Cyril Höschl

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.

Models of schizophrenia in humans and animals based on inhibition of NMDA receptors.

The research of the glutamatergic system in schizophrenia has advanced with the use of non-competitive antagonists of glutamate NMDA receptors (phencyclidine, ketamine, and dizocilpine), which change both human and animal behaviour and induce schizophrenia-like manifestations. Models based on both acute and chronic administration of these substances in humans and rats show phenomenological validity and are suitable for searching for new substances with antipsychotic effects. Nevertheless, pathophysiology of schizophrenia remains unexplained. In the light of the neurodevelopmental model of schizophrenia based on early administration of NMDA receptor antagonists it seems that increased cellular destruction by apoptosis or changes in function of glutamatergic NMDA receptors in the early development of central nervous system are decisive for subsequent development of psychosis, which often does not manifest itself until adulthood. Chronic administration of antagonists initializes a number of adaptation mechanisms, which correlate with findings obtained in patients with schizophrenia; therefore, this model is also suitable for research into pathophysiology of this disease.

Suicide prevention strategies revisited: 10-year systematic review.

BACKGROUND Many countries are developing suicide prevention strategies for which up-to-date, high-quality evidence is required. We present updated evidence for the effectiveness of suicide prevention interventions since 2005. METHODS We searched PubMed and the Cochrane Library using multiple terms related to suicide prevention for studies published between Jan 1, 2005, and Dec 31, 2014. We assessed seven interventions: public and physician education, media strategies, screening, restricting access to suicide means, treatments, and internet or hotline support. Data were extracted on primary outcomes of interest, namely suicidal behaviour (suicide, attempt, or ideation), and intermediate or secondary outcomes (treatment-seeking, identification of at-risk individuals, antidepressant prescription or use rates, or referrals). 18 suicide prevention experts from 13 European countries reviewed all articles and rated the strength of evidence using the Oxford criteria. Because the heterogeneity of populations and methodology did not permit formal meta-analysis, we present a narrative analysis. FINDINGS We identified 1797 studies, including 23 systematic reviews, 12 meta-analyses, 40 randomised controlled trials (RCTs), 67 cohort trials, and 22 ecological or population-based investigations. Evidence for restricting access to lethal means in prevention of suicide has strengthened since 2005, especially with regard to control of analgesics (overall decrease of 43% since 2005) and hot-spots for suicide by jumping (reduction of 86% since 2005, 79% to 91%). School-based awareness programmes have been shown to reduce suicide attempts (odds ratio [OR] 0·45, 95% CI 0·24-0·85; p=0·014) and suicidal ideation (0·5, 0·27-0·92; p=0·025). The anti-suicidal effects of clozapine and lithium have been substantiated, but might be less specific than previously thought. Effective pharmacological and psychological treatments of depression are important in prevention. Insufficient evidence exists to assess the possible benefits for suicide prevention of screening in primary care, in general public education and media guidelines. Other approaches that need further investigation include gatekeeper training, education of physicians, and internet and helpline support. The paucity of RCTs is a major limitation in the evaluation of preventive interventions. INTERPRETATION In the quest for effective suicide prevention initiatives, no single strategy clearly stands above the others. Combinations of evidence-based strategies at the individual level and the population level should be assessed with robust research designs. FUNDING The Expert Platform on Mental Health, Focus on Depression, and the European College of Neuropsychopharmacology.

The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders, Part III: Maintenance Treatment

Summary As with the two preceding guidelines of this series, these practice guidelines for the pharmacological maintenance treatment of bipolar disorder were developed by an international task force of the World Federation of Societies of Biological Psychiatry (WFSBP). Their purpose is to supply a systematic overview of all scientific evidence relating to maintenance treatment. The data used for these guidelines were extracted from a MEDLINE and EMBASE search, from recent proceedings from key conferences and various national and international treatment guidelines. The scientific justification of support for particular treatments was categorised into four levels of evidence (A-D). As these guidelines are intended for clinical use, the scientific evidence was not only graded, but also reviewed by the experts of the task force to ensure practicality.

