Microvascular dysfunction in schizophrenia: a case-control study.

BACKGROUND: Schizophrenia is a mental illness associated with cardiovascular disease at a younger age than in the general population. Endothelial dysfunction has predictive value for future cardiovascular events; however, the impact of a diagnosis of schizophrenia on this marker is unknown. AIMS: We tested the hypothesis that subjects with schizophrenia have impaired endothelial function. METHODS: A total of 102 subjects (34.5±7.5 years) participated in this study. This sample consisted of 51 subjects with a diagnosis of schizophrenia and 51 healthy subjects, who were matched for age (P=0.442), sex (P>0.999), and smoking status (P=0.842). Peripheral artery microvascular and conduit vessel endothelial function was measured using hyperemic velocity time integral (VTI), pulse arterial tonometry (PAT), and flow-mediated dilation (FMD). RESULTS: Significantly lower values of VTI were noted in subjects with schizophrenia (104.9±33.0 vs. 129.1±33.8 cm, P<0.001), whereas FMD (P=0.933) and PAT (P=0.862) did not differ between the two groups. A multivariable-linear-regression analysis, built on data from univariate and partial correlations, showed that only schizophrenia, sex, lipid-lowering medications, antihypertensive medications, and low-density lipoprotein (LDL)-cholesterol were predictive of attenuated VTI, whereas age, ethnicity, family history of cardiovascular disease, smoking status, systolic blood pressure, waist circumference, HDL-cholesterol, triglycerides, C-reactive protein, and homeostatic model assessment-insulin resistance (HOMA-IR), antidiabetic medications, antidepressant medications, mood stabilizers, benzodiazepines, and anticholinergic medications did not predict VTI in this model (adjusted R (2)=0.248). CONCLUSIONS: Our findings suggest that a diagnosis of schizophrenia is associated with impaired microvascular function as indicated by lower values of VTI, irrespective of many other clinical characteristics. It might be an early indicator of cardiovascular risk in schizophrenia, and might help to identify high-risk individuals.

No effects of antidepressants on negative symptoms in schizophrenia.

Negative symptoms are common in schizophrenia, but often difficult to differentiate from depression. They are associated with long-term impairment and do not respond well to current treatment approaches. Even though antidepressants are commonly prescribed in schizophrenia, their beneficial effect is still under debate. In the present study, we aimed to investigate the effect of serotonergic versus noradrenergic antidepressant add-on therapy on negative symptoms in schizophrenia. Fifty-eight patients with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and with predominant negative symptoms were randomized in a double-blind design to add-on treatment with citalopram, reboxetine, or placebo for 4 weeks. Analysis of covariance with repeated-measures design was used to compare improvement between treatment groups in scores of the Positive and Negative Syndrome Scale and the Hamilton Rating Scale for Depression. A χ² test was used to compare responder rates between treatment groups. Repeated-measures analysis of covariance revealed no differences between treatment groups over time (treatment × time, not statistically significant) for Positive and Negative Syndrome Scale subscales. Although a subgroup analysis in subjects fulfilling the criteria for minor depression was suggestive of higher responder rates in the citalopram group compared with reboxetine, the results did not reach significance level. Our findings do not support a beneficial effect of adjunctive antidepressant treatment on negative symptoms in schizophrenia. However, depressive symptoms are reduced in patients with minor depression by citalopram but not reboxetine, which is in line with previous findings.

Peptide fingerprinting of Alzheimer's disease in cerebrospinal fluid: identification and prospective evaluation of new synaptic biomarkers.

