Neurobiological mechanisms of panic anxiety: biochemical and behavioral correlates of yohimbine-induced panic attacks

The effects of yohimbine, an alpha 2-adrenergic receptor antagonist, on anxiety, blood pressure, heart rate, and plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and cortisol were determined in 20 healthy subjects and 68 patients who had agoraphobia with panic attacks or panic disorder. Yohimbine produced panic attacks meeting DSM-III criteria in 37 patients and one healthy subject. The patients reporting yohimbine-induced panic attacks had significantly larger increases in plasma MHPG, cortisol, systolic blood pressure, and heart rate than the healthy subjects. These findings support the hypothesis relating high noradrenergic neuronal activity to the pathophysiology of panic attacks in a subgroup of panic disorder patients.     

Increased anxiogenic effects of caffeine in panic disorders

The effects of oral administration of caffeine (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) and cortisol were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder. Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, palpitations, restlessness, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma caffeine levels. Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during panic attacks. Caffeine did not alter plasma MHPG levels in either the healthy subjects or patients. Caffeine increased plasma cortisol levels equally in the patient and healthy groups. Because caffeine is an adenosine receptor antagonist, these results suggest that some panic disorder patients may have abnormalities in neuronal systems involving adenosine. Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages.     

Endocrine and physiological changes during "spontaneous" panic attacks

Eight patients with DSM-III-defined panic attacks were compared to four normal subjects on hormonal and physiological variables measured at six predetermined times through 24 hr and also during nine "spontaneous" attacks. Levels at predetermined times were not different, other than a reduction of urinary unconjugated epinephrine in patients. Plasma prolactin was elevated at the peak of most of the attacks and correlated with attack severity. Plasma cortisol and growth hormone, and heart rate, were elevated during some attacks, and plasma norepinephrine showed small increases. Significant plasma epinephrine and MHPG changes were not observed.     

Abnormal regulation of noradrenergic function in panic disorders. Effects of clonidine in healthy subjects and patients with agoraphobia and panic disorder

Clonidine hydrochloride, an alpha 2-adrenergic receptor agonist that decreases noradrenergic function, was administered to 21 healthy subjects and 26 drug-free patients with agoraphobia and panic attacks. Clonidine produced significantly greater decreases in plasma MHPG levels and sitting and standing diastolic blood pressure and significantly smaller increases in growth hormone levels and self-rated drowsiness in the patients. These findings indicate that the regulation of noradrenergic activity is aberrant in some patients with panic disorder, since a previous study demonstrated that patients with panic disorder exhibit increased plasma MHPG levels, blood pressure, and behavioral responses to the alpha 2-adrenergic receptor antagonist yohimbine. The increased dynamic range of noradrenergic activity observed as an increased sensitivity to both clonidine and yohimbine may reflect abnormalities in the regulatory inputs to noradrenergic neurons, or dysfunction in the alpha 2-adrenergic receptor effector coupling mechanism or the intracellular effector system.     

Carbon dioxide-induced anxiety. Behavioral, physiologic, and biochemical effects of carbon dioxide in patients with panic disorders and healthy subjects

Carbon dioxide was administered for 15 minutes to patients with panic disorders (5% CO2, n = 14) and healthy subjects (5% CO2, n = 11; 7.5% CO2, n = 8). Following administration of CO2 and air placebo, changes in behavioral ratings, vital signs, and plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol, cortisol, growth hormone, and prolactin were measured over three hours. In the healthy subjects, CO2 produced dose-related increases in anxiety, somatic symptoms, vital signs, and plasma cortisol levels. In the patients, the frequency of panic attacks (in eight of 14 patients) and the increases in anxiety and somatic symptoms induced by 5% CO2 exceeded those in the healthy subjects and were similar to those induced by 7.5% CO2 in the healthy subjects. The physiologic and biochemical measurements obtained did not elucidate the mechanisms underlying CO2-induced anxiety or the greater anxiogenic effects of CO2 seen in patients with panic disorders.     

