MODERN
`CLINICAL
`
`
`
` PSYCHIATRY
`
`Eighth Edition
`
`LAWRENCE C. KOLB, M.D.
`
`Professor and Chairman, Department ofPsyc!'u'emy,
`Coliege of Physécéam and Surgeons, Coiumbia University,‘
`Director, New York Slate Psjlckiatric Institute and
`Psyckiairic Smvice, Presbyterian Hospitai qfNe'w Y01'}:
`
`_
`1973
`W. B. SAUNDERS COMPANY — Philadelphia — London — Toronto
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`W. B. Saunders Company: West Washington Square
`Philadelphia. Pa. [9105
`
`I2 Dyott Street
`London. WCIA IDB
`
`835 Oxford Street
`Toronto 18, Ontario
`
`Modern Clinical Psychiatry
`
`ISBN I}-7216-5-£36-X
`
`@ 1973 by W. B. Saunders Company. Copyright 1934. 1939, 1943. 1953. 1958. 1963 and 1968 by
`W. B. Saunders Company. Copyright under
`the International Copyright Union. All
`rights
`reserved. This book is protected by copyright. No part of it may be reproduced. stored in a
`retrieval system, or transmitted in any form or by any means. electronic, mechanical, photo-
`copying, recording, or otherwise. without written permission from the publisher. Made in the
`United States of America. Press of W. B. Saunders Company. Library of Congress Catalog
`card number 72-73957.
`
`PrintNo.: 9
`
`8
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`7
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`6
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`
`Chapter 32
`
`"We must recollect Eliot all O1!-:"I!J1'ortf.1:Eona..i igtgas in
`psychologjr will some tiny be based on on o-.='gam'c substructure.
`This makes it fifflba-bis that special 5-ttbsltmces and special
`chemical processes control the ofierorion. .
`.
`.”
`
`Sigmtmd Freud
`
`Pharmacological Therapy
`
`Following the introduction in 1952 of
`the phenothiazine chlorprornazine as a
`potent new pharmacological agent
`for
`the treatment of the psychoses, numerous
`analogs and other new compounds have
`been synthesized,
`tested, and placed in
`clinical usage. The effectiveness of
`the
`phenothiazine analogs and certain anti-
`depressant agents has altered particularly
`the inanagement of the psychoses. Their
`widespread prescription has
`superseded
`to a large extent
`the various forms of
`shock therapy and the use of psycho-
`surgery.
`
`capacity to
`the
`agents have
`These
`modify affective states without seriously
`impairing cognitive
`functions.
`In the
`latter respect they differ from the sedative
`and hypnotic drugs previously available.
`Since it is expected that the able psychia-
`trist comes to practice Eully knowledgeable
`from his previous medical studies of the
`well-known properties and clinical
`intli~
`cations of the long—known central nervous
`depressants such as
`the narcotics, anes-
`thetics, hypnotics, and intoxicants, as well
`as
`the stimulants, consicleration is not
`
`given to these drugs in this text. Their
`skillful prescription, often in conjunction
`with that of the "neuroleptics," still
`is
`demanded in practice.
`620
`
`PHARMACOLOGICAL
`ACTION AND BRAIN
`FUNCTION
`
`Both neuroleptic and antidepressant
`pharroacologic agents exert complex ac-
`tions upon various neural systems and the
`neuron itself. These actions have been
`
`demonstrated through changes brought
`about
`in animal behavior
`(particularly
`through analysis of
`responses obtained
`under conditions
`imposed by classical
`and instrtnnental conditioning),
`through
`depth
`electroencepl1alograpl1y,
`and
`through
`electrophysiological
`and
`bio-
`chemical studies of synaptic transmission.
`1\/Inch of
`the variation in effect
`pro—
`duced by the differing agents is thought
`to depend upon their differing actions
`at the synaptic junctions within the brain,
`where both cholinergic and nonchol~
`inergic transmission is thought
`to occur.
`It is considered that the passage of a nerve
`impulse
`from activated neurons
`takes
`place across the synaptic junction by dis-
`cliarge into the synaptic cleft of
`the
`stimulating catecholantine. norepineph-
`rine. That substance then activates the
`
`efiector site of the postsynaptic neuron.
