Advances in Management of Psychosis in Neurodegenerative Diseases.

PURPOSE OF THE REVIEW: Psychosis is broadly defined as a disengagement from reality. It describes syndromes that impair both thought content and thought process. Psychosis negatively impacts an individual's quality of life, in addition to the families caring for them. Psychosis with different types of hallucinations and delusions occurs in the context of delirium. Neuropsychiatric symptoms (NPS) are almost universal in the course of common neurodegenerative disorders (NDD) like Alzheimer's disease (AD) or Parkinson's disease (PD). In this paper, the authors took an effort to characterize AD and PD psychosis with a special focus on the most diagnostically reliable features. Effectiveness and limitations of pharmacological interventions are discussed. RECENT FINDINGS: Consensus diagnostic criteria have evolved for psychosis secondary to AD as well as psychosis in PD. Psychotropic medications can be effective in the treatment of NPS in NDD; however, clinicians must be mindful of the side effects. There is a consensus on benefit of initiating any acetylcholinesterase inhibitor (ACHI: donepezil, rivastigmine, and galantamine) as a first line of treatment for psychosis in AD, as it may reduce and/or avoid the need for the use antipsychotics. Pimavanserin, a selective-serotonin inverse agonist that preferentially targets 5-HT2A receptors, while avoiding activity at dopamine and other receptors commonly targeted by antipsychotics had recently been approved by FDA to treat hallucinations and delusions in PD. Quetiapine is widely prescribed for the treatment of psychosis in different NDD, but the data remains equivocal. Psychosis with different types of hallucinations and delusions may occur in the context of delirium and is almost universal as a neuropsychiatric symptom in the course of PD and AD. Currently, pimavanserin remains the only pharmacologic agent approved for treatment of psychosis in PD. In cases of other NPS in other than Parkinson's diseases, atypical antipsychotics are commonly used off-label. More research is greatly needed to advance this field and address NPS especially psychosis in geriatric population.

Genetic predictors of response to treatment with citalopram in depression secondary to traumatic brain injury.

OBJECTIVES: To determine which serotonergic system-related single nucleotide polymorphisms (SNPs) predicted variation in treatment response to citalopram in depression following a traumatic brain injury (TBI). METHODS: Ninety (50 M/40 F, aged 39.9, SD = 18.0 years) post-TBI patients with a major depressive episode (MDE) were recruited into a 6-week open-label study of citalopram (20 mg/day). Six functional SNPs in genes related to the serotonergic system were examined: serotonin transporter (5HTTLPR including rs25531), 5HT1A C-(1019)G and 5HT2A T-(102)C, methylene tetrahydrofolate reductase (MTHFR) C-(677)T, brain-derived neurotrophic factor (BDNF) val66met and tryptophan hydroxylase-2 (TPH2) G-(703)T. Regression analyses were performed using the six SNPs as independent variables: Model 1 with response (percentage Hamilton Depression (HAMD) change from baseline to endpoint) as the dependent variable and Model 2 with adverse event index as the dependent variable (Bonferroni corrected p-value < 0.025). RESULTS: MTHFR and BDNF SNPs predicted greater treatment response (R(2)= 0.098, F = 4.65, p = 0.013). The 5HTTLPR predicted greater occurrence of adverse events (R(2)= 0.069, F = 5.72, p = 0.020). CONCLUSION: Results suggest that polymorphisms in genes related to the serotonergic system may help predict short-term response to citalopram and tolerability to the medication in patients with MDE following a TBI.

Factor analysis of the Rivermead Post-Concussion Symptoms Questionnaire in mild-to-moderate traumatic brain injury patients.

Posttraumatic brain injury patients with depressive symptoms were compared with nondepressed mild and moderate traumatic brain injury (TBI) patients based on their scores on the Rivermead Post-Concussion Symptoms Questionnaire (RPCSQ). A factor analysis demonstrated that the items of the RPCSQ loaded into three factors: mood and cognition, general somatic, and visual somatic symptom groups. Factor scores based on this model were calculated for each group and it was found that depressed subjects reported a greater severity of all three symptom groups compared to nondepressed patients. These results suggest that depression post-TBI may influence patient perception of postconcussion symptoms.

