Regional cerebral metabolic asymmetries replicated in an independent group of patients with panic disorders.

BACKGROUND: Abnormal left/right (L/R) hemispheric ratios of regional cerebral glucose metabolic rates (rCMRglc) (hippocampus and inferior prefrontal cortex) have been noted in unmedicated panic disorder patients. METHODS: An independent group of panic disorder patients placed on imipramine was studied with positron-emission tomography, testing for evidence of normalization versus persistence of the abnormal rCMRglc ratios. Differences in orbital frontal rCMRglc values between the imipramine-treated and the previously reported unmedicated panic disorder patients were tested examining for evidence that the differences would resemble those noted in obsessive-compulsive disorder (OCD) patients treated with clomipramine. RESULTS: We found the same abnormally low L/R hippocampal and posterior inferior prefrontal rCMRglc ratios in the imipramine-treated panic disorder patients. In addition, we found posterior orbital frontal rCMRglc decreases in the imipramine-treated panic disorder patients compared with the unmedicated panic disorder patients. CONCLUSIONS: These abnormal asymmetries found in unmedicated panic disorder patients and now in imipramine-treated panic disorder patients may reflect a trait abnormality. The orbital frontal rCMRglc differences between the imipramine-treated and unmedicated patients are similar to changes noted in OCD patients treated with clomipramine and may reflect direct or indirect effects of imipramine treatment in panic disorder patients.

The relationship between plasma MHPG and NE: employing regression models in estimating centrally derived MHPG and peripheral NE turnover rate in panic disorder.

Studies investigating the role of the noradrenergic system in the pathophysiology of anxiety have focused on measuring plasma 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) levels. Fewer studies have examined norepinephrine levels. Basal plasma norepinephrine and free MHPG levels were simultaneously measured in 33 normal controls and 20 panic disorder (PD) patients. Norepinephrine levels were similar in patients and controls, but MHPG levels were significantly lower in patients (13.34 +/- 3.22 vs 18.37 +/- 4.49 pmol ml-1, p < 0.0001). Norepinephrine correlated significantly with plasma MHPG levels in controls (r = 0.538, p < 0.0001) and patients (r = 0.645, p < 0.002). Patients had a trend toward a lower y-intercept than controls, suggesting a lower contribution by the CNS to MHPG pool plasma levels (9.18 vs 12.51, p < 0.08). Norepinephrine turnover rate was similar in patients and controls. We propose that the dysregulation in the noradrenergic system in PD may be akin to animal studies of acute-on-top-of-chronic stress paradigms, whereby chronic stress results in normal or decreased basal NE turnover and sensitized responses to recurrent stresses.

Behavioral, sympathetic and adrenocortical responses to yohimbine in panic disorder patients and normal controls.

Yohimbine, an alpha 2 adrenoreceptor antagonist, enhances norepinephrine (NE) release and increases sympathetic activity. We examined the behavioral, peripheral sympathetic and adrenocortical responses to oral yohimbine in seven healthy controls and 11 patients diagnosed with agoraphobia with panic attacks (PD). Patients did not differ in baseline cardiovascular or neuroendocrine measures from controls despite significantly higher baseline anxiety ratings. Placebo caused no changes in baseline-corrected behavioral, cardiovascular or neurochemical responses in either group. Yohimbine induced a panic episode in six PD patients, but no controls. PD patients had significantly higher severity scores of autonomic anxiety symptoms. Yohimbine significantly raised systolic blood pressure (F = 3.07, P < 0.03), plasma NE levels (F = 12.11, P < 0.00) and cortisol levels (F = 4.82, P < 0.02), but had no effect on epinephrine levels. NE responses were similar in both groups, but patients had higher cortisol responses to yohimbine than controls (F = 7.14, P < 0.01). The correlational pattern between behavioral ratings and neuroendocrine responses in patients was opposite to that observed in controls. Despite similar increases in plasma NE levels between PD patients and healthy controls, PD patients had greater anxiogenic, cardiovascular and cortisol responses to yohimbine. Enhanced post-synaptic adrenoreceptor sensitivity may explain the noradrenergic dysregulation found in panic disorder.

A comparison of the effects of intravenous pentagastrin on patients with social phobia, panic disorder and healthy controls.

The present study sought to determine whether social phobics, like patients with panic disorder, have increased sensitivity to the panicogenic effects of pentagastrin. Intravenous pentagastrin and placebo were administered in a double-blind fashion to 19 social phobics, 11 patients with panic disorder, and 19 healthy controls while they participated in a structured social interaction task. Behavioral, cardiovascular, and neuroendocrine responses were obtained. Pentagastrin led to panic attacks in 47% of the social phobics, 64% of the panic disorder patients, and 11% of the healthy controls. The social interaction itself increased anxiety, blood pressure, and pulse in all three groups. These findings suggest that the panicogenic effects of pentagastrin are not limited to patients with panic disorder and provide further evidence for shared neurobiology in social phobia and panic disorder.

Effects of intravenous caffeine administered to healthy males during sleep.

