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Caffeine potentiation of taste in panic-disorder patients
BIOL PSYCHIATRY 1993;33:217-219
2 !7
Caffeine Potentiation of Taste in Panic-Disorder Patients William J. Apfeldorf and M. Katherine Shear
Introduction Researchers have long been interested in the relationship between caffeine ingestion and panic attacks. Caffeine provokes panic attacks in a high proportion of panic-disorder patients (Charney et al 1985; Uhde 1990). Panic patients also report a lower rate of caffeine consumption than other subjects (Boulenger et al 1984). However, the mechanism underlying the effects of caffeine in panic-disorder patients has not been well studied. The behavioral and physiological actions of caffeine have been linked to its properties as an adenosine receptor antagonist (Snyder and Sklar 1984). Studies in normal subjects demonstrate that caffeine enh . . . . . t n c t . . . . . ;ti,titl, to " v~,iety of compounds and this effect is reversed by adenosine administered topically (Schiffman et al 1985). This is most likely an action at peripheral adenosine receptors either at the taste cells or nerves of the chorda tympani branch of the facial nerve associated with them on the tongue. Therefore, study of the effects of caffeine on taste may be a way to characterize adenosine function. Recently a study of caffeine effects on quinine taste threshold showed higher enhancement in panic-disorder patients compared to normal subjects (DeMet et al 1989). We report a second study supporting the finding of heightened caffeine-mediated taste enhancement in panic-disorder patients.
Methods Two groups were recruited for the study: those meeting DSMIII-R criteria for panic disorder with and without agoraphobia and ~!~ose free of mental disorder~ Diagnosis was established by clinical evaluation and confirmed using the Structured Clinical Interview for DSM-III-R (SCID, Spitzer et al 1988). Normal subjects were determined to be free of mental disorder on the basis of structured interview (SCID) and to have no history of mental illness .i,-. their ~"~',,,o,~,,,,~,r-e',~~°,, relatives. All subjects were free of physical illness. Each was medication free for at least 2 weeks prior to participation, and any subject reporting neuroleptic
Fromthe Departmentof Psychiatry,New YorkHospital/ComellUniversityMedical College Cevter, New York, NY. Address reprintrequeststo Dr. Apfeldoff,PayneWhitneyClinic,New YorkHospital/Cornell Medical Center, 525 East 68th Street, New York, NY 10021. Dr. Shear's current address: Departmentof Psychiatry, Universityof Pittsburgh. ReceivedJune 22, 1992; revisedOctober29, 1992. © 1993 Societyof BiologicalPsychiatry
or antidepressant use was excluded from this report. Subjects refrained from caffeine and tobacco use for ! 5 hr before testing, allowing 3 half-lives of caffeine for elimination. Taste thresholds were determined by a forced selection paradigm (DeMet et al 1989)• Subjects were asked to separate by taste four paper cups containing 5 ml of quinine solution from four cups containing distilled water. Taste and rinse solutions were ejected rather than swallowed. The lowest concentration of quinine at which the cups were correctly identified is the taste threshold. Taste thresholds in the presence of caffeine were determined by inclusion of the drug in the reference, the rinse, and the quinine solutions. Caffeine sensitivity is the difference between taste thresholds for quinine measured in the presence and absence of I 0 -s mol/L caffeine. The current protocol differs from that of DeMet and coworkers (1989) by using only a single trial for each participant. The caffeine concentration chosen produces a maximal increase in the ability to taste quinine solutions, is reversed by the presence of adenosine, and is undetectable by •taste (Schiffman et al 1985).
