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This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals.

Although the clinical high risk for psychosis (CHR) paradigm has become well-established over the past two decades, one key component has received surprisingly little investigative attention: the predictive validity of the criteria for conversion or transition to frank psychosis. The current study evaluates the predictive validity of the transition to psychosis as measured by the Structured Interview for Psychosis-Risk Syndromes (SIPS) in CHR individuals. Participants included 33 SIPS converters and 399 CHR non-converters both from the North American Prodromal Longitudinal Study (NAPLS-2), as well as a sample of 67 separately ascertained first-episode psychosis (FEP) patients from the STEP program. Comparisons were made at baseline and one-year follow-up on demographic, diagnostic stability (SCID), and available measurement domains relating to severity of illness (psychotropic medication, psychosocial treatment, and resource utilization). Principal findings are: 1) a large majority of cases in both SIPS converters (n = 27/33, 81.8%) and FEP (n = 57/67, 85.1%) samples met criteria for continued psychosis at one-year follow-up; 2) follow-up prescription rates for current antipsychotic medication were higher in SIPS converters (n = 17/32, 53.1%) compared to SIPS non-converters (n = 81/397, 20.4%), and similar as compared to FEP cases (n = 39/65, 60%); and 3) at follow-up, SIPS converters had higher rates of resource utilization (psychiatric hospitalizations, day hospital admissions, and ER visits) than SIPS non-converters and were similar to FEP in most categories. The results suggest that the SIPS definition of psychosis onset carries substantial predictive validity. Limitations and future directions are discussed.

Abstract Background Although the clinical high risk (CHR) for psychosis paradigm has become well-established over the past two decades, one key component has received surprisingly little direct investigative attention: the validity of the conversion to psychosis or transition criteria. This lack of evidence is surprising because many CHR treatment and prediction studies rely on the conversion measure as an outcome. In the absence of such evidence, some observers have raised the possibility that conversions from CHR may be trivial. The aim of this study is to evaluate the predictive validity of the transition to psychosis as measured by the Structured Interview for Psychosis-Risk Syndromes (SIPS) in CHR individuals. To our knowledge, this is the first study to examine the CHR conversion to psychosis at one-year follow-up. It is hypothesized that CHR participants whose conversion to frank psychosis was ascertained by SIPS (SIPS CV) will show similar diagnostic stability and severity of illness compared to the FEP sample and will differ significantly from SIPS Non-Converters (NCV) on clinical severity. Methods Participants included 33 SIPS Converters (CV) (met criteria for conversion to frank psychosis (COPS) on SIPS) and 399 CHR NCV both from the North American Prodromal Longitudinal Study (NAPLS 2), as well as a sample of 67 separately-ascertained first-episode psychosis (FEP) patients from the STEP Coordinated Specialty Care (CSC) program in New Haven, CT. Comparisons using Chi-square and ANOVA were made at baseline and one-year follow-up on variables from demographic, diagnostic stability (SCID) and available measurement domains relating to severity of illness (psychotropic medication and resource utilization). Results The principal findings of the present study are: 1) large majority of cases in both SIPS CV (n=27/33, 81.8%) and FEP (n=57/67, 85.1%) samples continued to have current psychosis diagnoses at one year follow up, 2) exposure to antipsychotic medication was higher in SIPS CVs (n=17/32, 53.1%) compared to SIPS NCVs (n=81/397, 20.4%), and similar as compared to FEP cases (n=39/65, 60%), 3) at follow up, SIPS CV had higher rates of resource utilization (any psychiatric hospitalizations, day hospital admissions, and ER visits) than SIPS-NCV and were similar to FEP in most categories. Discussion The results suggest that the SIPS definition of psychosis onset carries substantial validity in that those with SIPS-defined psychosis demonstrate similar diagnostic stability and severity of illness at one-year follow as a first episode sample and greater severity of illness as compared to a SIPS-defined CHR con-converting sample. Limitations include the lack of functional assessments at follow-up in the SIPS-CV. Additional studies are needed to further validate the CHR vs transition to psychosis distinction. Since many patients who come to baseline evaluation for CHR are discovered to have previously unrecognized frank psychosis, future studies should aim to obtain additional evidence by following this important group.

