The N1 auditory evoked potential component as an endophenotype for schizophrenia: high-density electrical mapping in clinically unaffected first-degree relatives, first-episode, and chronic schizophrenia patients.

The N1 component of the auditory evoked potential (AEP) is a robust and easily recorded metric of auditory sensory-perceptual processing. In patients with schizophrenia, a diminution in the amplitude of this component is a near-ubiquitous finding. A pair of recent studies has also shown this N1 deficit in first-degree relatives of schizophrenia probands, suggesting that the deficit may be linked to the underlying genetic risk of the disease rather than to the disease state itself. However, in both these studies, a significant proportion of the relatives had other psychiatric conditions. As such, although the N1 deficit represents an intriguing candidate endophenotype for schizophrenia, it remains to be shown whether it is present in a group of clinically unaffected first-degree relatives. In addition to testing first-degree relatives, we also sought to replicate the N1 deficit in a group of first-episode patients and in a group of chronic schizophrenia probands. Subject groups consisted of 35 patients with schizophrenia, 30 unaffected first-degree relatives, 13 first-episode patients, and 22 healthy controls. Subjects sat in a dimly lit room and listened to a series of simple 1,000-Hz tones, indicating with a button press whenever they heard a deviant tone (1,500 Hz; 17% probability), while the AEP was recorded from 72 scalp electrodes. Both chronic and first-episode patients showed clear N1 amplitude decrements relative to healthy control subjects. Crucially, unaffected first-degree relatives also showed a clear N1 deficit. This study provides further support for the proposal that the auditory N1 deficit in schizophrenia is linked to the underlying genetic risk of developing this disorder. In light of recent studies, these results point to the N1 deficit as an endophenotypic marker for schizophrenia. The potential future utility of this metric as one element of a multivariate endophenotype is discussed.

Visual sensory processing deficits in patients with bipolar disorder revealed through high-density electrical mapping.

BACKGROUND: Etiological commonalities are apparent between bipolar disorder and schizophrenia. For example, it is becoming clear that both populations show similar electrophysiological deficits in the auditory domain. Recent studies have also shown robust visual sensory processing deficits in patients with schizophrenia using the event-related potential technique, but this has not been formally tested in those with bipolar disorder. Our goal here was to assess whether early visual sensory processing in patients with bipolar disorder, as indexed by decreased amplitude of the P1 component of the visual evoked potential (VEP), would show a similar deficit to that seen in those with schizophrenia. Since the P1 deficit has already been established as an endophenotype in schizophrenia, a finding of commonality between disorders would raise the possibility that it represents a measure of common genetic liability. METHODS: We visually presented isolated-check stimuli to euthymic patients with a diagnosis of bipolar disorder and age-matched healthy controls within a simple go/no-go task and recorded VEPs using high-density (72-channel) electroencephalography. RESULTS: The P1 VEP amplitude was substantially reduced in patients with bipolar disorder, with an effect size of f = 0.56 (large according to Cohen's criteria). LIMITATIONS: Our sample size was relatively small and as such, did not allow for an examination of potential relations between the physiologic measures and clinical measures. CONCLUSION: This reduction in P1 amplitude among patients with bipolar disorder represents a dysfunction in early visual processing that is highly similar to that found repeatedly in patients with schizophrenia and their healthy first-degree relatives. Since the P1 deficit has been related to susceptibility genes for schizophrenia, our results raise the possibility that the deficit may in fact be more broadly related to the development of psychosis and that it merits further investigation as a candidate endophenotype for bipolar disorder.

Visual sensory processing deficits in Schizophrenia and their relationship to disease state.