Results Seventeen panic-disorder patients and seven normal subjects completed the taste test. The results for each individual are presented in Table 1. For panic-disorder subjects, the mean log quinine threshold concentration without caffeine present was - 4 . 9 9 3 _ SD iL410 and with caffeine present - 5 . 3 9 3 ± SD 0.603. The mean log difference in quinine threshold concentration was 0.364 -+ SD 0.287. For normal subjects, the mean log quinine threshold concentration without caffeine present was - 5 . 2 6 3 "4- SD 0,189 and with c~ffeine present - 5 . 2 0 7 __ SD 0.257. The mean log d'fference in quinine threshold concentration was - 0 . 0 5 5 - SD 0.216. Analysis using the Mann-Whitney U test to compare taste thresholds in panic disorder and normal subjects reveals that taste enhancement by caffeine distinguishes the two subject groups (p -~ 0.01). If only female subjects are included in analysis, panic-disorder patients are still significantly different from normal controls (Mann-Whitney U test p < 0.01). Taste enhancement is the degree of potentiation of the ability to detect the bitter taste of quinine in the presence of caffeine. We defined a categorical variable, high taste enhancement, as I>!00% potentiation of quinine taste threshold (mean log difference t>0.301). Using this definition, 12 of 17 (71%) panic0006-3223/93/$06.00
218
BIOL PSYCHIATRY 1993;33:217-219
Brief Reports
Table t. Caffeine T~ste Enhancement by Subject Panic Disorder Datients Taste Threshold
Rank
Sex
Age
M
32 37 37 26 49 29 23 33 38 43 25 27 21 35 34 20 23
l
2.5 2.5 4 5 6 7 8 9 10.5 10.5 12.5 14 16 18 19 20
F F M F M F F M F F F F F M F M
Without caffeine (molar quinine) 2.62 2.31 9.24 i.08 6.17 1.39 4.93 2.16 2.72 6.94 6.94 1_08 924 !.23 8.61 1.39 1.23
x x x x x x x x x x x × x x x x x
10-6 10~ 10~ 10-3 10-6 10-3 10-3 10-3 10-6 lO~ 10-e I0 -3 10-6 10-5 IO: 10-3 10-5
With caffeine (molar quinine) 3.36 4.81
x x
10-7 10-7
1.93
x
10-~
Potentiation (%) 678 380 380 367 300 260 220 211 180 125 125 100 71 13 0 - 10
2.31 x 10-.6 ! .54 x 10-6 3.85 x 10.-6 1 . 5 4 x IO-5 6.94 x 10~ 9.62 x 10-7 3.08 x IO-6 3.08 x 10-6 5.34 x IO-6 5.38 × 10-6 1 . 0 8 x 10-5 8.61 x 10-S 1 . 5 4 x 10-3 ! . 3 8 x 10-5
-
14
Normal subjects -r,~,,, . . . . t~'-ezhold
Rank
Sex
Age
12.5 15 17 21 22 23 24
F F F F F F M
42 24 29 45 29 44 23
Without caffeine (molar quinine) 7.71 3.08 7.71 7.71 3.46 3.84 7.71
x x x x x x x
!0 -~ 10~ 10-6 I0~ IO-6 10-~ i04'
With caffeine (molar quinine) 3.85 2.48 6.94 9.24 5.38 6.94 !.54
x x x x x x x
10-6 10-6 10..6 iO~ 10-6 10-5 !0- 5
Potentiation (%) 100 20 !0 - 20 -56 - 80 -
100
Ranked by degree of enhancement. Mann-Whitney U test p < 0.01.
disorder subjects and only 1 of 7 (14%) normal subjects show high enhancement.
Discnssion The results demonstrate potentiation of quinine taste thresholds of caffeine in subjects with uniceat-~ panic disorder, but not in normal subjects. Although the sample size is limited, the effect was of such magnitude that the results were statistically significant. Nevertheless, the findings need further study with larger sample sizes. Work is underway to explore the relationship between taste-test findings and caffeine consumption and to explore the effects of treatment. The potentiation is also similar to the previously reported findings to DeMet and coworkers (1989), lending credence to our results. In their study, the mean log quinine threshold c o w centration was - 5.213 _+ SD 0.536 without caffeine, and - 5.633 -+ SD 0.398 with caffeine in panic-disorder subjects, and - 5.352 -+ SD 0.388 without caffeine, and - 5 . 5 9 3 _+ SD 0.396 with
caffeine in normal subjects. The threshold quinine concentration was slightly higher for each group in our sample and we failed to show caffeine potentiation of taste in the normal group. This may reflect differences in study design. In the current study, only medication-free panic-disorder patients were tested and single trial were conducted. DeMet and coworkers (1989) used three trials and included some subjects on medication. The observed caffeine-mediated taste enhancement s~ggests abnormal adenosine functioning in panic disorder. Adenosine has important roles both centrally and peripherally, primarily by inhibiting the release of excitatory neurotransmitters (Snyder and Sklar 1984; Dunwiddie 1985). This mechanism may underlie the known ability of caffeine to increase perceptual acuity for taste, vision, hearing, nociception, and other sensory pathways (Rail 1980). In animals, caffeine administered to the tongue leads to increased firing rates in the solitary h-act nucleus (Schiffman et al 1985). The heightened caffeine sensitivity in panic disorder may indicate an abnormality of adenosine functioning in impaired regulation o f excitatory neurotransmission and vulnerability to heightened perception. This may provide a neurobiologic link to
Brief Reports
observations made by cognitive behavioral researchers, which indicate heightened perception may occur in panic disorder (Clark 1988). Work is underway in our laboratory to explore the relationship between the taste-test findings and adenosine function.
