اختلال هراس و زیرگروه اختلال اجتماعی اضطراب در یک تست چالش کافئین

Abstract Studies have demonstrated the vulnerability of anxiety disorder patients to challenge tests. Our aim was to observe if panic disorder (PD) patients and generalized social anxiety disorder (GSAD) and performance social anxiety disorder (PSAD) patients respond in a similar way to the induction of anxiety symptoms and panic attacks by an oral caffeine challenge test. We compared 28 PD patients, 25 GSAD patients, 19 PSAD, and 26 control subjects after a 480-mg caffeine test. The patients had not received psychotropic drugs for at least a 4-week period. In a randomized double-blind experiment performed in two occasions 7 days apart, 480 mg of caffeine and a caffeine-free solution were administered and anxiety scales were administered before and after each test. A panic attack was induced in 17 (60.7%) PD patients, 4 (16.0%) GSAD patients, and 10 (52.6%) PSAD patients, during the caffeine test. None of the control subjects had a panic attack after the caffeine intake. Neither patients nor any control subject had a panic attack after drinking the caffeine-free solution. Our data suggest that there is an association between PD and PSAD hyperreactivity to an oral caffeine challenge test. The PD and PSAD patients had a higher number of induced panic attacks, some specific anxiety symptoms, and a more severe anxiety response than GSAD patients and normal volunteers.

. Introduction Some studies have demonstrated the vulnerability of different groups of patients with anxiety disorders to biochemical and respiratory challenge tests, and have confirmed that patients with panic disorder (PD) are particularly prone to experience panic attacks in response to these tests (Gorman et al., 1981, Perna et al., 1994 and Verburg et al., 1998). Caffeine is one of the most widely consumed psychoactive substances in the world as it is found in beverages, foods, and medications, although most caffeine consumed is derived from coffee, tea, and soft drinks (Uhde, 1990). It is a xanthine derivative that is used worldwide as a psychostimulant, and it may provide a useful biological model of an induced panic attack (Lee et al., 1988 and Uhde, 1990). In PD patients, oral administration of caffeine produces a significant increase in subject-rated anxiety, nervousness, fear, nausea, palpitations, restlessness and tremors (Charney et al., 1985), as well as significantly increased reactivity with respect to N2-P2 auditory evoked potential amplitude, N2 latency and electroencephalographic alpha waves (Bruce et al., 1992). Caffeine-induced panic attacks are relatively specific to PD, as healthy volunteers rarely panic with this agent (Nickell and Uhde, 1994–1995). In addition to panic attacks, long-lasting anxiety induced by caffeine includes insomnia and an increase in blood pressure. These symptoms occur at an increased rate and intensity in PD relative to healthy volunteers (Charney et al., 1985 and Uhde, 1990). Caffeine-induced anxiety symptoms did not appear to differ in social anxiety disorder (SAD) versus normal control subjects, and the symptoms induced by caffeine challenge in the SAD group did not mimic their naturally occurring symptoms (Tancer et al., 1995). Tancer et al. (1991) studied 11 subjects in each of three groups: SAD, PD, and normal controls. They found that cortisol levels, but not lactate levels, in SAD patients increased similarly to caffeine-induced increments found in patients with PD. The generalized subtype of social anxiety disorder (GSAD) is defined by the fear of most social situations, with the remainder of SAD described by various terms such as “discrete”, “circumscribed”, “performance” or “nongeneralized” (Mannuzza et al., 1995). The SAD group usually fears “performance” situations such as public speaking, eating, or writing in public. Persons with GSAD often complain of similar fears, but they also fear social interactions, such as informal conversation, speaking to authority figures, and attending social gatherings (Liebowitz et al., 1985 and Mannuzza et al., 1995). Mannuzza et al. (1995) reported that SAD subtypes could be distinguished reliably in a clinical sample of 129 SAD patients, even though the GSAD definition (fear of “most social situations”) is not fully operationalized. They found that persons with GSAD were often single, had earlier onsets of the disorder, were more often characterized by fear of interpersonal interactions, and had higher rates of major depression and alcoholism and lower rates of PD. Persons with performance social anxiety disorder (PSAD) seem to be responsive to β-blockers, usually have a sudden onset of symptoms, have an onset of disorder that is laterr than that of the GSAD, and seems to have fewercomorbidities (Liebowitz et al., 1985, Liebowitz et al., 1992, Heimberg et al., 1993, Mannuzza et al., 1995 and Nardi, 1996). The studies examining the subtype differences in response to various treatment modalities are few and inconclusive (Liebowitz et al., 1992 and Heimberg et al., 1993). Our research team has been focusing on challenge tests in anxiety and mood disorders, and the caffeine challenge test has been a major focus of our research (Nardi et al., 2007a, Nardi et al., 2007b and Nardi et al., 2008). Our samples have no overlap in these different trials. Each patient can participate only once in a challenge trial and even the control groups change in each trial for methodological, ethical, and therapeutic reasons. We decided to compare the response of PD patients, GSAD patients, PSAD patients, and a normal volunteers group to an oral caffeine challenge test. We hypothesized that PD and PSAD patients would have more panic attacks and a greater increase in anxiety levels during the test, and that the GSAD and the control group would react to caffeine in a similar way. All the tests were done without using any medication.

