The effectiveness and safety of dialectical behavior therapy for suicidal ideation and behavior in autistic adults: a pragmatic randomized controlled trial.

BACKGROUNDS: Many autistic people in mental health are suicidal. This study evaluated the effectiveness of dialectical behavior therapy (DBT) v. treatment as usual (TAU) in reducing suicidal ideation and suicide attempts. METHODS: At six Dutch mental health centers, 123 outpatients (18-65 years) with DSM-5 diagnosed autism spectrum disorder (ASD) and suicidal behavior were randomly assigned to the DBT intervention group (n = 63) or TAU control group (n = 60). Assessments were conducted at baseline, post-treatment at 6 months and 12-month follow-up. The primary outcomes were severity of suicidal ideation and frequency of suicide attempts. The severity of depression and social anxiety were secondary outcomes. RESULTS: At end-of-treatment, DBT significantly reduced both suicidal ideation (z = -2.24; p = 0.025; b = -4.41; s.e. = 197.0) and suicide attempts (z = -3.15; p = 0.002; IRR = 0.046; s.e. = 0.045) compared to TAU, but lost statistical significance at the 12-month follow-up. Depression severity significantly decreased with DBT (z = -1.99; p = 0.046: b = -2.74; s.e. = 1.37) remaining so at 12 months (z = -2.46; p = 0.014; b = -3.37; s.e. = 1.37). No effects were observed on social anxiety. Severe adverse events included two suicides in the TAU condition. CONCLUSIONS: DBT is an acceptable, safe, and short-term effective intervention to reduce suicidal ideation and suicide attempts in autistic adults with suicidal behavior.

Necrosome-positive granulovacuolar degeneration is associated with TDP-43 pathological lesions in the hippocampus of ALS/FTLD cases.

AIM: Granulovacuolar degeneration (GVD) in Alzheimer's disease (AD) involves the necrosome, which is a protein complex consisting of phosphorylated receptor-interacting protein kinase 1 (pRIPK1), pRIPK3 and phosphorylated mixed lineage kinase domain-like protein (pMLKL). Necrosome-positive GVD was associated with neuron loss in AD. GVD was recently linked to the C9ORF72 mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with transactive response DNA-binding protein (TDP-43) pathology (FTLD-TDP). Therefore, we investigated whether GVD in cases of the ALS-FTLD-TDP spectrum (ALS/FTLD) shows a similar involvement of the necrosome as in AD, and whether it correlates with diagnosis, presence of protein aggregates and cell death in ALS/FTLD. METHODS: We analysed the presence and distribution of the necrosome in post-mortem brain and spinal cord of ALS and FTLD-TDP patients (n = 30) with and without the C9ORF72 mutation, and controls (n = 22). We investigated the association of the necrosome with diagnosis, the presence of pathological protein aggregates and neuronal loss. RESULTS: Necrosome-positive GVD was primarily observed in hippocampal regions of ALS/FTLD cases and was associated with hippocampal TDP-43 inclusions as the main predictor of the pMLKL-GVD stage, as well as with the Braak stage of neurofibrillary tangle pathology. The central cortex and spinal cord, showing motor neuron loss in ALS, were devoid of any accumulation of pRIPK1, pRIPK3 or pMLKL. CONCLUSIONS: Our findings suggest a role for hippocampal TDP-43 pathology as a contributor to necrosome-positive GVD in ALS/FTLD. The absence of necroptosis-related proteins in motor neurons in ALS argues against a role for necroptosis in ALS-related motor neuron death.

The effect of dialectical behaviour therapy in autism spectrum patients with suicidality and/ or self-destructive behaviour (DIASS): study protocol for a multicentre randomised controlled trial.

