The identification, assessment and management of difficult-to-treat depression: An international consensus statement.

BACKGROUND: Many depressed patients are not able to achieve or sustain symptom remission despite serial treatment trials - often termed "treatment resistant depression". A broader, perhaps more empathic concept of "difficult-to-treat depression" (DTD) was considered. METHODS: A consensus group discussed the definition, clinical recognition, assessment and management implications of the DTD heuristic. RESULTS: The group proposed that DTD be defined as "depression that continues to cause significant burden despite usual treatment efforts". All depression management should include a thorough initial assessment. When DTD is recognized, a regular reassessment that employs a multi-dimensional framework to identify addressable barriers to successful treatment (including patient-, illness- and treatment-related factors) is advised, along with specific recommendations for addressing these factors. The emphasis of treatment, in the first instance, shifts from a goal of remission to optimal symptom control, daily psychosocial functional and quality of life, based on a patient-centred approach with shared decision-making to enhance the timely consideration of all treatment options (including pharmacotherapy, psychotherapy, neurostimulation, etc.) to optimize outcomes when sustained remission is elusive. LIMITATIONS: The recommended definition and management of DTD is based largely on expert consensus. While DTD would seem to have clinical utility, its specificity and objectivity may be insufficient to define clinical populations for regulatory trial purposes, though DTD could define populations for service provision or phase 4 trials. CONCLUSIONS: DTD provides a clinically useful conceptualization that implies a search for and remediation of specific patient-, illness- and treatment obstacles to optimizing outcomes of relevance to patients.

Non-linear response of summertime marine productivity to increased meltwater discharge around Greenland.

Runoff from the Greenland Ice Sheet (GrIS) is thought to enhance marine productivity by adding bioessential iron and silicic acid to coastal waters. However, experimental data suggest nitrate is the main summertime growth-limiting resource in regions affected by meltwater around Greenland. While meltwater contains low nitrate concentrations, subglacial discharge plumes from marine-terminating glaciers entrain large quantities of nitrate from deep seawater. Here, we characterize the nitrate fluxes that arise from entrainment of seawater within these plumes using a subglacial discharge plume model. The upwelled flux from 12 marine-terminating glaciers is estimated to be >1000% of the total nitrate flux from GrIS discharge. This plume upwelling effect is highly sensitive to the glacier grounding line depth. For a majority of Greenland's marine-terminating glaciers nitrate fluxes will diminish as they retreat. This decline occurs even if discharge volume increases, resulting in a negative impact on nitrate availability and thus summertime marine productivity.

Behaviours of concern following moderate to severe traumatic brain injury in individuals living in the community.

PRIMARY OBJECTIVE: Behaviours of Concern (BoC) following traumatic brain injury (TBI) have a significant negative impact on the daily functioning and quality of life for the individual and their family. However, there has been limited research examining the nature and severity of BoC beyond the acute recovery period, including the perspective of the individual with TBI as well as close others (COs). METHODS AND PROCEDURE: Eighty-nine individuals with predominantly severe TBI, at a mean of 11.4 years' post-injury, were identified through a no-fault accident compensation system database. Structured interviews were completed with 65 individuals with TBI, and 62 COs. Current BoC were documented using the Overt Behaviour Scale (OBS). MAIN OUTCOMES AND RESULTS: 70.5% of participants exhibited BoC on the OBS, with an average of 3 behaviours. Verbal aggression and socially inappropriate behaviour were the most common BoC. Self-report of behaviour change was endorsed by 81% of the sample. There was generally poor concordance between the perspectives of the individual with the TBI and their CO. CONCLUSION: Severe BoC, across multiple behaviour types, may be evident many years following predominantly severe TBI. There is a need to provide long-term behaviour support for these individuals.

Sibling dynamics and sport expertise.

Family members are known to be highly influential in the development of sport expertise. To date, much of the research in this area has focused on parents, with less known about sibling influences on expertise. This investigation explored associations between sport expertise, sibling characteristics, and sibling participation in sport and physical activity. Athletes representing three skill levels provided details of sibling characteristics and participation in sport and physical activity via the Developmental History of Athletes Questionnaire. Elite athletes were more likely to be later-born children, while pre-elite and non-elite athletes were more likely to be first-born. Compared with siblings of non-elite athletes, siblings of elite athletes were more likely to have participated in regular physical activity and were more likely to have participated in sport at the pre-elite and elite levels. These results suggest siblings may play a key role in sport expertise development.

Manipulating melatonin in managing mood.

