Schizophrenia is a chronic mental illness with a heterogeneous etiology and a polymorphic clinical picture. The symptoms of schizophrenia are classified into positive, negative, and cognitive. In addition to these main symptoms, frequently anxious and affective symptoms have been identified (1). Studies that assess functional connectivity in patients with schizophrenia have shown disturbances in information transfer between brain centers, particularly between the frontal lobe and cuneus and other neuronal regions (2–4).

The grouping of the clinical manifestations is a reflection of the changes in the neuronal organization as well as the changes in the different levels of loss of connectivity (5). Studies show that the left and right hemispheres are asymmetric in their morphological structure and in the cognitive functions they mediate (6). This asymmetry seems to underlie the development of basic cognitive processes, such as language acquisition (7), and it is suggested that variations in the development of this asymmetry also contribute to the pathogenesis of schizophrenia (7, 8). T. J. Crow suggests that the genetic variation associated with the evolution of homo sapiens and the hemispheric dominance of language development is also associated with an increased likelihood of developing psychotic symptoms (7). Other authors also suggest that the loss of left hemispheric dominance is a central neurological feature of this disease (3, 4, 9–11).

One method of assessing lateralization is to establish the dominant hand of the subject. Hand dominance has also been shown to correlate with cerebral lateralization of language expression (12), visual processing (13), declarative memory (14, 15), and emotional processing (16). An analysis of more than 40 studies has concluded that the left hand is more common in mental illness (17). When comparing the prevalence of left-handedness among 107 patients with psychotic disorders and in patients with affective disorders and anxiety, a significant difference was observed (18). In patients with psychotic disorders, some authors find a high percentage (including schizoaffective and schizophrenia) of up to 40% left-handedness (18). Other studies have found almost two times less left handers in patients with schizophrenia (between 15 and 20%) (17). There are also reverse studies. An assessment of several hundred patients showed no difference in lateralization in patients with schizophrenia, their relatives, and the control group (19).

Schizophrenia is a disease of various etiologies, and this could be the reason for the observed deviation in dominance in different studies due to the fact that different clinical subgroups have been studied. Several analyses point to such possible differences. Left-handed and those with cross-dominance with psychotic disorders report more severe impairment in social functioning and have poorer results in psychological studies (20, 21). These results may suggest that dominance may be considered a marker for a particular subtype of psychosis.

Although dominance is a constant feature (there is continuity over time) (22), a definite approach to dominance is not established in current research practice in psychiatry. A three-modal classification is most commonly used, in which subjects are classified into categories with left, right, and mixed dominance, although there are several authors who continue to view dominance as a simple dichotomy (23, 24). The mixed group includes individuals without a clear dominance or consistent preference of the hands, i.e., no pronounced lateralization. Mixed dominance is thought to reflect left hemispheric dysfunction, which may be the result of early (prenatal or perinatal) brain damage (25, 26) or other causes of neurodevelopment (27–29). Mixed dominance, which is more common in patients with schizophrenia than in normal subjects, is even considered characteristic of schizophrenia (28). An analysis of 93 patients with schizophrenia and 105 controls revealed cross-dominance in 20% of patients with psychosis compared with 3.8% in the control group (29). Another study with almost the same number of patients with schizophrenia (30) compared with controls found that the number of patients with pure left dominance was not different from that in the rest of the control group. The authors registered an increased frequency of those with mixed dominance in patients with psychosis (three times more often than the control group). They find that mixed dominance is more pronounced in chronic cases. The results of another research study suggest that some researchers consider schizophrenia as a disorder of lateralization of cerebral function. They analyze the eye/hand relationship for dominance. A meta-analysis found that 35% of right-handers and 57% of left-handers had a dominant left eye (31). Another study assessed the dominant eye in 68 patients with schizophrenia and 118 controls. The patients were aged 17–60 years, with a predominance of males −60 people, and females, 28 people, respectively. The authors found an increased incidence of cross-dominance in patients with schizophrenia. Interestingly, male patients with schizophrenia have an increased incidence of left eye dominance, and such a relationship is not found in females, given the fact that they are the smaller group in the study (32).

An increased incidence of cross-dominance has also been reported in patients with the first psychotic episode, but also associated with more pronounced mild neurological symptoms. The mixed dominance reported by them was associated with poorer school performance as well as poorer social adaptation in the premorbid period (20).

The definition of a mixed dominance category depends on the choice of a questionnaire that divides the continuum of the coefficients for considering dominance as mixed or as more pronounced on the left or right. With a few exceptions (33, 34), most existing hand questionnaires do not have valid criteria for separating dominance. In contrast, measures based on another widely used instrument in the Edinburgh Classification (EHI) (35) have repeatedly been the subject of arbitrary division of classes according to the degree of dominance.

The analysis gives us reason to draw the following conclusions: There are many studies with conflicting results on the topic. We did not find a study to analyze the differences in lateralization in patients with resistance to treatment and in patients in remission.

Working hypothesis: Based on the different results of the studies conducted in patients with schizophrenia, it can be assumed that they were conducted in different subgroups of patients. We hypothesize that we will find differences in functional lateralization in patients with resistance to treatment and in those in remission.

