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Many antidepressants are known to cause adverse sexual effects. Bupropion is an antidepressant with fewer reported adverse sexual effects. Studies of sexual side effects are often confounded by psychiatric and medical conditions affecting sexual function. In this study, the effects of bupropion on subjective and objective sexual functioning were measured in healthy men. Thirteen men without psychiatric or medical illness completed a 2-week, placebo-controlled, double-blind, crossover trial of bupropion sustained-release 300 mg/day. Subjects had a 1-week washout period between trials. Sexual function was measured using a validated, self-administered questionnaire and the RigiScan, an instrument measuring nocturnal penile tumescence and rigidity. No differences were found in self-reported sexual function, number of erections, total erection time, or penile rigidity in subjects taking bupropion compared with those taking placebo or baseline. These findings support that bupropion does not have subjective adverse sexual side effects and does not affect nocturnal erections in healthy men.

OBJECTIVES [corrected] To assess efficacy and safety of gabapentin in the treatment of bipolar disorder. METHODS This was a double-blind, placebo-controlled trial of adjunctive gabapentin (dosed flexibly between 900 and 3,600 mg/day). Patients with a lifetime diagnosis of bipolar disorder (type I), and who were currently suffering from symptoms of either mania, hypomania or a mixed state despite ongoing therapy with lithium, valproate, or lithium and valproate in combination were eligible for inclusion. The primary efficacy measures were the baseline to endpoint change in total score on the Young Mania Rating Scale (YMRS) and the Hamilton Depression Rating Scale (HAM-D). RESULTS Both treatment groups had a decrease in total YMRS from baseline to endpoint, but this decrease was significantly greater in the placebo group (-9) than the gabapentin group (-6) (p < 0.05). No difference between treatments was found for the total score on the HAM-D. Secondary efficacy measures were not different between treatment groups. More patients in the placebo group had changes made to their ongoing lithium therapy (n = 12) compared to the gabapentin group (n = 4). When these patients are removed from the efficacy analysis, the YMRS treatment difference still favors placebo, but is no longer statistically significant. Based on gabapentin plasma levels at termination, some patients did not take the study drug as prescribed. CONCLUSIONS The findings of this study did not demonstrate that gabapentin is an effective adjunctive treatment when administered to outpatients with bipolar disorder.

BackgroundData concerning appropriate treatment in panic disorder following an initial response to acute therapy are limited.AimsTo assess the safety and efficacy of continued fluoxetine treatment following successful acute therapy of panic disorder.MethodPatients who responded to acute fluoxetine treatment were randomised to 24 weeks of continued fluoxetine or placebo.ResultsFluoxetine responders randomised to continue on their acute-phase fluoxetine dose experienced statistically significant improvement in panic attack frequency and phobia rating scale score over 24 weeks of therapy, while those switched to placebo experienced statistically significant worsening in Hamilton Anxiety (HAM–A), Hamilton Depression (HAM–D) and SCL–90–R rating scores.ConclusionsFluoxetine was associated with improved clinical outcomes compared with placebo during continuation therapy.

Background: This study was designed to compare the efficacy, safety, tolerability profiles, and effects on quality of life of the serotonin selective reuptake inhibitor antidepressant sertraline versus the nonselective tricyclic antidepressant amitriptyline and placebo in patients with major depression. Method: Outpatients with DSM-III-R major depression were randomly assigned to double-blind treatment for 8 weeks with sertraline (50-200 mg daily), amitriptyline (50-150 mg daily), or matching placebo. Assessments included the Hamilton Rating Scale for Depression, Montgomery-Asberg Depression Rating Scale, Clinical Global Impressions-Severity of Illness scale, Clinical Global Impressions-Improvement scale, Global Assessment Scale, Profile of Mood States, Beck Depression Inventory, Quality of Life Enjoyment and Satisfaction Questionnaire, and Health-Related Quality of Life battery. Results: All treatment groups demonstrated statistically significant improvement from baseline in depression ratings by Week I and thereafter. The antidepressant effects of amitriptyline and sertraline were significantly (p

A series of European Panic Forum meetings presented a unique opportunity to gather data on patients with panic disorder and their treatment. Data were collected on nearly 1200 panic disorder patients by means of a postal questionnaire. The survey gathered data on patient history, presentation, healthcare resources and management. The average patient was in their mid-thirties and had suffered panic disorder for a mean period of almost 5 years. In addition to panic disorder, many patients experienced comorbid depression, agoraphobia or generalized anxiety. Over half the patients were seen by a cardiovascular specialist prior to being seen by a psychiatrist, suggesting poor recognition of panic disorder in general practice. Almost 50 per cent of patients were treated with tricyclic antidepressants (TCAs), almost 60 per cent with selective serotonin reuptake inhibitors (SSRIs) and over 80 per cent with benzodiazepines. Of the drug treatments, SSRIs were considered to be markedly or moderately effective in 68 per cent of patients, compared with 59 per cent receiving benzodiazepines and 58 per cent receiving TCAs. Few patients received psychological interventions. In patients receiving combined treatment with either a benzodiazepine plus an antidepressant, or cognitive-behavioural therapy plus drug therapy, treatment was considered effective in 98–99 per cent of cases. © 1997 John Wiley & Sons, Ltd.