BACKGROUND: Today, dementias are diagnosed late in the course of disease. Future treatments have to start earlier in the disease process to avoid disability requiring new diagnostic tools. The objective of this study is to develop a new method for the differential diagnosis and identification of new biomarkers of Alzheimer's disease (AD) using capillary-electrophoresis coupled to mass-spectrometry (CE-MS) and to assess the potential of early diagnosis of AD. METHODS AND FINDINGS: Cerebrospinal fluid (CSF) of 159 out-patients of a memory-clinic at a University Hospital suffering from neurodegenerative disorders and 17 cognitively-healthy controls was used to create differential peptide pattern for dementias and prospective blinded-comparison of sensitivity and specificity for AD diagnosis against the Criterion standard in a naturalistic prospective sample of patients. Sensitivity and specificity of the new method compared to standard diagnostic procedures and identification of new putative biomarkers for AD was the main outcome measure. CE-MS was used to reliably detect 1104 low-molecular-weight peptides in CSF. Training-sets of patients with clinically secured sporadic Alzheimer's disease, frontotemporal dementia, and cognitively healthy controls allowed establishing discriminative biomarker pattern for diagnosis of AD. This pattern was already detectable in patients with mild cognitive impairment (MCI). The AD-pattern was tested in a prospective sample of patients (n = 100) and AD was diagnosed with a sensitivity of 87% and a specificity of 83%. Using CSF measurements of beta-amyloid1-42, total-tau, and phospho(181)-tau, AD-diagnosis had a sensitivity of 88% and a specificity of 67% in the same sample. Sequence analysis of the discriminating biomarkers identified fragments of synaptic proteins like proSAAS, apolipoprotein J, neurosecretory protein VGF, phospholemman, and chromogranin A. CONCLUSIONS: The method may allow early differential diagnosis of various dementias using specific peptide fingerprints and identification of incipient AD in patients suffering from MCI. Identified biomarkers facilitate face validity for the use in AD diagnosis.

Inflammatory mechanisms in major depressive disorder.

PURPOSE OF REVIEW: As the 'monoamine hypothesis of depression' fails to explain all aspects of major depression, additional causes are being investigated. Several observations suggest that inflammatory mechanisms pay a role in the cause of major depressive disorder (MDD). This article reviews their role in major depression. RECENT FINDINGS: Recent studies support the concept that inflammatory mechanisms play a crucial role in the pathomechanisms of major depression. Major depression shares similarities with 'sickness behavior', a normal response to inflammatory cytokines. Elevations in proinflammatory cytokines and other inflammation-related proteins in major depression were found in plasma and cerebrospinal fluid (CSF) as well as in postmortem studies. Elevated levels of proinflammatory cytokines persist after clinical symptoms of depression are in remission and can also predict the onset of a depressive episode. Antidepressant treatment can lead to a normalization of elevated cytokine levels in major depression. Finally, we understand how inflammatory mechanisms affect the metabolism of tryptophan and how nonsteroidal antiinflammatory drugs (NSAIDs) can interfere with the effects of antidepressants. SUMMARY: Further studies are needed to fully understand the role of inflammatory mechanisms in major depression and the potential treatment implications.

Cardiovascular aspects of antipsychotics.

PURPOSE OF REVIEW: Schizophrenia is associated with increased mortality and reduced life expectancy, with cardiovascular disease being the most frequent cause of death. Antipsychotics have detrimental effects on different risk factors for cardiovascular disease. This review will focus on the relationship between antipsychotic treatment and cardiovascular disease. RECENT FINDINGS: The increased overall mortality and mortality from cardiovascular disease in schizophrenia are now well documented. Patients with schizophrenia are at risk of receiving less optimal treatment for cardiovascular disease. Patients with schizophrenia are at high risk of metabolic syndrome, a cluster of risk factors for cardiovascular disease. Some antipsychotics, in particular, clozapine and olanzapine, frequently cause weight gain, dyslipidemia and diabetes mellitus. Antipsychotics differ in their effects on body weight, lipids and glucose regulation. However, the long-term effects of these differences between individual antipsychotics on overall mortality and cardiovascular mortality are not well established. SUMMARY: More research is needed to better understand the relationship between schizophrenia, antipsychotic treatment and cardiovascular disease. More effective treatment strategies need to be developed to reduce the burden of cardiovascular disease in schizophrenia.

Variability of the in vivo metabolism of clozapine.