BIOLPSYCHIATRY 1993;33:217-219
219
If the relationship is confirmed, the taste-test paradigm may be a simple, noninvasive procedure to test an interesting neurobiologic mechanism that may have a role in vulnerability to panic disorder.
References Boulenger JP, Uhde TW, Wolff III EA, Post RM (1984): Increased sensitivity to caffeine in patients with panic disorders: preliminary evidence. Arch Gen Psychiatry 41:1067-1071. Charney DS, Heninger GR, Jatlow PI (1985): Increased anxiogenic effects of caffeine in panic disorders. Arch Gen Psychiatry 42:233-243. Clark DM (1988): A cognitive model of panic attacks. In Rachman S, Maser JD (eds), Panic: Psychological Perspectives. Hillsdale: NJ: Erlbaum, pp 71--89. DeMet E, Stein MK, Tran C, Chicz-DeMet A, Sangdahl C, Nelson J (1989): Caffeine taste test for panic disorder: Adenosine receptor supersensitivity. Psychiatry Res 30:231-242. Dunwiddie TV (1985): The physiological role of adenosine in the central nervous system, lnt Rev Neurobiol 27:63-!39.
Rail TW (1980): Central nervous system stimulants: The xanthines. In Goodman Gilman A, Goodman LS, and Gilman A (eds) Goodman and Gilman's The Pharmacological Basis of Therapeutics, 6th ed. New York: Macmillan, pp 592-607. Schiffman SS, Gill JM, Diaz C (1985): Methyl xanthines enhance taste: Evidence for modulation of taste by adenosine receptor. Pharmacol Biochem Behav 22:195-203. Synder SH, Sklar P (1984): Behavioral and molecular actions of caffeine: Focus on adenosine. J Psychiat Res 18:91-106. Spitzer RL, Williams JBW, Gibbon M, First MB (1988): Structured Clinical Interviewfor DSM-III-R (SCID-P,6/l/88). Biometrics Research Department, New York State Psychiatric Institute.
2 !7
Caffeine Potentiation of Taste in Panic-Disorder Patients William J. Apfeldorf and M. Katherine Shear
Introduction Researchers have long been interested in the relationship between caffeine ingestion and panic attacks. Caffeine provokes panic attacks in a high proportion of panic-disorder patients (Charney et al 1985; Uhde 1990). Panic patients also report a lower rate of caffeine consumption than other subjects (Boulenger et al 1984). However, the mechanism underlying the effects of caffeine in panic-disorder patients has not been well studied. The behavioral and physiological actions of caffeine have been linked to its properties as an adenosine receptor antagonist (Snyder and Sklar 1984). Studies in normal subjects demonstrate that caffeine enh . . . . . t n c t . . . . . ;ti,titl, to " v~,iety of compounds and this effect is reversed by adenosine administered topically (Schiffman et al 1985). This is most likely an action at peripheral adenosine receptors either at the taste cells or nerves of the chorda tympani branch of the facial nerve associated with them on the tongue. Therefore, study of the effects of caffeine on taste may be a way to characterize adenosine function. Recently a study of caffeine effects on quinine taste threshold showed higher enhancement in panic-disorder patients compared to normal subjects (DeMet et al 1989). We report a second study supporting the finding of heightened caffeine-mediated taste enhancement in panic-disorder patients.
