http://exhibits.library.stonybrook.edu/mfp/files/original/e014a6afb9c7514b91c71748685499ca.pdf 9f4aefec5e8c130c970f3538c3603299 PDF Text Text ELECTROENCEPHALOGRAPHIC AND BEHAVIORAL EFFECTS OF TOFRANIL Max Fink, M.D. Reprinted from “CANADIAN PSYCHIATRIC ASSOCIATION JOURNAL” Volume 4 Special Supplement, 1959 McGill University Conference on Depression and Allied States, Montreal, March 19-21, 1959 �ELECTROENCEPHALOGRAPHIC AND BEHAVIORAL EFFECTS OF TOFRKNIL MAX FINK* With the rapid increase in the number of potential psychopharmaceuticals, the need for screening technics has become more acute. In studies of the electro— graphic patterns of convulsive therapy, the hypothesis evolved that behavioral changes induced by new compounds could be related to their neurophysiologic effects as reflected by the type and degree of electrographic change (1, 2). This suggestion followed a similar one by Wikler (3) who stated that “regardless of the nature of the drug administered, shifts in the pattern of the electroencephalogram in the direction ofdesynchronization occurred in association with anxiety, hallucina— tions, fantasies, illusions or tremors, and in the direction of synchronization with euphoria, relaxation or drowsiness.” Studies with various psychotropics (4) and anticholinergic hallucinogens (5, 6) supported such a relationship. It is the purpose of this preliminary report to describe initial behavioral and electrographic observa— tions with Tofranil'l, a new psychopharmaceutical, and to relate these observations to the neurophysiologic—adaptive hypothesis of the mode of action of physiodynamic therapies (1). Methods Two types of studies were undertaken in an open—ward, voluntary hospitalized population. In 28 acute experiments, consecutive patients referred for physiodynamic therapies were tested in the EEG laboratory at various stages of treat— ment. Tofranil solution (10 mg/ml) was administered intravenously at a set rate (1 ml/4O sec.) until electrographic or behavioral changes became prominent, for a total of 40—125 mg (0.5—mg/kg). Behavioral observation and electrographic record— ing continued for one to three hours. A second group of 16 patients manifesting depressive, withdrawn or retarded behavior were referred by their therapists for pharmacotherapy. The patients received daily oral Tofranil, 75—250 mg. Behavioral observations and EEG recordings were made prior to and during treatment. Patients ranged in age from 17 to 58, and were diagnosed as suffering from schizophrenia, manic-depressive and involutional depressive psychoses, and psychoneuroses. ' Observations I. dcute Studies: On acute administration, there was an initial restlessness, associated with dizziness, dry mouth, “faintness,” nausea, and on four occasions, vomiting. These symptoms persisted for 10—20 minutes, and were accompanied by lassitude, heaviness of the extremities and eventual drowsiness. Heart rate was un— changed or slowed. Subsequently, subjects were relaxed, quiet and disinclined to activity, even when returned to their ward. The electrographic patterns accompanying these behavioral changes were initiated by a gradual decrease in voltages during the injection. By ten minutes, the per cent time alpha and mean alpha voltage had been halved. In four patients with moderate amounts of beta activity, such activity increased in voltage and low behavioral with association lassitude, time. minutes, By in cent twenty per voltage (to 50 microvolts) random theta frequencies (5-7 cps) appeared (Figures 1 and 2). *Department of Experimental Psychiatry, Hillside Hospital, Glen Oaks, L.I., N.Y. Aided in part by grants M-927 and MY-2092 of the National Institute of Mental Health, National Institutes of Health, U.S. Public Health Service; and by a grant from Geigy Pharmaceuticals. The technical assistance of Mrs. Hannah Mosquera in EEG recording is gratefully acknowledged. ’rTrade Mark. �Special Supplement pre-d rug WWW WWW LF-LO 8167 DEPRESSION AND ALLIED STATES W W after 75 mg after 30 minutes WNW RF-RO wWWv«w¢wanMV‘ I‘VWW LAT-LF RAT-RF k/\_Jl/L,Ah/L JL/\,JA/A,_JL/\, =72 #2638Hh WW W WWW HR after 45 minutes HR 50 Mv|—_l SEC. =74 HR =72 1 Fig. 1 Effect of intravenous Tofrinil on EEG delta (female, aged 46) pre—drug LF-LO «wwNWVHMWwNmN RF-RO WWW LAT-LF W W after 100 mg after 30 minutes hv after 30 minutes “NV“WJWWWWVVV¢ UWMerVkmeV4 WWW WWW RAT-RF LF-RF LPT-LO 0-0 EKG plvltul HR=84 #2138HH W MymMA/VW-WVN MWVWVWMN‘ HR=108 50/.1vl—__J 1 Fig. 2 HR=84 SEC. Effect of intravenous Tofrinil on EEG delta (male, aged 37) HR=9O �8168 Vol. 4, 1959 CANADIAN PSYCHIATRIC ASSOCIATION JOURNAL In six records with post—convulsive delta activity, there was a marked decrease in voltages and per cent time of slow wave activity. These electrographic patterns persisted for half—an-hour to two hours (Figure 3). There was considerable individual variability in the EEG response. In patients who received 100 mg or more of Tofranil, EEG and behavioral changes were Observed in all but three. In six patients, dosage Of Tofranil less than 50 mg were not associated with either EEG or behavioral changes. 