Double-blind parallel comparison of three dosages of sertraline and placebo in outpatients with obsessive-compulsive disorder.

BACKGROUND: Anecdotal evidence suggests patients with obsessive-compulsive disorder (OCD) are treated with selective serotonin uptake inhibitors at dosages significantly higher than those used with depressed patients. The current study examined the efficacy, safety, and optimal dosing strategy of sertraline in patients with OCD. METHODS: Three hundred twenty-four nondepressed outpatients with OCD from 11 sites followed identical protocols using a double-blind parallel design. Following 1 week of single-blind placebo, patients were randomly assigned to 12 weeks of treatment with one of three fixed dosages of sertraline (50, 100, or 200 mg/d) or placebo. RESULTS: Sertraline patients exhibited significantly greater improvement (P < .05) at end point than placebo patients on all three main efficacy measures in the 50-mg/d and 200-mg/d groups and on one measure in the 100-mg/d group. The placebo response was larger in this population of subjects with OCD than in those previously studied. Adverse experiences were common in the sertraline and placebo groups and appeared to be dose-related in the sertraline-treated patients. CONCLUSIONS: Results support the safety and efficacy of daily dosages of 50, 100, and 200 mg of sertraline in the short-term treatment of patients with OCD.

Secondary depression in panic disorder and agoraphobia. I. Frequency, severity, and response to treatment.

Depressive symptomatology in 481 subjects with panic disorder and phobic avoidance was studied as part of an investigation of the efficacy of alprazolam in panic disorder. Subjects who had a major depressive episode (MDE) before the onset of their panic disorder were not included in the trial. With this exclusion criterion, 31% of subjects had a secondary MDE occurring after the onset of the panic disorder. The occurrence of secondary MDE was related to the length of time subjects were ill with panic disorder. Compared with the subjects without depression, those subjects with current MDE had higher scores on measures of anxiety and depression but not on the number of panic attacks per week. The presence of depression and the degree of phobic avoidance contributed independently to measures of the severity of the panic illness. Alprazolam was effective in reducing panic and depressive symptomatology in both depressed and nondepressed subjects with panic disorder. The presence of an MDE was not predictive of the outcome of treatment for the panic and phobic symptoms. Subjects with or without depression responded similarly to alprazolam.

Brain circuits in panic disorder.

This paper reviews the pathophysiology of panic disorder (PD), within the context of newly described "fear circuitries," which have been well characterized in preclinical models. Substantial advances in the neurosciences have made it possible for clinical neuroscientists to refine our understanding of the pathophysiology of PD and the mechanisms of currently effective treatment. These advances have in turn helped generate testable hypotheses for future neurobiological and psychopharmacologic research. Perturbation of mutual modulation ("cross talk") between key brain transmitter systems (serotonin, norepinephrine, gamma-aminobutyric acid, corticotropin-releasing factor, and others) may underlie the pathogenesis of panic-anxiety. Restoration of normal homeostasis may be an important therapeutic component of antipanic therapy and may provide information about underlying neurocircuits. Neuroimaging, an important new tool, has already begun to bridge the gap between the preclinical and clinical neurosciences through confirmation of hypothesized dysfunction of the complex human prefrontal cortex and its subcortical components. In higher species, such as humans, dysfunction of cortical inhibition or excessive cortical activation of caudal limbic structures is postulated to lead to activation of the phylogenetically conserved amygdalofugal pathways. Consistent with probable subtypes of PD, overlapping theoretical models of panic neurocircuitries are proposed, including ventilatory dysregulation, which is coupled with neurovascular instability in a critical area of the panic neurocircuitry--the amygdalohippocampus. Neuroimaging appears a critical tool in guiding further elaboration of the interaction of cortical and subcortical components of the panic neurocircuitry, whereas challenge studies appear crucial in gathering further information regarding brain stem dysfunction.

