Critical Review of the Use of Second-Generation Antipsychotics in Obsessive-Compulsive and Related Disorders.

Currently, all second-generation antipsychotics are approved for schizophrenia. Many are also approved for bipolar disorder, with some also approved as adjunctive treatment for depression and autism-related irritability. Second-generation antipsychotics are increasingly being prescribed for indications other than those approved by the Food and Drug Administration, such as in dementia, anxiety, and post-traumatic stress disorder to name a few. Obsessive-compulsive and related disorders are a group of disorders characterized by preoccupation and repetitive behaviors. According to the latest edition of the Diagnostic and Statistical Manual of Mental Disorders, obsessive-compulsive disorder, body dysmorphic disorder, trichotillomania, hoarding disorder, and excoriation, the latter two being newly designated disorders, fall under obsessive-compulsive and related disorders. Due to a lack of well designed clinical studies specifically addressing the use of second-generation antipsychotics in obsessive-compulsive and related disorders, it is unknown whether these agents are clinically beneficial. Current research describing the pathophysiology of these disorders shows the involvement of similar brain regions and neurotransmitters across the five obsessive-compulsive and related disorders. Despite differences in the receptor binding profiles, second-generation antipsychotics share many common pharmacodynamics properties. This review sought to examine all the published reports of second-generation antipsychotics being used in the management of symptoms of the aforementioned diseases and compile evidence for clinicians who encounter patients who are unresponsive to standard treatment.

In vivo and in vitro effects of vortioxetine on molecules associated with neuroplasticity.

Neuroplasticity is fundamental for brain functions, abnormal changes of which are associated with mood disorders and cognitive impairment. Neuroplasticity can be affected by neuroactive medications and by aging. Vortioxetine, a multimodal antidepressant, has shown positive effects on cognitive functions in both pre-clinical and clinical studies. In rodent studies, vortioxetine increases glutamate neurotransmission, promotes dendritic branching and spine maturation, and elevates hippocampal expression of the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) at the transcript level. The present study aims to assess the effects of vortioxetine on several neuroplasticity-related molecules in different experimental systems. Chronic (1 month) vortioxetine increased Arc/Arg3.1 protein levels in the cortical synaptosomes of young and middle-aged mice. In young mice, this was accompanied by an increase in actin-depolymerizing factor (ADF)/cofilin serine 3 phosphorylation without altering the total ADF/cofilin protein level, and an increase in the GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor phosphorylation at serine 845 (S845) without altering serine 831 (S831) GluA1 phosphorylation nor the total GluA1 protein level. Similar effects were detected in cultured rat hippocampal neurons: Acute vortioxetine increased S845 GluA1 phosphorylation without changing S831 GluA1 phosphorylation or the total GluA1 protein level. These changes were accompanied by an increase in α subunit of Ca2+/calmodulin-dependent kinase (CaMKIIα) phosphorylation (at threonine 286) without changing the total CaMKIIα protein level in cultured neurons. In addition, chronic (1 month) vortioxetine, but not fluoxetine, restored the age-associated reduction in Arc/Arg3.1 and c-Fos transcripts in the frontal cortex of middle-aged mice. Taken together, these results demonstrated that vortioxetine modulates molecular targets that are related to neuroplasticity.

Differentiated effects of the multimodal antidepressant vortioxetine on sleep architecture: Part 2, pharmacological interactions in rodents suggest a role of serotonin-3 receptor antagonism.

