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.

[Hypnotics--state of the science]. / Hypnotika--Stand der Forschung.

This article provides an overview of the indications and effects of sleep-inducing drugs. Pharmacological treatment should only be considered in cases of insufficient response to non-pharmacological interventions. Benzodiazepines and benzodiazepine receptor agonists are indicated for the short-term treatment of acute insomnia. Due to the risk of tolerance and dependency, sedative antihistamines and antidepressants are widely used as long-term hypnotics. Other substances, including herbal compounds and melatonin have few side effects; however, the therapeutic efficacy is very limited. Currently, long-term data on the efficacy and tolerability of sleep-inducing substances are lacking. Specifically in cases of non-response to first line treatment, extended psychiatric and somatic evaluation and treatment of associated disorders are recommended.

[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.

Left temporal low-frequency rTMS for the treatment of tinnitus: clinical predictors of treatment outcome--a retrospective study.

BACKGROUND: There is increasing evidence that repetitive transcranial magnetic stimulation (rTMS) can reduce chronic tinnitus. However, treatment results are characterized by high interindividual variability. Therefore, the identification of predictors for treatment response is of high clinical relevance. METHODS: Clinical data of 194 patients with tinnitus were evaluated. All patients were treated with a standardized rTMS procedure (1 Hz, 10 days, 2000 stimuli/day, over the left temporal cortex). A potential influence on the outcome was analysed for the following parameters: age, gender, depression scores in Beck Depression Inventory (BDI) and tinnitus severity (TQ) before rTMS, lateralization, frequency and duration of tinnitus and extent of hearing loss. RESULTS: An effect of tinnitus laterality was observed. In patients with left-sided or bilateral tinnitus, rTMS resulted in a statistically significant reduction of TQ scores, whereas patients with right-sided tinnitus did not show a significant improvement after rTMS treatment. However, in correlation analyses, we found a trend which did not reach statistical significance that in the subgroup of treatment responders tinnitus duration influenced rTMS outcome. In addition, a multiple regression analysis identified the TQ score at baseline as a significant predictor for treatment outcome. For all other investigated parameters, no statistically significant effects were found. CONCLUSIONS: This study suggests that left temporal low-frequency rTMS has beneficial effects in left-sided and bilateral tinnitus, but not in right-sided tinnitus. In line with the results from earlier studies involving smaller samples, tinnitus duration was found to influence rTMS outcome.

[Frontotemporal dementia in association with a family history of dementia and ApoE polymorphism]. / Frontotemporale Demenz im Zusammenhang mit Familienanamnese Demenz und ApoE-Genotyp.

OBJECTIVE: To examine the association between apolipoprotein E (ApoE) and a family history of dementia in 1st- and 2nd-degree relatives of patients with frontotemporal dementia (FTD) with a dementia onset by age 70. METHODS: The study included 494 dementia patients (73 FTD patients) and 82 cognitively normal spousal control subjects. Neuropsychiatric examination, Consortium To Establish a Registry on Alzheimer's Disease (CERAD) testing, the clock-drawing test, and ApoE genotyping were performed in patients and controls. All patients were examined by magnetic resonance imaging. FTD patients fulfilled the Lund-Manchester criteria. RESULTS: All controls had normal Mini Mental State exam (MMSE > or =27). 28 of the 82 spousal controls were excluded because CERAD test results were consistent with the diagnosis of mild cognitive impairment (MCI) or the CERAD was incomplete. The remaining 54 spousal controls had CERAD test results with z-scores >/= -1.5. The number of dementia patients with FTD was 73. Apo epsilon4 homozygosity was found in 13.6% of the FTD patients. None of the spousal controls was homozygous for the Apo epsilon4 genotype (p=0.005). A positive family history of dementia was lowest among cognitively normal spousal controls (9.3%). It rose to 35.6% for FTD patients and was highest among Apo epsilon4 homozygous FTD patients (50.0%). CONCLUSIONS: Apo epsilon4 homozygosity is associated with a family history of dementia and FTD in our cohort if the current clinical criteria are employed. It is likely that autopsy might reveal amyloid beta deposits typical for Alzheimer's disease among the Apo epsilon4 homozygous patients with frontotemporal clinical presentation and neuroimaging consistent with FTD. Apo epsilon4 homozygosity has not yet been defined as an exclusion criterion for the diagnosis of FTD. In the future, a revision of the clinical criteria should consider the ApoE genotype.

Repetitive transcranial magnetic stimulation for the treatment of negative symptoms in residual schizophrenia: rationale and design of a sham-controlled, randomized multicenter study.

