mopern
`CLINICAL
`PSYCHIATRY
`
`
`
`1977
`W. B. SAUNDERS COMPANY
`Philadelphia, London, Toronto
`
`1 of 28
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`W. B. Saunders Company: West Washington Square
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`
`Listed hereis the latest translated edition ofthis
`book together with the language ofthe translation
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`Polish (6th edition) —Panst. Zaklad Wydawn.
`Lekarskich, Warsaw, Poland
`
`Spanish (8th edition) —La Prensa Medica Mexicana,
`Mexico City, Mexico
`
`Portuguese (8th edition) —Editora Interamericana Ltda.,
`Rio de Janeiro, Brazil
`
`Modern Clinical Psychiatry
`
`ISBN 0-7216-5483-5
`
`© 1977 by the W. B. Saunders Company. Copyright 1934, 1939, 1948, 1953, 1958, 1963, 1968, 1973
`by W. B. Saunders Company. Copyright under the International Copyright Union.
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`Last digit is the print number:
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`
`“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
`
`For the treatment of the major dis-
`turbances
`of
`personality—the
` psy-
`choses—the psychotropic drugs to be
`described are the primary therapeutic
`agents. Certain of these drugs are use-
`ful in providing symptomatic relief in
`the psychoneuroses and_ physiological
`disturbances, while others act specifi-
`cally in relation to certain symptoms, or
`are useful as enhancers for the effects
`of the neuroleptic.
`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-
`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 as dopa-
`mine-blocking
`agents.
`Included
`in
`the group are the phenothiazines, the
`butyrophenones, the dihydroindolines,
`the dibenzoxazepines, and the rauwol-
`fia alkaloids.
`The antidepressants are complex
`agents, with pharmacological effects in
`particular on the biogenic amines nore-
`pinephrine and serotonin. They include
`the tricyclic compounds and the hydrox-
`ide and nonhydroxide monoamine in-
`hibitors.
`The cerebral stimulants include the
`dextroamphetamines and methylpheni-
`date. These agents tend to produce a
`transient
`increase in psychomotor ac-
`tivity, must be considered as stimulants,
`and are not effectively antidepressant.
`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 extrapyramidalor the au-
`tonomic nervous systems, as do the
`neuroleptics. In general, whether taken
`with or without a prescription, over a
`period of time the individuals receiving
`
`
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`830
`
`PHARMACOLOGICAL THERAPY
`
`these agents develop a tolerance and
`may becomehabituated or-addicted or
`both. Because of the possibility of ad-
`diction,
`they have been classified in
`many countries
`as
`controlled
` sub-
`stances.
`The somnifacients include the well-
`known
`barbiturates,
`chlorohydrate,
`ethchlorvynol, glutethimide, methypry-
`lon, methaqualone, and flurazepam.
`Pharmacological effects are generally
`shorter but more intense than in 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 his previous medical
`studies of the well-known properties
`and clinical
`indications of the long-
`knowncentral nervous depressants such
`as the narcotics, anesthetics, hypnotics,
`and intoxicants, as well as the stimu-
`lants, consideration is not given to these
`drugs in this text. Their skillful pre-
`scription, often in conjunction with that
`of the neuroleptics,still is demanded in
`practice.
`
`tropic drugs have a long half-life in
`bodily fluids. The drugs and their me-
`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-
`uance.
`The
`psychopharmacological
`properties are generally manifest days
`to weeks later than the early effects on
`the other segments of the central ner-
`vous system. Thus, theside 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 in a later
`section.
`Much ofthe variation in effect pro-
`duced by
`the differing agents
`is
`thought to depend upontheir differing
`actions at the synaptic junctions 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 stimulating biogenic amines.
`These substances then activate the effec-
`tor site of the postsynaptic neuron.
`In Chapter 3 (The Brain and Behav-
`ior) and Chapter
`19
`(Schizophrenic
`Psychoses),
`respectively,
`the synaptic
`action of the various biogenic amines
`Theactive psychotropic drugs exert
`and the “dopamine hypothesis” as
`it
`complex actions upon various neural
`relates to schizophrenia were described.
