While the type 1/type 2 model of schizophrenia provides a plausible explanation for the variation in degree of persistence of symptoms, the three-syndrome model provides a more satisfactory account of the heterogeneity of symptom type. In particular, the evidence supports the hypothesis that the pathophysiology of schizophrenia disrupts the function of a diverse set of cerebral sites and that the type of symptoms is largely determined by the nature of function of the affected cerebral regions.
Any comprehensive account of the pathophysiology of schizophrenia must take account not only of the diverse types of symptoms that occur within the illness, but also of the time course of the illness. Several major longitudinal studies of childhood development, such as the study49 of the cohort born in Britain in March 1946 and the study50 of the cohort born in March 1958, have demonstrated that the earliest signs of illness can be detected, at least with hindsight, in early childhood development. For example, in the 1946 birth cohort, the odds ratio that a preschizophrenic child would fail to develop speech by age two was 4.8 compared with the remainder of the birth cohort. In both this birth cohort and in the 1958 birth cohort, the preschizophrenic children exhibited significant impairment in a range of cognitive and social functions. The cognitive deficits were most marked in the domains of language and arithmetical skills, while the behavioral development of the preschizophrenic children was characterized by social unease and inconsequential behaviors.
It is important to note that many preschizophrenic children perform in the normal range in cognitive tasks and some even achieve a superior level of function. However, the evidence from studies of identical twins discordant for schizophrenia indicates that even when both twins perform in the normal range, the affected twin usually performs less well than the unaffected co-twin, indicating that the illness has led to a relative impairment.51 Furthermore, despite the observation that the cognitive impairments in schizophrenia cover a wide range of aspects of cognition, there is great variability between cases,52 and the possibility that domains of high performance might co-exist with subtle defects in other areas remains to be excluded.
Typically, in adolescence a more discernible prodrome, characterized by social withdrawal and episodes of anxiety or depressive symptoms, develops.53 In many cases, this prodrome lasts for several years before the development of overt psychosis. The first psychotic episode is likely to include symptoms of reality distortion and/or marked disorganization and psychomotor excitation. Though psychomotor excitation is common, in some cases negative symptoms become worse, and in a substantial proportion of cases there is significant depression.54 In over half of the treated first episode cases, the initial florid episode abates within 3 months, and in about 85% of cases there is at least a partial remission within 1 year.55 Subsequently, the illness is characterized by further acute episodes superimposed on a state of enduring disability, cognitive impairment, and residual symptoms. The severity of the enduring residual symptoms and of social and occupational disability varies greatly between cases. In some cases, the person functions well, apart from an undue sensitivity to stress. In the most severe cases, the patient is unable to perform the essential functions of daily life.
The long-term prognosis is also variable, but in over 50% of cases there is a gradual resolution with full or partial recovery after several decades.56 In a minority of cases, the illness progresses to a state of profound cognitive impairment that resembles dementia, although in such cases there is no increase in the pathological features of Alzheimer's disease.57
The characteristic time course of illness indicates that the underlying pathophysiological mechanism is neither a progressive dementia nor a static encephalopthy. In general, the time course reflects the characteristics of a developmental disorder,58,59 though unlike many developmental disorders the degree of disability in schizophrenia does not usually achieve a stable level even in adulthood. Instead, during the younger adult years there are episodic exacerbations and then in later adulthood a tendency toward resolution in many cases.
This time course suggests a disorder in which a neuronal deficit progresses during childhood development. The florid episodes in young adulthood, which are often precipitated by stressful events or by stimulant drug abuse, suggest that the putative developmental deficit has weakened the regulation of the modulatory monoamine neurotransmitters, especially dopamine. Dopamine modulates the function of the various cortical and subcortical areas implicated in the expression of the three syndromes.60 Consequently, poorly regulated changes in the levels of modulatory neurotransmitters in response to stresses of various kinds might be expected to exacerbate any preexisting impairment of coordination between these cerebral sites. This would increase the likelihood of overt symptoms in previously asymptomatic cases or exacerbate symptoms in those with preexisting symptoms. In later adult life, age-related diminution in activity of the modulatory neurotransmitters would result in a tendency toward resolution of the illness.
The excessive release of endogenous dopamine following amphetamine administration in schizophrenic patients demonstrated by Laruelle et al.11 provides evidence that disregulation of monoamine neurotransmission does, in fact, occur in schizophrenia. Furthermore, Laruelle et al. found that the magnitude of the release of dopamine correlated with the severity of the positive symptoms induced by amphetamine administration.