Current meta-analysis revealed small, but significant effects of repetitive transcranial magnetic stimulation (rTMS) on negative symptoms in patients with schizophrenia. There is a need for further controlled, multicenter trials to assess the clinical efficacy of rTMS on negative symptoms in schizophrenia in a larger sample of patients. The objective of this multicenter, randomized, sham-controlled, rater- and patient-blind clinical trial is to investigate the efficacy of 3-week 10-Hz high frequency rTMS add on to antipsychotic therapy, 15 sessions per 3 weeks, 1,000 stimuli per session, stimulation intensity 110% of the individual motor threshold) of the left dorsolateral prefrontal cortex for treating negative symptoms in schizophrenia, and to evaluate the effect during a 12 weeks of follow-up. The primary efficacy endpoint is a reduction of negative symptoms as assessed by the negative sum score of the positive and negative symptom score (PANSS). A sample size of 63 in each group will have 80% power to detect an effect size of 0.50. Data analysis will be based on the intention to treat population. The study will be conducted at three university hospitals in Germany. This study will provide information about the efficacy of rTMS in the treatment of negative symptoms. In addition to psychopathology, other outcome measures such as neurocognition, social functioning, quality of life and neurobiological parameters will be assessed to investigate basic mechanisms of rTMS in schizophrenia. Main limitations of the trial are the potential influence of antipsychotic dosage changes and the difficulty to ensure adequate blinding.

[Insomnias: I. Aetiology, pathophysiology and diagnostics]. / Insomnien: I. Atiologie, Pathophysiologie und Diagnostik.

Difficulties to initiate or maintain sleep, early morning awakening and resulting impairment of daytime functioning are a frequent comorbidity of many psychiatric and medical disorders. The so-called primary or psychophysiological insomnia as a distinct independent form of insomnia is a far less frequent condition. This article gives an overview of the diagnostic process for insomniac disorders. Furthermore, up to date neurobiological models of insomnia are discussed.

Modulating cerebello-thalamocortical pathways by neuronavigated cerebellar repetitive transcranial stimulation (rTMS).

OBJECTIVES: Increasing evidence suggests that dysfunctions of the cortico-cerebello-thalamocortical circuit are involved in the pathophysiology of neuropsychiatric disorders. This study explores the effects of cerebellar repetitive transcranial magnetic stimulation (rTMS) on cerebello-thalamocortical pathways. METHODS: Ten healthy volunteers received MRI-guided rTMS in four separate sessions (120% motor threshold, 1000 stimuli) over either the medial or the right lateral cerebellum using frequencies of 1 and 10 Hz. Motor cortex excitability was assessed before and after the intervention by paired-pulse transcranial magnetic stimulation. RESULTS: Depending on stimulation frequency, cerebellar rTMS differentially modified intracortical inhibition. Low frequency rTMS increased short intracortical inhibition (SICI), whereas high frequency rTMS had no significant effect on SICI. CONCLUSIONS: These results suggest that rTMS over the cerebellum can modulate cerebello-thalamocortical pathways in a frequency-specific manner.

Functional imaging of chronic tinnitus: the use of positron emission tomography.

Recent advances in functional imaging have opened new possibilities for understanding tinnitus. Especially, positron emission tomography (PET) has been increasingly used in the last two decades to identify cortical networks, which are involved in the generation of various forms of chronic tinnitus. PET studies have confirmed that the anatomical location of the anomalies that cause many forms of tinnitus are regions of the brain that are normally involved in auditory processing as well as regions engaged in emotional processing. These findings have contributed to the development of new more causally oriented treatment strategies. In particular, identification of increased activity of the auditory cortex by PET has prompted the use of focal brain stimulation techniques such as electrical or transcranial magnetic stimulation in treatment of tinnitus. PET studies that map distinct neurochemical pathways and receptors by the use of specific ligands may in the future provide new possibilities for pharmacologically based treatment of some forms of tinnitus.

Tinnitus severity, depression, and the big five personality traits.

A growing number of self-report measures for the evaluation of tinnitus severity has become available to research and clinical practice. This has led to an increased awareness of depression and personality as predictors of tinnitus severity in addition to loudness and other psychoacoustic measures. However, the net impact of personality dimensions on tinnitus ratings has not been investigated when the effect of depressed mood is controlled. In the present study, we demonstrate the role of the big five personality traits, 'Neuroticism', 'Extraversion', 'Openness', 'Agreeableness', and 'Conscientiousness', in affecting scores on two standard instruments for grading tinnitus-related complaints, the tinnitus handicap inventory (THI), and the tinnitus questionnaire (TQ). When 72 individuals with chronic tinnitus were examined, 'Agreeableness' negatively correlated with THI scores (p=.003), whereas the anxiety trait 'Neuroticism' correlated both with depressive symptomatology (p<.001) and TQ scores (p=.028), but not with THI ratings (n.s.). In addition to confirming the established roles of trait anxiety and depression, low 'Agreeableness' was thus identified as a novel predictor of tinnitus severity on the THI.

