FormalPara Key Summary Points

A thorough clinical assessment of depression, including symptom profile, is required to effectively tailor treatment.

Clinicians should have a high index of suspicion for anxiety symptoms in patients with depression, and should treat anxious depression with vigilance and vigour.

Severe anxiety in a depressed patient is associated with increased suicidality and worse outcomes compared with non-anxious depression.

Agomelatine is an effective antidepressant with benefits on both symptoms and psychosocial function in patients with generalised anxiety disorder, as well as in patients with depression, including depression with severe anxiety symptoms.

Irrespective of the antidepressant used, the combination of psychotherapy and pharmacotherapy is more effective for depression than either treatment modality on its own.

Introduction

Depression is not a single homogenous entity; rather it is a condition that may have a number of different symptom domains, including anxiety, and its treatment should be tailored accordingly. Indeed, the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [1] and the 11th revision of the International Classification of Diseases (ICD-11) [2] include specifiers to improve the precision of the diagnosis of depression. In addition, the Research Domain Criteria framework provides an alternative approach that moves the focus away from diagnostic entities, while focussing on the underlying pathophysiological processes that account for transdiagnostic and coexisting symptoms [3].

The fact that there are multiple ways in which an individual patient can meet the diagnostic criteria for major depressive disorder (MDD) may contribute to current guidelines having only partial treatment success. The aims of the current commentary are to outline how a more detailed clinical characterisation of MDD may be useful in individualising treatment decisions, and to review the evidence base for pharmacotherapy and psychotherapy in patients with MDD and symptoms of anxiety. The discussion of pharmacotherapy focuses on agomelatine, and its efficacy in this specific patient population.

This commentary is based on content from a virtual symposium sponsored by Servier at the 33rd International College of Neuropsychopharmacology (CINP) World Congress in June 2022, Taipei, Taiwan. The commentary is based on previously conducted studies and does not contain any new studies with human participants or animals performed by the author.

Assessment of the Patient with Depression

In order to personalise the treatment of depression, it is essential to conduct a thorough clinical assessment and history taking [4]. This should cover a range of domains, including the patient’s symptom profile, clinical subtypes, severity and staging, personality factors, antecedent and concurrent psychiatric comorbidity, physical comorbidity, neurocognitive function, traumatic stressors in early life (e.g. trauma) or recently (e.g. bereavement), and protective factors [4]. Protective factors contribute to resilience, and can be remembered using the acronym SOCIAL, for Social resources, Occupation, Children and family, Income and material resources, Abilities/appearance/health, etc., and Love/sex in an intimate relationship [5]. However, such clinical assessments need to be culturally congruent.

During clinical assessment, anxiety is identified by the presence of at least two of the following symptoms: feelings of being keyed up or tense, having difficulty concentrating, restlessness, and fear that something awful may happen or that the patient may lose control [1]. There is evidence that the neurobiological profile of depression with anxiety differs from that of non-anxious depression, with greater dysregulation of immune and hypothalamic–pituitary–adrenal axis function, more marked cortical thinning, and changes in the functional pattern of corticolimbic pathways [6]. The presence of anxiety in a depressed patient calls for treatment to be undertaken with increased vigilance and vigour because anxious depression is associated with greater severity of depression [7], increased suicidality [7] and worse outcomes [6] compared with depression without concomitant anxiety.

Pharmacotherapy Considerations

There are surprisingly few data comparing the efficacy of antidepressant therapies in patients with anxious depression. However, a large network meta-analysis of antidepressant treatments found that all were significantly more effective than placebo for the treatment of depression (not specifically anxious depression), and that agomelatine, citalopram, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine and vortioxetine were more effective than other antidepressants [8]. This network meta-analysis also found that agomelatine, citalopram, escitalopram, fluoxetine, sertraline and vortioxetine were better tolerated than other antidepressants, based on the number of patients discontinuing treatment because of adverse events [8].

