Remission Of Positive Symptoms Research Articles

Comparing three-year extension of early intervention service to regular care following two years of early intervention service in first-episode psychosis: a randomized single blind clinical trial.

This study aimed to determine if, following two years of early intervention service for first-episode psychosis, three-year extension of that service was superior to three years of regular care. We conducted a randomized single blind clinical trial using an urn randomization balanced for gender and substance abuse. Participants were recruited from early intervention service clinics in Montreal. Patients (N=220), 18-35 years old, were randomized to an extension of early intervention service (EEIS; N=110) or to regular care (N=110). EEIS included case management, family intervention, cognitive behaviour therapy and crisis intervention, while regular care involved transfer to primary (community health and social services and family physicians) or secondary care (psychiatric outpatient clinics). Cumulative length of positive and negative symptom remission was the primary outcome measure. EEIS patients had a significantly longer mean length of remission of positive symptoms (92.5 vs. 63.6 weeks, t=4.47, p<0.001), negative symptoms (73.4 vs. 59.6 weeks, t=2.84, p=0.005) and both positive and negative symptoms (66.5 vs. 56.7 weeks, t=2.25, p=0.03) compared to regular care patients. EEIS patients stayed in treatment longer than regular care patients (mean 131.7 vs. 105.3 weeks, t=3.98, p<0.001 through contact with physicians; 134.8 ± 37.7 vs. 89.8 ± 55.2, t=6.45, p<0.0001 through contact with other health care providers) and received more units of treatment (mean 74.9 vs. 39.9, t=4.21, p<0.001 from physicians, and 57.3 vs. 28.2, t=4.08, p<0.001 from other health care professionals). Length of treatment had an independent effect on the length of remission of positive symptoms (t=2.62, p=0.009), while number of units of treatment by any health care provider had an effect on length of remission of negative symptoms (t=-2.70, p=0.008) as well as total symptoms (t=-2.40, p=0.02). Post-hoc analysis showed that patients randomized to primary care, based on their better clinical profile at randomization, maintained their better outcome, especially as to remission of negative symptoms, at the end of the study. These data suggest that extending early intervention service for three additional years has a positive impact on length of remission of positive and negative symptoms compared to regular care. This may have policy implications for extending early intervention services beyond the current two years.

An examination of components of recovery after five years of treatment in an early intervention program for psychosis

Recovery from psychotic disorders includes both symptomatic and functional components. Progress in understanding recovery requires careful replication and extension of findings using comparable measures. In the current paper, we present a study of five year recovery rates in an early intervention program in London, Canada with the same operational criteria as those used in a previous report from the OPUS cohort in Denmark. Our analysis extends the OPUS reports by including additional potential predictors of overall recovery, such as cognitive functioning, adherence to medication and early social support, and examining rates and predictors of individual components of recovery at five year follow-up. Consistent with reports from OPUS, we found younger age of onset and lower initial severity of negative symptoms to predict greater likelihood of overall recovery. Different patterns of predictors emerge when we examine individual components of recovery. Adherence to medication during the first year was the sole independent predictor of remission of positive symptoms, while early social adjustment and social support were more likely to predict negative symptom and functional aspects of recovery at five years. Cognitive functioning, as represented by IQ, did not predict any aspects of recovery. Our findings suggest the importance of examining the predictors of individual components in the quest to improve overall recovery.

Emergent, remitted and persistent psychosis-spectrum symptoms in 22q11.2 deletion syndrome

Individuals with 22q11.2 deletion syndrome (22q11DS) are at markedly elevated risk for schizophrenia-related disorders. Stability, emergence, remission and persistence of psychosis-spectrum symptoms were investigated longitudinally. Demographic, clinical and cognitive predictors of psychosis were assessed. Prospective follow-up over 2.8 years was undertaken in 75 individuals with 22q11DS aged 8–35 years. Mood, anxiety, attention-deficit hyperactivity disorders and psychosis-spectrum symptoms were assessed with the Kiddie-Schedule for Affective Disorders and Schizophrenia and Scale of Prodromal Symptoms (SOPS). Four domains of cognition were evaluated with the Penn Computerized Neurocognitive Battery (executive functioning, memory, complex cognition and social cognition). Psychotic disorder or clinically significant SOPS-positive ratings were consistently absent in 35%, emergent in 13%, remitted in 22% and persistent in 31% of participants. Negative symptoms and functional impairment were found to be predictive of the emergence of positive psychosis-spectrum symptoms and to reflect ongoing deficits after remission of positive symptoms. Dysphoric mood and anxiety were predictive of emergent and persistent-positive psychosis-spectrum symptoms. Lower baseline global cognition and greater global cognitive decline were predictive of psychosis-spectrum outcomes but no particular cognitive domain stood out as being significantly more discriminating than others. Our findings suggest that negative symptoms, functioning and dysphoric mood are important predictors of psychosis risk in this population.

