Gender differences in the epidemiology and treatment of anxiety disorders.

Women are more likely than men to develop anxiety disorders. Yet, relatively few studies have investigated whether women with anxiety disorders have characteristics that are distinct from those of men with the same disorders. The cause of the enhanced vulnerability to anxiety for women remains largely undetermined. Recent data suggest that female reproductive hormones and related cycles may play an important role. In addition to etiologic functions, reproductive hormones may substantially influence the clinical course of preexisting anxiety conditions in women. Psychotropic medications are more likely to be prescribed to women, and gender differences have been identified in the pharmacokinetics of psychotropic medication. Yet, relatively few systematic data are available concerning the potential clinical relevance or possible treatment implications of gender differences in the treatment of women with anxiety disorders. This article reviews the unique characteristics of primary anxiety disorders in women, summarizes the neurobiological effects associated with estrogen and progesterone, discusses gender differences in medication metabolism and the potential relevance of these differences in the pharmacologic management of women with anxiety disorders, and reviews issues specific to women (e.g., hormone therapy, oral contraceptives, menstrual cycle, pregnancy, lactation) that may impact treatment with psychotropic medication.

The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder.

BACKGROUND: This article describes the development of consensus medication algorithms for the treatment of patients with major depressive disorder in the Texas public mental health system. To the best of our knowledge, the Texas Medication Algorithm Project (TMAP) is the first attempt to develop and prospectively evaluate consensus-based medication algorithms for the treatment of individuals with severe and persistent mental illnesses. The goals of the algorithm project are to increase the consistency of appropriate treatment of major depressive disorder and to improve clinical outcomes of patients with the disorder. METHOD: A consensus conference composed of academic clinicians and researchers, practicing clinicians, administrators, consumers, and families was convened to develop evidence-based consensus algorithms for the pharmacotherapy of major depressive disorder in the Texas mental health system. After a series of presentations and panel discussions, the consensus panel met and drafted the algorithms. RESULTS: The panel consensually agreed on algorithms developed for both nonpsychotic and psychotic depression. The algorithms consist of systematic strategies to define appropriate treatment interventions and tactics to assure optimal implementation of the strategies. Subsequent to the consensus process, the algorithms were further modified and expanded iteratively to facilitate implementation on a local basis. CONCLUSION: These algorithms serve as the initial foundation for the development and implementation of medication treatment algorithms for patients treated in public mental health systems. Specific issues related to adaptation, implementation, feasibility testing, and evaluation of outcomes with the pharmacotherapeutic algorithms will be described in future articles.

A review of the efficacy of selective serotonin reuptake inhibitors in obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic illness associated with substantial morbidity; it often requires long-term medication. The best-studied therapeutic agent in the treatment of this disorder is the tricyclic antidepressant clomipramine. Since other tricyclic antidepressants appear to lack efficacy in OCD, that of clomipramine has been linked to its potent effects on serotonin. Consequently, agents that selectively inhibit serotonin reuptake have been the focus of several large-scale, placebo-controlled studies of OCD. Their efficacy in OCD is the focus of our review. DATA SOURCES: MEDLINE search (1966 to present) of OCD treatment with clomipramine or SSRI antidepressant medication using the key words obsessive-compulsive disorder, serotonin reuptake inhibitors, clomipramine, and pharmacology. STUDY FINDINGS: The selective serotonin reuptake inhibitors fluoxetine, sertraline, fluvoxamine, and paroxetine have, in separate multicenter trials, demonstrated efficacy and tolerability in the treatment of OCD. In contrast, clomipramine, though efficacious, is often associated with substantial adverse events, particularly anticholinergic side effects. While 2 recent meta-analyses support the superior efficacy of clomipramine over selective serotonin reuptake inhibitors in the treatment of OCD, 5 of 6 head-to-head comparisons of either fluoxetine or fluvoxamine versus clomipramine have found similar efficacy but a lower incidence of side effects with the selective serotonin reuptake inhibitor. A recently completed multicenter, 12-week, double-blind trial of paroxetine versus clomipramine versus placebo showed paroxetine to be as effective as clomipramine. With significantly fewer dropouts due to adverse effects than clomipramine, paroxetine was also associated with superior tolerability. CONCLUSION: The suggestion that selective serotonin reuptake inhibitors possess efficacy similar to that of clomipramine, but have a superior side effect profile, may have important implications for patients with OCD who require long-term treatment.

Obsessive-compulsive disorder: symptom overview and epidemiology.

