By E. Jensgar. Texas A&M University.

Other retrospective analyses have re- pressant starts were increasing or decreasing during the ported similar natural course of therapy findings but base study interval discount nortriptyline 25 mg on-line, or how a secular cost trend order nortriptyline 25 mg mastercard, if present nortriptyline 25mg low price, may a judgment of cost-effectiveness on finding a reduction in have interacted with the distribution of starts of individual overall 'depression-related' health care costs (42 purchase 25mg nortriptyline with visa,43). We briefly review the designs and results of available Other important limitations in the studies in Table 78. The first study comparing a newer non-SSRI with control antidepres- three studies, which sampled data from 1989 to 1994, found sants. These tables indicate for each study the sample size fluoxetine to be more cost-effective than sertraline or more in the administrative database, the time interval over which cost-effective than sertraline and paroxetine. A type of selec- data were sampled, the type of patient population, the newer tion bias that has been termed launch bias may have affected and control antidepressants analyzed, the stated principal these findings (46). The time frames of these studies over- economic outcome measure, the overall results on that out- lapped with the first year or two after launch of sertraline come measure as interpreted by the authors, and a brief and paroxetine. It is possible that a new antidepressant is discussion of methodologic limitations. One small pilot prescribed for a different type of patient in the early years study is not included in Table 78. Patients selected by their physicians to receive portedly found fluoxetine to be cost-effective in comparison a brand-new antidepressant may generally be more severely with TCAs (Skaer et al. Recent analyses have attempted to Simple vote counting across the studies in Table 78. However, another possibility is shows that the majority have concluded that SSRIs are more that patients selected by their prescribers to receive a brand- cost-effective than TCAs (seven favor at least one of the new antidepressant may on average have been more resistant studied SSRIs, none favor TCAs, and five are ties). Because treat- simple vote counting is unsatisfactory because these studies ment resistance correlates only partially with severity, ad- are subject to numerous methodologic limitations. The most important limitation of the studies in Table justment for severity of illness may only partially correct a 78. Most stud- different antidepressants may have changed during the ies attempting to control for previous treatment eliminate study interval (40,45). During this time period, important patients who received antidepressants in the 4 to 6 months influences on clinical practice totally unrelated to which before the start of the index antidepressant. Although this antidepressant was used may have changed, so that the influ- exclusion is somewhat reassuring, it still does not prevent ence of starts on one type of antidepressant versus another patients frombeing included in the analysis who were taking may have been confounded with the effect of changes in an antidepressant at the start of the study interval, then clinical influences. For example, during the period encom- stopped antidepressant therapy for 4 to 6 months, perhaps passed by the first study in Table 78. Such pa- care organizations independently reduced expenditures tients would be predicted to be relatively unlikely to respond through tighter management. Thus, a higher proportion of to treatment and relatively likely to incur treatment costs TCA starts may have occurred early in the study period, subsequent to the antidepressant start. To the extent that 1131 1132 Neuropsychopharmacology: The Fifth Generation of Progress TABLE 78. Are the patients who consent to random to DSM-IV 296. This assignment representative of the entire group of patients in restriction was intended to reduce the possibility of a selec- routine practice, or are they different in some important tion bias if the patients chosen to receive the newest medica- way? Relatively little attention has been paid to this issue tions were more refractory as a group than patients chosen in depression research, although in one study, the patients to receive more established medications. This possibility participating in a randomized trial of depression had signifi- may still have influenced the analysis because in subsequent cantly fewer comorbid diagnoses than did excluded patients studies, it was found that some patients with 'single-epi- and were more likely to have a single episode of depression sode' depression had had previous episodes that were (27). At present, only two prospective pharmacoeconomic The fourth study in Table 78. The initial report study, the time horizon (1995 through 1996) was 3 to 4 fromthe first study included data up to 6 months after years after the launch of sertraline and paroxetine. Patients were followed for 2 years after study found the three SSRIs to be equally cost-effective. Patients were enrolled fromparticipating pri- other newer non-SSRI antidepressants are similar to SSRIs mary care clinics in a large HMO in the United States. Patient out-of-pocket copayment prescription expenses The retrospective database method may be especially vul- were waived. Patient identification depended on primary nerable to publication bias. Because the retrospective studies care physician referral. Physicians were asked to refer pa- are inexpensive in comparison with prospective trials, and tients whomthey were starting on an antidepressant for because the number of potential study sites is large, the depression when both patient and physician were willing possibility is greater with retrospective studies that multiple to consider randomassignment. Of 621 patients referred, analyses are conducted but only a limited number pub- 579 (93%) were eligible, and 536 (93%) consented and lished. At baseline, 67% of randomized patients met DSM-III-R criteria for major depression; the remainder met criteria for either minor depression or dysthymia. The PROSPECTIVE COST-EFFECTIVENESS average score on the Hamilton Depression Scale at baseline TRIALS was below 14. Patients were randomly assigned to receive fluoxetine (N 173) or the commonly prescribed TCAs Prospective randomized cost-effectiveness experiments offer imipramine (N 182) or desipramine (N 181). After a potential 'gold standard' methodology for investigating randomization, the patients were free to switch antidepres- cost-effectiveness because of the internal validity arising sants.