Hippocampal damage mediated by corticosteroids - a neuropsychiatric research challenge

There is an increasing evidence that corticosteroids damage the hippocampus in rodents and in primates. Hippocampal atrophy induced by corticosteroids may play an important role in the pathogenesis of a range of neuropsychiatric disorders. Hippocampus is necessary for short-term memory consolidation and HPA axis regulation. Signs of hippocampal damage (HPA dysregulation in combination with memory impairment) are found in affective disorders, Alzheimer’s disease and in posttraumatic stress disorder. MRI volumetry reveals reduced hippocampal volume in these diseases. Evidence supporting the “glucocorticoid hypothesis” of psychiatric disorders is reviewed in the first part of the paper. Unresolved questions concerning temporary aspects of neurodegeneration, causality, reversibility, type of damage, factors increasing hippocampal vulnerability, and both pharmacological (CRH antagonists, antiglucocorticoid drugs, GABA-ergic, serotonergic, glutamatergic agents) and non-pharmacological (psychotherapy) treatment approaches are discussed in the second part.

ITAREPS: Information Technology Aided Relapse Prevention Programme in Schizophrenia

ITAREPS presents a mobile phone-based telemedicine solution for weekly remote patient monitoring and disease management in schizophrenia and psychotic disorders in general. The programme provides health professionals with home telemonitoring via a PC-to-phone SMS platform that identifies prodromal symptoms of relapse, to enable early intervention and prevent unnecessary hospitalizations. Its web-based interface offers the authorized physician a longitudinal analysis of the dynamics and development of possible prodromes. This work presents preliminary findings from a one-year mirror-design follow-up evaluation of the programmes clinical effectiveness in 45 patients with psychotic illness. There was a statistically significant 60% decrease in the number of hospitalizations during the mean 283.3+/-111.9 days of participation in the ITAREPS, compared to the same time period before the ITAREPS entry (sign test, p<0.004). Variables significantly influencing the number of hospitalizations after the ITAREPS entry (medication compliance along with factors intrinsic to the ITAREPS, i.e. adherence to the programme and involvement of a family member) suggest a critical role of the programme in controlling the number of relapses and subsequent hospitalizations in psychosis.

Brain structural signature of familial predisposition for bipolar disorder: replicable evidence for involvement of the right inferior frontal gyrus.

BACKGROUND To translate our knowledge about neuroanatomy of bipolar disorder (BD) into a diagnostic tool, it is necessary to identify the neural signature of predisposition for BD and separate it from effects of long-standing illness and treatment. Thus, we examined the associations among genetic risk, illness burden, lithium treatment, and brain structure in BD. METHODS This is a two-center, replication-design, structural magnetic resonance imaging study. First, we investigated neuroanatomic markers of familial predisposition by comparing 50 unaffected and 36 affected relatives of BD probands as well as 49 control subjects using modulated voxel-based morphometry. Second, we investigated effects of long-standing illness and treatment on the identified markers in 19 young participants early in the course of BD, 29 subjects with substantial burden of long-lasting BD and either minimal lifetime (n = 12), or long-term ongoing (n = 17) lithium treatment. RESULTS Five groups, including the unaffected and affected relatives of BD probands from each center as well as participants early in the course of BD showed larger right inferior frontal gyrus (rIFG) volumes than control subjects (corrected p < .001). The rIFG volume correlated negatively with illness duration (corrected p < .01) and, relative to the controls, was smaller among BD individuals with long-term illness burden and minimal lifetime lithium exposure (corrected p < .001). Li-treated subjects had normal rIFG volumes despite substantial illness burden. CONCLUSIONS Brain structural changes in BD may result from interplay between illness burden and compensatory processes, which may be enhanced by lithium treatment. The rIFG volume could aid in identification of subjects at risk for BD even before any behavioral manifestations.

