Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators?

Despite decades of basic and clinical research, our understanding of how benzodiazepines tend to lose their efficacy over time (tolerance) is at least incomplete. In appears that tolerance develops relatively quickly for the sedative and anticonvulsant actions of benzodiazepines, whereas tolerance to anxiolytic and amnesic effects probably does not develop at all. In light of this evidence, we review the current evidence for the neuroadaptive mechanisms underlying benzodiazepine tolerance, including changes of (i) the GABAA receptor (subunit expression and receptor coupling), (ii) intracellular changes stemming from transcriptional and neurotrophic factors, (iii) ionotropic glutamate receptors, (iv) other neurotransmitters (serotonin, dopamine, and acetylcholine systems), and (v) the neurosteroid system. From the large variance in the studies, it appears that either different (simultaneous) tolerance mechanisms occur depending on the benzodiazepine effect, or that the tolerance-inducing mechanism depends on the activated GABAA receptor subtypes. Importantly, there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site

Are scientific findings exaggerated? study finds steady increase of superlatives in PubMed abstracts.

Are scientists using language aimed at convincing editors and reviewers to publish their work? Joeri Tijdink, Christiaan Vinkers and Wim Otte present findings which suggest a rise in potentially exaggerated language. Potentially conflicting with the core values of science, the pressure to publish in high impact publications may be contributing to a paradigm of over-interpretation, overstatement and misreporting of scientific results

Olfaction and Depression: Does the Olfactory Bulbectomized Rat Reflect a Translational Model for Depression?

The olfactory bulbectomized (OBX) rat is extensively used as an animal model to detect putative antidepressant drugs. The model has some unusual characteristics, as it detects antidepressant activity of drugs only after medium to long-term administration, thereby reflecting the human situation, as antidepressants do not work acutely but only after long-term administration. The slow onset of action of antidepressants is a major drawback of current antidepressants and the availability of an animal depression model that potentially reveals rapid onset of antidepressant activity might be a great asset. Although an animal model of depression ideally should reflect correlates of human depression, several ‘surrogate’ parameters, like ‘hyperactivity’, reflect astonishingly well the ‘antidepressant’ profile of antidepressants in human depression. Using a new environment (open field) and a home cage to measure activity, imipramine, a classic tricyclic antidepressant, reduced hyperactivity in OBX rats, both in home cage and open field. Telemetrically measured, OBX-induced hyperactivity was already found after a couple of days and indicated that the OBX model is able to detect early (days) effects of (classic) antidepressants. Although imipramine treatment for 3, 7 and 14 days reduced OBX-induced hyperactivity, daily treatment with imipramine for 14 days, but not for 3 or 7 days, reduced hyperactivity (both in home cage and open field) of OBX rats up to 6 weeks after cessation of treatment, indicating neuroplastic changes in the brain. The attractiveness of the OBX model for detection of antidepressants lies in the resemblance to the human situation (onset of action). Moreover, the model suggests that long-term antidepressant treatment (in rats at least 14 days) leads to long-term behavioral changes that far outlast the presence of the antidepressant in the body. Whether this aspect contributes to efficient antidepressant effects needs further investigation

Disrupted upregulation of salience network connectivity during acute stress in siblings of schizophrenia patients

BACKGROUND: An adaptive neural stress response is essential to adequately cope with a changing environment. It was previously argued that sympathetic/noradrenergic activity during acute stress increases salience network (SN) connectivity and reduces executive control network (ECN) connectivity in healthy controls, with opposing effects in the late aftermath of stress. Altered temporal dynamics of these networks in response to stress are thought to play a role in the development of psychopathology in vulnerable individuals. METHODS: We exposed male healthy controls (n = 40, mean age = 33.9) and unaffected siblings of schizophrenia patients (n = 39, mean age = 33.2) to the stress or control condition of the trier social stress test and subsequently investigated resting state functional connectivity of the SN and ECN directly after and 1.5 h after stress. RESULTS: Acute stress resulted in increased functional connectivity within the SN in healthy controls, but not in siblings (group × stress interaction pfwe < 0.05). In the late aftermath of stress, stress reduced functional connectivity within the SN in both groups. Moreover, we found increased functional connectivity between the ECN and the cerebellum in the aftermath of stress in both healthy controls and siblings of schizophrenia patients. CONCLUSIONS: The results show profound differences between siblings of schizophrenia patients and controls during acute stress. Siblings lacked the upregulation of neural resources necessary to quickly and adequately cope with a stressor. This points to a reduced dynamic range in the sympathetic response, and may constitute a vulnerability factor for the development of psychopathology in this at-risk group

Childhood trauma and dysregulation of multiple biological stress systems in adulthood:Results from the Netherlands Study of Depression and Anxiety (NESDA)

