//MODERN
`% CLINICAL
`PSYCHIATRY
`
`
`
`TENTH EDITION
`
`‘[982
`
`w. B. SAUNDERS COMPANY
`
`Philadelphia. London, Toronto. Mexico City. Rio de Janeiro, Sydney. Tokyo
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`W. B. Saunders Company: West Washington Square
`Philadelphia, PA 19105
`1 St. Anne’s Road
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`Chiyoda-Ku, Tokyo 102, japan
`
`Library of Congress Cataloging in Publication Data
`
`Kolb. Lawrence Coleman, 1911-
`
`Modern clinical psychiatry.
`
`1. Title. [DNLM: 1. Mental disorders.
`1. Psychiatry.
`WM 100 K801m]
`
`AACR2
`
`RC4S4.K59 1982
`
`616.89
`
`81-40564
`
`ISBN 0-7216-5496-1
`
`Listed here are the latest translated editions of this
`book together with the language of the translation
`and the publisher.
`
`Polish (6:11 Edi£1'oit)—Panst, Zal-clad Wydawn
`LE1-'.al'S1{iC11, Warsaw, Poland
`
`Spanish (8.111. Edi£ion)—La Prensa Medica Mexicana
`Mexico City, Mexico
`
`Portuguese (8111 Edition) —Editora Interamericana Ltda.,
`Rio de janeiro, Brazil
`
`Japanese (81.11 Edition) -1-Iirokawa Publishing Co.
`Tokyo, Japan
`
`Italian (8:11 Ed:'t:'o1z)—Editrice Libraria V. Idelson
`Naples, Itaiy
`
`Modern Clinical Psychiatry
`
`ISBN 0-7216-5496-7
`
`© 1982 by w. B. Saunders Company. Copyright 1934. 1939, 1943, 1953, 1958, 1963, 1968, 1973, and 1977
`by W. B. Saunders Company. Copyright under the Uniform Copyright Convention. Simultaneously pub-
`lished in Canada. All rights reserved. This book is protected by copyright. No part of it maybe reproduced,
`stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying,
`recording, or otherwise, without written permission from the publisher. Made in the United States ofAmerica.
`Press of W. B. Saunders Company. Library of Congress catalog card number 81-40564.
`
`Last digit is the print number:
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`9
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`PHARMACOLOGICAL THERAPY
`
`"We must recollect that all our provisional ideas in psychology will some
`day be based on an organic substructure. This makes it probable that
`special substances and special chemical processes control the opera
`tion. .
`. "
`
`Sigmund Freud
`
`j. P. L. DELAY
`Codiscoverer (with P. Denil-tel‘) of tranquilizing effects of chlor-
`promazine.
`
`{From Kline. N. S.: Psychopharmacology Fmntiers. Boston. Little,
`Brown 8: Company. 1959. And: International Congress of Psy-
`chiatry. 2nd. 1957. Proc. of the Psychopharmacology Symposium.
`p. XIII.)
`
`For the treatment of the most severe
`
`mental disorders, psychotropic drugs
`are the primary therapeutic agents. Cer-
`tain of these drugs are useful in provid-
`ing symptomatic relief in the psycho-
`neuroses and physiological disturbances,
`while others act specifically in relation to
`certain symptoms, or are useful as en-
`hancers for the effects of other drugs.
`The agents now well recognized as
`modifying pathological behavior may
`
`be classified into the neuroleptics, the
`antidepressants, the anxiolytic sedatives,
`the psychostimulants, and the som-
`nifacients. The classification in Table
`32-1 is based on the recommendation
`
`of the Special Committee of the World
`Health Organization.
`The neuroleptics modify psychotic
`behavior in general and have become
`the major therapeutic agents, particu-
`larly in the treatment of the schiz-
`809
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`810
`
`PHAIINIACOLOGICAL THERAPY
`
`TABLE 32-1
`Classification of Psychotropic Drugs Used Therapeutioally
`CETEGO RY
`REPRES ENTATIV E it-[EM B ERS
`
`N eu roleptics
`
`Antidepressants and affective modulators
`
`Anxiolytic sedatives
`
`Psychostimulants
`
`Somnifacients
`
`Plienotliiazi nes
`Butyrophenones
`Thioxantltenes
`Dihydroindolines
`Dibenzoxazepines
`Rauwolfia alkaloids
`
`Monoamine oxidase (MAO) inhibitors
`Tricyclic compou ncls
`Lithium compounds
`
`Clycerols
`Diphenylmethanes
`Benzodiazepines
`
`Amphetamine, methylphenidate. dibenzoxepin
`Caffeine
`'
`
`Barbiturates
`Chloral Hydrate
`Ethchlorvynol
`Fluratepam
`Glutethimide
`Methyprylon
`Methaqualone
`Paralclehyde
`
`(Modified, updated. and expanded from the classification recommended by the Special Committee
`of the World Health Organization, 1967.)
