Culturally adapted psychosocial interventions (CaPSI) for early psychosis in a low-resource setting: study protocol for a large multi-center RCT.

BACKGROUND: Psychosis treatment guidelines recommend cognitive behaviour therapy (CBT) and family intervention (FI), for all patients with first episode psychosis (FEP), though guidance borrows heavily from literature in adults from high income countries. To our knowledge, there are few randomized controlled trials (RCTs) examining the comparative effect of these commonly endorsed psychosocial interventions in individuals with early psychosis from high-income countries and no such trials from low and middle-income countries (LMICs). The present study aims to confirm the clinical-efficacy and cost-effectiveness of delivering culturally adapted CBT (CaCBT) and culturally adapted FI (CulFI) to individuals with FEP in Pakistan. METHOD: A multi-centre, three-arm RCT of CaCBT, CulFI, and treatment as usual (TAU) for individuals with FEP (n = 390), recruited from major centres across Pakistan. Reducing overall symptoms of FEP will be the primary outcome. Additional aims will include improving patient and carer outcomes and estimating the economic impact of delivering culturally appropriate psychosocial interventions in low-resource settings. This trial will assess the clinical-efficacy and cost-effectiveness of CaCBT and CulFI compared with TAU in improving patient (positive and negative symptoms of psychosis, general psychopathology, depressive symptoms, quality of life, cognition, general functioning, and insight) and carer related outcomes (carer experience, wellbeing, illness attitudes and symptoms of depression and anxiety). CONCLUSIONS: A successful trial may inform the rapid scale up of these interventions not only in Pakistan but other low-resource settings, to improve clinical outcomes, social and occupational functioning, and quality of life in South Asian and other minority groups with FEP. TRIAL REGISTRATION: NCT05814913.

Motivational and neurocognitive deficits are central to the prediction of longitudinal functional outcome in schizophrenia.

OBJECTIVE: Functional impairment is characteristic of most individuals with schizophrenia; however, the key variables that undermine community functioning are not well understood. This study evaluated the association between selected clinical variables and one-year longitudinal functional outcomes in patients with schizophrenia. METHOD: The sample included 754 patients with schizophrenia who completed both baseline and one-year follow-up visits in the CATIE study. Patients were evaluated with a comprehensive battery of assessments capturing symptom severity and cognitive performance among other variables. The primary outcome variable was functional status one-year postbaseline measured using the Heinrichs-Carpenter Quality of Life Scale. RESULTS: Factor analysis of negative symptom items revealed two factors reflecting diminished expression and amotivation. Multivariate regression modeling revealed several significant independent predictors of longitudinal functioning scores. The strongest predictors were baseline amotivation and neurocognition. Both amotivation and neurocognition also had independent predictive value for each of the domains of functioning assessed (e.g., vocational). CONCLUSION: Both motivational and neurocognitive deficits independently contribute to longitudinal functional outcomes assessed 1 year later among patients with schizophrenia. Both of these domains of psychopathology impede functional recovery; hence, it follows that treatments ameliorating each of these symptoms should promote community functioning among individuals with schizophrenia.

Demographic and clinical correlates of suicidal ideation in individuals with at-risk mental state (ARMS): A study from Pakistan.

BACKGROUND: Suicide is a major public health concern and one of the leading causes of mortality worldwide. People with an at-risk-mental-state (ARMS) for psychosis are more vulnerable to psychiatric co-morbidity and suicide, however, there are limited data from low-middle-income countries. The present study aimed to identify the prevalence of depressive symptoms and suicidal ideation along with sociodemographic and clinical correlates of suicidal ideation in individuals with ARMS from Pakistan. METHOD: Participants between the age of 16 and 35 years who met the criteria for ARMS based on the Comprehensive Assessment of At-Risk Mental State (CAARMS), were recruited from the community, general practitioner clinics and psychiatric units across Pakistan (n = 326). Montgomery and Asberg Depression Rating Scale (MADRS) and Social-Occupational-Functional-Assessment-Scale (SOFAS) were administered to participants. RESULTS: The prevalence of depressive symptoms and suicidal thoughts in the sample at baseline were 91.1% (n = 297) and 61.0% (n = 199), respectively. There were significant mean differences between groups (mean difference [95% CI]; p-value) without suicidal ideation and with suicidal ideation on measures of MADRS (-5.47 [-7.14, -3.81]; p < .001), CAARMS non-bizarre ideas (-0.29 [-0.47, -0.11]; p = .002) and perceptual abnormalities (-0.23 [-0.41, -0.04]; p = .015). CONCLUSION: These findings indicate that suicidal ideation and depressive symptoms are highly prevalent in individuals with ARMS in Pakistan. Given the pivotal developmental stages that ARMS presents, and the poor outcomes associated with co-morbid depression, there is an urgent need to prioritize the development of low-cost and scalable evidence-based interventions to address psychiatric comorbidity and suicidality in the ARMS population in Pakistan.

