The Type 1type 2 Hypothesis

Crow3,4 produced a formulation of the pathophysiology of schizophrenia which has had a seminal influence on subsequent attempts to link the phenomena of the illness to the diverse abnormalities of brain structure and function that are associated with schizophrenia. The foundation of this formulation was the observation that the positive symptoms of schizophrenia tend to be transient, while the negative symptoms tend to persist. Positive symptoms are clinical features that reflect aberrant mental activity not present in healthy individuals. They include delusions, hallucinations, and formal thought disorder. Negative symptoms are clinical features that reflect a diminution of mental activity normally present in healthy individuals and include blunted affect, poverty of speech, and decreased voluntary activity. Positive symptoms usually respond to treatment with dopamine blocking medication, whereas negative symptoms are less responsive.8 Indirect evidence linked negative symptoms with indicators of overt structural brain damage, such as ventricular enlargement.9

On the basis of these observations, Crow proposed that two pathophysiological processes occur in schizophrenia: type 1 and type 2. The type 1 process entails dopaminergic overactivity and generates positive symptoms. The type 2 process involves structural brain damage and is responsible for negative symptoms. In its most strict formulation, this proposal implies that positive symptoms might be alleviated by blockade of dopamine, while negative symptoms are irreversible.

A substantial body of evidence provides at least partial support for Crow's proposal. In particular, a review of X-ray computed tomography (CT) scan studies by Lewis10 revealed that approximately half of the studies that had investigated the issue had found that ventricular enlargement was correlated with negative symptoms. More recently, in a study employing single-photon emission tomography (SPET) to measure endogenous dopamine release in response to administration of amphetamine, Laruelle et al.11 obtained evidence suggesting that schizophrenic patients exhibit an abnormally large release of dopamine and, furthermore, the amount of dopamine released correlates with the severity of induced positive symptoms.

Despite the evidence supporting Crow's type 1/type 2 formulation, there are several respects in which it does not provide an adequate account of the observable clinical features of schizophrenia.

1. The positive/negative dichotomy does not take into account the full range of symptoms of schizophrenia. In particular, it ignores the fact that excitation and depression are prevalent in schizophrenia.

2. While a minority of studies of the relationships between symptoms support the hypothesis that the characteristic symptoms of schizophrenia segregate into positive and negative groups,12 the majority of studies demonstrate that the characteristic symptoms segregate into at least three groups.5,613-16

3. Negative symptoms vary in severity over time and, in particular, resolve at least partially as florid episodes of illness subside.17

4. While negative symptoms are relatively resistant to treatment, there is evidence that they do respond at least partially to atypical antipsychotic medication.18

5. In some cases, positive symptoms persist despite a high level of blockade of dopamine D2 receptors.19

A more comprehensive formulation of the relationships between symptoms, mechanisms, and causes is necessary.

TABLE 1

Cognitive Deficits and Sites of Aberrant Regional Cerebral Activity Associated with the Three Characteristic Syndromes of Schizophrenia32

Symptoms Cognitive Deficit Increased rCBF Decreased rCBF

Reality distortion Delusions Hallucinations

Disorganization

Thought form disorder Inappropriate affect Psychomotor poverty

Monitoring and evaluation of mental activity

Selection between competing mental activities

L parahippocampal gyrus L hippocampus L lateral frontal cortex Ventral striatum

R anterior cingulate Thalamus

R posterior cingulate L temporo-parietal cortex

R ventrolateral frontal cortex L and R parietal cortex

L and R frontal cortex L parietal cortex

Blunted affect Planning and initiation of Caudate

Poverty of speech mental activity Thalamus

Decreased volition

Note: R = right, L = left, and rCBF = regional cerebral blood flow.

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