Noradrenaline or serotonin (5‐HT) reuptake‐inhibiting antidepressants such as reboxetine or citalopram acutely stimulate cortisol and adrenocorticotrophic hormone (ACTH) secretion in healthy ...volunteers, whereas mirtazapine acutely inhibits the ACTH and cortisol release, probably due to its antagonism at central 5‐HT2 and/or H1 receptors. These differential effects of antidepressants on cortisol and ACTH secretion in healthy subjects after single administration are also reflected by their different time course in the down‐regulation of hypothalamic‐pituitary‐adrenocortical (HPA) axis hyperactivity in depressed patients as assessed by serial dexamethasone (DEX)/corticotrophin‐releasing hormone (CRH) tests: Reuptake‐inhibiting antidepressants such as reboxetine gradually normalise HPA axis hyperactivity in depressed patients during several weeks of treatment via up‐regulation of mineralocorticoid and glucocorticoid receptor function and by step‐by‐step restoration of the disturbed feedback control. By contrast, mirtazapine markedly reduces HPA axis activity in depressed patients within 1 week, but there is a partial re‐enhancement of HPA hormone secretion after several weeks of therapy. In all studies performed to date, the short‐term effects of daily treatment with antidepressants on the DEX/CRH test results are comparable in responders and nonresponders. Moreover, a reduction in HPA axis activity is not necessarily followed by a favourable clinical response and some depressed patients keep on showing nonsuppression in the DEX/CRH test despite clinical improvement. Therefore, the importance of HPA axis dysregulation for the short‐term efficacy of antidepressants continues to be a matter of debate. However, there are convincing data suggesting that persisting nonsuppression in the DEX/CRH test despite clinical remission predicts an enhanced risk for relapse of depressive symptomatology with respect to the medium‐ and long‐term outcome.
Abstract In the past decades considerable evidence has emerged that so-called neuroactive steroids do not only act as transcriptional factors in the regulation of gene expression but may also alter ...neuronal excitability through interactions with specific neurotransmitter receptors such as the GABAA receptor. In particular, 3α-reduced neuroactive steroids such as allopregnanolone or allotetrahydrodeoxycorticosterone have been shown to act as positive allosteric modulators of the GABAA receptor and to play an important role in the pathophysiology of depression and anxiety. During depression, the concentrations of 3α,5α-tetrahydroprogesterone and 3α,5β-tetrahydroprogesterone are decreased, while the levels of 3β,5α-tetrahydroprogesterone, a stereoisomer of 3α,5α-tetrahydroprogesterone, which may act as an antagonist for GABAergic steroids, are increased. Antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs) or mirtazapine apparently have an impact on key enzymes of neurosteroidogenesis and have been shown to normalize the disequilibrium of neuroactive steroids in depression by increasing 3α-reduced pregnane steroids and decreasing 3β,5α-tetrahydroprogesterone. Moreover, 3α-reduced neuroactive steroids have been demonstrated to possess antidepressant- and anxiolytic-like effects both in animal and human studies for themselves. In addition, the translacator protein (18 kDa) (TSPO), previously called peripheral benzodiazepine receptor, is the key element of the mitochondrial import machinery supplying the substrate cholesterol to the first steroidogenic enzyme (P450scc), which transforms cholesterol into pregnenolone, the precursor of all neurosteroids. TSPO ligands increase neurosteroidogenesis and are a target of novel anxiolytic drugs producing anxiolytic effects without causing the side effects normally associated with conventional benzodiazepines such as sedation or tolerance. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.
Neutropenia and agranulocytosis (N&A) are relatively rare, but potentially fatal adverse drug reactions (ADR). This study presents cases of N&A related to one or more antipsychotic drugs (APDs) in ...psychiatric inpatients. Data on APD utilization and reports of N&A caused by APDs were analyzed by using data from an observational pharmacovigilance program in German-speaking countries—Arzneimittelsicherheit in der Psychiatrie (AMSP)—from 1993 to 2016. 333,175 psychiatric inpatients were treated with APDs for schizophrenia and other indications during the observation period. A total of 124 cases of APD-induced N&A were documented, 48 of which fulfilled the criteria for agranulocytosis, corresponding to a rate of 0.37, respectively, 0.14 in 1000 inpatients treated with APDs. Neutropenia was more often detected in women, whereas there was no difference regarding sex in cases of agranulocytosis. Clozapine had the highest relative risk for inducing N&A and was imputed alone as a probable cause of N&A in 60 cases (1.57‰ of all patients exposed). Perazine showed the second highest relative risk with 8 cases and an incidence 0.52‰, followed by quetiapine (15 cases resp. 0.23‰ of all patients exposed) and olanzapine (7 cases; 0.13‰ of all patients exposed). N&A most often occurred during the first 3 months of treatment. Overall N&A are severe and potentially fatal complications that can occur during treatment with APDs. The results from this study largely agree with the currently available literature, highlighting the positive effects of alertness and established appropriate monitoring.
