512
BIOL PSYCHIATRY 1991;30:512-514
CSF Opioids in Panic Disorder K. T. Brady, R. B. Lydiard, J. C. Ballenger, J. Shook, M. Laraia, and M. Fossey
Introduction
opioid system are nonspecific, both 13-endorphin and dynorphin A (1-8) activity were measured in the CSF of panic disorder patients and a nor-
Investigation of the potential role for endogenous opiates as a modulator of anxiety states control sample. has yielded variable results. Increased plasma [3-endorphin has been reported accompanying surgical stress (Pickar et al 1982) and with high M e t h o d s anxiety ratings in women during menstruation Patients and controls were interviewed via a (Veith et al 1984). Can" et al (1986) found no Suucmn~ ~ Interview for DSM-m (Spitzer significant change in plasma [3-endorphin during and Williams 1983) modified for DSM-III-R dilactate infusion before and after treatment with agnosis (American Psychiauic Association 1987). alprazolam in panic disorder patients or controls Patients with panic disorder were included if ~ y but did note a slight decrease in 13-endorphin had had at least one panic attack per week for at over time secondary to acclimatiza~'ion. Dager least I month. All patients had at least one panic et al (1989) found higher 13-endorphin levels in attack per week in the month prior to testing and panic disorder than in depressed patients and a were medication-free for 7 days prior to testing. slight decrease in plasma [3-endorphin during Patients with a lifetime or current history of malactate infusion in panic disorder patients, de- jor depression preceding the onset of panic atpressed patients, and controls. tacks or predominating the clinical picture were George et al (1989) found significantly higher excluded. Controls were excluded if they had a lifetime or family history of a mood or anxiety cently dctoxified alcoholics with panic disorder disorder. After 4 days of a low monoamine diet than in those without panic disorder. Eriksson and and 9 hr of bedrest, CSF was obtained between 8 co-workers (1989) found significantly elevated and 9 AM from 25 panic disorder patients (5 men levels of CSF ~-endorphin concentrations in panic and 20 women, ages 35.6 __ 8.8 yrs, mean _+ disorder patients when compared with controls. SD) and 17 normal controls (9 men and 8 won~n, To date, the only endogenous opiate mea- age 30.7 _ 7.7 yrs, mean + SD). Samples were sured in patients with anxiety disorders is frozen on dry ice and stored at - 70°(2 until as[3-endorphin. To further explore these findings say. and to assess whether changes in the endogenous Samples from an aliquot of the 15th to 26th cc of CSF o b ~ e ~ were assayed in duplicate for [3-endorphin (l-31) and dynorphin A (I-8) From the Department of Psychiau'y and Behavioral Sciences, Medby radioimmunoassay according to the methods ical University of South Carolina, Charleston, SC. Ad&-ess reprint requests to Kathleen Brady, Ph.D., M.D., Departof Hong et al (1984). The antiserum for dynorment of Psychiatry and Behavioral Sciences, Medical University phin A (1-8) has 0.02% a~d 0.01% cross-reacof South Carolina, 171 Ashley Avenue, Charleston, SC 29425. Received September 19, 1990; revised March 19, 1991. tivities for dynorphin A (1-13) and dynorphin
Brief
Rcpo~
A (1-17) a.d does n~. cross react with met-
enkephalin or leu-enkephalin. The sensitivity of this assay was 5F moifml. The antiserum for 13endo~hin (1-31) has 50% cross-reactivity with 13-1ipotmpin and no cross-reactivity with metenkephalin, Q- or ~/-endorphin. The sensitivity of this assay was ~ pgtml. Because of crossreactivity with a 13-1ipotropin, ~-endoq~fin levels actually reflect 13-endorphin-like activity. Using a standard 13-endorphin, 78 -+ 5% of the [~-endo:phin sample co-elute~ using HPLC. Between-group comparisons were performed utilizing Students t-test and the Mann-Whitney U test. Correlations were determined via Spearman's Rank Order correlation. Hamilton Anxiety Rating Scale (Hamilton 1959) was obtained on the morning of the procedure. Global Phobia Scale (Marks and Matthews 1976), and panic attack frequency were obtained the evening before the procedure.
