CLINICAL HANDBOOK OF SCHIZOPHRENIA

28 I. CORE SCIENCE AND BACKGROUND INFORMATIONIn the neurodevelopment/plasticity category, a prominent risk-conferring gene isneuregulin, thought to regulate neuronal migration, axonal guidance, myelin formation,and synapse formation—events coincident with the prenatal–natal environmental riskfactors for schizophrenia. Another is DISC1 (disrupted-in-schizophrenia-1), which has anallele associated with schizophrenia, reduced hippocampal gray matter, and hippocampalfunction abnormalities in functional MRI (fMRI) studies. DISC1, like neuregulin, isthought be involved in neural development and plasticity through a variety of roles inneuron migration and development, as well as receptor turnover.A wide variety of other genes, many thought to play supporting roles in the key functionsdescribed earlier, are being added to the list of schizophrenia risk factors. Theemerging picture from these findings is that schizophrenia risk develops through a complexinteraction between genes guiding development and plasticity, genes guiding neurotransmission,and their environmental context.Neurochemical HypothesesThe Dopamine HypothesisThe dopamine hypothesis postulates that the symptoms of schizophrenia result fromdysregulation of dopamine in the CNS. Four dopaminergic anatomical pathways are describedin this model. The mesolimbic pathway projects from the ventral tegmental area(VTA) to limbic areas. Excessive mesolimbic dopamine may lead to positive symptoms ofschizophrenia, such as delusions and hallucinations. The mesocortical pathway projectsfrom VTA to cortex, particularly prefrontal cortex. Low mesocortical dopamine is proposedto cause the negative symptoms and cognitive deficits of schizophrenia. Thenigrostriatal pathway, from the substantia nigra to the striatum, regulates movements;low nigrostriatal dopamine leads to Parkinsonian motor symptoms. The tuberoinfundibularpathway travels from the hypothalamus to the pituitary gland and inhibits prolactin secretion;blockade of tuberoinfundibular dopamine leads to elevated prolactin and resultantgalactorrhea, amenorrhea, and decreased libido.There remains some controversy over the role of excess mesolimbic dopamine in psychosis.On the one hand, drug effects support this model: Dopamine agonists such as amphetaminesand cocaine provoke psychotic symptoms in normal subjects and those withschizophrenia; likewise, effective antipsychotic drugs bind and block the D 2 subtype ofdopamine receptors. Early studies showed increased dopamine metabolites and dopaminereceptors in schizophrenia. Positron emission tomography (PET) imaging studies confirmincreased synthesis of dopamine, increased levels of synaptic dopamine, and increaseddopamine release in response to stressors such as amphetamine challenge.On the other hand, increased levels of mesolimbic dopamine and dopamine receptorshave not been consistently shown across studies and remain controversial. Furthermore,many cases of schizophrenia are unresponsive to D 2 blockade. Finally, some antipsychoticdrugs, such as the atypical agent clozapine, have relatively poor D 2 binding,which suggests that other neurotransmitters or receptors may be involved. On the whole,current evidence appears to support a central role for striatal D 2 receptors in acute psychosis.The role of low mesocortical dopamine in negative and cognitive symptoms is alsocontroversial. On the one hand, a correlation has been shown between low levels of dopaminemetabolites in cerebrospinal fluid (CSF), low cortical dopamine, and the poorperformance on working memory tasks are seen in schizophrenia. Likewise, dopamineagonists improve prefrontal activation and cognitive performance in schizophrenia. Yetpostmortem studies have not clearly shown altered dopamine receptor levels in prefrontalcortex in patients with schizophrenia. PET studies have shown increased, decreased, or