Linkage genome scan for loci predisposing to panic disorder or agoraphobia.

We conducted a 10 cM linkage genome scan in a set of 20 American pedigrees (153 subjects), ascertained through probands with panic disorder (PD). Several anxiety disorders segregate in these families; they were diagnosed on the basis of Schedule for Affective Disorders and Schizophrenia interview. In this article, we describe results for panic disorder and agoraphobia, which are closely related, common, heritable anxiety disorders. This is the first complete linkage genome scan for agoraphobia and the third for PD. A total of 407 markers (389 autosomal, 18 X chromosome) were genotyped. Multipoint LOD score and NPL analysis were completed using GENEHUNTER2. For PD, two genomic regions meet criteria for suggestive linkage. One of these regions is on chromosome 1 (LOD score = 2.04). This region coincides with a region that generated a LOD score of 1.1 in a previous genome scan by Crowe et al. [2001: Am J Med Genet (Neuropsychiatr Genet) 105:105-109]. The other (LOD score = 2.01) is located on chromosome 11p and occurs at marker CCKBR, one of eight candidate genes examined. For agoraphobia, the most promising potential linkage was on chromosome 3 (NPL score = 2.75; P = 0.005). This was accounted for primarily by a single family that by itself generated an NPL score of 10.01 (P = 0.0039) and a LOD score of 2.10. These results provide initial evidence for a genetic locus on chromosome 3 that contributes to risk for agoraphobia. They also support suggestive linkage to two risk loci for panic disorder. Additional potential loci were identified with lesser statistical support; several of these were consistent with previously reported panic disorder linkage results. Overall, the results presented here suggest that PD and agoraphobia are complex traits that share some, but not all, of their susceptibility loci. Published 2001 Wiley-Liss, Inc.

Early coadministration of clonazepam with sertraline for panic disorder.

BACKGROUND: There is debate about combining benzodiazepines with selective serotonin reuptake inhibitors in the acute treatment of panic disorder. Although this medication combination is widely used in clinical practice, there is no well-tested, optimal method of coadministering these medications for the treatment of panic disorder. The purpose of this study was to test the efficacy of early coadministration of clonazepam with sertraline in the treatment of panic disorder. METHODS: Fifty patients with panic disorder were randomized into a double-blind clinical trial. Patients received open-label sertraline for 12 weeks (target dose, 100 mg/d), and in addition were randomized to groups receiving either 0.5 mg of active clonazepam 3 times daily or placebo clonazepam for the first 4 weeks of the trial. The clonazepam dose was then tapered during 3 weeks and discontinued. RESULTS: Thirty-four (68%) of 50 patients completed the trial. Drop-out rates were similar in the sertraline/placebo vs the sertraline/clonazepam group (38% vs 25%) (P =.5). An intent-to-treat analysis (on last observation carried forward data) revealed a much greater proportion of responders in the sertraline/clonazepam compared with the sertraline/placebo group at the end of week 1 of the trial (41% vs 4%) (P =.003). There was also a significant between-group difference at the end of week 3 with 14 (63%) of 22 of the sertraline/clonazepam group responding to treatment vs 8 (32%) of 25 of the sertraline/placebo group (P =.05). This difference was not observed at other times during the trial. CONCLUSION: These data indicate that rapid stabilization of panic symptoms can be safely achieved with a sertraline/clonazepam combination, supporting the clinical utility of this type of regimen for facilitating early improvement of panic symptoms relative to sertraline alone.

Fluvoxamine in the treatment of panic disorder: a multi-center, double-blind, placebo-controlled study in outpatients.

Serotonergic mechanisms have been implicated in panic disorder, and several preliminary studies suggest that fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), is helpful in its treatment. This 8-week double-blind parallel-group study compared fluvoxamine with a placebo in 188 patients with DSM-III-R defined panic disorder with or without agoraphobia. Efficacy assessments included a Daily Panic Attack Inventory, the Sheehan Disability Scale, the Clinical Anxiety Scale and the Clinical Global Impression Scale. When compared with the placebo, fluvoxamine produced highly significant improvements in most measures of the frequency and severity of panic disorder and in the more global aspects of disability and distress. Significant improvement was evident as early as week 1 for some panic variables. Fluvoxamine is a potent anti-panic agent with a relatively rapid onset of action.