2. Chronic fldministmtion Studies: Sixteen patients, manifesting depressive symptoms with varying degrees of insomnia, anorexia, withdrawal, and agitation, have received Tofranil medication for four weeks or longer. Medication was given in oral divided doses of 100—250 mg per day. Behavioral changes generally appeared during the second and were maximal during the third week of treatment. LF-lO after 100 mg pre-drug W W WW W W WWW RF-RO RAT-RF LF-RF . LPT-LO 0-0 #2348 after 30 minutes after 15 minutes iv HR=86 HR=84 ,_~,\_M, amw HR=75 50 uv HR=72 l_ 1 __ SEC. _J Fig. 3 Effect Of Tofranil on EEG delta (female, aged 41: 24 hours post convulsion no. 7) The most prominent behavioral adaptation was euphoric denial, which was noted in eight patients. The depressive attitude was nO longer apparent. They participated more fully in ward activities, complained less of somatic symptoms, and denied, minimized or displaced their illness on inquiry. Agitation decreased, and complaints of insomnia became less. It became increasingly difficult to discuss significant life relationships as the patients pressed for an early discharge from the hospital. In three patients somatization and restlessness increased, and depressive affect persisted. In two of these, restlessness, insomnia and vomiting led to cessation of therapy. Sweating increased in most patients, but became a focus of attention in these subjects. NO change in symptoms were noted in five patients after four weeks of therapy. While no serious complications of therapy were noted, nausea, increased sweating, vomiting, dryness Of the mouth, restlessness and excitement, and increasing �Special Supplement DEPRESSION AND ALLIED STATES $169 insomnia were reported. These were prominent early in therapy, and except for the vomiting and restlessness, did not limit the treatment. In three subjects medica— tion was initially administered parenterally without untoward effects. Abnormal motor patterns and seizures were not noted in these patients at these dosages. Electrographic studies on chronic administration showed minimal changes. Voltages became lower and record modulation became poorer. Well—defined fast activity became more prominent, and in four subjects low-voltage theta (5—7 cps) activity was noted. Discussion These observations indicate that Tofranil is an active central nervous system agent in man, both on oral and intravenous administration. The neurophysiologic effects are manifest electrographically as desynchronization of rhythms and a shift-in frequency spectrum to the slower range. In depressed retarded subjects, Tofrinil administration is associated with such behavioral changes as decreased depressive affect with increased participation in ward activities, increased use of denial patterns (7) and occasional excitement. In comparison to our previous experience with other physiodynamic therapies, the behavioral and electrographic patterns of Tofranil are most like those seen with central anticholinergic agents. We observed desynchronization of frequencies, with an increase in theta activity, to be prominent with experimental anticholinergic compounds such as diethazine and benactyzine* (5, 6). In those studies, electro— graphic desynchronization was associated with behavioral alerting, excitement and illusory and hallucinatory activity. On Tofranil administration, similar electrographic patterns of desynchronization were observed, accompanied by euphoria and increased ward participation. While we have not observed hallucinatory activity at our dosage ranges, Lehmann (it a]. (9) have reported hallucinations and hypomanic excitement in 7 of 84 patients receiving Tofra‘mil. In earlier reports, Wikler (3, 10) suggested that the electrographic patterns of synchronization and desynchronization reflected neuron systems distinct from those neuron systems subserving such functions as ‘sensation,’ ‘ideation’ and ‘level of awareness.’ While these systems were frequently interlocked, dissociation between EEG pattern and behavior was observable under a variety of drug—induced states. In our earlier studies we were impressed that the electrographic and behavioral patterns seen after induced convulsions, anticholinergic compounds and phreno— tropic agents were directly related. On acute administration of Tofranil, however, electrographic desynchronization was associated with clinical sedation. These studies are consistent with Wikler’s suggestion. These observations permit the classification of the neuropharmacologic activity of Tofrinil in the central nervous system as predominantly anticholinergic. However, we have noted aspects of the electrographic and behavioral patterns reminis— cent of increased cholinergic activity. These include the electrographic shift to slower frequencies and sedative, euphoriant behavioral effects. Such observations suggest that there may also be an effective degree of central cholinergic activity. Summary Intravenous administration of Tofranil in 28 voluntary, open—ward psychiatric patients elicited electrographic patterns of desynchronization and an increase of theta rhythms, associated with behavioral alerting, relaxation and lassitude. Chronic administration of oral Tofrinil in 16 depressed and retarded psychiatric subjects elicited behavioral adaptations of euphoric denial in eight, restlessness 'A recent report by Abood and Meduna (8) relates the behavioral. improvement in depressed patients with a new central anticholinergic agent which has Similar electrographic patterns. J B-329, H ” �8170 CANADIAN PSYCHIATRIC ASSOCIATION JOURNAL Vol.4,1959 and somatization in three and no change in five. During the fifth week of adminis— tration, electrographic desynchronization was manifest. It is concluded that Tofranil is an active central nervous system agent, with a Spectrum of activity most like experimental anticholinergic hallucinogens. The theoretic significance for neurophysiologic-behavioral constructs is briefly discussed. Résumé Nous avons étudié la relation existant entre les efiets du Tofrinil sur le com— portement et sur le tracé électrographique, chez des patients atteints de psychoses aigués ou chroniques. Mét/zode Cas aigus: les patients retenus étaient examinés avant le traitement physioin— celui—ci. Tofranil Le de administré était stades divers ainsi en qu’a dynamique, jections intraveineuses d’une solution a 10 mg/ml, jusqu’a un total de 40—125 mg (0,5_2,5 mg/kg), concurremment avec des examens électro—encé—phalographiques. Cas chroniques: des patients présentant de la depression et un ralentissement du comportement étaient mis a la dose de 75—250 mg de Tofrz'mil par jour. Les examens encéphalographiques et du comportement étaient effectués avant le début du traitement, et a intervalles d’une semaine au cours de celui—ci. Observations 1° Cas aigus a) Comportement: au cours de l’administration du medicament, sur 28 cas, nous avons noté des nausées, des vertiges et de la faiblesse. Quatre fois des vomissements sont survenus. Le rythme cardiaque est demeuré inchangé, ou s’est ralenti. En 10 minutes ces symptOmes diminuaient d’intensité et les patients se détendaient. b) Electro-mcéphalogmmme: pendant le traitement, il y a eu une diminution du voltage dans toutes les fréquences. En 10 minutes le pourcentage de temps alpha baissait et les voltages tombaient a la moitié de leurs valeurs initiales. Chez les sujets a activité béta (4 cas), celle—ci devenait plus importante. Au bout de 20 5—7 de lentes ondes des minutes, cps, atteignant 50 microvolts, apparaissaient ici et la. Dans les enregistrements avec activité delta postconvulsive (6 cas) nous avons noté une baisse marquee des voltages et des pourcentages de temps danS l’activité des ondes lentes. Ces tracés électrographiques persistaient pendant M-Z heures. 