CONTEXT: Visual Evoked Potential (VEP) abnormalities have been a fairly consistent finding in patients with schizophrenia, and it has been suggested that electrophysiological markers of early sensory processing may be useful as trait markers for the illness, and for development as potential diagnostic measures. OBJECTIVE: Clear amplitude reductions in the occipital P1 component of the VEP (approximately 100 ms), have been repeatedly demonstrated in patients with schizophrenia. Here, we investigated whether the extent of this deficit was related to age, clinical symptoms, medication status and length of illness, in a large cohort of ethnically homogenous patients. DESIGN, SETTING AND PARTICIPANTS: VEP responses to simple isolated-check stimuli were examined in 52 DSM-IV diagnosed patients with schizophrenia, and compared with responses from 26 healthy age-matched control subjects. Using high-density electrical scalp recordings, we assessed the integrity of the visual P1 component across the two groups. This study was conducted at St.Vincent's Psychiatric Hospital in Fairview, Dublin, Ireland. RESULTS: Substantially reduced P1 amplitude was demonstrated in the patient group compared to controls. The deficit was not linked to age, length of illness or medication status. A small positive correlation, accounting for about 11% of the variance, was found between P1 amplitude and clinical symptoms scales (BPRS and SANS). In addition, we found that a slightly later (~110 ms) fronto-central component was relatively increased in the patient group, and was inversely correlated with the occipital P1 amplitude in the patients, but not in the healthy control subjects. CONCLUSIONS: Our findings clearly demonstrate a deficit in early visual processing in patients with schizophrenia (with a large effect size; Cohen's d = 0.7) that is unrelated to chronicity. The results are consistent with recent findings showing that the P1 deficit is endophenotypic of the disorder and related to genetic risk factors rather than the disease process itself.

Are auditory-evoked frequency and duration mismatch negativity deficits endophenotypic for schizophrenia? High-density electrical mapping in clinically unaffected first-degree relatives and first-episode and chronic schizophrenia.

BACKGROUND: Mismatch negativity (MMN) is a negative-going event-related potential (ERP) component that occurs in response to intermittent changes in constant auditory backgrounds. A consistent finding across a large number of studies has been impaired MMN generation in schizophrenia, which has been interpreted as evidence for fundamental deficits in automatic auditory sensory processing. The aim of this study was to investigate the extent to which dysfunction in MMN generation might represent an endophenotypic marker for schizophrenia. METHODS: We measured MMN to deviants in duration (25 msec, 1000 Hz) and deviants in pitch (50 msec, 1200 Hz) relative to standard tones (50 msec, 1000 Hz) in 45 chronic schizophrenia patients, 25 of their first-degree unaffected biological relatives, 12 first-episode patients, and 27 healthy control subjects. RESULTS: In line with previous work, MMN amplitudes to duration deviants (but not to pitch deviants) were significantly reduced in patients with chronic schizophrenia compared with control subjects. However, both duration and pitch MMNs were completely unaffected in the first-degree biological relatives and this was also the case for the first-episode patients. Furthermore, length of illness did not predict the extent of MMN deficit. CONCLUSIONS: These findings suggest that the MMN deficit seen in schizophrenia patients is most likely a consequence of the disease and that MMN, at least to basic auditory feature deviants, is at best only weakly endophenotypic for schizophrenia.

Early visual sensory deficits as endophenotypes for schizophrenia: high-density electrical mapping in clinically unaffected first-degree relatives.

CONTEXT: The imperative to establish so-called endophenotypes-quantifiable measures of risk for neurological dysfunction-is a growing focus of research in schizophrenia. Electrophysiological markers of sensory processing, observable in human event-related potentials, hold great promise in this regard, lying closer to underlying physiology than descriptive clinical diagnostic tests. OBJECTIVE: Early visual processing deficits, as measured by clear amplitude reductions in the occipital P1 component of the visual event-related potential, have been repeatedly demonstrated in patients with schizophrenia. However, before P1 amplitude may be considered as an endophenotypic marker for schizophrenia, it is necessary to establish its sensitivity to genetic liability. DESIGN, SETTING, AND PARTICIPANTS: Event-related potential responses to simple visual isolated-check stimuli were examined in 25 clinically unaffected first-degree relatives of patients with schizophrenia and 15 DSM-IV-diagnosed schizophrenia probands and compared with responses from 26 healthy, age-matched control subjects. Using high-density electrical scalp recordings, between-groups analysis assessed the integrity of the visual P1 component across the 3 groups. The study was conducted at St Vincent's Psychiatric Hospital in Fairview, Dublin, Ireland. RESULTS: Substantially reduced P1 amplitude was demonstrated in both relatives and probands compared with controls with topographical mapping and inverse source analysis localizing this deficit largely to midline regions in early visual sensory cortices and regions of the dorsal visual stream. Additional later differences between these groups, where the relatives actually show larger amplitude responses, may point toward compensatory mechanisms at play in relatives. CONCLUSIONS: Our findings demonstrate a deficit in early visual processing in clinically unaffected first-degree relatives of patients with schizophrenia, providing evidence that this deficit may serve as a genetic marker for this disorder. The efficacy of using P1 amplitude as an endophenotype is underscored by the observation of a large effect size (d=0.9) over scalp sites where the deficit was maximal.

