The Extrapyramidal Symptom Rating Scale and Its Abbreviated Version: A Critical Review of Clinimetric Properties.

BACKGROUND: The Extrapyramidal Symptom Rating Scale - Abbreviated (ESRS-A) is an abbreviated version of the Extrapyramidal Symptom Rating Scale (ESRS) with instructions, definitions, and a semi-structured interview that follows clinimetric concepts of measuring clinical symptoms. Similar to the ESRS, the ESRS-A was developed to assess four types of drug-induced movement disorders (DIMD): parkinsonism, akathisia, dystonia, and tardive dyskinesia (TD). SUMMARY: The present review of the literature provides the most relevant clinimetric properties displayed by the ESRS and ESRS-A in clinical studies. Comprehensive ESRS-A definitions, official scale, and basic instructions are provided. ESRS inter-rater reliability was evaluated in two pivotal studies and in multicenter international studies. Inter-rater reliability was high for assessing both antipsychotic-induced movement disorders and idiopathic Parkinson's disease. Guidelines were also established for inter-rater reliability and the rater certification processes. The ESRS showed good concurrent validity with 96% agreement between Abnormal Involuntary Movement Scale (AIMS) for TD-defined cases and ESRS-defined cases. Similarly, concurrent validity for ESRS-A total and subscores for parkinsonism, akathisia, dystonia, and dyskinesia ranged from good to very good. The ESRS was particularly sensitive for detecting DIMD-related movement differences following treatment with placebo, antipsychotics, and antiparkinsonian and antidyskinetic medications. ESRS measurement of drug-induced extrapyramidal symptoms was shown to discriminate extrapyramidal symptoms from psychiatric symptoms. KEY MESSAGES: The ESRS and ESRS-A are valid clinimetric indices for measuring DIMD. They can be valuably implemented in clinical research, particularly in trials testing antipsychotic medications, and in clinics to detect the presence, severity, and response to treatment of movement disorders.

Test-retest reliability of the Childhood Trauma Questionnaire in psychotic disorders.

BACKGROUND: Childhood trauma is common and associated with worse psychiatric outcomes. Yet, clinicians may not inquire about childhood trauma due to a misconception that patients cannot provide reliable reports. The goal of this study was to examine the reliability of self-reports of childhood trauma in psychotic disorders. METHODS: We examined the test-retest reliability of the Childhood Trauma Questionnaire (CTQ) in schizophrenia (SZ, n = 19), psychotic bipolar disorder (BD, n = 17), and healthy control (HC, n = 28) participants who completed the CTQ on ≥2 occasions over variable time periods (mean 19.6 months). We calculated the intraclass correlation (ICC) for the total CTQ score, each of the five CTQ domains, and the minimization/denial subscale for the three groups. For any CTQ domains showing low test-retest reliability (ICC < 0.61), we also explored whether positive, negative, depressive, and manic symptom severity were associated with CTQ variability. RESULTS: We found high ICC values for the total CTQ score in all three groups (SZ 0.82, BD 0.85, HC 0.88). The ICC values for CTQ subdomains were also high with the exceptions of scores for sexual abuse in BD (0.40), emotional neglect in SZ (0.60), and physical neglect in BD (0.51) and HC (0.43). In exploratory analyses, self-reports of sexual abuse in BD were associated with greater severity of depressive symptoms (ß = 0.108, p = 0.004). CONCLUSIONS: Patients with SZ and BD can provide reliable self-reports of childhood trauma, especially related to physical and emotional abuse. The presence of psychosis should not deter clinicians from asking patients about childhood trauma.

Clinical Utility of Semistructured Interview and Scales to Assess Withdrawal Syndromes With Dose Reduction or Discontinuation of Selective Serotonin Reuptake Inhibitors or Serotonin Norepinephrine Reuptake Inhibitors.

