Depression and physical comorbidities: an integrated review of challenges and treatment approaches

Depression and physical comorbidities: an integrated review of challenges and treatment approaches

Alessandro Cuomo1, Despoina Koukouna1, Simone Pardossi1, Mario Pinzi1, Maria Beatrice Rescalli1, Caterina Pierini1, Andrea Fagiolini1

1Department of Molecular and Developmental Medicine, University of Siena, Italy.

Summary. Depression is a highly prevalent and debilitating condition that frequently coexists with various physical illnesses, including cardiovascular, metabolic, neurological, oncological, pulmonary, and gastrointestinal diseases. This bidirectional relationship complicates diagnosis, exacerbates disease burden, and negatively impacts clinical outcomes, quality of life, and treatment adherence. The underlying mechanisms involve neuroinflammation, autonomic dysfunction, metabolic dysregulation, and behavioral factors. The pharmacological management of depression in patients with comorbid physical conditions requires careful selection of antidepressants to minimize adverse effects and drug interactions. Special considerations are necessary for patients with hepatic and renal impairment, as altered drug metabolism and clearance may increase the risk of toxicity or therapeutic inefficacy. Similarly, in pregnant and breastfeeding women, antidepressant selection must balance maternal benefits with fetal and neonatal safety. While SSRIs such as sertraline are generally preferred due to their relatively favorable safety profiles, medications like paroxetine and fluoxetine require caution due to potential teratogenic risks and higher infant exposure through breast milk. A comprehensive, multidisciplinary approach integrating psychiatric and medical care is essential to improve outcomes and ensure the safe and effective treatment of depression in individuals with chronic physical diseases and special populations.

Key words. Antidepressants, comorbidity, depression, pregnancy.

Depressione e comorbilità fisiche: sfide e approcci terapeutici.

Riassunto. La depressione è una condizione altamente diffusa e debilitante che spesso si associa a diverse patologie, tra cui malattie cardiovascolari, metaboliche, neurologiche, oncologiche, polmonari e gastrointestinali. Vi è una relazione bidirezionale tra depressione e malattie fisiche e la coesistenza di queste condizioni spesso rende più difficoltosa la diagnosi, peggiora la qualità della vita e determina minore aderenza al trattamento. I meccanismi sottostanti coinvolgono neuroinfiammazione, disfunzione autonomica, disregolazione metabolica e fattori comportamentali. La gestione farmacologica della depressione nei pazienti con comorbilità fisiche richiede un’attenta selezione degli antidepressivi per ridurre al minimo gli effetti avversi in una popolazione sicuramente più fragile e le possibili interazioni farmacologiche dovute alla terapia necessaria per ciascuna condizione. Sono dovute considerazioni particolari per i pazienti con insufficienza epatica e renale, poiché un metabolismo e una clearance alterati dei farmaci possono aumentare il rischio di tossicità o inefficacia terapeutica. Particolare attenzione è necessaria nelle donne in gravidanza e in allattamento, la selezione degli antidepressivi dipende infatti dalle condizioni cliniche della madre e dal rischio fetale e neonatale. Gli SSRI, come la sertralina, sono generalmente preferiti per il loro profilo di sicurezza relativamente favorevole; d’altra parte farmaci come paroxetina e fluoxetina richiedono cautela a causa dei potenziali rischi teratogeni e della maggiore escrezione attraverso il latte materno. Un approccio completo e multidisciplinare, basato su integrazione di assistenza psichiatrica e medica, è essenziale per migliorare i risultati e garantire un trattamento sicuro ed efficace della depressione negli individui con patologie mediche e in particolari momenti della vita.

Parole chiave. Antidepressivi, comorbilità, depressione, gravidanza.

Introduction

Depression is typically characterized by symptoms such as depressed mood, loss of interest or pleasure, sleep and appetite disturbances, fatigue, and difficulty concentrating1. Beyond its substantial impact on quality of life, depression is frequently associated with various medical conditions, establishing a bidirectional relationship that complicates both diagnosis and treatment2,3. A growing body of evidence demonstrates that depression and physical disorders commonly co-occur. This comorbidity is associated with a lower quality of life (QoL), worse outcomes for physical disorders, increased mortality, higher medical costs, greater disability, and a more profound functional impact than when either depression or a medical disease is present alone2,3.

