Improvement in cognitive functioning in patients with first-episode psychosis during treatment with quetiapine: an interim analysis.

BACKGROUND: The efficacies of second-generation antipsychotic medications in reducing symptoms are reasonably well-documented, but their effects on cognition are less clearly understood. AIMS: To under take an interim analysis of an open label, 2-year study examining the effects of quetiapine on cognition in patients with a first episode of schizophrenia and related disorders. METHOD: Cognitive testing was performed before quetiapine was initiated and repeated after 3, 6 and 12 months of treatment. To date, 13 patients have been fully assessed (mean dose 517.9 mg/day; s.d. = 225.8). RESULTS: Statistically significant improvement was noted on measures of attention (Continuous Performance Test; CPT), verbal productivity (Verbal Fluency Test) and executive function (Object Alternation Test) after 6 and 12 months of treatment. For the CPT, improvement was also noted after 3 months of treatment. CONCLUSIONS: During treatment for 1 year with quetiapine, cognitive performance was improved in young patients with psychosis. Continued controlled investigations of the effects of quetiapine on cognition are desirable.

Duration of untreated psychosis predicts treatment outcome in an early psychosis program.

For patients first presenting with a non-affective psychotic disorder, the duration of untreated psychosis (DUP; the time between the onset of positive psychotic symptoms and the initiation of appropriate treatment) varies widely, from a few weeks to several years. A number of studies report that a longer DUP is associated with poorer clinical outcomes. We studied DUP and its association with clinical outcomes in a group of patients with schizophrenia and related psychotic disorders treated in the naturalistic clinical setting of an early psychosis program. DUP was determined for 19 patients with a non-affective psychotic disorder (schizophrenia, schizoaffective disorder or schizophreniform disorder) and no previous treatment for psychosis, by use of the IRAOS, a retrospective structured interview carried out with patients and their families. Positive and Negative Syndrome Scale (PANSS) and Global Assessment of Function (GAF) ratings were available at baseline and 6month follow-up. For analysis, patients were categorized into a short DUP (n=9) or long DUP (n=10) group. The median DUP (57weeks) was used as the dividing point. At baseline, the two groups did not differ significantly on positive symptoms or total PANSS ratings. However, negative symptoms were more severe in the long DUP group at baseline (P=0.029), and the long DUP group had a significantly higher mean rating for the passive/apathetic social withdrawal item of the PANSS (P=0.024). At 6month follow-up, the long DUP group had significantly higher ratings for positive symptoms (P=0.028) and had lower GAF scores (P=0.044). Significantly more (P=0.033) long DUP patients had enduring positive psychotic symptoms. The results confirm both the wide range of DUP among patients first presenting with schizophrenia and related psychotic disorders and the association of long DUP, defined as greater than approximately 1year, with a poorer clinical outcome. This study highlights the importance of collecting data regarding DUP and supports the view that patients with a long DUP are likely to be less responsive to treatment in general and will require greater resources and more intensive interventions.

Towards an aggression-free health care environment.

Over the past few years, nurses across Canada have participated in surveys that have exposed the previously unspoken issue of nurse abuse. Reports from the registered nurses' associations in Manitoba and Ontario reveal that more than half of all RNs have been physically assaulted in the workplace. In a study of 600 nurses in the Toronto area, fully one-third had experienced some form of abuse at work in the five days prior to the study. A recent Nova Scotia study of more than 400 nurses found that 63 percent had experienced verbal abuse at work in the past year, while 35 per cent had experienced attempts of physical harm and 21 percent had been the victims of a physical attack.

Age, sex and strain differences in activity and habituation in SHR and WKY rats.

The highly inbred strain of Wistar-Kyoto spontaneously hypertensive rat (SHR) and its normotensive, genetic control (WKY) were examined with respect to strain differences in spontaneous activity scores in a novel environment (small activity cage) and in ability to habituate to that environment. These behaviors were examined in experimentally naive rats, 197 SHR and WKY, males and females, at varying ages from 4 to 56 weeks, in order to determine whether there are sex and age differences in addition to the well-known strain differences in these behaviors. Total activity scores, determined in a 15 min test in the activity cage, were higher in SHR than WKY rats; females were significantly more active than males in either strain, and activity scores varied significantly with age both within strains and between strains. Ability to habituate to the test cage was determined by repeating the 15 min activity test at hourly intervals for three additional trials on the same day. The results indicate that the SHR, males and females and at all ages tested, habituate poorly if at all to the test cage as compared with WKY rats. Moreover, despite the variability of baseline activity scores (first trial) observed across ages, sexes and strains, the habituation patterns of either strain remained relatively fixed throughout the first year of life.

