The Effect of Nabiximols on Driving Ability in Adults with Chronic Tic Disorders: Results of a Substudy Analysis of the Double-Blind, Randomized, Placebo-Controlled CANNA-TICS Trial.

Background: The multicenter, randomized, double-blind, parallel-group, phase IIIb CANNA-TICS (CANNAbinoids in the treatment of TICS) trial showed clear trends for improvement of tics, depression, and quality of life with nabiximols versus placebo in adult patients with Gilles de la Tourette syndrome and other chronic tic disorders. Although in general nabiximols was well tolerated, it is unclear whether treatment using this cannabis extract influences driving skills in patients with chronic tic disorders. Methods: Here we report results of the "Fitness to Drive" substudy of the CANNA-TICS trial. The key endpoint was fitness to drive as a binary criterion with a computerized assessment at baseline and after 9 weeks of stable treatment (week 13) with nabiximols or placebo. A patient was considered unfit to drive according to the German Federal Highway Research Institute guidelines. Results: In the substudy, a total of 64 patients (76.6% men, mean±standard deviation of age: 36.8±13.9) were recruited at two study sites. The number of patients who were fit to drive increased from 24 (55.8%) at baseline to 28 (71.8%) at week 13 among 43 patients treated with nabiximols, and decreased from 14 (66.7%) to 10 (52.6%) among 21 patients who received placebo. The risk difference (nabiximols - placebo) was 0.17 (95% confidence interval=-0.08 to 0.43) in favor of nabiximols. Specifically, only 2 of 24 (8.3%) patients in the nabiximols, but 4 of 14 (28.6%) patients in the placebo group changed for the worse from fit (at baseline) to unfit (at week 13) to drive, whereas 8 of 19 (42.1%) patients in the nabiximols, and only 2 of 7 (28.6%) patients in the placebo group improved from unfit to fit. Conclusion: Treatment with nabiximols does not impair skills relevant to driving in those patients with tic disorders who were fit to drive at baseline and even improved fitness to drive in a subset of patients who were unfit to drive before start of treatment. EudraCT number: 2016-000564-42.

Unstable Belief Formation and Slowed Decision-making: Evidence That the Jumping-to-Conclusions Bias in Schizophrenia Is Not Linked to Impulsive Decision-making.

BACKGROUND: Jumping-to-conclusions (JTC) is a prominent reasoning bias in schizophrenia (SCZ). While it has been linked to not only psychopathological abnormalities (delusions and impulsive decision-making) but also unstable belief formation, its origin remains unclear. We here directly test to which extend JTC is associated with delusional ideation, impulsive decision-making, and unstable belief formation. METHODS: In total, 45 SCZ patients were compared with matched samples of 45 patients with major depressive disorder (MDD) and 45 healthy controls (HC) as delusions and JTC also occur in other mental disorders and the general population. Participants performed a probabilistic beads task. To test the association of JTC with measures of delusions (Positive and Negative Syndrome Scale [PANSS]positive, PANSSpositive-factor, and Peter Delusions Inventory [PDI]), Bayesian linear regressions were computed. For the link between JTC and impulsive decision-making and unstable beliefs, we conducted between-group comparisons of "draws to decision" (DTD), "decision times" (DT), and "disconfirmatory evidence scores" (DES). RESULTS: Bayesian regression obtained no robust relationship between PDI and DTD (all |R2adj| ≤ .057, all P ≥ .022, all Bayes Factors [BF01] ≤ 0.046; α adj = .00833). Compared with MDD and HC, patients with SCZ needed more time to decide (significantly higher DT in ambiguous trials: all P ≤ .005, r2 ≥ .216; numerically higher DT in other trials). Further, SCZ had unstable beliefs about the correct source jar whenever unexpected changes in bead sequences (disconfirmatory evidence) occurred (compared with MDD: all P ≤ .004 and all r2 ≥ .232; compared with HC: numerically higher DES). No significant correlation was observed between DT and DTD (all P ≥ .050). CONCLUSIONS: Our findings point toward a relationship of JTC with unstable belief formation and do not support the assumption that JTC is associated with impulsive decision-making.