Alpha 2-adrenergic receptor sensitivity in depressed patients: relation between 3H-yohimbine binding to platelet membranes and clonidine-induced hypotension.

Alpha 2-adrenergic receptor changes during antidepressant treatment were studied using 3H-yohimbine binding to human platelet membranes and clonidine-induced hypotension. Twenty-six patients with major depressive disorder (MDD) participated for 4-6 weeks in a trial of imipramine (2.5 mg/kg/day), tyrosine (100 mg/kg/day), or placebo. Alpha 2-adrenergic receptors measured by 3H-yohimbine binding were not significantly changed following antidepressant treatment. Similarly, clonidine-induced hypotension did not differ significantly following treatment. No measure of alpha 2-adrenergic receptor sensitivity was significantly correlated with clinical improvement. The correlation between platelet receptor binding and clonidine-induced hypotension was not statistically significant, even though both tests are considered to be measures of alpha 2-adrenoceptor sensitivity.

Placebo-controlled trial of the CCK-B antagonist, CI-988, in panic disorder.

BACKGROUND: Based on the induction of panic-like symptoms by infusion of cholecystokinin (CCK) peptide in normals and panic disorder patients, it has been proposed that CCK may play a role in the disease mechanisms underlying anxiety disorders. Selective antagonists of CCK-B receptors can block the challenge-induced symptoms in a dose-dependent manner, leading to the hypothesis that these compounds may have anxiolytic effects. METHODS: A randomized, double-blind study was carried out to compare the effects of placebo with CI-988, a selective antagonist of the CCK-B receptors. Following a one-week placebo lead-in, patients with Panic Disorder with or without Agoraphobia received either placebo or CI-988 100 mg TID for six weeks. Panic attacks were recorded by a daily diary method. RESULTS: A total sample of 88 patients was planned but and interim analysis was carried out when about half the patients had been enrolled (n = 41). All patients improved during treatment and no difference in the weekly rate of panic attacks was seen between the treatment groups. The study was terminated at this point due to the remote likelihood of showing a treatment difference. CONCLUSIONS: CI-988 was not superior to placebo in reducing panic attacks. Several explanations are possible, including the poor pharmacokinetic characteristics of CI-988 which may make it unsuitable to test the CCK hypothesis of anxiety.

CSF diazepam-binding inhibitor concentrations in panic disorder.

Diazepam-binding inhibitor (DBI) is a neuropeptide that has been detected in the brain and cerebrospinal fluid (CSF). Previous studies have suggested the possible role of DBI as a potential endogenous anxiogenic ligand modulating GABAergic transmission at the benzodiazepine-GABA receptor complex. The measurement of DBI immunoreactivity (DBI-IR) in CSF of panic-disorder patients and normal controls was undertaken to assess whether there were differences in the CSF concentration of this peptide to assess possible relationships with other monoamines and peptides. Lumbar CSF was obtained from 18 panic patients (4 men, 14 women) and 9 controls (5 men, 4 women). As a group, no significant differences were found between panic patients' CSF concentration of DBI-IR (1.12 +/- 0.27 pmol/mL) and normal volunteers (1.23 +/- 0.27 pmol/mL). No gender differences were demonstrated. However, we did find a positive correlation between CSF levels of DBI and CSF corticotropin releasing hormone (CRH) in our panic patients.

Elevated plasma thymopoietin associated with therapeutic nonresponsiveness in major depression.

