The Use of Melatoninergic Antidepressants for Stabilization of Remission in Depression Comorbid with Alcohol Abuse, Anxiety or Neuropsychiatric Disorders: A Systematic Review

INTRODUCTION

Depression is one of the most prevalent mental disorders. In a global survey conducted by the WHO (World Health Organization), between 13.7% and 22% of respondents across various countries reported experiencing symptoms of depression in the preceding 12 months [1]. The prevalence of depression has been steadily increasing in recent years, partly due to the pandemic [2]. The presence of depressive symptoms significantly raises the risk of developing other mental and somatic disorders, including anxiety, substance dependence, neurodegenerative diseases, and other neurological conditions [3, 4]. According to some estimates, the comorbidity of depression with other mental health disorders ranges from 36.7% to 73.5% [5]. The presence of a comorbid condition with depression complicates treatment. It increases healthcare utilization while reducing adherence to treatment, makes it more difficult to select appropriate pharmacological therapies, and overall worsens disease outcomes [6]. At the same time, successful treatment of depressive symptoms is associated with a significant reduction in the clinical symptoms of the comorbid condition [7]. It is also worth noting that selection of pharmacological treatments for comorbid disorders is challenging, because randomized clinical trials for drug development often exclude participants with concurrent mental, neurological, or physical disorders [8]. Thus, studying and developing new approaches to treating depressive disorders comorbid with other mental and physical disorders is of significant research and practical importance.

The pathophysiological mechanisms underlying depression remain poorly understood. The chronobiological theory explains the connection between depressive symptoms and disruptions in sleep and circadian rhythms regulation as one of the most commonly observed symptoms [9–11]. Desynchronization of physiological rhythms may include reduced slow-wave sleep, shortened rapid eye movement (REM) sleep latency, disruptions in REM/non-REM cycles [12], daytime sleepiness [13], altered daily temperature patterns [14], and may vary from within-day to seasonal fluctuations [14, 15]. Sleep and circadian rhythm disruptions often occur in depression and typically persist across different stages of the disorder, including the prodromal period, acute episodes, and remission phases [16]. These disruptions may increase the risk of developing depression, exacerbate the symptoms of existing depressive disorders, reduce the quality of remission, and increase treatment resistance [17, 18]. However, a definitive explanation of the connection between chronobiological disturbances and depressive symptoms has yet to be established. One theory suggests that the simultaneous dysregulation of the circadian system and serotoninergic functions may be a contributing factor [19].

Melatonin, a serotonin metabolite and the primary hormone of the pineal gland, plays a key role in regulating circadian rhythms [20–22]. Additionally, disruptions in melatonin regulation are associated with impaired cardiovascular and immune system function, carcinogenesis, increased oxidative stress, and a number of other processes [19]. Given that depression is characterized by reduced melatonin levels, some researchers describe depression as a “low-melatonin syndrome” [19, 20].

Modern approaches to the treatment of depression are primarily grounded in monoamine theories of its pathophysiology and involve the use of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants, which are known to increase extracellular concentrations of monoamine neurotransmitters [21]. However, these antidepressants do not alleviate, and in some cases may worsen, sleep disturbances and disruptions of circadian and/or seasonal rhythms associated with depressive disorders [12, 22, 23].

Given the presence of chronobiological disturbances in depression and evidence regarding their treatment with the goal to reduce depressive symptoms, there is growing interest in the use of melatoninergic compounds. Agomelatine is the first authorized antidepressant whose action is primarily directed at the melatoninergic system. It acts as an agonist of the MT1 and MT2 melatonin receptors and as an antagonist of the 5HT2C serotonin receptor. Clinical studies indicate that agomelatine is comparable to other antidepressants in its ability to reduce symptoms of depression and anhedonia but surpasses them in how it improves sleep parameters with minimal side effects [15, 23–26]. However, some reports suggest that agomelatine may negatively affect liver function, and its long-term toxicity currently remains unclear [23, 24]. Fluvoxamine is an antidepressant belonging to selective serotonin reuptake inhibitors that also inhibits the catabolism of melatonin by suppressing the activity of the CYP1A2 and CYP2C19 cytochromes — enzymes involved in the metabolism of endogenous melatonin. This action increases nocturnal melatonin concentrations in the blood [27, 28]. While fluvoxamine is widely used to alleviate depressive symptoms, studies on its effects on circadian rhythms are limited and inconsistent. One study reported a worsening of sleep characteristics with fluvoxamine [29], whereas another noted significant improvements in sleep disturbances and polysomnographic parameters [30].

Comorbid depression and alcohol abuse

The prevalence of alcohol abuse and alcohol abuse among patients with depressive disorders significantly exceeds that in the general population, reaching 21–30% among patients with depression compared to 16% in the general population [31, 32]. Notably, some studies report even higher rates of these comorbid conditions (e.g., Kurhaluk [33] reports prevalence ranging from 12% to 79%), which may be explained by the heterogeneity of the included nosological entities for depression and alcohol abuse.