The CANNA-TICS Study Protocol: A Randomized Multi-Center Double-Blind Placebo Controlled Trial to Demonstrate the Efficacy and Safety of Nabiximols in the Treatment of Adults With Chronic Tic Disorders.

Background: Gilles de la Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by motor and vocal tics. First-line treatments for tics are antipsychotics and tic-specific behavioral therapies. However, due to a lack of trained therapists and adverse events of antipsychotic medication many patients seek alternative treatment options including cannabis. Based on the favorable results obtained from case studies on different cannabis-based medicines as well as two small randomized controlled trials using delta-9-tetrahydrocannabinol (THC), we hypothesize that the cannabis extract nabiximols can be regarded as a promising new and safe treatment strategy in TS. Objective: To test in a double blind randomized clinical trial, whether treatment with the cannabis extract nabiximols is superior to placebo in patients with chronic tic disorders. Patients and Methods: This is a multicenter, randomized, double-blind, placebo controlled, parallel-group, phase IIIb trial, which aims to enroll 96 adult patients with chronic tic disorders (TS or chronic motor tic disorder) across 6 centers throughout Germany. Patients will be randomized with a 2:1 ratio into a nabiximols and a placebo arm. The primary efficacy endpoint is defined as tic reduction of at least 30% (compared to baseline) according to the Total Tic Score of the Yale Global Tic Severity Scale (YGTSS-TTS) after 13 weeks of treatment. In addition, several secondary endpoints will be assessed including changes in different psychiatric comorbidities, quality of life, driving ability, and safety assessments. Discussion: This will be the first large, controlled study investigating efficacy and safety of a cannabis-based medicine in patients with TS. Based on available data using different cannabis-based medicines, we expect not only a reduction of tics, but also an improvement of psychiatric comorbidities. If the cannabis extract nabiximols is proven to be safe and effective, it will be a valuable alternative treatment option. The results of this study will be of high health-economic relevance, because a substantial number of patients uses cannabis (illegally) as self-medication. Conclusion: The CANNA-TICS trial will clarify whether nabiximols is efficacious and safe in the treatment of patients with chronic tic disorders. Clinical Trial Registration: This trial is registered at clinicaltrialsregister.eu (Eudra-CT 2016-000564-42) and clinicaltrials.gov (NCT03087201).

Glutamatergic Contribution to Probabilistic Reasoning and Jumping to Conclusions in Schizophrenia: A Double-Blind, Randomized Experimental Trial.

BACKGROUND: Impaired probabilistic reasoning and the jumping-to-conclusions reasoning bias are hallmark features of schizophrenia (SCZ), yet the neuropharmacological basis of these deficits remains unclear. Here we tested the hypothesis that glutamatergic neurotransmission specifically contributes to jumping to conclusions and impaired probabilistic reasoning in SCZ. METHODS: A total of 192 healthy participants received either NMDA receptor agonists/antagonists (D-cycloserine/dextromethorphan), dopamine type 2 receptor agonists/antagonists (bromocriptine/haloperidol), or placebo in a randomized, double-blind, between-subjects design. In addition, we tested 32 healthy control participants matched to 32 psychotic inpatients with SCZ-a state associated with compromised probabilistic reasoning due to reduced glutamatergic neurotransmission. All experiments employed two versions of a probabilistic reasoning (beads) task, which required participants to either sample individual amounts of sensory information to infer correct decisions or provide explicit probability estimates for presented sensory information. Our task instantiations assessed both information sampling and explicit probability estimates in different probabilistic contexts (easy vs. difficult conditions) and changing sensory information through random transitions among easy, difficult, and ambiguous trial types. RESULTS: Following administration of D-cycloserine, haloperidol, and bromocriptine, healthy participants displayed data-gathering behavior that was normal compared with placebo and was adequate in the context of all employed task conditions and trial level difficulties. However, healthy participants receiving dextromethorphan displayed a jumping-to-conclusions bias, abnormally increased probability estimates, and overweighting of sensory information. These effects were mirrored in patients with SCZ performing the same versions of the beads task. CONCLUSIONS: Our findings provide novel neuropharmacological evidence linking reduced glutamatergic neurotransmission to impaired information sampling and to disrupted probabilistic reasoning, namely to overweighting of sensory evidence, in patients with SCZ.

