Endocrine, cardiovascular, and behavioral effects of intravenous protirelin in patients with panic disorder.

The effects of protirelin administration on the anterior pituitary release of thyrotropin and prolactin were examined in 26 patients with panic disorder and 22 healthy volunteers. There were no differences observed in hormonal responses to protirelin between patients and controls. However, higher Beck Depression Inventory scores were associated with smaller baseline-corrected maximal changes in thyrotropin responses. Cardiovascular responses to protirelin did not differ between a subgroup of 15 patients with panic disorder and 15 age- and sex-matched healthy controls. Although protirelin produced robust increases in heart rate and blood pressure, only one patient with panic disorder experienced a panic attack during the infusion. The hormonal findings suggest that the presence of depressive symptoms may have a significant impact on various indexes of neuroendocrine responsivity and should be taken into consideration when looking at biologic measures in patients with panic disorder. The cardiovascular and behavioral findings do not support the hypothesis that all panic-producing stimuli are nonspecific and suggest that the induction of physical stimuli may be insufficient to produce panic attacks even in susceptible individuals.

Electroencephalographic sleep in panic disorder. A focus on sleep-related panic attacks.

Sleep electroencephalograms were studied in 13 patients with panic disorder, six of whom experienced panic from sleep, and seven controls. Sleep was disturbed in the patients, as manifested by increased sleep latency, decreased sleep time, and decreased sleep efficiency. Rapid eye movement (REM) latencies were not reduced in the patient group. All six of the panic awakenings were preceded by non-REM sleep, which could be further characterized as a transition from stage II toward delta sleep. The overall degree of sleep disturbance (ie, sleep latency, sleep efficiency) did not appear to be influenced by the occurrence of sleep panic. There was also an association of increased REM latency with nights of sleep panic.

Effects of one night's sleep deprivation on mood and behavior in panic disorder. Patients with panic disorder compared with depressed patients and normal controls.

The effects of one night's sleep deprivation on mood and behavior were evaluated in 12 patients with panic disorder, ten depressed patients, and ten controls. In contrast to the improvement in symptoms of anxiety and depression shown by the majority of depressed patients, the response of patients with panic disorder as a group did not differ from that of normal controls, although a subgroup did experience noticeable worsening in their symptoms of anxiety, with 40% experiencing panic attacks on the day following sleep deprivation. Electroencephalographic recordings with nasopharyngeal electrodes on the day following sleep deprivation were normal, further suggesting that patients with panic disorder do not have seizure activity characteristic of temporal lobe epilepsy.

Heart rate and plasma norepinephrine responsivity to orthostatic challenge in anxiety disorders. Comparison of patients with panic disorder and social phobia and normal control subjects.

Heart rate and plasma norepinephrine responsivity to a physiologic challenge, ie, orthostasis, were measured in 20 patients with panic disorder (PD) and 20 age- and sex-matched normal control subjects. While the two groups exhibited similar supine heart rates, patients with PD had a significantly greater heart rate response to orthostatic challenge. Plasma norepinephrine responses did not differ between patients with PD and normal control subjects. In a matched subgroup of 14 patients with PD, 14 normal control subjects, and 14 patients with social phobia, the patients with social phobia exhibited supine and upright plasma norepinephrine levels that were significantly higher than those of the other two diagnostic groups. Taken together, and in the context of findings from other studies, these preliminary observations suggest that the anxiety disorders may demonstrate differing patterns of autonomic dysfunction.

Dopaminergic effects of carbamazepine. Relationship to clinical response in affective illness.

Carbamazepine, a drug used widely to treat epilepsy and trigeminal neuralgia, has been shown to be effective in the acute and prophylactic treatment of manic-depressive illness. While the time course of its antimanic effects parallels that of classic neuroleptics, indirect clinical evidence, such as lack of parkinsonian side effects and tardive dyskinesia, suggests that carbamazepine does not act by blocking dopamine receptors. To assess the effects of carbamazepine on dopamine mechanisms, we measured the dopamine metabolite homovanillic acid (HVA) in the cerebrospinal fluid of affectively ill patients before and after treatment. Carbamazepine did not alter basal concentrations of HVA, but decreased probenecid-induced accumulations of HVA, paralleling results in animal studies. In 25 patients, lower baseline cerebrospinal fluid HVA levels were related to subsequent better acute antidepressive responses to carbamazepine. While the precise mechanism of carbamazepine's effects on dopaminergic systems remains to be determined, this study provides further evidence that carbamazepine does not have a biochemical profile typical of neuroleptics.

