The neuroleptic malignant syndrome-a systematic case series analysis focusing on therapy regimes and outcome.

INTRODUCTION: Neuroleptic malignant syndrome (NMS) is a rare, potentially life-threatening antipsychotic-associated disorder that requires an efficient and timely therapy. The aim of the study was to compare the effectiveness of different NMS therapies and to analyze its outcome depending on NMS severity. METHOD: Systematic search for NMS cases in biomedical databases. The focus of the analysis was on therapy with dantrolene, bromocriptine, and electroconvulsive therapy (ECT) when each was compared with symptomatic therapy. Primary outcomes were the survival rate and the duration of treatment. RESULT: 405 case reports were included. Overall, no statistically significant differences regarding mortality rate or duration of treatment were found between dantrolene, bromocriptine, or ECT compared to supportive care. A subgroup analysis regarding NMS severity showed that the mortality under specific NMS pharmacotherapy (dantrolene, bromocriptine) and under ECT was significantly lower than under purely symptomatic therapy in severe NMS (P = 0.018). The difference was not significant in mild and moderate cases. DISCUSSION: An overall superiority of the specific NMS therapy (dantrolene, bromocriptine, and ECT) was not found in this study. When regarding severity classification, specific therapies were superior but only in severe cases, and ECT showed the lowest mortality rate. In previous case series, an effect on survival or the duration of the disease could only be observed in part for specific therapies, but the evidence available is inconsistent. The results of this study support our hypothesis that NMS treatment with dantrolene, bromocriptine, and ECT is advantageous over purely symptomatic therapy in severe NMS cases.

Subjective Reasons for Non-Reporting of Adverse Drug Reactions in a Sample of Physicians in Outpatient Care.

INTRODUCTION: Drug safety surveillance strongly depends on the spontaneous reporting of adverse drug reactions (ADRs). A major limiting factor of spontaneous reporting systems is underreporting (UR) which describes incorrectly low reporting rates of ADRs. Factors contributing to UR are numerous and feature country-dependent differences. Understanding causes of and factors associated with UR is necessary to facilitate targeted interventions to improve ADR reporting and pharmacovigilance. METHODS: A cross-sectional questionnaire-based telephone survey was performed among physicians in outpatient care in a federal state of Germany. RESULTS: From n=316 eligible physicians n=176 completed the questionnaire (response rate=55.7%). Most of the physicians (n=137/77.8%) stated that they report ADRs which they have observed to the competent authority rarely (n=59/33.5%), very rarely (n=59/33.5%) or never (n=19/10.8%); the majority (n=123/69.9%) had not reported any ADRs in 2014. Frequent subjective reasons for non-reporting of ADR were (specified response options): lack of time (n=52/29.5%), the subjective evaluation that the required process of reporting is complicated (n=47/26.7%) or requires too much time (n=25/14.2%) or the assessment that reporting of an ADR is needless (n=22/12.5%); within open answers the participants frequently stated that they do not report ADRs that are already known (n=72/40.9%) and they only report severe ADRs (n=46/26.1%). DISCUSSION: Our results suggest a need to inform physicians about pharmacovigilance and to modify the required procedure of ADR reporting or to offer other reporting options.

Risk of bleeding related to selective and non-selective serotonergic antidepressants: a case/non-case approach using data from two pharmacovigilance databases.

