Introduction
Major depressive disorder (MDD) and alcohol use disorder (AUD), both individually or in comorbidity, are among the most prevalent mental disorders worldwide and are associated with a significant burden in terms of personal and social functioning and healthcare costs.Reference Murray, Barber and Foreman1
MDD is characterized by persistent low mood, anhedonia, or decreased interest in regular activity, as well as other symptoms such as feelings of guilt and worthlessness, suicidal thoughts, and alterations in appetite, sleep, psychomotor function, motivation, and cognition.2 The World Health Organization (WHO) estimates that more than 300 million people worldwide suffer from depression, and that by 2030 MDD will be the leading cause of disability.3
AUD is a chronic, highly disabling condition that affects almost 15 million individuals in Europe and more than 100 million globally.Reference Wittchen, Jacobi and Rehm4, 5 Despite its significant prevalence, AUD is often underdiagnosed and undertreated: it is estimated that, in Europe, only 10% of patients seek help, and more than two-thirds relapse within the first 12 months of treatment.Reference Kohn, Saxena and Levav6–Reference Guglielmo, Martinotti and Quatrale9
The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC-III) reported that MDD represents one of the psychiatric diseases most frequently associated with AUD.Reference Gilman and Abraham10, Reference Grant, Saha and Ruan11 Comorbid MDD + AUD patients show a more severe course of illness, serious cognitive impairments, worse adherence and response to therapies, higher risk of suicide, and detrimental outcomes in terms of mood improvement, drinking habits, and general functioning.Reference Schneider12–Reference Helle, Trull and Watts14
Despite the high prevalence and the increased severity of comorbid MDD and AUD, evidence currently available is still insufficient to outline patient-focused strategies of clinical management, and there is a lack of consensus on treatment guidelines. The National Institute for Health and Care Excellence (NICE)15 and the American Psychiatric Association (APA)16 guidelines recommend the use of antidepressants only in 3/4 weeks-abstinent AUD subjects with co-occurring major depression.
Systematic reviews have reported that selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs) showed some efficacy in improving both depressive symptoms and certain AUD-related features, including the number of drinks per drinking days and the number of patients maintaining abstinence.Reference Iovieno, Tedeschini and Bentley17–Reference Agabio, Trogu and Pani19 However, the overall response remains modest.Reference McHugh and Weiss13, Reference Strid, Hallgren and Forsell20 The treatment of this clinical population is further complicated by the frequent presentation of alcohol-related medical comorbidities that limit the range of medications potentially employed.
Vortioxetine is an antidepressant with a multimodal mechanism of action.Reference Cipriani, Furukawa and Salanti21 In addition to attenuating depressed mood, it has been demonstrated to improve both anhedonia and cognitive performance, two core mediators for psychosocial functioning and full functional recovery in MDD patients.Reference McIntyre, Lee and Mansur22–Reference Cao, Park and Subramaniapillai24 Moreover, vortioxetine demonstrates preliminary efficacy in the treatment of anhedonia in effort-based learning, suggesting that this compound may be beneficial for mental disorders characterized by disturbances in reward-based decision-making, for example, AUD.Reference Subramaniapillai, Mansur and Zuckerman25 Also, vortioxetine shows a good safety and tolerability profile, with low potential for clinically relevant pharmacodynamic drug interactions and misuse.Reference Pehrson, Cremers and Bétry26–Reference Orsolini, Tomasetti and Valchera28
To the best of our knowledge, studies on vortioxetine’s effectiveness in the treatment of depressive symptoms in adults with comorbid MDD + AUD are still not available. Herein, we primarily sought to determine whether vortioxetine would be capable of attenuating depressive symptoms in adults with comorbid major depression and AUD. In addition to assessing mood, we were also interested in evaluating outcomes with respect to anxiety, anhedonia, and cognition, as well as overall functioning and quality of life.
Methods
Participants
We retrospectively evaluated 57 MDD + AUD and 56 MDD outpatients matched for age, gender, and educational level, referring to the Department of Psychiatry of the Fondazione Policlinico Universitario “A. Gemelli” IRCCS in Rome, between July 2017 and January 2019.
