The new European Medicines Agency guideline on antidepressants: a guide for researchers and drug developers.

According to the World Health Organization (WHO), depressive disorders are currently considered as one of the most disabling medical conditions in the world with one of the highest disability-adjusted life years [1] and this situation has apparently been further worsened during the COVID-19 pandemic [2]. Up to two thirds of patients with major depressive disorders (MDD) do not achieve full remission following an adequate first line standard of care and/or experience residual symptoms such as anxiety, impaired cognition, fatigue, sleep disturbance, or anhedonia [3]. Several attempts are often needed to find the most suitable treatment [4]. Thus, there is a need for medicinal products with better efficacy (e.g., faster onset of action, higher rates of response and remission), improved safety and/or more personalised profiles [5].

Preclinical development of a vaccine against oligomeric alpha-synuclein based on virus-like particles.

Parkinson's disease (PD) is a progressive and currently incurable neurological disorder characterised by the loss of midbrain dopaminergic neurons and the accumulation of aggregated alpha-synuclein (a-syn). Oligomeric a-syn is proposed to play a central role in spreading protein aggregation in the brain with associated cellular toxicity contributing to a progressive neurological decline. For this reason, a-syn oligomers have attracted interest as therapeutic targets for neurodegenerative conditions such as PD and other alpha-synucleinopathies. In addition to strategies using small molecules, neutralisation of the toxic oligomers by antibodies represents an attractive and highly specific strategy for reducing disease progression. Emerging active immunisation approaches using vaccines are already being trialled to induce such antibodies. Here we propose a novel vaccine based on the RNA bacteriophage (Qbeta) virus-like particle conjugated with short peptides of human a-syn. High titres of antibodies were successfully and safely generated in wild-type and human a-syn over-expressing (SNCA-OVX) transgenic mice following vaccination. Antibodies from vaccine candidates targeting the C-terminal regions of a-syn were able to recognise Lewy bodies, the hallmark aggregates in human PD brains. Furthermore, antibodies specifically targeted oligomeric and aggregated a-syn as they exhibited 100 times greater affinity for oligomeric species over monomer a-syn proteins in solution. In the SNCA-OVX transgenic mice used, vaccination was, however, unable to confer significant changes to oligomeric a-syn bioburden. Similarly, there was no discernible effect of vaccine treatment on behavioural phenotype as compared to control groups. Thus, antibodies specific for oligomeric a-syn induced by vaccination were unable to treat symptoms of PD in this particular mouse model.

Altered resting-state connectivity in adolescent cannabis users.

BACKGROUND: Cannabis is the most commonly used illicit drug in adolescence. Heavy use is associated with deficits on a broad range of cognitive functions and heavy use during adolescence may impact development of gray and white matter. OBJECTIVES: To examine differences in intrinsic brain activity and connectivity associated with cannabis dependence in adolescence using whole-brain voxelwise approaches. METHODS: Adolescents admitted to a drug-treatment facility for cannabis dependence (n = 17) and age-matched controls (n = 18) were compared on a measure of oscillations in the low-frequency blood oxygen level-dependent signal at rest (the fractional amplitude of low-frequency fluctuations fALFF, 0.01-0.1 Hz) and interhemispheric resting-state functional connectivity (RSFC) using voxel-mirrored homotopic connectivity. RESULTS: The cannabis-dependent population showed increased fALFF activity compared to the control group in right hemisphere regions including the superior parietal gyrus, superior frontal gyrus, inferior frontal gyrus, inferior semilunar lobe of the cerebellum and the inferior temporal gyrus. Post-hoc analyses revealed stronger intra-hemispheric functional connectivity between these functionally defined regions of interest (ROIs) in the cannabis-dependent population than in the controls. Reduced interhemispheric connectivity was observed in the cannabis users compared to controls in the pyramis of the cerebellum and the superior frontal gyrus. Controls showed reduced interhemispheric connectivity compared to users in the supramarginal gyrus. CONCLUSIONS: The reduced interhemispheric RSFC in adolescent cannabis users complements previous reports of white matter deficits associated with cannabis use. The evidence of elevated connectivity within the right hemisphere may reflect a compensatory mechanism. Combined, the results suggest that altered intrinsic connectivity may be characteristic of adolescent cannabis dependence.

Small-molecule inhibitors at the PSD-95/nNOS interface have antidepressant-like properties in mice.

Previous studies have demonstrated that nitric oxide (NO) synthase inhibitors are as efficacious as tricyclic antidepressants in preclinical antidepressant screening procedures and in attenuating behavioural deficits associated with animal models of depression. The N-methyl-D-aspartate receptor (NMDA-R) complex gates Ca(2+), which interacts with calmodulin to subsequently activate NO synthase. We hypothesised that uncoupling neuronal nitric oxide synthase (nNOS) from the NMDA-R through the scaffolding protein postsynaptic density protein 95 (PSD-95) would produce behavioural antidepressant effects similar to NO synthase inhibitors. Small-molecule inhibitors of the PSD-95/nNOS interaction, IC87201 (0.01-2 mg/kg) and ZL006 (10 mg/kg) were tested for antidepressant properties in tests of antidepressant activity namely the tail suspension and forced swim tests in mice. We now report that IC87201 and ZL006 produce antidepressant-like responses in the forced swimming test (FST) and tail suspension test (TST) following a single administration in mice. By contrast to the tricyclic antidepressant imipramine (25 mg/kg), the effects are not observed 1 h following drug administration but are apparent 24 and 72 h later. Furthermore prior exposure to the TST or FST is required in order to observe the antidepressant-related activity. Similar delayed and sustained antidepressant-like effects were observed following TRIM (50 mg/kg) and ketamine (30 mg/kg) in the TST. The antidepressant-like effects of ZL006 also generalise to IC87201 in the TST. IC87201 was devoid of effects on locomotor activity and step-through latency in the passive avoidance cognition test. These data support the hypothesis that targeting the PSD-95/nNOS interaction downstream of NMDA-R produces antidepressant effects and may represent a novel class of therapeutics for major depressive disorders.

The PSD-95/nNOS complex: new drugs for depression?

Drug treatment of major depressive disorder is currently limited to the use of agents which influence monoaminergic neuronal transmission including inhibitors of presynaptic transporters and monoamine oxidase. Typically improvement in depressive symptoms only emerges after several weeks of treatment, suggesting that downstream neuronal adaptations rather than the elevation in synaptic monoamine levels are responsible for antidepressant effects. In recent years, the NMDA receptor has emerged as a promising target for treating CNS disorders including stroke, pain and depression. In this review, we outline the molecular mechanisms underlying NMDA receptor signalling in neurons and in particular provide an overview of the role of the NMDAR/PSD-95/nNOS complex in CNS disorders. We discuss novel drug developments made that suggest the NMDAR/PSD-95/nNOS complex as a potential target for the treatment of depression. The review also provides examples of how PDZ-based protein-protein interactions can be exploited as novel drug targets for disease.