Remission is a key goal after treating an acute episode of bipolar I disorder, but greater understanding is needed of the correlation between attaining remission at a specific time point and maintaining sustained remission. This post-hoc analysis assessed symptomatic point remission and sustained remission according to either a standard criterion (YMRS ≤ 12) or a set of more rigorous criteria (YMRS ≤ 7, MADRS ≤ 10, and CGI-I = 1) using data from a 26-week, randomized, double-blind, placebocontrolled study with the atypical antipsychotic aripiprazole in patients with bipolar I disorder.
Following ≥ 6 consecutive weeks' stabilization with open-label aripiprazole, 161 patients were randomized (1:1) to aripiprazole or placebo for up to 26 weeks. Symptomatic remission rates were determined at Weeks 8, 16, and 26; sustained remission rates were determined at each visit up until Weeks 8, 16, and 26, including a requirement to maintain remission for ≥ 8 consecutive weeks (frequency counts, LOCF analysis).
Compared with the standard criterion (YMRS ≤ 12), symptomatic and sustained remission criteria were fulfilled at a lower rate at all time points when defined with YMRS ≤ 7, and lower still with additional MADRS ≤ 10 and CGI-I = 1 criteria. In aripiprazole-treated patients, symptomatic remission rates were consistent at Weeks 8, 16, and 26; sustained remission rates at Week 8 were retained at Weeks 16 and 26.
When discerning an operational definition of remission in patients with a recent manic or mixed episode, the YMRS ≤ 7 criterion and sustaining this criterion for ≥ 8 weeks can be a useful clinical or research tool for assessing clinical recovery.
The failure of cholinesterase inhibitors to produce noticeable improvement in about half of patients with Alzheimer's disease (AD) may result from heterogeneity of neurotransmitter abnormalities in this disorder. This study examined whether pretreatment postural blood pressure (BP) drop, which presumably reflects sympathetic response, differed in patients who were responders or nonresponders to the cholinesterase inhibitor, HP 029. Twenty-three AD patients completed a double-blind dose-finding phase of a clinical trial in which four doses of HP 029 and placebo were administered. Evaluation for efficacy occurred after 7 days of treatment at each dose. Of the 23 patients, 12 were classified as responders in the dose-ranging phase of the study. Nonresponders demonstrated significantly greater decreases in pretreatment systolic postural BPs when going from a supine to sitting position than did responders. The greater postural BP drop in nonresponders may identify a subgroup of AD patients that responds poorly to cholinesterase inhibitors.
Tardive dyskinesia (TD) affects between 10 and 50 percent of all patients on long-term antipsychotic therapy, depending on the population studied. Various risk factors for TD have been reported; a correlation between TD and substance abuse has been suggested in some reports and not found in others. This study analyzes the association of substance abuse with the incidence of tardive dyskinesia in a schizophrenic population. All patients at the West Side Veterans Affairs Medical Center are evaluated prior to the initiation of neuroleptic therapy with the Dyskinesia identification System: Condensed User Scale (DISCUS); those with a diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder during the years 1986 through 1993 were included in this analysis. History of substance abuse was considered positive if there was clinician report or diagnosis of substance abuse. These data were collected and analyzed using ANOVA. In a sample of 1,027 subjects (97% male), 83.2 percent had a neuroleptic exposure of 10 or more years, and slightly more than half (50.8 percent) had a positive history of substance abuse. Using research diagnostic criteria, 28.9 percent of the sample had tardive dyskinesia. Analysis of variance showed history of substance abuse (p < .000) and years on neuroleptics (p < .000) to be strongly correlated to a diagnosis of TD. Age was less strongly correlated to the DISCUS score (p < .01), and there was no association of TD with diagnosis (p = .237). This study therefore demonstrates a robust correlation between TD and substance abuse. A mechanism of action involving N-methyl-D-aspartate (NMDA)-mediated excitotoxicity is proposed.
