Panic disorder and the respiratory system

Panic disorder

BIOL. PSYCHIATRY 1997;42:15-2975

stresS in animals (Harro at aI., 1993). Therefore, an attempt was done to reveaJ the significance of pre-experimental stress on CCK-induced anxiety In the elevated plus-maze. The male Wistar rats were divided Into four different

groups. Two groups of rats were handled In the experimental room In three

consequent days before the experiment. The other two groups of animals W8f8 broUght to the

experimental room Immediately before the beginning of experiment The handled and non-handled rats were divided into two groups aftet' the Injection of caerulein (5 /Lglkg), an agonist of CCK receptors. One half 01 animals was Isolated after the injection, whereas the other half was plaC8d back Into the home cage. The anxiogenic action of caerulein was the .wngest In rats brought to the experimental room Immediately before the pluIHnaZe exposure and kept Isolated after the injection of CCK agonist. By contrast. caeruleln did not cause any anxiety in the handling habituated and non-Isolated rats. Accordingly, the anxiogenlc action of caerulein was depen• dent on the level of pre-experimental stress In rats. The anxiogenic action of caeruleln In the stressed rats was dose-dependently reversed by L-365. 260 (1-100 ",glkg), an antagonist of CCKs receptors. The present study is in good agreement with the data showing that the administration of antibodies againSt corticotropin releasing factor (CRF) completely reversed the anxio• geniC action of CCK In the elevated plus·maze (Biro et al., 1993). It Is worthy to note that the similar Increase of sensitivity to CCK-induced anxiety has been desCribed In patients suffering from anxiety disorders (Shlik et al., 1997). In the second part of a study the behavioral and neurochemical effects of Iong-tenn treatment with L-365, 260, CCKe receptor antagonist, were studied. L·365, 260 (100 /Lglkg) was ad~inistered twice daily for 14 da¥s. The repeated treatment with L-365, 260 did not change the locomotor actiVity, IlIA reduC8cl the exploratory behavior of rats In the elevated plus-maze. The perfonned neurochemical studies demonstrated that L-365, 260 induced a tuIfiClenl blockade of CCKe receptors in the brain. Namely, the density of CCK receptors was Increased in the frontal cortex and the serum levels of ltlyIOlroPIlin were reduced due to the repeated administration of L-365, 260. (;oIIeCtive~ It is unlikely that CCK is directly involved into the neural networks mediating ~rociety. The anxiogenic effect of CCK is rather mediated via the 0lheI' neurotransmitter systems like CRF, GABA, 5-hydroxytryptamine, noradrenaline and nitriC oxide.

References

(1 J EllrO Eo. $amyal Zo, Penke B. (1993) Role of endogenous corticotropin-releasing fac• W il mediaUon of neuroendocrine and behavioral responses to cholecystokinin 0c• tapePtide IUWate ester In rats. Neuroendocrinology, 57: 340-345. ... oawson G.A., Rupniak N.M.J., Iversen S.D., Curnow R., lye 5., Stanhope K.J. and ~. Trlc;Ideb8Ilk M. D. (1995) Lack of effect of CCKe receptor antagonists in ethologl• C8I and condltJoned animal screens for anxlolylic drugs Psychopharmacology. 121: . 117 . .... 109- J Eo Bradwejn J. (1993) CCK In animal and human research on anXiety. "". HanO PtuI"';'cological Sciences. 14: 244-249. ~~ vasar E., BradweJn J. (1997) Cholecystokinin antagonists: potential role In f4J #Ie Ir88tment of neuropsychiatric disorders. Drugs (in press)

Vasar 'in

@7.g]

Provocative agents in panic disorder

rln Groupe de Recherche "Neuroblologle de l'Anx[ets",

~e~ent de Pharmacologle,

Facults de MBdeclne, 44035, Nantes.

