Cognitive-behavioral therapy for benzodiazepine discontinuation in panic disorder patients.

The discontinuation of benzodiazepine treatment in patients with panic disorder may be associated with emergent withdrawal and anxiety symptoms, relapse of panic, and the inability to complete benzodiazepine taper. Although some patients may respond to slow taper strategies or the use of pharmacologic adjuncts, many continue to experience significant difficulties during benzodiazepine discontinuation. This paper presents a cognitive-behavioral conceptualization of benzodiazepine discontinuation difficulties, emphasizing "fear of fear" cycles. From this perspective the discontinuation process is seen as exposing panic disorder patients to somatic sensations associated with panic at a time when there is both increased anxiety and concern about re-emergence or worsening of panic episodes. As a consequence, patients may re-enter a cycle of catastrophic interpretations of symptoms, increased vigilance and fear, and panic. Cognitive-behavioral interventions may ameliorate discontinuation-associated difficulties and prevent the return of the panic disorder. Preliminary data supporting the efficacy of these interventions are described.     

A dose-finding and discontinuation study of clomipramine in panic disorder

Eighty-one panic disorder patients with or without agoraphobia were treated with flexible doses of clomipramine under single-blind conditions. Fifty-seven (70.3%) reached operational criteria for full remission in 16.2 +/- 6.5 weeks, with a mean dose of 89.1 +/- 8.2 mg/day. Fifty-four (81%) of them received a continuous post-remission maintenance treatment at full doses of clomipramine for 4-6 months. No patient relapsed during the clomipramine maintenance phase. Their medication was then tappered and discontinued with placebo substitution under double-blind conditions. Fifty-one (63%) patients were followed-up until relapse or recurrence for up to 3 years, with periodic assessments. Three different outcome groups were identified: the first (n = 19, 19; 37.2%) experienced an early/immediate relapse (5.2 +/- 4.9 weeks after drug discontinuation); the second group (n = 22, 22; 43.1%) experienced recurrence after 42.9 +/- 35 weeks following discontinuation; and the third group (n = 10, 10; 19.6%) remained assymptomatic and functionally well throughout the follow-up. Predictors of early relapse were: (1) higher baseline score in the Beck Depression Inventory; (2) higher global score on the phobic avoidance scale after the full remission criteria; and (3) the need for higher clomipramine doses to reach full remission. The need for long-term or intermittent maintenance for most patients is emphasized.     

Cognitive-behavioral therapy for panic disorder in patients being treated for alcohol dependence: Moderating effects of alcohol outcome expectancies

Anxiety disorders commonly co-occur with alcohol use disorders and reliably mark a poor response to substance abuse treatment. However, treating a co-occurring anxiety disorder does not reliably improve substance abuse treatment outcomes. Failure to account for individual differences in the functional dynamic between anxiety symptoms and drinking behavior might impede the progress and clarity of this research program. For example, while both theory and research point to the moderating role of tension-reduction alcohol outcome expectancies (TR-AOEs) in the association between anxiety symptoms and alcohol use, relevant treatment studies have not typically modeled TR-AOE effects. We examined the impact of a hybrid cognitive-behavioral therapy (H-CBT) treatment for panic disorder (independent variable) on response to a community-based alcohol dependence treatment program (dependent variable) in patients with higher vs. lower TR-AOEs (moderator). The H-CBT treatment was generally effective in relieving participants' panic symptoms relative to controls. However, TR-AOEs interacted with study cohort (H-CBT vs. control) in predicting response to substance abuse treatment. As expected, the H-CBT was most effective in improving alcohol use outcomes among those with the highest TR-AOEs. The study's primary methodological limitations are related to the quasi-experimental design employed.     