BACKGROUND: Many persons with autism spectrum disorder (ASD) are treated in long-term specialised care. In this population, suicidal behaviour troubles patients, families, and specialists in the field because it is difficult to treat. At present, there is no documented effective therapy for suicidal behaviour in ASD (Autism Research 7:507-521, 2014; Crisis 35:301-309, 2014). Dialectical Behaviour Therapy (DBT) is an efficacious treatment programme for chronically suicidal and/or self-harm behaviour in patients with Borderline Personality Disorder (J Psychiatry 166:1365-1374, 2014; Linehan MM. Cognitive behavioural therapy of borderline personality disorder. 1993). This study will evaluate the efficacy of DBT in persons with ASD and suicidal/ self- destructive behaviour in a multicentre randomised controlled clinical trial. METHOD: One hundred twenty-eight persons with autism and suicidal and/or self-harming behaviour will be recruited from specialised mental healthcare services and randomised into two conditions: 1) the DBT condition in which the participants have weekly individual cognitive behavioural therapy sessions and a 2.5 h skills training group session twice per week during 6 months, and 2) the treatment as usual condition which consists of weekly individual therapy sessions of 30-45 min with a psychotherapist or social worker. Assessments will take place at baseline, at post-treatment (6 months), and after a follow-up period of 12 months. The mediators will also be assessed at 3 months. The primary outcome is the level of suicidal ideation and behaviour. The secondary outcomes are anxiety and social performance, depression, core symptoms of ASD, quality of life, and cost-utility. Emotion regulation and therapeutic alliance are hypothesised to mediate the effects on the primary outcome. DISCUSSION: The results from this study will provide an evaluation of the efficacy of DBT treatment in persons with ASD on suicidal and self-harming behaviour. The study is conducted in routine mental health services which enhances the generalisability of the study results to clinical practice. TRIAL REGISTRATION: ISRCTN96632579. Registered 1 May 2019. Retrospectively registered.

Serum neurofilament light chain levels as a marker of upper motor neuron degeneration in patients with Amyotrophic Lateral Sclerosis.

AIMS: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron degeneration disease with a diagnostic delay of about 1 year after symptoms onset. In ALS, blood neurofilament light chain (NfL) levels are elevated, but it is not entirely clear what drives this increase and what the diagnostic performance of serum NfL is in terms of predictive values and likelihood ratios. The aims of this study were to further explore the prognostic and diagnostic performances of serum NfL to discriminate between patients with ALS and ALS mimics, and to investigate the relationship between serum NfL with motor neuron degeneration. METHODS: The diagnostic performances of serum NfL were based on a cohort of 149 serum samples of patients with ALS, 19 serum samples of patients with a disease mimicking ALS and 82 serum samples of disease control patients. The serum NfL levels were correlated with the number of regions (thoracic, bulbar, upper limb and lower limb) displaying upper and/or lower motor neuron degeneration. The prognostic performances of serum NfL were investigated based on a Cox regression analysis. RESULTS: The associated predictive values and likelihood ratio to discriminate patients with ALS and ALS mimics were established. Serum NfL was associated with motor neuron degeneration driven by upper motor neuron (UMN) degeneration and was independently associated with survival in patients with ALS. CONCLUSIONS: Altogether, these findings suggest that elevated serum NfL levels in ALS are driven by UMN degeneration and the disease progression rate and are independently associated with survival at time of diagnosis.

Treatment of antisocial personality disorder: Development of a practice focused framework.

There is little to no evidence of effective treatment methods for patients with an antisocial personality disorder (ASPD). One of the reasons could be the fact that they are often excluded from mental healthcare and thus from studies. A treatment framework based on 'state of the art' methods and best practices, offering guidelines on the treatment of ASP and possibilities for more systematical research, is urgently needed. This research involved a literature search and an international Delphi-study (N = 61 experts in research, management and clinical practice focused on ASPD). The results suggested important preconditions with regard to organization of care, healthcare workers and therapy. Conclusions are that there are many ways to coordinate effective treatment and management and work toward the increased availability of evidence based care for persons with ASPD.

Integrated molecular landscape of amyotrophic lateral sclerosis provides insights into disease etiology.