BACKGROUND: Stress predisposes to major depression, and hyperactivity of the stress-activated hypothalamic-pituitary-adrenal (HPA) axis occurs in this disease. Thymopentin, an active fragment of thymopoietin (TP), reduces endocrine and behavioral responses to experimental stress, possibly by lowering plasma TP (pTP) levels. METHODS: Plasma TP and the HPA hormones arginine vasopressin (pAVP), adrenocorticotropic hormone (pACTH), and plasma cortisol (pCORT) were measured in 21 untreated depressed patients and 21 matched control subjects. Clinical responses to antidepressants were evaluated in 17 depressed patients. RESULTS: Plasma TP was elevated in depression (p < .002), with in 8 out of 21 (38%) depressed patients having significant elevations (p < .03). For 17 patients whose antidepressant responses were evaluated, nonresponsiveness occurred in 6 out of 7 (86%) with elevated pTP (>7.5 pg/mL) versus 3 out of 10 (30%) with normal pTP (p < .05). CONCLUSIONS: The significant association of elevated pTP with nonresponsiveness to antidepressant drugs may signify a distinct pathogenesis for the depression of patients with elevated pTP.

Dopamine blocking activity of clomipramine in patients with obsessive-compulsive disorder.

While many data suggest that Obsessive-Compulsive Disorder (OCD) is an illness accompanied by dysregulation of the serotonergic system, interesting clinical evidence and animal studies also suggest possible dysregulation of the dopaminergic (DA) system. In order to determine whether clomipramine (CMI), an antiobsessional agent, is capable of altering DA function, we performed a neuroleptic radioreceptor assay (NRRA) on plasma samples from OCD patients before and after treatment in a double-blind, placebo controlled trial of CMI. CMI produced mild but significant DA D-2 receptor binding activity in an in vitro assay. The degree of dopamine binding activity did not correlate with clinical response to clomipramine. Because it has been suggested that another drug with antiobsessional efficacy, fluoxetine, may also have dopamine blocking properties, it may be speculated that antidopaminergic activity in combination with serotonergic effects is involved in antiobsessional activity of effective agents for some patients.

Plasma pyridoxal phosphate in anxiety disorders.

One hundred and eighty-nine subjects with either generalized anxiety disorder, panic disorder, or obsessive-compulsive disorder were evaluated for plasma pyridoxal phosphate (PLP) levels and compared with normal controls. There was no difference in plasma PLP levels between the anxiety disorder groups and normal controls. Low levels of plasma PLP were found in 42% of the controls. Our results suggest that previous reports of low PLP levels in psychiatric patients are unlikely to be significant in the etiology of the psychiatric disorders.

Sleep Deprivation in social phobia and generalized anxiety disorder.

BACKGROUND: Sleep deprivation has been shown to improve depressive symptoms in some patients with major depressive disorder, but it has not been tested in patients with generalized anxiety disorder (GAD) or social phobia (SP). METHODS: To determine if sleep deprivation altered anxiety or depressive symptoms in patients with GAD (n = 7) or SP (n = 8), we sleep deprived patients and normal controls (n = 18) for one night. RESULTS: On one measure of anxiety, GAD patients improved compared with controls, but there were otherwise no significant change differences between controls and SP or GAD patients. CONCLUSIONS: The lack of benefit is consistent with previous findings that sleep deprivation provides no benefit to patients with other anxiety disorders. Sleep deprivation may be a biological intervention that distinguishes anxiety from affective disorders.

Abnormal peripheral benzodiazepine receptor density associated with generalized social phobia.

BACKGROUND: Peripheral benzodiazepine receptors (PBRs) are involved in regulating stress responses. Abnormally low numbers of platelet PBRs have been found in patients with panic disorder, posttraumatic stress disorder, and generalized anxiety disorder, but not in patients with obsessive-compulsive disorder (OCD) or major depressive disorder (MDD). The purpose of this study was to evaluate the PBR density on platelets from patients with generalized social phobia (GSP). METHODS: The density (Bmax) and dissociation constant (Kd) of platelet PBRs was determined for 53 medication-free patients with GSP and an equal number of control subjects (NC). RESULTS: The GSP group was found to have a significantly lower PBR Bmax than the NC group (GSP = 2764 +/- 1242 vs. NC = 4327 +/- 1850 fmol/mg protein, df = 1,100, F = 22.7, p = .00001). CONCLUSIONS: GSP shares this PBR abnormality with some other anxiety disorders but not with OCD or MDD. PBRs may play a role in the pathophysiology of some anxiety disorders.