Alterations of evoked potentials in the medial lemniscus of the rat due to acute and chronic elevations in blood pressure.

The influence of elevated blood pressure on evoked field potentials in the medial lemniscus induced by peripheral stimulation was studied in the rat. Acute hypertension as a result of phenylephrine infusions reduced the size of this response in individual Wistar Kyoto rats. Chronic renal hypertension in Sprague-Dawley rats also caused a reduction in the dorsal column-medial lemniscal evoked response. These results confirm an inhibitory action of elevated blood pressure on transmission through the dorsal column nuclei.

Genetically related rats with differences in hippocampal uptake of norepinephrine and maze performance.

The spontaneously hypertensive rat (SHR) and its progenitor strain, the Wistar-Kyoto (WKY) display marked differences in brain catecholamines and behavior. The behavioral differences are suggestive of alterations in hippocampal function and, in particular, the noradrenergic input to the hippocampus. To test these hypotheses we have analyzed the performance of the SHR and WKY in a spatial memory maze task that is specific to hippocampal function and determined the kinetics of norepinephrine (NE) uptake in synaptosomal preparations of the hippocampus. We have found that WKYs exhibit an abnormally strong bias tendency in T-maze arm preference that influences the rate of acquisition and the final level of maze performance. We have also found differences in noradrenergic uptake in hippocampal synaptosomes. WKYs exhibit higher NE uptake rates and higher kinetic constants for NE uptake when compared with SHRs, suggesting that strain differences in noradrenergic function may contribute to the observed behavioral differences.

Enhanced preganglionic sympathetic nerve responses in spontaneously hypertensive rats.

Sympathetic nerve responses to posterior hypothalamic stimulation were recorded from the preceliac splanchnic nerve in spontaneously hypertensive rats (SHR) and normotensive, Wistar-Kyoto rats (WKY) following interruption of the baroreceptor reflex. Responses to identical stimulation were then recorded following ganglionic blockade with hexamethonium. The enhanced preganglionic sympathetic nerve responses measured in SHR indicate that the sympathetic hyperresponsiveness strain occurs, at least in part, at a site within the central nervous system.

Locomotor activity, auditory startle and shock thresholds in spontaneously hypertensive rats.

A group of SHRs and a group of WKY normotensive controls were compared sequentially on open-field behavior, Y-maze activity, responsiveness and habituation of the auditory startle response, and shock thresholds. In the open field and Y maze the SHRs were more active than the WKYs, but the locomotor activity of the SHRs decreased more within sessions. However, the SHRs could be described as showing more, less or the same between-session habituation depending upon the apparatus and the portion of the session analyzed. The SHRs were less responsive than controls on the auditory startle response measure, and they did not differ from controls on startle-response habituation. The SHRs were less responsive than controls at low shock levels but more responsive at high shock levels. The relationship between SHRs and WKYs on the responsiveness dimension depended upon the modality and intensity of the stimulus, the response characteristics of the test situation, and the time sample of behavior taken.

Differences in transmission through the dorsal column nuclei in spontaneously hypertensive and Wistar Kyoto rats.

The medical lemniscal evoked potential in response to a range of footshock intensities was recorded in spontaneously hypertensive (SHR) and Wistar Kyoto rats (WKY). Input-output (I-O) relationships were constructed as the percent of maximum response at each intensity. The SHR had a steeper I-O relationship than did the WKY. This difference was also evident when SHR maintained normotensive from weaning with hydralazine were compared with identically treated WKY. The treatment itself steepened the I-O relationship of the SHR while leaving that of the WKY unchanged. These results indicate an inherent hyperresponsiveness in the SHR dorsal column nuclei and an inhibitory effect of elevated blood pressure on transmission through these nuclei.

Field-potential evidence for extrasynaptic alterations in the hippocampal CA1 pyramidal cell population during paired-pulse potentiation.

The mechanisms of paired-pulse potentiation of the CA1 pyramidal cell population were examined by determining input-output relations for control and potentiated responses originating from the activation of radiatum fibers in the hippocampal slice preparation. Two types of potentiation for synchronously discharging pyramidal cells (population spike) were observed. In the first type, the potentiation of the population spike was found to be a combination of synaptic and extrasynaptic factors. This form of potentiation was observed in 16 of 28 slices. In the second type, the potentiation of the population spike was attributed entirely to the potentiation of summated dendritic depolarizations (population EPSP). This synaptic process of potentiation was observed in 12 of 28 slices. The involvement of only extrasynaptic mechanisms in the paired-pulse potentiation of the population spike was not observed. For the potentiation originating from a combination of synaptic and extrasynaptic mechanisms, 60% of the potentiation of the population spike was a result of synaptic factors and 40% could be attributed to extrasynaptic factors. These results support the concept that alterations in the excitability of postsynaptic neurons serve as a component of the mechanisms of paired-pulse potentiation in the radiatum fiber-CA1 pyramidal cell system.

