The Psychomotor Disorders: Disorders of the Supervisory Mental Processes
The psychomotor disorders: disorders of the supervisory mental processes
P.F. Liddle 0
0 Royal Postgraduate Medical School, Hammersmith Hospital , Ducane Rd, London W120HS , UK
Clinical evidence suggests that three major patterns of disturbance of the supervisory mental processes that regulate selfgenerated mental activity can occur, either alone or together, in a variety of neurological and psychiatric conditions. Psychomotor poverty involves a diminished ability to initiate activity. Psychomotor disorganization reflects impaired ability to select between activities. Reality distortion, which is manifest as delusions and hallucinations, appears to reflect an abnormality of internal monitoring of mental activity. Each of these three syndromes is associated with a specific pattern of disordered function in multimodal association cortex and related subcortical nuclei. The evidence suggests that the neurotransmitter dopamine plays a major role in modulating the supervisory mental processes, though serotonin and noradrenaline are also implicated. While a particular neurotransmitter might have conflicting influences on ditTerent syndromes, the ditTerential involvement of ditTerent anatomic sites and ditTerent neuroreceptor types otTers the possibility of successful treatment even when ditTerent syndromes co-exist.
Association cortex -; Basal ganglia -; Depression -; Dopamine -; Frontal lobes -; Psychomotor disorder -; Schizophrenia
The supervisory mental processes are concerned with the
initiation, organization and monitoring of self-generated
mental activity. In contrast to routine mental functions
such as perception, the laying down of memory traces,
execution of a well-learned motor act, and logical reason
ing, in which the objective of the process is largely pre
determined by circumstances, the supervisory mental
processes are most relevant when there is ambiguity in
what is required. Disorders of these processes are most ap
parent under circumstances that call for initiative.
Disorders of the supervisory mental processes occur in
a variety of neurological and psychiatric conditions. In
some instances, the disorders result from destruction of
brain tissue, as in the famous case of Phineas Gage, the
American railway worker who suffered damage to his
frontal lobes when the premature detonation of an explos
ive charge drove a steel tamping rod through his skull. He
had been a reliable and responsible man, but was trans
formed into a feckless individual lacking in social grace
. Similar patterns of behaviour occur in
conditions in which there is less extensive damage to neu
rons. Although the disorders often arise from neuronal
destruction, degeneration or dysplasia, the evidence sug
gests that the characteristic clinical features reflect imbal
ance of the monoamine neurotransmitters which modulate
In many instances, these disorders are persistent, cause
serious disruption of the life of the sufferer, and impose a
heavy burden on those caring for them. In the past, these
disorders have often evoked a pessimistic response from
health care professionals, because of -limited understand
ing of the nature of the problems and poor response to
treatment. Recent advances in neuroscience, including
advances in brain imaging, have provided a foundation for
better understanding and treatment. This paperreviews the
clinical features of disorders of the supervisory mental
processes in various neurological and psychiatric con
ditions, presents a speCUlative synthesis of information
concerning the neural basis of these disorders, and exam
ines potential strategies for treatment.
PSYCHOMOTOR DISORDERS IN
More than 100 years ago,
phrenia, a disorder characterized by silly behaviour, frag
mentary delusions and self-neglect. His contemporary
identified catatonia, a disorder of the
control of voluntary movement. Early in this century,
combined hebephrenia, catatonia and
deteriorating paranoid disorders into a single entity which
we now call schizophrenia.
that the essential feature of schizophrenia is "that destruc
tion of conscious volition ... which is manifest as a loss of
energy and drive, in disjointed volitional behaviour".
More recently, Liddle and colleagues have carried out a
series of studies designed to delineate the nature of the
neuropathological processes that generate the symptoms
of schizophrenia. On the assumption that several dis
tinguishable though related pathological processes occur
in schizophrenia, Liddle
relationships between persistent schizophrenic symptoms,
and demonstrated' that these symptoms segregate into
three syndromes: psychomotor poverty (poverty of
speech, flat affect, decreased spontaneous movement),
disorganization (disorders ofthe form of thought, inappro
priate affect) and reality distortion (delusions, hallucina
tions). The component symptoms of these syndromes
resemble the clinical features ofthe three classical types of
psychotic illness which Kraepelin had amalgamated to
form schizophrenia. Although distinguishable, the three
syndromes often co-exist, implying that they share some
common feature, supporting Kraepelin's conclusion that
they belong to a single category of illness. Other studies
have reported a similar segregation of schizophrenic
symptoms into three syndromes.
Each syndrome is associated with a specific pattern of
ing that each arises from a different pattern of brain
malfunction. In a study of performance in tests of frontal
lobe function Liddle and Morris (1991) found that psycho
motor poverty is associated with impaired ability to
initiate activity, whilst disorganization is associated with
impaired ability to suppress inappropriate responses.
Meanwhile, in a study of patients with delusions and
Frith and Done (1989)
suggesting that reality distortion symptoms arise from
impaired monitoring of self-generated mental activities.
In a study using positron emission tomography (PET),
Liddle et al. (1992a) demonstrated that each of the three
syndromes is associated with a specific pattern ofregional
cerebral blood flow (rCBF) in areas of association cortex
and related subcortical nuclei. Psychomotor poverty was
associated with decreased rCBF in the left dorsolateral and
medial prefrontal cortex and parietal cortex, and with
increased rCBF in the corpus striatum. Disorganization is
associated with decreased rCBF in the right ventral pre
frontal cortex and contiguous insula, and with increased
rCBF in the right anterior cingulate cortex and thalamus.
Reality distortion is associated with increased rCBF in the
left medial temporal lobe and frontal cortex.
In addition to the three psychomotor syndromes typical
of chronic schizophrenia, there is a fourth syndrome, psy
chomotor excitation, characterized by motor overactivity,
pressure of speech and heightened labile effect, that occurs
during acute schizophrenic episodes, but is transient in
nature. Its neural basis has been less thoroughly
PSYCHOMOTOR DISORDERS FOLLOWING
FRONTAL LOBE INJURY
Psychomotor disorders have long been recognized in
patients with frontal lobes damaged by trauma, tumour or
attempted to delineate the
relationship between the location of the damage and
associated changes in personality. He found that patients
with orbital frontal lesions were likely to exhibit puerile
facetious behaviour, and unstable mood. Patients with
more dorsal lesions tended to have impoverished, stereo
typed thinking and to lack initiative.