Comorbidity of depression and alcohol abuse is 2–3 times more common in men [31, 34] and is associated with the presence of anxiety and personality disorders [34]. The high prevalence of this combination of disorders may be attributed to both hereditary factors and the shared neurobiological mechanisms involved in both conditions [31, 35, 36]. Comorbid depression and alcohol abuse are associated with greater severity and duration of both conditions, an increased risk of suicide, increased resistance to treatment, a higher number of hospitalizations, reduced quality of life, a higher recurrence rate, and elevated mortality [32, 34, 35, 37–39]. The presence of depressive symptoms alongside alcohol abuse also complicates disease diagnosis [31, 40, 41], particularly in determining whether the depressive state is secondary to alcohol abuse or precedes it. Comorbidity also poses challenges in selecting effective pharmacological treatments that can significantly reduce the symptoms of both conditions [40, 42, 43].

One approach to developing effective treatments for comorbid conditions is the assessment of the shared mechanisms underlying both disorders. As with the previously mentioned chronobiological approach to understanding the pathogenesis of depressive disorders, alcohol abuse is also characterized by circadian rhythm desynchronization, which, according to some studies, may serve as a marker of addiction severity [44]. Research indicates that even a single intake of a small dose of alcohol can alter body temperature, while a high dose affects the cortisol and melatonin levels; more significant and prolonged disruptions in melatonin production occur with the development of alcohol abuse [33, 38, 44]. Cravings for alcohol, as a form of reward-seeking motivation, may also be associated with circadian rhythms, alongside other personality and environmental factors [45, 46]. Further evidence of the link between circadian rhythms and alcohol abuse comes from findings indicating that individuals prone to late sleeping and waking patterns — the so-called “night owls” — are more predisposed to developing substance dependence [33, 44–46].

In this context, the study of pharmacological agents affecting the melatoninergic system (e.g., agomelatine and fluvoxamine) in comorbid depression and alcohol abuse holds significant theoretical and practical value.

Comorbid depression and anxiety disorders

Researchers believe that comorbid mental disorders in patients with depression are more the rule than the exception. It is widely acknowledged that depression and anxiety disorders (AD) often occur simultaneously, and that the presence of one disorder increases the risk of subsequent development of the other (comorbid) condition. Estimates suggest that the prevalence of AD in depressive patients ranges from 40% to 60% [47, 48]. Furthermore, comorbidity of depression and AD is associated with greater symptom severity and an increased risk of suicide [49]. There is also a high prevalence of alcohol and other psychoactive substance (PAS) abuse in this group of patients [50–52]. It is worth noting that depression combined with AD is associated with difficulties in social functioning and contributes to the disease burden and strain on the health care system. Some studies report lower levels of education, higher unemployment rates, and a history of childhood trauma in these patients [50, 53]. Despite numerous studies indicating common pathophysiological mechanisms in the development of both depression and AD, as well as the effectiveness of similar pharmacological treatments (e.g., SSRIs), treatment-resistant cases are more common among comorbid patients compared to those with a single disorder [54, 55]. Similar findings are reflected in the study by van Balkom et al. [56], where the presence of comorbid AD in patients with depression was associated with inadequate response to therapy, a reduced likelihood of positive outcomes, and a lower remission rate [56]. Therefore, improving treatment approaches for this group of patients is of significant practical importance. Research on the etiopathogenetic mechanisms of depression and AD continues. A particular focus is put on the chronobiological concept [57–59]. Given the disruption of melatonin metabolism, circadian rhythm desynchronization, and associated sleep disturbances seen in both depression and AD patients, evaluating drugs with melatoninergic effects (agomelatine, fluvoxamine) appears promising [60–62]. Despite the growing number of studies on the effectiveness of this drug class in depression and AD, there remains a lack of systematic data on their effectiveness and safety in cases of comorbidity.

Comorbid depression and epilepsy

Depressive disorder is one of the common manifestations of psychopathological disturbances observed in epilepsy as a consequence of chronic brain epileptization, significantly complicating the course of the underlying disease. In patients with uncontrolled seizures, the prevalence of depressive disorder ranges from 20% to 55% [63].

In a large study, sleep disturbances were observed twice as frequently in patients with epilepsy compared to the control group. The most common sleep disturbances in epilepsy patients include excessive daytime sleepiness, insomnia, and sleep-related breathing disorders [64, 65]. Melatonin plays a special role in maintaining sleep. It has neuromodulatory properties, exerts an inhibitory function in the central nervous system, and regulates circadian rhythms. Melatonin has antioxidant, neuroprotective, anticonvulsant, and anxiolytic effects. Various experimental models have shown that melatonin treatment, administered before or after kainic acid (KA)-induced status epilepticus, affects oxidative stress and the development of epileptogenesis. Melatonin treatment suppresses KA-induced seizure activity [66].

Despite the development of numerous antiepileptic drugs (AEDs) since the introduction of phenobarbital in 1912, the issue of seizure control remains relevant to this day. Polytherapy often leads to a number of adverse events, including neurological disturbances (drowsiness, ataxia, dizziness), mental and behavioral symptoms, as well as metabolic changes [67–69]. The need for better tolerability of AEDs for this group of people is even more pressing. The use of drugs with melatoninergic effects may be promising in maintaining seizure control, optimizing the tolerability of antiepileptic therapy, stabilizing comorbid mental disorders, and improving sleep quality [70, 71].

Comorbid depression and Parkinson’s disease

The types of depressive disorders observed in Parkinson’s disease (PD) include major depression, minor depression, and dysthymia. Patients with mild depression may not formally meet the criteria for a depressive disorder according to DSM-5, but the distressing symptoms significantly complicate the primary disease [72, 73]. Most cases of affective fluctuations in PD may represent episodes of mild or recurrent subsyndromal depression [74, 75]. It has been noted that the profile of depressive symptoms is not identical to the profile of idiopathic depression. Patients with PD tend to show higher levels of anxiety, intact short-term memory, and lower levels of suicidality [76].