Clinical Practice Guidelines for Management of Schizophrenia.

Clinical Practice Guidelines for Management of Schizophrenia.

Clozapine administration in clinical practice: once-daily versus divided dosing.

While it is recommended that clozapine be administered in a divided dosing regimen, it is unclear whether this recommendation is followed in real-world clinical practice. In two large datasets, we examined clozapine dosing frequency and patient characteristics across different dosing regimens. We conducted a cross-sectional survey, collecting data on patients receiving clozapine in August/September 2015 from the Centre for Addiction and Mental Health (CAMH) in Toronto, Canada, and The Zucker Hillside Hospital (ZHH) in New York, United States. Of 676 and 308 patients included in CAMH and ZHH datasets, clozapine was prescribed once daily in 75.1% and 74.4%, even though doses exceeding 200 mg/day were administered in 88.6% and 84.4% of the respective samples. No significant difference was found in the rates of positive symptom remission between once-daily vs. divided dosing (79.7% vs. 80.5%, P = 1.00). Higher clozapine dose and use of anticholinergic medications were significantly associated with divided dosing in both datasets. Older age or male gender was related to divided dosing in CAMH or ZHH dataset respectively. Despite the product monograph recommendation, clozapine is frequently prescribed once daily in North America. Further studies are needed to compare clinical outcomes between once-daily vs. divided clozapine dosing.

Therapeutic effectiveness and tolerability of aripiprazole as initial choice of treatment in first episode psychosis in an early intervention service: A one-year outcome study

IntroductionAripiprazole has been associated with a low prevalence of metabolic side effects as compared to other second generation antipsychotic (SGA) medications mostly in patients with long standing illness. The purpose of the present study was to assess specifically the effectiveness and safety of aripiprazole as a first choice for antipsychotic therapy for young patients presenting with a previously untreated first episode of a psychotic disorder (FEP). MethodsSeventy-three patients presenting with a FEP and with minimal prior exposure to antipsychotic medications were recruited to be part of an open label naturalistic outcome study using aripiprazole as the first choice of antipsychotic medication. Data on positive, negative and total symptom severity including general psychopathological symptoms, level of functioning and metabolic indices were collected prospectively over a one-year period. ResultsAs compared to baseline, patients treated with aripiprazole (mean dose 9.6mg) improved significantly on measures of positive (p<0.001), negative (p<0.001) and total severity-general psychopathology symptoms (p<0.001) and level of functioning (p<0.001). Seventy two percent of the participants achieved positive symptom remission and 50% achieved total remission (positive and negative) at one year of follow up. Unlike reports on patients with longer standing illness, significant weight gain (p<0.001) was observed, with 44% of participants experiencing >7% increase in body weight. ConclusionFEP patients starting treatment with aripiprazole improved on symptoms and social and occupational functioning. Aripiprazole was well tolerated except for a significant weight gain.

Clinical and cognitive insight in patients with acute-phase psychosis: Association with treatment and neuropsychological functioning

Background: The severity of psychopathology cannot fully explain deficits in the multi-dimensional construct of insight.Aims: The aim of this study was to evaluate the correlates and associations of clinical and cognitive insight in patients in an acute phase of psychosis and to analyse the impact of acute treatment on these variables.Methods: This study examined 47 inpatients who were recently hospitalized with acute exacerbation of schizophrenia. All subjects were assessed at both admission and discharge with the Positive and Negative Syndrome Scale (PANSS), Schedule for the Assessment of Insight-Expanded Version (SAI-E), Beck Cognitive Insight Scale (BCIS), and a neurocognition battery.Results: Patients with schizophrenia gained clinical insight after treatment. Cognitive insight did not change significantly after treatment. Insight showed significant negative correlations with positive symptoms and general psychopathology, but not with negative symptoms. Clinical insight was not associated with neuropsychological functioning in this cohort.Conclusion: Gaining clinical insight in the acute phase of illness was associated with the remission of positive symptoms, but not with neuropsychological functioning. Some significant correlations between clinical and cognitive insights were detected, which suggests that cognitive insight contributes to clinical insight but is not treatment-dependent. Long-term treatment may be required to understand the contribution of insight to the outcome of patients with schizophrenia.