`
`ophrenias. The neuroleptics have the
`capacity to modify affective states with-
`out seriously impairing cognitive func-
`tions. In this respect, they differ from
`the somnifacient drugs. In addition to
`their reaction upon the central nervous
`system in modifying behavior, they af-
`fect the functioning of the extrapyra-
`midal nervous system and the autonom-
`ic system. Generally, they act by block-
`ing dopamine receptors in the brain. In-
`cluded in the group are the phenothia-
`zines, the butyrophenones, the dihydro-
`indolines,
`the dibenzoxazepines. and
`the rauwolfia alkaloids.
`
`are complex
`The antidepressants
`agents, with pharmacological effects in
`particular on the biogenic amines nor-
`epinephrine and serotonin. They in-
`clude the tricyclic compounds and the
`liyciroxide and nonhydroxide 1nono-
`amine oxidase inhibitors.
`
`The cerebral stimulants include the
`
`clextroamphetamines and methylpheni-
`date. These agents tend to produce a
`transient increase in psychomotor activ-
`ity. They must be considered as stimu-
`lants and are not effectively antidepres-
`sant. However, they enhance the activity
`of certain of the antidepressants.
`The anxiolytic agents are sedative
`hypnotics that generally depress brain
`function. Pharmacologically,
`they do
`not affect the extrapyramidal or the au-
`tonomic nervous systems, as do the
`neuroleptics. Benzodiazepines are the
`most
`frequently prescribed drugs in
`this class. These drugs are more fre-
`quently prescribed than any other in
`America. Although they were thought
`to
`exert
`their psychotropic
`effects
`through action on the GABA or glycine
`neurotransmitter systems, it has recent-
`ly been shown that human brain con-
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`PHARMACO LOGICAL THERAPY
`
`311
`
`for benzodiazepines.
`receptors
`tains
`the possibilities exist that these
`Thus,
`drugs act by direct stimulation of re-
`ceptors, and that the brain may synthe-
`size compounds quite similar
`to the
`benzodiazepines.
`Individuals receiving these agents de-
`velop a tolerance and may become habi-
`tuated or addicted or both. Because of
`
`the possibility of addiction, they have
`been classified in many countries as
`controlled substances.
`The somnifacients include the well-
`
`chlorohydrate,
`barbiturates,
`known
`ethchlorvynol, glutethimide, methypry—
`lon, methaqualone, and flurazeparn.
`Pharmacological effects are generally of
`shorter duration and are more intense
`
`than those of the anxiolytic drugs.
`The anticholinergic agents are signif-
`icant as they are effective in the treat-
`ment of drug-induced parkinsonism, so
`common
`in
`administration of
`the
`
`neuroleptics.
`Since it is expected that the able psy-
`chiatrist comes to practice fully knowl-
`edgeable from previous medical studies
`of the well-known properties of and
`clinical
`indications
`for using central
`nervous system depressants such as the
`narcotics, anesthetics, hypnotics, and
`intoxicants, as well as the stimulants,
`consideration is not given to these drugs
`in this text. Their skillful prescription,
`often in conjunction with that of the
`neuroleptics,
`is demanded in practice.
`
`PHARMACOLOGICAL ACTION
`AND BRAIN FUNCTION
`
`The active psychotropic drugs exert
`complex actions upon various neural
`systems and the neuron itself. These
`actions
`have
`been
`demonstrated
`through changes brought about in ani-
`mal
`behavior
`(particularly
`through
`analysis of responses obtained by clas-
`sical and instrumental conditioning).
`through
`depth
`electroencephalog-
`raphy,
`through
`electrophysiological
`and biochemical
`studies of synaptic
`
`transmission, and through studies of
`drug metabolism within bodily tissues
`and changes in endocrine functions.
`It is well known now that the psycho-
`tropic drugs have a long half-life in
`bodily fluids. The drugs and their ine-
`tabolites accumulate in bodily tissues as
`administration is continued over time.