Olanzapine versus ziprasidone: results of a 28-week double-blind study in patients with schizophrenia.

OBJECTIVE: The efficacy and safety of olanzapine were compared with those of ziprasidone. METHOD: This was a multicenter randomized, double-blind, parallel-group, 28-week study of patients with schizophrenia. Patients were randomly assigned to treatment with 10-20 mg/day of olanzapine or 80-160 mg/day of ziprasidone. The primary efficacy measure was the Positive and Negative Syndrome Scale total score. Secondary efficacy and safety measures included Positive and Negative Syndrome Scale subscales as well as mood, quality of life, and extrapyramidal symptom scales. Safety was evaluated by recording treatment-emergent adverse events and measuring vital signs and weight. RESULTS: The study was completed by significantly more olanzapine-treated patients (165 of 277, 59.6%) than ziprasidone-treated patients (115 of 271, 42.4%). At 28 weeks, the olanzapine-treated patients showed significantly more improvement than the ziprasidone-treated patients on the Positive and Negative Syndrome Scale overall scale and all subscales and on the Clinical Global Impression ratings of severity of illness and improvement. The responder rate was higher for olanzapine than for ziprasidone. Extrapyramidal symptoms were not significantly different between groups in change-to-endpoint analyses, but results favored olanzapine on baseline-to-maximum changes. Weight change was significantly greater with olanzapine (mean=3.06 kg, SD=6.87) than with ziprasidone (mean=-1.12 kg, SD=4.70). Fasting lipid profiles were significantly superior in the ziprasidone group; there was no significant difference in fasting glucose level. CONCLUSIONS: Olanzapine treatment resulted in significantly greater psychopathology improvement and higher response and completion rates than ziprasidone treatment, while ziprasidone was superior for weight change and lipid profile.

Male patients with paranoid schizophrenia have greater ACTH and cortisol secretion in response to metoclopramide-induced AVP release.

Dynamic testing of the hypothalamic-pituitary-adrenal axis in schizophrenia has yielded conflicting results, which may be related to patient selection and previous exposure to psychotropic medication. The objective of this study was to determine the pattern of corticotropin (ACTH) and cortisol release in response to metoclopramide (a dopamine antagonist), which appears to be unique in its ability to release vasopressin (AVP), in drug naive patients with schizophrenia experiencing their first episode of psychosis. In this study, we examined AVP, ACTH and cortisol release in response to metoclopramide in 10 drug-naive, first-episode male patients with a DSM IV diagnosis of paranoid schizophrenia and compared them to healthy control subjects matched for age, sex and smoking status. Patients, as compared to controls had higher levels of baseline plasma cortisol (375.5+/-47.4/l vs. 273.8+/-42.2 nmol/l, respectively; t=2.48, df=9, p< 0.02) and plasma ACTH (14.9+/-0.85 vs. 11.3+/-0.57 pg/ml, respectively; t=4.29, df=9, p<0.001). AVP levels were lower in patients though this did not reach statistical significance (0.89+/-0.09 vs. 1.3+/-0.08 pmol/l, respectively; t=1.97, df=9, p<0.07). A repeated measures 2-way ANOVA to compare responses to metoclopramide over time between the two groups yielded a significant group by time interaction for cortisol (F=11.3, df=6, 108, p<0.001) and ACTH (F=15.65, df=6, 108, p<0.002). Post hoc Tukey's test revealed significant differences between the two groups at +30, +45, +60, +90 and +120 min for cortisol (p<0.01) and at +30, +45, +60 and +90 min for ACTH (p<0.01). The group by time interactions continued to remain significant when cortisol (F=10.9, df=6, 107, p<0.001) and ACTH (F=13.04, df=6, 108, p<0.002) were entered as co-variates. There was a significant positive correlation between AVP and cortisol responses in patients (r=0.65, df=8, p<0.01). Male patients with paranoid schizophrenia release greater amounts of ACTH and cortisol in responses to metoclopramide-induced AVP secretion than control subjects.