Epidemiological studies have highlighted that depression is one of the most common comorbidities in several physical illnesses, including cancer, metabolic disorders such as diabetes, inflammatory diseases, neurological disorders, and cardiovascular diseases4,5. This bidirectional association implies that patients with depression have a higher risk of developing physical illnesses and vice versa4,5. The underlying mechanisms of this relationship involve behavioral, biological, and pharmacological factors4,5.

Depression does not manifest solely through psychological symptoms but frequently includes a range of physical symptoms4,5. Among these, fatigue and low energy levels are particularly common, significantly impairing an individual’s ability to perform daily activities6. Changes in appetite, which may present as either increased or decreased food intake, are also frequently observed in patients with depression7. Sleep disturbances, including both insomnia and hypersomnia, are another hallmark feature of depression, further exacerbating the overall burden of the disorder8.

These physical symptoms not only contribute to the overall distress experienced by patients but also complicate the diagnostic process, as they may be mistakenly attributed to medical conditions other than depression9. Studies have highlighted that such somatic manifestations often lead to underdiagnosis or misdiagnosis, particularly in primary care settings10.

Depression and physical diseases: from clinical presentation to treatment

Cardiovascular diseases

Cardiovascular diseases account for over 20.5 million deaths annually, representing 31% of global mortality11. Studies indicate that the prevalence of major depressive disorder (MDD) in patients with ischemic heart disease (IHD) ranges from 15% to 45%, with even higher rates observed in post-myocardial infarction (MI) and heart failure (HF) populations12. Depression is particularly prevalent in several cardiovascular conditions. In patient with IHD, MDD is 2-3 times more prevalent than in the general population13. Up to 40% of patients with heart failure experience depressive symptoms14. Moreover, MDD is associated with poor blood pressure control, increasing the risk of stroke and cardiovascular complications15. MDD also occurs in 15-20% of patients following a MI, contributing to higher mortality and reduced adherence to treatment16.

The bidirectional relationship between depression and cardiovascular diseases is driven by a complex interplay of physiological and behavioral mechanisms17. Autonomic dysfunction, inflammation, and endothelial impairment contribute to the cardiovascular risk associated with depression. Reduced heart rate variability, elevated cytokines such as interleukin-6 and tumor necrosis factor-alpha, and increased platelet aggregation promote atherosclerosis and thrombotic events17. Additionally, depression-related lifestyle factors, including physical inactivity, poor diet, smoking, and low adherence to treatments, further exacerbate cardiovascular risk17.

Choosing the appropriate antidepressant therapy for patients with cardiovascular conditions is complex and requires careful consideration of each drug’s cardiac safety profile.

Among SSRIs, sertraline is considered one of the safest options, as demonstrated by the SADHART trial18. Fluoxetine can also be used, with some studies indicating that it may be associated with a 7% increase in ejection fraction in patients with heart failure, potentially offering additional benefits19. Paroxetine, however, should be used with caution due to its anticholinergic effects and its association with increased appetite and weight gain, which are not recommended in patients with cardiovascular disease20. Citalopram and escitalopram require careful monitoring, as a 2011 Food and Drug Administration (FDA) warning highlighted their potential to prolong the QTc interval, increasing the risk of torsades de pointes and sudden cardiac death21. Concerning SNRIs, venlafaxine is associated with QTc prolongation and, along with duloxetine, can lead to increased blood pressure, requiring monitoring in hypertensive or high-risk cardiovascular patients21. For desvenlafaxine, there is currently insufficient data to determine its cardiovascular safety profile21. Among other antidepressants, bupropion does not appear to be associated with QTc prolongation at in-label doses and does not contribute to weight gain, making it a potential choice for patients requiring a stimulating antidepressant21-23. Trazodone can be used at low doses, but at higher doses, its active-metabolite mCPP exhibits tricyclic-like properties, potentially leading to cardiac concerns22,23.

Mirtazapine may be useful at low doses, particularly for patients with insomnia or appetite loss, but higher doses require caution22,23. Vortioxetine is a valuable antidepressant in this patient population due to its excellent tolerability profile and its efficacy in treating anhedonia, a symptom frequently associated with depression in cardiovascular patients24. TCAs should be avoided in cardiovascular patients due to their strong anticholinergic effects which can lead to reflex tachycardia, orthostatic hypotension, QTc prolongation, and an increased risk of sudden cardiac death21,23.

