MRI and Prediction of Outcome in First-Episode Schizophrenia
We know that in fact there is large variability in response to the first antipsychotic prescribed. For example, in the large European First Episode Schizophrenia Trial (EUFEST) trial only ~55% of first-episode psychosis patients responded to antipsychotics in the first 12 months. Here response was defined as ≥50% response according to the Positive and Negative Syndrome Scale (PANSS) scores. Two other important first episode studies found higher remission rates of about 80%, even though they also used stringent criteria for remission. Although symptomatic response is thought to be one of the strongest predictors of subsequent functional and clinical outcome in psychosis, the relationship between response within the first 12 month of illness and brain structure at onset has not been extensively investigated.
We therefore searched Medline and EMBASE databases using the terms: ["schizophrenia" OR "psychosis" OR "schizo$"] AND ["response" OR "outcome" OR "antipsychotic" AND ["MRI NOT functional]. Abstracts were reviewed to assess the relevance of the articles identified and any duplicates were removed. Further, references were also examined for relevance and included if appropriate. The criterion of adherence to the keywords was defined as the presence of a significant number of keywords in either the text or the abstract. Since we did not follow a published prespecified protocol during our systematic review, the inclusion/exclusion criteria and search strategy were defined a priori. The inclusion criteria were: (1) publication between January 1976 and December 2015; (2) diagnosis of any functional psychotic illness; (3) age of patients between 16 and 80 years; (4) evaluation of brain structure with morphometric techniques that measured volume, shape, thickness, or surface area of gray matter structures or volume of white matter; (5) assessment of response to treatment, symptomatic outcome, or functional outcome conducted at any point in the first 12 months from onset; and (6) analysis of longitudinal data explicitly evaluating the relationship between structural brain measures at the time of first onset, and outcomes measured in the first 12 months. Exclusion criteria were as follows: (1) inclusion of high-risk subjects with no diagnosis of psychosis; (2) use of MRI sequences other that T1, T2, or dual spin echo, such as Diffusion Tensor Imaging; (3) absence of a longitudinal evaluation of outcome or evaluation conducted more than 12 months after illness onset; and (4) publication in the form of short reports or brief communications.
The articles included in this review are listed in Table 1.
We identified 5 articles that evaluated brain structure at illness onset and remission at 1 year. Fung and colleagues used voxel-based morphometry to study brain structure in 39 patients naïve to antipsychotics. They found that in female patients a larger striatothalamic volume was correlated with response to antipsychotic medications at the 1-year follow up (defined according to threshold score equal to 60 in the General Assessment of Function (GAF) scale). This is important as striatal volume has been previously linked to antipsychotic use, confirming a susceptibility of these structures to treatment. In this study however this correlation was not present in males, who were also less likely to be remitted at the follow-up evaluation. The authors suggest that gender effect may contribute to the potential for brain structural alterations to predict outcome. Males were less likely to have remitted from a first episode of illness also in an older study, mirroring clinical experience about the course of schizophrenia. In this study 70 patients were examined at their first psychotic episode, all treated according to a standardized pharmacological protocol with first generation antipsychotics. Patients were classified as remitted according to the positive psychotic symptom items (ie, suspiciousness, severity of delusions, severity of hallucinations, impaired understandability, bizarre behavior) of the Schedule for Affective Disorders (SADS) Change and Psychosis and Disorganization Scale and to Clinical Global Impression (CGI) severity scores. These authors, however, did not report a gender effect, and found that lateral and third ventricles abnormalities predicted longer time to remission. These data suggest that even in males the presence of brain alterations at onset seems associated with more resistant symptoms. In contrast, cortical or medial temporal lobe volumes were not predictive of time to remission. These findings were taken to suggest that medial temporal structures (hippocampus, amygdala) may be particularly involved in mediating the response to positive, rather than the more resistant negative, symptoms; in contrast, alterations in structures that may affect ventricular volumes may be particularly associated with poor outcome. However, the evidence from these studies remains largely correlative and cannot claim to have demonstrated causal effects. Furthermore, the hypothesis from this article was not confirmed by another study, which examined lateral ventricles and the hippocampus in patients with schizophrenia. Here, 45 patients at their first episode were classified at 1 year as having either stable psychopathology (defined as having an increase of PANSS scores below 10% of the baseline score, ~5 points) or bad outcome (increase of PANSS total score above 40% of baseline score, ~20 points) outcome. There were no differences between the 2 groups in lateral ventricular or hippocampal volumes. However, those patients with a poor outcome showed a smaller left anterior limb of the internal capsule. This tract contains fibres linking the frontal cortex with subcortical areas, and the authors interpreted this finding as reflecting a disturbance of frontothalamic connectivity.
