Precision psychiatry and Research Domain Criteria: Implications for clinical trials and future practice.

Psychiatric disorders are associated with significant social and economic burdens, many of which are related to issues with current diagnosis and treatments. The coronavirus (COVID-19) pandemic is estimated to have increased the prevalence and burden of major depressive and anxiety disorders, indicating an urgent need to strengthen mental health systems globally. To date, current approaches adopted in drug discovery and development for psychiatric disorders have been relatively unsuccessful. Precision psychiatry aims to tailor healthcare more closely to the needs of individual patients and, when informed by neuroscience, can offer the opportunity to improve the accuracy of disease classification, treatment decisions, and prevention efforts. In this review, we highlight the growing global interest in precision psychiatry and the potential for the National Institute of Health-devised Research Domain Criteria (RDoC) to facilitate the implementation of transdiagnostic and improved treatment approaches. The need for current psychiatric nosology to evolve with recent scientific advancements and increase awareness in emerging investigators/clinicians of the value of this approach is essential. Finally, we examine current challenges and future opportunities of adopting the RDoC-associated translational and transdiagnostic approaches in clinical studies, acknowledging that the strength of RDoC is that they form a dynamic framework of guiding principles that is intended to evolve continuously with scientific developments into the future. A collaborative approach that recruits expertise from multiple disciplines, while also considering the patient perspective, is needed to pave the way for precision psychiatry that can improve the prognosis and quality of life of psychiatric patients.

Association between MRI findings and clinical outcomes in a period of 5 years after lumbar spine microdiscectomy.

BACKGROUND: To evaluate the associations between magnetic resonance imaging (MRI) findings and pain, disability and quality of life before surgery and up to 5 years after lumbar microdiscectomy. MATERIALS AND METHODS: Sixty-one patients who underwent one-level lumbar microdiscectomy by the same surgeon participated in this analytic, observational, prospective study. Lumbar spine MRI was performed preoperatively and 5 years postoperatively. Pain, disability and quality of life were measured with VAS, ODI, Roland Morris and SF-36 pre- and up to 5 years postoperatively. Subsequently associations between radiological findings and clinical outcomes were recorded. RESULTS: Before surgery patients with disc extrusion or sequestration, with increased thecal sac compression (d > 2/3), with Modic changes (MC) 2 and 3 on the operated level and Pfirrmann grades IV and V on the operated and both adjacent discs presented the worst preoperative clinical outcomes. MC preoperatively were not related with postoperative results, in contrast with the type of disc herniation and thecal sac compression. Preoperative Pfirrmann grade IV and V on the operated and both adjacent discs and postoperative MC 2 and 3 on the operated level were related to poor clinical outcomes 36-60 months post-discectomy. CONCLUSIONS: Extrusion or sequestration of the operated disc, increased compression of thecal sac, MC 2 and 3 on the operated level and Pfirrmann grades IV and V on the operated and adjacent discs were associated with the worst clinical outcomes. Nerve root impingement, facet joint arthritis, perineural fibrosis and disc granulation tissue had no effect on clinical scores.

Clinical outcomes after lumbar spine microdiscectomy: a 5-year follow-up prospective study in 100 patients.

BACKGROUND: To evaluate the effect of lumbar microdiscectomy (LM) in pain, disability and quality of life in a 5-year period and to identify potential demographic and clinical risk factors. METHODS: One hundred patients who underwent LM by the same surgeon participated in this prospective study. Clinical assessment was made with validated questionnaires preoperatively and up to 5 years postoperatively. Subsequently, associations between clinical outcomes and demographic data were recorded. RESULTS: In every assessment questionnaire, there was a significant improvement in the first postoperative month, which lasted up to 1 year post-discectomy. After that, improvement was statistically significant (p < 0.05) but without clinical importance. Women reported more pain preoperatively and 1 month after surgery. Urban residents also presented more pain preoperatively. Older patients had more pain, disability and worse quality of life 1-5 years postoperatively. Similarly, patients with lower education presented the worst scores in every questionnaire at the same time. Smokers reported less pain 1.5-4 postoperative years. Higher alcohol consumption and obesity were associated with lower levels of preoperative pain. However, obese patients had worse SF-36 and ODI scores after the 6th postoperative month. Patients with heavy jobs presented the worst preoperative ODI scores. CONCLUSION: Significant clinical improvement was recorded from the first postoperative month to the first postoperative year; stabilization was noticed later on. Feminine gender, urban residency, older age, low level of education, obesity and heavy physical occupation were negative prognostic factors. Oddly smoking and alcohol were correlated with less pain.

Postoperative MRI findings 5 years after lumbar microdiscectomy.

