Experiences that matter in bipolar disorder: a qualitative study using the capability, comfort and calm framework.

BACKGROUND: When assessing the value of an intervention in bipolar disorder, researchers and clinicians often focus on metrics that quantify improvements to core diagnostic symptoms (e.g., mania). Providers often overlook or misunderstand the impact of treatment on life quality and function. We wanted to better characterize the shared experiences and obstacles of bipolar disorder within the United States from the patient's perspective. METHODS: We recruited 24 individuals diagnosed with bipolar disorder and six caretakers supporting someone with the condition. Participants were involved in treatment or support services for bipolar disorder in central Texas. As part of this qualitative study, participants discussed their everyday successes and obstacles related to living with bipolar disorder during personalized, open-ended interviews. Audio files were transcribed, and Nvivo software processed an initial thematic analysis. We then categorized themes into bipolar disorder-related obstacles that limit the patient's capability (i.e., function), comfort (i.e., relief from suffering) and calm (i.e., life disruption) (Liu et al., FebClin Orthop 475:315-317, 2017; Teisberg et al., MayAcad Med 95:682-685, 2020). We then discuss themes and suggest practical strategies that might improve the value of care for patients and their families. RESULTS: Issues regarding capability included the struggle to maintain identity, disruptions to meaningful employment, relationship loss and the unpredictable nature of bipolar disorder. Comfort related themes included the personal perception of diagnosis, social stigma and medication issues. Calm themes included managing dismissive doctors, finding the right psychotherapist and navigating financial burdens. CONCLUSIONS: Qualitative data from patients with bipolar disorder helps identify gaps in care or practical limitations to treatment. When we listen to these individuals, it is clear that treatments must also address the unmet psychosocial impacts of the condition to improve patient care, capability and calm.

Validity and severity thresholds for the depression subscale of the affective self rating scale: An equipercentile equating study using classical test theory.

BACKGROUND: The Affective Symptoms Scale (ASRS) is a unique instrument designed to separately measure depressive and manic symptoms in mood disorders. We validated the ASRS against the Patient Health Questionnaire (PHQ-9) and the Quick Inventory of Depressive Symptomatology (QIDS-16). METHODS: A retrospective study of 258 patients who completed the PHQ-9, QIDS-16 and ASRS as part of routine clinical care. To establish meaningful clinical thresholds for the depression subscale of the ASRS, it was equated with the QIDS and the PHQ-9. RESULTS: The depression subscale of the ASRS had significant positive correlations with the QIDS-16 and the PHQ-9 (respectively, r= 0.8, t[253] = 19.8, p < 0.001, and r= 0.8, t[245] = 28.2, p < 0.001). The equipercentile equating method with the PHQ-9 indicated that the thresholds corresponded to ASRS depression subscale scores of 5.4, 10.6, 16.1, and 23. Equating with the QIDS indicated that thresholds corresponded to ASRS depression subscale scores of 5.1, 11, 18.4, and 27.5. LIMITATIONS: Limitations include a small sample size that did not allow more detailed statistical analysis, such as Item Response Theory. The population is a heterogenous population at a university outpatient setting. CONCLUSIONS: The ASRS depression subscale significantly correlated with the PHQ-9 and QIDS-16. Our proposed threshold scores for the ASRS are 5, 11, 16 and 23 to indicated mild, moderate, severe and very severe depression respectively.

Functional MRI of sustained attention in bipolar mania.

We examined sustained attention deficits in bipolar disorder and associated changes in brain activation assessed by functional magnetic resonance imaging (fMRI). We hypothesized that relative to healthy participants, those with mania or mixed mania would (1) exhibit incremental decrements in sustained attention over time, (2) overactivate brain regions required for emotional processing and (3) progressively underactivate attentional regions of prefrontal cortex. Fifty participants with manic/mixed bipolar disorder (BP group) and 34 healthy comparison subjects (HC group) received an fMRI scan while performing a 15-min continuous performance task (CPT). The data were divided into three consecutive 5-min vigilance periods to analyze sustained attention. Composite brain activation maps indicated that both groups activated dorsal and ventral regions of an anterior-limbic network, but the BP group exhibited less activation over time relative to baseline. Consistent with hypotheses 1 and 2, the BP group showed a marginally greater behavioral CPT sustained attention decrement and more bilateral amygdala activation than the HC group, respectively. Instead of differential activation in prefrontal cortex over time, as predicted in hypothesis 3, the BP group progressively decreased activation in subcortical regions of striatum and thalamus relative to the HC group. These results suggest that regional activation decrements in dorsolateral prefrontal cortex accompany sustained attention decrements in both bipolar and healthy individuals. Stable amygdala overactivation across prolonged vigils may interfere with sustained attention and exacerbate attentional deficits in bipolar disorder. Differential striatal and thalamic deactivation in bipolar disorder is interpreted as a loss of amygdala (emotional brain) modulation by the ventrolateral prefrontal-subcortical circuit, which interferes with attentional maintenance.