Obsessive-compulsive disorder (OCD) is associated with substantial psychosocial impairment. Although large-scale population surveys suggest that OCD is fairly common, relatively few individuals receive adequate treatment. OCD symptoms characterized by "altered risk appraisal" versus a "need for completeness/symmetry" may differentiate distinct subgroups within OCD. Although females are more likely to develop OCD, males have an earlier age of onset. Full remission of OCD symptoms is rare, but episodic improvement in OCD symptoms is not uncommon. Reproductive hormone cycles may have a substantial impact on the course of OCD in women. Many OCD patients will have coexisting mood or anxiety disorders. Personality disorders are frequently diagnosed in OCD, but may remit with effective antiobsessional treatment(s). The differential diagnosis of OCD is extensive and includes neurological disorders, substance-induced conditions, and other primary psychiatric illnesses.

Acute intravenous administration of ondansetron and m-CPP, alone and in combination, in patients with obsessive-compulsive disorder (OCD): behavioral and biological results.

Obsessive-compulsive disorder (OCD) has been linked to abnormal function of brain serotonin (5-HT) pathways. Since ondansetron is a highly selective 5-HT3 receptor antagonist, the present study was undertaken to investigate 5-HT3 function in OCD. We administered m-CPP (0.08 mg/kg i.v.) and the potent 5-HT3 antagonist, ondansetron (0.15 mg/kg i.v.), to 11 OCD patients. All of the subjects received four separate challenges (m-CPP + placebo, m-CPP + ondansetron, ondansetron + placebo and placebo + placebo). In comparison to placebo, administration of m-CPP was associated with significant behavioral effects, particularly self-rated measures of anxiety, altered self-reality, functional deficit and OCD symptoms. Pretreatment with ondansetron did not affect any of the self-rated behavioral symptoms. After administration of m-CPP relative to placebo, significant increases in plasma cortisol and prolactin were found. These changes were not affected by ondansetron. In conclusion, our results do not support the hypotheses that 5-HT3 receptor-mediated mechanisms modulate m-CPP's behavioral and neuroendocrine effects in patients with OCD.

Behavioral, physiological and neuroendocrine responses in healthy volunteers to m-chlorophenylpiperazine (m-CPP) with and without ondansetron pretreatment.

Several serotonin3 (5-HT3) antagonists have been shown to attenuate the anxiogenic effects of the serotonergic agent, m-chlorophenylpiperazine (m-CPP), in animal models, but little data regarding possible effects of 5-HT3 antagonists on responses to m-CPP are available from studies in humans. Therefore, we studied the behavioral, physiological and neuroendocrine responses of 12 healthy volunteers to i.v. administered placebo and m-CPP (0.08 mg/kg), with and without i.v. pretreatment with the selective 5-HT3 antagonist, ondansetron (0.15 mg/kg). Compared to placebo, m-CPP given alone significantly increased ratings of anxiety and several other behavioral measures. m-CPP also produced statistically significant increases in temperature, systolic and diastolic blood pressure, heart rate, and in plasma concentrations of adrenocorticotropic hormone, cortisol, prolactin and norepinephrine. Responses to ondansetron given alone were no different from those of placebo. Pretreatment with ondansetron did not affect peak behavioral responses to m-CPP, but was associated with a significantly earlier return to baseline levels of ratings of anxiety and functional deficit as well as a summary measure of overall behavioral effects. Following ondansetron pretreatment, the increases produced by m-CPP in systolic and diastolic blood pressure and heart rate were no longer significantly different from placebo. Ondansetron pretreatment significantly reduced their plasma cortisol response to m-CPP without affecting the other plasma hormone responses. Plasma concentrations of m-CPP were unaffected by ondansetron pretreatment. These findings suggest that in normal human subjects some behavioral, cardiovascular and neuroendocrine effects of m-CPP may be partially modulated by 5-HT3 receptor-mediated mechanisms.

Biological and behavioral responses to D-amphetamine, alone and in combination with the serotonin3 receptor antagonist ondansetron, in healthy volunteers.

