Effect of Varenicline on Tardive Dyskinesia: A Pilot Study.

OBJECTIVE: Although evidence implicates striatal cholinergic impairment as a mechanism underlying tardive dyskinesia, trials of nonspecific cholinergic agents have been inconclusive. As a partial agonist at specific nicotinic receptor subtypes, varenicline reduces drug-induced dyskinesias in animal models suggesting promise as a treatment for tardive dyskinesia. METHODS: Three schizophrenia patients with tardive dyskinesia who were smokers underwent an open trial of varenicline. After a 2-week baseline, subjects received varenicline 1 mg twice daily. Changes from baseline on the Abnormal Involuntary Movement Scale were measured after a 4-week varenicline stabilization period, and 6 weeks after the smoking quit date in one patient. RESULTS: Varenicline had no effect on mean Abnormal Involuntary Movement Scale scores after 4 weeks. Although smoking decreased after 4 weeks on varenicline and diminished further in one patient after 10 weeks, this also appeared to have no effect on ratings of tardive dyskinesia. CONCLUSION: In contrast to animal models, no significant change in tardive dyskinesia occurred in response to varenicline replacement in three schizophrenia patients. Further investigations of cholinergic mechanisms in tardive dyskinesia are worthwhile as agents for specific cholinergic targets become available for treatment. In addition, treatment trials of tardive dyskinesia should control for smoking status, while patients on antipsychotics receiving nicotine replacement therapies for smoking should be studied further for changes in movement.

The effect of resilience on posttraumatic stress disorder in trauma-exposed inner-city primary care patients.

Posttraumatic stress disorder (PTSD) has previously been associated with increased risk for a variety of chronic medical conditions and it is often underdiagnosed in minority civilian populations. The current study examined the effects of resilience on the likelihood of having a diagnosis of PTSD in an inner-city sample of primary care patients (n=767). We measured resilience with the Connor-Davidson Resilience Scale, trauma with the Childhood Trauma Questionnaire and Trauma Events Inventory, and assessed for PTSD with the modified PTSD symptom scale. Multiple logistic regression model with presence/absence of PTSD as the outcome yielded 3 significant factors: childhood abuse, nonchild abuse trauma, and resilience. One type of childhood abuse in moderate to severe range (OR, 2.01; p = .0001), 2 or more types of childhood abuse in moderate to severe range (OR, 4.00; p < or = .0001), and 2 or more types of nonchildhood abuse trauma exposure (OR, 3.33; p < or = .0001), were significantly associated with an increased likelihood of PTSD, while resilience was robustly and significantly associated with a decreased likelihood of PTSD (OR, 0.93; p < or = .0001). By understanding the role of resilience in recovery from adverse experiences, improved treatment and interventional methods may be developed. Furthermore, these results suggest a role for assessing resilience in highly traumatized primary care populations as a way to better characterize risk for PTSD and direct screening/psychiatric referral efforts.

Moderating effects of resilience on depression in individuals with a history of childhood abuse or trauma exposure.

BACKGROUND: Influences of resilience on the presence and severity of depression following trauma exposure are largely unknown. Hence, we examined effects of resilience on depressive symptom severity in individuals with past childhood abuse and/or other trauma exposure. METHODS: In this cross-sectional study of 792 adults, resilience was measured with the Connor-Davidson Resilience Scale, depression with the Beck Depression Inventory (BDI), childhood abuse with the Childhood Trauma Questionnaire, and other traumas with the Trauma Events Inventory. RESULTS: Multiple linear regression modeling with depression severity (BDI score) as the outcome yielded 4 factors: childhood abuse (ß=2.5, p<0.0001), other trauma (ß=3.5, p<0.0001), resilience (ß=-0.5, p<0.0001), and other trauma × resilience interaction term (ß=-0.1, p=0.0021), all of which were significantly associated with depression severity, even after adjusting for age, sex, race, education, employment, income, marital status, and family psychiatric history. Childhood abuse and trauma exposure contributed to depressive symptom severity while resilience mitigated it. CONCLUSIONS: Resilience moderates depressive symptom severity in individuals exposed to childhood abuse or other traumas both as a main effect and an interaction with trauma exposure. Resilience may be amenable to external manipulation and could present a potential focus for treatments and interventions.

Functional interactions between endocannabinoid and CCK neurotransmitter systems may be critical for extinction learning.