OBJECTIVE: Disturbances in circadian rhythms have been associated with major depression and may be an underlying mechanism for the disorder. Resynchronisation of circadian rhythms may provide a new approach to treatment, especially by manipulating melatonin secretion. Melatonin is secreted at night and is a stable marker of circadian rhythms. The timing of its secretion can be changed by exogenous melatonin, agonism of specific melatonin receptors in the suprachiasmatic nucleus, its suppression by light and by sleep deprivation. METHOD: As part of a series of papers ['Chronobiology of mood disorders' Malhi & Kuiper. Acta Psychiatr Scand 2013;128 (Suppl. 444): 2-15; and 'Getting depression clinical practice guidelines right: time for change?' Kuiper et al. Acta Psychiatr Scand 2013;128 (Suppl. 444): 24-30.] addressing chronobiology, in this article, we conducted a selective review of studies that have examined the antidepressant effects of exogenous melatonin, light therapy, sleep deprivation and melatonin receptor agonists. RESULTS: Antidepressant effects were identified for bright light therapy, especially for seasonal affective disorder; sleep deprivation, although its antidepressant effect is time limited; and for the novel antidepressant agomelatine with agonistic properties for the MT1 and MT2 receptors and antagonism of 5HT2c receptor. The role of melatonin as an antidepressant has yet to be demonstrated. CONCLUSION: Shifting the circadian secretion of melatonin using the strategies reviewed offers a new approach to treating depression.

Factors associated with specialist assessment and treatment for hepatitis C virus infection in New South Wales, Australia.

Assessment and treatment for hepatitis C virus (HCV) in the community remains low. We evaluated factors associated with HCV specialist assessment and treatment in a cross-sectional study to evaluate treatment considerations in a sample of 634 participants with self-reported HCV infection in New South Wales, Australia. Participants having received HCV specialist assessment (n = 294, 46%) were more likely to be have been older (vs <35 years; 35-44 OR 1.64, P = 0.117; 45-54 OR 2.00, P = 0.024; ≥55 OR 5.43, P = 0.002), have greater social support (vs low; medium OR 3.07, P = 0.004; high OR 4.31, P < 0.001), HCV-related/attributed symptoms (vs none; 1-10 OR 3.89, P = 0.032; 10-21 OR 5.01, P = 0.010), a diagnosis of cirrhosis (OR 2.40, P = 0.030), have asked for treatment information (OR 1.91, P = 0.020), have greater HCV knowledge (OR 2.49, P = 0.001), have been told by a doctor to go onto treatment (OR 3.00, P < 0.001), and less likely to be receiving opiate substitution therapy (OR 0.10, P < 0.001) and never to have seen a general practitioner (OR 0.24, P < 0.001). Participants having received HCV treatment (n = 154, 24%) were more likely to have greater fibrosis (vs no biopsy; none/minimal OR 3.45, P = 0.001; moderate OR 11.47, P < 0.001; severe, OR 19.51, P < 0.001), greater HCV knowledge (OR 2.57; P = 0.004), know someone who has died from HCV (OR 2.57, P = 0.004), been told by a doctor to go onto treatment (OR 3.49, P < 0.001), were less likely to have been female (OR 0.39, P = 0.002), have recently injected (OR 0.42, P = 0.002) and be receiving opiate substitution therapy (OR 0.22, P < 0.001). These data identify modifiable patient-, provider- and systems-level barriers associated with HCV assessment and treatment in the community that could be addressed by targeted interventions.

Uptake and delivery of hepatitis C treatment in opiate substitution treatment: perceptions of clients and health professionals.

Uptake of treatment for hepatitis C virus (HCV) infection is very low particularly among people who have injected drugs. Opiate substitution treatment (OST) programs, with a high prevalence of people living with HCV, have been a site of growing interest in the delivery of hepatitis C treatment. There has been no exploration of OST clients' and health professionals' perceptions of the barriers and facilitators to uptake and delivery of HCV treatment in OST clinics from personal and organizational perspectives. This qualitative study involved interviews with 27 OST clients in New South Wales and a focus group and interviews with 22 Australian OST health professionals. Clients and health professionals viewed hepatitis C treatment in OST as a 'one-stop-shop' model which could increase access to and uptake of treatment and build on existing relationships of trust between OST client and health professional. Elements of the organizational culture were also noted as barriers to HCV treatment delivery including concerns about confidentiality, lack of discussion of HCV treatment and that HCV treatment was not perceived by clinicians as a legitimate activity of OST clinics. OST client participants also reported a number of personal barriers to engaging with HCV treatment including family responsibilities (and concerns about treatment side effects), unstable housing, comorbidities and perceptions of the unsatisfactory level of treatment efficacy. These findings emphasize the need for future research and delivery of services which addresses the complexity of care and treatment for people in marginalized social circumstances.