Introduction
Major Depressive Disorder (MDD) is one of the most common mental illnesses worldwide and is strongly associated with suicidality. Commonly used treatments for MDD with suicidality ...include crisis intervention, oral antidepressants (although risk of suicidal behavior is high among non-responders and during the first 10-14 days of the treatment) benzodiazepines and lithium. Although several interventions addressing suicidality exist, only few studies have characterized in detail patients with MDD and suicidality, including treatment, clinical course and outcomes. Patient Characteristics, Validity of Clinical Diagnoses and Outcomes Associated with Suicidality in Inpatients with Symptoms of Depression (OASIS-D)-study is an investigator-initiated trial funded by Janssen-Cilag
GmbH.
Objectives
For population 1 out of 3 OASIS-D populations, to assess the sub-population of patients with suicidality and its correlates in hospitalized individuals with MDD.
Methods
The ongoing OASIS-D study consecutively examines hospitalized patients at 8 German psychiatric university hospitals treated as part of routine clinical care. A sub-group of patients with persistent suicidality after >48 hours post-hospitalization are assessed in detail and a sub-group of those are followed for 6 months to assess course and treatment of suicidality associated with MDD. The present analysis focuses on a preplanned interim analysis of the overall hospitalized population with MDD.
Results
Of 2,049 inpatients (age=42.5±15.9 years, females=53.2%), 68.0% had severe MDD without psychosis and 21.2% had moderately severe MDD, with 16.7% having treatment-resistant MDD. Most inpatients referred themselves (49.4%), followed by referrals by outpatient care providers (14.6%), inpatient care providers (9.0%), family/friends (8.5%), and ambulance (6.8%). Of these admissions, 43.1% represented a psychiatric emergency, with suicidality being the reason in 35.9%. Altogether, 72.4% had at least current passive suicidal ideation (SI, lifetime=87.2%), including passive SI (25.1%), active SI without plan (15.5%), active SI with plan (14.2%), and active SI with plan+intent (14.1%), while 11.5% had attempted suicide ≤2 weeks before admission (lifetime=28.7%). Drug-induced mental and behavioral disorders (19.6%) were the most frequent comorbid disorders, followed by personality disorders (8.2%). Upon admission, 64.5% were receiving psychiatric medications, including antidepressants (46.7%), second-generation antipsychotics (23.0%), anxiolytics (11.4%) antiepileptics (6.0%), and lithium (2.8%). Altogether, 9.8% reported nonadherence to medications within 6 months of admission.
Conclusions
In adults admitted for MDD, suicidality was common, representing a psychiatric emergency in 35.9% of patients. Usual-care treatments and outcomes of suicidality in hospitalized adults with MDD require further study.
Disclosure of Interest
None Declared
Galactorrhea is a well-known adverse drug reaction (ADR) of numerous antipsychotic drugs (APD) and is often distressing for those affected. Methodological problems in the existing literature make it ...difficult to determine the prevalence of symptomatic hyperprolactinemia in persons treated with APDs. Consequently, a large sample of patients exposed to APDs is needed for more extensive evaluation. Data on APD utilization and reports of galactorrhea caused by APDs were analyzed using data from an observational pharmacovigilance program in German-speaking countries—Arzneimittelsicherheit in der Psychiatrie (AMSP)—from 1993 to 2015. 320,383 patients (175,884 female inpatients) under surveillance were treated with APDs for schizophrenia and other indications. A total of 170 events of galactorrhea caused by APDs were identified (0.97 cases in 1000 female inpatient admissions). Most cases occurred during the reproductive age with the highest incidence among patients between 16 and 30 years (3.81 cases in 1000 inpatients). The APDs that were most frequently imputed alone for inducing galactorrhea were risperidone (52 cases and 0.19% of all exposed inpatients), amisulpride (30 resp. 0.48%), and olanzapine (13 resp. 0.05%). In three cases, quetiapine had a prominent role as a probable cause for galactorrhea. High dosages of the imputed APDs correlated with higher rates of galactorrhea. Galactorrhea is a severe and underestimated condition in psychopharmacology. While some APDs are more likely to cause galactorrhea, we identified a few unusual cases. This highlights the importance of alertness in clinical practice and of taking a patient’s individual situation into consideration.
