Who stays, who benefits? Predicting dropout and change in cognitive behaviour therapy for psychosis

This study investigates predictors of outcome in a secondary analysis of dropout and completer data from a randomized controlled effectiveness trial comparing CBTp to a wait-list group (Lincoln et al., 2012). Eighty patients with DSM-IV psychotic disorders seeking outpatient treatment were included. Predictors were assessed at baseline. Symptom outcome was assessed at post-treatment and at one-year follow-up. The predictor x group interactions indicate that a longer duration of disorder predicted less improvement in negative symptoms in the CBTp but not in the wait-list group whereas jumping-to-conclusions was associated with poorer outcome only in the wait-list group. There were no CBTp specific predictors of improvement in positive symptoms. However, in the combined sample (immediate CBTp+the delayed CBTp group) baseline variables predicted significant amounts of positive and negative symptom variance at post-therapy and one-year follow-up after controlling for pre-treatment symptoms. Lack of insight and low social functioning were the main predictors of drop-out, contributing to a prediction accuracy of 87%. The findings indicate that higher baseline symptom severity, poorer functioning, neurocognitive deficits, reasoning biases and comorbidity pose no barrier to improvement during CBTp. However, in line with previous predictor-research, the findings imply that patients need to receive treatment earlier

The Effect of an Educating versus Normalizing Approach on Treatment Motivation in Patients Presenting with Delusions: An Experimental Investigation with Analogue Patients

Until recently a widespread recommendation for clinicians was not to respond to the content of patients' delusions but to stress at an early time point that the patient has a mental illness (educating approach). An opposed recommendation is to validate the patients’ symptoms and normalize them (normalizing approach). This study used an experimental design to compare the impact of these two approaches on treatment motivation (TM). A cover story about a person who develops persecutory delusions was used to guide a sample of 81 healthy participants who served as analogue patients into imagining experiencing delusions. This was followed by a random assignment to either an educating or a normalizing consultation with a fictive clinician. Consultations only differed in content. Finally, we assessed the participants' motivation to accept medication (Medication TM), psychological treatment (Psychological TM), and treatment offered by this particular clinician independent of the kind of treatment (Clinician-related TM). Participants in the normalizing condition showed higher Clinician-related and Psychological TM than those in the educating condition. Medication TM was unaffected by condition. Following our results using a normalizing approach seems to be advisable in a first-contact situation with patients with delusions and favourable to a simple educating approach

Correlates and Long-Term Consequences of Poor Insight in Patients With Schizophrenia. A Systematic Review

Between 50 and 80% of the patients diagnosed with schizophrenia have been shown to be partially or totally lacking insight into the presence of their mental disorder. Although a causal chain connecting poor insight with poor treatment adherence and thus with poorer outcome and functioning is straight forward, numerous studies investigating correlates and long-term impact of insight have provided differing results. In addition, higher levels of insight in schizophrenia have been associated with depression and hopelessness, but the causal direction of the relationship is unclear and the data are inconclusive. The current study provides a critical review of 88 studies on the assessment of insight and its impact on symptoms and functioning. Studies published by June 2006 were selected using a keyword search for English peer-reviewed articles in the databases PsycINFO and MEDLINE. The majority of studies support the assumption that insight is associated with adherence during treatment phase, but the association with long-term adherence remains unclear. Insight correlates with better long-term functioning, but this might be explained by its association with symptoms. There is a positive cross-sectional and longitudinal relationship between insight and depression, but the underlying processes need further clarification. In the concluding discussion, the problems relating to definition and study designs are considered responsible for many of the inconclusive findings. Suggestions for further research are derived

Induction of Tolerance to Human Arylsulfatase A in a Mouse Model of Metachromatic Leukodystrophy

A deficiency of arylsulfatase A (ASA) causes metachromatic leukodystrophy (MLD), a lysosomal storage disorder characterized by accumulation of sulfatide, a severe neurological phenotype and early death. The efficacy of enzyme replacement therapy (ERT) has previously been determined in ASA knockout (ASA−/−) mice representing the only available animal model for MLD. Repeated intravenous injection of human ASA (hASA) improved the nervous system pathology and function, but also elicited a progressive humoral immune response leading to treatment resistance, anaphylactic reactions, and high mortality. In contrast to ASA−/− mice, most MLD patients express mutant hASA which may entail immunological tolerance to substituted wildtype hASA and thus protect from immunological complications. To test this notion, a cysteine-to-serine substitution was introduced into the active site of the hASA and the resulting inactive hASA-C69S variant was constitutively expressed in ASA−/− mice. Mice with sub-to supranormal levels of mutant hASA expression were analyzed. All mice, including those showing transgene expression below the limit of detection, were immunologically unresponsive to injected hASA. More than 100-fold overexpression did not induce an overt new phenotype except occasional intralysosomal deposition of minor amounts of glycogen in hepatocytes. Furthermore, long-term, low-dose ERT reduced sulfatide storage in peripheral tissues and the central nervous system indicating that high levels of extracellular mutant hASA do not prevent cellular uptake and lysosomal targeting of substituted wildtype hASA. Due to the tolerance to hASA and maintenance of the MLD-like phenotype, the novel transgenic strain may be particularly advantageous to assess the benefit and risk of long-term ERT

Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis

Action myoclonus-renal failure syndrome (AMRF) is an autosomal-recessive disorder with the remarkable combination of focal glomerulosclerosis, frequently with glomerular collapse, and progressive myoclonus epilepsy associated with storage material in the brain. Here, we employed a novel combination of molecular strategies to find the responsible gene and show its effects in an animal model. Utilizing only three unrelated affected individuals and their relatives, we used homozygosity mapping with single-nucleotide polymorphism chips to localize AMRF. We then used microarray-expression analysis to prioritize candidates prior to sequencing. The disorder was mapped to 4q13-21, and microarray-expression analysis identified SCARB2/Limp2, which encodes a lysosomal-membrane protein, as the likely candidate. Mutations in SCARB2/Limp2 were found in all three families used for mapping and subsequently confirmed in two other unrelated AMRF families. The mutations were associated with lack of SCARB2 protein. Reanalysis of an existing Limp2 knockout mouse showed intracellular inclusions in cerebral and cerebellar cortex, and the kidneys showed subtle glomerular changes. This study highlights that recessive genes can be identified with a very small number of subjects. The ancestral lysosomal-membrane protein SCARB2/LIMP-2 is responsible for AMRF. The heterogeneous pathology in the kidney and brain suggests that SCARB2/Limp2 has pleiotropic effects that may be relevant to understanding the pathogenesis of other forms of glomerulosclerosis or collapse and myoclonic epilepsies.Samuel F. Berkovic, Leanne M. Dibbens, Alicia Oshlack, Jeremy D. Silver, Marina Katerelos, Danya F. Vears, Renate Lüllmann-Rauch, Judith Blanz, Ke Wei Zhang, Jim Stankovich, Renate M. Kalnins, John P. Dowling, Eva Andermann, Frederick Andermann, Enrico Faldini, Rudi D’Hooge, Lata Vadlamudi, Richard A. Macdonell, Bree L. Hodgson, Marta A. Bayly, Judy Savige, John C. Mulley, Gordon K. Smyth, David A. Power, Paul Saftig, and Melanie Bahl