Patients (105) with schizophrenia and consecutive psychotic episode were observed in a psychiatric clinic in a hospital setting. Of these, 45 have resistant schizophrenia, and the remaining 60 are in clinical remission.

The gender breakdown showed that 66 were women and 39 were men.

Inclusion criteria for patients with resistant schizophrenia are those who have met the resistance criteria of the published consensus on resistant schizophrenia (36). They are as follows:

The exclusion criteria are as follows:

The mean age of patients in the group of resistant schizophrenia was 36.98 years. The minimum age is 21 years, and the maximum is 60 years.

The mean age of patients in the group of schizophrenia in clinical remission was 37.25 years. The minimum is 23 years, and the maximum is 63 years.

We do not find a difference in the mean age of the patients in the both groups at the time of the study.

The use of a trimodal classification model to assess the lateralization of brain processes showed that our study did not reveal gender-related differences, unlike some studies that show one (40). We do not find gender-related differences in the lateralization of cerebral hemisphere dominance. Literature data show that there is a general prevalence of left-handed among males. A study conducted in Greece found that it was observed in 8.26% of men and 6.41% of females (40). In our sample, the difference between left-handed male and female left-handed patients is insignificant. This can be interpreted in the context of the observation of other authors that these gender differences are not universal (41).

Our results do not support the data of other authors on the predominance of left-handedness in patients with schizophrenia (17, 18). We find a high percentage of patients with mixed lateralization (i.e., cross use of hand, foot, or eye). Most likely, some studies did not look at cross-lateralization, but only left-handed or right-handed dominance, and did not use a trimodal classification, but a bimodal one. If we have to use the bimodal classification and look at the lateralization in terms of hand dominance, we found that seven of the patients have a dominant left hand. This makes 6.7% of all patients included in our study. The range of reported results of left-handedness in patients with schizophrenia varies from 7 to 31%. Our result is in the lower range of reported cases, and we do not confirm the data of other authors for high rates of dominance of the left hand in patients with schizophrenia—up to 40% (18). Other analyses show that differences in lateralization are not universal, and there are many divergent results (41). The results of other analyses indicate that left-handed people have a predominance in patients with schizophrenia. Using a bimodal classification, our study did not support these studies (17, 18). We find a low percentage of patients with a dominant left arm that is comparable with those in the general population. These results support the data of other researchers on the lack of differences in left-handed dominance in patients with schizophrenia and the general population (30). Our results show that when using a trimodal classification in patients with resistant symptoms, those with cross-dominance (mixed lateralization) predominate. We support the researchers' view that mixed dominance is typical of patients with schizophrenia, as we find that more than 40% of all patients have cross-dominance (28). The results of other studies also indicate that mixed or cross-dominance is three times more common in patients with schizophrenia than in the general population (30, 42). The data obtained by us (twice as many), in patients with mixed lateralization with resistance in comparison with those in remission, support the assessment of other authors for the more severe course of the disease in those with cross-dominance (20, 21, 30).

On the other hand, neurophysiological studies to assess the lateralization of background activity in the EEG also do not show the presence of dominant hemisphere in patients with schizophrenia with and without therapy, which also indirectly supports the idea of mixed dominance in patients with schizophrenia (43). Our study shows that the high frequency of cross-dominance we found is due to the left lateralization of eye dominance. Analyses by other authors also found left-sided dominance of the eye in patients with schizophrenia, which is more pronounced in male patients (32). Our study showed a slightly higher percentage of men with left eye dominance than women.

One of the limitations of our study is that due to the presence of psychotic production—delusions and hallucinations (we analyze patients with resistance), it was not possible to assess in detail the continuity of dominance with analysis of mixed forms and their weight in the assessment of refractoriness. On the other hand, an additional problem is the formation of social dysfunction with concomitant change in behavior in many patients, which also leads to a reduction in daily functioning and activity in the use of hands and eyes. A third important factor is the presence of additional comorbidity due to the fact that these patients do not conduct systematic treatment of their health problems, including the care of the visual analyzer, which would call into question attempts for accurate and detailed assessment.

Our study provides guidance for future studies related to resistance and disconnection syndrome in association with the fact that the very presence of cross-dominance raises the question of easier disruption of information flows in the crossover of the neural network associated with them.

We found an association between the presence of cross-dominance and the treatment resistance in patients with schizophrenia. We reported that cross-dominance was found in more than half of the patients with resistant schizophrenia. This increased frequency of mixed dominance in them is due to left-sided dominance of the eye. These observations of ours can also be of practical use. The assessment of the dominant eye as well as a more in-depth analysis of the overall lateralization of dominance would provide guidance for early assessment of future development of resistance during treatment. Opportunities for early assessment provide a basis for seeking complex methods of treatment earlier in the course of the development of the schizophrenic process in order to prevent psychosocial complications associated with resistance.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Ethics Commission of the University Hospital for Active Treatment, Stara Zagora. The patients/participants provided their written informed consent to participate in this study.

The author confirms being the sole contributor of this work and has approved it for publication.

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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