Amyotrophic lateral sclerosis (ALS) is a severe, progressive and ultimately fatal motor neuron disease caused by a combination of genetic and environmental factors, but its underlying mechanisms are largely unknown. To gain insight into the etiology of ALS, we here conducted genetic network and literature analyses of the top-ranked findings from six genome-wide association studies of sporadic ALS (involving 3589 cases and 8577 controls) as well as genes implicated in ALS etiology through other evidence, including familial ALS candidate gene association studies. We integrated these findings into a molecular landscape of ALS that allowed the identification of three main processes that interact with each other and are crucial to maintain axonal functionality, especially of the long axons of motor neurons, i.e. (1) Rho-GTPase signaling; (2) signaling involving the three regulatory molecules estradiol, folate, and methionine; and (3) ribonucleoprotein granule functioning and axonal transport. Interestingly, estradiol signaling is functionally involved in all three cascades and as such an important mediator of the molecular ALS landscape. Furthermore, epidemiological findings together with an analysis of possible gender effects in our own cohort of sporadic ALS patients indicated that estradiol may be a protective factor, especially for bulbar-onset ALS. Taken together, our molecular landscape of ALS suggests that abnormalities within three interconnected molecular processes involved in the functioning and maintenance of motor neuron axons are important in the etiology of ALS. Moreover, estradiol appears to be an important modulator of the ALS landscape, providing important clues for the development of novel disease-modifying treatments.

[Dialectical behaviour theory in the Netherlands: implementation and consolidation]. / Dialectische gedragstherapie in Nederland: implementatie en consolidatie.

BACKGROUND: More and more evidence-based treatments for severe personality disorders are becoming available. Nevertheless, there are problems with the implementation of these treatments and it is proving difficult to keep the treatment programmes running. However, teams which offer dialectical behavior therapy (DBT) seem to survive. AIM: To find out which factors enable dbt teams to survive. METHOD: Twenty-five Dutch DBT teams received a questionnaire about factors that could be influencing the continuation of the DBT treatment programmes. The questionnaire consisted of 9 open questions, 2 multiple-choice questions and 26 closed questions. RESULTS: The results show that the continued existence of the treatment programmes is due largely to the commitment of both the team and its managers. They all feel embedded in the organisation as a whole, feel connected with one another and are supportive of the method. CONCLUSION: A well-functioning consultation team seems to be of crucial importance for the continued existence of the DBT programme. We believe that independent external supervision is essential to keep the dbt teams alert and aware of current trends and developments.

C-kit is important for SOD1(G93A) mouse survival independent of mast cells.

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease leading to progressive and lethal paralysis. The disease process is multi-factorial and is characterized by selective motor neuron degeneration. Previous work demonstrated that the local concentration of various growth factors can influence motor neuron survival and disease progression. A potential role for c-kit, a growth factor receptor present in the spinal cord, in ALS is unknown. To dissect the role of c-kit in ALS we interbred SOD1(G93A) mice with kit(w-sh/w-sh) mice, which have a 70% decrease in c-kit expression in the spinal cord. kit(w-sh/w-sh) SOD1(G93A) mice have a reduced survival compared to SOD1(G93A) mice, while the amount of motor neurons at end stage is similar. By means of grip strength and nerve conductance analysis we show that kit(w-sh/w-sh) mice have diminished strength and slightly impaired compound muscle action potential latency, although the number of neurons is similar across genotypes. Decreasing kit gene expression in SOD1(G93A) mice is detrimental and our results imply that this effect is independent of mast cells, as tested by ketotifen administration. To conclude, our data expand on the protective role of growth factors in ALS, as decreasing c-kit by approximately 70% is detrimental in SOD1(G93A) mice.

[Short-term dialectical behaviour therapy for borderline personality disorder]. / Kortdurende klinische dialectische gedragstherapie voor de borderlinepersoonlijkheidsstoornis: ontwerp van programma en resultaten pilotstudie.

