The role of venlafaxine in the modern treatment of anxiety disorders: a critical update and expert clinical perspectives

ANDREA FAGIOLINI1, EMI BONDI2,3, FILIPPO CARACI4,5, GIOVANNI CAMARDESE6,7, BERNARDO DELL’OSSO8,9,10, MAURO PERCUDANI11, GABRIELE SANI12,13,14, ANDREA FIORILLO15

1Department of Molecular and Developmental Medicine, University of Siena, Italy; 2Department of Mental Health and Addiction Services (DSMD), ASST Papa Giovanni XXIII Hospital, Bergamo, Italy; 3Former President of the Italian Society of Psychiatry, Italy; 4Department of Drug and Health Sciences, University of Catania, Italy; 5Oasi Research Institute-IRCCS, Unit of Neuropharmacology and Translational Neurosciences, Troina (Enna), Italy; 6Department of Life Science, Health, and Health Professions, Link Campus University, Rome, Italy; 7Department of Neuroscience, Head-Neck and Chest, Section of Psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; 8Department of Biomedical and Clinical Sciences, University of Milan, Italy; 9Department of Mental Health and Addiction Services, ASST Fatebenefratelli-Sacco, Milan, Italy; 10Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Stanford University, Stanford, CA, Usa; 11Department of Mental Health and Addiction Services, Niguarda Hospital, Milan, Italy; 12Department of Neuroscience, Section of Psychiatry, Università Cattolica del Sacro Cuore, Rome, Italy; 13Psychiatry Department, Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, Italy; 14Lucio Bini Center, Rome, Italy; 15Department of Psychiatry, University of Campania “L. Vanvitelli,” Naples, Italy.

Summary. Anxiety disorders are among the leading contributors to global disability and frequently co-occur with major depressive disorder (MDD), chronic pain, and various psychiatric or somatic comorbidities. Effective management of these conditions necessitates a personalized approach informed by current scientific evidence. Extended-release (XR) venlafaxine, a serotonin-noradrenaline reuptake inhibitor, has emerged as a first-line pharmacological option, endorsed by international guidelines for generalized anxiety disorder, panic disorder, and social anxiety disorder. Its dose-dependent dual mechanism, initially serotonergic, progressing to noradrenergic, enables tailored therapeutic strategies aligned with symptom severity. This narrative review, integrating Italian expert consensus and recent literature, highlights the robust efficacy of XR venlafaxine across anxiety disorders, its favorable tolerability profile due to the osmotic pump zero-order release formulation, and its unique capacity to address residual symptoms such as anhedonia and SSRI-induced emotional blunting. Emerging evidence suggests additional roles for venlafaxine in immunomodulation and the promotion of neuroplasticity, which may further enhance its therapeutic benefit. Given the established role of XR venlafaxine as a key therapeutic option in the pharmacological management of anxiety disorders, and acknowledging the impact of CYP2D6 metabolic variability on its efficacy and tolerability, pharmacogenetic testing could be recommended to optimize treatment personalization. It holds particular promise for patients with comorbid or treatment-resistant profiles, offering measurable benefits in quality of life, functional outcomes, and long-term disease management.

Key words. Anxiety disorders, extended-release formulation, pharmacological therapy, SNRI, venlafaxine.

Il ruolo della venlafaxina nel trattamento moderno dei disturbi d’ansia: aggiornamento critico e prospettive cliniche degli esperti.

Riassunto. I disturbi d’ansia rappresentano una delle principali cause di disabilità a livello globale e frequentemente coesistono con il disturbo depressivo maggiore (DDM), il dolore cronico e diverse comorbilità psichiatriche o somatiche. La gestione efficace di queste condizioni richiede un approccio personalizzato, basato sulle più aggiornate evidenze scientifiche. La venlafaxina a rilascio prolungato (extended-release - XR), inibitore della ricaptazione della serotonina e della noradrenalina, si è affermata come opzione farmacologica di prima linea, raccomandata dalle linee guida internazionali per il disturbo d’ansia generalizzato, il disturbo di panico e il disturbo d’ansia sociale. Il suo duplice meccanismo d’azione dose-dipendente, inizialmente prevalentemente serotoninergico e successivamente noradrenergico, consente strategie terapeutiche mirate in funzione della gravità sintomatologica. Questa revisione narrativa, che integra il consenso di esperti italiani e la letteratura più recente, evidenzia la solida efficacia della venlafaxina XR nei diversi disturbi d’ansia, il suo favorevole profilo di tollerabilità attribuibile alla formulazione a rilascio a ordine zero mediante pompa osmotica e la sua peculiare capacità di intervenire su sintomi residui quali l’anedonia e l’appiattimento emotivo indotto dagli SSRI. Evidenze emergenti suggeriscono inoltre un possibile ruolo aggiuntivo della venlafaxina nell’immunomodulazione e nella promozione della neuroplasticità, aspetti che potrebbero ulteriormente potenziarne il beneficio terapeutico. Alla luce del ruolo consolidato della venlafaxina XR come opzione terapeutica chiave nella gestione farmacologica dei disturbi d’ansia e considerando l’impatto della variabilità metabolica del CYP2D6 sulla sua efficacia e tollerabilità, il ricorso al test farmacogenetico potrebbe essere raccomandato per ottimizzare la personalizzazione del trattamento. Tale approccio appare particolarmente promettente nei pazienti con comorbilità o con profili resistenti al trattamento, offrendo benefici misurabili in termini di qualità di vita, funzionamento e gestione della patologia nel lungo periodo.

Parole chiave. Disturbi d’ansia, formulazione a rilascio prolungato, SNRI, terapia farmacologica, venlafaxina.