France The neurobiology of panic disorder (PO) has been the SUbject of exhaustive

~ In recent years and new way of research are emerging. The

at provocative agents has greatly helped the understanding of the ~oglcal mechanisms of panic attacks. Som~ of them are specific of urotraOsmission system, other not. The two Widely used agents are • : IaCt8te and carbons dioxide (C02). IOdi ~ Intravenous perfusion of lactate 0.5-1 M Increased PA in 26 1~ per cent of patients presenting with panic disorder. This Is in contrast 10 ~ volunteers, In whom Intravenous sodium lactate Induces panic 10 In only 0 to 30 per cent of cases. It must be noted, however, that an overlap between results obtained from panic disorder patients and thefe ~rOIl1 healthy volunteers. Patients with major depression presenting ~~ paniC attacks have a response to intravenous sodium lactate with Is 'milar to panic disorder patients while patients with major depression ~panic attacks have panic responses similar to normal controls. There to be no difference In response with patients who have occasional ~ttaCkS and those with more persistent attacks. These studies suggest paniC!he panic-inducing response to lactate is related to panic attacks more !hat ic disorder. tJan to ~nhalation of air containing 4-7.5 per cent C02 clearly Induced 2) CO2 In patients with panic disorder, and a single Inhalation of 35 paniC ~ In oxygen Induced panic attacks in patients with panic disorder

attaek:S

per cent 1Ao'~

1975

but not In controls. The percentage of patients and healthy SUbjects that panic with C02 differs according to studies. This could be because different criteria are used to define panic attacks or because of the different methods used to administer the C02. Nevertheless, the result generally Indicate that panic disorder patients are hypertensive to the effects of C02 inhalation. As with lactate, the specificity of the diagnosis of a anxiety Induced by C02 Is contestable in that 64 per cent of women with premenstrual tension and without a previous history of panic can experience panic attack after a single administration of 35 per cent C02 in oxygen. Psychological factors play an important role In those who experience panic Induced by C02. Sanderson and colleagues found that when patients who presented with panic attacks had the Illusion of controlling the quantity of C02 Inhaled they panicked much less than when they did not have this Illusion. The activity of these two products could be explained through an action on respiratory centers inducing a "false suffocation", there Is the Donald Klein's theory. On the other hand, It Is possible to Induce panic attacks with agents stimUlating the noradrenergic system (isoprenaline, yohimbine) or the sero• toninergic system (rn-chlorophenylpiperazine, fenfluramine), It Is now well known that the cholecystokinin tetrapeptide (CCK4) induces panic attacks as well as In PO patients than in healthy volunteers. It is likely that systemic administration of CCK4 produces prominent respiratory and cardiovascular alterations In humans through a direct action on the brain stem. There Is considerable evidence that the brain stem contributes to the control of res• piration, to cardiovascular regulation and to other vital functions. Increase In breathing amplitUde, respiration blood pressure, and heart rate have been noted following electrical and pharmacological stimulation of the nucleus of the tractus solitarious, the medullary nuclei and the parabractial nucleus of the tractus solitarious in modulating cardiorespiratory function. There Is per• haps a final pathway between C02, sodium lactate and CCK4 mechanisms Inducing panic attacks. References [1) Bourin M., Mallnge M., Gullton B. (1995) Provocative agents In panic disorder. Theraple 50, 301-306. [2) Bourin M., Malinge M., Vasar E., Bradwejn J. (1996) Two laces 01 cholecystokinin: anxiety and schizophrenia. Fundam. Clin. Pharmaco/. 10,116-126. [3) Bourin M., Baker G.B., Bradwejn J. (In Press) Neurobiology of panic disorder. J. Psy•

chosom. Res.

167-31 Panic disorder and the respiratory system E.J.L Griez. University of Maastricht, Maaslrlcht, The Netherlands At least two lines of evidence suggest a link between panic disorder and the respiratory system. Panic disorder patients have an Increased childhood prevalence of respiratory disorders while patients with asthma and chronic obstructive pUlmonary disease may have an Increased Incidence of panic, Data from the above evidence will be briefly reviewed and critically examined. Several studies do show that inhaling hypercapnic gasses mixtures elicits sudden and clear symptoms of panic In most patients with Panic Disorder. The so-called 35% CO2 test has been most systematically Investigated on specificity, reliability and sensitiVity. One Vital capacity inhalation of 35% CO2 and 65% 02 mixture immediately Induces a clear feeling of acute anxiety with autonomic symptoms of panic In most patients with Panic Disorder, but falls to affect the anxiety level of healthy controls. The group of PO-patients was compared with a group of OCD-patients and healthy controls. OCD-subjects, in contrast PO-patients, reacted as normals. In another study 28 subjects with simple phobia and 30 normals were challenged with 35% C02, Subjects with animal phobias reacted as healthy controls, while situative phoblcs had C02 Induced anxiety levels similar to PO-patients. These results are in keeping with several data linking situative phobias and agoraphobia. The distinclion between panic and generalized anxiety is supported by GAD-patients failing to be C02 sensitive. We found social phoblcs to be Insensitive to CO2 inhalation although Pema and co-workers have suggested that patients with social phobia may be C02 susceptible. CO2 vulnerability is sensitive to a clinical and successful treatment, whether treated by fluvoxamine, toloxatone, patients with PO proved less sensitive to C02 after clinical improvement. In some PO-patients are hypersensitive to carbon dioxide and it has been shown that there is 86% probability to classify them as suffering from panic on the basis of SUbjective anxiety after a 35% CO2 challenge. Another set of data clearly shows that a sight from a high vulnerability to C02 panic disorder may be linked to a disordered respiratory system. Several studies have suggested an Increased prevalence of PO amongst subjects with chronic obstructive pulmonary decease and asthma. Panic Disorder was also highly prevalent amongst patients reporting for lung