BACKGROUND: Outpatient dialectical behaviour therapy (DBT) reduces severe suicidal and self-injurious behaviour in patients with borderline personality disorder. The Jelgersma center for personality disorders has developed an intensive inpatient dbt programme that lasts for 14 weeks and is designed to achieve a faster reduction in these borderline symptoms. AIM: To examine the effect of the Jelgersma programme by means of a pilot study in order to prepare a randomised clinical trial in which a short intensive course of DBT will be compared with standard outpatient DBT. METHOD: We compared the starting data and the final data for 39 female patients with borderline problems (DBT). We participated in 3½-month-long inpatient DBT programme. The collected data referred to (para)suicidal behaviour, drop-out, severity of borderline problems and the quality of life. RESULTS: The severity of borderline problems, particularly in the field of interpersonal problems, was significantly reduced. There was no significant reduction in (para) suicidal behaviours. The drop-out percentage was higher than in comparable studies. CONCLUSION: Short-term inpatient DBT had a positive effect on borderline problems. (Para)suicidal behaviour, however, was not reduced significantly. The randomised trial that began in 2012 should reveal whether the use of short-term inpatient DBT can lead to a faster decline of suicidal and self-injurious behaviour than does standard outpatient DBT.

Dantrolene is neuroprotective in vitro, but does not affect survival in SOD1(G9³A) mice.

Amyotrophic Lateral Sclerosis (ALS) is a devastating progressive neurodegenerative disease. One of the proposed disease mechanisms is excitotoxicity, in which excessive cytosolic calcium causes neuronal death. Although most calcium may originate from the extracellular space through activation of calcium-permeable AMPA receptors, we investigated in this study the contribution of endoplasmic reticulum calcium release by blocking the ryanodine receptor (RyR) using dantrolene. In vitro, dantrolene provides a significant protection to motor neurons exposed to a brief excitotoxic insult. However, daily administration of dantrolene to mice overexpressing superoxide dismutase 1 glycine to alanine at position 93 (SOD1(G93A)) does affect neither survival nor the number of motor neurons and ubiquitin aggregates indicating that calcium release through RyRs does not contribute to the selective motor neuron death in this animal model for ALS.

DBT in an outpatient forensic setting.

Literature shows that effective treatment of borderline personality disorder (BPD) has become possible. However, borderline patients in forensic psychiatry do not seem to benefit from this development. In forensic psychiatry, prevention of criminal recidivism is the main focus of treatment, not core borderline problems like parasuicidal and self-destructive behavior. A dialectical behavioral treatment program for BPD was implemented in an outpatient forensic clinic in The Netherlands. Sociodemographic, clinical, and treatment data were collected from ten male, and nineteen female forensic BPD patients, and compared with corresponding data from fifty-eight non-forensic BPD patients. The results show that it is possible to implement dialectical behavior therapy in an outpatient forensic clinic. The data indicate that the exclusion of forensic patients, and especially female forensic patients, from evidence-based treatment is unjustified given the highly comparable clinical and etiological characteristics they share with female BPD patients from general mental health settings.

Dialectical behavior therapy: is outpatient group psychotherapy an effective alternative to individual psychotherapy?: Preliminary conclusions.

OBJECTIVES: This study evaluates a 12-month-duration adapted outpatient group dialectical behavior therapy (DBT) program for patients with a borderline personality disorder in an unselected, comorbid population. If the results of this approach are comparable with the outcome rates of a standard DBT program, the group approach can have several advantages over individual treatment. One advantage is the possibility of treating more patients per therapist. METHOD: A pre-post design was used to measure the effectiveness of an outpatient group DBT. Data from the Beck Depression Inventory II, the Symptom Checklist 90-Revised, the State-Trait Anger Inventory, the State and Trait Anxiety Inventory, of 34 female patients (mean age, 32.65 years) were collected before and after a treatment period of 1 year. RESULTS: Overall, a significant reduction (P < .05) of depressive symptoms, suicidal thoughts, anxiety, and anger was experienced by the patients. CONCLUSIONS: This study is a first attempt in showing that DBT in an outpatient group setting can be effective in reducing psychiatric complaints and therefore has several advantages, such as the opportunity to treat more patients at once.