Participants were screened for MDD and AUD according to DSM-5 criteria.2 Diagnoses were confirmed using the Italian versions of the Structured Clinical Interview for DSM-5 Disorders Clinician Version (SCID-5-CV)Reference First, Williams and Karg29 and the Structured Clinical Interview for DSM-5 Personality Disorders (SCID-5-PD).Reference First, Williams and Benjamin30 The interviews were administered by trained clinicians and showed a good interrater reliability (κ = .85 for SCID-5-CV; κ = .87 for SCID-5-PD). Subjects with a Montgomery-Åsberg Depression Rating Scale (MADRS)Reference Montgomery and Asberg31 total score ≥26 and the current depressive episode lasting ≥3 months were eligible for the study. Comorbid AUD patients were suitable if abstinent from at least 4 weeks. Inclusion criteria were age 18 to 65 years, at least 8 years of education, fluency in spoken and written Italian. Exclusion criteria were psychotic features, history of substance use disorder (SUD), major medical disorders or organic brain syndromes, mental retardation or documented IQ < 70, and cognitive impairment based on a Mini-Mental State Examination (MMSE) score <26.Reference Folstein, Folstein and McHugh32 Subjects at any time undergoing relapse to heavy drinking or discontinuing the therapeutic-rehabilitation program were considered dropouts and excluded from subsequent evaluations.
Patients were prescribed vortioxetine (10-20 mg/d, based on clinical evaluation) as part of an integrated therapeutic-rehabilitation program. All participants were provided continuous psychosocial support throughout the treatment period. Data were obtained from measurements and assessments performed at baseline and after 1, 3, and 6 months treatment (endpoint).
Anonymity was guaranteed to all participants. The study protocol was approved by the Ethics Committee of the Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, Rome (Italy). It was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki (1964) and subsequent revisions. All subjects enrolled gave their written informed consent before their inclusion in the study and participated without receiving any form of retribution.
Procedures and assessment
Mood symptoms were assessed at baseline, 1 month, 3 months, and 6 months by the clinician-rated MADRS.Reference Montgomery and Asberg31 Patients were considered responders when obtaining an improvement of at least 50% of MADRS baseline scores and remitters when achieving a total score ≤7 at endpoint.Reference Riedel, Möller and Obermeier33 Mood relapses were defined as a new exacerbation of depressive symptoms (MADRS total score ≥18) after initial improvement.Reference Durgam, Chen and Migliore34
Anxiety levels were measured at the same time-points using the Hamilton Anxiety Rating Scale (HARS),Reference Hamilton35 while the overall severity of psychiatric symptoms was indagated by the Clinical Global Impression-Severity Scale (CGI-S)Reference Guy36 at baseline and endpoint.
Anhedonia was evaluated using the Snaith-Hamilton Pleasure Scale (SHAPS),Reference Snaith, Hamilton and Morley37, Reference Franken, Rassin and Muris38 a self-rating test exploring hedonic responses in common pleasurable situations, at baseline, 3 months, and 6 months. The presence of anhedonia was defined at baseline as SHAPS total score ≥3 and remission as a SHAPS score of <3 at follow-up.Reference Snaith, Hamilton and Morley37
Cognitive performance was indagated with the Digit Symbol Substitution Test (DSST)Reference Wechsler39 and the Perceived Deficits Questionnaire-Depression (PDQ-D).Reference Lam, Lamy and Danchenko40 DSST is used to explore cognitive skills involving attention, processing speed, spatial perception, visual scanning, and executive function, which has shown sensitivity to change in MDD subjects.Reference McIntyre, Harrison and Loft41 The DSST score was calculated by the clinician as the number of correct symbols at baseline, 3 months, and 6 months. Cognitive deficits were additionally evaluated at the same time-points using the self-reported questionnaire PDQ-D.
Patients’ functioning was assessed by clinicians at baseline, 3 months and 6 months using the Functioning Assessment Short Test (FAST).Reference Rosa, Sánchez-Moreno and Martínez-Aran42 Both total scores and subscales, investigating specific areas of functioning (autonomy, occupational, cognitive, financial, interpersonal, and leisure time) were considered. Quality of life was evaluated using the Quality of Life Index (QLI)Reference Spitzer, Dobson and Hall43 at baseline and endpoint.
Abstinence from alcohol was documented by participants’ self-evaluation and a family member interview. It was confirmed by determining blood alcohol concentration, hepatic indices [aspartate transaminase (AST), alanine transaminase (ALT), gamma glutamyl-transferase (GGT)], mean cellular volume (MCV), and blood carbohydrate-deficient transferrin (CDT) at each outpatient control.
