Network analysis of inflammation and symptoms in recent onset schizophrenia and the influence of minocycline during a clinical trial.

Attempts to delineate an immune subtype of schizophrenia have not yet led to the clear identification of potential treatment targets. An unbiased informatic approach at the level of individual immune cytokines and symptoms may reveal organisational structures underlying heterogeneity in schizophrenia, and potential for future therapies. The aim was to determine the network and relative influence of pro- and anti-inflammatory cytokines on depressive, positive, and negative symptoms. We further aimed to determine the effect of exposure to minocycline or placebo for 6 months on cytokine-symptom network connectivity and structure. Network analysis was applied to baseline and 6-month data from the large multi-center BeneMin trial of minocycline (N = 207) in schizophrenia. Pro-inflammatory cytokines IL-6, TNF-α, and IFN-γ had the greatest influence in the inflammatory network and were associated with depressive symptoms and suspiciousness at baseline. At 6 months, the placebo group network connectivity was 57% stronger than the minocycline group, due to significantly greater influence of TNF-α, early wakening, and pathological guilt. IL-6 and its downstream impact on TNF-α, and IFN-γ, could offer novel targets for treatment if offered at the relevant phenotypic profile including those with depression. Future targeted experimental studies of immune-based therapies are now needed.

Occurrence of psychosis and bipolar disorder in adults with autism: A systematic review and meta-analysis.

OBJECTIVE: Evidence suggests that individuals with autism spectrum disorder have increased rates of co-occurring psychosis and/or bipolar disorder. Considering the peak age of onset for psychosis and bipolar disorder occurs in adulthood, we investigated the co-occurrence of these disorders in adults with autism. METHODS: We conducted a systematic review and meta-analysis (PROSPERO Registration Number: CRD42018104600) to (1) examine the prevalence of psychosis and bipolar disorder in adults with autism, and (2) review potential risk factors associated with their co-occurrence. RESULTS: Fifty-three studies were included. The pooled prevalence for the co-occurrence of psychosis in adults with autism was 9.4 % (N = 63,657, 95 %CI = 7.52, 11.72). The pooled prevalence for the co-occurrence of bipolar disorders in adults with autism was 7.5 % (N = 31,739, 95 %CI = 5.79, 9.53). CONCLUSIONS: Psychosis and bipolar disorder occur at a substantially higher prevalence in adults with autism compared to general population estimates. While there is an overall dearth of research examining risk factors for these disorders in autism, males had increased likelihood of co-occurring psychosis, and females of co-occurring bipolar disorder. These results highlight the need for ongoing assessment and monitoring of these disorders in adults with autism.

The specific phenotype of depression in recent onset schizophrenia spectrum disorders: A symptom profile and network comparison to recent onset major depressive disorder without psychotic features.

The specific phenotype of depression in recent-onset schizophrenia spectrum disorders (SSD) and its relation to non-psychotic depression is unknown. Symptom profile and network analysis are complementary statistical techniques that may provide important insights into the presentation and relative importance of individual symptoms that give rise to depression. The aim of the current study was to characterise the profile and network of depressive symptoms in SSD and compare it to individuals with major depressive disorder (MDD) without psychotic features. This study involved analysis of baseline data pertaining to 109 individuals with comorbid SSD and depression and 283 with MDD without psychotic features. Study cohorts were the Psychosis Recent Onset GRoningen Survey (PROGR-S) and Youth Depression Alleviation (YoDA) trials, respectively. Profile and network analyses revealed that SSD and MDD differed in the profile and relative importance of individual depressive symptoms. While reported sadness was the primary hallmark of depression in both SSD and MDD, individuals with depression in SSD were more likely to sleep more, and have lower lassitude and pessimism. While sadness had great importance in MDD and SSD, in SSD but not MDD lassitude, sleep, appetite, concentration difficulties, and inability to feel were important in the network of depressive symptoms. The specific phenotype of depression might be different in SSD compared to MDD. Symptom inequivalence or underlying functional mechanisms in SSD might result in depression in SSD that is similar to MDD with atypical features.

Interrelationships between depressive symptoms and positive and negative symptoms of recent onset schizophrenia spectrum disorders: A network analytical approach.