`Wlletllel‘ norepinephrine alone "or
`the
`catecholznnine dopamine or the indole-
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`PHARMACOLOGICA L THERAPY
`
`621
`
`in
`participate
`also
`serotonin
`amine
`synaptic transmission is not known. Epi-
`nephrine probably does not, as it exists
`in low concentrations in the brain. In
`
`the neuron norepinephrine exists in two
`forms:
`the labile form, capable of release
`by stimulation or by sympathomimetic
`drugs such as amphetamine. and that
`form Contained in storage granules and
`released by reserpine. Wlien released from
`the interneuronal structure the riorepi-
`nephrine flows into the synaptic cleft and
`then is returned to the cell, where it
`is
`stored or oxi.di_zetl by the enzyme mono-
`amine oxidase. The monoamine oxidase
`
`inhibitors, such as iproniazid, increase the
`amount of intraneuronal norepinephrine,
`making more available. Reserpine depletes
`the intraneuronal amines,
`thus diminish-
`
`ing the amount available for activation.
`Both the phenothiazines and the im-
`inodibenzyls, such as imipramine, clinLin-
`ish cellular permeability. For this reason
`the released noiepinephrine is partially
`prevented from returning to the neuron
`and its concentration in the synaptic cleft
`is prolonged over
`time. But
`the avail-
`ability of the opposite site of the post-
`synaptic cell
`is decreased as well by the
`same pharmacologic agents. The principal
`action of the phenothiazines is to render
`the receptor sites less avilable so that the
`effect of
`the neurotransmitter is dimin-
`
`ished. Iinipramine and its analogs, on the
`other hand, prevent
`the resorption of
`norepinephrine into the activating nerve
`endings anti
`thus increase the action of
`the neurotransmitter. Thus those drugs
`which deplete or inactivate norepineph-
`rine in the brain usually produce seda-
`tive or depressive actions, while those that
`increase or potentiate it commonly bring
`about excitatory behavior and have anti-
`depressant
`effects. Norepinephrine and
`serotonin are found in highest concentra-
`tion in
`the hypothalamus. Dopamine
`exists
`in greatest concentration in the
`caudate and lenticular nucleus.
`
`their major effects
`Such drugs exert
`upon the brain stem and limbic systems,
`the structures of which, as has been noted
`in Chapter 3, are principally concerned
`
`with systems modulating and shaping
`emotional behavior. The phenothiazines
`decrease the excitability of limbic struc-
`tures, while reserpine does the opposite.
`Wliile the iminodibenzyls stimulate lim-
`bic structures,
`the antidepressant 1nono-
`amine oxidase inhibitors do not. The
`
`latter stimulate the 1'eti('.t1lar activating
`system, while the phenothiazines do not.
`The explanations given for the varying
`effects of
`the various neuroleptic agents
`on synaptic transmission and on functions
`of lirnbic or reticular activating systems
`do not entirely explain their impressive
`actions in modifying affect in the major
`psychoses. The effect of each agent rep-
`resents rather a little understood sum_ma-
`
`tion of its actions upon the totality of
`brain systems. What emerges from the
`pharmacological physiology is an appreci-
`ation of the differences of action of the
`
`various series of agents. :1 recognition that
`their functions vary, and therefore that
`the underlying neurohumoral constitu-
`tion of the class of patients in which each
`is effective may well be idiosyncratic for
`that disorder. Constitutional differences
`
`may have origins in genetic differences,
`expressed in subtle variations in produc-
`tion,
`transport, storage, and metabolism
`of neurotransmitters within the brain.
`
`Both the effectiveness and the toxicity of
`drugs may be based as much on such
`variables as on dosage levels,
`routes of
`administration. and absorption.
`
`NEUROLEPTIC AGENTS
`
`The phenothiazine nucleus from which
`the various analogs have been synthesized
`consists of two benzine rings joined by a
`sulfur and nitrogen atom. By alteration
`of R, and R._.
`in the formula, numerous
`derivatives have been developed (see at-
`companying table). From the attachment
`of a dimethylarnmopropyl sicle~chain at R,
`are derived chlorpromazine, promazine,
`and trillupromazine. Substitution of the
`piperazine side-chain in this position leads
`to the development of perphenazine, pro-
`chlorperazine,
`anti Lrilluoperazine. The
`
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`622
`
`PHARMACOLOGIGAL THERAPY
`
`re-
`piperidine side-cliain attached at R,
`sults in thioridazin and rnepazine. Com-
`pounds
`in
`the
`piperazine-substituted
`group are the most potent but also have
`the greatest
`tendency to produce symp-
`toms of extrapyramidal dysfunction.