Vagus nerve stimulation in psychiatry: a systematic review of the available evidence.

Invasive and non-invasive vagus nerve stimulation (VNS) is a promising add-on treatment for treatment-refractory depression, but is also increasingly evaluated for its application in other psychiatric disorders, such as dementia, schizophrenia, somatoform disorder, and others. We performed a systematic review aiming to give a detailed overview of the available evidence of the efficacy of VNS for the treatment of psychiatric disorders. Data derived from animal models, experimental trials without health-related outcomes, case reports, single-session studies, and reviews were excluded. From 1292 publications, 33 records were included for further analyses: 25 focused on VNS as treatment of unipolar or bipolar major depressive disorder and one investigated the neurocognitive improvement after VNS in major depressive disorder. Seven focused on the improvement of cognitive function in Alzheimer´s disease, improvement of schizophrenia symptoms, treatment of obsessive compulsive disorder (OCD), panic disorder (PD) and post-traumatic stress disorder (PTSD), treatment resistant rapid-cycling bipolar disorder, treatment of fibromyalgia, and Prader-Willi syndrome. A total of 29 studies used invasive VNS, while four studies used non-invasive, transcutaneous VNS. Only 7 out of 33 studies investigated conditions other than affective disorders. The efficacy data of VNS in affective disorders is promising, whereas more in controlled and naturalistic studies are needed. In other conditions like schizophrenia, Alzheimer's disease, OCD, PD, PTSD, and fibromyalgia, either no effects or preliminary data on efficacy were reported. At this point, no final conclusion can be made regarding the efficacy of VNS to improve symptoms in psychiatric disorders other than in affective disorders.

Head and neck cooling decreases tympanic and skin temperature, but significantly increases blood pressure.

BACKGROUND AND PURPOSE: Localized head and neck cooling might be suited to induce therapeutic hypothermia in acute brain injury such as stroke. Safety issues of head and neck cooling are undetermined and may include cardiovascular autonomic side effects that were identified in this study. METHODS: Ten healthy men (age 35±13 years) underwent 120 minutes of combined head and neck cooling (Sovika, HVM Medical). Before and after onset of cooling, after 60 and 120 minutes, we determined rectal, tympanic, and forehead skin temperatures, RR intervals, systolic and diastolic blood pressures (BP), laser-Doppler skin blood flow at the index finger and cheek, and spectral powers of mainly sympathetic low-frequency (0.04-0.15 Hz) and parasympathetic high-frequency (0.15-0.5 Hz) RR interval oscillations and sympathetic low-frequency oscillations of BP. We compared values before and during cooling using analysis of variance with post hoc analysis; (significance, P<0.05). RESULTS: Forehead skin temperature dropped by 5.5±2.2°C with cooling onset and by 12.4±3.2°C after 20 minutes. Tympanic temperature decreased by 4.7±0.7°C within 40 minutes, and rectal temperature by only 0.3±0.3°C after 120 minutes. Systolic and diastolic BP increased immediately on cooling onset and rose by 15.3±20.8 mm Hg and 16.5±13.4 mm Hg (P=0.004) after 120 minutes, whereas skin blood flow fell significantly during cooling. RR intervals and parasympathetic RR interval high-frequency powers increased with cooling onset and were significantly higher after 60 and 120 minutes than they were before cooling. CONCLUSIONS: Head and neck cooling prominently reduced tympanic temperature and thus might also induce intracerebral hypothermia; however, it did not significantly lower body core temperature. Profound skin temperature decrease induced sympathetically mediated peripheral vasoconstriction and prominent BP increases that are not offset by simultaneous parasympathetic heart rate slowing. Prominent peripheral vasoconstriction and BP increase must be considered as possibly harmful during head and neck cooling.