2° Cas chroniques a) Comporz‘emem: seize sujets ont été observes a ce jour. Les effets~initiaux de la medication furent des nausées, deS vomissements, de l’agitation et de l’excita— tion, une exagération de l’insomnie et une transpiration tres augmentée dont se plaignaient les malades. Le traitement a été interrompu dans deux cas avec agita— tion. Des 13 autres sujets, 6 ont vu leurs symptOmeS de depression S’amender et ont pu reprendre une plus grande activité; ils ont pu étre renvoyés chez euX, ou ont été prévus pour un prochain licenciement. Les autres n’ont guere présenté de chan— a la soumis été n’ont leurs thérapeutique que pendant dans symptOmes, ou gements un temps trop court. &) Electra—encéphdlogmmme: Les enregistrements obtenus pendant 1e traite— ment n’ont montré que peu de modifications. Leur modulation était appauvrie et leurs voltages abaissés. Une activité rapide bien caractérisée a pris de l’impor— 5—7 de a bas activité noté voltage 4 malades chez une cps. nous avons tance; Conclusion: 1° Chez les psychopathes, les effets electrographiques du Tofrinil sont une Ces a tracés has lentes d’ondes activité voltage. suivie une désynchronisation, par a alors ressemblent les traités, et dans chroniques moins cas prédominants sont ceux que l’on Obtient avec la benactyzine. ' �Special Supplement DEPRESSION AND ALLIED STATES 2° En ce qui concerne le comportement, nous constatons une $171 augmentation de la motilité, un changement dans l’humeur et un malade plus éveillé. 3° Ces observations concordent avec les hypotheses neuro—physiologico—adaptatives expliquant 1e mode d’action des traitements physiodynamiques des psychoses. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Fink, M.: Hillside Hosp. J. 6:197, 1957. Fink, M.: Alteration of brain function in therapy, in Kline, N. S.: Psychopharmacology frontiers, Boston, Little, Brown, 1959, pp. 325-333. Wilder, A.: J. Nerv. & Ment. Dis. 120:157, 1954. Fink, M.: EEG and behavioral effects of psychopharmacologic agents. Read at 1st International Congress of Neuro—psycho—pharmacology, Rome, September 1958. In press. Fink, M.: A. M. A. Arch. Neurol. 8: Psychiat. 80:380, 1958. Fink, M.: Electroencephalog. 8t Clin. Neurophysiol. 10:776, 1958. Weinstein, E. A., and Kahn, R. L.: Denial of illness: symbolic and physiological aspects, Springfield, 111., C. C. Thomas, 1955. 'Abood, L. G., and Meduna, L. J.: J. Nerv. & Ment. Dis. 127:546, 1958. Lehmann, H., Cahn, C. H., and de Verteuil, R.: Canad. Psychiat. A. J. 3:155, 1958. Wikler, A.: Proc. Soc. Exper. Biol. & Med. 79:26], 1952. General discussion from the floor (summarized) The question was asked whether administration of a large dose of Tofranil once a day would not be as effective as multiple dosage. This would of course be a tremendous saving in the time of the nurses involved. In answer it was stated that Tofrénil is best given not in one large daily dose but in a series of small doses such as 2 tablets t.i.d. It was also brought out that Tofranil has a tremendous influence on transference phenomena and that these can be analyzed in dreams and symbolisms. While such observa— tions have been made, definitive results must await an extensive study. Another discussant asked what is the difference between the effect of barbiturates and anticholin— ergic drugs on the EEG. One discussant felt that the EEG was a poor tool, since it could be modified in only two ways, synchronization or desynchronization, and firm conclusions should not be drawn from such changes. He therefore felt that analogies between diethazine and Tofrénil were dubious and that nausea was not a specific effect of Tofranil. He wondered if EEG changes would always exist in the absence of nausea, and felt it important to correlate EEG changes with clinical changes. In replying to these comments, Dr. Fink stated that he considered Tofrfinil an anticholinergic drug because of its similarity to other anticholinergic drugs in regard to its EEG patterns. Dr. Fink recalled that Dr. Sigg’s paper had also indicated that Tofrfinil was an anticholinergic drug. Many anticholinergic compounds appear to have rather specific central effects, and some are also experimental hallucinogens. In his experience, barbiturates produce not desynchronization, but rather synchronization. This becomes clear if the factors of dosage and time are considered. Thus the initial effect is hypersynchronization; if the drug is continued, sleep is of course produced and the initial effect disappears. The author replied to the criticism of his use of EEG. He agreed that it is a poor tool in many respects, but that it is possible to analyze EEG records for synchronization, desynchronization and fre uency shifts. One obtains different patterns with different agents even in the same patient. Dr. Fink explained that he was making a long—term study, and hoped that more conclusive data could be offered at a later time. ��’*” EEG uni nahtviernl striat: .2 nu nah, Torranil 3...». * 2h: rulltion hotvtcu thc filcetragrcphie and behaviortl «Itcctt at retranil in velunthry paychintrie pationtt wan datarnincd