Genetic rodent models of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective death of motor neurons in the motor cortex, brainstem, and spinal cord. A large number of rodent models are available that show motor neuron death and a progressive motor phenotype that is more or less reminiscent of what occurs in patients. These rodent models contain genes with spontaneous or induced mutations or (over) express different (mutant) genes. Some of these models have been of great value to delineate potential pathogenic mechanisms that cause and/or modulate selective motor neuron degeneration. In addition, these genetic rodent models play a crucial role in testing and selecting potential therapeutics that can be used to treat ALS and/or other motor neuron disorders. In this paper, we give a systematic overview of the most important genetic rodent models that show motor neuron degeneration and/or develop a motor phenotype. In addition, we discuss the value and limitations of the different models and conclude that it remains a challenge to find more and better rodent models based on mutations in new genes causing ALS.

Tau levels do not influence human ALS or motor neuron degeneration in the SOD1G93A mouse.

BACKGROUND: The microtubule-associated protein tau is thought to play a pivotal role in neurodegeneration. Mutations in the tau coding gene MAPT are a cause of frontotemporal dementia, and the H1/H1 genotype of MAPT, giving rise to higher tau expression levels, is associated with progressive supranuclear palsy, corticobasal degeneration, and Parkinson disease (PD). Furthermore, tau hyperphosphorylation and aggregation is a hallmark of Alzheimer disease (AD), and reducing endogenous tau has been reported to ameliorate cognitive impairment in a mouse model for AD. Tau hyperphosphorylation and aggregation have also been described in amyotrophic lateral sclerosis (ALS), both in human patients and in the mutant SOD1 mouse model for this disease. However, the precise role of tau in motor neuron degeneration remains uncertain. METHODS: The possible association between ALS and the MAPT H1/H2 polymorphism was studied in 3,540 patients with ALS and 8,753 controls. Furthermore, the role of tau in the SOD1(G93A) mouse model for ALS was studied by deleting Mapt in this model. RESULTS: The MAPT genotype of the H1/H2 polymorphism did not influence ALS susceptibility (odds ratio = 1.08 [95% confidence interval 0.99-1.18], p = 0.08) and did not affect the clinical phenotype. Lowering tau levels in the SOD1(G93A) mouse failed to delay disease onset (p = 0.302) or to increase survival (p = 0.557). CONCLUSION: These findings suggest that the H1/H2 polymorphism in MAPT is not associated with human amyotrophic lateral sclerosis, and that lowering tau levels in the mutant SOD1 mouse does not affect the motor neuron degeneration in these animals.

Amyotrophic lateral sclerosis and excitotoxicity: from pathological mechanism to therapeutic target.

Glutamate-induced excitotoxicity is responsible for neuronal death in acute neurological conditions as well as in chronic neurodegeneration. In this review, we give an overview of the contribution of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis (ALS). The selective motor neuron death that is the hallmark of this neurodegenerative disease seems to be related to a number of intrinsic characteristics of these neurons. Most of these characteristics relate to calcium entry and calcium handling in the motor neurons as intracellular free calcium concentrations increase quickly due to a high glutamate-induced calcium influx in combination with a low calcium buffering capacity. The high calcium influx is because of the presence of GluR2 lacking, calcium-permeable AMPA receptors while a low expression of calcium binding proteins explains the low calcium buffering capacity. In the absence of these proteins, mitochondria play an important role to remove calcium from the cytoplasm. While all of these characteristics make at least a subpopulation of motor neurons intrinsically very prone to AMPA receptor mediated excitotoxicity, this vulnerability is further increased by the disease process. Mutated genes as well as unknown factors do not only influence the intrinsic characteristics of the motor neurons, but also the properties of the surrounding astrocytes. In conclusion, excitotoxicity remains an intriguing pathological pathway that could not only explain the selectivity of the motor neuron death but also the role of surrounding non-neuronal cells in ALS. In addition, excitotoxicity is also an interesting drug-able target as indicated by the only FDA-approved drug, riluzole, as well as by a number of ongoing clinical trials.