Dissociation of genetic hyperactivity and hypertension in SHR.

The Wistar Kyoto strain of spontaneously hypertensive rat (SHR) has been characterized as behaviorally hyperactive as well as hypertensive. The relationship between these two inbred traits remains uncertain, and their coexistence in the SHR has complicated studies of central nervous system mechanisms underlying the hypertensive process. A breeding program was initiated to examine the possible genetic linkage of these two traits which, if separable, would allow us to develop substrains of SHR that are hypertensive without being hyperactive, or hyperactive without being hypertensive. We crossed SHR males with Wistar Kyoto, normotensive (WKY) female rats and produced F1 hybrids which were then randomly inbred to produce an F2 population. When tested at 12 weeks of age, F2 rats exhibited the expected wide range of mean systolic blood pressures (BP), from 111 to 174 mm Hg, as determined using indirect tail plethysmography. The BP in the parental rats at the time of breeding (16 weeks) was 187 +/- 4.5 mm Hg (SHR males, n = 7) and 111 +/- 2.4 (WKY females, n = 7). Locomotor activity was determined in an automated activity cage in F1 and F2 rats at 12 weeks of age. These strains exhibited a wide range of phenotypic distribution of locomotor activity scores, and the mean scores were intermediary between those of SHR rats and WKY rats of the same age. Among individual rats of both the F1 and F2 hybrid strains, there was no correlation between the activity score and the level of the BP at 12 weeks of age. These findings indicated that the genes responsible for the hypertensive trait and those responsible for the hyperactivity trait were not tightly linked in the hybrid populations, suggesting that different genetic factors were involved in the transmission of each of these traits. Accordingly, it should be possible to separate the two traits by further selective, recombinant inbreeding procedures.

Independence of blood pressure and locomotor hyperactivity in normotensive and genetically hypertensive rat.

The spontaneously hypertensive rat (SHR) exhibits locomotor hyperactivity in comparison to its normotensive progenitor Wistar-Kyoto (WKY) strain. We asked whether the hyperactive behavior was a direct consequence of elevated blood pressure in the hypertensive rat. Three experimental protocols were used to chronically alter blood pressure. In the first protocol, a group of adult SHRs was given hydralazine (20 mg/kg/day) in their drinking water to lower blood pressure. These animals exhibited a significant decrease in blood pressure, but no change in locomotor activity. In the second protocol, young SHRs (4 weeks of age) were treated with the same dosage of hydralazine until 16 weeks of age. Blood pressure was significantly decreased in these animals with no change in locomotor activity. In the third protocol, normotensive WKY and Sprague-Dawley (SD) rats were made hypertensive with unilateral renal clips. The resulting increase in blood pressure in these animals did not alter locomotor activity. These results suggest that locomotor hyperactivity is an inherent property of the SHR and is independent of blood pressure.

Baroreceptor reflex gain is not diminished in spontaneous hypertension.

The magnitudes of both spontaneous and hypothalamically evoked sympathetic nerve activity are greater in spontaneously hypertensive rats (SHR) than in normotensive Wistar-Kyoto rats (WKY). Because the baroreceptor reflex influences the magnitude and time course of the sympathetic response to hypothalamic stimulation, we evaluated the role of the baroreceptor reflex in this sympathetic hyperresponsiveness. Changes in spontaneous nerve activity following comparable shifts in mean blood pressure (static reflex gain) were not different between the two strains. The effect of alterations in prestimulation blood pressure on the size of the evoked sympathetic response (response gain) was greater in SHR. Baroreceptor reflex inhibition resulting from the evoked blood pressure rise during hypothalamic stimulation (dynamic gain) was also greater in SHR. Expressing response magnitudes and gains as a percent of the spontaneous activity eliminated these strain differences. Interruption of the baroreceptor reflex resulted in equivalent percent increases in spontaneous and evoked activity in the two strains. Postdenervation levels of spontaneous and evoked nerve activity were greater in SHR. The results show that sympathetic hyperreactivity in SHR is not due to deficient baroreceptor reflex function.

Cardiovascular responses elicited by electrical stimulation of the amygdala central nucleus in the rabbit.