CI-1007 is a novel dopamine autoreceptor agonist and partial dopamine D2/D3 agonist that is currently under development for the treatment of schizophrenia. This single-blind, rising, multiple-dose, inpatient bridging study was designed to evaluate the safety and tolerability of CI-1007 in consecutive panels of patients with schizophrenia. Following a 4-day placebo washout period, 16 patients (4 per panel) were assigned to receive one of four fixed-dosage regimens of CI-1007 (5, 10, 15, or 20 mg q12h for 9 doses). CI-1007 was generally well tolerated over the dose range evaluated. Adverse events, including mild to moderate sporadic orthostatic hypotension and/or nausea and vomiting, were most commonly observed after the initial drug dose and decreased after repeated dosing. Serum concentrations of growth hormone (GH) increased following the administration of CI-1007, confirming its central dopamine agonist activity. Changes in serum prolactin were not related to dose. The pharmacokinetics of CI-1007 and its active metabolite appear linearly related to dose. The results of this study suggest that patients with schizophrenia tolerate slightly higher initial doses of CI-1007 than do healthy subjects.
Ten patients with dementia and significant behavioral disturbances (mean age of 77.2 +/- 8.2 years) received citalopram, 10 mg/day for 3 days, followed by 20 mg/day for 2 weeks. Six of the 10 patients completing 17 days of treatment had a clinically impressive response, as assessed by significant improvement in six target items on the Neurobehavioral Rating Scale. Eight patients were also analyzed by measuring the racemic and enantiomeric plasma levels of citalopram (CIT) and desmethylcitalopram (DCIT). A sensitive high-performance liquid chromatography (HPLC) assay for citalopram enantiomers and metabolites was developed using ultraviolet detection. The lower limit of detection was 10 ng/ml for each enantiomer. Steady-state plasma level ranges were 11.2 to 92.2 ng/ml for the biologically active S(+) citalopram and 12.8 to 95.7 ng/ml for the inactive R(-) enantiomer. For the S and R enantiomers of desmethylcitalopram, plasma levels ranged from 11.0 to 22.0 ng/ml and 9.2 to 22.0 ng/ml, respectively. The racemic citalopram plasma level to dose ratio of 3.50 was higher than the ratio (1.96) reported by Overo (1982) for 55 younger patients. The stereoselective metabolism of the enantiomers for citalopram and desmethylcitalopram (S(+) and R(-) enantiomers) in these older subjects differed from that reported in younger patients, suggesting possible age-associated changes in CYP2C19 activities. We hypothesize that quantification of S(+) citalopram will permit a more accurate examination of dose/response relationships. This measure seems to be especially important for older subjects, given the wide ranges and higher concentrations evident from our preliminary results.
Some remarks about the antidepressant efficacy of AHR-1118 are warranted. The drug appeared to induce 'mobilization of affect' in all patients studied. Verbalization increased, psychomotor retardation decreased, and sleep and appetite improved. These changes usually became manifest by the end of the 1st week or the beginning of the 2nd week of treatment. The drug was very well tolerated and no adverse clinical or laboratory effects were noted.
This is the first reported controlled trial of a partial benzodiazepine agonist, abecarnil, utilized in the treatment of generalized anxiety disorder (GAD). It was a sequential dose-finding study comparing 15-30 mg/day, 7.5-15 mg/day, and 3-9 mg/day to placebo for 3 weeks of treatment followed by abrupt discontinuation through placebo substitution. Although the two higher dose groups had high incidence of central nervous system (CNS) sedative adverse effects, the 3-9 mg/day group tolerated the medication well with no dropouts. The 3-9 mg/day group, in comparison to the two higher doses and placebo, demonstrated efficacy in global improvement ratings and Hamilton Anxiety Scale (HAM-A) scores. At Week 3, 61 percent of the abecarnil 3-9 mg/day group was rated as at least 50 percent improved on the HAM-A, compared to 30 percent of the placebo group. With abrupt discontinuation there were mild to moderate withdrawal symptoms and loss of efficacy in the two higher dose groups. However, in the 3-9 mg/day abecarnil group, there were few withdrawal symptoms and almost no loss of efficacy following discontinuation.
Tryptophan depletion is a widely used paradigm to study serotonin system-related mechanisms in the pathophysiology and treatment of depression. There is convincing evidence that tryptophan depletion primarily and selectively affects serotonergic transmission. The behavioral data in healthy controls with and without genetic risk for depression, and in patient populations during the symptomatic phase of depression and when being remitted, suggest a trait abnormality of serotonin function in depression and that antidepressants may compensate for the underlying deficit. Tryptophan depletion may be a useful tool to create more integrative models for the pathophysiology of depression that take into account neurobiological systems beyond monoamines. More recent studies combining tryptophan depletion with genetic variables may provide an important approach for studying gene/environment interactions using candidate genes to define endophenotypes, which ultimately will improve currently used diagnostic categories and help to generate more advanced models to understand the neurobiology of depression. This may lead to the development of truly novel treatment approaches for depression.
