Meltzer 1979

download Meltzer 1979

of 6

Transcript of Meltzer 1979

  • 8/6/2019 Meltzer 1979

    1/6

    Am J Psychia try 136:12 , December /979

    1550 0002-953X /79/ 13/1550/06/$00.55 1979 American Psychia tric A ssocia tion

    Effect of C lozapine on Human Serum Prolactin Levels

    BY HERBERT Y . MELTZER , M .D ., DAVID J. GOODE, M .D ., PAUL M . SCHYVE, M .D .,M ICHAEL YOUNG , PH .D ., AND VICTOR S. FANG, PH .D .

    The authors determ ined serum prolactin levels in 13patients receiving clozapine, an antipsychotic drugthat does not produce extrapyram idal side effects.Morning serumn prolactin levels, I I hours after the lastdose, itere not elevated during chronic treatment w ithclozapine in any subject despite its therapeutic effects .Serumn prolactin levels ttere moderately increasedbettteen 90 m inutes and 4 hours after adm inistrationofvery high doses oforal clozapine in 4 patients but

    vere smaller than those produced by chlorpromazinein other subjects. The authors suggest that clozapinemay achieve its antipsychotic effect differently than doclassical neuroleptics and that sustained prolactinincreases are not essentialfor antipsychotic action.

    CLOZAPINE, A D IBENZOD IAZEPINE, is a n a ntip sy ch otic

    drug that has attracted great in terest because it m ayact via a mechanism different from that o f classicalneuro leptics. It does not produce extrapyram idal sideeffects in m an ( 1 -3) and its adm inistration m ay not leadto the developm ent of tard ive dysk inesia. In laborato -

    ry anim als, clozapine differs from classical neurolep-tics in its inability or lim ited ability to induce catalepsy

    or block apomorph ine-induced stereotypy (4), both ofwhich are characteristic of classical neuro lep tics andare believed to resu lt from dopam ine receptor b lock-ad e (5). These d ifferences have led various investiga-tors to propose that clozapine may exert its an tipsy-chotic effects by a m eans o ther than dopam ine recep-tor blockade (6-8) and that it m ay represent an

    Received Oct. 23, 1978; revised Jan. 31, 1979; accepted M arch 14,1979.

    D r. M eltzer is Professor of Psych iatry, U niversity of Chicago Pritz-ker School of M edicine, 950 East59th S t., C hicago, Ill. 60637,

    where D r. Fang is A ssociate Professor, Departm ent of M edicine.D r. M eltzer is also Professor of Psychiatry, Illino is S tate PsychiatricInstitute, Chicago, w here D r. Schyve is Associate D irector, Labora-to ry of Biological Psych iatry, an d Dr. Y oung is Research Psycholo-gist. D r. Goode is A ssociate Professor of Psych iatry, Bowman GreySchool of M edicine, W inston-Salem , N .C .

    This research w as supported in part by A lcohol, D rug Abuse, andM ental H ealth Adm inistration gran ts MH-30938an d M H-29206 fromthe National Institute of M ental H ealth. D r. M eltzer is the recipientof Research Scientist Award MH-47808 .

    The authors w ish to thank D r. Justine Petrie of the Rochester StateH ospital, Rochester, M inn., for supplying blood sam ples and clini-cal data from several patients.

    excep tion and thus a challenge to the dopam ine hpothesis o f sch izophren ia (8 ). C lozapine has beenported to disp lace 3H -haloperidol from striatal b ind insites in vitro at concentra tions that appear to be pr

    portional to its an tipsychotic po tency (9, 10). A recestudy ind icated that its ability to displace 3H -spiperonefrom striatal dopam ine recep tors is m uch less thwould be expected on the basis o f its clinical potency(1 1). Thus, there is still con troversy concern ingab ility of clozap ine to block dopam ine recep tors,w hich is believed to be the basis o f the an tipsychoticaction of the neurolep tics.