Differential patterns of brain activation over time in adolescents with and without attention deficit hyperactivity disorder (ADHD) during performance of a sustained attention task.

OBJECTIVE: Recent morphometric studies suggest that children with ADHD may demonstrate differential or delayed brain development compared with children without ADHD. This study examines the developmental course of brain activation patterns during the performance of an attention task. METHOD: Ten adolescents with ADHD and 14 healthy comparison adolescents performed a continuous performance task in an fMRI twice, one year apart. RESULTS: In the absence of performance differences, children with ADHD and healthy comparison subjects activated frontal-parietal regions while performing an attention task at initial testing. Children with ADHD appeared to require continued use of the right middle frontal gyrus during administration of testing one year apart while healthy comparison subjects did not activate this region at the time of the second testing. CONCLUSIONS: There appear to be developmental differences in brain activation patterns on an attentional task between ADHD and healthy controls. More research is needed for examining the longitudinal course of functional brain activation in children with ADHD.

The influence of religious affiliation on time to first treatment and hospitalization.

UNLABELLED: Longer duration of untreated psychosis (DUP) has been associated with treatment-refractory illness, significant cognitive decline, and poorer long-term outcomes. There are many factors, including social and cultural, that promote longer DUP. To date, there have been no studies to evaluate religion's effect on DUP. In this study, we evaluated the effect of certain religious affiliations and degree of religious practice on the DUP. METHODS: A total of 195 patients were recruited aged 18 to 45 years with the presence of at least 1 psychotic symptom (delusions, hallucinations, or prominent thought disorder). Patients were evaluated on their religious practice prior to the index episode using a Likert-style scale. Using a similar scale, patients were asked about their religious affiliation categorized as Catholic, Protestant, or neither. RESULTS: Correlational analysis revealed that the time to first treatment and time to first hospitalization were both was negatively related to degree of religious practice (r = -0.15, N = 161, p < 0.05 and r = -0.18, N = 161, p < 0.05, respectively). Between-group comparisons revealed longer DUP in the Protestant group compared to the no affiliation and Catholic groups (p = 0.05). CONCLUSION: From our results, it appears that the degree of religious practice does not affect length of time to treatment in psychotic patients. However, having a Protestant religious affiliation is strongly associated with having a greater delay in treatment seeking for psychosis. Factors contributing to a longer DUP in this group warrant further study.

The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings.

The authors review existing structural and functional neuroimaging studies of patients with bipolar disorder and discuss how these investigations enhance our understanding of the neurophysiology of this illness. Findings from structural magnetic resonance imaging (MRI) studies suggest that some abnormalities, such as those in prefrontal cortical areas (SGPFC), striatum and amygdala exist early in the course of illness and, therefore, potentially, predate illness onset. In contrast, other abnormalities, such as those found in the cerebellar vermis, lateral ventricles and other prefrontal regions (eg, left inferior), appear to develop with repeated affective episodes, and may represent the effects of illness progression and associated factors. Magnetic resonance spectroscopy investigations have revealed abnormalities of membrane and second messenger metabolism, as well as bioenergetics, in striatum and prefrontal cortex. Functional imaging studies report activation differences between bipolar and healthy controls in these same anterior limibic regions. Together, these studies support a model of bipolar disorder that involves dysfunction within subcortical (striatal-thalamic)-prefrontal networks and the associated limbic modulating regions (amygdala, midline cerebellum). These studies suggest that, in bipolar disorder, there may be diminished prefrontal modulation of subcortical and medial temporal structures within the anterior limbic network (eg, amygdala, anterior striatum and thalamus) that results in dysregulation of mood. Future prospective and longitudinal studies focusing on these specific relationships are necessary to clarify the functional neuroanatomy of bipolar disorder.

