Treatment of Negative
440
by William T. Carpenter, Jr.,
Douglas W. Heinrichs, and
Larry D. Alphs
Symptoms
Abstract
The rational treatment of the
negative symptoms of schizophrenia
requires a careful differentiation of
those secondary to a range of other
factors and those that constitute
enduring primary or deficit
symptoms. Secondary negative
symptoms are usually responsive to
treatment of the underlying cause. In
contrast, there is no intervention
currently available with established
efficacy in treating deficit symptoms.
These distinctions serve to reduce the
heterogeneity of negative symptoms.
A discussion of the diagnosis and
treatment of the various forms of
secondary negative symptoms is
followed by suggestions for future
research in the treatment of deficit
symptoms.
The manifestations of schizophrenic
psychopathology are diverse,
nonpathognomonic, and often
confusing (Carpenter, Strauss, and
Muleh 1973; Tsuang 1975; Pope and
Lipinski 1978; Carpenter and Strauss
1979; Fenton, Mosher, and Matthews
1981). Furthermore, cross-sectional
symptom expression has only a
modest predictive relationship to
natural course (Kendell, Brockington,
and Leff 1979; Strauss and Carpenter
1979) and treatment response
(Goldberg et al. 1972). It may be
useful to group symptoms into
meaningful, distinct dimensions and
Strauss, Carpenter, and Bartko
(1974) proposed three: positive, or
expressive, symptomatology;
negative, or deficit, symptomatology;
and social symptomatology. These
distinctions, consistent with initial
descriptions of dementia praecox
(Kraepelin 1971), have proved useful
in delineating the nature of chron-
icity and residual impairment for
diagnostic purposes (American
Psychiatric Association 1980), in
defining the continuity between early
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or premorbid signs and subsequent
course (Strauss and Carpenter 1974,
1979), and in calling critical attention
to shortcomings in treatment efficacy
studies that limit dependent measures
to a single domain (Carpenter,
Heinrichs, and Hanlon 1981). It is
the longstanding practice of reporting
treatment effects in terms of either
ill-defined global measures or
narrowly defined positive symptoms
that has left the field poorly
informed concerning the long-term
effect of antipsychotic drugs on core
aspects of schizophrenia (Carpenter
1980, 1984).
Systematic attention to the several
central psychopathological dimen-
sions in schizophrenia will make all
treatment studies more informative
as to the strengths, limitations, and
adverse effects of each treatment and
will focus attention on aspects of
psychopathology for which effective
therapeutics have not been
developed.
Hughlings Jackson (1884, 1894)
viewed negative symptoms as direct
manifestations of tissue injury or
necrosis, and positive symptoms as
secondary, disinhibitory phenomena.
He also characterized positive
symptoms as distortions and exagger-
ations of normal function, and
negative symptoms as loss of normal
function or capacity. It is in this
latter, more descriptive sense that
current workers are defining negative
symptoms (Strauss and Carpenter
1974; Krawiecka, Goldberg, and
Vaughan 1977; Crow 1980; Owens
and Johnstone 1980; Andreasen and
Olsen 1982; Lewine, Fogg, and
Meltzer 1983; Heinrichs, Hanlon, and
Carpenter 1984; Pogue-Geile and
Reprint requests should be sent to
Eh-. W.T. Carpenter, Jr., Maryland
Psychiatric Research Center, P.O. Box
3235, Baltimore, MD 21228.
VOL 11, NO. 3, 1985
Harrow 1984), although Crow (1980)
hypothesizes that exaggerated
dopaminergic function may underlie
the positive symptom dimension, and
structural impairment may underlie
the negative symptom dimension in
schizophrenia. Berrios (1985) recently
traced the negative/positive
terminology to a discussion of
Reynolds [in 1858] and believes de
Clerambault (1942) first emphasized
the distinction in psychiatry. In
contrast to Jackson, Reynolds
assumed independence rather than
interdependence of positive and
negative symptoms. This view is
accepted by most current workers.
An association between the negative
symptom dimension and structural
change is supported by computed
tomographic (CT) studies (Andreasen
et al. 1982; Pearlson et al. 1984) and
earlier pneumoencephalographic
work (Huber, Gross, and Schiittler
1975; Pearlson et al. 1984). The list
of specific symptoms generally
regarded as negative is lengthy and
controversial (Strauss and Carpenter
1974; Crow 1980; Owens and
Johnstone 1980; Andreasen and
Olsen 1982; Lewine, Fogg, and
Meltzer 1983; Pogue-Geile and
Harrow 1984; Heinrichs, Hanlon,
and Carpenter 1984; Allen, 1984)
(also see this issue of Schizophrenia
Bulletin) but includes restricted and
blunted affective arousal and respon-
sivity, narrowing of ideation and
curiosity, paucity in content of
speech, diminution in social drive,
apathy or inertia, and abulia.
