Brief Report

Cerebrospinal Fluid Monoamine Metabolites and Neuropeptides in Patients with Panic Disorder Ulla Lepola’, Jukka Jolkkonenl, Asla Pitkanen2, Paavo Riekkinen2 and Ranan Rimon3

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Concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol(MH PG) as well as somatostatin (SRIF) and bendorphin @-END)were assayed in the cerebrospinal fluid (CSF) of 34 patients with panic disorder and of ten neurological controls. No aberrations of the monoaminergic or peptidergic variables measured were found in the nonpanic state of patients with panic disorder. A modest correlation (P = 0.04) between total anxiety scores and CSF MHPG was observed.

Key words: CSF; monoamine metabolites; neuropeptides; panic disorder. (Annals of Medicine 22: 237-9,

1990)

Methods

Introduction Several studies have suggested the possibility of an abnormality of the central noradrenergic system in the generation and expression of panic attacks. Stirnulation of the locus coeruleus induces anxiety and fear in animals (1). Pharmacological agents which increase the release of noradrenaline, such as yohimbine, are anxiogenic (2), whereas those which lower the firing rate of noradrenergic neurons, e.g. clonidine, are generally anxiolytic (3). Indirect evidence suggests that patients with panic disorder have abnormalities in their a- and @-receptors(4). A similar relation seems to exist between the serotonergic system and anxiety (5). The efficacy of antidepressants acting “selectively” on serotonin uptake has provided pharmacological evidence of a serotonin dysfunction in patients with panic disorder (6). In addition, results showing reduced serotonin levels in plasma(7), a lower number of platelet binding sites to imipramine (8) and probable postsynaptic hypersensitivity of serotonin receptors (5) have been reported in patients with panic disorder. The aim of the present study was to detect possible abnormalities of monoamine neurotransmission in patients with panic disorder. Somatostatin (SRIF) and pendorphin (p-END) levels in CSF were measured in order to elucidate the role of neuropeptides in this condition. From the Vaajasalo Hospital, Kortejoki, 2Department of Neurology, University of Kuopio, Kuopio, and 3Department of Psychiatry, University of Helsinki, Helsinki, Finland. Address and reprint request: Ulla Lepola, M.D., Vaajasalo Hospital, SF-71130 Kortejoki, Finland. Received September 1, 1989; revision accepted March 5, 1990.

Pa t ien t s Thirty-four inpatients (16 men, 18 women) with panic disorder with or without agoraphobia according to DSM-Ill criteria who had been admitted for diagnostic investigation to Vaajasalo Hospital, Kuopio, Finland, were included in the present study. The mean age of the patients was 39.2 (range 25-51) years. The mean duration of illness before hospital adrnission was 7.0 years (range four months - 30 years), and mean frequency of panic attacks was 20 during three weeks (range two to 73 during three weeks). The patients had no other psychiatric or neurological diseases, but 21 had at some period during their lives been treated with psychotropic agents and seven patients were under such medication when admitted. On admission all psychotropic drugs were stopped, so before their spinal taps all patients had been without psychotropic medication for at least five days (range five days to three years). Six patients were on mild antihypertensive medication (p-blocking agents) which was not stopped during the trial. The control series comprised ten patients (six men, four women, mean age 34.1 years) with peripheral neurological diseases without any etiology of cerebral origin or symptoms of anxiety, depression or other psychiatric diseases. None of the control patients were being treated with psychotropic drugs. Patients gave their signed consent for participation after the purpose and the nature of the study had been explained. The study was approved by the Ethics Committee of Vaajasalo Hospital.

Ann Med 22

Lepola Jolkkonen

238

Pitkanen

Procedure Ten milliliters of lumbar CSF was collected from recumbent subjects at 8-10 a.m. after overnight fasting and at least ten hours of bed rest. The CSF specimens were taken three to five days after hospital admission and 12 hours to three days after the last panic attack. The CSF samples were immediately frozen in liquid nitrogen and stored at -70°C until assayed.

Psychological Rating Scales Hamilton Anxiety Scale (HAM-A) (9) and the Montgomery-Asberg Depression Rating Scale (MADRS) (10) were applied on admission one to two days before the spinal tap.

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Biochemical Measurements Levels of HVA, 5-HIAA, MHPG, SRIF-, and P-END-immunoreactivity in CSF were analysed as previously described (11).

Results CSF concentrations of monoamine metabolites and neuropeptides were similar in patients with panic disorder and the controls (Table 1). Age, sex, duration of illness, frequency of panic attacks, and administration of previous psychotropic or present antihypertensive drugs were not related to the CSF parameters investigated. The mean HAM-A total score of the patients was 22.2 8.0 and the mean MADRS total score was 8.4 f 5.9. Comparisons between the levels of monoamine metabolites and neuropeptides and total scores of anxiety and depression showed only one modestly significant correlation between the levels of CSF MHPG and the HAM-A total score (r = 0.302, P = 0.04). A significant inverse correlation was found between the duration of illness and the MADRS total score (r = 0.404, P = 0.01).

