Pavel Mohr

Mechanism of Action of Atypical Antipsychotic Drugs and the Neurobiology of Schizophrenia

Atypical antipsychotics have greatly enhanced the treatment of schizophrenia. The mechanisms underlying the effectiveness and adverse effects of these drugs are, to date, not sufficiently explained. This article summarises the hypothetical mechanisms of action of atypical antipsychotics with respect to the neurobiology of schizophrenia.When considering treatment models for schizophrenia, the role of dopamine receptor blockade and modulation remains dominant. The optimal occupancy of dopamine D2 receptors seems to be crucial to balancing efficacy and adverse effects — transient D2 receptor antagonism (such as that attained with, for example, quetiapine and clozapine) is sufficient to obtain an antipsychotic effect, while permanent D2 receptor antagonism (as is caused by conventional antipsychotics) increases the risk of adverse effects such as extrapyramidal symptoms. Partial D2 receptor agonism (induced by aripiprazole) offers the possibility of maintaining optimal blockade and function of D2 receptors. Balancing presynaptic and postsynaptic D2 receptor antagonism (e.g. induced by amisulpride) is another mechanism that can, through increased release of endogenous dopamine in the striatum, protect against excessive blockade of D2 receptors.Serotonergic modulation is associated with a beneficial increase in striatal dopamine release. Effects on the negative and cognitive symptoms of schizophrenia relate to dopamine release in the prefrontal cortex; this can be modulated by combined D2 and serotonin 5-HT2A receptor antagonism (e.g. by olanzapine and risperidone), partial D2 receptor antagonism or the preferential blockade of inhibitory dopamine autoreceptors.In the context of the neurodevelopmental disconnection hypothesis of schizophrenia, atypical antipsychotics (in contrast to conventional antipsychotics) induce neuronal plasticity and synaptic remodelling, not only in the striatum but also in other brain areas such as the prefrontal cortex and hippocampus. This mechanism may normalise glutamatergic dysfunction and structural abnormalities and affect the core pathophysiological substrates for schizophrenia.

Effect of Low-Frequency rTMS on Electromagnetic Tomography (LORETA) and Regional Brain Metabolism (PET) in Schizophrenia Patients with Auditory Hallucinations

Background: Auditory hallucinations are characteristic symptoms of schizophrenia with high clinical importance. It was repeatedly reported that low frequency (≤1Hz) repetitive transcranial magnetic stimulation (rTMS) diminishes treatment-resistant auditory hallucinations. A neuroimaging study elucidating the effect of rTMS in auditory hallucinations has yet to be published. Objective: To evaluate the distribution of neuronal electrical activity and the brain metabolism changes after low-frequency rTMS in patients with auditory hallucinations. Methods: Low-frequency rTMS (0.9 Hz, 100% of motor threshold, 20 min) applied to the left temporoparietal cortex was used for 10 days in the treatment of medication-resistant auditory hallucinations in schizophrenia (n = 12). The effect of rTMS on the low-resolution brain electromagnetic tomography (LORETA) and brain metabolism (18FDG PET) was measured before and after 2 weeks of treatment. Results: We found a significant improvement in the total and positive symptoms (PANSS), and on the hallucination scales (HCS, AHRS). The rTMS decreased the brain metabolism in the left superior temporal gyrus and in interconnected regions, and effected increases in the contralateral cortex and in the frontal lobes. We detected a decrease in current densities (LORETA) for the beta-1 and beta-3 bands in the left temporal lobe whereas an increase was found for beta-2 band contralaterally. Conclusion: Our findings implicate that the effect is connected with decreased metabolism in the cortex underlying the rTMS site, while facilitation of metabolism is propagated by transcallosal and intrahemispheric connections. The LORETA indicates that the neuroplastic changes affect the functional laterality and provide the substrate for a metabolic effect.

Effectiveness of the information technology-aided program of relapse prevention in schizophrenia (ITAREPS): a randomized, controlled, double-blind study.