These studies ported in depressed and suicidal patients with some sugges- have yielded mixed results suggesting that pindolol may tion that increased binding in suicidal patients may be inde- hasten response to antidepressants in milder or first-episode pendent of a diagnosis of major depression (51–53) buy nortriptyline 25 mg lowest price. As with the serotonin transporter buy nortriptyline 25mg lowest price, results here activity in suicide victims (66–68) nortriptyline 25mg cheap. GeneticStudies 5HT2a receptors are found in frontal cortex suggesting a A number of studies have explored the possible role of ge- role in the cognitive aspects of depression order 25mg nortriptyline visa. PET ligands have been developed to study 5HT2a activity 18 Long and short forms of the transporter gene appear to be in brain. One study employed [ F]- altanserin and reported relatively common in the general population. An early study a reduction in activity in right posterolateral frontal, orbito- indicated a relationship of the short form with an increased frontal, and anterior cingulate regions in depressives (58). In another study, no differences were found between nonsu- 18 Allelic variation has also been applied to predicting drug icidal depressives and controls using [ F-] setoperone (59). In three studies in Europe and the United States, The exclusion of patients with recent suicidal ideation may homozygotes or heterozygotes for the S-form were reported have played a role in not finding differences between pa- to show sluggish responses to SSRIs (70–72). Studies on effects of antidepressants on was found in a Korean study (73). Clearly, further work is 5HT2a binding using PET have also yielded mix results. More recently, Mann perone binding (60), whereas another recently reported that and colleagues (69) reported that the short form genotype 3 to 4 weeks of desipramine treatment resulted in a signifi- was associated with a diagnosis of major depression but not cant decrease in 5HT2 activity in multiple areas, particularly with suicide or 5HT-transporter binding in postmortem in frontal cortex (61). Depletion Studies 5HT2A receptors are coupled to the phosphoinositide second messenger system. When 5HT2a receptors are acti- Brain concentrations of serotonin are highly dependent on vated by agonists, phosphatidyl inositol 4,5 bisphosphate is circulating levels of tryptophan, which competes with other Chapter 72: Molecular and Cellular Mechanisms in Depression 1043 amino acids for transport into the brain. Charney and Del- theories of depression, DA has been emphasized far less in gado have pioneered in the use of an amino acid cocktail depression in spite of its being widely distributed in brain. In these lite, are decreased in depressives (2,85,86), although some studies, the drink was first administered to subjects who had studies have reported elevated CSF DA, but not HVA levels responded to various antidepressants and who were being (87). Urinary DOPAC levels are decreased in depressives maintained on medication. Diphenhydramine has been compared with controls (88); in one study, DOPAC levels commonly used as the comparison cocktail. Euthymic pa- appeared associated with suicidal behavior (85). Dopami- tients on SSRIs but not TCAs rapidly experienced depres- nergic agents such as psychostimulants, nomifensine, and sive symptoms when depleted of L-tryptophan, suggesting the dopamine agonist pramipexole all have antidepressant the need for maintaining adequate serotonin levels to ensure effects in nondelusional patients. Parallel decreases in glu- In contrast, elevated mesolimbic DA activity has been cose utilization in frontal and thalamic regions using PET hypothesized to play a role in delusional depression (89). In contrast, there are multiple chotic symptoms and agitation in major depression (89), reports of depletion not causing a clear recurrence of symp- and increased plasma DA and HVA levels have also been toms in patients treated with bupropion or electroconvul- reported in delusional depression (90,91). Studies have used a variety of dif- limbic DA activity has been postulated to occur secondary ferent methods (e. Recent studies in rats, nonhuman primates, and differences may account for the discrepant findings. The psychotic depressives suggest elevated glucocorticoid activ- degree and duration of response observed before the deple- ity could also result in altered or decreased prefrontal corti- tion challenge is administered may be of particular impor- cal dopamine metabolism and to alterations in attention tance (79). Patients who are in