Pulmonary diseases

Depression is highly prevalent in chronic obstructive pulmonary disease (COPD) patients, with global estimates ranging from 10% to 42%25,26. The presence of depression in COPD patients is associated with higher mortality rates, increased hospitalizations, and worsened functional capacity. COPD-related hypoxia, systemic inflammation, and progressive disability contribute to the onset and persistence of depressive symptoms25,26. Patients with asthma also exhibit a high prevalence of depression, with studies indicating rates between 12% and 30%. Depression in asthma patients is associated with poor adherence to treatment, increased exacerbations, and decreased lung function27. Depression in interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF), has been reported in 23% to 49% of patients. The progressive and irreversible nature of ILD significantly contributes to psychological distress and reduced quality of life28.

Among SSRIs sertraline and fluoxetine and among SNRIs venlafaxine show efficacy but require monitoring for interactions with bronchodilators and corticosteroids.

Mirtazapine may be beneficial for patients experiencing insomnia or appetite loss, common in pulmonary diseases. Bupropion, a norepinephrine-dopamine reuptake inhibitor (NDRI), may be useful due to its minimal impact on serotonin pathways and absence of respiratory depression.

Trazodone can be considered for its sedative properties, particularly in patients with comorbid insomnia29. Vortioxetine, an antidepressant with multimodal serotonergic activity, has shown efficacy in improving cognitive dysfunction and anhedonia, common in patients with chronic diseases30. Finally Cognitive Behavioral Therapy (CBT) has been effective in reducing depressive symptoms and improving quality of life in patients with chronic pulmonary conditions.

Addressing the comorbidity of depression and pulmonary diseases requires a multidisciplinary approach, integrating medical, psychological, and rehabilitative strategies to optimize patient outcomes31.

Diabetes mellitus

Among endocrine disorders, diabetes mellitus is the condition most strongly associated with comorbid depression, demonstrating the highest prevalence and clinical impact32,33. Depression is twice as prevalent in individuals with diabetes compared to the general population, with estimated global prevalence rates ranging from 15% to 30%32,33. Studies have shown that patients with type 2 diabetes (T2DM) are more prone to depression than those with type 1 diabetes (T1DM), likely due to lifestyle factors, insulin resistance, and metabolic dysregulation32,33. Moreover individuals with diabetes and depression have an increased risk of cardiovascular mortality, likely due to inflammation and autonomic dysfunction32,33. Finally, chronic pain and nerve damage in diabetic neuropathy are associated with higher rates of depression32,33. Depression and diabetes share common pro-inflammatory pathways, including elevated levels of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-a). The hypothalamic-pituitary-adrenal (HPA) axis is overactive in both depression and diabetes, contributing to insulin resistance and metabolic disturbances. Finally, changes in dopaminergic, serotonergic, and noradrenergic systems play a role in both mood regulation and glucose metabolism34. Treating depression in patients with diabetes mellitus is challenging, as certain antidepressants, particularly TCAs and SSRIs, can impact glucose metabolism and insulin sensitivity, while others, like mirtazapine and paroxetine, contribute to weight gain and metabolic disturbances. Additionally, depression is linked to lower adherence to diabetes medications, leading to poor glycemic control and increased complications35.

Among SSRIs fluoxetine and sertraline have demonstrated efficacy in reducing depressive symptoms with minimal impact on glucose metabolism36-38. SNRIs are beneficial for neuropathic pain and depression but require glucose monitoring36-38. Bupropion, a NDRI, may be preferred due to its neutral or weight-reducing effect36-38. Tricyclic antidepressants (TCAs) should be used cautiously due to their hyperglycemic potential and cardiac risk in diabetic patients36-38. Metformin, traditionally used for diabetes, has been studied for its potential antidepressant effects, possibly due to its role in reducing neuroinflammation. CBT has been proven effective in treating depression and improving glycemic control36-38.

Oncological diseases

Depression is highly prevalent among cancer patients, with reported rates ranging from 15% to 25%, significantly higher than the general population39,40. Cancer types most frequently associated with depression include breast, lung, colorectal, and pancreatic cancers. Moreover, cancer-related pain, fatigue, and cachexia contribute to depressive symptoms39,40.

The pathophysiology of depression in cancer patients involves multiple biological mechanisms41. Tissue damage, chronic inflammation, and dysregulation of the HPA axis contribute to depressive symptoms41. Elevated pro-inflammatory cytokines, including interleukin-6 (IL-6) and TNF-α, have been implicated in the pathogenesis of both depression and cancer-related fatigue41. Additionally, iatrogenic factors, such as chemotherapy-induced neurotoxicity, corticosteroid use, and hormonal therapies, may exacerbate depressive symptoms41. The bidirectional interaction between chronic stress, neuroimmune modulation, and oncogenesis underscores the complexity of this comorbidity41.