Age-related changes in regional activation during working memory in young adults: an fMRI study.

Several lines of evidence suggest that working memory diminishes with advancing age, with concomitant functional changes in associated neuronal activation in frontal cortical regions and hippocampi. No studies to date, however, have investigated age-related changes in neuronal activation in these regions during performance of a working memory task in younger subjects without working memory deficits. In this study, we utilized fMRI to examine changes in brain activation with increasing age in specific regions-of-interest. Eleven healthy subjects performed a "two-back" working memory task and a matched "zero-back" attention task during fMRI. There was no association between age and performance on either task. Left hippocampal activation significantly correlated with age (P = 0.01) and right hippocampal activation showed an association with age (P = 0.09). This study demonstrates that increasing age is associated with increased activation of hippocampus even in young patients without evidence of working memory deficits and suggests that functional changes may precede overt evidence of working memory deficits.

Changes in neuronal activation with increasing attention demand in healthy volunteers: an fMRI study.

Several lines of evidence suggest that structures involved in mediating attention differentially respond to increasing processing demand. Investigation of differences in neuronal activation, however, has been complicated by methodological inconsistencies and concomitant discrepancies in degree of difficulty and subject effort between disparate tasks. In this study, we utilized fMRI to compare neural activation patterns associated with two related attention tasks associated with different degrees of processing load while controlling for degree of performance difficulty. Healthy volunteers performed two continuous performance tasks, utilizing an identical pairs paradigm (CPT-IP) and a matched simple number recognition paradigm with degraded stimuli (CPT-DS) during a single fMRI scan. Degree of stimulus resolution degradation in the latter CPT was designed to equalize degree of performance difficulty between the two tasks. CPT-IP and CPT-DS were both associated with activation of frontal, limbic, subcortical, and sensory integratory structures. CPT-IP administration was associated with significantly greater activation of left dorsolateral prefrontal cortex, bilateral posterior temporal cortex, bilateral putamen, and thalamus. This study demonstrates both that differing attention tasks are associated with a high degree of functional overlap and that increasing processing demand is associated with increased activation of specific portions of attentional networks.

Reaction time measures of sustained attention differentiate bipolar disorder from schizophrenia.

Although continuous performance tasks (CPTs) are becoming more common in psychiatric research, it remains unclear which performance measures best differentiate psychiatric patient groups and along which psychological dimensions. To address this the authors examined sustained attention decrements in patients with bipolar disorder and schizophrenia using CPT measures of perceptual sensitivity, response bias, and psychomotor processing speed. Patients with bipolar disorder with psychotic features (N=20), schizophrenia (N=20), and healthy controls (N=20) were evaluated using structured clinical interviews. These patients were rated with the Scale for the Assessment of Positive Symptoms and the Young Mania Rating Scale before completing a degraded-stimulus version of the CPT. Psychomotor processing speed was the only measure that reliably differentiated the groups across the entire vigilance period and was the strongest predictor of group membership. These findings suggest that reaction time measures may be sensitive to differences in the sustained attention abilities of patients with bipolar disorder and schizophrenia. By incorporating reaction time measures into CPT assessments, discriminant ability may be enhanced.

Comparative efficacy and tolerability of drug treatments for bipolar disorder.

Lithium has been the backbone of treatment for bipolar disorder for several decades, although recent advances have identified a number of other medications that have efficacy in treating various phases of the illness. These include the antiepileptic drugs valproate semisodium (divalproex sodium) and carbamazepine and some new antiepileptic drugs (e.g. lamotrigine and topiramate), and the atypical antipsychotics (e.g. olanzapine, clozapine and risperidone). Conventional antipsychotics continue to be used frequently in bipolar disorder, although they may be somewhat less effective than other treatments. Otherwise, to date, none of these treatments have been shown to be consistently more effective than any other, so that drug adverse effects and tolerability often dictate which agents are used in an individual patient. Drugs commonly used for the treatment of bipolar disorder are generally tolerated by most patients in large samples. However, the unique adverse effect signature of a drug will often suggest that it will be less tolerable in some patients than in others. Identifying a specific treatment for a specific patient requires a careful individualised assessment of the risk of adverse effects for that patient's unique circumstances.