1985

BIOL. PSYCHIATRY 1997;42: I5-ms

function testing. We found a childhood prevalence of respiratory disorders of 40% In a sample of patients with PO, which was about 4 times higher than the rates found amongst subjects with OCO or eating disorders. Comparable results were found by Perna and c:o-workers. In a later. more sophisticated survey we found similar figures. Conclusion: Those who have panic seem to be hypersensitive to carbon dioxide which Is a basic factor In the control of breathing. At the same time there seerns to be a link between a history of disordered breathing and panic disorder. At present some hypotheses have been put forward to account lor a link between panic and resplration, the most elaborated thus far being the false suffocation alarm theory of O. Klein. Although these elaborations remain largely speculative they suggest interesting directions for Mure research.

167-41 Epidemiology of panic disorder F. Roulllon, C. Martineau. Department of Psychiatry Hopltal Louis Mourie" University of Paris VII'78 rue des Renouillers 92 70' Colombes,

France

The review 01 sixteen international community surveys using similar method shows that panic dlsorder, according to OSM III or OSM III·A crtterla, occura In adult with a lifetime prevalence 01 about 2% and a 6 month or one year prevalence 01 about 1%. The range Is small except for ZUAICH (3.1%) or TAIWAN (0.1% to 0.3%). Panic attacks are more commun (a lifetime rate of about 10%) but the agreement between the International studies reviewed Is less good for panic attack than lor panic disorder. The prevalence rates 01 panic dlsorder in non psychiatrlc medical setting are different according to the types 01 seeklng care (about 5% 01 patients who refer to emergency services and 20% 01 patients of ambulatory cardiology units). Finally 5 to 10% 01 psychiatrlc out patients have panic disorder. The mean age 01 onse1 01 panic dlsorder Is from the teens to 30 years. Then. Its course Is not uniform. In 1/3 01 cases, the outcome in unfavourable (chronicity or recurrence, sodaIlmpainnent, poor functioning and bad quality 01 life). Furthermore. panic disorder increases the sulcldaJ rlsk. Panic disorder allect aD soclodernographic groups. But, Its prevalence Is higher lor women. persons under the age of 20 years, divorced or separated people and IMng In urban area. Among the variables related to social class such as education. profession, Income, educational level Is the only one to be associated with panic. ThIs result suggests that cognitive factors may be Involved In the appraisal 01 stressful situation. Ethnic difference In the prevalence 01 panic disorderS seems to be due to socioeconomic status or to the psychological distress 01 immigration. Moreover the comparison of Intematlonal studies are remarkable lor cross cultural similarities In rates of panic disorder. Panic dlsorderllrequently cooccur with comorbid associations. The c:o• morbidity rat.. within anxiety dlsorderS' category II about 25% to 50%. The greatest c:omortIdity rates have been observed between panic dis• order and depressIOn whatever subtypes 01 mood disorders (MOE, BAD, dyshtymia. BP. minor depression...). A common complication of panic disor• der II alcoholism (7 to 54% of panic dIsorder patients are alcohol abusers or dependents). Panic dlsorder can also be associated to other psychiatric disorders on axe I or personality dlsorders (axe II) or somatic diseases. Three areal of research on risk factors 01 panic dlsorder have been developed: familial and genetic aspects, developmental varlables (loss and separation during childhood. ..) and stressful ute events or socloenvlronmen• tal conditions.