Results Due to volume restrictions, 13-endorphin measures were obtained in only 19 panic disorder patients and 16 controls. There were no significant differences between the panic disorder and the control group in age or sex. There were no significant differences in ~-endorphins or dynorphins between series or between the control group and the panic disorder groups in CSF 13-endorphin (control 97.4 _ 23.3 pg/ml; panic disorder 93.5 -- 28.0 pg/ml) (Figure 1) or dynorphin levels (control 26.0 __ 7.4 pg/ml; panic disorder 26.2 __ 10.5 mg/ml) (Figure 2). There were no signiticant sex differences in f~-endorg~in (male 94.6 _+ 6.3; female 94.9 _+ 5.5) or dynorphin (male 25.5 -+ 2.0; female 26.5 _+ 2.0) levels. Using height, age, or weight as a covariate did not affect our findings. For [3-endorphin activity in panic disorder patients, a negative correlation (r = 0.52, p < 0.04) with Global Phobia scores and a trend towards a negative conelation (r = - 0 . 4 3 , p ~< 0.08) with spontaneous panic attack frequency was found. There was no correlation between Hamilton Anxiety ratings and IB-endorphin or dynorphin in the panic disorder group. In the control group,
BI~. PSYa~.TIY
513
~eo
~40 e
e
!
• e
¢ 0
o
80
s
e
Q
60 e
40 20 t n~
n-lg
Figure 1. CSF 1 3 - e ~ concentration~ m control and panic disorder ~ e n t s . total Hamilton Anxiety rating scores w e ~ positive correlated (r = 0.68,p < 0.012) ~ t h fl-endorphin but not d y n o ~ levels.
Discussion In c o n ~ t to the findings of ~ s o n and coworkers (1989) and George et al (1989), we
70
60
50
40
30
20
8 8
o
|
®
e
8
!
t
|
o
10
i Contrc4 n=17
| Panic n=25
Figure 2. CSF dynorphin concentrations in control and panic disorder pa~ents.
514
Brief Repom
BIOL PSYCHIATRY 1991;30:512-514
found no significant difference in CSF 13-endorphin or dynorphin levels between the control group and the panic disorder patients. The reason for the discrepancy between the findings of these investigators and our findings is unclear. Ericksson and co-workers (1989) reported that levels in four controls and one patient were below the level of sensitivity of their assay, and also indicated that they were likely measuring other peptides which may be subunits of [3-endorph~n ( 1,3 I). Both their sample (n - 11) and ours (:~ = 19) were relatively small. George et al'~: (1989) sample of recently detoxified alcoholics with or without panic disorder was clearly different from our patient population. An interesting finding of this study is the positive correlation between the Hamilton Anxiety ratings and 13-endorphin activity in the control population and the negative correlation between 13-endorphin activity and G l o ~ l Phobia scores and spontaneous panic attacks (trend) in the panic disorder group. Some investigators have noted correlations in normals between surgical stress or state anxiety and elevated 13-endorphin levels (Pickar et al 1982; Veith et al, 1984). Both Post et al (1982) and Agren and co-workers (1982) reported a positive correlation between endorphin levels and anxiety measures in subjects with depression and/or agoraphobia. Ochers have found an inverse relationship between state anxiety at the time of lumbar puncture and CSF 13-endorphin in normal controls (Pickax et al 1982). In this regard, it i t n f i n t ~ r o e t t h a t t h oWrt V~, , * uv,Je e r u ~ e i t h , a ~wg,cglll~,,~nr~L WVLL~.: 44 l , . r q J o a L a v ~
lation between anxiety ratings and 13-endorphin activity in the control population but not in the panic disorder group. It is possible that the endogenou~ ¢pioid systems play a role in the norvere or prolonged anxiety, such as panic disorder patients, this regulation may be absent. In the panic disorder group, the negative correlation between [3-endorphin activity and Global Phobia sco~s and spontaneous panic attacks may tw lllh,~,% dysregulation r.a.._, of this system. Further studies will be helpful in understanding this relationship.
Antisera and tracers were a generous gift from Dr. LS. Hong, Laboratory of Molecular and Integrative Neuroscience, National Institute of Environmental Health Science, Research Triangle P~k, N.C.