The assessment of depression prevalence in PD is complicated by the overlap of somatic symptoms with coexisting cognitive issues and the side effects of dopaminergic drugs [77], and also depends on the approach used to evaluate depression in PD: the “inclusive” approach, where the presence of a symptom is assessed regardless of its origin, leads to a higher prevalence rate compared to the “exclusive”, diagnostic-etiological approach [78].

According to various researchers, depressive symptoms are present in approximately 20–30% of PD patients, with figures ranging from 2.7% to 90% in the available literature for this population [72, 79–83]. Between 20% and 25% of patients receiving specialized care are on antidepressants [84–86]. In the review by Reijnders et al. [79], the average prevalence of major depressive disorder was 17–24.8%, the prevalence of mild depressive symptoms was 22%–36.6%, and dysthymia was found in 13–22.5% [79, 87].

The risk factors for depression in patients with PD include female sex, late stages of PD, and the presence of cognitive impairments in the clinical presentation [72, 88].

The mechanism behind the onset of depression is not yet fully understood. The condition may result from the development of an endogenous disorder, a reaction to disability, an inherent part of PD, or a combination of any of these causes [81]. Pathogenetically, depression in PD is linked to the progression of neurodegenerative processes in the ventral striatum and mesolimbic dopaminergic denervation [89]. At the same time, depression may be associated with motor fluctuations and dyskinesias, which are more commonly seen in carriers of the G2019S mutation [90, 91]. Prognostically, it is known that depression has a significant impact on the prognosis of the primary disease: patients score lower on motor function and activities of daily living (ADL) scales, report more cognitive impairments, and a lower quality of life [92–94]. Additionally, there is an increased risk of uncontrolled use of antiparkinsonian drugs [95] and the burden on caregivers increases [96].

Sleep disturbances are registered in 40–90% of PD patients [97]. The major risk factors for insomnia include female sex, duration of the primary disease, the presence of anxiety-depressive disorders, characteristics of dopaminergic therapy, and circadian dysfunction [98, 99]. It should be noted that additional evidence is accumulating on circadian rhythm disturbances in PD as an important factor in the high incidence of insomnia in PD patients [100]. Several studies have shown a link between changes in the melatonin secretion profiles and the severity of PD symptoms [101, 102], as well as sleep disturbances in PD [103]. Additionally, the studies demonstrated a reduction in melatonin secretion amplitude in PD patients compared to the age-matched control group [104, 105]. Currently, the data is insufficient on the effectiveness and safety of any class of antidepressants for the treatment of PD to provide recommendations for their use [81, 106].

Thus, this study aims to provide a systematic review of studies on the use of antidepressants with a melatoninergic action (fluvoxamine and agomelatine) for the treatment of depression comorbid with alcohol abuse, anxiety disorders (phobic anxiety, panic, and generalized anxiety disorder), and neuropsychiatric diseases (Parkinson’s disease, epilepsy).

METHODS

The work on the systematic review was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions [107] and was carried out in several stages:

Development of the study protocol, including the main objectives of the work, inclusion and exclusion criteria, and the search algorithm;

Pre-registration of the review in the PROSPERO system (registration number #CRD42024536658);

Search and selection of relevant research studies;

Analysis of selected studies and quality assessment;

Narrative synthesis of the obtained results, including the description and evaluation of the effectiveness of the intervention under consideration.

The PICO system [107] was used in developing the search strategy for the systematic review.

Eligibility criteria

The inclusion criteria were the followings:

Participants: Adults with recurrent depressive disorder comorbid with anxiety disorders (phobic anxiety, panic, and generalized anxiety disorder), alcohol abuse, Parkinson’s disease, epilepsy.

Intervention: The use of antidepressants with melatoninergic action (fluvoxamine or agomelatine).

Comparison: Studies with or without a control group.

Outcomes: Primary — change in depressive symptoms; secondary — change in symptoms of the comorbid condition (alcohol abuse, anxiety disorders, epilepsy, Parkinson’s disease).

Study design: Any experimental design, systematic reviews, meta-analyses.

Exclusion criteria:

Publication language: Articles written in languages other than Russian or English.

Publication type: Studies that had not undergone a formal peer review process (e.g., conference abstracts) were excluded from the review.

Information sources

The search for the scientific articles was conducted in the following databases: PubMed, the Cochrane Library, and eLIBRARY. The choice of specific databases, as well as their number, was based on existing recommendations [108–110], as well as their availability to the authors of this study. Subsequently, both forward and backward searches were performed; i.e., searching the bibliographies of selected articles and among articles citing the identified materials. When possible and necessary, full-text versions of the articles were requested from the corresponding authors, as well as potential recommendations for other works related to the review.

Search strategy

In the PubMed and the Cochrane Library systems, the search was performed using controlled and contextual keywords with Boolean operators. The search was conducted by a group of six co-authors independently from each other, following a predefined search algorithm. The search algorithm for each of the scientific databases is presented in Appendix 1 in the Supplementary.