`The general
`indications for
`the pre-
`scription of the plienothiazine derivations
`are the same as those for chlorpromazine.
`Tliesedrugs differ more in their
`toxic
`properties than in their abilities to modify
`selectively various "target symptoms."
`Pharmacological
`experiments
`in ani-
`mals show that the phenothiazines reduce
`conditioned avoidance responses. They
`do not inhibit escape, nor do they affect
`the response to conditional stimuli as do
`the barbiturates. They impair vigilance
`but not cognitive actions. Seizure thresh-
`old to both electroshock and convulsive
`
`thiazines. The decidual reaction is pro-
`longed by them and lactation is inducetl.
`Infertility occurs. These agents are well
`absorbed from the intestine (50 to 80 per
`cent) and widely distributed in the body
`tissues, where they remain bound for
`prolonged periods (6 to 12 months) after
`administration has ceased. They are me-
`tabolized in the liver through hydrolysis
`and glucuronidization.
`
`ALIPI-IATIC DERIVATIVES
`
`Chlorprornazine Hydrochloride
`
`the
`This is :1 synthetic drug, one of
`series of all-tyl, amine derivatives of phe-
`nothiazine,
`its full chemical name being
`l0-(3-dimethylarninopropyl)-2-ch1orpheno-
`thiazine hydrochloride. It was developed
`in the Rhone-Poulenc Specia Laboratories
`in France during research on potentiating
`agents in anesthesia. The first clinical
`investigations with the drug were carried
`out in that country in 1952. In France, as
`in other European countries,
`it is mar-
`keted under
`the trade name Largactil.
`In the United States it is rnarlceted under
`the trade name of Thorazine.
`
`drugs is unchanged. With large doses only
`there appear slow (5 to 6 per second) low-
`voltage waves
`in the electroencephalo-
`gram. Hypothalamically regulated activi-
`ties are disrupted. Thus thermoregulation
`is impaired, adrenocorticotropic hormone
`(ACTH)
`secretion is diminished,
`and
`growth is diminished. Other endocrine
`effects are reduction in urinary gonada-
`tropins. In_ animals, the estrous cycle and
`Chlorpromazine is a white crystalline
`ovulation are suppressed by the pheno-
`PIlt.".|'I(JH't iazi-nes
`5
`TOTAL ORAL mum: nosace in MG.
`{mvroan ruro 2--1 noses)
`
`DUTPATIENT
`Hoselrat.
`
`,
`Rs
`u.s. 'raaoe NAM!-_‘
`ivnvoa
`RANGE
`
`{Classified by side chain)
`
`Tl1ora.zine
`Spa tine
`Vesprin
`Levoprome
`
`Mellaril
`Pacata]
`
`Aliphatic
`Cllltrrprornazirlr:
`I-‘roma zi ne
`Tiiflupromazine
`Levomepromazine
`Piperidine
`Tllioritiaziiie
`Mepazinc
`Pipcraziiie
`00-80
`40-60
`Tindal
`Acetophenazine
`50-400
`25-100
`Proketaaine
`Carplienazine
`30-150
`15-60
`Compazine
`Proclilorperazine
`30-150
`10-30
`Dartal
`Thiopropazate
`12-54
`8-24
`Trilafon
`Perphena zine
`5-30
`4-1 0
`Stelazine
`Trifluoperazine
`
`Fluphenazine 2-20 Prolixin; Permitil 1-3
`
`
`
`30-400
`75-200
`50-150
`150-300
`
`40-400
`75-200
`
`400-1000
`200-1000
`75-200
`150-300
`
`400-800
`200-500
`
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`P.HARl\»IACOLOG_l CAL THERAPY
`
`623
`
`powder that is readily soluble in water.
`Since only a small part of
`the drug is
`eliminated by the kidneys, most of it is
`presumably metabolized in the
`body,
`although the route is unknown.
`PHYSIOLOGICAL EFFECTS. One of
`
`the
`
`the administration of
`early effects of
`chlorpromazine is a fall in blood pressure
`according to dose and individual reaction.
`Other effects are slowing of the pulse and
`of respiration.