Antidepressants often disrupt sleep. Vortioxetine, a multimodal antidepressant acting through serotonin (5-HT) transporter (SERT) inhibition, 5-HT3, 5-HT7 and 5-HT1D receptor antagonism, 5-HT1B receptor partial agonism, and 5-HT1A receptor agonism, had fewer incidences of sleep-related adverse events reported in depressed patients. In the accompanying paper a polysomnographic electroencephalography (sleep-EEG) study of vortioxetine and paroxetine in healthy subjects indicated that at low/intermediate levels of SERT occupancy, vortioxetine affected rapid eye movement (REM) sleep differently than paroxetine. Here we investigated clinically meaningful doses (80-90% SERT occupancy) of vortioxetine and paroxetine on sleep-EEG in rats to further elucidate the serotoninergic receptor mechanisms mediating this difference. Cortical EEG, electromyography (EMG), and locomotion were recorded telemetrically for 10 days, following an acute dose, from rats receiving vortioxetine-infused chow or paroxetine-infused water and respective controls. Sleep stages were manually scored into active wake, quiet wake, and non-REM or REM sleep. Acute paroxetine or vortioxetine delayed REM onset latency (ROL) and decreased REM episodes. After repeated administration, vortioxetine yielded normal sleep-wake rhythms while paroxetine continued to suppress REM. Paroxetine, unlike vortioxetine, increased transitions from non-REM to wake, suggesting fragmented sleep. Next, we investigated the role of 5-HT3 receptors in eliciting these differences. The 5-HT3 receptor antagonist ondansetron significantly reduced paroxetine's acute effects on ROL, while the 5-HT3 receptor agonist SR57227A significantly increased vortioxetine's acute effect on ROL. Overall, our data are consistent with the clinical findings that vortioxetine impacts REM sleep differently than paroxetine, and suggests a role for 5-HT3 receptor antagonism in mitigating these differences.

Involvement of 5-HT7 receptors in vortioxetine's modulation of circadian rhythms and episodic memory in rodents.

Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders, antidepressants that target key 5-HT (serotonin) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility. Vortioxetine is a multimodal antidepressant that inhibits 5-HT1D, 5-HT3, 5-HT7 receptor activity, 5-HT reuptake, and enhances the activity of 5-HT1A and 5-HT1B receptors. In this study, we investigated the effects of vortioxetine on the period length of PER2::LUC expression, circadian behavior, and episodic memory, using tissue explants from genetically modified PER2::LUC mice, locomotor activity rhythm monitoring, and the object recognition test, respectively. Incubation of tissue explants from the suprachiasmatic nucleus of PER2::LUC mice with 0.1 µM vortioxetine increased the period length of PER2 bioluminescence. Monitoring of daily wheel-running activity of Sprague-Dawley rats treated with vortioxetine (10 mg/kg, s.c.), alone or in combination with the 5-HT1A receptor agonist flesinoxan (2.5 mg/kg, s.c.) or the 5-HT7 receptor antagonist SB269970 (30 mg/kg, s.c.), just prior to activity onset revealed significant delays in wheel-running behavior. The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the 5-HT7 receptor partial agonist AS19. Finally, in the object recognition test, vortioxetine (10 mg/kg, i.p.) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 (5 mg/kg, i.p.). In conclusion, the present study shows that vortioxetine, partly via its 5-HT7 receptor antagonism, induced a significant effect on circadian rhythm and presented promnesic properties in rodents.

The effects of combining serotonin reuptake inhibition and 5-HT7 receptor blockade on circadian rhythm regulation in rodents.

Disruption of circadian rhythms may lead to mood disorders. The present study investigated the potential therapeutic utility of combining a 5-HT7 antagonist with a selective serotonin (5-HT) reuptake inhibitor (SSRI), the standard of care in depression, on circadian rhythm regulation. In tissue explants of the suprachiasmatic nucleus (SCN) from PER2::LUC mice genetically modified to report changes in the expression of a key clock protein, the period length of PER2 bioluminescence was shortened in the presence of AS19, a 5-HT7 partial agonist. This reduction was blocked by SB269970, a selective 5-HT7 antagonist. The SSRI, escitalopram, had no effect alone on period length, but a combination with SB269970, yielded significant increases. Dosed in vivo, escitalopram had little impact on the occurrence of activity onsets in rats given access to running wheels, whether the drug was given acutely or sub-chronically. However, preceding the escitalopram treatment with a single acute dose of SB269970 produced robust phase delays, in keeping with the in vitro explant data. Taken together, these findings suggest that the combination of an SSRI and a 5-HT7 receptor antagonist has a greater impact on circadian rhythms than that observed with either agent alone, and that such a multimodal approach may be of therapeutic value in treating patients with poor clock function.

Circadian rhythm dysregulation in bipolar disorder.