Therapy for Alzheimer's Disease: How Effective are Current Treatments?

Available symptomatic therapies for the treatment of Alzheimer's disease (AD) have been based on known neurotransmitter dysfunctions associated with the illness. The second-generation cholinesterase inhibitors and the N-methyl D-aspartate receptor antagonist memantine have been widely prescribed and studied. Meta-analyses of these therapies were reviewed, focusing on effectiveness and tolerability. Although many of the meta-analyses demonstrate statistically significant improvements, some question if these benefits are sufficient to justify their current widespread and protracted use. This has spurred the development of new disease-modifying therapies that aim to have a greater impact on this debilitating illness.

Dopamine receptor oligomerization visualized in living cells.

G protein-coupled receptors occur as dimers within arrays of oligomers. We visualized ensembles of dopamine receptor oligomers in living cells and evaluated the contributions of receptor conformation to the dynamics of oligomer association and dissociation, using a strategy of trafficking a receptor to another cellular compartment. We incorporated a nuclear localization sequence into the D1 dopamine receptor, which translocated from the cell surface to the nucleus. Receptor inverse agonists blocked this translocation, retaining the modified receptor, D1-nuclear localization signal (NLS), at the cell surface. D1 co-translocated with D1-NLS to the nucleus, indicating formation of homooligomers. (+)-Butaclamol retained both receptors at the cell surface, and removal of the drug allowed translocation of both receptors to the nucleus. Agonist-nonbinding D1(S198A/S199A)-NLS, containing two substituted serine residues in transmembrane 5 also oligomerized with D1, and both were retained on the cell surface by (+)-butaclamol. Drug removal disrupted these oligomerized receptors so that D1 remained at the cell surface while D1(S198A/S199A)-NLS trafficked to the nucleus. Thus, receptor conformational differences permitted oligomer disruption and showed that ligand-binding pocket occupancy by the inverse agonist induced a conformational change. We demonstrated robust heterooligomerization between the D2 dopamine receptor and the D1 receptor. The heterooligomers could not be disrupted by inverse agonists targeting either one of the receptor constituents. However, D2 did not heterooligomerize with the structurally modified D1(S198A/S199A), indicating an impaired interface for their interaction. Thus, we describe a novel method showing that a homogeneous receptor conformation maintains the structural integrity of oligomers, whereas conformational heterogeneity disrupts it.

D2 dopamine receptor homodimerization is mediated by multiple sites of interaction, including an intermolecular interaction involving transmembrane domain 4.

In this study, we examined the mechanisms of intermolecular interaction involved in D2 dopamine receptor dimer formation to develop an understanding of the quaternary structure of G protein-coupled receptors. The potential role of two mechanisms was investigated: disulfide bridges and hydrophobic interactions between transmembrane domains. D2 dopamine receptor oligomers were unaffected by treatment with a reducing agent; however, oligomers of the D1 dopamine receptor dissociated following a similar treatment. This observation suggested that other forces such as hydrophobic interactions were more robust in the D2 receptor than in the D1 receptor in maintaining oligomerization. To elucidate which transmembrane domains were involved in the intermolecular hydrophobic interactions, truncation mutants were generated by successive deletion of transmembrane domains from amino and/or carboxyl portions of the D2 dopamine receptor. Immunoblot analyses revealed that all the fragments were well expressed but only fragments containing transmembrane domain 4 were able to self-associate, suggesting that critical areas for receptor dimerization resided within this transmembrane domain. Disruption of the helical structure of transmembrane domain 4 in a truncated receptor capable of forming dimers interfered with its ability to self-associate; however, a similar disruption of the transmembrane domain 4 helix structure in the full-length receptor did not significantly affect dimerization. These results indicated that there are other sites of interaction involved in D2 receptor oligomer assembly in addition to transmembrane domain 4.