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.

Audiovisual integration of speech is disturbed in schizophrenia: an fMRI study.

Speech perception is an essential part of social interaction. Visual information (lip movements, facial expression) may supplement auditory information in particular under inadvertent listening situations. Schizophrenia patients have been shown to have a deficit in integrating articulatory motions with the auditory speech input. The goal of this study was to investigate the neural basis of this deficit in audiovisual speech processing in schizophrenia patients by using fMRI. Disyllabic nouns were presented in congruent (audio matches visual information) and incongruent conditions in a slow event related fMRI design. Schizophrenia patients (n=15) were compared to age and gender matched control participants. The statistical examination was conducted by analysis of variance with main factors: audiovisual congruency and group membership. The patients' brain activity differed from the control group as evidenced by congruency by group interaction effects. The pertinent brain sites were located predominantly in the right hemisphere and comprised the pars opercularis, middle frontal sulcus, and superior temporal gyrus. In addition, we observed interactions bilaterally in the fusiform gyrus and the nucleus accumbens. We suggest that schizophrenia patients' deficits in audiovisual integration during speech perception are due to a dysfunction of the speech motor system in the right hemisphere. Furthermore the results can be also seen as a reflection of reduced lateralization of language functions to the left hemisphere in schizophrenia.

The myelin-pathogenesis puzzle in schizophrenia: a literature review.

Schizophrenia is a serious and disabling mental disorder with symptoms such as auditory hallucinations, disordered thinking and delusions, avolition, anhedonia, blunted affect and apathy. In this review article we seek to present the current scientific findings from linkage studies and susceptible genes and the pathophysiology of white matter in schizophrenia. The article has been reviewed in two parts. The first part deals with the linkage studies and susceptible genes in schizophrenia in order to have a clear-cut picture of the involvement of chromosomes and their genes in schizophrenia. The genetic linkage results seem to be replicated in some cases but in others are not. From these results, we cannot draw a fine map to a single locus or gene, leading to the conclusion that schizophrenia is not caused by a single factor/gene. In the second part of the article we present the oligodendrocyte-related genes that are associated with schizophrenia, as we hypothesize a potential role of oligodendrocyte-related genes in the pathology of the disorder.

Psychotomimesis mediated by kappa opiate receptors.

The kappa opioid agonists are analgesics that seem to be free of undesired morphine-like effects. Their dysphoric actions observed with the kappa agonist cyclazocine are thought to be mediated by an action at sigma-phencyclidine receptors. The benzomorphan kappa agonist MR 2033 is inactive at sigma-phencyclidine receptors. In male subjects, the opiate-active (-)-isomer, but not the (+)-isomer, elicited dose-dependent dysphoric and psychotomimetic effects that were antagonized by naloxone. Thus, kappa opiate receptors seem to mediate psychotomimetic effects. In view of the euphorigenic properties of mu agonists, our results imply the existence of opposed opioid systems affecting emotional and perceptual experiences.

Effects of quetiapine on cognitive functions in schizophrenic patients: a preliminary single-trial ERP analysis.

AIM: The study aimed to explore by means of single-trial event-related potentials (ERPs), whether and how the medication change from older neuroleptics to quetiapine in schizophrenic patients led to a significant cognitive enhancement. This single-trial ERP analysis helps to investigate attention and memory processes in the single patient before and after treatment. PATIENTS AND METHODS: Thirteen schizophrenic patients (mean age: 40.1+/-13.5 years) were followed up for 16 weeks and assessed for changes of clinical symptoms and ERP components P300 representing target detection processes and N400 indexing context integration in word recognition processes. Three subjects had to be excluded from the ERP recording sessions because of excessive blink artefacts and movements. RESULTS: Regarding the P300 components of the target detection, there were significant increases of amplitudes in 5 of 10 patients (50%) at week 16 comparing with week 0. Regarding the N400 components of the word recognition, there were significant increases of amplitudes in 4 of 10 patients (40%) at week 16 comparing with week 0. DISCUSSION: The mean scores of PANSS, MADRS, Bf-S, SCL-90 and CGI-S at the end of study (week 16) showed significant improvements compared to the baselines (week 0) (p<0.05). During the study, no extrapyramidal symptoms as well as akathisia were reported after quetiapine treatment. These preliminary data suggest that quetiapine might partially improve the cognitive functions in the context integration and target detection processing in these patients. This technical procedure (single-trial ERP) may help to differentially assess cognitive enhancements in each single patient under treatment.