简化认知行为疗法对惊恐障碍的疗效研究

目的探究简化认知行为疗法(SCBT)对轻中度惊恐障碍的临床疗效。方法收集山西医科大学第二医院精神卫生科住院轻中度惊恐障碍患者40例,随机分为3组:SCBT加药物组13例;支持性心理疗法加药物组12例;单药物组15例。干预时间为6周(每次1 h,共8次)。采用汉密尔顿焦虑量表(HAMA)-14、汉密尔顿抑郁量表(HAMD)-17、惊恐障碍严重程度(PDSS)和心理痛苦温度计(DT)量表评估干预效果。结果 3组HAMA-14、HAMD-17、PDSS、DT量表分数在干预前后差异有统计学意义(P<0.05)。第6周末时SCBT加药物组和支持加药物组在HAMA-14、HAMD-17量表得分上分别与单药物组差异有统计学意义(P<0.05)。3组在PDSS、DT量表得分上两两之间差异均有统计学意义(P<0.05)。结论 SCBT对轻、中度惊恐障碍患者疗效可;SCBT加药物治疗对患者的焦虑抑郁情绪有所改善,并优于单药物治疗;SCBT加药物治疗降低患者的惊恐障碍严重程度,缓解心理痛苦体验,并优于支持加药物治疗和单药物治疗。     

Effects of gradual discontinuation of selective serotonin reuptake inhibitors in panic disorder with agoraphobia

The aim of this investigation was to explore the prevalence and features of discontinuation syndromes ensuing with gradual tapering of selective serotonin reuptake inhibitors (SSRIs), in optimal clinical conditions in patients with panic disorder and agoraphobia. Twenty-six consecutive outpatients met the DSM-IV criteria for panic disorder and agoraphobia while taking SSRIs. Twenty remitted upon behavioural treatment. Antidepressant drugs were then tapered at the slowest possible pace and with appropriate patient education. Patients were assessed with the Discontinuation-Emergent Signs and Symptoms (DESS) checklist 2 wk, 1 month and 1 yr after discontinuation. Nine of the 20 patients (45%) experienced a discontinuation syndrome, which subsided within a month in all but three patients who had been taking paroxetine for a long time. Discontinuation syndromes appeared to be fairly common even when performed with slow tapering and during clinical remission. In some cases disturbances persisted for months after discontinuation.     

Rapid tryptophan depletion following cognitive behavioural therapy for panic disorder

Objective

The aim of this study was to examine the effect of rapid tryptophan depletion (RTD) combined with a panicogenic challenge in patients with panic disorder who had responded to treatment with cognitive behavioural therapy (CBT). We hypothesised that RTD (compared with the control drink) would result in an increase in anxiety symptoms when provoked by a panicogenic challenge with the benzodiazepine antagonist, flumazenil.

Methods

Nine patients with panic disorder who had responded to CBT received a tryptophan-free amino acid drink on one occasion and a control drink on the other in a double-blind crossover design. In addition, they received flumazenil and placebo infusions on each day.

Results

Our hypothesis regarding the effects of RTD was supported by findings of a significant interaction between RTD and flumazenil on measures from visual analogues scales (total) and the Spielberger State Anxiety inventory. A somewhat unexpected finding was that in this group of CBT responders, the panicogenic effect of flumazenil was not completely blocked by treatment. This meant that although four of the nine subjects (44%) reported a panicogenic effect of flumazenil on the RTD day, this was not significantly different from the rate of panic attacks in response to flumazenil on the control day.

Conclusion

We suggest that the partial return of symptoms in response to flumazenil reflects a vulnerability to RTD in this group of panic disorder patients who had responded to treatment with CBT.     

Duration of imipramine therapy and relapse in panic disorder with agoraphobia

It has been suggested that maintenance treatment of patients who have remitted panic disorder with agoraphobia beyond the six months of acute phase imipramine treatment may decrease the risk of relapse. This study further explores the relationship between relapse and duration of imipramine treatment in this population.Fifty-one patients, all in remission at the end of six months acute phase open trial with imipramine 2.25 mg/kg/day and randomized to double-blind maintenance or placebo substitution, discontinued imipramine treatment eventually and were followed over a 12-month risk period: 27 during first year placebo substitution, 7 after 12 months of imipramine maintenance in placebo substitution, and 17 after variable durations of imipramine maintenance in open discontinuation. There were no behaviorally oriented interventions or instructions at any time during the acute and maintenance phases of treatment or during imipramine discontinuation.Duration of imipramine treatment, the method of discontinuation (open versus placebo substitution), or any of the 9 variables from the demographic, clinical, and open treatment domains that were entered in a Cox proportional hazard model did not predict relapse. The rate of relapse after only 6 months of treatment (10 out of 27, 37%) was identical to the rate of relapse after 12 to 30 months of treatment (9 out of 24, 37.5%).The results suggest a lack of specific protective effects beyond prophylaxis and underscore the difficulty in predicting relapse in fully remitted panic disorder with agoraphobia patients. Early detection of relapse in patients who discontinue treatment may be a viable alternative to prediction.     