BACKGROUND: Lumbar microdiscectomy is a common procedure with satisfactory results; however, postoperative events like progressive adjacent level degeneration and perineural fibrosis can contribute to long-term pain. The purpose of the study was to evaluate MRI changes 5 years after lumbar microdiscectomy and assess their association with clinical parameters. MATERIALS AND METHODS: A prospective study enrolling 61 patients who underwent microdiscectomy. Changes between preoperative and postoperative MRI findings were recorded, and these findings were tested for associations with demographic, clinical and perioperative parameters. The measured imaging parameters were degeneration of the operated and adjacent discs and endplates, morphology of the disc herniation, facet joints arthritis and the presence of postoperative perineural fibrosis. RESULTS: Statistically significant differences were found between preoperative and postoperative morphology of the operated disc, facet joints arthritis and degeneration of the operated and caudal adjacent disc. There were no differences between preoperative and postoperative disc degeneration of the superior adjacent disc and in degeneration of the operated and adjacent endplates. Postoperatively perineural fibrosis was common; however, thecal sac compression and nerve root impingement were reduced. Age at the time of surgery was the only parameter associated with postoperative changes. CONCLUSION: Five years after microdiscectomy, several postoperative MRI changes including operated disc's morphology, facet joints arthritis and degeneration of the operated and caudal adjacent disc were shown. Taking into consideration that participants were on average middle-aged, these changes could be attributed not only to the impact of the surgery but also to the natural history of lumbar spine degeneration.

Brain-relevant antibodies in first-episode psychosis: a matched case-control study.

BACKGROUND: There has been much recent excitement about the possibility that some cases of psychosis may be wholly due to brain-reactive antibodies, with antibodies to N-methyl-D-aspartate receptor (NMDAR) and the voltage-gated potassium channel (VGKC)-complex reported in a few patients with first-episode psychosis (FEP). METHODS: Participants were recruited from psychiatric services in South London, UK, from 2009 to 2011 as part of the Genetics and Psychosis study. We conducted a case-control study to examine NMDAR and VGKC-complex antibody levels and rates of antibody positivity in 96 patients presenting with FEP and 98 controls matched for age and sex. Leucine-rich glioma inactiviated-1 (LGI1) and contactin-associated protein (CASPR) antibodies were also measured. Notably, patients with suspicion of organic disease were excluded. RESULTS: VGKC-complex antibodies were found in both cases (n = 3) and controls (n = 2). NMDAR antibody positivity was seen in one case and one control. Either LGI1-Abs or CASPR2-Abs were found in three cases and three controls. Neuronal antibody staining, consistent with the above results or indicating potential novel antigens, was overall positive in four patients but also in six controls. Overall, antibody positivity was at low levels only and not higher in cases than in controls. CONCLUSIONS: This case-control study of the prevalence of antibodies in FEP does not provide evidence to support the hypothesis that FEP is associated with an immune-mediated process in a subgroup of patients. Nevertheless, as other bio-clinical factors may influence the effect of such antibodies in a given individual, and patients with organic neurological disease may be misdiagnosed as FEP, the field requires more research to put these findings in context.

When the drugs don't work: the potential of glutamatergic antipsychotics in schizophrenia.

Currently available antipsychotic drugs target dopaminergic neurotransmission. Many patients do not respond fully to these treatments, and there has been considerable effort to investigate alternative targets. Here we summarise the rationale and recent evidence supporting efforts to develop glutamatergic antipsychotic drugs.

Psychotic Like Experiences in Healthy Adolescents are Underpinned by Lower Fronto-Temporal Cortical Gyrification: a Study from the IMAGEN Consortium.

BACKGROUND AND HYPOTHESIS: Psychotic Like Experiences (PLEs) are widely prevalent in children and adolescents and increase the risk of developing psychosis. Cortical gyrification characterizes brain development from in utero till about the first 2 years of life and can be measured in later years as static gyrification changes demonstrating neurodevelopment and dynamic gyrification changes reflecting brain maturation during adolescence. We hypothesized that PLEs would be associated with static cortical gyrification changes reflecting a neurodevelopmental abnormality. STUDY DESIGN: We studied 1252 adolescents recruited in the IMAGEN consortium. We used a longitudinal study design, with Magnetic Resonance Imaging measurements at age 14 years and age 19 years; measurement of PLEs using the Community Assessment of Psychic Experiences (CAPE) questionnaire at age 19 years; and clinical diagnoses at age 23 years. STUDY RESULTS: Our results show static gyrification changes in adolescents with elevated PLEs on 3 items of the CAPE-voice hearing, unusual experiences of receiving messages, and persecutory ideas-with lower cortical gyrification in fronto-temporal regions in the left hemisphere. This group also demonstrated dynamic gyrification changes with higher cortical gyrification in right parietal cortex in late adolescence; a finding that we replicated in an independent sample of patients with first-episode psychosis. Adolescents with high PLEs were also 5.6 times more likely to transition to psychosis in adulthood by age 23 years. CONCLUSIONS: This is the largest study in adolescents that demonstrates fronto-temporal abnormality of cortical gyrification as a potential biomarker for vulnerability to PLEs and transition to psychosis.