It is useful to describe the above
range of psychopathic features as
negative symptoms in schizophrenia,
but four caveats are required. First,
negative symptoms are not unique to
schizophrenia (Pogue-Geile and
Harrow 1984; Pearlson et al. 1984).
Second, even when they occur in
schizophrenia, they may have
multiple causes, not all intrinsic to
the schizophrenic illness. Third, their
course and treatment response are
variable. Fourth, the presence of
negative symptoms is not
synonymous with a deteriorating or
unremitting course. Thus, we believe
that the term "negative symptoms" is
best used descriptively without impli-
cations as to pathogenesis or perma-
nence (Carpenter, Wagman, and
Heinrichs 1984; Carpenter, Heinrichs,
and Wagman, in press).
It is useful to define secondary
negative symptoms as resulting from
factors extrinsic to schizophrenia or
as consequential to other psycho-
pathological dimensions of schizo-
phrenia (e.g., positive symptoms). In
contrast, negative symptoms without
such apparent causes are viewed as
core features of the illness and are
defined as primary. Often such
primary negative symptoms are
consistently present over long periods
of time (although they may vary in
intensity) despite fluctuations in
other aspects of the disease state.
Such symptoms are likely to have
important implications for prognosis
and subtyping, and can be distin-
guished by reserving the term "deficit
symptoms" for these enduring
primary negative symptoms. These
distinctions are of more than
academic interest. In the first place,
the controversy surrounding respon-
siveness of negative symptoms to
antipsychotic drugs might be
resolved if primary, enduring deficit
symptoms were distinguished from
secondary, transitory negative
symptoms. It seems evident that the
latter often respond if a simultaneous
reduction in positive symptoms is
obtained, while the former have not
yet been isolated for specific study.
In the second place, transitory
negative symptoms may prove of
little theoretical consequence, while
enduring negative symptoms
(deficits) may importantly subdivide
441
the schizophrenic syndrome and
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define a more homogeneous disease
entity (Crow 1980; Carpenter,
Wagman, and Heinrichs 1984;
Carpenter, Heinrichs, and Wagman,
in press). Finally, the deficit
symptoms may define a dimension
that merits close scrutiny in studies
concerning the pathological conse-
quences of genetic, gestational,
seasonal, neurological, and other risk
factors in schizophrenia (Crow 1980;
Owens and Johnstone 1980;
Andreasen et al. 1982; Dworkin and
Lenzenweger 1984; Carpenter,
Heinrichs, and Wagman, in press).
Although there is little empirical
evidence from well-designed studies
concerning treatment of negative
symptoms, the differentiation of
types of negative symptoms has
practical relevance for planning
therapeutics.
Treatment of Secondary
Negative Symptoms
The differential diagnosis of
secondary negative symptoms is
crucial, for treatment is generally
aimed at the primary factor. The
following are the more common
categories.
Negative Symptoms Associated With
Psychosis. Many patients are
observed to have an increase in
negative symptoms that coincides
with exacerbations of psychosis. The
mechanism of this association is
unclear. The disorganization of the
patient's psychic functions or the
psychotic preoccupation with
idiosyncratic inner experience may
both reduce cathexis to the
environment and impair the
individual's capacity to interact
meaningfully with others. Alterna-
tively, diminutions in emotional
expression, curiosity, and interper-
442
sonal involvement could constitute a
defensive maneuver to dampen
external stimuli in a person whose
cognitive and perceptual processes
are becoming overwhelmed and
dysfunctional. In either case,
negative symptoms of this sort ebb
and flow with the psychotic
experience, and effective treatment of
the psychosis ameliorates these
symptoms along with positive ones.
The literature has amply demon-
strated that negative as well as
positive symptoms improve in
response to neuroleptic drugs (Davis
1980). It may be this type of
psychosis-linked secondary negative
symptom that accounts for the obser-
vation of improvement. Any antipsy-
chotic drug can be expected to reduce
such symptoms, but some antipsy-
chotic drugs may prove more effica-
cious than others in this regard.
