Internet-delivered cognitive behavioural therapy programme to reduce depressive symptoms in patients with multiple sclerosis: a multicentre, randomised, controlled, phase 3 trial

BACKGROUND: Depression is three to four times more prevalent in patients with neurological and inflammatory disorders than in the general population. For example, in patients with multiple sclerosis, the 12-month prevalence of major depressive disorder is around 25% and it is associated with a lower quality of life, faster disease progression, and higher morbidity and mortality. Despite its clinical relevance, there are few treatment options for depression associated with multiple sclerosis and confirmatory trials are scarce. We aimed to evaluate the safety and efficacy of a multiple sclerosis-specific, internet-based cognitive behavioural therapy (iCBT) programme for the treatment of depressive symptoms associated with the disease. METHODS: This parallel-group, randomised, controlled, phase 3 trial of an iCBT programme to reduce depressive symptoms in patients with multiple sclerosis was carried out at five academic centres with large outpatient care units in Germany and the USA. Patients with a neurologist-confirmed diagnosis of multiple sclerosis and depressive symptoms were randomly assigned (1:1:1; automated assignment, concealed allocation, no stratification, no blocking) to receive treatment as usual plus one of two versions of the iCBT programme Amiria (stand-alone or therapist-guided) or to a control condition, in which participants received treatment as usual and were offered access to the iCBT programme after 6 months. Masking of participants to group assignment between active treatment and control was not possible, although raters were masked to group assignment. The predefined primary endpoint, which was analysed in the intention-to-treat population, was severity of depressive symptoms as measured by the Beck Depression Inventory-II (BDI-II) at week 12 after randomisation. This trial is registered at ClinicalTrials.gov, NCT02740361, and is complete. FINDINGS: Between May 3, 2017, and Nov 4, 2020, we screened 485 patients for eligibility. 279 participants were enrolled, of whom 101 were allocated to receive stand-alone iCBT, 85 to receive guided iCBT, and 93 to the control condition. The dropout rate at week 12 was 18% (50 participants). Both versions of the iCBT programme significantly reduced depressive symptoms compared with the control group (BDI-II between-group mean differences: control vs stand-alone iCBT 6·32 points [95% CI 3·37-9·27], p<0·0001, effect size d=0·97 [95% CI 0·64-1·30]; control vs guided iCBT 5·80 points [2·71-8·88], p<0·0001, effect size d=0·96 [0·62-1·30]). Clinically relevant worsening of depressive symptoms was observed in three participants in the control group, one in the stand-alone iCBT group, and none in the guided iCBT group. No occurrences of suicidality were observed during the trial and there were no deaths. INTERPRETATION: This trial provides evidence for the safety and efficacy of a multiple sclerosis-specific iCBT tool to reduce depressive symptoms in patients with the disease. This remote-access, scalable intervention increases the therapeutic options in this patient group and could help to overcome treatment barriers

Timing of cleft palate closure should be based on the ratio of the area of the cleft to that of the palatal segments and not on age alone

BACKGROUND: Retrospective and prospective serial spatiotemporal investigations were carried out primarily to determine whether the ratio of the size of the posterior cleft space relative to the palatal surface area limited laterally by the alveolar ridges can be used to select the appropriate time for surgical closure of the palatal cleft space. Two subsamples were compared to determine whether the size of the palate and velocity of palatal development in well growing cases differ from those in cases treated by vomer flap surgery. The prospective investigation asked whether presurgical orthopedics increases the rate of palatal growth and palatal size. METHODS: Using the palatal casts of 242 male and female individuals from eight institutions in the United States and Western Europe that followed a variety of treatment protocols, separate serial analyses were conducted of well growing cases with excellent aesthetics, dental occlusion, and speech and a control series of 17 cases of various clefts of the lip and alveolus and/or soft palate but no clefts in the hard palate. Twelve groupings of cases were established depending on their institutional location and type of cleft. RESULTS: Among the various institutions in the study, palatal growth rates and size were statistically similar. Growth in the various clinical series (size, mm2) was less than that of the control series. The ratio of cleft space size to palatal surface area medial to the alveolar ridges was 10 percent or less at 18 months of age in most cases. There was no statistical difference in total surface size between groups, except for one series whose total growth size was least of all. Right and left lateral palatal segments, whether large or small, grew at the same rate. The sample of bilateral cases was too small for statistical comparisons. Presurgical orthopedics did not stimulate palatal growth. The coefficient of variance was less than 10 percent in all measurements. CONCLUSIONS: Delaying all cleft closure surgery until 5 years of age and older is unnecessary to maximize palatal growth. The best time to close the palatal cleft space is when the palatal cleft size is 10 percent or less of the total palatal surface area bounded laterally by the alveolar ridges. The 10 percent ratio generally occurs between 18 and 24 months but can occur earlier or later. There is more than one good type of palatal cleft closure surgery