    The ab ility of neuroleptics to produce b lockadedopam ine receptors leads to augm ented prolactincretion in vivo (12) and in v itro (13), since the releasof prolactin is inh ibited by dopam ine (14). Th is effeof dopam ine is alm ost certainly exerted at the p itu itarlevel (13). The ab ility of neuroleptics to stimulate plactin secretion is proportional to antipsycho tictency in man (15) and in laborato ry rats (16). Thus,useful to consider the ability of clozapine to stim ulateprolactin secretion in relation to its clinical potencyThe m ean (SD ) clinical an tipsychotic dose of clozpine in 8 studies w as 241 162 m g/day (3, 17-23) com -pared w ith a mean of691411 m g/day for chlo rproma-zine in 1 1 stud ies (24). Th is would suggest clozap ineapproxim ately th ree tim es m ore poten t than ch loprom azine as an antipsychotic agen t. The m ean doof clozapine adm in istered in a recen t study was 800(25), which is in general agreem ent w ith our clin icaexperience; one would expect th is dose ofclozap ineincrease prolactin secretion at least as poten tly

    more po ten tly than ch lorprom azine. W e have reporteclozap ine can stimulate secretion of rat pro lactinbut it is on ly about one-half as poten t as chlo rprom a-zine in th is regard.

    W e have previously reported prelim inary evidence

    that clozap ine has little or no effect on human serumprolactin levels (16). W e w ish to report additional dthat indicate clozap ine can produce brief, sm allcreases in serum pro lactin levels in chron ic sch izophrenics. C lozap ine adm inistration has been greatlrestricted because of an unacceptab le incidenceagranulocy tosis (26, 27); therefore, w e have no furthopportun ity for add itional testing of its effectsserum pro lactin levels in m an , but the consistencyour findings indicates our resu lts are likely to be vaa nd g en er aliz ab le .

  • 8/6/2019 Meltzer 1979

    2/6

    Am J Psychia try 136:12, December /979 MELTZER, GOODE, SCHYVE, ET AL

    1551

    METHOD

    The subjects included 6 m ale and 7 fem ale chron icschizophren ic patients (diagnosed w ith the ResearchD iagnostic C riteria, 28) adm itted to the Illinois S tatePsych iatric Institute or the Rochester S tate Hospital.N one had received long-acting neuroleptics fo r at least1 month or short-acting neurolep tics for at least 1 w eekprio r to receiving clozap ine. A ll gave in form ed con-sen t for the drug trial and related endocrine studies.The initial dose ofclozapine was increased from 10 m gb.i.d. up to a maximum of 400 m g b.i.d. The rate ofincrease varied from subject to subject but m aximumdose was usually reached by 4 weeks. Two of the pa-tien ts also received standard neuro leptics fo llow ingthe clozap ine trial. In addition , w e w ill p resent serum

    prolactin levels from other sch izophrenic patien ts whoreceiv ed ch lo rp rom azin e.

    W e w ill p resent tw o types of serum pro lactin data.

    F irst, b lood samples w ere ob tained betw een 8:00 and8:30 a.m . (1 to 2 hours after w aking) at the end of thep lacebo period or during the medication period. Thisw as generally 1 1 hours after the last dose of medica-tion, which was given at 9 :00 a.m . and 9 :00 p .m . Sec-ond , in 4 sub jects, an indwelling catheter w as p laced inan an tecub ital vein at 10:00 p .m ., th ree b lood samplesw ere obtained at 20-m inute intervals, and then oralclozapine or p lacebo was given . Thereafter, bloodsamples w ere ob tained every 30 m inu tes over a 4-hourperiod. Iden tical stud ies w ere carried ou t in 13 patientsreceiv ing various doses of chlo rpromazine.

    Prolactin levels were determ ined by a double anti-

    body rad ioimmunoassay as prev iously described (29).Because of the natu re of the standard used, the levelsw e report are 3.8 tim es those generally found using

    conventional standards. This less pure standard per-m its the detection of relatively small changes in pro-lactin levels. Upper lim it of normal is 60 ng/m l for fe-m ales and 35 ng/m l for males in m orn ing samples. Theinterassay variation is less than 13% .

    C lin ical state w as assessed tw ice during the placeboperiod and weekly thereafter w ith the B rief Psych iatricRating Scale (BPRS) (30) and the C lin ical G lobal Im -pressions (CG I).

