Joachim Cordes

Relapse Prevention in Schizophrenia and Schizoaffective Disorder with Risperidone Long-Acting Injectable vs Quetiapine: Results of a Long-Term, Open-Label, Randomized Clinical Trial

Chronic management of schizophrenia and schizoaffective disorders is frequently complicated by symptomatic relapse. An open-label, randomized, active-controlled, 2-year trial evaluated 710 patients with schizophrenia or related disorders who were switched from stable treatment with oral risperidone, olanzapine, or conventional neuroleptics to risperidone long-acting injectable (RLAI) or oral quetiapine. Primary effectiveness evaluation was time-to-relapse. Safety evaluations included adverse events (AEs) reported for the duration of the study, Extrapyramidal Symptom Rating Scale (ESRS), clinical laboratory tests, and vital signs. A total of 666 patients (n=329 RLAI, n=337 quetiapine) were evaluable for effectiveness measures. Baseline demographics were similar between treatment groups. Kaplan–Meier estimate of time-to-relapse was significantly longer with RLAI (p<0.0001). Relapse occurred in 16.5% of patients with RLAI and 31.3% with quetiapine. RLAI and quetiapine were both safe and well tolerated. Weight gain affected 7% of patients with RLAI and 6% with quetiapine, with mean end point increases of 1.25±6.61 and 0±6.55 kg, respectively. There were no significant between-group differences in weight gain. ESRS total scores decreased similarly after randomization to either RLAI or quetiapine. Extrapyramidal AEs occurred in 10% of patients with RLAI and 6% with quetiapine. Treatment-emergent potentially prolactin-related AEs were reported in 15 (5%) patients with RLAI and 5 (2%) patients with quetiapine; hyperprolactinemia was reported in 43 (13.1%) patients with RLAI and 5 (1.5%) patients with quetiapine. Somnolence occurred in 2% of patients with RLAI and 11% with quetiapine. To our knowledge, this is the first report of a randomized clinical trial directly comparing relapse prevention with a second-generation long-acting injectable antipsychotic and oral therapy. Time-to-relapse in stable patients with schizophrenia or schizoaffective disorder was significantly longer in patients randomized to RLAI compared with those randomized to oral quetiapine. Both antipsychotics were generally well tolerated.

Relationship between cardiovagal modulation and psychotic state in patients with paranoid schizophrenia.

Disturbed autonomic nervous system (ANS) function in schizophrenia might contribute to increased cardiovascular mortality. We obtained heart rate variability indices from 40 unmedicated schizophrenic patients and 58 matched controls. Mainly we found that patients displaying stronger psychotic symptoms as assessed by the Brief Psychiatric Rating Scale exhibit more severe cardiac ANS disturbances compared with controls.

Prevalence and Treatment Outcome in Anxious Versus Nonanxious Depression: Results From the German Algorithm Project

