Delayed-Start Analyses in the Phase 3 Solanezumab EXPEDITION3 Study in Mild Alzheimer's Disease.

OBJECTIVE: A delayed-start design has been proposed to assess a potential disease-modifying effect in investigational drugs for Alzheimer's disease that target the underlying disease process. We extended this methodology to recently obtained data from the EXPEDITION3. METHODS: EXPEDITION3 was a Phase 3, double-blind study with participants randomized to solanezumab (400 mg) or placebo every 4 weeks for 80 weeks, with an optional extension of active treatment. The delayed-start analysis was designed to determine if a statistically significant treatment difference established during the placebo-controlled period is maintained (at predefined level) during the delayed-start period, which would suggest the active drug has a disease-modifying effect. The delayed-start analysis was assessed across multiple efficacy measures, and includes data from baseline in the placebo-controlled period and up to 9 months in the delayed-start period. RESULTS: No significant difference was observed between the placebo and solanezumab treatment groups at the end of the placebo-controlled period for the Alzheimer's Disease Assessment Scale-Cognitive 14-item subscale. A significant treatment difference was observed at the end of the placebo-controlled period for the Alzheimer's Disease Cooperative Study-Activities of Daily Living instrumental items, an effect also seen at 6 months in the delayed-start period, and the noninferiority criterion was met. No other efficacy measures met these criteria. CONCLUSIONS: Delayed-start statistical methodology was used to understand the longitudinal outcomes in EXPEDITION3 and its extension. The small treatment differences observed at the end of the placebo-controlled phase prevented adequate assessment of any putative disease modifying effect.

Predicting a 'combined treatment outcome' in chronic schizophrenia: the role of demographics, symptomatology, functioning and subjective well-being.

OBJECTIVES: The aim of this study was to determine what variables predict a 'combined treatment outcome' (COMBOUT) in patients with chronic schizophrenia. METHODS: This analysis (n=522) was based on a randomized, double-blind, flexible-dose, 12-week study that enrolled chronically-ill patients diagnosed with schizophrenia or a related disorder. COMBOUT was assessed using the PANSS for symptoms, CGI-S for overall clinical status, MADRS for depressive symptoms, QLS for functioning/QOL, and SWN-K for subjective well-being. Possible predictors included demographics as well as baseline scores (Model I), and early change (week 2) scores (Model II). RESULTS: Model I: significantly better outcome (higher COMBOUT score) was observed in patients with lower MADRS (T= - 6.36; p<0.001) or higher QLS (T=5.05; p<0.001) scores at baseline. Model II: significantly better COMBOUT was observed in patients with early improvement of QLS (T=4.93; p<0.001), SWN-K (T=3.88; p<0.001), PANSS (T= - 2.32; p=0.021) and CGI-S scores (T= - 2.22; p=0.027). Changes in EPS were not predictors of COMBOUT in the models tested. CONCLUSION: COMBOUT at endpoint was predicted by lower depressive symptom score and higher QOL at baseline and by early improvement in psychopathology, quality of life and subjective well-being.

The heterogeneity of antipsychotic response in the treatment of schizophrenia.

BACKGROUND: Schizophrenia is a heterogeneous disorder in terms of patient response to antipsychotic treatment. Understanding the heterogeneity of treatment response may help to guide treatment decisions. This study was undertaken to capture inherent patterns of response to antipsychotic treatment in patients with schizophrenia, characterize the subgroups of patients with similar courses of response, and examine illness characteristics at baseline as possible predictors of response. METHOD: Growth mixture modeling (GMM) was applied to data from a randomized, double-blind, 12-week study of 628 patients with schizophrenia or schizo-affective disorder treated with risperidone or olanzapine. RESULTS: Four distinct response trajectories based on Positive and Negative Syndrome Scale (PANSS) total score over 12 weeks were identified: Class 1 (420 patients, 80.6%) with moderate average baseline PANSS total score showing gradual symptom improvement; Class 2 (65 patients, 12.5%) showing rapid symptom improvement; Class 3 (24 patients, 4.6%) with high average baseline PANSS total score showing gradual symptom improvement; and Class 4 (12 patients, 2.3%) showing unsustained symptom improvement. Latent class membership of early responders (ER) and early non-responders (ENR) was determined based on 20% symptom improvement criteria at 2 weeks and ultimate responders (UR) and ultimate non-responders (UNR) based on 40% symptom improvement criteria at 12 weeks. Baseline factors with potential influence on latent class membership were identified. CONCLUSIONS: This study identified four distinct treatment response patterns with predominant representation of responders or non-responders to treatment in these classes. This heterogeneity may represent discrete endophenotypes of response to treatment with different etiologic underpinnings.