Behavioral sensitization in humans.

Behavioral sensitization is the process whereby repeated, intermittent stimulant administration produces a progressively greater and enduring behavioral response. For over two decades, behavioral sensitization has been reliably demonstrated in a number of different animal species and has been proposed as a model for the development of stimulant dependence. However, the application of this model to humans is limited since there have been relatively few studies of sensitization in human subjects. Nonetheless, results from these studies suggest that, similar to animal studies, enhanced behavioral responses do occur following repeated stimulant administration that resemble sensitization. Further research is necessary to examine characteristics of sensitization in humans, including the neurobiological systems involved.

Human response to repeated low-dose d-amphetamine: evidence for behavioral enhancement and tolerance.

Previously, we reported progressively greater behavioral responses to repeated d-amphetamine in human subjects that represented a potential model of behavioral sensitization. To extend this work, 59 healthy volunteers were randomly assigned to one of three protocols: (1) placebo administered on days 1, 3, and 5 (PPP); (2) placebo administered on days 1 and 3, and d-amphetamine (0.25 mg/kg) on day 5 (PPA); and (3) d-amphetamine administered on days 1, 3, and 5 (AAA). Comparisons were made among the three groups to determine whether repeated d-amphetamine produced an increased behavioral response. Subjective ratings of vigor and euphoria exhibited the greatest response following the third dose of the AAA group, as hypothesized. In contrast, drug liking was greatest following a single or first d-amphetamine dose. These effects were greater in women. Progressive changes in subjective responses following repeated d-amphetamine administration may occur in healthy human subjects, although this effect may be greater for women.

D3 dopamine receptor, behavioral sensitization, and psychosis.

Behavioral sensitization is a progressive, enduring enhancement of behaviors that develops following repeated stimulant administration. It is mediated in part by dopaminergic pathways that also modulate a number of psychiatric conditions including the development of psychosis. We propose that down-regulation of D3 dopamine receptor function in critical brain regions contributes to sensitization. Rodent locomotion, a sensitizable behavior, is regulated by the opposing influence of dopamine receptor subtypes, with D3 stimulation opposing concurrent D1 and D2 receptor activation. The D3 dopamine receptor has a 70-fold greater affinity for dopamine than D1 or D2 dopamine receptors. This imbalance in ligand affinity dictates greater occupancy for D3 than D1 or D2 receptors at typical dopamine concentrations following stimulant drug administration, resulting in differences in the relative tolerance at D3 vs D1 and D2 receptors. Sensitization may therefore result in part from accommodation of the inhibitory D3 receptor 'brake' on D1/D2 mediated behaviors, leading to a progressive locomotion increase following repeated stimulant exposure. The requirement for differential tolerance at D3 vs D1 and D2 receptors may explain the observed development of sensitization following application of cocaine, but not amphetamine, directly into nucleus accumbens. If correct, the 'D3 Dopamine Receptor Hypothesis' suggests D3 antagonists could prevent sensitization, and may interrupt the development of psychosis when administered during the prodromal phase of psychotic illness. Additional study is needed to clarify the role of the D3 dopamine receptor in sensitization and psychosis.

Verbal fluency in mania: relationship to number of manic episodes.

OBJECTIVE: The objective of this study was to examine verbal fluency in a group of patients with bipolar disorder (BPD) during an acute episode of mania, and to determine whether performance was related to disease chronicity. We hypothesized that manic patients with BPD would be impaired on verbal fluency, and that this impairment would be greatest in those individuals who had experienced a greater number of manic episodes. METHOD: Forty-five manic inpatients with bipolar disorder, and 30 healthy volunteers completed tests of phonemic and semantic verbal fluency. The patients were dichotomized into those experiencing their first episode of mania (FE) and those who had experienced multiple episodes (ME). RESULTS: On the phonemic fluency task, ME patients produced significantly fewer words than both healthy volunteers and FE patients, and they made a greater number of errors. No significant group differences in overall output were found on the semantic fluency task, although the ME group was more error-prone than were the other groups. CONCLUSIONS: These findings suggest that verbal fluency is more impaired in ME patients than in patients who have experienced only a single manic episode.

A double-blind, randomized, prospective evaluation of the efficacy and safety of risperidone versus haloperidol in the treatment of schizoaffective disorder.