The results presented describe a rather chronically anxious and depressed population of 119 long-term BZ users, with more than 90% having been given a psychiatric diagnosis. While for many patients BZ therapy appeared appropriate, for many others it was not, and other treatments, whether psychotherapeutic or psychopharmacologic, would appear to have been more appropriate. Most patients, besides suffering from anxiety and/or depression, also showed evidence of chronic psychiatric problems, and almost all were in need of a great deal of support and assurance. In fact, one hard-earned lesson is that long-term BZ users are in need of much more intensive psychiatric and social support than other anxious or depressed patients. A follow-up of 62 patients, 6 to 12 months after study participation, indicated that 24% of them were without medication, 37% had been treated with antidepressants, and 39% were still taking BZ's, frequently on an as-needed or low daily dosage. It was of interest to note that the subset of 10 patients without a psychiatric diagnosis had normal Hamilton Anxiety scores prior to discontinuation. In addition, while most of them experienced some withdrawal symptoms, the intensity was milder, and all were able to successfully withdraw. None of the 10 were in need of psychiatric medication after BZ discontinuation. This raises the intriguing possibility that the intensity of BZ withdrawal may be only partly a function of the chemistry of declining blood levels. Instead, the intensity of the BZ withdrawal syndrome may be partly a function of degree of psychopathology and other premorbid personality variables. This parallels the experience of Nelson et al. (1984) who found antidepressant side effects to be more correlated with premorbid psychopathology than actual antidepressant blood levels. Abrupt BZ discontinuation produced withdrawal symptoms in 82% of patients regardless of the type of BZ which they had been taking. Severity of withdrawal, however, was clearly related to benzodiazepine half-life, with short half-life BZ's producing a more severe withdrawal reaction during the first week of placebo substitution than long half-life BZ's. There was also a suggestion that the severity might be partly dependent on nonpharmacologic variables such as premorbid psychopathology. The results in general support the recommendation made earlier by this research group (Rickels, 1985a) that chronically anxious patients in need of BZ therapy should be treated only for short periods of time, their diagnosis should be frequently reassessed and, if found to be still in need of chronic BZ therapy, this should be offered on an intermittent rather than continuous basis. Emerging research suggests that optimum BZ therapy consists of just such judicious, circumspect, and critically monitored use of BZ's in terms of target symptoms and diagnoses. The very safety and effectiveness of BZ's have perhaps slowed the realization of these therapeutic goals.
The purpose of the present study was to establish the extent to which dopamine uptake inhibitors, for example, amfonelic acid (AFA) and GBR 12909, differentially affect the haloperidol- and clozapine-induced activation of dopamine neurons. In the striatum and nucleus accumbens, the haloperidol-induced increases in dopamine synthesis and metabolism, as well as striatal dopamine release, were either potentiated or unaffected by AFA or GBR 12909. In contrast, AFA or GBR 12909 markedly attenuated the clozapine-induced increases in dopamine synthesis, metabolism, and release. However, the clozapine-induced increase in dopamine synthesis within tuberoinfundibular dopamine neurons was not significantly altered by AFA treatment. AFA and GBR 12909, appear to differentially affect the haloperidol- and clozapine-induced activation of nigrostriatal and mesocorticolimbic dopamine neurons. However, the inhibitory effect of AFA on the clozapine-induced activation of dopamine neurons does not extent to the stimulatory effect of clozapine on tuberoinfundibular dopamine neurons.
Useful clinical strategies are adaptive, specifying the sequence of treatments that are alternatives, what it means for the treatment to "work," the rules for abandoning a treatment, and the subsequent treatments. Because combinatorial complexity precludes comparison of every possible whole strategy, current experiment-based methods rely on comparisons among a few options at particularly crucial decision points, and strategies are pieced together from scraps of information. Nonexperimental methods for strategy development offer a seductive alternative, but their advantages may be illusory. Clinical investigators deploy a wide range of study designs to compare treatment strategies in mental health. This article organizes the types of designs by their purpose and annotates this list with comments on the strengths and weaknesses of each type. We conclude with some general comments on the overall process of development of treatment strategies.