The safety and tolerability of vortioxetine were confirmed by physical examination, measurement of body weight and vital signs (blood pressure and pulse rate), routine laboratory and instrumental clinical tests (hematology, chemistry, urinalysis, electrocardiographs), and patients’ reports of any adverse events.
Statistical analysis
Descriptive data were summarized as the number of patients and percentage (%) or mean ± standard deviation (M ± SD). Comparisons between groups were obtained using independent samples t test for continuous variables or chi-square test/Fisher’s Exact Test for dichotomous variables.
Wilcoxon signed ranks test was used to determine whether there was a significant difference between the same variables within group (pre- and post-treatment).
The outcome measures—the mean changes from baseline to 1, 3, and 6 months of each efficacy variable—were analyzed using a mixed model for repeated measurements (MMRM). Analyses were performed on all patients with at least one valid postbaseline assessment of the variables (full-analysis set, FAS).
A significance level of .05 was used for each test. All analyses were conducted using IBM SPSS Statistics for Windows, v. 20.0.
Results
Demographic and clinical data
We included in this study a total of 113 patients (57 MDD + AUD, 56 MDD). All subjects were Caucasians. The two groups were similar in terms of demographic, clinical, and baseline psychometrics characteristics (Table 1). The rate of psychiatric comorbidity was also similar for both groups (MDD + AUD: 7 subjects [12.3%]; MDD: 7 subjects [12.5%]; χ 2 = 0.02, P = .87). Patients were permitted to take additional pharmacotherapy with mood stabilizers/anticonvulsants (valproate, topiramate, gabapentin), atypical antipsychotics (aripiprazole, olanzapine, quetiapine), benzodiazepines (diazepam, lorazepam) and, for MDD + AUD, specific AUD medications, such as naltrexone, nalmefene, and acamprosate (Table 2). No difference was found between the two groups with respect to baseline characteristics (Tables 1 and 2).
Table 1. Demographic and Clinical Baseline Characteristics
Data presented as n (%) or M ± SD.
Abbreviations: CGI-S, Clinical Global Impression-Severity Scale; df, degrees of freedom; DSST, Digit Symbol Substitution Test (number of correct symbols); FAST, Functional Assessment Short Test; HARS, Hamilton Anxiety Rating Scale; M, mean; MADRS, Montgomery-Åsberg Depression Rating Scale; P, P value (statistical significance); PDQ-D, Perceived Deficits Questionnaire-Depression; QLI, Quality of Life Index; SD, standard deviation; SHAPS, Snaith-Hamilton Pleasure Scale; t, Student’s t test; χ2, chi-square test.
Table 2. Other Medications Administered to Patients at Baseline
Data are expressed as number of patients (%).
Abbreviations: df, degrees of freedom; P, P value (statistical significance); χ2, chi-square test.
Primary outcome measures
Mean MADRS total scores significantly decreased during the treatment period in both groups (F = 4420, P < .001) with no differences between groups (F = 0.83, P = .36) (FAS, MMRM, Table 3).
Table 3. Psychometric Evaluation at Selected Time-Points (MMRM, FAS)
Significant results in bold. Abbreviations: CGI-S, Clinical Global Impression-Severity Scale; DSST, Digit Symbol Substitution Test (number of correct symbols); FAST, Functional Assessment Short Test; HARS, Hamilton Anxiety Rating Scale; M, mean; MADRS, Montgomery-Åsberg Depression Rating Scale; P, P value (statistical significance between groups); PDQ-D, Perceived Deficits Questionnaire-Depression; QLI, Quality of Life Index; SD, standard deviation; SE, standard error; SHAPS, Snaith-Hamilton Pleasure Scale.
At endpoint (6 months), in the MDD + AUD group, 26 patients (45.6%) were classified as remitters and 13 patients (22.8%) as responders, whereas 1 patient (1.8%) was a nonresponder and 2 patients (3.5%) relapsed. In the MDD group, 32 patients (57.1%) were classified as remitters and 14 patients (25%) as responders. No difference was observed between groups (χ 2 = 3.5, P = .36).