    RESULTS1

    The m ean ( SD ) clozap ine dose in our study(458228 mg/m l for fem ales, 5792 16 mg/m l for

    males) w as considerab ly h igher than that u tilized inm ost previous studies (1-3 , 17-23, 25). D espite thehigh dose of clozap ine, serum prolactin levels w ere notsign ifican tly d ifferen t from baseline in the 7 subjectsfor whom morning prolactin levels w ere availab le fromthe placebo period as w ell as during clozapine treat-m ent. For these 7 patients, pretreatm ent prolactin 1ev-

    Tables are available on request from D r. Meltzer.

    els were 59 17 ng/m l, and m ean serum prolactin levelswhile receiv ing clozapine were 5720 ng/m l. P ro lactinlevels during clozap ine treatm ent w ere 4622 ng/m lfor the 6 patien ts for whom no placebo period sam plesw ere availab le. Th is is no t sign ifican tly differen t fromthat of the 7 patien ts for whom pretreatm ent pro lactinlevels w ere availab le. P rolactin levels during p lacebotreatm ent or clozap ine treatm ent, or both, slightly ex-ceeded the upper lim it o f norm al in 4 of the m ale pa-tients and 4 ofthe female patients. W e have previously

    reported slight elevations in serum prolactin levels in

    untreated schizophren ic patien ts and attributed theseto stress effects or lingering increases from nocturnal

    elevation in pro lactin secretion (16).The mean peak serum pro lactin levels for the 6 male

    schizophrenic patients receiv ing I 50-800 m g of cloza-p ine w ere significantly less than those in 13 male sch iz-ophren ic patien ts receiving 800 m g of chlorpromazine:49.323.3 ng/m l versus 8535 ng/m l (t=2. 126, p

  • 8/6/2019 Meltzer 1979

    3/6

    PLACEBO

    FIGURE 1

    Morning Serum Prolactin Levels in a Schizophrenic Man GivenP lacebo and C lozapine

    50

    40

    30

    20o 1

    10 200!

    F 10 15 20 25 30

    DAYS

    FIGURE 2

    Serum Prolactin Levels Following O ral Adm inistra tion of C lozapine ina Schizophrenic W oman Receiving Chronic Clozapinea

    60

    50

    40

    E

    C

    z 30

    0

    -J0

    10

    30 60 90 120 150 180 210 240

    TIME (minutes)

    N ote normal baseline prolactin levels.

    #{149}lozap ine (400 m g p .o .)A Placebo

    00 0CJ

    CLOZAPINE AND PROLACTIN LEVELS Am J Psychiatry /36:12, December 197

    1552

    ment w ith the data from 8:00 a.m . serum prolactin lev-

    els and ind icates that clozap ine d id not produce pro-longed elevations in serum prolactin .

    A ll 4 of the patien ts who received clozapine had anincrease in serum prolactin levels during the 4-hour pe-riod after ingestion of clozapine. The increase began45-90 m inu tes after clozap ine adm inistration and was

    still p resent at 4 hours in all 4 subjects. The peakserum prolactin levels w ith in 4 hours after clozap inetreatm ent w ere sign ifican tly greater than observedbaseline-on-drug serum prolactin levels (pairedt=5 .36 , p< .O l). The tim e course of the serum pro-lactin response in one of these subjects who was ad-m inistered clozapine and placebo is g iven in figure 2.There w as no increase in serum prolactin levels overbaseline-on-drug in th is sub ject when given a p lacebowhereas serum pro lactin levels w ere clearly increased

    follow ing clozapine. Serum prolactin levels in 2 of the

    13 chlorpromazine-treated patients did not increa

    beyond baseline levels in the 4-hour period after chprom azine adm inistration. The m agnitude of the mincrease in serum pro lactin levels in the 4 clozapintreated patien ts w as less than that in 9 of 13 ch lpromazine-treated patients. However, because of

    relatively low baseline-on-drug serum pro lactin lein the clozapine-treated patients , the ra tio of p

    serum pro lactin to baseline-on-drug serum prolacwas higher in 2 of the clozapine patients than in all

    1 of the chlorpromazine-treated patien ts. Thus, clp ine elevates serum prolactin levels in m an , for ata 4-hour period , but the m agnitude of the increaseslight and barely exceeds the 95% upper lim it ofmal.

