Fibromyalgia as a Neuroimmune-Psychiatric Disorder

Fibromyalgia (FM) is a chronic disorder characterized by widespread allodynia and hyperalgesia, comorbid fatigue, cognitive impairment, and sleep disruption. It is characterized by central sensitization, which is one of the main mechanisms and an essential feature of altered pain-processing system at the level of the central nervous system (CNS), and is an example of a disorder of pain regulation affected by genetic, environmental and neurobiological factors. Another series of brain imaging studies demonstrate increased sensitivity to experimental pain stimuli, altered neurotransmitter function, and changes in resting-state functional connectivity. While FM has traditionally been considered a musculoskeletal disorder, an increasing number of studies suggest that FM should rather be viewed as a neuroimmune-psychiatric disorder, characterized by the dysregulation of the CNS, immune system and stress response pathways. Central sensitization developed in the presence of pro-inflammatory cytokines, altered cytokine profiles and neuroinflammation, and glial cell activation. The prevalence of psychiatric comorbidities, such as depression, anxiety and post-traumatic stress disorder (PTSD), is also high in FM. This paper discusses the neuroimmune pathways underlying FM, the commensurate pathways that connect FM and psychiatric illnesses, and recent treatment approaches, primarily focusing on pharmacological and non-pharmacological strategies to address impaired neuroimmune functioning as well as the psychiatric dimensions of FM. Viewing FM as an alteration of homeostasis may facilitate developing improved, multi-disciplinary treatment protocols.

INTRODUCTION

Fibromyalgia (FM) is a chronic disorder that affects around 2-4% of the worldwide population, with a higher frequency in females (twice as likely as males)¹ and an increasing incidence with age^2,3. In addition, people with rheumatic illness are at especially increased risk of subsequently developing FM⁴, with between 20 and 30% of patients with rheumatoid arthritis (RA) meeting FM diagnostic criteria⁴.

Characterized by widespread musculoskeletal pain, fatigue, cognitive disturbances (often referred to as “fibro fog”), and sleep disturbances, FM has historically been considered a disorder of pain processing⁵. Clinically, patients have diffuse pain for more than 3 months, often with fatigue, sleep, and cognitive or psychiatric symptoms⁵. Although the exact cause of FM remains unclear, it is recognized as a neuroimmune-psychiatric disorder, with multiple factors contributing to its onset and exacerbation⁶. These factors may be different from person to person but generally include physical stressors like infections (e.g., Epstein-Barr virus and Lyme disease), trauma (such as injuries or surgeries), and sleep disturbances⁶. Overexertion or inactivity can also trigger flare-ups⁶. Psychological stress, along with emotional stress, anxiety, depression, and major life events, is an important and well-documented factor for the onset and exacerbation of FM symptoms⁶. Hormonal changes, dietary deficiencies, and environmental causes such as changes in weather conditions or exposure to chemicals can also affect the severity of the condition⁶.

The classic definition of FM included a tender-point count of 11 or more out of 18 distinct sites⁷. However, tender point assessment is no longer required in the most recent diagnostic criteria. The clinical diagnosis is based on the American College of Rheumatology (ACR) diagnostic criteria, updated in 2016, focusing on the Widespread Pain Index (WPI) and Symptom Severity Scale (SSS)⁸. A diagnosis requires a WPI score of ≥ 7 combined with an SSS score of ≥ 5, or a WPI score of 4-6 with an SSS score of ≥ 9⁸. In addition, generalized pain must be present in at least four of five body regions (left upper, right upper, left lower, right lower, and axial regions, excluding the jaw, chest, and abdominal areas)⁸. Symptoms should be present for at least 3 months⁸. These criteria prioritize the extent of pain and symptom severity over time.

The ACTTION-APS Pain Taxonomy (AAPT) was developed through a collaborative initiative involving the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION), the US Food and Drug Administration (FDA), and the American Pain Society (APS). FM is included in this evidence-based classification system for chronic pain conditions, whose diagnostic criteria were published in 2019⁹. According to the AAPT⁹ criteria, the FM diagnosis requires:

• multisite pain, defined as pain in 6 or more of 9 specified sites (head, left arm, right arm, chest, abdomen, upper back and spine, lower back and spine, left leg, and right leg);
• moderate-to-severe sleep problems or fatigue.

