Psychosocial outcome in patients at clinical high risk of psychosis: a prospective follow-up

Purpose

In patients at clinical high risk (CHR) of psychosis, transition to psychosis has been the focus of recent studies. Their broader outcome has received less attention. We studied psychosocial state and outcome in CHR patients.

Methods

In the European Prediction of Psychosis Study, 244 young help-seeking CHR patients were assessed with the Strauss and Carpenter Prognostic Scale (SCPS) at baseline, and 149 (61.1 %) of them were assessed for the second time at the 18-month follow-up. The followed patients were classified into poor and good outcome groups.

Results

Female gender, ever-married/cohabitating relationship, and good working/studying situation were associated with good baseline SCPS scores. During follow-up, patients’ SCPS scores improved significantly. Good follow-up SCPS scores were predicted by higher level of education, good working/studying status at baseline, and white ethnicity. One-third of the followed CHR patients had poor global outcome. Poor working/studying situation and lower level of education were associated with poor global outcome. Transition to psychosis was associated with baseline, but not with follow-up SCPS scores or with global outcome.

Conclusion

The majority of CHR patients experience good short-term recovery, but one-third have poor psychosocial outcome. Good working situation is the major indicator of good outcome, while low level of education and non-white ethnicity seem to be associated with poor outcome. Transition to psychosis has little effect on psychosocial outcome in CHR patients. In treating CHR patients, clinicians should focus their attention on a broader outcome, and not only on preventing transition to psychosis.     

Prediction of psychosis in clinical high-risk patients by the Schizotypal Personality Questionnaire. Results of the EPOS project

ObjectiveSchizotypal features indicate proneness to psychosis in the general population. It is also possible that they increase transition to psychosis (TTP) among clinical high-risk patients (CHR). Our aim was to investigate whether schizotypal features predict TTP in CHR patients.MethodsIn the EPOS (European Prediction of Psychosis Study) project, 245 young help-seeking CHR patients were prospectively followed for 18 months and their TTP was identified. At baseline, subjects were assessed with the Schizotypal Personality Questionnaire (SPQ). Associations between SPQ items and its subscales with the TTP were analysed in Cox regression analysis.ResultsThe SPQ subscales and items describing ideas of reference and lack of close interpersonal relationships were found to correlate significantly with TTP. The co-occurrence of these features doubled the risk of TTP.ConclusionsPresence of ideas of reference and lack of close interpersonal relations increase the risk of full-blown psychosis among CHR patients. This co-occurrence makes the risk of psychosis very high.     

γ1- and γ2-melanocyte stimulating hormones induce central anxiogenic effects and potentiate ethanol withdrawal responses in the elevated plus-maze test in mice

Little is known about the endogenous functions of γ1- and γ2-melanocyte stimulating hormones (γ1- and γ2-MSH). Although γ-MSHs bind to melanocortin receptor subtypes 3 and 4, we have previously shown that these peptides also influence non-melanocortinergic processes, such as dopaminergic and GABAergic. The aim of this study was to determine the effects of γ1- and γ2-MSH (at doses 0.3, 1 and 2 nmol/mouse/5 μl) on the anxiety levels in mice in elevated plus maze. Three experimental paradigms were performed to assess the effects of peptides on: a) ethanol withdrawal; b) acute ethanol-induced anxiolytic action; c) peptides per se.We used ethanol as the model substance, since its action involves either dopaminergic/GABAergic or melanocortinergic processes. γ-MSHs were administered intracisternally in mice and behavioural responses were assessed in the elevated plus maze test. This study provides the first demonstration of an anxiogenic effect of γ1- and γ2-MSH, their synergistic/additive effect on ethanol withdrawal-induced anxiety behaviour, and an antagonism of peptides involved in the anxiolytic action of ethanol. Furthermore, results suggest that γ-MSHs belong to an anxiogenic peptide family that may play an important role in anxiety disorders as well as in the development of alcohol dependence and/or alcohol withdrawal-induced behaviours.     

Smooth-muscle effects of C-terminal tripeptide of substance P

The effects of the C-terminal tripeptide fragment of substance P(SP-C-TP) and its interactions with substance P(SP) were studied on isolated smooth-muscle preparations (rat musculus anococcygeus and vas deferens and rabbit ear central artery). Like SP, SP-C-TP (1 x 10(-8) M-1 x 10(-4)M) potentiated contractions of vas deferens and musculus anococcygeus elicited by low frequency electrical stimulation (LFES), the effect of the fragment being much weaker than that of the neuropeptide. The potentiating effect of SP was strongly reduced by SP-C-TP. The fragment slightly decreased the noradrenaline (NA)-induced contractions of vas deferens only. When the pharmacological agents were applied extralumenally only high SP concentrations (1 x 10(-7)M and 1 x 10(-6)M) significantly potentiated the LFES-evoked smooth-muscle contractions. SP-induced potentiation was abolished by SP-C-TP. Intralumenal administration of the neuropeptide and its fragment always led to a marked inhibition of the LFES contractile effects. The observed effects suggest that SP-C-TP acts as a competitive dualist of SP. The data is interpreted in terms of the hypothesis that the neuropeptide fragments might perform as a natural antagonist of the peptides and may control their effects.     