remission or have shown a and response inhibition (92,93). These data suggest in- prolonged response are unlikely to demonstrate significant creased HPA axis activity could affect DA turnover differ- worsening of moods (79). These data suggest recent re- ently in specific brain regions—alterations that have been sponders are those who are susceptible to experiencing re- suggested in schizophrenia. Antipsychotic drugs appear to lapse with depletion strategies. Depletion of unmedicated play a key role in treatment of delusional depression and euthymic depressives does not appear to induce recurrence, glucocorticoid receptor antagonists are being actively stud- indicating maintaining serotonin tone is important primar- ied in the disorder. Of interest is a recent report that women controls show GABA much lower rates of 5HT synthesis and a greater decrease in response to depletion than men do (80). This gender- GABA has become a focus of greater study over the past based difference is consistent with a recent observation that several years with the increasing use of anticonvulsants in chronically depressed women are more responsive to an mood disorders. GABA is a major inhibitory neurotransmit- SSRIthan men are (81). There are two types of Fenfluramine Challenge GABA receptors.

Neuropsychophar- entiated by agonist and antagonist binding—an autoradio- macology 1997;16:162–173 buy cheap nortriptyline 25 mg line. Plasma norepinephrine level major depression—postmortem evidence for decreased seroto- in affective disorders: relationship to melancholia discount nortriptyline 25mg on-line. Corticotropic- and depression: toward a unified hypothesis of cortico-striato- releasing hormone and serotonin interact in the human brain- pallido-thalamic function buy discount nortriptyline 25mg online. Discovery of the antidepressant and sustained administration of selective serotonin reuptake inhibi- anti-emetic efficacy of substance P receptor (NK1) antagonists purchase 25 mg nortriptyline fast delivery. Afferent connections of the tegmental area of the rat. Lack of behavioral areas of the brain measured by microdialysis. Brain Res 1999; effects of monoamine depletion in healthy subjects. The catecholamine hypothesis of affective disor- area histopathology with adult dementia. Arch Neurol 1988;45: ders: a review of supporting evidence. Repeated admin- ent alpha-noradrenergic receptor binding sites in rat brain: effect istration of desmethylimipramine blocks reserpine-induced in- of 6-hydroxydopamine. Possible role of dopamine release of corticotropin-releasing factor. Brain Res 1991;555: D1 receptor in the behavioural supersensitivity to dopamine 25–34. Clinical and psycho- leus, the nucleus of the solitary tract and the periaqueductal metric correlates of dopamine D2 binding in depression. Reduction of substance P after chronic antidepressants treatment in the releasing factor-containing axon terminals synapse onto cate- striatum, substantia nigra and amygdala of the rat. Brain Res cholamine dendrites and may presynaptically modulate other 1996;739:70–78. Br J Pharmacol 1998;123: cotropin-releasing factor targets locus ceruleus dendrites: sub- 746–752. In: Usdin E, et al, release in the locus ceruleus of conscious rats. New evidence of serotonin-deficient depres- neurochemical changes: An alternative explanaion for the origi- sions. Sympathetic nervous system mal models in human psychobiology. New York: Plenum, 1976: activity in major depression: basal and desipramine-induced al- 133–145. Projections of the dorsal raphe nucleus to Neurol 1997;382:394–400. Dopamine and depression: a review of recent evi- 340:11–26. Dopamine and depression: a review of recent evi- 'D1-like'- 'D2-like' interactions and 'D1-like' receptors not dence. Comparative expression in the locus ceruleus of depression-model rats and localization of serotonin 1A, 1C, and 2 receptor subtype rats exposed to short-and long-term forced walking stress. GABAergic innervation of sero- stimulation: stress and desmethylimipramine. Prog Neuropsycho- tonergic neurons in the dorsal raphe nucleus of the rat studied pharmacol Biol Psychiatry 1984;8:601–606. Is the caudomedial shell of the nucleus accumbens 1992;29:943–948. MINTUN With advances in imaging technology it is now possible precision. Initially primarily focused on older subjects, to examine subtle changes in both structure and regional structural studies have found both generalized and localized function that are associated with the pathophysiology of structural brain changes in major depression and bipolar affective illness. Understanding how