`systems and the neuron itself. These
`actions
`have
`been
`demonstrated
`Norepinephrine, dopamine, the indole-
`through changes brought about in ani-
`amine
`serotonin,
`gamma-aminobu-
`mal
`behavior
`(particularly
`through
`tyric acid or acetylcholine are differen-
`tially disposed throughthe brain stem.
`analysis of responses obtained by clas-
`sical and instrumental conditioning),
`Certain pathways have been identified
`
`
`through depth—electroencephalog- as principally containing and thereby ac-
`tivated by dopamine and noradrenaline
`raphy,
`through
` electrophysiological
`and biochemical
`studies of synaptic
`(Fig. 32-1).
`transmission, and through studies of
`As the storage, release, action, and
`drug metabolism within bodily tissues
`later re-uptake of norepinephrine, be-
`and changes in endocrine functions.
`lieved significant particularly in the af-
`fective disorders,
`is now well worked
`It is well known now that the psycho-
`
`PHARMACOLOGICAL ACTION
`AND BRAIN FUNCTION
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`PHARMACOLOGICAL THERAPY
`
`831
`
`NORADRENALINE
`
`DOPAMINE
`
`n accumbens
`
`n caudatus
`
`
`
`
`
`tub olfactorium
`
`
`
`
`n amygdaloid.
`hypothal.
`centralis
`amygdala
`dorsal
`bundle
`
`
`
`median
`emi
`NENCe
`substantia
`nigra
`
`gris:
`subst.
`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 pons; A6, cells in locus ceruleus; A8, 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. Acta Physiol. Scand. (Suppl.)367:1-48, 1971.)
`
`out, norepinephrine is used here as a
`model to indicate what are considered
`the sites of pharmacological action of
`the drugs used in treatment. Figure
`32-1 illustrates the events described
`hereafter in the text. In Chapter 19,
`where
`the dopamine hypothesis
`in
`schizophrenia was outlined,
`it was
`suggested that
`this hypothesis alone
`was insufficient to explain the effective
`action of the neuroleptics and an alter-
`native was described implicating as well
`the noradrenergic system.
`In the neuron, norepinephrineexists
`in two forms: the labile form, capable
`of release by stimulation or by sym-
`pathomimetic drugs such as ampheta-
`mine, and that
`form contained in
`storage granules and released by reser-
`
`pine. When released from the inter-
`neuronalstructure, the norepinephrine
`flows into the synaptic cleft and thenis
`returned to the cell, where it is stored
`or oxidized by the enzyme monoamine
`oxidase. The monoamine oxidase inhib-
`itors, such as iproniazid,
`increase the
`amount
`of
`intraneuronal
`norepi-
`nephrine, making more available. Re-
`serpine
`depletes
`the
`intraneuronal
`amines,
`thus diminishing the amount
`available for activation.
`Both the phenothiazines and the
`iminodibenzyls, such as imipramine, di-
`minish cellular permeability. For this
`reason, the released norepinephrine is
`partially prevented from returning to
`the neuron and its concentration in the
`synaptic cleft is prolonged over time.
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`832
`
`PHARMACOLOGICAL THERAPY
`
`Administration
`
`cratic for that disorder. Constitutional
`differences may haveorigins in genetic
`differences, expressed in subtle varia-
`tions in production, 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 ab-
`sorption.
`
`But the availability of the opposite site
`of the postsynaptic cell
`is decreased as
`well by the same pharmacologic agents.
`The principal action of the phenothia-
`zines is to render the receptorsites less
`available so that the effect of the neuro-
`transmitter is diminished. Imipramine
`and its analogues, on the other hand,
`prevent
`the
`resorption of norepi-
`nephrine into the activating nerve end-
`ings and thusincrease the action of the
`neurotransmitter. Thus
`those drugs
`which deplete or
`inactivate norepi-
`nephrine in the brain usually produce
`sedative or depressive actions, while
`There now exists a wide range of
`those that increase or potentiate it com-
`drugs in the various categories of the
`classification described in Table 32-1.
`monly bring about excitatory behavior
`Table 32-2 lists those presently avail-
`and have antidepressanteffects. Norep-
`able in the U.S.A., and gives the ge-
`inephrine and serotonin are found in
`highest concentration in the hypothal-
`neric name,
`the brand name, and the
`recommended range of daily dosage.
