The relationship between dose and serotonin transporter occupancy of antidepressants—a systematic review

Brain imaging techniques enable the visualization of serotonin transporter (SERT) occupancy as a measure of the proportion of SERT blocked by an antidepressant at a given dose. We aimed to systematically review the evidence on the relationship between antidepressant dose and SERT occupancy. We searched PubMed and Embase (last search 20 May 2021) for human in vivo, within-subject PET, or SPECT studies measuring SERT occupancy at any dose of any antidepressant with highly selective radioligands ([11C]-DASB, [123I]-ADAM, and [11C]-MADAM). We summarized and visualized the dose-occupancy relationship for antidepressants across studies, overlaying the plots with a curve based on predicted values of a standard 2-parameter Michaelis–Menten model fitted using the observed data. We included seventeen studies of 10 different SSRIs, SNRIs, and serotonin modulators comprising a total of 294 participants, involving 309 unique occupancy measures. Overall, following the Michaelis–Menten equation, SERT occupancy increased with a higher dose in a hyperbolic relationship, with occupancy increasing rapidly at lower doses and reaching a plateau at approximately 80% at the usual minimum recommended dose. All the studies were small, only a few investigated the same antidepressant, dose, and brain region, and few reported information on factors that may influence SERT occupancy. The hyperbolic dose-occupancy relationship may provide mechanistic insight of relevance to the limited clinical benefit of dose-escalation in antidepressant treatment and the potential emergence of withdrawal symptoms. The evidence is limited by non-transparent reporting, lack of standardized methods, small sample sizes, and short treatment duration. Future studies should standardize the imaging and reporting procedures, measure occupancy at lower antidepressant doses, and investigate the moderators of the dose-occupancy relationship.

Impact of Doxycycline on COVID-19 Patients with Risk Factors: DYNAMIC, a Multi-Centre, Randomised, Placebo-Controlled, Double-Blind Trial

Background: The DYNAMIC study is based on three properties of tetracyclines. (1) Tetracyclines are known to chelate zinc from matrix metalloproteinases. It is possible their chelating activity may help inhibit COVID-19 infection by limiting its ability to replicate in the host. (2) As seen with dengue virus, tetracyclines may also be able to inhibit the replication of positive polarity single-stranded RNA viruses, such as COVID-19. (3) Tetracyclines are also modulators of innate immunity (anti-inflammatory activity), a property that has been used to treat inflammatory skin diseases for many years. They could therefore participate in limiting the cytokine storm induced by COVID-19. Moreover, the lipophilic nature of tetracyclines and their strong pulmonary penetration could allow them to inhibit viral replication at this level. Among the tetracyclines, doxycycline has three advantages: its long safety history (side effects are uncommon with no notable risks), its short treatment duration and its low cost.Methods: The trial will involve 330 patients who are positive for SARS-CoV-2 infection and have one or more risk factors for worsening the disease. These patients will be included as outpatients for early treatment of illness. For logistical reasons and in order to be able to standardise the study as much as possible, recruitment will take place in 6 hospital departments covering the whole of France. For 14 days they will be given either 200mg of doxycycline a day or placebo. Our hypothesis is a considerable reduction in the number of patients hospitalised due to COVID-19 thanks to the treatment of doxycycline.Discussion: This study could have an impact on the overcrowding of patients with COVID-19 at the hospital which is one of the major world-wide problems of this pandemic. This treatment would therefore contribute to supporting the deconfinement strategy by blocking the viral infection early and reducing the infectious period.Trial Registration: On ClinicalTrials.gov, registration number NCT04371952, first published on 30 April 2020.