Focus on Agomelatine

Agomelatine, a first-in-class antidepressant with a non-monoaminergic mechanism of action was approved in Europe in 2009 for the treatment of MDD [9]. Agomelatine is both a melatonergic agonist and an antagonist of serotonin 2C (5-HT2C) receptors [9]. It is thought that these two mechanisms work synergistically to improve depressive symptoms, restore circadian rhythms, and favourably influence anxiety, sleep and sexual function [9]. Recent work has suggested a number of neurobiological mechanisms which may be involved in the response of anxiety symptoms to agomelatine [10].

Clinically, agomelatine has been shown to have two major effects: (1) relieving depressive symptoms [8], and (2) supporting symptomatic and functional recovery [11, 12]. In a network meta-analysis comparing different antidepressant agents, agomelatine was significantly more effective for depression than the reference comparator (reboxetine), which was not demonstrated for some of the other antidepressants in the analysis (Fig. 1) [8]. Moreover, in placebo-controlled studies, agomelatine proved to be effective in achieving both symptomatic and functional remission (Fig. 2a) and in maintaining remission over time (Fig. 2b) [11, 12].

Fig. 1
figure 1

Results of a network meta-analysis showing the comparative effect of different antidepressants compared with reboxetine (reference agent) in patients with depression [8]. *Moderate quality of evidence. †Low quality of evidence. ‡Very low quality of evidence. CrI credible interval, OR odds ratio. Reproduced in modified format from [8] Cipriani et al. (2018) (Supplementary appendix), under a Creative Commons Attribution 4.0 International License

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Fig. 2
figure 2

Functional and symptomatic remission in patients receiving agomelatine. a Proportion of patients achieving symptomatic and functional remission during 6–8 weeks of treatment with agomelatine or placebo [12]; and b Proportion of patients with functional remission over 6 months of treatment with agomelatine or placebo [11]. **p < 0.01 versus placebo. ***p < 0.001 versus placebo. HAM-D Hamilton Depression Rating Scale, SDS Sheehan Disability Scale

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A 2021 network meta-analysis of 42 randomised clinical trials of depression examined the effect of different antidepressants on functional outcomes, as measured by the Sheehan Disability Scale (SDS), in patients with MDD [13]. Using the surface area under the cumulative ranking curve to compare agents, agomelatine ranked best in terms of functional improvement in the domains of work/school, social/leisure activities, and family/home responsibilities [13].

The benefits of agomelatine on symptomatic and functional recovery have also been demonstrated in patients with generalised anxiety disorder (GAD). A meta-analysis of three studies in which patients with GAD were randomised to placebo or agomelatine found that agomelatine significantly ameliorated anxiety symptoms compared with placebo, with a mean 6.30-point difference in the Hamilton Anxiety Rating Scale (HAM-A) [14] in the overall cohort and a 6.49-point difference in the subgroup with the most severe GAD at baseline (HAM-A score ≥ 25). This was associated with a significantly higher rate of symptomatic response (≥ 50% reduction in HAM-A score) and remission (total HAM-A total score ≤ 7 at the last post-baseline evaluation) in the agomelatine- than the placebo-treated patients. In the subgroup with severe GAD, a symptomatic response was seen in 67.6% of patients receiving agomelatine versus 31.6% of those receiving placebo (p < 0.001), and symptomatic remission was seen in 38.2% versus 17.5%, respectively (p < 0.0001) [14]. Rates of functional response (SDS total score ≤ 12) and remission (SDS total score ≤ 6) were also significantly higher in patients receiving agomelatine than in those receiving placebo, including in the severe GAD subgroup, which showed functional response rates of 77.6% versus 41.2%, respectively (p = 0.003), and functional remission rates of 54.4% versus 23.7% (p < 0.0001), respectively [14].

