Schizophrenia subgroups

Before their removal in DSM-5, ³³ clinical subtypes of schizophrenia have been a consistent feature of diagnostic classification; however, their application in biological research has seen gradual decline. ^{Reference Tandon, Gaebel, Barch, Bustillo, Gur and Heckers13,Reference Braff, Ryan, Rissling and Carpenter34} This is at odds with the widely accepted notion that the (wider) schizophrenia definition most likely encompasses several biologically distinct disease entities. Identification of putative biological markers for schizophrenia will therefore have to consider not only variability introduced by general factors (such as disease onset, disease severity and so on), but also whether this marker relates to a common deficit or to a pathophysiological feature expressed in varying degrees across subgroups.

In this study, we provide evidence that regional variability of cortical thinning in schizophrenia is related to symptom profiles and distinct subgroups. Our findings add to an increasing body

of research highlighting the biological heterogeneity of schizophrenia, which could provide important hints to delineating universal v. specific pathological pathways. ^{Reference Takayanagi, Wentz, Takayanagi, Schretlen, Ceyhan and Wang22,Reference Voineskos, Foussias, Lerch, Felsky, Remington and Rajji35}

Recent studies have established that regional cortical thinning is not only present at disease onset in schizophrenia, but also is evident in high-risk individuals in some areas. ^{Reference Sprooten, Papmeyer, Smyth, Vincenz, Honold and Conlon4} In addition, several recent studies have addressed the influence of certain clinical factors of disease and genetic risk on cortical thinning in schizophrenia. ^{Reference Bergmann, Haukvik, Brown, Rimol, Hartberg and Athanasiu16,Reference Schultz, Nenadic, Koch, Wagner, Roebel and Schachtzabel18,Reference Assuncao Leme, Gadelha, Sato, Kiyomi Ota, de Jesus Mari and Melaragno36} Yang e t al have demonstrated that cortical thinning might also be observed in non-psychotic relatives of people with schizophrenia, although those with the disease had more pronounced thinning, especially in frontal and temporal areas. ^{Reference Yang, Nuechterlein, Phillips, Hamilton, Subotnik and Asarnow12} Although this establishes both alterations related to disease liability or general phenotypic variation, there is rather little data on the heterogeneity of cortical thickness within participant groups with schizophrenia that would reflect possible subgroups within the disease entity. There is recent evidence of an association between the deficit subtype of schizophrenia and regional cortical thinning, but the results have been mixed. Whereas one found a significant difference in anterior cingulate thickness and volume, ^{Reference Takayanagi, Wentz, Takayanagi, Schretlen, Ceyhan and Wang22} another study found mostly overlapping regional thinning in patients with and without deficits compared with a control group. ^{Reference Voineskos, Foussias, Lerch, Felsky, Remington and Rajji35} Therefore, cortical thickness may be unable to separate those subtypes, albeit other morphometric markers did diverge.

Compared with the subtypes used in our study, the deficit syndrome relies mostly on outcome, i.e. longitudinal aspects. Although this might result in higher temporal stability of subgrouping, it remains to be clarified whether the deficit subtype truly correlates with a distinct biological endophenotype or merely represents a more severe disease form. Before the introduction of DSM-5, schizophrenia subtypes in DSM-III-R ³⁷ and DSM-IV ²⁴ have been based on clinical prototypes rather than biological parameters. Their validity on biological grounds has been insufficiently supported by (biological) research. ^{Reference Tandon, Gaebel, Barch, Bustillo, Gur and Heckers13} Although our approach has also been based on psychopathology as a clinical phenotype, it has not utilised prototypes or assignment to a subgroup by clinical decision, but rather has used psychometric aspects of symptom ratings to develop a more stable clinical phenotype, which is less susceptible to clinical rating biases.

Differences in our findings between subgroups

The regional patterns in frontal, temporal and cingulate areas across our three subsamples merit some attention. Our findings in the negative symptoms subgroup most closely resemble a pattern of widespread cortical thinning, almost lacking regional specificity, as seen in some recent large samples. ^{Reference Rimol, Nesvag, Hagler, Bergmann, Fennema-Notestine and Hartberg6} Probably the greatest overlap between our three subgroups was seen in prefrontal regions, where all three groups showed convergence in areas covering both the orbitofrontal cortices (except left medial orbitofrontal cortex for the disorganised symptoms subgroup, which did not reach significance), superior and rostral middle frontal (again, except left superior frontal cortex for the disorganised symptoms subgroup) and right frontal pole regions. In contrast, temporal areas, such as the temporal pole, fusiform cortex and even superior temporal showed less convergence, as none of these areas showed thinning across all three groups. This was also the case for the medial temporal areas (parahippocampal and entorhinal). Our study did not include a detailed analysis of hippocampal thickness, which requires other analytical approaches to address the more convoluted topography. ^{Reference Brambilla, Perlini, Rajagopalan, Saharan, Rambaldelli and Bellani38}

Considering the three subgroups in terms of how many regions showed reduction of cortical thickness, it is noteworthy that the disorganised symptoms subgroup showed the least deficits, which is consistent with recent VBM studies, where the extent of deficits was also smallest in this subgroup. ^{Reference Koutsouleris, Gaser, Jager, Bottlender, Frodl and Holzinger19,Reference Nenadic, Sauer and Gaser20} Overall, the pattern of the negative symptoms subgroup showing the most widespread pathology is consistent with our previous study assessing cortical complexity, ^{Reference Nenadic, Yotter, Sauer and Gaser21} although cortical complexity variation (both reduction and increase) in the negative symptoms subgroup was not as widespread and extensive as the cortical thickness deficit.

Limitations

The study has some limitations. Given that this is a cross-sectional study with patients well past their first episode, the effects of disease progression, which might diverge between subgroups, ^{Reference Nenadic, Sauer, Smesny and Gaser39} cannot be controlled for. Subgroups might also have varied disease severity, which is difficult to assess, especially in the absence of unequivocal unidimensional markers. This is also the case for antipsychotic medication, which might at least have some subtle effects on cortical thickness (including frontal areas), although recent studies in psychosis are not suggestive of very strong effects ^{Reference Roiz-Santianez, Tordesillas-Gutierrez, Ortiz-Garcia de la Foz, Ayesa-Arriola, Gutierrez and Tabares-Seisdedos40} and actually demonstrate some reversibility of cortical thinning during short-term treatment. ^{Reference Goghari, Smith, Honer, Kopala, Thornton and Su41} In participants with chronic schizophrenia, cumulative intake of antipsychotics is often difficult to assess, and given potential non-adherence to treatment, is also difficult to assess retrospectively. Chlorpromazine equivalents, which are often used in clinical studies to calculate simple dose equivalents between different antipsychotics, are likely not to be useful for this type of study, since brain structural effects of antipsychotics are probably not only related to dopamine D₂ receptor occupancy or other pharmacological factors important for assessment of clinical efficacy. Finally, we also cannot rule out effects of alcohol intake or illicit substances. These effects are difficult to track, especially when assessed retrospectively.

Implications

We conclude from our findings, that although cortical thickness is reduced in schizophrenia across multiple areas, especially the prefrontal cortex, the spatial extent and effect size are variable across subgroups delineated by predominant symptoms. Our results warrant further exploration of the notion that different patterns of regional thinning might be related to different biological subtypes, which might then be used as different intermediate phenotypes for the dissociation of genetically distinct forms of the disease.