Neurochemical and neural mechanisms of positive and negative symptoms in schizophrenia.
It is difficult to come away from review of pharmacologic and metabolite studies without concluding that dopaminergic mechanisms play a significant role in mediating both negative and positive symptoms. Nevertheless, the characteristics of dopaminergic involvement are unclear. Whereas compelling evidence continues to link the mechanism of action of neuroleptic drugs, including therapeutic effects on negative and positive symptoms, to blockade of D2 receptors, neuroleptic-induced alterations in dopaminergic function are time-dependent and may include reductions in variability as well as in net dopamine activity. Moreover, pharmacologic enhancement of dopaminergic function may at least transiently improve symptomatology (negative greater than positive) and levels of CSF HVA appear to be reduced or are negatively correlated with symptoms in some schizophrenic patients. Thus, there is support for both increased and decreased dopamine function in schizophrenia. Functional brain imaging has, after only a few years of application, made significant contributions to our understanding of the pathophysiology of schizophrenia. Studies of cerebral metabolism and regional CBF have shown remarkable consistency in their identification of abnormal function of the frontal cortex in schizophrenia. It should be pointed out, however, that agreement across studies remains largely conceptual with significant discrepancies still existing with regard to the precise localization of dysfunction and its relationship to cognitive activation. Although less well documented than 'hypofrontality' itself, negative symptomatology appears to bear some relationship to this defect. The idea that positive symptoms might be associated with increased subcortical and/or metabolism is less well supported. The recent advances in our understanding of structure and function of CNS dopaminergic systems may help to integrate these two bodies of data into more dynamic models of dopaminergic defects in schizophrenia. For example, the concept that diminished mesocortical coupled with increased subcortical dopaminergic activity might be a 'substrate' for psychosis is compatible with neurochemical evidence suggesting both diminished and enhanced dopaminergic processes as well as with metabolic hypofrontality. Better understanding of the regulatory mechanisms involved in establishing functional balance between cortical and subcortical systems might, therefore, identify new possibilities for biological dysfunction in schizophrenia. The recent study by Weinberger et al. which correlates CSF HVA levels with neuropsychologically induced frontal CBF is an example of how neurochemistry can enhance brain imaging data.(ABSTRACT TRUNCATED AT 400 WORDS)
Pickar
D
D
Clinical Neuroscience Branch, National Institute of Mental Health, Bethesda, Md.
Litman
R E
RE
Konicki
P E
PE
Wolkowitz
O M
OM
Breier
A
A
D001921:Brain / Q000503:physiopathology*; D001931:Brain Mapping / Q000379:methods; D004298:Dopamine / Q000502:physiology; D006801:Humans; D019965:Neurocognitive Disorders / Q000503:physiopathology*; D018377:Neurotransmitter Agents / Q000502:physiology*; D011954:Receptors, Dopamine / Q000502:physiology; D017981:Receptors, Neurotransmitter / Q000502:physiology*; D012559:Schizophrenia / Q000503:physiopathology*; D012565:Schizophrenic Psychology
D018377:Neurotransmitter Agents; D011954:Receptors, Dopamine; D017981:Receptors, Neurotransmitter; D004298:Dopamine