The endocannabinoid system and the cannabinoid type 1 receptor (CB1R) are required for the extinction of conditioned fear. CB1 antagonists have been shown to prevent extinction when delivered both systemically and within the amygdala. Anatomical studies suggest that CB1Rs in the basolateral amygdala (BLA) are expressed on GABAergic interneurons expressing the anxiogenic peptide cholecystokinin (CCK). Pre-synaptic CB1Rs inhibit neurotransmitter release, suggesting that CB1R activation during extinction may decrease CCK peptide release as well as GABA release. Thus, we examined whether extinction involves the CB1R modulation of CCK2 receptor activation. We found that intracerebroventricular administration of the CCK2 agonist pentagastrin dose-dependently impaired extinction of conditioned fear. Systemic administration of a CB1 antagonist, rimonabant (SR141716), also potently inhibited extinction learning. This effect was ameliorated with systemic administration of a CCK2 antagonist, CR2945. Furthermore, the extinction blockade by systemic SR141716 was reversed with intra-BLA, but not intrastriatal, infusion of CR2945. Lastly, as extinction usually leads to an increase in Akt phosphorylation, a biochemical effect antagonized by systemic CB1 antagonist treatment, we examined whether CR2945 co-administration would increase extinction-induced p-Akt levels. We observed that extinction-trained animals showed increased Akt phosphorylation following extinction, CB1 antagonist-treated animals showed p-Akt levels similar to those of non-extinction trained animals, and co-administration of CR2945 with SR141716 led to levels of p-Akt similar to those of vehicle-treated, extinction-trained controls. Together, these data suggest that interactions between the endocannabinoid and CCKergic transmitter systems may underlie the process of extinction of conditioned fear.

The role of neuropeptide Y in the expression and extinction of fear-potentiated startle.

Neuropeptides are a promising target for novel treatments for anxiety and other psychiatric disorders and neuropeptide Y (NPY) has emerged as a key component of anxiolytic circuits in the brain. For this reason, we have evaluated the role of NPY in the expression and extinction of conditioned fear. We found that intracerebroventricular administration of NPY inhibits both baseline acoustic startle and the expression of fear-potentiated startle. Infusion of NPY (10 pmol/side) into the basolateral, but not the medial, nucleus of the amygdala reproduced the intracerebroventricular effect. Central administration of NPY (10 microg) also enhanced within-session extinction of fear-potentiated startle. This finding, coupled with the growing body of literature correlating NPY with resilience in humans, led us to the hypothesis that NPY may enhance the extinction of conditioned fear. When NPY (10 microg) is administered intracerebroventricularly before extinction training, extinction retention for both the contextual and cued components of conditioned fear is enhanced when tested 48 h later off drug. Additionally, we found that intra-basolateral amygdala administration of the NPY Y(1) receptor antagonist BIBO 3304 (200 pmol/side) before extinction training led to a profound deficit in extinction retention. This is the first evidence that NPY facilitates and an NPY antagonist blocks the extinction of conditioned fear. We believe that the role of NPY in the extinction of conditioned fear may, at least in part, explain the mechanism underlying the association between NPY and psychobiological resilience in humans.

Central oxytocin, vasopressin, and corticotropin-releasing factor receptor densities in the basal forebrain predict isolation potentiated startle in rats.

Individual differences in resiliency to particular stressors may be mediated by specific neuropeptide receptor patterns in the brain. Here, we explored this issue by using a multivariate approach to identify brain sites in which oxytocin (OTR), vasopressin (V1aR), and corticotropin-releasing factor type 1 (CRF1) or type 2 receptor binding covaried with a measure of isolation-induced anxiety: isolation potentiated startle (IPS). Partial least squares (PLS) analysis identified three binding sites, the shell of the nucleus accumbens (AccSh), lateral bed nucleus of the stria terminalis, and intermediate zone of the lateral septum, in which CRF1, V1aR, and OTR receptors, respectively, covaried with IPS. Multiple regression analysis demonstrated that the three binding sites accounted for more of the variation in IPS as a linear combination than when considered individually. Using the same multiple regression model, the linear combination of the same three binding sites/peptide receptors measured in a new group of animals successfully predicted their IPS values. There were no differences in binding between grouped and isolated animals, suggesting that the patterns are trait effects rather than a consequence of isolation. Based on the finding that CRF1 receptors in the AccSh were positively correlated with IPS, we infused CRF directly into the AccSh and found that it significantly potentiated startle after a short isolation period but not under grouped conditions. This result directly supported the predictions made by the combined PLS/regression approach. These results suggest that the integrated activity of neuropeptide systems mediating both social behavior and anxiety underlie IPS.