Cholecystokinin (CCK), a gastrin-like neuropeptide, exists in the central nervous system in several forms. The octapeptide (CCK-8) occurs in predominantly sulfated form (CCK-8S), and the tetrapeptide (CCK-4) occurs in smaller but significant quantities. This review highlights recent developments in preclinical and clinical research into the potential role for CCK in mediating anxiety states. Relevant animal and human studies of administration of CCK agonists are discussed, as well as recent data regarding the concentration of CCK-8S in cerebrospinal fluid from patients with panic disorder, bulimia nervosa, and obsessive compulsive disorder. Finally, the development of agents that specifically antagonize CCK receptors will be described, as will potential therapeutic uses for these new compounds.

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.

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 ofwhich are disturbed in patients with eating disorders. Although low concentrations of CSF �3-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 �-endorphin and dynorphin in drug-free female patients with DSM-III-R-defined bulimia nervosa and normal comparison subjects. Method: After 4 days ofa low monoamine diet and overnight bed rest, CSF was obtained (12-26 cc) I rom 1 1 women with bulimia and 1 7 normal comparison subjects (eight women and nine men). Results: The women with bulimia had significantly lower CSF concentrations of �3-endorphin than did the female comparison subjects. However, CSF concentrations of dynorphin were not significantly different in patients and female or male comparison subjects. �3-Endorphin concentrations were inversely correlated with Beck Depression Inventory scores and the depression subscale ofthe 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. (Am J Psychiatry 1992; 149:1086-1090)

Epidemiologic data as well as data from treatment-seeking populations indicate that substance abuse disorders and other psychiatric disorders co-occur more commonly than would be expected by chance. In particular, substance abuse, especially cocaine abuse or dependence and alcoholism, is a far more common phenomenon in the population of patients with bipolar affective disorder than in the general population. National Institute of Mental Health Epidemiologic Catchment Area data indicate that bipolar affective disorder is the axis I disorder most likely to be associated with some form of substance abuse or dependence. Evidence from patient samples seeking treatment for substance abuse disorders as well as for psychiatric disorders suggests that clinical samples reflect similar patterns. There is evidence that bipolar patients with substance abuse have a worse course of illness. Diagnosing bipolar affective disorder in the face of substance abuse is difficult because the effects of drugs of abuse, particularly with chronic use, can mimic nearly any psychiatric disorder. At present, the data concerning a genetic link between bipolar affective disorder and substance abuse disorders are inconclusive. There are very few controlled data addressing either clinical features of, or specific treatment efforts with, this population. There is some theoretic rationale for the use of anticonvulsant, antikindling agents in this population, but no controlled studies have as yet been reported. In particular, a comparison of a mood-stabilizing agent, such as lithium, with an antikindling agent, such as valproate or carbamazepine, would be of theoretic and practical interest.

Various antidepressants and anxiolytic agents have proved to be effective as short-term therapy for generalized anxiety disorder (GAD) and other anxiety disorders. However, less is known about their efficacy in the long-term treatment of GAD. This gap in our knowledge poses a problem for physicians, who treat GAD over several months or years. More information from long-term, placebo-controlled studies of the efficacy of drug therapy for GAD will help clinicians in treatment planning. Recently, the anxiolytic effectiveness exhibited by venlafaxine extended release (venlafaxine XR) in short-term, placebo-controlled studies of nondepressed patients was confirmed in 2 long-term, placebo-controlled trials. Venlafaxine XR maintained its efficacy for up to 6 months. Compared with placebo, it demonstrated statistically significant efficacy when administered once daily in doses ranging between 37.5 and 225 mg. In addition, the incidence of adverse events was low and generally comparable to that for placebo. In light of these results, venlafaxine XR has a unique role in the long-term treatment of GAD.

Background Fluoxetine and its active metabolite norfluoxetine have long half-lives of 4-6 days and 4-16 days, respectively. We postulated that, owing to the long elimination half-life, patients diagnosed with panic disorder might be maintained on fluoxetine taken once a week, after being treated initially with daily doses of fluoxetine. Method Ten patients with DSM-III-R panic disorder were treated openly with fluoxetine, 20-40 mg daily. Once panic free, these patients were switched to once-weekly dosing of fluoxetine, and dosage was titrated as needed. Results All 10 patients successfully switched to once-weekly dosing. One patient reported recurrence of panic attacks 18 months after the switch. After a brief treatment for 4 weeks with benzodiazepines and daily fluoxetine, the patient was once again maintained on once-weekly dosing when rechallenged. Patients have been maintained in a panic-free state for up to 26 months with a single weekly dose of fluoxetine ranging from 10 to 60 mg. The medication was well tolerated. Conclusion Fluoxetine at doses ranging from 10 to 60 mg administered once weekly appears to be effective maintenance treatment for patients with panic disorder who were initially treated successfully with daily fluoxetine. A once-weekly regimen may allow for considerable cost savings and may serve as a convenient alternative method for treating panic disorder.

Normal-weight bulimic patients have disturbed appetite, mood, and neuroendocrine function and often respond to antidepressants. Since these findings suggest abnormalities in brain monoaminergic pathways, the authors measured CSF monoamine concentrations in 27 normal-weight bulimic patients and 14 volunteers. Bulimic patients had a significantly lower mean CSF norepinephrine concentration. Levels of CSF 5-HIAA, the major serotonin metabolite, and CSF HVA, the major dopamine metabolite, were normal, although more frequent binge-eating in bulimic subjects was associated with a significantly lower CSF HVA level. Whether trait- or state-related, monoaminergic disturbances are part of this disorder's neurobiological syndrome. The lower CSF norepinephrine concentration suggests bulimia is not simply a variant of affective disorders.

