The association between alterations in motor and cognitive dimensions of schizophrenia-spectrum disorders: A systematic review.

Motor and cognitive alterations in schizophrenia-spectrum disorders (SSD) share common neural underpinnings, highlighting the necessity for a thorough exploration of the connections between these areas. This relationship is crucial, as it holds potential significance in unraveling the underlying mechanisms of SSD pathophysiology, ultimately leading to advancements in clinical staging and treatment strategies. The purpose of this review was to characterize the relationship between different hyper and hypokinetic domains of motor alterations and cognition in SSD. We systematically searched the literature (PROSPERO protocol CRD42019145964) and selected 66 original scientific contributions for review, published between 1987 and 2022. A narrative synthesis of the results was conducted. Hyper and hypokinetic motor alterations showed weak to moderate negative correlations with cognitive function across different SSD stages, including before antipsychotic treatment. The literature to date shows a diverse set of methodologies and composite cognitive scores hampering a strong conclusion about which specific cognitive domains were more linked to each group of motor alterations. However, executive functions seemed the domain more consistently associated with parkinsonism with the results regarding dyskinesia being less clear. Akathisia and catatonia were scarcely discussed in the reviewed literature. The present review reinforces the intimate relationship between specific motor alterations and cognition. Identified gaps in the literature challenge the formulation of definitive conclusions. Nevertheless, a discussion of putative underlying mechanisms is included, prompting guidance for future research endeavors.

Clonidine augmentation in patients with schizophrenia: A double-blind, randomized placebo-controlled trial.

INTRODUCTION: Noradrenergic imbalance in the brain of schizophrenia patients may underlie both symptomatology and deficits in basic information processing. The current study investigated whether augmentation with the noradrenergic α2-agonist clonidine might alleviate these symptoms. METHODS: In a double-blind placebo-controlled randomized clinical trial, 32 chronic schizophrenia patients were randomly assigned to six-weeks augmentation with either 50 µg clonidine or placebo to their current medication. Effects on symptom severity and both sensory- and sensorimotor gating were assessed at baseline, 3- and 6-weeks. Results were compared with 21 age- and sex-matched healthy controls (HC) who received no treatment. RESULTS: Only patients treated with clonidine showed significantly reduced PANSS negative, general and total scores at follow-up compared to baseline. On average, also patients treated with placebo showed minor (non-significant) reductions in these scores, likely indicating a placebo effect. Sensorimotor gating of patients was significantly lower at baseline compared to controls. It increased in patients treated with clonidine over the treatment period, whereas it decreased in both the HC and patients treated with placebo. However, neither treatment nor group effects were found in sensory gating. Clonidine treatment was very well tolerated. CONCLUSION: Only patients treated with clonidine showed a significant decrease on two out of the three PANSS subscales, while additionally retained their levels of sensorimotor gating. Given that there are only a few reports on effective treatment for negative symptoms in particular, our current results support augmentation of antipsychotics with clonidine as a promising, low-cost and safe treatment strategy for schizophrenia.

Longitudinal clinical and functional outcome in distinct cognitive subgroups of first-episode psychosis: a cluster analysis.

BACKGROUND: Cognitive deficits may be characteristic for only a subgroup of first-episode psychosis (FEP) and the link with clinical and functional outcomes is less profound than previously thought. This study aimed to identify cognitive subgroups in a large sample of FEP using a clustering approach with healthy controls as a reference group, subsequently linking cognitive subgroups to clinical and functional outcomes. METHODS: 204 FEP patients were included. Hierarchical cluster analysis was performed using baseline brief assessment of cognition in schizophrenia (BACS). Cognitive subgroups were compared to 40 controls and linked to longitudinal clinical and functional outcomes (PANSS, GAF, self-reported WHODAS 2.0) up to 12-month follow-up. RESULTS: Three distinct cognitive clusters emerged: relative to controls, we found one cluster with preserved cognition (n = 76), one moderately impaired cluster (n = 74) and one severely impaired cluster (n = 54). Patients with severely impaired cognition had more severe clinical symptoms at baseline, 6- and 12-month follow-up as compared to patients with preserved cognition. General functioning (GAF) in the severely impaired cluster was significantly lower than in those with preserved cognition at baseline and showed trend-level effects at 6- and 12-month follow-up. No significant differences in self-reported functional outcome (WHODAS 2.0) were present. CONCLUSIONS: Current results demonstrate the existence of three distinct cognitive subgroups, corresponding with clinical outcome at baseline, 6- and 12-month follow-up. Importantly, the cognitively preserved subgroup was larger than the severely impaired group. Early identification of discrete cognitive profiles can offer valuable information about the clinical outcome but may not be relevant in predicting self-reported functional outcomes.