167-51 Thel'lpeutlcs of panic disorder J. Bradwejn. O. KoszyckI. Psychobiology and CJJnJcaJ Trials Research Unit In Anxiety, CIarl
Antipsychotic drugs: New approaches

comorbld psychlatrlc disorders. personality traits/disorders and IamiJy and genetic pattems. These patient characterlstica are often considered in ~ ment planning despite the lack of empirlcal data demonstrating thallheN varlables are salient to treatment outcome. Other factors which are known to influence choice 01 treatment include the urgency to alleviate symptoms of panic and restore functioning, &he orientation and training of the treating physician, the side efteel profile 01 specific pharmacologic agents and treatment costs. Patient expectanc:y and desire for specific types of Interventions as well as access to trained c0gni• tive-behaviour therapists can also influence choice 01 treatment. f'hannaco. logical and psychological approaches are frequently prescribed c:oncurT'8nlIy or sequentially despite the absence of firm research evidence justifying 1I'lIS practice. For a high proporlion of patients. panic disorder follows a chronic ClCUM which necessitates long-term treatment For others, It Is time lirMed or episodic. In theory. specific choices of treatment for chronic cases might exist. However. differences among pharmacologic agents and between pharmacologic and psychological approaches in Influencing the COln8 01 the disorder have not yet been elucidated. This presentation will review these topics and propose systematic ep. prosches In the treatment of panic disorder.

68. Antipsychotic drugs: New approaches

168-1 I efficacy? New 8pproaches: New clinical points of view, new J.M. Vanelle. Hopltal Sainte Anne. Paris, France The goals of new antipsychotic drugs In schizophrenia and other psychotic disorders are very similar: Improved antipsychotic efficacy and reduced ~ effects. The results of clozaplne In resistant schizophrenia or the possI:lle action of amisulprlde on negative symptoms show that some neuroIeptica (NLP) could be effective in patients whose symptoms were not ~ by others. So the question can be asked: is there a new efficacy with new NlPs? OUr purpose Is tao analyse the data on these new antipsytholic: drugs: mar,olanzapine. rlsperldone, serlindole, zlprasidone. and zoteplne. Is there a real benefit with earlier onset 01 clinical Improvement, with a reduction of main symptoms of psychosis (positive and negative ~ disorganization, affective symptoms) and In terms 01 quality of Ife? 00 these drugs have special effects on a subject population (e. g. refractory schizophrenic patients. hebephrenic patients. patients with shizoaftec::tlwe disorders)? Is It possible to distinguish a profile of good responders to one or another of these new NLPs? The methodology of clinical trials 01 antipsychotic drugs on patients with psychosis should be reviewed: patient selection. scaJes available. triIlI design, etc. It Is quite evident that the particular interest of a new Nt..P Is better defined through long term studies and clinicaJ experiences.

168-31 Neurobiology of dopamine receptors, neuroleptlca 8nd schizophrenia

canada

Seeman Philip. Pharmacology and Psychiatry Departments, Medical Science BUilding, University of Toronto, Toronto, canada M5S 1AB, Canada

Panic disorder responds favourably to a wide range 01 treatments. Phar• macologic agents. Inctuding trlcycIic antidepressants. selective serotonin re• uptake Inhibitors. monoamine oxidase Inhibitors and benZodlazeplnes, have demonstrated antipanlc activity. Cognltlve-behavioural treatment methods have also emerged u an eftectiV. treatment 01 panic dlsorder. Even though cliniclanl have access to effective pharmacological and psychological ther· aples for panic disorder. the specifICity 01 action of these treatments and their active ingredient are unclear at this point While several consensus• based treatment algorithms have been published In recent years guidelines lor matelling 01 treatment lor Individual patients are still Iacklng. Interlndi• vidual dlllerences exist in panic dlsorder with respect to symptom profile 01 panic, subtype 01 panic attacks. panlc-related agoraphoblc avoidance,

Dopamine pathways may be overactive in schizophrenia and psychosis, because there Is evidence for an increased release 01 dopamine and an overactive dopamine receptor system: 1. Amphetamine given to unmedicated schizophrenia patients releases three times more dopamine than in control subjects, as seen using radioactive Iodobenzamide (lanJelie at aI., 1995). 2. The density of dopamine 01 receptors is down by 10% In schizophrenia patients (L Farde). Because 01 reduces the functional /llgh-&frinlty state 01 02. the low 01 permits an overactive D2. 3. The therapeutic concentrations of antipsychotic drugs In the spinallIuict are Identical to their concentrations which block D2 receptors. This also applies to clozapine.