Blumer and Benson (1975)
distinguished two frontal
lobe syndromes: pseudodepression characterized by apa
thy, indifference, slowness and decreased tendency to
initiate conversation; and the pseudopsychopathic syn
drome characterized by puerility, euphoria and garrulous
speech. Pseudodepression closely resembles the psycho
motor poverty syndrome seen in schizophrenia, while the
pseudopsychopathic syndrome resembles the dis
organization syndrome. There is controversy concerning
the location within the frontal lobe of lesions likely to
produce these two frontal syndromes. In accord with
Kleist, Blumer and Benson propose that pseudodepression
arises from lesions of the dorsal frontal lobe, while orbital
lesions result in the pseudopsychopathic syndrome. In
Kolb and Whishaw (1980)
suggest that pseudo
depression arises from left frontal lesions and the
pseudopsychopathic syndrome arises from right frontal
In a neurolinguistic analysis of the speech of patients
with frontal lesions,
found that patients
with left dorsolateral prefrontal lesions produce an excess
of simple sentences or sentence fragments, and show per
severation of propositions, a pattern similar to speech in
the psychomotor poverty syndrome. Patients with left
orbital frontal lesions show poor control of speech with
changes of course in response to external or internal
impulses, resembling the tangentiality and derailment
typical of the disorganization syndrome. Kaczmarek also
found evidence that right frontal lobe lesions produce
impairment of the global organization of the information
to be uttered.
Thus, frontal lobe lesions produce at least two dis
tinguishable patterns of impairment. One, characterized
by decreased mental activity, appears to be associated with
left dorsal lesions. The other, characterized by dis
organization of mental activity, is associated with orbital
and/or right-sided lesions.
PSYCHOMOTOR DISORDERS ASSOCIATED
WITH TEMPORAL LOBE EPILEPSY
Temporal lobe epilepsy can be associated with a schizo
phreniform psychosis characterized by delusions and hal
lucinations (reality distortion) but little evidence of either
disorganization or psychomotor poverty.
has reviewed the evidence that epileptic patients with psy
chosis, especially those with Schneiderian first rank symp
toms, have structural and functional abnormalities of the
left temporal lobe. In particular,
Gallhofer et al. (1985)
found an association between psychosis in epilepsy and
left temporal metabolic deficits. These findings are con
sistent with the evidence that reality distortion in schizo
phrenia is associated with altered rCBF in the left temporal
(Liddle et al., 1992a)
. It should be noted that Liddle
et al. found an increase in left temporal rCBF in patients
with persistent stable symptoms, whereas Gallhofer et al.
found decreased left temporal metabolism in patients who
were not necessarily suffering symptoms at the time of
scanning. This would be consistent with a switch from cer
ebral underactivity to overactivity at time of symptom
PSYCHOMOTOR DISORDERS ASSOCIATED
WITH BASAL GANGLION DEGENERATION
The frequent occurrence of psychomotor disorders in
basal ganglia disorders has led to the concept of subcorti
(Huber and Paulson, 1985)
, characterized by
slowing of mental operations, apathy, depression and
memory impairment. There has been debate as to whether
or not this clinical pattern is a direct expression of basal
ganglion malfunction, or a consequence of secondary cor
tical malfunction. If supervisory mental functions are
mediated by neuronal networks distributed in association
cortex and related subcortical nuclei, this debate is perhaps
irrelevant, since basal ganglion disorder might be
expected to produce malfunction of the relevant network.
Patients with Parkinson's disease who have difficulty ini
tiating actions fail to show the normal activation of the
medial and dorsolateral frontal cortex and the putamen
during a task that demands selection and initiation of
action (Playford et al., 1992). This demonstrates that there
is cortical underfunction in patients suffering from diffi
culty initiating activity associated with basal ganglion
Degenerative basal ganglion disorders typically prod
uce a picture of psychomotor poverty. In a study of the
prevalence of psychological symptoms in Huntington's
Caine and Shoulson (1983)
found that apathy and
inertia were the most common, but they also found fea
tures characteristic of the disorganization syndrome, such
as impaired organization of verbal material and lability of
PSYCHOMOTOR DISORDERS IN DEMENTIA
A substantial minority of patients with presenile dementia
present a clinical picture dominated by personality change
with unconcern, disinhibition, and economic, concrete
(Neary et al., 1988)
. These patients have reduced
(Neary et al., 1988)
. At post-mortem exam
ination, some of these patients show the histological
changes of Pick's disease, but some do not.
PSYCHOMOTOR DISORDERS IN DEPRESSION
AND IN MANIA
Psychomotor retardation, which entails slowing and dim
inution of thought and action, is a well-recognized feature
of depression. PET studies of depression (Baxter et al.,
1988) have shown hypometabolism in the frontal lobes,
which appears to resolve on recovery. Bench et al. (in
press) have shown that severity of retardation in
depression is correlated with decreased rCBF in the left
dorsolateral prefrontal cortex, and in the left parietal lobe
in a pattern virtually identical with that associated with
psychomotor poverty in schizophrenia, though unlike the
situation in schizophrenia, there is no evidence of basal
ganglia hyperperfusion. These findings suggest that there
is an overlap in the pathophysiological process underlying
impaired initiation of mental activity in depression and in
On the other hand,
Berman et al. (1993)
depressed patients, unlike patients with schizophrenia, do
not suffer a decreased ability to activate prefrontal cortex
during the performance of the Wisconsin card sorting test.
