Naturalistic pharmacotherapy of acute episodes of schizophrenic disorders in comparison to treatment guidelines.

INTRODUCTION: This study was designed to investigate to what extent guidelines regarding the pharmacological treatment of patients suffering from schizophrenia-like psychosis are adopted in a naturalistic treatment setting. METHODS: Medical records of n=819 patients undergoing inpatient treatment for schizophrenia-like psychosis in 11 psychiatric hospitals in northwestern Germany were retrospectively analyzed and findings were compared to current schizophrenia guideline recommendations. RESULTS: The prescription rate of second generation antipsychotics increased from 47.1% on admission to 62.5% at discharge. Only half the patients (52.3%) received antipsychotic monotherapy while 47.7% took between 2 and 4 antipsychotic substances at a time. Dosage increases occurred most frequently (in 60%) within the first week of inpatient treatment, 16.6% experienced an elevation between days 15 and 29. A change within the atypical medication was found in 19.3%. Clozapine prescriptions increased throughout the treatment but were combined with other antipsychotic substances in the majority of cases. CONCLUSION: Under naturalistic conditions guideline recommendations for treatment of schizophrenia-like psychosis are adhered to only partially. Combination therapy with 2 or more antipsychotic drugs is quite common despite a clear recommendation for monotherapy.

The tolerability of rTMS treatment in schizophrenia with respect to cognitive function.

INTRODUCTION: The purpose of this study was to assess tolerability and safety of high-frequency rTMS with regard to cognitive performance when conducted as "add-on" treatment in chronic schizophrenia in-patients (n=32). METHODS: Patients, who were on stable antipsychotic treatment, were randomly assigned to verum or sham condition (double-blind). In the verum group, ten sessions of 10 Hz rTMS with a total of 10 000 stimuli were applied over the left dorsolateral prefrontal cortex (PFC) at 110% of motor threshold over a period of two weeks. The sham group received corresponding sham stimulation. RTMS effects on cognitive performance were assessed with a neuropsychological test battery consisting of the following tests: trail making test A and B (TMT), Wisconsin card sorting test (WCST), D2 attention task and the "short test of general intelligence" (KAI). RESULTS: No statistically significant deterioration of cognitive performance was observed as a result of rTMS treatment. Moreover it was shown that in the verum group patients with a less favourable performance on the WCST at baseline tend to improve after rTMS treatment with regard to psychopathology as opposed to patients in the control group. DISCUSSION: The stability of cognitive function suggests good tolerability of rTMS treatment in schizophrenia. The absence of evidence for cognitive deterioration could be due to low and short stimulation parameters.

[Biological correlates of prefrontal activating and temporoparietal inhibiting treatment with repetitive transcranial magnetic stimulation (rTMS)]. / Biologische Korrelate präfrontal aktivierender und temporoparietal inhibierender Behandlung mit repetitiver transkranieller Magnetstimulation (rTMS).

Repetitive transcranial magnetic stimulation (rTMS) is a tool that enables clinicians and neuroscientists to modulate cortical activity in a non-invasive way. High-frequency rTMS has predominantly an activating effect on the stimulated brain region while low-frequency rTMS has an inhibitory effect. In addition to its usefulness as a research tool and in neurological diagnostics, rTMS may prove useful as a therapeutic option in psychiatry, especially in disorders that are associated with regional changes in cortical activity. For instance, rTMS is under current investigation in the treatment of depression and negative symptoms of schizophrenia. A hypofrontality or a fronto-limbic imbalance associated with both syndromes could be corrected by activating, high frequency rTMS. Conversely, a regional hyperactivity in the temporo-parietal cortex has been described in subjects suffering from auditory hallucinations and tinnitus. Low frequency, inhibitory rTMS is currently evaluated as a therapeutic option in these subjects. In addition to the effects on the directly stimulated brain area, other biological effects of rTMS may exert a beneficial influence on brain function. Amongst these are a modulation of cortico-cortical circuits (e. g. fronto-cingular and fronto-parietotemporal circuits), effects on monoaminergic neuromodulation and neuroendocrine effects. The current knowledge about the therapeutically relevant neurophysiological and neuroendocrine effects of rTMS are reviewed. An improved understanding of the neurophysiological basis of the therapeutic effects of rTMS and of the pathophysiology underlying neuropsychiatric diseases may lead to optimized therapeutic rTMS applications and new clinical indications for rTMS.