Analysis of the results

The results of the search and selection of articles were graphically presented in the form of a flowchart in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-2020) guidelines [111, 112] for each of the comorbid conditions (see Figures 1–4). The data from the identified publications were entered into an electronic spreadsheet consisting of the following sections: bibliographic details of the article, study design, participant characteristics, study setting, characteristics of the control group, recruitment procedure, diagnosis in the group, research methods used, clinical indicators before intervention, details of the pharmacological treatment, additional pharmacological or psychosocial interventions received by participants, study goal, study duration, detailed description of primary outcomes, detailed description of secondary outcomes, negative side effects of the drug, other study outcomes, and quality assessment of the study. Missing data were requested from the study authors when necessary and possible. The search and selection of articles were undertaken multiple times from April 21, 2024, to June 15, 2024. Disagreements regarding the selected articles were resolved through discussion and consultation with other co-authors. All participants had sufficient knowledge of English to perform the search, selection, and analysis of scientific materials.

Figure 1. PRISMA flow chart demonstrating the selection process of comorbid depression and alcohol abuse studies. Note: * — insufficient data provided in the article for analysis; ** — diagnosis of the study participants did not meet the eligibility criteria; *** — study type did not meet the eligibility criteria. Source: Klimanova et al., 2024

Figure 2. Flow chart demonstrating the selection process of comorbid depression and anxiety disorders studies. Note: * — did not meet eligibility criteria (diagnosis, publication type). Source: Klimanova et al., 2024

Figure 3. Flow chart demonstrating the selection process of comorbid depression and epilepsy studies. Note: *— did not meet eligibility criteria (diagnosis). Source: Klimanova et al., 2024

Figure 4. Flow chart demonstrating the selection process of comorbid depression and Parkinson`s disease studies. Note: * — did not meet eligibility criteria (diagnosis, publication type).

The quality of the selected studies was assessed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions [107] using the Cochrane Risk of Bias tools [113]. Researchers independently considered potential sources of bias in the study results. Any disagreements regarding the assessment of potential biases were resolved through discussion or consultation with other co-authors.

The results of the studies that met the inclusion criteria and were available in full-text format were analyzed and included in the review. Results were synthesized in a narrative format and grouped according to the studied comorbid conditions. The primary indicators reflected in the results included the impact of fluvoxamine or agomelatine on depression symptoms, symptoms of comorbid conditions (alcohol abuse, anxiety disorders, epilepsy, Parkinson’s disease), as well as the potential side effects of these medications. The results of the review were presented in tabulated format.

RESULTS

Comorbid depression and alcohol abuse

Based on the search algorithm, 277 publications were found, including 35 duplicates. Subsequently, 228 publications were excluded due to failure to meet eligibility criteria and 3 due to the unavailability of full-text versions. As a result, 11 publications were selected for further review. The study selection algorithm for the systematic review is shown in the flowchart (Figure 1).

Upon further assessment of eligibility, two studies were excluded due to insufficient data for the analysis provided in the article, eight studies were excluded since the condition in the study participants did not meet the eligibility criteria, and one study was excluded since the study type did not meet the eligibility criteria.

In most of the experimental studies, the sample of participants consisted of patients with mixed affective symptoms comorbid with alcohol abuse — mood disorders or obsessive-compulsive disorder [114], depressive episode (F32), or cyclothymia (F34) [115, 116]. Three studies included patients with comorbid alcohol abuse and a depressive episode (F32) [117–119]. In two studies, the diagnosis of the participants was not indicated [120, 121]. However, due to the limited data on the use of melatoninergic antidepressants in depression comorbid with alcohol abuse, these studies will be considered in more detail. The main characteristics of the studies reviewed are presented in Table S1 in the Supplementary.

All of the listed studies investigated the effect of fluvoxamine on comorbid depressive symptoms and alcohol abuse. It is also worth noting that seven of the reviewed studies were published by the same group of researchers based on the results of one sample of participants [115–121]. In general, all studies had relatively small sample sizes, ranging from 45 to 175 participants (a total of n=819 participants), with the majority of participants being male. Psychometric scales were used to assess affective symptoms, including the Hospital Anxiety and Depression Scale (used in all studies), the Hamilton Depression Rating Scale [115–121], the Beck Depression Inventory [119, 120], and the Montgomery-Åsberg Depression Rating Scale [114]. For assessing alcohol cravings, the Visual Analogue Scale (used in all studies), the Penn Alcohol Craving Scale [115, 116, 118–121], and the Scale of Pathological Addiction [116, 120, 121] were used. None of the studies formally assessed sleep disturbances. The Naranjo algorithm [114] and the UKU Side Effect Rating Scale [115–121] were used to assess adverse events. Assessments were performed on days 1, 7, 14, and 30 [114] and days 1, 9, and 16 of medication use [115, 116, 118–121]. The fluvoxamine dose in the studies ranged from 50 to 200 mg per day in one study [114] and 100 mg/day [50; 150] (Md [Q1; Q3]) in other studies [115, 116, 119—121]; none of the studies presented a methodology for determining or increasing the medication dosage. Three studies included comparison groups and a randomization procedure. In one case, the outcomes for participants receiving fluvoxamine were compared with those receiving other antidepressants [114]; in two other studies [115, 116], the effectiveness of medication prescriptions (fluvoxamine, mirtazapine, and carbamazepine) was compared based on the principle of generating recommendations for choosing a medication and its dose based on pharmacogenetic testing, and without it.