Posterior and anterior epidural and intradural migration of the sequestered intervertebral disc: Three cases and review of the literature.

Context: Dorsal migration of the sequestered lumbar intervertebral disc is an unusual and underrecognized pattern of lumbar disc herniation associated with pain and neurological deficit.Findings: Three patients presented with lower limb- and low back pain. MR imaging showed intracanalicular mass lesions with compression of the spinal cord and allowed precise localization of lesions in the extradural or intradural space. Diagnosis was straightforward for the patients with the posterior and anterior epidural disc fragments, whereas various differential diagnostic considerations were entertained for the patient with the intradural mass lesion. All patients underwent surgical removal of the sequestered disc fragments, and recovered full motosensory function. Surgical repair of the dura mater due to CSF leak was required for the patient with intradural disc herniation.Conclusion/clinical relevance: Posterior and anterior epidural, and intradural disc migration may manifest with clinical symptoms indistinguishable from those associated with non-sequestered lumbar disc hernias. Missed, migrated disc fragments can be implicated as a cause of low back pain, radiculopathy or cauda equina syndrome, especially in the absence of visible disc herniation. A high index of suspicion needs to be maintained in those cases with unexplained and persistent symptoms and/or no obvious disc herniation on MR images.

Examination of the neural basis of psychotic-like experiences in adolescence during processing of emotional faces.

Contemporary theories propose that dysregulation of emotional perception is involved in the aetiology of psychosis. 298 healthy adolescents were assessed at age 14- and 19-years using fMRI while performing a facial emotion task. Psychotic-like experiences (PLEs) were assessed with the CAPE-42 questionnaire at age 19. The high PLEs group at age 19 years exhibited an enhanced response in right insular cortex and decreased response in right prefrontal, right parahippocampal and left striatal regions; also, a gradient of decreasing response to emotional faces with age, from 14 to 19 years, in the right parahippocampal region and left insular cortical area. The right insula demonstrated an increasing response to emotional faces with increasing age in the low PLEs group, and a decreasing response over time in the high PLEs group. The change in parahippocampal/amygdala and insula responses during the perception of emotional faces in adolescents with high PLEs between the ages of 14 and 19 suggests a potential 'aberrant' neurodevelopmental trajectory for critical limbic areas. Our findings emphasize the role of the frontal and limbic areas in the aetiology of psychotic symptoms, in subjects without the illness phenotype and the confounds introduced by antipsychotic medication.

Examination of the Neural Basis of Psychoticlike Experiences in Adolescence During Reward Processing.

Importance: Psychoticlike experiences (PLEs) are subclinical manifestations of psychotic symptoms and may reflect an increased vulnerability to psychotic disorders. Contemporary models of psychosis propose that dysfunctional reward processing is involved in the cause of these clinical illnesses. Objective: To examine the neuroimaging profile of healthy adolescents at 14 and 19 years old points with PLEs, using a reward task. Design, Setting, and Participants: A community-based cohort study, using both a cross-sectional and longitudinal design, was conducted in academic centers in London, Nottingham, United Kingdom, and Dublin, Ireland; Paris, France; and Berlin, Hamburg, Mannheim, and Dresden, Germany. A group of 1434 healthy adolescent volunteers was evaluated, and 2 subgroups were assessed at ages 14 and 19 years. Those who scored as either high or low PLE (based on the upper and lower deciles) on the Community Assessment of Psychic Experiences Questionnaire (CAPE-42) at age 19 years were included in the analysis. The study was conducted from January 1, 2016, to January 1, 2017. Main Outcomes and Measures: Participants were assessed at age 14 and 19 year points using functional magnetic resonance imaging while performing a monetary incentive delay reward task. A first-level model focused on 2 predefined contrasts of anticipation and feedback of a win. The second-level analysis examined activation within the reward network using an a priori-defined region of interest approach. The main effects of group, time, and their interaction on brain activation were examined. Results: Of the 1434 adolescents, 2 groups (n = 149 each) (high PLEs, n = 149, 50 [33.6%] male; low PLEs, n = 149, 84 [56.4%] male) were compared at ages 14 and 19 years. Two regions within the left and right middle frontal gyri showed a main effect of time on brain activation (F1, 93 = 5.559; P = .02; F1, 93 = 5.009; P = .03, respectively); there was no main effect of group. One region within the right middle frontal gyrus demonstrated a significant time × group interaction (F1, 93 = 7.448; P = .01). Conclusion and Relevance: The findings are consistent with evidence implicating alterations in prefrontal and striatal function during reward processing in the etiology of psychosis. Given the nature of this nonclinical sample this may reflect a combination of aberrant salience yielding abnormal experiences and a compensatory cognitive control mechanism necessary to contextualize them.