Background: Childhood trauma (CT) is a risk factor for depressive and anxiety disorders. Although dysregulated biological stress systems may underlie the enduring effect of CT, the relation between CT and separate and cumulative activity of the major stress systems, namely, the hypothalamic-pituitary-adrenal (HPA)-axis, the immune-inflammatory system, and the autonomic nervous system (ANS), remains inconclusive. Methods: In the Netherlands Study of Depression and Anxiety (NESDA, n = 2778), we determined whether self-reported CT (as assessed by the Childhood Trauma Interview) was associated with separate and cumulative markers of the HPA-axis (cortisol awakening response, evening cortisol, dexamethasone suppression test cortisol), the immune-inflammatory system (C-reactive protein, interleukin-6, tumor necrosis factor-α), and the ANS (heart rate, respiratory sinus arrhythmia, pre-ejection period) in adulthood. Results: Almost all individuals with CT (n = 1330) had either current or remitted depressive and/or anxiety disorder (88.6%). Total-sample analyses showed little evidence for CT being significantly associated with the separate or cumulative stress systems’ activity in adulthood. These findings were true for individuals with and without depressive and/or anxiety disorders. To maximize contrast, individuals with severe CT were compared to healthy controls without CT. This yielded slight, but significantly higher levels of cortisol awakening response (AUCg, β =.088, p =.007; AUCi, β =.084, p =.010), cumulative HPA-axis markers (β =.115, p =.001), C-reactive protein (β =.055, p =.032), interleukin-6 (β =.053, p =.038), cumulative inflammation (β =.060, p =.020), and cumulative markers across all systems (β =.125, p =.0003) for those with severe CT, partially explained by higher rates of smoking, body mass index, and chronic diseases. Conclusion: While our findings do not provide conclusive evidence on CT directly dysregulating stress systems, individuals with severe CT showed slight indications of dysregulations, partially explained by an unhealthy lifestyle and poorer health

Clinical Trial Registration Patterns and Changes in Primary Outcomes of Randomized Clinical Trials from 2002 to 2017

This cross-sectional study evaluates the existence and timing of trial registration for randomized clinical trials (RCTs) published from 2002 to 2017 as well as substantive changes to the primary outcomes entered into registry information after those studies started

Lifelong CRF overproduction is associated with altered gene expression and sensitivity of discrete GABAA and mGlu receptor subtypes

RATIONALE: Repeated activation of corticotropin-releasing factor (CRF) receptors is associated with increased anxiety and enhanced stress responsivity, which may be mediated via limbic GABAergic and glutamatergic transmission. OBJECTIVE: The present study investigated molecular and functional alterations in GABA(A) receptor (GABA(A)R) and metabotropic glutamate receptor (mGluR) responsivity in transgenic mice that chronically overexpress CRF. METHODS: CRF(1) receptor, GABA(A)R, and mGluR sensitivity were determined in CRF-overexpressing mice using the stress-induced hyperthermia (SIH) test. In addition, we measured mRNA expression levels of GABA(A)R α subunits and mGluRs in the amygdala and hypothalamus. RESULTS: CRF-overexpressing mice were less sensitive to the anxiolytic effects of the CRF(1) receptor antagonists CP154,526 and DMP695, the GABA(A)R α(3)-selective agonist TP003 (0–3 mg/kg) and the mGluR(2/3) agonist LY379268 (0–10 mg/kg) in the SIH test. The hypothermic effect of the non-selective GABA(A)R agonist diazepam (0–4 mg/kg) and the α(1)-subunit-selective GABA(A)R agonist zolpidem (0–10 mg/kg) was reduced in CRF-overexpressing mice. No genotype differences were found using the GABA(A)R α(5)-subunit preferential compound SH-053-2′F-R-CH(3) and mGluR(5) antagonists MPEP and MTEP. CRF-overexpressing mice showed decreased expression levels of GABA(A)R α(2) subunit and mGluR(3) mRNA levels in the amygdala, whereas these expression levels were increased in the hypothalamus. CRF-overexpressing mice also showed increased hypothalamic mRNA levels of α(1) and α(5) GABA(A)R subunits. CONCLUSIONS: We found that lifelong CRF overproduction is associated with altered gene expression and reduced functional sensitivity of discrete GABA(A) and mGluR receptor subtypes. These findings suggest that sustained over-activation of cerebral CRF receptors may contribute to the development of altered stress-related behavior via modulation of GABAergic and glutamatergic transmission

Discontinuation of psychotropic medication: a synthesis of evidence across medication classes

Discontinuation; Psychotropic medication; Medication classesSuspensió; Medicación psicotrópica; Clases de medicamentosSuspensió; Medicació psicotròpica; Classes de medicacamentsPharmacotherapy is an effective treatment modality across psychiatric disorders. Nevertheless, many patients discontinue their medication at some point. Evidence-based guidance for patients, clinicians, and policymakers on rational discontinuation strategies is vital to enable the best, personalized treatment for any given patient. Nonetheless, there is a scarcity of guidelines on discontinuation strategies. In this perspective, we therefore summarize and critically appraise the evidence on discontinuation of six major psychotropic medication classes: antidepressants, antipsychotics, benzodiazepines, mood stabilizers, opioids, and stimulants. For each medication class, a wide range of topics pertaining to each of the following questions are discussed: (1) Who can discontinue (e.g., what are risk factors for relapse?); (2) When to discontinue (e.g., after 1 year or several years of antidepressant use?); and (3) How to discontinue (e.g., what’s the efficacy of dose reduction compared to full cessation and interventions to mitigate relapse risk?). We thus highlight how comparing the evidence across medication classes can identify knowledge gaps, which may pave the way for more integrated research on discontinuation