Noradrenergic function and the mechanism of action of antianxiety treatment. II. The effect of long-term imipramine treatment

Considerable preclinical and clinical evidence indicates that increased noradrenergic function is involved in the development of anxiety. Imipramine hydrochloride, which has complex effects on noradrenergic function in animals, is effective in patients with agoraphobia and panic disorder. To assess the effects of imipramine on noradrenergic function in patients, plasma levels of free 3-methoxy-4-hydroxyphenylglycol (MHPG) and yohimbine-induced increases in plasma MHPG levels, anxiety-nervousness, blood pressure, and somatic symptoms were studied before and during long-term imipramine treatment in 11 patients meeting DSM-III criteria for agoraphobia with panic attacks. Long-term imipramine treatment significantly decreased baseline plasma MHPG levels by 38% and modestly potentiated yohimbine-induced increases in blood pressure, but it did not alter yohimbine-induced increases in plasma MHPG levels or in patient ratings of anxiety-nervousness. The therapeutic effects of imipramine in panic disorder may relate more to the decrease in norepinephrine turnover than to alterations of alpha 2-adrenergic autoreceptor function.     

Possible mechanisms for lactate's induction of panic

Forty-three patients with panic disorder or agoraphobia with panic attacks and 20 control subjects received 0.5 M racemic sodium lactate intravenous infusions, single-blind as to duration and sequence. During the procedure, pulse; blood pressure; blood L-lactate and pyruvate; plasma ionized calcium, phosphate, prolactin, epinephrine, norepinephrine, and cortisol levels; and venous PCO2, pH, and bicarbonate were measured in an attempt to clarify the mechanism of lactate-induced panic attacks. During the infusion, 72% of the patients but none of the control subjects had panic attacks. The laboratory findings suggest that peripheral catecholamine surge is not the mechanism by which lactate causes panic, although elevated epinephrine may be a predisposing factor. Heightened central noradrenergic activity was present in many but not all of the attacks. Contrary to previous hypotheses, neither depression of ionized calcium nor induction of metabolic alkalosis appears sufficient to cause panic during lactate infusion.     

Doxapram-induced panic attacks and cortisol elevation

Numerous agents with differing biological properties and central nervous system (CNS) effects can induce panic attacks in predisposed individuals. A potential explanation of this finding is that panic disorder patients are more likely to panic than normal control subjects when given a panicogen due to an excessive fear response to somatic arousal. We test this hypothesis by using doxapram, a panicogen with minimal CNS effects, to induce panic in patients and control subjects. Doxapram was given to six subjects with panic disorder with or without agoraphobia and four healthy volunteers. Measures comprised the Acute Panic Inventory, the Borg Exertion scale, the 10-point Anxiety Scale, the 10-point Apprehension Scale, cortisol, prolactin, and MHPG, all obtained at baseline and multiple time points after the doxapram infusion. All panic disorder patients panicked with doxapram, whereas no control subjects had a panic attack. Panic patients had similar levels of breathlessness with doxapram compared with control subjects. Although panic patients had higher levels of anxiety and apprehension, these did not change significantly with doxapram compared with control levels. Doxapram led to similar increases in cortisol and prolactin in both groups, and MHPG was consistently elevated in panic patients, but unaffected by doxapram. These results show that doxapram is a useful panicogen in the study of panic disorder. Since the panic patients and control subjects had similar levels of physiological and psychological arousal, but the panic patients were more likely to have a panic attack, this lends support to the concept of a sensitized fear network in panic disorder patients.     

Plasma MHPG levels in lactate and isoproterenol anxiety states

It has been claimed that an increase in brain noradrenergic activity plays a role in panic disorder and that enhanced noradrenergic activity may be reflected by plasma levels of MHPG. We investigated plasma MHPG levels in panic disorder patients at baseline and during lactate- and isoproterenol-induced anxiety states. These infusions and 5% dextrose infusions were given to 10 panic disorder patients and 9 healthy control subjects. Each subject received all three infusions, double-blind, in random order, and at 1-week intervals. When compared to controls, plasma free MHPG levels in panic patients were not elevated at baseline, during lactate or isoproterenol infusions, at the point of panic, or up to 20 min after the onset of panic. MHPG values were also not elevated in subjects who panicked compared to those who did not. MHPG values were significantly lower in three patients who failed to panic with isoproterenol, but the patient panickers had MHPG values similar to those of controls. Significant correlations between MHPG levels and anxiety ratings were infrequent and could be accounted for by chance alone. These results did not support the noradrenergic model for panic anxiety states induced by lactate or isoproterenol.     