OBJECTIVES: Clozapine, the gold standard of antipsychotic treatment in treatment-refractory patients with schizophrenia, is metabolized in vivo to clozapine-N-oxide and N-desmethylclozapine (NDMC = norclozapine). N-desmethylclozapine is an active metabolite of clozapine and combines unique pharmacological properties. Because little is known about the rate of metabolic conversion of clozapine in vivo, we assessed the association between clozapine dose and plasma levels for clozapine and NDMC. METHODS: Plasma levels of clozapine and NDMC were measured in 485 blood samples from 108 patients with schizophrenia treated with clozapine. %NDMC, the ratio of NDMC to total clozapine (NDMC + clozapine), was used as a measure of the in vivo metabolism of clozapine. RESULTS: Daily clozapine doses correlated significantly with clozapine levels and NDMC levels, whereas %NDMC showed a weaker negative correlation with clozapine dose. The mean %NDMC value was 37.0% +/- 16.8%, with high variability between subjects. Repeated measurements in subjects treated with the same dose of clozapine showed a high within-subject variability of %NDMC. CONCLUSIONS: Our results suggest a high degree of between-subject and within-subject variability in the metabolism of clozapine in vivo. Direct administration of NDMC may be preferable to reliably achieve sufficient plasma levels of this compound.

Capillary electrophoresis mass spectrometry as a potential tool to detect lithium-induced nephropathy: Preliminary results.

Lithium remains the treatment of choice for many patients suffering from bipolar disorder. However, long-term treatment with lithium carries the potential to cause renal and thyroid dysfunction. Lithium-induced nephropathies are characterised by deterioration of urinary concentrating ability as well as, less frequently, a progressive and potentially irreversible decrease in glomerular filtration rate (GFR). Pathological changes after treatment with lithium include both tubulointerstitial and glomerular changes. Besides monitoring of the kidney-function, no screening-instruments exist for early identification of patients at risk of lithium-induced nephropathy. CE-MS (capillary electrophoresis coupled to a mass spectrometer) is a new technique that has been applied to the differential diagnosis of nephropathies. We sought to determine if CE-MS can be used to identify lithium-induced renal changes. A urine-sample was obtained from 14 subjects (7 males, 7 females, mean age 51.1 years) under long-term treatment with lithium (mean duration 17.4 years, range 8-35 years) without known nephropathy (mean creatinine 0.96 mg/dl; range 0.7-1.6). Urine samples were stored at -20 degrees C until analysis. CE-MS was performed according to standard procedures and a screen for nephropathies was used. Among the 14 urine samples, two subjects tested positive for a nephropathy. One further subject had a borderline result. Since 3/14 subjects with no known nephropathy showed some degree of pathological findings, CE-MS from a urine-sample may be helpful for the early detection of renal damage under treatment with lithium. However, a specific screen for lithium-induced nephropathies still needs to be developed.

Lithium-induced nephropathies.

Lithium, an alkali metal, remains the gold-standard of the pharmacological treatment of bipolar disorder. Over the past decades, the potential of lithium to cause renal damage has been an issue of debate. Polyuria, polydipsia, and, to a lesser degree, nephrogenic diabetes insipidus are frequently observed under treatment with lithium. The glomerular filtration rate (GFR) decreases progressively in a smaller proportion of subjects after several years of treatment with lithium. An even smaller number of patients continue to develop renal insufficiency, ultimately leading to hemodialysis in a small minority of subjects exposed to lithium. So far, no tests exist to identify subjects at risk of lithium-induced nephropathy at an early stage. Therefore, regular monitoring of creatinine and creatinine clearance are recommended in all subjects taking lithium.

Dose-dependent constipation with higher doses of quetiapine: a case series.

Quetiapine is a dopamine D2 and serotonin 5-HT2 antagonist with antipsychotic and mood-stabilizing properties. Recent studies suggest that higher doses of quetiapine combine superior therapeutic efficacy with good tolerability. We present five patients, in whom treatment with higher doses of quetiapine was associated with constipation. Our observations raise the question of dose-dependent constipation under treatment with quetiapine.