Refe~nces Agren H, Terenius L, Wahlstrom A (1982): Depressive phenon~nology and levels of cerebrospinai fluid endorphins. Ann N F Acad Sci 398:388-398. American Psychiatric Association (1987): Diagnostic and Statistical Manual of Memal Disorders ed 3 (revised) Washington, DC: APA Press. Can" DB, Sheehan DV, Sunnan OS, et al (1986): Neuroendocrine correlates of lactate-induced anxiety and their response to chronic alprazoiam therapy. Am J Psychiatry 143:483-494. Dater SR, Cowley DS, Dorsa DM, Dunner DL (i 989): Plasma [~-endorphin response to lactate infusion. Biol Psychiatry 25:243-245. Eriksson E, Westberg P, Thuresson K, et al (1989): cerebrospinal fluid of endorphin immunogeactivity in panic disorder. Neuropsychopharmacology 2:225-228. George DT. Comorbidity of alcoholism and panic disorder. Presented at the 142rid Annual Meeting of the American Psychiatric Association, May 6-1i, 1989, San Francisco. Hamilton M (1959): The assessment of anxiety states by rating. Br J Med Psychol 32:50--55. Hong JC, Yoshikawa K, Hedren RW (1984): Measurement of ~-endorphin and enkephalins in biological tissues and fluids. In Conn M (ed), Methods in En,,ymology. Hew York: Academic, pp 547-564. Marks IM, Mathews AM (1976): Brief standard se!frating for phobic patients. Behav Res Ther 17:26326?.
Pickar D, Cohen MR, Naber D, Cohen RM (1982): Clinical studies of the endogenous opioid system. Biol Psychiatry 17:!243-1275. Post gM, Gold P, Rubinow DR, et al (1982): Peptides in the cerebrospinal fluid of neumpsyci~atric patients: an approach to central nervous system stem peptide function. Life Sci 31: ! - 15. Spitzer R, Williams J (1983): Structured Interview for DSM-IH. New York State Psychiatric Institute, N'Y. Veith JL, Anderson J, Slade SA, Thompson P, Law gel GR, Getzlaf S (1984): Plasma [3-endorphin, pain thresholds and anxiety levels across the human menstrual cycle. Physical Behav 32:31-34.
BIOL PSYCHIATRY 1991;30:512-514
CSF Opioids in Panic Disorder K. T. Brady, R. B. Lydiard, J. C. Ballenger, J. Shook, M. Laraia, and M. Fossey
Introduction
opioid system are nonspecific, both 13-endorphin and dynorphin A (1-8) activity were measured in the CSF of panic disorder patients and a nor-
Investigation of the potential role for endogenous opiates as a modulator of anxiety states control sample. has yielded variable results. Increased plasma [3-endorphin has been reported accompanying surgical stress (Pickar et al 1982) and with high M e t h o d s anxiety ratings in women during menstruation Patients and controls were interviewed via a (Veith et al 1984). Can" et al (1986) found no Suucmn~ ~ Interview for DSM-m (Spitzer significant change in plasma [3-endorphin during and Williams 1983) modified for DSM-III-R dilactate infusion before and after treatment with agnosis (American Psychiauic Association 1987). alprazolam in panic disorder patients or controls Patients with panic disorder were included if ~ y but did note a slight decrease in 13-endorphin had had at least one panic attack per week for at over time secondary to acclimatiza~'ion. Dager least I month. All patients had at least one panic et al (1989) found higher 13-endorphin levels in attack per week in the month prior to testing and panic disorder than in depressed patients and a were medication-free for 7 days prior to testing. slight decrease in plasma [3-endorphin during Patients with a lifetime or current history of malactate infusion in panic disorder patients, de- jor depression preceding the onset of panic atpressed patients, and controls. tacks or predominating the clinical picture were George et al (1989) found significantly higher excluded. Controls were excluded if they had a lifetime or family history of a mood or anxiety cently dctoxified alcoholics with panic disorder disorder. After 4 days of a low monoamine diet than in those without panic disorder. Eriksson