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Cellular effects of the herbal anxiolytic and antiepileptic drug Aswal
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P.3 Anxiety disorders and anxiolytics
conditions, a high proportion of the cases necessarily received ratings of questionable. This was the group showing sulcal and ventricular sizes intermediate teween those of the normal and the definite pathological groups. The lack of a correlation beween frontal CSF enlargement and duration of illness suggests that these abnormalities are already present at the onset of the disorder and do not progress over the course of the illness, and thus may be considered morphological nulnerability markers. In particular, they are not caused by alcohol or drag dependence, both ogden associated .with anxiety disorders. Furthermore, the patients never met diagnostic driteria for major depression. Because 18 patients had concurrent symptoms of agoraphobia, questions remain as to whether the findings of the present study can be attributed only to panic disorder.
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Prefrontal enlargement of CSF spaces in agoraphobia: a qualitative CT-scan study
C. Wurthmann, J. Gregor, B. Bogerts. Department of Psychiatry and Psychotherapy, Philippusstifl Catholic Hospital, Essen, Germany This CT study was designed to assess brain morphology in agoraphobic patients without a history of panic disorder. The effects of pharmacotherapy on brain morphology were evaluated, too. Internal and external CSF spaces were evaluated by qualitative assessment on a 3-point scale (normal, questionable, abnormal). Twenty-one patients with DSM-IV diagnoses of agoraphobia (4 male, 17 female) and 21 normal control subjects (5 male, 16 female) were studied. The mean age of the patients and normal controls was 38.67 years (S.D. = 13.12 years) and 35.52 years (S.D. = 6.68 years), respectively (p > .05). The mean disease duration was 10.24 years (S.D. = 11.22 years). The mean total score on the Hamilton Anxiety Rating Scale was 19.65 (S.D. = 8.90); on the Hamilton Depression Rating Scale, 12.50 (S.D. = 6.58); on the Fear Questionnaire; 46.95 (S.D. = 14.48); and on the Hopkins Symptom Check List, 1.06 (S.D. = .47). Fourteen patients had never received any psychopharmacological treatment. The other patients had only been intermittently treated with antidepressants (n = 3), benzodiazepines (n = 3), and benzodiazepines, phytopharmaca and antidepressants (n = 1). Patients showed bilateral enlargement of prefrontal CSF spaces (p < .05). The rating "abnormal" was given in the left hemisphere to 6 (28.6%) of the patients, to 4 (19%) of the patients in the right hemis-phere, but to none (0%) of the normal controls. There was no correlation between duration of pharmacological treatment and pathomorphological ratings. The main finding of the present study is that by means of routine clinical assessment a prefrontal CSF enlargement in agoraphobia is obvious. However, these abnormalities were found only in up to 28.8% of the patients. The lack of a correlation between frontal CSF enlargement and duration of illness suggests that these abnormalities are already present at the onset of the disorder and do not represent a progressive reduction of brain morphology with ongoing illness. Furthermore, they cannot be attributed to other current or previous axis I diagnoses associated with alterations in brain morphology. In particular, they are not caused by depression, alcohol or drag dependence, both often comorbid with anxiety disorders. Wurthrnann et al (1997) found in panic disorder a frontal CSF enlargement, too. Yet, most of these patients also met diagnostic criteria for agoraphobia. Therefore, in the light of the present study, the pathomorphological findings of Wurthmaun et al (1997) may be a correlate of the agoraphobic symptoms and not of the panic attacks. The results of the present pilot study suggest that prefrontal CSF enlargement is a biological vulnerability marker in the etiology of agoraphobia. Since the function of the prefrontal cortex can be described in terms such as "planning" or "regulation and integration of behaviour" (Frith and Gmsby 1995) agoraphobic symptoms can be related in part to morphological alterations in this brain region. The main limitation of this qualitative CT scan study is that due to the enormous variability of the size of internal and external CSF spaces under normal and abnormal conditions the rating "questionable" was given in a high proportion of the cases. Therefore the present study should be a stimulus for more precise morphometric brain imaging studies.