TMS for treatment of chronic tinnitus: neurobiological effects.

Results of neurophysiological and neuroimaging studies suggest that some forms of chronic tinnitus can be regarded to be "hyperexcitability syndromes", caused by abnormal focal brain activity. Low frequency repetitive magnetic stimulation (rTMS) is an efficient method to selectively reduce the abnormally increased activity in distinct cortical areas. An increasing amount of clinical data suggest that low frequency rTMS might be an effective therapy that is directed at the cause of some forms of chronic tinnitus. To further explore the underlying neurobiological mechanisms we investigated the effect of rTMS on cortical excitability in healthy human subjects using the protocol, which has been successfully used for the treatment of tinnitus. We determined different parameters of motor cortex excitability (resting motor threshold, RMT; active motor threshold, AMT; short intracortical inhibition, ICI; short intracortical facilitation, ICF; and the duration of the cortical silent period, CSP) before and after 5 days of low frequency rTMS (2000 stimuli/day at 110% of RMT) over the left auditory cortex. Five sessions of low frequency rTMS resulted in a significant prolongation of the CSP. All other signs of cortical excitability that we studied remained unchanged. These findings suggest, that low frequency rTMS may evoke long-term depression (LTD)-like effects resulting in enhancement of subcortical inhibition.

Consensus for tinnitus patient assessment and treatment outcome measurement: Tinnitus Research Initiative meeting, Regensburg, July 2006.

There is widespread recognition that consistency between research centres in the ways that patients with tinnitus are assessed and outcomes following interventions are measured would facilitate more effective co-operation and more meaningful evaluations and comparisons of outcomes. At the first Tinnitus Research Initiative meeting held in Regensburg in July 2006 an attempt was made through workshops to gain a consensus both for patient assessments and for outcome measurements. It is hoped that this will contribute towards better cooperation between research centres in finding and evaluating treatments for tinnitus by allowing better comparability between studies.

Positron emission tomography findings in obstructive sleep apnea patients with residual sleepiness treated with continuous positive airway pressure.

Despite sufficient continuous positive airway pressure (CPAP) therapy, some patients with the obstructive sleep apnea syndrome (OSAS) still suffer from excessive daytime sleepiness (EDS). In some of them, no cause of the persistence of EDS can be found. Brain damage due to nocturnal hypoxemia is a potential cause for this unclear persistent sleepiness (UPS). This study was done to evaluate this hypothesis. Patients with UPS were identified among the OSAS patients, who came for a CPAP therapy checkup to our sleep laboratory. UPS was recognized when no explanation for persistent EDS could be yielded by standard diagnostic procedures. Out of 167 patients under CPAP therapy 13 had UPS. To investigate the brain morphology, positron emission tomography (PET) scanning with the tracer fluorine-18 fluorodeoxyglucose (FDG), called FDG-PET, were performed in 7 of the UPS patients. Abnormal PET findings were concentrated in frontal area (found in 4 patients). The frontal abnormality seems to distinguish the OSAS patients with UPS from the whole OSAS population, examined in previous studies.

[Depressive patients in primary care]. / Zögerliche antidepressive Therapie in der Hausarztpraxis. So behandeln Sie richtig.

The study aimed at investigating out-patient treatment of patients with depressive disorders referred to a psychiatric hospital by general practitioners (GP) and psychiatrists in private practice (PP). Data of the German psychiatric basic documentation system (DGPPN-BADO) of all depressive inpatients admitted to a psychiatric hospital in 2003 were analysed (n = 360). GP-patients had significantly less often a psychopharmalogical treatment before admission than PP-patients (59.4% vs. 89.7%). GP give significantly less often antidepressive drugs than PP do (53.1% vs. 87.9%). 4,7% of GP-patients and 17.9% of PP-patients received supportive psychotherapy, special psychotherapeutic treatment regimes were seldom in use during outpatient care (4,7% vs. 5,4%).

[123I]IBZM SPET analysis of dopamine D2 receptor occupancy in narcoleptic patients in the course of treatment.

