Antipsychotic polypharmacy in schizophrenia is much debated, since it is common and costly with unclear evidence for its efficacy and safety. We conducted a systematic literature search and a random effects meta-analysis of randomized trials comparing augmentation with a second antipsychotic vs. continued antipsychotic monotherapy in schizophrenia. Co-primary outcomes were total symptom reduction and study-defined response. Antipsychotic augmentation was superior to monotherapy regarding total symptom reduction (16 studies, N5694, standardized mean difference, SMD5-0.53, 95% CI: 20.87 to 20.19, p50.002). However, superiority was only apparent in open-label and low-quality trials (both p<0.001), but not in double-blind and high-quality ones (p50.120 and 0.226, respectively). Study-defined response was similar between antipsychotic augmentation and monotherapy (14 studies, N5938, risk ratio 5 1.19, 95% CI: 0.99 to 1.42, p50.061), being clearly non-significant in double-blind and high-quality studies (both p50.990). Findings were replicated in clozapine and nonclozapine augmentation studies. No differences emerged regarding all-cause/specific-cause discontinuation, global clinical impression, as well as positive, general and depressive symptoms. Negative symptoms improved more with augmentation treatment (18 studies, N5931, SMD5-0.38, 95% CI: 20.63 to 20.13, p<0.003), but only in studies augmenting with aripiprazole (8 studies, N5532, SMD5-0.41, 95% CI: 20.79 to 20.03, p50.036). Few adverse effect differences emerged: D2 antagonist augmentation was associated with less insomnia (p50.028), but more prolactin elevation (p50.015), while aripiprazole augmentation was associated with reduced prolactin levels (p<0.001) and body weight (p50.030). These data suggest that the common practice of antipsychotic augmentation in schizophrenia lacks double-blind/high-quality evidence for efficacy, except for negative symptom reduction with aripiprazole augmentation.

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ClinicalTrials.gov identifier: NCT01081418.

The higher impairment in specific symptoms observed in male schizophrenia patients was also present in subjects at HR for psychosis. Further studies are required to determine whether these symptoms are gender-specific predictors of transition to psychosis and whether they warrant gender-specific interventions. The high propensity to depression in the present cohort, which was particularly pronounced in the male cohort compared with the general population, in conjunction with the observed increase in negative symptoms and functional impairment, should alert clinicians to the necessity for the identification and treatment of HR subjects, irrespective of the degree to which these features are associated with transition risk.

EDIC lead to significantly higher proportions of patients achieving combined remission. Moderating variables included a reduction of DUP and EDIC, offering psychotherapeutic interventions.

Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.

The present study investigated whether the genetic determinants of neuroticism and depressive symptoms differ from those underlying perceived psychological stress. Multivariate structural equation models, which included age and sex as modifiers, were fitted to the total sample of 798 adolescents and young adults (female, n = 459; mean age 15.5 years). The sample included 139 monozygotic and 241 dizygotic twin pairs. Stress was measured using item response theory (IRT) scores, as derived from the Perceived Stress Scale and/or the Daily Life and Stressors Scale. Neuroticism was measured using the Neo-Five Factor Inventory or the Junior Eysenck Personality Questionnaire, depending on the age of the participant. Depressive symptoms were assessed using the IRT-scores of the Somatic and Psychological Health Report. The results suggest that the genetic effects underlying perceived psychological stress are largely shared with those that influence neuroticism and liability to depressive symptoms. However, separate genetic effects for perceived psychological stress that are not shared with neuroticism and depressive symptoms were also identified. The source of the identified trait specific effects requires further investigation.

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