these changes fit to- disorder across the age spectrum. Combining Recurrent Unipolar Major Depression anatomic MRI studies with functional studies has improved Studies of neuroanatomic structure in early-onset recurrent the localization of abnormalities in blood flow, metabolism, depression (EORD) have recently found evidence for and neurotransmitter receptor function and has the poten- depression-associated structural change (Table 74. Brain tial to provide a better-integrated model of depression. They comprise a neuroanatomic cir- clinical and treatment applications. In this chapter we re- cuit, which has been termed the limbic–cortical–stria- view studies of structural brain changes associated with tal–pallidal–thalamic (LCSPT) circuit (21).

Nevertheless generic nortriptyline 25 mg with visa, LSD remains a dangerous drug and use for any purpose is strongly discouraged generic 25 mg nortriptyline with amex. LSD was synthesised during medical research for a benign ergot derivative cheap nortriptyline 25 mg without prescription. Hallucinogens alter perception and mood without disorientation or memory disturbance (Abraham 25mg nortriptyline for sale, 2000). They bind strongly to the serotonin-2A receptor and act as partial agonists. The use of hallucinogens is frequently said to be increasing, however, there is evidence the use of LSD among US university students has been decreasing since a peak in 1978 (Pope et al, 2001). In 1997, the lifetime use of LSD prevalence of American high school seniors was 13. As LSD lacks the addiction potential of alcohol, cocaine, or opiates, use typically declines in the mid 20s. There is loss of cognitive, perceptual and affective control. As the effects subside there may be a sense of wellbeing or paranoid delusions. Adverse effects include “bad trip” (panic), hallucinogen persisting perception disorder, and prolonged psychosis. Panic reactions can be rapidly aborted with benzodiazepines, particularly diazepam and clonazepam (Learner et al, 2003). Recovery may occur over months or years following the last substance use, but approximately half of all afflicted individuals have permanent problems (Kawasaki and Purvin 1996). Coloured pin-point dots may be seen in the bright sky. Neurophysiological studies demonstrate disinhibition of the cortical regions which process visual information (Abraham, 1983). It may be that LSD excitotoxically stimulates and destroys serotonin-2A receptor bearing inhibitory neurons. As only a sub-group of those who use LSD develop hallucinogen persisting perception disorder, this disorder may depend on genetic vulnerability. Support and continuous assessment are necessary to prevent and provide help should comorbid disorders (major depressive disorder, alcohol dependency) develop. Clinically the picture resembles schizophrenia, but with more retention of affect and less thought disorder. Visual hallucinations like those of hallucinogen persisting perception disorder are a frequent feature and there may be mystical preoccupations. Some patients describe delusions and auditory hallucinations. The relationship of this disorder to schizophrenia remains to be elucidated. GD is similar to substance use disorder on clinical grounds. Heritability of GD is estimated at around 50%, similar to some substance use agents 60%; Nestler, 2013). GD and substance use disorders commonly occur together. The neuroimaging changes in GD are complicated and not the same as substance use disorder. One study (Koehlter et al, 2013) found increased grey matter volumes in the PFC and the striatum. Another (Jousta et al, 2011) found changes in white matter tracts. Of particular interest has been mesolimbic dopamine transmission – the major component of the brain reward system – which is markedly disrupted in substance use disorder. Abnormalities have been described in (GD), but there is divergence from the classic picture of drug addiction (Clarke, 2014). Persistent problematic gambling leading to impairment or distress, as indicated by the individual exhibiting at least 4 of the following in the last year. Needs to gamble increasing amounts of money in order to achieve the desired excitement. Is restless/irritable when attempting to cut down or stop 3. Often preoccupied with gambling, planning next venture, thinking of was to get money 5. Often gambles when feeling distressed (helpless, guilty, anxious) 6. Has jeopardized or lost a significant relationship/job through gambling 9. Relies on others to provide money to relieve desperate financial situations B. Gambling behaviour not explained by a manic episode.