[Empirical evidence for the use of anticonvulsants in personality disorders]. / Evidenz für den Einsatz von Antikonvulsiva bei Persönlichkeitsstörungen.

OBJECTIVE: There is a common practice of polypharmacy and an increased use of mood stabilizers in personality disorders (PD). This paper reviews all randomized controlled trials (RCTs) of anticonvulsants to evaluate the evidence base supporting their use in treatment of PD. METHODS: German and English language literature cited in Medline and published between 1970 and 2008 was searched using the following terms: Borderline/personality disorder, anticonvulsant, mood stabilizer, carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenytoine, pregabalin, tiagabine, topiramate, and valproate. RESULTS: Twelve RCTs were identified which included anticonvulsants in treatment of personality disorders. The anticonvulsants valproate and topiramate appeared to have the most empirical support for having a favorable effect on symptoms of borderline personality disorder. Evidence for the use of other anticonvulsants in patients with PD is sparse. CONCLUSIONS: Valproate and topiramate, probably also lamotrigine, carbamazepine, and oxcarbazepine as well, were useful in treating symptoms of affective dysregulation and impulsive aggression in PD. However, further RCTs of anticonvulsants are greatly needed as clinical use of these agents has risen without sufficient evidence supporting their efficacy and safety in personality disorders.

Dopamine and the action of opiates: a reevaluation of the dopamine hypothesis of schizophrenia. With special consideration of the role of endogenous opioids in the pathogenesis of schizophrenia.

It is suggested that the antipsychotic efficacy of opioids in patients suffering from schizophrenia may result from an interaction of opioids with the dopaminergic system. The modulatory effect of opioids on dopaminergic functions has already been demonstrated in basic experiments: Anatomical and biochemical data reveal an interaction between opioid receptors and dopamine (DA) actions on dopaminergic nerve terminals, cell bodies, and afferent nerve endings. Endogenous enkephalin levels correlate well with the endogenous dopamine content in various brain areas. Systemic or iontophoretic administration of morphine alters the spontaneous activity of ventral tegmental dopaminergic neurons. Morphine and enkephalin effectively enhance pituitary prolactin release, whereas dopamine inhibits it. Opioid agonists effectively alter DA release, DA reuptake, and DA metabolism in the striatum and substantia nigra. In reverse, chronic neuroleptic treatment enhances the synthesis and release of pituitary beta-endorphin. Opioids affect contralateral rotation elicited by dopamine agonists in animals with unilateral lesions of the nigrostriatal pathway. Phencyclidine, a psychotropic drug that shares certain pharmacological characteristics with the putative sigma-opioid receptor ligand SKF 10,047, indirectly mimics the effects of dopamine agonists on prolactin release, release of acetylcholine, etc. It is suggested that an imbalance of opiate-DA interaction might be involved in the pathogenesis of schizophrenia. Consequently, clinical studies on the effects of opioids on psychotic symptoms should also examine opioid influence on dopaminergic functions in these patients.

Regional cerebral glucose metabolism in anorexia nervosa measured by positron emission tomography.

Regional cerebral glucose metabolism was measured in five female anorectic patients, during the anorectic state and after weight gain, using the fluorodeoxyglucose method and positron emission tomography. In addition, these results were compared with those of 15 young male normals. During the anorectic state, significant caudate hypermetabolism was found bilaterally, unlike the finding in repeat measurements or in male normals. In some other brain structures (temporal cortex, lentiform nucleus, thalamus, and brainstem), significant hypermetabolism was also found during the anorectic state, but these results were not concordant for both sides and in both comparisons. There was no difference between patients after improvement and young male normals.