`This accumulation ceases when the sat-
`uration level is achieved. With cessation
`
`of administration, the tissues slowly re-
`lease the accumulated drugs. Thus,
`traces may be found in the urine for
`two or three months after discontin-
`
`psychopharmacoiogical
`The
`uance.
`properties are generally manifest days
`to weeks later than the early effects on
`the other segments of the central ner-
`vous system. Thus, the side effects fre-
`quently precede the therapeutic re-
`sponse. These well-recognized pharma-
`codynamic properties are most
`im-
`portant, particularly in relation to the
`modes of
`administration,
`prescrip-
`tion, and assessment of therapeutic re-
`sponse, as will be described.
`Much of the variation in effect pro-
`duced by
`the
`differing
`agents
`is
`thought to depend upon their differing
`actions at the synapticjunctions within
`the brain. It is considered that the pas-
`sage of a nerve impulse from activated
`neurons takes place across the synaptic
`junction by discharge into the synaptic
`cleft of the neurotransmitters. These
`
`substances then activate the receptors of
`the postsynaptic neuron.
`In Chapter 3 (The Brain and Behav-
`ior) and Chapter 18 (Schizophrenic Dis-
`orders),
`respectively,
`the
`synaptic
`action of the various biogenic amines
`and the “dopamine hypothesis" as
`it
`relates to schizophrenia were described.
`Norepinephrine, dopamine, the indole-
`amine
`serotonin,
`gamma—aminobu-
`tyric acid or acetylcholine are differen-
`tially disposed through the brain stem.
`Certain pathways have been identified
`as principally containing and thereby ac-
`tivated by dopamine and noradrenaline
`(Fig. 32-1).
`As the storage, release, action, and
`
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`812
`
`PH ARMACOLOGICAL THERAPY
`
`NOFIADFIENALINE
`
`DOPAMINE
`
`
`
`n accumbens
`
`tub olfactorium
`
`n caudatus
`
`n arnygdaloid
`centralis
`
`cingulum
`
`stria term.
`
`hYD0ihai-
`
`amygdala
`
`dorsal
`bundle
`
`median
`eminence
`
`substantia
`nigra
`
`
`
`centralis
`
`Figure 32-1
`Horizontal projection of the ascending NA and DA pathways.
`A1 and A2, cells in medulla oblongata; A4. cells sending axons to locus ceruleus;
`A5 and A7. cells in pens; A6. cells in locus ceruleus; AB. cell bodies caudal to
`substantia nigra; A9 and A10. cells in substantia nigra: A12. cells in N. arcuatus.
`(From Ungerstedt. U.: Stereotaxic mapping of the monoamine pathways in the
`rat brain. Acla Physiol. Scand. (Supp|.)367:1-43. 1971,}
`
`later re-uptake of the biogenic amines,
`believed significant particularly in the
`afiective disorders, are now well worked
`out, certain of the psychotropic drugs
`have been shown to affect these proc-
`esses. For example, the catecholamines
`exist in the neuron in two forms: the
`
`labile form, capable of release by stimu-
`lation or by sympathomimetic drugs
`such as amphetamine, and that form
`contained in storage granules and re-
`leased by reserpine. When released from
`the inter-neuronal structure, catechol-
`amines flow into the synaptic cleft and
`then are returned to the cell, where they
`are stored or oxidized by the enzyme
`monoamine oxidase. The monoamine
`
`oxidase inhibitors, such as iproniazid,
`-increase the amount of intraneuronal
`
`biogenic amines, making more available.
`Reserpine depletes the intraneuronal
`amines,
`thus diminishing the amount
`available for activation.
`
`The tricyclic antidepressants decrease
`the re-uptake of serotonin and nor-
`epinephrine. For
`this
`reason,
`these
`neurotransmitters are partially pre-
`vented from returning to the neuron
`and their concentration in the synaptic
`cleft is prolonged over time.
`The principal action of the pheno-
`thiazines is to render the receptor sites
`for dopamine less available so that the
`effect of the neurotransmitter is dimin-
`
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`PHAR WACOLOGICAL T1-{ERAPY
`
`813
`
`ished. Thus those drugs that deplete or
`inactivate biogenic amines in the brain
`usually produce sedative or depressive
`actions, while those that _ increase or
`potentiate it commonly bring about ex-
`citatory behavior and have antidepres-
`sant effects. Norepinephrine and sero-
`tonin are found in highest concentration
`in the hypothalamus. Dopamine exists
`in greatest concentration in the caudate
`and lenticular nucleus.
