Persistent Negative Symptoms Research Articles

Linking PANSS negative symptom scores with the Clinical Global Impressions Scale: understanding negative symptom scores in schizophrenia

Understanding how rating scale improvement corresponds to a clinical impression in patients with negative symptoms of schizophrenia may help define the clinical relevance of change in this patient population. We conducted post hoc equipercentile linking analyses of Positive and Negative Syndrome Scale (PANSS) outcomes (e.g., PANSS-Factor Score for Negative Symptoms [FSNS]) with Clinical Global Impressions-Improvement (CGI-I) and -Severity (CGI-S) ratings on data from patients treated with cariprazine (n = 227) or risperidone (n = 229) in a clinical study evaluating negative symptoms in schizophrenia. Patients were prospectively selected for persistent, predominant negative symptoms of schizophrenia (PNS), and minimal positive/depressive/extrapyramidal symptoms. Linking results demonstrated that greater improvement on PANSS-derived measures corresponded to clinical impressions of greater improvement, as measured by the CGI-I, and less severe disease states, as measured by the CGI-S. For example, CGI-S scores of 1 (normal), 2, 3, 4, 5, and 6 (severely ill) corresponded to PANSS-FSNS scores of 7, 13, 19, 24, 29, and 35, respectively. Likewise, CGI-I scores of minimally improved, much improved, and very much improved corresponded to a change from baseline in PANSS-FSNS scores of −27%, −49%, and −100%, respectively. These are important findings for the interpretation of the results of trials in patients with persistent negative symptoms.

Gender peculiarities of paranoid schizophrenia in the modern context

The purpose of the work is to study the clinical-psychopathological and social-psychological features of patients with paranoid schizophrenia in terms of gender aspect. Materials and methods. The article analyzes peculiarities of clinical and psychopathological phenomenology and social support in 53 men and 49 women with paranoid schizophrenia who were in inpatient treatment at the Vinnytsia Regional Psychoneurological Hospital Academic Yushchenko Memorial in 2015–2018. Results. It was established that the most common symptoms of paranoid schizophrenia were expressed and significant changes in the general behavioral quality (100.0 %), negative symptoms (96.1%) and persistent delusional symptomatology (93.1 %), while chronic paranoid symptoms (66.7 %) and delusion of mastery, influence or inactivity, and delusional perception (61.8 %), as well as verbal hallucinations (58.8 %) were less common. At the same time, men showed significantly more symptoms of alienation of mental processes (34.0 %versus 16.3 %, P < 0.05), persistent delusional ideas (98.1 % versus 87.8 %, P < 0.05), neologisms, sperrung, incoherent speech (24.5 %versus 8.2 %), catatonic behavior (13.2 % versus 2.0 %, P < 0.05) and negative symptoms (100.0 % versus 91.8 %, P < 0.05). Men had significantly greater severity of delusion (5.45 ± 0.82 points versus 4.96 ± 1.19 points, P < 0.05), thought disorder (4.42 ± 1.01 points versus 3.71 ± 0.74 points, P < 0.01), all the negative symptoms, motor retardation (3.74 ± 1.13 points versus 2.96 ± 1.37 points, P < 0.01), a decline in insight into illness (5.30 ± 1.07 points versus 4.80 ± 1.19 points, P < 0.05), disturbance of volition (4.49 ± 0.95 points versus 3.92 ± 0.86 points, P < 0.01), preoccupation (4.70 ± 0.82 points versus 4.27 ± 0.76 points, P < 0.05). Patients with paranoid schizophrenia ranked low on the disability scale, which corresponded to apparent dysfunction, and men showed significantly lower rates on all the scales. Correlation revealed relations between the symptoms of schizophrenia severity and disability rates. Patients with paranoid schizophrenia were characterized by high rates of depression (in general 58.39 ± 14.64 points, men – 63.34 ± 13.50 points, women – 53.04 ± 14.05 points, P <0.01), trait anxiety (48.83 ± 10.89 points, 51.74 ± 9.20 points, and 45.69 ± 11.77 points accordingly, P < 0.05), state anxiety (44.98 ± 7.44 points, 47.49 ± 5.54 points and 42.27 ± 8.30 points, P < 0,01), well-being (32.04 ± 4.37 points, 30.72 ± 3.47 points and 33.47 ± 4.82 points, P < 0.01), activity (29.03 ± 3.75 points, 28.04 ± 2.78 points, 30.10 ± 4.35 points, P < 0,01), mood (29.16 ± 4.46 points, 30.17 ± 3.50 points and 28.06 ± 5.12 points, P < 0.01). Patients with paranoid schizophrenia had a low family (0.47 ± 0.66 points, 0.36 ± 0.68 points and 0.59 ± 0.61 points, P < 0.05), friends (0.79 ± 0.74 points, 0.66 ± 0.78 points and 0.94 ± 0.66 points, P < 0.05) and significant others (0.56 ± 0.74 points, 0.40 ± 0.66 points and 0.73 ± 0.78 points, P < 0.05) social support. Conclusions. The obtained data testify to the presence of gender differences in clinical-psychopathological manifestations and social-psychological characteristics of patients with paranoid schizophrenia.