Antipsychotic effect of buprenorphine in schizophrenia.

The antipsychotic potency of the partial opiate agonist buprenorphine was evaluated in 10 neuroleptic-free schizophrenic patients suffering from frequent hallucinations, delusions, and severe formal thought disorders. Buprenorphine had a pronounced antipsychotic effect, which lasted about 4 hours, in patients with schizophreniform disorders (N = 4) and paranoid schizophrenia (N = 3).

Reduced dark-adaptation: an indication of lithium's neuronal action in humans.

Although lithium plays a major role in therapy and prophylaxis of affective psychoses, no direct indication of its neuronal action in humans exists. A lithium-induced strong reduction of foveal dark-adaptation was found in healthy volunteers, and a lithium-induced reduction was also measured in patients with affective psychoses. Dark-adaptation measurements apparently offer the opportunity for in vivo monitoring of lithium's CNS effects in humans and may predict lithium's clinical efficacy.

Current perspectives in the pharmacopsychiatry of depression and mania.

The observation that opiates and endorphins exert euphorogenic effects in normal probands points to a possible involvement of endorphins in different types of affective disorders. There are several powerful arguments that the activation of particular central opiate receptors (e.g. by "opium cure", beta-endorphin, partial agonists, release of endorphins via electroconvulsion) exerts curative effects in endogenous depression. Results from a double-blind investigation of the possible antidepressant action of the opiate partial agonist buprenorphine in patients with endogenous depression revealed a strong antidepressant effect of this substance. A series of anticonvulsants, possibly acting via a GABA-ergic-like mechanism (valproate, dipropylacetamide, carbamazepine and oxcarbazepine), have recently been shown by different groups to possess antimanic and also, partially, antidepressant properties. Furthermore, a synergistic mode of action in the prophylaxis of manic episodes has been observed as concerns valproate and lithium. On the other hand, there is some evidence from both in vitro and in vivo animal experiments that chronic application of lithium results in a modification of the GABA-turnover. The present paper reviews the present state of knowledge concerning the concept of a GABA-dependent regulation of affective states.

Use of calcium antagonists in mania.

The organic calcium antagonist verapamil in doses of 320-480 mg/day reduced manic symptomatology in seven of eight patients manifesting a manic or schizomanic syndrome in a placebo-controlled, double-blind study. The delayed onset of antimanic effects parallels the action of lithium in acute mania. Common pharmacological profiles of lithium, certain anticonvulsants, and neuroleptics with regard to calcium dependent processes are discussed.

Estradiol levels in psychotic disorders.

Estradiol has been postulated to constitute a protective factor for schizophrenia, which could provide women at risk to experience a psychotic episode with a relative protection in phases of high estradiol levels, i.e. before menopause and during the peri- and postovulatory phases of their cycle. Women suffering from schizophrenia have been reported to show significantly lower estradiol levels than the normal population and to experience first onset or recurrence of a psychotic episode significantly more often in low estrogen phases of the cycle with low estradiol levels. We examined estradiol levels in an open prospective study in 43 women admitted with a diagnosis of an acute psychotic episode and could confirm these findings for schizophrenia as well as other psychotic disorders. Only 28% of the women exhibited estradiol and progesterone levels indicating a peri- or postovulatory phase and all of the estradiol levels on admission were either within the lower part of the cycle-dependent normal range or below normal; comparison with a control group of healthy volunteers and patients admitted with different psychiatric diagnoses confirmed their estradiol levels to be significantly higher. However, when splitting this control group, the statistical difference would only hold between the study group of psychotic patients and the healthy control group. The group of patients with other diagnoses than a psychotic episode fell in between of the other two groups and did not differ significantly from either. Thus, an unspecific effect, i.e. a hypothalamic downregulation due to the stress of acute hospitalization must be born in mind when assessing hormone levels in acutely psychotic women.