The 5-HT2A receptor promoter -1438G/A polymorphism, which is in complete linkage disequilibrium with the 5-HT2A 102T/C polymorphism, may be related to antipsychotic response. The aim of this paper is to determine relationships between the -1438G/A polymorphism and olanzapine negative symptom response. DNA from 41 subjects with schizophrenia (as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) was analyzed for the -1438G/A polymorphism. Olanzapine (7.5-20 mg/day) was given for 6 weeks and response was assessed using the Scale for Assessment of Negative Symptoms (SANS). A linear regression used a dependent variable of percent change in SANS. Independent variables included 5-HT2A polymorphisms and interactions. The -1438G/A polymorphism and percent change in SANS showed a significant trend (P=.0542). The A/A genotype group had a 45% reduction in SANS compared with 19% in the other groups. We conclude that the A/A genotype may be associated with olanzapine negative symptom response, seen as a 2-fold greater percent reduction in SANS, and may be clinically relevant.
Major depression is commonly found in the child and adolescent population. Venlafaxine, a new antidepressant, has been used successfully in adults; however, its use in children and adolescents has been very limited. This study evaluated the efficacy and side effect profile of venlafaxine in the treatment of depression in children and adolescents. In a double-blind, placebo-controlled, 6-week study, 33 subjects between the ages of 8 and 17, who met DSM-IV criteria for major depression, were treated with either venlafaxine and therapy or placebo and therapy. Patient progress data were obtained by weekly rating assessments. Data on side effects were also obtained weekly. The statistical analysis indicated a significant improvement over time, but it could not be attributed to venlafaxine drug therapy. These findings are consistent with other studies where the efficacy of antidepressants in the treatment of major depression in this age population remains unproven. Low dosage and short length of treatment may account for the lack of efficacy. The findings did, however, suggest a low side-effect profile. Further studies are recommended to assess efficacy and to corroborate its safety in children and adolescents.
This article presents a metaanalysis of approximately 300 studies of drug treatment for affective disorders. Efficacy is proven beyond a shadow of a doubt in this overview from random-assignment, double-blind studies. The efficacy of maintenance antidepressants is supported by a large body of evidence. The size effect of drug versus placebo difference used to prevent recurrence of unipolar or bipolar affective disease is comparable to the size effect of drug versus placebo difference for the treatment of an acute episode.
Across ethnicity/race, prevalence rates of bipolar disorder are similar. However, African Americans and Latinos may receive less specialty mental health treatment and different medications, and may be less adherent to treatment regimens than European American patients. This study compared illness characteristics, treatment history, and overall functioning in a sample of European American, African American, and Latino patients with bipolar disorder.
The samples were drawn from the first 2,000 patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder. There were 1,686 European Americans, 65 African Americans, and 77 Latinos. The data were collected upon study entry, with structured interviews, clinicianrated forms, and self report.
African Americans had a greater likelihood of psychosis and fewer psychiatric medication prescriptions than did European Americans. Latinos had greater alcohol comorbidity, fewer psychiatric medication prescriptions and specialty treatment visits, and more frequent religious service attendance than did European Americans. Depression and manic episode severity and functional outcomes were similar across groups.
Patients with bipolar disorder who are members of ethnic/racial minority groups continue to receive less intensive specialized mental health treatment than do European American patients. These findings may be related to provider, patient, or provider-patient relationship variables. Despite treatment differences and greater comorbidity and sympomatology, there were no differences among the three groups in overall functioning, suggesting additional outcome measurement is warranted.
Treatment with standard antipsychotic medications causes side effects such as hyperprolactinemia and extrapyramidal symptoms. Because these side effects can cause noncompliance with antipsychotic medication and consequent relapse, they add to the morbidity of schizophrenia. A compound with antipsychotic efficacy but without the side effects of standard antipsychotic agents would improve compliance and treatment outcomes and enhance quality of life. Improved compliance, reduced relapse, and decreased hospitalization would also reduce the cost of treatment of schizophrenia. Seroquel (ICI 204,636), an atypical antipsychotic compound in Phase III development, was found to be well tolerated and effective in treating subjects with DSM-III-R schizophrenia in three Phase II clinical trials. Analysis of plasma prolactin concentrations obtained during these trials revealed that ICI 204,636 did not differ from placebo in its effect on plasma prolactin after up to 6 weeks of treatment; no significant difference was found in the degree of decline of plasma prolactin levels when subjects treated with ICI 204,636 and placebo were compared. A significant difference was found, however, between ICI 204,636- and chlorpromazine-treated subjects; prolactin levels in ICI 204,636-treated subjects fell to a greater degree than they did in chlorpromazine-treated subjects, however in all three trials, ICI 204,636 did not cause sustained elevation of prolactin.