One of the reviewed studies [114] indicated that fluvoxamine use contributes to a reduction in anxiety, depressive symptoms, and alcohol cravings, with the therapeutic effect being achieved by day 7 — faster compared to other antidepressants. The other studies also demonstrated a trend toward a decrease in anxiety, depression symptoms, and clinical manifestations of alcohol abuse following fluvoxamine administration [115, 116, 118–121]. All studies confirmed that fluvoxamine use did not result in significant negative or adverse effects. Additionally, some studies indicated the influence of the CYPD6 polymorphism on fluvoxamine efficacy and safety: participants with the GA genotype experienced a significantly greater reduction in depressive symptoms and a significantly slower onset of adverse effects compared to those with the GG genotype [119, 120].

No studies of agomelatine in a group with comorbid conditions were identified during the systematic search. However, isolated pilot studies on sleep disorders in alcohol abuse suggest that agomelatine may help reduce sleep disturbances in patients with alcohol abuse [122]. In another observational study, it was noted that agomelatine use in patients with major depressive disorder and alcohol abuse could lead to irreversible deterioration in liver enzyme parameters [123].

Thus, the available research suggests that fluvoxamine and agomelatine may be effective in reducing depressive symptoms, sleep disturbances, and alcohol cravings. However, due to the limited number of studies, it is currently impossible to draw definitive conclusions about the efficacy of these medications in alleviating affective disorders and improving circadian rhythms in patients with alcohol abuse.

Comorbid depression and anxiety disorders

Based on the search algorithm, 444 publications were identified, of which 288 were excluded, and 156 were thoroughly reviewed. During the screening process, an additional 77 publications were excluded due to the unavailability of full-text versions. Consequently, 79 publications were selected for eligibility assessment. The study selection algorithm for the systematic review is shown in the flowchart (Figure 2).

Despite the high prevalence of comorbid anxiety disorders among individuals with depression, current research on antidepressant therapy for comorbidities is extremely limited [124]. Instead, most studies focus on anxiety symptoms as part of depressive disorders and evaluate the effectiveness of treatment based on these symptoms. Given the lack of articles fully meeting the eligibility criteria for this systematic review, seven original studies conducted in Russia were reviewed in detail [125–131]. These studies assessed the effectiveness of the antidepressants under consideration in cases of anxiety-depressive disorder (F41.2) [125], adjustment disorder with mixed anxiety and depressed mood (F43.2) [130], anxiety-depressive spectrum conditions associated with chronic somatic disorders [127], and in a group of patients with various forms of depressive disorders with elevated anxiety indicators according to psychometric evaluations [126, 128–130]. The main characteristics of the reviewed studies are presented in Table S2 in the Supplementary.

The total number of participants was n=784; however, it should be noted that two studies [128, 130] were conducted on the same study sample. Six articles investigated the use of agomelatine [125–130]; and one studied, fluvoxamine [131]. In all studies [125–131], participants were recruited from inpatient and outpatient mental-health clinics; however, the participant recruitment procedures were not specified. In each study [125–131], the majority of participants were women (64% to 84%). Standardized psychometric scales were used to evaluate the efficacy of the medications, assessing depression and anxiety [125–131], anhedonia [127], sleep quality [126–129], quality of life [124], and overall clinical impression [126, 128–131]. To monitor adverse events and assess tolerability, scales for evaluating side effects were used [126, 128, 130, 131], along with general health assessments, including blood pressure measurements, heart rate, and blood chemistry analysis, among others [128, 130, 131]. Agomelatine was prescribed at doses of 25–50 mg once overnight, while fluvoxamine was administered at 100–300 mg/day. It was noted that dose increases were decided by the attending physician if the therapeutic effect was insufficient, but the specific methodologies were not detailed. In three studies [128–130], it was noted that other psychotropic medications were used alongside the antidepressants being studied, while other papers did not specify whether additional pharmacological or psychotherapeutic interventions were used. Participants in the agomelatine studies were followed for 6 weeks [126], 8 weeks [128–131], or 3 months [125, 127], while participants in the fluvoxamine study were observed for 8 weeks [131]. Results indicate that the use of these antidepressants led to statistically significant reductions in symptoms of depression and anxiety [125, 126, 127–131], anhedonia [127], and sleep disturbances [125, 127, 129], improvements in the quality of life [125], the severity of mental disorders [126, 129–131], and a decrease in suicidal ideation [128, 130]. These improvements were observed within the first two weeks [125–127, 129, 130]. Remission in depressive symptoms was achieved in approximately 70% of participants [128, 129, 131]. None of the studies reported adverse events that led to participant withdrawal.

However, despite the acceptable design of the studies and data indicating the effectiveness of therapy in reducing anxiety symptoms in depression, these studies could not be included in the current systematic review due to failure to meet the eligibility criteria. One study conducted outside of Russia [132] was dedicated to a theoretical review of various treatment options and strategies for patients with depression and comorbid, generalized anxiety disorder and was a narrative review, which also served as an exclusion criterion. The conclusions presented by the authors indicate the lack of clinical data and specific guidelines for the treatment of individuals with comorbid depression and anxiety disorders.

Comorbid depression and epilepsy

Based on the search algorithm, 235 publications were found, 1 of which was excluded, and 234 were thoroughly reviewed. During the screening process, an additional 83 publications were excluded due to the unavailability of full-text versions. Consequently, 151 publications were selected for eligibility assessment. The study selection algorithm for the systematic review is shown in the flowchart (Figure 3).