Cardiovagal modulation upon postural change is altered in Huntington's disease.

BACKGROUND: Cardiac autonomic nervous system (ANS) dysfunction in Huntington's disease (HD) might affect both the sympathetic and parasympathetic branch of the ANS. RESULTS AND CONCLUSIONS: The pattern of linear heart rate variability we found in mid stage HD patients points towards a predominately reduced cardiovagal modulation compared with healthy subjects, which might influence HD patients' susceptibility for cardiovascular complications such as syncopes and cardiac arrhythmias.

MRI changes associated with partial status epilepticus.

Neurological disorders of different etiology may cause identical clinical symptoms requiring additional diagnostic procedures for a precise differential diagnosis. Focal epileptic seizures have been shown to cause increased signal intensities in T2 and diffusion-weighted magnetic resonance images (MRI), mimicking other neurological disorders or diseases such as viral encephalitis. In some cases even the combination of neuroimaging and cerebrospinal fluid (CSF) analysis is not sufficient to obtain the final diagnosis, since epileptic seizures may cause pleocytosis as well. Some epilepsy centers presented cases of focal status epilepticus with severe but reversible MRI changes. These cases indicate that MRI-changes following focal seizures are reversible over a different time window compared to MRI changes associated with other etiologies, such as viral infection. This data further suggest that in cases where focal seizures can not be ruled out, a follow-up MRI scan within a few days following the onset of symptoms significantly improves the precision of the differential diagnosis. Recently new scientific data were reported in this review.

Autonomic responses of blood vessels and sweat glands in patients with schizophrenia treated with olanzapine or clozapine.

RATIONALE: Data comparing the in vivo effects on autonomic nervous system function of standard clinical doses of olanzapine and clozapine are sparse. OBJECTIVE: The goal of this study was to compare the skin conductance response (which is peripherally mediated via muscarinic m3-receptors) and the inspiratory gasp response (which is peripherally mediated via adrenergic receptors) between healthy controls and schizophrenics treated with clozapine or olanzapine. METHODS: Twenty patients with schizophrenia (according to DSM-III-R criteria) treated with either clozapine (200-500 mg/day) or olanzapine (10-20 mg/day) as well as ten matched controls underwent simultaneous recordings of the skin conductance response (SCR) of sweat glands and of the inspiratory gasp response (IGR) of acral blood vessels. A single, deep inspiration was used as the stimulus. Group differences for the SCR amplitudes and the post-IGR redilation times were compared using the Mann-Whitney test. RESULTS: Both clozapine- and olanzapine-treated patients showed a significant SCR reduction compared to controls. Interestingly, the reduction in SCR was significantly larger in the clozapine group compared to the olanzapine group (P<0.05). Moreover, only clozapine-treated patients showed a statistical trend towards a longer IGR redilation time compared to controls. CONCLUSION: The significantly stronger SCR reduction amongst clozapine-treated compared to olanzapine-treated patients suggests that olanzapine at a standard clinical dose exhibits a significantly smaller anticholinergic effect at peripheral m3-receptors in vivo compared to clozapine. The prolongation of IGR redilation can be explained by a prolonged release of noradrenaline due to the alpha2-antagonistic effect of clozapine.

Dysfunction of visual pathways in HIV-1 infection.

