Although schizophrenia was once considered the “graveyard of neuropathologists,”1
recent neuroimaging techniques have radically changed this view. Early studies using computerized tomography (CT) were pivotal in demonstrating ventricular abnormalities in the disorder but did not provide the resolution required to document alterations in regions with unclear boundaries such as the amygdala and various thalamic nuclei. With the advent of magnetic resonance imaging (MRI), these latter brain regions of interest have been evaluated in schizophrenia and found to be abnormal. In recent comprehensive reviews2,3
of MRI-documented morphological brain abnormalities in schizophrenia, most brain regions studied showed neuroanatomical alteration compared with the same regions in healthy controls. Nonetheless, a convergence of findings suggested that the major locus for brain abnormalities was the temporal lobe; fewer studies reported abnormalities in the lateral ventricles, prefrontal cortex, inferior parietal cortex, basal ganglia, thalamus, corpus callosum, or septum pellucidum.2,3
Note that, although many regions are involved in schizophrenia, they do not appear to be equally affected, and the temporal lobe regions are the most severely altered. (For a recent review of MRI findings in schizophrenia and a discussion comparing the various brain regions, see Shenton and colleagues.2
In many cases, however, these MRI findings are difficult to interpret, given the possible confounding effects of the chronicity of the psychotic illness and the medications used to treat it. Although the definition of a personality disorder4
requires that a person experience distress, the stress of chronic psychosis as seen in schizophrenia is arguably more relentless. McEwen and Margarinos5
have demonstrated that increased stress-induced adrenal cortisol release, along with excitatory amino acids, may result in atrophy of the hippocampal CA3 region. Such atrophy may help to explain some of the medial temporal lobe findings in schizophrenia (see section on temporal lobe structures, below).
Medications can also affect brain morphology. Chakos and colleagues6,7
compared the volume of the basal ganglia in patients taking traditional and atypical antipsychotics and found that the traditional antipsychotics increased caudate volume more than did the atypical medications. Other possible effects of medication on brain morphology have been reported for superior temporal gyrus volume.8
In addition, a recent animal model9
demonstrated increased volume and glial density in the prefrontal cortex with chronic exposure to conventional neuroleptics. The effect of anticholinergics, benzodiazepines, and anticonvulsants on specific brain regions has been less extensively examined.
One way to avoid the possible confounding effects of medication is to study patients during a first episode of schizophrenia, before they are treated with medications,10–15
as well as to investigate at-risk populations,16
including first-degree relatives of individuals with schizophrenia.17–23
An alternative approach is to study other populations presumed*
to have similar genetic vulnerability, such as patients with schizotypal personality disorder (SPD). Our review will focus on CT and MRI structural imaging studies of persons with SPD.
SPD is characterized by difficulties with social interaction and language, together with odd behavior and magical thinking. Because individuals with this disorder are not considered psychotic, they have generally not been prescribed medications. Nonetheless, persons with SPD and those with schizophrenia have a similar genetic predisposition, as suggested by multiple family studies24,27–31
reporting that 6–7% of individuals diagnosed with schizophrenia have a first-degree relative with SPD. Similarly, first-degree relatives of persons with SPD have a 6.9% chance of developing schizophrenia.27
In an early epidemiological study conducted in Denmark, Kety and colleagues29
found that the data supported the notion of a commonality between schizophrenia and schizophrenia-like disorders, and they grouped these conditions into the “schizophrenia spectrum disorders.” This work was followed by Kendler and colleagues’ Roscommon County family studies,27,30
which further supported the spectrum concept and encouraged the use of other research tools to define the phenotypic similarities between SPD and schizophrenia.
Other methodologies such as neurochemical analyses, behavioral studies, and neuropsychological and evoked-potential measures have also shown abnormalities in SPD that are similar to what has been demonstrated in schizophrenia.32
These include elevated homovanillic acid levels,33,34
reduced prepulse inhibition,39
and electrophysiological abnormalities.44–48
One hypothesis that attempts to incorporate findings from these various methodologies has been proposed by Siever (personal communication), who stated that the relative sparing in terms of symptoms and biological abnormalities in SPD compared with schizophrenia may be due to the fact that hypodopaminergic function emanates from the basal ganglia and extends to the frontal lobes. These projections may be “neuroprotective” to other regions such as the frontal lobes.32,49
Structural MRI studies of the basal ganglia and frontal lobes as well as functional studies examining dopaminergic function are needed to test this hypothesis further.
Another impetus for studying SPD, in addition to the disorder’s close genetic and biological ties with schizophrenia, is the importance of such research for the conceptualization of personality disorders. More specifically, personality disorders have traditionally not been thought to have a neurological basis. Now a wealth of data from multiple sources is radically challenging this view (see the studies cited in the previous paragraph). Moreover, with the neuroanatomical basis of SPD becoming more clearly established, investigations of the biological underpinnings of SPD may be a useful model to apply to other personality disorders.
The critical question that we ask, and seek to answer, in this review is: Do the imaging data support the notion that SPD is a less severe version of schizophrenia, or is it a distinct disorder? If the former, might we expect that persons with SPD will have fewer neuroanatomical abnormalities, and therefore less-severe clinical symptoms, than do individuals with schizophrenia? If the data support the idea that SPD is a less penetrant form of schizophrenia, then the next question concerns what abnormalities are present in schizophrenia but absent in SPD. Answers to this last question need to be examined in future studies and may help to direct attention to strategies for preventing the development of schizophrenia.
We performed a Medline search in February 2001 for English-language articles including the key words schizotypal personality disorder, schizophrenia, relatives, computerized tomography, and magnetic resonance imaging. We found and reviewed 17 studies. We began with investigations in which subjects met full DSM criteria for SPD, then continued with studies in which subjects had some of the features of SPD but did not meet the full criteria, reports of children with symptoms consistent with SPD, and finally other studies (i.e., reports of persons with SPD and schizophrenia analyzed together, or of individuals with SPD who have family members with schizophrenia). This organization reflects the different strategies used by researchers to enlist subjects with SPD for their studies. Such strategies include recruiting families of probands with schizophrenia, recruiting patients from clinics, recruiting community dwellers by means of newspaper advertisements, and recruiting college students who score high on scales of psychopathology thought to tap cognitive manifestations of SPD. Diagnostic criteria have also differed and range from meeting five out of the nine required DSM-IV criteria, to having some features of schizotypy derived by diagnostic impression during clinical interview, to scoring high on scales of psychopathology.
We included all 17 studies in our review, even though some included very few patients with SPD or SPD-like pathology. provides a summary of these studies.
Morphological Studies of SPD