Adolescent vs. adult onset of a first episode psychosis: Impact on remission of positive and negative symptoms

ObjectiveAdolescent-onset psychosis has traditionally been characterized as a more severe form of psychosis with a poorer prognosis. However, it is still unclear if patients with an adolescent-onset have worse symptom remission outcomes. Symptom remission is the principal clinical outcome known to predict quality of life and social functioning in the long term. The goal of this study is to clarify the influence of age of onset of psychosis on symptom remission in a sample of first-episode psychosis patients. MethodA total of 246 first-episode psychosis patients were recruited from a specialized early intervention program serving a defined epidemiological catchment area. Age of onset of psychosis (adolescence vs. adulthood) was used as the main predictor, and duration of untreated psychosis (DUP), baseline symptoms, baseline functioning, substance abuse diagnosis, medication adherence and gender were used as covariates in hierarchical regression models predicting the following positive and negative symptom remission outcomes: maximum continuous months in remission and early remission (i.e., occurring in the first three months of follow-up). ResultsAfter controlling for other variables, onset of psychosis in adulthood and shorter DUP predicted early remission of positive symptoms. This effect was stronger in patients with a diagnosis of a schizophrenia-spectrum disorder. Remission of negative symptoms did not depend on age of onset, and was only predicted by baseline negative symptoms. ConclusionPatients with onset of psychosis during adulthood are more likely to achieve early positive symptom remission than those with adolescent onset. This effect might be stronger in patients with a diagnosis of a schizophrenia-spectrum disorder.

Less is more Redux: Scheduled intermittent dosing to protect/prevent cognitive deterioration in schizophrenia

We propose a strategy of scheduled intermittent dosing in place of daily administration of antipsychotic medications for the treatment of patients with schizophrenia. Intermittent (extended) dosing has already been demonstrated to be at least equally effective as daily administration of antipsychotic medications. It is increasingly appreciated that remission of positive symptoms is not the same as recovery: a resumption of a productive and socially gratifying life. Our field has focused on positive symptoms to the exclusion of cognitive deterioration and emotional blunting. Dopamine is the primary neurotransmitter responsible for the accumulation and processing of new information as well as the expression of emotions modulated via the nucleus accumbens. Data suggests that patients receiving less accumulated antipsychotic agents do better over the years in achieving meaningful recoveries. In addition to clinical improvement, there is the financial benefit in giving less medication, which is often costly, over several decades. Finally, there is the possibility, albeit not yet demonstrated, that less accumulated antipsychotic agents might reduce the occurrence of significant weight gain, the metabolic syndrome, with its accompanying medical complications which not only impacts the quality of life and life expectancy of those who suffer from it, but also increases the financial burden to society.

Relationship of Cognition to Clinical Response in First-Episode Schizophrenia Spectrum Disorders.

First-episode schizophrenia (FES) spectrum disorders are associated with pronounced cognitive dysfunction across all domains. However, less is known about the course of cognitive functioning, following the first presentation of psychosis, and the relationship of cognition to clinical course during initial treatment. The present longitudinal study examined the magnitude of neurocognitive impairment, using the MATRICS Consensus Cognitive Battery, in patients experiencing their first episode of psychosis at baseline and after 12 weeks of randomized antipsychotic treatment with either aripiprazole or risperidone. At baseline, FES patients evidenced marked impairments in cognitive functioning. Notably, performance on the mazes task of planning and reasoning significantly predicted the likelihood of meeting stringent criteria for positive symptom remission during the first 12 weeks of the trial. Performance on indices of general cognitive function, working memory, and verbal learning improved over time, but these improvements were mediated by improvements in both positive and negative symptoms. We did not detect any differential effects of antipsychotic medication assignment (aripiprazole vs risperidone) on cognitive functioning. Our results suggest that a brief paper-and-pencil measure reflecting planning/reasoning abilities may index responsivity to antipsychotic medication. However, improvements in cognitive functioning over time were related to clinical symptom improvement, reflecting "pseudospecificity."