They argued that the mechanisms underlying prefrontal
dysfunction in depression and in schizophrenia are likely
to be different. This conclusion must be regarded with cau
tion because in their sample of 10 depressed patients, there
was no evidence of decreased frontal perfusion at rest,
whereas other studies
(e.g. Baxter etal., 1989)
frontal underactivity at rest in depression, at least in those
cases exhibiting psychomotor retardation (Bench et al., in
press). Clinical observation indicates that psychomotor
poverty in depression is usually less persistent than psy
chomotor poverty in schizophrenia suggesting that the pri
mary cause is more persistent in schizophrenia, but this
does not preclude possibility that there is substantial over
lap in the mechanism of symptom production in both
In mania, there is not only psychomotor excitation, but
also disorganization of activity, and in some cases,
delusions and hallucinations. The distractibility and for
mal thought disorder of mania are very similar to the dis
organization symptoms of schizophrenia
. The major feature that distinguishes the thought
disorder of mania from that of schizophrenia is that in
mania the tendency to derailment is accompanied by
Pardo et al. (1990)
found that the right anterior cingu
late cortex is the cerebral area most strongly activated in
normal individuals performing the Stroop task, which
demands the suppression of a tendency to respond to irrel
evant aspects of a stimulus. The site of maximal activation
lies within the area of anterior cingulate cortex that is over
active in schizophrenic patients with the disorganization
(Liddle et aI., 1992a,b)
, suggesting that patients
with disorganization are continually engaged in a struggle
to suppress inappropriate responses.
Frith et al. (1992)
demonstrated that in normal individ
uals engaged in learning a novel eye-movement task
Decreases in rCBF
idity of thought, whereas in schizophrenia thinking tends
to exhibit poverty of content and lack of linguistic com
(Morice and Ingram, 1982)
. Thus, the observed
differences between manic and schizophrenic thought dis
order might be accounted for by the greater tendency for
disorganization in schizophrenia to co-exist with psycho
motor poverty whereas in mania, disorganization co
exists with psychomotor excitation.
THE NEUROANATOMICAL BASIS OF
The clinical evidence suggests that psychomotor dis
orders, especially psychomotor poverty and disorganiza
tion, are associated with aberrant activity of association
cortex, especially in the frontal lobes, and related subcorti
) studies of patients with frontal
lobe lesions led him to propose that the frontal lobes are
responsible for programming, regulation and verification
of activity. More recently,
Norman and Shallice (1980)
have proposed the existence of a frontal supervisory atten
tional system which modulates a lower level contention
scheduling system responsible for selection of routine
actions. The supervisory attentional system is involved in
generating willed actions and in making decisions in situa
tions where routine procedures for selecting action would
described two types of
abnormality that would be expected to result from failure
of the supervisory system: behavioural rigidity with a
tendency to perseverate, and distractibility with a tend
ency to be side-tracked into irrelevant associations.
Studies of primates confirm that the frontal lobes play
an important role in supervisory mental functions. On the
basis of an extensive review,
the dorsal and orbital aspects of the prefrontal cortex have
distinguishable roles. He concluded that the dorsal pre
frontal cortex is concerned with time sequencing, while
the ventral prefrontal cortex is concerned with the inhi
bition of inappropriate responses.
has identified a distributed network embracing prefrontal,
cingulate, parietal and temporal cortex which is respon
sible for regulation of behaviour in primates.
PET has been used to study the pattern of rCBF in nor
mal human subjects during the performance of various
tasks that depend heavily on supervisory mental functions.
Frith et al. (1991)
demonstrated that the internal gener
ation of words, and also the internal generation of a
sequence of motor acts, was accompanied by activation of
the dorsolateral and medial prefrontal cortex. The area of
left dorsolateral prefrontal cortex activated in normal in
dividuals during the internal generation of words coin
cided with the area in which rCBF is negatively correlated
with severity of psychomotor poverty in schizophrenia
(Liddle et al., 1992a,b)
Increases in rCBF 11111
Increases in r (BF
which would be expected to make heavy demands upon
the internal monitoring of self-generated activity, there is
increased rCBF in various areas of association cortex. The
locus of maximum activation (apart from association areas
specifically concerned with detection of movement of vis
ual stimuli and with eye movement) is in the left parahip
pocampal gyrus at a site coinciding with the site of
increased rCBF in schizophrenic patients with delusions
(Liddle et al., 1992a,b)
patients with delusions and hallucinations engage in a
pathological degree of internal monitoring of their own
THE PHARMACOLOGY OF PSYCHOMOTOR
On conceptual grounds, it might be expected that neuro
modulatory neurotransmitters would playa major role in
the processes responsible for the initiation and selection of
mental activity. A neuromodulator regulates the electrical
properties of neurons to allow the choice of different res
ponses under different circumstances. Much evidence
suggests that dopamine can act as a neuromodulator. For
Morgenson and Yim (1981)
demonstrated that in
rats release of dopamine in the nucleus accumbens by
stimulation of the ventral tegmental area produces no
direct excitatory or inhibitory responses in neurons in the
nucleus accumbens under resting conditions, but does
attenuate the excitation in the accumbens generated by
stimulation of the amygdala. Thus, it appears that the
dopamine released in the nucleus accumbens in rats (hom
ologous with the ventral striatum in humans) modulates
the action of the glutaminergic neurons projecting from
amygdala to nucleus accumbens.
V sing PET,
Friston et al. (1992)
have obtained evidence
suggesting that apomorphine, a dopamine agonist, and also
buspirone, a 5-HT1A serotonin agonist, exert neuromodula
tory actions in humans. They showed that apomorphine
attenuates the prefrontal activation during a memory task,
while buspirone attenuates the parahippocampal and
retrosplenial activation during the same memory task.
Effects of dopamine agonists on motor activity
Robbins and Sahakian (1983)
have reviewed the behavi
oural effects of drugs, such as amphetamine and L-dopa,
which enhance dopaminergic neurotransmission, in ani
mals and in humans. In general, gross locomotor activity
shows an inverted V-shaped relationship to dose. As dose
increases, locomotor activity initially increases, but then
decreases as locomotion gives way to stereotyped behavi
our.1t is clear that the entire spectrum of abnormal behavi
ours in response to psychomotor stimulants does not
reflect a continuum of activity in a single neuronal system.