INTRODUCTION: There is increasing evidence for an association between treatment with selective serotonin reuptake inhibitors (SSRI) and an increased risk of bleeding events. The most important underlying mechanism appears to be inhibition of serotonin uptake in platelets, an effect that is also present in antidepressants with non-selective serotonin-reuptake inhibition (NSRI). Accordingly, also NSRI may be associated with an increased risk of bleeding. However, there is little data in this regard. METHODS: Based on data (spontaneous reports of adverse drug reactions) from 2 pharmacovigilance databases (WHO-database/Vigibase™; BfArM/AkdÄ-database in Germany) we used a case/non-case approach and calculated reporting odds ratios (ROR) as measures for disproportionality regarding the association of treatment with an agent of the group SSRI/NSRI and haemorrhages. RESULTS: Whereas both positive control agents (ASS and diclofenac) were statistically associated with haemorrhages in both databases (ASS: BfArM/AkdÄ, ROR 13.62 [95% CI 12.76-14.53]/WHO, ROR 12.96 [95% CI 12.75-13.16]; diclofenac: BfArM/AkdÄ, ROR 3.01 [95% CI 2.71-3.21]/WHO, ROR 2.11 [95% CI 2.05-2.16]), none of the agents of the group SSRI (ROR<1) was associated with haemorrhages. In group NSRI, only St. John's wort/hypericum was associated with haemorrhages (WHO-database, ROR 1.31 [95% CI 1.06-1.63]). DISCUSSION: Signal detectioning in 2 pharmacovigilance databases suggest that serotonin reuptake inhibition is not associated with an increased risk of bleeding. However, underreporting may have accounted for the evaluated absent associations, particularly concerning SSRI. Regarding the detected increased risk of bleeding associated with hypericum, pharmacokinetic drug-drug interactions may be relevant independent of serotonin reuptake inhibition.

[Questionnaire for Investigating Therapeutic Alliance in Forensic Setting (FTBF): Results of a Pilot Study]. / Fragebogen zur therapeutischen Beziehung in der Forensik (FTBF): Ergebnisse einer Pilotstudie.

The relation between patient and therapist has a substantial effect on the success of psychotherapy. So far, in German-speaking regions questionnaires translated from English have been used, particularly for studying outpatients. Studies investigating and concerned with specialised features of hospitalised forensic psychiatry patients are sparse. The preliminary results of this study evaluating a recently developed questionnaire aimed to investigate the quality of the therapeutic relationship in forensic psychiatry ("Fragebogen zur therapeutischen Beziehung in der Forensik, FTBF") are reported. The data were collected both in general and forensic psychiatry departments. Factor analyses yielded two essential factors, namely "positive emotional aspects" (12 items, main features trust, respect, helpfulness, harmony, and sympathy; Cronbach's α = .933) and "negative emotional aspects" (4 items, main features power divide and punishment; Cronbach's α = .805). Forensic patients experienced power divide and punishment tendencies more intensively than general psychiatry patients (p < 0.001). Our questionnaire therefore demonstrates not only excellent reliabilities but also differential validity, enabling a differentiation between general and forensic psychiatry patients. Studies with larger samples would enable conclusions about the impact of the therapists' perspective, specific diagnostic subgroups and different psychotherapeutic orientations, on the patient-therapist relationship in forensic psychiatry.

Clozapine-associated development of second-onset obsessive compulsive symptoms in schizophrenia: impact of clozapine serum levels and fluvoxamine add-on.

Among antiserotonergic second generation antipsychotics (SGA), particularly treatment with clozapine (CLZ) is associated with the development of second-onset obsessive compulsive symptoms (OCS) in schizophrenia. However, less is known regarding the factors that increase the individual susceptibility for the development of SGA-associated second-onset OCS in schizophrenia. Here we present the case of a 29-year-old female patient with disorganized schizophrenia who exhibited OCS due to fluvoxamine-induced elevation of CLZ serum levels via inhibition of CYP 1A2 und 2C19. The severity of the observed OCS featured an association with CLZ serum levels. The case illustrates the interaction between fluvoxamine add-on and CLZ serum levels on the development of OCS in schizophrenia and emphasizes the need of regular therapeutic drug monitoring.

[Animal hoarding: a mental disorder with implications for public health]. / Animal Hoarding: eine psychische Störung mit Implikationen für die Öffentliche Gesundheit.

Animal hoarding (AH) is a mental disorder that is characterised by an excessive number of kept animals, inability to maintain minimal standards of animal care and hygiene, and deficient insight into the thereby developing failures and problems. Although AH as a disease concept is neither represented in the DSM-5 nor the ICD-10, it may be classified as a subform of the hoarding disorder (DSM-5 300.3) that was implemented in the DSM-5 as an obsessive-compulsive disorder. Due to the hygienic deficiencies of the living spaces and the insufficient keeping of animals there is an increased risk of epizootic diseases and zoonoses. Specific epidemiological studies do not exist, however, women seem to be affected more frequently. AH is diagnosed mostly in late adulthood. Besides thorough somatic and psychiatric medical diagnostics, cooperation with the veterinary offices and authorities is usually necessary. Comorbid mental disorders (particularly depressive, obsessive-compulsive and personality disorders) are frequent. Currently, no evidence-based therapies exist. Social therapy and cognitive-behavioural psychotherapeutic interventions as well as sufficient treatment of comorbid mental disorders are recommended.

