Schizophrenia is a complex and multi-dimensional disorder and one of the most incapacitating conditions worldwide.1 The course of the disorder can be marked by psychotic episodes with positive symptoms, negative symptomatology, and cognitive impairment, which results in functional outcome impairment.2 Schizophrenia and first-episode psychosis are characterized by heterogeneity of symptoms, illness course, and psychosocial and pharmacological treatment response.

This variability in the clinical presentation at onset may be sex-related, as it has been well demonstrated that sex differences with respect to schizophrenia spectrum disorders are an important factor in the understanding of the heterogeneity manifestation and development of the illness).3,4 In this context, already from the first stages of the illness, men and women show different symptomatology and different levels of social functioning.5 It has been suggested than men tend to present more negative symptoms than women, whereas women show higher levels of depressive symptomatology. In addition, it has also been reported than females present more functioning unmet needs for care, but higher levels of insight into illness in comparison to males.5,6 A recent review and meta-analysis including thirty-five studies has also reported that men experienced more negative symptomatology than women, whereas women experienced more depressive symptomatology, had a lower prevalence of substance abuse and had higher functioning.7 Notwithstanding, prior literature on sex/gender differences in symptoms of schizophrenia have been inconclusive, due to the difficulties to differentiate between sex and gender in the different studies; that is, whether differences in clinical profiles are due to biologic sex differences or if gender may also play a role in these profiles.7 In this line, given the stability and validity of its definition, the study of the sex variable may help explain at least part of these phenotypical differences, a comprehensive summary of evidence on the early course of illness is necessary.3

Negative symptoms are a heterogeneous clinical construct that constitutes an independent core psychopathological domain of schizophrenia. This symptomatology can be stable or transient and is divided into primary, when they are intrinsic to the illness, or secondary, originated from confounding conditions (medication side effects, positive, affective symptoms, and/or environmental deprivation).8 Patients with the presence of primary and enduring negative symptoms (lasting>1 year) are said to meet the criteria for the deficit syndrome (DS) of schizophrenia, while those patients without these symptoms have non-deficit schizophrenia.9 Besides the DS, other concepts have been raised for the assessment of negative symptomatology, as predominant negative symptoms (PNS). This symptomatology is characterized by the presence of moderate-to-sever negative symptomatology that are more severe than co-occurring positive symptomatology.9 Nonetheless, general negative symptomatology is known to predict disease burden better than positive symptoms and worsened quality of life target.10,11 In this line, the study of risk factors associated to primary and persistent negative symptomatology has gained special relevance.12,13

Moreover, negative symptomatology is multidimensional, comprising five subdomains (anhedonia, avolition, asociality, blunted affect, alogia) with two higher-order dimensions: expression (EXP), and motivation and pleasure (MAP), both of which have more basic subordinate domains (MAP=anhedonia, avolition, asociality; EXP=blunted affect, alogia). Both factors represent separable treatment targets with distinct pathophysiology and different impacts on functional outcomes.9

Although most first-episode of schizophrenia (FES) patients may improve their symptomatology after antipsychotic treatment, many may continue to have long-term impairments in functioning and persistence of some symptomatology.9 The early identification of clinical, cognitive and socio-demographic features may be important in identifying subsets of patients with similar characteristics, facilitating personalized treatment approaches.14 Thus, identifying specific dimensions and risk factors that underlie the development of PNS from early stages of schizophrenia could improve the understanding and treatment of such invalidating symptomatology and the prevention of DS diagnose at long-term.11–13

A subtyping strategy according to meeting criteria for predominant negative symptomatology and according to the sex of the patients has been utilized to identify homogeneous clinical profiles from the first stages after the FES. We analyzed a cohort of FES patients to examine the potential risk factors that may play a role in the development of predominant negative symptoms in later stages. Our aims were (1) to analyze those potential clinical and socio-demographic predictors of PNS, and (2) to determine whether there were sex-differences for socio-demographic, clinical, and cognitive variables between PNS and non-PNS groups. We hypothesized that (1) there will be specific risk factors that predict the development of PNS, and (2) there will be distinct clinical risk factors between females and males in terms of developing PNS after one-year of evolution.