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Cellular effects of the herbal anxiolytic and antlepileptlc drug Aswal
H. Grunze I , J. Walden2. 1LMU Department of Psychiatry, NussbaumsO:. 7, 80336 Munich; 2Department of Psychiatry, HauptsO:. 5, 79104 Freiburg, Germany Herbal remedies play an increasing role in modern Western medicine due to their popular demand by patients. Traditional experience and small clinical trials suggest efficacy mostly in minor states of anxiety, depressed mood and sleep disturbances. Besides this, two drugs have also demonstrated anticonvulsant activity, thus making them to obviously potent CNS depressant substances: The kava-pyrone kawain and Aswal, prepared from dried roots of Withania somnifera, a traditional Indian remedy which has recently been released in Switzerland. On the receptor level, both compounds have reasonable GABAergic properties. For kawain, we previously described its effects on ionic membrane fluxes (Walden et al., 1997, Grunze and Walden, 1999). To further evaluate the effects of Aswal on ionic fluxes and neuronal excitation, we performed extracellular and whole cell patch clamp recordings on CA 1 pyramidal neurons of guinea pigs and Long-Evans rats. Standard methods for preparation and composition of the artificial cerebrospinal fluid were employed as described for the kawain experiments. Aswal (100--250 mg/l) was administered systemically, and its effects on the rate of synchronized extracellular field potentials (EFP), membrane parameters, action potentials and postsynaptic potentials were recorded. Results: a. Extracellular Recordings: In the low magnesium model, Aswal (100 mg/1) showed a reduction of the EFP rate of 56% after 30 min of administration. b. Intraeellular Recordings 1. Resting membrane potential, action potential (AP) threshold and input resistance remained unchanged with Aswal in both concentrations tested (100 and 250 mg/1) 2. Repetitive AP firing was elicited by injecting currents from 150450 pA. The effect of Aswal on repetitive firing in response to current injection was heterogeneous. 2/5 cells showed a small reduction, 2/5 an increase of the frequency, and 1/5 was not affected. The AP amplitude remained unchanged in all cells. 3. Recording postsynaptic potential in 5 cells elicited by stratum radiatum stimulation, we saw in 4/5 cells a 38 + 20% reduction of the excitatory postsynaptic potential (EPSP) with Aswal. Discussion: The extracellular results are consistent with calcium antagonistic properties. As a fact, calcium antagonists are effective antiepileptic drugs in vitro and can exert mood stabilizing properties in patients. Thus, calcium antagonism may be an mechanism underlying the action of Aswal. Similar to anticonvulsants with calcium antagonistic features, and to nimodipine, Aswal exerts also antikindling properties in oivo. Intracellular recordings suggest that a direct sodium antagonistic effect as seen in many antiepileptic drugs plays no significant role. However, results in 3) may hint to indirect sodium antagonism through glutamate antagonistic properties and have to be further evaluated. Taken together, the cellular actions of Aswal appears heterogeneous with calcium antagonism playing a prominent role in counteracting excitation. A role of increased intracellular calcium concentration has been implied for such different conditions as epilepsies, mood disorders and anxiety. Thus, Aswal may be a potentially effective drug for these disorders.
References [l] Walden, J. et al.. (1997): Effects of Kawain and Dihydromethysticinonfield potential changes in the hippocampus. Prog Neuro-Psychopharmacol& Biol Psychiat 21, 697-706 [2] Grunze, H. and Walden, 1 (1999): Kawain limits excitation in CA1 pyramidal neurons of rats by modulating ionic currents and attenuating excitatory postsynaptie transmission. Hum PsychopharmacolClin Exp 14, 63~6
P.3 Anxiety disorders and anxiolytics
conditions, a high proportion of the cases necessarily received ratings of questionable. This was the group showing sulcal and ventricular sizes intermediate teween those of the normal and the definite pathological groups. The lack of a correlation beween frontal CSF enlargement and duration of illness suggests that these abnormalities are already present at the onset of the disorder and do not progress over the course of the illness, and thus may be considered morphological nulnerability markers. In particular, they are not caused by alcohol or drag dependence, both ogden associated .with anxiety disorders. Furthermore, the patients never met diagnostic driteria for major depression. Because 18 patients had concurrent symptoms of agoraphobia, questions remain as to whether the findings of the present study can be attributed only to panic disorder.
•
Prefrontal enlargement of CSF spaces in agoraphobia: a qualitative CT-scan study
C. Wurthmann, J. Gregor, B. Bogerts. Department of Psychiatry and Psychotherapy, Philippusstifl Catholic Hospital, Essen, Germany This CT study was designed to assess brain morphology in agoraphobic patients without a history of panic disorder. The effects of pharmacotherapy on brain morphology were evaluated, too. Internal and external CSF spaces were evaluated by qualitative assessment on a 3-point scale (normal, questionable, abnormal). Twenty-one patients with DSM-IV diagnoses of agoraphobia (4 male, 17 female) and 21 normal control subjects (5 male, 16 female) were studied. The mean age of the patients and normal controls was 38.67 years (S.D. = 13.12 years) and 35.52 years (S.D. = 6.68 years), respectively (p > .05). The mean disease duration was 10.24 years (S.D. = 11.22 years). The mean total score on the Hamilton Anxiety Rating Scale was 19.65 (S.D. = 8.90); on the Hamilton Depression Rating Scale, 12.50 (S.D. = 6.58); on the Fear Questionnaire; 46.95 (S.D. = 14.48); and on the Hopkins Symptom Check List, 1.06 (S.D. = .47). Fourteen patients had never received any psychopharmacological treatment. The other patients had only been intermittently treated with antidepressants (n = 3), benzodiazepines (n = 3), and benzodiazepines, phytopharmaca and antidepressants (n = 1). Patients showed bilateral enlargement of prefrontal CSF spaces (p < .05). The rating "abnormal" was given in the left hemisphere to 6 (28.6%) of the patients, to 4 (19%) of the patients in the right hemis-phere, but to none (0%) of the normal controls. There was no correlation between duration of pharmacological treatment and pathomorphological ratings. The main finding of the present study is that by means of routine clinical assessment a prefrontal CSF enlargement in agoraphobia is obvious. However, these abnormalities were found only in up to 28.8% of the patients. The lack of a correlation between frontal CSF enlargement and duration of illness suggests that these abnormalities are already present at the onset of the disorder and do not represent a progressive reduction of brain morphology with ongoing illness. Furthermore, they cannot be attributed to other current or previous axis I diagnoses associated with alterations in brain morphology. In particular, they are not caused by depression, alcohol or drag dependence, both often comorbid with anxiety disorders. Wurthrnann et al (1997) found in panic disorder a frontal CSF enlargement, too. Yet, most of these patients also met diagnostic criteria for agoraphobia. Therefore, in the light of the present study, the pathomorphological findings of Wurthmaun et al (1997) may be a correlate of the agoraphobic symptoms and not of the panic attacks. The results of the present pilot study suggest that prefrontal CSF enlargement is a biological vulnerability marker in the etiology of agoraphobia. Since the function of the prefrontal cortex can be described in terms such as "planning" or "regulation and integration of behaviour" (Frith and Gmsby 1995) agoraphobic symptoms can be related in part to morphological alterations in this brain region. The main limitation of this qualitative CT scan study is that due to the enormous variability of the size of internal and external CSF spaces under normal and abnormal conditions the rating "questionable" was given in a high proportion of the cases. Therefore the present study should be a stimulus for more precise morphometric brain imaging studies.
