Pentagastrin has panic-inducing properties in obsessive compulsive disorder

The effects of the CCK_B-receptor agonist pentagastrin, a synthetic analogue of the cholecystokinin tetrapeptide (CCK-4), were studied in seven patients suffering from obsessive compulsive disorder (OCD) and seven healthy controls. All subjects were challenged with an IV dose of 0.6 µg/kg pentagastrin or placebo under double blind placebo controlled conditions, on two separate occasions, with a minimum interval of 1 week. Six (86%) out of seven OCD patients experienced a panic-like reaction after pentagastrin administration, against only two (29%) in the control group. These differences failed to reach statistical significance, probably due to the small sample size. No increases were observed in obsessions or compulsive behaviors as assessed with the Yale-Brown Obsessive Compulsive Challenge Scale, neither in the pentagastrin, nor in the placebo condition. These findings suggest that pentagastrin has panic-inducing properties in OCD patients, without affecting the core symptoms. The panic-inducing properties of pentagastrin are not specific for panic disorder patients, which might be indicative of a common neurobiological dysfunction in panic disorder and OCD at the level of CCK-B receptors.     

Effect of the selective serotonin reuptake inhibitor fluvoxamine on CCK-4 induced panic attacks

Data from animal studies suggest a functional relationship between the cholecystokinin-ergic (CCK) and the serotonergic (5-HT) system. There is increasing evidence that the cholecystokinin-4 (CCK₄) challenge test could be a valid experimental model for panic attacks in man. The aim of the present study is twofold; 1) to validate this model further and 2) to shed more light on the putative CCK\5-HT interaction. To this end, we studied the effect of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine on CCK₄-induced panic attacks. Twenty-six panic disorder (PD) patients received, before and after a double blind 8-week treatment period with fluvoxamine (n = 17) or placebo (n = 9), a single blind bolus injection with 50 μg CCK₄. Treatment with fluvoxamine (150 mg daily) significantly decreased the sensitivity of PD patients for CCK₄ while placebo was without effect. Of the patients who responded to treatment, 83% no longer experienced a panic attack when rechallenged with CCK₄, whereas in the non-responders group this was only 28%. In the fluvoxamine group the treatment response evaluated by the Hamilton Anxiety Scale (HAS) showed a statistically significant treatment effect. The results of this study strengthen the validity of the CCK₄ test as an experimental human model for panic attacks and yield evidence supporting the hypothesis that both CCK and serotonin are implicated in the regulation of anxiety. Received: 15 April 1996/Final version: 27 September 1996     

Delayed increase in LDL cholesterol following pentagastrin-induced panic attacks

Objective Panic disorder (PD) has been associated with an increased risk for cardiovascular (CV) morbidity and mortality. There are inconsistent reports of increased low-density lipoprotein cholesterol (LDL-C) in patients with PD. Studies have reported a correlation between cholesterol levels and the intensity and frequency of panic attacks (PAs), suggesting that an elevation in cholesterol could be due to physiological and neurochemical changes that occur during and after a PA. The objective of our study was to show that the occurrence of a PA is associated with an increase in LDL-C. Materials and methods We used a double-blind, placebo-controlled crossover design with randomized injections of placebo and pentagastrin in 18 patients with PD (11 men, 7 women) and 33 healthy-control subjects (24 men, 9 women). Results Pentagastrin-induced PAs were associated with a statistically significant 10.4% delayed (24 h) increase in LDL-C levels in male subjects. Such an effect was not observed in female subjects. Conclusion LDL-C levels are directly affected by the occurrence of a PA in males. These findings, in association with previous reports of increased cholesterol levels in PD patients, suggest that a chronic increase in LDL-C as a result of frequent PAs may be one of the mechanisms that contributes, at least in male patients, to previously reported increased CV risk in patients with PD. The gender difference and the temporal association between PAs and increased LDL-C may explain the inconsistency in the findings of previous investigations of cholesterol levels in PD patients.     

