A randomized, naturalistic, parallel-group study for the long-term treatment of panic disorder with clonazepam or paroxetine

This long-term extension of an 8-week randomized, naturalistic study in patients with panic disorder with or without agoraphobia compared the efficacy and safety of clonazepam (n = 47) and paroxetine (n = 37) over a 3-year total treatment duration. Target doses for all patients were 2 mg/d clonazepam and 40 mg/d paroxetine (both taken at bedtime). This study reports data from the long-term period (34 months), following the initial 8-week treatment phase. Thus, total treatment duration was 36 months. Patients with a good primary outcome during acute treatment continued monotherapy with clonazepam or paroxetine, but patients with partial primary treatment success were switched to the combination therapy. At initiation of the long-term study, the mean doses of clonazepam and paroxetine were 1.9 (SD, 0.30) and 38.4 (SD, 3.74) mg/d, respectively. These doses were maintained until month 36 (clonazepam 1.9 [SD, 0.29] mg/d and paroxetine 38.2 [SD, 3.87] mg/d). Long-term treatment with clonazepam led to a small but significantly better Clinical Global Impression (CGI)-Improvement rating than treatment with paroxetine (mean difference: CGI-Severity scale -3.48 vs -3.24, respectively, P = 0.02; CGI-Improvement scale 1.06 vs 1.11, respectively, P = 0.04). Both treatments similarly reduced the number of panic attacks and severity of anxiety. Patients treated with clonazepam had significantly fewer adverse events than those treated with paroxetine (28.9% vs 70.6%, P < 0.001). The efficacy of clonazepam and paroxetine for the treatment of panic disorder was maintained over the long-term course. There was a significant advantage with clonazepam over paroxetine with respect to the frequency and nature of adverse events.     

Combined paroxetine and clonazepam treatment strategies compared to paroxetine monotherapy for panic disorder

Despite the widespread application of combined selective serotonin reuptake inhibitors (SSRI) and benzodiazepine treatment for panic disorder, there has been relatively little systematic assessment of the safety and efficacy of this therapeutic strategy. Although the limited number of studies to date suggest a more rapid onset of benefit with combined treatment, this study is the first to address the critical question of whether continued combined treatment confers superior efficacy. This study is a randomized, double-blind, three-arm study in patients with panic disorder (n = 60), comparing the efficacy and safety of paroxetine and placebo (PP), paroxetine coadministered with clonazepam followed by a tapered benzodiazepine discontinuation phase (PC-D), and ongoing combination treatment (PC-M). All treatment groups demonstrated significant improvement by endpoint. There was a significant advantage for the combined treatment groups early in treatment but, subsequently, outcome in all three groups was similar. A trend towards greater achievement of endpoint remission status for the PC-D group was attenuated when variability in baseline severity was considered. The results of this study should be interpreted in the context of a relatively moderate sample size and higher rates of early dropout. Combined treatment with paroxetine and clonazepam resulted in more rapid response than with the SSRI alone, but there was no differential benefit beyond the initial few weeks of therapy. Initiating combined treatment followed by benzodiazepine taper after a few weeks may provide early benefit while avoiding the potential adverse consequences of long-term combination therapy.     

Increased cholesterol levels after paroxetine treatment in patients with panic disorder

Panic disorder (PD) is associated with an increased cardiovascular risk. We examined serum cholesterol and plasma catecholamine levels in PD before and after paroxetine treatment. The serum cholesterol and plasma catecholamine levels were not different between the PD patients and control subjects before the treatment. However, the levels of total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were significantly increased in the 28 PD patients after 3 months of paroxetine treatment, whereas the body mass index and plasma catecholamine levels were unchanged. Paroxetine should be used cautiously for PD patients who have overt or covert cardiovascular disorders.     

电针与帕罗西汀治疗惊恐障碍的临床疗效

目的 比较电针疗法与帕罗西汀片治疗惊恐障碍的疗效和安全性。方法 将59例随机分为电针组(30例)和帕罗西汀组(29例),疗程为4周。在治疗前及治疗1、2、4、8周时采用焦虑自评量表(SAS)、汉密尔顿抑郁量表(HAMA)、疗效指数(CGI-EI)、Barthel指数(BI)量表评定疗效和不良反应。结果 电针组总有效率为86.66%,帕罗西汀组为82.76%,两组疗效差异无统计学意义;疗效指数及起效时间两组间有显著差异,电针组起效时间短、不良反应少。结论 两种方法治疗惊恐障碍疗效相当,但电针疗法起效时间短、疗效指数高、不良反应少。     

11-year-old boy with panic disorder responding to paroxetine

We experienced an 11-year-old boy with panic disorder responding remarkably to paroxetine. Only a few studies have reported the clinical application of selective serotonin reuptake inhibitors (SSRIs) on children with panic disorder. In Japan, there are reports of child depression, autism, and school phobia; no study has focused on paroxetine treatment for children with panic disorder. Therefore, the case is discussed in this study.     