The Puzzle of Functional Recovery in Schizophrenia-Spectrum Disorders-Replicating a Network Analysis Study.

BACKGROUND AND HYPOTHESIS: Recovery from psychosis is a complex phenomenon determined by an array of variables mutually impacting each other in a manner that is not fully understood. The aim of this study is to perform an approximated replication of a previous network analysis study investigating how different clinical aspects-covering psychopathology, cognition, personal resources, functional capacity, and real-life functioning-are interrelated in the context of schizophrenia-spectrum disorders. STUDY DESIGN: A sample of 843 subjects from a multisite cohort study, with the diagnosis of a schizophrenia-spectrum disorder, was used to estimate a network comprising 27 variables. The connectivity and relative importance of the variables was examined through network analysis. We used a quantitative and qualitative approach to infer replication quality. STUDY RESULTS: Functional capacity and real-life functioning were central and bridged different domains of the network, in line with the replicated study. Neurocognition, interpersonal relationships, and avolition were also key elements of the network, in close relation to aspects of functioning. Despite significant methodological differences, the current study could substantially replicate previous findings. CONCLUSIONS: Results solidify the network analysis approach in the context of mental disorders and further inform future studies about key variables in the context of recovery from psychotic disorders.

A Network of Psychopathological, Cognitive, and Motor Symptoms in Schizophrenia Spectrum Disorders.

Schizophrenia spectrum disorders (SSDs) are complex syndromes involving psychopathological, cognitive, and also motor symptoms as core features. A better understanding of how these symptoms mutually impact each other could translate into diagnostic, prognostic, and, eventually, treatment advancements. The present study aimed to: (1) estimate a network model of psychopathological, cognitive, and motor symptoms in SSD; (2) detect communities and explore the connectivity and relative importance of variables within the network; and (3) explore differences in subsample networks according to remission status. A sample of 1007 patients from a multisite cohort study was included in the analysis. We estimated a network of 43 nodes, including all the items from the Positive and Negative Syndrome Scale, a cognitive assessment battery and clinical ratings of extrapyramidal symptoms. Methodologies specific to network analysis were employed to address the study's aims. The estimated network for the total sample was densely interconnected and organized into 7 communities. Nodes related to insight, abstraction capacity, attention, and suspiciousness were the main bridges between network communities. The estimated network for the subgroup of patients in remission showed a sparser density and a different structure compared to the network of nonremitted patients. In conclusion, the present study conveys a detailed characterization of the interrelations between a set of core clinical elements of SSD. These results provide potential novel clues for clinical assessment and intervention.

Raloxifene augmentation in men and women with a schizophrenia spectrum disorder: A study protocol.

Although acute psychotic symptoms are often reduced by antipsychotic treatment, many patients with schizophrenia are impaired in daily functioning due to the persistence of negative and cognitive symptoms. Raloxifene, a Selective Estrogen Receptor Modulator (SERM) has been shown to be an effective adjunctive treatment in schizophrenia. Yet, there is a paucity in evidence for raloxifene efficacy in men and premenopausal women. We report the design of a study that aims to replicate earlier findings concerning the efficacy of raloxifene augmentation in reducing persisting symptoms and cognitive impairment in postmenopausal women, and to extend these findings to a male and peri/premenopausal population of patients with schizophrenia. The study is a multisite, placebo-controlled, double-blind, randomised clinical trial in approximately 110 adult men and women with schizophrenia. Participants are randomised 1:1 to adjunctive raloxifene 120 mg or placebo daily during 12 weeks. The treatment phase includes measurements at three time points (week 0, 6 and 12), followed by a follow-up period of two years. The primary outcome measure is change in symptom severity, as measured with the Positive and Negative Syndrome Scale (PANSS), and cognition, as measured with the Brief Assessment of Cognition in Schizophrenia (BACS). Secondary outcome measures include social functioning and quality of life. Genetic, hormonal and inflammatory biomarkers are measured to assess potential associations with treatment effects. If it becomes apparent that raloxifene reduces psychotic symptoms and/or improves cognition, social functioning and/or quality of life as compared to placebo, implementation of raloxifene in clinical psychiatric practice can be considered.