Early onset of treatment effects with oral risperidone.

BACKGROUND: The dogma of a delayed onset of antipsychotic treatment effects has been maintained over the past decades. However, recent studies have challenged this concept. We therefore performed an analysis of the onset of antipsychotic treatment effects in a sample of acutely decompensated patients with schizophrenia. METHODS: In this observational study, 48 inpatients with acutely decompensated schizophrenia were offered antipsychotic treatment with oral risperidone. PANSS-ratings were obtained on day 0, day 1, day 3, day 7 and day 14. RESULTS: Significant effects of treatment were already present on day 1 and continued throughout the study. The PANSS positive subscore and the PANSS total score improved significantly more than the PANSS negative subscore. CONCLUSION: Our results are consistent with the growing number of studies suggesting an early onset of antipsychotic treatment effects. However, non-pharmacological effects of treatment also need to be taken into consideration.

Comparison of the in-vivo muscarinic cholinergic receptor availability in patients treated with clozapine and olanzapine.

Clozapine and olanzapine are two atypical antipsychotics that bind to a broad range of receptors in vitro. Our group previously reported on the binding of clozapine and olanzapine to muscarinic receptors in vivo. Based on these data, a direct comparison of the muscarinic receptor availability in vivo under treatment with these atypical antipsychotics was performed. [123I]IQNB SPECT scans were obtained in seven subjects treated with a high dose (20 mg) of olanzapine and seven subjects treated with a moderate dose (mean 275.0 mg, range 200-450 mg) of clozapine. Muscarinic receptor-binding indices were determined for basal ganglia, cortex, thalamus and pons. When comparing moderate-dose clozapine with high-dose olanzapine, significantly lower muscarinic receptor availability was found for clozapine in all four cortical regions of interest. Our results suggest that treatment with clozapine results in a stronger blockade of the muscarinic cholinergic receptors than with olanzapine. These results are compatible with the higher rates of anticholinergic side-effects seen with clozapine in clinical practice.

CSF-studies in neuropsychiatric disorders.

Cerebrospinal fluid (CSF) is a clear and colourless fluid that surrounds the brain and spine. Due to the close proximity of CSF to the brain, pathological brain-processes are likely to be reflected in CSF. CSF can be obtained through lumbar puncture and is frequently performed in the differential diagnosis of neuropsychiatric disorders. Beyond clinical applications, CSF has been studied as part of different research-protocols. In this review, we will focus on CSF-analysis in Alzheimer Disease, major depression and schizophrenia. We will review both clinical applications as well as research applications in all three disorders. We will also assess new technological advances that have made it possible to study large numbers of proteins in CSF and how these advances may change CSF-analysis in the years to come.

Megestrol attenuates the hormonal response to CCK-4-induced panic attacks.

Progestational hormones may have anxiolytic properties. CCK-4 (cholecystokinin tetrapeptide) can be used pharmacologically to induce panic attacks both in normal controls and patients suffering from panic disorder. In this study we compared the effects of pretreatment with the progestational hormone megestrol and placebo on CCK-4-induced panic attacks and stress hormone release in healthy male controls. Using a double-blind balanced design, we pretreated 10 medically and psychiatrically healthy male controls with placebo or megestrol 160 mg at 11 p.m. and 8 a.m. (sigma=320 mg) prior to the experiment. Following 1 h of rest, 12 blood samples were drawn between 1,000 h and 1,300 h and analyzed for ACTH and cortisol levels. At 1,100 h, subjects received an intravenous injection of 50 microg CCK-4. Clinical ratings were performed at 1,045 h and 1,110 h, and included the Acute Panic Inventory (API), International Diagnostic Checklist (IDCL), as well as a visual analog scale (VAS) for anxiety and tension. CCK-4 significantly increased anxiety and tension. Pretreatment with megestrol showed no significant effect on clinical ratings. Baseline ACTH and cortisol levels, as well as ACTH and cortisol levels after administration of CCK-4, were significantly reduced after pretreatment with megestrol. In a sample of healthy male controls, pretreatment with megestrol had a profound effect on the hypothalamic-pituitary-adrenal (HPA) axis, whereas the clinical effects on panic attacks were weak. Further studies in a larger sample of subjects, including both females and patients suffering from panic disorder, seem warranted.

