Treatment of Early Onset Schizophrenia: Recent Trends, Challenges and Future Considerations

Early onset schizophrenia (onset before adulthood) is a rare, severe, and chronic form of schizophrenia. The clinical presentation of schizophrenia at this unusually early age of onset has been associated with premorbid developmental abnormalities, poor response to neuroleptic treatment, greater admission rates, and poor prognosis. This is a brief, condensed review of current treatment strategies for the early onset population highlighting the need for novel treatment strategies for these generally treatment-refractory cases. Based on the current literature, second-generation antipsychotics remain the mainstay of treatment, although current medications provide suboptimal response at best. Based on the adult literature, combining antipsychotic treatment with psychotherapeutic intervention may be a more comprehensive treatment strategy. Indeed, early detection, identification of relevant biomarkers, coupled with advancing knowledge of the neurochemical and neuroanatomic pathways may help design informed and novel treatment strategies

Using Multivariate Machine Learning Methods and Structural MRI to Classify Childhood Onset Schizophrenia and Healthy Controls

Introduction: Multivariate machine learning methods can be used to classify groups of schizophrenia patients and controls using structural magnetic resonance imaging (MRI). However, machine learning methods to date have not been extended beyond classification and contemporaneously applied in a meaningful way to clinical measures. We hypothesized that brain measures would classify groups, and that increased likelihood of being classified as a patient using regional brain measures would be positively related to illness severity, developmental delays, and genetic risk. Methods: Using 74 anatomic brain MRI sub regions and Random Forest (RF), a machine learning method, we classified 98 childhood onset schizophrenia (COS) patients and 99 age, sex, and ethnicity-matched healthy controls. We also used RF to estimate the probability of being classified as a schizophrenia patient based on MRI measures. We then explored relationships between brain-based probability of illness and symptoms, premorbid development, and presence of copy number variation (CNV) associated with schizophrenia. Results: Brain regions jointly classified COS and control groups with 73.7% accuracy. Greater brain-based probability of illness was associated with worse functioning (p = 0.0004) and fewer developmental delays (p = 0.02). Presence of CNV was associated with lower probability of being classified as schizophrenia (p = 0.001). The regions that were most important in classifying groups included left temporal lobes, bilateral dorsolateral prefrontal regions, and left medial parietal lobes. Conclusion: Schizophrenia and control groups can be well classified using RF and anatomic brain measures, and brain-based probability of illness has a positive relationship with illness severity and a negative relationship with developmental delays/problems and CNV-based risk

A randomized, parallel study of the safety and efficacy of 45 mg primaquine versus 75 mg bulaquine as gametocytocidal agents in adults with blood schizonticide-responsive uncomplicated falciparum malaria [ISCRTN50134587]

BACKGROUND: The WHO recommends that adults with uncomplicated P. falciparum successfully treated with a blood schizonticide receive a single dose of primaquine (PQ) 45 mg as a gametocytocidal agent. An earlier pilot study suggested that 75 mg of bulaquine (BQ), of which PQ is a major metabolite, may be a useful alternate to PQ. METHODS: In a randomized, partial blind study, 90 hospitalized adults with Plasmodium falciparum malaria that was blood schizonticide-responsive and a gametocytemia of > 55/μl within 3 days of diagnosis were randomized to receive single doses of either PQ 45 mg or BQ 75 mg on day 4. We assessed gametocytemia on days 8, 15, 22 and 29 and gametocyte viability as determined by exflagellation (2° end point) on day 8. RESULTS: On day 8, 20/31 (65%) primaquine recipients versus 19/59 (32%) bulaquine recipients showed persistence of gametocytes (P = 0.002). At day 15 and beyond, all patients were gametocyte free. On day 8, 16/31 PQ and 7/59 BQ volunteers showed gametocyte viability (p = 0.000065). CONCLUSION: BQ is a safe, useful alternate to PQ as a Plasmodium falciparum gametocytocidal agent and may clear gametocytemia faster than PQ

The anatomical distance of functional connections predicts brain network topology in health and schizophrenia.