Gould (1983) hypothesizes that
neuroleptics which block calcium ion
channels may be uniquely therapeutic
in the alleviation of negative
symptoms. The data reviewed show
a slight posttreatment advantage in
negative symptom ratings in patients
treated with calcium-blocking neuro-
leptics, but the major effect is the
pretreatment to posttreatment
decrease in symptomatology
produced by all classes of antipsy-
chotics. The apparent slight
advantage associated with calcium
channel blockers may relate to
reduced side effects, noncomparable
dose, different effects on calcium ion
channels, or other factors. The study
designs do not permit isolation of
effects on enduring deficit symptoms.
Nonpharmacological therapeutic
interventions that ameliorate
psychosis (e.g., enhancing coping,
decreasing stress) are also likely to be
of benefit with respect to negative
symptoms secondary to psychotic
decompensation. These strategies
may be especially relevant to long-
term outpatient treatment aimed at
preventing relapse (Falloon and
Liberman 1983).
It is noteworthy that most studies
of negative symptoms to date have
focused on actively psychotic, hospi-
talized patients. Conclusions drawn
from this work are at least partially
applicable to the type of secondary
negative symptom under discussion
here. Whether primary negative
symptoms respond directly to these
treatments requires testing during
clinical stability of psychotic
symptoms.
Negative Symptoms Secondary to
Antipsychotic Drugs. Drug side
effects may mimic negative
symptoms (e.g., akinesia, sedation)
(Hollister 1974). Such manifestations
may be subtle and occur in the
absence of frank parkinsonism. A
high index of observer sensitivity is
needed to detect them consistently.
Treatment options include anticholin-
ergic drugs, reduction in neuroleptic
dose, use of a different neuroleptic
agent, or drug discontinuation within
a targeted pharmacological approach
(Herz, Szymanski, and Simon 1982;
Carpenter and Heinrichs 1983).
Although not well established on
the basis of existing data, there is a
potentially more fundamental
relationship between neuroleptic drug
action and negative symptoms.
Psychological and behavioral changes
similar to negative symptoms (e.g.,
apathy, lack of spontaneity, and
impaired affective arousal) have been
induced in infrahuman primates
(McKinney et al. 1980; Carlson 1981;
McKinney and Moran 1981) and
nonpsychotic humans (Baldessarini
1980) by neuroleptic drugs.
Furthermore, preclinical evidence
suggests that the negative symptom-
like effects of neuroleptic drugs
cannot be simply ascribed to a gener-
alized motor depression resulting
SCHIZOPHRENIA BULLETIN
from sedation. Silverman (1965) has
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demonstrated that although chlorpro-
mazine reduces mating and
aggression in rats, it does not
produce changes in exploratory
activity, and it actually increases
escape behavior. His work suggests
that chlorpromazine results in a
general blunting of exteroceptive cues
associated with the presence of other
rats. Besides the effects on mating
and aggression, there was also a
reduction of the sensitivity to
amphetamine normally associated
with placing animals in crowded
living quarters. Similarly, McKinney
et al. (1980) have examined the social
behavior of rhesus monkeys after
chronic chlorpromazine treatment.
They too observed significant social-
behavioral effects (withdrawal from
or indifference to social and
nonsocial environment). However,
the doses of drugs they used were
high, and sedative effects were
prominent.
Some investigators have noted that
chemical lesions of the noradrenergic
reward system result in decreased
auto-stimulation and rewarded
behaviors. On this basis they have
proposed that schizophrenic
symptoms may result from
disruption of the central noradren-
ergic reward system (Stein and Wise
1971). Although neuroleptics do not
produce neuroanatomical lesions,
noradrenergic receptor blockade by
these drugs would theoretically be
functionally equivalent and, as such,
might produce negative symptoms
like anhedonia by a similar
mechanism (Stein and Wise 1971;
Strauss and Carpenter 1972; Mackay
1980). Based on these considerations,
patients in whom negative symptoms
are an enduring feature of their
illness should be considered as candi-
dates for drug reduction (Kane et al.
1979, 1982) or discontinuation
(Carpenter et al. 1982; Herz,
VOL. 11, NO. 3, 1985
Szymanski, and Simon 1982;
Carpenter and Heinrichs 1983).
Negative Symptoms in Response to
Understimulating Environments.
