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.

[Gender aspects in female and male physicians : Occupational and psychosocial stress]. / Gender-Aspekte bei Ärztinnen und Ärzten : Berufsleben und psychosoziale Belastungen.

BACKGROUND: International studies have shown that physicians have an elevated risk of developing depression or burnout syndrome. Gender aspects with regard to occupation are discussed in German politics and society. Currently, there is little data comparing female and male physicians with regard to stress at work, depression, and burnout. OBJECTIVES: Are there differences between male and female physicians with respect to psychosocial strain, emotional exhaustion, and depression? METHODS: In different cross-sectional studies, anaesthetists, psychiatrists and dentists filled out a questionnaire containing questions on personal data, occupation, past medical history and medication intake. Additional standardized questionnaires (Beck Depression Inventory (BDI) and Maslach Burnout Inventory (MBI)) were performed. RESULTS: The return rate was 51.8 % (n = 3782). Male and female physicians vary significantly in social data, participation in the job, and health status. Female physicians are on average not married (p < 0.001) and have significantly fewer children (p < 0.05). Leading positions are mostly held by male physicians (p < 0.001); female physicians more often work in part-time jobs (p < 0.001). Female physicians reached higher scores of emotional exhaustion (MBI) (p < 0.01) and depression (BDI) (p < 0.001). DISCUSSION: The study shows big differences between male and female physicians with respect to their occupation, personal life, and psychosocial wellbeing. Female physicians more often report burnout and depression. Causes might be family and job strain, gender aspects in hierarchy, as well as different recognition and interpretation of symptoms.

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.

A systematic review of the clinical relevance of repetitive transcranial magnetic stimulation.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) is an approved treatment for depression. The clinical relevance of its efficacy is unclear. The clinical relevance of findings in the rTMS literature was assessed by translating Hamilton Depression Rating Scale (HAMD) data into Clinical Global Impression-Improvement scale (CGI-I) scores. METHOD: We performed electronic searches of MEDLINE, Embase, PsycINFO, PubMed and Cochrane Central Register of Controlled Trials for RCTs and non-RCT trials on rTMS using Hamilton Depression Rating Scale (HAMD). Articles were included if published in English before January 2014. We translated HAMD scores into nominal CGI-I scores for rTMS for depression and for treatment-resistant depression (TRD). RESULTS: About 960 abstracts were retrieved. Sixty-three studies were included, yielding 130 study arms. For depression, the mean percentage change in HAMD scores in all sham-controlled rTMS treatment arms was 35.63 (SD 16.35) and for sham-rTMS 23.33 (SD 16.51). For TRD, active rTMS in sham-controlled studies showed a mean HAMD percentage reduction of 45.21 (SD 10.94) versus 25.04 (SD 17.55) for sham-rTMS. When aggregated scores were translated into notional CGI-I scores, for the treatment of depression, the notional CGI-I score difference between rTMS and sham-rTMS was 0.5 in favour of rTMS; for TRD, it was 0.75 in favour of rTMS. Differences between rTMS and sham-rTMS were bigger when all study arms were combined. CONCLUSION: Whilst rTMS appears to be efficacious for both non-refractory and treatment-resistant depression, the clinical relevance of its efficacy is doubtful.

[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.

[Botulinum toxin for the treatment of major depressive disorder]. / Botulinumtoxin bei der Behandlung depressiver Störungen.

OBJECTIVE: Botulinum toxin (BTX) plays an important role in the treatment and prophylaxis of migraine and is also used for the treatment of focal dystonia, spasm, hypersalivation, and hyperhydrosis. Recent clinical trials suggest that BTX treatment of muscles involved in the development of negative emotions may also have an antidepressant effect. This article gives a systematic review of the literature regarding BTX in the treatment of major depression. METHODS: We screened the databases of Medline and Scopus using the search terms [("botulinum toxin" OR "botox") AND ("antidepressant" OR "depression" OR "depressed")]. The website www.clinicaltrials.gov was screened with the same search terms in order to detect current studies. RESULTS: As of April 2013, we identified 3 studies that evaluated the antidepressant effects of BTX in the treatment of major depression. An improvement in mood after treatment with BTX was seen in a case series of 10 depressed patients. In a randomised, placebo-controlled study of thirty patients assigned to a verum (BTX, n = 15) or placebo (saline, n = 15) group, treatment with BTX has also shown a positive effect on mood. Another prospective, open-label study evaluated the antidepressive effect of BTX in 25 subjects with major depression. On www.clinicaltrials.gov we identified 2 ongoing studies, which are currently investigating the antidepressant effect of BTX. CONCLUSION: Recently published studies have shown a reduction of depressive symptoms after treatment of the glabellar frown lines with BTX injections. Further clinical studies in larger patient samples are necessary to prove the efficacy and safety of BTX injections used for the treatment of depressive disorders.