Both of these criteria must be met for a minimum of 3 months. Another pain disorder or co-occurring symptoms do not rule out the diagnosis of FM (AAPT criteria). Nonetheless, clinicians should perform a comprehensive clinical examination to exclude other aetiologies that may account for the symptoms, or add to their severity^10,11.

While there are no specific lab tests for diagnosing FM, routine tests are essential for excluding other potential underlying conditions^10,12. Tests such as complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and thyroid-stimulating hormone (TSH) are commonly used to evaluate general health and, more specifically, to identify anemia, infection, or hypothyroidism. Other tests may be ordered depending on the clinical findings, such as 25-hydroxy vitamin D, vitamin B12, magnesium, iron studies, and creatine kinase level^10,12. Given the high prevalence of conditions that may mimic or exacerbate FM symptoms, a strategic assessment is essential to determine which patients require further diagnostic testing^10,12.

Patients with FM often present psychiatric comorbidities such as major depressive disorder (MDD), generalized anxiety disorder (GAD), and post-traumatic stress disorder (PTSD)¹³. Moreover, evidence of neuroinflammation, altered immune signaling, and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis suggest a neuroimmune-psychiatric framework for understanding FM^14,15.

The literature for this narrative review was identified through searches of major biomedical databases, including PubMed/MEDLINE and Scopus, focusing on English-language articles published until May 2025, with additional inclusion of earlier seminal studies considered highly relevant to the topic. The main search terms included combinations of “fibromyalgia”, “neuroinflammation”, “cytokines”, “central sensitization”, “glial activation”, “HPA axis”, “psychiatric comorbidity”, “depression”, “anxiety”, “PTSD”, and “treatment”.

NEUROIMMUNE MECHANISMS IN FIBROMYALGIA

Chronic Neuroinflammation and Immune Dysregulation

Neuroinflammation has been considered a player in the pathophysiology of FM¹⁶: FM patients might present with systemic and neuroinflammation, which could contribute to pain sensitization and psychiatric-related symptoms¹⁷. Cytokine and chemokine dysregulation is indeed an important determinant of pain, fatigue, and cognitive impairment that occur broadly¹⁶, and their levels can be altered in FM, contributing to central sensitization, pain amplification, and neuroinflammation. Elevated levels of interleukin-6 (IL-6) have been found in the serum, cerebrospinal fluid (CSF), and muscle tissues of FM patients¹⁹. IL-6 is believed to contribute to pain sensitization, fatigue, and mood disturbances by stimulating the hypothalamic-pituitary-adrenal (HPA) axis, thereby promoting neuroinflammation¹⁹. Similarly, interleukin-8 (IL-8, CXCL8) levels are significantly increased in both serum and CSF; its pro-inflammatory properties attract neutrophils and activate glial cells, further contributing to central sensitization and hyperalgesia¹⁹.

Tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) also occur in higher levels in the skin of FM patients²⁰. Both cytokines possess pro-inflammatory effects and may be implicated in peripheral sensitization and neuroimmune activation, which could contribute to the enhanced perception of pain in FM. TNF-α, for instance, promotes nociceptive sensitization through its actions on peripheral nerve terminals and skin immune cells, thereby intensifying pain and inflammatory processes in FM. The elevated levels of IL-6, IL-8, TNF-α, and IL-1β indicate a chronic inflammatory state, while altered chemokine signaling further contributes to both pain sensitization and cognitive dysfunction²¹. These elevated pro-inflammatory cytokines, coupled with dysregulated chemokine signaling, might enhance central sensitization by increasing neuronal excitability and impairing the body’s endogenous pain-inhibition mechanism²¹.

Beyond pro-inflammatory cytokines, alterations in anti-inflammatory cytokines also contribute to FM pathology: IL-10, which usually inhibits the production of pro-inflammatory cytokines, is reduced in FM patients, while transforming growth factor-beta (TGF-β) levels are inconsistent across studies, suggesting dysregulation¹⁸.

Moreover, the chronic inflammatory state in FM, characterized by cytokine imbalances, overlaps with conditions like depression and chronic fatigue syndrome (CFS), suggesting a shared inflammatory mechanism linking FM and mood disorders, including MDD^22,23.

