Adolescents and adults at clinical high-risk for psychosis: age-related differences in attenuated positive symptoms syndrome prevalence and entanglement with basic symptoms.

BACKGROUND: The attenuated positive symptoms syndrome (APSS) is considered an at-risk indicator for psychosis. However, the characteristics and developmental aspects of the combined or enriched risk criteria of APSS and basic symptom (BS) criteria, including self-experienced cognitive disturbances (COGDIS) remain under-researched. METHOD: Based on the Structured Interview of Prodromal Syndromes (SIPS), the prevalence of APSS in 13- to 35-year-old individuals seeking help in an early recognition program for schizophrenia and bipolar-spectrum disorders was examined. BS criteria and COGDIS were rated using the Schizophrenia Proneness Instrument for Adults/Children and Youth. Participants meeting APSS criteria were compared with participants meeting only BS criteria across multiple characteristics. Co-occurrence (APSS+/BS+, APSS+/COGDIS+) was compared across 13-17, 18-22 and 23-35 years age groups. RESULTS: Of 175 individuals (age = 20.6 ± 5.8, female = 38.3%), 94 (53.7%) met APSS criteria. Compared to BS, APSS status was associated with suicidality, higher illness severity, lower functioning, higher SIPS positive, negative, disorganized and general symptoms scores, depression scores and younger age (18.3 ± 5.0 v. 23.2 ± 5.6 years, p < 0.0001) with age-related differences in the prevalence of APSS (ranging from 80.3% in 13- to 17-year-olds to 33.3% in 23- to 35-year-olds (odds ratio 0.21, 95% confidence interval 0.11-0.37). Within APSS+ individuals, fewer adolescents fulfilled combined risk criteria of APSS+/BS+ or APSS+/COGDIS+ compared to the older age groups. CONCLUSIONS: APSS status was associated with greater suicidality and illness/psychophathology severity in this help-seeking cohort, emphasizing the need for clinical care. The age-related differences in the prevalence of APSS and the increasing proportion of APSS+/COGDIS+ may point to a higher proportion of non-specific/transient, rather than risk-specific attenuated positive symptoms in adolescents.

Changes in neurocognitive functioning during transition to manifest disease: comparison of individuals at risk for schizophrenic and bipolar affective psychoses.

BACKGROUND: Neurocognitive deficits are important aspects of schizophrenic disorder because they have a strong impact on social and vocational outcomes. Previously it was assumed that cognitive abilities progressively deteriorate with illness onset. However, recent research results have contradicted this with observations of continuous or even improved performance in individuals at risk for psychosis or manifest schizophrenia. The objective of our longitudinal study was to examine neurocognitive functioning in help-seeking individuals meeting basic symptoms or ultra-high-risk criteria for schizophrenic psychosis (HRSchiz) or risk criteria for affective psychosis (HRBip). The progression of cognitive functioning in individuals converting to psychosis was compared with that of at-risk individuals who did not convert during the follow-up period. METHOD: Data were available from 86 study participants who completed neurocognitive and clinical assessments at baseline and, on average, 12.8 (s.d. = 1.5) months later. Neurocognitive measures were grouped according to their load in factor analysis to five cognitive domains: speed, attention, fluency, learning and memory, and working memory. RESULTS: Neurocognitive functioning in HRSchiz and HRBip individuals generally improved over time. Subjects converting to manifest psychosis displayed a stable neurocognitive profile from baseline to follow-up. Compared with non-converters, they had already demonstrated a significantly lower level of performance during their baseline examinations. CONCLUSIONS: Our data provide no evidence for a progressive cognitive decline in individuals at risk of psychosis. In line with the neurodevelopmental model, our findings suggest that cognitive deficits are already present very early, before or during the prodromal stage of the illness.

Neurocognitive profiles in help-seeking individuals: comparison of risk for psychosis and bipolar disorder criteria.