The gamma(2)-MSH peptide mediates a central analgesic effect via a GABA-ergic mechanism that is independent from activation of melanocortin receptors

Using the latency for tail-flick after thermal stimulation we have assessed the effects of alpha-, gamma(1)- and gamma(2)-MSH on nociceptive threshold in the mice. Intracisternal injections of gamma(2)-MSH induced a distinct analgesia, while gamma(1)-MSH in the same doses gave only a minor analgesia. Intracisternal alpha-MSH instead gave a short-term hyperalgesia. The effect of gamma(2)-MSH was not blocked by any of the MC(4)/MC(3)receptor antagonist HS014, naloxone or by the prior intracisternal administrations of gamma(1)-MSH. However, the gamma(2)-MSH analgesic response was completely attenuated by treating animals with the GABA(A)antagonist bicuculline. The gamma(2)-MSH analgesic effect was moreover additive to the analgesia afforded by muscimol and ethanol, but not to that afforded by diazepam. In addition both gamma(1)- and gamma(2)-MSH induced moderate catalepsy, but could at the same time attenuate haloperidol induced catalepsia. We conclude that gamma(2)-MSH mediates a central analgesic effect via GABA-receptor dependent pathway that is distinct from melanocortic- and opioid-receptors. Moreover, the mechanism for gamma(2)-MSH's analgesic effect appears to be distinct from that causing moderate catalepsia by gamma-MSH's.     

Frequency doubling illusion VEPs and automated perimetry in multiple sclerosis

We examined frequency doubling (FD) illusion based automated perimetry (FDT) and dichoptic FD multifocal visual evoked potentials (FDmfVEPs) in Normal and multiple sclerosis (MS) subjects. Contrast thresholds were determined at 17 visual field locations using an FDT perimeter. The stimuli presented to each location were 0.25 cpd gratings presented with rapid (25 Hz) counterphase flicker and thus displayed the spatial FD illusion. Dichoptic mfVEPs were recorded by concurrently stimulating eight regions/eye with FD stimuli presented at 95% contrast. Recordings were obtained from 27 Normal subjects, 26 MS patients who had experienced Optic Neuritis (MS_ON) and 24 MS patients without a history of ON (MS_NON). The FDT thresholds showed enhanced contrast sensitivity for MS_ON patients (P < 0.0001) but not for MS_NON patients. Response amplitudes for the central four regions of the mfVEP stimulus were reduced in both patient groups (P < 0.005). A classification model based upon the FDT thresholds performed at a specificity of 96% for a sensitivity of 97% in MS_ON patients, but the accuracy (simultaneously largest sensitivities and specificities) was poor (∼60%) in MS_NON patients. Discriminant models based on the FDT thresholds and FDmfVEPs were able to diagnose more that 90% MS_ON patients but performed poorly for MS_NON patients.     

Kv3.4 subunits enhance the repolarizing efficiency of Kv3.1 channels in fast-spiking neurons

Neurons with the capacity to discharge at high rates--'fast-spiking' (FS) neurons--are critical participants in central motor and sensory circuits. It is widely accepted that K+ channels with Kv3.1 or Kv3.2 subunits underlie fast, delayed-rectifier (DR) currents that endow neurons with this FS ability. Expression of these subunits in heterologous systems, however, yields channels that open at more depolarized potentials than do native Kv3 family channels, suggesting that they differ. One possibility is that native channels incorporate a subunit that modifies gating. Molecular, electrophysiological and pharmacological studies reported here suggest that a splice variant of the Kv3.4 subunit coassembles with Kv3.1 subunits in rat brain FS neurons. Coassembly enhances the spike repolarizing efficiency of the channels, thereby reducing spike duration and enabling higher repetitive spike rates. These results suggest that manipulation of K3.4 subunit expression could be a useful means of controlling the dynamic range of FS neurons.     

Distinct influence of atypical 1,4-dihydropyridine compounds in azidothymidine-induced neuro- and cardiotoxicity in mice ex vivo

This study demonstrates the effective protection by compounds of atypical 1,4-dihydropyridine (DHP) series cerebrocrast, glutapyrone and tauropyrone against neuro- and cardiotoxicity caused by the model compound azidothymidine, a well-known mitochondria-compromising anti-HIV drug. In previous in vitro experiments, we have demonstrated distinct effects of these DHP compounds to influence mitochondrial functioning. In the present in vivo experiments, DHP compounds were administered intraperitoneally in mice daily for 2 weeks, per se and in combinations with azidothymidine at doses: azidothymidine 50 mg/kg; cerebrocrast 0.1 mg/kg; glutapyrone 1 mg/kg; and tauropyrone 1 mg/kg. At the end of the experiment, mice were killed, heart and brain tissues were removed and examined ex vivo histopathologically and immunohistochemically. NF-kappaBp65 and caspase-3 were used as the markers indicating inflammatory and apoptotic events, respectively. Cerebrocrast (dicyclic structure) was the most potent DHP, which effectively reduced azidothymidine-induced overexpression of NF-kappaBp65 and caspase-3 in mouse myocardium and brain cortex. Glutapyrone per se increased the number of caspase-3-positive cells in the brain, whereas it reduced NF-kappaBp65 and caspase-3 expression in cardiac tissue caused by azidothymidine. Tauropyrone showed dual action: per se it increased caspase-3 in the brain and NF-kappaBp65 expression in the heart, but it considerably reduced these activations in azidothymidine-treated mice. This study provides the first demonstration of a distinct pharmacological action for atypical DHP compounds in cardiac and brain tissues. The dicyclic structure of cerebrocrast is considered beneficial for neuro- and cardioprotection at least in part via mitochondrial targeting and consequent regulation of inflammatory and apoptotic processes.