•
Cellular effects of the herbal anxiolytic and antlepileptlc drug Aswal
H. Grunze I , J. Walden2. 1LMU Department of Psychiatry, NussbaumsO:. 7, 80336 Munich; 2Department of Psychiatry, HauptsO:. 5, 79104 Freiburg, Germany Herbal remedies play an increasing role in modern Western medicine due to their popular demand by patients. Traditional experience and small clinical trials suggest efficacy mostly in minor states of anxiety, depressed mood and sleep disturbances. Besides this, two drugs have also demonstrated anticonvulsant activity, thus making them to obviously potent CNS depressant substances: The kava-pyrone kawain and Aswal, prepared from dried roots of Withania somnifera, a traditional Indian remedy which has recently been released in Switzerland. On the receptor level, both compounds have reasonable GABAergic properties. For kawain, we previously described its effects on ionic membrane fluxes (Walden et al., 1997, Grunze and Walden, 1999). To further evaluate the effects of Aswal on ionic fluxes and neuronal excitation, we performed extracellular and whole cell patch clamp recordings on CA 1 pyramidal neurons of guinea pigs and Long-Evans rats. Standard methods for preparation and composition of the artificial cerebrospinal fluid were employed as described for the kawain experiments. Aswal (100--250 mg/l) was administered systemically, and its effects on the rate of synchronized extracellular field potentials (EFP), membrane parameters, action potentials and postsynaptic potentials were recorded. Results: a. Extracellular Recordings: In the low magnesium model, Aswal (100 mg/1) showed a reduction of the EFP rate of 56% after 30 min of administration. b. Intraeellular Recordings 1. Resting membrane potential, action potential (AP) threshold and input resistance remained unchanged with Aswal in both concentrations tested (100 and 250 mg/1) 2. Repetitive AP firing was elicited by injecting currents from 150450 pA. The effect of Aswal on repetitive firing in response to current injection was heterogeneous. 2/5 cells showed a small reduction, 2/5 an increase of the frequency, and 1/5 was not affected. The AP amplitude remained unchanged in all cells. 3. Recording postsynaptic potential in 5 cells elicited by stratum radiatum stimulation, we saw in 4/5 cells a 38 + 20% reduction of the excitatory postsynaptic potential (EPSP) with Aswal. Discussion: The extracellular results are consistent with calcium antagonistic properties. As a fact, calcium antagonists are effective antiepileptic drugs in vitro and can exert mood stabilizing properties in patients. Thus, calcium antagonism may be an mechanism underlying the action of Aswal. Similar to anticonvulsants with calcium antagonistic features, and to nimodipine, Aswal exerts also antikindling properties in oivo. Intracellular recordings suggest that a direct sodium antagonistic effect as seen in many antiepileptic drugs plays no significant role. However, results in 3) may hint to indirect sodium antagonism through glutamate antagonistic properties and have to be further evaluated. Taken together, the cellular actions of Aswal appears heterogeneous with calcium antagonism playing a prominent role in counteracting excitation. A role of increased intracellular calcium concentration has been implied for such different conditions as epilepsies, mood disorders and anxiety. Thus, Aswal may be a potentially effective drug for these disorders.
References [l] Walden, J. et al.. (1997): Effects of Kawain and Dihydromethysticinonfield potential changes in the hippocampus. Prog Neuro-Psychopharmacol& Biol Psychiat 21, 697-706 [2] Grunze, H. and Walden, 1 (1999): Kawain limits excitation in CA1 pyramidal neurons of rats by modulating ionic currents and attenuating excitatory postsynaptie transmission. Hum PsychopharmacolClin Exp 14, 63~6