Relapse risk assessment in early phase psychosis: the search for a reliable and valid tool.

A significant advance in the field of mental health during the past 2 decades has been the recognition that early and optimal, phase-specific treatment of mental illness results in better clinical and functional outcome.1-4 A framework for SEI services for psychosis, focused on the critical period of the first 5 years following the onset of illness,5 and comprised of pharmacological and psychosocial interventions,6-9 has been shown to have superior effectiveness in comparison with routine care.10-12 Importantly, relatively high rates of symptomatic remission rates in response to early intervention and treatment have been reported.13 However, there is considerable variation in remission rates (24% to 82%), which may be attributed to variation in the criteria used for remission (for example, inclusion of remission of negative symptoms),14 duration of follow-up period,15 aspects of the multi-component treatments used,16 and possible pharmacological treatment options17 (for example, oral, compared with long-acting injectable) used.While remission of symptoms is an important early goal of treatment, the principal objective of treatment of early phase of psychosis should be to promote full recovery. Recently, there has been a more optimistic outlook on recovery generated from SEI services, as it is assumed that patients in the early phase are likely to have retained greater motivation and skills to engage in a process that could lead to full recovery in all dimensions.18, 19 Although recovery is defined on multiple dimensions,20-23 remission of symptoms still remains an important part of the road to recovery, whether guided by clinical, functional,14 or a patient's subjective perspective.23 However, one clinical barrier toward remission, and thus recovery, is the high rate of relapse and the lack of an assessment tool for identification of risk of relapse at this early phase of illness.Relapse in Early Phase PsychosisWhile remission rates are high and recovery is more tangible in early phase psychosis, a sobering statistic that clinicians, patients, and their families face is the relatively high rate of relapse during the first 5 years following initial treatment. In fact, in regular care, 80% of patients with a diagnosis of a first episode of schizophrenia have been reported to experience relapse, often multiple, within 5 years of treatment or remission from their index episode.24,25 Rates of relapse in SEI services are lower than that reported in regular care,26,27 but still remain a substantial barrier to recovery. These lower rates (20% to 30% during 2 years) may be, at least partly, associated with the better medication adherence rates27 achieved in these programs through better engagement in the multiple components of treatment provided. The significantly high risk of relapse, even with enhanced treatment offered in SEI services, exposes our lack of capacity to predict relapse with any degree of confidence. A reliable prediction of risk for relapse would ensure early intervention and thereby reduce the associated negative effects of relapse and improve overall outcomes.Why Is Relapse of Psychosis an Important Concern for Clinicians?Relapse in early phase psychosis can have significant consequences for patients and their families. The most obvious consequence of relapse is its relation to functional outcome through interruption of sustained remission. Indeed, length of remission of both positive and negative symptoms has recently been shown to be by far the most significant predictor of functional outcome (employment, school, and social relationships) at 1 and 2 years follow-up of patients with early phase psychosis.28 In the latter study, conducted on a large sample of patients with early phase psychosis in an SEI service, length of remission of negative symptoms contributed most to functional outcome at 1 year, while length of positive symptom remission played an even more significant role at 2 years. …

The relative contribution of cognition and symptomatic remission to functional outcome following treatment of a first episode of psychosis.

Functional recovery remains the primary goal following treatment of a psychotic disorder, especially after a first episode. Evidence regarding relative contributions of predictors of functional outcome, including symptoms and cognition, remains equivocal. The objective of the study was to determine the relative contribution of cognition, in particular verbal memory, and symptomatic remission to social and occupational functioning while controlling for established predictors of functioning in a large sample of patients presenting with a first episode of a schizophrenia spectrum or affective psychosis. Patients (aged 14-35 years) met DSM-IV criteria for a first episode of a schizophrenia spectrum or affective psychosis and had been admitted to the Prevention and Early Intervention Program for Psychoses, Montreal, Quebec, Canada, between 2003 and 2009 for treatment and follow-up for 2 years. Established predictors (duration of untreated psychosis, medication adherence, age at onset, substance use, premorbid adjustment), verbal memory, and length of positive and negative symptom remission were regressed on functioning (using the Strauss Carpenter Scale) at 1 (n = 208) and 2 (n = 159) years. Regressions were conducted with established predictors in the first step, followed by verbal memory and consecutive months of combined positive and negative symptom remission in the third step. Regressions were then repeated with length of positive and negative symptom remission, respectively. Length of combined positive and negative symptom remission explained the most variance in functioning at 1 (R² adjusted = 0.35, F₉,₁₂₉ = 9.33, P < .001) and 2 (R² adjusted = 0.38, F₉,₉₇ = 8.21, P < .001) years, and verbal memory contributed only slightly to such outcome. While length of remission of negative symptoms was a stronger predictor of functioning than remission of positive symptoms at 1 year, length of positive symptom remission also made a large contribution at 2 years. These results highlight the importance of achieving and maintaining remission of both negative and positive symptoms for longer periods in patients with a first episode of a psychotic disorder and the need for effective interventions to do so.

