A feasibility trial of an intervention in alcohol dependence for structured preparation before detoxification versus usual care: the SPADe trial results.

BACKGROUND: Individuals who are 'moderately' or 'severely' dependent consume alcohol at levels that are likely to have a severe impact on their own health and mortality, the health and behaviours of others (family members) and to have economic and social implications. Treatment guidelines suggest that treatment needs to be planned with medically assisted withdrawal (also referred to as detoxification), and aftercare support but outcomes are poor with low proportions engaging in after care and high relapse rates. An approach of structured preparation before alcohol detoxification (SPADe) puts an emphasis on introducing lifestyle changes, development of coping strategies for cravings, stress and emotions as well as introducing changes to the immediate family and social environment in advance of alcohol cessation. Such a pre-habilitation paradigm compliments the established treatment approach. The key research question was: can we design a large scale, randomised controlled trial (RCT) that will answer whether such an approach is more effective than usual care in helping individuals to maintain longer periods of alcohol abstinence? METHODS: This is a pragmatic, parallel, two-arm, feasibility RCT comparing SPADe and usual care against usual care only in maintaining alcohol abstinence in adults with alcohol dependence receiving care in two community addiction services in London. Feasibility outcomes, exploration of primary and secondary clinical outcomes and health economic outcomes are analysed. The trial follows the guidelines of phase 2 of the Medical Research Council (MRC) for complex interventions. RESULTS: We were able to recruit 48/50 participants during a period of 9 months. Retention in the trial for the whole period of the 12 months was 75%. Treatment compliance was overall 44%. Data completion for the primary outcome was 65%, 50% and 63% at 3, 6 and 12 months, respectively. The intervention group had more days abstinent in the previous 90 days at the 12 months (n = 54.5) versus control (n = 41.5). CONCLUSIONS: The results of this feasibility trial indicate that with the appropriate modifications, a full multicentred trial would be possible to test the effectiveness and cost-effectiveness of a pre-habilitation approach such as the SPADe group intervention in addition to usual care against usual care only. TRIAL REGISTRATION: Name of registry: ISRCTN; Trial Registration Number: 14621127 ; Date of Registration: 22/02/2017.

A feasibility study of an intervention for structured preparation before detoxification in alcohol dependence: the SPADe trial protocol.

BACKGROUND: Alcohol-related harm is currently estimated to cost the National Health Service (NHS) in England £3.5 bn a year. Of the estimated 1.6 million people with some degree of alcohol dependence, some 600,000 are believed to be moderately or severely dependent and may benefit from intensive treatment. Outcomes from medically assisted withdrawal, also referred to as detoxification, are often poor, with poor engagement in relapse prevention interventions and subsequent high relapse rates. Detoxification is costly both financially and to the individual. It has been found that people who experience multiple detoxifications show more emotional and cognitive impairments. These changes may confer upon them the inability to resolve conflict and increased sensitivity to stress thus contributing to increased vulnerability risk of relapse. The study aims to test the feasibility of using a group intervention aiming to prepare participants for long-term abstinence before, rather than after, they have medically assisted detoxification. The current study will establish key parameters that influence trial design such as recruitment, compliance with the intervention, retention, and sensitivity of alternative outcome measures, in preparation for a future randomised controlled trial (RCT). This paper presents the protocol of the feasibility study. METHODS: The study corresponds to phase 2 of the Medical Research Council (MRC) complex interventions guidelines which cover the development and feasibility testing of an intervention. The work is in three stages. The development, adaptation and implementation of the Structured Preparation before Alcohol Detoxification (SPADe) intervention (stage 1), a randomised feasibility study with economic evaluation (stage 2) and a qualitative study (stage 3). Fifty participants will be recruited from two community alcohol treatment services in England. Participants will be randomised in two arms: the treatment as usual arm (TAU), which includes planned medically assisted detoxification and aftercare and the intervention arm in which participants will receive structured group preparation before detoxification in addition to TAU. The main outcomes are duration of continuous abstinence with no incidents of lapse or relapse, percentage of days abstinent and time to relapse. DISCUSSION: The socioeconomic harms associated with alcohol have been well-documented, yet existing treatment options have not been able to reduce high relapse rates. This study will build on existing naturalistic studies underpinned by psychological interventions offered early and before detoxification from alcohol, which aim to reverse automatised habitual behaviours and thus may help us to understand how better to support people to remain abstinent and improve post detoxification outcomes. TRIAL REGISTRATION: ISRCTN, 14621127; Registered on 22 Feb 2017.