    A ll of the patien ts who received clozapine improvduring the drug trial period when com pared w ith

    cebo, as evidenced by changes in total BPRS scand CG I. Before treatm ent w ith standard neurolep ticw as initiated, 2 of the patien ts had major exacerbations of psychotic symptoms when clozapine tre

    ment w as stopped.

    DISCUSSION

    Prolactin levels were not significantly different f

    baseline-before-drug in serum sam ples obtainedhours after the last dose in I 3 patients treated chrocally w ith relatively h igh doses ofclozapine. A ll 1tients experienced moderate to m arked therapeutic

    benefit from clozap ine; there is little question thaantipsycho tic dose levels clozap ine differs qual

    tively from the classical antipsychotic drugs in regto effects on pro lactin secretion. The latter p rodupersisten t increases in serum prolactin levels insub jects after a few days of treatm ent (29). W e did

    observe increases in serum pro lactin in the in itialo f treatm ent w ith clozap ine; therefo re, lack of ancrease in serum prolactin levels w as not due to toance.

    W hen we monitored serum pro lactin levels for u4 hours after ingestion of h igh doses of clozapine,found that clozapine had a sligh t and transien t abto stim ulate prolactin secretion. Serum prolactincreased in all 4 subjects. The increases w ere lessthose produced by relatively smaller doses of chpromazine. P lacebo had no effect on prolactin level

    I of the clozapine-treated patien ts and 6 of the chpromazine-treated patien ts.

    The difference between the effects o f clozap inechlorpromazine (and other neurolep tics) on serumlactin is unlikely to be entirely due to decreasedsorp tion or rapid d isappearance of clozapine. Thesorp tion half-life of bo th drugs is sim ilar: clozap ine,m inutes2; ch lorprom azine, 1-2 hours (31). The enation of clozapine is biphasic w ith half-lives of

    2 nvestigators Manual for Leponox Sandoz, Inc., East

    o ve r, N .J .

  • 8/6/2019 Meltzer 1979

    4/6

    Am J Psychiatry 136:12, December /979 MELTZER, GOODE, SCHYVE, ET AL

    1553

    and 38 hours; for ch lorprom azine, elim ination half-lifehas recently been reported as 17.7 hours (31). Becauseof the ex tensive metabo lism of chlorpromazine, thisfigure m ay not reflect the functional half-life of chlo r-promazine. The available data indicate that the lack of

    effect o f clozap ine on serum prolactin levels at 1 1hours after the last dose is probab ly no t solely the re-su lt o f an absence of clozap ine from plasm a. The per-

    sistence of clozap ine for at least 1 1 h ours after the lastdose is suggested by drow siness, hypotension , and se-dation in some sub jects, even though serum pro lactinlevels are no t elevated beyond placebo levels.

    C lozapine appears to be a weaker b locker of p itui-tary dopam ine receptors in man than would be ex-pected on the basis of its antipsycho tic po tency. W ehave found that the IC50 (concentration producing a50% inhibition) fo r clozapine for displacem ent of 3H -sp iroperidol from rat pitu itary m em branes is 132086nm ol com pared to 72.64 .7 nm ol ch lorprom azine (32).For those classical neuro leptics studied to date, the

    ability to stim ulate prolactin secretion in m an or rats iscorrelated w ith an tipsycho tic po tency (15 , 16).

    The capacity of classical neuro leptics to disp lace3H -spiroperidol from calf pituitary dopam ine receptorsin vitro is correlated w ith an tipsycho tic potency (33).C lozap ine is distinctly less poten t in its in vivo effects

    on pro lactin secretion in both rat and m an and in its inv itro effects on 3H -spiroperidol binding than would bepred icted on the basis of its an tipsychotic po tency.There is con troversy concerning its po tency to d is-p lace 3H -sp iroperidol from striatum in relation to itsantipsychotic effect (9 -Il). These apparent quan tita-tive d ifferences betw een clozap ine and classical neuro-lep tics raise the possib ility that clozap ine may achieveits antipsychotic effects via a nondopam inergic m echa-