The prognostic significance of early remission of positive symptoms in first treated psychosis

We examine the relationship between achieving remission of positive symptoms within 3 months in first episode psychosis and outcomes 5 years later. Time to remission of positive symptoms, other early characteristics and 5 year outcomes were assessed in a prospective study of 132 patients being treated for the first time for a psychotic disorder. Just under 60% of patients showed remission of positive symptoms within 3 months. In comparison to later remitters, they showed lower levels of positive symptoms, greater likelihood of competitive employment and less likelihood of collecting a disability pension at 5 years. Earlier remission of positive symptoms may have prognostic significance for longer term outcomes.

Famotidine Augmentation in Schizophrenia: Hope or Hype?

J Clin Psychiatry 2013;74(9):e855–e858 (doi:10.4088/JCP.13f08707) © Copyright 2013 Physicians Postgraduate Press, Inc. A medication does not always result in the remission of positive symptoms in patients with schizophrenia. Furthermore, in many patients in whom positive symptoms substantially or completely remit, negative symptoms, cognitive disturbances, and other impairments often remain. Antipsychotic augmentation is one of many strategies to which clinicians turn in an attempt to reduce the burden of these residual symptoms, and famotidine is one of many unconventional augmentation agents that has been studied in this context. Histamine mechanisms may play a role in schizophrenia.1,2 Famotidine is a potent, selective histamine H2 receptor antagonist that poorly penetrates the blood-brain barrier.3,4 Although H2 receptors are present in the brain, there does not seem to be a strong argument made for the involvement of the H2 receptor in schizophrenia; nevertheless, many case reports and small open studies suggest that famotidine may improve outcomes in patients with schizophrenia.

Remission of positive symptoms according to the “remission in Schizophrenia Working Group” criteria: A longitudinal study of cognitive functioning

Schizophrenia patients in positive symptomatic remission (PSR; n=39) were assessed using a longitudinal research design. The patients were found to exhibit widespread cognitive impairments that were stable over the three-year follow-up period. The findings support a generalized and stable cognitive impairment profile among schizophrenia patients in partial symptomatic remission.

Interpersonal conflict strategies and their impact on positive symptom remission in persons aged 55 and older with schizophrenia spectrum disorders

Although interpersonal interactions are thought to affect psychopathology in schizophrenia, there is a paucity of data about how older adults with schizophrenia manage interpersonal conflicts. This paper examines interpersonal conflict strategies and their impact on positive symptom remission in older adults with schizophrenia spectrum disorders. The schizophrenia group consisted of 198 persons aged 55 years and over living in the community who developed schizophrenia before age 45. A community comparison group (n = 113) was recruited using randomly selected block-groups. Straus' Conflict Tactics Scale (CTS) was used to assess the ways that respondents handled interpersonal conflicts. Seven conflict management subscales were created based on a principal component analysis with equamax rotation of items from the CTS. The order of the frequency of the tactics that was used was similar for both the schizophrenia and community groups. Calm and Pray tactics were the most commonly used, and the Violent and Aggressive tactics were rarely utilized. In two separate logistic regression analysis, after controlling for confounding variables, positive symptom remission was found to be associated significantly with both the Calm and Pray subscales. The findings suggest that older persons with schizophrenia approximate normal distribution patterns of conflict management strategies and the most commonly used strategies are associated with positive symptom remission.