Introduction

Anxiety disorders represent a heterogeneous group of psychiatric conditions characterized by excessive worry, motor tension, hypervigilance and somatic symptoms, such as palpitations, sweating, tremors, gastrointestinal disturbances and insomnia1. As of 2021, approximately 359 million people worldwide were affected by an anxiety disorder, accounting for 4.4% of the global population. This makes anxiety disorders the most prevalent among all mental health conditions2. More than 50% of patients with an anxiety disorder have multiple anxiety disorders, and nearly 30% have three or more anxiety or related conditions. Around 60-80% of these patients have at least one other comorbid psychiatric disorder, while 14-61% have specific comorbidities, such as mood disorders3-5. According to the DSM-5-TR classification, they include generalized anxiety disorder (GAD), panic disorder (PD), specific phobia, social anxiety disorder (SAD), agoraphobia, separation anxiety, selective mutism, and substance- or medical condition-induced anxiety disorders1,6. GAD is characterized by persistent and uncontrollable worry extending across multiple aspects of daily life7. PD involves recurrent, unexpected panic attacks accompanied by intense somatic and psychological fear, often followed by avoidance behaviors and anticipatory anxiety8. SAD is defined by a marked fear of social or performance situations, while agoraphobia involves fear of being in situations or places where escape may be difficult or help unavailable in case of a panic attack9. The functional impact of these disorders may be particularly pronounced in young adults and older individuals10. Due to their high prevalence, chronic course, and frequent comorbidities, the World Health Organization (WHO) ranks anxiety disorders as the ninth leading cause of disability worldwide11. Anxiety disorders are frequently associated with mood disorders, substance use, insomnia, and somatic diseases such as cardiovascular, dermatological and gastrointestinal disorders and chronic pain12-15. When anxiety is comorbid with major depression disorder (MDD), the prognosis of the latter worsens significantly, with delayed response to treatment and longer time to remission. Patients with MDD and anxious symptoms present greater psychosocial impairment and a lower quality of life compared to those without anxious comorbidity16.

Pharmacological treatment selection for anxiety disorders must consider multiple clinical and individual factors. Patient preferences and motivation, as well as their engagement in treatment, are crucial. Symptom severity is a key determinant in therapeutic decisions, together with clinical expertise. The availability of psychological support is relevant, as combined pharmacological and psychotherapeutic interventions may enhance efficacy. Previous treatment response and comorbidities should also be carefully evaluated, as they influence both drug selection and prognosis3.

Treatment of anxiety disorders includes psychotherapeutic, pharmacological, and integrated approaches. International guidelines recommend cognitive-behavioral therapy (CBT) as the first-line intervention for many patients17. However, in severe, chronic, or treatment-resistant cases, pharmacotherapy remains essential18. In pharmacological management, the World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine (NE) reuptake inhibitors (SNRIs) as first-line pharmacological treatments for anxiety disorders because of their efficacy and tolerability profiles. For patients with inadequate response to first-line therapy, treatment should be individualized and this may include dose adjustment, switching to another drug in the same class, or introducing a second-line agent based on the clinical profile. Pregabalin is considered a second-line option due to its abuse potential, while benzodiazepines should only be used in the first line when SSRIs or SNRIs are not tolerated and their use is limited to 4 weeks19,20. The British Association for Psychopharmacology (BAP) guidelines similarly prioritize SSRIs as first-line therapy, with SNRIs or pregabalin as alternatives when SSRIs are unsuitable3,21. Patients not responding to two different first-line treatments should be referred for specialist evaluation to consider third-line therapies or more complex combination strategies3,22-24. Among SNRIs, extended-release (XR) venlafaxine is a particularly interesting therapeutic option due to its dose-dependent mechanism of action. At low doses (≤75 mg/day), it acts as an SSRI, modulating serotonergic pathways involved in mood and anxiety regulation. At higher doses (225-375 mg/day), it also inhibits NE reuptake, enhancing noradrenergic transmission and producing stronger antidepressant and anxiolytic effects25. Additional support for a dose-dependent effect is provided by a study demonstrating that venlafaxine inhibits the NE transporter in patients with major depressive disorder (MDD) only at higher doses (225 mg/day and 300 mg/day), but not at lower doses (75 mg/day or 150 mg/day)26.

This dual action provides broad therapeutic efficacy, targeting two key neurotransmitter systems implicated in the pathophysiology of anxiety disorders27,28.

The aim of this article is to provide a review and update on the use of XR venlafaxine across various anxiety disorders, based on evidence from both the scientific literature and clinical practice. The objective is to support the positioning of XR venlafaxine as a first-line treatment option in anxiety disorders.

Methods

A multidisciplinary panel of clinical experts, including psychiatrists, clinical pharmacologists, and researchers, convened to re-evaluate the role of XR venlafaxine in the treatment of anxiety disorders.

Literature search strategy

A structured narrative literature search was conducted prior to the meeting to identify relevant evidence. The following electronic databases were consulted: PubMed/MEDLINE, Scopus, Embase, and PsycINFO. The search covered publications from January 2000 to March 2025.

The search strategy combined Medical Subject Headings (MeSH) and free-text terms using Boolean operators. The core search string was structured as follows: “venlafaxine” OR “venlafaxine extended release” OR “XR venlafaxine” OR “osmotic pump” AND “anxiety disorders” OR “generalized anxiety disorder” OR “panic disorder” OR “social anxiety disorder” AND “pharmacokinetics” OR “pharmacogenetics” OR “CYP2D6” OR “therapeutic drug monitoring” OR “immunomodulation”.

Additional focused searches were conducted for zero-order release formulations, discontinuation syndrome, comparative efficacy with duloxetine and pregabalin and therapeutic drug monitoring guidelines.

Eligibility criteria

Included publications were randomized controlled trials, meta-analyses and systematic reviews, international guideline documents, pharmacokinetic and pharmacogenetic studies and relevant translational research. Non-English publications, case reports, and conference abstracts without peer review were excluded.

A structured literature search was performed across the selected databases to identify studies relevant to the topic. Titles and abstracts were screened for relevance, and full-text articles were evaluated when appropriate. Publications considered most pertinent to the aims of this narrative review were included in the qualitative synthesis.

Consistent with the narrative design of this review, a formal PRISMA flow diagram was not constructed.

Consensus methodology

During the July 2025 meeting, the panel discussed the synthesized evidence and integrated it with clinical expertise. Consensus statements were developed through structured discussion and iterative revision of key points. Although a formal modified Delphi procedure was not employed, agreement was reached through unanimous consensus among panel members.