Recent behavioral and anatomical evidence suggests the involvement of the amygdala central nucleus projection to medullary cardioregulatory nuclei in the expression of conditioned bradycardia during aversive Pavlovian conditioning in the rabbit 6,7,11,15. The present study sought to determine the extent to which electrical stimulation of the central nucleus produces bradycardia in the rabbit, and the extent to which any bradycardia elicited varies with stimulation at sites within as opposed to adjacent to the medial component of the central nucleus, the component from which the projection to cardioregulatory nuclei originates. Over 900 sites in 30 rabbits anesthetized with alpha-chloralose were explored. Monopolar stimulation (30-100 Hz; 0.5 ms pulse duration; 5.0 s train duration; 100-500 microamperemeter) at sites within the central nucleus produced bradycardia and depressor responses. Maximum bradycardia was produced from sites within the anterior, medial component of the nucleus. This response usually began within one second of stimulus onset, reached peak magnitude within two seconds of stimulus onset and in many instances was followed by a slight tachycardia following stimulus termination. The accompanying depressor responses occurred at longer latencies than the bradycardia responses. The responses persisted following artificial ventilation and immobilization by Flaxedil and were attenuated by i.v. injections of atropine methylnitrate. While bradycardia and depressor responses were elicited from sites immediately dorsal, ventral and lateral to the medial central nucleus, component. The results are consistent with previous evidence which suggests a contribution for the central nucleus in the expression of cardiovascular responding during aversive Pavlovian conditioning in the rabbit.

Periodic fluctations in synaptic transmission and enhancement of transmission in hippocampal slices.

The properties of the synchronously activated radiatum fiber-CA1 synaptic population were examined with the in vitro hippocampal slice preparation. Periodic fluctuations in synaptic transmission and in the enhancement of synaptic transmission were observed with periods ranging from 8 to 20 s. Such periodic fluctuations did not arise from fluctuations in afferent radiatum fiber activity. The period and amplitude of the cyclic variations in the enhancement of synaptic transmission were found to be altered with repeated electrical stimulation of the radiatum fibers. These results reflect cooperative synaptic actions which must be taken into consideration in the delineation of the mechanisms of potentiation.

Effect of hypothalamic stimulation in spontaneously hypertensive and Wistar-Kyoto rats.

This study was undertaken to determine if central nervous system differences in blood pressure regulation exist between spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) controls. Central control mechanisms were examined by observing the effects of posterior hypothalamic (PH) stimulation upon preganglionic sympathetic activity in 14--18 week old SHR and WKY rats. A bipolar, concentric electrode was stereotaxically placed in the PH. Stimulation was delivered at 20, 60 and 100 Hz (3-sec duration, 0.1 msec pulse width) at a voltage twice that producing an increase in blood pressure (less than 5 mm Hg) at 60 Hz. Sympathetic activity was recorded from a portion of the splanchnic nerve just distal to the diaphragm. Blood pressure was measured from a femoral artery catheter. SHR responded with greater increases in sympathetic activity than WKY; the differences were statistically significant at 60 and 100 Hz. SHR also responded with significantly greater increases in blood pressure at all frequencies of stimulation. To determine if the enhanced sympathetic response to PH stimulation seen in adult SHR is an intrinsic difference rather than secondary to sustained hypertension, we maintained SHR normotensive from four weeks of age with antihypertensive drug therapy (clonidine or hydralazine). Chronically treated animals were then tested at 14--18 weeks of age while on antihypertensives or four days after drug discontinuance. Sympathetic and blood pressure responses to PH stimulation were significantly greater in SHR maintained normotensive than untreated or chronically treated WKY. These data support the concept that a central factor is involved in the etiology of hypertension in the SHR.

Ascending collaterals of cutaneous neurons in the fasciculus gracilis of the cat.

Primary sensory neurons with myelinated axons in the sural nerve of the cat were found to be divisible into 3 systems on the basis of the length of their central collaterals in the dorsal columns. The short system consists of neurons that ascend only a segment or two in the fasciculus gracilis above their level of entry into the spinal cord. It is composed of all neurons with peripheral conduction velocities in the Adelta range and thus includes both D hair and nociceptive neurons. Approximately 35% of the Aalpha neurons join the intermediate system and ascend 4-12 segments before leaving the forsal columns. This system is composed of all sural type I neurons, as well as about 40% of the G2 hair, 40% of the intermediate field, and 50% of the F2 field neurons in the nerve. Those nociceptive neurons conducting at Aalpha velocities also contribute to the intermediate system. The remaining G2 hair, intermediate field, and F2 field neurons, together with almost all the sural type II, G1 hair, intermediate hair and F1 field neurons, join the long system and ascend to the nucleus gracilis. Fibers in the intermediate system showed a relatively abrupt decrease in conduction velocity usually of 50% or more (median 71%) a few millimeters rostral to their entry into the spinal cord. Members of the long system also decreased in conduction velocity at this point, but the magnitude of the changes was typically less than 50% of the peripheral velocity (median 36%). In addition, the ascending collaterals of the long system underwent a second reduction in conduction velocity near the cervical enlargement.