Treatments of Negative Symptoms in Schizophrenia: Meta-Analysis of 168 Randomized Placebo-Controlled Trials.

OBJECTIVES: Existing treatments for schizophrenia can improve positive symptoms, but it is unclear if they have any impact on negative symptoms. This meta-analysis was conducted to assess the efficacy of available treatments for negative symptoms in schizophrenia. METHODS: All randomized-controlled trials of interventions for negative symptoms in schizophrenia until December 2013 were retrieved; 168 unique and independent placebo-controlled trials were used. Negative symptom scores at baseline and follow-up, duration of illness, doses of medication, type of interventions, and sample demographics were extracted. Heterogeneity was addressed with the I (2) and Q statistic. Standardized mean difference in values of the Negative Symptom Rating Scale used in each study was calculated as the main outcome measure. RESULTS: 6503 patients in the treatment arm and 5815 patients in the placebo arm were included. No evidence of publication biases found. Most treatments reduced negative symptoms at follow-up relative to placebo: second-generation antipsychotics: -0.579 (-0.755 to -0.404); antidepressants: -0.349 (-0.551 to -0.146); combinations of pharmacological agents: -0.518 (-0.757 to -0.279); glutamatergic medications: -0.289 (-0.478 to -0.1); psychological interventions: -0.396 (-0.563 to -0.229). No significant effect was found for first-generation antipsychotics: -0.531 (-1.104 to 0.041) and brain stimulation: -0.228 (-0.775 to 0.319). Effects of most treatments were not clinically meaningful as measured on Clinical Global Impression Severity Scale. CONCLUSIONS AND RELEVANCE: Although some statistically significant effects on negative symptoms were evident, none reached the threshold for clinically significant improvement.

The prevalence and mechanisms of metabolic syndrome in schizophrenia: a review.

Metabolic syndrome (MetS), a constellation of central obesity, hypertension, dyslipidaemia and glucose intolerance, is highly prevalent in individuals with schizophrenia and conveys significant cardiovascular risk and mortality. Associated risk factors are female sex, some ethnic groups, advanced age, long duration of illness, smoking and exposure to antipsychotic agents. The prevalence of MetS varies across countries and psychiatric populations, and its development can be very rapid. Regular monitoring of all features of MetS is the cornerstone of its early detection and management. Future research needs to focus more on genetic determinants of MetS in the context of schizophrenic illness. This review aims to update the reader with the latest knowledge about the prevalence of MetS in schizophrenia and what might be the underlying pathophysiological mechanisms.

Interventions for the metabolic syndrome in schizophrenia: a review.

The metabolic syndrome (MetS) is an increasingly prevalent condition in people with schizophrenia. It remains highly prevalent in the general population in developed countries, but recently health promotion campaigns and greater awareness of the high associated mortality rates have resulted in improvements in the rates of cardiovascular risk factors. This is not the case for people with schizophrenia who continue to have more than twice the rates of MetS and significantly higher mortality rates than the general population. Various behavioural and pharmacological interventions have been used to improve conditions that are linked to MetS, mainly smoking and obesity. This review aims to provide an update of the latest knowledge about the behavioural, pharmacological and other interventions that might help to combat this life-threatening problem in people with schizophrenia.

Schizophrenia as segmental progeria.

Schizophrenia is associated with a variety of physical manifestations (i.e. metabolic, neurological) and despite psychotropic medication being blamed for some of these (in particular obesity and diabetes), there is evidence that schizophrenia itself confers an increased risk of physical disease and early death. The observation that schizophrenia and progeroid syndromes share common clinical features and molecular profiles gives rise to the hypothesis that schizophrenia could be conceptualized as a whole body disorder, namely a segmental progeria. Mammalian cells employ the mechanisms of cellular senescence and apoptosis (programmed cell death) as a means to control inevitable DNA damage and cancer. Exacerbation of those processes is associated with accelerated ageing and schizophrenia and this warrants further investigation into possible underlying biological mechanisms, such as epigenetic control of the genome.