Adjunctive use of reboxetine in schizophrenia.

BACKGROUND: Schizophrenia is frequently complicated by depressive or negative symptoms that respond only moderately to treatment with antipsychotic drugs. Reboxetine is a novel antidepressant, which inhibits the reuptake of norepinephrine. We sought to study the efficacy and tolerability of the adjunctive use of reboxetine in a cohort of schizophrenic patients with prominent depressive or negative symptoms. METHODS: Sixteen schizophrenic inpatients were recruited for this study. All subjects received 4-8 mg of reboxetine/day while the antipsychotic medication (typical antipsychotics = 4; atypical antipsychotics = 12) was continued. All subjects underwent a standardized assessment including PANSS, CGI, HAMD, and CDSS before and after treatment with reboxetine (mean 26 +/- 17 d). RESULTS: All subjects tolerated treatment with reboxetine. Adverse effects were mild and did not require discontinuation of reboxetine. All clinical scores (PANSS 93.1 vs. 63.1; CGI 5.4 vs. 4.1; HAMD 20.4 vs. 8.1; CDSS 12.5 vs. 4.6) improved significantly under adjunctive treatment with reboxetine (all P < 0.01). CONCLUSION: The adjunctive use of reboxetine in schizophrenic patients was safe and well-tolerated. Our results suggest that the adjunctive use of reboxetine may be an effective treatment for depressive and negative symptoms in schizophrenia.

Risperidone in the treatment of acute schizophrenia.

INTRODUCTION: Atypical antipsychotics have proven efficacy and tolerability in the treatment of schizophrenia. While a lot is known about maintenance treatment with atypical antipsychotics, less is known about their role in the management of acute psychotic decompensations. To evaluate the efficacy of the atypical antipsychotic risperidone, we conducted an open-label observational study among admissions to a secure unit. METHOD: Treatment with risperidone was offered to acutely psychotic schizophrenic patients with the requirement of a minimum score of > or =4 on 2 items of the PANSS positive symptoms subscale. Subjects were treated with 4 to 8 mg risperidone in divided doses (mean dose 5.7 +/- 1.5 mg/d). Benzodiazepines and anticholinergics were allowed as co-medications. Clinical Global Impression ratings and Positive and Negative Syndrome Scale ratings were obtained weekly for 4 weeks. RESULTS: Forty-eight subjects (25 males, 23 females; mean age 36.9 +/- 13.4 years, range 18 to 68 years) participated in this study. The mean duration of treatment was 13.4 +/- 9.7 days (range 1 to 31 days). Risperidone was well tolerated, and 26 (54%) patients completed the study. Reasons for discontinuation were need of intramuscular antipsychotic medication (8 subjects), switch to a different antipsychotic (11 subjects), side effects (1 subject), and noncompliance (2 subjects). Treatment with risperidone reduced the mean CGI score from 5.9 to 4.8 (P < 0.001). Likewise, the total PANSS score improved from 110.9 to 86.0 (P < 0.001) with similar reductions in all subscales. DISCUSSION: Our results demonstrate that risperidone is an effective and well-tolerated medication for the pharmacologic management of acutely psychotic schizophrenic subjects.

Acute effects of megestrol on the hypothalamic-pituitary-adrenal axis.