Interestingly, in a recent study, Bodnar and colleagues specifically examined another medial temporal area, the parahippocampal gyrus. They studied 3 subregions of this gyrus (entorhinal, perirhinal, parahippocampal), together with verbal memory, in 42 nonremitted and 17 remitted first-episode schizophrenia patients, classified according to the Remission criteria of the Schizophrenia Working Group (based on a reduction in 8 core PANSS symptoms to 3 (mild) or less, which has to be sustained for at least 6 months over the first year of illness). Using a manual segmentation method, the authors found that patients who did not remit showed a smaller volume of the parahippocampal cortex, but not of the entorhinal or perirhinal cortices. Furthermore, this reduction was associated with social withdrawal and severe memory deficits, suggestive of abnormalities in a posterior memory network involving both medial temporal areas and their connections to the prefrontal cortex.
The presence of functional deficits in relation to altered brain structure was also investigated in 2 studies that specifically measured functional rather than symptomatic outcome. Prasad and colleagues used the Strauss–Carpenter Scale to assess functional outcome (which includes frequency of social contacts, employment duration, symptomatology, and duration of re-hospitalization) in 27 antipsychotic-naïve patients with schizophrenia or schizoaffective disorder. They found the dorsolateral prefrontal (DLPF) cortex volume, but not intracranial volume, was a significant predictor of functional outcome at 1 year. A second study conducted in a sample of 32 male only patients with a first-episode schizophrenia evaluated functional outcome with the GAF: patients with scores below or equal to 60 were classified as having poor functioning, and those with GAF score above 60 as good functioning. Using voxel-based morphometry, this study found that patients with poor functioning had smaller volumes than those with good functioning in the left prefrontal region and extending to the inferior, middle, and superior frontal gyri. Again, alterations in these frontal areas may be reflected in emotional and cognitive dysfunctions that affect the individual's ability to carry out everyday activities and experience pleasure.
Only 2 studies have evaluated the relationship between brain structure and treatment response in the first 6 months of illness. One study was conducted by Bodner and colleagues in the same clinical group evaluated also at 1 year and discussed in the previous section. These authors evaluated symptomatic response at 6 months in 68 never-treated patients with schizophrenia, using the Remission in Schizophrenia Working Group consensus criteria, and conducted a brain-wide analysis using voxel-based morphometry (VBM). This showed that parahippocampal volume was significantly smaller in those 40 patients who had not remitted, compared with the 28 who had achieved remission after 6 months of treatment. The authors also built a classification model using parahippocampal grey matter concentration, and found that this model could correctly classify remission status 79% of the time. In contrast, Molina and colleagues evaluated 19 patients, examining the relationship between percentage of change in PANSS scores over 6 months across 3 dimensions (positive, negative and disorganization), and volumes of the cerebrospinal fluid, dorsolateral-prefrontal and temporal regions and hippocampus. They found that none of these measures predicted response at 6 months, although Cerebro Spinal Fluid (CSF) volume of the dorsolateral-prefrontal and temporal regions were associated with baseline symptom severity.
Studies that have looked at outcomes shorter than 6 months are only few (n = 3). One study from our group evaluated a different neuroanatomical measure, cortical gyrification, as a predictor of treatment response at 12 weeks in patients at their first episode of any psychosis. Cortical gyrification is a marker that suggests early neurodevelopmental disturbances, and it has been associated with psychotic symptoms resistant to treatment. We defined response to treatment according to the symptomatic criteria of the Schizophrenia Working Group. Our data showed that, already at illness onset, the 40 patients who subsequently did not respond to treatment had significant cortical folding defects (hypogyria) of several frontotemporal regions and the insula when compared with the 40 patients who did respond. The nonresponders also had more widespread deficits in gyrification extending to the precuneus, angular gyrus, and lingual gyrus when compared with healthy controls. Another study looked at cortical pattern (asymmetry) and cortical thickness measures, in 39 patients with first episode schizophrenia. The study found greater frontal cortical asymmetry in patients who showed symptomatic improvement, which occurred on average following 7.8 weeks of treatment. This finding was also taken to suggest the presence of a neurodevelopmental disruption of the normal brain asymmetry. Patients with symptomatic improvement also showed greater occipital cortical thickness, a finding consistent with evidence of increased metabolism and activity in this area in relation to treatment response. Interestingly, a greater thickness in temporal regions was associated with shorter time in the response to antipsychotics in another study, consistently with findings from patients with treatment resistant schizophrenia. Finally, one study looked at very early response to treatment. In this study, 26 patients with first episode of schizophrenia, schizophreniform, delusional disorder, and psychotic disorder not otherwise specified were treated with haloperidol 2mg per day for 1 week. At this point, response was defined as a reduction of at least 15% in PANSS baseline scores. Brain measures were collected at baseline for total CSF volume, ventricular volume, sulcal volume, total grey matter volume, cortical grey matter volume, and white matter volume. An improvement in positive and negative symptoms at the end of the first week was significantly associated only with greater cortical grey matter volume. In contrast, there was only a trend level association with sulcal and total CSF volume, and total grey matter volume. The authors again suggest that the magnitude of these global abnormalities may indeed represent a stable deficit, possibly reflected in a poorer ability to respond to treatment with antipsychotics.