However, available evidence remains heterogeneous: studies differ substantially in sample size, patient selection, biological matrices, and assay methods. Potential confounders that could impact the inflammatory state, such as obesity, sleep disturbance, physical inactivity, psychiatric comorbidity, and medication use, should also be considered. Moreover, many studies are cross-sectional, which limits causal inference. Therefore, inflammatory abnormalities in FM should be interpreted with caution, as they may reflect partially overlapping mechanisms rather than a single, consistent biomarker profile.

Glial Cell Activation and Central Sensitization

In recent years, the term “gliopathy” has been used to describe the active role of glial cells in the initiation and maintenance of chronic pain syndromes²⁴. Glial cells, particularly microglia and astrocytes, are key mediators of neuroimmune interactions in FM^24,25. In response to chronic stress, injury, or systemic inflammation, microglia become hyperactive, releasing pro-inflammatory cytokines, chemokines, and reactive oxygen species (ROS)²⁶. This leads to an amplification of pain signals, a process known as central sensitization²⁷. Astrocytes also play a central role in the pathophysiology of FM²⁸: their dysfunction contributes to increased glutamate excitotoxicity, which enhances pain signaling and perpetuates chronic pain, participating in central sensitization and neuroinflammation, a hallmark of both FM and mood disorders²⁹.

Direct evidence linking glial activation to symptom severity in FM remains limited, and much of the current framework relies on translational models or indirect neuroimaging findings. Although the concept of “gliopathy” is biologically compelling, its precise clinical relevance in FM still requires further confirmation.

HPA Axis Dysregulation and Stress Response

FM patients also often exhibit a deranged stress response, in particular impacting the hypothalamic-pituitary-adrenal (HPA) axis¹⁵. Many FM patients exhibit a flattened diurnal cortisol rhythm, characterized by lower morning cortisol levels and blunted responsiveness to stressors³⁰.

The HPA axis is central to the body’s stress response, regulating cortisol and other glucocorticoids secretion. In FM patients, the HPA axis has been shown to be underactive, as evidenced by reduced basal plasma cortisol and 24-hour urinary free cortisol excretion³¹. Dynamic testing also reveals an increased adrenocorticotropic hormone (ACTH) response and an impaired cortisol response to corticotropin-releasing hormone (CRH), suggesting possible CRH deficiency and leading to adrenal under-stimulation³¹. Also, chronic stress is known to downregulate the responses of HPA axis through mechanisms that involve serotonergic neurotransmission. The downregulation can have extra effects to reduce the body’s ability to resist stress, a factor that may worsen or trigger FM symptoms³².

This dysregulated HPA axis activity has also been seen in PTSD and MDD where inadequate cortisol production fails to properly suppress inflammation, perpetuating symptoms of pain and fatigue^33,34. It has also been shown a correlation between gut microbiota and the HPA axis³⁵. Gut microbiota is involved in the central sensitization of chronic pain as well as inflammatory diseases such as FM by regulating microglia, astrocytes and immune cells³⁶.

Neurotransmitter Dysregulation and Neuroplasticity Impairment

FM is linked with dysregulation of numerous important neurotransmitters³⁶.

Serotonergic neurons, located in the raphe nucleus, project to various brain regions where they regulate mood, emotions like anxiety and fear, and essential behaviors such as eating, sleep, sexual activity, and pleasure³⁷. Noradrenergic neurons in the locus coeruleus similarly send projections to the same brain areas that regulate attention and cognition, while their projections to the cerebellum aid motor function³⁷. In addition to these ascending pathways, neurons in the caudal raphe nucleus and the locus coeruleus send descending projections to the spinal cord, where they inhibit sensory input from the intestines and skeletal muscles³⁷. Dysfunction in these descending pathways results in hyperalgesia, an enhanced pain response, and allodynia, a perception of painfulness in ordinarily non-painful stimuli³⁷. Alterations in the serotonergic and noradrenergic systems may drive a variety of psychological, somatic, and painful symptoms, thus representing a common mechanism between pain and depression^37,38.

Patients with FM have also demonstrated altered dopaminergic signaling, affecting the reward system intertwined with chronic pain and thus increasing pain sensitivity³⁹. The hippocampus, crucial for memory, learning, and nociception, relies on dopamine, and dysfunction in dopaminergic systems can lead to cognitive deficits. Dopamine is also critical for executive functions such as working memory. For these reasons drugs like dopamine agonists have been suggested as potential analgesics, as they also influence autonomic functions, behavior, and sleep³⁹. In the prefrontal cortex, dopamine and noradrenaline interact, and blocking noradrenaline transporters could elevate both neurotransmitters, potentially improving cognitive deficits in FM³⁹.