When circadian rhythms - the daily oscillations of various physiological and behavioral events that are controlled by a central timekeeping mechanism - become desynchronized with the prevailing light:dark cycle, a maladaptative response can result. Animal data based primarily on genetic manipulations and clinical data from biomarker and gene expression studies support the notion that circadian abnormalities underlie certain psychiatric disorders. In particular, bipolar disorder has an interesting link to rhythm-related disease biology; other mood disturbances, such as major depressive disorder, seasonal affective disorder and the agitation and aggression accompanying severe dementia (sundowning), are also linked to changes in circadian rhythm function. Possibilities for pharmacological intervention derive most readily from the molecular oscillator, the cellular machinery that drives daily rhythms.

Development of tolerance in D3 dopamine receptor signaling is accompanied by distinct changes in receptor conformation.

The D3 but not D2 dopamine receptors exhibit a tolerance property in which agonist-induced D3 receptor response progressively decreases upon repeated agonist stimulation. We have previously shown that the D3 receptor tolerance property is not mediated by receptor internalization, persistent agonist binding or a decrease in receptor binding affinity. In this paper, we test the hypothesis that alterations in D3 receptor conformation underlie the tolerance property. Structural models of wild type and mutant human D3 receptors were generated using the beta adrenergic receptor crystal structure as a template. These models suggested that the agonist-bound D3 receptor undergoes conformational changes that could underlie its tolerance property. To experimentally assess changes in receptor conformation, we measured the accessibility of native cysteine residues present in the extracellular and transmembrane regions of the human D3 receptor to two different thiol-modifying biotinylating reagents. The accessibilities of the native cysteine residues present in the D3 receptor were assessed under control conditions, in the presence of agonist and under conditions that induced receptor tolerance. By comparing the accessibility of D3 receptor cysteine residues to hydrophobic and hydrophilic thiol-modifying biotinylating reagents, we show that the alteration of D3 receptor conformation during tolerance involves the net movement of cysteine residues into a hydrophobic environment. Our results show that the conformation state of the D3 receptor during tolerance is distinct from the conformation under basal and agonist-bound conditions. The results suggest that the D3 receptor tolerance property is mediated by conformational changes that may uncouple the receptor from G-protein signaling.

The tolerance property of human D3 dopamine receptor is determined by specific amino acid residues in the second cytoplasmic loop.

The D2 and D3 dopamine receptor subtypes are structurally homologous and couple to the same signal transduction pathways. Nevertheless, their evolutionary conservation suggests that the two subtypes might exhibit unique signaling characteristics. We previously determined that D3 but not D2S dopamine receptor exhibits a tolerance property in which the D3 receptor-activated G-protein coupled inward rectifier potassium currents progressively decreases upon repeated agonist stimulation. In this paper, using AtT-20 neuroendocrine cells stably expressing either human D3 or D2S receptor, we show that the tolerance property is also observed in the D3 receptor-adenylyl cyclase and D3 receptor-mitogen-activated protein kinase signaling pathways. We have previously shown that the second cytoplasmic loop of D3 receptor is required for tolerance. Here, using site-directed mutagenesis, we identified the specific amino acids in the D3 second cytoplasmic loop involved in the tolerance property. The results show that substitution of a non-conserved cysteine residue at position 147 with positively-charged lysine or arginine residues abolishes tolerance. Interestingly, the cysteine 147 residue is embedded in a putative phosphorylation site adjacent to two serine residues. Mutation of these serine residues to alanine also attenuates tolerance. Taken together, these structural studies suggest a role for phosphorylation in D3 receptor tolerance property.

Identification and characterization of novel properties of the human D3 dopamine receptor.

Among dopamine receptors, the function and properties of the D3 receptor subtype are poorly understood. Here we report the identification and characterization of two unique properties of the human D3 receptor. The D3 receptor exhibits a tolerance property wherein the magnitude of the second agonist-induced response is reduced by 60% compared to the first response and progressively decreases upon repeated agonist application. In addition, unlike the D2 dopamine receptor, the D3 receptor response terminates 15-fold more slowly upon agonist removal. Using D3/D2S chimeric receptors, we demonstrate that D3 receptor tolerance property is mediated by a novel conformational mechanism involving the D3 receptor second cytoplasmic region. The slow response termination rate property requires the third cytoplasmic region and is due to the high affinity of the D3 receptor for ligand as well as its unique G-protein signaling mechanism.