Reductions in occipital cortex GABA levels in panic disorder detected with 1h-magnetic resonance spectroscopy.

BACKGROUND: There is preclinical evidence and indirect clinical evidence implicating gamma-aminobutyric acid (GABA) in the pathophysiology and treatment of human panic disorder. Specifically, deficits in GABA neuronal function have been associated with anxiogenesis, whereas enhancement of GABA function tends to be anxiolytic. Although reported peripheral GABA levels (eg, in cerebrospinal fluid and plasma) have been within reference limits in panic disorder, thus far there has been no direct assessment of brain GABA levels in this disorder. The purpose of the present work was to determine whether cortical GABA levels are abnormally low in patients with panic disorder. METHODS: Total occipital cortical GABA levels (GABA plus homocarnosine) were assessed in 14 unmedicated patients with panic disorder who did not have major depression and 14 retrospectively age- and sex-matched control subjects using spatially localized (1)H-magnetic resonance spectroscopy. All patients met DSM-IV criteria for a principal current diagnosis of panic disorder with or without agoraphobia. RESULTS: Patients with panic disorder had a 22% reduction in total occipital cortex GABA concentration (GABA plus homocarnosine) compared with controls. This finding was present in 12 of 14 patient-control pairs and was not solely accounted for by medication history. There were no significant correlations between occipital cortex GABA levels and measures of illness or state anxiety. CONCLUSIONS: Panic disorder is associated with reductions in total occipital cortex GABA levels. This abnormality might contribute to the pathophysiology of panic disorder.

Current perspectives on the pathophysiology of schizophrenia, depression, and anxiety disorders.

This article reviews the rapidly changing concepts related to the pathophysiology of major psychiatric disorders. The current era is an exciting one for psychiatric research and the rapidity with which advances are being made is a source of hope to patients with these disorders and for society.

Neurobiology of generalized anxiety disorder.

On reviewing the literature on GAD and trying to summarize the various developments in the field of neurobiology of GAD, we see that a range of hypotheses try to explore and integrate the observations found into potentially meaningful theories. Abnormal serotonergic and GABAergic function occur in many patients with GAD. Functional imaging data have shown increased cortical activity and decreased basal ganglia activity in patients with GAD, which reverses with treatment, but it is apparent that no one theory is sufficiently comprehensive to propose a unitary hypothesis for the development of GAD and other anxiety disorders. GAD is a relatively new diagnosable condition, first introduced into the classification system of psychiatric disorders in 1980, and since then has undergone a series of changes in its conceptualization, with some investigators questioning the existence of the condition as a distinct entity. Any inferences that may be drawn from various studies must be guarded, and it is appropriate to compare studies using the same diagnostic criteria. Significant research has been done and may lead to exciting new discoveries in the treatment of anxiety disorders in general and GAD in particular. Gray's model of behavioral inhibition, in which the septohippocampal system acts by assessing stimuli for the presence of danger and, when that is detected, activates the behavioral-inhibition circuit, provides a neuroanatomic conceptualization that has been expanded by preclinical research. Some exciting work has been done on CRF and the concept of development, vulnerability, and kindling and some investigators have contributed to this area of interest. This concept supports the hypothesis that a genetic predisposition, coupled with early stress, in the crucial phases of development may result in a phenotype that is neurobiologically vulnerable to stress and may lower an individual's threshold for developing anxiety or depression on additional stress exposure. The pharmaceutical industry is exploring treatment options using CRF antagonists, and research on other neuropeptides, especially NPY, will be of interest. Research on neurosteroids also may bring the opportunity for pharmacologic treatment approaches. Future research on the startle reflex and on the NMDA and the metabotropic glutamate receptors is important. Future studies of a more homogenous patient population and using more sophisticated techniques, such as molecular genetic strategies and better imaging techniques, may answer some of the outstanding questions.