Increased sensitivity to caffeine in patients with panic disorders. Preliminary evidence.

The results of a caffeine consumption inventory indicated that patients with panic anxiety disorder, but not affectively ill patients or normal controls, had levels of self-rated anxiety and depression that correlated with their degree of caffeine consumption. In addition, this self-report survey suggested that patients with panic disorder had an increased sensitivity to the effects of one cup of coffee. This apparent sensitivity to caffeine was also documented by the observation that more patients with panic disorder reported the discontinuation of coffee intake due to untoward side effects than controls. These results, based on self-reports, suggest that the hypothesis that patients with panic disorder are more reactive to caffeine should be directly tested using caffeine challenges and that the mechanisms underlying caffeine's effects on anxiety should be further explored.

Carbamazepine and thyroid function in affectively ill patients. Clinical and theoretical implications.

Thyroid function was examined in 50 affectively ill patients before and four weeks after carbamazepine treatment. Carbamazepine significantly and substantially decreased peripheral thyroid hormone levels while increases in thyrotropin levels, although significant, were of much smaller magnitude. Furthermore, the decreases in levels of thyroxine (T4) and free T4 were significantly greater in carbamazepine responders than in nonresponders. These findings are discussed in light of current theories of the role of the thyroid axis in affective illness.

Cognitive-behavioral and pharmacological treatments of social phobia. A controlled study.

Sixty-five patients with social phobia were treated in a study that compared a cognitive-behavioral group treatment program with pharmacotherapy with alprazolam, phenelzine sulfate, or pill-placebo plus instructions for self-directed exposure to phobic stimuli. Statistically significant repeated-measures effects were shown on all measures, indicating that the treatments studied were associated with substantial improvements in patients with severe and chronic social phobia. Patients who were treated with phenelzine were rated by clinicians as more improved on a measure of work and social disability than patients who were treated with alprazolam or placebo (patients in the cognitive-behavior therapy group were not rated on this measure). Subjects showed positive cognitive changes from before to after treatment, and there were no differences between treatment groups on the cognitive measure. We discuss the implications of these findings within the context of demographic and clinical predictors of response.

Behavioral and physiologic effects of short-term and long-term administration of clonidine in panic disorder.

We evaluated the behavioral and physiologic effects of clonidine hydrochloride, a centrally active alpha 2-adrenergic agonist, in two separate studies of patients with panic disorder. In the first study, intravenous clonidine (2 micrograms/kg) and placebo were administered on a blind basis to 12 patients with panic disorder and ten normal controls. Clonidine produced significantly greater decrements in anxiety at one hour in the patients with panic disorder than in the controls. The changes in pulse, blood pressure, and ratings of sleepiness did not differ significantly between patients and controls. In the second study, oral clonidine was administered to 18 patients in a double-blind, flexible-dose treatment trial averaging ten weeks in duration. While anxiolytic effects were noticed in some patients, these effects did not persist in the group as a whole. These two studies indicate that while clonidine has short-term anxiolytic effects in patients with panic disorder, these effects do not persist with long-term administration in most patients.

Carbamazepine and its -10,11-epoxide metabolite in plasma and CSF. Relationship to antidepressant response.

Levels of carbamazepine and its -10,11-epoxide metabolite were measured in plasma and CSF of affectively ill patients treated only with carbamazepine for an average of 33 days at an average dosage of 1,055 mg/day. The CSF levels of carbamazepine were 2.06 micrograms/mL (ie, 31% of plasma levels, which equaled 6.55 micrograms/mL); CSF -10,11-epoxide concentrations averaged 0.91 micrograms/mL in 18 subjects (63% of those found in plasma). Carbamazepine levels in plasma or CSF were not related to degree of antidepressant or antimanic response. In contrast, concentrations of the -10,11-epoxide metabolite were correlated with the degree of antidepressant response. This preliminary study suggests the possibility that the -10,11-epoxide metabolite of carbamazepine may be related to the degree of clinical efficacy in affectively ill patients and may thus possess active psychotropic properties in man in addition to its reported anticonvulsant effects in animals.