Secondary outcomes measures
Reductions from baseline to endpoint were observed in the HARS (F = 2560, P < .001), CGI-S (F = 3074, P < .001), and SHAPS scores (F = 568, P < .001) in both groups, with no between-group differences (HARS: F = 1.9, P = .16; CGI-S: F = 0.7, P = .39; SHAPS: F = 0.08, P = .77), except for HARS scores at 3 months (FAS, MMRM; Table 3).
We found that 73.7% (n = 42) of MDD + AUD and 69.6% (n = 39) of MDD patients reached the cut-off for anhedonia at baseline, with no difference between groups (χ 2 = 0.11, P = .83). In these patients, the remission rates at 6 months were 66.7% (n = 28) for MDD + AUD and 76.9% (n = 30) for MDD; no difference between groups was found (χ 2 = 0.57 P = .71).
The mean DSST scores significantly increased over time in both samples (F = 4650, P < .001), with no differences between groups (F = 0.85, P = .36) (FAS, MMRM, Table 3). Additionally, patients also self-reported improvement in cognitive symptoms, as assessed by the PDQ-D (F = 301, P < .001) (FAS, MMRM, Table 3), with no differences between groups (F = 0.22, P = .64).
Improvements in FAST total scores were observed in both groups at all time points (F = 849, P < .001) (FAS, MMRM, Table 3), with no differences between groups (F = 1.29, P = 0.26). Similar improvements were found in all FAST subscales in both MDD + AUD and MDD subjects with no differences between groups (Table 3).
Patients also displayed increased QLI scores at endpoint (F = 2095, P < .001), with no differences between groups (F =1.9, P = .17) (FAS, MMRM; Table 3).
Safety/tolerability profile and drop-out rates
Two patients for each group (n = 4; 3.5%) reported newly emergent adverse events (ie, nausea/vomiting); of these, only one MDD + AUD patient (0.9%) needed to discontinue vortioxetine treatment as a result of tolerability concerns (persisting nausea with vomiting and dizziness). The overall drop-out rate was 26.3% (n = 15, of which six for relapse to heavy drinking) in the MDD + AUD group and 17.9% (n = 10) in the MDD group (χ 2 = 1.17, P = .37). All dropouts occurred after the third month of treatment.
Besides, MDD + AUD patients displayed significant reductions of liver function tests at 6 months (AST: 18.2 ± 4.3 UI/L vs 16.3 ± 3.3 UI/L, Z = −3.3, P = .001; ALT: 18.2 ± 7.8 UI/L vs 16.3 ± 6 UI/L, Z = −2.6, P = .01; GGT: 28.6 ± 16 UI/L vs 23.3 ± 11.4 UI/L, Z =−3.7, P < .001). In the MDD group, no changes pre and post treatment were observed in AST (18.9 ± 6.3 UI/L vs 19 ± 5.4 UI/L, Z = −1.2, P = .22), ALT (18.7 ± 8.7 UI/L vs 18.8 ± 9.5 UI/L, Z = −1.04, P = .23) and GGT levels (18.3 ± 10.8 UI/L vs 18.2 ± 8.7 UI/L, Z = −0.54, P = .59).
Discussion
In this retrospective 6-month study, MDD subjects with AUD comorbidity, treated with vortioxetine as part of an integrated therapeutic approach, obtained a significant reduction of depressive symptoms over time, with a substantial rate of clinical remission. Similar progresses were observed on other clinical dimensions, such as anxiety, anhedonia, and overall severity of psychiatric symptoms, as well as on cognitive functions, both self-perceived and evaluated by the clinician. Finally, treatment with vortioxetine was safe and well-tolerated and was associated with an advance in global functioning and quality of life. To our knowledge, this is the first study to assess the effectiveness of vortioxetine in a well-characterized sample of adults with MDD and concurrent AUD.