The effects of tianeptine or paroxetine on 35% CO2 provoked panic in panic disorder

Antidepressants that inhibit the reuptake of serotonin (5-HT) are particularly effective in the treatment of panic disorder. Evidence suggests that increased 5-HT availability is important for the anti-panic effect of serotonergic drugs and in maintaining the response to selective serotonin reuptake inhibitors (SSRIs). Tianeptine is an antidepressant with 5-HT reuptake enhancing properties (i.e. the opposite pharmacological profile to that of SSRIs). Therefore, no effect would be expected in panic disorder. The aim of the present study was to compare the effect of tianeptine with that of paroxetine, a selective 5-HT reuptake inhibitor with demonstrated efficacy in panic disorder, on the vulnerability to a laboratory panic challenge in panic disorder patients. Twenty panic disorder patients were treated with either tianeptine or paroxetine for a period of 6 weeks, in a randomized, double-blind, separate group design. The reaction to a 35% CO(2) panic challenge was assessed at baseline and after treatment. Improvement on several clinical scales was also monitored. Tianeptine, as well as paroxetine, showed a significant reduction in vulnerability to the 35% CO(2) panic challenge. In spite of their opposite influence on 5-HT uptake, both tianeptine and paroxetine appeared to reduce the reaction to the panic challenge. These results raise questions about the necessity of 5-HT uptake for the therapeutic efficacy of anti-panic drugs.     

Treatment of panic disorder: focus on paroxetine

Panic disorder is a chronic and disabling condition associated with significant morbidity. Treatment of panic disorder has evolved significantly in the past 20 years with the availability of serotonergic antidepressants, including the selective serotonin reuptake inhibitors (SSRIs). Of these, paroxetine was the first to receive an indication for treatment of panic disorder and has been extensively studied in this area. A series of randomized, double-blind, placebo-controlled studies have demonstrated the efficacy and safety of paroxetine treatment of panic disorder, with a majority of patients achieving panic-free status during 12-week studies. Continued treatment with paroxetine results in sustained rates of remission compared with placebo. The combination of paroxetine and cognitive behavioral therapy appears to offer benefits of efficacy and sustained therapeutic response.     

A randomized controlled trial of venlafaxine ER and paroxetine in the treatment of outpatients with panic disorder

Rationale Nitrous oxide (N₂O) can initially lower core temperature (T _core), but hypothermic tolerance develops with chronic administration. Therefore, one or both of T _core’s controlling determinants, heat production (HP) and heat loss (HL), must adapt across repeated N₂O administrations. Simultaneous measurements of HP, HL, and T _core during chronic N₂O administrations will elucidate this adaptive process and constitute a rigorous model for studying the systems-level dynamics of tolerance in both mature and young animals. This approach is justified by the need to better understand the increased vulnerability to addiction associated with adolescent drug use. Objectives The objective of the study was to measure HL and HP across repeated steady-state administrations of 60% N₂O in young and mature rats. Materials and methods Synchronous measurements of HP (indirect calorimetry), HL (direct calorimetry), and T _core (telemetry) were obtained during 60% N₂O administrations in adolescent (28–45 days, n = 11) and mature rats (>90 days, n = 8). Rats received five 90-min drug exposures (every other day). Results Compared to mature rats, adolescents initially exhibited greater hypothermia, but acquired tolerance more rapidly and actually developed hyperthermia during the fifth administration. In both groups, N₂O consistently increased HL, but progressive increases of intrasessional HP over repeated administrations prevented hypothermia and subsequently promoted hyperthermia in adolescent rats. Conclusions Adolescent rats hyper-adapt to N₂O hypothermia. Increases of intrasessional HP across N₂O administrations explained both tolerance to N₂O hypothermia and the unexpected hyperthermia observed in adolescents. These findings raise the possibility that the increased vulnerability to addiction associated with adolescent drug use involves a hyper-adaptive tolerance mechanism.     

High plasma concentrations of paroxetine impede clinical response in patients with panic disorder