Distinguishing clinical depression from cancer-related symptoms is complex due to significant overlap. Fatigue, weight loss, cognitive impairment, and sleep disturbances are common in both conditions, complicating diagnosis41,42. While cancer-related fatigue is persistent and independent of mood, depression-associated fatigue is often linked to anhedonia and emotional distress. Similarly, weight loss in cancer stems from metabolic dysregulation or cachexia, whereas in depression, it is driven by appetite changes and reduced motivation41,42. Cognitive impairment (“chemo brain”) and sleep disturbances also present challenges in differentiation41,42. Additionally, psychological factors contribute to underdiagnosis41,42. Patients, caregivers, and clinicians often attribute mood disturbances to cancer itself, normalizing emotional distress as an expected reaction rather than recognizing it as clinical depression41,42. Stigma surrounding mental health further discourages patients from reporting symptoms, fearing it may be perceived as a sign of weakness or distract from oncological care41,42. These factors necessitate a nuanced, multidisciplinary approach to improve detection and management41,42.

When selecting psychopharmacological therapy for patients with comorbid cancer and depression, it is crucial to consider not only the common side effects of psychiatric medications but also their potential interactions with oncological treatments41,43. One of the most well-documented interactions involves tamoxifen, a selective estrogen receptor modulator used in breast cancer, and certain antidepressants, particularly paroxetine41,43,44. Paroxetine inhibits cytochrome CYP2D6, the enzyme responsible for converting tamoxifen into its active metabolite endoxifen, thereby reducing its antitumor efficacy41,43,44. Fluoxetine and, to a lesser extent, fluvoxamine have similar inhibitory effects on CYP2D6, though to a lesser degree41,43,44.

In these cases, sertraline is often preferred as it has a lower impact on tamoxifen metabolism, though some interaction may still occur41,43,44,45.

Vortioxetine, an antidepressant recognized for its favorable tolerability profile and its efficacy in addressing anhedonia, represents a valid alternative in these complex scenarios30.

For oncological patients undergoing hormonal therapies – which may exacerbate PMS-like symptoms – SNRIs such as venlafaxine can be beneficial41,43. In addition to their antidepressant effects, SNRIs also provide relief in pain management, which is particularly relevant in this patient population41,43. For patients experiencing fatigue and lack of energy, bupropion may be indicated due to its activating properties41,43.

Regarding the TCAs, they can be particularly useful in managing neuropathic pain and insomnia, but their use is often limited due to a less favorable tolerability profile compared to other antidepressant classes41,43. However, their anticholinergic properties can be leveraged to counteract diarrhea induced by oncological pathology or chemotherapy41,43.

Neurological disorders

Depression affects approximately 30%-50% of patients with neurological disorders46-48. Depression is frequently observed in patients with major neurocognitive disorder (Alzheimer’s disease), post-stroke, Parkinson’s disease, Huntington’s disease, multiple sclerosis (MS), traumatic brain injury (TBI) and epilepsy46-48.

The presence of depression in patients with neurological disorders significantly affects disease outcomes46-48. It is associated with reduced quality of life, increased functional impairment, and higher mortality rates. Depression can also complicate the management of neurological conditions by diminishing treatment adherence and hindering rehabilitation efforts46-48. Moreover, it may amplify cognitive deficits and contribute to a greater overall disease burden46-48. Addressing depression in the context of neurological disorders is crucial, as effective management can lead to improved patient outcomes, enhanced quality of life, and better overall disease prognosis46-48.

Neuroinflammation, neurodegeneration, and neurotransmitter imbalances contribute to the bidirectional relationship between neurological disorders and depression. Depression can be elicited by neurological illnesses, and conversely, depression may increase the risk of developing certain neurological disorders46-48.

Chronic inflammation within the central nervous system is a common feature in both depression and various neurological disorders49. Elevated levels of pro-inflammatory cytokines can alter neurotransmitter metabolism and neural plasticity, leading to mood disturbances49. This neuroinflammatory process is considered a significant pathophysiological mechanism underlying depression49.

Neuroimaging studies have identified structural and functional abnormalities in specific brain regions involved in mood regulation among individuals with depression and neurological disorders. For example, alterations in the dorsal nexus, an area within the dorsomedial prefrontal cortex, have been associated with increased connectivity between brain networks, potentially contributing to depressive symptoms50.