The genetics of drug-related movement disorders, an umbrella review of meta-analyses.

This umbrella review investigates which genetic factors are associated with drug-related movement disorders (DRMD), in an attempt to provide a synthesis of published evidence of candidate-gene studies. To identify all relevant meta-analyses, a literature search was performed. Titles and abstracts were screened by two authors and the methodological quality of included meta-analyses was assessed using 'the assessment of multiple systematic reviews' (AMSTAR) critical appraisal checklist. The search yielded 15 meta-analytic studies reporting on genetic variations in 10 genes. DRD3, DRD2, CYP2D6, HTR2A, COMT, HSPG2 and SOD2 genes have variants that may increase the odds of TD. However, these findings do not concur with early genome-wide association studies. Low-power samples are susceptible to 'winner's curse', which was supported by diminishing meta-analytic effects of several genetic variants over time. Furthermore, analyses pertaining to the same genetic variant were difficult to compare due to differences in patient populations, methods used and the choice of studies included in meta-analyses. In conclusion, DRMD is a complex phenotype with multiple genes that impact the probability of onset. More studies with larger samples using other methods than by candidate genes, are essential to developing methods that may predict the probability of DRMD. To achieve this, multiple research groups need to collaborate and a DRMD genetic database needs to be established in order to overcome winner's curse and publication bias, and to allow for stratification by patient characteristics. These endeavours may help the development of a test with clinical value in the prevention and treatment of DRMD.

Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia.

Schizophrenia is highly heritable, yet its underlying pathophysiology remains largely unknown. Among the most well-replicated findings in neurobiological studies of schizophrenia are deficits in myelination and white matter integrity; however, direct etiological genetic and cellular evidence has thus far been lacking. Here, we implement a family-based approach for genetic discovery in schizophrenia combined with functional analysis using induced pluripotent stem cells (iPSCs). We observed familial segregation of two rare missense mutations in Chondroitin Sulfate Proteoglycan 4 (CSPG4) (c.391G > A [p.A131T], MAF 7.79 × 10-5 and c.2702T > G [p.V901G], MAF 2.51 × 10-3). The CSPG4A131T mutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4V901G mutation was nominally enriched in cases (11 cases vs. 3 controls, P = 0.026, OR 3.77, 95% CI 1.05-13.52). CSPG4/NG2 is a hallmark protein of oligodendrocyte progenitor cells (OPCs). iPSC-derived OPCs from CSPG4A131T mutation carriers exhibited abnormal post-translational processing (P = 0.029), subcellular localization of mutant NG2 (P = 0.007), as well as aberrant cellular morphology (P = 3.0 × 10-8), viability (P = 8.9 × 10-7), and myelination potential (P = 0.038). Moreover, transfection of healthy non-carrier sibling OPCs confirmed a pathogenic effect on cell survival of both the CSPG4A131T (P = 0.006) and CSPG4V901G (P = 3.4 × 10-4) mutations. Finally, in vivo diffusion tensor imaging of CSPG4A131T mutation carriers demonstrated a reduction of brain white matter integrity compared to unaffected sibling and matched general population controls (P = 2.2 × 10-5). Together, our findings provide a convergence of genetic and functional evidence to implicate OPC dysfunction as a candidate pathophysiological mechanism of familial schizophrenia.

Weight changes associated with antiepileptic mood stabilizers in the treatment of bipolar disorder.

