this study 30 patients with social phobia (DSM-IIIR) were treated with the selective and reversible MAO-A inhibitor brofaromine, using a 12-week double-blind placebo controlled design. A clinical relevant improvement was seen in 80% of the patients treated with brofaromine (150 mg daily). A significant improvement was found on measures of social anxiety, phobic avoidance, general (or anticipatory) anxiety and interpersonal sensitivity in patients on brofaromine, but not on placebo. Biochemical measurements revealed a decrease in turnover of noradrenaline, serotonin and dopamine as assessed by the plasma metabolite levels, and an increase in nocturnal release of melatonin. Most prominent side-effect was middle sleep disturbance. No changes in blood pressure were observed. During a follow-up period of 12 weeks a further improvement was found in patients treated with brofaromine.

Topics: Adult; Blood Pressure; Double-Blind Method; Female; Humans; Hydrocortisone; Male; Melatonin; Methoxyhydroxyphenylglycol; Monoamine Oxidase Inhibitors; Phobic Disorders; Piperidines; Psychiatric Status Rating Scales

Clinical and preclinical data suggest a link between serotonin [5-hydroxytryptamine (5-HT)] function and certain psychopathologic dimensions of anxiety disorders. Antidepressants consistently have been found to exert a favorable effect in anxiety disorders, particularly panic disorders. Clinical studies with 5-HT-selective drugs have shown that 5-HT neurons may comprise the site at which anxiolytic drugs exert a significant proportion of their action. Thus, fluvoxamine, a selective 5-HT uptake inhibitor, but not maprotiline, a selective noradrenaline uptake inhibitor, was found to be efficacious in panic disorder. The clinical effect of fluvoxamine revealed a noteworthy time course. After an initial increase in anxiety, improvement was attained gradually. On the basis of this finding, we tentatively hypothesized that stimulation of the 5-HT receptors, resulting from uptake inhibition, would worsen the condition of the patient, while down-regulation of the 5-HT receptors, resulting from chronic treatment, would account for the clinical efficacy. Thus, we performed a study in which ritanserin, a putative 5-HT2 antagonist, was compared with fluvoxamine. Ritanserin was found to be ineffective in the treatment of panic disorder symptoms, suggesting that 5-HT2 receptors may not be critically involved in the mechanism underlying the anxiolytic activity of 5-HT uptake inhibitors. It would seem, therefore, that other 5-HT-receptor subtypes, e.g., 5-HT1, may be implicated in this effect. Recent studies with selective 5-HT1 agonists support this hypothesis.

Topics: Adolescent; Adult; Aged; Agoraphobia; Brain; Clinical Trials as Topic; Fear; Female; Fluvoxamine; Humans; Male; Middle Aged; Oximes; Panic; Phobic Disorders; Piperidines; Psychological Tests; Random Allocation; Receptors, Serotonin; Ritanserin

The neurokinin-1 (NK1) receptor is abundantly expressed in the fear circuitry of the brain, including the amygdala, where it modulates stress and anxiety. Despite its proposed involvement in psychopathology, only a few studies of NK1 receptor availability in human subjects with anxiety disorders exist. Here, we compared NK1 receptor availability in patients with social anxiety disorder (SAD; n = 17) and healthy controls (n = 17) using positron emission tomography and the radiotracer [11C]GR205171. The Patlak Graphical plot using a cerebellar reference region was used to model the influx parameter, Ki measuring NK1 receptor availability. Voxel-wise statistical parametric mapping analyses revealed increased NK1 receptor availability specifically in the right amygdala in SAD patients relative to controls. Thus, we demonstrate that exaggerated social anxiety is related to enhanced NK1 receptor availability in the amygdala. This finding supports the contribution of NK1 receptors not only in animal models of stress and anxiety but also in humans with anxiety disorders.

Topics: Adult; Amygdala; Case-Control Studies; Female; Humans; Male; Neuroimaging; Neurokinin-1 Receptor Antagonists; Phobic Disorders; Piperidines; Positron-Emission Tomography; Receptors, Neurokinin-1; Tetrazoles

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

Topics: Adult; Anesthesia, Spinal; Anesthetics, Intravenous; Female; Humans; Lidocaine; Lidocaine, Prilocaine Drug Combination; Phobic Disorders; Physician-Patient Relations; Piperidines; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prilocaine; Remifentanil

Topics: Adult; Anesthetics, Intravenous; Cesarean Section; Elective Surgical Procedures; Female; Humans; Hypnotics and Sedatives; Infant, Newborn; Needles; Obesity, Morbid; Phobic Disorders; Piperidines; Pregnancy; Pregnancy Outcome; Remifentanil

Topics: 1-Naphthylamine; Adolescent; Cisapride; Drug Therapy, Combination; Humans; Male; Nausea; Phobic Disorders; Piperidines; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Sertraline

The clinically tested reversible inhibitors of monoamine oxidase A (RIMAs) include brofaromine, moclobemide and toloxatone. Moclobemide has shown unequivocal antidepressant activity against serious depressive illness in 4 placebo-controlled double-blind trials. It has been compared with amitriptyline, imipramine, clomipramine, desipramine, maprotiline, fluoxetine, fluvoxamine, tranylcypromine, toloxatone, mianserin and amineptine in the treatment of depressive disorders. Meta-analysis showed convincing evidence of moclobemide efficacy, comparable with the most potent antidepressants available. The efficacy of moclobemide has been demonstrated in psychotic and non-psychotic depression, in depression with and without melancholia, in endogenous depression (both unipolar and bipolar), in retarded depression and in agitated depression. The efficacy of moclobemide, allied to the unusually benign side effect profile, has led to exploration of its use in other disorders. Two small studies have given encouraging results in the treatment of attention-deficit hyperactivity disorder. Large placebo-controlled studies have shown the activity of moclobemide in the depression that accompanies dementia (such as senile dementia of Alzheimer type). The results also suggested that, in this patient population, cognitive ability improved in parallel. Social phobia has also been shown to improve on treatment with either moclobemide or brofaromine. Clinical trials are in progress on the effect of moclobemide in chronic fatigue syndrome. Moreover, there are encouraging results with the use of brofaromine and moclobemide in panic disorder. Other disorders in which treatment with RIMA is of interest include agoraphobia, bulimia, borderline personality disorder, post-traumatic stress disorder, compulsive hair pulling (trichotillomania), dysmorphophobia, kleptomania as well as various anxiety syndromes.

Topics: Alzheimer Disease; Antidepressive Agents, Tricyclic; Attention Deficit Disorder with Hyperactivity; Benzamides; Humans; Moclobemide; Monoamine Oxidase Inhibitors; Oxazoles; Oxazolidinones; Panic Disorder; Phobic Disorders; Piperidines

Eleven patients with panic disorder were administered ritanserin, a post-synaptic serotonin S2 antagonist, during a 4 week period at a daily dose of 10-20 mg. The treatment resulted in a decrease in the number of panic attacks, and a diminution of agoraphobic avoidance. The possible practical and theoretical signification of these findings is discussed.

Topics: Adult; Agoraphobia; Escape Reaction; Fear; Female; Humans; Male; Panic; Phobic Disorders; Piperidines; Ritanserin; Serotonin Antagonists

Topics: Aged; Aggression; Animals; Antidepressive Agents; Chemical Phenomena; Chemistry; Depression; Drug Therapy, Combination; Female; Haplorhini; Humans; Male; Mental Disorders; Middle Aged; Obsessive-Compulsive Disorder; Phobic Disorders; Piperidines; Rabbits; Rats; Satiation; Serotonin Antagonists; Sexual Behavior