Actarit

Effect sizes of psychotherapies currently stagnate at a low‐to‐moderate level. Personalizing psychotherapy by algorithm‐based modular procedures promises improved outcomes, greater flexibility, and a better fit between research and practice. However, evidence for the feasibility and efficacy of modular‐based psychotherapy, using a personalized treatment algorithm, is lacking. This proof‐of‐concept randomized controlled trial was conducted in 70 adult outpatients with a primary DSM‐5 diagnosis of major depressive disorder, a score higher than 18 on the 24‐item Hamilton Rating Scale for Depression (HRSD‐24), at least one comorbid psychiatric diagnosis according to the Structured Clinical Interview for DSM‐5 (SCID‐5), a history of at least “moderate to severe” childhood maltreatment on at least one domain of the Childhood Trauma Questionnaire (CTQ), and exceeding the cut‐off value on at least one of three measures of early trauma‐related transdiagnostic mechanisms: the Rejection Sensitivity Questionnaire (RSQ), the Interpersonal Reactivity Index (IRI), and the Difficulties in Emotion Regulation Scale‐16 (DERS‐16). Patients were randomized to 20 sessions of either standard cognitive‐behavioral therapy alone (CBT) or CBT plus transdiagnostic modules according to a mechanism‐based treatment algorithm (MoBa), over 16 weeks. We aimed to assess the feasibility of MoBa, and to compare MoBa vs. CBT with respect to participants’ and therapists’ overall satisfaction and ratings of therapeutic alliance (using the Working Alliance Inventory ‐ Short Revised, WAI‐SR), efficacy, impact on early trauma‐related transdiagnostic mechanisms, and safety. The primary outcome for efficacy was the HRSD‐24 score at post‐treatment. Secondary outcomes included, among others, the rate of response (defined as a reduction of the HRSD‐24 score by at least 50% from baseline and a score <16 at post‐treatment), the rate of remission (defined as a HRSD‐24 score ≤8 at post‐treatment), and improvements in early trauma‐related mechanisms of social threat response, hyperarousal, and social processes/empathy. We found no difficulties in the selection of the transdiagnostic modules in the individual patients, applying the above‐mentioned cut‐offs, and in the implementation of MoBa. Both participants and therapists reported higher overall satisfaction and had higher WAI‐SR ratings with MoBa than CBT. Both approaches led to major reductions of depressive symptoms at post‐treatment, with a non‐significant superiority of MoBa over CBT. Patients randomized to MoBa were nearly three times as likely to experience remission at the end of therapy (29.4% vs. 11.4%; odds ratio, OR = 3.2, 95% CI: 0.9‐11.6). Among mechanism‐based outcomes, MoBa patients showed a significantly higher post‐treatment effect on social processes/empathy (p<0.05) compared to CBT patients, who presented an exacerbation on this domain at post‐treatment. Substantially less adverse events were reported for MoBa compared to CBT. These results suggest the feasibility and acceptability of an algorithm‐based modular psychotherapy complementing CBT in depressed patients with psychiatric comorbidities and early trauma. While initial evidence of efficacy was observed, potential clinical advantages and interindividual heterogeneity in treatment outcomes will have to be investigated in fully powered confirmation trials.

Crucial brain functions such as neurotransmission, myelination, and signaling pose a high demand for lipids. Lipid dysregulation is associated with neuroinflammation and neurodegeneration. Astrocytes protect neurons from lipid induced damage by accumulating and metabolizing toxic lipids in organelles called lipid droplets (LDs). LDs have long been considered as lipid storage compartments in adipocytes, but less is known about their biogenesis and composition in the brain. In particular, proteins covering the LD surface are not yet fully identified. Here, we report that the presynaptic protein Mover/TPRG1L, which regulates the probability of neurotransmitter release in neurons, is a component of the LD coat in astrocytes. Using conventional and super-resolution microscopy, we demonstrate that Mover surrounds naive and oleic acid induced astrocytic LDs. We confirm the identity of astrocytic LDs using the neutral lipid stains Bodipy and LipidTox, as well as immunofluorescence for perilipin-2, a known component of the LD coat. In astrocytes, recombinant Mover was sufficient to induce an accumulation of LDs. Furthermore, we identified point mutations that abolish targeting to LDs and show similarities in the required binding sequences for association to the presynapse and LDs. Our results show that Mover is not only a presynaptic protein but also a candidate for LD regulation. This highlights the dual role of Mover in synaptic transmission and regulation of astrocytic LDs, which may be particularly important in the context of lipid-related neurological disorders.