    nism . However, it is conceivable that clozapine m ightselectively block dopam ine receptors in the hum andopam inerg ic lim bic system . Determ ination of the ab il-ity of clozapine to d isplace classical dopam ine antag-onists from hum an lim bic dopam ine recep tors w ill behelp ful in testing this hypothesis. A nimal studies m di-cate that clozapine can affect dopam ine metabo lism inboth the striatum and lim bic reg ions, bu t results con-flict as to whether clozap ine has a greater effect on lim -bic (34-38) or stria ta l (39, 40) dopam ine metabolism or

    an equal effect in bo th areas (41 , 42). Bartho lini andassociates (43) and W ilk and associates (40) havepo in ted ou t that some effects o f clozapine on rat b rainare briefer than those of classical neuroleptics, possi-b ly because the recep tor blockade produced by cloza-

    pine is of the surm ountable type. This cou ld also be true

    of its effects on the hum an pituitary and account fo rthe brief, sm all pro lactin increases. C lozap ine m ay alsoaffect dopam inerg ic inhib ition of pro lactin secretion bya m echanism other than b lockade of dopam ine recep-to rs, a possibility w e have d iscussed elsewhere (7).

    N air and associates (44) have reported that cloza-pine caused a slight (17% ) but sign ifican t elevation inbasal serum prolactin levels. The sm all m agnitude ofthe d ifference m akes th is finding of questionable relia-

    b ility . M ore importantly, they observed a very markedinhib ition of the apom orphine-induced increase ingrow th hormone in 6 or 7 sub jects treated w ith 200 m gofclozap ine over a 3-day period. These resu lts suggestthat clozapine can b lock the hypothalam ic dopam inereceptors which m ediate th is apomorph ine effect andtogether w ith our data ind icate an im portant differencein the dopam ine recep tors in pitu itary and the hypo-

    thalamus. It w ould be of interest to determ ine whetherclozapine inh ibited the apom orph ine-induced decreasein serum pro lactin levels in m an .

    It is w ell known that a variety of neuro transm itters

    (e.g ., acety lcholine, serotonin , endorph ins, GABA,and possib ly norepmnephrine) can affect p rolactin Se-cretion (45-54) and that ex trap itu itary brain areas m ayparticipate in the regu lation of pro lactin secretion (12,13 , 16). L imbic region stim ulation can prom ote pro-la ctin se cre tio n (55). Clozap ine has clearly been shownto affect cholinerg ic, sero tonergic, and adrenergic neu-rotransm ission (8-12, 56, 57) and to have definite lim -bic effects (34-42). Conceivably, these factors rather

    than dopam inergic receptor b lockade cou ld accountfor the ability of clozap ine to stim ulate pro lactin secre-tion. so this would ind icate a fundamental differencebetw een clozapine and classical neuroleptics and fur-ther support the thesis that clozapine should no t beconsidered just ano ther neuroleptic. W hether a d if-ference in the m echan ism by which prolactin secretionis s timulated also indicates a difference in the means of

    antipsycho tic action rem ains to be determ ined.The proven efficacy ofclozap ine as an an tipsychotic

    agent in the absence of any m ajor effect on prolactinsecretion is additional ev idence that the increase inpro lactin levels produced by neurolep tics has little sig-nificance for their antipsycho tic action. Because of the

    concern that pro lactin elevations m ay increase the riskof mammary carcinom a in wom en at h igh risk for th istumor (e.g., those w ith a strong fam ily histo ry or thosewho have had treatm ent fo r a pro lactin -dependen tm ammary carcinoma) (58), clozapine may be specifi-cally ind icated in the treatm ent of such indiv iduals.This, however, has to be weighed against the greater

    risk ofagranulocytosis from clozapine, which m igh t bea special p rob lem follow ing chem otherapy or radiationfor a pro lactin -dependent carcinoma.