Studies in social psychiatry (Barton
1959; Wing and Brown 1970) have
stressed that custodial institutional
environments can so reduce stimu-
lation and social demands that
dysfunction in the form of negative
symptoms such as decreased sponta-
neity, reduction in curiosity and
ideation, reduced drive to interact,
and blunted affect may result. The
extent to which similar deprivation is
found in more extensive community-
based programs is uncertain, but the
naive hopes that deinstitutional-
ization would eradicate this problem
have been replaced by the knowledge
that many patients live in circum-
stances presenting minimal inter-
action and social expectations. To
the extent that negative symptoms
are associated with understimulation,
treatment must include attention to
environmental conditions and the
adoption of strategies to alter the
circumstances in which the patient
lives. A patient whose time is spent
mostly alone in a room may thus be
encouraged to spend more time in a
partial care center, in interacting
with family, in undertaking certain
structured tasks, and in assuming
increased responsibilities. The need
to enrich the patient's environment
must be balanced with the risk of
inducing psychosis by unrealistic
expectations or excessive stimulation
(Hirsch 1976; Wing 1977, 1978;
Carpenter and Heinrichs 1980;
Schooler and Spohn 1982). Indeed,
when efforts to mobilize the patient
are excessive, the experience of
impending psychotic disintegration
may lead to an exacerbation of
negative symptoms as the patient
engages in a defensive withdrawal
from the environment. When this
occurs, a temporary backing away
from new demands and expectations
may lessen negative symptoms that
are secondary to the threat of
psychosis. A general guideline for
determining the appropriate level of
environmental stimulation is not
possible. Each case must be carefully
titrated on a trial and error basis,
taking into account the full range of
factors influencing the patient at a
given time. In some cases, training in
social skills and coping strategies
(Liberman et al. 1980; Wallace et al.
1980; Falloon and Liberman 1983)
may allow patients to lead richer
lives without inducing stress-precipi-
tated psychosis.
Negative Symptoms Associated With
Dysphoric Affect. Episodes of
depression are a common occurrence
in schizophrenic patients (McGlashan
and Carpenter 1976a, 1976b, 1979;
Mandel et al. 1982). This should not
be surprising as schizophrenic
patients typically have much to be
depressed about, including the stigma
of a major mental illness, impaired
occupational achievement, disrupted
social relationships, loss of sense of
self and esteem, and exposure to
drugs that may be depressogenic. If
schizophrenia provides any immunity
to a depressive reaction to loss and
stress, it is through processes such as
reduced affect arousal and distorted
thinking—characteristics that
themselves may lead to a state of
chronic demoralization. Clinicians
may be less sensitive to dysphoric
affect in the psychotic individual,
and impaired ability to integrate
inner experiences and feelings may
make the recognition of depression
more difficult in these patients. The
most prominent manifestation, then,
may be negative symptoms—
anhedonia, apathy, abulia, decreased
social drive, and poverty of speech.
Since spontaneous manifestations of
443
depressive affect may be muted, a
careful probing may be needed to
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uncover depressive themes. Negative
symptoms secondary to depression
respond to treatment of the
depression per se. Although general
efficacy is not robust, some patients
respond to traditional antidepressant
drugs (Becker 1970, 1983; Hanlon,
Ota, and Kurland 1970; Simpson et
al. 1972; Chouinard et al. 1975;
Siris, van Kammen, and Docherty
1978; Prusoff et al. 1979; Waehrens
and Gerlach 1980). There is, of
course, the theoretical concern that
these medications may exacerbate
schizophrenic psychosis, but evidence
to date suggests this is not a frequent
complication (Siris, van Kammen,
and Docherty 1978). Careful
monitoring of the patient's clinical
state is critical, and antipsychotic
drugs may be increased if psychosis
worsens. If depression is secondary
to use of drugs, then drug reduction
or discontinuation may be
considered. Psychotherapeutic inter-
vention may focus on sources of
impaired self-esteem, the devel-
opment of realistic expectations in
pursuit of which the patient can
experience success, and support in
implementing improvements in life
circumstances.
A similar consideration can be
given to the role of anxiety in
causing anhedonia and social disen-
gagement. Interpersonal therapeutics
aimed at stress management and the
reestablishment of social and work
functions may be beneficial. Antipsy-
chotic drugs may diminish anxiety
during symptomatic periods. During
periods of stability in psychosis,
antianxiety drugs also merit consider-
ation. To date, the usefulness of
anxiolytics and, more specifically,
benzodiazapines in the treatment of
schizophrenia has only been
examined in preliminary studies. This
work suggests that benzodiazapines
444
are superior to placebo in reducing
anxiety and some psychotic
symptoms of schizophrenia in
subpopulations of schizophrenic
patients and are unhelpful in others.