Maintenance therapy with fluoxetine in posttraumatic stress disorder: a placebo-controlled discontinuation study

The effect of fluoxetine (FLU) in posttraumatic stress disorder was studied in a one-year trial. Subjects received open-label treatment for 6 months, followed by double-blind randomized treatment with FLU or placebo (PBO) for 6 months. Rates of relapse were compared using the Clinical Global Impressions of Improvement. One hundred twenty-three subjects entered open-label treatment, of whom 114 returned at least once. Sixty-two subjects were randomized to receive FLU or PBO, of whom 57 returned at least once and were analyzed. The dose of FLU ranged from 10 to 60 mg/d; at randomization, mean doses were 48.6 and 42.1 mg for FLU and PBO groups. Rates of relapse were 22% for FLU versus 50% for PBO (P = 0.02), and time to relapse on FLU was longer than for PBO (P = 0.02, log-rank statistic). The odds ratio for relapse on PBO relative to FLU was 3.50. No significant differences were found on other measures. Fluoxetine was well tolerated during double-blind treatment.     

Benzodiazepine overdosage: Plasma concentrations and clinical outcome

Plasma concentrations and their relation to clinical outcome were evaluated in 21 patients who reached emergency treatment facilities following acute overdosage with benzodiazepine derivatives. Diazepam was implicated in 18 of the 21 cases, with plasma diazepam levels ranging from 585–8,635 ng/ml. In four cases of overdosage with diazepam alone, patients were minimally sedated and were discharged within 24 h, despite diazepam doses as high as 750 mg and plasma levels as high as 4,792 ng/ml. However, concurrent ingestion of diazepam together with other central depressant drugs (such as ethanol, barbiturates, analgesics, or tricyclic antidepressants) produced serious intoxication in 5 of the remaining 14 patients, regardless of the diazepam dosage or plasma concentration. Thus the severity of poisoning following benzodiazepine overdosage is determined largely by co-ingestion of other central depressants rather than the amount of benzodiazepine ingested or its concentration in plasma.     

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.     

Prevalence of headache syndromes in panic disorder.

We investigated the prevalence of headache in a group of patients attending a psychiatric clinic because suffering from panic disorder, according to DSM-IV criteria. The psychopathological assessment was performed with the 'Panic Disorder/Agoraphobia Questionnaire' and the presence of headache was evaluated according to the criteria of the International Headache Society. The results showed that two-thirds of patients met the criteria for a diagnosis of headache, with migraine without aura being the most frequent form, followed by tension headache, while two patients only were affected by migraine with aura. When we compared panic patients with and without headache, those with headache had a longer duration of panic disorder, a higher number of attacks and a heavier family loading for panic disorder and headache. This suggests that the comorbidity of headache with panic disorder renders this condition more severe and possibly responsive to different treatments compared to panic disorder alone.     

Paroxetine influences respiration in rats: implications for the treatment of panic disorder.

Since hyperventilation and shortness of breath are characteristic features of panic attacks, and since the attacks can be elicited by CO(2) inhalation, an involvement of central or peripheral chemoreceptors in the pathophysiology of panic disorder has been suggested. Prompted by clinical reports suggesting that the susceptibility to spontaneous as well as CO(2)-induced anxiety and hyperventilation is attenuated by serotonin reuptake inhibitors (SRIs), we undertook the present study in order to explore the possible effect of an SRI, paroxetine, on baseline respiration and CO(2)-induced hyperventilation in freely moving Wistar rats. A significant increase in baseline respiratory rate was seen both after 5 and 15 weeks of treatment with paroxetine. CO(2) exposure induced a dose-dependent increase in respiratory rate, but not tidal volume, in both paroxetine-treated rats and controls; this response was reduced after 15 weeks of paroxetine treatment, but not after 5 weeks of treatment. We suggest that an influence on the regulation of respiration may be of importance for the anti-panic effect of SRIs.     