Anxiety disorders are frequent and highly disabling diseases with considerable socio‐economic impact. In the treatment of anxiety disorders, benzodiazepines (BZDs) as direct modulators of the GABAA ...receptor are used as emergency medication because of their rapid onset of action. However, BZDs act also as sedatives and rather quickly induce tolerance and abuse liability associated with withdrawal symptoms. Antidepressants with anxiolytic properties are also applied as first line long‐term treatment of anxiety disorders. However, the onset of action of antidepressants takes several weeks. Obviously, novel pharmacological approaches are needed that combine a rapid anxiolytic efficacy with the lack of tolerance induction, abuse liability and withdrawal symptoms. Neurosteroids are potent allosteric modulators of GABAA receptor function. The translocator protein (18 kDa) (TSPO) plays an important role for the synthesis of neurosteroids by promoting the transport of cholesterol from the outer to the inner mitochondrial membrane, which is the rate‐limiting step in neurosteroidogenesis. Etifoxine not only exerts anxiolytic effects as a TSPO ligand by enhancing neurosteroidogenesis, but also acts as a weak direct GABAA receptor enhancer. The TSPO ligand XBD173 enhances GABAergic neurotransmission via the promotion of neurosteroidogenesis without direct effects at the GABAA receptor. XBD173 counteracts pharmacologically‐induced panic in rodents in the absence of sedation and tolerance development. Also in humans, XBD173 displays antipanic activity and does not cause sedation and withdrawal symptoms after 7 days of treatment. XBD173 therefore appears to be a promising candidate for fast‐acting anxiolytic drugs with less severe side‐effects than BZDs. In this review, we focus on the pathophysiology of anxiety disorders and TSPO ligands as a novel pharmacological approach in the treatment of these disorders.
Tryptophan hydroxylase (TPH), being the rate-limiting enzyme in the biosynthesis of serotonin plays a major role as candidate gene in several psychiatric disorders. Recently, a second TPH isoform ...(TPH2) was identified in mice, which was exclusively present in the brain. In a previous post-mortem study of our own group, we could demonstrate that TPH2 is also expressed in the human brain, but not in peripheral tissues. This is the first report of an association study between polymorphisms in the TPH2 gene and major depression (MD). We performed single-nucleotide polymorphism (SNP), haplotype and linkage disequlibrium studies on 300 depressed patients and 265 healthy controls with 10 SNPs in the TPH2 gene. Significant association was detected between one SNP (P=0.0012, global P=0.0051) and MD. Haplotype analysis produced additional support for association (P<0.0001, global P=0.0001). Our findings provide evidence for an involvement of genetic variants of the TPH2 gene in the pathogenesis of MD and might be a hint on the repeatedly discussed duality of the serotonergic system. These results may open up new research strategies for the analysis of the observed disturbances in the serotonergic system in patients suffering from several other psychiatric disorders.
Evidence-based data on prevalence and risk factors of suicidal intentions and behavior in dementia are as scarce as the data on assisted dying. The present literature review aimed on summarizing the ...current knowledge and provides a critical discussion of the results.
A systematic narrative literature review was performed using Medline, Cochrane Library, EMBASE, PSYNDEX, PSYCINFO, Sowiport, and Social Sciences Citation Index literature.
Dementia as a whole does not appear to be a risk factor for suicide completion. Nonetheless some subgroups of patients with dementia apparently have an increased risk for suicidal behavior, such as patients with psychiatric comorbidities (particularly depression) and of younger age. Furthermore, a recent diagnosis of dementia, semantic dementia, and previous suicide attempts most probably elevate the risk for suicidal intentions and behavior. The impact of other potential risk factors, such as patient's cognitive impairment profile, behavioral disturbances, social isolation, or a biomarker based presymptomatic diagnosis has not yet been investigated. Assisted dying in dementia is rare but numbers seem to increase in regions where it is legally permitted.
Most studies that had investigated the prevalence and risk factors for suicide in dementia had significant methodological limitations. Large prospective studies need to be conducted in order to evaluate risk factors for suicide and assisted suicide in patients with dementia and persons with very early or presymptomatic diagnoses of dementia. In clinical practice, known risk factors for suicide should be assessed in a standardized way so that appropriate action can be taken when necessary.
The serotonergic system is involved in the pathophysiology of major depression as well as in the early central nervous system development and adult neuroplasticity. The aim of the study was to ...examine in 77 patients with major depression and 77 healthy controls the association between the triallelic polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) and gray matter (GM) brain volumes measured with 1.5 T magnetic resonance imaging. Voxel-based morphometry were estimated on magnetic resonance images and genotyping was performed. We found that healthy controls have a strong association between the 5-HTTLPR and GM volumes of the dorsolateral prefrontal cortex, left anterior gyrus cinguli, left amygdala as well as right hippocampus, whereas there is no such association in patients with major depression. Healthy subjects carrying the S- or L(G)-allele have smaller GM volumes than those with the L(A)-allele, indicating that 5-HTTLPR contributes to the development of brain structures. Patients with depression show reduced GM volumes, particularly when they are homozygous for the L(A)-allele, suggesting that these patients are more vulnerable for morphological changes during depressive episodes.
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