Results

Pharmacological profile of venlafaxine

The pharmacokinetic and pharmacodynamic profile of venlafaxine underpins its clinical efficacy across depressive and anxiety disorders, reflecting its extensive metabolism, dual serotonergic-noradrenergic mechanism of action, and variability according to individual metabolic capacity29. Venlafaxine is well absorbed following oral administration (approximately 92%), although it exhibits relatively low bioavailability (around 45%). Peak plasma concentrations are generally reached within 2-3 hours for the immediate-release formulations and between 5.5 and 9 hours for the XR ones. The plasma protein binding of venlafaxine ranges from 27% to 30%, while the apparent volume of distribution is approximately 7.5 L/kg. Venlafaxine undergoes extensive hepatic metabolism, primarily via the cytochrome P450 enzyme system, in particular through CYP2D630. The elimination half-life varies according to the formulation and is approximately 5 ± 2 hours for the immediate-release form, 6.8 ± 1.6 hours for the XR besylate formulation, and 10.7 ± 3.2 hours for the XR hydrochloride formulation. In patients with renal or hepatic impairment, the elimination half-life may be prolonged. The majority of venlafaxine is excreted in the urine (approximately 87% of the administered dose): 5% as unchanged drug, 29% as unconjugated O-desmethylvenlafaxine, and 26% as conjugated O-desmethylvenlafaxine. Additionally, about 27% of the dose is eliminated as minor inactive metabolites31. The therapeutic efficacy of venlafaxine in depressive and anxiety disorders is closely related to its biotransformation into the active metabolite O-desmethylvenlafaxine (DVS), which mediates the dual serotonergic and noradrenergic mechanism of action. In vitro studies have shown that both venlafaxine and its active metabolite are potent and selective inhibitors of neuronal reuptake of serotonin and NE, and weak inhibitors of dopamine reuptake32. In fact, the clinical efficacy of venlafaxine is largely attributed to its synergistic action with DVS, which exhibits significantly greater affinity for the NE transporter than venlafaxine and accounts for approximately 62% of the pharmacologically active fraction. Moreover, DVS shows a distinct selectivity profile, with a higher affinity for norepinephrine (NE) reuptake inhibition compared to serotonin (5-HT), more closely resembling the profile observed with duloxetine33. Venlafaxine has demonstrated superior response and remission rates compared to placebo and SSRIs in several clinical trials and is generally well tolerated34. At lower doses, the action of venlafaxine is predominantly on serotonin reuptake, while the inhibition of NE reuptake becomes clinically significant only at higher doses, typically above 150 mg/day, enhancing its therapeutic effect. This pharmacological profile makes venlafaxine a valuable option, especially for patients with severe or treatment-resistant depression26-28. However, not all studies have demonstrated consistent dose-response relationships, and some trials have reported modest effect sizes, particularly in patients with milder baseline symptom severity. Furthermore, heterogeneity in study design, patient selection, and outcome measures limits direct comparability across trials. These findings underscore the variability of individual treatment response and highlight the importance of personalized therapeutic strategies35.

This gradual engagement of noradrenaline contributes to improved efficacy in patients with residual depressive symptoms, such as anhedonia or low motivation, which may persist when only serotonergic pathways are targeted36. This dose-dependent synergy not only enhances the therapeutic effect but also transforms what could be considered a pharmacodynamic limitation into a clinical advantage. Indeed, although increased noradrenergic activity has traditionally been associated with the potential exacerbation of anxiety symptoms, clinical and preclinical evidence indicates that, when noradrenergic activation occurs in the context of enhanced serotonergic transmission, it actually contributes to anxiety reduction. This phenomenon, known as the “noradrenergic paradox,” is explained by the fact that the balance between serotonergic and noradrenergic neurotransmission improves the regulation of limbic circuits involved in the anxiety response37. Venlafaxine is indicated only for patients aged 18 years and older and should not be used in children or adolescents. The medication should be taken with food and must not be combined with alcohol, as this may increase sedation. According to the Summary of Product Characteristics38, the recommended starting dose for the treatment of MDD is 75 mg once daily, administered either in the morning or evening. In patients who do not respond at a starting dose of 75 mg/day the daily dose may be gradually increased up to a maximum of 375 mg. Dose increases are typically recommended every 2 weeks or longer, based on clinical response and tolerability. The maximum recommended dose is 375 mg per day. Treatment is generally continued for several months or longer, and maintenance therapy should be administered at the lowest effective dose.

For GAD, the initial recommended dose is also 75 mg once daily. If needed, the dose can be increased to a maximum of 225 mg per day. Dose titration should occur no more frequently than every 2 weeks, and treatment duration is typically long-term.

In the treatment of SAD, the effective dose is 75 mg once daily. While higher doses have not demonstrated superior efficacy, an increase up to a maximum of 225 mg daily may be considered in patients who do not respond adequately to the initial dose. As with other indications, dose adjustments should be based on individual clinical response and made at intervals of 2 weeks or longer.

For patients with PD, treatment should begin at a lower dose of 37.5 mg once daily during the first week to reduce the risk of initial side effects. This can then be increased to 75 mg once daily, with further increases, up to a maximum of 225 mg per day, introduced gradually every 2 weeks or more, based on tolerability and symptom control.

The clinical efficacy and tolerability of venlafaxine can vary significantly based on CYP2D6 genotype, which determines individual metabolic capacity. Patients can be classified into four main metabolizer phenotypes: i) extensive metabolizers, who show normal conversion of venlafaxine into DVS, typically resulting in a predictable therapeutic response; ii) poor metabolizers, who exhibit reduced enzymatic activity, leading to elevated venlafaxine plasma concentrations and a potential risk of adverse effects or diminished clinical response; iii) intermediate metabolizers, who demonstrate partially impaired metabolism, resulting in intermediate levels of venlafaxine and DVS and iv) ultrarapid metabolizers, who rapidly metabolize venlafaxine, potentially reducing therapeutic efficacy due to lower plasma drug levels. Additionally, concomitant use of CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, bupropion, or duloxetine) should be avoided, as they may significantly impair venlafaxine metabolism and alter clinical response. Thus, CYP2D6 genotyping may be useful to optimize venlafaxine therapy and minimize the risk of treatment failure or toxicity39,40.

Dosage, formulations, and therapeutical indications of venlafaxine: a focus on XR venlafaxine

Venlafaxine is available in immediate-release tablets at doses of 25 mg, 37.5 mg, 50 mg, 75 mg, and 100 mg, while XR formulations are available at 37.5 mg, 75 mg, 150 mg, 225 mg and 300 mg. Immediate-release tablets can be split or crushed, but ER formulations must be swallowed whole to ensure the gradual release of the drug29. XR venlafaxine was introduced in 1997 for the treatment of GAD, SAD, and PD41,42. It has also shown efficacy in PTSD and obsessive-compulsive disorder (OCD), although evidence in these indications is more limited43. Beyond its approved uses, venlafaxine is frequently used off-label for conditions such as attention-deficit disorder, fibromyalgia, complex pain syndromes, cataplexy, hot flashes, PTSD, OCD, premenstrual dysphoric disorder, and migraine prophylaxis44,45. Additionally, the American Academy of Neurology recommends its use for diabetic neuropathy, supporting its role in neurological conditions and chronic pain management29.