Background Irritable bowel syndrome (IBS) is a chronic disorder that has been found to be associated with psychiatric disorders and a history of physical and/or sexual abuse. To date, the relationship of posttraumatic stress disorder (PTSD) and IBS has not been investigated. The primary purpose of this study was to examine the relationship of IBS and PTSD. Method Fifty consecutive IBS patients admitted to a clinical treatment study were assessed for IBS, trauma history, and psychiatric disorders. Results Twenty-seven IBS patients (54%) met criteria for a psychiatric diagnosis at some time in their lives. Twenty-two patients (44%) reported a trauma history. Eighteen (36%) were diagnosed with PTSD. Those IBS patients with a trauma history were more likely to have other comorbid psychiatric diagnoses. Conclusion These results suggest that IBS is often associated with psychiatric disorders, indicating that assessment and treatment of these comorbid conditions may be important in the treatment of IBS. PTSD, which had not been previously investigated in relation to IBS, had a high prevalence, indicating the need for careful trauma and PTSD assessment in patients with IBS. Patients with IBS who have a trauma history may be more at risk for other comorbid psychiatric disorders than IBS patients without a trauma history.

OBJECTIVE The authors evaluated the frequency of body dysmorphic disorder in patients with a primary diagnosis of anxiety disorders and major depression. METHOD Patients with social phobia (N = 54), obsessive-compulsive disorder (N = 53), generalized anxiety disorder (N = 32), panic disorder (N = 47), and major depression (N = 42) and normal comparison subjects (N = 33) were studied. RESULTS Body dysmorphic disorder was most common in patients with social phobia (11%) and obsessive-compulsive disorder (8%); it was less prevalent among patients with panic disorder (2%), generalized anxiety disorder (0%), and major depression (0%) and among normal subjects (0%). CONCLUSIONS These findings suggest that body dysmorphic disorder may share etiologic elements with social phobia and obsessive-compulsive disorder.

The authors compared the distribution of somatic symptoms associated with generalized anxiety disorder in 28 patients with "pure" generalized anxiety disorder and 77 patients with generalized anxiety disorder plus comorbid current or lifetime psychiatric diagnoses. They found no significant differences in individual symptom endorsement between the two groups, indicating that the basic symptoms of generalized anxiety disorder are specific to the disorder itself.

Irritable bowel syndrome (IBS) is a common and potentially disabling functional gastrointestinal disorder characterized by abdominal pain and altered bowel patterns. A significant amount of clinical and research data suggest the importance of the brain-gut interaction in IBS. This review examines the observed high prevalence of psychiatric disorders in patients with IBS. The published literature indicates that fewer than half of individuals with IBS seek treatment for it. Of those who do, 50% to 90% have psychiatric disorders, including panic disorder, generalized anxiety disorder, social phobia, posttraumatic stress disorder, and major depression, while those who do not seek treatment tend to be psychologically normal. Both physiologic and psychosocial variables appear to play important roles in the development and maintenance of IBS. Recent information suggests that the association of IBS and psychiatric disorders may be more fundamental than was previously believed. A brain-gut model for IBS is presented, and the role of traumatic stress and corticotropin-releasing factor as modulators of the brain-gut loop is discussed. Finally, the rationale for the use of psychotropic agents in the treatment of IBS with or without psychiatric symptoms is presented.

OBJECTIVE The goal of this study was to test the validity of generalized anxiety disorder as an independent diagnostic entity and to evaluate the prevalence and type of other psychiatric disorders coexisting with generalized anxiety disorder. Although a few published studies have addressed the subject, this study presents data from a larger group of subjects and excludes concurrent major depression as a potential confound. METHOD The authors studied patients with a primary diagnosis of generalized anxiety disorder assigned after evaluation with the Structured Clinical Interview for DSM-III-R. Patients with a concurrent major depressive episode were excluded. All diagnoses for which the patient met criteria were determined, including lifetime occurrence of major depressive episode and substance use. RESULTS One hundred nine patients with generalized anxiety disorder were included in the analysis. Twenty-eight (26%) of these patients were not given any other lifetime psychiatric diagnosis. The most prevalent comorbid diagnoses were social phobia (25 [23%] of the patients) and simple phobia (23 [21%] of the patients). Forty-six (42%) of the patients with generalized anxiety disorder had experienced at least one major depressive episode during their lifetime. CONCLUSIONS These results support previous findings of high rates of psychiatric comorbidity in generalized anxiety disorder and validate the usefulness of generalized anxiety disorder as a separate diagnostic entity.

Background We assessed the tolerability and utility of switching fluoxetine nonresponders to citalopram the day that fluoxetine therapy was stopped. Method Fifty-eight outpatients with DSM-IV major depressive episode and prospectively confirmed nonresponse to fluoxetine (mean final dose = 31 mg/day) were switched directly to citalopram (20 mg/day). Of the 58 patients, 44 (76%) had never been successfully treated with antidepressant medication. During a 12-week open-label treatment period, citalopram could be titrated up to a maximum dose of 60 mg/day. Response was evaluated using the Clinical Global Impressions (CGI) scale, the 24-item Hamilton Rating Scale for Depression, and several other measures. Results Eighty-one percent (N = 47) completed the trial, and citalopram (mean dose = 38.8 mg/day) was well tolerated. The intent-to-treat CGI response rate was 46% (26/57) at week 6 and 63% (36/57) at study endpoint; the completer response rate was 76% among the 47 patients who completed the 12-week trial. Improvement from baseline on all dependent measures was statistically significant after the first week of citalopram treatment. Conclusion Fluoxetine nonresponders can be quickly switched to citalopram, with good tolerability and reasonable chance of therapeutic benefit. Further work is necessary to assess the merits of this treatment strategy relative to other options.