Differentiating schizoaffective and bipolar I disorder in first-episode psychotic mania

ObjectiveThis study aims to differentiate schizoaffective disorder (SAD) and bipolar-I-disorder (BD) in first-episode psychotic mania (FEPM). MethodsAll 134 patients from an epidemiological first-episode psychosis cohort (N=786) with FEPM and an 18-month follow-up final diagnosis of SAD (n=36) or BD (n=98) were assessed with respect to pre-treatment, baseline and outcome differences. Second, patients with baseline BD who shifted (shifted BD) or did not shift to SAD (stable BD) over the follow-up period were compared regarding pre-treatment and baseline differences. ResultsSAD patients displayed a significantly longer duration of untreated psychosis (DUP; effect size r=0.35), a higher illness-severity at baseline (r=0.20) and more traumatic events (Cramer-V=0.19). SAD patients displayed a significantly higher non-adherence rate (Cramer-V=0.19); controlling for time in treatment and respective baseline scores, SAD patients had significantly worse illness severity (CGI-S; partial η2=0.12) and psychosocial functioning (GAF; partial η2=0.07) at 18-months, while BD patients were more likely to achieve remission of positive symptoms (OR=4.9, 95% CI=1.8–13.3; p=0.002) and to be employed/occupied (OR=7.7, 95% CI=2.4–24.4, p=0.001). The main discriminator of stable and shifted BD was a longer DUP in patients shifting from BD to SAD. ConclusionsIt is difficult to distinguish BD with psychotic symptoms and SAD in patients presenting with FEPM. Longer DUP is related to SAD and to a shift from BD to SAD. Compared to BD, SAD had worse outcomes and higher rates of non-adherence with medication. Despite these differences, both diagnostic groups need careful dimensional assessment and monitoring of symptoms and functioning in order to choose the right treatment.

Moderated Online Social Therapy for Recovery From Early Psychosis

Moderated Online Social Therapy for Recovery From Early Psychosis

Impact of symptom resolution on medication adherence in first episode psychosis

Adequate adherence to medication confers benefits on patients with psychotic illness, but is difficult to achieve. Efficacy of medication influences adherence in patients in advanced phases of illness and may have a similar influence on patients with a first episode of psychosis (FEP). We assessed medication adherence and efficacy in 216 FEP patients at program entry and at 3 and 6months later. “Efficacy” was evaluated as the ability of medication to reduce positive or negative symptoms to below established thresholds for clinical remission at each evaluation. Adherence was defined as adequate (>75%) or not. Resolution of negative symptoms by month 3 of treatment was associated with inadequate adherence at months 3 and 6. In contrast, rapid resolution of positive symptoms showed no relationship to adherence. In a multivariate analysis taking into account other determinants of adherence in FEP, the role of early negative symptom remission was confirmed, and we found that a 3-month sustained remission of positive symptoms was associated with adequate adherence. Medication efficacy may promote adherence if it produces sustained remission of positive symptoms. However, many patients who benefit from medication, particularly those with rapid improvement of negative symptoms, fail to adhere to the treatment.

Apathy in first episode psychosis patients: One year follow up

Introduction This study describes how the negative subsyndrome of apathy develops over the first year in first episode psychosis (FEP) patients, with an emphasis on the prevalence of enduring apathy and the relationship between apathy, other symptoms and functioning. Methods Eighty four FEP patients were assessed both at baseline and after one year with the abridged clinical version of the Apathy Evaluation Scale (AES-C-Apathy). Other symptoms were assessed with the Positive and Negative syndrome scale (PANSS) and functioning with the split version of the Global Assessment of Functioning Scale (GAF-F). Results The mean level of AES-C-Apathy decreased from baseline to the one year follow up for the whole group of FEP patients. High levels of apathy at 1 year were best predicted by high levels of apathy at baseline, a long DUP and a diagnosis within the Schizophrenia spectrum. The presence of depression and level of medication only had a minor influence. AES-C-Apathy had a stronger association to GAF-F than other PANSS symptom areas. Twenty five (30%) FEP patients had high enduring levels of apathy. This group consisted of significantly more males, had a longer duration of untreated psychosis, a greater likelihood of a Schizophrenia spectrum diagnosis, fewer were in remission of positive symptoms and they had significantly poorer functioning at both baseline and follow up. Conclusion This study confirms that the negative subsyndrome of apathy is significantly related to poor functioning in FEP. Including negative symptoms and its subsyndromes in early detection strategies are warranted.