Dysphoric mania. Clinical and biological correlates.

Patients studied at peak severity of a manic episode showed substantial degrees of depression (dysphoria) and anxiety. Compared with nondysphoric manics (n = 26), the dysphoric manics (n = 22) had a significantly greater number of previous hospitalizations, and they displayed less rapid cycling both in the year before and during the index hospitalization admission. The severity of manic dysphoria tended to correlate with the number of previous hospitalizations, a finding that was highly significant in women (n = 27). Medication-free manic patients (n = 22) had significant elevations in cerebrospinal fluid norepinephrine concentrations compared with depressed and euthymic patients and normal volunteers, and the degree of elevation correlated significantly with the degree of manic dysphoria, anger, and anxiety rated at the time of the lumbar puncture. Patients with dysphoric mania, recognized by Kraepelin to have poor prognoses, have been reported to respond poorly to lithium carbonate but may be among those who respond to carbamazepine. Clinical, biologic, and pharmacologic response characteristics of manic subgroups, particularly those with extreme dysphoric components to their illness, appear to be clinically meaningful and deserving of further investigation.

Plasma cortisol responses to clonidine in depressed patients and controls. Evidence for a possible alteration in noradrenergic-neuroendocrine relationships.

Plasma cortisol responses to the intravenous administration of clonidine hydrochloride and placebo were evaluated in depressed patients and controls. Depressed patients had higher mean baseline cortisol levels than controls. Cortisol levels decreased during the morning study period following both placebo and 2 micrograms/kg of clonidine hydrochloride in the depressed patients, but the cortisol decrease was sixfold greater on the day of clonidine administration; these placebo-clonidine differences were statistically significant, whether calculated on an absolute decrement basis or as a percent change. In contrast, controls responded to clonidine with only a 1.5-fold greater cortisol reduction than that found after placebo, a nonsignificant difference from the day of placebo administration. Reductions in the concentration of plasma 3-methoxy-4-hydroxyphenylglycol following clonidine administration were significantly negatively correlated with baseline plasma cortisol levels, raising the possibility that abnormalities in the responsiveness of the alpha 2-noradrenergic system may be associated with the hypothalamo-pituitary-adrenal (HPA) axis dysfunction found in depressed patients.

Cortisol response to clonidine in panic disorder: comparison with depressed patients and normal controls.

Abnormalities in regulation of noradrenergic function have been proposed as part of the pathology of depressive and panic anxiety disorders. However, abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function have largely been limited to patients with depressive disorders. Using the cortisol response to clonidine, an alpha 2-adrenergic receptor agonist, this study examined the relationship between the noradrenergic system and the HPA axis in 10 patients with major depression (4 unipolar, 6 bipolar), 10 patients with panic disorder, and 10 normal controls. Baseline cortisol was significantly elevated in depressed as compared with panic patients, but not with controls. Depressed patients also tended to exhibit a greater absolute fall in plasma cortisol (5.2 +/- 4.0 micrograms/dl) compared with panic patients (1.7 +/- 2.4 micrograms/dl) (p less than 0.06, t-test). When expressed as a percentage of baseline, however, the cortisol response to clonidine did not differ significantly between diagnostic groups (p greater than 0.10). Basal levels of cortisol were highly correlated with the degree of decrease in cortisol induced by clonidine in the group of 30 subjects (r = -0.81, p less than 0.0001). These findings are discussed in the context of the utility of clonidine as a probe of the functional relatedness of the noradrenergic system and the HPA axis in these disorders.

New studies and perspectives on the noradrenergic receptor system in depression: effects of the alpha 2-adrenergic agonist clonidine.