[Optical Coherence Tomography (OCT)--a new diagnostic tool in psychiatry?]. / Optische Kohärenztomografie (OCT)--ein neues diagnostisches Instrument in der Psychiatrie?

Optical coherence tomography (OCT) is a non-invasive, contact-less imaging method which provides an "in vivo" representation of the retina. It allows the quantitative measurement of retinal nerve fibre layer thickness (RNFLT) and macula thickness (MT) and, in addition, is suitable to measure volumes (e.g., macula volume/MV). In the research of neurodegenerative diseases, OCT has been increasingly used and has shown its potential as a possible diagnostic tool over the course of the last few years. In recent years, the hypothesis that mental disorders like schizophrenia or unipolar depressive disorder have a degenerative component was established through a variety of volumetric MRI studies. This review article aims to present the method of OCT, to display its recent use in medicine and psychiatry, as well as to examine possible additional applications in the field of psychiatry.

Agomelatine and hepatotoxicity: implications of cumulated data derived from spontaneous reports of adverse drug reactions.

Considering the antidepressant agomelatine (AGM) there is a discrepancy between the widespread knowledge of the potential of AGM to cause hepatotoxic adverse drug reactions (ADR) and the availability of corresponding published data. This impedes an adequate assessment of the hepatotoxicity profile of AGM. We conducted a query of the database of a German Medical Regulatory Body (BfArM) and analyzed spontaneous reports of hepatotoxic ADR. We identified n=58 cases of AGM-related hepatotoxic ADR. Most frequent ADR was asymptomatic increase of liver enzymes (79%); n=6 patients (10%) with AGM-related toxic hepatitis were reported. Characteristics of patients: female sex (69%), age > 50 years (mean 54 years), polypharmacy (57%), and presence of cardiovascular risk factors (58.5%). Most of the hepatotoxic ADR (90%) were reported to have improved/recovered after discontinuation of AGM. Our evaluation suggests that AGM features a potential to cause severe forms of hepatotoxicity and emphasizes that a pre-existing liver disease is a contraindication for treatment with AGM. Secondly, increased age, female sex and polypharmacy may be risk factors for the development of AGM-related hepatotoxic ADR.

Non-fatal and fatal liver failure associated with valproic acid.

Little is known about hepatotoxicity associated with valproic acid (VPA), a widely used substance in neuropsychiatry.All reported cases to the German Federal Institute for Drugs and Medical Devices between 1993 and 2009 of VPA-induced serious hepatic side effects were evaluated.A total of 132 cases of serious VPA-associated liver failure were identified. Approximately one third (34.8%) occurred under VPA monotherapy, while the majority was seen with VPA plus co-medication, most frequently antiepileptics (34.8%) and benzodiazepines (16.7%). A subgroup of 34 cases (25.8%) had a fatal outcome, the largest number reported to date. Of these, 32.4% were under VPA monotherapy and 67.6% under VPA plus concomitant medication. Within the study period a significant increase in the total number of reported cases and the subgroup of fatal cases was found.This first pharmacovigilance study of VPA-associated liver failure indicates a higher rate of non-fatal and fatal liver failure when VPA is given with co-medication as compared to monotherapy. However, co-medication per se does not increase the risk of fatalities.

[Succinic semialdehyde dehydrogenase deficiency: an inheritable neurometabolic disease]. / Succinat-Semialdehyd-Dehydrogenase-Mangel: eine vererbbare neurometabolische Erkrankung.

