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.     

Anxiogenic effects of caffeine in patients with anxiety disorders.

The effects on measures of anxiety from two doses of oral caffeine (250 and 500 mg) and placebo were compared in 12 patients with generalized anxiety disorder (GAD), 12 patients with panic disorder, and 12 normal subjects. Caffeine produced significantly less decrease in electroencephalographic alpha wave activity, greater decrease in N1-P2 auditory evoked potential amplitude, and greater increased in skin conductance level, systolic and diastolic blood pressure, critical fusion flicker frequency, and self-ratings of anxiety and sweating in patients with GAD than in normal patients. Patients with panic disorder showed different reactivity than normal patients did with respect to electroencephalographic alpha waves, N2 latency, N2-P2 auditory evoked potential amplitude, and physical tiredness but were less reactive than patients with GAD on several variables. It is concluded that patients with GAD are abnormally sensitive to caffeine and that the data support the view that panic disorder is a separable disorder from GAD.     

Metergoline blocks the behavioral and neuroendocrine effects of orally administered m-chlorophenylpiperazine in patients with obsessive-compulsive disorder

The pharmacological probe, meta-chlorophenylpiperazine (m-CPP), administered orally to patients with obsessive-compulsive disorder (OCD) has been shown to induce an acute exacerbation in OCD symptoms as well as an exaggerated anxiogenic response in comparison with controls. The mechanism of m-CPP's behavioral effects in humans remains controversial. To further study m-CPP's actions in OCD patients, we completed a series of double-blind pharmacological challenges in 12 OCD patients. Six OCD patients received four separate challenges: placebo, metergoline, m-CPP, and metergoline plus m-CPP; the second group (n = 6) received metergoline and metergoline plus m-CPP in separate challenges. OCD patients receiving placebo or metergoline alone failed to show evidence of significant changes on any of the behavioral rating scales, in contrast to the patients who received m-CPP alone who exhibited significant increases in anxiety and OCD symptoms. However, the 12 OCD patients who received pretreatment with metergoline before m-CPP experienced no significant changes from baseline OCD symptoms or other behavioral changes. m-CPP's ability to elicit elevations in plasma prolactin was blocked by metergoline pretreatment. Metergoline's ability to block m-CPP's effects on behavior and plasma prolactin lends further support to a serotonergic mediation of m-CPP's effects, including its elicitation of OCD symptoms.     

Serotonergic function in obsessive-compulsive disorder. Behavioral and neuroendocrine responses to oral m-chlorophenylpiperazine and fenfluramine in patients and healthy volunteers.

To evaluate serotonergic (5-hydroxytryptamine) function in obsessive-compulsive disorder, behavioral and neuroendocrine responses to m-chlorophenylpiperazine (m-CPP; 0.5 mg/kg orally) and fenfluramine hydrochloride (60 mg orally) were examined in 20 patients and 10 healthy controls under double-blind, placebo-controlled conditions. Following m-CPP, but not fenfluramine or placebo, 55% (11/20) of the patients with obsessive-compulsive disorder experienced a transient exacerbation of obsessive-compulsive disorder. Prolactin response was blunted in patients following m-CPP but not following fenfluramine. Patients with greater behavioral response to m-CPP had smaller prolactin responses. Cortisol response to m-CPP and fenfluramine did not significantly differ between the groups. Behavioral and neuroendocrine responses appeared divergent. This does not suggest simply upregulation or downregulation of 5-hydroxytryptamine receptors, but rather complex mechanisms involving multiple neurotransmitter and neuromodulator systems.     

Plasma 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and growth hormone responses to yohimbine in panic disorder patients and normal controls

Eleven patients with a DSM-III diagnosis of panic disorder and seven normal controls received yohimbine (20 mg) or placebo orally in a double-blind paradigm on two separate days. Compared to normal control subjects, the panic disorder patients had similar behavioral responses to placebo but a greater anxiogenic response to yohimbine. Compared to placebo, yohimbine produced a significant increase in plasma 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) levels (p less than 0.02), with a trend toward greater MHPG rises in the panic disorder patients compared to the normal controls. In the patients, but not in the controls, there was a significant positive correlation between yohimbine-induced peak changes in MHPG and increased ratings of panic anxiety. Yohimbine had no effect on plasma growth hormone (GH) levels in either patients or controls. These results are discussed within the context of the noradrenergic theory of panic disorder.     