BACKGROUND: Withdrawal syndromes can occur after dose reduction or discontinuation of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Few measurement instruments are available to assess them: Diagnostic Clinical Interview for Drug Withdrawal 1-New Symptoms of SSRI and SNRI (DID-W1) and Discontinuation Emergent Signs and Symptoms (DESS) checklist. We assessed their interrater reliability, verified the percent agreement between the two, and tested DESS sensitivity and specificity on the basis of the diagnoses formulated via the DID-W1. METHODS: One-hundred thirty-four subjects who referred for withdrawal at 3 outpatient facilities were enrolled and assessed via the DESS and the DID-W1. Percent agreement and Cohen κ were calculated to measure DID-W1 and DESS interrater reliability, as well as the agreement between DID-W1 and DESS items. Sensitivity and specificity of DESS were derived from the identification of true-positive, false-negative, true-negative, and false-positive on the DID-W1. RESULTS: Both tools showed excellent interrater reliability (DID-W1 Cohen κ = 0.958; DESS Cohen κ = 0.81-1). The degree of agreement between DID-W1 and DESS items was poor or fair (Cohen κ < 0.40) for some items and moderate (Cohen κ = 0.41-0.60) for others. Sensitivity and specificity of DESS were 0.937 (true-positive = 60, false-negative = 4) and 0.285 (true-negative = 20, false-positive = 50), respectively. CONCLUSIONS: DID-W1 was a reliable method to identify and diagnose withdrawal syndromes. The DESS checklist showed to be a useful tool for detecting withdrawal SSRI/SNRI symptoms when the aim is to achieve high sensitivity to identify true positives.

Abnormal Brain Bioenergetics in First-Episode Psychosis.

BACKGROUND: Converging evidence indicates impaired brain energy metabolism in schizophrenia and other psychotic disorders. Creatine kinase (CK) is pivotal in providing adenosine triphosphate in the cell and maintaining its levels when energy demand is increased. However, the activity of CK has not been investigated in patients with first-episode schizophrenia spectrum disorders. METHODS: Using in vivo phosphorus magnetization transfer spectroscopy, we measured CK first-order forward rate constant (k f ) in the frontal lobe, in patients with first-episode psychosis (FEP; n = 16) and healthy controls (n = 34), at rest. RESULTS: CK k f was significantly reduced in FEP compared to healthy controls. There were no differences in other energy metabolism-related measures, including phosphocreatine (PCr) or ATP, between groups. We also found increase in glycerol-3-phosphorylcholine, a putative membrane breakdown product, in patients. CONCLUSIONS: The results of this study indicate that brain bioenergetic abnormalities are already present early in the course of schizophrenia spectrum disorders. Future research is needed to identify the relationship of reduced CK k f with psychotic symptoms and to test treatment alternatives targeting this pathway. Increased glycerol-3-phosphorylcholine is consistent with earlier studies in medication-naïve patients and later studies in first-episode schizophrenia, and suggest enhanced synaptic pruning.

White Matter Measures and Cognition in Schizophrenia.

White matter (WM) abnormalities are commonly reported in schizophrenia but whether these arise from the axon or myelin compartments or both is not known. In addition, the relationship between WM abnormalities and cognitive function is not fully explored in this condition. We recruited 39 individuals with schizophrenia spectrum disorders and 37 healthy comparison subjects. All participants underwent MRI scanning at 4 Tesla to collect data in the prefrontal white matter on magnetization transfer ratio (MTR) and diffusion tensor spectroscopy (DTS) which provide information on myelin and axon compartments, respectively. We also collected Matrics Composite Cognitive Battery (MCCB) and Stroop cognitive data. We found an elevated N-acetylaspartate (NAA) apparent diffusion coefficient in schizophrenia in this cohort as in our previous work; we also observed poorer performance on both the MCCB composite and the Stroop in schizophrenia patients compared to controls. The MTR measure was correlated with the MCCB composite (r = 0.363, p = 0.032) and Stroop scores (r = 0.387, p = 0.029) in healthy individuals but not in schizophrenia. Since this is the first exploration of the relationship between these WM and cognitive measures, we consider our analyses exploratory and did not adjust for multiple comparisons; the findings are not statistically significant if adjusted for multiple comparisons. These findings indicate that WM integrity is associated with cognitive function in healthy individuals but this relationship breaks down in patients with schizophrenia.