. Results We selected 28 PD patients (19 women; mean age 37.4 years ± 8.6); 25 GSAD patients (14 women; mean age 41.5 years ± 10.2), 19 PSAD patients (9 women; mean age 38.2 years ± 9.7), and 26 subjects for the control group (13 women; mean age 35.5 years ± 12.1). There were no gender, age, educational level, marital status, occupation, or previous psychiatric treatment differences among the groups. We compared some clinical aspects of our groups (Table 1). The PD and the PSAD patients had a higher family history of PD; the disorder started significantly later than in the GSAD patients; and they had less history of previous alcohol abuse. Table 1. Clinical characteristics in panic disorder (PD), generalized social anxiety disorder (GSAD), and performance social anxiety disorder (PSAD). Yes No Family history of panic disorder⁎ PD n = 28 21 (75.0) 7 (25.0) GSAD n = 25 10 (40.0) 15 (60.0) χ2 = 15.80, df = 2, P < 0.001 PSAD n = 19 13 (68.4) 6 (31.6) Age disorder started (years ± SD) PD 22.8 ± 9.2 GSAD 16.1 ± 6.3 Mann–Whitney P < 0.001 PSAD 23.6 ± 7.0 Previous depressive episodes⁎⁎ PD n = 28 20 (71.4) 8 (28.6) GSAD n = 25 15 (60.0) 10 (40.0) χ2 = 29.40, df = 2, P < 0.001 PSAD n = 19 5 (26.3) 14 (73.7) Previous alcohol abuse⁎⁎⁎ PD n = 28 8 (28.6) 20 (71.4) GSAD n = 25 19 (76.0) 6 (24.0) χ2 = 29.60, df = 2, P < 0.001 PSAD n = 19 7 (36.8) 12 (63.2) ⁎PD vs. GSAD: χ2 = 10.80, df = 1, P = 0.001; PD vs. PSAD: χ2 = 0.26, df = 1, P = 0.870; GSAD vs. PSAD: χ2 = 11.80, df = 1, P = 0.001. ⁎⁎PD vs. GSAD: χ2 = 2.17, df = 1, P = 0.141; PD vs. PSAD: χ2 = 77.3, df = 1, P < 0.001; GSAD vs. PSAD: χ2 = 43.20, df = 1, P < 0.001. ⁎⁎⁎PD vs. GSAD: χ2 = 29.60, df = 1, P < 0.001; PD vs. PSAD: χ2 = 1.83, df = 1, P = 0.176; GSAD vs. PSAD: χ2 = 41.80, df = 1, P < 0.001. Table options The PD (71.4%) and GSAD groups (60.0%) had more previous depressive episodes than the PSAD group (26.3%) — Table 1. No patient fulfilled the criteria for major depressive episode during our study, but this comorbidity is quite common in anxiety disorder, and PSAD patients seem to have a lower probability of cormorbid depression than PD and GSAD patients. There were no heavy or moderate-to-heavy caffeine users in our study's sample. The consumption pattern of caffeine of all subjects was as follows: 75.0% consumed soft drinks regularly, 69.4% chocolate products, 65.3% coffee, and 27.8% tea. The average and median potential daily intakes of caffeine by the sample were 2.51 ± 0.86 for PD, 2.44 ± 1.05 for GSAD, 2.67 ± 0.96 for PSAD, and 2.13 ± 1.15 mg/kg for the control group (Mann–Whitney, P = 0.803). No patient mentioned any problem/symptom that appeared to be associated with abstinence from caffeine during the period preceding the caffeine testing. A panic attack was induced in 17 (60.7%) PD patients, in 10 (52.6%) PSAD patients, and in 4 (16.0%) GSAD patients after the caffeine test (χ2 = 25.4, df = 2, P < 0.001). None of the control subjects had a panic attack after the 480-mg caffeine intake (χ2 = 75.4, df = 3, P < 0.001). Neither patients nor control subjects had a panic attack after drinking the caffeine-free solution. The self-rating of SUDS before the caffeine test was 2.4 ± 1.8 for PD; 2.1 ± 1.5 