*

Discussion Although CSF monoamine metabolite measures may not be the most valid reflections of central events, our

Table 1. Levels of monoamine metabolites and neuropep tides in the CSF of patients with panic disorder. ~

Group Panic disorder (34) Control patients (10)

Panic disorder (34)

Control Datients (10)

(nmolll)

5-HIAA (nmolll)

218f68 201*73

157*37 49599 137f37 54f11

SRlF (pmolll)

(pmolll)

HVA

63.4 7.4 19.6f 4.7 63.6f 6.9 19.8 f 5.6

Values are expressed as mean

Ann Med 22

*

P-END

f

SD.

MHPG

(nmoill)

Riekkinen

Rimon

results and previous data suggest that noradrenergic hyperactivity is not a prerequisite for panic disorder. Our results, however, do not exclude localised central abnormalities in noradrenaline release which are not reflected in CSF levels, or augmented noradrenaline release during panic attacks. Previous neurochemical studies on central serotonergic and dopaminergic functions in patients with panic disorder are scarce. Augmented hormonal responses to challenge tests point to a possible hypersensitivity of the postsynaptic serotonin receptors (5). Furthermore, anxiety and 5-HIAA in CSF have been shown to be inversely related in depressed patients (12), a finding, however, that was not corroborated by the present study. Previous studies suggest that the reduced level of CSF SRlF reflects cortical loss in patients with Alzheimer’s disease (13). In patients with panic disorder, no abnormalities of cortical functions are reported, but a parahippocampal and brain stem dysfunction is suggested being responsible for panic symptomatology (14). Despite the fact that the control series of this study was small and that instead of healthy volunteers it comprised patients with various neurological diseases, the lack of differences between the groups suggests that major alterations in the neuromodulatory systems involving SRlF and 0-END are not present in panic disorder. The correlation analyses showed only one significant relationship between the total HAM-A anxiety score and CSF MHPG concentration indicating increased noradrenergic tone in association with anxiety. Since a similar correlation has been found in patients with mania and depression, the relationship may be common to psychiatric disorders characterized by anxiety. On the other hand, HAM-A is not specific for anxiety, but measures some depressive symptoms as well.

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1976;116:502-10. 2. Charney DS, Heninger GR, Breier A. Noradrenergic function in panic anxiety: effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry 1984;41: 751-63. 3. KO ON, Elsworth JD, Roth RH, Rifkin BG, Leigh H, Redmond E Jr. Panic-inducedelevation of plasma MHPG levels in phobic-anxiouspatients. Arch Gen Psyhiatry 1983; 40:425-30. 4. Heninger GR, Charney DS, Price LH. Noradrenergic and serotonergic receptor system function in panic disorder and depression. Acta Psychiatr Scand 1988;77 (sugpl341): 138-50. 5. Kahn RS,van Praag HM. A serotonin hypothesis of panic disorder. Hum Psychopharmacol 1988;3: 285-8. 6. Sheehan DV, Zak JP, Miller JA, Fanous BSL. Panic disorder: The potential role of serotonin reuptake inhibitors. J Clin Psychiatry 1988;49: 30-6. 7. SchneiUer P, Evans L, Ross-LeeL, Withshlre B, Eadie M, Kenardy J, Hoey H. Plasma biogenic amine levels in agoraphobia with panic attacks. Pharmacopsychiatry 1987;20: 102-4. 8. Lewis DA, Noyes R Jr, Coryell W, Clancy J. Tritiated irnipramine binding to platelets is decreased in patients with agoraphobia. Psychiatry Res 1985;16: 1-9.

CSF

Neurotransmitters in Panic Disorder

with cerebrospinal fluid 5-hydroxyindoleacetic acid in depressed women. J Neural Transrn 1977; 41: 135-43. 13. Reinikainon K, Riekkinen PJ, Jolkkonen J, Kosma V-M, Soininen H. Decreased somatostatin-like irnrnunoreactivity in cerebral cortex and cerebrospinal fluid in Alzheimer's disease. Brain Res 1987; 402: 103-8. 14. Reiman EM, Raichle ME, Robins E, Mintum MA, Fusselman MJ, Fox PT, Pice JL, Hackman KA. Neuroanatomical correlates of a lactate-induced anxiety attack. Arch Gen Psychiatry 1989; 46: 493-500.

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9. Hamilton MA. The assessment of anxiety states by rating. Br J Med Psycho1 1959; 32: 50-5. 10. Montgomery SA, Asberg M. A new depression rating scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382-9. 11. Lepola U, Jolkkonen J, Rimon R, Riekkinen P. Long-term effects of alprazolam and irniprarnine on cerebrospinal fluid rnonoamine metabolites and neuropeptides in panic disorder. Neuropsychobiology 1989; 21: 182-6. 12. Banki CM. Correlation of anxiety and related symptoms

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Cerebrospinal fluid monoamine metabolites and neuropeptides in patients with panic disorder.

Concentrations of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol (MHPG) as well as somatostatin (SRIF) ...
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