Cerebrospinal fluid corticotropin-releasing factor concentrations in patients with anxiety disorders and normal comparison subjects.

Cerebrospinal fluid (CSF) concentrations of corticotropin-releasing factor (CRF) were measured in a group of patients with anxiety disorders and normal comparison subjects (NC) to explore the hypothesis that abnormalities in CRF neuronal regulation occur in patients with anxiety disorders. Analysis of variance (ANOVA) revealed no differences in CSF CRF concentrations between the four diagnostic categories: panic disorder (PD), generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), and NCs. Male OCD patients had higher CSF CRF concentrations than men with PD and GAD and male NCs. CSF CRF concentration was positively correlated with age in women but not in men. These findings suggest that central neuronal CRF regulation may be affected by both age and gender.

CSF prostaglandin-E in agoraphobia with panic attacks.

Prostaglandins are thought to act as neuromodulators of both central catecholamine and endocrine systems. Abnormalities of these systems have been described in affective disorders, in general, and in agoraphobia with panic attacks, in particular. This study measured basal prostaglandin-E (PGE) cerebrospinal fluid (CSF) levels in 20 patients with agoraphobia with panic attacks and 10 nonpsychiatric controls. In a subgroup of patients and controls, CSF levels of adrenocorticotrophic hormone (ACTH) and corticotropin-releasing factor (CRF) were also measured. There was no significant difference in CSF PGE levels between patients and controls. However, patients with higher depression scores had lower CSF PGE levels. CSF PGE levels tended to correlate with CSF ACTH, but not CSF CRF in the patient group, in general, and in the female patients, in particular. These findings do not support an abnormality in basal CNS PGE production in agoraphobia with panic attacks, but suggest further study of the PGE modulatory effect on the hypothalamic-pituitary-adrenal axis in this disorder.

Panic disorder and gastrointestinal symptoms: findings from the NIMH Epidemiologic Catchment Area project.

OBJECTIVE: Clinical experience and recent reports suggest that there is a high prevalence of gastrointestinal symptoms in patients with panic disorder and that there is a high prevalence of panic disorder in patients with irritable bowel syndrome, a functional gastrointestinal disorder. To assess gastrointestinal symptoms in a nonpatient, community-based sample, the authors surveyed the prevalence of gastrointestinal symptoms in individuals with panic disorder and other or no psychiatric disorders obtained in a national community survey. METHOD: Subjects were 13,537 respondents at four sites of the National Institute of Mental Health (NIMH) Epidemiological Catchment Area project. DSM-III diagnoses were determined by using the NIMH Diagnostic Interview Schedule (DIS). Gastrointestinal symptoms were assessed from the somatization disorder section of the DIS. RESULTS: Individuals with panic disorder had a significantly higher rate of endorsing gastrointestinal symptoms, including those typically associated with irritable bowel syndrome, than those with other or no psychiatric diagnosis. CONCLUSIONS: Findings suggest a diagnostic overlap between panic disorder and irritable bowel syndrome, with similar demographic and clinical characteristics of patients. Limitations of the study are discussed in terms of medical assessment and self-report inventories. Practical and theoretical implications are discussed.

Cocaine abuse among schizophrenic patients.

Initial studies have indicated that stimulant abuse is prevalent among schizophrenic persons. To assess the phenomenon of cocaine abuse by patients with schizophrenia, 17 male cocaine-abusing schizophrenic patients were compared with 22 male schizophrenic patients who did not use cocaine. The cocaine-abusing subjects had been hospitalized more frequently, were more likely to be of the paranoid subtype, and were more likely to be depressed at the time of interview. It appears that cocaine abuse may influence both the psychopathologic presentation of schizophrenic patients and the intensity of care that they require.

CSF beta-endorphin and dynorphin in bulimia nervosa.

