San Sebastian, Guipuzcoa, Spain

Processes and Circuitry Underlying Threat Sensitivity as a Treatment Target for Co-morbid Anxiety and Depression

This mechanistic study of major depressive disorder (MDD), anxiety disorders (AD) and comorbid anxiety and depression (AD-MDD) aims to break down threat sensitivity into acute threat (AT) and potential threat (PT). A well validated startle task (Neutral, Predictable, Unpredictable or NPU-threat task) and a cutting-edge computational functional magnetic resonance imaging (fMRI) probe of predator escape decisions (Flight Initiation Distance or FID task) will be used to determine whether AD-MDD show increased PT or AT and how the behavioral dynamics of escape decisions are most impaired in AD-MDD. Based on prior studies, we hypothesize that AD is associated with exaggerated PT, whereas MDD is associated with blunted reward/salience responding. Thus, AD-MDD may differ from AD through blunted AT/salience (periaqueductal grey/insula circuitry and Fear-Potentiated Startle [FPS]) and may differ from MDD through increased PT (hippocampal - ventromedial prefrontal cortex (vmPFC) - amygdala dependent circuitry and Anxiety-Potentiated Startle [APS]). To causally probe this circuitry, we will manipulate gamma-aminobutyric acid (GABA) to demonstrate different responses in PT between these three groups, providing further evidence for PT as a targetable process. This mechanistic R01 uses a benzodiazepine within an experimental medicine approach to causally modulate the threat processing system and associated circuits in AD-MDD (N=50), MDD (N=50), and AD (N=50). After the ~2.5 hr screening session, participants will complete two identical ~5 hr experimental sessions, each of which include a 30 min electromyography (EMG) session and a 1.5 hr functional magnetic resonance imaging (fMRI) session. The total time involved in the study is approximately 10.5 hours. In a double-blind placebo crossover design, participants will receive a single 1mg dose of Lorazepam/Placebo and complete threat tasks that delineate PT/AT during startle EMG (NPU task; unpredictable vs predictable shock) and fMRI (FID task; slow vs fast threat). Specific aims of this project are: Aim 1: Determine EMG signatures of dysregulated threat processing in AD-MDD. Hypothesis 1 A (H1A): AD-MDD/AD will exhibit higher PT sensitivity (greater APS) than MDD (NPU APS: AD-MDD > MDD; AD > MDD). Hypothesis 1 B (H1B): AD-MDD/MDD will exhibit lower AT sensitivity (smaller FPS) than AD (NPU FPS: AD-MDD < AD; MDD < AD). Aim 2: Determine neural computational signatures of dysregulated threat processing in AD-MDD. Hypothesis 2 A (H2A): AD-MDD and AD will show higher hippocampal-vmPFC-amygdala responses to FID slow threat (PT) than MDD (FID slow: AD-MDD > MDD; AD > MDD). Hypothesis 2 B (H2B): AD-MDD and MDD will show lower periaqueductal grey/insula responses to FID fast threat (AT) than AD. (FID fast: AD-MDD < AD; MDD < AD). Hypothesis 2 C (H2C): Utility functions for the FID task will show both blunted reward and exaggerated threat valuation in AD-MDD, leading to less optimal choices than both MDD and AD. Aim 3: Determine the relevance of comorbidity to GABAergic manipulation of threat circuitry. Hypothesis 3 A (H3A): In the NPU task Lorazepam will decrease APS (PT) but not FPS (AT) in AD and AD-MDD but not MDD. Hypothesis 3 B (H3B): In the FID task Lorazepam will decrease neural response to slow (PT) but not fast (AT) threat and decrease the computational threat valuation parameter in AD and AD-MDD but not MDD. Significance: These aims seek to mechanistically define and pharmacologically probe process dysfunction and associated targetable circuitry unique to AD-MDD and provide evidence that AD-MDD and MDD should be separated in future clinical trials. This will also inform intervention strategies with circuit-based targets (e.g. for neuromodulation treatments) for AD-MDD, which is a large but under-served treatment resistant group.