The cholecystokinin-B receptor antagonist CI-988 failed to affect CCK-4 induced symptoms in panic disorder patients

The effects of the cholecystokinin-B (CCK-B) receptor antagonist CI-988 on symptoms elicited by the cholecystokinin tetrapeptide (CCK₄) were studied in DSM-IIIR patients with panic disorder. The study employed a double-blind, two-period incomplete block design. Patients (n = 14) received two different dosages of CI-988 (50 mg or 100 mg) or placebo 2 h prior to an IV bolus injection of CCK₄ (20 μg) on two separate occasions. The primary efficacy parameter was the total intensity score on the Panic Symptoms Scale (PSS). Secondary parameters were the number of panic symptoms, time to and occurrence of the first panic symptoms, duration of symptoms, intensity of apprehension and the percentage of patients who did not have a panic attack. The PSS failed to show a statistically significant treatment effect on any of these outcome measures. The average panic rate was 50%, 14.3% and 37.5% after placebo, 50 and 100 mg CI-988, respectively. The differences in panic rate were not statistically significant. The results of this study suggest that CI-988 in doses up to 100 mg is not effective in reducing symptoms of panic anxiety induced by CCK₄. Received: 13 May 1996/Final version: 27 September 1996     

Tryptophan depletion does not modify response to CCK-4 challenge in patients with panic disorder after treatment with citalopram

Rationale Data by [Bell et al. J Psychopharmacol (2002) 16:5–14] suggest that a decrease in 5-HT neurotransmission predisposes to panic attacks and that the antipanic effect of SSRIs depends upon the availability of 5-HT in the brain.Objectives Our aim was to assess the effect of acute tryptophan depletion (TD) on cholecystokinin-tetrapeptide (CCK-4)- induced symptoms in patients with panic disorder (PD) who had responded to a 10-week treatment with a selective serotonin (5-HT) reuptake inhibitor (SSRI), citalopram.Materials and methods A total of 18 patients (6 males and 12 females, mean age 34.5 years) received a tryptophan-free amino acid drink and a control drink, each followed by a CCK-4 challenge (25 μg), 1 week apart in a double-blind crossover design.Results The results showed no significant differences in response to the CCK-4 challenge between the TD and the control conditions. Panic rate after the CCK-4 challenge was 27.8% after depletion and 33.3% after control drink (χ ²=0.13, p=0.72). No significant effects of TD were observed in panic intensity scores, subjective anxiety, or cardiovascular indices.Conclusions This study demonstrates that an acute lowering of brain 5-HT availability with TD does not affect response to a CCK-4 challenge in PD patients successfully treated with citalopram. Thus, the reduction of CCK-4 sensitivity following SSRI-treatment in patients with PD may be related to mechanisms other than 5-HT availability in the brain, possibly to a reduction in brain cholecystokinin receptor sensitivity.     

A serotonin hypothesis of panic disorder

Despite numerous animal studies indicating an important role of serotonin (5-HT) in anxiety, 5-HT's function in the regulation of human anxiety has hardly been studied. Recent clinical studies suggest an involvement of 5-HT systems in panic disorder. This paper will briefly review the pertinent data on 5-HT and panic disorder and propose a specific hypothesis on 5-HT abnormalities in that disorder.     

Differences in beta-adrenergic receptor sensitivity between women and men with panic disorder

This study was conducted on patients with panic disorder (PD) to examine the gender differences in the pathophysiology of PD by evaluating and comparing the value of CD(25)/wt, the chronotropic 25 dose of isoproterenol (CD(25)) divided by the body weight, which reflects the in vivo index of beta-adrenergic receptor sensitivity. This study included a total of 70 subjects, including 35 patients with PD (female: 13, male: 22) along with 35 healthy control subjects (female: 13, male: 22). There were significant differences in the mean value of CD(25)/wt (0.073+/-0.045 microg/kg vs. 0.032+/-0.019 microg/kg; p=0.006) and the serum epinephrine (EPI) level (77.3+/-64.1 pg/ml vs. 31.6+/-10.3 pg/ml; p=0.001) between the female panic patients and the female control subjects. However, there were no differences in either the CD(25)/wt value or the EPI level between the male panic patients and the male control subjects. These results suggest that the beta-adrenergic receptor sensitivity decreased in the female patients, but not in the male patients, which provides evidence for the possible existence of a gender difference in the pathophysiology of PD.     