Evidence of basal pituitary-adrenal overactivity in first episode, drug naïve patients with schizophrenia.

BACKGROUND: Evidence for basal hypothalamic-pituitary-adrenal (HPA) axis dysfunction in schizophrenia is less consistent than that seen in major depression. Potential reasons include sampling procedures and the use of patients on antipsychotic medications which may suppress the HPA axis. Therefore, the objective of this study was to determine whether first episode, drug naïve patients with schizophrenia have evidence of basal HPA axis dysfunction by measuring plasma levels of AVP, ACTH and cortisol from 13:00 to 16:00 h, a time frame which is believed to reflect 24 h concentrations of HPA axis activity. METHOD: In this cross-sectional study, plasma levels of AVP, ACTH and cortisol were measured in 12 (7 males and 5 females) (mean age +/-SD=33.6+/-12.6 years) patients with DSM-IV schizophrenia and compared with those found in age- and sex-matched healthy controls. RESULTS: Patients and controls did not differ in terms of their 13:00 h cortisol and AVP. However, patients with schizophrenia had higher levels of ACTH as compared to control subjects at 13:00 h (41.3+/-14.6 vs. 12.4+/-1.1 pg/ml respectively; t=1.99, df=11, p <0.05). In comparison to controls subjects, patients with schizophrenia, had higher mean (+/-SE) AUC of ACTH (26.3+/-6.2 vs. 13.9 nmol/l, respectively; t=2.86, df=11, p <0.02) and cortisol (279.4+/-26.0 vs. 213.1+/-18.4 nmol/l, respectively; t=3.72, df=11, p <0.01). Though, patients with schizophrenia, in comparison to control subjects, had lower mean (+/-SE) AUC of AVP (0.87+/-0.24 vs. 1.42+/-0.34 pmol/l, respectively; t=2.29, df=11, p <0.02). CONCLUSIONS: First episode, drug naïve patients with schizophrenia show evidence of basal overactivity of the pituitary-adrenal axis.

Metabolic disturbance in first-episode schizophrenia.

BACKGROUND: Schizophrenia shortens life, e.g. through suicide and obesity-related diseases such as type 2 diabetes mellitus. It is assumed that medications play a major role, but most of the evidence for this comes from studies poorly controlled for variables such as lifestyle and medication status. AIMS: To determine whether schizophrenia is associated (independently of medication) with the development of certain metabolic disturbances and whether these might be explained by stress axis dysfunction. METHOD: Literature review. RESULTS: Most studies did not control for confounding factors such as previous usage of medication, lifestyle, age and ethnicity. A few conducted in drug-naïve patients with first-episode schizophrenia appear to indicate that these patients have higher than expected rates of visceral obesity and impaired fasting glucose concentrations, which may be related to a subtle disturbance of the hypothalamic-pituitary-adrenal axis. CONCLUSIONS: Schizophrenia is independently associated with physical illnesses that have a metabolic signature. Therefore, patients need to have a thorough physical assessment at diagnosis and at regular intervals thereafter. Metabolic disturbances have been found in drug-naïve patients with first-episode illness and may be an inherent part of the illness.

The effects of atypical antipsychotics on visceral fat distribution in first episode, drug-naive patients with schizophrenia.