OBJECTIVE: To present up-to-date information and recommendations on the management of body weight changes during the use of antiepileptic mood stabilizers in bipolar disorder to help clinicians and patients make well-informed, practical decisions. DATA SOURCES: Umbrella review. Systematic reviews and meta-analyses on the prevention, treatment, and monitoring of body weight changes as a side effect of the mood stabilizers valproate, lamotrigine, topiramate, and carbamazepine were identified in Embase (2010-2015, no language restrictions). STUDY SELECTION: The search yielded 18 relevant publications on antiepileptic mood stabilizers and weight changes in bipolar disorder. DATA EXTRACTION: Relevant scientific evidence was abstracted and put into a clinical perspective by a multidisciplinary expert panel of clinicians with expertise in the treatment of bipolar disorders across all age groups and a patient representative. RESULTS: Valproate has been proven to be associated with weight gain in up to 50% of its users, and can be detected 2-3 months after initiation. Carbamazepine has been proven to have a low risk of weight gain. Lamotrigine and topiramate are associated with weight loss. Other option for this sentence = Weigth gain has been proven to be associated with valproate use in up to 50% of its users, and can be detected within 2-3 months after initiation. CONCLUSION: Each antiepileptic mood stabilizer has specific effects on body weight and accordingly requires a discrete education, prevention, monitoring, and treatment strategy. Clinicians are recommended to adopt an active, anticipatory approach, educating patients about weight change as an important side effect in order to come to informed shared decisions about the most suitable mood stabilizer.

Asymmetric Drug-Induced Parkinsonism and Psychopathology: A Prospective Naturalistic Study in Long-Stay Psychiatric Patients.

BACKGROUND: Drug-induced parkinsonism (DIP) is the most common movement disorder induced by antipsychotics. Although DIP is mostly symmetric, asymmetric DIP is reported in a substantial part of the patients. We investigated the frequency of motor asymmetry in DIP and its relationship to the severity of psychopathology in long-stay psychiatric patients. METHODS: We obtained data from a cohort study of 207 long-stay psychiatric patients on the frequency and risk factors of tardive dyskinesia, akathisia, tardive dystonia, and DIP. From July 2003 to May 2007 (mean follow-up, 1.1 year) drug-induced movement disorders were assessed at least two times in each patient, with a frequency of persistent DIP of 56.2%. All patients who had at least one time parkinsonism in the upper/lower limb(s) were included for analyses (190 patients, 79 women; mean age, 48.0 ± 12.9 years). The Unified Parkinson Disease Rating Scale motor scale was used to calculate the frequency of asymmetric parkinsonism. Multilevel mixed models were built to explore the relationship between asymmetry in parkinsonism and the severity of psychopathology, measured on the Clinical Global Impression-Schizophrenia scale severity index (CGI-SCH SI). RESULTS: The frequency of asymmetric parkinsonism was 20.8%. Asymmetry in parkinsonism was associated with symptom severity on all CGI-SCH SI scales (ß range, 0.37-3.74) and significantly associated with the positive symptom scale (ß, 3.74; 95% CI, 0.35-7.31). CONCLUSION: DIP is asymmetric in a substantial part of patients. Asymmetric presentation of DIP is of clinical relevance as it is related to the severity of psychopathology and may alert the clinician of more severe psychopathology. Future research is recommended to provide insight into the neuropsychopathology and clinical value of asymmetric parkinsonism for psychiatric patients.

Blink rate is associated with drug-induced parkinsonism in patients with severe mental illness, but does not meet requirements to serve as a clinical test: the Curacao extrapyramidal syndromes study XIII.