SPECT [I-123]iomazenil measurement of the benzodiazepine receptor in panic disorder.

BACKGROUND: Alterations in benzodiazepine receptor function have long been hypothesized to play a role in anxiety. Animal models of anxiety involving exposure to chronic stress have shown a specific decrease in benzodiazepine receptor binding in frontal cortex and hippocampus. The purpose of this study was to examine benzodiazepine receptor binding patients with panic disorder and comparison subjects. METHODS: A quantitative measure related to benzodiazepine receptor binding (Distribution Volume (DV)) was obtained with single photon emission computed tomography (SPECT) imaging of [123I]iomazenil and measurement of radioligand concentration in plasma in patients with panic disorder and healthy controls. DV image data were analyzed using statistical parametric mapping (spm96). RESULTS: A decrease in measures of benzodiazepine receptor binding (DV) was found in left hippocampus and precuneus in panic disorder patients relative to controls. Panic disorder patients who had a panic attack compared to patients who did not have a panic attack at the time of the scan had a decrease in benzodiazepine receptor binding in prefrontal cortex. CONCLUSIONS: Findings of a decrease in left hippocampal and precuneus benzodiazepine receptor binding may be related to alterations in benzodiazepine receptor binding, or other factors including changes in GABAergic transmission or possible endogenous benzodiazepine compounds. Benzodiazepine receptor function in prefrontal cortex appears to be involved in changes in state-related panic anxiety.

Effects of the CCK(B) antagonist CI-988 on responses to mCPP in generalized anxiety disorder.

In order to evaluate the effect of the CCK(B) antagonist CI-988 on behavioral, neuroendocrine, and physiologic responses to the mixed, post-synaptic serotonin (5-HT) agonist/antagonist mCPP, 16 patients with a principal DSM-III-R diagnosis of generalized anxiety disorder (GAD) were enrolled in a study that involved two challenge tests. On one day, patients received a single oral dose of CI-988 followed 30 min later by an i.v. infusion of 0.1 mg/kg mCPP. On a second test day patients received placebo CI-988 followed 30 min later by active i.v. mCPP. The sequence of CI-988 was randomly assigned and the testing was conducted in double-blind fashion. In an initial dose-finding phase (N = 6) with a dose of CI-988 of 25 mg, there were no significant between-test differences in behavioral response to mCPP. Accordingly, the second phase of the study was conducted with a CI-988 dose of 100 mg in another of patients (N = 10). CI-988 (100 mg) was well tolerated and had no significant effects on pretest anticipatory anxiety. There was no significant blunting of the anxiety response to mCPP as a result of CI-988 administration, nor did CI-988 affect physiologic or neuroendocrine measures. Correlations between peak changes in plasma levels of CI-988 and mCPP-induced anxiety in the high-dose patient group were not significant. Overall, these findings did not provide evidence of anxiolytic effects of CI-988 in patients with GAD. The lack of effect of CI-988 on neuroendocrine and physiological measures further suggests that CI-988's pharmacological effects could be independent of 5-HT function. However, follow-up studies using higher doses of CI-988 are indicated to confirm this preliminary finding as are studies more closely evaluating the interrelationship between CCK and 5-HT function in GAD.

Pretreatment patient factors predicting attrition from a multicenter randomized controlled treatment study for panic disorder.