OBJECTIVE: Preclinical and clinical evidence suggests that central opioid dysfunction may play a role in the pathophysiology of the eating disorders. In particular, endogenous opioids are known to regulate feeding behavior, mood, perception, and neuroendocrine function, all of which are disturbed in patients with eating disorders. Although low concentrations of CSF beta-endorphin have been reported in low-weight patients with anorexia nervosa, central opioid activity in normal-weight patients with bulimia nervosa has not been reported. The authors therefore measured CSF concentrations of beta-endorphin and dynorphin in drug-free female patients with DSM-III-R-defined bulimia nervosa and normal comparison subjects. METHOD: After 4 days of a low monoamine diet and overnight bed rest, CSF was obtained (12-26 cc) from 11 women with bulimia and 17 normal comparison subjects (eight women and nine men). RESULTS: The women with bulimia had significantly lower CSF concentrations of beta-endorphin than did the female comparison subjects. However, CSF concentrations of dynorphin were not significantly different in patients and female or male comparison subjects. beta-Endorphin concentrations were inversely correlated with Beck Depression Inventory scores and the depression subscale of the Eating Disorders Inventory. CONCLUSIONS: These data support a role for central opiates in the mediation of the pathophysiology of the signs and symptoms of bulimia nervosa, although it is impossible to rule out the effects of depression on the results.

Emergence of depressive symptoms in patients receiving alprazolam for panic disorder.

The authors relate their clinical experience with 46 panic disorder patients who were receiving 3-10 mg/day of alprazolam. Fifteen (33%) developed symptoms consistent with DSM-III criteria for major depression despite remission of their panic symptoms. Clinicians should be alert to this potentially reversible complication.

Alprazolam plasma concentrations and treatment response in panic disorder and agoraphobia.

OBJECTIVE: The authors' goal was to evaluate the relationship between plasma concentrations of alprazolam and both treatment response and side effects in patients with panic disorder and agoraphobia. METHOD: Ninety-six patients with panic disorder and agoraphobia were treated at three sites in a 6-week, fixed-dose, double-blind, placebo-controlled, dose-response study of 2 mg/day or 6 mg/day of alprazolam. Assessments were made of panic attacks, avoidance behavior, generalized anxiety, and global response. Blood samples were collected throughout the study and analyzed for alprazolam and other benzodiazepines. RESULTS: Patient compliance with the protocol was judged to be good on the basis of plasma concentrations. According to logistic regression analysis, the relationships between plasma alprazolam concentration and response, as reflected by number of panic attacks reported, phobia ratings, physicians' and patients' ratings of global improvement, and the emergence of side effects, were significant. However, there was no significant relationship between plasma alprazolam concentration and the degree of generalized anxiety symptoms. CONCLUSIONS: The authors conclude that plasma concentration of alprazolam is related to treatment response, particularly in panic attacks. The alprazolam concentration associated with treatment response or with emergence of a given side effect varied widely among individuals, highlighting the necessity for individualized dose adjustment to obtain optimal treatment response while minimizing side effects.

CSF cholecystokinin concentrations in patients with panic disorder and in normal comparison subjects.

Cholecystokinin concentrations in the CSF of 25 patients with panic disorder and 16 normal comparison subjects were ascertained by radioimmunoassay. The patients with panic disorder had significantly lower CSF concentrations of cholecystokinin, which may reflect increased CNS cholecystokinin receptor sensitivity, reduced numbers of receptors, or a compensatory reduction in cholecystokinin octapeptide secondary to theoretically increased central cholecystokinin tetrapeptide activity.

Rate-sensitive inhibition of ACTH release in depression.

Rate-sensitive inhibition of ACTH release is abnormal in Cushing's disease but uncharacterized in depression. The authors found that two of 10 depressed patients had paradoxical responses, suggesting the existence of a hypothalamic-pituitary-adrenal axis abnormality in depression that is independent of dexamethasone suppression test results.