[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.

Withdrawal and discontinuation phenomena associated with tranylcypromine: a systematic review.

Tranylcypromine (TCP) is an effective antidepressant with a complex pharmacological profile and a relevant risk of abuse and dependence. Withdrawal phenomena (WP, in the case of TCP-abuse/dependence) or discontinuation phenomena (DP, in the case of absent TCP-abuse/dependence) subsequent to abrupt termination of TCP are a potentially severe clinical syndrome. We conducted a systematic review of all previously published WP/DP cases following abrupt termination of TCP in order to identify typical clinical presentations and risk factors of WP/DP and frequency of TCP abuse or dependence within these patients. By searching the Medline and Scopus databases we identified n=25 cases (cohort WP: n=18, cohort DP: n=7). Delirium was found in n=13 patients (cohort WP: 10/55.6%; cohort DP: 3/42.9%), n=6 demonstrated WP/DP without delirium (WP: 6/33.3%; DP: 0/0%) and n=5 rapid relapse in depression (WP: 1/5.6%; DP: 4/57.1%). Mean time until development of WP/DP was 1.9 (WP) and 2.2 (DP) days. Mean duration of WP/DP was 5.7 (WP) and 11.3 (DP) days. All patients of cohort WP were described to feature TCP-abuse/dependence. Patients with delirium were on average older (41.8 years vs. 37.8 years) and featured higher mean prescribed (71.0 mg vs. 38.3 mg) and actually taken daily TCP dosages (285.8 mg vs. 187.7 mg). In conclusion, even termination of lower daily dosages of TCP may result in delirium. Thrombocytopenia features diagnostic value in patients with deliria of unknown etiology. TCP should be administered with great care, especially in dependence-prone patients.·

Aseptic gingivitis related to quetiapine hemifumarate.

Quetiapine hemifumarate (QF) is widely used in psychiatry and is associated with regularly occurring side effects such as dizziness and metabolic problems. Apart from these typical adverse events the agent has attracted attention for several rare phenomena (priapism, cholestasis, rhabdomyolysis) that indeed feature anecdotal character, but are nevertheless indispensable for a comprehensive understanding of the factual risk profile of quetiapine. We present the first report of aseptic gingivitis associated with QF in a patient with mental retardation.

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.

[Relapse prevention in alcohol dependence: acamprosate and naltrexone as a combined pharmacological strategy]. / Rückfallprävention bei Alkoholabhängigkeit: Acamprosat und Naltrexon als kombinierte pharmakologische Strategie.

Acamprosate and naltrexone are established strategies for pharmacologic relapse prevention in patients with alcohol dependence. Regarding pharmacodynamic and pharmacokinetic considerations the combination of both agents for this indication is a reasonable treatment option that has been described to be safe and effective in clinical studies. However, this combination is uncommon in clinical practice. We report the case of a patient with severe alcohol and benzodiazepine dependence who achieved the longest interval of abstinence under combined treatment with acamprosate and naltrexone since the development of addiction. In addition, the currently available evidence regarding efficacy, safety and tolerability of both agents is discussed. In summary the combined treatment with both agents should be considered in patients who did not achieve abstinence under monotherapy unless contraindications are present.

[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.

[Liquid ecstasy in general psychiatry: a case series]. / Liquid ecstasy in der allgemeinpsychiatrie: eine fallserie.