A study⁴⁰ found that, in FM individuals, there was also an upregulation of glutamate levels, in particular in the insula and anterior cingulate cortex, which correlated with both pain and cognitive dysfunctions. Elevated glutamate levels in certain brain regions, such as the spinal cord and cortex, may enhance pain perception in FM patients, contributing to central sensitization⁴¹. Glutamate’s activation of NMDA receptors in the brain and spinal cord leads to the hyperexcitability of neurons, which further intensifies pain perception⁴². High levels of glutamate in the brain can activate glial cells, including astrocytes and microglia, leading to increased pain and inflammation⁴³. This persistent glutamate-induced neuroinflammation contributes to the long-term pain experience in FM patients⁴³. The abnormal glutamate activity is also linked to mood and cognitive disturbances; it can interfere with brain functions related to mood regulation, cognitive processing, and memory^32,43.

PSYCHIATRIC COMORBIDITIES AND NEUROBIOLOGICAL OVERLAP

FM is often linked to high rates of psychiatric disorders, especially MDD, anxiety disorders and PTSD⁴⁴. Not only do these conditions coexist with the chronic pain of FM, but they further exacerbate it, resulting in a vicious cycle of distress that can heighten emotional and physical symptoms⁴⁴. MDD is frequently present in FM patients, and the comorbidity between the two conditions is commonly bidirectional, with depression increasing pain sensitivity, and increased pain sensitivity exacerbating the somatic symptoms of depression⁴⁴. Similarly, anxiety disorders, such as generalized anxiety disorder and panic disorder, are common and can amplify pain perception and lead to muscle tension and hyperarousal⁴⁴. PTSD, often linked to traumatic events, can further complicate FM, intensifying pain, sleep disturbances, and emotional dysregulation⁴⁴. The strong overlap of psychiatric disorders with FM underscores the need for an integrated approach to treatment that addresses both the somatic and psychological components of the disease⁴⁵.

Depression and Anxiety in FM

Up to 70% of FM patients also meet the criteria for MDD or GAD, which points to the strong link between chronic pain and psychiatric comorbidities⁴⁴. Neurobiologically, both FM and MDD share several features, including reduced hippocampal volume, altered amygdala function, and dysregulated serotonin and norepinephrine pathways, as well as an inflammatory component^46,47. Elevated levels of CRP and IL-6 as previously reported have been observed in both conditions, highlighting the shared inflammatory basis⁴⁸. While many affective and anxiety-related symptoms in FM are a direct response to chronic pain, research suggests the relationship is more complex⁴⁹. Abnormalities in regions such as the prefrontal cortex, amygdala, and insula suggest that dysregulation of neural circuits, separate from pain perception, may contribute to development of psychiatric conditions like depression and anxiety in FM⁵⁰. This shows that both altered pain processing and disrupted emotional regulation pathways play crucial roles in the psychiatric comorbidities observed in FM.

Post-Traumatic Stress Disorder (PTSD) and FM

Recent data suggest a twofold-increased risk of PTSD among FM patients compared to the general population, with 30-50% of FM patients fulfilling the diagnostic criteria for PTSD. This prevalence is considerably greater than the 7-8% in the general population⁵¹. It is also known that both FM and PTSD share similar neurobiological mechanisms, involving disturbances in the activity of brain regions that are highly involved in the regulation of stress, emotion processing, sleep, and pain, including the amygdala, prefrontal cortex, and hippocampus⁵¹. Despite the clear association between FM and PTSD, the exact temporal relationship between traumatic events and the onset of FM symptoms or PTSD remains uncertain. FM patients whose chronic pain acts as a chronic stressor, can provoke the onset or exacerbation of PTSD, but traumatic events or previously existing PTSD can sensitize the central nervous system and might increase the risk of FM development⁵¹. Additionally, both conditions involve dysregulation of neurotransmitters such as serotonin and norepinephrine, which are essential for regulating mood and pain perception⁵¹. FM and PTSD both involve dysregulation of the HPA axis, a central component of the stress management system that is disrupted by chronic stress³³. This dysregulation is capable of maintaining psychological distress and physical pain alike³³. Multi-disciplinary interventions, including CBT, trauma-focused therapies and pharmacological therapies (e.g., antidepressants, pain modulators) may target both FM and PTSD symptoms⁵¹.