A Study of Mianserin in Combination With SSRIs in Depression With Sleep Problems

Evaluating Sublingual Dexmedetomidine For Moderate To Severe Agitation In Inpatients With Schizophrenia Or Bipolar Disorder

This is an open-label, randomized control trial where patients (N=32) with schizophrenia or bipolar disorder are randomized to receive either sublingual dexmedetomidine or oral lorazepam monotherapy for the treatment of episodic agitation. For moderate agitation (PANSS-EC score ≥14 and <20), patients will receive either sublingual dexmedetomidine 120mcg or oral lorazepam 2mg. For severe agitation (PANSS-EC ≥20), patients will receive either sublingual dexmedetomidine 180mcg or oral lorazepam 2mg. The PANSS-EC and ACES will be evaluated at baseline and after 15, 30, 60, and 120 minutes.

Therapies for Down Syndrome Regression Disorder

Recent published case reports and clinical experience of the investigators indicate Down Syndrome Regression Disorder (DSRD) may be successfully treated with immune-modulating therapies, in addition to current pharmacologic options. This study is a multidimensional clinical trial designed to advance the understanding of the etiology of DSRD and to evaluate the safety and efficacy of three distinct therapeutic approaches to treating DSRD: (1) the benzodiazepine lorazepam (Ativan™) (2) intravenous immunoglobulin (IVIG, Gammagard™) or (3) the JAK inhibitor tofacitinib (Xeljanz™). Participants will be randomized into one of the three treatment arms above for the 12-week study period, with a subset of participants undergoing an initial 12-week observational period. Specific Aims: 1. To define the relative safety profile of lorazepam, IVIG, and tofacitinib in DSRD. 2. To compare the efficacy of lorazepam, IVIG, and tofacitinib in DSRD. 3. To investigate potential mechanisms underlying DSRD and its response to therapies.

Acute Agitation in Emergency Psychiatry

The initial treatment of acute agitation aims to reduce suffering, abort the immediate risk of harm to self or others, and prevent the use of coercive measures such a physical and mechanical restraint. With this research project, we aim to build the initial structure of a visionary platform design and to examine the efficacy, tolerability, and safety of two hitherto under-investigated compounds versus the current standard of care for acutely agitated patients when de-escalation techniques have failed. After obtaining the results of the initial phase, we plan to apply for future funding to maintain and expand the platform design with the addition of relevant experimental arms. The proposed platform design aims to anwer the question What is the best treatment for acutely agitated patients in inpatient psychiatric settings?

Blood Concentration in Lorazepam and Treatment in Adult Catatonia

Effect of Ketanserin, Olanzapine, and Lorazepam After LSD Administration on the Acute Response to LSD in Healthy Subjects

LSD is investigated as treatment for various psychiatric (e.g., depression and anxiety) but also somatic disorders (e.g., cluster headache). In Switzerland, compassionate use of psychedelics including LSD is possible based on single authorizations of the federal office of public health in treatment-resistant patients. Additionally, current social and political changes demonstrate a shift of how psychedelics are seen and how they might be used in therapy in the future. Despite the good safety profile of LSD, a broader use might increase the number of adverse psychological reactions to LSD. For such occasions, health professionals should have a tool to not only psychologically but also pharmacologically interfere and end states of acute psychedelic-induced distress. In clinical practice, the gamma-butyric acid (GABA) agonistic acting benzodiazepine lorazepam or the atypical neuroleptic olanzapine with affinity to the 5-HT2A, 5-HT2C and dopamine D1-4 receptors are primarily used for the treatment of drug-induced psychotic symptoms. However, the ability of these drugs to block these effects after LSD intake remains to be investigated. The primary goal of the present study is therefore to investigate whether ketanserin, olanzapine and lorazepam administration after LSD administration might attenuate and shorten the LSD response compared to administration of LSD alone. Additionally, the present study examines changes in quality of the LSD experience after administration of ketanserin, olanzapine or lorazepam and effects on sensorimotor gating and sleep. The study provides insight into the receptor mechanisms involved in alterations of consciousness and specifically the relevance of ongoing 5-HT2A receptor stimulation in the mediation of the psychedelic response to LSD and psychotic symptoms.