BACKGROUND: Neurocognitive deficits are important aspects of the schizophrenic disorders because they have a strong impact on social and vocational outcomes. We expanded on previous research by focusing on the neurocognitive profiles of persons at high risk (HR) or ultra-high risk (UHR) for schizophrenic and affective psychoses. Our main aim was to determine whether neurocognitive measures are sufficiently sensitive to predict a group affiliation based on deficits in functional domains. METHOD: This study included 207 help-seeking individuals identified as HR (n = 75), UHR (n = 102) or at high risk for bipolar disorder (HRBip; n = 30), who were compared with persons comprising a matched, healthy control group (CG; n = 50). Neuropsychological variables were sorted according to their load in a factor analysis and were compared among groups. In addition, the likelihood of group membership was estimated using logistic regression analyses. RESULTS: The performance of HR and HRBip participants was comparable, and intermediate between the controls and UHR. The domain of processing speed was most sensitive in discriminating HR and UHR [odds ratio (OR) 0.48, 95% confidence interval (CI) 0.28-0.78, p = 0.004] whereas learning and memory deficits predicted a conversion to schizophrenic psychosis (OR 0.47, 95% CI 0.25-0.87, p = 0.01). CONCLUSIONS: Performances on neurocognitive tests differed among our three at-risk groups and may therefore be useful in predicting psychosis. Overall, cognition had a profound effect on the extent of general functioning and satisfaction with life for subjects at risk of psychosis. Thus, this factor should become a treatment target in itself.

Prepulse inhibition of the startle reflex and its attentional modulation in the human S-ketamine and N,N-dimethyltryptamine (DMT) models of psychosis.

Patients with schizophrenia exhibit diminished prepulse inhibition (PPI) of the acoustic startle reflex and deficits in the attentional modulation of PPI. Pharmacological challenges with hallucinogens are used as models for psychosis in both humans and animals. Remarkably, in contrast to the findings in schizophrenic patients and in animal hallucinogen models of psychosis, previous studies with healthy volunteers demonstrated increased levels of PPI after administration of low to moderate doses of either the antiglutamatergic hallucinogen ketamine or the serotonergic hallucinogen psilocybin. The aim of the present study was to investigate the influence of moderate and high doses of the serotonergic hallucinogen N,N-dimethyltryptamine (DMT) and the N-methyl-D-aspartate antagonist S-ketamine on PPI and its attentional modulation in humans. Fifteen healthy volunteers were included in a double-blind cross-over study with two doses of DMT and S-ketamine. Effects on PPI and its attentional modulation were investigated. Nine subjects completed both experimental days with the two doses of both drugs. S-ketamine increased PPI in both dosages, whereas DMT had no significant effects on PPI. S-ketamine decreased and DMT tended to decrease startle magnitude. There were no significant effects of either drug on the attentional modulation of PPI. In human experimental hallucinogen psychoses, and even with high, clearly psychotogenic doses of DMT or S-ketamine, healthy subjects failed to exhibit the predicted attenuation of PPI. In contrast, PPI was augmented and the startle magnitude was decreased after S-ketamine. These data point to important differences between human hallucinogen models and both animal hallucinogen models of psychosis and naturally occurring schizophrenia.

Checking the predictive accuracy of basic symptoms against ultra high-risk criteria and testing of a multivariable prediction model: Evidence from a prospective three-year observational study of persons at clinical high-risk for psychosis.