Clozapine's critical role in treatment resistant schizophrenia: ensuring both safety and use.

INTRODUCTION: Clozapine was first introduced as an antipsychotic in the 1970's but a cluster of deaths, later linked to the drug's risk of agranulocytosis, led to its withdrawal in most countries. However, work in the 1980's established its unique efficacy in treatment resistant schizophrenia (TRS), which constitutes as many as 30% of those with the illness. Clozapine was reintroduced with this indication shortly thereafter, but because of this risk its use requires routine hematologic monitoring. AREAS COVERED: An update is provided regarding clozapine's risk of neutropenia, agranulocytosis, and associated mortality. In addition, updates are provided on other side effects, specifically myocarditis and bowel obstruction, as evidence suggests these are more common than agranulocytosis and associated with higher mortality rates. EXPERT OPINION: Clozapine remains the only treatment indicated in TRS, but it is dramatically underutilized. Clearly there are serious side effects associated with its use, and while the focus has historically been on hematologic concerns, we highlight other side effects that also demand systematic monitoring. Because it is the only effective treatment option we have for TRS, though, efforts must be implemented that ensure its use in this population while maximizing safety.

Motivated to do well: an examination of the relationships between motivation, effort, and cognitive performance in schizophrenia.

The uncertain relationship between negative symptoms, and specifically motivational deficits, with cognitive dysfunction in schizophrenia is in need of further elucidation as it pertains to the interpretation of cognitive test results. Findings to date have suggested a possible mediating role of motivational deficits on cognitive test measures, although findings from formal examinations of effort using performance validity measures have been inconsistent. The aim of this study was to examine the relationships between motivation, effort exerted during cognitive testing, and cognitive performance in schizophrenia. Sixty-nine outpatients with schizophrenia or schizoaffective disorder were evaluated for psychopathology, severity of motivational deficits, effort exerted during cognitive testing, and cognitive performance. Motivation and degree of effort exerted during cognitive testing were significantly related to cognitive performance, specifically verbal fluency, verbal and working memory, attention and processing speed, and reasoning and problem solving. Further, effort accounted for 15% of the variance in cognitive performance, and partially mediated the relationship between motivation and cognitive performance. Examining cognitive performance profiles for individuals exerting normal or reduced effort revealed significant differences in global cognition, as well as attention/processing speed and reasoning and problem solving. These findings suggest that cognitive domains may be differentially affected by impairments in motivation and effort, and highlight the importance of understanding the interplay between motivation and cognitive performance deficits, which may guide the appropriate selection of symptom targets for promoting recovery in patients.

Seminal plasma biochemical markers and their association with semen analysis findings.

OBJECTIVES: To examine the clinical value of six seminal plasma components in the evaluation of sperm quality and in the differential diagnosis of men with infertility. METHODS: We analyzed 202 seminal plasmas for prostate-specific antigen, glucose, pepsinogen C, insulin-like growth factor binding protein-3, prostaglandin D synthase (PGDS), and BRCA1-like immunoreactive protein (BRCA1-LIP) using quantitative immunofluorometric procedures. The semen donors were categorized in four clinical groups: normal, oligospermic, azoospermic, and vasectomy patients. We then evaluated whether any of these biochemical markers were associated with other parameters of sperm quality, including patient age, total cell concentration, percentage of motility, and percentage of normal morphology. RESULTS: We found that only PGDS concentration was significantly associated with other parameters of sperm quality. PGDS concentration correlated positively with total cell concentration (r = 0.55), percentage of motility (r = 0.31), and percentage of normal morphology (r = 0.31). Median PGDS concentration in seminal plasma decreased progressively from normal to oligospermic to azoospermic to vasectomy patients (P <0.001). There was no overlap between seminal plasma PGDS concentration of normal subjects versus vasectomy patients. The only other parameter that was moderately decreased in vasectomy patients was BRCA1-LIP. The source of PGDS in seminal plasma was determined with various techniques, including immunohistochemistry. This protein is produced and secreted by the Sertoli cells. CONCLUSIONS: Our findings suggest that PGDS concentration in seminal plasma correlates with other known indicators of semen quality and is a new marker of post-testicular obstruction. This biochemical parameter could be used to aid in the differential diagnosis of obstructive and nonobstructive azoospermia in men with infertility.