It is immediately evident from this literature that there are relatively few studies that have assessed this topic and most have been relatively underpowered. These studies show large variability in findings, and are often inconsistent. Also, it is difficult to establish to what extent the treatment effects predicted from MRI are actually carried-forward severity differences from before treatment, unless baseline scores of the outcome of interest is controlled for in the analyses. Nevertheless, alterations in medial temporal and prefrontal cortical areas, and in the networks that connect them with other subcortical structures, seem to show promise as potential neuroanatomical markers of poor response to treatment. This is supported by studies in individuals at chronic illness stages, which have also reported hippocampal and frontal volume reductions in patients with poor response to antipsychotics. Furthermore, there is evidence that partially responsive patients with larger frontal brain volumes may be more likely to benefit from clozapine treatment. It is also possible that prefrontal and temporal pathology affects the ability to learn novel situations and impair those behaviors that rely on pre-existing cognitive strategies, and memory, which when affected could eventually lead to poor functional outcomes. The next section will discuss the limitations of this evidence, and the aspects that would need to be addressed before neuroanatomical alterations at illness onset could be used as predictors of response to treatment in clinical practice.
Brain Structure at the First Psychotic Episode as a Predictor of Outcome and Response to Treatment
We know that in fact there is large variability in response to the first antipsychotic prescribed. For example, in the large European First Episode Schizophrenia Trial (EUFEST) trial only ~55% of first-episode psychosis patients responded to antipsychotics in the first 12 months. Here response was defined as ≥50% response according to the Positive and Negative Syndrome Scale (PANSS) scores. Two other important first episode studies found higher remission rates of about 80%, even though they also used stringent criteria for remission. Although symptomatic response is thought to be one of the strongest predictors of subsequent functional and clinical outcome in psychosis, the relationship between response within the first 12 month of illness and brain structure at onset has not been extensively investigated.
We therefore searched Medline and EMBASE databases using the terms: ["schizophrenia" OR "psychosis" OR "schizo$"] AND ["response" OR "outcome" OR "antipsychotic" AND ["MRI NOT functional]. Abstracts were reviewed to assess the relevance of the articles identified and any duplicates were removed. Further, references were also examined for relevance and included if appropriate. The criterion of adherence to the keywords was defined as the presence of a significant number of keywords in either the text or the abstract. Since we did not follow a published prespecified protocol during our systematic review, the inclusion/exclusion criteria and search strategy were defined a priori. The inclusion criteria were: (1) publication between January 1976 and December 2015; (2) diagnosis of any functional psychotic illness; (3) age of patients between 16 and 80 years; (4) evaluation of brain structure with morphometric techniques that measured volume, shape, thickness, or surface area of gray matter structures or volume of white matter; (5) assessment of response to treatment, symptomatic outcome, or functional outcome conducted at any point in the first 12 months from onset; and (6) analysis of longitudinal data explicitly evaluating the relationship between structural brain measures at the time of first onset, and outcomes measured in the first 12 months. Exclusion criteria were as follows: (1) inclusion of high-risk subjects with no diagnosis of psychosis; (2) use of MRI sequences other that T1, T2, or dual spin echo, such as Diffusion Tensor Imaging; (3) absence of a longitudinal evaluation of outcome or evaluation conducted more than 12 months after illness onset; and (4) publication in the form of short reports or brief communications.
The articles included in this review are listed in Table 1.