and and 9 hr of bedrest, CSF was obtained between 8 co-workers (1989) found significantly elevated and 9 AM from 25 panic disorder patients (5 men levels of CSF ~-endorphin concentrations in panic and 20 women, ages 35.6 __ 8.8 yrs, mean _+ disorder patients when compared with controls. SD) and 17 normal controls (9 men and 8 won~n, To date, the only endogenous opiate mea- age 30.7 _ 7.7 yrs, mean + SD). Samples were sured in patients with anxiety disorders is frozen on dry ice and stored at - 70°(2 until as[3-endorphin. To further explore these findings say. and to assess whether changes in the endogenous Samples from an aliquot of the 15th to 26th cc of CSF o b ~ e ~ were assayed in duplicate for [3-endorphin (l-31) and dynorphin A (I-8) From the Department of Psychiau'y and Behavioral Sciences, Medby radioimmunoassay according to the methods ical University of South Carolina, Charleston, SC. Ad&-ess reprint requests to Kathleen Brady, Ph.D., M.D., Departof Hong et al (1984). The antiserum for dynorment of Psychiatry and Behavioral Sciences, Medical University phin A (1-8) has 0.02% a~d 0.01% cross-reacof South Carolina, 171 Ashley Avenue, Charleston, SC 29425. Received September 19, 1990; revised March 19, 1991. tivities for dynorphin A (1-13) and dynorphin
Brief
Rcpo~
A (1-17) a.d does n~. cross react with met-
enkephalin or leu-enkephalin. The sensitivity of this assay was 5F moifml. The antiserum for 13endo~hin (1-31) has 50% cross-reactivity with 13-1ipotmpin and no cross-reactivity with metenkephalin, Q- or ~/-endorphin. The sensitivity of this assay was ~ pgtml. Because of crossreactivity with a 13-1ipotropin, ~-endoq~fin levels actually reflect 13-endorphin-like activity. Using a standard 13-endorphin, 78 -+ 5% of the [~-endo:phin sample co-elute~ using HPLC. Between-group comparisons were performed utilizing Students t-test and the Mann-Whitney U test. Correlations were determined via Spearman's Rank Order correlation. Hamilton Anxiety Rating Scale (Hamilton 1959) was obtained on the morning of the procedure. Global Phobia Scale (Marks and Matthews 1976), and panic attack frequency were obtained the evening before the procedure.
Results Due to volume restrictions, 13-endorphin measures were obtained in only 19 panic disorder patients and 16 controls. There were no significant differences between the panic disorder and the control group in age or sex. There were no significant differences in ~-endorphins or dynorphins between series or between the control group and the panic disorder groups in CSF 13-endorphin (control 97.4 _ 23.3 pg/ml; panic disorder 93.5 -- 28.0 pg/ml) (Figure 1) or dynorphin levels (control 26.0 __ 7.4 pg/ml; panic disorder 26.2 __ 10.5 mg/ml) (Figure 2). There were no signiticant sex differences in f~-endorg~in (male 94.6 _+ 6.3; female 94.9 _+ 5.5) or dynorphin (male 25.5 -+ 2.0; female 26.5 _+ 2.0) levels. Using height, age, or weight as a covariate did not affect our findings. For [3-endorphin activity in panic disorder patients, a negative correlation (r = 0.52, p < 0.04) with Global Phobia scores and a trend towards a negative conelation (r = - 0 . 4 3 , p ~< 0.08) with spontaneous panic attack frequency was found. There was no correlation between Hamilton Anxiety ratings and IB-endorphin or dynorphin in the panic disorder group. In the control group,
BI~. PSYa~.TIY
513
~eo
~40 e
e
!
• e
¢ 0
o
80
s
e
Q
60 e
40 20 t n~
n-lg
Figure 1. CSF 1 3 - e ~ concentration~ m control and panic disorder ~ e n t s . total Hamilton Anxiety rating scores w e ~ positive correlated (r = 0.68,p < 0.012) ~ t h fl-endorphin but not d y n o ~ levels.
Discussion In c o n ~ t to the findings of ~ s o n and coworkers (1989) and George et al (1989), we
70
60
50
40
30
20
8 8
o
|
®
e
8
!
t
|
o
10
i Contrc4 n=17
| Panic n=25
Figure 2. CSF dynorphin concentrations in control and panic disorder pa~ents.