No clear pattern of symptoms
characterizing these populations has
yet emerged, and more controlled
followup studies are necessary to
establish their efficacy with respect to
negative symptoms (Donaldson et al.
1983).
Postpsychotic depression deserves
special emphasis. Although treatment
considerations are similar to those
described above, a phase-specific
syndrome characterized by apathy,
social withdrawal, blunted affect,
and reduced initiative is a frequent
sequel to psychotic episodes in
schizophrenic patients (McGlashan
and Carpenter 1976b). Its etiology
and pathogenesis are unclear. It has
sometimes been viewed as a
depressive reaction to the psychotic
experience, but it is generally not
responsive to antidepressants
(McGlashan and Carpenter 1976b).
Conversely, it has been viewed as a
restitutive phase needed to reestablish
psychic equilibrium after a period of
psychological disorganization
(McGlashan and Carpenter 1976b).
The syndrome may be self-limiting
after a period of several months. It
has been argued that the patient's
regression and increased dysfunction
should be met with reduced demands
coupled with consistent but nonin-
trusive interpersonal support
(McGlashan and Carpenter 1976b)
until this phase resolves. Such a
strategy in an age of brief hospitali-
zation requires considerable
education of others in the patient's
community setting, such as family
members (Anderson, Hogarty, and
Reiss 1980). There are data
suggesting that the depression
observed after stabilization of active
psychosis is a perseverance of
previously unnoticed depression and
that antipsychotic drugs may delay
the resolution of this depression
(McGlashan and Carpenter 1976b;
Schooler and Spohn 1982).
Furthermore, differentiating this
phase of schizophrenia from demor-
alization is difficult.
Treatment of Primary,
Enduring Negative (Deficit)
Symptoms
Even with optimal treatment of all
secondary symptoms, a subgroup of
schizophrenic patients manifests
enduring negative symptoms of a
primary nature. It is this form of
negative symptom that has stood at
the core of clinical descriptions of
schizophrenia since Kraepelin (1971)
and Bleuler (1950). Thus defined,
such symptoms provide a basis for
Crow (1980) to distinguish between
type I and type II schizophrenia.
Frequently appearing irreversible,
they may mark the presence of a
psychopathological process absent in
patients whose schizophrenic
manifestations are either exclusively
positive or positive with transient
negative manifestations. This type of
symptomatology has not proved
pathognomonic of schizophrenia but
is found to occur far more frequently
during stable followup periods in
schizophrenic patients than in
patients with affective disorders
(Pogue-Geile and Harrow 1984). It is
possible that with careful differenti-
ation between primary and
secondary attributes, the deficit
syndrome may prove highly discrimi-
nating for one type of schizophrenia
(e.g., process schizophrenia). This
psychopathological dimension may
be related to the personality disrup-
tions that underlie the schizophrenia
spectrum and differentiate it from
acute, good prognosis psychotic
illnesses (Kety et al. 1968; McCabe et
al. 1971; Gottesman and Shields
SCHIZOPHRENIA BULLETIN
1976; Carpenter and Stephens 1982;
Kendler and Gruenberg 1984;
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Dworkin and Lenzenweger 1984). It
is this psychopathological process for
which there are virtually no
treatment results based on controlled
studies and for which there is
presently no known effective remedy.
Experimental approaches to the
treatment of deficit symptoms based
on hypotheses about their nature and
mechanism are sorely needed. The
following presents two possible
avenues for future research in this
regard.
• Do deficit symptoms reflect a
relative deficiency in brain amine
activity? Both preclinical and clinical
evidence suggests that disruption of
central catecholaminergk neurotrans-
mitter systems may underlie the
expression of negative symptoms.