BACKGROUND: Clinical observations suggest that prolonged treatment with megestrol can lead to Cushing-like symptoms, while withdrawal of prolonged treatment with megestrol may result in adrenal insufficiency. However, only little is known about the acute effects of megestrol on the hypothalamic-pituitary-adrenal (HPA) axis. As part of an endocrine study, we evaluated the acute effects of megestrol, hydrocortisone and placebo on morning cortisol and ACTH levels. METHOD: . Using a balanced double-blind design, ten healthy male subjects were treated at 11:00 p.m. and 8:00 a.m. with megestrol (total dose 320 mg), hydrocortisone (total dose 30 mg) or placebo. After 1 h of rest, blood was drawn at 10:00 a.m. and 10:30 a.m. for determination of cortisol and ACTH levels. RESULTS: . Compared to placebo, acute administration of megestrol resulted in a significant decrease in morning ACTH and cortisol levels. The suppression of ACTH after pretreatment with megestrol was less pronounced than after pretreatment with hydrocortisone. CONCLUSIONS: Our results suggest that megestrol exerts glucocorticoid-like effects and has an acute depressing effect on the HPA axis. Therefore alterations in the steroid system should be included in the differential diagnosis of all subjects under treatment with megestrol.

Central muscarinic acetylcholine receptor availability in patients treated with clozapine.

Clozapine is the prototypical atypical antipsychotic. In vitro, clozapine antagonizes a broad range of receptors, including dopamine, serotonin and muscarinic acetylcholine receptors. In vivo, receptor occupancy studies have shown moderate dopamine D(2) receptor blockade as well as high serotonin 5HT(2) receptor blockade for clozapine. Using [I-123]IQNB SPECT, we explored the influence of clozapine on muscarinic receptors in vivo. Eight schizophrenia patients underwent a total of 12 [I-123]IQNB SPECT scans after treatment with low to moderate doses of clozapine (mean 210 mg/day, range 50-450 mg/day). Muscarinic receptor availability was determined for basal ganglia, cortex, thalamus, and pons. A group of 12 age- and sex-matched unmedicated schizophrenia patients was used for comparison. Compared to unmedicated patients, [I-123]IQNB binding was lower in all regions in subjects treated with clozapine and decreased with increasing dose. In patients treated with a daily clozapine dose of at least 200 mg (mean 275+/-88 mg/day), these differences were highly significant (p <0.003) with mean reductions of muscarinic receptor availability of 45% for basal ganglia, 58% for cortex, 66% for pons, and 79% for thalamus. These preliminary data indicate that reduction of muscarinic receptor availability by clozapine can be measured in vivo and that moderate daily doses are associated with moderate to high reductions of muscarinic receptor availability. These results may explain, at least in part, the lack of extrapyramidal side effects as well as some side effects seen with clozapine.

In vivo determination of muscarinic acetylcholine receptor availability in schizophrenia.

OBJECTIVE: Postmortem studies have implicated the central muscarinic acetylcholine system in schizophrenia. However, central muscarinic receptor availability has not previously been studied in vivo. Using [I-123]iodoquinuclidinyl benzilate ([(123)I]IQNB) single photon emission computed tomography (SPECT), the authors sought to compare the muscarinic receptor availability in vivo in unmedicated patients with schizophrenia and normal subjects. METHOD: Twelve medication-free patients with schizophrenia underwent an [(123)I]IQNB SPECT scan during approximate-equilibrium conditions. A group of 10 age- and gender-matched normal comparison subjects were given the same kind of scan under similar conditions. Regions of interest were analyzed in the cortex, basal ganglia, thalamus, and pons. Binding data were analyzed as nCi/ml tissue per mCi injected dose. RESULTS: Muscarinic receptor availability was significantly less in patients with schizophrenia than in normal subjects in all regions of interest except the pons. Reductions ranged from -33% in the caudate to -20% in the occipital cortex. Positive symptoms of schizophrenia correlated negatively with muscarinic receptor availability in the striatum and the frontal cortex. CONCLUSIONS: These results indicate a reduction in muscarinic acetylcholine receptor availability in vivo in unmedicated patients with schizophrenia, confirming results from postmortem studies and adding further evidence that the muscarinic system is involved in the pathophysiology of schizophrenia.