OBJECTIVE: There is a need to better understand the interrelationships between positive and negative symptoms of recent-onset schizophrenia spectrum disorders (SSD) and co-occurring depressive symptoms. Aims were to determine: (1) whether depressive symptoms are best conceptualised as distinct from, or intrinsic to, positive and negative symptoms; and (2) bridging symptoms. METHODS: Network analysis was applied to data from 198 individuals with depressive and psychotic symptoms in SSD from the Psychosis Recent Onset GRoningen Survey (PROGR-S). Measures were: Montgomery-Åsberg Depression Rating Scale and Positive and Negative Syndrome Scale. RESULTS: Positive symptoms were just as likely to be associated with depressive and negative symptoms, and had more strong associations with depressive than negative symptoms. Negative symptoms were more likely to be associated with depressive than positive symptoms, and had more strong associations with depressive than positive symptoms. Suspiciousness and stereotyped thinking bridged between positive and depressive symptoms, and apparent sadness and lassitude between negative and depressive symptoms. CONCLUSIONS: Depressive symptoms might be best conceptualised as intrinsic to positive and negative symptoms pertaining to deficits in motivation and interest in the psychotic phase of SSD. Treatments targeting bridges between depressive and positive symptoms, and depressive and such negative symptoms, might prevent or improve co-occurring depressive symptoms, or vice-versa, in the psychotic phase of SSD.

The psychometric validity of the Montgomery-Åsberg Depression Rating Scale (MADRS) in recent onset schizophrenia spectrum disorders.

Earlier recognition and accurate assessment of depressive symptoms is important to improving outcomes in individuals with recent-onset schizophrenia spectrum disorders (termed SSD hereafter)-regardless of whether positive psychotic symptoms are present or have resolved. The Montgomery-Åsberg Depression Rating Scale (MADRS) is frequently used to assess depressive symptoms in SSD, but no study has examined the psychometric validity of MADRS scores in individuals exclusively with SSD and sub-grouped by those with and without positive psychotic symptoms. This study involved baseline data from the Psychosis Recent Onset GRoningen Survey (PROGR-S). Measures used were: MADRS, depressive and negative subscales of Positive and Negative Syndrome Scale (PANSSD, PANSSN), and Schedules for Clinical Assessment in Neuropsychiatry (SCAN). The MADRS total score had sufficient concurrent validity with PANSSD (evidence by ρ≥0.70), and insufficient divergent validity with PANSSN (evidenced by ρ ≥0.30), in the full cohort and when sub-grouped by positive psychotic symptoms. In symptom networks, divergent communities comprising either MADRS or PANSSN items were found, except the MADRS item inability to feel overlapped with PANSSN items. The most divergent MADRS items were sadness, pessimism, and suicidal thoughts. The MADRS total score had sufficient predictive validity for determining caseness for MDD based on SCAN, but the optimal cut-off differed in those with and without positive psychotic symptoms (MADRS≥18 versus MADRS≥11). The MADRS has sufficient validity for assessing depressive symptoms in SSD. Since scores might depend upon symptoms of SSD, MADRS≥11 and the presence of sadness, pessimism, or suicidal ideation might be the best indicator of MDD in SSD.

Depressive psychopathology in first-episode schizophrenia spectrum disorders: a systematic review, meta-analysis and meta-regression.

BACKGROUND: Despite knowing for many decades that depressive psychopathology is common in first-episode schizophrenia spectrum disorders (FES), there is limited knowledge regarding the extent and nature of such psychopathology (degree of comorbidity, caseness, severity) and its demographic, clinical, functional and treatment correlates. This study aimed to determine the pooled prevalence of depressive disorder and caseness, and the pooled mean severity of depressive symptoms, as well as the demographic, illness, functional and treatment correlates of depressive psychopathology in FES. METHODS: This systematic review, meta-analysis and meta-regression was prospectively registered (CRD42018084856) and conducted in accordance with PRISMA and MOOSE guidelines. RESULTS: Forty studies comprising 4041 participants were included. The pooled prevalence of depressive disorder and caseness was 26.0% (seven samples, N = 855, 95% CI 22.1-30.3) and 43.9% (11 samples, N = 1312, 95% CI 30.3-58.4), respectively. The pooled mean percentage of maximum depressive symptom severity was 25.1 (38 samples, N = 3180, 95% CI 21.49-28.68). Correlates of depressive psychopathology were also found. CONCLUSIONS: At least one-quarter of individuals with FES will experience, and therefore require treatment for, a full-threshold depressive disorder. Nearly half will experience levels of depressive symptoms that are severe enough to warrant diagnostic investigation and therefore clinical intervention - regardless of whether they actually fulfil diagnostic criteria for a depressive disorder. Depressive psychopathology is prominent in FES, manifesting not only as superimposed comorbidity, but also as an inextricable symptom domain.

