Rationale and study design of a trial to assess rTMS add-on value for the amelioration of negative symptoms of schizophrenia (RADOVAN).

BACKGROUND: Schizophrenia is a severe and often difficult to treat psychiatric illness. In many patients, negative symptoms dominate the clinical picture. Meta-analysis has suggested moderate, but significant effects of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) on these symptoms. For treatment of depression a much shorter protocol - intermittent theta burst stimulation (iTBS) - has shown to be non-inferior to conventional high-frequency rTMS. This randomized, sham-controlled, rater-blinded clinical trial assesses the effects of conventional HF-rTMS as well as of iTBS of the left dorsolateral prefrontal cortex in comparison with sham. METHODS: The study will be conducted at two psychiatric university hospitals in Germany and at two in the Czech Republic. Assuming an effect size of 0.64 to be detected with a power of 80%, the calculated sample size is 90 patients. Primary outcome will be the difference in the Scale for the Assessment of Negative Symptoms (SANS) score between each active arm and the sham arm at end of treatment.In addition, the trial investigates effects on depressive symptoms, cognitive performance and cigarette smoking. Recording magnetic resonance imaging (MRI) and electroencephalography (EEG) data will serve to assess whether treatment success can be predicted by neural markers and is related to specific neurobiological changes. DISCUSSION: This is a clinical trial directly comparing 10 Hz-rTMS and iTBS in a sham-controlled manner in treating negative symptoms of schizophrenia. If successful, this would present an interesting treatment option for a chronic and severe condition that can be applied at most psychiatric hospitals and only takes up a few minutes per day. TRIAL REGISTRATION NUMBER: This trial has been registered at clinicaltrials.gov, Identifier: NCT04318977. DATA DISSEMINATION: Results from the trial shall be published in peer-reviewed journals and presented at meetings and conferences.

Antidepressant effect of repetitive transcranial magnetic stimulation is not impaired by intake of lithium or antiepileptic drugs.

INTRODUCTION: The effect of concomitant medication on repetitive transcranial magnetic stimulation (rTMS) outcomes in depression remains understudied. Recent analyses show attenuation of rTMS effects by antipsychotic medication and benzodiazepines, but data on the effects of antiepileptic drugs and lithium used as mood stabilizers or augmenting agents are sparse despite clinical relevance. Preclinical electrophysiological studies suggest relevant impact of the medication on treatment, but this might not translate into clinical practice. We aimed to investigate the role of lithium (Li), lamotrigine (LTG) and valproic acid (VPA) by analyzing rTMS treatment outcomes in depressed patients. METHODS: 299 patients with uni- and bipolar depression treated with rTMS were selected for analysis in respect to intake of lithium, lamotrigine and valproic acid. The majority (n = 251) were treated with high-frequency (10-20 Hz) rTMS of the lDLPFC for an average of 17 treatment sessions with a figure-of-8 coil with a MagVenture system aiming for 110% resting motor threshold, and smaller groups of patients were being treated with other protocols including intermittent theta-burst stimulation and bilateral prefrontal and medial prefrontal protocols. For group comparisons, we used analysis of variance with the between-subjects factor group or Chi-Square Test of Independence depending on the scales of measurement. For post-hoc tests, we used least significant difference (LSD). For differences in treatment effects between groups, we used an ANOVA with the between-subjects factor group (groups: no mood stabilizer, Li, LTG, VPA, Li + LTG) the within-subjects factor treatment (pre vs. post treatment with rTMS) and also Chi-Square Tests of independence for response and remission. RESULTS: Overall, patients showed an amelioration of symptoms with no significant differences for the main effect of group and for the interaction effect treatment by group. Based on direct comparisons between the single groups taking mood stabilizers against the group taking no mood stabilizers, we see a superior effect of lamotrigine, valproic acid and combination of lithium and lamotrigine for the response and remission rates. Motor threshold was significantly and markedly higher for patients taking valproic acid. CONCLUSION: Being treated with lithium, lamotrigine and valproic acid had no relevant influence on rTMS treatment outcome. The results suggest there is no reason for clinicians to withhold or withdraw these types of medication from patients who are about to undergo a course of rTMS. Prospective controlled work on the subject is encouraged.

Concomitant lorazepam use and antidepressive efficacy of repetitive transcranial magnetic stimulation in a naturalistic setting.