Predictors of risk for relapse in patients with schizophrenia or schizoaffective disorder during olanzapine drug therapy.

PURPOSE: To evaluate the relationship of dose decrease, symptom worsening, and baseline covariates on subsequent relapse during olanzapine treatment in patients with schizophrenia or schizoaffective disorder. METHODS: In two 28-week, randomized, double-blind clinical trials, a Cox proportional hazards model was used to determine potential correlates of relapse (defined as > or =20% worsening on PANSS total and CGI-Severity 3) among patients (N=271) who responded to 8 weeks of olanzapine treatment (10-20mg/day). Variables examined included: demographics, illness characteristics, baseline symptoms, symptom change, dose, adverse events, and functioning. RESULTS: Patients with a lower last dose relative to the preceding visit interval were 4 times more likely to relapse during that visit interval than other patients (p<.001). A similar finding was observed for a decrease in interval modal dose, although this variable was more predictive of relapse in the visit interval immediately following dose decrease (p=.027). In a subgroup analysis by gender, there was a significantly greater incidence of relapse in men with a dose decrease, whereas a dose decrease in women did not correlate with relapse. Relapse was also correlated with the emergence or worsening of a psychiatric adverse event during the same (p<.001) and preceding (p=.007) visit intervals, and with increased rating scale measures of psychopathology. The occurrence of a non-psychiatric adverse event was not associated with relapse. CONCLUSION: Dose decrease is a significant predictor of relapse in male but not female patients. Psychiatric adverse events also predicted relapse. Patients should be periodically reassessed to determine the need for maintenance treatment with appropriate dose.

Cardiac safety parameters of olanzapine: comparison with other atypical and typical antipsychotics.

Alterations of electrocardiogram results and cases of sudden cardiac death have been reported since the beginning of neuroleptic treatment. In particular, a temporal association exists between some antipsychotics and prolongation of the heart rate-corrected QT interval (QTc), an event that may increase the risk for developing a potentially fatal ventricular tachycardia arrhythmia known as torsades de pointes if it significantly exceeds normal intraindividual and interindividual variation. Although the incidence of serious adverse cardiac events in response to antipsychotic medications is relatively low, any possibility for the occurrence of cardiotoxicity warrants continued study. The present article reviews important differences among antipsychotic drugs in the potential for, and occurrence of, serious adverse cardiac outcomes and suggests that olanzapine, as therapeutically administered to patients with schizophrenia and related psychoses, does not contribute significantly to a QTc prolongation that could result in potentially fatal ventricular arrhythmias.

Social defeat alters the acquisition of cocaine self-administration in rats: role of individual differences in cocaine-taking behavior.

RATIONALE: It is known that social defeat can modulate cocaine self-administration. However, it is unclear whether this psychosocial stressor affects drug-taking behavior to the same extent across all individual animals, particularly those with differing propensities to self-administer psychostimulants. OBJECTIVE: This study examined the effect of social defeat on cocaine self-administration in animals that differ in novelty-seeking behavior that predicts differences in drug self-administration. METHODS: Male Sprague-Dawley rats were first classified into high-responder (HR) and low-responder (LR) groups. HR and LR rats were categorized based on their locomotor activity in a novel environment, with HR rats exhibiting higher locomotor activity than LR rats. Then, male rats were exposed on four occasions to an aggressive Long Evans male rat over the course of 4 days. Control rats were not exposed to the social defeat. All rats were subsequently implanted with jugular catheters and 3 days later placed into the self-administration box to study the acquisition of cocaine self-administration (0.25 mg per infusion). RESULTS: HR non-defeated animals self-administered more cocaine than the LR non-defeated animals. Following social defeat, the acquisition of cocaine self-administration is significantly delayed in HR rats and enhanced in LR rats. CONCLUSION The unique patterns of responsiveness in the HR and LR animals suggest that social defeat plays a role of equalizer of individual differences in drug-taking behavior.