Foveal and conventional full field pattern-shift visual evoked potentials (f-VEPs and c-VEPs) were recorded bilaterally in 100 HIV seropositive homosexual men (HIVs) and in 40 age-matched healthy controls. In HIVs, both f-VEPs and c-VEPs revealed a significant mean increase in P100 latency (p < 0.001). In stage WR2 early conduction changes were detected in 17% of the stimulated eyes by f-VEPs and in 3% by c-VEPs. In patients with CD4 cell counts below 100/microliters a 33% reduction in the mean c-VEP amplitude was found (ANOVA p < 0.01). Multivariate analyses (MANCOVA) revealed that CD4 cell depletion was independently associated with lower (p < 0.01) and zidovudine treatment with higher c-VEP amplitudes (p < 0.05). Also patients with severe CD4 cell depletion showed a trend towards higher c-VEP amplitudes (p = 0.09) and lower f-VEP latencies (p = 0.08) after long lasting zidovudine treatment (Kruskal-Wallis test). Our data suggest that f-VEPs are a sensitive measure of subclinical optic fiber dysfunction in early HIV-1 infection and that axonal loss of optic fibers emerges with manifest immune deficiency. The inverse correlation of VEP changes and zidovudine treatment merits further studies on the question, whether inhibition of HIV replication may preserve visual pathway function.

Alcoholism, peripheral neuropathy (PNP) and cardiovascular autonomic neuropathy (CAN).

In contrast to diabetic autonomic neuropathy, cardiovascular autonomic neuropathy (CAN) in long-term alcoholics has been studied rarely. Using both standardized bedside tests and computer-assisted analysis of heart rate variability (HRV), we prospectively compared autonomic neurocardial function between 35 strictly selected, detoxified alcoholics (DSM-III-R), and 80 well matched healthy controls. Evidence for a potential CAN was found in 25.7% of all the alcoholics studied and in 41% of those with clinically manifest PNP (n=22). Overall, our results demonstrated a significant association between the presence of a CAN and peripheral neuropathy (PNP) amongst chronic alcoholics (chi-square test P<0.05); there was no evidence of a CAN in any of the alcoholics without a clinically manifest PNP. The CAN was characterized by a dissociated appearance of parasympathetic and sympathetic disorders. Our findings provide reason to suspect that the total lifetime dose of alcohol and the duration of alcohol dependence are the most important factors contributing to the pathogenesis of both PNP and sympathetic dysfunction. As is the case with diabetics, computer-assisted measurements of HRV including spectral analysis appear to be far superior to conventional bedside tests for detecting evidence of cardiovagal dysfunction in long-term alcoholics.

Autonomic neurocardiac function in patients with major depression and effects of antidepressive treatment with nefazodone.

BACKGROUND: Major depression (MD) is associated with an augmented risk of cardiovascular mortality. One possible explanation for this association is that MD influences autonomic neurocardiac regulation (ANR). However, previous studies on this subject revealed conflicting results. METHODS: Using an autonomic test battery, which consisted of standardised measurements of heart rate variability (HRV) and blood pressure, we (1) compared ANR between 25 patients with DSM-III-R diagnosed MD and 60 healthy controls, and (2) investigated the autonomic effects of antidepressive treatment with nefazodone. RESULTS: Following multivariate analysis of all tests a significant reduction in HRV could only be shown for the Valsalva ratio amongst the depressives compared to controls. There was a significant inverse correlation between the HRV during deep respiration and both the severity of depression and the duration of the depressive episode. Serial HRV recordings revealed that both the mean resting heart rate and systolic blood pressure significantly decreased after 21 days of nefazodone treatment (average dosage 413 mg/day), whereas after 10 days (average dosage 270.8 mg/day) there were no striking changes compared to the pre-treatment values. During nefazodone treatment no significant changes in parasympathetic tone occurred. LIMITATIONS: ANR was not assessed in a randomised, placebo-controlled fashion. CONCLUSIONS: (1) Patients with MD may suffer from functional disturbances in the interaction between the sympathetic and parasympathetic autonomic tree. (2) The pattern of autonomic changes during treatment suggests that nefazodone induced a dose dependent, serotonergically-mediated down-regulation of the sympathetic tone. This mechanism might be responsible for nefazodone's properties of reducing anxiety.

Questionning aggravation of the headache during migraine attacks.