Depression is often associated with imbalances in neurotransmitters such as serotonin, norepinephrine, and dopamine51. Neurological disorders can disrupt these neurotransmitter systems, contributing to depressive symptoms51. For instance, diminished dopaminergic neurotransmission has been implicated in major depression51. For example dopaminergic and serotonergic dysregulation plays a crucial role in depression associated with Parkinson’s disease and stroke51.

In the context of neurological disorders comorbid with depression, the choice of antidepressant is critical and requires careful consideration, with attention to potential risks such as serotonin syndrome and QT prolongation47. SSRIs and SNRIs are generally well tolerated; however, they may increase apathy, agitation, or insomnia and may exacerbate motor symptoms, especially in Parkinson’s disease47. In such cases, sertraline is preferable, as at higher doses it also increases dopamine levels, or venlafaxine, which can reduce muscle tension and improve psychomotor retardation47.

Attention must be given to the potential anticholinergic effects of various classes of antidepressants, particularly TCAs and SSRIs such as paroxetine, as these can not only cause constipation, urinary retention, and dry mouth but also significantly worsen the patient’s cognitive profile. Among TCAs, those with the lowest anticholinergic burden include nortriptyline and desipramine47,52.

Another important consideration is the potential lowering of the seizure threshold associated with certain antidepressants, such as clomipramine or bupropion53.

Trazodone may be beneficial for the behavioral and psychological symptoms of dementia54.

Vortioxetine has an excellent tolerability profile with pro-cognitive effects due to its action on the 5-HT7 receptor and anti-anhedonic properties via 5-HT3 antagonism55. Ketamine and esketamine have been shown to exert neurotrophic effects, potentially increasing brain-derived neurotrophic factor (BDNF) levels and promoting synaptic plasticity56,57. This suggests their potential in treating neurological disorders. However, further clinical trials are necessary to evaluate their efficacy and safety in neurological contexts.

Monoamine oxidase inhibitors (MAO-Is) are rarely used due to their poor tolerability profile and dietary58.

Gastroenterological diseases

Depression is highly prevalent among patients with gastrointestinal (GI) disorders, with rates between 30% and 50% particularly in irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and gastroesophageal reflux disease (GERD)59.

A mendelian randomization analysis has found that a genetic predisposition to depression is associated with an increased risk of several gastrointestinal diseases, suggesting a potential causal relationship60. The gut-brain axis plays a pivotal role in the interplay between depression and GI diseases. The brain-gut-microbioma-axis (BGMA) facilitates two-way communication between the central nervous system and the enteric nervous system through immune, endocrine, neural, and metabolic pathways. Altered gut microbiota composition, increased intestinal permeability, and dysregulation of the vagus nerve contribute to depressive symptoms. Chronic inflammation and elevated circulating cytokines further exacerbate the disease burden59.

SSRIs such as sertraline, fluoxetine, and escitalopram are first-line treatments for depression and have demonstrated efficacy in GI disorders, particularly IBS and functional dyspepsia61. They enhance serotonergic transmission, which may modulate visceral hypersensitivity and improve motility61. However, SSRIs can cause diarrhea and nausea, which may exacerbate symptoms in some patients61.

SNRIs such as duloxetine and venlafaxine are effective for depression and may be particularly useful in GI disorders with a pain component, such as IBS and IBD62. Duloxetine has shown benefit in neuropathic pain and visceral hypersensitivity, but its potential to induce gastric irritation and constipation necessitates careful patient selection62. TCAs such as amitriptyline and nortriptyline are widely used in patients with IBS with diarrhea-predominance (IBS-D) and functional GI pain syndromes62. Their anticholinergic properties help reduce diarrhea and visceral pain. However, they may worsen constipation, cause weight gain, and induce sedation, which limits their use in patients with IBS with constipation-predominance (IBS-C) and GERD62.

Mirtazapine, an atypical antidepressant with noradrenergic and serotonergic effects, is beneficial in patients with functional dyspepsia and weight loss associated with GI disorders62. It enhances appetite and has antiemetic properties, making it suitable for patients experiencing nausea and anorexia62.

Bupropion, a NDRI, has minimal serotonergic activity, making it less likely to exacerbate GI symptoms such as diarrhea63. It is a preferred option for patients with comorbid depression and fatigue or anhedonia. However, it may induce gastric irritation and increase anxiety in some patients63.