BACKGROUND: The aim of this study was to critically examine the prognostic validity of various clinical high-risk (CHR) criteria alone and in combination with additional clinical characteristics. METHODS: A total of 188 CHR positive persons from the region of Zurich, Switzerland (mean age 20.5 years; 60.2% male), meeting ultra high-risk (UHR) and/or basic symptoms (BS) criteria, were followed over three years. The test battery included the Structured Interview for Prodromal Syndromes (SIPS), verbal IQ and many other screening tools. Conversion to psychosis was defined according to ICD-10 criteria for schizophrenia (F20) or brief psychotic disorder (F23). RESULTS: Altogether n=24 persons developed manifest psychosis within three years and according to Kaplan-Meier survival analysis, the projected conversion rate was 17.5%. The predictive accuracy of UHR was statistically significant but poor (area under the curve [AUC]=0.65, P<.05), whereas BS did not predict psychosis beyond mere chance (AUC=0.52, P=.730). Sensitivity and specificity were 0.83 and 0.47 for UHR, and 0.96 and 0.09 for BS. UHR plus BS achieved an AUC=0.66, with sensitivity and specificity of 0.75 and 0.56. In comparison, baseline antipsychotic medication yielded a predictive accuracy of AUC=0.62 (sensitivity=0.42; specificity=0.82). A multivariable prediction model comprising continuous measures of positive symptoms and verbal IQ achieved a substantially improved prognostic accuracy (AUC=0.85; sensitivity=0.86; specificity=0.85; positive predictive value=0.54; negative predictive value=0.97). CONCLUSIONS: We showed that BS have no predictive accuracy beyond chance, while UHR criteria poorly predict conversion to psychosis. Combining BS with UHR criteria did not improve the predictive accuracy of UHR alone. In contrast, dimensional measures of both positive symptoms and verbal IQ showed excellent prognostic validity. A critical re-thinking of binary at-risk criteria is necessary in order to improve the prognosis of psychotic disorders.

Mismatch negativity: Alterations in adults from the general population who report subclinical psychotic symptoms.

BACKGROUND: Deficits of mismatch negativity (MMN) in schizophrenia and individuals at risk for psychosis have been replicated many times. Several studies have also demonstrated the occurrence of subclinical psychotic symptoms within the general population. However, none has yet investigated MMN in individuals from the general population who report subclinical psychotic symptoms. METHODS: The MMN to duration-, frequency-, and intensity deviants was recorded in 217 nonclinical individuals classified into a control group (n=72) and three subclinical groups: paranoid (n=44), psychotic (n=51), and mixed paranoid-psychotic (n=50). Amplitudes of MMN at frontocentral electrodes were referenced to average. Based on a three-source model of MMN generation, we conducted an MMN source analysis and compared the amplitudes of surface electrodes and sources among groups. RESULTS: We found no significant differences in MMN amplitudes of surface electrodes. However, significant differences in MMN generation among the four groups were revealed at the frontal source for duration-deviant stimuli (P=0.01). We also detected a trend-level difference (P=0.05) in MMN activity among those groups for frequency deviants at the frontal source. CONCLUSIONS: Individuals from the general population who report psychotic symptoms are a heterogeneous group. However, alterations exist in their frontal MMN activity. This increased activity might be an indicator of more sensitive perception regarding changes in the environment for individuals with subclinical psychotic symptoms.

Peripheral vascular effects of ketanserin and nifedipine during cardiopulmonary bypass.

Ketanserin, a selective S2-serotonergic receptor antagonist with alpha 1-adrenergic receptor-blocking properties, as well as nifedipine, a classic calcium channel blocker, is used as an antihypertensive agent during and following cardiac surgery. In a double-blind prospective study, using hypothermic cardiopulmonary bypass as a study model, ketanserin (10 mg i.v.) and nifedipine (2 mg i.v.) were evaluated with respect to their effects on the peripheral circulation. The results showed that ketanserin and nifedipine dilate the arterial side of the vasculature, but that ketanserin, unlike nifedipine, also dilates the venous capacitance vessels; nifedipine even caused a short-lasting venous vasoconstriction. Since venous tone is increased during and following cardiopulmonary bypass, antihypertensive treatment with ketanserin might be advantageous under these circumstances.

Prepulse inhibition in psychiatric disorders--apart from schizophrenia.