While questioning patients about aggravation of the headache by routine physical activity, sensitivity of walking stairs and lifting a heavy object versus head movements and bending down in terms of aggravating the headache was aimed to be determined. Eighty-one migraine patients were questioned about the aggravation of their headaches with two sets of question groups. (The first set: walking stairs and lifting a heavy object; The second set: rotating the head side to side and bending down). 38 and 72 patients gave clear answers to the first and second set of questions respectively. Clear information was obtained from the first and second group of questions by 38 and 72 patients respectively. Some patients with severe migraine headaches may prevent themselves from rigorous daily activities while they could bend or make sudden head movements inadvertently during the attack. We think that aggravation of the headache due to head movements or bending down during migraine attacks seems more sensitive than walking stairs or lifting a heavy object to migraine patients.

Clinical features and therapy of medication overuse headache.

Inappropriate use of headache medication (>15 times/month) for the treatment of headache episodes may contribute to the development of chronic headache which is refractory to most treatments. Physicians experienced in the treatment of migraine and other headaches are well aware that the daily intake of antipyretic or antiinflammatory analgesics, opioids, ergot alkaloids and "triptans" may result in chronic daily headache. Conversely, if a patient complains of chronic headache and takes pain medication every day, this headache is most likely to be caused and sustained by the medication and will vanish or improve with abstinence. Treatment includes drug withdrawal followed by structured acute therapy and initiation of migraine prophylactic treatment.

Epidemiology of chronic daily headache.

Over the last 10 years an increasing amount of data regarding the prevalence of chronic daily headache (CDH) has been published. The economic implications of chronic daily headache have now grown in importance in view of the increasingly limited financial resources in the health care system. In addition to recording data regarding the prevalence of this disease, epidemiological studies have also dealt with analysing and evaluating the quality of life of the afflicted patients. According to population-based data from the USA, Europe and Asia, approx. 4-5% of the population suffer from chronic daily headache. These have been equated up until now with chronic tension-type headache (CTTH). More recent epidemiological studies have resulted in an adaptation of this point of view. Currently it is assumed that approx. 2-3% of the population suffer CTTH, which preferably affects females (approximately twice as frequently); approx. 2 % suffer chronic migraine (transformed migraine = TM) and 0.2 % are afflicted with a so-called new daily persistent headache or very rarely a hemicrania continua.

Oligosymptomatic neurosyphilis with false negative CSF-VDRL in HIV-infected individuals?

The true prevalence of neurosyphilis in HIV-infection is unknown, since a sufficiently sensitive and specific test is lacking. In a prospective study we found reactive serum TPHA and FTA-ABS IgG tests in 95 (31%) of 307 HIV-infected patients. Three of 11 patients with latent syphilis revealed reactive CSF-VDRL tests, six others only demonstrated CSF abnormalities. Resolution of CSF abnormalities during a six month follow up after high dose antibiotic therapy led to the diagnosis of oligosymptomatic or asymptomatic neurosyphilis in all nine patients. Thus, the specificity of the CSF-VDRL was 100%, but the sensitivity was only 33%. The overall prevalence of neurosyphilis was 2.9%, increasing to 9.5% in patients with a reactive serum TPHA. Our study emphasizes the importance of antibiotic therapy for presumptive neurosyphilis in HIV-infected patients with latent syphilis and CSF abnormalities but nonreactive CSF-VDRL tests, even if they are neurologically asymptomatic or present with complaints inconclusive of neurosyphilis.

Wernicke's encephalopathy: unusual contrast enhancement revealed by magnetic resonance imaging.

Wernicke's encephalopathy is a serious neurologic disorder caused by vitamin-B1 or thiamine deficiency. The classical triad of clinical symptoms described by Wernicke (gait ataxia, ophthalmoplegia, and confusion) are found in only a third of patients upon initial examination. Typical findings upon MR imaging in patients with Wernicke's encephalopathy are well documented, with signal intensities in the medial thalami and periaqueductal regions of the midbrain. We report a case of Wernicke's encephalopathy revealing an unusual contrast enhancement. It is therefore important to note that the acute stage of Wernicke's encephalopathy may be associated with an intense contrast enhancement upon MR-imaging reflecting the disruption of the blood-brain barrier and inflammatory processes caused by thiamine deficiency. As a consequence from the guideline for managing Wernicke's encephalopathy by the Royal College of Physicians early B-vitamin treatment in suspected is recommended cases.