Lines of supporting evidence follow:
(1) Deficit symptoms observed in the
social isolation model of schizo-
phrenia in rhesus monkeys are
associated with specific changes in
catecholamine metabolites that
parallel those that have been
reported in schizophrenic patients
with prominent negative symptoms
(McKinney et al. 1980). In rats, 6-
hydroxydopamine lesions of the
noradrenergic reward system result in
symptoms reminiscent of the negative
symptoms of schizophrenia in man
(Stein and Wise 1971; Strauss and
Carpenter 1972). Specifically, investi-
gators have observed decreased
autostimulation of the medial
forebrain bundle and other rewarded
behaviors. Furthermore, the
behaviors resulting from 6-hydroxy-
dopamine administration can be
specifically inhibited when rats are
pretreated with chlorpromazine
before 6-hydroxydopamine adminis-
tration (Stein and Wise 1971). These
observations lead to the suggestion
that in the schizophrenic patient
VOL. 11, NO. 3, 1985
dopamine is co-released from presyn-
aptic noradrenergic terminals of the
medial forebrain bundle. This
dopamine is autoxidized to 6-
hydroxydopamine, which gradually
destroys local noradrenergic vesicles
and nerve endings. The loss of the
structural integrity of the noradren-
ergic reward system is proposed as
causing many of the negative
symptoms characteristic of schizo-
phrenia. (2) Prolonged administration
of cr-methyl-p-tyrosine, a drug that
inhibits tyrosine hydroxylase and
thus limits synthesis of catechola-
mines, has been shown to result in a
syndrome characterized by decreased
social interactions, decreased social
initiative, changes in posture and
facial expression suggesting
withdrawal and lack of concern for
the environment, and retarded motor
activity. Some of these symptoms
appeared to be partially reversed
with L-dopa treatment, and all were
reversed when a-methyl-p-tyrosine
was discontinued (Redmond et al.
1971). (3) Parkinson's disease, an
illness associated with the loss of
dopaminergic neurons in the
substantia nigra and, consequently,
decreased dopaminergic activity, is
characterized by flat affect and other
negative symptoms similar to those
found in schizophrenia. (4) Encepha-
litis lethargica, a presumed viral
illness with a propensity to affect
dopaminergic systems, is associated
with emotional deterioration and
"psychic torpor" similar to that
associated with negative symptoms
(Economo 1931). (5) As detailed
earlier in this review, the adminis-
tration of neuroleptics is frequently
associated with affective flattening,
anhedonia, loss of initiative, and
apathy. Furthermore, these character-
istics are associated with specific
effects of neuroleptic drugs on neuro-
transmitter systems and not with
their nonspecific sedative effects
(Wise 1982). (6) Homovanillic acid
accumulation in human cerebrospinal
fluid has been reported to be particu-
larly decreased in schizophrenics with
poor prognosis as characterized by
emotional blunting, poor premorbid
social adjustment, and schizoid
personality (Bowers 1974). (7)
Apomorphine-induced growth
hormone response in schizophrenic
patients, otherwise controlled for sex,
age, and weight, significantly corre-
lates with negative symptom scores
on the Schedule for Affective
Disorders and Schizophrenia-Change
Version (SADS-C), suggesting that
these individuals may have some
derangement of one of their central
dopaminergic pathways. (8) Finally,
there are several reports that
treatment of schizophrenic patients
with dopamine agonists may result in
significant, if incomplete, treatment
of negative symptoms. Specifically,
Angrist, Rotrosen, and Gershon
(1980) have demonstrated that neuro-
leptic-free patients with predomi-
nantly negative symptomatology
treated with a single dose of d-
amphetamine (0.5 mg/kg) show
significant reduction of negative
symptoms 3 hours after adminis-
tration of the drug. However, this
effect was not observed in patients
with predominantly positive
symptoms. Similarly, prolonged
treatment with L-dopa has been
reported to be effective in improving
blunted affect, emotional
withdrawal, and apathy in patients
with prominent negative symptoms.
(Gerlach and Liihdorf 1975; Alpert
and Rush 1983; Friedhoff 1983).
• Do deficit symptoms reflect
frontal lobe dysfunction7 Personality
alterations similar to negative
symptoms (and to other schizo-
phrenic symptoms as well) frequently
accompany known frontal lobe
disease (Teuber 1964; Luria 1966,
1973; Blumer and Benson 1975).
445
Among these are blunted aHect,
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apathy, impaired social judgment,
inability to sustain motivation and
carry tasks to completion, constricted
curiosity, difficulty changing mental
set, and psychomotor abnormalities.
While there is no conclusive evidence
of frontal lobe disease in schizo-
phrenia, there are some suggestions
that at least a subgroup of schizo-
phrenics have frontal lobe
dysfunction, either as a result of
direct frontal lobe damage or of
abnormalities in subcortical systems
that innervate the frontal lobes.
Blunted affect in schizophrenia has
been shown to correlate with
impairment on motor tasks that
depend on frontal lobe integrity (Cox
and Ludwig 1979; Manschreck 1983;
Manschreck and Ames 1984). In
addition, blood flow to the frontal
lobes has been shown in some
patients to decrease when tasks that
rely heavily on frontal lobes are
attempted (Berman et al. 1984).