Selective serotonin reuptake inhibitors are thought to interact with serotonergic neurons and be effective for treatment of panic disorder. In the present study, the authors investigated an association between plasma concentrations of paroxetine in patients with panic disorder and clinical response to initial treatment with paroxetine. Subjects were 21 unrelated Japanese patients who fulfilled DSM-IV-TR criteria for a diagnosis of panic disorder (6 males, 15 females, mean age 35.9 +/- 11.3 years). Subjects were administered 10 mg/day of paroxetine for 2 weeks as initial treatment. Improvement of the symptoms of the disorder was assessed with the Panic and Agoraphobia Scale (PAS). In the range of plasma levels >20 ng/mL, none of the subjects showed the reduction ratio in PAS score >0.2. The subjects whose plasma concentrations of paroxetine were less than 20 ng/mL had a significantly higher mean reduction ratio in PAS score than the subjects whose plasma concentrations of paroxetine were >20 ng/mL. Multiple regression analysis showed that the plasma concentration of paroxetine was the only significant factor and accounted for 28.0% of the variability in the reduction ratio of PAS score of the subjects. The final model of correlation was: reduction ratio in PAS score = 0.423 - 0.009 x (plasma concentrations of paroxetine) (R = 0.529, P = 0.014, coefficient of determination (R2) = 0.280). Assuming that the reduction ratio in PAS score was 0.2 in the equation above, plasma concentration of paroxetine is calculated to be about 25 ng/mL, which is suggested to be the upper end of the therapeutic window for the initial phase of the treatment with paroxetine for panic disorder.     

Possible cross-sensitivity between sertraline and paroxetine in a panic disorder patient

Cross-sensitivity due to paroxetine and sertraline, the SSRIs, is rarely reported in the literature. We report an adverse drug reaction to paroxetine and sertraline in a patient of panic disorder, who initially developed a maculopapular, erythematous, pruritic rash in the third week with sertraline 50 mg/day. The rash resolved within 2 days of its discontinuation and oral supplementation of diphenhydramine and betamethasone. 10 days following discontinuation of sertraline, the patient was shifted on sustain release paroxetine 12.5 mg/day when another skin reaction with the same appearance and distribution appeared on day 4 of it, suggesting a possibility of cross-sensitivity, a drug class effect. This case report intends to improve the awareness among clinicians to use caution when choosing an alternative SSRIs.     

Clomipramine, clonazepam, and clonidine treatment of obsessive-compulsive disorder.

Serotonergic reuptake inhibitors have been the primary medications for treatment of obsessive-compulsive disorder (OCD); however, other serotonergic and alpha 2-adrenergic medications also have been reported to reduce obsessive-compulsive symptoms. In this study, we compare three medications with reported efficacy in OCD to a control medication, diphenhydramine, a medication without theoretical or demonstrated treatment benefit. The three active medications were clomipramine, a serotonergic reuptake inhibitor; clonazepam, a benezodiazepine with putative serotonergic properties; and clonidine, an alpha 2-adrenergic agonist. Twenty-eight subjects with DSM-III-R diagnosis of OCD rotated through 6-week trials of each of the four medications in a randomized, double-blind, multiple crossover protocol. Clomipramine and clonazepam were both effective relative to the control medication in reducing OCD symptoms. There was a significant cross-response between these two medications; however 40% of subjects failing clomipramine trials had a clinically significant response to clonazepam treatment. The control medication, diphenhydramine, itself produced a significant decrement in symptoms, whereas clonidine was ineffective in reducing OCD symptoms. Clonazepam improvement was unrelated to changes in anxiety and occurred early in treatment. Clonazepam was significantly more effective than the other medications during the first 3 weeks of treatment. The results confirm the efficacy of clomipramine in the treatment of OCD and suggest that clonazepam might be a useful alternative treatment for patients with this disorder.     

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

Thirty-four consecutive patients with panic disorder or agoraphobia with panic attacks were treated with nortriptyline at the LAC-USC Medical Center's Anxiety Disorders Clinic. Fourteen (67%) of the 21 completers totally lost their panic attacks, five (24%) showed partial improvement, and two (10%) showed no improvement. The relationship of treatment outcome to pretreatment and posttreatment measures of depression is discussed, in addition to the potential role of nortriptyline in treating panic attacks in clinical practice.     

Diagnosis and treatment of agoraphobia with panic disorder

Agoraphobia with panic disorder is a phobic-anxious syndrome where patients avoid situations or places in which they fear being embarrassed, or being unable to escape or get help if a panic attack occurs. During the last half-century, agoraphobia has been thought of as being closely linked to the recurring panic attack syndrome, so much so that in most cases it appears to be the typical development or complication of panic disorder. Despite the high prevalence of agoraphobia with panic disorder in patients in primary-care settings, the condition is frequently under-recognised and under-treated by medical providers. Antidepressants have been demonstrated to be effective in preventing panic attacks, and in improving anticipatory anxiety and avoidance behaviour. These drugs are also effective in the treatment of the frequently coexisting depressive symptomatology. Among antidepressant agents, SSRIs are generally well tolerated and effective for both anxious and depressive symptomatology, and these compounds should be considered the first choice for short-, medium- and long-term pharmacological treatment of agoraphobia with panic disorder. The few comparative studies conducted to date with various SSRIs reported no significant differences in terms of efficacy; however, the SSRIs that are less liable to produce withdrawal symptoms after abrupt discontinuation should be considered the treatments of first choice for long-term prophylaxis. Venlafaxine is not sufficiently studied in the long-term treatment of panic disorder, while TCAs may be considered as a second choice of treatment when patients do not seem to respond to or tolerate SSRIs. High-potency benzodiazepines have been shown to display a rapid onset of anti-anxiety effect, having beneficial effects during the first few days of treatment, and are therefore useful options for short-term treatment; however, these drugs are not first-choice medications in the medium and long term because of the frequent development of tolerance and dependence phenomena. Cognitive-behavioural therapy is the best studied non-pharmacological approach and can be applied to many patients, depending on its availability.     