Evaluate the alternative approach of delivering different services to different levels of risk nortriptyline 25mg low price, rather than the current focus on the very highest level of risk order 25mg nortriptyline with amex. Investigate the effects of emergency admission risk stratification tools on vulnerable populations and health inequalities generic 25mg nortriptyline otc. Conduct a secondary analysis of the Predictive Risk Stratification: A Trial in Chronic Conditions Management data set by condition type buy nortriptyline 25 mg on-line. Explore the acceptability of predictive risk stratification and communication of risk scores to patients and practitioners. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals xxv provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. SCIENTIFIC SUMMARY Trial and study registration The trial is registered as ISRCTN55538212 and the study is registered as PROSPERO CRD42015016874. Funding Funding for this study was provided by the Health Services and Delivery Research programme of the National Institute for Health Research. A recent Health Foundation and Nuffield Trust report estimates that up to one in five emergency admissions are avoidable,10 especially where they relate to ambulatory care-sensitive conditions – conditions amenable to community prevention. Recent analysis in England suggests that better management of ambulatory care could achieve yearly savings of > £1. In England and Wales, > 16 million people have a long-term (or chronic) condition – and their care accounts for 70% of expenditure on health and social care. They shared key features of early identification and response to patient needs, joined-up care, and holistic support centred on the person rather than on specific conditions. Both models championed risk profiling as a means of identifying patients at risk (case finding) who may benefit from proactive management. The English model included systematic risk profiling as one of three primary drivers for the model, alongside integrated locality teams and systematised support for patients to manage themselves. This proactive targeting of services at people at defined risk has retained prominence in UK Government policy ever since, notably within efforts to introduce integrated care. The approach is based on proactive targeting and support for those at risk, with the aim of preventing health deterioration and emergency admissions to hospital. To be cost-effective, however, preventative interventions must use case-finding techniques that target those 3 15 18, , at risk. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 1 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. INTRODUCTION Identifying those at risk A number of approaches to identifying patients at risk have been explored. One approach is to ask clinicians to select at-risk patients based on their knowledge and experience, but a study by Allaudeen et al. An alternative is to use a criteria-based approach, whereby individuals meeting certain conditions are selected for intervention. For example, in the UK Evercare pilots, in nine English primary care trusts (PCTs), patients aged ≥ 65 years with two or more emergency admissions in the previous year were eligible for case management by community matrons. The intervention did not show an effect, however, with the accuracy of the approach to identifying patients at risk criticised. The resulting clinical prediction models are intended to help clinicians make better decisions by providing more objective 2324, estimates of probability as a supplement to other clinical information. Building on the successful implementation of risk models predicting diabetes mellitus (e. QDiabetes®) and cardiovascular disease (Framingham Risk Score25), emergency admission risk prediction (EARP) models have been widely developed – Table 1 provides examples. In calculating individualised risk for a given population, the models use data from up to three sources: self-reported data from patients; routinely collected administrative data; and data from the clinical record or other primary data source. Those models that performed best (in terms of predictive accuracy, as measured by c-statistics of > 0. These better-performing models all used routinely collected clinical patient data rather than self-reported patient data, and it is recognised that models reliant on self-reported (questionnaire) data are limited by response rates, recall issues and respondent burden. A 2015 NHS England paper on the Next Steps for Risk Stratification in the NHS recognised the need for robust evidence, and a pressing need for further research and evaluation, using high-quality study designs. The review confirms that the most common intervention used in emergency admission avoidance are various forms of case management. Although definitions of case management vary, Hutt et al. Case management often covers a range of activities, but it is recognised that these can vary widely between programmes. A 2013 review found good evidence that many common aspects of case management are effective, including continuity of care with a general practitioner (GP), structured discharge planning and advanced care planning (as cited in Lewis15).