The use of anticonvulsants to augment antidepressant medication.

Combination therapy that couples classical antidepressants with other psychoactive compounds is one of the major therapeutic strategies in therapy-resistant depression. The authors review reports on the antidepressive effects of the mood stabilizers carbamazepine and valproate and focus on the pharmacodynamic and clinical aspects of combining these compounds with antidepressant drugs. In addition, a pivotal study (N=10 outpatients) demonstrates the use and efficacy of a low-dose combination therapy of carbamazepine and amitriptyline. It is concluded that low-dose combination of classical antidepressants and mood stabilizers appears to be well tolerated and highly effective.

Effects of synthetic delta9-tetrahydrocannabinol on binocular depth inversion of natural and artificial objects in man.

Binocular depth inversion represents an illusion of visual perception that is sensitive to various behavioural and psychiatric conditions. It is affected by cannabinoids, reflecting associated changes in perception. The present study investigated the differences in binocular depth inversion of different classes of natural and artificial objects and the effect of synthetic delta9-tetrahydrocannabinol (Dronabinol) on these illusionary perceptions. Using this model, the effects of orally administered Dronabinol on binocular depth inversion were investigated in 17 healthy male volunteers. Pictures from natural and artificial objects were presented stereoscopically and the depth perception of the volunteers was scored in an operationalized way. The timecourse of the effects of Dronabinol on binocular depth inversion was analyzed with regard to the stimulus classes (natural and synthetic objects). Significant differences in binocular depth inversion of the different groups of stimuli were revealed. Objects with a higher degree of everyday familiarity were generally seen as more illusionary than those with a lower degree of everyday familiarity. A strong impairment of binocular depth inversion due to Dronabinol was found in most classes of objects. Analysis of different stimulus classes provides further information on the underlying perceptual processing of binocular depth inversion. An impairment of top-down processing of visual sensory data by Dronabinol is suggested. The anandamidergic system seems to be involved in areas of visual information processing.

Effects of flumazenil on recovery sleep and hormonal secretion after sleep deprivation in male controls.

The effects of flumazenil, a benzodiazepine antagonist, on the sleep electroencephalogram (EEG) and neuroendocrine secretion in early morning recovery sleep (0500-0800 hours) following sleep deprivation (SD; 2300-0500 hours) were studied in seven healthy men. SD induced an increase in slow wave sleep (SWS), a decrease in sleep onset latency (SOL), an enhancement of EEG delta and theta power in non-rapid-eye-movement sleep, an increase in plasma human growth hormone (GH) concentration, and a decrease in plasma cortisol levels in recovery sleep (0500-0800 hours). Plasma GH, but neither plasma cortisol nor adrenocorticotrophic hormone (ACTH) concentration was attenuated during SD as compared to sleep (2300-0445 hours). The administration of flumazenil (3 x 1 mg intravenously) during recovery sleep resulted in an inhibition in SWS, an increase in stage 2 sleep, a selective reduction in delta and theta power, and a tendency to prolongation of SOL. Plasma GH concentration was decreased but plasma cortisol and ACTH remained unaffected. Since the SD-induced changes in sleep EEG and plasma GH secretion were antagonized by flumazenil, it is suggested that electrophysiological and hormonal effects of SD are mediated at least in part through GABAergic mechanisms.

Reduced binocular depth inversion in schizophrenic patients.