Cognitive Dysfunction and “Fibro Fog”

Patients with FM often have complaints of attention, memory, and decision-making difficulties, analogous to cognitive impairment found with MDD and CFS⁵². Based on functional MRI studies, it seems that communication among the prefrontal cortex, the default mode network, and limbic regions is affected in FM patients. Studies have shown that chronic pain, through its impact on neuroplasticity and brain network connectivity, can lead to impairments in cognitive functioning^53,54. Specifically, alterations in brain regions such as the prefrontal cortex, which is involved in executive functions and decision-making, and the hippocampus, which is key for memory and learning, have been observed in FM patients^55,56. Additionally, neuroinflammation and increased central sensitization in FM may also contribute to the development of cognitive impairments, as inflammatory cytokines and neurotransmitter dysregulation play a role in both pain processing and cognitive functioning³⁶. Moreover, the disruption of the default mode network, a network of the brain correlated with self-referential thinking and clouded states, has also been linked to both FM and disorders with cognitive manifestations such as MDD and CFS, which also provides support for a shared neurobiological mechanism for cognitive dysfunction across these different disorders^57,58.

THERAPEUTIC PERSPECTIVES

Pharmacological Approaches

Serotonin-norepinephrine reuptake inhibitors (SNRIs) such as duloxetine and milnacipran, target both serotonin and norepinephrine, thereby improving both pain and mood symptoms by modulating descending pain pathways and reducing neuroinflammation⁵⁹. Norepinephrine especially plays an important role in pain modulation via descending pathways within the central nervous system that facilitate inhibition of pain transmission. Ultimately, SNRIs, through elevation of norepinephrine levels, augment these pain-inhibiting pathways, resulting in pain relief in these patients with FM⁵⁹. Moreover, SNRIs target the mood-related symptoms often associated with FM, such as depression and anxiety, which are clearly linked to the dysfunction within serotonin. Clinical studies have shown that SNRIs significantly reduce pain, improve physical function, and enhance quality of life in FM patients, making them more effective for managing the condition compared to SSRIs alone⁶⁰.

Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, paroxetine, and sertraline have also been investigated in FM. These medications primarily target serotonergic transmission and may be particularly useful in patients with prominent depressive or anxiety symptoms. However, compared with SNRIs or tricyclic antidepressants, SSRIs appear to have more limited effects on pain modulation, and their benefits are generally considered modest and mainly related to mood improvement⁶¹.

Tricyclic antidepressants (TCAs), particularly low-dose amitriptyline, represent another pharmacological option frequently used in the management of FM: indeed, amitriptyline has been shown to improve pain, sleep quality, and fatigue, likely by modulating serotonergic and noradrenergic pathways involved in descending pain inhibition⁶². Although TCAs are generally used at lower doses than those employed in MDD, their use may be limited by anticholinergic adverse effects, sedation, and tolerability issues. Nevertheless, several clinical trials and systematic reviews suggest that low-dose amitriptyline may provide modest but clinically meaningful improvements in pain and sleep disturbances in FM patients⁶¹.

Anticonvulsants like pregabalin and gabapentin decrease neuronal hyperexcitability and reduce central sensitization through calcium channel modulation; FM-associated pain and anxiety have been effectively treated with such medications⁶³. These drugs mainly act on voltage-gated calcium channels, especially at the α2δ subunit of the calcium channel, which resides in presynaptic terminals of neurons. Binding to this subunit inhibits the influx of calcium ions into neurons, reducing the release of excitatory neurotransmitters such as glutamate⁶³. This modulation helps dull the excessive neural signaling that contributes to the amplification of pain signals in the central nervous system⁶³. Additionally, by reducing neural hyperactivity, these anticonvulsants help manage anxiety symptoms, likely linked to their ability to decrease the excitability of both pain and anxiety-related pathways within the brain and spinal cord⁶⁴.

Non-Pharmacological Approaches

Cognitive-Behavioral Therapy (CBT) enhances coping mechanisms, reduces catastrophic thinking, and modulates pain perception via neuroplasticity changes. It can significantly reduce pain severity, fatigue, and depression in FM patients⁶⁵.

Moderate physical activity, particularly aerobic exercise, reduces inflammatory markers and improves neurotransmitter balance⁶⁶. Also mind-body practices (Yoga and Tai Chi) modulate the autonomic nervous system, reducing stress and improving neuroimmune function⁶⁷.

