One major issue is the placebo response which seems to have increased in recent trials of neuropathic pain and may lead to an underestimation of drug effects.Placebo response has been found to be higher in HIV-related neuropathies,and in patients with low or variable pain scores at inclusion.Conversely it seems to be lower in postherpetic neuralgia.The use of diagnostic algorithms for neuropathic pai and screening tools should contribute to reducing diagnostic heterogeneity . Lastly, a largely debated issue concerns the heterogeneity of patient phenotypes in clinical trials, which may reflect various underlying mechanisms.Interestingly, the results of a number of very recent trials or posthoc analyses of recent trials suggest that some drugs might be differentially effective in patients classified based on their sensory phenotypes.Our updated therapeutic algorithm for neuropathic pain based on GRADE differs in many ways from prior therapeutic recommendations. The latter generally proposed TCAs, pregabalin, gabapentin and lidocaine patches as first line for neuropathic pain. We now also propose gabapentin ER/enacarbil, duloxetine and venlafaxine as first line based on strong GRADE recommendation for use. We no longer recommend lidocaine patches as first line because of weak final quality of evidence. However, owing to an excellent safety profile, high values and preferences, paucity of alternative well tolerated and safe medications, short term positive studies, we propose a weak GRADE recommendation for use as generally second line for peripheral neuropathic pain. Strong opioids are now recommended as third line, contrasting with several prior recommendations in which they were generally considered as first or second line.This mainly stems from the consideration of potential risk of abuse,vertical farming technology particularly with high doses and concerns about a recent increase in prescription opioid-associated overdose mortality, diversion, misuse and other opioid-related morbidity particularly in USA, Canada and UK.

High concentration capsaicin patches and cannabinoids are considered for the first time in therapeutic recommendations for neuropathic pain. Capsaicin patches are proposed as second-line for peripheral neuropathic pain because of high quality of evidence, but modest effect size, training requirements, and potential safety concerns on sensation with long-term use.We provide a weak recommendation against the use of cannabinoids in neuropathic pain, mainly because of negative results, potential misuse, abuse, diversion and long term mental health risks particularly in susceptible individuals.One important issue when proposing recommendations is to assess to what extent they are applied by practitioners and whether this may contribute to improving their practice. Few studies have investigated the real-life impact of evidence-based recommendations on physicians’ practices. It has recently been reported that the drug treatment of postherpetic neuralgia by primary care physicians was roughly consistent with the US recommendations issued some years before.In contrast, a recent large study of general practitioners’ adherence to current French recommendations observed a paucity of appropriate recall of first-line drugs.One important educational objective of the present guidelines will be to facilitate their dissemination and subsequently assess their real life implementation in various countries.Interest in early detection and prevention of schizophrenia and other psychotic disorders stems from evidence of brain structural changes and decline in function around the time of psychosis onset, suggesting that the pre-onset or ‘prodromal’ period affords a window of opportunity for preventive intervention. Identifying predictors and mechanisms of conversion to psychosis among such individuals ascertained to be in a clinical high risk or prodromal clinical state are critical steps in the search for preventive strategies. Achieving these aims requires sample sizes much larger than those typically available at a single research centre within a reasonable time period. The North American Prodrome Longitudinal Study is a consortium of eight programs focusing on the psychosis prodrome.

The sites are located at Emory University, Harvard University, University of Calgary in Canada, University of California at Los Angeles, University of California at San Diego, University of North Carolina at Chapel Hill, Yale University, and Zucker Hillside Hospital. In a prior phase of the project, these sites collaborated to combine previously collected datasets and produced a series of analyses on predictors of psychosis in the largest sample of longitudinally followed prodromal subjects worldwide . Results of these analyses indicated that risk for the onset of psychosis in this population was 35% after 2 ½ years of follow-up, with a decelerating rate of conversion over this period. The NAPLS data set was used to derive a psychosis prediction algorithm with high positive predictive power , but only modest sensitivity . The published prediction algorithm included genetic risk , more severe unusual thought content, and greater social impairment. These preliminary efforts led to a five year prospective study “Predictors and Mechanisms of Conversion to Psychosis”, funded by NIMH in 2008, also referred to as NAPLS 2 that included all eight NAPLS sites. The number of subjects in NAPLS 2 is anticipated to be sufficient to address fundamental questions about the neurobiological correlates of the development of psychosis. The goal of recruiting a sample of 720 clinical high risk participants and 240 healthy controls will be achieved by the end of 2012, and based on the previously collected NAPLS 1 data, a conversion rate of approximately 30% is expected with up to two year follow-up. This paper describes the overall methodology of the NAPLS 2 project and reports on the ascertainment and demographics of the first half of the CHR sample and 180 of the healthy controls.The central pathophysiologic assumption underlying the project is that schizophrenia reflect a process of brain volume reduction involving pruning of synapses and dendrites, that result in reduced cortical connectivity , particularly in prefrontal and superior and medial temporal lobe regions governing attention, executive, auditory-language, and memory-related functions. The first project aim is to determine whether the NAPLS 1 psychosis risk prediction algorithm can be replicated in a new and larger sample of CHR individuals.