Vortioxetine, a multimodal serotonergic agent, has shown pro-cognitive effects and may be beneficial in patients with depression and GI disorders. While it has a lower likelihood of causing GI side effects, some patients report mild nausea, particularly at higher doses64.

Psychopharmacology in special populations

Older adults

Epidemiological data

The prevalence of late-life depression (LLD) significantly varies across the world65. A recent epidemiological meta-analysis of 57,486 older adults estimated the average prevalence of LLD at 31.8%. Subgroup analysis revealed a higher pooled prevalence in developing countries (40.78%) compared to developed countries (17.05%)66.

Differential diagnosis between depression and other conditions (es. dementia)

LLD and neurocognitive disorders (NCDs) are prevalent among the elderly, posing considerable challenges in both differential diagnosis and treatment. Despite its significant impact, LLD is often underdiagnosed and underestimated, where in contrast, NCDs are categorized under the “Neurocognitive Disorders” section of the DSM-5, alongside delirium, and are further divided into major and mild NCDs67. Late-life depressive symptoms are linked to an increased likelihood of a subsequent dementia diagnosis and may represent an early manifestation or a reaction to preclinical neurodegenerative processes68. Recent neuroimaging research has identified specific structural and functional brain changes that may help differentiate depression from early dementia, including patterns of hippocampal atrophy and altered connectivity in the default mode network. Findings indicate disrupted connectivity patterns within the prefrontal branch of the default-mode network in acutely depressed elderly individuals69. This altered functional connectivity is significantly associated with increased white-matter hyperintensity volume69. Additionally, a partial restoration of functional connectivity in the default-mode network following a positive treatment response has been observed69. LLD and mild cognitive impairment are associated with medial temporal lobe structural abnormalities. Distinct abnormalities in hippocampal functional networks are observed in both LLD and mild cognitive impairment when they occur independently70. However, when these conditions coexist, the hippocampal networks exhibit greater dysfunction, potentially serving as a marker of disease severity and an indicator of impending cognitive decline70.

Polypharmacy challenges

In older adults, depression is frequently misdiagnosed, resulting in suboptimal or inappropriate treatment. The efficacy and safety of pharmacotherapy in older adults differ from those in younger individuals due to several factors. These include age-related physiological changes affecting pharmacodynamics and pharmacokinetics, a high prevalence of comorbid conditions and an increased risk of drug interactions due to polypharmacy71. Antidepressants frequently interact with other medications during metabolic processes, primarily through the hepatic CYP system. The heightened risk of adverse drug events (ADEs) may partly result from dosing regimens that fail to consider age-related pharmacokinetic changes and drug interactions72.

Due to the increased likelihood of polypharmacy in older adults when selecting therapy, it is important to consider the potential for drug-drug interactions72. Therapeutic drug monitoring (TDM) is a valuable tool in managing depression in this patient population, enabling personalized dose adjustments to enhance efficacy while minimizing adverse effects72. TDM involves measuring drug concentrations in serum or other body fluids to ensure optimal therapeutic outcomes with minimal side effects. It aids in identifying drug interactions, understanding treatment resistance, and assessing the influence of genetic variability73. Given these challenges, there is a growing focus on individualized therapy, with TDM playing a crucial role in optimizing treatment and reducing adverse effects73.

Evidence-based treatment approaches

Variations in pharmacokinetics may lead to distinct antidepressant effects in older adults. Age-related metabolic changes can influence the concentration of active substances by affecting drug metabolism and elimination. For instance, aging is associated with a gradual decline in liver mass and blood flow, as well as a continuous reduction in renal creatinine clearance, which can impact drug processing and excretion71. Citalopram, escitalopram, and sertraline are the SSRIs with the most favorable safety profile for elderly patients, as they have the lowest potential for drug-drug interactions based on their cytochrome P-450 metabolism. Additionally, venlafaxine, mirtazapine, and bupropion are considered relatively safe regarding drug interactions74. In contrast, SSRIs such as fluoxetine, paroxetine, and fluvoxamine carry a higher risk of drug-drug interactions74. Sertraline has the strongest evidence supporting its use in older adults with depression who are on polypharmacy75.