`lowering of
`temperature
`and of basal metabolic rate, and transient
`leukopenia. Also, it frequently causes dry-
`ness of the mucous membranes and nasal
`
`congestion. It has an antiemetic effect as
`well. In large doses, chlorprornazine pro-
`duces motor retardation, muscular hypo-
`tonia, and an unsteady gait. During the
`first
`two or three days of treatment. pa-
`tients show varying degrees of somno-
`lence but can be awakened without dith-
`
`culty and are able to take food. However,
`as a rule,
`the increased need for sleep is
`reduced after a few days. Patients may
`complain of feeling faint, weak, cold, and
`drowsy, but the sensuriurn remains clear.
`The action of the drug is maximal at one
`hour after administration and apprecia-
`ble elfects continue for six hours. It po-
`tentiates the elfects of barbiturates and
`of narcotics.
`
`is
`Chlorprornazine
`ADMINISTRATION.
`available in 10-, 25-, 50-, 100-, and 200-mg.
`tablets, and also in 25-mg.
`(1-ml.) and
`50-mg. (2-ml.) arnpuls. There is no stand-
`ard dose of
`the drug;
`this must be
`individualized. Chlorpromazine may be
`administered by oral or by intramuscular
`routes; however,
`it
`is so irritant that
`it
`should not be administered subcutane-
`
`ously. Intramuscular injections should be
`given deeply in the upper and outer
`quadrant of the buttock, and when in-
`jected
`the
`solution supplied by
`the
`manufacturer
`should be diluted with
`
`physiological salt solution or a 2 per cent
`procaine solution and administered very
`slowly. Massaging the site of the injection
`for
`three or
`four minutes will help to
`reduce local
`irritation. Some physicians
`add hyaluronidase in order to facilitate
`absorption and prevent
`abscess
`forma-
`
`tion. If quick action is desired, the patient
`may receive 25 mg. by deep intramuscular
`injection, and if this amount is not effec-
`tive, an additional 25—mg.
`injection may
`be given within an hour unless contra-
`indicated by marked hypotension. Subse-
`quent
`intramuscular
`dosages may
`be
`increased gradually, even up to 400 mg.
`every six hours. The higher doses should
`be readied over a period of several days.
`If,
`as
`frequently occurs,
`the acutely
`disturbed patient becomes quiet within
`48 hours, oral doses (milligram for milli-
`gram or higher) may gradually replace
`intramuscular
`doses.
`Injections
`should
`not be continued for more than three or
`
`four days without being replaced with
`oral
`therapy. It will not usually be nec-
`essary to increase oral administration to
`more than 800 mg. a day, but if sedation
`is not secured, the dosage may gradually
`be increased up to as much as 1200 mg.
`a day. Usually this amount
`is suflicient
`for
`a maximum dose, although some
`psychiatrists give a maximum of 2000 mg.
`in 24 hours. Amounts up to 4000 mg.
`have been given, but
`large doses cause
`confusion and are not to be recommended.
`
`the patient begins to grow quiet,
`As
`the dose may gradually be reduced over
`a period of weeks or months. If signs of
`returning symptoms appear,
`the amount
`should be
`increased immediately and
`additional parenteral doses
`should be
`given if necessary. Wlien the patient is no
`longer disturbed, the close may usually be
`reduced gradually and then continued
`for an indefinite period, the amount being
`the smallest
`that will control symptoms.
`Usually in the chronically disturbed pa-
`tient
`this will be approximately 600 to
`800 mg. daily. If there has been no im-
`provement in symptoms after the patient
`has received these amounts daily for two
`months,
`the drug should be gradually
`discontinued.
`
`In the less acutely agitated patient,
`treatment may be begun with 50 mg.
`given orally three times
`a day. This
`should be increased gradually until an
`eifective and tolerable level
`is
`reached.
`
`Frequently doses of 100 to 400 mg. daily,
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`624
`
`PHARMACOLOGICAL THERAPY
`
`if continued over a long period, will
`maintain sedation.
`
`The most obvious response to chlor-
`protnazine is somnolence, varying from
`slight drowsiness
`to deep sleep. The
`somnolence is most marlted within 15 to
`
`20 minutes after an injection: however,
`even when the sornnolence is deepest, it
`is possible to rouse the patient. easily. He
`shows
`little or none of
`the
`residual
`
`follows
`that
`clouding of consciousness
`comparable barbiturate sedation. Acutely
`agitated, restless, or excited patients show
`a greater response than. do less disturbed
`patients. The tranquilizing eifect does not
`seem in any way related to the underlying
`nature of
`the excitement: whether it is
`
`schizophrenic, manic, or confusional. If
`the patient responds well to the drug, he
`develops an attitude of indifference both
`to his surroundings and to his symptoms.