BACKGROUND: In emergency medicine and anesthaesiology liquid ecstasy (LE), the street name for GHB, GBL or 1,4-B, has become infamous for causing severe intoxications and withdrawal. In general psychiatry, however, it is little known. Therefore, we set out to gather data about the role of LE in general psychiatry, typical users and common clinical problems associated with the use of LE. METHODS: We retrospectively identified and studied all patients with a reported the use of LE seen at the Department of Psychiatry, University of Ulm, Germany, between 1998 and 2011. RESULTS: In 14 years, 19 users of LE were identified, the first dating from 2005. The majority reported a use of GBL (63 %), GHB was less common, and 1,4-B was not reported. Patients were predominantly young men (median age 25 years, 79 % men) with a history of multiple substance abuse. Ten patients had only a former use of LE, the other nine patients used it at the time of presentation. Of these, every third patient had to be transiently treated in an intermediate care unit, usually because of very severe and sudden withdrawal symptoms. Otherwise, detoxification was possible in psychiatry, but often required high doses of benzodiazepines. Three patients met the criteria for dependence from GBL. CONCLUSIONS: In recent years, a small number of users of LE is seen also in general psychiatry, The problem is rather the severity of withdrawal than the number of cases. Close cooperation with intermediate care units is needed. In any case of coma of unknown origin or delirium with sudden onset LE use or withdrawal has to be taken into consideration, respectively. Many clinical problems result from the fact that LE cannot be detected in routine drug screenings. According to our experience, withdrawal from LE can be controlled with benzodiazepines.

Effect of 1 Hz repetitive transcranial magnetic stimulation over the auditory cortex on audiometry and otoacustic emissions.

Repetitive transcranial magnetic stimulation (rTMS) at low frequencies (≤1 Hz) delivered to the primary motor cortex for 15 min or longer has been shown to reduce motor cortex excitability. Over the visual cortex, 1 Hz rTMS led to increased phosphene thresholds and over the auditory cortex rTMS reduced auditory evoked potentials. rTMS above the auditory or temporo-parietal cortex has also been reported to reduce the severity of auditory hallucinations and the perception of tinnitus. However, possible unwanted effects on hearing function have not yet been investigated systematically. 12 right-handed normal hearing subjects (5 male, mean age 28.2 ± 4.3) received a single session of 18 min 1 Hz rTMS at 90% resting motor threshold intensity using an established coil positioning method targeting the Heschl's area of the left superior temporal gyrus. Standard pure tone audiometry and distortion-products otoacustic emissions (DPOAE) were performed before and immediately after stimulation. The main finding was that one session of 1 Hz rTMS over the temporal cortex modified neither the auditory threshold meaningfully nor the presence of DPOAE in healthy subjects. In conclusion, we found in this pilot approach no obvious indication for auditory dysfunctions due to direct electromagnetic stimulation of the superior temporal gyrus after one session of rTMS in healthy controls that may be interpreted as unwanted side effects. Nevertheless monitoring of auditory functions is strongly recommended in future clinical trials stimulating the auditory cortex, as this has not been done systematically in the past.

Pregabalin-associated elevation of clozapine serum levels.

We report our experience with a 34-year-old patient with schizophrenia, paranoid subtype, who demonstrated an elevation of clozapine serum levels subsequent to pregabalin comedication used for the treatment of schizophrenic anxiety. This observation turned to be dose-dependent. Although the pharmacokinetic profile of pregabalin suggests an exclusive renal elimination, our report supports the presumption of a possible direct or indirect hepatic "effect" of pregabalin.

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.

The grapes of war. Somatoform pain disorder and history of early war traumatization in older people.

Persistent pain is not a normal part of aging. Nevertheless, many older patients have long-lasting, more or less medically unexplained pain symptoms and, consequently, are often severely disabled, incur high health care costs, and have high comorbidity rates. Moreover, the effects of early traumatization, especially due to wars, and even below the level of posttraumatic stress disorder (PTSD) are apparent. However, the developmental and neurobiological underpinnings of somatoform pain disorder, especially in pain-prone elderly patients, and its correlations with a history of war traumatization even decades after the incident remain unclear. Furthermore, a management strategy for this disorder tailored to older people and their special needs is lacking. Adequate therapeutic regimens such as adjusted psychotherapeutic procedures for elderly patients can only be promoted through a better understanding of the neurobiological and biographical underpinnings of this still controversial disorder.