The hypothesis is that each of four factors: genetic vulnerability to schizophrenia with recent deterioration in functioning, higher levels of unusual thought content, higher levels of suspicion-paranoia, greater social impairment at baseline, will independently predict a higher risk for conversion to psychosis, and that combining all of these indicators will substantially reduce false positive psychosis predictions over two years of follow-up. The second is to determine whether biological and neurocognitive abnormalities preceding psychosis onset contribute to predicting psychosis independently of the clinical algorithms and whether they can be combined with the clinical measures to enhance predictive utility. The third aim is to determine whether neuroanatomical, neurophysiological, neurocognitive, and neurohormonal abnormalities that precede psychosis represent stable vulnerability markers or markers of progression during the prodromal phase. This will enable us to determine whether CHR individuals who convert to psychosis show a steeper rate of change in neurobiological risk indicators compared to non-converters and healthy controls. The final aim is to develop a repository of DNA and RNA from participants meeting diagnostic criteria for a CHR state and from demographically similar healthy participants. The clinical component of the project attempts to replicate and refine the major NAPLS 1 prediction findings. The biomarkers component tests potential mechanisms of illness onset and/or progression in the neuroanatomical, electrophysiological, neurohormonal, neuropsychological,future vertical farming and genomic domains. Selection of measures attempted to reflect both vulnerability-related and progressive neuromaturational processes. Selection was limited to measures for which evidence existed with relevance to the psychosis prodrome, and which were likely to reflect pathophysiologic changes associated with clinical and/or functional deterioration. We required proven methods for the reliable collection and aggregation of data across measurement points and across sites. The selected measures span multiple critical levels of analysis . Such a multilevel perspective was assumed to be necessary given that the aberrant molecular and cellular processes underlying psychotic disorders were likely to reflect cascading influences across these five critical domains. Baseline only measures include demographics, premorbid functioning, life events and childhood trauma. Six monthly clinical assessments include SIPS, anxiety, depression, substance use and social functioning. Logs of medications, psychosocial treatments and resource utilization are updated every 6 months. Biomarker assessments of neurocognition, electrophysiology, cortisol, blood draws, and imaging occur at baseline, 1 and 2 years. Should a participant convert to psychosis, then the complete assessment is done at the time of conversion with a one year post conversion assessment to determine the diagnosis. NAPLS participants are help-seeking. They are referred from health care providers, educators, or social service agencies or they self-refer in response to intensive community education efforts. These initiatives included academic detailing, grand rounds, educational talks, mailings, postings, websites and internet hits, and public service announcements. Each site has developed extensive referral sources in their area, and routinely contact them personally, with mail outs, and through educational efforts. Potential participants undergo a telephone screen. Those who screen positive are invited to an in-person eligibility and consent evaluation. The first half of the sample N=360 was recruited over a 2 year period from January 2009 until January 2011. Overall, 1749 referrals were received as depicted in Figure 1. Based on a phone screen 618 clearly did not meet CHR criteria, but 52% were found to be suitable for a screening interview.

Of those deemed not suitable at screening some were psychotic. Examples of other reasons included not having prodromal symptoms, calling about other problems such as anxiety, depression, severe autism, non-English speaking, or outside the age range. Of those offered screening, 28% did not keep their scheduled interview and 28% were found not to meet CHR criteria. Examples of reasons for not meeting criteria at the assessment included prodromal symptoms being longstanding, not frequent enough or no longer present. Outcome of all referrals are presented in Figure 1. There were some site differences. Yale and ZHH received significantly more referrals and ruled out more at phone screening. UNC had a higher proportion of referrals that they were unable to contact further. San Diego, Emory and Yale had a higher proportion of no shows. Figure 2 depicts the referral sources and the number meeting prodromal criteria from each source. Overall, significantly more referrals came from self and family, although the majority of such referrals did not meet criteria. UCLA, Harvard, UCSD and Calgary recruited from a wide range of clinical and community services. Although Yale did receive some referrals from clinical services the majority of Yale’s were self-referrals. Referrals for ZHH were made primarily by the outpatient department intake staff and other clinical services that informed parents to contact the program directly. The majority of the referrals at Emory and UNC were self-referrals, followed by family and friends. Figure 3 elaborates on the marketing strategies and their effectiveness. Presentations and web and internet searches seemed to be the most successful, as was “word of mouth”. This was the case at most of the sites; the one exception being Emory where the majority of the referrals resulted from advertising in public places. The clinical high risk sample met the Criteria of Prodromal Syndromes which is based on the Structured Interview for Prodromal Syndromes . After a comprehensive assessment that includes administering the Structure Clinical Interview for DSM-IV and the SIPS, vignettes are developed for each CHR participant for the purpose of obtaining a consensus diagnosis. The attenuated psychotic symptoms rated on the Scale of Prodromal Symptoms are described at length and include both recent and longstanding symptoms. The vignette is written so that another rater can review the information under each symptom category and provide a reliable rating. Once approved at the site level, the vignette is presented on a conference call for a consensus decision on the symptom ratings as well as the diagnosis. The NAPLS-2 consensus call, chaired by JA, is held once a week and is attended by members of each of the eight study sites including the authors of the SIPS, Drs McGlashan and Walsh, who act as co-chairs. Submitted vignettes are individually reviewed and a consensus must be reached on each symptom rating, diagnosis and ultimate admission into the study. It is often challenging making differentiations with respect to some of the exclusion criteria listed below. But we use our calls to discuss issues such as the impact of substance abuse and use of antipsychotics. Such decisions can later be reviewed when we have followed the sample and determined the outcome of the participants in terms of conversion and remission.