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Annu. Rev.
1994.OF
45:219–34
CROW
PATHOGENESIS
&Med.
HARRINGTON
PSYCHOSIS
Copyright © 1994 by Annual Reviews Inc. All rights reserved
ETIOPATHOGENESIS AND
TREATMENT OF PSYCHOSIS
T. J. Crow
Clinical Research Centre, Division of Psychiatry, Northwick Park Hospital, Watford
Road, Harrow, Middlesex, HA1 3UJ, United Kingdom
C. A. Harrington
National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA,
United Kingdom
KEY WORDS: schizophrenia, cerebral asymmetry, dopamine receptors
ABSTRACT
Psychotic illnesses (schizophrenia and schizoaffective and affective psychosis)
have a lifetime prevalence of 2–3% and probably occur at a similar rate in all
human societies. No etiologically significant environmental precipitants have
been identified, and this suggests that these diseases are primarily genetic.
Brain studies reveal that in schizophrenic patients, development of cerebral
asymmetry is arrested, which may be associated with a small reduction in
cortical mass. Episodes of illness can be ameliorated by dopamine (in particular D2) antagonists, drugs that are antipsychotic rather than merely antischizophrenic. The discovery of at least five dopamine receptor subtypes and
their genes paves the way for new approaches to treatment. However, whether
psychotic patients undergo a primary disturbance of dopaminergic transmission remains unclear.
0066-4219/94/0401-0219$05.00
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CROW & HARRINGTON
DEFINITION OF PSYCHOSIS
Psychoses (schizophrenic, schizoaffective, and affective illnesses) are common (with a lifetime prevalence of 2–3%) and account for a high percentage of
the serious morbidity associated with psychiatric disease. The magnitude of
their social impact stems from their onset in early adult life coupled with a
strong tendency to recur, or in some cases, to persist and even progress. The
defining characteristics of psychoses are psychotic symptoms such as a delusion (a belief held despite evidence to the contrary), a hallucination (sensory
experience without adequate external stimulus), or thought disorder. Without a
clear understanding of pathogenesis, or a laboratory diagnostic test, such
symptoms serve as the clinician’s principal guide to prognosis and treatment.
This review examines advances in our understanding of pathogenesis, with a
particular focus on brain morphology and neurochemistry studies, and explores innovations in treatment in the context of our current knowledge of
etiology and outcome.
ORIGINS AND LIMITS OF THE CONCEPT OF
SCHIZOPHRENIA
The term schizophrenia covers diverse conditions, [the “group of schizophrenias,” according to Eugen Bleuler (1)] but their subdivision has sparked heated
controversy, and the distinction between schizophrenia and manic-depressive
psychoses, the other major catergory of recurrent adult illnesses, has come
under increasing scrutiny. Both of these types of disorders are still classified as
functional psychoses, which implies that no change in brain structure occurs.
This view is supported in textbooks stating that whereas structural brain
changes related to cognitive and intellectual impairments occur in the dementias (chronic organic psychosis), such neural and psychological changes are
absent in schizophrenia. However, schizophrenic patients sometimes exhibit
severe intellectual impairments, and structural changes in the brain can also
occur (2, 3).
Although such cases represent one extreme of the spectrum of severity of
schizophrenic illnesses, the boundary between schizophrenia and affective
disorder at the other end has given rise to considerable doubt as well. Recent
studies reveal that these two diseases overlap, thereby refuting the Kraepelinian binary system, which purports that schizophrenia and manic-depressive
illness are distinct entities and thus implies that they have different etiologies.
Even Kraepelin himself began to question his original findings, and in 1920
(4) he wrote of
…the difficulties which still prevent us from distinguishing reliably between
manic-depressive insanity and dementia praecox. No experienced psychiatrist
PATHOGENESIS OF PSYCHOSIS
221
will deny that there is an alarmingly large number of cases in which it seems
impossible, in spite of the most careful observation, to make a firm diagnosis.…Nevertheless it is becoming increasingly clear that we cannot distinguish
satisfactorily between these two illnesses and this brings home the suspicion
that our formulation of the problem may be incorrect.