A specific XR formulation of venlafaxine, based on an innovative osmotic pump delivery system, provides zero-order drug release, meaning the drug is released at a constant rate, regardless of dose strength (e.g., 75 mg or 225 mg)46. This mechanism maintains plasma concentrations within a narrow therapeutic window (approximately 300-400 ng/mL), thereby maximizing efficacy and minimizing adverse effects. By reducing plasma level fluctuations, the formulation helps mitigate noradrenergic-related side effects such as headache or elevated blood pressure, often linked to desvenlafaxine formation47. Improved tolerability and adherence, now recognized by regulatory agencies as key components of treatment efficacy, are supported by the sustained and controlled release properties of this system46. The osmotic pump formulation ensures greater pharmacokinetic stability compared to immediate-release versions, offering consistent therapeutic coverage throughout the day48. The osmotic core, coated with a semipermeable membrane, absorbs water post-ingestion, leading to dissolution of the active ingredient and an increase in hydrostatic pressure that drives venlafaxine outward48. This enables a quasi-zero-order release profile that minimizes peak plasma levels and is particularly beneficial for drugs with narrow therapeutic windows, enhancing both safety and efficacy. Furthermore, the extended and consistent release allows for once-daily dosing, which promotes better compliance and long-term treatment success47.

XR venlafaxine, functioning as a dose-dependent SSRI-SNRI, may be strategically titrated to first enhance serotonin transmission, particularly beneficial for managing anxiety symptoms, and subsequently increase NE activity to address residual depressive symptoms such as fatigue, low energy and anxiety, supporting a symptom cluster-based approach to optimize treatment response in MDD28. It can be administered as monotherapy or as part of combination treatment strategies. While both the XR venlafaxine tablets compared to the original capsule formulations are bioequivalent and contain the same active ingredient, the tablet form is available in a 225 mg or 300 mg strength, facilitating a once-daily dose for patients with major depressive disorder who require the maximum approved dose. This reduces pill burden, potentially enhances adherence, and lowers cost to both patients and society49.

Although safety concerns have also been reported in cases of overdose, XR venlafaxine remains an effective and generally well-tolerated treatment option for anxiety disorders50.

Guideline-endorsed use of venlafaxine in anxiety and mood disorders treatment

The therapeutic positioning of venlafaxine in anxiety and mood disorders has been well established through multiple international guidelines, which consistently highlight its efficacy and tolerability across GAD, PD, and SAD. A structured overview of indications, recommended dose ranges, comparative data, and guideline positioning is provided in table 151-65.




Based on the WFSBP guidelines, venlafaxine is recommended as an effective antidepressant option with broad clinical utility, particularly in moderate to severe depression and in patients with incomplete response to SSRIs66. According to these guidelines, venlafaxine is considered an effective first-line treatment in GAD, supported by strong clinical trial data demonstrating efficacy in reducing both somatic and psychological symptoms of anxiety. Also, WFSBP guidelines consider venlafaxine as a first-line agent in particularly in its XR formulation for PD and SAD and as a second-line treatment in post-traumatic stress disorder (PTSD), due to somewhat less consistent evidence compared to SSRIs like paroxetine and sertraline24.

The National Institute for Health and Care Excellence (NICE) guideline (2011) lists venlafaxine as a first-line treatment for PD and second-line option for GAD, typically considered after inadequate response to SSRIs, due to concerns about its side effect profile, especially elevated blood pressure at higher doses64.

According to the Anxiety Disorders Association of Canada (ADAC) and the American Psychiatric Association (APA) guidelines XR venlafaxine represent a first-line treatment of PD and SAD3,67. XR velanfaxine is also considered a first-line treatment of SAD by the ADAC and the Anxiety and Depression Association of American (ADAA)3,67.

According to the German Guidelines for the Treatment of Anxiety Disorders (First Revision), pharmacotherapy with SNRIs and SSRIs represents the first-line pharmacological approach for the treatment of anxiety disorders, including PD, GAD, and SAD59. Within this group, venlafaxine, administered at doses ranging from 75 to 225 mg/day, is strongly recommended (Level of evidence Ia, Grade A+) for all three major anxiety disorders. The guideline emphasizes the importance of continuing pharmacological treatment for 6-12 months after clinical remission to prevent relapse. Furthermore, dose titration should be gradual to minimize early adverse effects, such as jitteriness or nausea, which may occur during initial therapy. The guidelines advise against benzodiazepines as first-line options due to their dependence potential, positioning venlafaxine and other SNRIs as safer long-term alternatives. In patients who exhibit partial response after 4-6 weeks, dose escalation may be considered before switching to another antidepressant. Venlafaxine is also listed as an effective option for elderly patients, though caution is advised due to potential sensitivity to cardiovascular or autonomic side effects. Overall, the German S3 guideline supports venlafaxine as a high-evidence, first-choice medication for the pharmacological management of PD, GAD, and SAD, either as monotherapy or in combination with CBT59.

According to the Dutch Pharmacogenetics Working Group (DPWG), venlafaxine is not recommended for CYP2D6 poor and intermediate metabolizers due to reduced conversion of the parent drug into its active metabolite, DVS68. This metabolic limitation results in higher plasma concentrations of venlafaxine, lower DVS levels, and an increased likelihood of adverse effects, such as gastrointestinal discomfort, hypertension, and tachycardia. When alternative antidepressants not primarily metabolized by CYP2D6, such as duloxetine, mirtazapine, citalopram, or sertraline, are unavailable, venlafaxine may still be used cautiously. In such cases, the DPWG recommends dose reduction based on clinical response and, when possible, therapeutic drug monitoring of both venlafaxine and ODV levels. For CYP2D6 ultrarapid metabolizers, increased enzymatic activity accelerates the conversion of venlafaxine to DSV, potentially lowering the total concentration of active compounds and diminishing therapeutic efficacy. The DPWG therefore advises that the dose may be increased up to 150% of the standard regimen, or alternatively, an antidepressant less dependent on CYP2D6 metabolism should be considered if dose titration and plasma monitoring are not feasible. Normal metabolizers, representing the majority of patients, can be treated using the standard dosing range (typically 75-225 mg/day), with no specific genetic adjustment required. In summary, the Dutch guidelines highlight the clinical importance of pharmacogenetic profiling in optimizing venlafaxine therapy, recommending avoidance or adjustment of dosage in genetically determined CYP2D6 poor, intermediate, and ultrarapid metabolizers to improve safety and efficacy41,68.