Olfactory identification dysfunction, aggression and impulsivity in war veterans with post-traumatic stress disorder.

BACKGROUND: Due to neuropsychological conceptualizations of orbitoprefrontal cortex (OFC) dysfunction underpinning impulsive aggression and the incidence of such behaviour in post-traumatic stress disorder (PTSD), this study aimed to explore olfactory identification (OI) ability in war veterans with PTSD as a probe of putative OFC dysfunction; and to explore the utility of OI ability in predicting aggressive and impulsive behavior in this clinical population. METHOD: Participants comprised 31 out-patient male war veterans with PTSD (mean=58.23 years, s.d.=2.56) recruited from a Melbourne Veterans Psychiatry Unit, and 31 healthy age- and gender-matched controls (mean=56.84 years, s.d.=7.24). All participants were assessed on clinical measures of PTSD, depression, anxiety, and alcohol misuse; olfactory identification; neurocognitive measures of dorsolateral prefrontal, lateral prefrontal and mesial temporal functioning; and self-report measures of aggression and impulsivity. RESULTS: War veterans with PTSD exhibited significant OI deficits (OIDs) compared to controls, despite uncompromised performance on cognitive measures. OIDs remained after covaring for IQ, anxiety, depression and alcohol misuse, and were significant predictors of aggression and impulsivity. CONCLUSIONS: This research contributes to emerging evidence of orbitoprefrontal dysfunction in the pathophysiology underlying PTSD. This is the first study to report OIDs as a predictor of aggression and impulsivity in this clinical population. It prompts further exploration of the potential diagnostic utility of OIDs in the assessment of PTSD. Such measures may help delineate the clinical complexity of PTSD, and support more targeted interventions for individuals with a greater susceptibility to aggressive and impulsive behaviors.

A randomized, placebo-controlled study of oxcarbazepine in painful diabetic neuropathy.

OBJECTIVES: To evaluate the efficacy and safety of oxcarbazepine (1200 mg/day) in patients with painful diabetic neuropathy in a multicentre, double-blind, placebo-controlled, 16-week study. METHODS: A total of 141 patients were randomized to oxcarbazepine (1200 mg/day) (n = 71) or placebo (n = 70). The primary efficacy variable was the change in mean visual analogue scale (VAS) score from baseline to the last week the patient participated in the study. RESULTS: The reduction in mean VAS score from baseline to the last study week was similar between the oxcarbazepine and placebo groups. The majority of adverse events (most of which first occurred during titration) were mild to moderate in severity and resolved over the course of the study. CONCLUSIONS: In this study, no statistically significant difference in therapeutic effect was observed between oxcarbazepine (1200 mg/day) and placebo. However, further studies are necessary to assess the effective dose range of oxcarbazepine in the treatment of painful diabetic neuropathy.

Higher cortical deficits influence attentional processing in dementia with Lewy bodies, relative to patients with dementia of the Alzheimer's type and controls.

BACKGROUND: Attentional dysfunction is believed to be a prominent and distinguishing neuropsychological feature of dementia with Lewy bodies (DLB); yet, the specific nature of the attentional deficit and factors that can potentially influence attentional processing in DLB have not been fully defined. AIMS: To clarify the nature of the attentional deficit in early-stage DLB relative to patients with early-stage dementia of the Alzheimer's type (DAT) and elderly controls, and examine the effect of task complexity and type of cognitive load on attentional processing in DLB. METHODS: Attentional impairment and fluctuating attention were investigated in three groups of subjects--patients with clinical features of early probable DLB (n = 20), a group with early probable DAT (n = 19) and healthy elderly controls (n = 20)--using an experimental computerised reaction time paradigm. RESULTS: Patients with DLB showed greater attentional impairment and fluctuations in attention relative to patients with DAT and elderly controls. The attentional deficit was generalised in nature but increased in magnitude as greater demands were placed on attentional selectivity. Attentional deficits in DLB were most pronounced under task conditions that required more active recruitment of executive control and visuospatial cognitive processes. CONCLUSIONS: Attentional deficits in DLB are widespread and encompass all aspects of attentional function. Deficits in higher cortical function influence the degree of attentional impairment and fluctuating attention, suggesting that attentional processing in DLB is mediated by interacting cortical and subcortical mechanisms. These findings serve to clarify the nature of the attentional deficit in DLB and have potentially important ramifications for our understanding of the neurocognitive underpinnings of fluctuations.

