Bright Times: Issue 1

Clinical Focus

Escitalopram: Translating Molecular Properties into Clinical Benefit

Depression is linked to reduced serotonergic activity,¹ and a number of drugs that directly or indirectly enhance serotonergic activity have been used in its management. Selective serotonin reuptake inhibitors (SSRIs) such as escitalopram have superior clinical efficacy in major depressive disorder.² Escitalopram, an  S-enantiomer of citalopram causes a high degree of stereo-selectivity,³ causes most of the inhibitory activity of racemic citalopram.^{3, 4} Escitalopram has the affinity for primary as well as allosteric sites on serotonin transporter (SERT).³

Serotonin transporters are present on terminals and cell bodies of the presynaptic serotonergic neurons. SERTs re-uptake excess serotonin (5-hydroxytryptamine, 5HT) from the synaptic cleft in to presynaptic neurons. This regulates optimal serotonin activity at post-synaptic serotonin receptors. SERT has high affinity primary or orthosteric binding site for SERT inhibitors like SSRIs. The binding of an antagonist at orthosteric site blocks the interaction of agonist/substrate and receptor/transporter. There is also a more functional role of antagonists, which is their interaction with one or more sites other than orthosteric site viz.allosteric binding site/s.³ The ligand binding at allosteric site in turn regulate the affinity characteristics at orthosteric site. Escitalopram has been demonstrated to have high affinity for orthosteric and allosteric binding sites ofSERT.^{3, 5}

The inactive enantiomer of citalopram (R-citalopram) antagonizes the binding of S-enantiomer (escitalopram) at allosteric site on SERT.^{3, 4} Thus, the binding of escitalopram to the allosteric site is beneficial to patients with depression due not only to increase in serotonin levels at the synapse but also other mechanisms.

Escitalopram: Allosteric Serotonin Reuptake Inhibitor

Escitalopram causes a more complete inhibition of serotonin reuptake by binding to both orthosteric and allosteric binding sites. Hence, there is a higher bioavailability of serotonin at target.³ This high bioavailability of serotonin results in faster 5-HT_1A auto-receptor desensitization and hence greater efficacy and faster onset of action.⁶

Allosteric Inhibition by Escitalopram

Allosteric inhibition by escitalopram has been well evaluated from several molecular pharmacological studies and target site structural characterisation studies.³

Escitalopram and SERT-allosteric site interaction enhances escitalopram binding at the orthosteric site by decreasing dissociation rate from the orthosteric site. The clinically significant pharmacodynamic properties of escitalopram include³:

• Increased serotonergic neurotransmission leads to neuronal remodeling, neuroadaptation, increase in brain derived neurotrophic factor (BDNF) levels, and neurogenesis
• Prolongation of escitalopram own dissociation from the orthosteric site
• Escitalopram can influence the modulation of interactions between SERT
• The association of escitalopram to the orthosteric site is inhibited by R-citalopram
• R-citalopram may interferes with the allosteric function of escitalopram and its ability to inhibit 5-HT reuptake.

The clinically significance of these pharmacodynamic properties of escitalopram are given in Figure 1³.

Of the available SERT related antidepressants, escitalopram and paroxetine are the only drugs that  show positive allosteric mechanism, but this property is weaker with paroxetin compared to escitalopram.³

Benefits of Escitalopram as Compared to Racemic Mixture

In radio-ligand binding study with [³H]-escitalopram has demonstrated that R-citalopram attenuates the association rate of escitalopram to human SERT [hSERT] in a dose dependent manner (Figure 2).⁶

The R-citalopram 250 mg/kg i.v was shown to have blocked the suppressant effect on neuronal firing activity of both escitalopram 100 mg/kg i.v. and paroxetine 500 mg/kg i.v. but not fluoxetine (10 mg/kg i.v.,) (Figure 3.)⁶

Figure 3. Suppressant effect of SSRIs on the firing activity of murine serotonergic neurons in presence or absence of R-citalopram

The data are expressed as percentage of basal values. The numbers at the bottom of the columns indicate the number of rats tested (in each rat only one neuron was tested). * p<0.05 and ** p<0.01, using the Mann–Whitney U test.