Purpose. To evaluate the effectiveness of the Information Technology-Aided Program of Re lapse Prevention in Schizophrenia (ITAREPS). Methods. Relapse-prone outpatients with schizophrenia or schizoaffective disorder were randomized to the active (n=75) or control group (n=71). In the active arm, according to the protocol, investigators were prompted to increase the antipsychotic dose upon occurrence of a pharmacological inter vention requiring event (PIRE) detected by ITAREPS. Results. Intention-to-treat (ITT) analysis found no between-group difference in the hospitalization-free survival rate at 12 months. However, the trial suffered from high non-adherence of investigators in the active group, with no antipsychotic dose increase in 61% of PIREs. Furthermore, Cox regression analysis showed a 11-fold increased risk of hospitalization in the absence of pharmacological intervention following a PIRE (hazard ratio [HR]=10.8; 95% confidence interval [CI] 1.4–80.0; p=0.002). Therefore, a post-hoc as-treated analysis was performed, which demonstrated a nine-fold reduction in the risk of hospitalization in ITAREPS Algorithm-Adherers (IAAs, n=25) compared with the ITAREPS Non-interventional group (INIs, n=70; Kaplan-Meier survival analysis, HR=0.11, 95% CI 0.05–0.28, p=0.009; number needed to treat [NNT]=4, 95% CI 3–10). A significant difference in favor of the IAA group was seen in the number of inpatient days (p<0.05) and costs (p<0.05). Conclusion. Future ITAREPS trials should target the underlying mechanisms that cause low investigator adherence to the program. Trial registration: Clinical Trials NCT00712660 (Journal of Psychiatric Practice 2012;18:269–280)

Determination of steroid metabolome as a possible tool for laboratory diagnosis of schizophrenia.

Metabolomic studies represent a promising tool for early diagnosis of schizophrenia. The aim of this study was to find differences in the steroid spectrum in patients and controls, and to assess the diagnosis of schizophrenia by building a predictive model based on steroid data. Thirty-nine serum steroids (22 neuroactive steroids and their metabolites and 17 polar conjugates) representing steroid metabolome were measured by gas chromatography-mass spectrometry in 22 drug-naive (first episode) schizophrenia patients (13 men and 9 women) before and after six-month treatment with atypical antipsychotics. The results were compared to the data from healthy subjects (22 males, 25 females). In summary the following significant differences were found: (1) In both sexes higher levels of pregnenolone sulfate and sulfated 5α- as well as 5β-saturated metabolites of C21-steroids in progesterone metabolic pathway were found in patients, pointing to decreased activity of sulfatase. (2) In a few instances decreased levels of the respective 5α-metabolites of C21 steroids were found in patients. (3) As C19 steroids concern, in both sexes there were considerably lowered levels of 5β-reduced metabolites in patients. On the other hand, with only a few exceptions, the treatment did not significantly influence most steroid levels. Further, to assess the relationships between schizophrenia status and steroid levels and to build the predictive model of schizophrenia, multivariate regression with reduction of dimensionality (the method of orthogonal projections to latent structures, OPLS) was applied. Irrespective of the small number of patients, use of this model enabled us to state the diagnosis of schizophrenia with almost 100% sensitivity. Our findings suggest that the assessment of steroid levels may become a valid and accurate laboratory test in psychiatry. A limitation of our study is the absence of subjects with a diagnosis other than schizophrenia, so we cannot conclude whether the results are specific for schizophrenia. On the other hand, steroid metabolome model may be used as a diagnostic tool for further studies.