Prepulse inhibition (PPI) is a robust operational measure of sensorimotor gating. In schizophrenic patients PPI is deficient. The aim of our review was to investigate the state of science regarding PPI and psychiatric disorders aside from schizophrenia. We used the online database PubMed in order to search for original published reports on PPI studies. The terms "prepulse inhibition", "sensorimotor gating", "blink recovery", and "blink reflex excitability" have been combined with the names of psychiatric disorders. We found that PPI is deficient in obsessive compulsive disorder (OCD) and Gilles de la Tourette's syndrome (GTS). In bipolar disorder dysfunctional PPI seems to be rather state dependent. Studies on depression and attention deficit/hyperactivity disorder (ADHD) consistently report no alterations. Evidence regarding sensorimotor gating in anxiety, autism, fragile X syndrome, posttraumatic stress disorder (PTSD), substance disorders, and Huntington's disease is still poor. There is a strong need for further studies on PPI in psychiatric disorders. PPI is highly applicable for translational research and might also be a very useful tool to investigate the mode of action of innovative, neuro-modulative techniques. Future PPI studies should control for influencing variables such as smoking, sex, or medication.

Examination of the effect of acute levodopa administration on the loudness dependence of auditory evoked potentials (LDAEP) in humans.

RATIONALE: The loudness dependence of the auditory evoked potential (LDAEP) is considered a noninvasive in vivo marker of central serotonergic functioning in humans. Nevertheless, results of genetic association studies point towards a modulation of this biomarker by dopaminergic neurotransmission. OBJECTIVE: We examined the effect of dopaminergic modulation on the LDAEP using L-3,4-dihydroxyphenylalanine (levodopa)/benserazide (Madopar®) as a challenge agent in healthy volunteers. METHODS: A double-blind placebo-controlled challenge design was chosen. Forty-two healthy participants (21 females and 21 males) underwent two LDAEP measurements, following a baseline LDAEP measurement either placebo or levodopa (levodopa 200 mg/benserazide 50 mg) were given orally. Changes in the amplitude and dipole source activity of the N1/P2 intensities (60, 70, 80, 90, and 100 dB) were analyzed. RESULTS: The participants of neither the levodopa nor the placebo group showed any significant LDAEP alterations compared to the baseline measurement. The test-retest reliability (Cronbachs Alpha) between baseline and intervention was 0.966 in the verum group and 0.759 in the placebo group, respectively. CONCLUSIONS: The administration of levodopa showed no effect on the LDAEP. These findings are in line with other trials using dopamine receptor agonists.

[Does cannabis use lead to schizophrenia?]. / Führt Cannabiskonsum zu Schizophrenie?

There is a high comorbidity between cannabis use and schizophrenia. Several factors contribute to this comorbidity: secondary development of addiction, cannabis-related induction of psychosis and shared neurobiological alterations. Meanwhile, there is evidence that cannabis use is associated with an increased risk of schizophrenia. Prospective epidemiological studies have shown that a frequent cannabis use doubles the risk for schizophrenia. Interestingly, schizophrenic patients with comorbid cannabis use often show significantly better performances in neuropsychological tests than patients without cannabis use. This is nevertheless not due to a positive effect of cannabis, but a sign of cannabis-related psychosis induction in subjects with a higher level of function and less cognitive impairment. Whether cannabis use leads to schizophrenia is determined by the individual vulnerability.

Neuronal correlates of visual and auditory alertness in the DMT and ketamine model of psychosis.

Deficits in attentional functions belong to the core cognitive symptoms in schizophrenic patients. Alertness is a nonselective attention component that refers to a state of general readiness that improves stimulus processing and response initiation. The main goal of the present study was to investigate cerebral correlates of alertness in the human 5HT(2A) agonist and N-methyl-D-aspartic acid (NMDA) antagonist model of psychosis. Fourteen healthy volunteers participated in a randomized double-blind, cross-over event-related functional magnetic resonance imaging (fMRI) study with dimethyltryptamine (DMT) and S-ketamine. A target detection task with cued and uncued trials in both the visual and the auditory modality was used. Administration of DMT led to decreased blood oxygenation level-dependent response during performance of an alertness task, particularly in extrastriate regions during visual alerting and in temporal regions during auditory alerting. In general, the effects for the visual modality were more pronounced. In contrast, administration of S-ketamine led to increased cortical activation in the left insula and precentral gyrus in the auditory modality. The results of the present study might deliver more insight into potential differences and overlapping pathomechanisms in schizophrenia. These conclusions must remain preliminary and should be explored by further fMRI studies with schizophrenic patients performing modality-specific alertness tasks.