GAD is characterised by both psychic and somatic symptoms. In a pooled analysis of three randomised placebo-controlled trials of agomelatine in patients with GAD, the subgroup of patients with prominent somatic anxiety (HAM-A somatic subscore ≥ 14) derived a significant benefit from agomelatine compared with placebo across all domains of anxiety (HAM-A total score, somatic subscore, and psychic subscore), as well as in functional domains (SDS total score; Fig. 3) [15].

Fig. 3
figure 3

Somatic, psychic and functional benefits of agomelatine over placebo in a pooled analysis of three randomised controlled trials [15]. Analysis included patients with generalised anxiety disorder and prominent somatic anxiety (HAM-A somatic subscore ≥ 14; n = 280). HAM-A Hamilton Anxiety Rating Scale, SDS Sheehan Disability Scale

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Agomelatine has also been shown to be efficacious and well tolerated in patients with MDD, including those with concomitant anxiety symptoms [16]. A pooled analysis of data from six agomelatine studies (three placebo-controlled and three with active comparators—fluoxetine, sertraline and venlafaxine) found that agomelatine was significantly more effective than placebo at relieving the anxiety subscore on the Hamilton Depression Rating Scale (HAM-D; items 10 and 11) [16]. The difference between agomelatine and placebo was even more marked in the subgroup of patients with more severe anxiety symptoms at baseline (i.e. those with a HAM-D score on items 10 and 11 of ≥ 5) [16].

Psychotherapy Considerations

There are surprisingly few comparative data on the efficacy of pharmacotherapy versus psychotherapy for anxious depression. However, a meta-analysis by Cuijpers and colleagues found that pharmacotherapy and psychotherapy were similarly effective in achieving a response in patients with depression (i.e. a 50% reduction in depressive symptomatology) [17]. The relative risk (RR) for response with psychotherapy versus pharmacotherapy was 0.99 [95% confidence interval (CI) 0.92–1.08], but the combination of psychotherapy and pharmacotherapy was significantly more effective than either form of therapy alone [RR of 1.27 (95% CI 1.14–1.39) versus psychotherapy alone and RR of 1.25 (95% CI 1.14–1.7) versus pharmacotherapy alone]. Similar results were seen in terms of remission, with the RR for psychotherapy versus pharmacotherapy being 1.01 (95% CI 0.93–1.01), while the RR for the combination versus psychotherapy was 1.22 (95% CI 1.08–1.9), and versus pharmacotherapy was 1.23 (95% CI 1.09–1.39). In addition, acceptability (based on study dropout for any reason) was significantly better with combined treatment [RR 1.23 (95% CI 1.05–1.45)] and psychotherapy alone [RR 1.17 (95% CI 1.02–1.32)] versus pharmacotherapy alone, which may be related to the tolerability of antidepressant agents. The combination of pharmacotherapy and psychotherapy may maximise the benefits of pharmacotherapy in achieving symptomatic relief and of psychotherapy in consolidating early gains into long-term remission.

The World Mental Health Surveys, conducted among 80 332 individuals from 16 countries, found that patients with a lifetime history of depression often have to repeatedly seek treatment until they find a therapy that is helpful [18]. Overall, 68.2% of these patients obtained treatment that they perceived as helpful, but the remaining 31.8% stopped seeking treatment when therapies did not provide the relief they were looking for. Among those projected to persist through 10 health professionals, 93.9% would receive a treatment that helped them, but only 21.5% of patients would persist through this number of treatment attempts. The number of comorbid anxiety disorders did not affect these results [18]. Analogous data on GAD also emphasise the importance of persisting with treatment [19].

Conclusions

Major depression requires individualised assessment including assessment of anxiety, and a personalised approach to therapy that aims at both symptomatic and functional improvement. Patients with concomitant anxiety symptoms are more likely to suffer from severe depression, attempt suicide, and have worse outcomes than patients without anxiety symptoms. Such individuals deserve robust intervention, and data from network meta-analyses of interventions for depression may be useful in guiding the choice of antidepressant. In addition, concomitant psychotherapy may increase the likelihood of response and remission. Furthermore, the importance of persistence with treatment should be emphasised to patients.