Three main findings emerged from the present study. Firstly, we found a different clinical and cognitive profile between males and females with a first episode of schizophrenia. Secondly, compared to non-PNS, PNS group reported a significantly higher severity of negative symptomatology at baseline, more depressive symptoms, poorer premorbid adjustment, poorer functionality, more amotivation, and more alterations in expressivity. In the cognitive area, PNS patients presented a worse cognitive reserve, lower estimated IQ, worse verbal memory, and worse fluency. Thirdly, a distinct pattern of risk factors for the development of predominant negative symptomatology was found between females and males. In the male group, verbal memory and amotivation, but not diminished expressivity, were the main predictors of PNS. Finally, in females, a poor premorbid adjustment was the main clinical risk factor for developing predominant negative symptomatology at short-term after a first episode of schizophrenia.

Focusing on sex differences at baseline in the present FES sample, our results suggest that in comparison to females, male group presented a poorer premorbid adjustment, greater cannabis and tobacco use, more had presence of personal psychiatric history, a worse psychosocial functioning, and more severe general and negative symptomatology, especially more amotivation alterations instead of expressivity deficits. In this line, several clinical studies have observed similar sex-outcome differences in first-episode and schizophrenia patients.3,4,7 These results are also in accordance with previous literature that remarks that compared to females, who have been reported more affective symptoms and alterations in alogia and avolition-apathy dimensions,27 males show a higher incidence of the disorder, an earlier age of onset, more negative symptomatology (specially alterations in social withdrawal and blunted affect), a poorer premorbid adjustment, worse functional outcome, and a more severe progression of the illness.3,5,6 Related to cognitive functioning, the present results suggested few differences in cognitive performance between males and females, only suggesting a worse performance in executive functions in the female group. These lack of significant differences found in the present study between both sexes in the cognitive area are in line with previous studies in first-episode and schizophrenia samples.28,29 Notwithstanding, in first-episode schizophrenia patients, mixed results have been found; one study found few gender differences in a sample of unmedicated first-episode schizophrenia patients,30 while other studies found gender and sex differences in relation with clinical profiles.31 Thus, sex differences in neurocognitive performance are a controversial issue as results remain inconclusive. The discrepancy in these findings could be explained by the heterogeneity in cognitive assessments and in the duration of illness of the samples.28 These controversies make further studies with such samples of particularly clinical interest and, specifically in samples with predominance of negative symptomatology at early stages of the illness.31

As potentially expected according to previous literature that reports that up to one-third of patients with a schizophrenia diagnosis might have idiopathic and stable (primary) negative symptoms,9 in the present study, around 25% of the patients met PNS criteria at one-year follow-up. Given that males have been reported to be more likely to present greater severity in negative symptomatology, to be more resistant to treatments, and to present more severe illness courses than females, an association between PNS -and potential deficit syndrome development at long-term- and being male was expected in the present study. More specifically, in the present FES sample almost thirty per cent of the males developed predominant negative symptoms versus twenty per cent of the females. It is worthy to mention that men group had also more antipsychotic doses, which could be related with the presence of more negative symptomatology secondary to the medication.9 Focusing on the baseline differences between PNS and non-PNS groups, and taking the whole sample into consideration (without differentiating by sex), results also suggested clinical and socio-demographical variances between groups that are also in accordance with previous studies.8,12 In the present study, patients that developed PNS at one year had more negative and depressive symptoms at baseline, less general functioning, a poorer premorbid adjustment, more amotivation, alterations in expressivity, worse cognitive reserve, lower estimated IQ, and presented a worse performance in verbal memory and fluency. In accordance with these results, literature has reported that all these parameters, that is, premorbid adjustment, general functioning, verbal fluency and verbal memory, baseline negative symptomatology, and cognitive reserve, have been extensively associated with long-term negative symptomatology persistence.11,25,32

Focusing on sex differences in PNS and non-PNS groups, FES females who developed PNS had a poorer premorbid adjustment, higher negative and depressive symptomatology at baseline, more amotivation, more severe diminished expressivity, and a worse functional outcome. In comparison, males with PNS also presented more baseline negative symptoms, more amotivation and expressivity, more severe depressive symptomatology, poorer premorbid adjustment, and worse general functioning than non-PNS group. However, in contrast to females, males with PNS also presented alterations in verbal memory performance, and verbal fluency. The association between males and primary negative symptomatology could reflect sex-related factors influencing severity without being etiologic per se. Subsequently, the presence of a deficit syndrome would be an indicator of greater severity of the illness. Such a plausible sex-related factor could be estrogens, which have been proposed to play a protective role by decreasing the risk for schizophrenia.33