Succinic semialdehyde dehydrognase deficiency (SSADHD) is a neurometabolic disease with autosomal recessive inheritance. Although only about 450 cases are known worldwide, SSADHD is a frequent paediatric disorder of the neurotransmitter metabolism. SSADHD is caused by a mutation of the Aldh5a1-gene resulting in a dysfunction of the enzyme succinic semialdehyde dehydrogenase. This is followed by an accumulation of γ-aminobutyric acid and succinic semialdehyde that is alternatively metabolised via succinic semialdehyde reductase to γ-hydroxybutyric acid. The clinical phenotype is unspecific with pronounced interindividual variability. However, delayed acquisition of motor and language developmental milestones as well as epilepsy, mental retardation, sleep disorder, ataxia, muscle hypotonia, and behavioural disturbances are frequent. First symptoms frequently occur in the first year of life while the general course of the disease is non-progressive. Currently, no causal therapy exists.

Successful treatment of major depression with electroconvulsive therapy in a pregnant patient with previous non-response to prefrontal rTMS.

The treatment of psychiatric disorders during pregnancy poses a challenge particularly regarding limited pharmacological possibilities. Repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT) have been described to be successful in single cases, however, guidelines are lacking. In order to contribute to the pool of empirical data that is necessary to create evidenced-based recommendations we present a case of successful treatment of major depression with ECT in a pregnant patient with previous non-response to rTMS.

[Cerebral amyloid angiopathy--an update]. / Zerebrale Amyloidangiopathie--ein Update.

Cerebral amyloid angiopathy (CAA) belongs to the group of amyloidoses and is characterised by the deposition and accumulation of beta-amyloid (Aß) in small arterial vessels of the brain. Hereditary forms of CAA exist but sporadic CAA is much more frequent. Deposition of Aß induces degenerative changes of the cerebral vascular system (thickening of the vessel wall, constriction of vascular lumen, microaneurysms, dissection) that trigger the development of the typical clinical presentation of CAA, that is spontaneous intracerebral haemorrhage. Apart from haemorrhages, also cerebral ischaemia, transient neurological symptoms, leukencephalopathy as well as cognitive decline and dementia can occur in association with CAA. The definite diagnosis of CAA is only possible by means of pathological examination, even though neuroimaging and clinical findings allow the diagnosis of a probable CAA. Currently, no specific causal therapy exists. Although CAA is located in the range of neurological diseases psychiatric symptoms might occur. In the review, we discuss epidemiological, pathogenetic, clinical and diagnostic aspects and possible psychiatric implications of CAA.

[Pharmacotherapeutic treatment strategies for smoking cessation]. / Pharmakologische Strategien zur Unterstützung einer Raucherentwöhnung.

Regular tobacco smoking occurs in about 35% of the male and 25% of the female German population. Individual attempts to independently quit smoking and to remain abstinent for 1 year have been shown to be successful in less than 5% of cases. This rate can be doubled by means of individual consulting and cognitive-behavioral interventions and additional pharmacological treatment might increase abstinence rates up to 25%. Apart from nicotine substitution (e.g. transdermal, oral and inhalative applications) and bupropion, recent studies have shown beneficial effects of varenicline for smoking cessation and abstinence. Varenicline, a selective partial nicotinergic agonist, has been specifically developed for the purpose of smoking cessation. Currently available data suggest that varenicline is more effective compared to nicotine substitution therapy and bupropion, increasing the abstinence likelihood by a factor of 2.3 compared to a placebo. Recent data regarding anti-nicotine vaccines suggest that this approach might yield a comparable treatment outcome and probably even better relapse-preventing effects than conventional psychopharmacological strategies. The first anti-nicotine vaccines are expected to be approved by national authorities within the forthcoming 1-2 years.

[Pathological gambling induced by dopamine agonists]. / Dopaminergika-induziertes Pathologisches Glücksspiel.

Problems with impulse control and pathological gambling are known as possible side effects of dopaminergic therapy in patients with Parkinson's disease. We report 2 cases of pathological gambling induced by dopamine agonists in patients without Parkinson's disease. The first patient, a 46-year-old man, was treated with ropinirole for restless legs syndrome and had lost huge amounts of money in the context of internet-based poker game. Another 46-year-old male patient developed pathological gambling under treatment with cabergoline administered for prolactinoma. The two cases implicate pathological gambling as a possible consequence of dopaminergic treatment and support the increasing evidence regarding pathological gambling as an adverse drug reaction of dopaminergic treatment, also in patients who do not suffer from Parkinson's disease.