BACKGROUND/OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) has been established as an effective therapeutic intervention for the treatment of depression. Preliminary data suggest that the efficacy of rTMS is reduced in patients taking benzodiazepines (BZD). Here, we use real-world data from a large sample to investigate the influence of lorazepam on the effectiveness of rTMS. METHODS: From a retrospective cohort of clinically depressed patients that were treated with rTMS, we compared 176 patients not taking any BZD with 73 patients taking lorazepam with respect to changes in the Hamilton Depression Rating Scale (HRDS). RESULTS: Both groups improved during rTMS according to HRDS scores, but the amelioration of symptoms was significantly less pronounced in patients taking lorazepam (18% vs. 38% responders in the non-lorazepam group). We could not see any association of intake regimen of lorazepam with response in rTMS. CONCLUSION: Our observational study suggests that intake of lorazepam impedes the response to rTMS. The impact of lorazepam and other BZD on rTMS should receive more attention and be further investigated in prospective, hypothesis-based treatment studies to determine causal relationships between medication treatments and outcome. This could lead to specific recommendations for pharmacological treatment for depressed patients undergoing rTMS.

Structural brain changes are associated with response of negative symptoms to prefrontal repetitive transcranial magnetic stimulation in patients with schizophrenia.

Impaired neural plasticity may be a core pathophysiological process underlying the symptomatology of schizophrenia. Plasticity-enhancing interventions, including repetitive transcranial magnetic stimulation (rTMS), may improve difficult-to-treat symptoms; however, efficacy in large clinical trials appears limited. The high variability of rTMS-related treatment response may be related to a comparably large variation in the ability to generate plastic neural changes. The aim of the present study was to determine whether negative symptom improvement in schizophrenia patients receiving rTMS to the left dorsolateral prefrontal cortex (DLPFC) was related to rTMS-related brain volume changes. A total of 73 schizophrenia patients with predominant negative symptoms were randomized to an active (n=34) or sham (n=39) 10-Hz rTMS intervention applied 5 days per week for 3 weeks to the left DLPFC. Local brain volume changes measured by deformation-based morphometry were correlated with changes in negative symptom severity using a repeated-measures analysis of covariance design. Volume gains in the left hippocampal, parahippocampal and precuneal cortices predicted negative symptom improvement in the active rTMS group (all r⩽-0.441, all P⩽0.009), but not the sham rTMS group (all r⩽0.211, all P⩾0.198). Further analyses comparing negative symptom responders (⩾20% improvement) and non-responders supported the primary analysis, again only in the active rTMS group (F(9, 207)=2.72, P=0.005, partial η 2=0.106). Heterogeneity in clinical response of negative symptoms in schizophrenia to prefrontal high-frequency rTMS may be related to variability in capacity for structural plasticity, particularly in the left hippocampal region and the precuneus.

[Hypothermia under olanzapine treatment: clinical case series and review of current literature]. / Hypothermie unter Olanzapin : Eine Fallserie mit Literaturübersicht.

BACKGROUND: Antipsychotic drugs may lead to hypothermia as well as hyperthermia. Although known for decades and clinically highly relevant, the mechanisms by which antipsychotic drugs alter thermoregulatory processes in the human body are still far from being fully understood. In clinical practice, much attention is paid to antipsychotic drug-induced elevation of body core temperature as observed in the neuroleptic malignant syndrome (NMS). But also hypothermia is a clinically highly relevant adverse reaction to antipsychotic drugs. MATERIAL AND METHODS: Here we report a case series of three patients who developed severe hypothermia after administration of olanzapine. A review of the current literature is given with a focus on risk factors for the development of antipsychotic drug-induced hypothermia and its pathophysiologic mechanisms. RESULTS: A 51-year-old female patient suffering from catatonic schizophrenia, cachectic nutritional condition and hypothyroidism developed severe hypothermia of 30.0°C body core temperature after administration of 30 mg olanzapine per day under comedication with lorazepam and L-thyroxine. A 48-year-old female patient with catatonic schizophrenia showed hypothermia of 31.0°C (rectal measurement) after single-dose administration of olanzapine 10 mg orally and a total of 3 mg lorazepam (1-1-1 mg). The third case report describes a 69-year-old male patient with acute delusional disorder exhibiting hypothermia of 33.0°C (rectal measurement) in combination with a reversible atrioventricular block grade III without any further comedication. CONCLUSION: A review of the current literature reveals that thermoregulatory disturbances as sequelae of antipsychotic drug administration depend on individual disposition as well as various independent risk factors such as environmental temperature, somatic comorbidities, endocrinological abnormalities (e.g. hypothyroidism) and structural damage of the brain. A complex interaction of dopaminergic regulatory mechanisms in the ventral hypothalamus and peripheral vaso- and sudomotor adjustments seems to be causative. Hypothermia following antipsychotic drug administration represents a serious adverse drug reaction and a potentially life-threatening event.