The effects on brain metabolism of the intravenous (i.v.) administration of dextroamphetamine was assessed by positron emission tomography (PET) with [18F]-fluorodeoxyglucose (18-FDG) in 8 adults with attention-deficit hyperactivity disorder (ADHD). During the 3-hour 18-FDG PET session, each adult underwent the initial scan following i.v. infusion of placebo and a second scan following i.v. infusion of 0.15 mg/kg dextroamphetamine in a single-blind design. All subjects showed increased systolic/diastolic blood pressure and improved continuous performance task scores after dextroamphetamine. Global and regional metabolic rates were not significantly altered by the stimulant. When regional and global rates were normalized, the metabolic rates of only three cortical regions differed significantly between conditions. Individually, global metabolism increased in 4 subjects, was unchanged in 2, and decreased in 2 after stimulant infusion. No clinical characteristics differentiated these patients. I.V. infusion of dextroamphetamine did not significantly alter brain metabolism in ADHD adults in this preliminary study.
Previous research has demonstrated the existence of two distinct dopamine receptor subtypes (Kebabian & Calne, 1979; Creese et al., 1983), possessing unique pharmacologic and biochemical properties. D1 dopamine receptors stimulate adenylate cyclase activity (Hyttel, 1978), while D2 dopamine receptors inhibit this enzyme (Stoof and Kebabian, 1981; Onali et al., 1984; Battaglia et al., 1985). However, both receptor subtypes co-exist in many tissues making the determination of their respective physiological and behavioral roles difficult. All neuroleptics, commonly used drugs in the treatment of schizophrenia, have been shown to be either mixed D1/D2 dopamine receptor antagonists or selective D2 dopamine receptor antagonists. Thus, D2 dopamine receptors have been implicated as the site mediating the antipsychotic and antidopaminergic activity of neuroleptics (Creese et al., 1976; Seeman et al., 1976). By inference, D2 dopamine receptors have been considered to mediate dopaminergic agonists’ behavioral effects as well (Seeman, 1981).
BW-234U is a well-tolerated antipsychotic agent in this acute schizophrenic population and has a low potential for inducing extrapyramidal or autonomic side effects. The efficacy which was seen needs to be confirmed by further controlled studies. The full dose range of this drug has yet to be determined.
A 24-month naturalistic, prospective longitudinal followup study was conducted on 33 patients with anorexia nervosa who had participated in an intensive, multidisciplinary inpatient treatment program and were receiving fluoxetine as part of their continuing treatment regimen. Data on course, outcome, and treatment exposure in this cohort were obtained using standardized, comprehensive interviews administered at 6-month intervals after hospital discharge. Longitudinal course data for these patients were compared with data for matched historical controls who had received identical inpatient and followup treatment but without adjunctive fluoxetine. Analyses failed to show that fluoxetine had a significant effect on the cumulative probability of remaining at target weight during the followup period, the risk of sustained weight loss, or other clinical measures of outcome. Thus, adjunctive treatment with fluoxetine may not have additive long-term therapeutic benefit when measured against the effects of sustained and intensive followup treatment.
We previously investigated the functional neuroanatomy of familial pure depressive disease (FPDD) using positron emission tomography (PET) measurements of regional blood flow and obtained evidence that flow is increased in the left prefrontal cortex, amygdala, and medial thalamus and is decreased in the medial caudate. These data along with other evidence suggested that circuits involving the prefrontal cortex, amygdala, and related parts of the striatum, pallidum, and medial thalamus are involved in the pathophysiology of FPDD. One of these circuits, the limbic-thalamo-cortical circuit, which includes the amygdala, the medio-dorsal thalamus, and parts of the ventral and medial prefrontal cortex, may be engaged in abnormal reverberatory activity that maintains the cognitive and emotional set of depression. Using this hypothesis as a neural model to investigate antidepressant treatment mechanisms, we review evidence that the changes in dopaminergic, serotonergic, and noradrenergic function induced by somatic antidepressant therapies may yield modulatory effects on limbic-thalamo-cortical activity. We also discuss preliminary findings of treatment-associated changes in this circuit in studies comparing PET images acquired before and during antidepressant treatment.