Therapeutic drug monitoring and pharmacokinetic optimization

Therapeutic drug monitoring (TDM) represents a clinically relevant tool for optimizing venlafaxine treatment, particularly in patients with insufficient response, adverse effects, suspected non-adherence, drug-drug interactions, or genetically determined metabolic variability.

According to the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) consensus guidelines for therapeutic drug monitoring in psychiatry (2017 update), venlafaxine carries a Level 1 recommendation for TDM, indicating strong evidence supporting its clinical utility69.

The AGNP guidelines define a therapeutic reference range for the active moiety (venlafaxine + O-desmethylvenlafaxine [ODV]) of 100-400 ng/mL. Concentrations below this range may be associated with reduced efficacy, whereas levels exceeding 400 ng/mL increase the risk of dose-dependent adverse effects, including hypertension and serotonergic or noradrenergic overstimulation32,70. Key TDM parameters, reference values, and their clinical interpretation are summarized in table 271, in accordance with AGNP recommendations.




An additional clinically informative parameter is the metabolic ratio (MR) between venlafaxine and ODV (VEN/ODV), which reflects CYP2D6 metabolic activity. In extensive metabolizers, the typical MR ranges approximately between 0.25 and 0.35. A higher MR (elevated venlafaxine relative to ODV) suggests reduced CYP2D6 activity (poor or intermediate metabolizers), potentially associated with increased adverse effects. A lower MR may indicate ultrarapid metabolism, possibly leading to subtherapeutic exposure32.

Integration of TDM with CYP2D6 genotyping may further refine dose selection and therapeutic optimization. In cases where genotyping is unavailable, the VEN/ODV ratio itself can serve as a functional phenotyping tool.

In routine clinical practice, TDM may be particularly valuable in:

• treatment-resistant anxiety or anxious depression;

• patients receiving CYP2D6 inhibitors;

• elderly individuals with altered pharmacokinetics;

• individuals experiencing unexpected tolerability issues.

Thus, embedding TDM into the therapeutic algorithm transforms venlafaxine prescribing from a purely symptom-driven strategy to a pharmacokinetically informed and precision-based approach exposure32.

Clinical evidence on the efficacy of venlafaxine in anxiety disorders

XR venlafaxine in generalized anxiety disorder associated or not with major depressive disorder

XR venlafaxine has demonstrated significant efficacy in the treatment of GAD. In a randomized controlled trial, patients received XR venlafaxine at doses of 75 mg, 150 mg, or 225 mg/day, or placebo, over 8 weeks. Statistically significant improvements in HAM-A scores were observed as early as week 1, sustained through week 8, compared to placebo. These findings indicate that XR venlafaxine effectively reduces GAD symptoms from the early stages of treatment and maintains this benefit over time. The therapeutic effect was also dose-dependent, with greater clinical benefit at higher doses, and the tolerability profile was generally favorable, supporting the use of XR venlafaxine as a safe and effective therapeutic option for GAD51. In a comparative study, XR venlafaxine (75-225 mg/day) showed similar, although lower, efficacy to pregabalin (300-600 mg/day), with a more favorable impact on functional improvement and quality of life outcomes60. When GAD co-occurs with MDD, a treatment strategy that target both anxious and depressive symptom dimensions has to be preferred, making dual-acting agents, such as venlafaxine, particularly useful in such contexts57. Indeed, in a pooled analysis of four placebo-controlled trials that enrolled patients with MDD associated with GAD, XR venlafaxine (75-225 mg/day) demonstrated significantly greater improvements in fatigue-related symptoms compared to placebo, with effects emerging as early as week 2 for energy (p=0.0049) and week 3 for lassitude (p=0.0307), and further increasing through week 8 (both p<0.0001). Thanks to its multiple mechanisms of action, venlafaxine is particularly effective in disorders where anxiety and depression coexist, due to its integrated modulation of both neurotransmitter systems28.

XR venlafaxine in panic disorder

XR venlafaxine is approved for the treatment of PD and has demonstrated robust efficacy in reducing panic attack frequency, anticipatory anxiety, and avoidance behaviors. Titration protocols, starting at 37.5 mg/day for 7 days, increasing to 75 mg, and then up to 225 mg/day, have proven essential to minimize initial activation and enhance treatment adherence38,52,72. The XR formulation minimizes plasma concentration fluctuations, which is particularly beneficial for somatically sensitive patients73. In a double-blind, placebo-controlled trial published in the British Journal of Psychiatry, XR venlafaxine achieved a significantly higher rate of clinical remission (CGI-I ≤2) compared to placebo53. In another large-scale RCT comparing XR venlafaxine with paroxetine and placebo in 664 patients with DSM-IV PD, XR venlafaxine resulted in 54-61% of patients being panic-free at 12 weeks, compared to 35% with placebo. Additionally, approximately 75% of patients responded to treatment, and 45% achieved remission. XR venlafaxine was comparable to paroxetine in efficacy, with mild to moderate adverse events reported in both active treatment groups61. Further placebo-controlled studies confirmed venlafaxine’s effectiveness in both acute treatment and relapse prevention of PD54. Compared to SSRIs, venlafaxine may offer a faster onset of action74, and while benzodiazepines provide rapid relief, venlafaxine has shown superior long-term efficacy and lower risk of dependence55. It should be noted that response rates in some controlled trials were numerically close to placebo in specific subgroups, underscoring the substantial placebo effect commonly observed in PD studies75,76. Moreover, variability in study design, endpoint definitions, and baseline severity may influence reported remission and response rates76. Long-term comparative data with other first-line agents remain relatively limited, and these factors should be considered when interpreting overall efficacy findings61.

In a randomized controlled trial of XR venlafaxine (75-225 mg/day) for PD, dose titration was key to clinical efficacy. While 55% of patients were panic-free at study end (vs. 52.4% with placebo), higher doses (mean 163 mg/day by week 10) were associated with significantly greater reductions in panic frequency, anticipatory anxiety, and functional impairment. XR venlafaxine showed dose-dependent improvements in global response and remission rates, with good tolerability maintained across the dose range, supporting a flexible, individualized dosing strategy in the treatment of PD52.