    REFERENCES

    I . Gross H , Langner E: Das w irkungsprofil e ines chernisch

    neuartigen breitbandneuroleptikum s der dibenzodiazepin-

    gruppe. W ien M ed Wochenschr 116:814-816,1966

    2. B erzew ski H , Helmchen H , Hippius H , et a l:Dal klin ische w ir-kungsspektrum eines neuen dibenzdiazepin-derivates. ArzneimF ors ch 1 9:4 96 -4 98 , 1969

    3. Simpson GM , Varga E : C lozapine-a new antipsychotic agent.Current Therapeutic Research 16:679-686, 1974

    4. S tille G , Lauener H , Eichenberg E: The pharm acology of 8-chloro-l l-(4-m ethyl-i-piperazinyl)-5H -dibenzo[b,eJ[l ,4jdiaze-pine) (clozapine). Il Farm aco 26:603-625, 1971

    5. Y ork DH : Am ine receptors in CNS:II. D opamine, in BiogenicAm ine Receptors. Edited by Iversen LE, Iversen SD , Snyder

  • 8/6/2019 Meltzer 1979

    5/6

    CLOZAPINE AND PROLACTIN LEVELS Am J Psychiatry 136:12, December 1979

    1554

    SH . N ew York, Plenum Press, 19756. H yttel J : Effect of neuro leptics on the d isappearance rate of

    (4Cl labelled catecholam ines form ed from [4C1 tyrosine inmouse brain. J Pharm Pharm acol 26:588-596, 1974

    7. M eltzer HY , D aniels S. Fang VS: Clozapine increases rat serumprolactin levels. L ife Sci 17:339-342, 1975

    8. Burki HR. Eichenberger E . Sayers AC, et al: C lozap ine and thedopam ine hypothesis of schizophrenia, a critical appraisa l.

    Pharmakopsychiatr Neuropsychopharm akol 8:115-121, 1975

    9. Burt DR. C reese I, Snyder SH : Properties of [3H ]haloperidoland [H ldopam ine b inding associated w ith dopam ine receptorsin calf brain membranes. M ol Pharmacol 12:800-812, 1976

    10. Seem an P. Lu 1, Chan-W ong M , Wong K : Antipsychotic drugdoses and neuroleptic/dopam ine receptors. N ature 261 :717-7 18,

    1 9 7 6

    II. Leysen HE, Gommeren W , Laduron PM : Spiperone: a ligandof choice for neuro leptic recep tors. I. K inetics and character-istics ofin vitro binding. B iochem Pharmacol 27:307-316, 1978

    12 . Meites J, Clemens J : H ypothalam ic control of prolactin secre-tion . V itam Horm 30:165-221, 1972

    13. M acLeod RM : Regulation ofprolactin secre tion, in Frontiers in

    N euroendocrinology. Edited by M artini L, G anong WF. N ew

    York, Raven Press, 1975

    14. Lu KH, Amenomori Y , Chen CL, et al: Effects ofcentral actingdrugs on serum and pitu itary prolactin levels in ra ts. Endocri-

    nology 87:667-672. 1970

    IS. Langer G . Sachar EJ, G ruen PH , et al: Human prolactin re-

    sponses to neuroleptic drugs correlated w ith antisch izophrenicpotency . N ature 266:639-640, 197716. M eltzer FlY , Goode D i, Fang VS: The effect of psychotropic

    drugs on endocrine function. I. N euroleptics, precursors andagonis ts, in Psychopharm acology: A Generation of P rogress.

    Edited by Lipton MA , D iM ascio A , K illam KF. N ew York,Raven Press, 1978

    17. N ikkanen P. A chte K , Haskari M , et al: Results of a double-

    blind study comparing clozapine and chlorpromazine in the

    treatm ent of sch izophrenia. Psychiatria Fennica 307-313 , 1974

    18. Chouinard G , Annable L: Clozapine in the treatm ent of new lyadm itted schizophrenic patients. A pilot study. J C Iin Pharm a-col 16:289-296. 1976

    19. Gerlach I, K oppelhus P. H elweg E, et al: Clozapine and halo-peridol in a single-blind cross-over tria l: therapeutic and bio-

    chem ical aspects in the trea tment of schizophrenia. Acta P sy-

    chia tr Scand 50:410-424. 1974

    20. Leon CA , Estrada H : Efectos terapeuticos de Ia clozapina sobrelos sin tom as de psicosis. Revis ta Colombiana de Psiquia tna