Fine mapping by genetic association implicates the chromosome 1q23.3 gene UHMK1, encoding a serine/threonine protein kinase, as a novel schizophrenia susceptibility gene.

BACKGROUND: Linkage studies by us and others have confirmed that chromosome 1q23.3 is a susceptibility locus for schizophrenia. Based on this information, several research groups have published evidence that markers within both the RGS4 and CAPON genes, which are 700 kb apart, independently showed allelic association with schizophrenia. Tests of allelic association with both of these genes in our case control sample were negative. Therefore, we carried out further fine mapping between the RGS4 and CAPON genes. METHODS: Twenty-nine SNP and microsatellite markers in the 1q23.3 region were genotyped in the United Kingdom based sample of 450 cases and 450 supernormal control subjects. RESULTS: We detected positive allelic association after the eighth marker was genotyped and found that three microsatellite markers (p = .011, p = .014, p = .049) and two SNPs (p = .004, p = .043) localized in the 700 kb region between the RGS4 and CAPON genes, within the UHMK1 gene, were associated with schizophrenia. Tests of significance for marker rs10494370 remained significant following Bonferroni correction (alpha = .006) for multiple tests. Tests of haplotypic association were also significant for UHMK1 (p = .009) using empirical permutation tests, which make it unnecessary to further correct for both multiple alleles and multiple markers. CONCLUSIONS: These results provide preliminary evidence that the UHMK1 gene increases susceptibility to schizophrenia. Further confirmation in adequately powered samples is needed. UHMK1 is a serine threonine kinase nuclear protein and is highly expressed in regions of the brain implicated in schizophrenia.

Failure to confirm allelic and haplotypic association between markers at the chromosome 6p22.3 dystrobrevin-binding protein 1 (DTNBP1) locus and schizophrenia.

BACKGROUND: Previous linkage and association studies may have implicated the Dystrobrevin-binding protein 1 (DTNBP1) gene locus or a gene in linkage disequilibrium with DTNBP1 on chromosome 6p22.3 in genetic susceptibility to schizophrenia. METHODS: We used the case control design to test for of allelic and haplotypic association with schizophrenia in a sample of four hundred and fifty research subjects with schizophrenia and four hundred and fifty ancestrally matched supernormal controls. We genotyped the SNP markers previously found to be significantly associated with schizophrenia in the original study and also other markers found to be positive in subsequent studies. RESULTS: We could find no evidence of allelic, genotypic or haplotypic association with schizophrenia in our UK sample. CONCLUSION: The results suggest that the DTNBP1 gene contribution to schizophrenia must be rare or absent in our sample. The discrepant allelic association results in previous studies of association between DTNBP1 and schizophrenia could be due population admixture. However, even positive studies of European populations do not show any consistent DTNBP1 alleles or haplotypes associated with schizophrenia. Further research is needed to resolve these issues. The possible confounding of linkage with association in family samples already showing linkage at 6p22.3 might be revealed by testing genes closely linked to DTNBP1 for allelic association and by restricting family based tests of association to only one case per family.

Failure to confirm allelic association between markers at the CAPON gene locus and schizophrenia in a British sample.

BACKGROUND: Linkage studies have confirmed that chromosome 1q23.3 is a susceptibility locus for schizophrenia. It was then claimed that markers at the carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON) gene showed allelic association with schizophrenia in Canadian families. A second Chinese study found a base pair polymorphism at the CAPON gene also associated with schizophrenia. METHODS: We attempted replication using eight markers from the Canadian study in a UK based sample of 450 cases and 450 supernormal controls. RESULTS: We found no evidence for allelic or haplotypic association with schizophrenia for any of the markers found to be associated in the Canadian sample. CONCLUSIONS: The negative results might reflect genetic heterogeneity between the Canadian, Chinese and UK samples or be due to methodological problems. The present finding weakens the evidence that mutations or variation in the CAPON gene are causing genetic susceptibility to schizophrenia in European populations.

Serum creatine kinase elevation associated with olanzapine treatment.