The relative efficacy and safety of risperidone versus haloperidol in the treatment of schizoaffective disorder was studied. Sixty-two patients (29 depressed type; 33 bipolar type) entered a three-site, randomized, double-blind, 6-week trial of risperidone (up to 10 mg/day) or haloperidol (up to 20 mg/day). Trained raters assessed baseline, weekly, and end-of-study levels of psychopathology with the Positive and Negative Syndrome Scale (PANSS), the 24-item Hamilton Rating Scale for Depression (HAM-D-24) and the Clinician-Administered Rating Scale for Mania (CARS-M). The authors were unable to statistically distinguish between risperidone and haloperidol in the amelioration of psychotic and manic symptoms. In addition, there was no difference in worsening of mania between the two agents in either subgroup (i.e., depressed or bipolar subgroups). For the total PANSS, risperidone produced a mean decrease of 16 points from baseline compared with a 14-point decrease with haloperidol. For the total CARS-M scale, risperidone and haloperidol produced mean change scores of 5 and 8 points, respectively, and for the CARS-M Mania subscale, 3 and 7 points, respectively. Additionally, risperidone produced a mean decrease of 13 points from the baseline 24-item HAM-D, compared with an 8-point decrease with haloperidol. In those patients who had more severe depressive symptoms (i.e., HAM-D baseline score >20), risperidone produced at least a 50% mean improvement in 12 (75%) of 16 patients in comparison to 8 (38%) of 21 patients receiving haloperidol. Haloperidol produced significantly more extrapyramidal side effects and resulted in more dropouts caused by any side effect. There was no difference between risperidone and haloperidol in reducing both psychotic and manic symptoms in this group of patients with schizoaffective disorder. Risperidone did not demonstrate a propensity to precipitate mania and was better tolerated than haloperidol. In those subjects with higher baseline HAM-D scores (i.e., >20), risperidone produced a greater improvement in depressive symptoms than haloperidol.

Health-related quality of well-being in chronically hospitalized patients with schizophrenia: comparison with matched outpatients.

Quantifying the functional consequences of illness in terms of quality of life can enhance our understanding of both mental and physical disorders. However, little is known about the quality of life among older inpatients vs. outpatients with schizophrenia. We present the results of health-related quality of life assessments in 54 middle-aged and elderly long-term inpatients with schizophrenia and a demographically matched outpatient sample. Assessments were performed using the Quality of Well-Being (QWB) scale, along with standard measures of psychopathology and global cognitive impairment. Compared with outpatients, the inpatients had a significantly lower health-related quality of life, as measured by the QWB. In the inpatient and outpatient groups, higher levels of positive symptoms were associated with lower health-related quality of life. Health-related quality of life remained fairly stable among the inpatients who remained hospitalized over 6 months. In both inpatients and outpatients, baseline cognitive status and psychopathology predicted QWB scores at the 6-month follow-up. These findings further support the use of the QWB in severely mentally ill populations; implications for improving health-related quality of life among older patients with schizophrenia are discussed.

Frequency and severity of religious delusions in Christian patients with psychosis.

The influence of religious activity on the severity of religious delusions is unclear. This study examined whether Catholic and Protestant patients experienced more religious delusions than non-religiously affiliated patients. We also explored whether the severity of religious delusions, according to the Religious Delusions item on the Scale for the Assessment of Positive Symptoms (SAPS), was associated with the amount of religious activity. The Protestants experienced more religious delusions than Catholics and those without religious affiliation. Although when the groups were combined, patients who were more religiously active experienced more severe religious delusions (n=133), there was no difference in the severity of religious delusions across the non-religious, Catholic and Protestant groups. Religious affiliation may influence the frequency of religious delusions, particularly in Protestant individuals, but religious affiliation appears to be independent of religious delusion severity.

Persistent attentional dysfunction in remitted bipolar disorder.