Pregnancy

Epidemiological data

The World Health Organization reports that approximately 10% of pregnant women and 13% of postpartum women experience mental disorders, primarily depression. In developing countries, these rates are even higher, reaching 16% during pregnancy and 20% after childbirth. Despite variations in study design and methodology, research on postpartum depression consistently indicates a high global prevalence, estimated between 10% and 20% during the perinatal period76. Prenatal depression poses significant risks to both maternal and fetal health and heightens the likelihood of postpartum depression. If left untreated during pregnancy, depression is associated with adverse outcomes, including an increased risk of suicidal ideation, miscarriage, and neonatal growth complications77. Moreover, gestational bleeding, spontaneous abortion, increased uterine artery resistance, low Apgar scores, neonatal intensive care unit admission, impaired fetal growth, preterm labor, fetal death, low birth weight, small-for-gestational-age infants, perinatal and birth complications, preterm delivery, and elevated cortisol levels in newborns at birth can occur77.

Evidence-based treatment approaches

During pregnancy, SSRIs and SNRIs are the most frequently prescribed antidepressants. SSRIs, including citalopram, escitalopram, paroxetine, and fluoxetine, as well as the SNRI duloxetine, have been linked to maternal comorbidities and potential risks to the embryo78. However, research has shown that sertraline is effective in this population, with comparatively lower associated risks79. Sertraline has an exceptional safety profile, noting its reliability even during pregnancy and lactation79.

Approximately one-third of neonates exposed to SSRIs during pregnancy require careful monitoring, emphasizing the importance of individualized treatment strategies80. Paroxetine remains particularly concerning, with multiple studies consistently highlighting its elevated risk of cardiac malformations, while fluoxetine’s prolonged half-life and enhanced placental transfer continue to make it a less favorable choice for pregnant patients managing depressive symptoms81.

Breastfeeding

Epidemiological data

The prevalence of postpartum depression is estimated to range from 5.0% to 26.32%, depending on the country82, while antidepressant prescription rates during the postpartum period are approximately between 2.4% and 4.1%83. Recent epidemiological data reveals a complex landscape of antidepressant use during breastfeeding, with approximately 10-15% of postpartum women requiring pharmacological intervention for mood disorders84.

Evidence-based treatment approaches

A review of Arbitman et al. highlights significant variations in infant exposure to antidepressants, demonstrating that mothers taking SSRIs are 60% more likely to discontinue breastfeeding due to concerns about potential infant risks85.

The consensus among recent systematic reviews suggests that sertraline and paroxetine exhibit the most favorable risk-benefit profiles, with minimal infant exposure through breast milk86. The consensus panel recommendations from 2024 emphasize that while only one comprehensive meta-analysis and 69 case studies provide definitive insights, the overall risk to breastfed infants appears relatively low when appropriate medication selection and dosing are implemented86.

In terms of infant risk, the relative infant dose (RID) for most SSRIs remains below the critical 10% threshold, with sertraline exhibiting the lowest transfer levels87. A systematic review on neonatal outcomes highlights potential short-term effects, such as mild behavioral changes, transient adaptation symptoms, and minimal neurological differences87. These considerations must be weighed against the significant benefits of breastfeeding, including strengthened maternal-infant bonding, enhanced immune function in infants, and potential protective effects against postpartum depression87. Medications to avoid during breastfeeding include fluoxetine due to its long half-life and higher infant exposure, venlafaxine with its potential for increased infant irritability, and all monoamine oxidase inhibitors87. Clinicians should prioritize sertraline and citalopram as first-line options, with careful monitoring of infant development and maternal mental health88.

Hepatic and renal failure

Antidepressants may undergo hepatic and/or renal metabolism.

Hepatic metabolism

Concerning hepatic metabolism antidepressants primarily are metabolised through phase I and phase II enzymatic processes, to facilitate their elimination from the body. Phase I metabolism involves oxidation, reduction, and hydrolysis reactions, primarily mediated by cytochrome P450 (CYP) enzymes. These reactions introduce or expose functional groups, increasing the polarity of the drug, and in some cases, produce active metabolites with pharmacological effects89.

Among antidepressants fluoxetine is metabolized by CYP2D6 to its active metabolite, norfluoxetine, which has a prolonged half-life and contributes to the drug’s efficacy90. Paroxetine is primarily metabolized by CYP2D690. Sertraline undergoes metabolism by CYP3A4, producing an active metabolite, desmethylsertraline, with a much lower pharmacological activity than the parent drug90. Trazodone is also metabolized by CYP3A4, forming the active metabolite mCPP (meta-chlorophenylpiperazine), which contributes to its serotonergic effects but may also increase the risk of serotonin syndrome90. Fluvoxamine is metabolized by CYP1A2 and CYP2C1990. Finally citalopram and escitalopram are metabolized primarily via CYP2C19, with minor contributions from CYP3A4 and CYP2D690.