In an attempt to understand the dynamics of noradrenergic function in depression, we evaluated neuroendocrine, biochemical, cardiovascular, and behavioral responses to the acute intravenous administration of the alpha 2-adrenergic agonist, clonidine, in depressed patients and normal controls. Significantly more variance was observed in the depressed patients than the controls for most indices of basal noradrenergic output including plasma norepinephrine (NE) and 3-methoxy-4-hydroxyphenylglycol (MHPG). Growth hormone, plasma MHPG, and heart rate responses to clonidine were reduced in the depressed patients compared to the controls, all suggesting reduced responsiveness of alpha 2-adrenergic receptors in depression. Baseline levels of cortisol were elevated in the depressed patients compared to the controls. Clonidine decreased cortisol to normal levels in the depressed patients but had little effect in the controls. Thus the depressed patients manifested a significantly increased cortisol response to clonidine. These data raise the possibility that the hypercortisolemia of depression may be related to noradrenergic dysfunction. Clonidine also significantly reduced anxiety in the depressed patients, particularly those with elevated basal plasma MHPG, but not in controls. These results suggest that diminished alpha 2-adrenergic responsiveness as documented by decreased endocrine, biochemical, and physiological responses to clonidine may be related to the depressive and anxiety symptoms as well as the neuroendocrine disturbances characteristic of many depressed patients.

Effect of yohimbine on plasma homovanillic acid in panic disorder patients and normal controls.

The effects of oral yohimbine (20 mg) or placebo or both drugs on plasma homovanillic acid (HVA) were evaluated in patients with panic disorder and normal controls. Panic disorder patients had similar HVA values at baseline compared with normal controls, and yohimbine failed to produce appreciable changes in HVA in both groups. These findings are discussed within the context of catecholaminergic theories of panic disorder.

Growth hormone response to intravenous clonidine in social phobia: comparison to patients with panic disorder and healthy volunteers.

The growth hormone (GH) response to intravenous administration of clonidine hydrochloride (2 micrograms/kg) was assessed in 16 patients with DSM-III-R social phobia, 13 patients with DSM-III-R panic disorder, and 31 healthy controls. Compared to the healthy volunteers, both social phobic and panic-disorder patients had significantly blunted GH increments after clonidine. The social phobic patients demonstrated a similar degree of GH "blunting" to clonidine as did the patients with panic disorder.

The QKd interval in panic disorder: an assessment of end-organ thyroid hormone responsivity.

The QKd interval was utilized as a presumptive index of end-organ thyroid hormone effect to test the hypothesis that patients with panic disorder might have abnormal tissue-level responsivity to normal levels of peripherally circulating thyroid hormones. No significant differences in QKd intervals were found between 15 patients with panic disorder (230 +/- 50 msec) and 20 normal controls (224 +/- 29 msec) while drug-free. These findings suggest that patients with panic disorder have normal tissue-level responsivity to thyroid hormone.

Lack of efficacy of the adenosine reuptake inhibitor dipyridamole in the treatment of anxiety disorders.

We administered dipyridamole, an adenosine reuptake inhibitor, to 12 outpatients with DSM-III-R anxiety disorders (2 patients with generalized anxiety disorder, 10 patients with panic disorder). Dipyridamole was administered at a flexible dose in a single-blinded fashion following a placebo washout phase and elimination of placebo responders. The mean duration of active treatment with dipyridamole was 46 days (range 21-88 days); the mean peak dose of dipyridamole was 202 +/- 55 mg/day (range 100-300 mg/day). Symptom ratings were completed at regular intervals by the patient and by a research nurse unaware of the treatment condition. Clinically significant improvement in anxiety symptoms was not demonstrated. The implications of these findings for an adenosinergic dysfunction model of panic disorder are discussed.

Paradoxical growth-hormone responses to thyrotropin-releasing hormone in panic disorder.

Thyrotropin-releasing hormone (TRH) has been reported to stimulate growth hormone (GH) release in a variety of pathological conditions, including some studies of major depression. Because of the considerable phenomenological and neuroendocrine overlap between major depression and panic disorder, we investigated the rate of positive GH responses to TRH in 38 patients with panic disorder and 23 normal controls. There were no between-group differences in mean GH response to TRH or in the proportion of subjects with positive responses. These findings are discussed in the context of neuroendocrine regulation of GH secretion and the relationship between anxiety and affective disorders.

Platelet [3H]imipramine binding in patients with panic disorder.

[3H]imipramine binding to platelets was measured in 17 drug-free panic disorder patients and 14 healthy controls. No difference in Bmax or Kd values was found between the two groups. Patients with a past history of major melancholic depression or severe agoraphobia had similar binding parameters as panic disorder patients without a history of depression or severe agoraphobia.