Evidence that serotonin3 (5-hydroxytryptamine3, 5-HT3) antagonists attenuate behavioral responses to D-amphetamine and cocaine suggests that 5-HT3 receptors modulate brain dopamine in animals. This study examined the potential interactions of the 5-HT3 antagonist ondansetron and D-amphetamine in 10 healthy human volunteers. After the subjects were pretreated with placebo or ondansetron (0.15 mg/kg, i.v.), 5-h challenge tests with oral D-amphetamine (0.5 mg/kg) were performed. As animal studies and early clinical studies with ondansetron have suggested nonlinear dose-response relationships, three subjects also underwent pilot studies with three doses of ondansetron (0.15, 0.05, and 0.015 mg/kg) before they received D-amphetamine. Administration of D-amphetamine increased plasma levels of cortisol, prolactin, growth hormone; elevated blood pressure, pulse, and temperature; and tended to increase self-ratings of activation/euphoria and anxiety. Amphetamine-induced increases in plasma prolactin were significantly reduced by ondansetron pretreatment, but the other neuroendocrine responses were unchanged. Diastolic blood pressure elevations were also significantly attenuated after administration of the lower ondansetron doses, but the other physiologic responses were unchanged. In subjects with minimal or moderate activation/euphoria responses, ondansetron pretreatment only minimally affected these effects of D-amphetamine. Preliminary data, however, indicate that those subjects with robust activation-euphoria responses to D-amphetamine had attenuated responses after ondansetron pretreatment. Taken together, these results suggest that some but not most of D-amphetamine's biological and behavioral effects may be modified by a 5-HT3 antagonist in healthy human volunteers.

Comparison of obsessions and compulsions in patients with anorexia nervosa and obsessive compulsive disorder.

Patients with anorexia nervosa (n = 18) and patients with obsessive-compulsive disorder (OCD) (n = 16) had similar scores on the Yale-Brown Obsessive Compulsive Scale (19 + or - 9 vs. 22 + or - 6). This suggests that these disorders have similar magnitude of impairment from obsessions and compulsions; however, OCD patients endorsed a wide variety of obsessions and compulsions, whereas anorexics tended to endorse symptoms that were related to symmetry and order.

OCD: where the serotonin selectivity story begins.

Since concomitant anxiety is frequent and prominent, obsessive-compulsive disorder (OCD) is classified as an anxiety disorder. However, effective antidepressant and anxiolytic agents that are nonserotonin-selective are generally ineffective in significantly reducing OCD symptoms, while the potent serotonin reuptake inhibitor, the tricyclic clomipramine, and several serotonin selective reuptake inhibitors (SSRIs) are efficacious. These results suggest that serotonergic transmission may be important in achieving significant antiobsessive efficacy. Although no significant differences in efficacy between SRIs and SSRIs have been demonstrated in the treatment of OCD, there are important differences in side effect profiles and pharmacokinetic factors. Further research in the treatment of OCD is required on comparative efficacy of SRIs, the choice of SRI agents following initial nonresponse, and effects resulting from the long-term use of SRIs.

Cerebrospinal fluid levels of kynurenine pathway metabolites in patients with eating disorders: relation to clinical and biochemical variable.

In brain, most L-tryptophan is metabolized to indoleamines, whereas in systemic tissues L-tryptophan is catabolized to kynurenine pathway metabolites. Among these latter compounds are: quinolinic acid, an N-methyl-D-aspartate receptor agonist; kynurenic acid, an antagonist of excitatory amino acid receptors that also reduces quinolinic acid-mediated neurotoxicity; and L-kynurenine, a possible convulsant. Because the metabolism of L-tryptophan through the kynurenine pathway is dependent upon adequate nutrition, we sought to determine whether the impaired nutrition characteristic of eating-disordered patients might be associated with specific disturbances in this metabolic pathway. Cerebrospinal fluid levels of L-tryptophan, quinolinic acid, kynurenic acid, L-kynurenine, and 5-hydroxyindoleacetic acid were measured in medication-free female patients meeting DSM-III-R criteria for either anorexia nervosa (n = 10) or normal-weight bulimia nervosa (n = 22), studied at varying stages of nutritional recovery. Eight healthy, normal-weight females served as a comparison group. Cerebrospinal fluid levels of kynurenic acid were significantly reduced in underweight anorectics, compared to normal females, but returned to normal values with restoration of normal body weight. Although cerebrospinal fluid quinolinic acid levels were not different from controls, the ratio of quinolinic acid to kynurenic acid was significantly increased during the underweight phase of anorexia nervosa. Furthermore, in the eating-disordered patients, kynurenic acid levels in cerebrospinal fluid correlated positively with percent-of-population average body weight.(ABSTRACT TRUNCATED AT 250 WORDS)

Obsessive compulsive disorder: comorbid conditions.

According to DSM-IV criteria, obsessive compulsive disorder (OCD) is an anxiety disorder that is characterized by recurrent, intrusive images or thoughts and/or stereotyped, repetitive behaviors that are associated with marked distress, anxiety, or psychosocial impairment. The differential diagnosis of OCD can be quite difficult since OCD symptomatology can occur as either primary or secondary phenomena. Comorbid depression or personality disorder is not uncommon in patients with primary OCD. Other comorbid conditions that occur with OCD can be divided into three major groups based on core features: (1) disorders of altered risk assessment; (2) incompleteness/habit-spectrum disorders; and (3) psychotic spectrum disorders. Such a categorization of core dimensions and comorbid conditions may prove useful in identifying distinct OCD subtypes that share underlying neurobiological or treatment response characteristics.