Brain Structure and Prediction of Outcome at 1 Year
We identified 5 articles that evaluated brain structure at illness onset and remission at 1 year. Fung and colleagues used voxel-based morphometry to study brain structure in 39 patients naïve to antipsychotics. They found that in female patients a larger striatothalamic volume was correlated with response to antipsychotic medications at the 1-year follow up (defined according to threshold score equal to 60 in the General Assessment of Function (GAF) scale). This is important as striatal volume has been previously linked to antipsychotic use, confirming a susceptibility of these structures to treatment. In this study however this correlation was not present in males, who were also less likely to be remitted at the follow-up evaluation. The authors suggest that gender effect may contribute to the potential for brain structural alterations to predict outcome. Males were less likely to have remitted from a first episode of illness also in an older study, mirroring clinical experience about the course of schizophrenia. In this study 70 patients were examined at their first psychotic episode, all treated according to a standardized pharmacological protocol with first generation antipsychotics. Patients were classified as remitted according to the positive psychotic symptom items (ie, suspiciousness, severity of delusions, severity of hallucinations, impaired understandability, bizarre behavior) of the Schedule for Affective Disorders (SADS) Change and Psychosis and Disorganization Scale and to Clinical Global Impression (CGI) severity scores. These authors, however, did not report a gender effect, and found that lateral and third ventricles abnormalities predicted longer time to remission. These data suggest that even in males the presence of brain alterations at onset seems associated with more resistant symptoms. In contrast, cortical or medial temporal lobe volumes were not predictive of time to remission. These findings were taken to suggest that medial temporal structures (hippocampus, amygdala) may be particularly involved in mediating the response to positive, rather than the more resistant negative, symptoms; in contrast, alterations in structures that may affect ventricular volumes may be particularly associated with poor outcome. However, the evidence from these studies remains largely correlative and cannot claim to have demonstrated causal effects. Furthermore, the hypothesis from this article was not confirmed by another study, which examined lateral ventricles and the hippocampus in patients with schizophrenia. Here, 45 patients at their first episode were classified at 1 year as having either stable psychopathology (defined as having an increase of PANSS scores below 10% of the baseline score, ~5 points) or bad outcome (increase of PANSS total score above 40% of baseline score, ~20 points) outcome. There were no differences between the 2 groups in lateral ventricular or hippocampal volumes. However, those patients with a poor outcome showed a smaller left anterior limb of the internal capsule. This tract contains fibres linking the frontal cortex with subcortical areas, and the authors interpreted this finding as reflecting a disturbance of frontothalamic connectivity.
Interestingly, in a recent study, Bodnar and colleagues specifically examined another medial temporal area, the parahippocampal gyrus. They studied 3 subregions of this gyrus (entorhinal, perirhinal, parahippocampal), together with verbal memory, in 42 nonremitted and 17 remitted first-episode schizophrenia patients, classified according to the Remission criteria of the Schizophrenia Working Group (based on a reduction in 8 core PANSS symptoms to 3 (mild) or less, which has to be sustained for at least 6 months over the first year of illness). Using a manual segmentation method, the authors found that patients who did not remit showed a smaller volume of the parahippocampal cortex, but not of the entorhinal or perirhinal cortices. Furthermore, this reduction was associated with social withdrawal and severe memory deficits, suggestive of abnormalities in a posterior memory network involving both medial temporal areas and their connections to the prefrontal cortex.
The presence of functional deficits in relation to altered brain structure was also investigated in 2 studies that specifically measured functional rather than symptomatic outcome. Prasad and colleagues used the Strauss–Carpenter Scale to assess functional outcome (which includes frequency of social contacts, employment duration, symptomatology, and duration of re-hospitalization) in 27 antipsychotic-naïve patients with schizophrenia or schizoaffective disorder. They found the dorsolateral prefrontal (DLPF) cortex volume, but not intracranial volume, was a significant predictor of functional outcome at 1 year. A second study conducted in a sample of 32 male only patients with a first-episode schizophrenia evaluated functional outcome with the GAF: patients with scores below or equal to 60 were classified as having poor functioning, and those with GAF score above 60 as good functioning. Using voxel-based morphometry, this study found that patients with poor functioning had smaller volumes than those with good functioning in the left prefrontal region and extending to the inferior, middle, and superior frontal gyri. Again, alterations in these frontal areas may be reflected in emotional and cognitive dysfunctions that affect the individual's ability to carry out everyday activities and experience pleasure.
