Updated perspectives on the clinical significance of negative symptoms in patients with schizophrenia

Giordano, Giulia; Caporusso, Edoardo; Pezzella, Pasquale; Galderisi, Silvana

doi:10.1080/14737175.2022.2092402

Cited by 19 publications

(25 citation statements)

References 205 publications

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“…Key features of schizophrenia include the negative symptoms, which are responsible for a significant proportion of patients’ long-term morbidity and poor functional results [ 36 ]. Although described as the most frequent initial symptom of schizophrenia, negative symptoms can occur at any time over the course of the illness.…”

Section: Introductionmentioning

confidence: 99%

The Impact of Antipsychotic Treatment on Neurological Soft Signs in Patients with Predominantly Negative Symptoms of Schizophrenia

et al. 2022

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Schizophrenia is a complex and incompletely elucidated pathology that affects sensorimotor function and also produces numerous therapeutic challenges. The aims of this cross-sectional study were to identify the profile of neurological soft signs (NSS) in patients with predominantly negative symptoms of schizophrenia (PNS) compared with patients with schizophrenia who do not present a predominance of negative symptoms (NPNS) and also to objectify the impact of treatment on the neurological function of these patients. Ninety-nine (n = 99; 56 females and 43 males) patients diagnosed with schizophrenia according to DSM-V were included; these patients were undergoing antipsychotic (4 typical antipsychotics, 86 atypical antipsychotics, and 9 combinations of two atypical antipsychotics) or anticholinergic treatment (24 out of 99) at the time of evaluation, and the PANSS was used to identify the patients with predominantly negative symptoms (n = 39), the Neurological Evaluation Scale (NES) was used for the evaluation of neurological soft signs (NSS), and the SAS was used for the objectification of the extrapyramidal side effects induced by the neuroleptic treatment, which was converted to chlorpromazine equivalents (CPZE). The study’s main finding was that, although the daily dose of CPZE did not represent a statistically significant variable, in terms of neurological soft signs, patients with PNS had higher rates of NSS.

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Section: Introductionmentioning

confidence: 99%

The Impact of Antipsychotic Treatment on Neurological Soft Signs in Patients with Predominantly Negative Symptoms of Schizophrenia

et al. 2022

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“…1 Although these medications have demonstrated measurable efficacy for treating the positive symptoms of schizophrenia, they have limited efficacy for negative and cognitive symptoms. Moreover, positive symptoms are refractory or resistant to treatment in 20% to 30% of patients [2][3][4] and adverse effects such as extrapyramidal motor symptoms, risk for developing tardive dyskinesia (TD), weight gain, and somnolence contribute to poor tolerability and adherence. 5,6 There is a significant need for antipsychotics with different mechanisms of action, improved efficacy, and better safety and tolerability than current treatments.…”

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Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia

Kaul,

Sawchak,

Walling

et al. 2024

JAMA Psychiatry

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ImportanceA significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents. Xanomeline is a dual M1/M4 preferring muscarinic receptor agonist with no direct D2 dopamine receptor blocking activity. KarXT combines xanomeline with the peripheral muscarinic receptor antagonist trospium chloride with the goal of reducing adverse events due to xanomeline-related peripheral muscarinic receptor activation. In prior trials, xanomeline-trospium chloride was effective in reducing symptoms of psychosis and generally well tolerated in people with schizophrenia.ObjectiveTo evaluate the efficacy and safety of xanomeline-trospium vs placebo in adults with schizophrenia.Design, Setting, and ParticipantsEMERGENT-3 (NCT04738123) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 5-week trial of xanomeline-trospium in people with schizophrenia experiencing acute psychosis, conducted between April 1, 2021, and December 7, 2022, at 30 inpatient sites in the US and Ukraine. Data were analyzed from February to June 2023.InterventionsParticipants were randomized 1:1 to receive xanomeline-trospium chloride (maximum dose xanomeline 125 mg/trospium 30 mg) or placebo for 5 weeks.Main Outcomes and MeasuresThe prespecified primary end point was change from baseline to week 5 in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measures were change from baseline to week 5 in PANSS positive subscale score, PANSS negative subscale score, PANSS Marder negative factor score, Clinical Global Impression–Severity score, and proportion of participants with at least a 30% reduction in PANSS total score. Safety and tolerability were also evaluated.ResultsA total of 256 participants (mean [SD] age, 43.1 [11.8] years; 191 men [74.6%]; 156 of 256 participants [60.9%] were Black or African American, 98 [38.3%] were White, and 1 [0.4%] was Asian) were randomized (125 in xanomeline-trospium group and 131 in placebo group). At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium , −20.6; placebo, −12.2; least squares mean difference, −8.4; 95% CI, −12.4 to −4.3; P &lt; .001; Cohen d effect size, 0.60). Discontinuation rates due to treatment-emergent adverse events (TEAEs) were similar between the xanomeline-trospium (8 participants [6.4%]) and placebo (7 participants [5.5%]) groups. The most common TEAEs in the xanomeline-trospium vs placebo group were nausea (24 participants [19.2%] vs 2 participants [1.6%]), dyspepsia (20 participants [16.0%] vs 2 participants [1.6%]), vomiting (20 participants [16.0%] vs 1 participant [0.8%]), and constipation (16 participants [12.8%] vs 5 participants [3.9%]). Measures of extrapyramidal symptoms, weight gain, and somnolence were similar between treatment groups.Conclusions and RelevanceXanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the previously reported and consistent results from the EMERGENT-1 and EMERGENT-2 trials, support the potential of xanomeline-trospium to be the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity.Trial RegistrationClinicalTrials.gov Identifier: NCT04738123