There is also evidence that the disregulation of dopamine might arise from subtle structural deficits. Breier et al.61 demonstrated that an increase in production of the dopamine metabolite, homovanillic acid, in response to the stress of transient glucose deprivation is abnormally large in schizophrenia. The magnitude of this effect is inversely correlated with frontal lobe volume. The molecular mechanism by which a structural deficit might produce disregulation of dopamine remains speculative. Pycock et al.62 were the first of many investigators to report that lesions of the frontal lobes produce changes in subcortical dopaminergic function in rats. While the details of these findings have remained controversial, subsequent studies show that frontal lobe lesions in animals lead to increased dopamine release in the nucleus accumbens (homologous to the ventral striatum in man).63
It is likely that the structural defects in schizophrenia are due, at least in part, to abnormal brain development. Subtle developmental anomalies are prevalent in schizophrenia.64 In particular, there is evidence of disordered development of coordination between diverse brain areas. For example, Woodruff et al.65 reported that the normal correlation between frontal lobe volume and temporal lobe volume is decreased in schizophrenia. Since this correlation is thought to reflect the function linkage between these brain areas, the lack of correlation in schizophrenia implies a lack of coordination during development.
In summary, the time course of the illness, together with the evidence regarding the nature of the cerebral abnormalities of schizophrenia that we have reviewed, suggests that schizophrenia might best be described as a disorder arising from developmental disregulation of cerebral function. According to this hypothesis, the primary pathological process is a subtle dysplasia that affects coordination between cerebral regions. Impaired coordination of function results in enduring cognitive deficits and also causes impaired regulation of monoaminergic neuromodulatory transmitters. At times of stress or following administration of stimulant drugs, there is a tendency for excessive monoamine release leading to florid psychosis. The proposed links between causal factors, patho-physiological processes, and symptom profiles are illustrated in Figure 1.
This developmental disregulation hypothesis predicts that cases in which the developmental dys-plasia mainly affects the regulation of monoaminergic transmission will exhibit few residual symptoms, apart from oversensitivity to stress, and relatively minor cognitive impairments during stable phases of
the illness. In contrast, cases with extensive dysplasia affecting multiple cerebral areas would suffer substantial persistent symptoms and cognitive impairments. Nonetheless, in such cases, symptoms might be exacerbated by excessive monoaminergic neurotransmitter release at times of stress.
The proposed pathological mechanism leads to several predictions about the observable relationships between symptoms, cognitive deficits, and underlying neuronal abnormalities. In particular, in the stable phase of the illness, the profile of cognitive impairment, and also of persisting symptoms, will be determined largely by the location of cerebral regions that are affected by the primary dysplasia. Monoamine disregulation would be expected to play a relatively minor role in the stable phase. It would be predicted that in this phase of illness, symptom profile and pattern of cognitive impairment would show consistent relationships, as found in the studies reviewed in Section III.B. However, during episodes of acute florid disturbance, variation between subjects in the type and severity of symptoms will be determined not only by the location of the regions affected by the primary dysplasia, but also by variation in the severity of monoamine disregulation. In this phase of illness, the factors influencing the severity of symptoms and cognitive impairment would be much more complex.
The developmental disregulation hypothesis predicts that patients with persistent, severe illness will have relatively marked disruption of coordination between the cerebral sites implicated in one or more of the three syndromes at all phases of the illness. In such patients, a strong correlation between the severity of a particular group of symptoms and severity of impairment of the cognitive processes that engage the cerebral sites implicated in relevant syndrome would be expected. However, the hypothesis also predicts that patients with remitting illness will have a relatively minor disruption of coordination between the cerebral sites implicated in the syndromes at baseline. In these cases, the major abnormality is impaired regulation of the monoamine neurotransmitters. During florid episodes of illness, the severity of both symptoms and cognitive impairments will be determined mainly by the severity of monoamine disregulation. Because the effects of monoamine disregulation are not confined to the neural pathways linking cerebral sites implicated in the syndromes, the relationship between symptoms and cognitive impairment would be expected to be weaker. The studies by Baxter and Liddle27 and Ngan and Liddle28 that have compared patterns of correlations between symptoms and cognitive impairments in cases with severe persistent illness with those in patients with remitting illness have confirmed this prediction.
Baxter and Liddle27 demonstrated that in patients with persistent illness, the severity of psy-chomotor poverty was correlated with impairment in a two-choice guessing task that tested the ability to produce a response that was entirely self-generated. This correlation was absent in patients with remitting illness. Ngan and Liddle28 demonstrated that in patients with persistent illness, psychomotor poverty was associated with slowed simple reaction time, while disorganization was correlated with impaired choice reaction time. In patients with remitting illness, these relationships were much weaker.
The developmental disregulation hypothesis predicts that florid symptoms will respond to treatment with medication that reduces monoaminergic neurotransmission, especially dopaminergic neurotransmission. The more enduring symptoms and cognitive deficits that are a direct consequence of the primary dysplasia would be expected to be less responsive to treatment. Nonetheless, insofar as the evidence indicates that the primary problem is impaired coordination of activity between cerebral areas rather than overt loss of neurons, there is potential for successful treatment by agents that modulate neurotransmission. Assuming that regularly active connections tend to be reinforced, the hypothesis predicts that symptoms that persist for prolonged periods will be reinforced. Conversely, alleviation of the baseline abnormalities of coordination between cerebral areas is likely to require prolonged treatment, whether using psychological strategies or pharmacological agents that promote healthy patterns of coordination between cerebral areas.
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