As well as synthesising the extant literature on empathy in schizophrenia, this study considerably expanded past work by examining the moderating effect of clinical (positive, negative, general, medication effect, age at diagnosis and duration of illness), demographic (age, gender, education, ethnicity and year of publication) and cognitive (verbal/pre-morbid IQ, general IQ and global neuro-cognition) variables on cognitive and affective empathy. In doing this, we went beyond examining basic associations observed in the literature and developed an evidence-based taxonomy of empathy in schizophrenia. Consistent with our hypotheses, we found, healthy controls reported higher levels of affective empathy than schizophrenia patients (a small effect size). For cognitive empathy, the difference in reporting between the two groups was of a medium effect, with healthy controls reporting higher perspective-taking ability then the patient group. Amongst the variables studied, duration of illness and age at illness onset significantly moderated the difference in performance between patients and controls on measures of cognitive empathy. Besides these, none of the other moderators reached statistical significance. The effect sizes reported in this study are in line with previous reviews on this topic [11,12].
Duration of illness and empathy
For the moderating effect of duration of illness, we found, for every one-year increase in illness duration, the difference in perspective-taking ability between patients and healthy controls increased by 0.012 points. This observation is consistent with a previous meta-analysis on this topic . Adding further, we found this effect to be independent of any age-related decline in schizophrenia. Cross-sectional studies are the norm rather than the exception in this field of research. However, as the current evidence points to a progressive decline in self-reported cognitive empathy, our findings can be said to provide indirect, longitudinal evidence of deterioration over time. This can be explained by several reasons. For example, the distress caused by psychotic thinking, perhaps due to poorer clinical insight can make people with a diagnosis of schizophrenia mistrustful of others, which in turn could lead to social withdrawal  or a restriction in their social network . Over time, this can lead to patients having fewer opportunities to socialise and hone their empathic skills, thus increasing the probability of empathic atrophy over time. Besides this, long-term residual symptom experiences, medication side-effects, sensitivity to stress, and substance misuse may also affect key cortical regions associated with empathy [23,32,39]. High level of stigma associated with schizophrenia , as well as a loss of morale and self-esteem over time can also lead to a loss of hope, confidence and motivation in people with schizophrenia , all of which can negatively impede a patient’s ability to engage confidently or communicate effectively in an empathetic manner.
Age at clinical diagnosis also had a moderating effect on cognitive empathy. As the age at diagnosis decreased, the difference in performance between patients and controls on self-reported cognitive empathy increased. This means that those with an earlier diagnosisreported havinggreater difficulties in perspective-taking then those whose symptom onset was at a later age. Duration of illness and age at diagnosis are related. Both are reliable indicators of severity of illness in schizophrenia (i.e. the earlier the onset, the worse it is regarding functional outcome, and the longer it persists without remission, the less likely you are to improve) . Therefore, it will be important to address the underlying mechanisms of this deficit in future work.
Clinical symptoms and empathy
We found none of the schizophrenia symptoms (i.e. positive, negative and general symptoms) moderated the effect sizes for cognitive or affective empathy. Amongst the included studies (k = 39), only a few studies reported a significant association between severity of clinical symptoms and empathy [58,37,46,47,51,61,62], with several studies not finding any statistically significant relationship between either one of the core schizophrenia symptoms and self-reported empathy [10,23,29,32,36,39,40,42,43,47,58,64,69]. A closer inspection of the clinical profile of the schizophrenia group we were analysing indicated that this group was on a stable dosage of antipsychotics at the time of testing and were, therefore, only really experiencing symptoms residually (Table 5). Therefore, a restricted range in the symptom severity score or the fact that most patients were not experiencing symptoms acutely could explain the lack of relationship with empathy.
We found no moderating effect of chlorpromazine equivalents (mg/day) on self-reported cognitive and affective empathy. These findings are consistent with studies that directly compared the effects of chlorpromazine equivalent on self-reported empathy [29,32,44,46,47]. These findings also extend to haloperidol equivalents [32,39,40]. Singh, et al.,  also reported having found no effect of duration of antipsychotic drug taken on any of the IRI scores in an enduring schizophrenia sample. Also, in one of the largest sample study comparing patients treated on conventional versus atypical antipsychotic drugs on social cognitive abilities, Kucharska-Pietura and colleagues  found no clear advantage of atypical antipsychotics over typical antipsychotics on emotional functioning in patients with schizophrenia. Results from several longitudinal studies  have also indicated no significant effect of antipsychotic drug treatment on several other related social-cognitive domains (e.g. facial affect perception). Thus, it appears that while antipsychotic drugs are useful in treating core symptoms of schizophrenia, deficits in empathy may perhaps be resistant to pharmacological intervention.
Demographic variables and empathy
This study included many studies which provided us with a large sample to examine several demographic variables more thoroughly. These included; the impact of age-related decline, a higher proportion of male patients (compared to female patients), ethnicity (higher proportion of non-Caucasian schizophrenia patients compared to Caucasian patients), and lower educational attainment in the schizophrenia group (compared to the healthy group), on self-reported cognitive and affective empathy. None of these demographic variables directly moderated the difference in performance between patients and controls on self-reported measures of empathy, which is consistent with several independent studies in the literature. In relation toage, several studies included this variable as a covariate and consistent with the current findings, found schizophrenia patients and controls continued to differ on empathic abilities [46,74]. Similarly, a direct examination of gender-related effects in schizophrenia patients, on measures of cognitive and affective empathy, also revealed no significant interaction [39,40,58,105] or any impact of lower education attainment on empathy [36,46,61,67]. Collectively, these findings suggest other risk factors not observed here may have superseded current demographic risk factors in patients with schizophrenia.