Increased central alpha2-adrenoceptor sensitivity in panic disorder

Cardiovascular responses to an intravenous challenge dose of clonidine (1.5 g/kg) were measured in eight patients with DSM III panic disorder. In comparison with an age- and sex-matched control population panic patients showed significantly greater falls in systolic and diastolic blood pressure, with similar falls in heart rate. These observations support the view of a biological abnormality in panic disorder.This work was performed in Oxford University Department of Psychiatry at the Research Unit Littlemore Hospital and the Warneford Hospital     

Effects of flumazenil on cholecystokinin-tetrapeptide-induced panic symptoms in healthy volunteers

The neuropeptide cholecystokinin-tetrapeptide (CCK-4) has potent anxiogenic action in human and animal subjects. On the basis of prior work which demonstrated that benzodiazepine (BZD) receptor agonists antagonized CCK-induced excitation of rat hippocampal neurons we studied whether BZD receptors mediated the anxiogenic effect of CCK-4. To examine this possibility we determined whether the BZD receptor antagonist flumazenil could antagonize the effects of CCK-4 (50 µg) in healthy volunteers. Thirty subjects (10 females; 20 males) were pretreated with flumazenil (2 mg in saline) or placebo (0.9% NaCl in water) 15 min prior to CCK-4 challenge in a randomized double-blind crossover design. Flumazenil had no impact on the behavioral and cardiovascular effects of CCK-4, suggesting that BZD receptors do not mediate the anxiogenic action of CCK-4. The influence of GABA and non-GABA-related mechanisms on response to CCK-4 remains to be considered.     

Irritability in panic disorder: Effects of imipramine treatment

To establish the presence and magnitude of irritability in panic disorder, and its relationship with anxiety and depression, ratings of each variable were monitored in 18 patients with panic disorder before and during imipramine treatment. Pretreatment ratings of inward-and outward-directed irritability demonstrated borderline levels of morbidity. Over the duration of treatment, irritability ratings fell, and there were substantial reductions in ratings of depression, but only small reductions in ratings of state anxiety. There were a number of significant correlations between pre- and post-treatment ratings of irritability and depression, but little association between these and ratings of anxiety.     

Clinical evaluation of alprazolam in patients with panic disorder: A double-blind comparison with imipramine

The antipanic effect and tolerability of alprazolam and imipramine were compared during 9 weeks in 55 inpatients with panic disorder with or without agoraphobia. Both drugs decreased significantly the frequency of panic attacks, alprazolam as early as 3 weeks of treatment. The symptoms of generalized anxiety and depression decreased similarly in both groups. The tolerability of alprazolam appeared slightly better than that of imipramine. Drug-induced anticholinergic side-effects were more frequent in the imipramine group, whereas sedation, impotency, and myoclonic jerks appeared more often in the alprazolam group.     

SSRIs抗抑郁剂联合黛力新治疗惊恐障碍的疗效观察

目的:探讨黛力新对于SSRIs抗抑郁剂治疗惊恐障碍的增效作用.方法:将符合CCMD-3诊断标准的30例惊恐障碍患者随机分为两组,SSRIs抗抑郁剂联合黛力新和单独使用SSRIs抗抑郁剂,治疗4周,根据疗效判定标准评定疗效.结果:联合黛立新组病例第一周伞部见效.单用SSRIs抗抑郁剂药物治疗组第1周均无明显效果,第二周开始见效.4周后合并黛立新组痊愈率66.67%,单用SSRIs组痊愈率53.34%.结论:联合黛力新对于SSRIs抗抑郁剂治疗惊恐障碍有增效作用.     