OBJECTIVES: Although previous research has shown that attentional dysfunction is common during acute mood episodes in individuals with bipolar disorder (BPD), few studies have examined whether attentional deficits are evident during periods of symptom stability. The goal of this study was to determine whether clinically stable individuals with BPD would have attentional disturbances relative to healthy subjects. METHODS: Fourteen patients with BPD and 12 healthy comparison subjects participated in the study, and were administered the Degraded Stimulus Continuous Performance Test (DSCPT), Digit Span Distractibility Test (DSDT) and Grooved Pegboard Test (GPT). Psychiatric symptoms were assessed with the Young Mania Rating Scale and the Scale for the Assessment of Positive Symptoms. Medication side effects were measured with the Simpson Rating Scale. RESULTS: The patient group responded significantly more slowly than the control group on the DSCPT (z = -2.52, p = 0.01) and the GPT (z = -3.37, p = 0.001). There was a trend towards the BPD patients demonstrating impaired perceptual sensitivity on the DSCPT (z = 1.68, p = 0.09). The two groups did not differ on the DSDT (z = -1.06, p = 0.3). Poor performance on the GPT and DSCPT target reaction time were not associated with symptom ratings or medications. CONCLUSION: The findings suggest that impairments in fine motor skills and reaction time may be present in clinically stable patients with BPD, even after accounting for psychiatric symptoms and medication effects. Performance decrements on attentional tasks may be in part reflective of motor impairments in patients with BPD.

Prior stimulant treatment in adolescents with bipolar disorder: association with age at onset.

OBJECTIVES: To compare demographic and clinical characteristics between bipolar adolescents with and without a history of stimulant treatment, we hypothesized that adolescents treated with stimulants would have an earlier age at onset of bipolar disorder, independent of co-occurring attention-deficit-hyperactivity disorder (ADHD). METHOD: Thirty-four adolescents hospitalized with mania were assessed using the Washington University at St Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS). We systematically evaluated age at onset of bipolar disorder and pharmacological treatment history. RESULTS: Bipolar adolescents with a history of stimulant exposure prior to the onset of bipolar disorder had an earlier age at onset of bipolar disorder than those without prior stimulant exposure. Additionally, bipolar adolescents treated with at least two stimulant medications had a younger age at onset compared with those who were treated with one stimulant. There was no difference in age at onset of bipolar disorder between bipolar adolescents with and without ADHD. CONCLUSIONS: Our results suggest that stimulant treatment, independent of ADHD, is associated with younger age at onset of bipolar disorder. A behavioral sensitization model is proposed to explain our findings. There are several limitations to our study including the small sample size, the retrospective assessment of stimulant exposure and age at onset of bipolar disorder, and the inclusion of only hospitalized patients, who may be more likely to present with a severe illness. Nonetheless, future prospective longitudinal investigations that systematically assess the effects of stimulant medications in children with or at genetic risk for bipolar disorder are warranted.

A pilot study of rapid lithium administration in the treatment of acute mania.

OBJECTIVES: The use of rapid lithium dosage administration, a strategy that could lead to rapid improvement in mania, has been largely unexamined. In this open-label, pilot, acute-treatment study, we sought to determine the safety and tolerability of lithium administered at 20 mg/ kg/day. A secondary aim was to provide preliminary data regarding the efficacy of this strategy in ameliorating manic, depressive, and psychotic symptoms. METHODS: Fifteen patients hospitalized with DSM-IV bipolar disorder, manic or mixed, and who provided written informed consent, received lithium 20 mg/kg/day for up to 10 days. Patients were evaluated for adverse effects daily. Lithium levels were obtained on days 2, 3, 4, 5, 7, and 10 or at study termination. Electrocardiograms (EKGs) were performed at baseline and on days 1-5, 7, and 10 or at study termination. Symptomatic improvement was assessed daily using the Young Mania Rating Scale, 24-item Hamilton Depression Rating Scale, and the Scale for Assessment of Positive Symptoms (SAPS). RESULTS: Five of the 15 patients completed the 10-day study period. Two patients dropped out due to adverse events. Seven patients did not complete the inpatient trial because of improvement sufficient to allow hospital discharge. All patients achieved serum lithium concentrations > or =0.6 mEq/L after 1 day of treatment; the mean + SD concentration on day 5 was 1.1 (+/- 0.1) mEq/L on day 5. There were significant reductions from baseline to endpoint on all rating scales, except the SAPS bizarre behavior subscale. CONCLUSIONS: These pilot data suggest that lithium 20 mg/kg/day was well tolerated and that this strategy may produce rapid improvement in affective and psychotic symptoms. These impressions require confirmation in double-blind, randomized trials.