`
`Most psychotropic drugs exert their
`major effects upon the brain stern 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 explanations given for the effects
`of the various neuroleptic agents on
`synaptic transmission and on functions
`of limbic or reticular activating systems
`and other organ systems do not entirely
`explain their impressive actions in mod-
`ifying affect
`in the major psychoses.
`What emerges from the pharmacologi-
`cal physiology is an appreciation of the
`differences of action of the various
`
`series of agents, and a recognition that
`their functions vary. The underlying
`neurohumoral constitution of the class
`
`of patients in which each is effective
`may well be idiosyncratic for that dis-
`order. Constitutional differences may
`have origins in genetic differences, ex-
`pressed 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 sttch
`variables as on dosage levels, routes of
`administration, and absorption.
`
`Administration
`
`There now exists a wide range of
`drugs in the various categories of the
`classification described in Table 32-1.
`
`Table 32-2 lists those presently avail-
`able in the U.S.A., and gives the ge-
`neric name,
`the brand name, and the
`recommended range of daily dosage.
`
`The selection of the appropriate drug
`depends upon the nature of the psy-
`chopathology observed in the indivi-
`dual patient. In general, neuroleptics
`will be used in the treatment of schiz-
`
`conditions
`psychotic
`and
`ophrenia
`other than the affective. The antide-
`
`pressant agents will be used for the af-
`fective psychoses, while the anxiolytics
`are indicated for symptomatic relief in
`the neuroses, psychophysiological reac-
`tions, certain personality disorders, and
`some special symptoms.
`It is recommended that the psychia-
`trist'become experienced in the use ofa
`single agent or two in each class and
`generally
`prescribe
`such agents
`in
`practice. The administration of more
`than one agent in a class to a patient
`(polypharmacy) is to be avoided. There
`are both synergic and anergic antagon-
`istic effects when prescribing across ca-
`tegories. These must be fully under-
`stood and will be described later in this
`chapter. The value of having available
`the large number of analogues in the
`various classes is the potential of vary-
`ing the medication as the patient
`is
`found unresponsive to one or another
`in a series. In other words, the treat-
`
`ment may be varied to fit the pecuiiar
`metabolic constitution of the individual.
`As with other pharmacologcal treat-
`ment, the physician will consider in de-
`termining the dosage the individual’s
`body weight, age, sex, and type and se-
`verity of illness. The dosage and type
`of drug will be varied, depending upon
`the individual’s tolerance or resistance.
`As with other agents, the dosage should
`be prescribed within the ranges recom-
`mended in the provider's descriptive
`package insert, except where there are
`clear clinical
`indications otherwise. In
`
`keeping with the known pharmacologi-
`cal properties of
`these drugs—their
`iong half—life in serum and their ten-
`dency to accumulate in tissues—-admin-
`istration is unnecessary more than once
`or twice a day. Generally, since in most
`of
`the psychopatliological conditions
`sleep is affected, and also as a means of
`
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`
`814
`
`PI-I AR MACOLOGICAL _Tl-[ERA PY
`
`TABLE 32-2 Classification of Psychotherapeutic Agents and Daily Dosage Range
`
`GENERIC NAME
`
`BRAND NAME
`
`DAILY DOSE
`
`CHLORPROMAZINE
`MG. EQUIVALENT
`
`30-1000 mg.
`40-1000
`20-200
`150-300
`
`100 (Standard)
`200
`25
`
`NEU ROLEPTICS
`PHENOTHIAZINES
`Alipliafic
`Thorazine, Sonazine
`Sparine
`Vesprin
`Levoprome
`
`Pi-,berid1'ne
`
`Quide
`Serentil
`Meilaril
`_
`Tindal
`
`Piperazine
`
`Repoise
`Pmketazine
`P1'Oli)Lil'l,
`Permitil
`Trilafon
`Compazine
`Darnal
`Stelaziue
`MISCELLANEOUS
`Thfoxarttlzerles
`
`Taractan
`Navane
`
`-
`
`I-Ialdo]
`
`Mohan
`
`Bargwapfxenmze
`
`Dihydraéndofine
`
`Dibenzaxazepirte
`
`20-160
`25-400
`50-300
`
`30-120
`
`15-100
`25-400
`
`1-20
`4-54
`15-150
`10-150
`2-40
`
`30-600
`6-60
`0.5-1
`
`l-100
`
`20-225
`
`10
`50
`100
`
`I0»-toU133
`
`10
`
`10
`
`Chlorpromazine
`Promazine
`Trifiupromazine
`Levomepromazine
`
`Piperacetazine
`Meson-idazine
`Thiolidazine
`
`Acetophenazine
`Butapcrazine
`Carphenazine
`Fluphenazine
`
`Perphenazine
`P1‘or:l1lo1'pe1'azine
`Thiopropazate
`Trifluoperazine
`
`Chlo1-prothixine
`Thiothixene
`Flupenthixo}
`
`I-Ialoperidol
`
`Molindone
`
`Loxapine
`
`Amin-iptyline
`Desipramine
`
`Doxepin
`Imipramine
`Nortriptyline
`Protriptyline
`
`Isocarboxazid
`Pheuelzine Sulfate
`
`Trallylcypromine Sulfate
`
`Acetamidobcnzoate
`
`Amphetamine
`Dextroarnphetamine
`Methamphetamine
`Methylphenidate
`Pernoline
`Pemylenetetrazol
`
`20-250 mg.