There are three relevant dopaminergic systems: nigrostria
tal, mesolimbic and mesocortical. In rats, dopamine
depletion in the nucleus accumbens (mesolimbic system)
attenuates the locomotor activity produced by low doses
(Kelly et al., 1975)
while depletion in the
corpus striatum attenuates stereotypic sniffing and head
movements induced by high dose amphetamine
and Iverson, 1974)
Cortical modulation of subcortical dopaminergic activity
Not only does the evidence suggest that dopamine can act
as a neuromodulator, but there is evidence indicating that
subcortical dopaminergic activity is 'itself modulated by
cortico-subcortical glutaminergic projections. Although
the original findings reported by
Pycock et al. (1980)
6-hydroxydopamine-induced lesions of the prefrontal cor
tex increase dopamine turnover and dopamine receptor
density in the rat striatum have not been confirmed, sub
sequent studies have shown that fronto-subcortical projec
tionsdo influence dopamine receptors in the basal ganglia.
Reibaud et al. (1984)
found that dopaminer
gic denervation of the nucleus accumbens (produced by
lesioning the ventral tegmental area) does not produce the
expected denervation hypersensitivity of accumbens Dl
dopamine receptors while the prefrontal cortex remains
intact. However, after prefrontal lesions that destroy the
fronto-subcortical glutaminergic projections, dopaminer
gic denervation of the nucleus accumbens does produce
Dopaminergic involvement in psychomotor disorders in humans
(Van Praag et al., 1975; Banki, 1977)
shown that dopamine turnover, as measured by the
concentration of homovanillic acid (HVA) in the CSF, is
decreased in depressed patients with psychomotor retar
dation, but not in those without retardation. Wolfe et al.
(1990) demonstrated that low HVA in CSF was associated
with poor performance in frontal lobe tests in depression,
Parkinson's disease and in dementia.
The dopamine precursor L-dopa is an effective treat
ment in some cases of depression, especially those with
(Goodwin et al., 1970; Matussek et al.,
. Indirect dopamine agonists such as amphetamine
produce rapid clinical improvement in apathetic,
depressed elderly patients
(Askinazi et al., 1986; Chiarello
and Cole, 1987)
. In Parkinson's disease, L-dopa relieves
not only hypokinesia, but also a "simple" depressive state,
resembling psychomotor poverty, characterized by
asthenia, inertia and sadness, though it does not relieve
major depression associated with depressive cognitions
such as guilt
(de Aguriaguerra, 1971)
In schizophrenia, low levels of HVA in the CSF are
associated with catatonic symptoms and underactivity
and with failure to activate the pre
frontal cortex during performance in the Wisconsin card
sorting test, which demands flexibility in problem solving
(Weinberger et al., 1988)
Daniel et al.
found that dextroamphetamine alleviated the
failure of frontal activation during this task.
Geraud et al.
found that the dopamine agonist piribedil reversed
the relative frontal hypoperfusion in chronic schizo
phrenic patients in the resting state.
Goldberg et al. (1991)
demonstrated that a single dose
of dextroamphetamine administered to schizophrenic
patients receiving sustained treatment with haloperidol,
produced a modest improvement in affect and in perform
ance of the Wisconsin card sorting test. They argued that it
was likely that these effects were mediated by activation of
cortical dopamine D 1 receptors, since the haloperidol
would be expected to have blocked subcortical dopamine
D2 receptors. This interpretation is consistent with the
Sawaguchi and Goldman-Rakic (1991)
that the Dl agonists SCH23390 and SCH39166 produce
improved performance in working memory tasks when
injected in the prefrontal cortex of monkeys.
proposed that in schizophrenia poverty of
speech and flat affect (cardinal features of the psycho
motor poverty syndrome) reflect structural brain damage
which is manifest as ventricular enlargement. Even if the
fundamental cause of such symptoms is irreversible struc
tural damage, this would not preclude the possibility that
the mechanism of symptom expression entails a disturb
ance of function that can be alleviated by pharmacological
means. In fact,
Goldberg et al. (1991)
found that ventric
ular enlargement was a predictor ofresponsiveness to dex
troamphetamine' confirming that structural damage can
be associated with reversible biochemical imbalance.
Overall, the effects of dopamine agonists on psycho
motor disorders are complex. While the bulk of the evi
dence suggests that dopamine agonists are likely to relieve
psychomotor poverty symptoms, they are likely to exacer
bate other psychomotor symptoms. In the case of schizo
phrenia, dopamine agonists cause improvement in chronic
patients who are withdrawn and apathetic
but exacerbate symptoms such as delusions
and hallucinations in other cases (Janowsky and Davis,
1976). Chronic administration of amphetamine tends to
produce a syndrome resembling mania. As documented in
a review by
, the clinical features include
psychomotor excitation and thought disorders typical of
the disorganization syndrome, as well as delusions and
In general, the evidence suggests that psychomotor pov
erty is associated with dopaminergic underactivity, while
psychomotor excitation, disorganization and reality dis
tortion are associated with dopaminergic overactivity.
However, it is important to realize that disorganization and
reality distortion can occur alone or can co-exist with each
other, and with either psychomotor excitation or psycho
motor poverty. The various psychomotor disorders reflect
at least three distinct dimensions of psychopathology
(Liddle, 1984, 1987a)
. The extent to which psychomotor
poverty and psychomotor excitation are opposite poles of
a single dimension has yet to be determined.
The role of other monoamine neurotransmitters
The well-known hallucinogenic properties of serotonin
5-HT1C and 5-HT2 receptor agonists suggest that serotonin
can be involved in reality distortion. There is also evidence
from studies of animals that serotonin can modulate the
effects of dopamine on levels of motor activity. For
example, the serotonin 5-HT3 agonist, 2-methyl-5-HT,
enhances locomotor activity induced by amphetamine,
while the 5-HT3 antagonist, ondansetron, can inhibit hyp
eractivity induced by dopamine infusion in the nucleus
accumbens in rats, but does not inhibit normal locomotor
Costall et al., 1991
). 5-HT3 receptors are found in
limbic areas, leading Costall et al. to propose that 5-HT3
receptors influence mesolimbic dopaminergic function
without affecting nigrostriatal dopaminergic activity.