Visual hallucinations associated with multimodal hallucinations, suicide attempts and morbidity of illness in psychotic disorders.

BACKGROUND: Visual hallucinations (VH) are a common, but understudied symptom of psychosis, experienced by individuals across diagnostic categories of psychotic and neuropsychiatric conditions. There are limited data on VH and associated clinical phenotypes in adult idiopathic psychotic disorders, which are needed to elucidate their relevance to psychotic illness paradigms. METHOD: In this cross-sectional study, we examined clinical risk factors for VH in a well-characterized sample of 766 patients with adult psychotic disorders across diagnostic categories of schizophrenia (n = 227), schizoaffective disorder (n = 210), and bipolar I disorder (n = 329). The Structured Clinical Interview for DSM-IV-TR was used for diagnosis and symptom measurements. RESULTS: The prevalence of VH was 26.1% (200/766). Multivariate logistic regression showed that VH were independently associated with the presence of hallucinations in other modalities, including auditory, tactile, olfactory, and gustatory hallucinations. History of a suicide attempt and catatonic behavior were also associated with VH. In addition, specific delusions were associated with VH, in particular, delusions of control, and religious, erotomanic and jealousy delusions. Diagnosis, negative symptoms, and family history of psychosis were not independent predictors of VH. CONCLUSIONS: Results showed the clinical and disease relevance of VH as they were associated with severe morbidity of illness, including suicide attempts and catatonic behavior. Findings also suggest a phenotype associated with hallucinations in other modalities and specific types of delusions. Based on our findings, VH may be a significant factor in assessing for suicidality and illness severity, warranting clinical attention and further study of underlying mechanisms.

Impaired insulin signaling in unaffected siblings and patients with first-episode psychosis.

Patients with psychotic disorders are at high risk for type 2 diabetes mellitus, and there is increasing evidence that patients display glucose metabolism abnormalities before significant antipsychotic medication exposure. In the present study, we examined insulin action by quantifying insulin sensitivity in first-episode psychosis (FEP) patients and unaffected siblings, compared to healthy individuals, using a physiological-based model and comprehensive assessment battery. Twenty-two unaffected siblings, 18 FEP patients, and 15 healthy unrelated controls were evaluated using a 2-h oral glucose tolerance test (OGTT), with 7 samples of plasma glucose and serum insulin concentration measurements. Insulin sensitivity was quantified using the oral minimal model method. Lipid, leptin, free fatty acids, and inflammatory marker levels were also measured. Anthropometric, nutrient, and activity assessments were conducted; total body composition and fat distribution were determined using whole-body dual-energy X-ray absorptiometry. Insulin sensitivity significantly differed among groups (F = 6.01 and 0.004), with patients and siblings showing lower insulin sensitivity, compared to controls (P = 0.006 and 0.002, respectively). Body mass index, visceral adipose tissue area (cm2), lipids, leptin, free fatty acids, inflammatory markers, and activity ratings were not significantly different among groups. There was a significant difference in nutrient intake with lower total kilocalories/kilogram body weight in patients, compared to siblings and controls. Overall, the findings suggest that familial abnormal glucose metabolism or a primary insulin signaling pathway abnormality is related to risk for psychosis, independent of disease expression and treatment effects. Future studies should examine underlying biological mechanisms of insulin signaling abnormalities in psychotic disorders.

The Diagnostic clinical Interview for Drug Withdrawal 1 (DID-W1) ­ New Symptoms of Selective Serotonin Reuptake Inhibitors (SSRI) or Serotonin Norepinephrine Reuptake Inhibitors (SNRI): inter-rater reliability