`amus. Dopamineexists in greatest con-
`centration in the caudate and lenticular
`The selection of the appropriate drug
`nucleus.
`depends upon the nature of the psy-
`chopathology observed in the indivi-
`Such drugs exert their major effects
`upon the brain stem and limbic sys-
`dual patient. In general, neuroleptics
`will be used in the treatment of schiz-
`tems,
`the structures of which, as has
`been noted in Chapter 3, are princi-
`
`
`ophrenia and_psychotic conditions
`pally concerned with systems modulat-
`other than the affective. The antide-
`ing and shaping emotional behavior.
`pressant agents will be used for the af-
`The phenothiazines decrease the excit-
`fective psychoses, while the anxiolytics
`ability of limbic structures, while reser-
`are indicated for symptomatic relief in
`pine does the opposite. While the imin-
`the neuroses, psychophysiological reac-
`odibenzyls stimulate limbic structures,
`tions, certain personality disorders, and
`the
`antidepressant monoamine oxi-
`somespecial symptoms.
`dase inhibitors do not. The latter stim-
`It is recommended that the psychia-
`ulate the reticular activating system
`trist become experienced ‘in the use of a
`while the phenothiazines do not.
`single agent or two in each class and
`The explanations given for the vary-
`generally prescribe such agents in his
`ing effects of the various neuroleptic
`practice. The administration of more
`than one agent in a class to a patient
`agents on synaptic transmission and on
`(polypharmacy) is to be avoided, as it
`functions of limbic or reticular activat-
`ing systems and other organ systems do
`has no therapeutic effect. There are
`both synergic and anergic antagonistic
`not entirely explain their impressive ac-
`tions in modifying affect in the major
`effects when prescribing across
`ca-
`tegories. These must be fully under-
`psychoses. What emerges
`from the
`stood, and will be describedlaterin this
`pharmacological physiology is an ap-
`preciation of the differences of action
`chapter. The value of having available
`of the various series of agents, and a
`the large number of analogues in the
`variousclasses is the potential of vary-
`recognition that
`their functions vary.
`The underlying neurohumoral consti-
`ing the medication as the patient
`is
`tution of the class of patients in which
`found unresponsive to one or another
`each is effective may well be idiosyn-
`in a series. In other words, the treat-
`
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`PHARMACOLOGICAL THERAPY
`
`833
`
`TABLE 32-1
`
`Classification of Psychotropic Drugs Used Therapeutically
`
`CATEGORY
`
`REPRESENTATIVE MEMBERS
`
`
`Neuroleptics
`
`Antidepressants and affective modulators
`
`Anxiolytic sedatives
`
`Psychostimulants
`
`Somnifacients
`
`Phenothiazines
`Butyrophenones
`Thioxanthenes
`Dihydroindolines
`Dibenzoxazepines
`Rauwolfaalkaloids
`
`Monoamine oxidase (MAO) inhibitors
`Imipramine andother tricyclic compounds
`Lithium compounds
`
`Glycerols
`Diphenylmethanes
`Benzodiazepines
`
`Amphetamine, methylphenidate, dibenzoxepin
`Caffeine
`
`Barbiturates
`
`Chloral Hydrate
`Ethchlorvynol
`Flurazepam
`Glutethimide
`Methyprylon
`Methaqualone
`Paraldehyde
`
`(Modified, updated, and expanded from the classification recommended by the Special Committee
`of the World Health Organization, 1967.)
`
`ment may be varied to fit the peculiar
`metabolic constitution of the individual.
`As with other pharmacological treat-
`ment, the physician will consider in de-
`termining the dosage the individual’s
`body weight, age, sex, and type andse-
`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
`long half-life in serum andtheir ten-
`dency to accumulate in tissues—admin-
`istration is unnecessary more than once
`or twice a day. Generally, since in most
`of
`the psychopathological conditions
`sleep is affected, and also as a means of
`
`avoiding the minorsideeffects, it is ad-
`visable to prescribe the total daily dos-
`age 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 administrative
`regimen not only has been found to
`increase the likelihood of the patient
`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 administeringit.