Impact of primary negative symptoms on functional outcomes in schizophrenia.

OBJECTIVE: Negative symptoms are known to undermine functional outcomes in people with schizophrenia; however, most studies have not accounted for whether these symptoms were primary or secondary to other psychopathological factors. The present study examined the impact of primary negative symptoms on functional outcomes in patients with schizophrenia. METHOD: The sample included 1427 patients with schizophrenia who completed the baseline visit in the CATIE study. Symptoms were assessed with the Positive and Negative Syndrome Scale and Calgary Depression Scale, extrapyramidal side effects with the Simpson-Angus scale, and functional status with the Heinrichs-Carpenter Quality of Life Scale. RESULTS: Negative symptoms were significantly and inversely related to each domain of functioning examined. These relationships remained after statistically controlling for the influence of potential sources of secondary negative symptoms. In addition, the relationships between negative symptoms and specific domains of functioning remained in patients who had mild/absent positive, depressive, anxiety and extrapyramidal symptoms. Negative symptoms were associated with functional outcomes even in antipsychotic-free patients. CONCLUSIONS: Primary negative symptoms significantly contribute to the functional impairment seen in people with schizophrenia. A better understanding of the etiology and pathobiology of these symptoms is required to guide the search for effective therapeutics that promote functional recovery.

Prediction of longitudinal functional outcomes in schizophrenia: the impact of baseline motivational deficits.

Emerging evidence suggests that motivational deficits are a central component of negative symptoms in schizophrenia, and linked to functional impairment characterizing this illness. This study extends previous cross-sectional findings by examining the concurrent contributions of baseline motivational deficits, other negative symptoms, and other symptom domains on longitudinal functional outcomes in schizophrenia. Results of this longitudinal examination of 18 patients from our previous pilot study reveal that amotivation accounts for 74% and 72% of the variance in functional outcomes at baseline and 6-month follow-up, respectively. These findings further suggest a fundamental role for motivational deficits in predicting functional outcomes in schizophrenia.

Motivational deficits as the central link to functioning in schizophrenia: a pilot study.

Negative symptoms have consistently been found to contribute to functional impairment in schizophrenia. In this pilot study, we sought to delineate the core negative symptoms that contribute to this functional impairment. Adult outpatients with schizophrenia were evaluated for the severity of positive, negative, cognitive, and depressive symptoms. The Quality of Life Scale was used to assess current functioning. Results from 21 participants revealed that a motivation was the sole predictor of functioning, accounting for 74% of the variance in current functioning. This suggests that motivational deficits are the central link between negative symptoms and functional impairment in schizophrenia.

Identification and molecular characterization of a novel member of the siglec family (SIGLEC9).

Using the positional cloning approach, we have identified siglec-9 (HGMW-approved symbol SIGLEC9) a novel member of the sialic acid-binding Ig-like lectin (Siglec) family, which belongs to the immunoglobulin superfamily (IgSF). We characterized the genomic structure of this gene and determined its chromosomal localization, its homology to other members of the siglec family, and its tissue expression profile. The siglec-9 gene is composed of seven exons, with six intervening introns. The coding region consists of 1392 nucleotides and produces a 463-amino-acid protein. Furthermore, we have localized this gene to 19q13.4, 43.19 kb more telomeric than KLK14 (a member of the kallikrein gene family) through genomic sequencing data and restriction mapping with EcoRI. This novel siglec shows a high degree of homology to many members of the siglec family, including siglec-7 (80%), siglec-8 (72%), siglec-5 (65%), and CD33 (64%). This high degree of homology is also conserved in the extracellular Ig-like domains. Through RT-PCR, we have examined the expression of siglec-9 in a large number of tissues and have found relatively high-level expression in bone marrow, placenta, spleen, and fetal liver. Based on its homology to CD33, we speculate that this gene may also have some utility as a target for immunological antineoplastic therapy.

Molecular characterization of a Siglec8 variant containing cytoplasmic tyrosine-based motifs, and mapping of the Siglec8 gene.