`He shows decreased interest
`in and re-
`
`sponse to his hallucinatory experiences
`and a less assertive expression of his
`delusional ideas.
`
`INDICATIONS roe USE. Chlorpromazine
`usually exerts a tranquilizing effect in a
`wide variety of disttubed psychiatric states
`—-tension, psychomotor overactivity, agi-
`tation, impnlsiveness, aggressive outbursts,
`destructiveness, and overtly anxious an-
`tagonistic, Iharanoid reactions.
`It has a. wide field of usefulness
`
`in
`
`scitizo-,tJh1'enitt_. both in acute reactions
`and in overactive chronic reactions. The
`
`more destructive and aggressive the pa-
`tient, the more likely is he to respond to
`chlorprornazine. In the acutely ill. schizo-
`phrenic hallucinations
`and delusional
`ideas frequently disappear within the first
`two weeks of treatment. The longer the
`schizopl11'en_ic patient has been ill, the less
`are his chances of attaining a moderate
`or market] improvement. Of schizophren-
`ics who receive chlorpromazine (or reser-
`pine} relatively early in their illness, more
`are able to leave the hospital and make
`adequate social adjustment than has been
`the case with any previous method of
`treatment. Among them will be many
`who, despite electroconvulsive or insulin
`coma and other forms of treatment, have
`
`psy-
`shown no improvement. Chronic
`chotic patients
`should be
`treated for
`extended periods (six to eight months)
`before the results are assessed. Best results
`
`are secured with patients who have not
`been ill for more than two years. Among
`these the results will depend largely on
`the clinical manifestations of
`the dis-
`
`the degree of improvement being
`order,
`much greater in the overactive, disturbed
`patlents.
`Many patients previously so ill and
`preoccupied with the symptoms of their
`illness that
`they remained indifferent or
`hostile to attempts to alter their behavior,
`thinking, or emotional set become more
`amenable to therapy when taking chlor-
`proroazirle. Although many schizophrenics
`who have been hospitalized for years show
`some improvement, not more than 5 per
`cent of
`those hospitalized for
`five con-
`tinuous years becorne able to leave the
`hospital.
`From 30 to 35 per cent of the chronic
`schizophrenics who have long been hos-
`pitalized will not be materially improved
`by administration of chlorproinazine, yet
`the care of the approximately 60 per cent
`who do improve but are not able to leave
`the hospital
`is greatly eased. Delusions.
`and hallucinations may persist but are
`usually
`no
`longer disturbing
`to
`the
`patient. The sullen, sarcastic, and antago-
`nistic lhatient
`is
`less
`irritable and fre-
`quently becomes quiet, cooperative, and
`accessible, and there is
`a
`remarkable
`improvement
`in disturbed patients. Al-
`though the withdrawn,
`inactive, unre-
`sponsive,
`regressed schizophrenic patient
`does not usually improve sufficiently to
`leave die hospital, he frequently is able
`to modify his behavior, discontinue soil-
`ing, and no longer discard his clothing.
`The relief from the anguish, bitterness,
`hostility, and despair from which many
`patients suifer
`is of
`incalculable value.
`The chronic schizophrenic who improves
`should continue on a carefully deter-
`mined maintenance dose for an extended
`
`‘
`period.
`In tnnn.ic—dep1“essith’: psychosis, Chlor-
`promazine 15 not a substitute for electro-
`
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`
`PHARMACOLOGICAL THERAPY
`
`525
`
`convulsive therapy. but in the early stages
`of the manic phase it is a useful adjunct
`if the patient is overactive and unmanage-
`able and the period required for recovery
`is usually shortened. It is often desirable
`to administer the drug by intramuscular
`injections for two or three days and then
`to continue it by mouth in 50 per cent
`larger doses. If the depressed patient
`is
`agitated, chlorpromazine will usually re-
`lieve, or perhaps more accurately mask,
`the agitation. However, reactive depres-
`sions do not respond particularly well
`to
`chlorprornazine. _
`the
`The usually difficult problem of
`restless or agitated patient suffering from
`senile dementia is often rendered much
`
`easier by the use of chlorpromazine. Se-
`dation by means of the barbiturates may
`confuse him still further. Under chlor-
`
`in amounts of 25 to 50 mg.