Differential expression of c-fos mRNA within neurocircuits of male hamsters exposed to acute or chronic defeat.

Chronic exposure to stress has been implicated in physical and mental illness, and such experiences can produce alterations in the connectivity and number of neurones within the brain to variations in the expression of specific genes. The purpose of this study was to determine how repeated exposure to social defeat affects neuronal activation patterns within the male Syrian hamster brain. Toward this end, the levels c-fos mRNA were compared among three groups: (1) handled controls (HC); (2) acutely defeated males (AD); and (3) chronically defeated males (15 min aggression daily, 7 days) exposed to an acute challenge (CD). Plasma glucocorticoids were also measured and compared among groups as an index of neuroendocrine activity. The results show a selective pattern of habituation of immediate early gene expression within the brains of chronically defeated males. In particular, c-fos mRNA levels were significantly decreased within the paraventricular nucleus of the hypothalamus (PVN), supraoptic nucleus of the hypothalamus, septohypothalamic nucleus, intermediate subdivision of the lateral septum, central amygdaloid nucleus, and the amygdalohippocampal area in the CD group exposed to an acute challenge when compared to males defeated only once. In contrast, c-fos expression within the anterior and ventromedial nuclei of the hypothalamus, dorsal periaqueductal grey, dorsal raphe, cuneiform nucleus, and locus coeruleus did not differ between AD and CD groups. Similarly, plasma levels of cortisol and corticosterone in CD group were equivalent to those observed after a single defeat experience. We discuss the possibility that decreased expression of c-fos mRNA within the PVN and other brain regions of defeated animals-in the presence of elevated adrenal steroids-may reflect a state of molecular plasticity that could alter neurotransmission within the limbic-hypothalamo-pituitary-adrenocortical axis. In contrast, brain areas that maintain relatively high levels of c-fos mRNA following repeated defeat may reflect processes less likely to adapt such as defensive behaviour.

Principles of psychoneuroendocrinology.

The goal of this article is to describe some of the central nervous system circuits involved in the regulation of the hypothalamopituitary-adrenocortical (HPA) axis, with an emphasis on animal models believed to mimic the human experience of emotional stress. First, the basic constitutive elements of the HPA axis that control glucocorticoid secretion are reviewed. A description of the neural systems assumed to regulate the activity of the HPA axis, both anatomically and functionally, follows. It is argued that hypothalamic, septal and bed nucleus of the stria terminalis neurons are involved in the regulation of the HPA axis by situations eliciting emotional responses.

Social stress in hamsters: defeat activates specific neurocircuits within the brain.

During an agonistic encounter, subordinate male hamsters display defensive and submissive postures and show increased secretion of glucocorticoids, whereas dominant males do not. To determine whether specific neuronal pathways are activated during the behavioral and neuroendocrine responses of subordinate males, expression of c-fos mRNA within the brains of subordinate males was compared with the pattern in dominant males after fighting. After 1 week of handling, pairs of hamsters were either swapped between cages (handled control males), or were allowed to interact for 30 min [dominant (DOM) males and subordinate (SUB) males]. A second group of control animals that received no handling or social stimulation (unhandled control males) were also included. After testing, all animals were killed by decapitation, their brains were removed for c-fos in situ hybridization, and trunk blood was collected for analysis of plasma cortisol and corticosterone levels. Exposure of males to their partner's cage for 30 min resulted in increased expression of c-fos mRNA in multiple brain regions. In addition, fighting increased c-fos expression in the medial amygdaloid nucleus of both DOM and SUB males as well as having more selective effects. In DOM males, c-fos expression was elevated within the supraoptic nucleus of the hypothalamus. In SUB males, c-fos expression increased within a multitude of brain areas, including cingulate cortex, lateral septum, bed nucleus of the stria terminalis, medial preoptic area, several hypothalamic nuclei, central amygdaloid nucleus, amygdalohippocampal area, dorsal periaqueductal gray, dorsal raphe, cuneiform nucleus, and locus coeruleus. These findings are discussed in relation to neurocircuits associated with behavioral arousal and stress.