`Loxitane
`ANTIDEPRESSA-NTS (PSYCHOANALEPTIC DRUGS}
`T1-icyclic Derivatives
`
`20-300
`
`Elavii
`Norprzlmin,
`25-200
`Pe1'tof1'ane
`25-300
`Sinequan
`30-300
`Tofranil
`30-100
`Aventyl
`15-60
`Vivactil
`Monomnirze Oxidase I-Jtmbilorzc
`H)rdrazi1:es
`
`Marplan
`Nardil
`
`Nrmhydrazimzs
`
`10-30 mg.
`15-75 mg.
`
`10-30 mg_
`Parnate
`CEREBRAL STIMULANTS
`Deaner
`50-300 mg.
`Benzedrine
`5-60 mg.
`Dexedrine
`5-60 mg.
`Desoxyn
`2.5-25 mg.
`Ritalin
`10-00 mg.
`Cylert
`37.5-112.5 mg".
`Metrazol
`300-500 mg.
`
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`
`PI-IARMACO LOGICAL THERAPY
`
`815
`
`TABLE 32-2 Classification of Psychotherapeutic Agents and
`Daily Dosage Flange (Continued)
`C}-ILORPROMAZINE
`MG. EQUIVALENT
`
`BRAND NAME
`
`DAILY oosr.
`
`GENERIC NAME
`
`Meprobamate
`Tybamate
`
`Hydroxyline
`
`Chlordiazepoxide
`Clorazepate
`Diazepam
`Oxazepam
`
`Arnobarbital
`Aprobarbital
`Butabarbital
`Mephobarbital
`Pentobarbital
`Phenobarbital
`Secobarbital
`Vinbarbital
`
`SOMNIFACIENTS
`Borbitmrdes
`Amytal and others
`Alurate
`Butisol and others
`Mebaral and others
`Nembutal and others
`Luminal and others
`Seconal and others
`Delvinal
`
`Nonbarbitwates
`
`ANXIOLYTIC AGENTS
`Glycerol Derivatives
`1200-2400
`Equanil. Miltown
`750-3000
`Tybatran
`Dipfieiiyimethoiae Den'vm‘i-hes
`Atarax, Vistaril
`Benzadiazepim: Derivatives
`Lib rium
`Tranxene
`Valium
`Serax
`
`50-400 mg.
`
`10-200
`15-60
`2-40
`30-120
`
`65-500 mg.
`40-160 mg.
`50-120 mg.
`100-400 mg.
`30-200 mg.
`100-500 mg.
`50-300 mg.
`100-400 mg.
`
`Chloral Hydiate
`Ethchlorvynol
`Ethinamate
`Glutethimide
`Methaqualone
`Methyprylon
`Flurazepam Hydrochloride
`
`500 mg.-2 g.
`Noctec and others
`200 mg.—1 g.
`Placidyl
`500 mg.-2 g.
`Valmid.
`250 mg.-1 g.
`Doriden
`150 mg.-400 mg.
`Quaalucle, Sopor
`150 mg.-300 mg.
`Noludar
`15 mg.-30 mg.
`Dalmane
`ANTICHOLINERGIC DRUGS
`
`Benztropine Mesylate
`Biperiden
`Cycrimine HCL
`Trihexyphenidyl HCL
`Procyclidine I-ICL
`
`Cogentin
`Akineton
`Pagitane
`Artane
`Kemadrin
`
`1-8 mg.
`2-3 mg.
`3.75-20 mg.
`1-15 mg.
`6-20 mg.