Social anxiety disorder is an extremely common and potentially disabling psychiatric disorder. Generalized social anxiety disorder, a subtype of the disorder, is believed to be the most common and most severe form. It is also the form that is most often associated with other psychiatric disorders. Unless the clinician has a high index of suspicion, social anxiety disorder may remain undetected. The clinical and treatment implications of the most common psychiatric comorbidities associated with social anxiety disorder are discussed in this article, with a focus on major depression, panic disorder, posttraumatic stress disorder, and alcohol abuse/dependence. Other psychiatric disorders and some medical conditions commonly associated with social anxiety disorder are briefly mentioned. Finally, a differential diagnosis of social anxiety disorder is described. Individuals who present for treatment of other anxiety disorders, mood disorders, or alcohol/substance abuse disorders should be considered at risk for current but undetected social anxiety disorder.

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.

A 12-week, open label flexible dosing study was conducted to evaluate the efficacy of bupropion-SR in the treatment of generalized social phobia. The primary outcome measures include the Clinical Global Impression of Improvement (CGI-I) and the Brief Social Phobia Rating Scale (BSPS). A total of 18 subjects were enrolled. Five of the ten subjects who completed all 12 weeks were considered as responders. Response to treatment was defined as a CGI-I score of 1 or 2, ("much improved" or "very much improved," respectively) and a50% decrease in BSPS score. The final doses for the completers ranged between 200 and 400 mg/day (mean 366 +/- 68 mg/day). The medication was generally well tolerated. Findings from this open-label trial suggest that bupropion-SR may be useful in treating generalized social phobia.

A randomized, double-blind, placebo-controlled, parallel-group study was conducted to evaluate the efficacy and safety of gabapentin in relieving the symptoms of panic disorder. One hundred three patients were randomly assigned to receive double-blind treatment with either gabapentin (dosed flexibly between 600 and 3,600 mg/day) or placebo for 8 weeks. No overall drug/placebo difference was observed in scores on the Panic and Agoraphobia Scale (PAS) (p = 0.606). A post hoc analysis was used to evaluate the more severely ill patients as defined by the primary outcome measure (PAS score > or = 20). In this population, the gabapentin-treated patients showed significant improvement in the PAS change score (p = 0.04). In patients with a PAS score of 20 or greater, women showed a greater response than men regardless of treatment. Adverse events were consistent with the known side effect profile of gabapentin and included somnolence, headache, and dizziness. One patient experienced a serious adverse event during the study. No deaths were reported. The results of this study suggest that gabapentin may have anxiolytic effects in more severely ill patients with panic disorder.

Data from early studies of selective serotonin reuptake inhibitors have shown that these agents are effective in the treatment of social anxiety disorder (social phobia). This review highlights the outcomes of three large clinical trials of paroxetine in patients with social anxiety disorder. In two of the studies, patients received a flexible dose of paroxetine (20-50 mg/day) or placebo; the third trial was a fixed-dose study, in which patients received paroxetine 20, 40, or 60 mg/day, or placebo. A total of 861 subjects were randomized to treatment for 12 weeks, in centers across the U.S.A., Canada, Europe, and South Africa. The primary outcome measures were the Clinical Global Impressions (CGI) Global Improvement item and Liebowitz Social Anxiety Scale (LSAS) Total Score. In each of the studies, 45-66% of patients receiving paroxetine were rated as responders (very much or much improved on the CGI scale). Paroxetine treatment improved symptoms of social anxiety, as measured by the LSAS, compared with placebo. Differences between paroxetine and placebo groups were statistically significant and were clinically relevant within each study. In general, paroxetine was well tolerated. Paroxetine is effective for the treatment of social anxiety disorder. Based on the findings from these studies, a starting dose of 20 mg/day is recommended. The range of efficacy appears to be 20-50 mg/day for most patients.

ContextGeneralized anxiety disorder (GAD) is a chronic disorder that is associated with debilitating psychic and somatic symptoms. Venlafaxine extended-release (XR) capsules have been shown to be effective in short-term treatment of patients with GAD without major depressive disorder (MDD), but long-term data are needed to establish whether this agent confers persistent benefits.ObjectiveTo compare the 6-month efficacy and safety of a flexible dosage of venlafaxine XR in outpatients with GAD without associated MDD.DesignSix-month, randomized, double-blind, placebo-controlled, parallel-group trial conducted May 1996 to October 1997.SettingFourteen outpatient clinics and private psychiatric practices in the United States.ParticipantsA total of 251 outpatients aged 18 years or older who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for GAD, had sufficient symptoms to require treatment, and did not have coexisting MDD.InterventionsParticipants were randomly assigned to receive either placebo (n=127) or venlafaxine XR (75, 150, or 225 mg/d, as required to control symptoms; n=124) for 28 weeks.Main Outcome MeasuresChanges from baseline in the Hamilton Rating Scale for Anxiety (HAM-A) total score, the HAM-A psychic anxiety factor score, and the Clinical Global Impressions (CGI) scale Severity of Illness and Global Improvement scores, compared by intervention group.ResultsDuring weeks 6 through 28, response rates in the venlafaxine XR group were 69% or higher compared with rates of 42% to 46% in the placebo group (P