Major depression is frequently comorbid with AUD, with about one in five depressed subjects developing AUD during their lifetime.Reference Hunt, Malhi and Lai44 Epidemiological studies suggest that the presence of either disorder doubles the risk of developing the other.Reference McHugh and Weiss13, 45–Reference Hasin, Sarvet and Meyers47 Boschloo and colleagues demonstrated that the severity of AUD predicts the first incidence of a depressive episode in a linear fashion and may be useful in identifying a clinical population at high risk for depressive disorder that could benefit from prevention strategies.Reference Boschloo, van den Brink and Penninx48 Remission from one disorder strongly relates to remission from the other, and replicated evidence found that the co-occurrence of depression is a predictor of AUD relapse following detoxification.Reference McHugh and Weiss13, Reference Blow, Serras and Barry49
MDD and AUD share some predisposing genetic factors and pathophysiological features, such as mutations in the serotonin transporter gene (5-HTTLPR), alterations in glutamate neurotransmission, impaired intracellular transduction systems (i.e., cyclic-adenosine monophosphate [AMP] signalling), reduced production of brain-derived neurotrophic factor (BDNF), dysfunctions in the reward circuit, childhood maltreatment, and stress vulnerability.50–Reference Shin, Ksinan Jiskrova and Yoon57 Also, prolonged exposure to alcohol induces some neurophysiological and metabolic changes that, in turn, might promote the onset of depressive symptoms.Reference Boden and Fergusson45, Reference McEachin, Keller and Saunders58
From a psychosocial perspective, MDD could lead to AUD according to the “self-medication theory,” i.e., depressive symptoms facilitate alcohol consumption in order to alleviate negative feelings. Vice versa, AUD may induce depression through negative social consequences of drinking habits.Reference Otten, van der Zwaluw and Engels54, Reference McEachin, Keller and Saunders58 AUD is also highly comorbid with other affective disorders, i.e., bipolar disorders,Reference Di Nicola, Moccia, Ferri and Preedy59 is especially frequent during depressive phases,Reference Iasevoli, Valchera and Di Giovambattista60, Reference Janiri, Di Nicola and Martinotti61 and might contribute to the onset of mixed symptoms.Reference Di Nicola, Pepe and Modica62 Functional and structural brain characteristics, as well as the presence of specific psychopathological features and affective temperaments, might explain, at least in part, this high co-occurrence of depressive episodes and alcohol abuse.Reference Iasevoli, Valchera and Di Giovambattista60, 63–Reference Hong, Ha and Lee66
The clinical presentation of MDD + AUD comorbidity is highly heterogeneous, thus increasing the complexity of diagnosis and treatment.Reference McHugh and Weiss13 A promising pharmacological intervention is a combined, simultaneous approach, where patients are prescribed both antidepressants and medications specifically targeting alcohol dependence.Reference Pettinati, O’Brien and Dundon67 So far, clinical trials focused on the efficacy of certain antidepressants, mainly SSRIs, SNRIs, and TCAs, in treating comorbid MDD + AUD subjects. However, compounds with different mechanisms of actions have not been extensively investigated yet.Reference Agabio, Trogu and Pani19
Vortioxetine is a multimodal antidepressant, acting as an inhibitor of the serotonin (5-HT) transporter and as a serotonin receptor agonist (5-HT1A), partial agonist (5-HT1B), and antagonist (5-HT3, 5-HT7, and 5-HT1D) at the indicated targets.Reference Bang-Andersen, Ruhland and Jørgensen68 It also indirectly potentiates the activity of different neurotransmitter systems, such as the dopaminergic, noradrenergic, cholinergic, and the glutamatergic system, which is thought to be crucial in the pathogenesis of both MDD and AUD.Reference Caraci and Di Sciascio69
Alongside its antidepressant effects, vortioxetine has shown effectiveness on other dimensions, such as anhedonia, cognition, and functioning.Reference McIntyre, Lee and Mansur22, Reference Cao, Park and Subramaniapillai24, 70–Reference Christensen, Loft and McIntyre72 Also, according to a recent study, vortioxetine appears to improve measures of reward-based decision-making, as evidenced by performance on the effort expenditure for reward task (EEfRT).Reference Subramaniapillai, Mansur and Zuckerman25 Taken together, the benefits that vortioxetine exerts on general cognitive systems, as well as preliminary data on its activity on both anticipatory and consummatory reward, provide further basis for hypothesizing that this compound would be useful on other mental disorders characterized by general disturbances in impulsivity and in reward-based decision-making (e.g., AUD, SUDs).
In our sample, mood improvements were evident already after 1 month of treatment with vortioxetine, became clinically significant after 3 months, and continued throughout the observation period until the endpoint, a result in line with previous studies on other antidepressants.Reference Davis, Wisniewski and Howland73 Comparable results were observed on anxiety symptoms, though to a less extent in comorbid patients at 3 months.