The authors selected one paper for detailed study [133]. The main characteristics of this study are presented in Table S3 in the Supplementary.

However, on closer examination, this study did not meet the eligibility criteria as the study sample in which the antidepressant with melatoninergic action (agomelatine) was studied consisted of patients with epilepsy comorbid with mixed anxiety, depressive symptoms, and sleep disorders. Therefore, it was not clarified whether the aforementioned symptoms reached clinically significant levels or if any of these patients were diagnosed with recurrent depressive disorder according to ICD-10 or major depressive disorder according to DSM-5. However, due to the limited research available at this time on the use of melatoninergic antidepressants in epilepsy comorbid with depression, the study by Jiang et al. [133] will be discussed in more detail.

The aim of this observational cohort retrospective study was to evaluate the effectiveness of agomelatine compared to escitalopram. Participants (n=113) were randomized into one of two groups depending on the medication they received. Group 1 (agomelatine): 52 patients (26 males [50%], mean age 31.5 years, mean age of epilepsy onset 21.5 years, with the majority having epilepsy of unknown etiology 38 [73.08%]; focal seizures 10 [19.23%], bilateral tonic-clonic seizures with focal onset 42 [80.77%]. Most patients received two or more antiseizure medications (n=35; 67.03%)]. Group 2 (escitalopram): 61 patients (34 males [55.74%], mean age 26 years, mean age of epilepsy onset 19 years, with the majority having epilepsy of unknown etiology — 41 [67.21%]; focal seizures — 16 [26.23%], bilateral tonic-clonic seizures with focal onset — 45 [73.77%]. Most participants received two or more antiseizure medication [n=48, 78.69%]). The groups did not differ significantly in terms of demographic or clinical characteristics. The duration of medication use was 8 weeks, with assessments of participants’ condition before and after the treatment course. The primary assessment methods used were the Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, and the Pittsburgh Sleep Quality Index.

The results of the study showed that during the follow-up assessment period after the medication course, Group 1 (agomelatine) had significantly lower levels of anxiety and sleep disturbances (p=0.001) compared to Group 2 (escitalopram), while depression scores in both groups did not differ significantly (p=0.712). Both antidepressants contributed to a reduction in depressive symptoms by an average of 77% from the baseline. A negative correlation was also found between the number of antiepileptic drugs taken and the level of depression (p=0.004; τ= -0.320).

Some adverse events (headache, nausea, dizziness) were reported equally in both groups. All patients underwent laboratory testing to exclude other causes of the symptoms. However, no participants were excluded.

Thus, the use of melatoninergic antidepressants, specifically agomelatine, in epilepsy patients showed clinical effectiveness in reducing the severity of affective symptoms and sleep disorders. Agomelatine was more effective than the SSRI antidepressant in reducing symptoms of anxiety and sleep disturbances. An interesting finding was the negative correlation between the number of antiepileptic drugs used and the level of depression. It is possible that underestimation of concomitant therapy influenced the study results. The main limitations of the study were as follows: the lack of verification of comorbid mental disorders according to ICD-10 or DSM-5, the severity of epilepsy and the influence of concomitant antiepileptic therapy, insufficient information on the doses of antidepressants and antiepileptic drugs taken. Therefore, bias in the following domains may have affected the study results: confounding factors, participant selection, potential deviation from the planned intervention, missing data, and outcome assessment.

Current research is more focused on determining the impact of antidepressants on the neurological aspect of epilepsy (frequency and severity of seizures). A promising direction is the study of comorbid conditions within the biopsychosocial paradigm.

Comorbid depression and Parkinson’s disease

Based on the search algorithm, 190 publications were identified, of which 17 were excluded, and 173 were thoroughly reviewed. The study selection algorithm for the systematic review is shown in the flowchart (Figure 4).

Based on the eligibility criteria used in this review, a search was conducted for articles on recurrent depressive disorder comorbid with PD. However, no original clinical studies fully meeting the search parameters were found. Several studies evaluated the effectiveness of antidepressants affecting the melatoninergic neurotransmission (agomelatine and fluvoxamine) in depressive states in patients with PD. In three cases, the authors of the published articles were contacted for clarification of the study methodology. In the work by Fedorova et al. [134], it is noted that the sample consisted of “35 patients with PD with affective disorders and sleep disturbances”, but the specific depressive disorders included were not specified.

Thus, for further review, 6 articles were selected: 3 clinical studies without a control group [135–137], one study with a control group (without treatment) [134], and two systematic reviews [81, 107]. The main characteristics of the selected experimental articles are provided in Table S4 in the Supplementary.

It should be noted that in all four selected clinical studies, agomelatine was used as the antidepressant. All included studies were open-label, prospective studies. The only two-arm study [134] examined the effectiveness of agomelatine compared to a group of patients who did not receive an antidepressant (the groups were comparable in terms of sex, age, and severity of PD). In one study, participants were followed for six months [135]; in another, for two months [137], and in the remaining studies, participants were followed for 6 and 4 weeks, respectively [134, 136].

A total of 117 participants were included in the studies. The mean number of participants in the studies was about 29, with a minimum sample size of 18 [137] and a maximum of 40 participants [136]. The mean age of participants in one study was 75.2±8.3 years [135], while in the other three studies, it was lower: 65.5±12.5 years, 65.0±6.5 years, and 63±1.9 years, respectively [134, 136, 137].