To Sum it up...

The SERT is the main site of action for a number of antidepressant drugs such as SSRIs. It exhibits both primary and allosteric sites for interaction with ligands. Ligand interaction at allosteric site modulates the binding kinetics at the primary site. Antidepressant drugs such as, escitalopram shows most potent allosteric interactions at SERT, hence it is also known as allosteric serotonin reuptake inhibitor. Allosteric interactions at SERT exhibit high degree of stereo selectivity.

The allosteric mechanisms cause escitalopram to have higher dissociation half-life at primary site. This results in increase in the serotonin levels at the target site and faster onset of action. Thus, allosteric inhibition of escitalopram leads to its clinically proven beneficial effects in patients with depression.

References

1. S?nchez C. The pharmacology of citalopram enantiomers: The antagonism by R-citalopram on the effect of S-citalopram.Basic Clin Pharmacol Toxicol. 2006;99(2):91-5.
2. Ali MK, Lam RW. Comparative efficacy of escitalopram in the treatment of major depressive disorder. Neuropsychiatr Dis Treat. 2011;7:39-49.
3. Zhong H, Haddjeri N, S?nchez C. Escitalopram, an antidepressant with an allosteric effect at the serotonin transporter--a review of current understanding of its mechanism of action. Psychopharmacology (Berl). 2012;219(1):1-13.
4. S?nchez C, Bergqvist PB, Brennum LT, et al. Escitalopram, the S-(+)-enantiomer of citalopram, is a selective serotonin reuptake inhibitor with potent effects in animal models predictive of antidepressant and anxiolytic activities. Psychopharmacology (Berl). 2003;167(4):353-62.
5. Chen F, Larsen MB, S?nchez C, et al. The S-enantiomer of R,S-citalopram, increases inhibitor binding to the human serotonin transporter by an allosteric mechanism. Comparison with other serotonin transporter inhibitors.Eur Neuropsychopharmacol. 2005;15(2):193-8.
6. Mansari ME, Wiborg O, Mnie-Filali O, Benturquia N, S?nchez C, Haddjeri N.Allosteric modulation of the effect of escitalopram, paroxetine and fluoxetine: in-vitro and in-vivo studies. Int J Neuropsychopharmacol. 2007;10(1):31-40.

Challenges in Depression Management

Anxiety and Residual Depressive Symptoms are linked to New-onset Suicidal Ideation in Patients with MDD

Suicide risk evaluation is considered as one of the most challenging assessments of patients with major depressive disorder (MDD), despite the advances in psychiatric treatment. Even after adequate treatment, suicidal ideation continues to be a residual symptom in few patients, while suicidal ideation emerges in others after the treatment has started.¹ Poor response to antidepressant treatment has also led to the persistence or emergence of suicidal ideation during the course of treatment.² During the early course of antidepressant treatment, severity of depression and young age are the risk factors for the onset of suicidal ideation. Various studies have focused on the early course of antidepressant treatment in evaluating emergence or persistence of suicidal ideation. But, initial evaluation may be insufficient in predicting the emergence of suicidal ideation during the maintenance period. Therefore, evaluating the new-onset suicidal ideation in the long-term in the real-world setting is essential.¹

Increased Emergence or Persistence of Suicidal Ideation in MDD after 6 Months of Antidepressant Therapy¹

Researchers evaluated factors associated with emergence or persistence of suicidal ideation 6 months after initiating antidepressant treatment in MDD patients. Patients with MDD (n=300) defined by DSM-IV-TR criteria were interviewed at baseline and 6 months later. Findings revealed that:

• Around 10.9% of patients without suicidal ideation at baseline and 28.4% with suicidal ideation at baseline reported suicidal ideation during the 6-month.
• Patients without suicidal ideation at baseline showed a higher rate of symptom improvement at 6-month, including remission and partial response. Baseline and follow-up symptom characteristics of patients are shown in Table 1.
• After controlling for age, sex, baseline severity of suicide risk, depression and lifetime history of suicide attempts:
  • In those without suicidal ideation at baseline, emergence of suicidal ideation was found to be significantly associated with anxiety at baseline (t=2.127, p=0.039) and severity of depression symptoms at 6 month (t=-3.028, p=0.004)
  • In those with suicidal ideation at baseline, persistence of suicidal ideation was found to be associated with moderate to severe depression at 6 month (t=-4.962, p<0.001).

Therefore, anxiety and residual depressive symptoms were warning signs of suicidal ideation in patients with MDD.

SD, standard deviation; HAM-D, the Hamilton Depression Rating Scale; BDI, BAI, Beck's anxiety inventory; MDQ, mood disorder questionnaire; HCL-32, hypomania symptom checklist-32; PHQ-9,patient health questionnaire-9

Summary

Suicidal risk evaluation is challenging in patients with MDD. Suicidal thoughts continue to emerge in patients even after adequate anti-depressant treatment. Patients with suicidal ideation at baseline report high risk of suicidal ideation compared to those without suicidal ideation. Emergence of suicidal ideation is associated with anxiety and persistence with severity of depression. Therefore, anxiety and residual depressive symptoms are associated with new-onset suicidal ideation in MDD.

References

1. Baek JH, Heo JY, Fava M et al. Anxiety symptoms are linked to new-onset suicidal ideation after six months of follow-up in outpatients with major depressive disorder. J Affect  Disord. 2015;187:183-7.
2. Courtet P, Jaussent I, Lopez-Castroman J et al. Poor response to antidepressants predicts new suicidal ideas and behavior in depressed outpatients. Eur Neuropsychopharmacol. 2014; 24(10): 1650-8.

Talking Point

Online Social Networking Addiction and Depression

Social media is being used increasingly across the world among young adults. A new research has suggested that there is an association between the use of social media and depression. In a recent survey of 1,787 adults between the ages 19 to 32 about social media use and depression, those with highest time spent on social media had significantly increased odds of depression as compared to those who spent the lowest time spent on social media. Hence, it can be said with certainty that social media use can be significantly associated with increased depression.¹

According to Lin et al, depression due to exposure to social media may turn fuel more use of social media. Also, exposure to highly idealized representations of peers on social media makes envy and be the cause of distorted belief that others are happier and have more successful lives.

Also, social media use could be fueling "Internet addiction," a proposed psychiatric condition closely associated with depression. Increased time spent on social media can also increase a person’s risk of being exposed to cyber-bullying or other similar negative interactions, which leads to depression. However, researchers are of opinion that it is not just the use of social medic, but an addiction to social media that connects it to depression.

The world of psychiatry has over the last decade seen a substantial increase in addictive technological behaviours.  Also, there is a strong association between addictive use of technology and comorbid psychiatric disorders.  In a study of 23,533 adults (mean age 35.8 years, ranging from 16 to 88 years) was conducted to examining if demographic variables, symptoms of attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), anxiety, and depression could explain variance in addictive use (i.e., compulsive and excessive use associated with negative outcomes) of two types of modern online technologies: social media and video games.

Researchers found correlations between symptoms of addictive technology use and mental disorder symptoms and age was inversely related to the addictive use of these technologies. A significant finding of the study was that being male was significantly associated with addictive use of video games, while being female was significantly associated with addictive use of social media.²

However, mental health experts are of opinion that Internet addiction (Internet addiction disorder, IAD) , may have same effects as substance abuse or gambling addiction.  In an article published in 2012 by the in Current Psychiatry Reviews, researchers reported that Internet addiction "ruins lives by causing neurological complications, psychological disturbances, and social problems.