Anhedonia is a persistent feature in mood disorders, shows a poor response to most available antidepressants, and is a main mediator of poor functional outcome.Reference Cao, Park and Subramaniapillai24, Reference Di Nicola, De Risio and Battaglia74, Reference Vinckier, Gourion and Mouchabac75 In AUD subjects, higher levels of anhedonia are associated with greater alcohol use severity, and anhedonia is relevant during alcohol withdrawal and abstinence.Reference Otten, van der Zwaluw and Engels54, 76–Reference Cano, de Dios and Correa-Fernández78 Anhedonia might also act as a vulnerability factor for substance initiation and transition to addiction.Reference Garfield, Lubman and Yücel79, Reference Pettorruso, Martinotti and Fasano80 Dysregulations of reward pathways and reward hyposensitivity have been demonstrated in both MDD and AUD; within this framework, anhedonia might represent an underlying construct linking these conditions and partly explaining the high prevalence of their comorbidity.Reference Destoop, Morrens and Coppens55 Of note, a large population-based study reported that anhedonia is significantly more severe in comorbid MDD + AUD patients than in subjects with MDD alone,Reference Carton, Pignon and Baguet81 highlighting the need for targeted interventions.
Treatment with vortioxetine ameliorates anhedonia in MDD patients, and these improvements mediate the association between advances in overall depressive symptoms severity and social functioning.Reference Cao, Park and Subramaniapillai24 In addition, vortioxetine improves reward-based behavior (e.g., sucrose preference) in a preclinical model of depression.Reference Lu, Ho and McIntyre82
Intriguingly, we found that vortioxetine reduced anhedonia in MDD + AUD subjects. In our sample, anhedonic symptoms were on average moderate, although more than two thirds of the examined subjects reached the cutoff for the presence of anhedonia at baseline, and we observed a constant reduction of these symptoms over time. As anhedonia is related to increased risk of drinking relapses, poorer functioning, worse long-term outcome, and higher risk of suicide, vortioxetine could represent a rationale treatment in MDD + AUD patients or in AUD subjects with subthreshold depression but clinically relevant anhedonic features.
Cognitive dysfunctions, both self-perceived and objectively assessed, are highly prevalent in depressed patients, often persist despite mood improvements, and hinder the achievement of full-functional recovery.Reference McIntyre, Lee and Mansur22 Prolonged alcohol use induces cognitive deficits in multiple domains, some of them requiring a long-term abstinence to restore.Reference Staples and Mandyam83 However, in AUD patients, other causes (i.e., the co-occurring presence of depressive symptoms) might contribute to the extent of cognitive deficits, which reduce the efficacy of therapeutic interventions and portend dropout and relapses.Reference D’Hondt, Lescut and Maurage84 Accordingly, MDD + AUD patients display significantly greater cognitive impairments than MDD subjects.Reference Carton, Pignon and Baguet81 In major depression patients, vortioxetine was the only antidepressant showing procognitive effects that were independent from mood improvement and associated with functional recovery.Reference McIntyre, Lee and Mansur22, Reference McIntyre, Lophaven and Olsen70, Reference Baune, Brignone and Larsen71 Preclinical studies suggest that vortioxetine may promote cognition by indirectly increasing glutamate neurotransmission (via inhibition of gamma-aminobutyric acid [GABA] interneurons expressing 5-HT3 heteroreceptors), modulating the monoaminergic system, inducing the production of neurotrophins (e.g., BDNF), and supporting neuroplasticity in brain regions relevant to cognitive function, such as hippocampus and prefrontal cortex.Reference Lu, Ho and McIntyre82, 85–Reference Sanchez, Asin and Artigas87
Our results show that, in comorbid patients, treatment with vortioxetine was associated with improvements in cognitive performance, both self-perceived and as assessed by clinicians. Observed changes were significant after 3 months of treatment and continued throughout the follow-up until endpoint.
Both depression and alcohol abuse are known to produce detrimental effects in psychosocial, financial, and occupational functioning which, in turn, affect the overall quality of life and other patient-reported outcomes. Therefore, employment of agents promoting improvements in these features should be considered in the management of MDD + AUD patients. Replicated evidence demonstrated that treatment with vortioxetine is linked to a significant progress in functional outcomes in MDD patients.Reference McIntyre, Lee and Mansur22, Reference Christensen, Loft and McIntyre72 Again, in this study, we observed similar advances in psychosocial functioning and quality of life in MDD + AUD patients.