Aim: A wide range of clinical phenomena have been reported with dose reduction or drug discontinuation of Selective Serotonin Reuptake Inhibitors (SSRIs) or Serotonin Norepinephrine Reuptake Inhibitors (SNRIs). In 2015, a new classification of SRIs/SNRIs withdrawal (i.e., new withdrawal symptoms, rebound symptoms withdrawal, persistent post-withdrawal disorders) was outlined on the basis of the literature and clinical observations. A semistructured clinical interview, the Diagnostic clinical Interview for Drug Withdrawal 1 - New Symptoms of SSRI and SNRI (DID-W1), was developed for identifying and differentiating such syndromes. Its inter-rater reliability has been tested. Methods: Seventeen consecutive outpatients with a history of SSRI or SNRI dose reduction or discontinuation were assessed independently by 2 clinicians at different times during the same day. Percent agreement, Cohen's kappa, and the squared correlation coefficient were used to measure inter-rater reliability. Results: The percent agreement for the whole interview was 97.06%, the Cohen's kappa 0.85 (95% CI of 0.61-1.08), the squared correlation coefficient 0.72. Discussion and conclusions: The kappa values indicated excellent inter-rater agreement. Validity evaluation and comparison with other instruments need to be performed. The DID-W1 may help diagnosing the clinical phenomena related to SSRI and SNRI discontinuation, their differentiation from relapse, and the potential iatrogenic origin of psychiatric symptoms in clinical practice.

Brain lactate and pH in schizophrenia and bipolar disorder: a systematic review of findings from magnetic resonance studies.

Converging evidence from molecular to neuroimaging studies suggests brain energy metabolism abnormalities in both schizophrenia and bipolar disorder. One emerging hypothesis is: decreased oxidative phosphorylation leading to accumulation of lactic acid from glycolysis and subsequent acidification of tissue. In this regard, integrating lactate and pH data from magnetic resonance spectroscopy (MRS) studies in both diseases may help us understand underlying neurobiological mechanisms. In order to achieve this goal, we performed a systematic search of case-control studies examining brain lactate or pH among schizophrenia and/or bipolar patients by using MRS. Medline/Pubmed and EBSCO databases were searched separately for both diseases and outcomes. Our search yielded 33 studies in total composed of 7 lactate and 26 pH studies. In bipolar disorder, 5 out of 6 studies have found elevated lactate levels especially in the cingulate cortex and 4 out of 13 studies reported reduced pH in the frontal lobe. In contrast, in schizophrenia a single study has examined lactate and reported elevation, while only 2 out of 13 studies examining pH have reported reduction in this measure. There were no consistent patterns for the relationship between lactate or pH levels and medication use, disease type, mood state, and other clinical variables. We highlight the need for future studies combining 1H-MRS and 31P-MRS approaches, using longitudinal designs to examine lactate and pH in disease progression across both schizophrenia and bipolar disorders.

Abnormalities in High-Energy Phosphate Metabolism in First-Episode Bipolar Disorder Measured Using 31P-Magnetic Resonance Spectroscopy.

BACKGROUND: Brain energy metabolism is critical for supporting synaptic function and information processing. A growing body of evidence suggests abnormalities in brain bioenergetics in psychiatric disorders, including both bipolar disorder (BD) and schizophrenia. 31P magnetic resonance spectroscopy provides a noninvasive window into these processes in vivo. Using this approach, we previously showed that patients with BD show normal adenosine triphosphate (ATP) and phosphocreatine levels at rest but cannot maintain normal ATP levels in the visual cortex during times of high energy demand (photic stimulation). Because ATP is replenished from phosphocreatine via the creatine kinase reaction, we have now measured the creatine kinase forward reaction rate constant in BD. METHODS: We studied 20 patients experiencing a first episode of BD and 28 healthy control participants at 4T and quantified creatine kinase forward reaction rate constant using 31P magnetization transfer magnetic resonance spectroscopy as described previously. RESULTS: We found a significant reduction in creatine kinase forward reaction rate constant in the BD group (F = 4.692, p = .036), whereas brain ATP and phosphocreatine concentrations, as well as brain parenchymal pH, were normal. CONCLUSIONS: These results pinpoint a specific molecular mechanism underlying our previous observation of an inability to replenish brain ATP during times of high energy demand in BD.

Antipsychotic-Induced Dopamine Supersensitivity Psychosis: Pharmacology, Criteria, and Therapy.