Two paragraphs later he added,
It is common to find cases of undeniable schizophrenia which show transitory
or at times longer-lasting manic-depressive symptoms, and it may be quite
impossible to distinguish them from the circular forms of insanity.
The alternative to the Kraepelinian concept is the idea of a continuum of
psychotic illness that extends from unipolar depression through bipolar
(manic-depressive) and schizoaffective psychosis to schizophrenia, with increasing severities of defect state (5). The most compelling evidence for this
hypothesis is genetic in nature. Several studies have examined whether the
psychoses breed true within families. For example, Angst et al (6) concluded
that the dichotomy between schizophrenia and affective disorder was highly
questionable and found a continuum of psychopathology between the two
disorders. However, these authors did not support the hypothesis of a “unitary
psychosis”. The psychoses exhibit significant differences, and as Kraepelin
emphasized, the form of a psychosis relates to its outcome. In general, psychoses with a substantial affective element have a better outcome than those that
are more typically schizophrenic in form. Nevertheless, no etiologically meaningful dividing line can be drawn between the different types of psychoses.
The existence of the continuum and the variations in form of psychosis within
it provide important clues to the origin of psychosis.
The most recent contribution to research on families with psychosis was
made by Maier & Lichtermann (7), who studied 525 consecutive hospital
admissions with unipolar and bipolar affective, schizoaffective, and schizophrenic psychoses, comparing them with 109 randomly selected controls. The
Schedule for Affective Disorders and Schizophrenia-Lifetime version (SADSL) was used to interview 1250 first-degree relatives. The information obtained
was supplemented with interviews to determine polydiagnostic classification
(Table 1).
Because the study included a group of control probands, one can assess
whether the incidence of the various disorders for first-degree relatives is
higher than for the general population. The increase in risk of unipolar (UP)
affective disorder for the relatives in all categories of psychotic proband is the
salient feature of the study, precluding any simple interpretation of the findings. The prevalence of schizophrenia (SCHIZ) and schizoaffective (SA) disorder in the relatives of probands with bipolar (BP) illness and the excess of
bipolar disorder in the relatives of patients with schizoaffective disorder refute
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CROW & HARRINGTON
Table 1 First-degree relatives lifetime risk (%) (Ref.7)
Patients’ diagnosis
SCHIZ
SA
BP
UP
Schizophrenia
Schizoaffective
5.1
4.1
3.3
5.3
1.9
5.4
19.6
20.4
Bipolar affective
Unipolar affective
1.2
0.8
1.0
0.9
8.8
1.6
23.6
21.6
Health controls
0.4
0.3
1.2
9.9
any suggestion that a classical Kraepelinian line of demarcation can be drawn
between schizoaffective disorders (which thereby are allocated to the category
of schizophrenia) and bipolar affective disorder.
The findings are more consistent with the concept of a psychotic continuum
(5) than with the original Kraepelinian concept of two distinct diseases. The
continuum can be represented graphically as in Figure 1.
In Figure 1, the continuum extends from unipolar depression through bipolar (manic-depressive) illness to schizoaffective disorder, to schizophrenia
with and then without significant mood disturbance, and finally to schizophrenia with a defect state (the presence of negative symptoms such as affective
flattening or poverty of speech). In such a scheme, one can define boundaries
that act as markers for particular positions along the continuum. Such markers
include the presence of elation, mood-incongruent delusions, nuclear (first
rank or Schneiderian) symptoms, and negative symptoms, as well as the presence or absence of significant mood disturbance. Of these markers, nuclear
symptoms delineate a group of illnesses that (as Schneider suggested) can be
reliably identified and may be characterized by a distinctive pathophysiology.
For example, Trimble suggested (8) that nuclear symptoms are pathognomonic
of left temporal lobe disturbance.