Brain Structure and Prediction of Outcome Earlier Than 1 Year
Only 2 studies have evaluated the relationship between brain structure and treatment response in the first 6 months of illness. One study was conducted by Bodner and colleagues in the same clinical group evaluated also at 1 year and discussed in the previous section. These authors evaluated symptomatic response at 6 months in 68 never-treated patients with schizophrenia, using the Remission in Schizophrenia Working Group consensus criteria, and conducted a brain-wide analysis using voxel-based morphometry (VBM). This showed that parahippocampal volume was significantly smaller in those 40 patients who had not remitted, compared with the 28 who had achieved remission after 6 months of treatment. The authors also built a classification model using parahippocampal grey matter concentration, and found that this model could correctly classify remission status 79% of the time. In contrast, Molina and colleagues evaluated 19 patients, examining the relationship between percentage of change in PANSS scores over 6 months across 3 dimensions (positive, negative and disorganization), and volumes of the cerebrospinal fluid, dorsolateral-prefrontal and temporal regions and hippocampus. They found that none of these measures predicted response at 6 months, although Cerebro Spinal Fluid (CSF) volume of the dorsolateral-prefrontal and temporal regions were associated with baseline symptom severity.
Studies that have looked at outcomes shorter than 6 months are only few (n = 3). One study from our group evaluated a different neuroanatomical measure, cortical gyrification, as a predictor of treatment response at 12 weeks in patients at their first episode of any psychosis. Cortical gyrification is a marker that suggests early neurodevelopmental disturbances, and it has been associated with psychotic symptoms resistant to treatment. We defined response to treatment according to the symptomatic criteria of the Schizophrenia Working Group. Our data showed that, already at illness onset, the 40 patients who subsequently did not respond to treatment had significant cortical folding defects (hypogyria) of several frontotemporal regions and the insula when compared with the 40 patients who did respond. The nonresponders also had more widespread deficits in gyrification extending to the precuneus, angular gyrus, and lingual gyrus when compared with healthy controls. Another study looked at cortical pattern (asymmetry) and cortical thickness measures, in 39 patients with first episode schizophrenia. The study found greater frontal cortical asymmetry in patients who showed symptomatic improvement, which occurred on average following 7.8 weeks of treatment. This finding was also taken to suggest the presence of a neurodevelopmental disruption of the normal brain asymmetry. Patients with symptomatic improvement also showed greater occipital cortical thickness, a finding consistent with evidence of increased metabolism and activity in this area in relation to treatment response. Interestingly, a greater thickness in temporal regions was associated with shorter time in the response to antipsychotics in another study, consistently with findings from patients with treatment resistant schizophrenia. Finally, one study looked at very early response to treatment. In this study, 26 patients with first episode of schizophrenia, schizophreniform, delusional disorder, and psychotic disorder not otherwise specified were treated with haloperidol 2mg per day for 1 week. At this point, response was defined as a reduction of at least 15% in PANSS baseline scores. Brain measures were collected at baseline for total CSF volume, ventricular volume, sulcal volume, total grey matter volume, cortical grey matter volume, and white matter volume. An improvement in positive and negative symptoms at the end of the first week was significantly associated only with greater cortical grey matter volume. In contrast, there was only a trend level association with sulcal and total CSF volume, and total grey matter volume. The authors again suggest that the magnitude of these global abnormalities may indeed represent a stable deficit, possibly reflected in a poorer ability to respond to treatment with antipsychotics.
It is immediately evident from this literature that there are relatively few studies that have assessed this topic and most have been relatively underpowered. These studies show large variability in findings, and are often inconsistent. Also, it is difficult to establish to what extent the treatment effects predicted from MRI are actually carried-forward severity differences from before treatment, unless baseline scores of the outcome of interest is controlled for in the analyses. Nevertheless, alterations in medial temporal and prefrontal cortical areas, and in the networks that connect them with other subcortical structures, seem to show promise as potential neuroanatomical markers of poor response to treatment. This is supported by studies in individuals at chronic illness stages, which have also reported hippocampal and frontal volume reductions in patients with poor response to antipsychotics. Furthermore, there is evidence that partially responsive patients with larger frontal brain volumes may be more likely to benefit from clozapine treatment. It is also possible that prefrontal and temporal pathology affects the ability to learn novel situations and impair those behaviors that rely on pre-existing cognitive strategies, and memory, which when affected could eventually lead to poor functional outcomes. The next section will discuss the limitations of this evidence, and the aspects that would need to be addressed before neuroanatomical alterations at illness onset could be used as predictors of response to treatment in clinical practice.