In this line, given the potential confounding effect of sex, it seems to be essential to control for sex-differences in studies comparing deficit and non-deficit syndrome on variables on which males and females could differ (e.g. severity of symptoms, age of onset, premorbid adjustment, cognitive functioning, etc.). Contrary to our expectations, age of onset, family psychiatric history, and/or medication dosage were not related to PNS development. Related with the DUP, only females showed statistical differences between those who meet PNS criteria and those who not, presenting more DUP the female PNS group. Focusing on cognitive reserve, as prophesied, male PNS group showed poorer reserve than non-PNS. Against what we expected, this difference between groups were not found in females. Notwithstanding, these results must be taken into consideration with caution as it would be of clinical interest to follow these patients in larger samples and in the long-term to study the stability of this symptomatology and the maintenance of PNS criteria at long-term.

Additionally, it has been described a positive relationship between the negative symptomatology and cognitive alterations.31,34 Some studies have proposed that negative symptomatology mediates the relationship between neurocognitive performance and functional. Specifically, the association between verbal memory impairments and negative symptomatology has been well-documented during the early stages of psychosis, and both have been linked to functional outcomes.32,34 In a previous study, negative symptomatology has already been related to verbal recall and verbal fluency in male samples, whereas no similar association emerged in the female group.35 In our study, we have also found these differences in this domain between males and females and the role that it plays in the development of predominant negative symptomatology in the short- and potential long-term for the male group. In this line, given that negative symptoms are difficult to treat, our results highlight verbal memory deficits in males as treatment target with enhanced therapeutic potential.32 In this way, these findings suggest that potential sex-personalized treatments, as cognitive remediation, metacognitive training psychological interventions – specially in females–, functional remediation, cognitive reserve enhancement, and preventing relapse programs are evidence-based interventions that should be included consistently into clinical guidelines for the treatment of individuals with schizophrenia from its early stages25,36–38 and even in high-risk psychosis populations.39

It is worthy to mention that, while deficit syndrome only applies to schizophrenia spectrum disorder, the current study demonstrates that prominent and predominant negative symptoms can be present from the first stages of the illness. Accordingly, this may suggest that this subgroup of potential primary negative symptoms is not only relevant for patients with a long-standing diagnosis of schizophrenia.40 Adding more evidence and focusing on negative symptom dimensions, affective flattening and alogia (EXP-factor) have been suggested to represent the “core negative symptoms” contributing to poorer functional outcomes.8 Thus, affective flattening has been shown to be significantly more severe in deficit syndrome when compared to non-deficit syndrome patients.9 However, in first-episode, blunted affect and alogia have not always been the most prominent negative symptoms.40 In a previous study, low levels of the ‘diminished expression’ subdomain were found in a cohort of patients with persistent negative symptoms. Hence, it was plausible that these low levels of affective flattening in FES greatly impacted the prevalence of deficit syndrome.40 Contrary to these results, the EXP domain was not associated with PNS in our study. By contrast, in males, the MAP domain was associated with PNS, but not in females. Again, these results underline the relevance of treating negative symptoms separately and by domains and not merely as a single construct.

This study has some limitations which must be considered. Firstly, no specific scale was used to assess negative symptomatology and the use of a transversal proxy/cut-off to stablish predominant negative symptom criteria. Moreover, although the PANSS is widely used for the assessment of negative symptoms, we acknowledge that it has several limitations; for instance, it was not designed to evaluate negative symptoms exclusively; the PANSS can measure the two-correlated factor, but it was not designed for this purpose either; third, it does not evaluate the symptom anhedonia.8 Future studies making use of newer and improved negative symptom scales – such as the Brief Negative Symptom Scale (BNSS) or the Clinical Assessment Interview for Negative Symptoms (CAINS) may be more appropriate for the evaluation of negative symptoms, since they capture both manifestations of the symptom, internal motivation and real-world behavior.8 Also, our study was based on previously collected data, and DSM-IV-TR diagnostic criteria, instead of DSM-5, were applied, which we recognize as an additional limitation. Another potential constraint was that after observing the role of the premorbid adjustment on the development of predominant negative symptomatology in females, it would have been of clinical interest to take into consideration not only the total premorbid adjustment functioning, but also to analyze the individual components of this construct separately, such as the academic and social factors. In addition, a limitation present in all cognitive reserve studies undertaken on a psychiatric population is not having used a valid instrument to measure this parameter, so criteria established and replicated in previous studies were followed.25 Finally, due to a high percentage of patients discontinued the study before the follow-up visit (particularly due to they refused the re-evaluation), this resulted in a small sample size of women's group. Because of this, some aspects should have been considered with caution in order to extrapolate the present findings. For example, results suggest the presence of more women with lower functioning and higher positive symptomatology, and men with higher cannabis consumption that discontinued the study and not completed the follow-up. In this line, according to the design and inclusion criteria of this study, it is important to remark that probably the most clinically severe patients, who tend to present a second relapse within the first years after the FEP, are not often well represented in these longitudinal studies, due to they often stop coming voluntarily for follow-up visits, which is a common difficulty in all studies with a longitudinal design. In the present project, to reduce this discontinuity, personal contact was established with patients and their families when arranging visits and outpatient follow-up was conducted by the psychiatrists participating in the study. Nonetheless, as strength points, it is worthy to remark that it is a naturalistic and multicenter study with a representative and well-characterized sample of non-affective FES on a stable clinical phase.