Memory in sub-clinical obsessive-compulsive checkers.

In a series of experiments we extended the research on possible memory deficits in subclinical obsessive-compulsive Ss who reported excessive checking. Using a variety of memory tests we compared 20 subclinical checkers to 20 Ss without obsessive-compulsive symptomatology. Contrary to hypothesis, checkers remembered self-generated words better than read words just as much as did normals, but they were more likely than normals to report thinking they had studied words that, in fact, had not been on the study list. Further, they more often confused whether they read or generated the words at study. Checkers did not appear to perseverate on already-recalled words on repeated free recall tests any more than did normals. However, checkers remembered fewer actions overall and more often misremembered whether they had performed, observed, or written these actions. Such memory deficits may contribute to the development of excessive checking.

Relation of dissociative phenomena to levels of cerebrospinal fluid monoamine metabolites and beta-endorphin in patients with eating disorders: a pilot study.

Dissociation is made manifest by a failure to integrate thoughts, feelings, memories, and actions into a unified sense of consciousness. Although dissociation is presumed to be a special state of consciousness manifested by state-dependent memory and physiology, the psychobiology of dissociation is poorly understood. In this study, we examined cerebrospinal fluid levels of the major monoamine metabolites and beta-endorphin in patients with eating disorders (11 with anorexia nervosa, 16 with bulimia nervosa), while they were acutely ill. Dissociative capacity was measured using the Dissociative Experiences Scale (DES). We provide evidence that neurochemical changes in dopaminergic, serotonergic, and opioid systems may be associated with the clinical expression of dissociation in patients with eating disorders during the acute phase of their illness. These preliminary results are compatible with previous studies of neurochemical disturbances in the eating disorders and suggest that future work in dissociation should specifically include examination of these neurobiologic systems.

Double-blind study of adjuvant buspirone for fluoxetine-treated patients with obsessive-compulsive disorder.

In a double-blind, crossover study, 13 fluoxetine-treated patients with obsessive-compulsive disorder were given adjuvant buspirone and placebo for 4 weeks each. There were no significant differences between buspirone and placebo in obsessive-compulsive, depressive, or anxiety symptoms.

Lack of evidence for Huntington's disease-like cognitive dysfunction in obsessive-compulsive disorder.

Cognitive deficits in patients with structural lesions of the basal ganglia (e.g., Huntington's disease) commonly include slowed processing, reduced verbal fluency, difficulty switching set, impaired egocentric spatial ability, poor recall, and impaired acquisition of motor skills. The goal of this study was to determine if patients with obsessive-compulsive disorder (OCD) would have a similar pattern of cognitive dysfunction. A battery of neuropsychological tests, including reaction time-based measures of cognitive processing speed and a test of procedural, motor-skill learning, was administered to 17 unmedicated OCD patients and 16 age-and education-matched normal controls. Eleven individuals with trichotillomania, matched with the OCD patients on age, education, age at symptom onset, depression, and anxiety were also tested. Contrary to expectation, neither the OCD nor trichotillomania patients were impaired on any of the measures in the battery. The essentially normal performance by these patients suggests that the brain regions responsible for cognitive dysfunction in patients with Huntington's disease may differ from those associated with OCD.

A comparison of the behavioral effects of oral versus intravenous mCPP administration in OCD patients and the effect of metergoline prior to i.v. mCPP.

In prior studies form three centers, an exacerbation of obsessive-compulsive disorder (OCD) symptoms was reported in some (55%-83%) patients with OCD receiving the serotonergic agonist m-chlorophenylpiperazine (m-CPP) orally, whereas intravenously administered mCPP produced anxiety but no OCD symptom exacerbation. In the present replication attempt, 27 OCD patients were given mCPP either orally (n = 17) or intravenously (n = 10) under double-blind conditions, using identical behavioral rating measures. OCD symptoms were significantly increased after intravenous mCPP (0.1 mg/kg), but not after oral mCPP (0.5 mg/kg). Anxiety and other ratings were markedly elevated after intravenous mCPP administration. After oral mCPP administration, anxiety and most other self-ratings were only slightly elevated in comparison to placebo administration, and behavioral rating increases were no different for the OCD patients compared to age-matched healthy controls. Pretreatment with the potent serotonin (5-HT) antagonist, metergoline, prior to intravenous mCPP was associated with essentially complete blockade of the exacerbation in OCD symptoms and the other behavioral responses in the OCD patients. These results suggest that the behavioral response of OCD patients to mCPP are variable and depend on the route and dose of mCPP. In addition, the ability of metergoline to antagonize the behavioral effects of intravenous mCPP suggests that these responses are mediated by 5-HT1/5-HT2 receptors.