Pharmacological challenge paradigms have been useful for elucidating the phenomenology and neurobiology of panic attacks. A drawback of the pharmacological challenge method is that individual differences in baseline arousal and outcome expectancy can lead to different subjective and physiological drug responses. One method for eliminating differences in baseline arousal and expectancy is to perform pharmacological challenges during non-rapid eye movement (non-REM) sleep. In the present study, fourteen healthy male volunteers received caffeine (5 mg/kg) and placebo (normal saline) during non-REM sleep on two successive nights, in a single-blind manner. Caffeine, compared to placebo, was associated with increased arousal, sleep disruption, and elevations in adrenocorticotropic hormone (ACTH) and cortisol. In one subject, caffeine infusion during sleep induced a panic attack. These findings indicate that caffeine leads to increased arousal and hypothalamic-pituitary-adrenal axis (HPA) axis activation in the absence of high baseline anxiety and expectancy bias. Further, they suggest that similar techniques can be employed in patient populations to elucidate the neurobiology of sleep panic attacks.

Role of serotonin drugs in the treatment of social phobia.

Social phobia is a common anxiety disorder that is underdiagnosed and undertreated. To date, three classes of serotonin drugs have been used to treat patients suffering from social phobia. These include the serotonin selective reuptake inhibitors (SSRIs), the partial 5-HT1A agonist buspirone, and the 5-HT3 antagonist ondansetron. Although none of the serotonin agents have yet been directly compared with the gold standard monoamine oxidase inhibitor phenelzine or the high potency triazolobenzo-diazepines alprazolam or clonazepam, the SSRIs, as a class, appear to be clinically useful agents. Further studies using larger sample sizes and double-blind methodology are needed to clarify the role of serotonin drugs in the treatment of social phobia.

Rapid onset: a valid panic disorder criterion?

This study examined the value of the DSM-IV time criterion for panic disorder (PD) requiring an abrupt onset to panic attacks (PAs) with a time to peak intensity (TTPI) of less than 10 min, and evaluated features distinguishing rapid onset (TTPI < 10) from prolonged onset (TTPI > 10) panickers. Eight hundred and sixty-four respondents to the National Institute of Mental Health Panic Disorder Questionnaire (NIMH PQ) who met the first three PD criteria were compared based on the time criterion. The prolonged onset panickers (18.2%) did not differ significantly from rapid onset panickers (81.8%) on any of 100 items assessing clinical symptoms, course of illness, and comorbidity of PD. These results suggest that many patients with otherwise classic features of PD have a prolonged TTPI of PAs, and that patients with prolonged-onset PAs are similar to patients with rapid-onset PAs on most measures. The reliability, validity, and clinical relevance of the current DSM-IV TTPI criterion should be evaluated in future studies.

Psychiatric characteristics of children with selective mutism: a pilot study.

OBJECTIVE: To ascertain characteristics of children with selective mutism. METHOD: Subjects with selective mutism were evaluated by means of parent and teacher rating scales and structured diagnostic interviews. RESULTS: Thirty children were evaluated. Mutism severity varied markedly in different environmental settings. Ninety-seven percent of the subjects were diagnosed with social phobia or avoidant disorder of childhood or adolescence or both and 30% with simple phobia. No other psychiatric disorders were common. Parent and teacher rating scales showed high levels of anxiety symptoms, especially social anxiety, and low levels of all other psychiatric symptoms. Anxiety and social anxiety severity correlated with mutism severity. First-degree family history of social phobia and of selective mutism, obtained by family history method, was present in 70% and 37% of families, respectively. There was no evidence of a causal relationship between psychologically or physically traumatic experiences and development of selective mutism. CONCLUSIONS: Selective mutism may be a symptom of social anxiety, rather than a distinct diagnostic syndrome. Further study of the characteristics of children with selective mutism and their families is warranted.

Treatment of elective mutism with fluoxetine: a double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy of treatment with fluoxetine in reducing symptoms associated with elective mutism. METHOD: Sixteen subjects with elective mutism were treated with placebo (single-blind) for 2 weeks. Fifteen placebo nonresponders were then randomly assigned to double-blind treatment with fluoxetine at a dose of 0.6 mg/kg/day (N = 6) or continued placebo (N = 9) for an additional 12 weeks. Outcome ratings were completed by the treating psychiatrist, parents, and teachers. RESULTS: Significant improvements over time on ratings of elective mutism, anxiety, and social anxiety, rated by clinician, parents, and teachers, were demonstrated in both fluoxetine- and placebo-treated subjects. Subjects treated with fluoxetine were significantly more improved than placebo-treated subjects on parent's ratings of mutism change and global change. Clinician and teacher ratings did not reveal significant differences between treatment groups. Although improved, most subjects in both treatment groups remained very symptomatic at the end of the study period. Side effects were minimal. CONCLUSION: Fluoxetine may be beneficial and safe in the treatment of children with elective mutism. Longer periods of treatment may yield more substantial therapeutic benefits. Further study is indicated.

Anxiety and growth disturbance: is there a connection? A review of biological studies in social phobia.