[The role of ceruloplasmin in the differential diagnosis of neuropsychiatric disorders]. / Die Bedeutung des Coeruloplasmins für die Differenzialdiagnose neuropsychiatrischer Störungen.

The blue copper protein ceruloplasmin has been of interest to psychiatrists for decades following Heilmeyer's observation of elevated serum copper levels in schizophrenic patients. Immunoturbidimetry, however, does not yield elevated serum ceruloplasmin concentrations in schizophrenia while ceruloplasmin-related oxidase activity appears to be elevated in patients with schizophrenia and reduced in patients with Alzheimer's disease. Low serum concentrations of immuno-turbidimetrically measured ceruloplasmin, and of oxidase activity, are typical of Wilson's disease, Menkes' disease, and aceruloplasminemia, three familial neurodegenerative disorders of pronounced variability, with regard to both genotype and phenotype. Especially patients with Wilson's disease may exhibit behavioural symptoms only over a long period. Heterozygous carriers of Wilson's disease and aceruloplasminaemia may have low serum ceruloplasmin concentrations; they will not develop somatic symptoms, but the significance of these carrier states, or of "hypoceruloplasminaemia", with regard to mental disorders is unknown.

Latency and amplitude variability in serial median nerve SEP recordings.

OBJECTIVES: Intra-individual variability of SEP parameters was investigated by serial SEP recordings. METHODS: Median nerve SEP of 53 normal subjects (mean age 25.5+/-2.7 years) were evaluated. Recordings were repeated 1 week, 2 weeks, and 6 months after the initial recording. RESULTS: Mean values of latencies from right median nerve stimulation were slightly longer (+0.1 ms) as compared to the left. The intra-individual (within stimulation side) variance did not depend on the time interval between recordings. The total within-stimulation-side variance of latencies was 0.056 ms2 for N20 (C3/4' vs. Fz), 0.070 ms2 for N13 (C7 vs. Fz), 0.048 ms2 for N10 (Erb's point vs. Fz), 0.111 ms2 for P9 (C3/4' vs. contralateral forearm), and 0.148 ms2 for P14 (C3/4' vs. contralateral forearm), and was about 3 times smaller than between-side variability with regard to cortical or spinal potentials. Upper limits for latency differences and lower limits for amplitude ratios in repeated recordings, as well as upper and lower limits for between-side latency differences and amplitude ratios were calculated, using F distributions with worst-case assumptions for degrees of freedom and error probability P = 0.05. Upper limits of within-stimulation-side latency differences were 0.55 ms for N20, 0.62 ms for N13, 0.51 ms for N10, 0.78 ms for P9, and 0.90 ms for P14, and corresponding lower limits of amplitude ratios were 0.69, 0.62, 0.66, 0.45, and 0.50, respectively. CONCLUSIONS: Our results demonstrate a small systematic, and a larger random difference between right and left side stimulation, one arising from the peripheral, and the other one from the central pathway proximal to the source of N10.

Limbic activity in slow wave sleep in a healthy subject with alpha-delta sleep.

All-night electroencephalographic (EEG) activity was recorded in a healthy subject with known alpha-delta sleep. Recordings were made from all 19 of the 10/20 system electrode sites, and low resolution electromagnetic tomography (LORETA) was used to estimate intracerebral current densities. Sleep stages were compared within classical frequency bands by statistical parametric mapping (SPM). With the onset of sleep, occipital alpha abated. With increasing depth of sleep, alpha power increased in a region comprising the left frontal lobe, the anterior and parietal cingulum, and the anterior and medial right front lobe. In slow wave sleep (SWS), frontal alpha power was much greater than in wakefulness. The maximum of frontal alpha power of SWS was localised symmetrically in the left and right anterior cingulum. The observed alpha activity was different from the occipital alpha characteristic of wakefulness; it was a distinct activity of separate origin. The anterior limbic lobes seemed to play an active part in SWS in this healthy volunteer with an alpha-delta sleep pattern.