On 2 May 2008, a 25-year-old male patient on olanzapine 15 mg developed mild central chest pain, and blood tests revealed a high creatine kinase (CK) value at 1016 iu/l. Troponin, CK-MB, CK:MB ratio, full blood count (FBC), urea and electrolytes (U&E), C reactive protein (CRP) and glucose were all normal. Liver enzymes were marginally raised: alanine aminotransferase (ALT) 91 iu/l, γ-glutamyl transferase (GGT) 46 iu/l, alkaline phosphatase (ALP) 137 iu/l. The ECG was normal and the chest pain later resolved and was thought likely to be due to costochondritis. A repeat blood test on 7 May revealed further elevation of CK at 1391 iu/l and olanzapine was stopped. CK continued to rise: 19 May 2857 iu/l, 20 May 3285 iu/l, and 22 May 3646 iu/l. On 30 May CK dropped to 708 iu/l, on 20 June it was 593 iu/l, and on 30 June CK was 343 iu/l. The patient was started on amisulpiride on 15 July and CK began to rise again: on 18 July it was 445 iu/l and on 31 July CK was 480 iu/l, at which time the medication was stopped. The patient did not have any signs or symptoms of physical disorder on this occasion.We have never seen a patient develop such high CK values in the absence of any clinical or other significant laboratory abnormalities. We can rule out exercise as the cause as he attends an inpatient unit and we are aware that his exercise has been light to moderate at most; also, he stopped exercising at our request on 7 May 2008, yet CK continued to rise. There is no clinical indication of other causes of elevated CK such as myositis, and CK-MB and CK-MB:CK ratio were normal throughout, so it was not cardiac in origin. We believe olanzapine caused the elevated CK value. When the patient was rechallenged with amisulpiride on 15 May his CK again rose and the medication therefore had to be stopped. There are three similar cases that have been reported in the past when patients on second generation antipsychotics developed CK elevation in the absence of other clinical or laboratory abnormalities. We therefore believe this is an important finding to report.

Failure to confirm genetic association between schizophrenia and markers on chromosome 1q23.3 in the region of the gene encoding the regulator of G-protein signaling 4 protein (RGS4).

The chromosome 1q23.3 region, which includes the RGS4 gene has been implicated in genetic susceptibility to schizophrenia by two linkage studies with lod scores of 6.35 and 3.20 and with positive lod between 2.00 and 3.00 scores in several other studies. Reduced post mortem RGS4 gene expression in the brain of schizophrenics was reported as well as positive allelic association between markers at the RGS4 gene locus and schizophrenia. We have attempted to replicate the finding of allelic association with schizophrenia in a UK based sample of 450 subjects with schizophrenia and 450 supernormal controls. We genotyped the same SNP marker alleles investigated in the earlier studies and also a di-nucleotide (GT)14 repeat microsatellite marker, which was 7 kb distal to RGS4. In the new UK sample there was no evidence for allelic or haplotypic association between RGS4 markers and schizophrenia. This might reflect genetic heterogeneity between the population samples, genotyping or other methodological problems. The finding weakens the evidence that mutations or variation in the RGS4 gene have an effect on schizophrenia susceptibility.

The Epsin 4 gene on chromosome 5q, which encodes the clathrin-associated protein enthoprotin, is involved in the genetic susceptibility to schizophrenia.

Chromosome 5q33 is a region that has previously shown good evidence of linkage to schizophrenia, with four LOD scores >3.00 in independent linkage studies. We studied 450 unrelated white English, Irish, Welsh, and Scottish research subjects with schizophrenia and 450 ancestrally matched supernormal controls. Four adjacent markers at the 5' end of the Epsin 4 gene showed significant evidence of linkage disequilibrium with schizophrenia. These included two microsatellite markers, D5S1403 (P=.01) and AAAT11 (P=.009), and two single-nucleotide-polymorphism markers within the Epsin 4 gene, rs10046055 (P=.007) and rs254664 (P=.01). A series of different two- and three-marker haplotypes were also significantly associated with schizophrenia, as confirmed with a permutation test (HapA, P=.004; HapB, P=.0005; HapC, P=.007; and HapD, P=.01). The Epsin 4 gene encodes the clathrin-associated protein enthoprotin, which has a role in transport and stability of neurotransmitter vesicles at the synapses and within neurons. A genetically determined abnormality in the structure, function, or expression of enthoprotin is likely to be responsible for genetic susceptibility to a subtype of schizophrenia on chromosome 5q33.3.