    3:309-318, 1974

    21 . Battegay R, Cotar B , F leischhauer J, et al: Results and side ef-fects of trea tment w ith clozapine ( L eponex#{174}). Compr Psychia-

    try 18:423-428 , 197122 . Fischer-Cornellsen KA, Ferner V i: An example of European

    multicenter trials: multispectral analysis of clozapine . Psycho-

    p h a rm Bull 12:34-39, 1976

    23. A ckenheil M , Beckmann H , G reil W , et al: Antipsychotic effica-

    cy of clozapine in correlation to changes in catecholam ine me-

    tabolism in man, in The Phenothiazines and Structura lly Re-

    lated D rugs. Edited by Forrest IS , Can Ci, U sdin E. N ew York,

    Raven Press, 1974

    24 . K lein DF, D avis JM : D iagnosis and D rug Treatm ent of Psych i-atric D isorders. Baltim ore, W illiam s & W ilkins,1969

    25 . S impson GM , Lee JH , Shrivastava RK: C lozap ine in tardivedyskinesia. Psychopharm acology 56:75-80 , 1978

    26 . Amster HA , Teerenhovi L , Barth E, et al: A granulocytosis inp at ie nt s t re at ed w it h clozapine. A cta Psychiatr Scand 56:241-248, 1977

    27 . I d#{227}np#{227}#{228}n -He ikki l #{227}, A lhava E, O lkinuora M , et a l: A granu-

    locytosis during treatment w ith clozapine . EurJ C lin P harm acol11:193-198 , 1977

    28 . Sp i t z e r RL , End i c o t t J , Ro b i n s E : Research D iagnostic Criteria(RDC) for a Selected G roup of Functional D isorders, 2nd ed.N ew York, N ew York State Psychiatric Institute, Biom etricsResearch, 1975

    2 9 . Me l t z e r HY, Fang VS: The effect of neuroleptics on serum pro-

    lactin in schizophrenic patients . A rch G en Psychia try 33:279

    286, 1976

    30 . Overall JE , G orham DR: B rief Psych iatric Rating Scale.cho l Rep 10:799-812 , 1962

    31 . W hitfleld LR, Kaul PN , Clark ML: Chlorprom azine m etalism . IX . Pharm acokinetics of chlorprom azine follow ingadm inistration in m an. J Pharm acokinet Biopharm 6:187-11978

    32 . M eltzer HY , So R , M iller RI, et al: Comparison ofthe effect

    substituted benzam ides and standard neuroleptics on the bining of 3H-spiroperidol in the rat pituitary andstriatum w ith invivo effects on ra t prolac tin secre tion. L ife Sd 24:573-584, 19

    33. C reese I, Schneider R, Snyder SH: 3H -Spiroperidol labels do

    mine receptors in pitu itary and brain . Eur I Pharmacol 46:377

    3 81 , 1 97 7

    34. And#{233}n N-E, Stock G : E ffect of clozapine on the turnover

    dopam ine in the corpus striatum and in the lim bic systemPharm Pharm acol 25 :346-348, 1973

    35. Zivkovic B , Guidotti A , Revuelta A , et a l: Effect of th ioridazine,

    clozapine and other antipsychotics on the k inetic state ofs ine hydroxylase and on the turnover ra te of dopamine in str

    turn and nucleus accurnbens. J Pharm acol Exp Ther 194:37-1975

    36. Stawarz R i, H ill H , Robinson SE, et al: O n the significancethe increase in homovanillic acid (HVA ) caused by antipchotic drugs in corpus striatum and lim bic forebrain. Psycpharm acologia (Berl) 43: 125-130, 1975

    37. Bartholini G : D ifferential effect of neuroleptic drugs on dmine turnover in the extrapyram idal and limbic system . J Phar

    Pharm acol 28 :429-433, 197638. Waldrneier PC, M aitre L: On the relevance of preferentia l

    creases of m esolimbic versus striata l dopam ine turnover for

    prediction of antipsychotic activ ity of psychotropic drugsNeurochem 27:587-597 , 1976