BACKGROUND: Drug-induced parkinsonism (DIP) has a high prevalence and is associated with poorer quality of life. To find a practical clinical tool to assess DIP in patients with severe mental illness (SMI), the association between blink rate and drug-induced parkinsonism (DIP) was assessed. METHODS: In a cohort of 204 SMI patients receiving care from the only mental health service of the previous Dutch Antilles, blink rate per minute during conversation was assessed by an additional trained movement disorder specialist. DIP was rated on the Unified Parkinson's Disease Rating Scale (UPDRS) in 878 assessments over a period of 18 years. Diagnostic values of blink rate were calculated. RESULTS: DIP prevalence was 36%, average blink rate was 14 (standard deviation (SD) 11) for patients with DIP, and 19 (SD 14) for patients without. There was a significant association between blink rate and DIP (p < 0.001). With a blink rate cut-off of 20 blinks per minute, sensitivity was 77% and specificity was 38%. A 10% percentile cut-off model resulted in an area under the ROC curve of 0.61. A logistic prediction model between dichotomous DIP and continuous blink rate per minute an area under the ROC curve of 0.70. CONCLUSIONS: There is a significant association between blink rate and DIP as diagnosed on the UPDRS. However, blink rate sensitivity and specificity with regard to DIP are too low to replace clinical rating scales in routine psychiatric practice. TRIAL REGISTRATION: The study was started over 20 years ago in 1992, at the time registering a trial was not common practice, therefore the study was never registered.

Risk Factors for Tremor in a Population of Patients with Severe Mental Illness: An 18-year Prospective Study in a Geographically Representative Sample (The Curacao Extrapyramidal Syndromes Study XI).

BACKGROUND: The aim was to assess incidence, prevalence and risk factors of medication-induced tremor in African-Caribbean patients with severe mental illness (SMI). METHOD: A prospective study of SMI patients receiving care from the only mental health service of the previous Dutch Antilles. Eight clinical assessments, over 18 years, focused on movement disorders, medication use, and resting tremor (RT) and (postural) action tremor (AT). Risk factors were modeled with logistic regression for both current (having) tremor and for tremor at the next time point (developing). The latter used a time-lagged design to assess medication changes prior to a change in tremor state. RESULTS: Yearly tremor incidence rate was 2.9% and mean tremor point prevalence was 18.4%. Over a third of patients displayed tremor during the study. Of the patients, 5.2% had AT with 25% of cases persisting to the next time point, while 17.1% of patients had RT of which 65.3% persisted. When tremor data were examined in individual patients, they often had periods of tremor interspersed with periods of no tremor. Having RT was associated with age (OR=1.07 per year; 95% confidence interval 1.03-1.11), sex (OR=0.17 for males; 0.05-0.78), cocaine use (OR=10.53; 2.22-49.94), dyskinesia (OR=0.90; 0.83-0.97), and bradykinesia (OR=1.16; 1.09-1.22). Developing RT was strongly associated with previous measurement RT (OR=9.86; 3.80-25.63), with previous RT severity (OR=1.22; 1.05-1.41), and higher anticholinergic load (OR= 1.24; 1.08-1.43). Having AT was associated with tremor-inducing medication (OR= 4.54; 1.90-10.86), cocaine use (OR=14.04; 2.38-82.96), and bradykinesia (OR=1.07; 1.01-1.15). Developing AT was associated with, previous AT severity (OR=2.62 per unit; 1.64-4.18) and tremor reducing medication (OR=0.08; 0.01-0.55). CONCLUSIONS: Long-stay SMI patients are prone to developing tremors, which show a relapsing-remitting course. Differentiation between RT and AT is important as risk factors differ and they require different prevention and treatment strategies.

Effect of Antipsychotic Type and Dose Changes on Tardive Dyskinesia and Parkinsonism Severity in Patients With a Serious Mental Illness: The Curaçao Extrapyramidal Syndromes Study XII.