Oxcarbazepine in painful diabetic neuropathy: results of a dose-ranging study.

OBJECTIVES: To evaluate the efficacy and safety of oxcarbazepine in patients with diabetic neuropathy in a multicenter, double-blind, placebo-controlled, dose-ranging 16-week study. METHODS: A total of 347 patients were randomized to oxcarbazepine 600 mg/day (n = 83), 1,200 mg/day (n = 87), 1,800 mg/day (n = 88), or placebo (n = 89). The primary efficacy variable was change in mean visual analog scale (VAS) score from baseline to the last week of the study. RESULTS: No difference between any oxcarbazepine group and the placebo group was noted for the primary efficacy variable. Both the 1,200- and 1,800-mg/day groups showed a trend toward statistical significance (P = 0.101, P = 0.096, respectively). Statistically significant differences were found between the oxcarbazepine 1,200-mg/day (P = 0.038) and 1,800-mg/day (P = 0.005) groups and placebo in the overall mean weekly VAS scores for the entire double-blind treatment phase. CONCLUSIONS: Although the primary efficacy variable did not reach statistical significance, patients taking oxcarbazepine 1,200 and 1,800 mg/day showed improvements in VAS scores compared with placebo. Oxcarbazepine may provide clinically meaningful pain relief in patients with painful diabetic neuropathy.

Receiving a hepatitis C-positive diagnosis.

BACKGROUND: There is a paucity of academic literature that describes patients' experiences of receiving a hepatitis C-positive diagnosis, doctors' explanations of the infection and referral to support services. AIM: The aim of the present study was to report findings on receiving a positive diagnosis from a study of people with hepatitis C infection. METHOD: A cross-sectional study of people with hepatitis C infection living in New South Wales, Australia, was carried out (n=504). RESULTS: Of participants diagnosed with hepatitis C infection from 1989 to 2001 (n= 17), just under one-third (29.5%, n=123) reported that they had received 'no explanation' about their infection from their doctor at diagnosis. Women and those diagnosed from 1989 to 1996 were significantly more likely to report receiving no explanation than men and those diagnosed later (35.4 vs 23.7% and 37.5 vs 23.0%, respectively). Similarly, current injecting drug users and those diagnosed from 1989 to 1996 were significantly more likely to report receiving no post-test counselling than those who were not currently injecting and those diagnosed later (42.9 vs 30.2% and 37.6 vs 25.9%, respectively). Participants diagnosed from 1997 to 2001 were significantly more likely to report receiving pamphlets about hepatitis C infection (39.2 vs 23.7%), information about treatments (24.5 vs 16.2%) and advice regarding natural therapies (9.1 vs 3.8%) than those diagnosed earlier. CONCLUSIONS: These data provide evidence of an increase in the dissemination of hepatitis C information by doctors at diagnosis during the late 1990s. Continued effort is needed to improve doctors' provision of information and referral to specialists and support agencies for people newly diagnosed with hepatitis C.

Idiopathic recurrent stupor: a warning.

A proposal that an endogenous benzodiazepine-like agent named endozepine-4 might be responsible for presentations of recurrent stupor has gained wide acceptance. A case of recurrent stupor over two decades is presented with many similarities to previous cases of "endozepine stupor". This case, however, was caused by exogenous benzodiazepine administration and serves as a warning to clinicians to beware of this diagnosis.

Fluctuating cognition in dementia with Lewy bodies and Alzheimer's disease is qualitatively distinct.

OBJECTIVES: To document and illustrate qualitative features of fluctuating cognition as described by care givers of patients with probable dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). To determine whether the quality of the fluctuations differs between DLB and AD. To examine the clinical utility of two recently developed rating scales. METHODS: Care givers of 13 patients with early probable DLB and 12 patients with early probable AD were interviewed using the Clinician Assessment of Fluctuation and the One Day Fluctuation Assessment Scale, both developed recently. Descriptions of fluctuating cognition were recorded verbatim, analysed, and rated. RESULTS: Descriptions of fluctuating cognition in DLB had a spontaneous, periodic, transient quality, which appeared to reflect an interruption in the ongoing flow of awareness or attention that impacted on functional abilities. Descriptions of fluctuations in AD frequently highlighted episodes of memory failure, or a more enduring state shift in the form of "good" and "bad" days, typically occurring in response to the cognitive demands of the immediate environment. These qualitative differences could be detected reliably by independent raters, but were not always captured in standard severity scores. CONCLUSION: Fluctuations occurring in DLB have particular characteristics that are distinguishable from fluctuations occurring in AD. Interpretation and application of the fluctuation criterion continues to limit the diagnostic sensitivity of the consensus criteria for DLB. Findings suggest that explicit documentation and a wider appreciation of these distinctions could improve the reliability with which less experienced clinicians identify this core diagnostic feature in the clinical setting.