The first-line treatment for psychotic disorders remains antipsychotic drugs with receptor antagonist properties at D2-like dopamine receptors. However, long-term administration of antipsychotics can upregulate D2 receptors and produce receptor supersensitivity manifested by behavioral supersensitivity to dopamine stimulation in animals, and movement disorders and supersensitivity psychosis (SP) in patients. Antipsychotic-induced SP was first described as the emergence of psychotic symptoms with tardive dyskinesia (TD) and a fall in prolactin levels following drug discontinuation. In the era of first-generation antipsychotics, 4 clinical features characterized drug-induced SP: rapid relapse after drug discontinuation/dose reduction/switch of antipsychotics, tolerance to previously observed therapeutic effects, co-occurring TD, and psychotic exacerbation by life stressors. We review 3 recent studies on the prevalence rates of SP, and the link to treatment resistance and psychotic relapse in the era of second-generation antipsychotics (risperidone, paliperidone, perospirone, and long-acting injectable risperidone, olanzapine, quetiapine, and aripiprazole). These studies show that the prevalence rates of SP remain high in schizophrenia (30%) and higher (70%) in treatment-resistant schizophrenia. We then present neurobehavioral findings on antipsychotic-induced supersensitivity to dopamine from animal studies. Next, we propose criteria for SP, which describe psychotic symptoms and co-occurring movement disorders more precisely. Detection of mild/borderline drug-induced movement disorders permits early recognition of overblockade of D2 receptors, responsible for SP and TD. Finally, we describe 3 antipsychotic withdrawal syndromes, similar to those seen with other CNS drugs, and we propose approaches to treat, potentially prevent, or temporarily manage SP.

Brain bioenergetics and redox state measured by 31P magnetic resonance spectroscopy in unaffected siblings of patients with psychotic disorders.

BACKGROUND: Brain bioenergetic anomalies and redox dysregulation have been implicated in the pathophysiology of psychotic disorders. The present study examined brain energy-related metabolites and the balance between nicotinamide adenine dinucleotide metabolites (oxidized NAD+ and reduced NADH) using 31P-magnetic resonance spectroscopy (31P-MRS) in unaffected siblings, compared to first episode psychosis (FEP) patients and healthy controls. METHODS: 21 unaffected siblings, 32 FEP patients (including schizophrenia spectrum and affective psychoses), and 21 controls underwent 31P-MRS in the frontal lobe (6×6×4cm3) on a 4T MR scanner, using custom-designed dual-tuned surface coil with outer volume suppression. Brain parenchymal pH and steady-state metabolite ratios of high energy phosphate compounds were measured. NAD+ and NADH levels were determined using a 31P-MRS fitting algorithm. 13 unaffected sibling-patient pairs were related; other patients and siblings were unrelated. ANCOVA analyses were used to examine 31P-MRS measures, with age and gender as covariates. RESULTS: The phosphocreatine/adenosine triphosphate ratio was significantly reduced in both unaffected siblings and FEP patients, compared to controls. NAD+/NADH ratio was significantly reduced in patients compared to siblings and controls, with siblings showing a reduction in NAD+/NADH compared to controls that was not statistically significant. Compared to patients and controls, siblings showed significantly reduced levels of NAD+. Siblings did not differ from patients or controls on brain pH. DISCUSSION: Our results indicate that unaffected siblings show some, but not all the same abnormalities in brain energy metabolites and redox state as FEP patients. Thus, 31P-MRS studies may identify factors related both to risk and expression of psychosis.

McLean OnTrack: a transdiagnostic program for early intervention in first-episode psychosis.