EPIDEMIOLOGY OF SCHIZOPHRENIA
One of the most characteristic features of psychosis is its age of onset. Psychotic disorders rarely manifest themselves before puberty, but their incidence
then rises sharply, earlier in males than females. This discrepancy between the
sexes with respect to onset of schizophrenia (the mean age for males is approximately 25 years vs 28 years for females) is the best established but least
understood epidemiological fact about the disease. Schizoaffective and affective disorders have a somewhat later age of onset. In general, earlier onset is
associated with worse outcome, as illustrated in a recent comparison of case
register findings by Eaton and colleagues (9).
PATHOGENESIS OF PSYCHOSIS
223
Whether schizophrenia and manic-depression occur with equal incidence in
all societies or whether incidence varies significantly remains an important
question. The anthropoparity principle (the assumption of constancy across
different societies and over time) has generally been taken for granted, but this
assumption is based on limited evidence without thorough examination of its
singularity. Lately, however, the principle has been challenged (10, 11). This
controversy stimulated a cross-cultural study of incidence conducted under the
auspices of the World Health Organization (WHO) (12). In 10 countries,
teams in centers collaborated to ascertain incidence in defined catchment areas
using standardized criteria. Using a broad definition, they observed significant
differences, but as the criteria narrowed, the differences diminished. The teams
concluded that schizophrenia, when restrictively diagnosed, occurs probably at
approximately the same rate in societies with gross differences in climatic,
physical, industrial, and cultural environments. The WHO studies are rendered
credible by their attention to diagnostic reliability and comparability of methods of case identification. Within the limitations of what appear to have been
the most careful epidemiological studies yet conducted, the incidence of
schizophrenia seems to be a cross-cultural constant.
Figure 1 Markers of severity and form of illness according to a continuum concept. UP, unipolar;
BP, bipolar; SA, schizoaffective; S + A, schizophrenia plus affective change; S − A, schizophrenia
minus affective; S + D, schizophrenia plus defect.
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CROW & HARRINGTON
GENETIC VS ENVIRONMENTAL CONTRIBUTIONS TO
ETIOLOGY
Twin and adoption studies [reviewed by Gottesman (13)] confirm a genetic
predisposition to etiology, and estimates of heritability in excess of 70%
demonstrate the strength of its influence. The key question remaining is
whether environmental contributions also play a role.
A number of arguments suggest that if environmental contributions do
exist, they are minimal. For example, adoption of a child from a family in
which schizophrenia is present does not reduce the adoptee’s risk of illness.
Although the onset of schizophrenia in adult life might suggest the involvement of an environmental agent, in cases in which two siblings contract the
illness, it strikes at the same age, not at the same time (14). Thus intrinsic
rather than extrinsic factors determine onset. Moreover, if incidence of the
disease is relatively constant across populations in widely differing geographic, climatic, industrial, and social environments, as the WHO studies
suggest, possible pathogenic agents whose distribution would not be expected
to vary as widely across such conditions cannot be easily identified.
The recent literature has proposed two specific pathogens: birth injury and
in utero exposure to influenza. However, a prospectively studied cohort of the
UK population [the Perinatal Mortality survey and National Child Development study sample (15)], which included approximately 17,000 individuals
born in a single week in March 1958, showed no evidence that those subsequently admitted to psychiatric hospitals with a diagnosis of schizophrenia
were more at risk of perinatal complications than the rest of the sample.
Moreover, some of these individuals were exposed to the 1957 epidemic of
Asian influenza. The study found that those exposed in the second trimester
were at no greater risk for subsequent schizophrenia than those who were not
exposed at all (16).
BRAIN CHANGES
Structure—Brain Size and Asymmetry
Recent morphological studies have cast light on the nature of schizophrenia.