Cardiovascular effects of sildenafil citrate (Viagra): a naturalistic cross-over study.

In a cross-over study we investigated the effects of sildenafil (single doses of 25- or 50mg) on cardiovascular autonomic nervous system (ANS) function assessed by serial recordings of blood pressure, conventional 12-lead electrocardiograms and standardized, time-and frequency domain indices of heart rate variability (HRV) in 21 men with erectile dysfunction. More than half of these patients had multiple comorbidities. Sildenafil induced significant mean reductions from baseline in resting blood pressure, accompanied by a reflex increase in heart rate. There were no significant changes after administration of sildenafil in any other of the ANS function indices. These preliminary findings suggest that sildenafil does not significantly affect cardiac ANS function in patients with erectile dysfunction.

[Therapeutic options for weight management in schizophrenic patients treated with atypical antipsychotics]. / Möglichkeiten des Gewichtsmanagements in der Behandlung schizophrener Psychosen mit atypischen Antipsychotika.

Extensive, selective literature review of 2500 articles from the last years (up to December 2007) predominantly from Medline and Cochrane, using as search terms "antipsychotic or schizophrenia or individual drug names (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone)" and the terms "BMI, weight gain, metabolic syndrome, diabetes, lipid(s), cholesterol, triglycerides" was conducted. Regardless of the advantages ascribed to atypical antipsychotics and the special effectiveness of clozapine in patients resistant to therapy and at risk for suicide, the probability of weight gain is considerably increased for some of these substances. Patients with schizophrenia have a considerably reduced life expectancy associated with an increased prevalence of cardiovascular risk factors. There is a lack of practical guidelines integrated into clinical psychiatric care for the management of cardiovascular risk factors. The monitoring of patients treated with atypics, which has been recommended in the APA/ADA Consensus Paper in light of these facts, is insufficiently established in clinical practice. A regular monitoring can convey self control and motivation to the patient. In the case of corresponding risk constellations further decisions regarding indication and therapy have to be considered. Especially patients with a high cardiovascular risk profile are highly recommended to participate in a weight-management program for prevention purposes. Such a special program should include elements of dietetic treatment and behaviour and exercise therapy. First controlled studies suggest an effective prevention of weight gain and metabolic changes when applying such a structured program. The practice oriented step by step concept presented here is meant to provide points of reference for the implementation of required medical and psychoeducative measures facilitating the management of weight and further cardiovascular risk factors in the context of psychiatric care in patients with schizophrenia.

[40 years beta-adrenoceptor blockers in psychiatry]. / 40 Jahre Beta-Blocker in der Psychiatrie.

Beta-adrenoceptor blockers belong to the most successful drug classes of medicine. Mainly they are used in internal medicine. 40 years ago beta-adrenoceptor blockers have occasionally been used in psychiatry for the treatment of anxiety disorders. Over the past four decades, the effects of beta-adrenoceptor blockers in the treatment of schizophrenic and manic psychoses, withdrawal syndromes and aggressive behaviour with temper outbursts has been investigated. Beta-adrenoceptor blockers are also used in the treatment of side-effects of psychopharmacological agents like neuroleptic or antidepressant-induced tachycardias, lithium-induced tremor, antipsychotic-induced akathisia or tardive dyskinesia as well. Since the mid-nineties it has been attempted to improve the efficacy of antidepressant agents by means of the 5-HT-(1a)-receptorantagonist pindolol. Presumedly memory consolidation of traumatic events can be enhanced by adrenergic activation. Therefore some open clinical trials investigated the effects of propranolol, a lipid soluble drug, which crosses the blood-brain barrier easily, to reduce the manifestation of PTSD. The present review presents the results of the literature with respect to the indications for beta-blockers in psychiatry. Considering evidence-based-medicine criteria beta-blockers are indicated to treat lithium-induced tremor, antipsychotic-induced akathisia and to reduce aggressive behavior of patients with brain-injuries.