There has also been some prelim-
inary evidence from cerebral blood
flow and positron emission tomog-
raphy (PET) studies suggesting a
relative hypofrontality in schizo-
phrenia (Ingvar and Franzen 1974;
Farkas et al. 1980; Widen et al. 1981;
Buchsbaum et al. 1982), although
this finding is controversiiil
(Sheppard 1983; Buchsbaum et al.
1984). Neurophysiological deficits
have been reported in schizophrenic
subjects with the specific symptoms
of anhedonia, and Roth (1977) and
Miller, Simons, and Lang (1984) have
demonstrated that P300 and negative
slow waves are deficient after low
probability, hedonic stimuli in both
schizophrenic patients and college
students with high levels of
anhedonia.
If negative symptoms reflect
frontal lobe dysfunction, an
approach to treatment is suggested.
Recent years have seen the devel-
446 SCHIZOPHRENIA BULLETIN

opment of specific cognitive rehabil- considerably more treatable. This episode. If the patient is currently in

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itation strategies geared for
impairments characteristic of various
cerebral defects in patients with
known organic lesions. Although
such therapies with frontal lobe
patients have proved to be more
difficult than for many other lesions
(Gudeman, Golden, and Craine
1978), some techniques appear
promising (Luria 1963, 1974; Craine
1982). Included among those that
may be applicable to schizophrenic
patients with deficit symptoms are
the following: (1) problem-solving
strategies that stress the use of
formalized programs to develop
stepwise solutions to complex tasks;
(2) articulated feedback to help
patients assess the consequences of
incorrect solutions and counterpro-
ductive behavior; (3) exercises to
develop verbal fluency; (4) exercises
to instill intellectual flexibility—that
is, the ability to change set; (5)
training that enables patients to use
verbal programs from others, and
eventually from themselves, to
regulate behavior no longer
controlled by unconscious and
task can be complicated in that
primary and secondary negative
symptoms can co-exist, as can
multiple forms of secondary negative
symptoms. Figure 1 presents a model
for the comprehensive assessment
and treatment of negative symptoms.
If negative symptoms are present,
the initial consideration is whether
they are linked to a current psychotic
Figure 1. Model for assessment and treatment of negative
symptoms.
If negative symptoms
I
Actively psychotic?
tf negative
symptoms
No
If negative
Dysphoria?
symptoms
an episode of psychosis, any negative
symptoms present could be manifes-
tations of the same process or a
defensive reaction to it. In this case,
the symptoms should respond to the
same therapeutics that are effective in
treating the psychosis per se. Thus,
the use of neuroleptic drugs and
environmental manipulation to
reduce stimulation, including
Yes
Neuroleptlc8
Reduce stimulation
Yes
Antichollnergics
Reduce neuroleptlcs
Yes

automatic sequencing schemata that No

Antl depressants
rely heavily on frontal lobe integrity;
and (6) that possible behavior can be If negative Anxiolytics
Recent
analyzed and consequences antici- psychosis? symptoms
pated. Work in this area is prelim- Reduce neuroleptlcs

inary, and further developments and Psychotherapy

assessment of specific techniques are
No
needed; yet the effort to date is Yes
encouraging with patients with
known frontal lesions and could be Supportive therapy
If negative
attempted in schizophrenic patients Understlmulating
environment? symptoms Wait and reassess
with deficit symptoms.
Yes
No
Increase activity
An Assessment/Treatment Chronic If negative
Skills training
Model medication? symptoms

Yes
It is critical for the treatment of
negative symptoms to differentiate
Decrease or discontinue
secondary from primary symptoms, Probable If negative neuroleptlcs
since the former are likely to be deficit
symptoms
symptoms
VOL 11, NO. 3, 1985
hospitalization when necessary, is
advised.
Once the psychosis is resolved, or
if the patient has not been in a
psychotic episode, the possibility that
negative symptoms are drug-induced
(e.g., akinesia, sedation) should be
considered. Although the presence of
other extrapyramidal symptoms is
suggestive, akinesia can be subtle and
need not be accompanied by parkin-
sonian manifestations. Therefore, a
trial of anticholinergic agents, a
reduction in neuroleptic dose, or
both can be useful strategies.