MAO inhibitors in panic disorder: clinical effects of treatment with brofaromine

There is considerable evidence that antidepressants, particularly serotonin uptake inhibitors, are effective in the treatment of panic disorder (PD). Monoamine oxidase inhibitors (MAOI) may also have beneficial effects in PD. In this study 30 patients with PD with or without agoraphobia (DSM-III-R) were treated with the selective and reversible MAO-A inhibitor brofaromine (150 mg daily) in a 12-week double-blind placebo controlled design. A clinical relevant improvement was found in more than 70% of the patients treated with brofaromine, whereas no significant improvement was observed on placebo. After an increase in anxiety in the first week, a clinically relevant improvement in anxiety symptoms was found, followed by a subsequent reduction in agoraphobic avoidance in patients treated with brofaromine. A similar improvement was observed on distress scores related to panic attacks, although there was no significant reduction in the number of panic attacks. The most prominent side-effects were middle sleep disturbance and nausea. No increase in blood pressure was observed. During a follow-up period of another 12 weeks a further improvement was found in patients treated with brofaromine.     

集体心理治疗对惊恐障碍疗效分析

目的观察集体心理治疗对惊恐障碍的临床疗效。方法以集体心理治疗联合抗焦虑药（治疗组）与单用抗焦虑药物治疗（对照组）共80例,采用汉密顿焦虑量表（HAMA）14项及临床疗效总评量表CGI-SI评定疗效。于治疗后1、2、3个月各评定一次。结果治疗组3个月末HAMA总分,CGI-SI总分降低明显大于对照组。结论集体心理治疗对惊恐发作是一种安全有效的治疗。     

<Emphasis Type="SmallCaps">L</Emphasis>-5-Hydroxytryptophan induced increase in salivary cortisol in panic disorder patients and healthy volunteers

BACKGROUND: Hypersensitivity of brain serotonin receptors has been proposed as a causal mechanism in the pathophysiology of panic disorder. This theory can be tested, using serotonergic stimulation of the HPA axis. Up to now, plasma cortisol has generally been used as the outcome measure in such studies. Assessment of salivary cortisol is a non-invasive alternative to measure HPA axis activity.METHOD: Salivary cortisol levels were measured in 24 panic disorder patients and 24 healthy volunteers, following ingestion of 200 mg L-5-hydroxytryptophan or placebo.RESULTS: A significant rise in cortisol was observed in both patients and controls following ingestion of L-5-hydroxytryptophan. No such effects were seen in the placebo condition.CONCLUSION: The results show that L-5-hydroxytryptophan stimulated salivary cortisol is a useful probe of serotonin function in healthy volunteers as well as panic disorder patients, and provide some evidence against a serotonin receptor hypersensitivity in panic disorder.     

d-Fenfluramine in panic disorder: a dual role for 5-hydroxytryptamine

Rationale: 5-Hydroxytryptamine (5-HT) appears to modulate different forms of anxiety in different ways, but the importance of this in human anxiety disorders is unknown. Objectives: To investigate whether the 5-HT releasing agent d-fenfluramine (dFEN) has different effects on resting and panic anxiety in panic disorder. Methods: Thirteen drug-free patients with DSM-IIIR panic disorder were tested in a double-blind placebo-controlled crossover design. Carbon dioxide 7% (CO₂) was given as a panic challenge 270 min after administration of dFEN or placebo. Results: Compared to placebo, dFEN increased anxiety and arousal, maximal at 120 min, but tended to reduce CO₂-induced anxiety and panic attacks with a significant reduction in Panic Visual Analogue Scale ratings (P=0.040). Anxiety following CO₂, but not dFEN, administration resembled panic attacks (compared to Acute Panic Inventory symptom profile during patients’ usual attacks). Patients with more severe disorders exhibited enhanced behavioural responses and blunted prolactin responses to dFEN. Conclusions: dFEN caused anxiety similar to generalised anxiety in panic disorder patients but reduced anxiety following 7% CO₂ challenge, a laboratory analogue of naturally occurring panic attacks. These findings are consistent with a dual role for 5-HT in pathological anxiety. Patients with more severe symptoms differed in 5-HT function compared to more mildly affected individuals. Received: 4 August 1999 / Final version: 14 November 1999     

Genetic and pharmacokinetic factors affecting the initial pharmacotherapeutic effect of paroxetine in Japanese patients with panic disorder