Investigation of the potential role for endogenous opiates as a modulator of anxiety states has yielded variable results. Increased plasma [3-endorphin has been reported accompanying surgical stress (Pickar et al 1982) and with high anxiety ratings in women during menstruation (Veith et al 1984). Can" et al (1986) found no significant change in plasma [3-endorphin during lactate infusion before and after treatment with alprazolam in panic disorder patients or controls but did note a slight decrease in 13-endorphin over time secondary to acclimatiza~'ion. Dager et al (1989) found higher 13-endorphin levels in panic disorder than in depressed patients and a slight decrease in plasma [3-endorphin during lactate infusion in panic disorder patients, depressed patients, and controls. George et al (1989) found significantly higher

While parenting is a universal human behavior, its neuroanatomic basis is currently unknown. Animal data suggest that the cingulate may play an important function in mammalian parenting behavior. For example, in rodents cingulate lesions impair maternal behavior. Here, in an attempt to understand the brain basis of human maternal behavior, we had mothers listen to recorded infant cries and white noise control sounds while they underwent functional MRI (fMRI) of the brain. We hypothesized that mothers would show significantly greater cingulate activity during the cries compared to the control sounds. Of 7 subjects scanned, 4 had fMRI data suitable for analysis. When fMRI data were averaged for these 4 subjects, the anterior cingulate and right medial prefrontal cortex were the only brain regions showing statistically increased activity with the cries compared to white noise control sounds (cluster analysis with one-tailed z-map threshold of P0.001 and spatial extent threshold of P0.05). These results demonstrate the feasibility of using fMRI to study brain activity in mothers listening to infant cries and that the anterior cingulate may be involved in mothers listening to crying babies. We are currently replicating this study in a larger group of mothers. Future work in this area may help (1) unravel the functional neuroanatomy of the parent-infant bond and (2) examine whether markers of this bond, such as maternal brain response to infant crying, can predict maternal style (i.e., child neglect), offspring temperament, or offspring depression or anxiety.

Data concerning appropriate treatment in panic disorder following an initial response to acute therapy are limited.To assess the safety and efficacy of continued fluoxetine treatment following successful acute therapy of panic disorder.Patients who responded to acute fluoxetine treatment were randomised to 24 weeks of continued fluoxetine or placebo.Fluoxetine responders randomised to continue on their acute-phase fluoxetine dose experienced statistically significant improvement in panic attack frequency and phobia rating scale score over 24 weeks of therapy, while those switched to placebo experienced statistically significant worsening in Hamilton Anxiety (HAM-A), Hamilton Depression (HAM-D) and SCL-90-R rating scores.Fluoxetine was associated with improved clinical outcomes compared with placebo during continuation therapy.

Treatment guidelines which are available are intended for treatment of medically healthy patients. There is little information in the literature regarding the treatment of patients who are medically ill. Anxiety and anxiety disorders are frequently encountered in patients with serious medical disorders. These medically ill patients may have substantial changes in pharmacokinetic factors as a result of their current illness or treatment. Also, treatment considerations related to their accompanying medical treatment(s) are sometimes required. These various factors may result in a different initial choice of agents, alterations in the dosage of a given agent, or even preclude the use of some standard agents. In this chapter, we first present a review of the current psychopharmacologic treatment of anxiety disorders. In the second section, we review the potential pharmacokinetic consequences of serious hepatic renal, pulmonary and cardiac disease relevant to the pharmacological treatment of anxiety.

Depression and anxiety often coexist. When they co-occur, both anxiety and depression appear to be more severe. Increased morbidity, poorer acute and long-term outcome, increased suicide risk, and increased treatment resistance are associated with comorbid anxiety and depression. The term anxious depression has taken on newer meaning with the changes in the diagnostic system that allow for concurrent diagnosis of anxiety disorders and major depression. Attention to the subtype of both anxiety and depression could have significant effects on treatment choice by the clinician. The authors review some historical aspects of anxious depression and also highlight some of the advances in differential diagnosis and treatment of coexisting depression and anxiety.

Although panic attacks account for only a portion of the morbidity of panic disorder and panic attack frequency assessments are unreliable, studies of drug efficacy in panic disorder have generally used reduction in panic attack frequency as the primary measure of improvement. The authors studied the efficacy of fluoxetine treatment in panic disorder and measured the relative contributions of changes in symptoms to overall improvement.Patients with a diagnosis of panic disorder (N = 243) were randomly assigned to treatment with 10 or 20 mg/day of fluoxetine or placebo. Primary outcome measures were change in panic attack frequency and clinician-rated Clinical Global Impression improvement scores. Other assessments included a panic attack inventory, clinician-rated and patient-rated versions of the Panic and Phobic Disorder Change Scale, a phobia rating scale, the Hamilton Anxiety Rating Scale, the 21-item Hamilton Depression Rating Scale, and the Sheehan Disability Scale. Correlations were determined between outcomes in individual symptom domains and overall clinical outcome.Fluoxetine, particularly the 20-mg/day dose, was associated with more improvement than was placebo in patients with panic disorder across multiple symptom measures, including global improvement, total panic attack frequency, phobic symptoms, and functional impairment. Global improvement was most highly correlated with reductions in overall anxiety and phobic symptoms and least correlated with reduction in panic attacks. Fluoxetine treatment for panic disorder was well tolerated, with a safety profile consistent with that observed for fluoxetine in other disorders.These data provide support for the efficacy and safety of fluoxetine treatment in reducing panic attacks, phobic symptoms, anxiety, and depressive symptoms in patients with panic disorder. Reductions in panic attack frequency in subjects given either fluoxetine or placebo were less closely related to overall clinical improvement than reductions in phobic avoidance, anxiety, depressive symptoms, and functional impairment, suggesting that outcome measures in this disorder should be more broadly based.