This study examined pretreatment factors associated with attrition from a clinical trial for panic disorder. The study group consisted of 162 patients who began 11-visit treatments. Six domains (demography, panic disorder severity, psychiatric comorbidity, illness/treatment attributions, coping styles, and personality styles) with 52 variables were used to predict attrition. One hundred twenty-two patients completed and 40 dropped out from treatment. Final multivariate regression analyses showed that the following two variables were independently associated with attrition: lower household income and negative treatment attitudes; attributing the panic disorder to life stressors and greater age were independently associated with attrition at the trend level. Preliminary analyses suggested, in addition, associations between attrition and lower education, shorter length of prior treatment, higher anxiety sensitivity, lower agoraphobic avoidance, and a coping style of seeking social support that were not confirmed by best predictor analysis. Psychiatric comorbidity and personality styles were unrelated to attrition. The implications of these findings for future research and clinical practice are discussed.

Efficient allocation of patients to treatment cells in clinical trials with more than two treatment conditions.

OBJECTIVE: Clinical trials generally allocate patients to equal-sized treatment groups. The authors propose that it may be more efficient to allocate unequal proportions of the total sample size to treatments when more than two treatments are being compared. METHOD: This proposal is illustrated with two examples. One involved a comparison of three treatments and used a dichotomous categorical outcome. The other involved comparison of three treatments and used a continuous measure. RESULTS: In both examples, a considerable increase in efficiency was realized by reducing the number of patients assigned to the placebo cell. CONCLUSIONS: Unequal allocation of patients to treatments should be considered when more than two groups are compared.

Toward an integrated neurobiology of panic disorder.

Panic disorder is a common psychiatric illness that causes considerable short- and long-term morbidity. Although drug treatment and cognitive behavior therapy are beneficial, the etiology of panic disorder and the mechanisms of effective treatment remain unclear. Developments in the preclinical neuroanatomy and neurophysiology of neuronal structures relevant to fear and anxiety promise to provide fresh insights into the neurobiology of panic. In this article, we propose a functional neuroanatomic model of fear and anxiety and review brain imaging studies of panic disorder with this model in mind. In addition, we discuss the implications of integrating functional neuroanatomy and the clinical neurochemistry of panic disorder. An integrated neurobiology of panic disorder will provide a broader conceptual framework with which to tackle the complex questions about the pathophysiology and treatment of this condition.

Plasma levels of gamma-aminobutyric acid and panic disorder.

Low levels of gamma-aminobutyric acid (GABA) in plasma have been associated with the presence of mood disorders in patients with major depressive disorder. We examined plasma GABA in patients with panic disorder, a disorder that is often comorbid with major depression, and in a group of control subjects. Patients with panic disorder had plasma GABA levels that did not differ significantly from levels in controls subjects. These data support the specificity of low plasma GABA as a marker for mood disorders.

Effects of tryptophan depletion on responses to yohimbine in healthy human subjects.

There is considerable evidence that both the norepinephrine (NE) and serotonin (5-HT) systems are involved in the regulation of human anxiety and fear responses. To assess the modulating effects of central 5-HT levels on NE function, 11 healthy human subjects were studied with placebo-controlled challenge tests involving tryptophan depletion followed by administration of the alpha-2-adrenergic antagonist yohimbine 0.4 mg/kg IV. Five of the 11 subjects reported a marked increase in feelings of nervousness (> or = 25 mm on a 100 mm analog scale) following the combination test, while 1/11 had this response to yohimbine alone. No subjects had an increase in nervousness during other control tests. The increase in nervousness after the tryptophan depletion-yohimbine test was statistically significant for the whole group, but there were no other unique changes in behavioral, physiologic or biochemical (MHPG, cortisol) variables with this test. These data are discussed in terms of possible functional interactions between the 5-HT and NE neurotransmitter systems.

Response to meta-chlorophenylpiperazine in panic disorder patients and healthy subjects: influence of reduction in intravenous dosage.