514
Brief Repom
BIOL PSYCHIATRY 1991;30:512-514
found no significant difference in CSF 13-endorphin or dynorphin levels between the control group and the panic disorder patients. The reason for the discrepancy between the findings of these investigators and our findings is unclear. Ericksson and co-workers (1989) reported that levels in four controls and one patient were below the level of sensitivity of their assay, and also indicated that they were likely measuring other peptides which may be subunits of [3-endorph~n ( 1,3 I). Both their sample (n - 11) and ours (:~ = 19) were relatively small. George et al'~: (1989) sample of recently detoxified alcoholics with or without panic disorder was clearly different from our patient population. An interesting finding of this study is the positive correlation between the Hamilton Anxiety ratings and 13-endorphin activity in the control population and the negative correlation between 13-endorphin activity and G l o ~ l Phobia scores and spontaneous panic attacks (trend) in the panic disorder group. Some investigators have noted correlations in normals between surgical stress or state anxiety and elevated 13-endorphin levels (Pickar et al 1982; Veith et al, 1984). Both Post et al (1982) and Agren and co-workers (1982) reported a positive correlation between endorphin levels and anxiety measures in subjects with depression and/or agoraphobia. Ochers have found an inverse relationship between state anxiety at the time of lumbar puncture and CSF 13-endorphin in normal controls (Pickax et al 1982). In this regard, it i t n f i n t ~ r o e t t h a t t h oWrt V~, , * uv,Je e r u ~ e i t h , a ~wg,cglll~,,~nr~L WVLL~.: 44 l , . r q J o a L a v ~
lation between anxiety ratings and 13-endorphin activity in the control population but not in the panic disorder group. It is possible that the endogenou~ ¢pioid systems play a role in the norvere or prolonged anxiety, such as panic disorder patients, this regulation may be absent. In the panic disorder group, the negative correlation between [3-endorphin activity and Global Phobia sco~s and spontaneous panic attacks may tw lllh,~,% dysregulation r.a.._, of this system. Further studies will be helpful in understanding this relationship.
Antisera and tracers were a generous gift from Dr. LS. Hong, Laboratory of Molecular and Integrative Neuroscience, National Institute of Environmental Health Science, Research Triangle P~k, N.C.
Refe~nces Agren H, Terenius L, Wahlstrom A (1982): Depressive phenon~nology and levels of cerebrospinai fluid endorphins. Ann N F Acad Sci 398:388-398. American Psychiatric Association (1987): Diagnostic and Statistical Manual of Memal Disorders ed 3 (revised) Washington, DC: APA Press. Can" DB, Sheehan DV, Sunnan OS, et al (1986): Neuroendocrine correlates of lactate-induced anxiety and their response to chronic alprazoiam therapy. Am J Psychiatry 143:483-494. Dater SR, Cowley DS, Dorsa DM, Dunner DL (i 989): Plasma [~-endorphin response to lactate infusion. Biol Psychiatry 25:243-245. Eriksson E, Westberg P, Thuresson K, et al (1989): cerebrospinal fluid of endorphin immunogeactivity in panic disorder. Neuropsychopharmacology 2:225-228. George DT. Comorbidity of alcoholism and panic disorder. Presented at the 142rid Annual Meeting of the American Psychiatric Association, May 6-1i, 1989, San Francisco. Hamilton M (1959): The assessment of anxiety states by rating. Br J Med Psychol 32:50--55. Hong JC, Yoshikawa K, Hedren RW (1984): Measurement of ~-endorphin and enkephalins in biological tissues and fluids. In Conn M (ed), Methods in En,,ymology. Hew York: Academic, pp 547-564. Marks IM, Mathews AM (1976): Brief standard se!frating for phobic patients. Behav Res Ther 17:26326?.
Pickar D, Cohen MR, Naber D, Cohen RM (1982): Clinical studies of the endogenous opioid system. Biol Psychiatry 17:!243-1275. Post gM, Gold P, Rubinow DR, et al (1982): Peptides in the cerebrospinal fluid of neumpsyci~atric patients: an approach to central nervous system stem peptide function. Life Sci 31: ! - 15. Spitzer R, Williams J (1983): Structured Interview for DSM-IH. New York State Psychiatric Institute, N'Y. Veith JL, Anderson J, Slade SA, Thompson P, Law gel GR, Getzlaf S (1984): Plasma [3-endorphin, pain thresholds and anxiety levels across the human menstrual cycle. Physical Behav 32:31-34.