`Both elderly patients and children
`must be treated with caution. For the
`elderly, the initial dose recommended
`is one third to one half that of younger
`adults. The customary formula relating
`to children should be applied to each
`child, with particular attention to bodily
`weight.
`In light of the long retention of the
`
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`834
`
`PHARMACOLOGICAL THERAPY
`
`TABLE 32-2 Classification of Psychotherapeutic Agents and Daily Dosage Range
`
`GENERIC NAME
`
`BRAND NAME
`
`CHLORPROMAZINE
`DAILY DOSE
`MG. EQUIVALENT
`
`
`30-1000 mg.
`40-1000
`20-200
`150-300
`
`100 (Standard)
`200
`25
`
`NEUROLEPTICS
`PHENOTHIAZINES
`
`Aliphatic
`Thorazine, Sonazine
`Sparine
`Vesprin
`Levoprome
`
`Quide
`Serentil
`Mellaril
`
`Tindal
`
`Piperidine
`
`Piperazine
`
`Repoise
`Proketazine
`Prolixin,
`Permitil
`Trilafon
`Compazine
`Dartal
`Stelazine
`MISCELLANEOUS
`Thioxanthenes
`
`‘Taractan
`Navane
`
`Haldol
`
`Moban
`
`ise
`Butyrophenone
`
`Dihydroindoline
`
`Dibenzoxazepine
`
`20-160
`25-400
`50-800
`
`80-120
`
`15-100
`25-400
`
`1-20
`4-64
`15-150
`10-150
`2-40)
`
`30-600
`6-60
`0.5-1
`
`1-100
`
`20-225
`
`10
`50
`100
`
`20
`
`10
`25
`
`2
`10
`15
`10
`5
`
`100
`2
`
`2
`
`10
`
`10
`
`20-250 mg.
`Loxitane
`ANTIDEPRESSANTS (PSYCHOANALEPTIC DRUGS)
`Tricyclic Derivatives
`
`20-300
`
`Elavil
`Norpramin,
`25-200
`Pertofrane
`25-300
`Sinequan
`30-300
`Tofranil
`30-100
`Aventyl
`15-60
`Vivactil
`Monoamine Oxidase Inhibitors
`Hydrazines
`
`Chlorpromazine
`Promazine
`‘Triflupromazine
`Levomepromazine
`
`Piperacetazine
`Mesoridazine
`Thioridazine
`
`Acetophenazine
`Butaperazine
`Carphenazine
`Fluphenazine
`
`Perphenazine
`Prochlorperazine
`Thiopropazate
`Trifluoperazine
`
`Chlorprothixine
`Thiothixene
`Flupenthixol
`
`Haloperidol
`
`Molindone
`
`Loxapine
`
`Amitriptyline
`Desipramine
`
`Doxepin
`Imipramine
`Nortriptyline
`Protriptyline
`
`Isocarboxazid
`Phenelzine Sulfate
`
`Tranylcypromine Sulfate
`
`Acetamidobenzoate
`Amphetamine
`Dextroamphetamine
`Methamphetamine
`Methylphenidate
`Pemoline
`Pentylenetetrazol
`
`
`
`Marplan
`Nardil
`
`Nonhydrazines
`
`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
`10-60 mg.
`Cylert
`37.5-112.5 mg.
`Metrazol
`300-600 mg.
`
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`

`PHARMACOLOGICAL THERAPY
`
`835
`
`GENERIC NAME
`
`CHLORPROMAZINE
`BRAND NAME
`DAILY DOSE
`MG. EQUIVALENT
`
`
`Meprobamate
`Tybamate
`
`Hydroxyline
`
`Chlordiazepoxide
`Clorazepate
`Diazepam
`Oxazepam
`
`Amobarbital
`Aprobarbital
`Butabarbital
`Mephobarbital
`Pentobarbital
`Phenobarbital
`Secobarbital
`Vinbarbital
`
`ANXIOLYTIC AGENTS
`Glycerol Derivatives
`1200-2400
`Equanil, Miltown
`750-3000
`Tybatran
`Diphenylmethane Derivatives
`Atarax, Vistaril
`Benzodiazepine Derivatives
`Librium
`‘Tranxene
`Valium
`Serax
`
`10-200
`15-60
`2-40
`30-120
`
`50-400 mg.