Computed tomography (CT) scan and magnetic resonance imaging (MRI)
studies have clearly shown that patients with schizophrenia exhibit a degree of
ventricular enlargement. Recent findings indicate that this enlargement is not
confined to a subgroup, but rather is characteristic of all schizophrenic patients
(17, 18). A second group of studies [including some on postmortem brain by
Pakkenberg (19) and Bruton et al (20)] suggests that the brains of patients with
schizophrenia (perhaps particularly those with an early onset) are slightly
smaller than those of controls, which may result from a reduction in volume of
PATHOGENESIS OF PSYCHOSIS
225
the cerebral cortex (21). Such changes manifest themselves early and may
reflect an arrest of development.
While the changes in the cortex are generalized, a localizing feature—deviant asymmetry—is present as well. Enlargement is greater in the temporal
horns than elsewhere in the ventricular system and is more prominent on the
left side of the brain than the right (22, 23). No such asymmetry has been
found in the enlargement associated with Alzheimer-type dementia (22). One
may therefore conclude that schizophrenia is a disease of the left brain, but an
alternative interpretation is that a loss of asymmetry occurs. The left temporal
horn is usually smaller than the right, presumably because the planum temporale (which corresponds approximately to Wernicke’s area) is larger on the
left in most individuals (24). This asymmetry (together with brain size) distinguishes humans from other primates.
A number of studies support the loss of asymmetry interpretation. The
Sylvian fissure (the lower boundary of which is defined posteriorly by the
planum temporale) is longer on the left side of the brain than on the right (25).
In schizophrenia, however, this asymmetry is diminished or lost entirely (26,
27). MRI assessments of the planum in schizophrenic patients show that the
normal bias to the left is reduced or even reversed (28, 29). Most healthy
individuals do not have uniform brain width—the frontal lobe is slightly wider
on the right and the occipital lobe is wider on the left (the Yakovlevian torque).
In schizophrenic patients, however, the torque is diminished or absent (30).
This loss can be detected in groups with an early onset (31) and in patients
experiencing the first episode of illness (32).
What do these changes signify? If the human brain evolved by a process of
increasing hemispheric specialization, one would expect brain size and asymmetry to be closely related and functions such as language that are most central
to the process to display the greatest degree of lateralization (33). Such functions might also vary considerably among individuals. The age at which brain
size reaches a plateau represents a critical parameter. The plateau level and the
time at which it is reached are influenced by genetic factors, which must have
been subject to recent evolutionary pressures. In this context, the brain
changes in psychosis can be viewed as an arrest of development (34), resulting
in a less lateralized brain and a smaller cortical mass.
According to this view, the variation in brain structure in psychosis lies
along the trajectory of recent evolution and represents an aspect of diversity in
the general population. One can assume that individuals with psychosis constitute one extreme of a dimension of variation on which brain size and the
development of asymmetry reach a plateau relatively early.
The above discussion suggests that psychosis is a developmental anomaly
associated with a structural, and therefore presumably fixed, brain deficit.
However, psychoses are characteristically episodic illnesses, particularly with
226
CROW & HARRINGTON
respect to positive symptoms (delusions, hallucinations, thought disorder).
Such symptoms may remit, and they often respond to neuroleptic medication.
These observations imply that the disease process involves not only structural
components, but variable, presumably neurochemical, ones as well.
Neurochemistry—Dopamine Hypothesis of Schizophrenia and
Recent Developments in Dopamine Receptor Research
The prevailing neurochemical hypothesis posits that overactivity of dopamine
pathways is central to the disease. The dopamine hypothesis of schizophrenia
is based on two sets of observations: (a) evidence that the efficacy of neuroleptics correlates with their binding to dopamine D2 receptors (35–37), and (b) the
observation that chronically administered stimulants such as amphetamine and
cocaine, which increase activity of central catecholaminergic pathways, can
induce psychotic episodes (38, 39). Nonetheless, direct evidence that dopaminergic systems are perturbed in schizophrenia has not been forthcoming,
although the structural changes in brain morphology described above are
associated with some dopamine projection areas such as the amygdalohippocampal formation (40). The possibility that dopamine receptors are elevated
in neuroleptic-naive schizophrenics, thus providing a mechanism for overactive dopamine synapses, has been examined. Studies using in vivo positron
emission tomography (PET) and receptor binding in postmortem brains to
measure differences in D2 receptor levels in schizophrenics vs controls have
produced conflicting results. At present, therefore, the question of raised D2
levels in the etiology of schizophrenia remains unresolved (41–43).