Binocular depth inversion represents an illusion of visual perception, serving to invert the perception of implausible hollow objects, e.g. a hollow face into a normal face. Such inversion occurs frequently, especially when objects with a high degree of familiarity (e.g. photographs of faces) are displayed. Under normal conditions, cognitive factors apparently override the binocular disparity cues of stereopsis. This internal mechanism--a kind of "censorship" of perception balancing "top-down" and "bottom-up" processes of perception--appears to be disturbed in psychotic states. The clinical and neuropsychological performance of schizophrenic patients was assessed using the Brief Psychiatric Rating Scale (BPRS), the Positive And Negative Symptoms Scale (PANSS), the Clinical Global Impression Scale (CGI), the Mehrfach-Wahlwortschatz Intelligence Test (MWT-B) and the binocular depth inversion test (BDIT) using pictures with a high degree of familiarity. In schizophrenic patients, the performance in the BDIT differed significantly from healthy controls and from patients with major depression. The schizophrenic patients were more veridical in their judgements in the BDIT. During antipsychotic treatment, BPRS and PANSS scores improved and the inversed faces were seen as more illusionary, driven by an increase in top-down processing. At the end of treatment, there was no significant difference between the patient group and the healthy controls in the score of binocular depth inversion. These findings suggest that testing of binocular depth inversion can detect specific dysfunctions in visual perception and might be useful as a state-marker for psychotic states.

Elevated endogenous cannabinoids in schizophrenia.

Evidence suggests that cannabinoid receptors, the pharmacologcial target of cannabis-derived drugs, and their accompanying system of endogenous activators may be dysfunctional in schizophrenia. To test this hypothesis, we examined whether endogenous cannabinoid concentrations in cerebrospinal fluid of schizophrenic patients are altered compared to nonschizophrenic controls. Endogenous cannabinoids were purified from cerebrospinal fluid of 10 patients with schizophrenia and 11 non-schizophrenic controls by high-performance liquid chromatography, and quantified by isotope dilution gas-chromatography/mass-spectrometry. Cerebrospinal concentrations of two endogenous cannabinoids (anandamide and palmitylethanolamide) were significantly higher in schizophrenic patients than non-schizophrenic controls (p < 0.05). By contrast, levels of 2-arachidonylglycerol, another endogenous cannabinoid lipid, were below detection in both groups. The findings did not seem attributable to gender, age or medication. Elevated anandamide and palmitylethanolamide levels in cerebrospinal fluid of schizophrenic patients may reflect an imbalance in endogenous cannabinoid signaling, which may contribute to the pathogenesis of schizophrenia.

High frequency repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in schizophrenic patients.

Repetitive transcranial magnetic stimulation (rTMS) has been tried therapeutically in major depression. In order to investigate the therapeutic efficacy of rTMS in psychotic patients, 12 participants (four women, eight men) with schizophrenia according to DSM-IV criteria, aged 25 to 63 years (mean (+/-s.d) 40.4+/-11.0), were enrolled in the study. Following a double-blind crossover design, patients were treated at random with 2 weeks of daily left prefrontal rTMS (20 2s 20 Hz stimulations at 80% motor threshold over 20 min, dorsolateral preforntal cortex) and 2 weeks of sham stimulation. The Brief Psychiatric Rating Scale decreased under active rTMS (p <0.05), whereas depressive symptoms (BDI) and anxiety (STAI) did not change significantly. Prefrontal rTMS might be effective in the non-pharmacological treatment of psychotic patients.

Impaired binocular depth inversion in patients with alcohol withdrawal.

Binocular depth inversion represents an illusion of visual perception. Such inversion does not occur in all cases, especially when objects with a higher degree of familiarity (e.g. photographs of faces) are displayed. Cognitive factors are assumed to override the binocular disparity cues of stereopsis. We tested the hypothesis that during alcohol withdrawal the human CNS is unable to correct the implausible perceptual hypothesis. Measurements of binocular depth inversion in perception of 3D objects were performed in 10 patients with mild alcohol withdrawal and in 11 healthy volunteers. The binocular depth inversion scores were highly elevated in the patients group in comparison to the healthy volunteers. The data demonstrates a strong impairment of binocular depth inversion in alcohol withdrawal and support the view that alcohol withdrawal may be accompanied by a disorganization of the interaction between sensory input and generation of perceptual hypotheses.