Another approach is based on the modulation of neuroinflammation specifically on gut dysbiosis. Preliminary evidence suggests that probiotics may help modulate neuroinflammation^68,69. Furthermore the Mediterranean diet, rich in omega-3 fatty acids and polyphenols may have protective effects against FM-related inflammation and psychiatric symptoms⁷⁰.

Moreover, multidisciplinary pain management programs have been increasingly recommended for FM: these approaches typically integrate patient education, graded physical activity, in addition to psychological interventions and individualized pharmacological treatment. Multidisciplinary programs may improve pain, physical functioning, and quality of life more effectively than isolated interventions, particularly in patients with complex clinical presentations^2,71. Finally, given that sleep disturbances represent a core feature of FM and may significantly contribute to pain amplification, fatigue, and cognitive dysfunction, interventions targeting sleep quality should also be considered⁷². These may include sleep hygiene measures, cognitive-behavioral therapy for insomnia (CBT-I), and appropriate management of comorbid sleep disorders when present. Improving sleep architecture may help reduce symptom severity and enhance overall functioning in patients with FM⁷³.

CONCLUSION AND FUTURE DIRECTIONS

Therefore, FM should be reconceptualized as a complex neuroimmune-psychiatric disorder which includes objective signs reported by patients with concomitant detectable biological changes^6,74. Due to their common neurobiological and physiological pathways, psychiatric symptoms in FM patients should not be viewed as simple consequences, but rather important elements of the underlying disease process. The co-morbidity of FM with psychiatric disorders, such as depression and anxiety, is in part mediated by the distress associated with chronic pain, but there are also underlying neurobiological factors contributing to the disorder⁷⁴. Neuroinflammatory markers, altered cytokine levels, and structural brain abnormalities, including gray matter reductions in regions involved in pain processing and emotional regulation such as the prefrontal cortex and insula, further support this framework. Increased levels of proinflammatory cytokines such as IL-6 and TNF-alpha have been documented repeatedly in FM patients^6,74. By recognizing FM as a disorder that spans neurology, immunology, and psychiatry, clinicians can adopt a more integrated, multidisciplinary approach to diagnosis and treatment. At the same time, several limitations of the current literature should be acknowledged. Much of the available evidence derives from cross-sectional studies involving relatively small and clinically heterogeneous samples, which limits causal inference and may contribute to variability in biological findings. Future longitudinal and multimodal studies integrating clinical, neuroimaging, and immunological data will be essential to better clarify the underlying mechanisms of FM^6,74. Addressing the neuroimmune and psychological dimensions of FM, clinicians can better manage symptoms, improve quality of life, and promote long-term wellness for patients^6,74. Advances in neuroimaging, such as functional MRI, and immunological biomarkers provide a deeper understanding of the disease, highlighting the need for more personalized and targeted therapeutic strategies^6,74. The aim is to move away from overreliance on medications and emphasize a holistic, personalized care plan that includes both pharmacological and non-pharmacological strategies. A patient-centered approach should be adopted, integrating education, regular physical activity, CBT, stress management and pharmacological interventions.

Future directions may include research into the role of specific cytokines, expression of glial markers in the pathophysiology of FM, the ability of new anti-inflammatory agents to ameliorate symptoms and the effects of gut microbiota modulation on neuroimmune interactions in FM.

Conflicts of interest statement

Andrea Fagiolini has received research grants and/or has been a consultant for, and/or has been a speaker for: Allergan, Angelini, Apsend, Generici DOC, Lundbeck, Italfarmaco, Janssen, Otsuka, Pfizer, Recordati, Roche, Sanofi Aventis, Sunovion; Alessandro Cuomo is/has been a consultant and/or a speaker for Angelini, Glaxo Smith Kline, Lundbeck, Janssen, Otsuka, Pfizer, Recordati.

Funding

None

Authors contributions

S.P.: methodology, investigation, writing - original draft; D.K.: investigation, writing - original draft; A.C.: validation, writing-review & editing; G.G.: investigation, writing - original draft; M.P.: investigation, writing - original draft; G.P.: investigation, writing - original draft; A.F.: conceptualization, validation, writing-review & editing, supervision.

Ethical consideration

Ethics committee approval and informed consent were not required for this study, as this manuscript is a narrative review based exclusively on previously published literature.