Clozapine augmentation strategies - a systematic meta-review of available evidence. Treatment options for clozapine resistance.

Treatment options for clozapine resistance are diverse whereas, in contrast, the evidence for augmentation or combination strategies is sparse. We aimed to extract levels of evidence from available data and extrapolate recommendations for clinical practice. We conducted a systematic literature search in the PubMed/MEDLINE database and in the Cochrane database. Included meta-analyses were assessed using Scottish Intercollegiate Guidelines Network criteria, with symptom improvement as the endpoint, in order to develop a recommendation grade for each clinical strategy identified. Our search identified 21 meta-analyses of clozapine combination or augmentation strategies. No strategies met Grade A criteria. Strategies meeting Grade B included combinations with first- or second-generation antipsychotics, augmentation with electroconvulsive therapy for persistent positive symptoms, and combination with certain antidepressants (fluoxetine, duloxetine, citalopram) for persistent negative symptoms. Augmentation strategies with mood-stabilisers, anticonvulsants, glutamatergics, repetitive transcranial magnetic stimulation, transcranial direct current stimulation or cognitive behavioural therapy met Grades C-D criteria only. More high-quality clinical trials are needed to evaluate the efficacy of add-on treatments for symptom improvement in patients with clozapine resistance. Applying definitions of clozapine resistance would improve the reporting of future clinical trials. Augmentation with second-generation antipsychotics and first-generation antipsychotics can be beneficial, but the supporting evidence is from low-quality studies. Electroconvulsive therapy may be effective for clozapine-resistant positive symptoms.

Persistent negative symptoms in individuals at Ultra High Risk for psychosis

Persistent negative symptoms (PNS) defined as negative symptoms that persist for at least six months in the absence of high levels of positive, depressive and extrapyramidal symptoms, are evident early in the course of schizophrenia from the first episode of psychosis. However, their presence even earlier in the illness, in those at Ultra High Risk of psychosis, has not been investigated. In this study, we examined the prevalence, baseline correlates and outcome of PNS in 363 Ultra High Risk individuals. Assessments were conducted at baseline and 2–14 years later (mean follow up time 7.4 years). Baseline assessments included demographic, clinical and neurocognitive measures, which were repeated at follow up. The prevalence of PNS in the UHR group was 6.1%. Poor premorbid social adjustment, deficits in verbal fluency and childhood maltreatment, specifically emotional neglect, were evident at baseline in the PNS group compared to the group without PNS. PNS were associated with poor psychosocial functioning and deficits in processing speed at follow up. Our findings suggest that PNS can be detected early, allowing for the identification of a subset of Ultra High Risk patients who are likely to have poor outcome. These individuals could be the target for specific intervention. Further research is needed into the pathophysiology of these PNS to develop specific interventions.

Revisiting the persistent negative symptoms proxy score using the Clinical Assessment Interview for Negative Symptoms

ObjectiveThe present study aimed to validate a severity cut-off of negative symptoms for persistent negative symptoms (PNS) identification using the Clinical Assessment Interview for Negative Symptoms (CAINS). MethodA total of 206 patients with schizophrenia were recruited and divided into the PNS group (n = 57) and the Non-PNS group (n = 149) using PNS criteria based on the SANS and the SAPS. To determine the appropriate cut-offs on the CAINS in identifying PNS, Receiver Operating Characteristic (ROC) curve analysis was conducted in the PNS and Non-PNS groups. ResultsOur results showed that the cutoffs for identifying PNS on the CAINS total score, the Motivation and Pleasure (MAP) subscale score and the Expression (EXP) subscale score were 25, 17, and 5 respectively. Area Under the Curve (AUC) analysis indicated excellent discrimination of the PNS group from the Non-PNS group using the cut-off for the CAINS total score. However, discrimination was somewhat better for the MAP subscale score than the EXP subscale score. The Positive Predictive Value (PPV) and Negative Predictive Value (NPV) of the MAP subscale were 81.54% and 97.16%. ConclusionWe found that the cut-off scores derived from the CAINS to identify PNS are comparable to existing scales. The CAINS offers an alternative means in identifying PNS patients in clinical trials that overcomes methodological and conceptual limitations of older scales.