Through efforts to investigate the CD33-like subgroup of sialic acid binding immunoglobulin-like lectins (Siglecs), which are believed to be located on chromosome 19q13.4, we have identified the precise genomic region containing the Siglec8 gene. It is located on chromosome 19q13.4, approximately 330 kb downstream of the Siglec9 gene. Further, we have identified a novel Siglec8 variant, named Siglec8-Long (Siglec8-L), which differs in its last two exons from the previously published mRNA sequence of Siglec8 (GenBank Accession No. AF195092). Both Siglec8 and Siglec8-L are comprised of seven exons, of which the first five are identical, followed by marked differences in exon usage and mRNA splicing. The 499 amino acid protein encoded by the Siglec8-L open reading frame has a molecular weight of 54 kDa. Like the other members of the CD33-like subgroup of Siglecs, except for the previously published Siglec8, Siglec8-L also contains the two tyrosine-based motifs that have been found to recruit both SH2 domain-containing tyrosine and inositol phosphatases.

Molecular characterization, tissue expression, and mapping of a novel Siglec-like gene (SLG2) with three splice variants.

The sialic acid binding immunglobulin-like lectin (Siglec) family is a recently described member of the immunoglobulin superfamily. Within the Siglec family, there exists a subgroup, which bears a high degree of homology with the molecule CD33 (Siglec-3), and has thus been designated the CD33-like subgroup of Siglecs. Members of this subgroup have been localized to chromosome 19q13.4. Through the positional candidate approach, we identified a novel potential member of this subgroup of Siglecs. We have characterized the complete genomic structure of this gene, determined its chromosomal localization, its homology to other members of the Siglec family, and its tissue expression profile. This new Siglec-like gene is comprised of 11 exons, with 10 intervening introns, and is localized 278 kb telomeric to Siglec-9 and 35 kb centromeric to Siglec-8 and on chromosome 19q13.4. The coding region consists of 2094 base pairs, and encodes for a putative 76.6 kDa protein. All Siglec-conserved structural features, including V-set domain, three C-set domains, transmembrane domain, ITIM and SLAM motifs, were found in this Siglec-like gene. Also, it has the conserved amino acids essential for sialic acid binding. The Siglec-like gene has 40-66% homology with members of the CD33-like subgroup, including Siglecs 5-9. Through RT-PCR we have examined the expression profile of this new gene in a panel of human tissues and found it to be primarily expressed in the bone marrow, spleen, brain, small intestine, colon, and spinal cord. We were also able to identify three different splice variants of the new gene. This gene may represent the latest novel member of the CD33-like subgroup of Siglecs, and, given its high degree of homology, it may also serve a regulatory role in the proliferation and survival of a particular hematopoietic stem cell lineage, as has been found for CD33 and Siglec-7.

Cloning and molecular characterization of two splice variants of a new putative member of the Siglec-3-like subgroup of Siglecs.

The sialic acid binding immunoglobulin-like lectin (Siglec) family is a recently described member of the immunoglobulin superfamily. Within this Siglec family there exists a subgroup of molecules which bear a very high degree of homology with the molecule Siglec-3 (CD33), and has thus been designated the Siglec-3-like subgroup of Siglecs. The members of this subgroup have been localized to chromosome 19q13.4, through both in situ hybridization and precise genomic mapping at the nucleotide level. Through the positional cloning approach we have identified and characterized a Siglec-like gene (SLG), a putative novel member of the Siglec-3-like subgroup of Siglecs. We have characterized the complete genomic structure of SLG, as well as two alternative splice variants, and determined its chromosomal localization. The short isoform, SLG-S, consists of seven exons, with six intervening introns, while the longer isoform, SLG-L, consists of eight exons and seven intervening introns. The SLG gene is localized 32.9 kb downstream of Siglec-8 on chromosome 19q13.4. The putative SLG-S and SLG-L proteins, of 477 and 595 amino acid residues, respectively, show extensive homology to many members of the Siglec-3-like subgroup. This high degree of homology is conserved in the extracellular Ig-like domains, as well as in the cytoplasmic tyrosine-based motifs. Interestingly, the SLG-L protein contains two N-terminal V-set Ig-like domains, as opposed to SLG-S and other Siglec-3-like subgroup members which contain only one such domain. Through RT-PCR we have examined the expression profile of both SLG splice variants in a panel of human tissues and have found that SLG-S is highly expressed in spleen, small intestine and adrenal gland, while SLG-L exhibits high levels of expression in spleen, small intestine, and bone marrow. This gene is quite likely the latest novel member of the CD33-like subgroup of Siglecs, and given its high degree of homology, it may also serve a regulatory role in the proliferation and survival of a particular hematopoietic stem cell lineage, as has been found for CD33 and Siglec7.