The aim of this study was to determine the location of antipsychotic-induced weight gain in drug naïve, first episode patients with schizophrenia. Various fatness and fat distribution parameters (by Computerized Tomography scanning and anthropometry) and 1600 hr plasma cortisol were measured in 19 (15 men and 4 women) subjects with schizophrenia (mean age = 31.0 years; mean body mass index [BMI] = 24.6 kg/m2) and an equal number of age- and sex- matched controls (mean age = 32.6 yr; mean BMI = 23.0 kg/m2). Patients were then given either olanzapine or risperidone. Sixteen patients were re-tested following a treatment period lasting approximately 6 months. Patients with schizophrenia, had significantly more intra-abdominal fat [IAF] (116.8 +/- 20.2 cm2 vs. 38.0 +/- 4.8 cm2, respectively; t = 3.80, df = 18, p < 0.0001) and had higher levels of plasma cortisol (360.2 +/- 49.6 nmol/L vs. 192.7 +/- 19.7 nmol/L, respectively; t = 3.13, df = 18, p < 0.003) than appropriately matched control subjects. Treatment with atypical antipsychotics did not result in a significant increase in IAF (116.8 +/- 20.2 cm2 vs. 131.7 +/- 20.9 cm2; p = NS) though visceral fat stores still remained significantly higher than those seen in controls (38.0 +/- 4.8 cm2) (F = 9.34; df = 2, 51; p < 0.0003). However, plasma levels of cortisol did significantly decrease (360.2 +/- 49.6 nmol/L +/- vs. 316.2 +/- 48.4 nmol/L; p < 0.05). Pre-treatment levels of IAF did not differ between those who received risperidone and those who were given olanzapine (123.0 +/- 35.9 cm2 vs. 113.1 +/- 15.7 cm2, respectively; t = 0.20, df = 16, p < 0.84). The increase in IAF did not differ between those given risperidone and those who received olanzapine (26.9 +/- 12.1 cm2 vs. 18.24 +/- 11.44 cm2, respectively; t = 0.50, df = 16, p < 0.63). Patients with drug naïve, first episode, schizophrenia have higher levels of visceral fats stores as compared to matched control subjects. Treatment with atypical antipsychotics does not result in a significant increase in IAF distribution.

A preliminary study of baclofen-induced growth hormone release in generalised social phobia.

OBJECTIVE: The authors sought to examine central GABA(B) receptor responses in patients with generalised social phobia using the growth hormone (GH) response to baclofen. METHOD: Baclofen 20 mg was administered to 15 patients and 15 healthy matched controls and plasma growth hormone was monitored over a 3 h period. RESULTS: The GH response in patients was significantly reduced in comparison to that of controls when calculated as both area under the curve (AUC) and delta (Delta) response. CONCLUSIONS: The results suggest an abnormality of central GABA(B) receptor function in this disorder.

Impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia.

OBJECTIVE: This study examined the prevalence of impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia. METHOD: In this cross-sectional study, fasting plasma levels of glucose, insulin, lipids, and cortisol were measured in 15 male and 11 female hospitalized Caucasian patients with DSM-IV schizophrenia (mean age=33.6 years) and age- and sex-matched healthy comparison subjects. The patients and comparison subjects were also matched in terms of various life-style and anthropometric measures. RESULTS: More than 15% of the drug-naive, first-episode patients with schizophrenia had impaired fasting glucose tolerance, compared to none of the healthy volunteers. Compared with the healthy subjects, the patients with schizophrenia had significantly higher fasting plasma levels of glucose (mean=88.2 mg/dl, SD=5.4, for the healthy subjects versus mean=95.8 mg/dl, SD=16.9, for the patients), insulin (mean=7.7 micro u/ml, SD=3.7, versus mean=9.8 micro u/ml, SD=3.9), and cortisol (mean=303.2 nmol/liter, SD=10.5, versus mean=499.4 nmol/liter, SD=161.4) and were more insulin resistant, as measured with homeostasis model assessment (mean=1.7, SD=0.7, for the healthy subjects versus mean=2.3, SD=1.0, for the patients). CONCLUSIONS: First-episode, drug-naive patients with schizophrenia have impaired fasting glucose tolerance and are more insulin resistant and have higher levels of plasma glucose, insulin, and cortisol than healthy comparison subjects.