The optimal assessment of treatment outcome for studies assessing the efficacy of treatments for panic disorder has been a controversial topic. A recent National Institute of Mental Health (NIMH)-sponsored consensus conference addressed this important topic, and a summary paper regarding assessment of essential elements of the disorder resulted. Among other conclusions, it was agreed that several different domains should be considered as essential. This article reviews three pivotal studies assessing the efficacy of paroxetine for the treatment of panic disorder, and evaluates these studies for inclusion of those variables considered essential. Additionally, some data were reanalyzed to determine the percentage of individuals in these studies who are unequivocal responders (i.e., were both panic-free and rated on global assessment as responders). A longer-term treatment and relapse study is also mentioned briefly.

Panic disorder and major depression frequently coexist in the clinical setting. Patients with overlapping symptoms of depression and panic disorder may have more severe symptoms, may require earlier treatment, earlier and more frequent hospitalization, and may have worse outcomes. In addition, such patients are at greater risk for suicide than those having either disorder alone. In light of the importance of these clinical consequences, the authors will review the available literature on the prevalence and prognosis of comorbid depression and panic disorder and will highlight the major clinical characteristics of panic disorder in depressed patients and the treatment strategies most often used.

Objective: The anxiogenic and panicogenic effects of peripheral administration of the cholecystokinin-B receptor agonist pentagastrin and placebo were evaluated in patients with generalized anxiety disorder and normal comparison subjects. Method: Seven patients with generalized anxiety disorder and seven age- and sex-matched normal subjects received an intravenous bolus of placebo and pentagastrin. Results: Panic attacks occurred in five patients with generalized anxiety disorder (71%) and in one normal subject (14%). Patients with generalized anxiety disorder were more likely to report more nonpanic anxiety than were normal subjects. Conclusions: Patients with generalized anxiety disorder appear to exhibit greater subjective sensitivity to pentagastrin than do normal subjects. (Am J Psychiatry 1997; 154:700‐702) C holecystokinin tetrapeptide (CCK-4) is a neurotransmitter that has high affinity for the cholecystokinin-B (CCK-B) receptors in the central nervous system and may play a role in the modulation of anxiety in animals and humans (1). Specifically, in patients with panic disorder, an intravenous bolus of CCK-4 or the synthetic analog pentagastrin reliably provokes panic attacks in the majority of subjects (2‐4). Since the administration of CCK-4 to healthy normal subjects also induces panic attacks at substantially higher doses than in patients with panic disorder, it is hypothesized that enhanced sensitivity to CCK stimulation may be present in panic disorder (4). To explore whether CCK sensitivity may be present in anxiety disorders other than panic disorder, we compared the panicogenic and anxiogenic effects of pentagastrin and placebo infusion in patients with generalized anxiety disorder and in normal subjects.

There has been significant progress over the past 30 years in our understanding of the treatment of panic disorder. There are now several different classes of pharmacological treatments, as well as cognitive-behavioral treatments that have been shown to have efficacy in treating panic disorder. Despite the increase in the knowledge base, many patients are only partially responsive or unresponsive to initial treatment efforts. A differential diagnostic approach to reviewing possible causes for treatment failure is presented. These causes include coexisting psychiatric disorders, unrecognized medical factors, environmental stressors, and others. Additionally, a review of factors specifically related to elderly and to very young treatment-resistant panic disorder patients is presented, along with some suggestions for evaluation and treatment. Based on the limited literature and clinical experience, practical clinical suggestions for approaching identified factors are presented.

Billions of dollars are spent annually in the process of developing and marketing new therapeutic agents. While the methods for testing and assuring safety of these newer agents receive intense scrutiny, the methods by which the patient samples for psychotropic agent studies are recruited has received relatively little attention. It appears that symptomatic volunteers who enter clinical psychopharmacology studies are clinically comparable to treatment-seeking patient samples. There is almost no information regarding the actual proportions of "recruited" to treatment-seeking patients or how many symptomatic volunteers participate in more than one study, and the expense of advertising for symptomatic volunteers has not been investigated. We surveyed 18 experienced investigators around the United States to identify: (1) the relative proportion of clinical trial participants who are symptomatic volunteers versus treatment-seeking patients; (2) the proportion of study volunteers who entered more than one clinical trial; and (3) the cost of recruitment for investigators who conduct these studies. The findings indicate that an average of 87.2 percent of subjects entering trials were recruited via advertising. Most participate in only one study. The expense of identifying and recruiting appropriate symptomatic volunteers is significant, and appears to be increasing. Implications of these findings will be discussed.