Objective  The objective of this study was to evaluate genetic and pharmacokinetic factors affecting the initial pharmacotherapeutic effect of paroxetine (PAX) in Japanese patients with panic disorder (PD). Method  Plasma concentration of PAX was determined by high performance liquid chromatography. Serotonin transporter gene-linked polymorphic region (5-HTTLPR) variants were determined by polymerase chain reaction techniques. PD severity was assessed using the Panic and Agoraphobia Scale (PAS). Results  Multiple regression analysis revealed that the plasma concentration of PAX, 5-HTTLPR genotype, and comorbid physical illness were significant factors affecting the initial pharmacotherapeutic effect of PAX in PD and indicated that these factors accounted for 52.4% (R ² = 0.524) of the variability in the percent reduction in PAS score. The final model was described by the following equation (P = 0.001): percent reduction in PAS score (%) = 68.5 − 1.2 × [plasma concentration of PAX (ng/ml)] − 33.0 × (L/S = 1, S/S = 0) − 21.8 × (with comorbid physical illness = 1, without comorbid physical illness = 0). Conclusion  The high plasma concentration of PAX, the L/S genotype of 5-HTTLPR, and comorbid physical illness might be associated with a poor response to the initial phase of pharmacotherapy of PD with PAX.     

Influence of clonidine on psychopathological, endocrine and respiratory effects of cholecystokinin tetrapeptide in patients with panic disorder

The influence of clonidine pretreatment on psychopathological, endocrine and respiratory effects of cholecystokinin tetrapeptide (CCK-4) was characterized. Patients with panic disorder (DSM-III-R) were given 50 μg CCK-4 IV at 1100 hours on 2 separate study days. In a randomized double-blind design they were additionally infused with 150 μg clonidine or placebo from 1040 to 1110 hours. After CCK-4 all patients experienced symptom attacks. No effects of clonidine on panic psychopathology or blood gas parameters were observed. After CCK-4, in the clonidine condition the pituitary release of adrenocorticotropin (ACTH) and prolactin was seemingly enhanced compared to placebo. Our results suggest that CCK-4-induced panic attacks are not suppressible by presynaptic alpha-2 receptor stimulation. Moreover, they point to a synergistic postsynaptic action of clonidine to CCK-4 upon pituitary hormone secretion. The diverging sites of action might possibly explain the discrepancies of psychopathological alterations and stress hormone secretion. Received: 28 November 1996 /Final version: 13 March 1997     

Neuroendocrine evidence for serotonin receptor hypersensitivity in panic disorder

Normal controls (NC) (n=15), patients with panic disorder (PD) (n=13) and patients with major depression (MD) (n=17) were challenged with a single, oral dose (0.25 mg/kg) of the selective 5HT agonist m-chlorophenyl-piperazine (MCPP) or placebo. Blood samples were assayed for cortisol and MCPP levels every 30 min. The PD group had an augmented cortisol release when compared to the other two groups. Finally, a significant correlation was found across all subjects between clinical anxiety level and cortisol release on MCPP. These data support the hypothesis of 5HT receptor hypersensitivity in PD.     

舍曲林和氯丙咪嗪治疗68例惊恐障碍的疗效比较

目的评价舍曲林治疗惊恐障碍的疗效和安全性。方法采用随机单盲病例对照研究,为期24周．以临床判断和PASS、HAMD、HAMA量表来评定临床效果,以TESS来评定药物不良反应。结果入组68例舍曲林组36例,氧丙味嗪组32例）．舍曲林组最高剂量平均132．5±25．25mg·d^-1。氯丙咪嗪组为153．62mg·d^-1．临床疗效。第四周末舍曲林有效率为77．7％,氯丙咪嗪组为65．6％．两组有统计学盖异（P〈0．05）,而二十四周末两组的有效率分别为100％和96．9％,两组无明显差异。从PASS、HAMD、HAMA量表来看舍曲林组从第二周末开培有明显下降,而氯丙咪嗪组则在第三或第四周以后才开始明显改变。从副反应来看舍曲林组总的发生率13．61%。明显低于氛丙味嗪组的24．68％。结论舍曲林治疗惊恐障碍和氯丙咪嗪比较具有起效快,疗效好。副作用小等特点。是一种安全有效的治疗惊恐障碍药物。