If negative symptoms remain after
treatment of suspected side effects,
the affective state of the patient
should be considered. If the patient is
suffering from depression or anxiety,
it is possible that negative symptoms
are a manifestation of an underlying
affective disturbance, and antide-
pressants or anxiolytics may prove
useful. Since it has been argued that
neuroleptics may induce depression
in some patients, a reduction in
neuroleptic dose may be indicated. In
addition, psychotherapy may be
beneficial in dealing with issues in
the patient's life that have played a
role in inducing dysphoria.
If negative symptoms remain after
adequate treatment of the patient's
dysphoria or if no dysphoria is
present, the possibility of a
postpsychotic depression should be
considered. If the patient has recently
recovered from a psychotic episode,
one might anticipate a period,
usually lasting several months, in
which negative symptoms are
pronounced. There is no specific
treatment for this condition. A
supportive therapeutic relationship,
nonpressuring but consistent, is
considered to be important. In
addition, the patient and family
should be informed about this aspect
of the postpsychotic state and
encouraged to persevere. The patient
should be followed closely and
periodically reassessed.
If negative symptoms continue to
be unresolved long beyond the
psychotic episode, the possibility that
the patient is exposed to a chron-
ically understimulating environment
should be considered. If there are
insufficient demands, interpersonal
stimulation, and activity, the patient
should be urged to increase activity
and involvement with others in a
series of manageable steps. This
process is facilitated by helping the
patient develop the necessary inter-
personal and instrumental skills to
meet the requirements of increased
participation in living.
If negative symptoms persist in
spite of an adequately stimulating
environment, the possibility should
be considered that neuroleptic
medication is inducing the
symptoms. This process refers not to
akinesia but to a direct undermining
of these functions. Although specu-
lative, this possibility should be
considered after all of the above
possibilities have been excluded.
Patients on chronic neuroleptic
medication with enduring negative
symptoms may have drugs decreased
or discontinued as long as there is no
evidence of an acute psychotic
episode.
If enduring negative symptoms are
present in spite of the systematic
exploration of the above sources of
secondary effects, the clinician is
reasonable in assuming that a
primary deficit syndrome is present.
Unfortunately, the prospects for the
successful treatment of the deficit
state are poor. Hence, it is especially
important to avoid the premature
assumption that the deficit state
exists when in fact the patient may
be suffering from a treatable form of
secondary negative symptoms. The
model herein proposed is designed to
facilitate a systematic exploration of
447
the latter possibility. Changes in the
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patient's clinical state and life
situation will require periodic
reassessment of the possible sources
of negative symptoms. The list of
therapeutic interventions in the
model proposed is not exhaustive;
rather it simply contains therapeutic
interventions that most specifically
relate to each type of secondary
negative symptom.
Conclusions
Renewed interest in negative
symptoms is heartening. Preoccu-
pation with positive symptoms has
led to a neglect of this area, which
constitutes the most debilitating and
refractory aspect of psychopathology
for many schizophrenic patients. The
distinction between primary (deficit)
and secondary negative symptoms is
important because accurate detection
of the latter can lead to efficacious
treatments. Research on the
treatment of deficit symptoms is
sorely needed, and several potential
avenues for future work have been
suggested. Educating patients and
their families about these symptoms
can play a valuable role in
preventing adverse consequences
associated with misunderstanding.
Delineating the pathogenesis and
treatment of primary negative
symptoms constitutes the greatest
current challenge to those responsible
for the care of the schizophrenic
patient. A clear distinction between
transitory negative symptoms and
deficit processes offers new leverage
in reducing the heterogeneity of the
schizophrenic syndrome.
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Acknowledgment
The work reported was supported in
The Family Support Group of the
Northeast Ohio Chapter of Alliance
for the Mentally 111 is compiling a
resource list of all facilities that are
available to and provide services for
those afflicted with schizophrenia.
All information, inquiries, and
SCHIZOPHRENIA BULLETIN
part by grant MH-35996 from the
National Institute of Mental Health.
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The Authors
William T. Carpenter, Jr., M.D., is
Director; Douglas W. Heinrichs,
M.D., is Chief, Outpatient Research
Programs; and Larry D. Alphs,
M.D., Ph.D., is Clinical Chief,
Inpatient Research Programs,
Maryland Psychiatric Research
Center, Baltimore, MD. In addition,
Dr. Carpenter is Professor of
Psychiatry, and Drs. Heinrichs and
Alphs are Assistant Professors of
Psychiatry, University of Maryland
School of Medicine, Baltimore, MD.
cooperation are solicited. Please
contact:
M. J.ffe
2447 Edgerton Road
Cleveland, OH 44118