XR venlafaxine in social anxiety disorder

XR venlafaxine is also effective in the treatment of SAD. A multicenter study demonstrated significant reductions in SPIN scores (Social Phobia Inventory) among patients treated with venlafaxine 75-225 mg/day compared to placebo56. A 12-week clinical trial comparing XR venlafaxine, paroxetine and placebo in 440 patients with at least 6 months of SAD showed that venlafaxine significantly improved anxiety symptoms (as measured by LSAS and SPIN) from the first week of treatment, with sustained effects. Notably, XR venlafaxine showed greater efficacy than paroxetine during the first 2 weeks for some social anxiety parameters. At week 12, response rates were significantly higher with XR venlafaxine (58.6%) and paroxetine (62.5%) compared to placebo (36.1%), with a similar tolerability profile for both active treatments62.

Therapeutic positioning of venlafaxine

Comparison to other antidepressants and anxiolytics

In the treatment of anxiety disorders, the choice between antidepressants and anxiolytics must weigh both clinical efficacy and long-term tolerability and safety. In this context, SSRIs and SNRIs are generally preferred over benzodiazepines, despite their potential to cause discontinuation symptoms if abruptly discontinued. Benzodiazepines carry a high risk of dependence and are typically recommended for use only for up to 4 weeks77. Venlafaxine, in particular, represents a valuable therapeutic option in elderly patients. Although specific studies in older adults with GAD remain limited, some evidence suggests that CBT may be less effective in patients over 65 years compared to younger adults. Among pharmacological options studied in this age group, duloxetine, venlafaxine, pregabalin, and quetiapine have all shown efficacy. However, the increased vulnerability of older adults to side effects, such as anticholinergic burden, orthostatic hypotension, ECG changes, risk of falls, and paradoxical reactions to benzodiazepines, necessitates careful drug selection59.

Benzodiazepines may still be indicated in selected cases, such as those with severe cardiac disease, suicidality or contraindications to first-line treatments. Nevertheless, their use should be avoided in patients with a history of substance misuse78. When necessary, short-term benzodiazepine co-administration with an SSRI or SNRI may be considered during the initial treatment phase, particularly in cases of acute anxiety or agitation, while waiting for the therapeutic effects of antidepressants to emerge. However, guidelines emphasize that benzodiazepines should only be used first-line when SSRIs or SNRIs are not tolerated21.

A further advantage of SSRIs and SNRIs lies in their generally lower potential for pharmacokinetic interactions compared to benzodiazepines. Although some antidepressants inhibit cytochrome P450 enzymes, their risk of interaction with psychotropic or somatic medications is usually modest. Discontinuation symptoms, while possible with SSRIs and SNRIs, tend to be less frequent and severe than those observed with benzodiazepines. Among SSRIs, such symptoms are more commonly reported with paroxetine than with sertraline or fluoxetine79,80.

Venlafaxine may be particularly beneficial in clinical situations where SSRIs are insufficiently effective, such as in the presence of emotional blunting, mental fatigue, or persistent anhedonia. It also represents a reasonable switch option in partial responders to SSRIs. In patients with MDD accompanied by anxiety and anhedonia – clinical features often associated with greater severity and lower treatment response – XR venlafaxine has demonstrated efficacy in reducing both depressive and anxiety symptoms, including anhedonia and amotivation, with improvement observed as early as the second week in some studies65.

Discontinuation syndrome and tapering strategies

Discontinuation symptoms represent a clinically relevant aspect of venlafaxine treatment, particularly in the context of abrupt dose reduction or sudden treatment interruption. Antidepressants with shorter elimination half-lives, such as paroxetine, venlafaxine, desvenlafaxine, and duloxetine, have been associated with an increased risk of withdrawal syndrome following treatment discontinuation81,82.

Reported symptoms may include dizziness, nausea, headache, irritability, insomnia, paresthesia (“electric shock” sensations), anxiety exacerbation, and flu-like symptoms. These manifestations typically emerge within a few days of abrupt cessation and are usually self-limiting, although they may cause significant distress and functional impairment83.

The risk appears to be dose-dependent and more pronounced in patients treated with higher doses or longer treatment durations. XR formulations may partially mitigate abrupt plasma fluctuations; however, they do not eliminate the risk of discontinuation phenomena83,84.

To minimize withdrawal symptoms, gradual tapering is recommended. Although no universally standardized protocol exists, most guidelines suggest dose reductions of 37.5-75 mg at intervals of at least 1-2 weeks, depending on the initial dose, treatment duration, and individual tolerability. In patients experiencing significant withdrawal symptoms, reinstatement of the previous dose followed by slower tapering may be necessary83,84.

Particular caution is warranted in patients with comorbid anxiety disorders, where discontinuation symptoms may overlap with relapse or rebound anxiety, potentially leading to misinterpretation of clinical deterioration. Careful clinical monitoring during tapering is therefore essential85.

Patient education plays a crucial role in preventing premature discontinuation and improving adherence. Informing patients about the possibility of transient withdrawal symptoms and planning a structured tapering schedule may substantially reduce treatment discontinuation rates85.

Venlafaxine in the treatment of anxiety disorders: clinical positioning and comparative advantages – expert opinion

The experts agree that venlafaxine stands out among pharmacological treatments for GAD and other anxiety-related conditions due to its robust efficacy, dose-dependent mechanism, and high-level guideline endorsements. It is consistently recommended as a first-line treatment in major international guidelines, including those from NICE, and the World Federation of Societies of Biological Psychiatry64,66, not only for GAD but also for PD and SAD. At lower doses (37.5-75 mg/day), venlafaxine acts as a potent SSRI with high selectivity for the serotonin transporter, making it particularly suited for PD, where low-dose serotonergic modulation is preferred. Its noradrenergic activity emerges only above 150 mg/day, allowing clinicians to titrate based on therapeutic goals and patient tolerability, especially in anxious or somatically preoccupied individuals. In particular, the experts agree on the clinical advantages of XR venlafaxine, which, by using an osmotic pump-based release mechanism ensures more stable plasma concentrations thus helping to reduce peak-related side effects and improves overall tolerability. This pharmacokinetic profile is especially relevant in anxious patients, where avoiding fluctuations in drug levels can minimize activation symptoms, due to sudden increase in serotonin or NE activity, and enhance adherence. The once-daily dosing, combined with reduced gastrointestinal impact and smoother titration, supports the XR formulation as a preferred option in routine clinical practice.