`
`SOMNIFACIENTS
`Barbiturates
`Amytal and others
`Alurate
`Butisol and others
`Mebaral and others
`Nembutal and others
`Luminal and others
`Seconal and others
`Delvinal
`
`Nonbarbiturates
`
`65-500 mg.
`40-160 mg.
`50-120 mg.
`100-400 mg.
`30-200 mg.
`100-600 mg.
`50-300 mg.
`100-400 mg.
`
`Chloral Hydrate
`Ethchlorvynol
`Ethinamate
`Glutethimide
`Methaqualone
`Methyprylon
`Flurazepam Hydrochloride
`
`500 mg.-2 g.
`Noctec and others
`200 mg.-l g.
`Placidyl
`500 mg.-2 g.
`Valmid
`250 mg.-1 g.
`Doriden
`150 mg.-400 mg.
`Quaalude, Sopor
`150 mg.-300 mg.
`Noludar
`15 mg.-30 mg.
`Dalmane
`ANTICHOLINERGIC DRUGS
`Cogentin
`1-8 mg.
`Benztropine Mesylate
`Akineton
`2-8 mg.
`Biperiden
`Pagitane
`3.75-20 mg.
`Cycrimine HCL
`Artane
`1-15 mg.
`Trihexyphenidyl HCL
`
`Procyclidine HCL 6-20 mg. Kemadrin
`
`
`Thelist 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 HygieneFacilities. Prepared
`by the N.Y.S.D.M.H. Committee on Therapeutics: S. Malitz, Chairman, H. Glassman, B. Kobrynski,
`E. E. Scerebim, and G. Simpson, 1977.)
`
`neuroleptics, antidepressants, and anx-
`iolytics within the body, sustained re-
`lease capsules are contraindicated. The,
`liquid forms of the medication are in-:
`dicated only when the patient has dif-
`ficulty swallowing tablets or capsules,
`or tends to hoard the medication.
`Whenthe mosteffective 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 over
`weekends or recommendthat the agent
`be given on alternate days following es-
`tablishment of the maintenancelevel. It
`has been foundthat this does not mod-,
`ify the therapeutic effect.
`It is particularly important for the
`
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`

`836
`
`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-
`pression of the psychopathology, 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 medicalstaff support
`these expectations by indicating the po-
`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
`
`PHARMACOLOGICAL THERAPY
`
`be more active in their relations with
`these patients,
`to be more positive in
`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 sametraits
`then are necessary to maintain patients
`in pharmacological treatment programs
`as in psychotherapeutic programs. ‘The
`experienced psychiatrists, nurses, and
`mental 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-
`apist noting nonresponse will
`inquire
`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 take 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 upon the
`long-acting injectable depot products.
`
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`

`

`PHARMACOLOGICAL THERAPY
`
`837
`
`NEUROLEPTIC 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 alteration of R, and R, in the
`formula, numerous derivatives have
`been developed. From the attachment
`of a dimethylammopropylside-chain at
`R, are derived chlorpromazine, pro-
`mazine, and triflupromazine. Substitu-
`tion of the piperazine side-chain in this
`position leads to the development of
`perphenazine, prochlorperazine, and
`trifluoperazine. The piperidine side-
`chain attached at R, results in thiorida-
`zine, piperacetazine, and mesoridazine.
`Compounds in the piperazine-substi-
`tuted group are the most potent, but
`also have the greatest
`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 notinhibit escape, nor do they
`affect the response to conditional stim-
`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-voltage waves in
`the
`electroencephalogram. Hypotha-
`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 well 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 months) 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 flu-
`phenazine, may be prescribed in long-
`acting injectable forms.
`There follows a description of the
`therapeutic action of the first
`intro-
`duced,still the most widely used, and
`the least expensive of the series —chlor-
`promazine. The description serves as a
`model for the actions of all the neuro-
`leptics. The variable indications and
`complications will be reviewedlater.