The molecular cloning of a family of genes encoding the dopamine receptors [reviewed in (44–46)] has greatly increased our knowledge of these receptors over the last several years. To date, five dopamine receptor genes have
been identified. These are divided into two subfamilies corresponding to the
D1 and D2 receptor classes defined by Kebabian & Calne (47). The D1-like
receptor genes, designated D1 and D5 in humans, encode similar proteins with
a pharmacology consistent with that of a D1 receptor. The three genes that
encode D2-like receptor subtypes have been designated D2, D3, and D4. (A
simplified nomenclature for dopamine receptor subtypes has been proposed
(48), with the D1-like subtypes designated D1a and D1b and the D2-like subtypes designated D2a, D2b, and D2c, but this terminology is currently not in
general use). Alternative processing of the D2 gene transcript produces two
functional receptor isoforms that differ in size by 29 amino acids [D2L(ong) and
D2S(hort)], giving a minimum of four D2-like receptor subtypes (49). The
receptor proteins encoded by the D2, D3, and D4 genes display ligand binding
profiles generally representative of a D2 receptor; however, potentially important differences in their pharmacology have been observed. Significantly, the
PATHOGENESIS OF PSYCHOSIS
227
Table 2 Dopamine receptor family
Gene
D1
D1-like subtypes
D5
D2
D2-like subtypes
D3
Chromoso- 5q 35.1
mal location
4p 15.1–15.3
llq 22–23
3q 13.3
Receptor
subtypes
expressed
1
1
2
(alternative
processing)
1a
Highest
RNA
density in
brainb
Caudateputamen,
Nucleus
accumbens,
Olfactory
tubercle
SCH 23390
Hippocampus,
Hypothalamus
Caudateputamen,
Nucleus
accumbens,
Olfactory
tubercle
Haloperidol UH232
AJ76
Characteristic
antagonist
SCH 23390
D4
11p 15.5
1 (per gene)
(variant
alleles in
human
population)
Islands of
Frontal
Calleja,
cortex,
Hypothalamus, Medulla,
Nucleus
Midbrain,
accumbens
Amygdala
Clozapine
a
Two D3 receptor isoforms generated by alternative splicing have been reported in the mouse (49).
Results of RNA distribution measured in rat, primate, and human brains.
b
D4 receptor has an affinity for the atypical neuroleptic clozapine 10 times
higher than that of the D2 receptor (50).
Distribution studies of specific RNA transcripts for each of the dopamine
receptor subtypes in rat, primate, and human brains have revealed that each
subtype has a distinct expression pattern. D1 and D2 subtypes are expressed at
the highest levels overall, whereas the D3 and D4 subtypes are expressed at
lower levels, but with a higher proportion of expression in limbic regions and
frontal cortex. Biochemical and behavioral studies in humans and animals
have led to the proposal that abnormalities in these latter regions may be
responsible for the psychotic symptoms of schizophrenia (51, 52). Therefore,
the therapeutic effectiveness of clozapine treatment and its lack of extrapyramidal side effects may reflect D4 receptor localization in the central nervous system (CNS), which is low in motor control areas such as the nigrostriatal system but relatively high in regions associated with mood and cognition.
The D5 receptor shows a more restricted pattern, with expression largely
limited to the hippocampus, hypothalamus, and parafascicular thalamic nucleus. A recent report suggests that D5 transcripts are also present in primate
motor cortex (53).