Co-morbid depressive disorder is associated with better neurocognitive performance in first episode schizophrenia spectrum.

BACKGROUND: Both major depressive disorder (MDD) and first episode schizophrenia spectrum (FES) are associated with significant neurocognitive deficits. However, it remains unclear whether the neurocognitive deficits in individuals with FES are more severe if there is comorbid depressive disorder. The aim of this study was to compare the neurocognitive profiles between those with and without full-threshold depressive disorder in FES. METHOD: This study involved secondary analysis of baseline data from a randomized controlled trial of vocational intervention for young people with first-episode psychosis (N = 82; age range: 15-25 years). RESULTS: Those with full-threshold depressive disorder (n = 24) had significantly better information processing speed than those without full-threshold depressive disorder. Severity of depressive symptoms was also associated with better information processing speed. LIMITATIONS: In additional to the cross-sectional design, limitations of this study include the absence of assessing insight as a potential mediator. CONCLUSIONS: After the first psychotic episode, it could be speculated that those with better information processing speed may be more likely to develop full-threshold depressive disorder, as their ability to efficiently process information may allow them to be more aware of their situations and environments, and consequently to have greater insight into the devastating consequences of FES. Such novel findings support the examination of full-threshold depressive disorder in relation to neurocognitive performance across illness phases in future work.

The psychometric validity of the Center for Epidemiological Studies - Depression Scale (CES-D) in first episode schizophrenia spectrum.

Depressive pathology is common in first-episode schizophrenia spectrum disorders (FES), and is frequently assessed using the Center for Epidemiological Studies - Depression Scale (CES-D), an instrument designed for use in community samples. Despite its widespread use, no prior study has examined the psychometric validity of the CES-D in assessing depressive pathology in FES. The aim of this study was to examine the psychometric validity of the CES-D in FES. This study involved secondary analysis of baseline data from a single blind, randomized controlled trial of vocational intervention for individuals with FES (N=91; age range: 15-25 years). Measures used were: CES-D, Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms (SANS), and Structured Clinical Interview for DSM-IV-TR (SCID-I/P). The CES-D strongly correlated with the depression subscale of the BPRS, and with the presence of full-threshold depressive disorder on the SCID-I/P. There was minimal overlap between the CES-D and SANS, with weak correlations emerging for avolition and anhedonia, and not for affective flattening, alogia, and attention. The CES-D cut-off of ≥23 produced high sensitivity and specificity values for determining full-threshold comorbid depressive disorder. Such findings indicate that the CES-D is effective for assessing and measuring depressive pathology in FES.

The effect of comorbid depression on facial and prosody emotion recognition in first-episode schizophrenia spectrum.

BACKGROUND: Comorbid depression is common in first-episode schizophrenia spectrum (FES) disorders. Both depression and FES are associated with significant deficits in facial and prosody emotion recognition performance. However, it remains unclear whether people with FES and comorbid depression, compared to those without comorbid depression, have overall poorer emotion recognition, or instead, a different pattern of emotion recognition deficits. The aim of this study was to compare facial and prosody emotion recognition performance between those with and without comorbid depression in FES. METHODS: This study involved secondary analysis of baseline data from a randomized controlled trial of vocational intervention for young people with first-episode psychosis (N=82; age range: 15-25 years). RESULTS: Those with comorbid depression (n=24) had more accurate recognition of sadness in faces compared to those without comorbid depression. Severity of depressive symptoms was also associated with more accurate recognition of sadness in faces. Such results did not recur for prosody emotion recognition. LIMITATIONS: In addition to the cross-sectional design, limitations of this study include the absence of facial and prosodic recognition of neutral emotions. CONCLUSIONS: Findings indicate a mood congruent negative bias in facial emotion recognition in those with comorbid depression and FES, and provide support for cognitive theories of depression that emphasise the role of such biases in the development and maintenance of depression. Longitudinal research is needed to determine whether mood-congruent negative biases are implicated in the development and maintenance of depression in FES, or whether such biases are simply markers of depressed state.