Psychological effects of (S)-ketamine and N,N-dimethyltryptamine (DMT): a double-blind, cross-over study in healthy volunteers.

INTRODUCTION: Pharmacological challenges with hallucinogens are used as models for psychosis in experimental research. The state induced by glutamate antagonists such as phencyclidine (PCP) is often considered as a more appropriate model of psychosis than the state induced by serotonergic hallucinogens such as lysergic acid diethylamide (LSD), psilocybin and N,N-dimethyltryptamine (DMT). However, so far, the psychological profiles of the two types of hallucinogenic drugs have never been studied directly in an experimental within-subject design. METHODS: Fifteen healthy volunteers were included in a double-blind, cross-over study with two doses of the serotonin 5-HT2A agonist DMT and the glutamate N-methyl-D-aspartate (NMDA) antagonist (S)-ketamine. RESULTS: Data are reported for nine subjects who completed both experimental days with both doses of the two drugs. The intensity of global psychological effects was similar for DMT and (S)-ketamine. However, phenomena resembling positive symptoms of schizophrenia, particularly positive formal thought disorder and inappropriate affect, were stronger after DMT. Phenomena resembling negative symptoms of schizophrenia, attention deficits, body perception disturbances and catatonia-like motor phenomena were stronger after (S)-ketamine. DISCUSSION: The present study suggests that the NMDA antagonist model of psychosis is not overall superior to the serotonin 5-HT2A agonist model. Rather, the two classes of drugs tend to model different aspects or types of schizophrenia. The NMDA antagonist state may be an appropriate model for psychoses with prominent negative and possibly also catatonic features, while the 5-HT2A agonist state may be a better model for psychoses of the paranoid type.

Effects of the hallucinogen psilocybin on habituation and prepulse inhibition of the startle reflex in humans.

Schizophrenic patients exhibit deficits in indices of sensorimotor gating, such as habituation and prepulse inhibition (PPI) of the startle reflex. Hallucinogenic drug-induced states are putative models for the early and acute stages of schizophrenic and schizophrenia-spectrum disorders. Hallucinogenic drugs have been shown to disrupt PPI and/or retard habituation of the startle reflex in animal models of schizophrenia, consistent with the view of hallucinogen-induced states as 'model psychoses'. We evaluated the effects of the hallucinogen psilocybin on PPI and habituation of the startle reflex in a double-blind, placebo-controlled human study with 12 healthy subjects. In contrast to animal studies, in our small human sample, psilocybin increased PPI, while having no clear effect on habituation (n = 6). These findings must be considered preliminary because several factors, including dose regimens and experimental parameters, may influence the results of studies on startle plasticity. Further investigations both with psychotic patients in different stages of the disease and with human and animal models of schizophrenia are needed in order to explore the effects of hallucinogens on sensorimotor gating and the relationship between information processing in hallucinogenic drug-induced states and the naturally occurring psychoses.

Effects of the hallucinogen psilocybin on covert orienting of visual attention in humans.

Hallucinogenic drug-induced states are considered as models for acute schizophrenic disorders (experimental psychoses). In a double-blind study with healthy volunteers we investigated the influence of the serotonergic hallucinogen psilocybin, the ecstasy-like drug 3,4-methylenedioxyethylamphetamine (MDE), the stimulant d- methamphetamine and placebo on covert orienting of spatial attention (n = 8 in each group). Reaction times were prolonged after ingestion of psilocybin > MDE, but not after d-methamphetamine. In addition, subjects on psilocybin exhibited particularly slow reaction times in invalid trials at short cue target intervals and failure of response inhibition in valid trials at long cue target intervals for right visual field targets. Despite some methodological limitations, these results are in line with both bilateral impairment of disengagement of attention and a lateralized impairment of inhibition of return (IOR) in productive psychotic states. Additional investigations with larger samples, different hallucinogenic substances (serotonergic agonists vs. NMDA antagonists) and different dose regimens are needed in order to further explore the suggested relationship between visuospatial attentional dysfunction and acute psychotic conditions.