Escitalopram augmentation improves negative symptoms of treatment resistant schizophrenia patients – A randomized controlled trial

Serum interleukin (IL)-6 levels in schizophrenia correlate with the severity of negative symptoms. This study aimed to explore the potential immune mechanism of SSRI augmentation in the management of patients with treatment-resistant schizophrenia, assessing changes in IL-6 and CRP amounts. This was a randomized double-blind, placebo-controlled, 8-week study of escitalopram augmentation in 62 schizophrenic patients treated in 2016–2017 at the Shandong Mental Health Center. Twenty-nine healthy controls were also included. Patients received add-on escitalopram or placebo for 8 weeks. Serum IL-6 and CRP were measured at baseline and 8 weeks. The primary outcome was the Positive and Negative Syndrome Scale (PANSS). After 8 weeks of treatment, reductions in total PANSS, negative subscore, and affective subscore were more important in escitalopram treated patients than in the placebo group (all P < 0.05). Escitalopram significantly decreased CRP and IL-6 levels (both P < 0.05). At baseline, IL-6′s effects on negative and cognitive symptoms represented 16.2% and 20.1%, respectively; at week 8, these effects were 22.7% and 20.8% on negative and cognitive symptoms, respectively. CRP had no impact on any PANSS score. Overall, escitalopram augmentation may be a useful addition for schizophrenic patients with persistent negative symptoms. Changes in IL-6 may be associated with negative and cognitive symptoms.

Understanding the course of persistent symptoms in schizophrenia: Longitudinal findings from the pattern study

The Pattern study was conducted to provide longitudinal observational data for individual patients with persistent symptoms of schizophrenia. Pattern is an international, multicenter, non-interventional, prospective cohort study of schizophrenia outpatients who were not considered to be in recovery. In the longitudinal phase reported herein, patients were assessed over 1 year using different clinical rating scales. Patient management followed routine local clinical practice. Primary outcome was disease state, defined by the Positive and Negative Syndrome Scale (PANSS), Negative Symptom Factor Score (NSFS), Positive Symptom Factor Score (PSFS), and Personal and Social Performance (PSP) Scale. In total, 1344 protocol-compliant patients (70.9% male) were included. Patients showed a high stability in disease state between consecutive study visits. Persistent negative persistent symptoms and symptomatic remission were the most prevalent and stable disease states. Patients in relapse generally transitioned to negative persistent symptoms or to symptomatic remission. PANSS, PSP, and quality of life ratings remained relatively stable. Relapses occurred in 10% of patients; probability of relapse was associated with younger age, extra-pyramidal symptoms, and more antipsychotic medications. Despite treatment, schizophrenia symptoms tend to remain stable over time, without overall improvement. One of the greatest challenges in schizophrenia is attainment of full symptom remission.

T123. PERSISTENT NEGATIVE SYMPTOMS IN FIRST EPISODE PSYCHOSIS: PREVALENCE, PREDICTORS AND PROGNOSIS

BackgroundNegative symptoms are a core component of schizophrenia. These symptoms have been shown to impact on a range of outcomes, and often are resistant to pharmacological and psychosocial interventions treatment. The goal of this study was to investigate the prevalence, baseline predictors and long-term impact of persistent negative symptoms (PNS) within a large representative cohort of people with first episode psychosis.MethodsThe study had prospective design. Patients recruited into the OPUS trial (1998–2000) with a first time diagnosis within the schizophrenia spectrum (F20-28) were included. People were classified with persistent negative symptoms, if they experienced enduring negative symptoms that were not secondary to psychotic symptoms, depression or due to medication side effects. Clinical data collected at baseline, 1 year, 2 years and 10 years was used to identify predictors of PNS and long-term outcomes.ResultsFull clinical data was available on 369 people. A total of 90 people (24%) displayed PNS, two years after diagnosis. Significant univariable predictors of PNS at baseline were low functioning, male sex, cannabis use, poor pre-morbid social functioning and high levels of negative symptoms. People that displayed PNS had significantly lower functioning and higher levels of psychopathology at 10 year follow-up. A total 3% of people with PNS were recovered at 10 year follow-up compared to rate of 20% recovered without PNS (OR 7.42, p<0.01).DiscussionA significant proportion of the cohort displayed persistent negative symptoms and these symptoms significantly impacted on long-term outcomes. Researchers and clinicians need to continue to develop effective interventions that can ameliorate these symptoms and potentially impact on illness prognosis within schizophrenia.