Methods Two groups were recruited for the study: those meeting DSMIII-R criteria for panic disorder with and without agoraphobia and ~!~ose free of mental disorder~ Diagnosis was established by clinical evaluation and confirmed using the Structured Clinical Interview for DSM-III-R (SCID, Spitzer et al 1988). Normal subjects were determined to be free of mental disorder on the basis of structured interview (SCID) and to have no history of mental illness .i,-. their ~"~',,,o,~,,,,~,r-e',~~°,, relatives. All subjects were free of physical illness. Each was medication free for at least 2 weeks prior to participation, and any subject reporting neuroleptic
Fromthe Departmentof Psychiatry,New YorkHospital/ComellUniversityMedical College Cevter, New York, NY. Address reprintrequeststo Dr. Apfeldoff,PayneWhitneyClinic,New YorkHospital/Cornell Medical Center, 525 East 68th Street, New York, NY 10021. Dr. Shear's current address: Departmentof Psychiatry, Universityof Pittsburgh. ReceivedJune 22, 1992; revisedOctober29, 1992. © 1993 Societyof BiologicalPsychiatry
or antidepressant use was excluded from this report. Subjects refrained from caffeine and tobacco use for ! 5 hr before testing, allowing 3 half-lives of caffeine for elimination. Taste thresholds were determined by a forced selection paradigm (DeMet et al 1989)• Subjects were asked to separate by taste four paper cups containing 5 ml of quinine solution from four cups containing distilled water. Taste and rinse solutions were ejected rather than swallowed. The lowest concentration of quinine at which the cups were correctly identified is the taste threshold. Taste thresholds in the presence of caffeine were determined by inclusion of the drug in the reference, the rinse, and the quinine solutions. Caffeine sensitivity is the difference between taste thresholds for quinine measured in the presence and absence of I 0 -s mol/L caffeine. The current protocol differs from that of DeMet and coworkers (1989) by using only a single trial for each participant. The caffeine concentration chosen produces a maximal increase in the ability to taste quinine solutions, is reversed by the presence of adenosine, and is undetectable by •taste (Schiffman et al 1985).
Results Seventeen panic-disorder patients and seven normal subjects completed the taste test. The results for each individual are presented in Table 1. For panic-disorder subjects, the mean log quinine threshold concentration without caffeine present was - 4 . 9 9 3 _ SD iL410 and with caffeine present - 5 . 3 9 3 ± SD 0.603. The mean log difference in quinine threshold concentration was 0.364 -+ SD 0.287. For normal subjects, the mean log quinine threshold concentration without caffeine present was - 5 . 2 6 3 "4- SD 0,189 and with c~ffeine present - 5 . 2 0 7 __ SD 0.257. The mean log d'fference in quinine threshold concentration was - 0 . 0 5 5 - SD 0.216. Analysis using the Mann-Whitney U test to compare taste thresholds in panic disorder and normal subjects reveals that taste enhancement by caffeine distinguishes the two subject groups (p -~ 0.01). If only female subjects are included in analysis, panic-disorder patients are still significantly different from normal controls (Mann-Whitney U test p < 0.01). Taste enhancement is the degree of potentiation of the ability to detect the bitter taste of quinine in the presence of caffeine. We defined a categorical variable, high taste enhancement, as I>!00% potentiation of quinine taste threshold (mean log difference t>0.301). Using this definition, 12 of 17 (71%) panic0006-3223/93/$06.00
218
BIOL PSYCHIATRY 1993;33:217-219
Brief Reports
Table t. Caffeine T~ste Enhancement by Subject Panic Disorder Datients Taste Threshold
Rank
Sex
Age
M
32 37 37 26 49 29 23 33 38 43 25 27 21 35 34 20 23
l
2.5 2.5 4 5 6 7 8 9 10.5 10.5 12.5 14 16 18 19 20
F F M F M F F M F F F F F M F M
Without caffeine (molar quinine) 2.62 2.31 9.24 i.08 6.17 1.39 4.93 2.16 2.72 6.94 6.94 1_08 924 !.23 8.61 1.39 1.23
x x x x x x x x x x x × x x x x x
10-6 10~ 10~ 10-3 10-6 10-3 10-3 10-3 10-6 lO~ 10-e I0 -3 10-6 10-5 IO: 10-3 10-5
With caffeine (molar quinine) 3.36 4.81
x x
10-7 10-7
1.93
x
10-~
Potentiation (%) 678 380 380 367 300 260 220 211 180 125 125 100 71 13 0 - 10
2.31 x 10-.6 ! .54 x 10-6 3.85 x 10.-6 1 . 5 4 x IO-5 6.94 x 10~ 9.62 x 10-7 3.08 x IO-6 3.08 x 10-6 5.34 x IO-6 5.38 × 10-6 1 . 0 8 x 10-5 8.61 x 10-S 1 . 5 4 x 10-3 ! . 3 8 x 10-5
-
14
Normal subjects -r,~,,, . . . . t~'-ezhold
Rank
Sex
Age
12.5 15 17 21 22 23 24
F F F F F F M
42 24 29 45 29 44 23
Without caffeine (molar quinine) 7.71 3.08 7.71 7.71 3.46 3.84 7.71
x x x x x x x
!0 -~ 10~ 10-6 I0~ IO-6 10-~ i04'
With caffeine (molar quinine) 3.85 2.48 6.94 9.24 5.38 6.94 !.54
x x x x x x x
10-6 10-6 10..6 iO~ 10-6 10-5 !0- 5
Potentiation (%) 100 20 !0 - 20 -56 - 80 -
100
Ranked by degree of enhancement. Mann-Whitney U test p < 0.01.
disorder subjects and only 1 of 7 (14%) normal subjects show high enhancement.