In a placebo-controlled, multicenter study, 180 male and female outpatients, ages 18-65, with DSM-III-R generalized anxiety disorder, were treated with abecarnil (a partial benzodiazepine agonist), alprazolam, or placebo for 4 weeks. This was followed by a rapid (1-week) taper, during which patients were assessed for any taper-related symptoms. All patients were identified via a structured clinical interview for DSM-III-R and randomly assigned to one of the three treatment groups. More than 70% of each treatment group completed the study. In the acute-treatment phase, both abecarnil and alprazolam showed evidence for efficacy that was significantly better than that of placebo. Both active agents were tolerated well. After the swift taper, a significantly greater number of taper-related symptoms occurred in the alprazolam-treated group than in the abecarnil-treated group, which was not different than in the placebo-treated group. Additionally, less residual improvement followed the taper in the alprazolam-treated and the placebo-treated groups. These data indicate that the partial benzodiazepine agonist abecarnil may be useful as a safe, effective, short-term treatment for anxiety. Theoretical and practical implications of these findings are discussed.

Despite the considerable revisions to diagnostic criteria, recent data indicate that generalized anxiety disorder (GAD) is one of the most common anxiety disorders. Growing evidence also indicates that GAD is a serious illness, which frequently causes moderate impairment and often requires prolonged treatment. Thus, investigation of the biological correlates of GAD may be helpful in the development of effective treatments for this disorder. Recent data suggest possible abnormalities in the regulatory mechanisms of several important biological components in GAD patients. Maladaptive responses to stressful stimuli have been observed in the locus-ceruleus-norepinephrine-sympathetic nervous system, the hypothalamic-pituitary-adrenocortical axis, and the cholecystotin system. Abnormalities in other important CNS modulators, such as 5-HT and gamma-aminobutyric acid, may also be involved in the biology of GAD. In the following article, the authors will review the existing information regarding these potential biological abnormalities in GAD.

The association between the irritable bowel syndrome (IBS) and psychiatric disorders is well-known to most clinicians, but the nature of the relationship is far from clear. There is an increased prevalence of psychiatric illness in IBS patients and an increase in IBS in psychiatric patients. Whether this association exists outside of treatment-seeking populations (i.e., in IBS sufferers who do not seek treatment) has not been well investigated. This paper will selectively review the existing literature regarding the association of IBS and psychiatric illness in both patient and nonpatient samples. A model of the brain-gut interaction will be presented, as will practical implications of this model for treatment of individuals with IBS.

Intense anger, easy irritability, and low frustration tolerance are frequently encountered in clinical practice and may occur as part of the constellation of symptoms associated with a number of Axis I and Axis II diagnoses. Recent studies have suggested the efficacy of fluoxetine in treating anger in depressed and borderline patients. The present study examines the treatment of anger as a target symptom regardless of accompanying psychopathology.In this preliminary trial, 11 subjects experiencing intense anger were treated in an open-label fashion with fluoxetine over an 8-week period. Anger was measured by a clinician-administered Clinical Global Impressions-Severity (CGI-S) scale and a self-report anger inventory, the Multidimensional Anger Inventory (MAI). The Hamilton Rating Scale for Depression was administered at baseline and final visits.All 11 enrolled patients completed the study, and all patients demonstrated clinical improvement as measured by both the CGI-S and the MAI. Nine patients were rated as responders and 2 as nonresponders according to prospectively established criteria. Fluoxetine was well tolerated and showed rapid onset of action.This study is limited by small sample size and nonblinded, open-label design, but nonetheless suggests that fluoxetine may be useful in moderating anger as it occurs as part of the symptomatology of a number of Axis I and Axis II disorders. Controlled studies are warranted.

Anxiety disorders are the most prevalent mental disorders in the United States. In the past 3 decades, substantial advances have been made in the ability to identify and treat anxiety disorders including panic disorder (PD), social phobia (SP), obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), and posttraumatic stress disorder (PTSD). It is now known that these common, usually chronic disorders confer significant disability to untreated sufferers. This overview highlights some of the important advances in pharmacological treatment of anxiety disorders. Evidence for efficacy of the various pharmacological agents (including relevant oral dosing and plasma-level data) and of acute and long-term treatment, and the disadvantages of medication treatment are discussed. Finally, some important clinical questions remaining to be addressed by psychopharmacological research are reviewed.

Previous work from our group has examined the relationship between stress and immunodepression in medical students taking National Boards, Part I, and has described a relationship between stress intrusion scores (SIS) and immunodepression. We have also shown that a high proportion of individuals with generalized anxiety disorders (GAD) and panic disorders (PD) exhibit enhanced stress intrusion (SI) and are more prone to upper respiratory infections (URI). In the present preliminary study, we sought to establish a model to evaluate further the role of SI level on the extent of immunodepression. This would serve to assess in further studies the mechanism(s) of stress-induced immunodepression, its relationship to morbidity, and the role of therapeutic interventions. In 14 GAD patients and 14 controls, we correlated the expression of interleukin-2 receptors (CD25) on T lymphocytes stimulated with anti-CD3 in short term cultures and the frequency of URI and the SIS to assess the relationships among these parameters. A decreased expression of CD25 correlates linearly with increasing SIS and with a higher number of sick days with URI. These results support our previous observations that GAD patients are more susceptible to URI. Moreover, they suggest that there may be a direct relationship between immunodepression and morbidity and between SIS and immunodepression.