Elevated levels of central D2 dopamine receptors were found on postmortem examination in cases of human narcolepsy. In vivo investigations using positron emission tomography (PET) and single photon emission tomography (SPET) found no changes of D2 binding in the striatal structures. To investigate whether the elevated D2 receptors in postmortem investigations are due to long-term treatment effects, we applied 123I-labeled (S)-2-hydroxy-3-iodo-6-methoxy-([1-ethyl-2-pyrrolidinyl]methyl) benzamide (IBZM) ([123I]IBZM, a highly selective CNS D2 dopamine receptor ligand) and SPET in narcoleptic patients in the course of treatment with stimulants and/or antidepressants. Before treatment we found no changes in D2 binding in 10 patients (in comparison to 10 normal controls). After treatment (performed in five patients for 3 months) we found changes in D2 binding in four of them, indicating that the results of the postmortem studies could have been influenced by long-term medications. Human narcolepsy seems not to be related to a striatal D2 dopaminergic disturbance.

Test-retest reliability and validity of the Structured Interview for Sleep Disorders According to DSM-III-R.

OBJECTIVE: The purpose of this study was to evaluate the reliability of sleep disorder diagnoses in DSM-III-R by using a newly developed interview, the Structured Interview for Sleep Disorders According to DSM-III-R (SIS-D) and to evaluate the concordance between these diagnoses and sleep laboratory data. In addition, the sources of disagreements between two interviewers in the diagnoses given to the same patient were determined. METHOD: Two different interviewers used the SIS-D to diagnose 68 patients with complaints of sleep disorders. The concordance between these interviewers' diagnoses and polysomnographic findings was investigated by using kappa statistics. RESULTS: There were excellent reliabilities for almost all current main diagnostic categories and good concordance between diagnoses made on the basis of the structured interview and polysomnographic data. The main source of disagreement between interviewers was found in the symptom information given by the patient. CONCLUSIONS: These findings provide support for the utility of DSM-III-R sleep disorder diagnoses and for their retention in DSM-IV. These findings also accord well with a recent literature review of the DSM-III-R diagnosis of primary insomnia by the DSM-IV Work Group on Sleep Disorders. The good concordance between interview diagnoses and polysomnographic data suggests that a structured interview such as the SIS-D may be a useful screening instrument. The authors discuss the implications of these findings for the polysomnographic evaluation of chronic insomnia.

Salivary cortisol in panic attacks.

OBJECTIVE: Documentation of hypothalamic-pituitary-adrenal (HPA) axis disturbance in panic disorder has been inconsistent. Increased cortisol levels have been associated with altered HPA function due to stress. The authors examined salivary cortisol levels in spontaneously occurring, unprovoked panic attacks. METHOD: Patients with panic disorder (N=25) collected saliva samples when panic attacks occurred. Levels of cortisol in the saliva samples were determined and were compared with levels in comparison samples of saliva obtained 24 hours after the panic attack occurred. RESULTS: During spontaneous panic attacks there was a subtle but significant elevation of cortisol levels, compared with levels obtained 24 hours later. No significant correlations were found between the cortisol elevations during panic attacks and the severity of the attack as measured by using the Acute Panic Inventory or the severity of illness as measured by using the Panic and Agoraphobia Scale. CONCLUSIONS: Saliva sampling may be a useful method for investigating neuroendocrine parameters during spontaneously occurring panic attacks.

Smoking modulates neuroendocrine responses to ipsapirone in patients with panic disorder.

Reduced 5-HT1A-receptor responsiveness has been reported in patients with panic disorder(PD) and/or agoraphobia (PDA). Although many of these patients are regular smokers, it has not been examined whether psychological or neurobiological effects induced by the selective 5-HT1A-receptor agonist, ipsapirone, are affected by the smoking status of the patients. In order to clarify this question neuroendocrine challenges with oral doses of ipsapirone (0.3 mg/kg) and placebo were performed in 39 patients with PDA, and results were compared between patients who smoked (>10 cigarettes per day, n = 17) and patients who had been non-smokers for at least two years (n = 22). Patients who were smokers (but did not smoke during the challenge procedure) had significantly reduced baseline concentrations of cortisol and a significantly lower body temperature. In comparison to placebo, administration of ipsapirone was associated with significant increases of various psychological symptoms and plasma cortisol concentrations. The subgroup of PD patients who were smokers showed significantly higher cortisol responses to ipsapirone than non-smokers. In conclusion, smoking status has to be taken into account when assessing the responsiveness of 5-HT1A receptors in patients with psychiatric disorders. The prevention of smoking during challenge sessions might not be the ideal approach in heavy smokers, since sudden abstinence from smoking is likely to affect neurobiological and possibly psychological responses to ipsapirone.