OBJECTIVE The objective of this study was to explore the prevalence of anxious depression in an inpatient population, to describe its clinical and sociodemographic correlates, and to compare treatment outcomes between patients with anxious and nonanxious depression. Furthermore, the efficacy of algorithm-guided treatment versus treatment as usual in patients with anxious versus nonanxious depression was evaluated. METHOD Data were collected on 429 inpatients with the diagnosis of a depressive episode (according to ICD-10) and a score of ≥ or = 15 on the 21-item Hamilton Depression Rating Scale (HDRS-21). The German Algorithm Project, phase 3 (GAP3), was conducted between 2000 and 2005 in 10 psychiatric departments throughout Germany. A baseline HDRS-21 anxiety/somatization factor score of ≥ or = 7 was considered indicative of anxious depression. Remission was defined as an HDRS-21 score or ≤ = 9. To evaluate the efficacy of algorithm-guided treatment, patients were randomly assigned into 3 groups: 2 different treatment algorithms or treatment as usual. RESULTS The prevalence of anxious depression was 49%. Patients with anxious depression were more likely than those with nonanxious depression to be older (mean ± SD = 45.3 ± 12.8 vs 42.9 ± 12.0 years, odds ratio [OR] = 1.02 [95% CI, 1.00-1.03], P = .046), retired (70% vs 30%, OR = 3.09 [95% CI, 1.70-5.62], P = .000), without school qualification (74% vs 26%, OR = 3.11 [95% CI, 1.09-8.83], P = .035), more severely depressed (mean ± SD HDRS-21 score = 20.1 ± 5.0 vs 18.5 ± 4.4, OR = 1.08 [95% CI, 1.03-1.12], P = .001), and more likely to have a longer duration of the current episode (mean ± SD = 20.9 ± 26.2 vs 13.7 ± 14.3 weeks, OR = 1.02 [95% CI, 1.01-1.03], P = .011). Patients with anxious depression were more likely to display a variety of melancholic features. In patients with anxious depression compared to those with nonanxious depression, remission was less likely to be achieved (48.6% vs 61.5%, OR = 0.63 [95% CI, 0.42-0.92], P = .018) and took longer to occur (mean ± SD = 44 ± 3.4 vs 30 ± 2.8 days, HR = 0.65 [95% CI, 0.50-0.85], P = .001). There was no significant interaction with the treatment mode with regard to remission (Wald = 0.20, P = .890). CONCLUSIONS Anxious depression is common in patients diagnosed with depression. The poorer treatment outcome in patients with anxious depression demonstrates the need to address the issue of specific treatment strategies for this subgroup. However, anxious depression has no moderating effect on the efficacy of algorithm-guided treatment. TRIAL REGISTRATION http://www.germanctr.de/ Identifier: DRKS00000161.

Left Prefrontal High-Frequency Repetitive Transcranial Magnetic Stimulation for the Treatment of Schizophrenia with Predominant Negative Symptoms: A Sham-Controlled, Randomized Multicenter Trial

BACKGROUND Investigators are urgently searching for options to treat negative symptoms in schizophrenia because these symptoms are disabling and do not respond adequately to antipsychotic or psychosocial treatment. Meta-analyses based on small proof-of-principle trials suggest efficacy of repetitive transcranial magnetic stimulation (rTMS) for the treatment of negative symptoms and call for adequately powered multicenter trials. This study evaluated the efficacy of 10-Hz rTMS applied to the left dorsolateral prefrontal cortex for the treatment of predominant negative symptoms in schizophrenia. METHODS A multicenter randomized, sham-controlled, rater-blinded and patient-blinded trial was conducted from 2007-2011. Investigators randomly assigned 175 patients with schizophrenia with predominant negative symptoms and a high-degree of illness severity into two treatment groups. After a 2-week pretreatment phase, 76 patients were treated with 10-Hz rTMS applied 5 days per week for 3 weeks to the left dorsolateral prefrontal cortex (added to the ongoing treatment), and 81 patients were subjected to sham rTMS applied similarly. RESULTS There was no statistically significant difference in improvement in negative symptoms between the two groups at day 21 (p = .53, effect size = .09) or subsequently through day 105. Also, symptoms of depression and cognitive function showed no differences in change between groups. There was a small, but statistically significant, improvement in positive symptoms in the active rTMS group (p = .047, effect size = .30), limited to day 21. CONCLUSIONS Application of active 10-Hz rTMS to the left dorsolateral prefrontal cortex was well tolerated but was not superior compared with sham rTMS in improving negative symptoms; this is in contrast to findings from three meta-analyses.

The temporal lobe in schizophrenia from uni- and multiply affected families

To investigate the effect of genetic loading on brain structure in schizophrenia, we hypothesized that separating families into uniaffected and multiply affected would reveal effects of schizophrenia and family type. Volumes and asymmetries of the amygdala-hippocampus-complex (AHC) and sylvian fissure (SF) were determined using magnetic resonance imaging of subjects with schizophrenia from 12 uniaffected and 14 multiply affected families, and ten healthy controls. AHC volume was reduced in schizophrenia, particularly on the right side in subjects from uniaffected families. AHC asymmetry was disturbed, too. Enlargement of the right SF and disturbed SF asymmetry was demonstrated in subjects from uniaffected families as well. Comparing subjects from uni- and multiply affected families may be a useful strategy to reduce variability for future studies of environmental interactions with genetic risk for schizophrenia.