`
`The list contains commercially available psychotherapeutic and anticholinergic agents. Doses listed
`are those suggested in the manufacturer's package insert. (Modified from the Manual for the Use
`of Psychotherapeutic Drugs in the New York State Department of Mental Hygiene Facilities. Prepared
`by the N.Y.S.D.M.I-I. Committee on Therapeutics: S. Malitz, Chairman, H. C-lassman, B. Kobrynski.
`E. E. Scerebim, and G.'Simpson, 1977.)
`
`is
`it
`avoiding the minor side effects,
`sometimes advisable to prescribe the
`total daily dosage at bedtime. If there is
`a need to continue a tranquilizing effect
`early in the day, one third of the dose
`may be given in the morning and two
`thirds before bedtime. Such an adminis-
`
`regularly taking medication, but also is
`less costly since it allows the utilization
`of larger tablet strength, and, in hospi-
`tals. saves staff time in administration
`of the compound.
`For the elderly, the initial dose rec-
`ommended is one third to one half that
`
`trative regimen not only has been found
`to increase the likelihood of the patient
`
`adults-. The customary
`for younger
`formula relating to children should be
`
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`

`
`816
`
`' PI-l ARM ACO LOGICAL TH ERAPY
`
`applied to each child, vith particular
`attention to bodily weight.
`When the most effective maintenance
`
`level of the appropriate agent has been
`achieved, it is both possible and advis-
`able to reduce the dosage to a lower
`level, in view of the accumulating po-
`tential of the agents as described. Fur-
`thermore,
`it
`is then possible to allow
`the patient drug-free days. Many physi-
`cians discontinue administration one
`
`day a week following establishment of
`the maintenance level.
`It has been
`
`this does not modify the
`found that
`therapeutic effect.
`It. is particularly important for the
`psychiatrist to recognize that many who
`are presumed resistant
`to pharmaco-
`logical
`therapy are simply failing to
`take the prescribed medication. This
`resistance arises often as a direct ex-
`
`the psychopathology, of
`pression of
`their personality make—up and con-
`sequent attitudes toward physicians, or
`of certain ingrained cultural attitudes
`toward the taking of medicine. For ex-
`ample, many psychotic patients deny
`the existence of illness. Particularly in
`the paranoid, sometimes the ingestion
`or acceptance of medication is per-
`ceived delusionally as a means of poi-
`soning. Others reject medication as a
`result of
`family attitudes
`equating
`illness as weakness or from fear derived
`
`from early childhood experiences of
`illness. Still others will refuse to accept
`medications prescribed by routes other
`than the ones customarily used within
`their culture. Thus, in the U.S.A. and
`Great Britain, sedative medications are
`customarily taken by mouth, in Italy by
`injection, and in France by anal sup-
`pository.
`The prescribing and giving of medi-
`cation should be recognized in the con-
`text of the patient-physician relation-
`ship. All medications, as with placebos,
`hold the potential
`for meeting the
`magical expectations of the sick indivi-
`duals, who often eagerly anticipate relief
`or cure of their distress. It is important
`that the attending medical staff support
`
`these expectations by indicating the pi).
`tential efficacy of the prescribed medi-
`cations, while at the same time provid-
`ing an outlet
`for
`the later use of
`analogues by describing the individual
`differences
`in metabolizing
`specific
`agents.
`The attitude of the attending physi-
`cians
`is
`particularly significant,
`as
`shown by studies examining the dif-
`ferences in approach of those physi-
`cians successful in treating patients in
`low socioeconomic groups, where drop-
`outs in treatment programs are com-
`mon. The successful physicians tend to
`be more active in their relations with
`
`to be more positive in
`these patients,
`dealing with and responding to them,
`and to practice more personalized in-
`terviews. The inference made from
`
`these investigations is that the success-
`ful physicians seemed to be more em-
`pathic with their patients, yet did not
`give them direct
`reassurance. These
`physicians rate their patients as sicker
`and at the same time tend to have a
`
`more positive prognostic outlook. They
`more frequently call
`their patients by
`name. are vocal and facially animated,
`and expend more time with the indi-
`vidual.
`
`In contrast, “high dropout" therapists
`are passive, wait for the patient to speak,
`are less enthusiastic and more certain
`
`that the drugs will act. The same traits
`then are necessary to maintain patients
`in pharmacological treatment programs
`as in psychotherapeutic programs. The
`experienced psychiatrists, nurses, and
`tnental health personnel will under-
`stand the transactional meaning be-
`tween themselves and the patient and
`recognize their roles as parental surro-
`gates and authorities.