Discnssion The results demonstrate potentiation of quinine taste thresholds of caffeine in subjects with uniceat-~ panic disorder, but not in normal subjects. Although the sample size is limited, the effect was of such magnitude that the results were statistically significant. Nevertheless, the findings need further study with larger sample sizes. Work is underway to explore the relationship between taste-test findings and caffeine consumption and to explore the effects of treatment. The potentiation is also similar to the previously reported findings to DeMet and coworkers (1989), lending credence to our results. In their study, the mean log quinine threshold c o w centration was - 5.213 _+ SD 0.536 without caffeine, and - 5.633 -+ SD 0.398 with caffeine in panic-disorder subjects, and - 5.352 -+ SD 0.388 without caffeine, and - 5 . 5 9 3 _+ SD 0.396 with
caffeine in normal subjects. The threshold quinine concentration was slightly higher for each group in our sample and we failed to show caffeine potentiation of taste in the normal group. This may reflect differences in study design. In the current study, only medication-free panic-disorder patients were tested and single trial were conducted. DeMet and coworkers (1989) used three trials and included some subjects on medication. The observed caffeine-mediated taste enhancement s~ggests abnormal adenosine functioning in panic disorder. Adenosine has important roles both centrally and peripherally, primarily by inhibiting the release of excitatory neurotransmitters (Snyder and Sklar 1984; Dunwiddie 1985). This mechanism may underlie the known ability of caffeine to increase perceptual acuity for taste, vision, hearing, nociception, and other sensory pathways (Rail 1980). In animals, caffeine administered to the tongue leads to increased firing rates in the solitary h-act nucleus (Schiffman et al 1985). The heightened caffeine sensitivity in panic disorder may indicate an abnormality of adenosine functioning in impaired regulation o f excitatory neurotransmission and vulnerability to heightened perception. This may provide a neurobiologic link to
Brief Reports
observations made by cognitive behavioral researchers, which indicate heightened perception may occur in panic disorder (Clark 1988). Work is underway in our laboratory to explore the relationship between the taste-test findings and adenosine function.
BIOLPSYCHIATRY 1993;33:217-219
219
If the relationship is confirmed, the taste-test paradigm may be a simple, noninvasive procedure to test an interesting neurobiologic mechanism that may have a role in vulnerability to panic disorder.
References Boulenger JP, Uhde TW, Wolff III EA, Post RM (1984): Increased sensitivity to caffeine in patients with panic disorders: preliminary evidence. Arch Gen Psychiatry 41:1067-1071. Charney DS, Heninger GR, Jatlow PI (1985): Increased anxiogenic effects of caffeine in panic disorders. Arch Gen Psychiatry 42:233-243. Clark DM (1988): A cognitive model of panic attacks. In Rachman S, Maser JD (eds), Panic: Psychological Perspectives. Hillsdale: NJ: Erlbaum, pp 71--89. DeMet E, Stein MK, Tran C, Chicz-DeMet A, Sangdahl C, Nelson J (1989): Caffeine taste test for panic disorder: Adenosine receptor supersensitivity. Psychiatry Res 30:231-242. Dunwiddie TV (1985): The physiological role of adenosine in the central nervous system, lnt Rev Neurobiol 27:63-!39.
Rail TW (1980): Central nervous system stimulants: The xanthines. In Goodman Gilman A, Goodman LS, and Gilman A (eds) Goodman and Gilman's The Pharmacological Basis of Therapeutics, 6th ed. New York: Macmillan, pp 592-607. Schiffman SS, Gill JM, Diaz C (1985): Methyl xanthines enhance taste: Evidence for modulation of taste by adenosine receptor. Pharmacol Biochem Behav 22:195-203. Synder SH, Sklar P (1984): Behavioral and molecular actions of caffeine: Focus on adenosine. J Psychiat Res 18:91-106. Spitzer RL, Williams JBW, Gibbon M, First MB (1988): Structured Clinical Interviewfor DSM-III-R (SCID-P,6/l/88). Biometrics Research Department, New York State Psychiatric Institute.