Impact of Doxycycline on COVID-19 Patients with Risk Factors: DYNAMIC, a Multi-Centre, Randomised, Placebo-Controlled, Double-Blind Trial

Background: The DYNAMIC study is based on three properties of tetracyclines. (1) Tetracyclines are known to chelate zinc from matrix metalloproteinases. It is possible their chelating activity may help inhibit COVID-19 infection by limiting its ability to replicate in the host. (2) As seen with dengue virus, tetracyclines may also be able to inhibit the replication of positive polarity single-stranded RNA viruses, such as COVID-19. (3) Tetracyclines are also modulators of innate immunity (anti-inflammatory activity), a property that has been used to treat inflammatory skin diseases for many years. They could therefore participate in limiting the cytokine storm induced by COVID-19. Moreover, the lipophilic nature of tetracyclines and their strong pulmonary penetration could allow them to inhibit viral replication at this level. Among the tetracyclines, doxycycline has three advantages: its long safety history (side effects are uncommon with no notable risks), its short treatment duration and its low cost.Methods: The trial will involve 330 patients who are positive for SARS-CoV-2 infection and have one or more risk factors for worsening the disease. These patients will be included as outpatients for early treatment of illness. For logistical reasons and in order to be able to standardise the study as much as possible, recruitment will take place in 6 hospital departments covering the whole of France. For 14 days they will be given either 200mg of doxycycline a day or placebo. Our hypothesis is a considerable reduction in the number of patients hospitalised due to COVID-19 thanks to the treatment of doxycycline.Discussion: This study could have an impact on the overcrowding of patients with COVID-19 at the hospital which is one of the major world-wide problems of this pandemic. This treatment would therefore contribute to supporting the deconfinement strategy by blocking the viral infection early and reducing the infectious period.Trial Registration: On ClinicalTrials.gov, registration number NCT04371952, first published on 30 April 2020.

Average duration of treatment with antipsychotics among concession card holders in Australia

Objective: To analyse average treatment duration with antipsychotics reimbursed for concession card holders under the Pharmaceutical Benefits Scheme; the proportion of initial prescribing by general practitioners, psychiatrists and other physician; and the trend in drug choice in Australia. Method: Based on a representative 10% sample of patients receiving Pharmaceutical Benefits Scheme prescriptions since 2005, antipsychotics redeemed by concession card holders in the period from 2010 to 2013 were analysed. A 5-year baseline period was used to exclude prevalent users from incident users. Treatment duration was estimated using the epidemiological equation: prevalence/incidence = average duration. Results: The overall average treatment duration was 3.0 years, ranging from 1.5 years in patients aged 75 years and older to more than 4 years among patients aged 25–64 years. The most commonly used antipsychotics were olanzapine, risperidone and quetiapine, with average duration of 2.9, 2.1 and 1.7 years, respectively. Amisulpride was used longest with an average duration of 3.7 years. Quetiapine is currently the most prescribed antipsychotic and the main antipsychotic prescribed by psychiatrists to new users. The increased prescribing of quetiapine among general practitioners explains the rapid increase in the overall use of quetiapine. General practitioners initiated therapy in about 70% of cases, while psychiatrists and other physicians in about 15% each. In children younger than 15 years of age, paediatricians initiated such treatment in 47%. Conclusion: General practitioners both initiate and maintain treatment with antipsychotics for most adults, while paediatricians mainly begin such treatment in children. The substantial increase in use of quetiapine among general practitioners, along with the short treatment duration for quetiapine, strengthens a concern about antipsychotics increasingly used for less severe disorders. Increased collaboration between paediatricians and psychiatrists regarding the youngest and between general practitioners and psychiatrists or geriatricians regarding adults and older patients seems required.

Models for Measuring Induced Affective Change: Some Neglected Methodological Considerations

The measurement of affect and other personality characteristics has usually been carried out in a predispositional, correlational framework. However, the measurement of varying levels of affect induced by different treatments during an experiment has received less attention because of the methodological problems involved. Typical weaknesses of research concern test-retest effects, test sensitization, test-wiseness, lack of control groups, inductive construct validity of measures, emotional boundedness, purging effects, and short treatment duration. A manageable design paradigm for gaining sound results on experimentally induced affect is presented.