Physiological and subjective anxiety responses to caffeine and stress in nonclinical panic

Physiological and subjective anxiety responses to the combination of caffeine and film, cold pressor, and mental arithmetic stressors were examined in 24 healthy females with and without nonclinical panic. Caffeine (3.3 mg/kg) and placebo were administered in a within-subject, double-blind, counterbalanced design on two consecutive days. Repeated measurements of blood pressure, cardiac interbeat interval, skin conductance, and subjective anxiety were obtained during a predrug resting baseline, a postdrug resting baseline, stressor tasks, and a recovery baseline. Panic subjects in the caffeine/placebo drug order exhibited a significantly greater anxiety response on the caffeine day, which combined additively with increases produced by stress. Caffeine and stress also produced additive increases in physiological arousal, although no significant group differences were observed.     

Acute intravenous administration of ondansetron and m-CPP,alone and in combination,in patients with obsessive–compulsive disorder (OCD): behavioral and biological results

Obsessive–compulsive disorder (OCD) has been linked to abnormal function of brain serotonin (5-HT) pathways. Since ondansetron is a highly selective 5-HT₃ receptor antagonist, the present study was undertaken to investigate 5-HT₃ function in OCD. We administered m-CPP (0.08 mg/kg i.v.) and the potent 5-HT₃ antagonist, ondansetron (0.15 mg/kg i.v.), to 11 OCD patients. All of the subjects received four separate challenges (m-CPP+placebo, m-CPP+ondansetron, ondansetron+placebo and placebo+placebo). In comparison to placebo, administration of m-CPP was associated with significant behavioral effects, particularly self-rated measures of anxiety, altered self-reality, functional deficit and OCD symptoms. Pretreatment with ondansetron did not affect any of the self-rated behavioral symptoms. After administration of m-CPP relative to placebo, significant increases in plasma cortisol and prolactin were found. These changes were not affected by ondansetron. In conclusion, our results do not support the hypotheses that 5-HT₃ receptor-mediated mechanisms modulate m-CPP's behavioral and neuroendocrine effects in patients with OCD.     

Quantitative electroencephalographic effects of caffeine in panic disorder.

It has been demonstrated that patients with panic disorder are more sensitive than normal control subjects to the anxiogenic effects of caffeine. The underlying physiologic basis for this difference is unclear. We examined the electroencephalographic (EEG) activity of seven patients with panic disorder and seven normal control subjects during the randomized double-blind, placebo-controlled administration of oral caffeine (7 mg/kg). EEG data were collected on-line from 28 electrodes; artifact-free epochs were selected manually for off-line Fourier transformation. Caffeine was associated with a significant increase in peak occipital alpha frequency and significant decreases in occipital alpha amplitude, central beta amplitude, and central theta amplitude. Despite the observation that caffeine increased anxiety more in the patients with panic disorder than in the normal control subjects, the two groups did not differ in their EEG responses to caffeine.     

Anxiogenic effects of caffeine on panic and depressed patients

Caffeine increases anxiety in people with anxiety disorders. To determine whether caffeine exerts a similar effect in depression, the authors compared retrospective reports of caffeine intake and symptoms produced by caffeine ingestion in patients with panic disorder, patients with major depression, and control subjects. Panic patients consumed less caffeine and reported more symptoms than depressed or control subjects. Although depressed patients did not differ from control subjects in caffeine intake or most symptoms, more depressed patients reported that caffeine induced anxiety. These data support prior reports that panic patients have increased sensitivity to caffeine; some depressed patients may also have increased sensitivity.     

Behavioral and cerebrovascular effects of caffeine in patients with anxiety disorders

Caffeine is believed to induce anxiety in normal people and anxiety disorder patients and panic attacks in panic disorder patients. The drug is also known to reduce cerebral blood flow (CBF). Findings suggesting an anxiety-related cerebral vasoconstrictive factor have been reported. We examined the relationship between changes in anxiety and CBF induced by intravenously injecting 250 mg of caffeine (comparable to 2 cups of coffee) in 8 patients with generalized anxiety disorder, 9 patients with panic disorder and 9 normal controls. CBF measurements were also obtained before and after an injection of normal saline in another group of 9 normal volunteers. The anxiety disorder patients did not show any evidence of increase in anxiety and panic after caffeine. Both patients and controls who received caffeine but not normal controls who received saline showed significant CBF decrease. The CBF changes were unrelated to changes in mood, autonomic activity and carbon dioxide levels.     