The diagnosis of depression was made according to the DSM-4 criteria [135, 136]. In the study by Fedorova et al. [134], the US National Institute of Neurological Disorders and Stroke (NINDS) guidelines were used to diagnose depression in PD: the presence of at least one of the following two symptoms for a minimum of two weeks (low mood and/or loss of interest in or pleasure from life events). Additionally, patients with PD were required to have four or five additional symptoms, along with the two primary symptoms (sleep disturbances, low self-esteem; feeling of guilt, self-deprecation; tendency towards self-blaming for past events; bleak, pessimistic view of the future; increased fatigue, decreased concentration, and decision-making ability; significant fluctuation in appetite; psychomotor retardation, suicidal ideation, and recurrent thoughts of death) [138]. In one study [137], diagnostic criteria were not specified but it was noted that patients with “PD and moderate depressive disorders” were included. The criteria for diagnosing PD were described in only one study [133].

The results of a study of the efficacy of the antidepressant in the treatment were presented as continuous data, such as the mean score or mean score change on standardized rating scales. In all studies, complete data on the total number of dropouts were provided, including those due to adverse effects. However, in one study, the level of statistical significance of the results was not indicated [136].

As a secondary outcome measure, most studies assessed sleep quality using scales and questionnaires. However, only one study [135] used an objective method for sleep assessment, in particular video polysomnography (XLTEK EEG, NatusNeurology). The study by Gustov et al. [137] did not specify the method used to assess the severity of sleep disturbances. Only two studies assessed the severity of affective disturbances [134, 137].

The quality of the included studies was assessed independently by two authors (YYV and KYV) using the Cochrane Risk of Bias in Non-randomized Studies of Interventions [113].

In the study with a control group [134], the randomization procedures and participant allocation were not specified, so we assessed the risk of bias as for non-randomized studies. We found the methodological quality of the included studies to be low (Figure 5).

Figure 5. Assessment of risk of bias in non-randomized studies according to Cochrane guidelines. Note: D1— Risk of bias due to confounding; D2 — Risk of bias in selection of participants into the study; D3 — Risk of bias in classification of interventions; D4 — Risk of bias due to deviations from intended interventions; D5 — Risk of bias due to missing data; D6 — Risk of bias arising from measurement of the outcome; D7 — Risk of bias in selection of the reported result; Overall — Overall risk of bias. Source: Klimanova et al., 2024

Overall, the risk of bias in the reviewed studies can be considered high. In all the studies, the methods for addressing missing data were not specified, leading to a moderate risk assessment. The risk of bias in outcome measurement was rated as moderate in three studies, as bias may arise when outcome assessors are aware of the intervention status. In one study [137], the “Hospital Anxiety and Depression Scale” (HADS) was used, which relies on subjective patient self-assessment, resulting in a high-risk rating.

A significant reduction in depressive symptoms was observed during treatment with agomelatine in all the studies (Table S1 in the Supplementary). Improvements in sleep parameters were also reported in three studies [134, 135, 137], based on various scales and questionnaires. In one study [135], video polysomnography data showed improvements in periodic limb movement indices and a reduction in the number of awakenings (p <0.005 and p <0.05, respectively). Improvements in daily activities and quality of life were demonstrated in the studies by Avila et al. [135] and Fedorova et al. [134], respectively. A significant reduction in anxiety symptoms was reported in two studies [134, 137]; and in apathy, in one study [134]. Given that significant changes in Parkinson’s disease motor symptoms (based on UPDRS Part III) during agomelatine treatment were observed in only one study [28], drawing definitive conclusions about the treatment efficacy remains premature.

The most commonly reported side effects of agomelatine included constipation, nausea, dizziness, headaches, and rash [135]. Notably, in only one study [135] did three patients withdraw from treatment after 12 weeks: two due to side effects (rash, nausea, headache, and dizziness) and one due to delirium. This study had the longest observation period (6 months) and the widest dose range (25–50 mg). In another study [134], only two patients experienced mild transient headaches at the start of treatment, which did not prevent them from continuing therapy. No significant adverse effects were reported in the studies by Golubev et al. [136] and Gustov et al. [137], both of which used a daily dose of 25 mg of agomelatine. Furthermore, Golubev et al. [136] emphasized the absence of nausea, vomiting, increased constipation, urinary disorders, weight loss, reduced sexual function, or dizziness, which are important for this nosologic group.

In 2003, two systematic reviews assessed the efficacy and safety of antidepressant therapy in idiopathic PD [81, 106]. While the findings of these reviews were similar, only one of the three included studies focused on comparing fluvoxamine with amitriptyline [139]. Unfortunately, the detailed results were not available in the abstract and the full-text version could not be accessed.

The limitations of the aforementioned studies stem from the small number of published works meeting quality criteria, heterogeneity, and, in many cases, small sample sizes. This heterogeneity is due to the varying severity and intensity of comorbid depressive symptoms, as well as the differences in the dose and duration of treatment.

DISCUSSION

This work aimed to provide a systematic review of studies on the use of melatoninergic drugs (fluvoxamine and agomelatine) for treating depression comorbid with alcohol abuse, anxiety disorders (phobic anxiety, panic, and generalized anxiety disorder), and neuropsychiatric diseases (epilepsy, Parkinson’s disease). The study was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions [107]. The search was performed in the scientific databases PubMed, Cochrane Library, and eLIBRARY. The search algorithm was preregistered in the PROSPERO system (registration number #CRD42024536658).