Given the increasing use of social media, psychiatrists should identify mechanisms to make critical intervention that address social media use and depression. Also, clinicians should be aware of these associations, which may be valuable in treating patients with depressive disorders. For instance, treating clinician can enquire about social media use patterns and determine if those patterns are maladaptive. This may help in managing individuals with depressive disorder better.

References

1. Lin LY, Sidani JE, Shensa A, et al. Association between social media use and depression among u.s. young adults. Depression and Anxiety, 2016; DOI: 10.1002/da.22466.
2. Andreassen SC, Billieux J, Griffiths MD, et al. The relationship between addictive use of social media and video games and symptoms of psychiatric disorders: A large-scale cross-sectional study. Psychol Addict Behav. 2016; 30(2):252-62.
3. Cash H, Rae CD, Steel AH, Winklerb A. Internet Addiction: A brief summary of research and practice. Curr Psychiatry Rev. 2012; 8(4): 292–8.

Current News

Eating- and Weight-related Factors Linked to Depressive Symptoms in Adulthood

A study published recently in the journal Eating Behaviours has reported that restrained eating is significantly associated with depressive symptoms in both men and women. According to the researchers, eating- and weight-related disturbances (EWRDs) are key factors associated with depressive symptoms. This study by Rawana et al was conducted to determine the association between EWRDs, body appreciation, and depressive symptoms among emerging adults. The study included 473 women and 35 men who completed measures of restrained eating, emotional eating, external eating, drive for muscularity, body appreciation, and depressive symptoms.

The key finding of the study was that the restrained eating was significantly associated with depressive symptoms. However, emotional and external eating was significantly related to depressive symptoms only in women.

Further, in both men and women, body appreciation was also associated negatively with depressive symptoms. The researchers are of opinion that the clinicians should assess for EWRDs in emerging adults.

Eat Behav. 2016; 22: 101-8

Higher High-density Lipoprotein Cholesterol Related to Increased Risk of Depressive Symptoms

Serum cholesterol has been shown to be associated with late-life depression. In a recent study researchers assessed the associations between serum lipid levels and depressive symptoms in middle-aged adults. The study included 8207 participants aged 40-64 years who completed a questionnaire about their experience of depressive symptoms over the last year. Blood samples after at least 8 h fasting was taken. The serum levels of total cholesterol (TC), high-density

lipoprotein cholesterol (HDL-C), and triglycerides (TG) were measured  and low-density lipoprotein cholesterol (LDL-C) level was calculated. After analysis of the data, researchers are of the opinion that higher HDL-C level was significantly associated with increased risk of depressive symptoms (odds ratio=1.32; 95% confidence interval=1.09-1.60).

Psychiatry Res. 2016; 241: 172-4

Depression and Anxiety is Significant in Patients with Somatoform Disorders

In a study researchers compared the severity of depression and anxiety in patients (n=152, group 1) with somatoform disorders, panic disorder (n=56, group 2), other depressive/anxiety disorders (n=85, group 3) and compared them with healthy controls (179). These four groups reported on the Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI) for depressive and anxiety symptoms, respectively.

According to the DSM-IV-TR-based diagnostic interviews, we recruited 152 subjects with somatoform disorders (SG), 56 with panic disorder (PG), 85 with other depressive/anxiety disorders (OG), and 179 without any psychiatric disorder (NG).

Researchers then determined the effects of demographic factors and psychiatric diagnoses on depressive and anxiety symptoms separately. BDI-II scores were not significantly different in Groups 1, 2, and 3 but were higher than control group. Groups 1 and 2 had the highest BAI scores, whereas control group had the lowest. The factors associated with BDI-II were gender, residential location, somatoform disorders, panic disorder, major depressive disorder, and generalized anxiety disorder. The BAI was significantly associated with somatoform disorders, panic disorder, and MDD. The researchers are of opinion that in patients with somatoform disorders, clinical assessment of depressive and anxious is essential.

Psychiatry Res. 2016; 241: 165-71