Stein and Wise (1971)
proposed that underactivity of
the cortical noradrenergic reward system might account
for deficits of goal-directed behaviour in schizophrenia.
The evidence regardmg noradrenergic activity in schizo
phrenia is inconsistent, possibly because noradrenergic
activity varies depending on the state of the illness. There
is substantial evidence that noradrenergic activity is low in
the stable phase of the illness and high during relapse of
(Van Kammen, 1991)
. Van Kammen
proposes that noradrenaline modulates dopaminergic
function in schizophrenia. Furthermore, in animals,
noradrenergic activity can modulate dopaminergic function
in a region-specific manner. Herve et at. (1982) found that
des truction of noradrenergic fibres in the ventral tegmen
tal area in rats reduced dopamine utilization in prefrontal
cortex but did not in the nucleus accumbens.
Overall, the evidence indicates that dopamine plays a
central role in the modulation of the supervisory mental
functions, but dopaminergic activity is itself modulated
not only by cortico-subcortical glutaminergic projections,
but also by the other monoaminergic neurotransmitters,
serotonin and noradrenaline.
PSYCHOSOCIAL FACTORS AND
Because the supervisory mental functions are most rel
evant when there is ambiguity in what activity is required,
the degree to which disorders of these processes are mani
fest depends greatly on circumstances. It is possible that
the severity of the disorder itself can be exacerbated or
ameliorated by psychosocial factors. In a study of long
stay patients in three mental hospitals,
Wing and Brown
demonstrated that an impoverished environment
with little social or occupational stimulation was associ
ated with greater tendency for the patients to be mute and
apathetic. Furthermore, changes in the level of environ
mental stimulation and opportunity for self-responsibility
were followed by reciprocal changes in psychomotor pov
erty symptoms. However, overstimulation of patients with
schizophrenia is likely to promote relapse with florid
symptoms of psychomotor disorganization and/or reality
(MalIa et at., 1990)
. Studies of animals provide
evidence that links psychosocial factors to dopaminergic
activity in the frontal cortex. Rats subjected to isolation
have decreased frontal dopaminergic activity and height
ened sensitivity to stress
(Blanc et al., 1980)
. While dopa
mine appears to playa cardinal role in the response of the
frontal cortex to stress, noradrenaline and serotonin playa
role in the response of the hypothalamic-pituitary-adrenal
(HPA) axis by promoting release of adrenocorticotrophic
hormone, apparently mediated by corticotrophin releasing
factor neurons in the hypothalamus
(Delbende et al.,
. The relationship of the HPA axis response to stress
and cortical responses requires further exploration.
In principle, the first issue to consider in treatment of psy
chomotor disorders is treatment of the underlying primary
condition. In practice, this is rarely a fruitful approach
because in many instances the underlying problem is neur
onal dysplasia or degeneration. However, the existence of
common clinical and pharmacological features of psycho
motor disorders arising from a variety of different primary
conditions, some of which are reversible, implies that
aspects of the pathophysiological processes that generate
the symptoms are common to psychomotor disorders aris
ing from various causes, and these common aspects are
The issue of treatment is complex because the evidence
suggests that both pharmacological and psychosocial
strategies that alleviate psychomotor poverty are prone to
exacerbate psychomotor disorganization and reality dis
tortion. In general, enhancement of dopaminergic activity
and psychosocial stimulation are likely to be effective in
alleviating psychomotor poverty. Dopamine blockade and
reduction ofunnecessary stimulation are likely to be effec
tive in treating disorganization and reality distortion.
In conditions such as the early phase of Parkinson's dis
ease where there is a negligible predisposition to dis
organization or reality distortion, symptomatic treatment
with dopaminergic agonists is very successful. In the treat
ment of mania and of acute episodes of schizophrenia,
where the need to control the symptoms of disorganization
and reality distortion is paramount, treatment with dopa
mine blocking agents and reduction of external stimu
lation is effective.
However, in the case of conditions such as Huntington's
chorea, and chronic schizophrenia, where there is a predis
position to psychomotor poverty as well as disorganiza
tion and reality distortion, a more complex balancing of
treatments is required. The evidence that these three syn
dromes reflect distinct dimensions of psychopathology
implies that the problem is not so much a matter of contra
dictory treatment objectives, as a need to deal simul
taneously with several different requirements. The
possibility that anatomically distinct dopaminergic neuro
nal systems might be involved in different aspects of the
regulation of brain activity
(Creese and Iverson, 1974;
Kelly et al., 1975)
suggests that one approach is to seek
drugs acting differentially on the different dopaminergic
systems. Alternatively, the strategy employed by Gold
berg et al. (1991) of combining haloperidol with dextro
amphetamine offers the possibility of blocking the
subcortical D2 receptors implicated in florid schizo
phrenic symptoms, while producing an indirect agonist
effect at the cortical D 1 receptors implicated in psychomo
tor poverty symptoms. Although Goldberg's preliminary
results demonstrating modest improvement in affect and
in cognitive performance must be treated with caution,
they indicate that this strategy should be explored further.
However, as it is likely that neurotransmitters other than
dopamine are involved, pharmacological agents that act
on several different neurotransmitter systems might pro
vide an alternative approach. This possibility is consistent
with the evidence that clozapine, which acts on a wide var
iety of neurotransmitter receptors including dopamine D 1,
D2 and D4 receptors, serotonin 5-HT2 receptors and nor
adrenaline alpha-2 receptors, is effective in treating the
entire gamut of schizophrenic symptoms, including psy
chomotor poverty, disorganization and reality distortion
Reports that a low ratio of the dopamine metabolite,
homovanillic acid, to the serotonin metabolite, 5-hy
droxyindole acetic acid, is predictive of response to cloza
(Pickar et al., 1992)
suggestthat restoring the balance
between dopaminergic activity and serotoninergic activity
is a factor in the action of clozapine. The potential import
ance of the balance between dopamine and serotonin is
reinforced by evidence that drugs such as risperidone that
simultaneously block 5-HT2 serotonin receptors and D2
dopamine receptors are effective in alleviating core nega
tive schizophrenic symptoms (psychomotor poverty) as
well as delusions and hallucinations (reality distortion)
(Heylen and Gelders, 1990)
However, there is also evidence that the action of cloza
pine includes influence on the noradrenergic system.