`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 byoral 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
`
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`

`

`838
`
`PHARMACOLOGICAL THERAPY
`
`hour. If none are noticed, the drugis
`upper and outer quadrant of the but-
`prescribed in 50 to 200 mg. dosesorally
`tock; the solution supplied by the man-
`every hour for six to eight hours, de-
`ufacturer should be diluted with physi-
`pending upon the behavioral
`state.
`ological salt solution or a 2 per cent
`Whentheinitial disturbed psychotic be-
`procaine solution and administered
`havior has diminished within the first
`very slowly. Some physicians add hya-
`six hours—including as end_points
`luronidase to facilitate absorption and
`strong sedation or sleep—the dosageis
`prevent abscess formation. If quick ac-
`arranged in successive days at
`two
`tion is desired, the patient may receive
`thirds the total required initially. Each
`25 mg. by deep intramuscularinjection,
`day thereafter the dosage is reviewed
`and if this amount is not effective, an
`and modified, depending upon the ob-
`additional 25-mg.
`injection may be
`served behavior.
`In the first several
`given within an hour unless contrain-
`days, well-tranquilized patients sleep a
`dicated by marked hypotension. Sub-
`good part of the day. After the third
`sequent intramuscular dosages may be
`day, there generally takes place a con-
`increased gradually, even up to 400
`siderable
`reduction of
`drowsiness.
`mg. every six hours. The higher doses
`Often, side effects, too, diminish at this
`should be reached over a period of sev-
`time. Only after this day is the total
`eral days.
`level of medication reduced.
`If, as frequently occurs, the acutely
`intra-
`If oral medication is refused,
`disturbed patient becomes quiet within
`muscular dosages of one third the oral
`48 hours, oral doses (milligram for mil-
`may be substituted.
`ligram or higher) may gradually re-
`High Dosage Regimens. On the effec-
`place intramuscular doses.
`Injections
`tiveness of high dosage regimens of
`should not be continued for more than
`chlorpromazine (over 2000 mg. per
`three or four days. It will not usually be
`day)
`against
`low dosage
`treatment
`necessary to increase oral administra-
`among groups
`of
`chronic
` schizo-
`tion to more than 800 mg. a day, butif
`phrenics, Prien et al., reporting from
`sedation is not secured, the dosage may
`the
`Psychopharmacology
`Research
`gradually be increased up to as much as
`Branch Collaborative Group Study on
`1200 mg. a day. Usually, this amountis
`120 such patients, found that high dos-
`sufficient
`for a maximum dose,
`al-
`ages were significantly more effective
`though some psychiatrists give a max-
`when given to patients under 40, hospi-
`imum of 2000 mg. in 24 hours.
`talized less than 15 years, who had been
`SPECIAL
`‘THERAPEUTIC
`REGIMENS.
`receiving a nonpiperazine phenothia-
`Rapid Tranquilization. The immediate
`zine beforehand. There waslittle dif-
`treatment of the acutely psychotic with
`ference in high dosage and low dosage
`the maximally tolerated dosages of
`regimens in other patient subgroups.
`phenothiazines is advocated by some to
`Those who had been on higher dosages
`facilitate ego reorganization and social
`beforehand were more likely to fail.
`adaptation. Such treatment seems to be
`For older patients, high dosage caused
`particularly valuable when the patient
`a great increase in side effects. Dyskine-
`is seriously confused and incapable of
`sias occur in as high as 25 per cent of
`engaging in meaningful verbal com-
`patients treated with high dosage regi-
`munication with others.
`mens, particularly among the aged.
`This method of treatment requires
`Long-Acting
`Agents. Fluphenazine
`the quick establishment of a maximal
`hydrochloride has been foundto retain
`daily dosage for each individual. Polak
`its physiological activity longer than any
`and Laycomb recommendthat the pa-
`tient be given an initial dose of 25 to
`other phenothiazine. This is probably
`due to its higherfat solubility than that
`50 mg. of chlorpromazine orally and be
`observed closely for side effects for one
`of the other analogues. When com-
`
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`

`PHARMACOLOGICAL THERAPY
`
`839
`
`(en-
`bined with various acid esters
`anthic, decanoic, and lauric), its release
`from fatty tissue is
`further
`slowed.
`Thus the hydrochloride will demon-
`strate action for from twoto