Naltrexone for alcohol dependence: a randomized controlled trial.

AIM: We examined the efficacy of naltrexone (an opioid antagonist) for alcohol dependence in a sample of alcohol-dependent men. DESIGN: A 12-week randomized placebo-controlled clinical trial. SETTING: The outpatient clinic of a combined war veteran and general teaching hospital in Melbourne, Australia. PARTICIPANTS: Male alcohol-dependent subjects recruited from the community and from veteran groups. INTERVENTION: Alcohol-dependent subjects were treated with 50 mg of naltrexone or placebo daily for 12 weeks. Both treatment groups attended a weekly education support group. Subjects were assessed weekly. MEASUREMENTS: Primary study outcomes were the maintenance of abstinence and relapse to drinking. FINDINGS: Fifty-five subjects were randomized to naltrexone and 56 to placebo. Forty subjects did not complete 12 weeks of therapy (17 naltrexone, 23 placebo). In the intention-to-treat sample (N = 111) fewer naltrexone treated subjects relapsed (p = 0.001). Among patients who completed the 12-week trial, naltrexone reduced the consumption of alcohol. Naltrexone was well tolerated and there were few adverse experiences. CONCLUSIONS: These findings demonstrate that naltrexone is effective in preventing relapse to drinking in the setting of limited psychosocial treatment. Further studies should examine the duration of treatment needed to maintain the effect long term.

TLE patients with postictal psychosis: mesial dysplasia and anterior hippocampal preservation.

The authors studied six patients with refractory temporal lobe epilepsy and postictal psychosis using quantitative MRI and histopathology, and compared the results with 45 patients with temporal lobe epilepsy without postictal psychosis. Total hippocampal volumes were not different between the two groups. However, patients with postictal psychosis had a relatively preserved anterior hippocampus, and temporal lobe dysplasia was more frequent (p = 0.006, chi-square test). These findings may be associated with the clinical symptoms.

An operating room scheduling strategy to maximize the use of operating room block time: computer simulation of patient scheduling and survey of patients' preferences for surgical waiting time.

UNLABELLED: Determining the appropriate amount of block time to allocate to surgeons and selecting the days on which to schedule elective cases can maximize operating room (OR) use. We used computer simulation to model OR scheduling. Inputs in the computer model included different methods to determine when a patient will have surgery (on-line bin-packing algorithms), case durations, lengths of time patients wait for surgery (2 wk is the median longest length of time that the outpatients [n = 367] surveyed considered acceptable), hours of block time each day, and number of blocks each week. For block time to be allocated to maximize OR utilization, two parameters must be specified: the method used to decide on what day a patient will have surgery and the average length of time patients wait to have surgery. OR utilization depends greatly on, and increases as, the average length of time patients wait for surgery increases. IMPLICATIONS: Operating room utilization can be maximized by allocating block time for the elective cases based on expected total hours of elective cases, scheduling patients into the first available date provided open block time is available within 4 wk, and otherwise scheduling patients in "overflow" time outside of the block time.

Negative symptoms, depression, and parkinsonian symptoms in chronic, hospitalised schizophrenic patients.

BACKGROUND: Negative symptoms of schizophrenia are often confounded by overlapping depressive and parkinsonian symptoms. The role of medication as an aetiological factor in the development of these symptoms is an important issue for prevention and treatment. METHODS: A total of 45 inpatients in chronic wards who met RDC criteria for schizophrenia were assessed with the Hamilton depression rating scale (HDRS) and negative symptom rating scale (NSRS) and the targeting abnormal kinetic effect scale (TAKE). RESULTS: No significant correlation was found between the total scores on the vegetative superfactor of the HDRS and the NSRS. Duration of neuroleptic treatment was positively correlated with depressive symptoms (r=0.299, P < 0.05) and negative symptoms (r=0.443, P < 0.001). Dose of antipsychotic was also correlated positively with negative symptoms (r=0.260, P < 0.05). Age was negatively correlated with depressive symptoms as assessed by the HDRS (r=0.306, P <0.05). CONCLUSION: The data suggest that depressive and negative symptoms can be separated in chronic schizophrenia, while pointing to a possible role of antipsychotic medication in the aetiology. LIMITATIONS: The study was conducted in a small chronically hospitalised population treated with relatively high doses of antipsychotics. It is not clear that the results obtained here would be applicable to an acute patient population.