F109. BOUNDARIES BETWEEN DEFICIT AND NONDEFICIT SCHIZOPHRENIA: LONG TERM STABILITY AND OUTCOMES

BackgroundNegative symptoms of schizophrenia are admittedly associated with a poorer outcome regarding aspects such as functionality, quality of life and cognitive performance. Patients with prominent, persistent and primary negative symptoms have been considered to manifest a putative subtype called “Deficit schizophrenia” (DS). However, the boundaries of deficit and nondeficit forms were put in question since the publication of a study that considered separately a group of patients with persistent negative symptoms whose primary nature could not be asserted, the “ambiguous nondeficit” group, who would be otherwise categorized as nondefict according to the gold standard instrument: the Schedule for the Assessment of the Deficit Syndrome (SDS). Those patients presented psychopathological features, quality of life, insight and cognitive function quite different from the nondeficit group, and closer to the deficit group. The objectives of the present study are to investigate the stability of the categorization regarding the presence of DS in three groups: “deficit”(DS), “nondeficit” (ND) and “ambiguous nondeficit” (SND) over a long term follow-up and to evaluate clinical outcomes in the different groups.MethodsWe will contact 85 patients with schizophrenia, considered clinically stable in the previous year, who participated in a study about the DS in 2009/2010. Back then, they were recruited in two sites: an outpatient service of a university general hospital (49 patients) and a community-based mental health service (36 patients). Patients will be assessed with the same instruments adopted in the first study: a questionnaire for clinical and demographic information; BPRS, SAPS, SANS, Calgary Depression Scale, the SDS, QLS, and a battery of neurocognitive tests. We started the recruitment by the patients originally treated in the outpatient clinic.ResultsHere we present partial results. Of the 49 patients, 5 refused to participate in the follow-up study, 3 died prematurely, and 1 had the diagnostic changed for bipolar disorder. Assessment interval was 6.9 years ± 0.5 Among the 20 reassessed patients, mean age at baseline was 36.9 ± 8.9 years, mean duration of mental illness was 16 ± 10.1 years, and 75% were men. They had in mean, 10.7 ± 3.3 years of education, only 20% had any work activity, 15% were married and 55% had a low socioeconomic position. These demographic aspects slightly worsened: only 15% had an occupation at follow-up, and 60% fell in the lower socioeconomic position. Regarding the SDS classification, 4 of 9 ND patients at the baseline were reclassified as DS; 1 of 7 DS was reclassified as ND, the other 6 remained DS; from the AND, 3 were considered DS and 1 ND, from a total of 4. At the end, there were 13 DS and 7 ND, while at the baseline they were: 7 DS, 9 ND and 4 AND. Concerning psychopathology, 80% of the patients had an increase in SANS and the most expressive increase was in nondeficit group (an average of 5.4 points), although the average in DS group remained the higher (18.9 points). Still, SAPS and Calgary remained low in all three subgroups, with a mean of 6.20 and 2.20 points, respectively. As to medication, 70% of the baseline were in use of Clozapine (67% of ND, 57% of DS and 100% of the AND group) and that total number remained the same during the follow up.DiscussionOur preliminary results are derived from a small sample. Although we cannot draw definite conclusion, these outcomes suggest trends that are worth observing: the worsening of negative symptoms among patients and the tendency of conversion to DS group, especially among the “ambiguous” group. This advocates against the dichotomous division of deficit and nondeficit schizophrenia and speaks in favor of a dimensional understanding of negative symptoms.