Amygdala volumes in mood disorders — Meta-analysis of magnetic resonance volumetry studies

BACKGROUND The amygdala plays an important role in the regulation of emotions and has been implicated in the pathophysiology of mood disorders. Studies of amygdala volumes in mood disorders have been conflicting, with findings of increased, decreased and unchanged amygdala volumes in patients relative to controls. We present the largest meta-analysis of amygdala volumes in mood disorders and the first one to investigate modifying effects of clinical, demographic and methodological variables. METHODS We reviewed 40 magnetic resonance imaging studies investigating amygdala volumes in patients with unipolar or bipolar disorders. For meta-analysis we used standardized differences in means (SDM) and random effect models. In the search for sources of heterogeneity, we subdivided the studies based on diagnosis, setting, age, medication status, sex, duration of illness, slice thickness, interrater reliability of tracing and anatomical definitions used. RESULTS The volumes of the left and right amygdala in bipolar (N=215) or unipolar (N=409) patients were comparable to controls. Bipolar children and adolescents had significantly smaller left amygdala volumes relative to controls (SDM=-0.34, 95%CI=-0.65; -0.04, z=-2.20, p=0.03), whereas bipolar adults showed a trend for left amygdala volume increases (SDM=0.46, 95%CI=-0.03; 0.96, z=1.83, p=0.07). Unipolar inpatients had significantly larger left (SDM=0.35, 95%CI=0.03; 0.67, z=-2.17, p=0.03) amygdala volumes than controls, with no significant amygdala volume changes in unipolar outpatients. LIMITATIONS Heterogeneity of included studies. CONCLUSIONS The absence of overall differences in amygdala volumes, in the presence of significant and sometimes mirror changes in patient subgroups, demonstrates marked heterogeneity among mood disorders. Amygdala volume abnormalities may not be associated with mood disorders per se, but rather may underlie only some dimensions of illness or represent artifacts of medication or comorbid conditions.

Smaller hippocampal volumes in patients with bipolar disorder are masked by exposure to lithium: a meta-analysis.

BACKGROUND Smaller hippocampal volumes relative to controls are among the most replicated neuroimaging findings in individuals with unipolar but not bipolar depression. Preserved hippocampal volumes in most studies of participants with bipolar disorder may reflect potential neuroprotective effects of lithium (Li). METHODS To investigate hippocampal volumes in patients with bipolar disorder while controlling for Li exposure, we performed a meta-analysis of neuroimaging studies that subdivided patients based on the presence or absence of current Li treatment. To achieve the best coverage of literature, we categorized studies based on whether all or a majority, or whether no or a minority of patients were treated with Li. Hippocampal volumes were compared by combining standardized differences between means (Cohen d) from individual studies using random-effects models. RESULTS Overall, we analyzed data from 101 patients with bipolar disorder in the Li group, 245 patients in the non-Li group and 456 control participants from 16 studies. Both the left and right hippocampal volumes were significantly larger in the Li group than in controls (Cohen d = 0.53, 95% confidence interval [CI] 0.18 to 0.88; Cohen d = 0.51, 95% CI 0.21 to 0.81, respectively) or the non-Li group (Cohen d = 0.93, 95% CI 0.56 to 1.31; Cohen d = 1.07, 95% CI 0.70 to 1.45, respectively), which had smaller left and right hippocampal volumes than the control group (Cohen d = -0.36, 95% CI -0.55 to -0.17; Cohen d = -0.38, 95% CI -0.63 to -0.13, respectively). There was no evidence of publication bias. LIMITATIONS Missing information about the illness burden or lifetime exposure to Li and polypharmacy in some studies may have contributed to statistical heterogeneity in some analyses. CONCLUSION When exposure to Li was minimized, patients with bipolar disorder showed smaller hippocampal volumes than controls or Li-treated patients. Our findings provide indirect support for the negative effects of bipolar disorder on hippocampal volumes and are consistent with the putative neuroprotective effects of Li. The preserved hippocampal volumes among patients with bipolar disorder in most individual studies and all previous meta-analyses may have been related to the inclusion of Li-treated participants.

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.