`Before prescribing, the physician will
`inquire into the patient’s family’s atti-
`tude and responses to drug-taking in
`the past. The prescription then will be
`tailored to suit the individual attitudes
`
`of the patient. Those likely to reject
`prescriptions may often be identified.
`If this is not the case, the sensitive ther-
`
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`

`
`817
`
`PHARMACOLOGICAL THERAPY
`
`inquire
`apist noting nonresponse will
`from both the patient and members of
`his family or others, particularly if the
`individual
`is
`in outpatient
`treatment,
`whether the individual has filled the
`
`prescription, delayed its usage, forgot-
`ten to talte medications, taken less than
`indicated, or discontinued before rec-
`ommendation.
`In the instances of those individuals
`who discontinue medication, and who
`frequently have exacerbations of symp-
`toms,
`it
`is wise to place them on the
`long—acting injectable depot products.
`
`NE UROLEPTIC AGENTS
`
`Phenothiazines
`
`from
`nucleus
`The phenothiazine
`which the various analogues have been
`synthesized consists of
`two benzine
`rings joined by a sulfur and a nitrogen
`atom. By the addition of side-chains to
`the formula, numerous derivatives have
`
`been developed. From the attachment
`of
`a dimethylamopropyl
`side-chain
`are derived chlorpromazine, proma-
`zine, and ti-ifluprornazine. Substitution
`of
`the piperazine side-chain in this
`position leads to the development of
`perphenazine, prochlorperazine, and
`trifluoperazine. The plperidine side-
`chain results in thioridazine, piperaceta—
`zine, and mesoridazine. Compounds in
`the piperazine-substituted group are
`the most potent, but also have the great-
`est tendency to produce symptoms of
`extrapyramidal dysfunction.
`The general indications for the pre-
`scription of the phenothiazine deriva-
`tions are the same as those for chlor-
`
`promazine. These drugs differ more in
`.their toxic properties than in their abili-
`ties to modify selectively various “target
`symptoms.”
`Pharmacological experiments in ani-
`mals show that the phenothiazines re-
`duce conditioned avoidance responses.
`They do not inhibit escape, nor do they
`affect the response to conditional sti1n-
`
`uli, as do the barbiturates. They impair
`vigilance but not cognitive actions. Sei-
`zure threshold to both electroshock and
`
`convulsive drugs is unchanged. With
`large doses only, there appear slow (5
`to 6 per second),
`low-voitage waves in
`the
`electroencephalograrn. Hypothet-
`lamically regulated activities are dis-
`rupted. Thus thermoregulation is im-
`paired, adrenocorticotropic hormone
`(ACTH) secretion is diminished, and
`growth is diminished. Another endo-
`crine effect
`is
`reduction in urinary
`gonadotropins. In animals, the estrous
`cycle and ovulation are suppressed by
`the
`phenothiazines. The
`decidual
`reaction is prolonged by them and
`lactation
`is
`induced.
`Infertility oc-
`curs.
`In women patients
`receiving
`phenothiazines who develop inappro-
`priate lactation and amenorrhea, pro-'
`lactin levels become elevated, basal lu-
`teinizing hormone
`levels vary, and
`absence of midcycle peaks occurs, while
`estrogen and progesterone levels have
`been reported as similar to those dur-
`ing the follicular phase of a normal
`cycle.
`In men receiving such drugs,
`plasma testosterone is either
`low or
`normal and rises on withdrawal of the
`
`drug.
`These agents are weli absorbed from
`the intestine (60 to 80 per cent} and
`widely distributed in the body tissues,
`where they remain bound for pro-
`longed periods (6 to 12 mondis) after
`administration has ceased. They are
`metabolized in the liver through hydrol-
`ysis and glucuronidization.
`Of the classes of phenothiazines in
`general,
`the aliphatic and piperidine
`series provide more sedative effect than
`the piperazine. The latter series, by
`weight, contain the more potent com-
`pounds, but these also are more likely
`to produce the parkinsonism and other
`basal ganglia side effects. The therapist
`has available many analogues in these
`various groups, and some, notably Hu-
`phenazine, may be prescribed in long-
`acting injectabie forms.
`There follows a description of the
`
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`

`
`818
`
`PHARMACOLOGICAL THERAPY
`
`intro-
`therapeutic action of the first
`duced, still the most widely used, and
`the least expensive of the series—chlor-
`prornazine. The description serves as a
`model for the actions of all the neuro-
`
`leptics. The variable indications and
`complications will be reviewed later.