Elevated expression of integrin alpha(IIb) beta(IIIa) in drug-naïve, first-episode schizophrenic patients.

BACKGROUND: Patients with schizophrenia have an increased risk over the general public of developing cardiovascular illness. It is unknown if there are functional changes in platelet surface receptors in schizophrenia. We therefore analyzed the surface expression of glycoprotein (GP)Ib, the integrin receptor alpha(IIb)beta(IIIa), CD62 (P-selectin), and CD63, and investigated platelet function in schizophrenic patients compared with healthy volunteers. METHODS: Nineteen drug-naive, first-episode patients with a DSM IV diagnosis of paranoid schizophrenia were compared with matched healthy controls. Flow cytometry was used to assess platelet surface expression levels of GPIb, alpha(IIb)beta(IIIa), CD62, and CD63. Adenosine diphosphate-induced platelet aggregation was assayed. RESULTS: The schizophrenic patients had a significantly (p < .0001) increased number of 68,145 +/- 8,260.1 alpha(IIb)beta(IIIa) receptors, platelet compared with 56,235 +/- 8,079.4 receptors, platelet in healthy controls. CONCLUSIONS: Patients with schizophrenia have increased platelet expression of alpha(IIb)beta(IIIa), which may contribute to their increased risk of cardiovascular illness compared with the general population.

A preliminary study of dopamine-mediated prolactin inhibition in generalised social phobia.

The biology of social phobia has been little studied, but a possible role for dopamine has been implicated in this disorder. The aim of this study was to examine central dopaminergic function in patients with generalised social phobia using the prolactin response to quinagolide, a dopamine D2 receptor agonist, and to compare responses with those of normal controls. The study included 14 patients with moderate or severe generalised social phobia and 14 healthy age- and gender-matched comparison subjects. Quinagolide (0.5 mg) was administered orally and prolactin responses were measured over 4 h. There was no significant difference between prolactin responses in patients and healthy controls, nor was there a correlation between prolactin response and age, sex, or severity of illness. This would suggest that tuberoinfundibular dopamine D2 receptor sensitivity is normal in this disorder.

A preliminary study of buspirone stimulated prolactin release in generalised social phobia: evidence for enhanced serotonergic responsivity?

Serotonergic dysfunction has been postulated to play a role in the aetiology of social phobia. Buspirone, which is a partial agonist at 5HT1A receptors, increases prolactin release and may be used as a probe to examine serotonergic responses, dysfunction of which may be relevant to the pathophysiology of social phobia. We compared buspirone stimulated prolactin release in 14 patients with generalised social phobia and 14 healthy controls. Buspirone 30 mg was administered orally and prolactin release over 180 min was monitored. Overall, patients with generalised social phobia had greater prolactin release in response to buspirone challenge than healthy comparison subjects. There was no correlation between prolactin response and measures of severity of social phobia. Patients with generalised social phobia had enhanced central serotonergic responses, an abnormality shared with some other anxiety disorders and which may be of aetiological significance.

Physical consequences of schizophrenia and its treatment: the metabolic syndrome.

Schizophrenia is a life shortening illness. Unnatural causes and natural causes are put forward as reasons for this excess mortality. In terms of the latter, a host of different physical disorders occur with increased frequency in schizophrenia. When taken together, some of these illnesses such as type 2 diabetes mellitus and cardiovascular disorders constitute the Metabolic Syndrome; a characteristic phenotype of those with this syndrome is excessive visceral fat distribution. The exact reasons why this particular syndrome occurs in schizophrenia is as yet unclear though factors such as life style, poor diet and lack of exercise may contribute to it's development. Alternatively, overactivity of the hypothalamic-pituitary-adrenal axis leading to hypercortisolaemia can also result in excessive visceral fat accumulation. This minireview aims to explore the potential role of these issues and medication in terms of the increased morbidity and mortality observed in schizophrenia.