MHPG and heart rate as correlates of nonresponse to drug therapy in panic disorder patients A preliminary report

Little is known about biological predictors of treatment response in panic disorder (PD). In the present study heart rate, blood pressure, plasma cortisol and plasma MHPG were investigated at baseline in a sample of 44 PD patients as possible predictors for nonresponse to treatment. We used a strict definition of nonresponse to find patients who did not respond at all after 12 weeks of treatment with brofaromine or fluvoxamine. Patients were considered nonresponders when they fulfilled two criteria: they did not show a 50% reduction of agoraphobic avoidance and they still experienced panic attacks at endpoint. The variables that differed significantly between the groups were used to predict nonresponse to drug therapy. Using this strict definition of nonresponse, 15 patients (32.6%) were considered nonresponders. These patients were characterised by a higher plasma MHPG concentration and a higher heart rate at baseline. These variables were subsequently used to predict nonresponse. Received: 29 December 1995 /Final version: 16 May 1996     

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.     

Pentagastrin induced panic attacks: enhanced sensitivity in panic disorder patients

The effects of pentagastrin, a synthetic analogue of the cholecystokinin tetrapeptide (CCK₄), were studied in 15 patients with panic disorder and 15 healthy controls. Three different intravenous dosages of pentagastrin (0.1, 0.3 and 0.6 µg/kg) and saline were investigated. Subjects were randomly allocated to two of the four treatment groups and tested on two separate occasions, 1 week apart, using an unbalanced double-blind incomplete block design. The mean panic rate with pentagastrin was 55% (12/22) for patients and 5% (1/22) for controls. None of the subjects panicked with saline. The frequency of panic attacks between the three pentagastrin doses in patients was not different. One control subject had a panic-like attack at the highest dose of pentagastrin. These findings concur with previous studies on the panicogenic effect of CCK₄ and pentagastrin and suggest a greater sensitivity for CCK receptor agonists in patients suffering from panic disorder than in healthy controls.     

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。     

Do urinary MHPG and plasma drug levels correlate with response to amitriptyline therapy?

Twenty-nine inpatients with primary affective disorder were treated with 150 mg amitriptyline (AT) daily for 28 days. Pretreatment urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured in two or three 24-h urine samples. Plasma levels of AT and nortriptyline (NT) were determined after 14, 21, and 28 days of treatment. MHPG excretion was significantly correlated with clinical response to treatment. Responders defined by two different methods showed higher pretreatment MHPG excretion than nonresponders. Correspondingly, high MHPG excretors (median split) showed significantly more improvement than low excretors. These relationships were even more apparent when possibly incomplete urine samples (creatinine excretion below 1000 mg/24 h) were excluded. The high and low MHPG subgroups did not significantly differ from each other in their plasma levels of AT, NT, or AT plus NT. A significant rank correlation between clinical response and plasma levels of AT and/or NT did not exist, but there was a trend towards lower levels in responders.Dedicated to Prof. Heimann on the occassion of his 60th birthday     

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     

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.     

Serotonin function in panic disorder: a double blind placebo controlled study with fluvoxamine and ritanserin

In order to evaluate serotonin (5-HT) function in panic disorder, a double blind placebo controlled study was conducted with ritanserin, a specific 5-HT₂ receptor antagonist, and fluvoxamine, a selective 5-HT reuptake inhibitor, in 60 patients with panic disorder. Patients were treated for 8 weeks with 150 mg fluvoxamine, 20 mg ritanserin or placebo; these dose levels were reached after 1 week. In addition, as an index of 5-HT function in panic disorder, plasma concentration of -endorphin, cortisol and 5-hydroxyindolacetic-acid (5-HIAA) were measured. Furthermore, 5-HT uptake in blood platelets was assessed. Noradrenergic function was assessed by measuring plasma MHPG concentration. In addition, plasma melatonin concentration was measured. Treatment with fluvoxamine resulted in a profound reduction in the number of panic attacks, followed by a decrease in avoidance behavior. Treatment with ritanserin appeared to be ineffective. During treatment no significant changes were observed in plasma concentrations of -endorphin, cortisol, 5-HIAA and MHPG. With respect to 5-HT kinetics in blood platelets, a substantial increase in K_m was observed after treatment with fluvoxamine, whereas V_max decreased. After treatment with fluvoxamine, plasma concentration of melatonin was significantly increased, which suggests that melatonin synthesis is in part under serotonergic control. The findings of the present study do not support the hypothesis that 5-HT₂ receptors are supersensitive in patients suffering from panic disorder, but allow no conclusions about the involvement of other 5-HT receptor subtypes.     

Subjective and neurovegetative changes in healthy volunteers and panic patients performing simulated public speaking

Drug-free symptomatic panic patients, drug-treated nonsymptomatic patients and healthy controls were submitted to simulated public speaking. Subjective anxiety, cognitive impairment and discomfort measured by the visual analog mood scale as well as skin conductance level were higher in symptomatic patients than in controls at the beginning of the experimental session, nonsymptomatic patients lying in between. Subjective sedation, spontaneous fluctuations of skin conductance, heart rate and blood pressure were similar in the three groups. Preparation and performance of speech decreased sedation while increasing anxiety, cognitive impairment, level and fluctuations of skin conductance, heart rate and blood pressure. Anxiety, cognitive impairment and conductance level were less increased in symptomatic patients than in controls. Electrodermal activity, but not cardiovascular measures of sympathetic arousal correlated with anticipatory anxiety. Chronic treatment with serotonin uptake inhibitors attenuated the differences between panic patients and controls, supporting the participation of serotonin in panic disorder.     