As a further test of the hypothesis of serotonin hypersensitivity in panic disorder (PD), the serotonin agonist meta-chlorophenylpiperazine (MCPP) was administered intravenously in a dose of 0.05 mg/kg to 27 PD patients and 22 normal control subjects. This is one-half the dose used in our previous study of PD patients, where the dose may have been too high to provide evidence of hypersensitivity to the agent. Responses of anxiety and nervousness were statistically indistinguishable by analysis of variance in the two groups, replicating our previous findings. Panic attack symptom score (PASS) ratings were significantly higher in the PD group, compared with a trend toward higher PASS ratings in the 0.1 mg/kg study. Cortisol, human growth hormone, and male prolactin responses showed no significant differences in the two groups by analysis of variance. Prolactin responses were significantly blunted in the female patients. The unexpected blunted prolactin response to MCPP in female PD patients may reflect a nonspecific blunting of prolactin response to stress. The PASS data provide some evidence of serotonergic hypersensitivity in PD.

Effects of the serotonin reuptake inhibitor fluvoxamine on yohimbine-induced anxiety in panic disorder.

To assess the effects of the selective serotonin reuptake blocker fluvoxamine on noradrenergic function in patients with panic disorder, an intravenous yohimbine challenge test was administered to eight patients with panic disorder before and after 8 weeks of fluvoxamine treatment and to a parallel group of eight patients treated with placebo. Fluvoxamine treatment reduced yohimbine-induced anxiety while placebo treatment had no effect on this variable. Both fluvoxamine and placebo treatment had little effect on biochemical or physiologic responses to yohimbine.

Dynamic SPECT imaging of dopamine D2 receptors in human subjects with iodine-123-IBZM.

We studied the uptake, distribution, metabolism and washout of the dopamine D2 receptor ligand [123I]IBZM in healthy subjects (n = 12) with dynamic brain SPECT. The highest radioactivity level was detected in the striatum. Operationally-defined striatal "specific" uptake peaked at 69 min postinjection of radioligand and showed a gradual decline of 15% per hour thereafter. "Specific" uptake at maximal counts represented 53% of the total striatal radioactivity. Two subjects received haloperidol (20 micrograms/kg i.v.) 80 min postinjection of radioligand. Haloperidol caused a 2.6-fold increase in the rate of washout of specific striatal activity in comparison to that in the 10 control subjects and was consistent with drug-induced displacement of radioligand from the dopamine D2 receptor. Two classes of metabolites were detected in plasma and urine: a polar fraction, not extracted by ethyl acetate, and a nonpolar, extractable fraction consisting of parent compound and two compounds having shorter retention times on reversed-phase HPLC. Greater than half the plasma parent was metabolized within 10-15 min after administration. The volume of distribution, estimated from the peak arterial plasma concentration at 50-75 sec, was 7.7-10.2 l; the free (nonprotein bound) fraction of [123I]IBZM after in vitro incubation with blood or plasma was 4.4% +/- 0.4%. These results suggest that [123I]IBZM exhibits uptake in brain regions with high D2 receptor density and shows a relatively stable washout during which drugs affecting dopaminergic transmission may be administered.

Pharmacokinetics of the SPECT benzodiazepine receptor radioligand [123I]iomazenil in human and non-human primates.

The pharmacokinetics of [123I]iomazenil (Ro 16-0154) in 5 healthy human volunteers were compared to those in 2 hypothermic and 3 normothermic anesthetized monkeys. Following intravenous injection in humans and monkeys, [123I]iomazenil rapidly diffused outside the vascular bed and was cleared from the arterial plasma triexponentially. The clearance half-times in hypothermic animals were protracted to values closer to those of the human. [123I]Iomazenil was metabolized mainly to a polar radiometabolite (not extracted by ethyl acetate) in the human whereas an additional lipophilic radiometabolite was detected in the monkey. In vitro and in vivo studies showed that [123I]iomazenil established equal concentrations in association with the cellular and plasma component of the blood, indicating that the plasma clearance of [123I]iomazenil mirrors that of the blood. Analysis of organs from a monkey given [123I]iomazenil showed that the parent compound was actively taken up by peripheral organs; the polar radiometabolite accumulated mainly in the bile and the kidneys whereas the non-polar radiometabolite accumulated in the urine and kidneys. Greater than 90% of the radioactivity in the different regions of the brain was unchanged parent [123I]iomazenil.