`ADMINISTRATION. Chlorpromazine
`is available in 10-, 25-, 50-, 100-, and
`200-mg. tablets, and also in 25-mg. (1-
`ml.) and 50—mg. (2-ml.) ampules. There
`is no standard dose of the drug;
`this
`must be individualized. Chlorproma-
`zine may be administered by oral or by
`intramuscular routes; however, it is so
`irritant that it should not be adminis-
`tered subcutaneously.
`Intramuscular
`injections should be given deeply in the
`upper and outer quadrant of the but-
`tock; the solution supplied by the man-
`ufacturer should be diluted with physi-
`ological salt solution or a 2 per cent
`procaine solution and administered
`very slowly. Some physicians add hya-
`luronidase to facilitate absorption and
`prevent abscess formation. If quick ac-
`tion is desired, the patient may receive
`25 mg. by deep intramuscular injection,
`and if this amount is not effective, an
`
`injection may be
`additional 25-mg.
`given within an hour unless contrain-
`dicated by marked hypotension. Sub-
`sequent intramuscular dosages may be
`increased gradually, even up to 400
`mg. every six hours. The higher doses
`should be reached over a period of sev-
`eral days.
`the acutely
`If, as frequently Occurs,
`disturbed patient becomes quiet within
`.48 hours, oral doses (milligram for mil-
`ligram or higher) may gradually re-
`place intramuscular closes.
`Injections
`should not be continued for more than
`
`three or four days. It will not usually be
`necessary to increase oral administra-
`tion to more than 300 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
`sufficient
`for a maximum dose,
`al-
`
`though some psychiatrists give a max-
`imum of 2000 mg. in 24 hours.
`SPECIAL
`THERAPEUTIC
`REGIMENS.
`
`Rapid Tranquiiization. The immediate
`treatment of the acutely psychotic with
`the maximally tolerated dosages of
`phenothiazines is advocated by some to
`facilitate ego reorganization and social
`adaptation. Such treatment seems to be
`particularly valuable when the patient
`is seriously confused and incapable of
`engaging in meaningful verbal com-
`munication with others.
`
`This method of treatment requires
`the quick establishment of a maximal
`daily dosage for each individual. Polalt
`and Laycomb recommend that the pa-
`tient be given an initial dose of 25 to
`50 mg. of chlorpromazine orally and be
`observed closely for side effects for one
`hour. If none are noticed, the drug is
`prescribed in 50 to 200 mg. doses orally
`every hour for six to eight hours, de-
`pending upon the behavioral
`state.
`When the initial disturbed psychotic be-
`havior has diminished within the first
`
`six hours—including as end points
`strong sedation or sleep—the dosage is
`arranged in successive days at
`two
`thirds the total required initially. Each
`day thereafter the dosage is reviewed
`and modified, depending upon the ob-
`served behavior.
`In the first several
`
`days, well-tranquilized patients sleep a
`good part of the day. After the third
`day, there generally takes place a con-
`siderable
`reduction
`of
`drowsiness.
`Often, side effects, too, diminish at this
`time. Only after this day is
`the total
`level of medication reduced.
`If oral medication is refused, intra-
`muscular dosages of one third the oral
`may be substituted.
`High Dosage Regimens. On the effec-
`tiveness of high dosage regimens of
`chlorpromazine (over 2000 mg. per
`day)
`against
`low dosage
`treatment
`among
`groups of
`chronic
`schizo-
`phrenics, Prien et al., reporting from
`the
`Psychopharmacology
`Research
`Branch Collaborative Group Study on
`120 such patients, found that high dos-
`ages were significantly more effective
`when given to patients under 40, hospi-
`talized less than 15 years, who had been
`receiving a nonpiperazine phenothia-
`
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`

`
`Pl-l ARA-IACOLOG ICAL THERAPY
`
`819
`
`zine beforehand. There was little dif-
`
`vidual reaction. Other effects are slow-
`
`ference in high dosage and low dosage
`regimens in other patient subgroups.
`Those who had been on higher dosages
`beforehand were more likely to fail.
`For older patients, high dosage caused
`a great increase in side effects. Dyskine-
`sias occur in as high as 25 per cent of
`patients treated with high dosage regi-
`mens, particularly among the aged.
`Lang-Acting
`Agents. Fluphenazine
`hydrochloride has been found to retain
`its physiological activity longer than any
`other phenothiazine. This i