Repetitive transcranial magnetic stimulation (rTMS) improves facial affect recognition in schizophrenia.

OBJECTIVE Facial affect recognition, a basic building block of social cognition, is often impaired in schizophrenia. Poor facial affect recognition is closely related to poor functional outcome; however, neither social cognitive impairments nor functional outcome are sufficiently improved by antipsychotic drug treatment alone. Adjunctive repetitive transcranial magnetic stimulation (rTMS) has been shown to enhance cognitive functioning in both healthy individuals and in people with neuropsychiatric disorders and to ameliorate clinical symptoms in psychiatric disorders, but its effects on social cognitive impairments in schizophrenia have not yet been studied. Therefore, we evaluated the effects of sham-controlled rTMS on facial affect recognition in patients with chronic schizophrenia. METHOD Inpatients (N = 36) on stable antipsychotic treatment were randomly assigned to double-blind high-frequency (10 Hz) rTMS or sham stimulation for a total of ten sessions over two weeks. In the verum group, each session consisted of 10 000 stimuli (20 trains of 5 s) applied over the left dorsolateral prefrontal cortex at 110% of motor threshold. Facial affect recognition was assessed before (T0) and after (T1) the ten sessions. RESULTS Facial affect recognition improved significantly more after rTMS (accuracy change: mean = 8.9%, SD = 6.0%) than after sham stimulation (mean = 1.6%, SD = 3.5; Cohens d = 1.45). There was no correlation with clinical improvement. CONCLUSION Our results indicate that prefrontal 10 Hz rTMS stimulation may help to ameliorate impaired facial affect recognition in schizophrenia.

Cognitive Effects of High-Frequency rTMS in Schizophrenia Patients With Predominant Negative Symptoms: Results From a Multicenter Randomized Sham-Controlled Trial

Cognitive impairments are one of the main contributors to disability and poor long-term outcome in schizophrenia. Proof-of-concept trials indicate that repetitive transcranial magnetic stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (DLPFC) has the potential to improve cognitive functioning. We analyzed the effects of 10-Hz rTMS to the left DLPFC on cognitive deficits in schizophrenia in a large-scale and multicenter, sham-controlled study. A total of 156 schizophrenia patients with predominant negative symptoms were randomly assigned to a 3-week intervention (10-Hz rTMS, 15 sessions, 1000 stimuli per session) with either active or sham rTMS. The Rey Auditory Verbal Learning Test, Trail Making Test A and B, Wisconsin Card Sorting Test, Digit Span Test, and the Regensburg Word Fluency Test were administered before intervention and at day 21, 45, and 105 follow-up. From the test results, a neuropsychological composite score was computed. Both groups showed no differences in any of the outcome variables before and after intervention. Both groups improved markedly over time, but effect sizes indicate a numeric, but nonsignificant superiority of active rTMS in certain cognitive tests. Active 10-Hz rTMS applied to the left DLPFC for 3 weeks was not superior to sham rTMS in the improvement of various cognitive domains in schizophrenia patients with predominant negative symptoms. This is in contrast to previous preliminary proof-of-concept trials, but highlights the need for more multicenter randomized controlled trials in the field of noninvasive brain stimulation.