T27. DYSFUNCTIONAL ATTITUDES IN ADOLESCENTS WITH EARLY-ONSET PSYCHOSIS: PRELIMINARY RESULTS

BackgroundDysfunctional attitudes such as defeatist performance beliefs (DPB) and asocial beliefs (AB) have been linked to negative symptoms and functional outcome in chronic schizophrenia (Campellone et al., 2016; Grant and Beck, 2010) and in adults with recent onset schizophrenia (Ventura et al., 2014). Adolescents with early-onset psychosis (EOP) are at major risk of having persistent negative symptoms (Puig et al., 2017) but no previous study has examined dysfunctional attitudes in this population. We aimed: (1) to examine if more DPB and AB were present in adolescents with EOP compared with normal controls, and (2) to study the relationships between DPB and AB with symptoms and functioning.MethodsSample: 15 adolescents with EOP (11♀, age=15.33 ± 1.23) and 10 healthy controls (8♀, age=15.60 ± 1.51), participants in a trial about cognitive and behavioral social skills treatment in EOP developing in Hospital Clínic of Barcelona (baseline data). Patients were under antipsychotic meds. Inclusion criteria: having an early-onset schizophrenia spectrum disorder diagnosed between 9–18 years-old (schizophrenia, schizoaffective disorder, psychosis n.o.s.); being within the 5 first years after the disease onset; clinical stability. Exclusion criteria: IQ<70; comorbid substance dependence disorder; neurological disorders. Instruments: PANSS (Kay et al., 1987), Calgary Depression Scale (CDS, Addington et al., 1990), Children’s Global Assessment Scale (C-GAS, Shaffer et al., 1983), Social and Role Functioning Scales (GF:S, GF:R, Cornblatt et al., 2007), Life Skills Profile - Adolescent version (Puig et al., 2013), Dysfunctional Attitudes Scale - Spanish version (DAS, Sanz et al., 1993); Asocial Beliefs Scale (Grant and Beck, 2010). DPB was extracted from the DAS scale following Beck et al. (2013). Groups were compared with T-test or Chi-square tests. Pearson correlations were computed for examining relationships between variables.ResultsEOP and control groups were homogeneous in age (t=-0.49, p=0.632) and sex (X2=0.15, p=0.702). All subjects were living with their parents. Family SES was lower in EOP group (X2=10.69, p=0.030). All subjects but one patient were studying although patients had repeated more courses (t=4.00, p=0.001). EOP subjects had a predominance of negative symptoms (positive symptoms=14.07 ± 3.85; negative symptoms=23.50 ± 13.79; general symptoms=31.86 ± 7.28). Mean score of CDS in EOP was low (3.77 ± 4.76). EOP group had lower scores in all functional measures than controls (C-GAS: 51.14 ± 9.38 vs 93.70 ± 4.45, GF:S: 5.71 ± 1.07 vs 9.00 ± 0.47, GF:R: 5.21 ± 1.12 vs 8.80 ± 0.42, LSP: 67.64 ± 12.30 vs 44.13 ± 3.60; t>6.67, p<0.001). Regarding dysfunctional attitudes, EOP group had higher scores in dysfunctional attitudes scales than healthy controls (DPB: 55.60 ± 19.57 vs 33.00 ± 9.37, AB: 6.67 ± 3.42 vs 3.00 ± 2.11; t>3.02, p<0.006). In EOP, DPB and AB scores were negatively correlated with functioning (DPB: C-GAS r=-0.60, GF:S r=-0.66, GF:R r=-0.66, LSP r=0.65; p<0.002; AB: C-GAS r=-0.45, GF:S r=-0.55, GF:R r=-0.49, LSP r=0.53; p<0.029). No significant correlation were found between dysfunctional attitudes and negative symptoms in EOP.DiscussionThese preliminary results showed that adolescents with EOP had higher levels of dysfunctional attitudes than controls. Accordantly to recent literature, defeatists performance beliefs and asocial beliefs were correlated with poorer functioning. However, dysfunctional attitudes were not associated with negative symptoms. It might be that dysfunctional attitudes do not contribute to negative symptoms but in functional outcome in youngs with EOP although larger samples are required. Acknowledgments: Fundación Alicia Kolplowitz.

T86. COGNITIVE SUBTYPES IN FIRST-EPISODE PSYCHOSIS: AN EMPIRICAL LONGITUDINAL STUDY OF RELATIONSHIP TO COGNITIVE, SYMPTOM AND FUNCTIONAL OUTCOMES

BackgroundVariable outcomes following a first-episode of psychosis are partly attributable to heterogeneity in cognitive functioning. Previous work in first episode psychosis has identified clinically meaningful cognitive sub-types based on pre-specified differences in estimated premorbid and current cognitive functioning. We used an empirical clustering technique to examine whether these cognitive profiles can be replicated with an unbiased method, their relationship with clinical, cognitive and global functioning at psychosis onset as well as their stability over time.MethodsPatients attending NHS early intervention services following a first episode of psychosis were recruited to a double-blind clinical trial of minocycline for negative symptoms of psychosis (BeneMin) which found no treatment effect. Participants were assessed on clinical, cognitive and global functioning at baseline (n=169) and 12-month follow-up (n=107). K-means analysis was used to empirically cluster participants on the basis of estimated premorbid IQ (WTAR), and baseline cognitive functioning (derived from 4 sub-tests of the WAIS IV, verbal fluency (COWAT) and verbal learning scores (AVLT)). Clinical and global functioning was assessed using the Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale (CDS) and Global Assessment of Functioning (GAF).ResultsK-means cluster analysis revealed three cognitive subgroups: 28% showing preserved premorbid and current IQ (PIQ); 29% displaying compromised premorbid and current IQ (CIQ); and 43% with normal premorbid but deteriorated current IQ (DIQ). There were no significant differences between groups in age, gender, CDS, cannabis use or olanzapine equivalent antipsychotic dose. The PIQ group performed significantly better than the DIQ group on all baseline cognitive measures, who performed significantly better than the CIQ group. At baseline, there were significant differences in GAF scores (F(2,168) = 4.267, p=0.016; PIQ >DIQ, LIQ). At 12-months, all three groups had improved over time on cognitive function with no group x time interactions except verbal fluency (F(2, 97) = 5.204,p=0.007) where only the DIQ group improved. All groups improved on positive and total symptom scores but only the PIQ and DIQ groups significantly improved on negative and general symptom scales. There was no significant change in GAF score in any of the groups over time. At follow-up there were significant differences between groups in negative syndrome scores (F(2, 104) = 8.720, p=0.004: LIQ > PIQ, DIQ) and global functioning (F(2,101) = 5.880 p=0.004; PIQ > DIQ, LIQ).DiscussionUsing an unbiased method to define cognitive subgroups at first episode, we confirmed in a new sample, previous findings which used pre-specified criteria. A large subgroup showed evidence of a decline in IQ at psychosis onset and 12-months later this subgroup had neither continued to deteriorate nor returned to premorbid levels of cognition. Patients with preserved normal and compromised cognitive function at psychosis onset showed no deterioration over 12 months. The cognitive sub-groupings were clinically meaningful. The preserved group showed better general function which persisted over 12 months. General functional outcome in the IQ decline group was as poor as the compromised group and the compromised group had more persistent negative symptoms.

