Update on GPCR-based targets for the development of novel antidepressants

Traditional antidepressants largely interfere with monoaminergic transport or degradation systems, taking several weeks to have their therapeutic actions. Moreover, a large proportion of depressed patients are resistant to these therapies. Several atypical antidepressants have been developed which interact with G protein coupled receptors (GPCRs) instead, as direct targeting of receptors may achieve more efficacious and faster antidepressant actions. The focus of this review is to provide an update on how distinct GPCRs mediate antidepressant actions and discuss recent insights into how GPCRs regulate the pathophysiology of Major Depressive Disorder (MDD). We also discuss the therapeutic potential of novel GPCR targets, which are appealing due to their ligand selectivity, expression pattern, or pharmacological profiles. Finally, we highlight recent advances in understanding GPCR pharmacology and structure, and how they may provide new avenues for drug development.

Do Newer Antidepressant Drugs Really Have Reduced Side Effects? Examining a Random “Real World” Sample of 300+ Receivers of Medications

Newer antidepressant drugs are frequently cited as having reduced side effect profiles to that of their older counterparts. However, recent studies have begun to dispute this claim, citing selective sampling, short clinical trials, and clinical trial environments as influencing reported outcomes. At present, little research on antidepressant side effects draws on RWD (Real-World Data). Despite this, interest in examining RWD samples for antidepressant drug side effects is increasing as of 2020. The reported study asked a random sample of 300+ individuals taking a variety of different antidepressant medications to complete online drug side effect self-report scales with previously high validity. Newer antidepressants belonging to the atypical antidepressant drug class were reported as having only slightly reduced side effects of weight gain compared with older SSRI-class medications. No reduced side effects of increased depression, anxiety, sexual dysfunction (SD), sleepiness, or suicidal ideation (SI) were found for the newer atypical-class medications vs older SSRI-class agents. Medication adherence did not differ significantly between SSRI and atypical classes. No evidence for reduced side effects was found for newer SSRI and atypical antidepressants vs older same-class drugs when comparing six new and old medications drawn from atypical and SSRI classes. However, atypical antidepressants were associated with increased use of adjunct medications to bolster primary treatment.

Depression increases the risk of inflammatory bowel disease, which may be mitigated by the use of antidepressants in the treatment of depression

ObjectiveDepression is associated with IBD, but the effect of antidepressants on IBD has been sparsely studied. We assessed the impact of depression and antidepressant therapies on the development of IBD.DesignThe Health Improvement Network (THIN) was used to identify a cohort of patients with new-onset depression from 1986 to 2012. THIN patients who did not meet the defining criteria for depression were part of the referent group. The outcome was incident Crohn’s disease (CD) or ulcerative colitis (UC). Cox proportional hazards modelling was performed to evaluate the rate of Crohn’s disease or UC development among patients with an exposure of depression after controlling for age, sex, socioeconomic status, comorbid conditions, smoking, anxiety and antidepressant use including atypical antidepressants, mirtazapine, monoamine oxidase inhibitors (MAOI), serotonin norepinephrine reuptake inhibitors (SNRI), selective serotonin reuptake inhibitors (SSRI), serotonin modulators; and tricyclic antidepressants (TCA).ResultsWe identified 403 665 (7.05%) patients with incident depression. Individuals with depression had a significantly greater risk of developing CD (adjusted HR=2.11, 95% CI 1.65 to 2.70) and UC (adjusted HR=2.23, 95% CI 1.92 to 2.60) after controlling for demographic and clinical covariates. SSRI and TCA were protective against CD, whereas mirtazapine, SNRI, SSRI, serotonin modulators and TCA were protective for UC.ConclusionPatients with a history of depression were more likely to be diagnosed with IBD. In contrast, antidepressant treatments were selectively protective for Crohn’s disease and UC. These results may impact counselling and management of depression and IBD.

Adherence to and Persistence with Antidepressant Medication during Pregnancy: Does It Differ by the Class of Antidepressant Medication Prescribed?