In comparisons with pregabalin, both agents have demonstrated efficacy in GAD and are supported by randomized controlled trials. Pregabalin may be particularly useful in patients with prominent somatic symptoms, sleep disturbance, or intolerance to antidepressants, and it is characterized by a relatively rapid onset of anxiolytic effect.

Venlafaxine, by contrast, exerts its effects through dual serotonergic and noradrenergic mechanisms and may be advantageous in patients with comorbid depressive symptoms or prominent anhedonia. While some comparative trials, such as that by Kasper et al., reported similar overall efficacy between pregabalin and venlafaxine, dose-related differences and study design characteristics limit direct generalization to routine clinical practice60.

Pregabalin is typically administered at doses ranging from 300 to 600 mg/day in clinical trials, and dose-dependent adverse effects such as dizziness and somnolence may occur in some patients. Venlafaxine, particularly in its XR formulation, may be associated with activation symptoms or blood pressure increases at higher doses. Therefore, tolerability profiles differ between the two agents and should be considered in light of individual patient characteristics and functional needs.

In clinical practice, treatment selection between pregabalin and venlafaxine should be guided by symptom profile, comorbid depression, risk of misuse, prior treatment response, and patient preference rather than assumptions of superiority. The BAP guidelines recommend SSRIs as first-line pharmacological treatment, with SNRIs and pregabalin considered alternative first-line options when SSRIs are unsuitable21. Other international guidelines acknowledge pregabalin’s efficacy in GAD while recommending careful patient selection and monitoring due to potential misuse/abuse liability (e.g., as a second-line option)19.

The opinion of the experts is that, when compared to mirtazapine, venlafaxine offers advantages in terms of metabolic profile. While both agents have anxiolytic properties and may be useful in patients with comorbid depression and insomnia, mirtazapine is associated with greater weight gain, potentially exceeding that seen with paroxetine and comparable to amitriptyline over long-term use. Venlafaxine, by contrast, shows minimal weight increase, which contributes to better long-term adherence.

The experts highlighted that, compared to paroxetine, venlafaxine causes less weight gain, has fewer pharmacokinetic interactions, and lower anticholinergic activity, making it more tolerable in long-term treatment. They also underscore that fluvoxamine, while effective for obsessive-compulsive disorder, lacks formal approval for anxiety disorders in the USA and exhibits a narrower antidepressant profile, with low efficacy in GAD or PD. In contrast, venlafaxine offers broad-spectrum anxiolytic efficacy supported by both regulatory approval and clinical use.

When compared with sertraline, which is not formally indicated for GAD, the experts also agree that venlafaxine shows superior regulatory positioning. Moreover, sertraline has mild but relevant pharmacokinetic interactions, which venlafaxine largely avoids. Duloxetine, while effective, is perceived as more activating, especially in the early phase of treatment, potentially problematic in anxious patients. Venlafaxine offers smoother titration and better control of activation symptoms in the initial treatment phase.

Unlike vortioxetine, which is indicated only for major depressive disorder and lacks data in anxiety, or bupropion, which does not modulate serotonergic transmission and may worsen anxiety, venlafaxine provides direct serotonergic and noradrenergic modulation critical for managing anxiety symptoms. This dual-action pharmacology contributes to venlafaxine’s broad efficacy across anxious-depressive spectra.

They call attention to data from the EMBARC study suggest that patients with early-onset depression and high levels of neuroticism are more likely to develop comorbid anxiety and anhedonia. Importantly, cognitive control was found to be inversely correlated with anxiety severity, indicating a potential protective role. These findings emphasize the clinical relevance of assessing both personality traits and cognitive function in the evaluation of depressed patients86. In this context, the experts agree that venlafaxine may offer particular benefit due to its dual serotonergic and noradrenergic action, which could be advantageous in targeting the neurobiological dysregulations associated with neuroticism and comorbid anxiety.

Despite the experts supporting the use of venlafaxine over most comparators, because of the greater number of high-quality clinical studies, they highlight the need for remaining vigilant about potential issues such as discontinuation symptoms, particularly with abrupt cessation, and dose-dependent increases in blood pressure, typically at doses exceeding 225 mg/day. However, their opinion is that these risks are mitigated by the XR formulation, which ensures smoother plasma levels and enhanced tolerability.

In sum, the opinion of the experts is that venlafaxine offers a well-balanced profile of efficacy, tolerability, and clinical flexibility across a range of anxiety and mood disorders. Its broad-spectrum monoaminergic activity, minimal pharmacokinetic interactions, and favorable side effect profile, especially when compared to pregabalin, mirtazapine, support its role as a first-line or early-line agent, particularly when individualized to the patient’s clinical profile.

Bipolar spectrum considerations

Before implementing dose escalation strategies aimed at enhancing noradrenergic transmission, careful diagnostic assessment is warranted, particularly in patients presenting with prominent anxiety, emotional dysregulation, or mixed depressive features. Anxiety disorders and major depressive disorder frequently overlap with bipolar spectrum conditions, and subthreshold hypomanic symptoms may remain underrecognized87.

Although venlafaxine is an effective treatment for anxiety and depressive disorders, antidepressant-induced mood switching has been reported with serotonergic and dual-acting agents, especially in individuals with undiagnosed bipolar disorder88. The risk appears to be related more to individual vulnerability than to a specific pharmacological profile; nevertheless, clinicians should systematically assess for past hypomanic episodes, family history of bipolar disorder, early age at onset, and mood instability before pursuing higher-dose noradrenergic potentiation.

In patients with suspected bipolar spectrum features, mood stabilizer co-prescription or alternative treatment strategies may be considered according to guideline recommendations89. This precautionary approach does not limit the therapeutic value of venlafaxine but supports a safer and more personalized prescribing framework.

Neurobiological mechanisms of venlafaxine: current evidence and future therapeutic opportunities

In patients with MDD comorbid with GAD, research indicates the presence of more pronounced neurobiological alterations compared to MDD alone. Recent studies have highlighted the role of elevated neuroticism and adult life stress in the development of MDD-GAD comorbidity. Specifically, increases in peripheral inflammatory markers, such as α2-macroglobulin and Toll-like receptor 1 (TLR-1), alongside reductions in chemokine CCL2 have been observed in patients with both diagnoses. These findings suggest a mechanistic pathway involving the neuroticism-stress-inflammation axis, emphasizing the need for personalized therapeutic approaches90.