Major depression is a common mental disorder with a lifetime prevalence of approximately 15% of the general population, affecting almost twice as many females as males. Panic disorder is a severe anxiety disorder with a lifetime prevalence of 2-3% or more. Like major depression, panic disorder affects nearly twice as many females as males. Both panic disorder and major depression are often chronic conditions, resulting in significant morbidity and mortality. Among patients who seek treatment for either panic disorder or major depression, both conditions are present in approximately one-third of the patient population. Substantial information suggests that individuals who suffer from both panic disorder and major depression respond poorly to acute treatment, are more likely to remain ill over the long term, require more psychiatric treatment, and are at approximately twice the risk of suicide attempts than individuals who suffer from either condition alone. There has been very little systematic study of individuals with coexisting panic disorder and major depression. This has left significant gaps in our knowledge about optimal treatment for the substantial subgroup of individuals suffering from both disorders simultaneously. Social phobia is a common disorder which affects 2-8% (females more than males) of the population. Recent advances in the pharmacological treatment of social phobia are reviewed. Patterns of comorbidity, effects of coexisting psychiatric disorders on disability, health care utilization and suicidality are discussed, together with treatment implications for coexisting social phobia and major depression.

Despite the considerable attention that has been focused on the anxiety disorders by the medical and research communities over the last decade, relatively little attention has been devoted to the investigation of generalized anxiety disorder (GAD). However, the available population-based studies have provided clinically relevant information about this disorder. The emerging picture is that GAD is a common and chronic disorder, affecting primarily women, and one that leads to significant distress and impairment. Subjects with GAD frequently utilize health care services and require medication treatment. Since a major portion of health care services is consumed by a small fraction of patients, early detection and effective intervention may reduce unnecessary and costly health care.

The use of pharmacologic challenges and the application of new brain imaging technologies in the study of patients with anxiety disorders have led to an improvement in the understanding of the neurobiologic basis of these disorders. Abnormal function of noradrenergic, serotonergic, GABAergic, and dopaminergic neural systems as well as abnormal chemoreceptor reactivity have all been implicated in the pathophysiology of anxiety. Functional imaging data have revealed abnormal patterns of cortical and subcortical activity in anxiety patients. These data have allowed significant improvements in the available anatomic models of the anxiety disorders. Further improvements in research technique and technology likely will lead in the near future to a significantly clearer image of the neurobiologic processes involved in anxiety disorders.

Advances over the past 2 decades in our understanding of the biology of panic disorder have paralleled a remarkable increase in the development of new pharmacological agents with antipanic effects. Although we can not presently use biological tests to help with our choice of therapeutic agent for individual patients, we can use this biological understanding in the development of overall pharmaco-therapeutic strategies. Current evidence does not support the hypothesis that panic disorder is associated with a primary disorder in one neurotransmitter system. Rather, the data suggest that the biological aetiology of panic disorder is related to abnormalities in the function of a variety of neurotransmitters including serotonin (5-hydroxytyrptamine; 5-HT), noradrenaline (norepinephrine), gamma-aminobutyric acid (GABA), dopamine, and cholecystokinin. It is likely, however, that panic disorder is a biologically heterogeneous condition and that biological subtypes may exist in which the primary abnormality may involve one or a few neurotransmitter systems. Currently, the data best support the hypothesis that pharmacotherapeutic agents with primary action at sites within the GABA and serotonin systems are the most effective in the treatment of panic disorder. Nevertheless, some patients will respond well to drugs with predominant activity in other systems, or may require pharmacotherapy designed to affect the function of more than 1 neurotransmitter. As our understanding of the biological aetiology of panic disorder evolves, the pharmacotherapeutic agents and strategies used in the treatment of this disorder will continue to evolve as well.

The coexistence of other psychiatric disorders in patients with bulimia nervosa is of major clinical and theoretical interest. We therefore studied a group of consecutively evaluated bulimic patients.The Structured Clinical Interview for DSM-III-R (SCID) was administered to a sample of 59 female patients with DSM-III-R-defined bulimia nervosa.The following frequencies of lifetime Axis I comorbid diagnoses were found (in decreasing frequency): any affective disorder (75%), major depressive disorder (63%), any anxiety disorder (36%), any substance abuse disorder (20%), social phobia (17%), generalized anxiety disorder (12%), and panic disorder (10%). In the 44 cases with an affective disorder, 27 (61%) had the onset of affective disorder, 27 (61%) had the onset of their affective disorder prior to the onset of their bulimia, 15 (34%) afterward, and 2 (5%) concurrently. In the 21 cases with any anxiety disorder, 15 (71%) had the onset of their anxiety disorder prior to the onset of their bulimia, 4 (19%) afterward, and 2 (10%) concurrently.These data confirm previous reports of a strong association between bulimia nervosa and affective illness, which in most cases precedes the eating disorder. In addition, a high frequency of anxiety disorders, particularly social phobia, is seen in bulimic patients.

Persons with physical disabilities cannot be diagnosed as having social phobia under current DSM-III-R criteria. The DSM-III-R social phobia diagnosis excludes persons where a physical disorder causes the distress and phobic avoidance. However, the authors have noted in clinical practice that social phobia and physical disabilities sometimes coexist. A review of the published literature reveals that stutterers and BET patients frequently have social phobia-like symptoms. No prevalence data on comorbid DSM-III-R-defined social phobia were found in these groups (i.e., social phobia occurring in areas where the disability does not cause the distress and avoidance). Further research is warranted to determine the prevalence of social phobic behaviors occurring in conjunction with certain physical disabilities.

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.