Mating-induced expression of c-fos in the male Syrian hamster brain: role of experience, pheromones, and ejaculations.

This study was designed to investigate the effects of pheromonal cues and specific behaviors within the male copulatory sequence on c-fos expression in the medial nucleus of the amygdala (Me), the bed nucleus of the stria terminalis (BNST), and the medial preoptic area (MPOA) of the Syrian hamster brain. Sexually experienced male hamsters were placed into clean testing arenas and were either: 1) left alone as handled controls; 2) exposed to female hamster vaginal secretion (FHVS) on cotton swabs; or mated to various end points of copulation with a sexually receptive female: 3) five intromissions, 4) one ejaculation, 5) five ejaculations, or 6) long intromissions, A seventh group of sexually naive control males 7) was left alone in the arena. The brains of these males were compared to those of the sexually experienced controls to determine whether exposure to cues associated with prior sexual experience could alter c-fos expression. In males exposed only to FHVS, Fos immunoreactivity (Fos-ir) increased within the posterodorsal Me, the anterodorsal part of the posteromedial BNST, and the magnocellular medial preoptic nucleus (MPNmag). Following one ejaculation, Fos-ir increased within the caudal posterodorsal Me, the dorsolateral MPOA, and the paraventricular nucleus of the hypothalamus. After multiple ejaculations, additional labeling was observed within the posteroventral part of the posteromedial BNST, the medial preoptic nucleus (MPN), the central tegmental field, and in cell clusters of the caudal posterodorsal Me and rostral posteromedial BNST. Fos-ir also increased within the posterodorsal Me, MPN, and MPNmag in sexually experienced control males exposed to the empty test chamber compared to sexually naive males exposed to an identical chamber. These results demonstrate that the mating-induced pattern of neuronal activation in sexually experienced males is dependent upon multiple factors, including prior sexual experience in the testing environment, investigation of FHVS, and the number of ejaculations achieved.

Mating and agonistic behavior produce different patterns of Fos immunolabeling in the male Syrian hamster brain.

Previous work has shown that mating induces the expression of Fos protein within the chemosensory pathways of the male Syrian hamster brain. However, it is not known if this pattern of labeling is specific to mating or the result of social interactions in general. To determine the behavioral specificity of activation within these pathways, Fos immunostaining following mating was compared to that following agonistic behavior. Both mating and agonistic behavior are dependent upon chemosensory cues and gonadal steroids (reviewed in Refs 64, 65) and areas belonging to the olfactory and vomeronasal pathways process chemosensory and hormonal information (reviewed in Ref. 48). The results of this study demonstrate both similarities and differences in brain activation patterns following these two social behaviors. Agonistic behavior increased the number of Fos-immunoreactive neurons within most subdivisions of the medial amygdala, the anteromedial and posterointermediate bed nucleus of the stria terminalis, the ventrolateral septum and the ventral premammillary nucleus of the hypothalamus in a pattern comparable to that observed after mating. This pattern of activation common to mating and agonistic behavior may reflect an increase in an animal's general state of arousal during social interactions. In contrast, although mating and agonistic behavior both activated neurons within the caudal subdivision of the medial nucleus of the amygdala, the anterodorsal level of posteromedial bed nucleus of the stria terminalis and the paraventricular and ventromedial nuclei of the hypothalamus, in these areas either the distribution and/or number of Fos-immunoreactive neurons differed. In addition, agonistic behavior selectively activated neurons within the anterolateral bed nucleus of the stria terminalis, the anterior nucleus of the hypothalamus and the dorsal periaqueductal gray, whereas mating alone activated neurons within the posteroventral level of posteromedial bed nucleus of the stria terminalis and the medial preoptic area. No differences were found between dominant and subordinate males following agonistic behavior. These observations along with results from other laboratories suggest that mating and agonistic behavior activate distinct neural circuits.