in taut. and thrsnic ntudioa. _ Kathodnr latto: Ganaaeutiva patiants rcturrod for phytiodynunic thtrupiol ttntod not: prior to and at yariatu itngal Of therapy. With 330 rocordinc, retruail nelution (10 ng/oc) was adminintorud intruvanouuly for I total of h0~125 I; (0.S~2.5 ng/ks). chronic: Pttiontp annitslting duprctuivo tad rotnrdod bchlvior aura plnoud an rogiucua o: 7S~2oe lg renunil daily. EEG oxnniuntionn and hchuyiornl obsothtiaus war. and. prior to and It weekly int-yttla during troutncnt. Oblarvntianus 1. Acute Stadielt a. Buhfiyiora Baring drug zduiniltrutiou in 25 albjoata, 3.13033, EIuIIncoo in! Ionknoan wort rcpcrtud. Viniting ocearrcd an tour oecaaicnc. fictrt rgto was Inshtngod, tr nluvcd. In 1&3 Iinutca, th... aynptoun were 103:, und puticnta war. roluxod. b. EEG: During ndninistrttion thtrc was a dccruuuc in yoltagc a: all trcquonans. By tan minuttu, thc par cant tint alpha ducronsed, lad valtngea were halt at thc initial values. In pationts with sodurnto anonntn of but. uctiyity (h), auch activity hocuno morc yroxincnt. fly taunty mintha, slow It?! nativity of k-7 apt, up to 50 uiarovclta upponrnd, rundouly. In roenrd: with poat~eenvulaiva daltg activity (6), thert in a nurkcd docrotio in voltngcn and in par tent tin. of claw wave nativity. tutu: electraartphic pattcrn: pcraictcd far 2. Chrunia I studioat _Bchnvi¢rn i. rittouu patient: hay. 2 hours.\ boon under ebccrvutiou to data. -Iai -n a van a at nodicntian inaludod nanaou (a) vaulting (a), roatlouuuocn lad axaitantnt (2), insomnin oxaggorntod (35, And aonplainta o: oxacstivo uwiating (11). In tha tun pationtn with roitlsasnoal, nedic;~. tit» at: diaoontinund. a: the thirtaon pntionts, nix Innitcttni In 3110'iatiun or symptoms a: doprnulion with incronnad pnrtiaipation in activitics, Ind hava Bean dilahargad or rccaunoudcd tar diuehnrga. Th: rcaaiuing buy. nhaun littlc engage in a tan. (3) at thcrapy ht! baan patitntl udniniltorud for too thort a ptriod (hgfp 3:. mm: In neat-d. «ht-sin“ during hottmnt, tiniaul change: taro obIcrvoa. fieduiation a: rucordu was poortr with lcwor yoltncct. H011 dutinod rant activity bee... not. proninont; tad in tour subject. 10v waltago 5~7 cps activity VI! noted. conclusion. Ll Sloetrozrtphic extactn o: Totrunil in payehiutriu patiuntc are thus: of duayuehroniantion, tullowod by law voltngo slaw wtva nativity. * Iron thc Duplrtuant at magazinpnttl Payehintry, nilluidc Rhapital, glig ggk" L010 301% �.2th¢to pattorna arc 1.0: proninnnt an chrcnie udntnintrntiau, tad rononblo that. or bnunctynin0¢ 2) Dihtviornl offset: arc that; of alurtiuc, Iced ch¢n¢a and inurilnnd motility. «autistant with fiha nauraphyszolagtau :Athivu hypathuntu at :h: act. at action or physiodyuania thcrupion 3) Thnss abaorvution¢ nae of paychoucu. � Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Published Works Text A resource consisting primarily of words for reading. Examples include books, letters, dissertations, poems, newspapers, articles, archives of mailing lists. Note that facsimiles or images of texts are still of the genre Text. Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. For more information see, http://dublincore.org/documents/dces/. Title A name given to the resource Electroencephalographic and behavioral effects of tofranil. Can Psychiatr Assoc J. 1959;4(Suppl):166-71. Type The nature or genre of the resource Text Identifier An unambiguous reference to the resource within a given context mfp-02-01-003-38a-004 Date A point or period of time associated with an event in the lifecycle of the resource 1959 Creator An entity primarily responsible for making the resource <a title="Fink, Max, 1923-" href="http://id.loc.gov/authorities/names/n79039548" target="_blank">Fink, Max, 1923-</a> Subject The topic of the resource Published Works -- Articles and Reviews Relation A related resource The Max Fink Collection Description An account of the resource Reprint from CANADIAN PSYCHIATRIC ASSOCIATION JOURNAL Volume 4 Special Supplement, 1959 McGill University Conference on Depression and Allied States, Montreal, March 19-21, 1959 Rights Information about rights held in and over the resource <a title="IN COPYRIGHT - EDUCATIONAL USE PERMITTED" href="http://rightsstatements.org/vocab/InC-EDU/1.0/" target="_blank">IN COPYRIGHT - EDUCATIONAL USE PERMITTED</a> Source A related resource from which the described resource is derived Special Collections and University Archives, University Libraries. 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