Pickar et al. (1992)
found that while clozapine resembles
fluphenazine (a typical dopamine blocking antipsychotic
drug) in its effects on plasma homovanillic acid, it differs
from fluphenazine in producing a substantial increase in
plasma noradrenaline, indicating an enhancement of nor
adrenergic activity. Furthermore, Litman et al. (in press)
demonstrated that adding idazoxan, an alpha-2 adreno
receptor blocking agent which would be expected to
increase noradrenergic activity by blocking presynaptic
alpha-2 receptors, to concurrent treatment with fluphena
zine, alleviates negative symptoms in schizophrenia.
Since alpha-2 agents can modulate ventral tegmental area
(Grenhoff and Svensson, 1989)
and furthermore, noradrenergic activity in the ventral teg
mental area promotes mesocortical but not mesolimbic
dopaminergic activity (Herve et ai., 1982), it is possible
that idazoxan alleviates negative symptoms by producing
a selective enhancement of frontal dopaminergic activity.
There appear to be several characteristic patterns of dis
turbance of supervisory mental processes that occur either
alone or in combination, in a variety of different diseases.
It is probable that the nature of the primary disease deter
mines which of the characteristic patterns are likely to
occur, and also the likelihood that symptoms will either
persist or remit spontaneously. However, the neuroana
tomical sites and neurotransmitter systems implicated in
the production of each of the characteristic patterns of
symptoms appear to be the same in different diseases. The
evidence from brain imaging studies suggests that the
three major syndromes, psychomotor poverty, dis
organization and reality distortion, are associated with
three different patterns of disturbance in function of
association cortex and related subcortical nuclei. The
monoamine neurotransmitters, especially dopamine,
appear to influence the expression of each of these syn
dromes. Although a particular neurotransmitter, such as
dopamine, might have opposing influences on different
syndromes, the differential involvement of different ana
tomic sites offers the possibility of successful treatment
even when different syndromes co-exist.
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Andreasen NC ( 1979 ) Thought, language, and communication disorders. II. Diagnostic significance . Archives of General Psychiatry , 36 , 1325 - 1330 .
Arndt S , Alliger RJ and Andreasen NC ( 1991 ) The distinction of positive and negative symptoms. The failure of a two-dimensional model . British Journal of Psychiatry , 158 , 317 - 322 .
Askinazi C , Weintraub RJ and Karamouz N ( 1986 ) Elderly depressed females as a possible subgroup of patients responsive to methylphenidate . Journal of Clinical Psychiatry , 47 , 467 - 469 .
Banki CN ( 1977 ) Correlation between CSF metabolites and psychomotor activity in affective disorders . Journal of Neurochemistry , 28 , 255 - 257 .
Baxter LR , Schwartz JM , Phelps ME , Maziotta JC , Guze BH , Selin CE , Gerner MD and Sumida RM ( 1989 ) Reduction in prefrontal cortex glucose metabolism common to three types of depression . Archives of General Psychiatry , 46 , 243 - 250 .
Berman KF , Doran AR , Pickar D and Weinberger DR ( 1993 ) Is the mechanism of prefrontal function hypofunction in depression the same in depression as in schizophrenia? Regional cerebral blood flow during cognitive activation . British Journal ofPsychiatry , 162 , 183 - 192 .
Bilder RM , Mukherjee S , Rieder RO and Pandurangi AK ( 1985 ) Symptomatic and neuropsychological components of defect states . Schizophrenia Bulletin , 11 , 409 - 419 .
Blanc G , Herve D , Simon H , Lisoprawski A , Glowinski J and Tassin JP ( 1980 ) Response to stress of mesocortico-frontal dopaminergic neurones in rats after long term isolation . Nature (London) , 284 , 265 - 267 .
Blumer D and Benson DF ( 1975 ) Personality changes with frontal lobe lesions . In: Psychiatric Aspects ofNeurological Disease (Eds DFBenson and D Blummer) ,pp. 151 - 170 . Grune& Stratton, New York.
Caine ED and Shoulson I ( 1983 ) Psychiatric syndromes in Huntington's disease . American Journal of Psychiatry , 140 , 728 - 733 .
Cesarec Z and Nyman AK ( 1985 ) Differential response to amphetamine in schizophrenia . Acta Psychiatrica Scandinavica , 71 , 523 - 538 .
Chiarello RJ and Cole JO ( 1987 ) The use of psychostimulants in general psychiatry: a reconsideration . Archives of General Psychiatry , 44 , 286 - 295 .
Costal B , Domeney AM , Hagan RM , Kelly ME , Naylor RJ , Oakley NR and Tyers MB ( 1991 ) Preclinical evidence for the use of ondansetron in schizophrenia and psychoactive substance abuse . In: Biological Psychiatry , Vol. 2 (Eds G Racagni, N Brunello and T Fukuda ), pp. 877 - 880 . Elsevier, Amsterdam.
Creese I and Iverson SD ( 1974 ) A role of forebrain dopamine systems in amphetamine-induced stereotyped behaviour in the rat . Psychopharmacologia , 39 , 345 - 357 .
Crow TJ ( 1980 ) Molecular pathology of schizophrenia: more than one disease process? British Medical Journal , 280 , 1 - 9 .
Daniel 00, Weinberger DR , Breslin DW , Jones IE , Kleinman IE , Zigun JR , Coppola R , Bigalow LB , Berman KF and Goldberg TE ( 1990 ) The effects of dopamine agonists on CBF (133Xe dynamic SPECT) and negative symptoms in schizophrenia . Schizophrenia Research , 3 , 28 .