Alprazolam, propranolol, and placebo in the treatment of panic disorder and agoraphobia with panic attacks

Fifty-five patients completed a 5-week double-blind study comparing alprazolam, propranolol, and placebo in the treatment of panic disorder and agoraphobia with panic attacks. There was no concomitant behavioral treatment. Patient and therapist rating scales included Sheehan's Panic and Anxiety Attack Scales, the Marks-Sheehan Phobia Scale, the Hamilton Anxiety Scale, the Hamilton Depression Scale, and the Side Effects Checklist. The results generally support the efficacy of alprazolam, but not propranolol, in the treatment of panic disorder and agoraphobia with panic attacks. The significance of the results are discussed, as well as a number of the unique aspects of our procedures and patient population.     

文拉法辛缓释剂和帕罗西汀治疗惊恐障碍的随机对照研究

目的:比较文拉法辛缓释剂和帕罗西汀治疗惊恐障碍的有效性和安全性。方法:将73例符合CCMD-3R的惊恐障碍病人随机分为2组,分别给予文拉法辛(38例,初始剂量75 mg·d~(-1))和帕罗西汀(35例,初始剂量10 mg·d~(-1))。采用惊恐症状评定量表(PASS)、汉密尔顿焦虑量表(HAMA)、临床总体印象量表(CGI)和不良反应量表(TESS)分别在治疗前,治疗后wk 2、4、8末各评定1次,并进行对比分析。结果:2组间在治疗后wk 2、4末PASS、HAMA、CGI评分有显著差异(P<0.05);在wk 8末2组间差异无显著意义(P>0.05);文拉法辛组PASS、HAMA、CGI评分在治疗后wk 2末比治疗前明显降低(P<0.05),在wk 4、8末有进一步改善(P<0.01);帕罗西汀组PASS、HAMA、CGI评分在治疗后wk 4、8末与治疗前相比均降分明显(P<0.01)。2组不良反应发生率无显著差异。结论:文拉法辛是一种快速有效且安全性较高的治疗惊恐障碍的药物。     

Determinants of pharmacodynamic trajectory of the therapeutic response to paroxetine in Japanese patients with panic disorder

Purpose  

The objective of this study was to evaluate genetic and pharmacokinetic factors to establish the pharmacotherapeutic effect of paroxetine (PAX) in patients with panic disorder (PD).     

氯硝西泮合并帕罗西汀治疗酒依赖伴抑郁的临床分析

目的:观察氯硝西泮合并帕罗西汀治疗酒依赖伴抑郁的疗效。方法:本组20例患者入院即采用氯硝西泮合并帕罗西汀治疗,氯硝西泮2~6mg/d,分2~4次肌注;帕罗西汀20~40mg/d,早上7:00一次性服用。结果:20例患者中,生理依赖症状完全消除18例,好转2例;心理依赖症状好转16例。抑郁症状完全消除10例,进步6例,有效2例,无效2例,总有效率为90%。结论:氯硝西泮合并帕罗西汀治疗酒依赖伴抑郁疗效显著,戒断症状少,安全性高。     

The acute phase response in panic disorder

An acute-phase response (APR), manifested as an increase of acute-phase proteins has been shown in major depression. Panic disorder (PD) may share some aetiopathogenic mechanisms with depression, but APR has not been studied in this disorder. Forty-one panic patients in the first stages of their illness were compared with 32 healthy subjects of comparable sex, age, and body mass index. Clinical diagnosis was established with the mini international neuropsychiatric interview, and severity with the panic disorder severity scale and the CGI scale. Laboratory determinations included four acute phase proteins (APPs) [albumin, gammaglobulins, fibrinogen, C-reactive-protein (CRP)] and basal cortisol level. Patients were studied after 8-wk follow-up taking selective serotonin reuptake inhibitors (SSRIs) to assess the evolution of the APPs. Gammaglobulin levels were lower, and both cortisol and CRP levels were higher in PD patients than in controls. APP did not differ between patients with or without agoraphobia. At follow-up, patients who responded to SSRIs presented a decrease in albumin levels, and a trend towards a decrease in cortisol and CRP compared with levels at intake. The conclusions of this study are that there is an APR in patients suffering from PD, and this APR tends to diminish after a successful treatment with SSRIs.