Diminished emotional expression in schizophrenia: an interdisciplinary approach based on behavioral interventions.

Negative symptoms represent the main cause of disability in schizophrenia, having recently been grouped into two general dimensions: avolition and diminished emotional expression, which includes affective flattening and alogia. The aim of this study was to explore the response of these two symptoms to a set of behavioral interventions based on contingency management, performed in an interdisciplinary context. Behaviors of interest were monitored and evaluations before and after the treatment were performed on 9 schizophrenic inpatients with persistent negative symptoms. The program included 12 group double sessions aimed at developing facial expression and verbal communication, and a nursing care plan to generalize and strengthen these behaviors synergistically. there were appreciable differences in facial expression, which were less clear for alogia. The clinical evaluation using PANSS-N did not find notable differences at group level, but the nursing assessment using NOC indicators did. although difficult to modify, negative symptoms are not insensitive to the influence of behavioral interventions. Specific psychological interventions that address negative symptoms as a priority focus of attention and care need to be promoted and developed, particularly when considering the crucial role of context in their progression.

Antipsychotic drugs for patients with schizophrenia and predominant or prominent negative symptoms: a systematic review and meta-analysis.

Negative symptoms are the core of schizophrenia, but whether antipsychotics are efficacious for their treatment is unclear. Moreover, there is debate whether patients in relevant trials should have predominant negative symptoms or whether prominent negative symptoms are also acceptable. We systematically reviewed randomised, blinded antipsychotic drug trials in patients with schizophrenia and either predominant or prominent negative symptoms (last search Dec 12, 2017). Separate pairwise meta-analyses were conducted in these two populations. The primary outcome was negative symptoms. Depressive, symptoms, positive symptoms, and extrapyramidal side-effects were analysed as causes of secondary negative symptoms. We included 21 randomized-controlled trials with 3451 participants which revealed the following significant differences in the primary outcome: in patients with predominant negative symptoms amisulpride was superior to placebo (N = 4; n = 590, SMD 0.47, CI 0.23, 0.71), olanzapine was superior to haloperidol in a small trial (n = 35) and cariprazine outperformed risperidone (N = 1, n = 456, SMD - 0.29, CI - 0.48, - 0.11). In patients with prominent negative symptoms, olanzapine and quetiapine were superior to risperidone in single trials. Overall, studies in prominent negative symptoms were potentially more confounded by improvements of secondary negative symptoms. Amisulpride is the only antipsychotic that outperformed placebo in the treatment of predominant negative symptoms, but there was a parallel reduction of depression. Cariprazine was better than risperidone in a large trial that was well-controlled for secondary negative symptoms, but the trial was sponsored by its manufacturer. Future trials should apply scientifically developed definitions such as the deficit syndrome and the persistent negative symptoms concept.

Persistent Negative Symptoms in First-Episode Psychosis: Early Cognitive and Social Functioning Correlates and Differences Between Early and Adult Onset.