Astrocytes in amyotrophic lateral sclerosis: direct effects on motor neuron survival.

Selective motor neuron death during amyotrophic lateral sclerosis (ALS) is a non-cell autonomous process in which non-neuronal cells induce and/or contribute to the disease process. The non-neuronal cells that are clearly involved in the pathogenesis of the disease are the surrounding astrocytes. Under normal conditions, astrocytes remove glutamate from the synaptic cleft and release trophic factors. In addition, these cells determine the functional characteristics of motor neurons. Recent evidence suggests that activation of astrocytes in a degenerative disease like ALS disturbs the crosstalk between astrocytes and motor neurons, which could contribute to and/or accelerate selective motor neuron death. These new insights may contribute to the development of therapeutic approaches to slow this fatal neurodegenerative disease.

[Dialectical behaviour therapy for adolescents; a literature review]. / Dialectische gedragstherapie bij adolescenten;een literatuuronderzoek.

BACKGROUND: According to several randomised controlled trials (rct's) dialectical behaviour therapy (dbt) is effective in treating adults diagnosed with borderline personality disorder (bpd) who present with self-injurious and suicidal behaviour. In recent years there have been several studies about dbt in adolescents with varying problems and disorders. AIM: To review the literature for evidence of the effectiveness of dbt in adolescents aged 12 to 18. METHOD: With the help of PubMed and Medline and using the search-terms 'dialectical', 'adolescent', 'suicide attempt' and 'deliberate self harm', we searched the literature for references to dbt in adolescents. RESULTS: There were no rct's involving dbt in adolescents, but we did find one quasi-experimental design and several other studies with a pre-post treatment design. However, the studies were difficult to compare. In some cases it was doubtful whether the treatment could still be called dbt. The results suggested that dbt may be just as effective with adolescents as it is with adults in reducing bpd symptoms, suicidal ideation, and comorbid depressive disorder symptoms, and in reducing the need for hospitalisation. The results also indicated that dbt might be effective in treating eating disorders, bipolar disorder, oppositionality, aggression and nonsuicidal self-injurious behaviour (nsib) in a variety of treatment settings. CONCLUSION: dbt is possibly effective for treating adolescents with nsib and/or bpd symptoms. It may also be an effective treatment for various other affective and behavioural disorders. rct's are needed.

Whole-grain consumption, dietary fibre intake and body mass index in the Netherlands cohort study.

OBJECTIVES: To assess the association of whole-grain and (cereal) fibre intake with body mass index (BMI) and with the risk of being overweight (BMI> or =25) or obese (BMI> or =30 kg m(-2)). SUBJECTS: A total of 2078 men and 2159 women, aged 55-69 years, were included in the analysis, after exclusion of subjects with diagnosed cancer or deceased within 1 year after baseline or with missing dietary information. RESULTS: We found an inverse association between whole-grain consumption and BMI and risk of overweight and obesity in men as well as women. The association in men was stronger than in women; the risk of being obese as compared to normal weight was 10% (95% CI: 2-16%) and 4% (95% CI: 1-7%) lower for each additional gram of (dry) grain consumption in men and women, respectively. Fibre and cereal fibre intake were inversely associated with BMI in men only. Associations were similar after exclusion of likely under- and overreporters of energy. A retrospective analysis of baseline fibre intake and weight gain after the age of 20 years also showed a slight inverse association. CONCLUSIONS: Whole-grain consumption may protect against becoming overweight or obese; however, the cross-sectional design of the study does not allow conclusions about the causality of the association.