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.     

Relationship between serum cholesterol levels and meta-chlorophenylpiperazine-induced cortisol responses in healthy men and women

We investigated the effect of cholesterol on serotonergic receptor function in 20 healthy male and 10 healthy female subjects using cortisol responses to meta-chlorophenylpiperazine (m-CPP) neuroendocrine challenge tests. M-CPP, a metabolite of the antidepressant trazodone, has been widely used in psychopharmacology research as a probe of serotonin function. In the human brain, m-CPP binds both to various serotonergic receptors, mainly 5-HT(2C), and to alpha(2)-adrenoceptors. After an overnight fast, the subjects received m-CPP (0.5 mg/kg) or identical placebo capsules orally in a randomized, double blind, crossover design. Blood was obtained for measurement of cholesterol and cortisol. In some analyses, especially in males, there were significant positive correlations between serum cholesterol levels and cortisol responses. These findings suggest the possibility that serum cholesterol levels may be positively associated with serotonergic receptor function. The existence of such an association may provide an explanation for reported increases in depression, suicide and violence in individuals with low or lowered cholesterol.     

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.     

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.     

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.     

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.     

A randomized,double-blind,placebo-controlled study of the effects of adjunctive paroxetine in panic disorder patients unsuccessfully treated with cognitive-behavioral therapy alone

BACKGROUND: Both cognitive-behavioral therapy and treatment with selective serotonin reuptake inhibitors (SSRIs) have proved to be effective in the treatment of panic disorder. The present study examined the effects of paroxetine added to continued cognitive-behavioral therapy in patients who were unsuccessfully treated with initial cognitive-behavioral therapy alone. METHOD: 161 patients with panic disorder with or without agoraphobia (DSM-IV criteria) underwent a manual-guided cognitive-behavioral therapy of 15 sessions. Forty-three unsuccessfully treated patients from this group were included in a double-blind, placebo-controlled, next-step treatment study consisting of continued cognitive-behavioral therapy plus adjunctive paroxetine at a dose of 40 mg/day or continued cognitive-behavioral therapy plus placebo. RESULTS: Overall, patients in the cognitive-behavioral therapy plus paroxetine condition improved significantly on agoraphobic behavior (p < .05) and anxiety discomfort (p < .01), whereas patients in the cognitive-behavioral therapy plus placebo condition did not. Effect sizes in the cognitive-behavioral therapy plus paroxetine condition ranged from 1.0 to 1.8 and in the cognitive-behavioral therapy plus placebo condition, from 0.4 to 1.0. CONCLUSION: Patients with panic disorder who are unsuccessfully treated with initial cognitive-behavioral therapy may benefit from the addition of an SSRI as a second treatment modality. The importance of timely evaluation of treatment results is emphasized.     

Increased antipanic efficacy in combined treatment with clomipramine and dixyrazine

A double-blind 12 week trial was undertaken to compare the effects of clomipramine + dixyrazine with clomipramine + placebo in the treatment of panic disorder with or without agoraphobia. Of 45 patients included (21 dixyrazine, 24 placebo), 16 dropped out (6 dixyrazine, 10 placebo). The number of panic attacks and the scores on the panic disorder subscale of the Hamilton Anxiety Rating Scale were significantly reduced in response to both treatment regimens, but the reduction was significantly greater in the dixyrazine group. The patients’ daily functioning was significantly more improved with the dixyrazine combination. The serum concentration of desmethylclomipramine monotherapy was significantly higher and the side effects significantly lower in the combined treatment with dixyrazine than with clomipramine monotherapy. Clomipramine combined with dixyrazine seems superior to clomipramine in the treatment of panic disorder.     

Trazodone in the treatment of panic disorder and agoraphobia with panic attacks

Eleven patients with panic disorder or agoraphobia with panic attacks completed an 8-week single-blind trial of trazodone (300 mg/day) without concurrent behavioral instructions. The measures of change included ratings of generalized and panic anxiety, phobias, and depression and a behavioral avoidance test, which were administered during a baseline period of placebo administration and at 4 and 8 weeks of the trial. There was significant improvement on all symptom dimensions, which suggests that trazodone may have specific antipanic and antiphobic actions and underscores the importance of serotonergic mechanisms in these anxiety disorders.     

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.