The Application of Vagus Nerve Stimulation and Deep Brain Stimulation in Depression

Despite the progress in the pharmacotherapy of depression, there is a substantial proportion of treatment-resistant patients. Recently, reversible invasive stimulation methods, i.e. vagus nerve stimulation (VNS) and deep brain stimulation (DBS), have been introduced into the management of treatment-resistant depression (TRD). VNS has already received regulatory approval for TRD. This paper reviews the available clinical evidence and neurobiology of VNS and DBS in TRD. The principle of VNS is a stimulation of the left cervical vagus nerve with a programmable neurostimulator. VNS was examined in 4 clinical trials with 355 patients. VNS demonstrated steadily increasing improvement with full benefit after 6–12 months, sustained up to 2 years. Patients who responded best had a low-to-moderate antidepressant resistance. However, the primary results of the only controlled trial were negative. DBS involves stereotactical implantation of electrodes powered by a pulse generator into the specific brain regions. For depression, the targeted areas are the subthalamic nucleus, internal globus pallidus, ventral internal capsule/ventral striatum, the subgenual cingulated region, and the nucleus accumbens. Antidepressant effects of DBS were examined in case series with a total number of 50 TRD patients. Stimulation of different brain regions resulted in a reduction of depressive symptoms. The clinical data on the use of VNS and DBS in TRD are encouraging. The major contribution of the methods is a novel approach that allows for precise targeting of the specific brain areas, nuclei and circuits implicated in the etiopathogenesis of neuropsychiatric disorders. For clinical practice, it is necessary to identify patients who may best benefit from VNS or DBS.

Subanesthetic dose of ketamine decreases prefrontal theta cordance in healthy volunteers: implications for antidepressant effect

BACKGROUND Theta cordance is a novel quantitative electroencephalography (QEEG) measure that correlates with cerebral perfusion. A series of clinical studies has demonstrated that the prefrontal theta cordance value decreases after 1 week of treatment in responders to antidepressants and that this effect precedes clinical improvement. Ketamine, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, has a unique rapid antidepressant effect but its influence on theta cordance is unknown. METHOD In a double-blind, cross-over, placebo-controlled experiment we studied the acute effect of ketamine (0.54 mg/kg within 30 min) on theta cordance in a group of 20 healthy volunteers. RESULTS Ketamine infusion induced a decrease in prefrontal theta cordance and an increase in the central region theta cordance after 10 and 30 min. The change in prefrontal theta cordance correlated with ketamine and norketamine blood levels after 10 min of ketamine infusion. CONCLUSIONS Our data indicate that ketamine infusion immediately induces changes similar to those that monoamineric-based antidepressants induce gradually. The reduction in theta cordance could be a marker and a predictor of the fast-acting antidepressant effect of ketamine, a hypothesis that could be tested in depressive patients treated with ketamine.

Prolactin response to D-fenfluramine challenge test as a predictor of treatment response to haloperidol in acute schizophrenia.

D-fenfluramine has been identified as a highly selective serotonin (5-HT) releaser and re-uptake inhibitor. The objective of our study was to investigate prolactin response to D-fenfluramine challenge in non-medicated, first episode schizophrenics. We hypothesized that 5-HT reactivity can predict a response to the neuroleptic treatment. Twenty-three inpatients, 11 males and 12 females, at the Prague Psychiatric Center participated in the study. Inclusion criteria were: ICD-10 diagnosis of schizophrenia, first episode or duration of illness shorter than 36 months. D-fenfluramine challenge test was performed before 4 weeks of the haloperidol treatment. During the test, prolactin plasma levels were measured. The Brief Psychiatric Rating Scale (BPRS) was administered before and after the treatment. A statistically significant negative correlation was found between prolactin response to the D-fenfluramine challenge and improvement of psychopathology measured by the change in total BPRS score (p = 0.0004), in positive (p = 0.0403), negative (p = 0.0267), and anxiety-depression symptoms of BPRS (p = 0.0014). Our data support the original hypothesis that there is a relationship between 5-HT system activity and treatment response. The higher responsiveness of the 5-HT system in first episode, non-medicated schizophrenics, was associated with a poorer treatment response to haloperidol, an antidopaminergic neuroleptic.