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“…Negative symptoms are a fundamental aspect of schizophrenia, closely linked to poor quality of life and ineffective response to treatment. [1][2][3][4][5][6][7][8][9][10][11][12] Despite their significance, they are still an unmet need in schizophrenia care, burdening patients, families and healthcare systems. 2, [13][14][15][16][17] Negative symptoms can be either primary or secondary manifestations of the disease; in the latter scenario, they can be subsequent to positive and depressive symptoms, or extrapyramidal side effects.…”

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confidence: 99%

“…2, [13][14][15][16][17] Negative symptoms can be either primary or secondary manifestations of the disease; in the latter scenario, they can be subsequent to positive and depressive symptoms, or extrapyramidal side effects. 2,6 The conceptualisation of negative symptoms proposed in the early 1900s included two aspects: the reduction of emotional expression and the loss of motivation. 18 Indeed, Eugen Bleuler reported that people with schizophrenia had expressionless faces, were apathetic and lacked the desire to act on their own initiative or at the request of another.…”

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confidence: 99%

“…4,[24][25][26] This model is consistent with the observation that different behavioural features, neurophysiological bases as well as clinical and social outcomes are associated with the two dimensions. 2,6,[27][28][29][30][31][32][33][34][35][36] However, evidence from recent multicentre studies utilising confirmatory factor analysis (CFA) has questioned the adequacy of this two-factor model. [37][38][39][40][41][42][43] These studies suggested that a fivefactor model or a hierarchical model better fit the data, irrespective of assessment scale, sample nationality/language or stage of illness.…”

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The structure stability of negative symptoms: longitudinal network analysis of the Brief Negative Symptom Scale in people with schizophrenia

Rucci,

Caporusso,

Sanmarchi

et al. 2023

BJPsych open

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Background The structure of negative symptoms of schizophrenia is still a matter of controversy. Although a two-dimensional model (comprising the expressive deficit dimension and the motivation and pleasure dimension) has gained a large consensus, it has been questioned by recent investigations. Aims To investigate the latent structure of negative symptoms and its stability over time in people with schizophrenia using network analysis. Method Negative symptoms were assessed in 612 people with schizophrenia using the Brief Negative Symptom Scale (BNSS) at baseline and at 4-year follow-up. A network invariance analysis was conducted to investigate changes in the network structure and strength of connections between the two time points. Results The network analysis carried out at baseline and follow-up, supported by community detection analysis, indicated that the BNSS's items aggregate to form four or five distinct domains (avolition/asociality, anhedonia, blunted affect and alogia). The network invariance test indicated that the network structure remained unchanged over time (network invariance test score 0.13; P = 0.169), although its overall strength decreased (6.28 at baseline, 5.79 at follow-up; global strength invariance test score 0.48; P = 0.016). Conclusions The results lend support to a four- or five-factor model of negative symptoms and indicate overall stability over time. These data have implications for the study of pathophysiological mechanisms and the development of targeted treatments for negative symptoms.

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Updated perspectives on the clinical significance of negative symptoms in patients with schizophrenia

Cited by 19 publications

References 205 publications

The Impact of Antipsychotic Treatment on Neurological Soft Signs in Patients with Predominantly Negative Symptoms of Schizophrenia

The Impact of Antipsychotic Treatment on Neurological Soft Signs in Patients with Predominantly Negative Symptoms of Schizophrenia

Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia

The structure stability of negative symptoms: longitudinal network analysis of the Brief Negative Symptom Scale in people with schizophrenia

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