OBJECTIVE: To test the efficacy of current treatment recommendations for parkinsonism and tardive dyskinesia (TD) severity in patients with severe mental illness (SMI). METHODS: We present an 18-year prospective study including all 223 patients with SMI (as defined by the 1987 US National Institute of Mental Health, which were based on DSM-III-R diagnostic criteria) receiving care from the only psychiatric hospital of the former Netherlands Antilles. Eight clinical assessments (1992-2009) focused on movement disorders and medication use. Tardive dyskinesia was measured by the Abnormal Involuntary Movement Scale and parkinsonism by the Unified Parkinson's Disease Rating Scale. Antipsychotics were classified into first-generation antipsychotic (FGA) versus second-generation antipsychotic (SGA) and high versus low dopamine 2 (D2) affinity categories. The effect that switching has within each category on subsequent movement scores was calculated separately by using time-lagged multilevel logistic regression models. RESULTS: There was a significant association between reduction in TD severity and starting/switching to an FGA (B = -3.54, P < .001) and starting/switching to a high D2 affinity antipsychotic (B = -2.49, P < .01). Adding an SGA to existing FGA treatment was associated with reduction in TD severity (B = -2.43, P < .01). For parkinsonism, stopping antipsychotics predicted symptom reduction (B = -7.76, P < .01 in FGA/SGA-switch model; B = -7.74, P < .01 in D2 affinity switch model), while starting a high D2 affinity antipsychotic predicted an increase in symptoms (B = 3.29, P < .05 in D2 affinity switch model). CONCLUSIONS: The results show that switching from an FGA to an SGA does not necessarily result in a reduction of TD or parkinsonism. Only stopping all antipsychotics reduces the severity of parkinsonism, and starting an FGA or a high D2 affinity antipsychotic may reduce the severity of TD.

Likelihood of mechanistic roles for dopaminergic, serotonergic and glutamatergic receptors in tardive dyskinesia: A comparison of genetic variants in two independent patient populations.

OBJECTIVES: An established theory for the pathogenesis of tardive dyskinesia is disturbed dopaminergic receptor sensitivity and/or dopaminergic intracellular signaling. We examined associations between genetic variants of neurotransmitter receptors and tardive dyskinesia. METHODS: We assessed tardive dyskinesia in Caucasian psychiatric inpatients from Siberia (N = 431) and a long-stay population from the Netherlands (N = 168). These patients were genotyped for 43 tag single nucleotide polymorphisms in five neurotransmitter receptor genes, and the results for the two populations were compared. RESULTS: Several significant associations with tardive dyskinesia were identified, but only GRIN2A (rs1345423) was found in both patient populations. This lack of agreement was probably due to the small effect size of the associations, the multiple testing and the small sample size of the Dutch patient population. After reviewing the literature, we propose that the constitutive stimulatory activity of serotonergic type 2 receptors may be relevant. CONCLUSIONS: Inactivity of the serotonergic, type 2C receptor or blockade of these receptors by atypical antipsychotic drugs may decrease the vulnerability to develop tardive dyskinesia.

Antipsychotic-induced movement disorders in long-stay psychiatric patients and 45 tag SNPs in 7 candidate genes: a prospective study.

OBJECTIVE: Four types of antipsychotic-induced movement disorders: tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia, subtypes of TD (orofacial and limb truncal dyskinesia), subtypes of parkinsonism (rest tremor, rigidity, and bradykinesia), as well as a principal-factor of the movement disorders and their subtypes, were examined for association with variation in 7 candidate genes (GRIN2B, GRIN2A, HSPG2, DRD3, DRD4, HTR2C, and NQO1). METHODS: Naturalistic study of 168 white long-stay patients with chronic mental illness requiring long-term antipsychotic treatment, examined by the same rater at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia. The authors genotyped 45 tag SNPs in 7 candidate genes, associated with movement disorders or schizophrenia in previous studies. Genotype and allele frequency comparisons were performed with multiple regression methods for continuous movement disorders. RESULTS: Various tag SNPs reached nominal significance; TD with rs1345423, rs7192557, rs1650420, as well as rs11644461; orofacial dyskinesia with rs7192557, rs1650420, as well as rs4911871; limb truncal dyskinesia with rs1345423, rs7192557, rs1650420, as well as rs11866328; bradykinesia with rs2192970; akathisia with rs324035; and the principal-factor with rs10772715. After controlling for multiple testing, no significant results remained. CONCLUSIONS: The findings suggest that selected tag SNPs are not associated with a susceptibility to movement disorders. However, as the sample size was small and previous studies show inconsistent results, definite conclusions cannot be made. Replication is needed in larger study samples, preferably in longitudinal studies which take the fluctuating course of movement disorders and gene-environment interactions into account.