Anatomical distribution studies in rats (54) have also demonstrated the
presence of D2 and D3 transcripts in the substantia nigra, indicating that these
receptor subtypes may function as dopamine autoreceptors (receptors involved
in regulating dopamine synthesis and release and impulse flow in dopamin-
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CROW & HARRINGTON
ergic neurons). Several compounds known to preferentially bind dopamine
autoreceptors show selectivity for the D3 receptor (46). However, a recent
report by Landwehrmeyer et al (55) questions whether D3 expression in the
substantia nigra actually occurs in the human brain. In general, it should also
be recognized that distribution patterns based on RNA expression profiles may
not directly reflect receptor protein levels. The recent and continuing development of subtype-specific antibodies and binding assays that distinguish receptor subtypes will allow for more direct measurement of receptor protein distribution patterns in the future.
As discussed above, genetic factors likely contribute to the development of
psychotic illness. The identification and human chromosomal mapping of the
dopamine receptor subtypes has enabled investigators to search for linkage
between these genes and psychotic illness in schizophrenic pedigrees. To date,
however, researchers have observed no such linkage and have, in fact, strongly
excluded linkage for the D2 gene in many of the families studied (56–59). One
report suggested an association between schizophrenia and homozygosity at
the D3 locus (60), but another study (61) found no evidence of a D3 linkage in
their schizophrenic families. Interestingly, although widespread polymorphism occurs in the coding region of the human D4 gene (62), no linkage to
psychotic illness has been observed (57, 63). The receptors expressed by the
D4 allelic variants differ with respect to clozapine and spiperone binding.
Attempts have been made to directly correlate D4 alleles with susceptibility to
schizophrenia and response to drug treatment (64, 65), but these have proven
unsuccessful thus far.
INNOVATIONS IN TREATMENT
Clozapine, Remoxipride, and Risperidone
Three compounds (clozapine, remoxipride, and risperidone) have attracted
recent interest because of their potential advantages over established neuroleptics either in terms of their range of efficacy or the relative absence of undesirable side effects.
Clozapine, a dibenzodiazepine first introduced in the 1970s, was subsequently withdrawn from use in some countries after several cases of agranulocytosis were reported. Nevertheless, clozapine was reportedly more effective
than standard neuroleptic agents (e.g. chlorpromazine), particularly in severely
ill and refractory patients. This claim was reinforced in a landmark trial (66) in
which 268 inpatients who had proven refractory to at least three different
neuroleptics were randomly allocated to clozapine (up to 900 mg/day) or
chlorpromazine (up to 1800 mg/day). Thirty percent of the clozapine-treated
patients were classified as responders, compared with only 4% of chlorproma-
PATHOGENESIS OF PSYCHOSIS
229
zine-treated patients. Clozapine’s apparent superiority among this group of
patients may be explained by its relatively high affinity for 5HT2, histamine,
and muscarinic acetylcholine as well as for D1 receptor sites. Of particular
interest is clozapine’s relatively lower occupancy (as demonstrated in PET
studies) of D2 receptor sites and its high affinity for the D4 receptor.
Remoxipride is a substituted benzamide that provides better access to the
CNS than the previously available sulpiride. Remoxipride has displayed
higher affinities for 3H-raclopride than for 3H-spiperone–labeled D2 receptors
and for extrastriatal rather than striatal receptors. Remoxipride has an antipsychotic potency comparable to that of standard neuroleptics (67) but induces
fewer extrapyramidal symptoms.
Risperidone is a potent antagonist of the dopamine D2 and serotonin S2
receptors. In a clinical trial comparison (68), 6 mg/day of risperidone proved
more effective than 20 mg/day of haloperidol in reducing psychotic symptoms.
It also induced fewer extrapyramidal effects. As in the case of clozapine,
investigators have suggested that risperidone is more effective than existing
neuroleptics in ameliorating negative symptoms such as affective flattening
and social withdrawal. Such claims are potentially important but difficult to
evaluate because negative symptoms can be assessed in a number of different
ways. However, comparative studies between these three compounds and
existing neuroleptics may clarify the mechanism and scope of the antipsychotic effect.