    39. W iesel FA , Sedvall G : E ffect of antipsychotic drugs on hom

    vanillic acid levels in s tria tum and olfactory tubercle of the

    Eur J Pharm acol 30:264-267, 197540 . WiIk S, W atson E. S tanley ME: D ifferential sensitivity of

    dopam inergic s tructures in rat bra in to haloperidol and to cloz

    pine. I Pharm acol Exp Ther 195:265-270, 1975

    41. Bartholin i G , K eller HH , Pletscher A : D rug-induced changedopam ine turnover in striatum and lim bicsystem of the rat. IPharm Pharrnacol 27:439-441, 1975

    42. W ilk 5, G lick SD: Dopam ine metabolism in the nucleus accum

    b en s: t he e ff ec t of cl oz ap in e. E ur J P ha rm ac ol 3 7: 20 3- 20 6, 1 97 6

    43. Bartholini G , H aefely W , ialfre M , et al: Effects ofclozapine

    cerebral catecholam inergic neurone system s. Br I Pharm ac46:736-740, 1972

    44. Nair NPV, La l 5, Cervan tes P , et al: Effect of clozapineapomorphine-induced grow th hormone secretion and seru

    prolactin concentration in schizophrenia. Neuropsychobiology

    5 :1 36 -1 42 , 1 97 9

    45. L ibertun C, M cCann SM : Blockade ofthe re lease of gonadotro-pins and prolactin by subcutaneous or in traventricular injectio

    of atrop ine in m ale and fem ale rats. Endocrinology 92:171 72 4, 1 97 3

    46. K am bera IA , M ical RS, Porter JC: Effects of m elatonin aseroton in on the release of FSH and prolactin. Endocrino logy8 8: 12 88 -1 29 3, 1 97 1

    47. Lu K-H , M eites I: Effect ofserotonin precursors and melatonin

    on se ru m pr ol ac t in r el ea se in rats. E ndocrinology 93 :152 -155 ,

    197348. Rivier C, V ale W , Ling N , et al: S tim ulation in vivo of the s

    tion of prolactin and grow th hormone by f3-endorphin. Endonology 100:238-241, 1977

    49. Meltzer HY , M iller Ri, Fessler RG , et al: Effects of enkephaanalogues on prolactin release in the rat. Life Sci 22 : 1931-191978

    50. Rivier C , Vale W : Effect of GABA and histam ine on PRL sec

    tion. Endocrinology 101:506-511, 197751 . Schally AV , ReddingTW , A rirnura A , et al: Iso lation of GA

    from pig hypothalam i and demonstration of its PIF activity

  • 8/6/2019 Meltzer 1979

    6/6

    Am J Psychiatry /36:12, December 1979 MELTZER, GOODE, SCHYVE, ET AL

    1555

    vivo and in vitro . Endocrinology 100:681-691, 1977

    52. S imonovic M , M eltzer HY , Fang VS: The effect of GABA andmuscirno l onplasma prolactin in m ale rats. FedProc 37:555,1978

    53 . Carr LA, Conway PM , Voogt JL: Role of norepinephrine in therelease of pro lactin induced by suckling and lactation. Brain Res133:305-314, 1977

    54 . Meltzer HY , Fessler RG , Fang VS: Effect of p iperoxane on ratplasm a prolactin . Communications in Psychopharm acology2:237-242, 1978

    55 . Lichtensteiger W , K eller P1 : Tubero-infundibular dopam ineneurons and the secretion of luteinizing hormone and prolactin:

    ex trahypothalam ic influences, interaction w ith cholinergictem s and the effect of urethane anesthesia. B rain Res 74:279303, 1974

    56. H aubrich DR . W ang PFL, H erm an RL, et al: A cety lcholines y nt h es i s i n r a t b r a i n: d i ss i mi l ar e f fe ct s o f c l oz a pi n e and chlor-prom azine. L ife Sci 17:739-748 , 1975

    57. Ruch W , Asper H , BU rki HR: Effect of clozapine on the m etao lism of serotonin in rat b rian . Psychopharm acologia (Be46:103-109, 1976

    58. Schyve P. Sm ithline F, M eltzer HY: Neuroleptic-induced pr

    lactin elevation and breast cancer: an emerging clinical issue.

    A rch G en Psychiatry 25:1291-1301, 1978