Early experience with the new DORA daridorexant in patients with insomnia disorder and comorbid mental disturbances: Results of a naturalistic study with 3 months follow-up.

Insomnia disorder may affect mental health, increasing suicidal risk. Targeting insomnia is crucial in the clinical practice. Sixty-six consecutive patients with insomnia disorder according with the DSM-5-TR criteria were treated with the dual orexin receptor antagonist, daridorexant 50 mg. Baseline (T0), 1 month (T1) and 3 month (T2) evaluations were performed. Insomnia severity (Insomnia Severity Index), mood, anxiety symptoms and suicidal risk (Beck Depression Inventory-II, Young Mania Rating Scale, Self-Reported Anxiety Scale, Suicidal Ideation Scale), dysfunctional insomnia-cognitive factors and pre-sleep arousal (Dysfunctional Beliefs About Sleep, Pre-Sleep Arousal Scale) were evaluated. The final sample included 66 patients (n = 36, 54% females, mean age 60 ± 13.6 years). Most of them, 64%, suffered from insomnia disorder comorbid with unipolar/bipolar depression, anxiety disorders and substance use disorders. Repeated ANOVA analyses showed that Insomnia Severity Index, Dysfunctional Beliefs About Sleep and Pre-Sleep Arousal Scale total score decreased across time (F = 68.818, p < 0.001; F = 47.561, p < 0.001; F = 28.142, p < 0.001, respectively). Similarly, Beck Depression Inventory-II, Self-Reported Anxiety Scale, Young Mania Rating Scale, and Suicidal Ideation Scale significantly decreased over time (p < 0.001). Predictors of insomnia remission (Insomnia Severity Index < 8) at T1 were improvement of Insomnia Severity Index at T1 (F = 60.205, p < 0.001), and improvement of Dysfunctional Beliefs About Sleep at T1 (F = 4.432, p = 0.041). Insomnia remission at T2 was best predicted by improvement of Dysfunctional Beliefs About Sleep at T2 (F = 3.993, p = 0.023). Multiple-regression models showed that clinical improvement of Beck Depression Inventory-II was best predicted by improvement in Dysfunctional Beliefs About Sleep at T1 and T2, manic symptoms by Insomnia Severity Index at T2, anxiety symptoms by Dysfunctional Beliefs About Sleep, Insomnia Severity Index and somatic Pre-Sleep Arousal Scale at T1 and T2. With the caution of a naturalistic design, early experience with daridorexant showed that by targeting insomnia it may be possible to improve not only insomnia symptoms but also comorbid symptoms.

Pharmacological Strategies for Bipolar Disorders in Acute Phases and Chronic Management with a Special Focus on Lithium, Valproic Acid, and Atypical Antipsychotics.

Bipolar disorders (BDs) are a heterogeneous group of severe affective disorders generally described by the alternation of (hypo)manic, depressive, and mixed phases, with euthymic intervals of variable duration. BDs are burdened with high psychiatric and physical comorbidity, increased suicide risk and reduced life expectancy. In addition, BDs can progress into complicated forms (e.g., mixed states, rapid/irregular cycling), which are more difficult to treat and often require personalized pharmacological combinations. Mood stabilizers, particularly Lithium and Valproic acid (VPA), still represent the cornerstones of both acute and chronic pharmacotherapies of BDs. Lithium is the gold standard in BD-I and BDII with typical features, while VPA seems more effective for atypical forms (e.g., mixed-prevalence and rapid-cycling). However, despite appropriate mood stabilization, many patients show residual symptoms, and more than a half recur within 1-2 years, highlighting the need of additional strategies. Among these, the association of atypical antipsychotics (AAPs) with mood stabilizers is recurrent in the treatment of acute phases, but it is also being growingly explored in the maintenance pharmacotherapy. These combinations are clinically more aggressive and often needed in the acute phases, whereas simplifying pharmacotherapies to mood stabilizers only is preferable in the long-term, whenever possible. When mood stabilizers are not enough for maintenance treatment, Quetiapine and, less consistently, Aripiprazole have been proposed as the most advisable adjunctive strategies, for their safety and tolerability profiles. However, in view of the increased risk of serious adverse effects, a careful patient-centered balance between costs and benefits is mandatory.

Is Adult Hippocampal Neurogenesis Really Relevant for the Treatment of Psychiatric Disorders?

Adult neurogenesis consists in the generation of newborn neurons from neural stem cells taking place in the adult brain. In mammals, this process is limited to very few areas of the brain, and one of these neurogenic niches is the subgranular layer of the dentate gyrus (DG) of the hippocampus. Adult newborn neurons are generated from quiescent neural progenitors (QNPs), which differentiate through different steps into mature granule cells (GCs), to be finally integrated into the existing hippocampal circuitry. In animal models, adult hippocampal neurogenesis (AHN) is relevant for pattern discrimination, cognitive flexibility, emotional processing and resilience to stressful situations. Imaging techniques allow to visualize newborn neurons within the hippocampus through all their stages of development and differentiation. In humans, the evidence of AHN is more challenging, and, based on recent findings, it persists through adulthood, even if it declines with age. Whether this process has an important role in human brain function and how it integrates into the existing hippocampal circuitry is still a matter of exciting debate. Importantly, AHN deficiency has been proposed to be relevant in many psychiatric disorders, including mood disorders, anxiety, post-traumatic stress disorder and schizophrenia. This review aims to investigate how AHN is altered in different psychiatric conditions and how pharmacological treatments can rescue this process. In fact, many psychoactive drugs, such as antidepressants, mood stabilizers and atypical antipsychotics (AAPs), can boost AHN with different results. In addition, some non-pharmacological approaches are discussed, as well.