Psychoimmunoendocrine aspects of panic disorder.

Immunological, neuroendocrine and psychological parameters were examined in 14 psychophysically healthy subjects and in 17 panic disorder patients before and after a 30-day course of alprazolam therapy. T lymphocyte proliferation in response to the mitogen phytohemagglutinin, lymphocyte beta-endorphin (beta-EP) concentrations, plasma ACTH, cortisol and beta-EP levels were examined in basal conditions and after corticotropin-releasing hormone (CRH) stimulation. Cortisol inhibition by dexamethasone (DST) and basal growth hormone (GH) and prolactin levels were also examined. Depression, state or trait anxiety, anticipatory anxiety, agoraphobia, simple and social phobias, severity and frequency of panic attacks were monitored by rating scales. The immune study did not reveal any significant difference between patients and controls, or any effect of alprazolam therapy. The hormonal data for the two groups were similar, except for higher than normal basal ACTH and GH plasma levels, lower than normal ratios between the ACTH and cortisol responses to CRH, and blunted DST in some patients. All the impairments improved after alprazolam therapy, in parallel with decreases in anxiety and in severity and frequency of panic attacks.     

Neuroendocrine and monoaminergic responses to acute administration of alprazolam in normal subjects

The effect of a single dose (3 mg) of alprazolam on plasma cortisol, growth hormone (GH), prolactin, norepinephrine (NE) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) was studied in 10 healthy males. Alprazolam and placebo were administered orally in a crossover design and blood was sampled for 24 h. In comparison to placebo, alprazolam significantly reduced plasma cortisol levels and raised plasma GH levels. Prolactin levels were elevated by 100% from 2 to 8 h after alprazolam administration. The robust increase in prolactin levels is less consistent with previously reported data on traditional benzodiazepines. Plasma NE levels following alprazolam were lower than following placebo administration only at one time point, and MHPG concentrations were not affected. The lack of change in NE and MHPG levels suggests that the acute effect of alprazolam in normal subjects is not mediated via the central noradrenergic system.     

24-h Monitoring of plasma norepinephrine, MHPG, cortisol, growth hormone and prolactin in depression

Depression is associated with alterations in hormone and catecholamine circadian rhythms. Analysis of these alterations has the potential to distinguish between three neurobiological models of depression, the catecholamine model, the phase advance model and the dysregulation model. Although a number of studies of 24-h rhythms have been reported, inconsistencies among the findings have complicated efforts to model the chronobiology of depression. The present study takes advantage of frequent plasma sampling over the 24-h period and a multioscillator cosinor model to fit the 24-h rhythms. METHOD: Plasma levels of norepinephrine, cortisol, prolacatin and growth hormone were sampled at 30-min intervals, and MHPG at 60-min intervals, over a 24-h period in 22 patients with major depressive disorder and 20 healthy control volunteers. RESULTS: The depressed patients had phase advanced circadian rhythms for cortisol, norepinephrine and MHPG, phase advanced hemicircadian rhythms for cortisol and prolactin, and a phase advanced ultradian rhythm for prolactin compared to healthy control subjects. In addition, the rhythm-corrected 24-h mean value (mesor) of norepinephrine was lower in the depressed patients compared to the healthy controls. There also was a poorer goodness-of-fit for norepinephrine to the circadian oscillator in the depressed patients relative to the healthy controls. CONCLUSIONS: These findings provide partial support for the dysregulation model of depression and are consistent with those studies that have found phase advances in cortisol, norepinephrine and MHPG rhythms in depression.     