BackgroundDrugs that induce psychosis may do so by increasing the level of task-irrelevant random neural activity or neural noise. Increased levels of neural noise have been demonstrated in psychotic disorders. We tested the hypothesis that neural noise could also be involved in the psychotomimetic effects of delta-9-tetrahydrocannabinol (Δ(9)-THC), the principal active constituent of cannabis.MethodsNeural noise was indexed by measuring the level of randomness in the electroencephalogram during the prestimulus baseline period of an oddball task using Lempel-Ziv complexity, a nonlinear measure of signal randomness. The acute, dose-related effects of Δ(9)-THC on Lempel-Ziv complexity and signal power were studied in humans (n = 24) who completed 3 test days during which they received intravenous Δ(9)-THC (placebo, .015 and .03 mg/kg) in a double-blind, randomized, crossover, and counterbalanced design.ResultsΔ(9)-THC increased neural noise in a dose-related manner. Furthermore, there was a strong positive relationship between neural noise and the psychosis-like positive and disorganization symptoms induced by Δ(9)-THC, which was independent of total signal power. Instead, there was no relationship between noise and negative-like symptoms. In addition, Δ(9)-THC reduced total signal power during both active drug conditions compared with placebo, but no relationship was detected between signal power and psychosis-like symptoms.ConclusionsAt doses that produced psychosis-like effects, Δ(9)-THC increased neural noise in humans in a dose-dependent manner. Furthermore, increases in neural noise were related with increases in Δ(9)-THC-induced psychosis-like symptoms but not negative-like symptoms. These findings suggest that increases in neural noise may contribute to the psychotomimetic effects of Δ(9)-THC.

Gamma (γ)-band oscillations play a key role in perception, associative learning, and conscious awareness and have been shown to be disrupted by cannabinoids in animal studies. The goal of this study was to determine whether cannabinoids disrupt γ-oscillations in humans and whether these effects relate to their psychosis-relevant behavioral effects. The acute, dose-related effects of Δ-9-tetrahydrocannabinol (Δ(9)-THC) on the auditory steady-state response (ASSR) were studied in humans (n=20) who completed 3 test days during which they received intravenous Δ(9)-THC (placebo, 0.015, and 0.03 mg/kg) in a double-blind, randomized, crossover, and counterbalanced design. Electroencephalography (EEG) was recorded while subjects listened to auditory click trains presented at 20, 30, and 40 Hz. Psychosis-relevant effects were measured with the Positive and Negative Syndrome scale (PANSS). Δ(9)-THC (0.03 mg/kg) reduced intertrial coherence (ITC) in the 40 Hz condition compared with 0.015 mg/kg and placebo. No significant effects were detected for 30 and 20 Hz stimulation. Furthermore, there was a negative correlation between 40 Hz ITC and PANSS subscales and total scores under the influence of Δ(9)-THC. Δ(9)-THC (0.03 mg/kg) reduced evoked power during 40 Hz stimulation at a trend level. Recent users of cannabis showed blunted Δ(9)-THC effects on ITC and evoked power. We show for the first time in humans that cannabinoids disrupt γ-band neural oscillations. Furthermore, there is a relationship between disruption of γ-band neural oscillations and psychosis-relevant phenomena induced by cannabinoids. These findings add to a growing literature suggesting some overlap between the acute effects of cannabinoids and the behavioral and psychophysiological alterations observed in psychotic disorders.

Rationale: The sampling throughput of immediate drop‐on‐demand technology (I.DOT) coupled with an open port sampling interface (OPSI) is limited by software communication. To enable much‐needed high‐throughput mass spectrometry (MS) analysis capabilities, a novel software was developed that allows for flexible sample selection from a 96‐well plate and for maximized analysis throughput using I.DOT/OPSI‐MS coupling. Methods: Wells of a 96‐well I.DOT plate were filled with propranolol solution and were used to test maximum sampling throughput strategies to minimize analysis time. Demonstration of chemical reaction monitoring was done using acid‐catalyzed ring closure of 2,3‐diaminonaphthalene (DAN) with nitrite to form 2,3‐naphthotriazole (NAT). Analytes were detected in positive electrospray ionization mode using selected reaction monitoring. Results: A maximum throughput of 1.54 s/sample (7.41 min/96‐well plate with three technical replicates) was achieved, and it was limited by the peak width of the MS signal resulting in an occasional slight overlap between the peaks. Relative standard deviation was 10 ± 1% with all tested sampling strategies. Chemical reaction monitoring of DAN to NAT using nitrite was successfully accomplished with 2 s/sample throughout showing almost complete transformation in 10 min with no signal overlap. Conclusions: This work illustrates the development of a noncontact, automated I.DOT/OPSI‐MS system with improved throughput achieved through an optimized software interface. Its achievable analysis time and precision make it a viable approach for drug discovery and in situ reaction monitoring studies. [ABSTRACT FROM AUTHOR]