The human brain is a topologically complex network embedded in anatomical space. Here, we systematically explored relationships between functional connectivity, complex network topology, and anatomical (Euclidean) distance between connected brain regions, in the resting-state functional magnetic resonance imaging brain networks of 20 healthy volunteers and 19 patients with childhood-onset schizophrenia (COS). Normal between-subject differences in average distance of connected edges in brain graphs were strongly associated with variation in topological properties of functional networks. In addition, a club or subset of connector hubs was identified, in lateral temporal, parietal, dorsal prefrontal, and medial prefrontal/cingulate cortical regions. In COS, there was reduced strength of functional connectivity over short distances especially, and therefore, global mean connection distance of thresholded graphs was significantly greater than normal. As predicted from relationships between spatial and topological properties of normal networks, this disorder-related proportional increase in connection distance was associated with reduced clustering and modularity and increased global efficiency of COS networks. Between-group differences in connection distance were localized specifically to connector hubs of multimodal association cortex. In relation to the neurodevelopmental pathogenesis of schizophrenia, we argue that the data are consistent with the interpretation that spatial and topological disturbances of functional network organization could arise from excessive "pruning" of short-distance functional connections in schizophrenia.PEV is supported by the Medical Research Council (grant number MR/K020706/1). This work was supported by the Neuroscience in Psychiatry Network (NSPN) which is funded by a Wellcome Trust strategy award to the University of Cambridge and University College London. ETB is employed half-time by the University of Cambridge and half-time by GlaxoSmithKline; he holds stock in GSK.This is the final published version. It first appeared at http://onlinelibrary.wiley.com/doi/10.1111/jcpp.12365/full

Trajectories of brain change during development: understanding risk and resilience factors for emerging mental illness

Mental disorders like schizophrenia, mood disorders and substance abuse begin in adolescence and early adulthood. This is a time of active brain changes as adolescents mature into adulthood. Such maturational changes provide the context for understanding how and why these disorders arise during this critical period of development. I will first summarise the findings from the Melbourne early psychosis and prodromal studies examining premorbid and progressive brain changes during and following the onset of psychosis. I will consider whether the evidence supports these as risk-related markers of illness onset and transition. I will also examine evidence from studies of childhood schizophrenia (Gogtay et al., 2011). The findings suggest that biomarkers should be examined longitudinally to assess normal and abnormal trajectories during maturation and with the emergence of mental disorders (Pantelis et al., 2005; 2009). These trajectories include evidence for (a) neurodevelopmental lag, (b) neurodevelopmental arrest, and (c) neuroprogressive changes. These trajectories can also be considered to reflect the impact of both risk and resilience factors. Finally, I will consider the importance of examining trajectories of acute relapse and remission (Cropley et al., 2013, 2014)

Child Psychiatry Branch of the National Institute of Mental Health Longitudinal Structural Magnetic Resonance Imaging Study of Human Brain Development

The advent of magnetic resonance imaging, which safely allows in vivo quantification of anatomical and physiological features of the brain, has revolutionized pediatric neuroscience. Longitudinal studies are useful for the characterization of developmental trajectories (ie, changes in imaging measures by age). Developmental trajectories (as opposed to static measures) have proven to have greater power in discriminating healthy from clinical groups and in predicting cognitive/behavioral measures, such as IQ. Here we summarize results from an ongoing longitudinal pediatric neuroimaging study that has been conducted at the Child Psychiatry Branch of the National Institute of Mental Health since 1989. Developmental trajectories of structural MRI brain measures from healthy youth are compared and contrasted with trajectories in attention-deficit/hyperactivity disorder (ADHD) and childhood-onset schizophrenia. Across ages 5-25 years, in both healthy and clinical populations, white matter volumes increase and gray matter volumes follow an inverted U trajectory, with peak size occurring at different times in different regions. At a group level, differences related to psychopathology are seen for gray and white matter volumes, rates of change, and for interconnectedness among disparate brain regions

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3 Mapping cortical change in Alzheimer’s disease, brain development