A preliminary investigation of the lifetime prevalence of anorexia and bulimia nervosa in patients with obsessive compulsive disorder.

BACKGROUND: Obsessive compulsive disorder (OCD) is currently classified as an anxiety disorder although it possesses many characteristics that distinguish it from other anxiety disorders. Clinically and neurobiologically, OCD appears to overlap somewhat with the eating disorders. METHOD: To assess in a controlled fashion the lifetime prevalence of the eating disorders in patients with OCD, we administered portions of the Structured Clinical Interview for DSM-III-R, Patient Version (SCID-P), to 62 patients (31 men, 31 women) with a primary DSM-III-R diagnosis of OCD. RESULTS: Among the OCD patients, the lifetime prevalence of anorexia nervosa and/or bulimia nervosa was 12.9% (N = 8), and an additional 17.7% (N = 11) met subthreshold criteria for either anorexia or bulimia nervosa. Interestingly, unlike multiple epidemiologic studies that have reported a substantial female preponderance among patients diagnosed with anorexia or bulimia nervosa, there was no significant gender difference in the lifetime prevalence of eating disorders among the patients with OCD. Almost 13% (N = 4) of the men and 6.5% (N = 2) of the women with OCD met criteria for a lifetime diagnosis of anorexia nervosa and 3.2% (N = 1) of the men and 6.5% (N = 2) of the women with OCD met criteria at some time in their lives for bulimia nervosa. In addition, subthreshold criteria for anorexia nervosa or bulimia nervosa were met by an additional 12.9% (N = 4) of the men and 22.6% (N = 7) of the women. CONCLUSION: These data suggest that OCD patients, regardless of gender, have a substantial lifetime prevalence of anorexia and/or bulimia nervosa.

Plasma and cerebrospinal fluid measures of arginine vasopressin secretion in patients with bulimia nervosa and in healthy subjects.

Bulimia nervosa is a psychiatric syndrome associated with intense hunger, deficient satiety mechanisms, an obsessional preoccupation with the adverse consequences of eating, ritualistic binge eating, and subsequent purging to forestall the effects of the binge. The morbidity of this illness reflects both the psychological suffering associated with a life organized around pathological eating behaviors, as well as medical complications such as fluid and electrolyte imbalances that occur largely as a result of purging and laxative abuse. We report here a study of the osmoregulation of plasma arginine vasopressin secretion and of vasopressin levels in the cerebrospinal fluid. This study was undertaken because vasopressin not only functions as the antidiuretic hormone, and thus as a principal modulator of fluid and electrolyte balance, but also because, in animals, centrally directed vasopressin delays the extinction of behaviors acquired during aversive conditioning. Thirteen normal-weight female patients with bulimia nervosa were studied after at least 1 month of nutritional stabilization and supervised abstinence from binge eating and purging. Plasma vasopressin, plasma sodium, and subjective thirst were measured serially before and during a 2-h infusion of 3% hypertonic saline (0.1 ml/kg min). In addition, cerebrospinal fluid was obtained by lumbar puncture upon admission and at 1 week before hypertonic saline infusion in 11 of these patients and in an additional 11 female patients who did not participate in the hypertonic infusion study. Fifteen healthy normal weight individuals (4 female, 11 male) served as controls for the hypertonic saline infusion and a separate group of 11 healthy normal weight female controls underwent puncture. Compared to controls, bulimic subjects showed a significant reduction in the plasma vasopressin response to hypertonic saline; in 12/13, plasma vasopressin correlated closely with plasma sodium, whereas in one patient vasopressin fluctuated erratically, with no relation to plasma sodium. Cerebrospinal fluid vasopressin levels were significantly higher in patients, and correlated positively with basal thirst level, which was enhanced in bulimics. Compared to controls, patients showed significant polyuria. We conclude that patients with bulimia nervosa have abnormal levels of vasopressin in their plasma and cerebrospinal fluid during abstinence from binge eating and purging. The disturbance in osmoregulation may aggravate the maintenance of adequate fluid volume in these patients, while the increase in centrally directed vasopressin may have relevance to their obsessional preoccupation with the aversive consequences of eating and weight gain.