`promazine,
`three times a day, he often becomes calm
`and manageable and can be cared for at
`home. Memory loss and disorientation
`are, of course, unaffected.
`
`Chlorpromazine has proved of value
`in treatment of patients with the psy-
`chophysiologic disorders,
`including the
`pruritic dermatides,
`acne,
`rheumatoid
`arthritis, and asthma.
`
`Occasionally, especially in institutions
`for their care, epileptic patients are sub-
`ject to episodic or chronic disturbed states
`in which the patients may be hyperactive,
`noisy, hostile,
`aggressive,
`resistive,
`as-
`saultive, destructive, and given to temper
`outbursts or
`furor states. A parenteral
`injection of 100 mg. of dilorpromazine
`is highly effective in quieting the acute,
`excited states. Most epileptic patients who
`exhibit chronic disturbed states are also
`
`quieted and relaxed by the drug. This
`may at first be given as 300 mg. daily and
`later
`reduced to 150 mg. Since chlor-
`promazine tends to potentiate tl1e activity
`of barbiturates,
`it
`is well
`to reduce the
`
`the latter drug during the ad-
`dose of
`ministration of the former.
`
`In relatively large doses, chlorpron1a-
`zine is extremely helpful in the manage-
`ment of acute alcoholic states. It produces
`prompt control of motor excitement and
`
`of nausea and vomiting, permits restful,
`relaxed sleep, and contributes to the relief
`of tension and anxiety. lts sedative effect
`hastens recovery in delirium tremens. It is
`definitely beneficial
`in nearly all short-
`lived mental disturbances of a delirious
`
`type. The use of chlorpromazine should
`supplement and not replace the admin-
`istration of glucose solution, of insulin,
`and of vitamin B complex. It
`is not, of
`course, of value in the treatment of Kor-
`saltoff's syndrome or in the alleviation of
`chronic alcoholism.
`Uzvrownan EFFI-ICTS. Mention has al-
`
`ready been made of some of the physio-
`logical effects of chlorpromazine. At times
`these side-effects are troublesome, but they
`rarely lead to serious complications. Occa-
`sionally
`the
`sornnolence may become
`excessive and require a
`reduction of
`dosage. Usually. however,
`it disappears
`after the first or second Week of therapy.
`Not infrequently an unpleasant taste and
`a dryness of the mouth and “stuffmess" of
`the nose result in discomfort. Tachycardia,
`palpitation, persistent constipation even
`to the point of fecal impaction, heaclaches.
`pyrexia, and pains in the legs or abdomen
`may occur. A _pale and “pinchecl" facial
`appearance is common in patients receiv-
`ing full intramuscular doses.
`Both
`chlorpromazine
`and reserpine
`cause irypotension of the orthostatic type.
`This may .lead to sensations of faintness
`or to actual fainting, especially on chang-
`ing from a recumbent to a standing posi-
`tion. Both ‘drugs should be given with
`great caution to patients suffering from
`atlierosclerosis, cardiovascular disease, or
`other condi Lions in which a sudden drop
`in blood pressure may be undesirable.
`Skin reactions occur in about 5 per cent
`of patients administered chlorpromazine.
`The urticarial, maculopapular, edema-
`tons, or petechial
`response takes place
`within one to five weeks after initiation of
`
`treatment. Vvlien drug administration is
`stopped,
`the sltin clears and may remain
`clear even if the same treatment
`is
`re-
`
`sumed later. This is regarded as a hyper-
`sensitivity response.
`Photosensitinity confined to areas ex-
`
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`8 of 21
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`Alkermes, Ex. 1056
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`

`
`526
`
`PHARMACOLOGICAL THERAPY
`
`posed to sunlight may be produced by
`chlorpromazine. Usually this will
`result
`merely in redness and itching, but some-
`times it will
`lead to edema and vesicle
`
`formation. Ordinarily interruption of the
`drug,
`the application of bland lotions,
`and the administration of antihistamines
`are sufficient
`treatment of the dermato-
`
`logical reactions.