To characterize the early cognitive and social functioning characteristics of a sample of first-episode psychosis patients with and without persistent negative symptoms (PNS) and to examine the prevalence and cognitive and functional correlates of PNS in patients with early-onset versus adult-onset first-episode psychosis. Participants were 235 patients with first-episode psychosis (51 early-onset, 184 adult-onset) and 240 healthy controls from a multicenter longitudinal study (recruited between 2009 and 2011). Standard instruments were used to evaluate symptoms, cognition, and social functioning. Diagnoses were determined according to DSM-IV criteria. PNS proxy was derived from clinical assessments (Positive and Negative Syndrome Scale and Montgomery-Asberg Depression Scale) at 2-, 6-, and 12-month follow-up. Association tests were used to compare the prevalence of PNS in the early-onset versus adult-onset groups. Multivariate analysis of variance was used to examine differences in early cognitive and social functioning (at the 2-month assessment) between patients with and without PNS and between early-onset and adult-onset patients with PNS. Thirty-eight patients (16.2%) met criteria for PNS during the first year. This PNS group showed a selective deficit in executive functions and in global, community, and occupational functioning (P < .05). Having PNS was associated with a diagnosis of a schizophrenia spectrum disorder at the 12-month follow-up. The prevalence of PNS was almost double for those patients with an early-onset (0.25 vs 0.14; OR = 2.18; 95% CI, 1.02-4.64), and this was associated with greater cognitive (P < .05) but not social deficits. There was an early, detectable, social and executive dysfunction associated with PNS in first-episode psychosis and a high risk of having PNS in early-onset first-episode psychosis, which in turn was associated with more widespread cognitive impairment. Specific therapeutic interventions for PNS in early-onset first-episode psychosis might be needed.

Relationship Between Persistent Negative Symptoms and Findings of Neurocognition and Neuroimaging in Schizophrenia.

Negative symptoms are defined as loss or reduction of otherwise present behaviors or functions in illness situation, and they have constituted an important aspect of schizophrenia. Although negative symptoms have usually been considered as a single entity, neurobiological investigations yielded discrepant results. To overcome challenges that derive from this discrepancy, researchers have proposed several approaches to structure negative symptoms into more homogenous constructs. Concept of persistent negative symptoms (PNS) is one of the proposed approaches, and includes both primary and secondary negative symptoms that persist after adequate treatment. PNS is relatively easy to assess, and by definition, more inclusive; yet it represents an unmet therapeutic need. Therefore, it is a target of several neurobiological and pharmacological studies. There are several structural and functional brain alterations associated with negative symptoms. On the other hand, neurocognitive investigations in patients with schizophrenia have revealed deficits in several domains that showed correlations with negative symptoms. There are several shared features between negative symptoms and neurocognitive deficits in schizophrenia such as prevalence rates, course through the illness, prognostic importance, and impact on social functioning. However, exact mechanisms behind the neurobiology of PNS and how it interacts with neurocognition remain to be explained. Earlier reviews on neuroimaging and neurocognitive correlates of PNS have been focused on studies with broadly defined negative symptoms that were selected by methodological closeness to PNS. In this review, we focus on neural correlates and neurocognitive associations of PNS, and we discuss PNS findings available to date.

Asenapine versus Olanzapine in People with Persistent Negative Symptoms of Schizophrenia: Erratum

Asenapine versus Olanzapine in People with Persistent Negative Symptoms of Schizophrenia: Erratum

Treatment for Negative Symptoms in Schizophrenia: A Comprehensive Review.

Negative symptoms (such as amotivation and diminished expression) associated with schizophrenia are a major health concern. Adequate treatment would mean important progress with respect to quality of life and participation in society. Distinguishing primary from secondary negative symptoms may inform treatment options. Primary negative symptoms are part of schizophrenia. Well-known sources of secondary negative symptoms are psychotic symptoms, disorganisation, anxiety, depression, chronic abuse of illicit drugs and alcohol, an overly high dosage of antipsychotic medication, social deprivation, lack of stimulation and hospitalisation. We present an overview of reviews and meta-analyses of double-blind, controlled randomised trials, in which the efficacy of pharmacological and non-pharmacological interventions for negative symptoms was assessed. Unfortunately, there have been very few clinical trials focusing on primary negative symptoms and selecting chronically ill patients with predominant persistent negative symptoms. An important limitation in many of these studies is the failure to adequately control for potential sources of secondary negative symptoms. At present, there is no convincing evidence regarding efficacy for any treatment of predominant persistent primary negative symptoms. However, for several interventions there is short-term evidence of efficacy for negative symptoms. This evidence has mainly been obtained from studies in chronically ill patients with residual symptoms and studies with a heterogeneous study population of patients in both the acute and chronic phase. Unfortunately, reliable information regarding the distinction between primary and secondary negative symptoms is lacking. Currently, early treatment of psychosis, add-on therapy with aripiprazole, antidepressants or topiramate, music therapy and exercise have been found to be useful for unspecified negative symptoms. These interventions can be considered carefully in a shared decision-making process with patients, and are promising enough to be examined in large, well-designed long-term studies focusing on primary negative symptoms. Future research should be aimed at potential therapeutic interventions for primary negative symptoms since there is a lack of research in this field.