While statistical analyses in these studies have been adjusted for confounding variables such as age purchase nortriptyline 25mg visa, gender quality 25mg nortriptyline, race generic nortriptyline 25 mg mastercard, and several comorbidities buy generic nortriptyline 25mg on line, it is difficult to identify all variables which could potentially affect the size of the risk. These unknown variables make it impossible to assign cause and effect, and the confidence intervals were sometimes so wide that the associations with eGFR could be spurious. Eight cohort studies examined the association between different eGFR levels and several outcomes of interest in populations with concomitant cardiovascular disease; specifically high-risk hypertension,118 acute myocardial infarction,119,120 heart failure,121 acute coronary syndrome,122 coronary disease,123 coronary artery disease124 and peripheral arterial disease. The mean age of people with higher eGFR (typically >60 ml/min/1. A very large US cohort study (N=1,120,295, follow-up 2. This study was rejected as there was little statistical analysis of the results; only mortality rates were presented. Quality of life outcomes such as cognitive impairment, frailty, and disability were assessed in postmenopausal women124 or in older populations with varying levels of serum creatinine132 or eGFR. The effects of age and gender on mortality and kidney disease progression were examined in people with stage 3 CKD in a Norwegian population study (N=3027, median observation time 3. The prevalence of frailty increased with decreasing GFR (p for trend <0. Black ethnicity and female gender were associated with increased likelihood of frailty. Black race and female gender were associated with increased likelihood of disability. There was NS risk of cognitive impairment at eGFR 45–49 or 30–44 ml/min/1. The risk of mortality was highest in those <60 years old. Again the risk was highest in those <60 years of age. Female gender was associated with an increased change in eGFR compared to men (+0. In an age- and sex- matched cohort, the matched risk ratio was 2. For people with proteinuria and eGFR 30–59 ml/min/1. For people with proteinuria and eGFR 15–29 ml/min/1. For people with proteinuria and creatinine clearance (CrCl) 64. ALL-HAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ARIC = Atherosclerosis Risk in Communities; LVEF = left ventricular ejection; MI = myocardial infarction. Not all studies stratified patients according to whether or not they had diabetes and this may affect estimates of the risk of death. The evidence suggested that if the GFR is less than 60 ml/min/1. There was limited evidence about outcomes in older people. However, given that they are at increased absolute risk of mortality and cardiovascular events it was agreed that even small increases in relative risk in older people are of significance. The GDG considered that the evidence suggested that the risk of mortality and cardiovascular events increased considerably when the GFR was less than 45 ml/min/1. This led to the proposal to adopt the sub-division of stage 3 CKD into stages 3A and 3B, defined by an eGFR 45–59 ml/min/1. It was noted that the presence of proteinuria was associated with a doubling of CVD risk and mortality at all levels of GFR. Evidence from longitudinal population studies and from meta-analysis of progression risk and level of proteinuria suggested that an ACR ≥30 mg/mmol should be used as a marker of the increased risk (roughly equivalent to a PCR ≥50 mg/mmol or proteinuria values ≥0. The GDG agreed not to recommend age-related decision points for eGFR. However, it seemed clear that in people aged >70 years, an eGFR in the range 45–59 ml/min/1. R21 For the purposes of this classification define proteinuria as urinary albumin:creatinine ratio (ACR) ≥30 mg/mmol or PCR ≥50 mg/mmol (approximately equivalent to urinary protein excretion ≥0. Identification of high-risk groups can help clinicians monitor renal function and identify people with CKD at an earlier disease stage. Although general population screening may not be cost-effective, targeted screening directed at subgroups of the population who might derive the most benefit from CKD detection was shown to be an effective strategy. This work suggested that a vascular check programme would prevent 4000 people a year from developing diabetes and could also detect at least 25,000 cases of diabetes or kidney disease earlier. In those conditions where the prevalence of CKD is high and the risks of preventable complications are increased, testing for CKD is clearly warranted.