Noradrenergic neuronal dysregulation in panic disorder: the effects of intravenous yohimbine and clonidine in panic disorder patients.

In order to evaluate possible abnormal noradrenergic neuronal functional regulation in patients with panic disorder, the behavioral, biochemical and cardiovascular effects of intravenous yohimbine (0.4 mg/kg) and clonidine (2 micrograms/kg) were determined in 15 healthy subjects and 38 patients with panic disorder. A subgroup of 24 panic disorder patients were observed to experience yohimbine-induced panic attacks and had larger yohimbine-induced increases in plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) than healthy subjects and other panic disorder patients. A blunted growth hormone response to clonidine and a significant clonidine-induced decrease in plasma MHPG was also observed in this subgroup of panic disorder patients. These data replicate and extend previous investigations, which are consistent with a large body of preclinical and human data relating increased noradrenergic neuronal function to human anxiety and fear states.     

Normal urinary free cortisol and plasma MHPG in panic disorder: clinical and theoretical implications

Abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis and noradrenergic function have been reported in patients with panic disorder. Mean urinary free cortisol and plasma MHPG were measured in 12 medication-free panic disorder patients and 12 normal controls. No significant difference in urinary free cortisol and plasma MHPG was observed between the patients and controls. There was no relationship between plasma MHPG and urinary free cortisol in the panic patients or normal controls. These findings are described within the context of current concepts of stress and noradrenergic dysfunction in panic disorder.     

Prolactin and sodium lactate-induced panic

Sodium lactate infusions reliably induce panic attacks in panic disorder patients but not in normal controls, but the mechanism underlying this response is unknown. We studied the plasma prolactin response to infusion of 0.5 molar sodium lactate in 38 patients with panic disorder or agoraphobia with panic attacks, and 16 normal controls. As expected, baseline plasma prolactin was significantly higher in female subjects than in male subjects. However, the males who experienced lactate-induced panic had significantly elevated baseline prolactin levels compared to male nonpanickers and controls. Prolactin levels increased in all groups during lactate infusion, which may reflect osmotic effects, but were blunted in the late panickers compared to nonpanickers and controls. The elevated baseline prolactin for male panickers supports a relationship between prolactin and anticipatory anxiety. The blunted prolactin response for late panickers suggests a net diminution, rather than a sensitization, of prolactin response in panic anxiety.     

Behavioral, neuroendocrine, and biochemical effects of 5-hydroxytryptophan administration in panic disorder

L-5-Hydroxytryptophan (5HTP) was administered to 20 patients suffering from panic disorder and to 20 healthy controls. Subjects received 60 mg 5HTP in 300 ml saline solution. Before, during, and up to 2 hours after 5HTP administration, symptoms of anxiety and depression were assessed. In addition, plasma 5HTP, 3-methoxy-4-hydroxyethylglycol (MHPG), cortisol, beta-endorphin, and melatonin levels were measured at several time points, and the kinetics of 5-hydroxytryptamine (5HT) in blood platelets were measured. During and after the infusion of 5HTP, none of the patients showed an increase in anxiety or depressive symptoms, despite the presence of severe side effects. Some patients even experienced the 5HTP infusion as a relief. In contrast to the patients, nine control subjects reported depressed mood, although no increases in anxiety were noted. In both patients and controls, the 5HTP infusion led to substantial increases in plasma cortisol and beta-endorphin levels, while the plasma MHPG level was unchanged. Plasma melatonin increased significantly after 5HTP administration, suggesting that increasing 5HT availability in man might affect melatonin synthesis. The results of this study are at odds with the hypothesis that there is a supersensitivity of 5HT2 receptors in panic disorder.     

Effects of citalopram treatment on behavioural, cardiovascular and neuroendocrine response to cholecystokinin tetrapeptide challenge in patients with panic disorder.