Objective: Pregnant women are often concerned about the impact of medication use on their pregnancy, such as congenital abnormalities. This study examined the rate of adherence to and persistence with antidepressant medications during pregnancy based on the class of antidepressants prescribed. Methods: Women who gave birth between 2012 and 2015 in Alberta, Canada; had ≥1 diagnosis of depression within 1 year of preconception in outpatient physician claims, emergency department, or hospitalization administrative data; and were adherent (medication possession ratio ≥80%) to ≥2 consecutive antidepressant prescriptions during the preconception year ( n = 1865) were included in this retrospective cohort study. The rates of adherence and persistence (prescription refill gap ≤30 days) were calculated by antidepressant class and were compared using chi-square tests. Results: During pregnancy, 834 (44.7%; 95% CI, 42.4% to 47.0%) women discontinued antidepressants. Among those continuing antidepressants, the overall rate of adherence was 62.6% (95% CI, 59.4% to 65.7%). The rate differed significantly by medication class ( P < 0.0001), with a rate of 75.1% (95% CI, 68.3% to 80.9%) for serotonin-norepinephrine inhibitors, 60.9% (95% CI, 57.2% to 64.5%) for selective serotonin reuptake inhibitors, 42.8% (95% CI, 19.9% to 69.3%) for nonselective monoamine reuptake inhibitors, and 37.5% (95% CI, 22.5% to 55.4%) for atypical antidepressants. Only, 40.7% (95% CI, 37.5 to 44.1) of women were persistent with antidepressants for the full pregnancy period—the rate differed significantly by medication class ( P < 0.0001). Conclusions: Adherence to and persistence with antidepressants is low during pregnancy and varies by medication class. Low adherence and persistence can interfere with a therapeutic effect of antidepressants, which may contribute to the worsening of depression symptoms.

The role of selective serotonin reuptake inhibitors in preventing relapse of major depressive disorder

The objective of this review was to evaluate the efficacy of selective serotonin reuptake inhibitors (SSRIs) and SSRIs compared with other treatment modalities in preventing relapse after an episode of major depressive disorder (MDD). An Ovid MEDLINE and PsycINFO search (from 1987 to August 2017) was conducted using the following terms: selective serotonin reuptake inhibitors, antidepressants, depression, prevention, prophylaxis, relapse and MDD. Using predefined criteria, two authors independently selected and reached consensus on the included studies. Sixteen articles met the criteria: 10 compared the relapse rate of selective SSRIs with placebo or other SSRIs; one discussed the effectiveness of SSRIs plus psychotherapy, two compared SSRI versus tricyclic antidepressants (TCAs), two were mainly composed of TCAs plus psychotherapy, and one compared SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs). According to the included studies, the relapse risk in adults was lower when SSRIs were combined with psychotherapy. Results comparing SSRIs and SNRIs were inconclusive. TCAs may be equally as effective as SSRIs. Atypical antidepressants (mirtazapine and St John’s Wort) had no significant difference in efficacy and remission rates compared with SSRIs. Escitalopram appeared to fare better in efficacy than other SSRIs, owing to a higher prophylactic efficacy and lower side effects; however, according to the current data, this difference was not significant. To conclude, this review provides evidence that continuing SSRIs for 1 year reduces risk of MDD and relapse. Furthermore, the combination of SSRIs and cognitive behavioural therapy may effectively reduce relapse. Escitalopram appeared to yield better results and fewer side effects than did other SSRIs or SNRIs. The effectiveness in reducing relapse of SSRIs was similar to that of TCAs and atypical antidepressants.

Antidepressants in critical illness

Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and atypical antidepressants are considered first-line agents for depression in the intensive care unit (ICU) setting, and are preferred over older antidepressants due to their more benign side effect profile and tolerability. This chapter reviews the literature on the use of antidepressants in the ICU. Common side effects of SSRIs include insomnia and gastrointestinal discomfort, while citalopram may uniquely cause prolongation of the QTc interval. All SSRIs carry a risk for the development of serotonin syndrome following overdose. SNRIs are similar to SSRIs in their side effect profile, although they are more likely to cause hypertension. Mirtazapine is strongly associated with sedation and weight gain. Stimulants may also be used to treat depression in the medically ill, and can be particularly effective in treating apathy, low energy, and loss of appetite. Monotherapy is typically the initial treatment strategy and low doses are generally recommended in the ICU setting. Efficacy may not be apparent for up to 8 weeks. Patients who have been taking an antidepressant prior to their arrival in the ICU should continue on the medication so as to prevent discontinuation syndrome. Delirium may warrant cessation of the antidepressant and potentially dangerous medication interactions also need to be evaluated. At present, there is no evidence to suggest that an antidepressant should be initiated after a significant physical or emotional trauma.