AIMS: Most programs specializing in the treatment of first-episode psychosis in the United States focus on schizophrenia. However, many early psychosis patients do not fit into this diagnostic category. Here we describe McLean OnTrack, an intensive outpatient treatment program that accepts all comers with first-episode psychosis. METHODS: We assessed baseline characteristics of patients in the 2.5 years since program initiation. We examined how initial referral diagnoses compare with current diagnoses, calculating the proportion of diagnostic changes. RESULTS: At 2.5 years, patients in McLean OnTrack consist of 30 (33.0%) individuals with primary psychotic disorder, 40 (44.0%) with affective psychosis, 19 (20.9%) with psychotic disorder not otherwise specified (NOS) who do not meet full criteria for either category and two (2.2%) individuals with no psychosis. Although patients with affective psychosis had higher pre-morbid functioning, all three categories of psychosis had similar rates of prior hospitalizations and substance use. The retention rate in the psychotic disorder NOS group was lower than that in affective and primary psychotic disorders. Finally, diagnoses changed over the course of treatment in 50.5% of patients. CONCLUSIONS: Diagnostic heterogeneity appears to be the norm among patients with first-episode psychosis, and diagnoses commonly evolve over the illness course. Baseline indices of illness severity were similar across categories and suggest the need for early intervention, irrespective of specific diagnosis. We discuss the benefits and challenges of a transdiagnostic approach to early intervention in first-episode psychosis, treating patients who share many but not all characteristics.

A review of abnormalities in the perception of visual illusions in schizophrenia.

Specific abnormalities of vision in schizophrenia have been observed to affect high-level and some low-level integration mechanisms, suggesting that people with schizophrenia may experience anomalies across different stages in the visual system affecting either early or late processing or both. Here, we review the research into visual illusion perception in schizophrenia and the issues which previous research has faced. One general finding that emerged from the literature is that those with schizophrenia are mostly immune to the effects of high-level illusory displays, but this effect is not consistent across all low-level illusions. The present review suggests that this resistance is due to the weakening of top-down perceptual mechanisms and may be relevant to the understanding of symptoms of visual distortion rather than hallucinations as previously thought.

Factors associated with overweight and obesity in schizophrenia, schizoaffective and bipolar disorders.

Evidence suggests abnormal bioenergetic status throughout the body in psychotic disorders. The present study examined predictors of elevated body mass index (BMI) across diagnostic categories of schizophrenia, schizoaffective and bipolar disorders. In a cross-sectional study, we studied demographic and clinical risk factors for overweight and obesity in a well-characterized sample of 262 inpatients and outpatients with schizophrenia (n=59), schizoaffective disorder (n=81) and bipolar I disorder (n=122). Across the three diagnostic categories, the prevalence of overweight (29.4%) and obesity (33.2%) combined was 62.6% (164/262). Logistic regression analyses, adjusted for age, sex and ethnicity, showed that schizoaffective disorder, lifetime major depressive episode, presence of prior suicide attempt, and more than 5 lifetime hospitalizations were significantly associated with BMI≥25. Patients with schizophrenia had significantly lower risk for overweight and obesity. Overall, we found that affective components of illness were associated with elevated BMI in our cross-diagnostic sample. Our results show that patients with schizoaffective disorder have a greater risk for obesity. Identifying predictors of elevated BMI in patients with psychotic and mood disorders will help prevent obesity and related cardiovascular and cerebral complications. Future studies are needed to elucidate the mechanistic nature of the relationship between obesity and psychiatric illness.

Diffusion tensor imaging in first degree relatives of schizophrenia and bipolar disorder patients.

OBJECTIVES: White matter (WM) abnormalities are one of the most widely and consistently reported findings in schizophrenia (SZ) and bipolar disorder (BD). If these abnormalities are inherited determinants of illness, suitable to be classified as an endophenotype, relatives of patients must also have them at higher rate compared to the general population. In this review, we evaluate published diffusion tensor imaging (DTI) studies comparing first degree relatives of SZ and BD patients and healthy control subjects. METHODS: We searched PubMed, Embase and PsychInfo for DTI studies which included an unaffected relative and a healthy comparison group. RESULTS: 22 studies fulfilled the inclusion criteria. WM abnormalities were found in many diverse regions in relatives of SZ patients. Although the findings were not completely consistent across studies, the most implicated areas were the frontal and temporal WM regions and the corpus callosum. Studies in relatives of BD patients were fewer in number with less consistent findings reported across studies. CONCLUSIONS: Our review supports the concept of WM abnormalities as an endophenotype in SZ, with somewhat weaker evidence in BD, but larger and higher quality studies are needed to make a definitive comment.