for GSAD; 2.2 ± 1.2 for PSAD, and 2.4 ± 2.0 for the control group. After the test the ratings were 8.3 ± 5.6 for PD; 7.9 ± 5.0 for PSAD; 3.6 ± 3.5 for GSAD; and 3.8 ± 3.2 for the control group. All groups were highly sensitive and had an increased anxiety level after the test. The PD and PSAD groups had a significant increase in relation to the other groups, and a difference was also detected in relation to time: before vs. after (two-way ANOVA: the groups by time interaction: F = 35.41, df = 3, 96, P = 0.003. The effect of time: F = 45.63, df = 3, 96, P < 0.001. Fisher's protected least significant difference: PD vs. GSAD, P < 0.001; PD vs. PSAD, P = 0.532; PSAD vs. GSAD; P < 0.001). All patients were analyzed from the panic attack symptoms and some anxiety symptoms after the test (Table 2). The symptoms were more frequent in the PD patients, and PSAD patients experienced fear of dying, chest/pain discomfort, shortness of breath, and paresthesias. The symptoms that were more frequent in the GSAD and in the control groups were dizziness/lightheadedness, depersonalization/derealization, chills/hot flushes, palpitations, tremor/shaking, and headache. There were no differences among the four groups in symptoms such as sweating, nausea/abdominal distress, feelings of choking, losing control/going crazy, increase in systolic blood pressure, and insomnia in the night after the test. Table 2. Frequency of panic attack and anxiety symptoms after the 480-mg caffeine challenge test in panic disorder (PD) patients, generalized social anxiety disorder (GSAD) patients, performance social anxiety disorder (PSAD) patients, and control subjects. Symptoms PD GSAD PSAD Control analysis N (%) 28 (%) 25 (%) 19 (%) 26 (%) Fear of dying 24 (85.7) 11 (44.0) 15 (78.9) 10 (38.5) χ2 = 31.5, df = 3, P < 0.001 Chest pain/discomfort 23 (82.1) 9 (36.0) 13 (68.4) 10 (38.5) χ2 = 21.3, df = 3, P < 0.001 Shortness of breath 20 (71.4) 12 (48.0) 14 (73.7) 13 (50.0) χ2 = 10.4, df = 3, P = 0.005 Paresthesias 25 (89.3) 10 (40.0) 16 (84.2) 12 (46.1) χ2 = 31.9, df = 3, P < 0.001 Feelings of choking 19 (67.9) 15 (60.0) 11 (57.9) 14 (53.8) χ2 = 8.70, df = 3, P = 0.013 Dizziness/lightheaded 13 (46.4) 21 (84.0) 8 (42.1) 20 (76.9) χ2 = 46.8, df = 3, P < 0.001 Depersonalization/derealization 15 (53.6) 18 (72.0) 9 (47.4) 19 (73.1) χ2 = 20.6, df = 3, P < 0.001 Losing control/going crazy 13 (46.4) 12 (48.0) 9 (47.4) 14 (53.8) χ2 = 0.62, df = 3, P = 0731 Chills/hot flushes 18 (64.3) 20 (80.0) 11 (57.9) 21 (80.8) χ2 = 41.1, df = 3, P < 0.001 Nausea/abdominal distress 17 (60.7) 14 (56.0) 13 (68.4) 14 (53.8) χ2 = 3.30, df = 3, P = 0.192 Palpitations 16 (57.10) 22 (88.0) 10 (52.6) 23 (88.5) χ2 = 71.0, df = 3, P < 0.001 Sweating 14 (50.0) 16 (64.0) 9 (47.4) 16 (61.5) χ2 = 4.22, df = 3, P = 0.121 Trembling/shaking 12 (42.9) 22 (88.0) 7 (36.8) 21 (80.8) χ2 = 48.9, df = 3, P < 0.001 Other anxiety symptoms Headache 10 (35.7) 19 (76.0) 8 (42.1) 18 (69.2) χ2 = 25.0, df = 3, P < 0.001 Increase in blood systolic blood pressure (more than 5 mm Hg) 14 (50.0) 15 (60.0) 10 (52.6) 16 (61.5) χ2 = 4.64, df = 3, P = 0.098 Insomnia in the night after the test 10 (35.7) 14 (56.0) 8 (42.1) 14 (53.8) χ2 = 7.45, df = 3, P = 0.064