Individualized rTMS neuronavigated according to regional brain metabolism ( 18 FGD PET) has better treatment effects on auditory hallucinations than standard positioning of rTMS: a double-blind, sham-controlled study

Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) of the left temporo-parietal cortex (LTPC) has been proposed as a useful therapeutic method for auditory hallucinations (AHs). Stereotactic neuronavigation enables the magnetic coil to be targeted according to the individual parameters obtained from neuroimaging. Individualized rTMS neuronavigated according to 18-fluorodeoxyglucose positron emission tomography (18FDG PET) allows us to focus the coil explicitly on a given area with detected maxima of specific abnormalities, thus presuming a higher therapeutic effect of the method. The objective of this study is to test clinical efficacy of neuronavigated LF-rTMS administered according to the local maxima of 18FDG PET uptake of LTPC and to compare it with treatment effects of standard and sham rTMS. In a double-blind, sham-controlled design, patients with AHs underwent a 10-day series of LF-rTMS using (1) 18FDG PET-guided “neuronavigation,” (2) “standard” anatomically guided positioning, and (3) sham coil. The effect of different rTMS conditions was assessed by the Auditory Hallucinations Rating Scale (AHRS) and the Positive and Negative Syndrome Scale (PANSS). Fifteen patients were randomized to a treatment sequence and ten of them completed all three treatment conditions. The intention-to-treat analysis of AHRS score change revealed superiority of the 18FDG PET-guided rTMS over both the standard and the sham rTMS. The analyses of the PANSS scores failed to detect significant difference among the treatments. Our data showed acute efficacy of 18FDG PET-guided rTMS in the treatment of AHs. Neuronavigated rTMS was found to be more effective than standard, anatomically guided rTMS.

High-dose treatment with haloperidol: the effect of dose reduction.

High doses of antipsychotic medications are sometimes prescribed in clinical practice, although the efficacy and safety of such treatment have not been established. The purpose of this study was to determine whether high-dose, long-term antipsychotic treatment prescribed on the basis of clinical judgment can be justified. Patients who were receiving high doses of haloperidol were screened, and those patients whose plasma levels were at least 15 ng/mL were randomly assigned to an experimental group (N = 11) or to a control group (N = 12). The experimental group underwent a dose reduction to achieve the target plasma level of 10 ng/mL. The reduction was gradual over a period of 12 weeks. The control group treatment was maintained at the original level. Both groups were then followed up for another 16 weeks, during which the plasma levels of haloperidol were kept constant. The study used double-blind procedures. Both groups showed an average slight symptom reduction. There was no significant difference in the severity of symptoms between the two groups at any time point. The dose reduction had no apparent adverse effects. Thus, the results of this study did not provide justification for high-dose, long-term antipsychotic treatment. However, these results must be interpreted with caution because the sample studied here was small and biased.

Experience of stigma and discrimination reported by people experiencing the first episode of schizophrenia and those with a first episode of depression: The FEDORA project

Aim: To record and measure the nature and severity of stigma and discrimination experienced by people during a first episode of schizophrenia and those with a first episode of major depressive disorder. Methods: The Discrimination and Stigma Scale (DISC-12) was used in a cross-sectional survey to elicit service user reports of anticipated and experienced discrimination by 150 people with a diagnosis of first-episode schizophrenia and 176 with a diagnosis of first-episode major depressive disorder in seven countries (Austria, Croatia, Czech Republic, Poland, Romania, Sweden and Turkey). Results: Participants with a diagnosis of major depressive disorder reported discrimination in a greater number of life areas than those with schizophrenia, as rated by the total DISC-12 score (p = .03). With regard to specific life areas, participants with depression reported more discrimination in regard to neighbours, dating, education, marriage, religious activities, physical health and acting as a parent than participants with schizophrenia. Participants with schizophrenia reported more discrimination with regard to the police compared to participants with depression. Conclusion: Stigma and discrimination because of mental illness change in the course of the mental diseases. Future research may take a longitudinal perspective to better understand the beginnings of stigmatisation and its trajectory through the life course and to identify critical periods at which anti-stigma interventions can most effectively be applied.