Linking persistent negative symptoms to amygdala\u2013hippocampus structure in first-episode psychosis

Early persistent negative symptoms (PNS) following a first episode of psychosis (FEP) are linked to poor functional outcome. Reports of reduced amygdalar and hippocampal volumes in early psychosis have not accounted for heterogeneity of symptoms. Age is also seldom considered in this population, a factor that has the potential to uncover symptom-specific maturational biomarkers pertaining to volume and shape changes within the hippocampus and amygdala. T1-weighted volumes were acquired for early (N=21), secondary (N=30), non-(N=44) PNS patients with a FEP, and controls (N=44). Amygdalar–hippocampal volumes and surface area (SA) metrics were extracted with the Multiple Automatically Generated Templates (MAGeT)-Brain algorithm. Linear mixed models were applied to test for a main effect of group and age × group interactions. Early PNS patients had significantly reduced left amygdalar and right hippocampal volumes, as well as similarly lateralized negative age × group interactions compared to secondary PNS patients (P<0.017, corrected). Morphometry revealed decreased SA in early PNS compared with other patient groups in left central amygdala, and in a posterior region when compared with controls. Early and secondary PNS patients had significantly decreased SA as a function of age compared with patients without such symptoms within the right hippocampal tail (P<0.05, corrected). Significant amygdalar–hippocampal changes with age are linked to PNS after a FEP, with converging results from volumetric and morphometric analyses. Differential age trajectories suggest an aberrant maturational process within FEP patients presenting with PNS, which could represent dynamic endophenotypes setting these patients apart from their non-symptomatic peers. Studies are encouraged to parse apart such symptom constructs when examining neuroanatomical changes emerging after a FEP.

Categorizing and assessing negative symptoms.

To provide a review on studies published in the last year relevant to the categorization and assessment of negative symptoms. Recent research supported the validity of the 'deficit/non-deficit schizophrenia' categorization. Few studies confirmed the validity of the category 'persistent negative symptoms', whereas no recent study explored the validity of the category 'predominant negative symptoms'. The two-factor structure of the negative dimension is supported by studies reporting different correlates for the two subdomains: diminished expression and avolition/apathy. The need to further split avolition/apathy in two distinct components, that is anhedonia and amotivation, is confirmed in recent papers. Additional approaches to the assessment of negative symptoms have been proposed, including the self-assessment of negative symptoms, and the evaluation of negative symptoms in daily life and their assessment by means of computerized analyses. Negative symptoms represent an unmet need in the care of schizophrenia, as they are associated to poor response to available treatments and to poor functional outcome. Their accurate categorization and assessment represent a major challenge for research on neurobiological substrates and new treatment strategies.

The Evolution of negative symptom constructs

IntroductionNegative symptoms represent a separate dimension of schizophrenia psychopathology, distinct from positive symptoms, disorganization and cognitive impairment. It is increasingly acknowledged that negative symptoms are associated with poor functional outcome and represent an unmet need in schizophrenia treatment. Improvement in definition of their phenomenology, assessment instruments and experimental models are needed in order to improve schizophrenia prognosis.AimsThe presentation will review key aspects of the evolution of negative symptom constructs. In particular, findings concerning phenomenology, clinical assessment, association with functional outcome and brain imaging correlates will be presented.MethodsWe searched PubMed for English full-text publications with the keywordsSchizophrenia AND “negative symptoms”/“primary negative symptoms”/“deficit schizophrenia”/“persistent negative symptoms”/“affective flattening”/alogia/“expressive deficit”/apathy/asociality/“social withdrawal”/anhedonia/“anticipatory anhedonia”/avolition/neuroimaging.ResultsThe distinction between secondary negative symptoms (i.e., those due to identifiable factors, such as drug effects, psychotic symptoms or depression), and primary or persistent negative symptoms (i.e., those etiologically related to the core pathophysiology of schizophrenia) is grounded on solid research evidence and might have major implications for both treatment development and clinical care. The evidence that negative symptoms cluster in motivation- and expressive-related domains is founded on large consensus and empirical evidence and will foster pathophysiological modeling. The motivation-related domain is a stronger predictor of functional outcome than the expressive one.ConclusionsAn improved definition and assessment of negative symptoms needs to translate in large-scale studies to advance knowledge. In the short-term, the improved identification of treatable causes of secondary negative symptoms can translate into better care for people with schizophrenia.Disclosure of interestAM received honoraria or advisory board/consulting fees from the following companies: Janssen Pharmaceuticals, Otsuka, Pfizer and Pierre Fabre.SG received honoraria or advisory board/consulting fees from the following companies: Lundbeck, Janssen Pharmaceuticals, Hoffman-La Roche, Angelini-Acraf, Otsuka, Pierre Fabre and Gedeon-Richter.