Abrupt discontinuation of alprazolam and cognitive style in patients with panic disorder: early effects on mood, performance, and vital signs

The objective of this study was to ascertain the relationship of alprazolam plasma levels and an anxiety-prone cognitive style to the characteristics and severity of early withdrawal after abrupt discontinuation of alprazolam in 26 patients with panic disorder. After 8 and 9 weeks of fixed-dose treatment, patients were hospitalized for 24 hours. On 1 admission, ordered at random, treatment was maintained; on the other, placebo was substituted double blind. The Anxious Thoughts and Tendencies questionnaire was administered before treatment. Alprazolam plasma levels were measured 7 times on the day after each admission. Before each blood sampling, the Profile of Mood States and performance tasks were administered, and vital signs were recorded. On the day after abrupt discontinuation of alprazolam, Profile of Mood States anxiety, depression, fatigue, and confusion increased; vigor and elation decreased; speed on the digit symbol substitution task improved; and systolic blood pressure increased substantially over time. High Anxious Thoughts and Tendencies scores were related specifically to more anxiety. Our findings (1) confirm that dysphoric mood, fatigue, low energy, confusion, and elevated systolic blood pressure are part of the early syndrome of withdrawal from alprazolam in patients with panic disorder, notably as the drop in plasma levels approaches 50%; (2) indicate a psychomotor deficit persisting beyond dose stabilization; (3) suggest that an anxiety-prone cognitive style measurable before undertaking treatment may be a risk factor for more severe anxiety upon discontinuation; and (4) provide a rationale for applying cognitive behavior therapy during benzodiazepine taper.     

Serotonin in panic disorder: platelet uptake and concentration

Platelet serotonin uptake and platelet serotonin concentrations were measured in 17 patients (5 males, 12 females) with panic attacks and 15 controls (8 males, 7 females). Higher Vmax values were found in the patient group compared with controls (65 +/- 7 vs. 47 +/- 3 pmol/10(8) platelets/min; p less than 0.05) while the affinity constant Km was not significantly different (0.6 +/- 0.1 vs. 0.5 +/- 0.1 microM). Platelet serotonin concentrations were not significantly different between the two groups (38 +/- 4 vs. 41 +/- 4 ng/10(8) platelets). These results confirm our earlier finding of increased serotonin uptake in patients with panic attacks and suggest that platelet serotonin levels are normal.     

The epidemiology of panic disorder and agoraphobia in Europe.

A literature search, in addition to expert survey, was performed to estimate the size and burden of panic disorder in the European Union (EU). Epidemiologic data from EU countries were critically reviewed to determine the consistency of prevalence estimates across studies and to identify the most pressing questions for future research. A comprehensive literature search focusing on epidemiological studies in community and clinical settings in European countries since 1980 was conducted (Medline, Web of Science, Psychinfo). Only studies using established diagnostic instruments on the basis of DSM-III-R or DSM-IV, or ICD-10 were considered. Thirteen studies from a total of 14 countries were identified. Epidemiological findings are relatively consistent across the EU. The 12-month prevalence of panic disorder and agoraphobia without history of panic were estimated to be 1.8% (0.7-2.2) and 1.3% (0.7-2.0) respectively across studies. Rates are twice as high in females and age of first onset for both disorders is in adolescence or early adulthood. In addition to comorbidity with agoraphobia, panic disorder is strongly associated with other anxiety disorders, and a wide range of somatoform, affective and substance use disorders. Even subclinical forms of panic disorder (i.e., panic attacks) are associated with substantial distress, psychiatric comorbidity and functional impairment. In general health primary care settings, there appears to be substantial underdiagnosis and undertreatment of panic disorder. Moreover, panic disorder and agoraphobia are poorly recognized and rarely treated in mental health settings, despite high health care utilization rates and substantial long-term disability.