Figure 2 Response of psychotic symptoms to pimozide (solid line) and placebo (dashed line) in
patients with elvated and depressed mood and no significant mood change. Taken from Ref. 69.
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CROW & HARRINGTON
Form of Illness and Response to Treatment
It is generally assumed that the efficacy of neuroleptic medication is confined
to schizophrenic illnesses. For example, affective psychoses, though sometimes treated with neuroleptics, respond more specifically to lithium. This
assumption is challenged by the findings of the Northwick Park functional
psychosis trial (69, 70). This trial included patients with psychotic symptoms
with no identifiable organic cause. The patients were not otherwise allocated
to a diagnostic category, although they were divided into three groups: predominantly elevated mood, predominantly depressed mood, and no consistent
mood change. Pimozide (a dopamine D2 antagonist), lithium, a combination of
the two medications, or placebo were then randomly administered to the 120
patients entered into the trial. Pimozide consistently reduced psychotic symptoms, proving equally effective for patients in all three groups (Figure 2).
In contrast, the only significant effect of lithium was to reduce elevated
mood. Thus, the effects of neuroleptic medication (as exemplified by pimozide) seem relevant to the resolution of psychotic symptoms in all types of
functional psychotic illness. These compounds are antipsychotic rather than
antischizophrenic, whereas lithium may only be helpful in cases of mood
disturbance.
The benefits of pimozide extended into the follow-up phase of the trial (70).
Of the patients who had recovered on trial medication, those who continued on
pimozide fared significantly better (p = 0.01) than those who continued on
placebo. The benefits of lithium continuation, on the other hand, were insignificant. These findings do not support the view of the diagnostic distinction
between the affective and schizophrenic psychoses as a critical predictor of
response to neuroleptic treatment, and they raise the question of whether such
medication can play a broader role in prophylaxis of affective illnesses than
current practice implies.
Can antipsychotic medication prevent deterioration? Two studies have revealed a strong relationship between duration of symptoms before first admission and risk of relapse thereafter (71, 72). One could attribute this relationship
to the fact that illnesses with a poor outcome are generally associated with a
delay in admission, but it could also signify that early treatment prevents the
development of an element of chronicity (73).
CONCLUSIONS
The etiology of psychotic (schizophrenic, schizoaffective, and affective) illness remains obscure. These illnesses have an impact throughout the reproductive phase of life and, particularly in the case of schizophrenia, substantially
decrease fertility. No environmental factors have proven relevant, and the
PATHOGENESIS OF PSYCHOSIS
231
unvarying incidence (as demonstrated in the WHO studies) in societies with
gross differences in climatic, social, and industrial environments suggests that
psychotic illness is intrinsic to the human condition, i.e. that it is a part of
genetic variation maintained by selective factors. Studies of brain structure
provide insight into the nature of these factors, indicating that schizophrenic
illnesses involve an arrest of development of cerebral asymmetry. This finding
is consistent with the hypothesis that the psychoses form a part of the spectrum
of variability generated in the course of the evolution of hemispheric specialization and language.
Although morphological studies suggest that psychosis is an arrest of development, why these diseases have a defined onset, are often episodic in
course, and respond to neuroleptic medication still awaits explanation. These
characteristics are consistent with the concept of a reversible neurochemical
element. The efficacy of dopamine (particularly D2) antagonists in treatment
and of some dopamine agonists as psychotomimetics confirms the dopamine
hypothesis as the prevailing heuristic model of psychotic symptoms. Despite
these findings, genetic linkage, isotope imaging, and biochemical studies provide no direct support for primary aberrations in dopaminergic systems in
schizophrenia; whether dopamine receptor numbers are increased remains a
controversial subject. The recent discovery of multiple dopamine receptor
subtypes with distinct distribution and drug binding profiles opens up new
avenues of exploration for disease mechanisms and for the development of
new, more selective drugs.
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