In our sample, vortioxetine was generally safe and well-tolerated and only one patient reported side effects which required to stop the treatment.
Vortioxetine does not interact with the pharmacokinetics of several compounds (alcohol, lithium, and benzodiazepines) nor demonstrates addictive properties.Reference Chen, Nomikos and Affinito27, Reference Orsolini, Tomasetti and Valchera28 Because treatments with antidepressants are typically long-term, a concomitant intake of other central nervous system–active agents is not unlikely; therefore, in this perspective, vortioxetine represents a reasonably safe option.
Preclinical studies also show that a single injection of vortioxetine increases levels of serotonin, but not dopamine or noradrenaline, in the nucleus accumbens, thus limiting the potential for abuse.Reference Pehrson, Cremers and Bétry26 This might be useful in subjects particularly prone to develop addictive behaviors.
Although this study has some strengths, such as samples homogeneous at baseline, the careful assessment of multiple outcomes, and the medium-term follow-up, some limitations must be acknowledged. For example, the retrospective nature of our observations, the relatively small sample size, and the reliability of the self-administered questionnaires. Also, a significant rate of patients was undergoing multiple pharmacological treatments, and all of them were provided with continuous psychosocial support, factors that might have contributed to the observed results. Therefore, our findings in this sample may not be generalizable to other groups of subjects in other settings. Further studies involving larger samples and control groups are certainly needed to replicate these results.
Conclusions
Because of its clinical implications and high prevalence, the comorbidity of MDD and AUD is a major public health concern. The assessment of co-occurring MDD and AUD is complicated by overlapping features, including the mood-depressant effects of alcohol abuse, or psychomotor agitation, anxiety, and insomnia that occur in both alcohol withdrawal and depressive episodes. Current guidelines recommend that a diagnosis of an independent (ie, not substance-induced) depressive disorder should be done only after a period of abstinence, typically 4 weeks. However, studies indicate that substance-induced depression is associated with increased risk for subsequent independent MDD. Therefore, some authors suggest that treatment should be considered even in substance-induced depression.Reference McHugh and Weiss13
The evaluation of further clinical and psychopathological dimensions, such as anhedonia, cognitive features, and overall functioning, might be useful to better understand the full spectrum of severity of MDD + AUD comorbidity, including their subclinical presentations. A better knowledge of the clinical variables within MDD + AUD patients and of the multiple dimensions involved should lead to more personalized treatments, specifically addressing indicated targets, which might eventually improve response.
In conclusion, given its effectiveness in treating depressive symptoms and anhedonia, as well as its procognitive effects, its favorable safety and tolerability profile, and low potential for misuse, vortioxetine can represent a valid pharmacological option in comorbid MDD + AUD patients as part of an integrated therapeutic-rehabilitation program.
Acknowledgments
The authors would like to thank Dr. Raffaella Franza and Dr. Angela Gonsalez del Castillo for their commitment in providing continuous psychosocial support to all patients.
Financial Support
This research received no specific grant from any funding agency, commercial or not-for-profit sectors.
Conflicts of Interest
Marco Di Nicola, Maria Pepe, Isabella Panaccione, Lorenzo Moccia, Luigi Dattoli, Marzia Molinaro, Gabriele Sani, Luigi Janiri, and Roger S. McIntyre do not have any conflicts.
Disclosures
Roger S. McIntyre has received research grants from Stanley Medical Research Institute, CIHR, GACD, and Chinese National Natural Research Foundation; has received speakers’ fees from Lundbeck, Janssen, Shire, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, and Minerva. Marco Di Nicola*, Maria Pepe, Isabella Panaccione, Lorenzo Moccia, Luigi Dattoli, Marzia Molinaro, Gabriele Sani, and Luigi Janiri declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Authorship Contributions
Study design, data interpretation, and article writing, M.D.N., I.P., L.J., and R.S.M; Data collection and data interpretation, M.P., L.D., and M.M; Data entry and database management, M.P., I.P., and L.M.; Statistical analysis, M.D.N. and I.P.; Data interpretation and article writing, G.S. All authors personally revised and approved the final version of the manuscript.