In conclusion, the main findings of this study suggest a different clinical and cognitive profile at baseline between FES patients that will develop predominant negative symptomatology in comparison to those with non-predominant negative symptoms. More specifically, a distinct pattern of risk factors for the development of PNS was found between both sexes. For males, amotivation, but not diminished expressivity, and verbal memory were the main predictors of predominant negative symptomatology development; whereas, for females, the main risk factor was a poorer premorbid adjustment. In the short term, the deficit and non-deficit differences could not be attributed to other clinical and demographic features such as age of onset, a positive family psychiatric history, and/or the severity of hallucinations, delusions, or formal thought disorder. Thus, the present results suggest that sex may be an important confounder in studies comparing patients that develop predominant negative symptoms or potential deficit schizophrenia. In this line, sex-specific and larger longitudinal studies on the development of predominant negative symptomatology and deficit syndrome in first-episode schizophrenia populations are warranted to establish early interventions and to design targeted personalized treatments.

This work was supported by: Instituto de Salud Carlos III, the Spanish Ministry of Science, Innovation and Universities, the European Regional Development Fund (ERDF/FEDER) (PI08/0208, PI11/00325, PI18/01055 and PI14/00612); CIBERSAM, with CIBERSAM Intramural Projects 2010: Flamm-PEPs study (PI2010-FLAMMPEPs); the CERCA Program/Generalitat de Catalunya, and Secretaria d’Universitats i Recerca del Departament d’Economia I Coneixement (2017SGR1355).

MBe has been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory board of AB-Biotics, Adamed, Angelini, Casen Recordati, Janssen-Cilag, Menarini, Roviand Takeda. EV has received research support from or served as consultant, adviser or speaker for AB-Biotics, Actavis, Allergan, Angelini, AstraZeneca, Bristol-Myers Suibb, Dainippon Sumitomo Pharma, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, Telefónica, the Brain and Behavior Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), the Seventh European Framework Program (ENBREC), and the Stanley Medical Research Institute. MBi has been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory board of has received honoraria from talks and/or consultancy of Adamed, Angelini, Casen-Recordati, Ferrer, Janssen-Cilag, Lundbeck, Neuraxpharm, Otsuka, Pfizer and Sanofi, and grants from Spanish Ministry of Health, Instituto de Salud Carlos III (PI20/01066).RRJ has been a consultant for, spoken in activities of, or received grants from: Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (FIS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid Regional Government (S2010/BMD-2422 AGES; S2017/BMD-3740), JanssenCilag, Lundbeck, Otsuka, Pfizer, Ferrer, Juste, Takeda, Exeltis, Casen-Recordati, Angelini.EB has received research support from Esteve and Monteloeder S.L. AI has received research support from or served as speaker or advisor for Janssen-Cilag, Lundbeck and Otsuka. LPC holds grants from Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (PI17/01997, PI20/1342) and has received fees from Rubió. AGP has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Sanofi-Aventis, Exeltis, the Spanish Ministry of Science and Innovation (CIBERSAM), the Ministry of Science (Carlos III Institute), and the Basque Government.JMG is partly funded by a grant from Ministerio de Ciencia y Tecnologia – Republica de Colombia (Convocatoria 885/2020) and has been an advisor/speaker for, or received travel support from Janssen, Eurofarma, Servier, Sanofi, Lilly, and Pfizer.

The rest of authors report no biomedical financial interests or potential conflicts of interest.