Functional differences in the hypothalamic-pituitary-gonadal axis are associated with alternative reproductive tactics based on an inversion polymorphism.

The evolution of social behavior depends on genetic changes, yet, how genomic variation manifests itself in behavioral diversity is still largely unresolved. Chromosomal inversions can play a pivotal role in producing distinct behavioral phenotypes, in particular, when inversion genes are functionally associated with hormone synthesis and signaling. Male ruffs exhibit alternative reproductive tactics (ARTs) with an autosomal inversion determining two alternative morphs with clear behavioral and hormonal differences from the ancestral morph. We investigated hormonal and transcriptomic differences in the pituitary and gonads. Using a GnRH challenge, we found that the ability to synthesize testosterone in inversion carriers is severely constrained, whereas the synthesis of androstenedione, a testosterone precursor, is not. Inversion morphs were able to produce a transient increase in androstenedione following the GnRH injection, supporting the view that pituitary sensitivity to GnRH is comparable to that of the ancestral morph. We then performed gene expression analyses in a second set of untreated birds and found no evidence of alterations to pituitary sensitivity, gonadotropin production or gonad sensitivity to luteinizing hormone or follicle-stimulating hormone across morphs. Inversion morphs also showed reduced progesterone receptor expression in the pituitary. Strikingly, in the gonads, inversion morphs over-expressed STAR, a gene that is located outside of the inversion and responsible for providing the cholesterol substrate required for the synthesis of sex hormones. In conclusion, our results suggest that the gonads determine morph-specific differences in hormonal regulation.

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.

Methylphenidate intoxication: somnolence as an uncommon clinical symptom and proof of overdosing by increased serum levels of ritalinic acid.

There is considerable evidence for an increase of methylphenidate (MPH) abuse; thus, physicians might be confronted more frequently with MPH intoxications. Possible symptoms of intoxications with MPH are orofacial, stereotypic movements and tics as well as tachycardia, cardiac arrhythmias, arterial hypertension, hyperthermia, hallucinations and epileptic seizures. Here we report a patient who demonstrated somnolence as an uncommon clinical feature of MPH intoxication. The patient exhibited subnormal MPH serum levels (3 µg/l), however markedly increased serum levels of ritalinic acid (821 µg/l; inactive metabolite of MPH), that finally confirmed the initially suspected MPH intoxication. Due to the short half-life of orally administered MPH (t1/2~3 h) the sole measurement of MPH serum levels might be misleading concerning the proof of MPH overdosing in some cases. Parallel measurement of MPH and ritalinic acid is recommended in cases with suspected MPH intoxication and insufficient anamnestic data.

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.

[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.

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.

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.·

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.

Sparse ensemble neural code for a complete vocal repertoire.

The categorization of animal vocalizations into distinct behaviorally relevant groups for communication is an essential operation that must be performed by the auditory system. This auditory object recognition is a difficult task that requires selectivity to the group identifying acoustic features and invariance to renditions within each group. We find that small ensembles of auditory neurons in the forebrain of a social songbird can code the bird's entire vocal repertoire (∼10 call types). Ensemble neural discrimination is not, however, correlated with single unit selectivity, but instead with how well the joint single unit tunings to characteristic spectro-temporal modulations span the acoustic subspace optimized for the discrimination of call types. Thus, akin to face recognition in the visual system, call type recognition in the auditory system is based on a sparse code representing a small number of high-level features and not on highly selective grandmother neurons.

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.

Anakinra: a safe and effective first-line treatment in systemic onset juvenile idiopathic arthritis (SoJIA).

Systemic onset juvenile idiopathic arthritis (SoJIA) is a rare inflammatory disorder. It can result in disease and treatment-related disability. SoJIA is characterized by remitting fevers, evanescent rash, generalized lymphadenopathy, hepatomegaly/splenomegaly, and/or serositis. Non-responsiveness to standard therapy with corticosteroids and disease modifying antirheumatic drugs is not uncommon. IL-1ß has been shown to be a main contributor to the pathogenesis of SoJIA. Anakinra, a recombinant IL-1ß receptor antagonist, was shown to be effective in small cohorts of therapy-resistant adult and pediatric Still's patients. In order to assess the efficacy and safety of first-line anakinra treatment in SoJIA, we reviewed the charts of all SoJIA patients in our institution from 2005 to 2010, searching for first-line anakinra-treated patients. We report the clinical and laboratory course of four SoJIA patients. The mean follow-up was 13.5 (range: 2-50) months. Anakinra was started at doses from 1.5 to 4 mg/kg for a median duration of 3 (range: 3-18) months. Two patients responded to anakinra mono-therapy; two cases required corticosteroids. Normalized body temperatures and the absence of evanescent rashes were achieved after a median of 4 (range: 2-10) days. We did not see treatment-related adverse reactions other than local injection site inflammation. This is the first single-center series, reporting anakinra as first-line treatment in SoJIA. We show rapid efficacy of anakinra in early SoJIA with reduced treatment-related side effects. A subset of patients remains corticosteroid dependent. Further studies are warranted to follow larger cohorts and to assess long-term safety.