`Abnormal
`slain -pign1entat:’on., appear-
`ing as a gray-blue discoloration in areas
`exposed to the sun, has developed in some
`patients after prolonged high-dosage ad-
`ministration. Similarl deposits of pseudo-
`melanin have occurred in the cornea and
`
`lens, but only in rare instances have such
`deposits impaired vision. I)-Penicillamine
`given in doses of 0.3 gin. three times daily
`for six days with mineral supplement sub-
`stitution on tl1e last day has been reported
`successful
`in reducing the pigmentation.
`Jttttndicc, usually appearing from the
`second to the eighth week after use of the
`drug was started, develops in approxi-
`mately 4 per cent of
`the cases, and its
`duration is variable. Since there is no
`
`evidence of damage to the hepatic pa-
`renchyrna,
`the jaundice is undoubtedly
`cholestatic in origin. The total bilirubin
`content of
`the blood is greatly ele-
`vated, and the alkaline cholesterol
`is
`
`the percentage of
`much increased, as is
`eosinophils. However, there is little or no
`disturbance of the cephalin flocculation
`and thymol turbidity. The obstruction is
`within the intralobular canaliculi and a
`
`result of a pericanalicular
`infiltration.
`
`lyrnphocytic
`
`If the patient’s mental state is such that
`he can note and report his observations.
`it is well to ask him if there has been any
`change in the color of his urine or stools.
`also if he has been aware of pruritus. As a
`precursory symptom of jaundice,
`this has
`been known to occur within two days
`after the adrninistration of chlorproma-
`zine. Since it is simple and can easily be
`done at
`the bedside as a screening meas-
`ure, some internists advise doing a sodium
`bilirubiuate test
`twice a weelt for three
`
`IE jaun-
`weeks after beginning the drug.
`dice appears,
`the drug should be discon-
`
`tinued and glucose administered intra-
`venously, if indicated. Vitamins should be
`given, and also a liigh-carbohydrate. high-
`protein, and low-fat diet.
`It
`is often
`clifficult
`to determine whether the jaun-
`dice is caused by the drug or by extra-
`hepatic obstruction. Surgery for supposed
`disease of
`the biliary tract should be
`avoided. Liver function tests should prob-
`ably be continued until
`they show that
`normal function has been restored. To
`
`the liver will suffer
`if any.
`what extent,
`the result of
`long-
`harmful effects as
`continued administration of chlorproma-
`zine is as yet unknown. Although the
`jaundice is apparently related not so much
`to dosage as to a special sensitivity on the
`part of the patient, the drug may be re-
`sumed after normal
`function has been
`
`restored. The beginning dosage should
`not exceed 25 mg. given three times a day
`and should be increased slowly thereafter.
`Chlorpromazine depresses the produc-
`tion of
`leukocytes. Agramtlocytosis
`is
`fortunately of
`low incidence. probably
`less than 0.3 per cent, and it occurs within
`three to six weeks after the beginning of
`treatment. It is more frequent in women,
`particularly in those between 40 and 60
`years of age, and its onset
`is sudden.
`Patients should be asked to report at once
`the sudden appearance of sore throat or
`of lesions in the mouth. Any rise in tem-
`perature should also suggest an immediate
`blood count. These cannot be relied upon
`as the sole criterion for agranulocytosis. In
`case blood tlyscrasia develops, clLlorpro-
`mazine should be stopped at once and
`penicillin and the lJ'l’0'd[l-S]3EC[l"|.1[[l anti-
`biotics
`should be given immediately.
`Corticotropin (ACTH)
`is also usually
`employed, and transfusion is often ad-
`visable. In spite of active treatment,
`the
`outcome is often fatal.
`
`Pnrltinsonism appears in about 10 per
`cent of the patients receiving full doses of
`clilorprornazine. The clinical picture is
`the usual one of muscular rigidity, slow-
`ing of movement, festinating gait, sia1or-
`rhea, and at
`times a pill-rolling tremor.
`The condition is always reversible and
`may be relieved with benztropine meth-
`
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`
`9 of 21
`
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`
`

`
`PHARMACOLOGICAL THERAPY
`
`627
`
`1 mg.
`
`twice a
`
`anesulfonate (Cogentin),
`day.
`Other tlysftiiienas which occur during
`the use of chlorpromazine (although much
`more commonly witli
`the piperazine de-
`rivatives) are t11e alcathisias and tlystonias.
`Oral
`dyskinesias,
`sometimes persistent,
`have been noticed to occur
`following
`phenothiazine treatment. Neither
`their
`incidence nor the etiologic role played by
`the drugs in their induction is certain.