Neuro-cognition and empathy
Several neuro-cognitive variables were examinedin relation toempathy. These included: Verbal/pre-morbid IQ, general IQ and global neuro-cognition. Regarding general and pre-morbid/verbal IQ, neither variable moderated the differences in performance between patients and controls. This finding is consistent with several studies in which differences on measures of empathy remained between groups of interest after controlling for these initial differences [40,42,74]. Together these findings indicate, that while impairments in general and verbal/pre-morbid IQ remain apparent in patients with more severe and enduring schizophrenia [29,30,36,38,58,59,60,67,73,74] they do not adequately account for the heterogeneity observed in empathy in this or previous reviews .
In this study, instead of examining individual neuro-cognitive domains, we examined what we termed ‘global neuro-cognitive abilities’ by including studies that assessed all, few or one of the six neuro-cognitive domains defined and recommended by the MATRICS panel [71,72] as well as an additional, cognitive flexibility/inhibitory control domain. Overall, we did not find any impact of this variable on cognitive or affective empathy which is consistent with several of the published studies in the field [23,27,58]. However, as it is well established that like IQ, neuro-cognitive deficits do exist in patients with more severe and enduring schizophrenia  and is an essential component of empathy [31,36,47,51,73]. Therefore, the lack of association is somewhat surprising. It may be that this moderator was somewhat underpowered, or there was a lack of dispersion in the neuro cognitive scores. Alternatively, it may have been that for neuro-cognitive abilities to relate to empathy; tasks need tapping into specific cognitive abilities. In other words, specific executive function tasks (e.g. emotion-regulation) relating to empathy [77,101] is perhaps necessary to find a significant effect.
Affective empathy and heterogeneity
For affective empathy, we found, healthy controls reported higher affective empathy then schizophrenia patients, with a small effect size (Hedges’ g = 0.29) with significant heterogeneity (I2 = 61.31%), both findings are consistent with previous reviews in the field [11,12]. However, none of the moderators we examined explained the observed heterogeneity. This may be due to variability in the affective responses by the included patients. Across individual studies, we found, three affective responses: (1) Some patients reported to have deficits in affective empathy (i.e. lower levels than healthy controls) [ 26-29,31-33,36,37,47,51,58,67,68,73]. (2) Other studies reported comparable levels of affective empathy in schizophrenia patients and healthy controls [10,24,39,59,60,62] and (3) the remaining, reported higher levels of affective empathy in patients than in controls [27,29,30,35,43,50,87]. Thus, under the rubric of schizophrenia, several affective responses may have beenpresent, which could explain both, the small effect size and lack of moderator influence found in this study.
We found an interesting effect of publication bias on current findings. For affective empathy, we found that the missing studies increased the overall effect size from the observed Hedges’ g = 0.29 to Hedges’ g = 0.37. In the studies we included, we found, patients were medically stable at the time of testing (symptom severity score; Table 5). The nature of some symptoms, especially negative symptoms means social withdrawal and anhedonia are common, and as such, patients with these experiences are unlikely to participate in research studies. Therefore, for affective empathy, the publication bias is perhaps reflective of missing studies of patients with predominantly negative symptoms where deficits in affective empathy are likely to be more pronounced.
For cognitive empathy the opposite held. In total, nine studies were identified as missing (Figure 5) and including them would have reduced the effect size from Hedges’ g = 0.53 to Hedges’ g = 0.41. This observation is consistent with a previous meta-analysis in the field  and together highlight two important issues: (1) The need to also publish nil findings and (2) where possible, include schizophrenia samples at different stages of the illness course, particularly at the earlier phase, where deficits in perspective-taking are likely to be less pronouncedthen in the more severe and enduring phase.
Measures of empathy: Self-report
Our findings for empathy are reported from self-report measures. Thus, they must be interpreted as showing how patients perceive their abilities as opposed to their actual abilities, which may differ . We did not include performance-based measures since few studies have been published and a lack of psychometric properties was available for those measures . Moreover, self-reported measures are more acceptable to patients, and since they tap into a wide range of situations, they are more apt in providing broader estimates of empathy levels than other measures (e.g. performance-based) which evaluate responses to specific circumstances.
Impact of additional variables
The impact substance misuse (drugs and alcohol), co-morbid medical illness, and family history of psychiatric illness has on self-reported empathy was not be examined as no or insufficient data was available for these variables. Nonetheless, these are important variables commonly found to affect patients with a diagnosis of schizophrenia [23,26,32,39] and may have therefore conflated current findings. Thus, it is important that readers take this into account when interpreting current results and report on these additional variables in future work.
Generalisability of current findings
We did not find any impact of year of publication on reported effect sizes. This means, over the years, there have been no significant changes in the methodology and samples recruited. We found schizophrenia samples in this, and previous reviews [10-12], can be classified as ‘stereotypical schizophrenia samples’. This includes a predominantly chronic, male sample, on medication, with core schizophrenia symptoms stable, with minimum (if any) negative symptoms. Since schizophrenia is a heterogenous syndromic disorder, care must be taken in term of the extent to which we generalise current findings to other phases or schizophrenia samples.
Also, over 90 percent of the studies included were conducted in developed countries (Table 1). Better outcomes have been found in many developing compared to developed countries . Thus, findings from this study may not be fully general is able to those recovering in developing countries.