Eight patients with panic disorder were administered 20 micrograms of cholecystokinin tetrapeptide (CCK-4) before and after 8 weeks of treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram. All patients responded to treatment by showing a significant general improvement and reaching a panic-free state for 2 weeks. At the rechallenge with CCK-4, patients displayed a marked reduction in the intensity and number of panic symptoms. The frequency of panic attacks induced with CCK-4 decreased by 50% after treatment. Citalopram treatment had no substantial effect on cardiovascular (heart rate and blood pressure) or hormonal (cortisol, prolactin and growth hormone) responses to CCK-4. Patients who still had panic attacks after treatment demonstrated a blunted growth hormone response to CCK-4 that was not seen in those who did not have panic attacks. This study suggests that treatment with an SSRI can reduce an enhanced sensitivity to CCK-4 without modifying cardiovascular and neuroendocrine responses to CCK-4 in patients with panic disorder.     

Behavioral biochemical and neuroendocrine concomitants of lactate-induced panic anxiety

In a single-blind study using sodium lactate infusions to provoke panic attacks, 11 of 15 patients with panic disorder panicked with lactate. None of the 15 control subjects panicked during lactate administration. Before receiving lactate, higher preinfusion anxiety levels were present in the patient group as compared to controls. Preinfusion Acute Panic Inventory (API) scores were significantly higher in patients who panicked compared to nonpanicking patients. In addition, patients who panicked during lactate infusion showed a higher mean plasma MHPG level at baseline. During lactate infusion, however, no increase in plasma MHPG was seen in patients who panicked, nor in nonpanickers and controls. Several other biochemical and hormonal variables were measured. No single biochemical or neuroendocrine variable was found to correlate with lactate-induced panic attacks. It is argued that the baseline arousal level of patients with panic disorder may be increased, which renders these patients more vulnerable to panic attacks.     

Endocrine and amine responses to D,L-fenfluramine in normal subjects.

To investigate indirectly the central neurotransmitter mechanisms of D,L-fenfluramine-induced hormone release, prolactin, adrenocorticotropic hormone, cortisol, growth hormone, 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5HIAA) responses to D,L-fenfluramine (60 mg, oral) were examined in a single-blind, placebo-controlled trial in 14 normal subjects. As compared with placebo, D,L-fenfluramine significantly increased both prolactin and cortisol. There was a significant correlation between the cortisol and prolactin responses. HVA levels were also significantly increased, but there were no changes in MHPG or 5HIAA. The elevation in HVA significantly correlated with increases in both prolactin and cortisol. These findings are consistent with recent animal studies suggesting that D,L-fenfluramine-induced prolactin and cortisol release may be mediated, at least in part, by catecholaminergic systems.     

Yohimbine-induced withdrawal and anxiety symptoms in opioid-dependent patients.

BACKGROUND: Alteration in noradrenergic regulation as well as alteration in the hypothalamic-pituitary-adrenal (HPA) axis have been associated with opioid dependence and acute abstinence symptoms. METHODS: This double-blind, placebo-controlled study evaluated subjective, physiologic, and biochemical responses to yohimbine (.4 mg/kg, IV) in eight patients receiving methadone and compared results to those from a pool of nine healthy volunteers. All subjects were compared for panic anxiety symptom scale (PASS) scores, systolic and diastolic blood pressure, heart rate, plasma 3-methoxy-4 hydroxyphenethyleneglycol (MHPG), and cortisol. RESULTS: Yohimbine elicited objective and subjective opioid withdrawal and elevated craving for opioid drugs in methadone patients. Significant yohimbine effects were seen across the combined subject group for PASS, physiologic measures, MHPG, and cortisol. Methadone patients had lower baseline MHPG levels. Methadone group interactions with yohimbine were seen for systolic blood pressure and cortisol levels. CONCLUSIONS: Methadone-maintained patients are sensitive to the postsynaptic effects of noradrenergic-facilitating medications, experiencing greater physiologic and psychological symptoms, including an increase in craving. The effect on cortisol supports the above conclusion and is consistent with HPA axis perturbation in opioid dependence as reported in other studies and extends these observations to stable methadone-maintained patients. Medications that increase synaptic noradrenaline should be used with care in opioid-dependent patients.