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.     

Heart rate variability as predictor of nonresponse to mirtazapine in panic disorder: a preliminary study

Using spectral analysis of heart rate, several studies have shown that panic disorder patients are characterized by a reduced heart rate variability (HRV), indicative of abnormalities in autonomous nervous system (ANS) function. We recently reported that patients with panic disorder, who did not respond to pharmacotherapy, were characterized at baseline by a higher heart rate. In this study, ANS functioning is investigated as a possible predictor of nonresponse to pharmacotherapy. Twenty-eight medication-free panic disorder patients entered a 12-week open-label treatment study with mirtazapine. Five-minute HRV recordings were obtained before treatment and were analysed using spectral analysis. The data of 17 patients could be used. The total spectrum and low frequency power of responders to mirtazapine were significantly higher than those of nonresponders. Our findings suggest that nonresponders to short-term mirtazapine treatment are characterized at baseline by a lowered output of the ANS. The results are preliminary in view of the small sample studied.     

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.     

Peripheral-type benzodiazepine receptor binding sites in platelets of patients with panic disorder associated to separation anxiety symptoms

Rationale Although it is still a matter of debate whether panic disorder (PD) and separation anxiety (SA) are associated or causally linked disorders, some investigators have suggested that SA may be a specific subtype of panic-agoraphobic spectrum. Several psychiatric disorders, including PD, are associated with lower levels of peripheral-type benzodiazepine receptor (PBR). Objectives The aim of the present study was to evaluate the kinetic binding parameters of the specific PBR ligand, PK 11195, in platelets from patients with PD in relation to the presence and severity of adulthood SA. Methods Using the specific radioligand, [³H] PK 11195, the kinetic binding parameters of PBR were determined on platelet membranes of 27 adult outpatients with a DSM-IV diagnosis of PD and 18 healthy controls. Patients were assessed with the SCID-I, the Panic Disorder Severity Scale, the Structured Clinical Interview for Separation Anxiety Symptoms and the Adult Separation Anxiety Checklist. Results PD patients had significantly lower PBR density than controls. However, the lower density was only evident in the subgroup of PD patients who also fulfilled the DSM-IV criteria for adult separation anxiety disorder. PBR density was negatively correlated with each of the two SA scales total scores. Conclusions Patients with SA symptoms had significantly lower densities of PBRs. PBR expression might become a useful biological marker of these two associated conditions.     

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     

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.     

Biological challenge procedures used to study co-occurring nicotine dependence and panic disorder

A wide array of biological challenge procedures - including carbon dioxide inhalation, hyperventilation, and breath holding - have been used to model panic in laboratory settings. Originally used to study developmental processes in panic disorder (PD), these procedures, along with nicotine patch administration and self-administered smoking, have recently been applied to help understand the etiology of co-occurring nicotine dependence and PD. The goals of the present paper are to review studies that have employed biological challenges to study the comorbid condition, identify the advantages and limitations of the various procedures, describe desirable outcome measures for use in biological challenges, and present recommendations for future challenge studies in this field. We argue that biological challenges, though in need of standardization, are useful for studying the development, maintenance, prevention, and treatment of comorbid nicotine dependence and PD.     

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     

比索洛尔对轻中度高血压心率及心率变异性的影响

目的观察比索洛尔对轻中度高血压在心率和心率变异性上的效应。方法63例轻中度高血压患者随机分为两组比索洛尔组接受比索洛尔片5~10mg,4周;对照组则接受硝苯地平控释片20mg,4周。治疗前后均作动态血压(ABPM)监测,并作心率变异性分析。结果两组治疗后SBP及DBP均有明显的下降(P<0.01),组间比较无明显差异(P>0.05)。比索洛尔组治疗后HR从(81±9)b/min下降到(68±7)b/min,有明显减慢心率的作用(P<0.01);而对照组则无此效应。两组治疗后心率变异性分析显示各项指标均有改善,以比索洛尔组为优(P<0.05)。结论比索洛尔能有效地降低血压,减慢心率,改善高血压患者的心率变异性,从而防止高血压患者心血管事件发生。     

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。     

广泛性焦虑患者心率变异性昼夜变化的临床分析

目的探讨广泛性焦虑（GAD）患者心率变异性（HRV）昼夜节律变化。方法选取43例GAD患者为研究组,43例健康成人为对照组,两组均进行24 h动态心电图监测及HRV分析。结果研究组各项HRV时域指标均明显低于对照组,差异有统计学意义（P〈0.05）,研究组白天与夜间SDNN、SDANN、rMSSD、PNN50比较,差异无统计学意义（P〉0.05）。对照组白天与夜间比较,四个指标差异均有显著统计学意义（P〈0.01）。结论 GAD患者存在自主神经功能紊乱,昼夜节律性消失,以迷走神经张力下降,交感神经张力相对亢进为主要表现。