Current knowledge of the neurobiology of social anxiety and social phobia is reviewed within the framework of chemical models of anxiety. Preliminary evidence for noradrenergic, serotonergic, and adenosinergic systems in the neurobiology of social phobia is presented and discussed within the context of medical model versus continuum theories of anxiety. The clinical and theoretical implications of a hypothesized linkage between anxiety disorders and hypothalamic-growth hormone dysfunction are presented. The author recommends that additional research strategies be developed to examine growth patterns and the function of growth hormone and other growth factors in children and adults with anxiety disorders; moreover, the rationale for additional longitudinal investigations of children with growth hormone deficiency short stature and psychosocial short stature is presented. It is hypothesized that individuals with growth hormone deficiency may be at high risk for the development of anxiety disorders.

Imipramine in patients with chest pain despite normal coronary angiograms.

BACKGROUND: Ten to 30 percent of patients undergoing cardiac catheterization because of chest pain are found to have normal coronary angiograms. Because these patients may have a visceral pain syndrome unrelated to myocardial ischemia, we investigated whether drugs that are useful in chronic pain syndromes might also be beneficial in such patients. METHODS: Sixty consecutive patients underwent cardiac, esophageal, psychiatric, and pain-sensitivity testing and then participated in a randomized, double-blind, placebo-controlled three-week trial of clonidine at a dose of 0.1 mg twice daily (20 patients), imipramine at a dose of 50 mg nightly with a morning placebo (20 patients), or placebo twice daily (20 patients); this treatment phase was compared with an identical period of twice-daily placebo for all patients (placebo phase). RESULTS: Thirteen (22 percent) of the 60 patients had ischemic-appearing electrocardiographic responses to exercise, 22 of the 54 tested (41 percent) had abnormal esophageal motility, 38 of 60 (63 percent) had one or more psychiatric disorders, and 52 of 60 (87 percent) had their characteristic chest pain provoked by right ventricular electrical stimulation or intracoronary infusion of adenosine. During the treatment phase, the imipramine group had a mean (+/- SD) reduction of 52 +/- 25 percent in episodes of chest pain, the clonidine group had a reduction of 39 +/- 51 percent, and the placebo group a reduction of 1 +/- 86 percent, all as compared with the placebo phase of the trial. Only the improvement with imipramine was statistically significant (P = 0.03). Repeat assessment of sensitivity to cardiac pain while the patients were receiving treatment showed significant improvement only in the imipramine group (P = 0.01). The response to imipramine did not depend on the results of cardiac, esophageal, or psychiatric testing at base line, or on the change in the psychiatric profile during the course of the study, which generally improved in all three study groups. CONCLUSIONS: Imipramine improved the symptoms of patients with chest pain and normal coronary angiograms, possibly through a visceral analgesic effect.

Normal urinary free cortisol and postdexamethasone cortisol in social phobia: comparison to normal volunteers.

In primates, social stress is associated with activation of the hypothalamic-pituitary-adrenal (HPA) axis. Social phobia is a common, often disabling, form of pathological anxiety characterized by marked distress in situations involving possible scrutiny or evaluation. Little is known about HPA function in patients with social phobia. We examined 24-hour excretion of urinary free cortisol (UFC) in 54 patients with social phobia and post-dexamethasone cortisol levels in 64 patients with social phobia and found no evidence of HPA-axis overactivity compared to normal controls, despite pathological levels of anxiety.

Inherited deafness among nervous pointer dogs.

A high incidence of deafness, confirmed by brainstem auditory evoked response testing, was found in a colony of pointer dogs selectively bred for excessive nervous behavior. The results of outcross and F1 backcross breedings were consistent with an autosomal recessive mode of inheritance of deafness in this family of dogs.

Growth hormone response to clonidine in the nervous pointer dog model of anxiety.

Blunted growth hormone responses to clonidine have been reported in most studies of humans with panic disorder but have been an inconsistent finding in the study of other anxiety syndromes. The growth hormone response to oral clonidine (100 micrograms/kg) was investigated in the adult nervous pointer dog, a genetic animal model of anxiety. Compared with placebo, clonidine produced significant increases in plasma levels of growth hormone; however, there were no differences in the growth hormone (GH) responses to clonidine in the nervous compared with the normal pointer dogs. Findings in this animal model are discussed within the context of noradrenergic-hypothalamic-GH dysfunction reported in some but not all types of anxiety disorders in humans.

Dose-response effects of intravenous caffeine in normal volunteers.

The administration of caffeine has been developed as a chemical model for the study of anxiety. However, previous researchers investigating caffeine-induced anxiety states in humans have administered oral caffeine. In this dose-response study, we investigated the effects of blindly administered intravenous caffeine (3, 5, and 7 mg/kg) versus placebo in normal control subjects. We report the first series of subjects experiencing olfactory hallucinations (10 of 10 subjects, 24 of 30 infusions) immediately following intravenous caffeine infusion. In addition, consistent with our previous work with oral caffeine, we found dose-related increases in ratings of anxiety and blood levels of cortisol and lactate. One subject experienced a DSM-III-R panic attack. Further questioning revealed that his mother suffers panic attacks. Our findings of olfactory hallucinations are discussed within the context of localized limbic system dysfunction, noting the phenomenologic and possible neuroanatomic overlap between panic disorder and complex partial seizures.