The results of this systematic review confirm that, despite the high prevalence of depression comorbid with other mental and neurological disorders (ranging from 36.7% to 73.5%), the number of studies on the use of melatoninergic antidepressants remains extremely limited. For three out of the four comorbid conditions under review, the systematic literature search yielded no results, constituting what is termed an “empty review” in Cochrane terminology [140]. Given that this study aimed to review available data on the basis of which it could be possible to create clinical guidelines for the use of melatoninergic antidepressants in conditions comorbid with recurrent depressive disorder, as well as to identify research gaps and future directions for investigation, other types of systematic reviews (e.g., scoping reviews) were deemed less appropriate for this work [141, 142]. Broadening the search criteria to include more articles could have significantly shifted the focus point of the work. For example, adding “depressive episode” combined with alcohol abuse to the search parameters, in addition to recurrent depressive disorder, would lead to the inclusion of studies with patient samples that have comorbid disorders and those experiencing depressive states as part of substance withdrawal syndrome; i.e., without true comorbid conditions. Therefore, the preliminary conclusions regarding the efficacy of melatoninergic antidepressants in three comorbid conditions (recurrent depression with alcohol abuse, anxiety disorders, and epilepsy) were drawn based on studies involving participant groups with various affective disorders or affective disorders other than recurrent depressive disorder. As a result, these studies did not meet the predefined eligibility criteria.

The study results indicate that the use of fluvoxamine and agomelatine in alcohol abuse may be effective in reducing depressive symptoms, sleep disturbances, and cravings for alcohol. It is noteworthy, however, that more studies on the efficacy of fluvoxamine were identified compared to agomelatine. Some studies indicated the possibility of potential adverse effects, such as increased liver enzyme levels, associated with the concurrent use of agomelatine and alcohol abuse. In contrast, no significant adverse effects were reported with fluvoxamine. In addition, the use of pharmacogenetic testing to develop guidelines on drug selection and doses significantly enhances the effectiveness of fluvoxamine treatment. However, due to the limited number of studies specifically addressing comorbid depression and alcohol abuse, it is currently not possible to draw definitive conclusions about the efficacy and safety of these medications.

The results of this systematic review on the use of melatoninergic antidepressants in patient groups with depressive and anxiety symptoms suggest their potential efficacy in reducing anxiety, depression, anhedonia, sleep disturbances, and improving the quality of life, reducing the severity of mental disorders, and decreasing suicidal ideation. However, the review also highlights the lack of clinical data and specific treatment guidelines for individuals with comorbid depression and anxiety disorders.

The evaluation of existing studies on comorbid depression and epilepsy indicates that most of the research has focused on determining the impact of antidepressants on the neurological aspect of epilepsy (frequency and severity of seizures). In the only available study examining the use of agomelatine in patients with epilepsy and mixed affective states (depressive and anxiety symptoms and sleep disturbances), agomelatine demonstrated greater efficacy in reducing anxiety and sleep disturbances compared to another antidepressant (escitalopram). Additionally, a negative correlation was identified between depression levels and the number of antiepileptic drugs taken. Given the limited number of studies and the heterogeneous nosologies in the study sample, it is currently not possible to draw definitive conclusions regarding the efficacy and safety of melatoninergic antidepressants in comorbid depression and epilepsy conditions.

A review of studies on the use of agomelatine in PD with comorbid affective disorders suggests that this medication may contribute to significant reduction in depressive symptoms, improvements in sleep parameters and periodic limb movement indices, a decreased number of awakenings, better daily functioning and quality of life, as well as reductions in anxiety and apathy. One study also reported changes in motor symptoms associated with PD. However, based on the reviewed studies, it is not possible to draw definitive conclusions about the efficacy and safety of agomelatine in comorbid depression and PD due to the limited number of high-quality published studies, the clinical heterogeneity of the affective disorders examined, small sample sizes that preclude a generalization of the results to the broader population, the variability in doses and treatment durations, and the lack of consistency in efficacy and safety assessment measures.

Limitations

This systematic review is the first effort to classify and summarize the available data on the use of antidepressants with melatoninergic mechianism of action for depression comorbid with other mental and neuropsychiatric disorders. Overall, the results suggest potential efficacy of these drugs in alleviating symptoms of comorbid conditions. However, the study has several limitations. Primarily, there is a noted lack of research in this field. For most of the comorbid conditions examined, no studies on the use of melatoninergic antidepressants were identified, leading to a reliance on studies addressing similar symptomatology. Consequently, preliminary conclusions were drawn based on studies excluded from the review. As a result, the authors highlighted significant gaps in the research on the pharmacological effects of melatoninergic antidepressants for the comorbid conditions under consideration but were unable to answer the question posed regarding the clinical effectiveness of their use. Furthermore, it should be noted that the reviewed studies often involved small groups of participants, rarely used controlled and randomized designs, included heterogeneous diagnostic samples, and varied in terms of dose and duration of medication interventions.

CONCLUSION

Given the high prevalence of comorbid conditions in depressive disorders and the difficulty in selecting effective pharmacological treatments, further investigation into the use of melatoninergic antidepressants could have both theoretical and practical significance. Future directions for research may include the development and conduct of randomized, double-blind clinical trials to study the use of antidepressants with a melatoninergic mechanism of action in depression comorbid with other disorders (alcohol abuse, anxiety disorders, epilepsy, Parkinson’s disease).

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