`Wlictlier, in the elderly, the occurrence is
`associated with underlying basal ganglia
`brain disorder is unclear. Roxburgh re-
`ports successful control of this complica-
`tion with treatment by thiopropazate
`hydrochloride in 30 to 50 mg. doses daily.
`Improvement occurs within 48 hours of
`administration of the drug. It has been
`suggested that the plienothiazine-induced
`extrapyramitlal reactions are due to some
`genetic determinant.
`A few cases of sudden death in the
`
`course of high—dosage phenothiazine treat-
`ment have been reported. It has been
`proposed that death was caused by ven-
`tricular fibrillation or asphyxia during a
`drug-induced seizure or by food aspiration.
`Suicide attempts have been made with
`the various phenothiazines and die vari-
`ous antidepressants. Nevertheless
`these
`agents are much less toxic than the bar-
`biturates or minor tranquilizers, and few
`of such attempts have been successful.
`With chlorpromazine as much as 30,000
`mg. has been ingested with recovery. Fol-
`lowing these attempts
`the vasopressor
`levarterenol
`is
`indicated. When convul-
`
`sions occur, great care must be taken in
`attempting their control with barbiturates,
`as
`these drugs are potentiated by the
`phenothiazines.
`Phenothiazines may lead to elevation
`of the cerehrospinal fluid proteins. Fur-
`thermore, immunological diagnostic preg-
`nancy tests appear unreliable in women
`receiving chlorpromazine and other phe-
`nothiazines, as they yield a high incidence
`of false-positive results.
`Miosis or blurring of vision is noted at
`times.
`
`Occasionally
`
`nurses who
`
`administer
`
`troublesome
`tlevelop a
`chlorpromazine
`contact dermatitis that clears when fur-
`
`ther exposure is avoitled. The irritant
`qualities of the drug were dramatically
`illustrated in the case of one patient who
`rubbed an eye with a tablet of chlorpro-
`rnazine. An extensive and violent inflam-
`
`matory process resulted in loss of vision.
`DIsooNTINu.-woe.
`It
`is not difficult
`to
`decide when the administration of chlor-
`
`protnazine should be discontinued in the
`case of acute, confusional excitement or
`
`in the case of acute manic episode of
`manic-depressive psychosis. In the former,
`its use may be terminated soon after the
`sensorium becomes fully clear. In the lat-
`ter, the dose may be reduced as the symp-
`toms
`subside, and the drug may be
`discontinued after mood and motor ac-
`
`tivity have been entirely normal for two
`weeks. Experience thus far suggests that
`in chronic schizophrenia the drug should
`be continued indefinitely in optimal indi-
`vidual dosage. Although undesirable side
`effects of the drug usually appear within
`two months after its use is begun. the pa-
`tient who continues on a maintenance
`
`dose after leaving the hospital should re-
`port frequently to a physician.
`after
`Witlidrawal of chlorpromazine
`prolonged administration should be car-
`ried out with deliberation. Sudden with-
`
`drawal, particularly in those patients who
`have been taking simultaneously an anti-
`parlcinsonian agent. may be followed by
`marked restlessness,
`insomnia, perspira-
`tion, and tremor.
`SPECIAL
`THERAPEUTIC
`
`R.EotMENs.
`
`Rapid Tmnqttilization. The immediate
`treatment of
`the acutely psychotic with
`the maximally
`tolerated
`dosages
`of
`phenothiazines is advocated by some to
`facilitate much ego reorganization and
`social adaptation. Such treatment seems to
`be particularly valuable when the patient
`is seriously confused and incapable of
`engaging in a meaningful verbal commu-
`nication with others.
`
`This metllotl of treatment requires the
`quick establishment of a maximal daily
`dosage for each individual. Polalt and
`Laycomb recommend that the patient be
`
`10 of21
`
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`
`10 of 21
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`
`

`
`623
`
`PI-IARMACOLOGICAL THERAPY
`
`given an essential dose of 25 to 50 mg. of
`chlorpromazine orally and be observed
`closely for side effects for one hour.
`11
`none are noticed.
`tl1e drug is prescribed
`in 50 to 200 mg. doses orally every hour
`for six to eight hours, depending upon
`his behavioral state. Wlien the initial dis-
`
`turbed psychotic behavior has diminished
`within the first six hours—including as
`e