De Ajuriaguerra J ( 1971 ) Etude psychopathologique des Parkinsoniens . In: Monoamines, Noyaux Gris Centraux et Syndrome de Parkinson (Eds J de Ajuriaguerra and G Gauthier). George, Geneva.
Delbende C , Delarue C , Lefebre H , Tranchand Bunel D , Szafarczyk A , Mocaer E , Kamoun A , Jegou S and Vaudry H ( 1992 ) Glucocorticoids, transmitters and stress . British Journal of Psychiatry , 160 , 24 - 34 .
Fibiger HC ( 1991 ) The dopamine hypothesis of schizophrenia and mood disorders: contradictions and speculations . In: The Mesolimbic Dopamine System: From Mechanism to Action (Eds P Willner and J Scheel-Kruger). Wiley, New York.
Frith CD and Done J ( 1989 ) Experiences of alien control in schizophrenia reflect a disorder in the central monitoring of action . Psychological Medicine , 19 , 359 - 363 .
Frith CD , Friston KJ , Liddle PF and Frackowiak RSJ ( 1991 ) Willed action and the prefrontal cortex in man: a study with PET . Proceedings of the Royal Society B , 244 , 241 - 246 .
Frith CD , Friston KJ , Liddle PF and Frackowiak RSJ ( 1992 ) PET imaging and cognition in schizophrenia . Journal ofthe Royal Society ofMedicine , 85 , 222 - 224 .
Friston KJ , Grasby PM , Bench CJ , Frith CD , Cowen PJ , Liddle PF , Frackowiak RSJ and Dolan RJ ( 1992 ) Measuring the neuromodulatory effects of drugs in man with positron emission tomography . Neurosciences Letters , 141 , 106 - 110 .
Fuster JM ( 1980 ) The Prefrontal Cortex . Raven Press, New York.
Gallhofer B , Trimble MR , Frackowiak R , Gibbs J and Jones T ( 1985 ) A study of cerebral blood flow and metabolism in epileptic psychosis using positron emission tomography and oxygen . Journal ofNeurology, Neurosurgery and Psychiatry , 48 , 201 - 206 .
Geraud G , Arne-Bes MC , Guell A and Bes A ( 1987 ) Reversibility of haemodynamic hypofrontality in schizophrenia . Journal of Cerebral Blood Flow and Metabolism , 7 , 9 - 12 .
Goldberg TE , Bigelow LB , Weinberger DR , Daniel 00 and Kleinamn IE ( 1991 ) Cognitive and behavioural effects of the coadministration of dextroamphetamine and haloperidol in schizophrenia . American Journal ofPsychiatry , 148 , 78 - 84 .
Goldman-Rakic PS ( 1988 ) Topography of cognition: parallel distributed networks in primate association cortex . Annual Review ofNeuroscience , 11 , 137 - 156 .
Goodwin FK , Brodie HK , Murphy DL and Bunney WE ( 1970 ) Administration of a peripheral decarboxylase inhibitor with L-dopa to depressed patients . Lancet, i , 908 .
Grenhoff J and Svensson TH ( 1989 ) Clonidine modulates dopamine cell firing in the rat ventral tegmental area . European Journal ofPharmacology , 165 , 11 - 18 .
Harlow 1M ( 1848 ) Passage of an iron rod through the head . Boston Medical and Surgical Journal , 39 , 389 - 393 .
Hecker E ( 1871 ) Die Hebephrenia . Virchows Archivfur Pathologie und Anatomie , 52 , 394 - 429 .
Herve D , Blanc G , Glowinski J and Tassin JP ( 1982 ) Reduction of dopamine utilization in the prefrontal cortex but not in the nucleus accumbens after selective destruction of noradrenergic fibres innervating the vental tegmental area in the rat . Brain Research , 237 , 510 - 516 .
Heylen SLE and Gelders YG ( 1990 ) Combined serotonin 5-HT2 and dopamine D2 receptor antagonism in the treatment of schizophrenia . Schizophrenia Research , 3 , 46 - 47 .
Huber SJ and Paulson GW ( 1985 ) The concept of sub-cortical dementia . American Journal ofPsychiatry , 142 , 1312 - 1317 .
Janowsky DS and Davis 1M ( 1976 ) Methyl phenidate, dextroamphetamine, and levanfetamine . Archives of General Psychiatry , 33 , 304 - 308 .
Kaczmarek BU ( 1984 ) Neurolinguistic analysis of verbal utterances in patients with focal lesions of frontal lobes . Brain and Language , 21 , 52 - 58 .
Kahlbaum KL ( 1874 ) Catatonia (Transl . Y Levij and T Pridan , 1973 ). Johns Hopkins University Press, Baltimore.
Kelly PH , Seviour P and Iverson SD ( 1975 ) Amphetamine and apomorphine responses in the rat following 6-0HDA lesions of the nucleus accumbens septi and corpus striatum . Brain Research , 94 , 507 - 522 .
Kleist K ( 1934 ) Gehirnpathologie . Barth, Leipzig.
Kolb B and Wishaw IQ ( 1980 ) Fundamentals of Human Neuropsychology . Freeman, San Francisco.
Kraepelin E ( 1919 ) Dementia Praecox and Paraphrenia (Transl . RM Barclay, facsimile edn published 1971 ). Kreiger, New York.
Kraepelin E ( 1920 ) Die Erscheinungsformen des Irresciens . Transl. H Marshall, in: Themes and Variations in European Psychiatry (Eds SR Hirsch and M Shepherd) , 1974 . John Wright, Bristol.
Liddle PF ( 1984 ) Chronic schizophrenic symptoms, cognitive junction and neurological impairment . Membership examination thesis , Royal College of Psychiatrists, London.
Liddle PF ( 1987a ) The symptoms of chronic schizophrenia: a re-examination of the positive-negative dichotomy . British Journal ofPsychiatry , 151 , 145 - 151 .
Liddle PF ( 1987b ) Schizophrenic syndromes, cognitive performance and neurological dysfunction . Psychological Medicine , 17 , 49 - 57 .
Liddle PF and Morris D ( 1991 ) Schizophrenic syndromes and frontal lobe performance . British Journal ofPsychiatry , 158 , 340 - 345 .