Effects of 10 Hz repetitive transcranial magnetic stimulation (rTMS) on clinical global impression in chronic schizophrenia

UNLABELLED We conducted a randomized, sham-controlled repetitive transcranial magnetic stimulation (rTMS) study in chronic schizophrenia in-patients (n=35) to evaluate the therapeutic efficacy of 10 Hz stimulation. Patients, who were on stable antipsychotic treatment, were randomly assigned to the active or sham condition. In the active rTMS group, ten sessions with a total of 10,000 stimuli were applied over the left dorsolateral prefrontal cortex at 110% of motor threshold. The sham group received corresponding sham stimulation. Clinical improvement was measured by the Clinical Global Impression scale (primary outcome measure), the Global Assessment of Functioning Scale (GAF) and the Positive and Negative Symptom Scale (PANSS; secondary outcome measures). Between-group comparisons revealed no significant differences in clinical outcome variables. Only a subgroup of patients with pronounced negative symptoms developed some clinical improvement as indicated by significant changes in the GAF-scale. Besides there is some evidence for a more favourable clinical outcome within this subgroup after rTMS in the CGI-S and PANSS negative scale, too. In line with earlier investigations, our results suggest a moderate - potentially clinically relevant - treatment effect of prefrontal 10 Hz rTMS stimulation in chronic patients. However, in our study this beneficial effect was restricted to subjects with pronounced negative symptoms. CLINICAL TRIAL REGISTRATION INFORMATION ClinicalTrial.gov Identifier: NCT00169689, http://www.clinicaltrials.gov.

Epidemiology, Symptoms, and Treatment Characteristics of Hyponatremic Psychiatric Inpatients

Abstract Hyponatremia is a common phenomenon in psychiatry occurring as an adverse effect to drugs or following polydipsia. We performed a retrospective in-depth analysis of hyponatremia cases in a large unselected population of psychiatric inpatients. During a 3-year period, all cases of hyponatremia were identified among patients admitted to a large psychiatric state and university hospital by the institution’s electronic laboratory database. Demographic, treatment-related, and laboratory data were obtained by consecutive chart review, respectively. Hyponatremia occurred in 347 (4.9%) of 7113 cases, of which the majority (78%) displayed only a mild manifestation. Symptoms were recorded in 28.8% of cases, already occurred in mild forms, and comprised gait impairment (45%, including falls), confusion (30%), sedation (26%), and dyspepsia (41%). Age, female sex, nonpsychiatric drug polypharmacy—particularly with thiazides and/or angiotensin-converting enzyme inhibitors—and diagnosis of a mood disorder were associated with more severe hyponatremia, respectively. The proportion of hyponatremic patients treated with venlafaxine, trazodone, carbamazepine, oxcarbazepine, and first-generation antipsychotics, respectively, was significantly higher in the hyponatremia sample than in the normonatremic population. This was, surprisingly, not the case with selective serotonin reuptake inhibitors or any other antidepressant drug class. We found prescription with second-generation antipsychotics to be significantly associated with less severe hyponatremia. Hyponatremia may be mainly attributed to the syndrome of inappropriate antidiuretic hormone secretion, as indicated by decreased serum osmolarity in our sample. Besides old age and female sex, treatment with certain drugs—rather than whole drug classes—carries a substantially increased risk.

Potential Clinical Targets of Repetitive Transcranial Magnetic Stimulation Treatment in Schizophrenia

Despite the introduction of atypical antipsychotic drugs, treatment-resistant symptoms still represent a serious problem in schizophrenia. Currently, there is evidence from clinical studies suggesting that treatment with repetitive transcranial magnetic stimulation (rTMS) may improve schizophrenia symptoms. Our review provides an overview of clinical rTMS studies in schizophrenic patients. A systematic search of the literature (Cochrane and Medline databases up to December 2005) was conducted. Most studies showed methodological problems due to their explorative character and small sample sizes. In some studies, a treatment effect of high-frequency rTMS applied over the prefrontal cortex was seen with respect to negative symptoms. On the other hand, low-frequency rTMS in the temporal lobe area might lead to a suppression of auditory hallucinations. It is concluded that larger sham-controlled studies are required to allow an adequate assessment of the clinical and neurobiological effects of rTMS in schizophrenic patients. The currently available data provide insufficient evidence to support the use of rTMS as an adjuvant treatment for schizophrenic psychopathology, but encourage further investigation of rTMS as a novel treatment approach.