Within this context, venlafaxine stands out due to its immunomodulatory and neurotrophic properties. At intermediate doses (150 mg/day), it has been shown to increase the production of transforming growth factor beta 1 (TGF-β1), an anti-inflammatory cytokine potentially beneficial in managing anxiety associated with systemic inflammation or autoimmune comorbidities91. Experimental evidence supports this hypothesis: in a murine model of acute demyelination, venlafaxine reduced microglial activation, limited myelin loss, and improved both cognitive and behavioral performance92. In an in vitro astrocyte-microglia co-culture model, venlafaxine restored astrocytic membrane potential, enhanced TGF-β release, reduced interleukin-6 (IL-6) and interferon gamma (IFN-γ) levels, and promoted a shift of microglia toward a quiescent phenotype, demonstrating a monoaminergic pathway-mediated anti-inflammatory effect93. However, it is important to note that most of these findings derive from preclinical or in vitro experimental models. Although mechanistically informative, such models do not fully capture the complexity of human neuropsychiatric disorders. Consequently, the extent to which these immunomodulatory effects translate into clinically meaningful outcomes in patients with comorbid MDD and GAD remains to be clearly established.

Further supporting these findings, antidepressants such as venlafaxine have been shown to increase brain-derived neurotrophic factor (BDNF) expression and promote neuroplasticity, contributing to the remodeling and strengthening of neuronal connections. Venlafaxine also exerts neuroinflammation-reducing effects94,95, likely mediated by its enhancement of NE levels, which appear to stimulate the expression of anti-inflammatory cytokines, such as TGF-β196.

Additional evidence from female murine models exposed to chronic stress (chronic subordinate instability, CSI) demonstrated that venlafaxine exerts partial anti-inflammatory effects, reducing the IL-6/IL-10 ratio in the striatum and increasing glucocorticoid receptor (GR) expression in the hippocampus, although behavioral recovery remained incomplete. These data suggest a sex-specific modulation of neuroinflammatory pathways and stress responses by venlafaxine97. While these observations provide intriguing insights into potential neurobiological mechanisms, robust clinical studies directly linking inflammatory modulation to symptomatic improvement in anxiety or MDD-GAD comorbidity are still limited98. Therefore, these findings should be considered hypothesis-generating and supportive of further translational research rather than definitive evidence of clinical mechanism.

Conclusions and future directions

XR venlafaxine remains a highly effective and versatile therapeutic strategy for anxiety disorders, particularly in complex clinical conditions characterized by comorbidity with MDD, anhedonia, somatization, or treatment resistance to first-line interventions. Its dose-dependent mechanism of action, initially serotonergic and subsequently noradrenergic, allows for dynamic treatment adaptation based on the clinical profile of the patient. The value of venlafaxine XR lies not only in its documented efficacy in disorders such as GAD, SAD, and PD, but also in its favorable pharmacokinetic profile. The osmotic-release formulation ensures plasma level stability and reduces dose-dependent adverse effects. Clinical experience shows that patients with anxious depression, mixed disorders, or SSRI-induced anhedonia may derive particular benefit from venlafaxine, especially when a personalized titration strategy is implemented based on genetic (e.g., CYP2D6), clinical, and functional parameters. The growing focus on precision psychiatry makes such individualized approaches essential for optimizing therapeutic outcomes, particularly in slow or ultra-rapid metabolizers where risks of inefficacy or toxicity are higher. Moreover, its immunomodulatory and neuroplastic properties open promising avenues in neuropsychiatric disorders involving neuroinflammation, oxidative stress, and neurobiological alterations associated with high trait neuroticism, as highlighted by recent studies (box 1)3,24,64,66.




Despite its favorable clinical profile, some areas still require further investigation. Comparative studies between XR venlafaxine and other SNRIs (e.g., duloxetine) or SSRIs in specific populations (e.g., frail older adults, patients with somatic comorbidities, young adults at suicide risk) could better clarify the drug’s positioning. Moreover, the identification of predictive biomarkers of treatment response, particularly inflammatory or genetic, could support a more rational and targeted use of the drug, avoiding empirical approaches.

In this context, real-world evidence on outcomes such as quality of life, social and occupational functioning, and patient satisfaction is crucial to understanding venlafaxine’s long-term impact beyond standard symptom scales. Future studies should also investigate shared neurobiological mechanisms between anxiety and depression, including the neuroticism-stress-inflammation axis, as well as the potential for sex-specific modulation. These areas offer fertile ground for developing new personalized therapeutic strategies based on the neurobiological profile of individual patients.

In conclusion, in an evolving therapeutic landscape, XR venlafaxine represents a well-established but still underutilized resource. Its informed, integrated, and evidence-based use, driven by clinical expertise and supported by ongoing research, can significantly enhance therapeutic outcomes in anxiety disorders, contributing to a more precise and personalized model of care.

Conflict of interests: Andrea Fagiolini has served as a consultant and/or speaker and/or has received research funding from Angelini, Boehringer Ingelheim, Idorsia, Italfarmaco, Lundbeck, Janssen, Medicamenta, Mylan, Otsuka, Pfizer, Recordati, Rovi, Sunovion, Teva, and Viatris. Bernardo Dell’Osso has served as a consultant for Lundbeck, Otsuka, Angelini, Neopharmed Gentili, Neuraxpharm, Viatris, Pfizer, Bromatech, Johnson & Johnson, Boehringer Ingelheim, Recordati, Italfarmaco, Teva, and Rovi. Mauro Percudani has served on advisory boards and has received grants, honoraria, and personal support for participation in scientific congresses from Janssen Cilag, Otsuka, Lundbeck, Rovi, Angelini Pharma, Italfarmaco, Neuraxpharm, and Viatris.

Acknowledgements: The authors thank Aashni Shah, Valentina Attanasio Ph.D., Lara Vecchi Ph.D., Raffaella Gatta, PhD, and Massimiliano Pianta (Polistudium Srl, Milan, Italy) who provided medical writing assistance with the unconditional support of Italfarmaco S.p.A. Italfarmaco S.p.A. did not interfere with the opinion of the panel and was not involved in the preparation of the manuscript. At all stages, the authors had full control over the content of the manuscript, which was approved by all authors and for which all authors take full responsibility.

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