Liddle PF , Friston KJ , Frith CD , Jones T , Hirsch SR and Frackowiak RSJ ( 1992a) Patterns of cerebral blood flow in schizophrenia . British Journal ofPsychiatry , 160 , 179 - 186 .
Liddle PF , Friston KJ , Frith CD and Frackowiak RSJ (1992b) Cerebral blood flow and mental processes in schizophrenia . Journal ofthe Royal Society ofMedicine , 85 , 224 - 227 .
Lindstrom LH ( 1985 ) Low HVA and normal5-HlAA CSF levels in drug-free schizophrenic patients compared to healthy volunteers: correlations to symptomatology and heredity . Schizophrenia Research , 14 , 265 - 274 .
Litman RE , Hong WW , Weissman MD , Su T , Potter WZ and Pickar D (In press) Idazoxan, an alpha2 antagonist, augments fluphenazine in schizophrenic patients: a pilot study . Journal ofClinical Psychopharmacology.
Luria A ( 1966 ) Higher Cortical Functions in Man . Basic Books, New York.
MalIa A , Cortese L and Shaw T ( 1990 ) Life events and relapse in schizophrenia: a prospective one year follow-up study . Social Psychiatry and Psychiatric Epidemiology , 25 , 221 - 224 .
Matussek N , Benkert 0, Schneider K , Otten H and Pohlmeir H ( 1970 ) L-dopa plus decarboxylase inhibitor in depression . Lancet, ii, 660 .
Meltzer HY ( 1992 ) Dimensions of outcome with clozapine . British Journal ofPsychiatry, 160 (Suppl. 17) , 46 - 53 .
Morgenson GJ and Yim CY ( 1981 ) Electrophysiological and neuropharmacological behavioural studies of the nucleus accumbens and implications for its role as a limbic-motor interface . In: The Neurobiology of the Nucleus Accumbens (Eds RB Chronister and RF DeFrance) , pp. 220 - 229 . Haer Institute, Brunswick.
Morice RD and Ingram JCL ( 1982 ) Language analysis in schizophrenia: diagnostic implications . Australian and New Zealand Journal ofPsychiatry , 16 , 11 - 21 .
Neary D , Snowden JS , Northen B and Goulding P ( 1988 ) Dementia of frontal lobe type . Journal ofNeurology, Neurosurgery and Psychiatry , 51 , 353 - 361 .
Norman DA and Shallice T ( 1980 ) Attention to action: willed and automatic control ofbehaviour . Centre for Human Information Processing (Technical Report, No. 99).
Pardo IV , Pardo PJ , Janer KW and Raichle ME ( 1990 ) The anterior cingulate mediates processing selection in the Stroop attentional conflict paradigm . Proceedings of the National Academy ofSciences , 87 , 256 - 259 .
Peralta V , de Leon J and Cuesta MJ ( 1992 ) Are there more than two syndromes in schizophrenia? A critique of the positivenegative dichotomy . British Journal of Psychiatry , 161 , 335 - 343 .
Pickar D , Owen RR , Litman RE , Konica E , Gatierrez R and Rappaport MH ( 1992 ) Clinical and biological response to clozapine in patients with schizophrenia . Archives of General Psychiatry , 49 , 345 - 353 .
Playford D , Jenkins HI , Passingham R , Nutt J , Frackowiak RSJ and Brooks DJ ( 1992 ) Impaired mesial frontal and putamen activation in Parkinson's disease: a PET study . Annals of Neurology , 32 , 151 - 161 .
Pycock CJ , Kerwin RW and Carter CJ ( 1980 ). Effects oflesion of cortical dopamine terminals on sub-cortical dopamine receptors in rats . Nature (London) , 286 , 74 - 77 .
Reibaud M , Blanc G , Studler J , Glowinski J and Tassin J ( 1984 ) Non-DA prefronto-cortical efferents modulate D, receptors in the nucleus accumbens . Brain Research , 305 , 43 - 50 .
Robbins TW and Sahakian BJ ( 1983 ) Behavioural effects of psychomotor stimulant drugs: clinical and neuropsychological implications . In: Stimulants: Neurochemical, Behavioural and Clinical Perspectives (Ed. I Creese ) . Raven Press, New York.
Sawaguchi T and Goldman-Rakic PS ( 1991 ) Dl dopamine receptors in prefrontal cortex: involvement in working memory . Science , 251 , 947 - 951 .
Shallice T ( 1989 ) From Neuropsychology to Mental Structure . Cambridge University Press, Cambridge.
Stein L and Wise CD ( 1971 ) Possible etiology of schizophrenia: progressive damage to the noradrenergic reward system by 6-hydroxy dopamine . Science , 171 , 1032 - 1036 .
Trimble M ( 1992 ) Neurological models of schizophreniaregional implications . Clinical Neuropharmacology , 15 ( Suppl . lA) , 395 - 396 .
Van Kammen DP ( 1991 ) The biochemical basis of relapse and drug response in schizophrenia: review and hypothesis . Psychological Medicine , 21 , 881 - 895 .
Van Praag HM , Korf J , Lakke JPWF and Schut T ( 1975 ) Dopamine metabolism in depression, psychoses, and Parkinson's Disease: the problem of the specificity in biological variables in behaviout disorders . Psychological Medicine,S, 138.
Weinberger DR , Berman KF and Illowsky BP ( 1988 ) Physiological dysfunction ofthe dorsolateral prefrontal cortex in schizophrenia III. A new cohort and evidence for a monoaminergic mechanism . Archives of General Psychiatry , 45 , 609 - 615 .
Wing JK and Brown GW ( 1970 ) Institutionalization and Schizophrenia . Cambridge University Press, Cambridge.
Wolfe N , Katz DL and Albert ML ( 1990 ) Neutopsychological profile linked to low dopamine in Alzheimer's disease, major depression and Parkinson's disease . Journal of Neurology, Neurosurgery and Psychiatry , 53 , 915 - 917 .
(Received 10 January 1993 ; accepted 15 February 1993 )
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