Even though the DST has not proved successful as a marker for depression, it has stimulated a considerable amount of research into the interaction between neuroendocrine function and mood states. With the objective of perfecting the DST methodology, investigators have explored the interaction between dexamethasone plasma concentrations and cortisol response, and have found that there is a significant inverse correlation between dexamethasone concentrations and cortisol concentrations. Although this relationship is one of the factors that affects cortisol response in depressed patients, it usually explains less than 20 percent of the variance of cortisol response. One can only conclude that the affective state explains a certain amount of the remaining variance. Dexamethasone plasma concentrations may be altered by a variety of drug and disease interactions. Many enzyme inducers, including phenytoin, carbamazepine, and phenobarbital, increase dexamethasone CL, but some drugs that might be expected to alter dexamethasone CL, such as cimetidine and tobacco smoke, do not affect it. Any disease that causes hepatic dysfunction could be expected to decrease dexamethasone CL, whereas renal failure may increase dexamethasone CL. Neither Cushing's syndrome nor congenital adrenal hyperplasia appear to alter dexamethasone CL. Alcoholism has a dual effect on the DST. Chronic alcohol abuse may cause a cushingoid state, which could interfere with the DST interpretation. Also, chronic alcohol use may result in hepatic dysfunction, or an induction of P-450 enzymes. As a result of these different actions, alcohol could result in either an increase or decrease in dexamethasone CL. Studies of dexamethasone pharmacokinetics conducted in depressed patients are few, but they generally agree that DST nonsuppressors exhibit an increased dexamethasone CL when compared with suppressors. The only two studies to investigate this population longitudinally report somewhat contradictory results; one study reports an increase in dexamethasone CL following recovery from depression, and the other a decrease. Since only one of the studies was conducted using intravenous dexamethasone, differences in bioavailability might explain some of the differences in results between the two studies. In spite of the unresolved questions, these studies have stimulated research into an entirely new area: the possibility that affective diseases may alter the pharmacokinetics of some drugs.
The Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) is a self-report measure designed to enable investigators to easily obtain sensitive measures of the degree of enjoyment and satisfaction experienced by subjects in various areas of daily functioning. The summary scores were found to be reliable and valid measures of these dimensions in a group of depressed outpatients. The Q-LES-Q measures were related to, but not redundant with, measures of overall severity of illness or severity of depression within this sample. These findings suggest that the Q-LES-Q measures may be sensitive to important differences among depressed patients that are not detected by the measures usually employed.
Principal component (PC) analysis is a statistical technique that has been used to identify core depression symptoms on the Hamilton Rating Scale for Depression (HAM-D). PC analysis is also a useful method to identify unidimensional scales of the HAM-D that are more sensitive to change following antidepressant treatment. Although there have been previous PC investigations of various versions of the HAM-D, there have been no investigations of the 31-item HAM-D scale or investigations that include subjects administered bupropion SR. We performed a PC analysis on data from 910 outpatients who participated in randomized, double-blind trials evaluating bupropion SR versus placebo for major depression. The goal of our analysis was to 1) identify components (domains) of the 31-item HAM-D and 2) determine patient response to bupropion SR using the domains identified. PC analysis produced a solution comprised of 7 domains of the HAM-D that accounted for approximately 49% of the total variance. Bupropion SR demonstrated a significant reduction (p<.01, least square mean change) in symptoms over placebo on 4 domains (cognitive, retardation, fatigue/interest, and anxiety items).
Present understanding of the neural circuitry of anxiety has come from a variety of sources, including animal, clinical, and most recently, neuroimaging studies. Evidence from these sources has converged to form a translational bridge from animal models to human pathophysiology. In particular, the classical fear conditioning paradigm has served as a foundation for this bridge. Proposed models for the neural circuitry of normal anxiety as well as the anxiety disorders are discussed. A brief review of specific findings from neuroimaging studies of posttraumatic stress disorder, specific phobia, social phobia, obsessive-compulsive disorder, and generalized anxiety disorder is also provided.