Phase II metabolism involves conjugation reactions that further enhance drug elimination by increasing water solubility. These reactions include glucuronidation, sulfation, acetylation, and methylation. Lorazepam and oxazepam, often prescribed for depression-associated anxiety, undergo direct glucuronidation via UGT2B15, making them suitable for patients with hepatic impairment91. Sertraline and venlafaxine are also metabolized via glucuronidation, contributing to their renal excretion90.

The clinical implications of considering the hepatic antidepressant metabolism have an impact on drug-drug interactions, for example CYP3A4 substrates like sertraline interact with enzyme CYP 3A4 inducers such as carbamazepine and rifampin, reducing their efficacy; CYP2D6 inhibitors such as fluoxetine and paroxetine increase plasma levels of TCAs, requiring dose adjustments92. Finally patients with hepatic impairment who takes drugs primarily undergoing phase I metabolism (e.g., fluoxetine, paroxetine) may require dose adjustments in liver disease, whereas phase II-metabolized drugs (e.g., lorazepam, oxazepam) remain largely unaffected92.

Renal metabolism

The renal metabolism of antidepressants is a critical consideration in clinical psychopharmacology, particularly for patients with impaired kidney function. While many antidepressants undergo extensive hepatic metabolism, the kidneys play a significant role in the excretion of both parent compounds and their metabolites93. In cases of renal impairment, the accumulation of these substances can lead to increased plasma concentrations and heightened risk of adverse effects93.

Among SSRIs, sertraline is primarily metabolized hepatically with minimal renal excretion, making it a suitable option for CKD patients without significant dose adjustments94.

Regarding citalopram although the parent drug is hepatically metabolized, approximately 15% of its metabolites are excreted renally95. In patients with moderate to severe renal impairment, accumulation of these metabolites has been reported, but dose adjustments are generally not required unless there is severe renal dysfunction. Concerning escitalopram being the S-enantiomer of citalopram, it follows a similar hepatic metabolic pathway, with 8% excreted renally as unchanged drug and the rest as metabolites96.

While dose adjustments are not necessary in mild-to-moderate renal impairment, caution is advised in end-stage renal disease (ESRD), where reduced clearance of metabolites may increase the risk of side effects, including QT prolongation.

In patients with renal impairment, studies have shown that the pharmacokinetics of fluoxetine and norfluoxetine are not significantly altered. Research involving depressed patients undergoing hemodialysis demonstrated that steady-state plasma concentrations of fluoxetine and norfluoxetine were comparable to those in patients with normal renal function97. This suggests that neither renal failure nor the hemodialysis process substantially affects the metabolism or elimination of fluoxetine and its major metabolite97.

In patients with renal impairment, particularly those with creatinine clearance below 30 mL/min, plasma concentrations of paroxetine can be approximately four times higher than in individuals with normal renal function98. This increase is due to reduced clearance of the drug and its metabolites. Therefore, it is recommended to reduce the initial dosage in patients with severe renal impairment and adjust upward cautiously if necessary98.

Concerning SNRIs in patients with renal impairment, the clearance of both venlafaxine and desvenlafaxine is reduced, leading to increased plasma concentrations and prolonged elimination half-lives. Consequently, dosage adjustments are recommended for patients with moderate to severe renal impairment, including those undergoing hemodialysis99. Specifically, it is advised to reduce the total daily dose by 25% to 50% in patients with creatinine clearance less than 70 mL/min99.

In patients with mild to moderate renal impairment (creatinine clearance ≥30 mL/min), pharmacokinetic studies have shown that dose adjustments for duloxetine are not necessary. However, in patients with end-stage renal disease (ESRD) or severe renal impairment (creatinine clearance <30 mL/min), the exposure to duloxetine and its metabolites is expected to increase. Therefore, duloxetine is not generally recommended for these patients100.

Conclusions

The intricate relationship between physical and psychiatric pathologies necessitates a comprehensive and personalized therapeutic approach. Emerging evidence underscores the bidirectional influence between somatic diseases and mental health disorders, highlighting the imperative for integrated treatment strategies.

Personalized medicine in psychiatry emphasizes tailoring interventions based on an individual’s unique physiological and psychological characteristics. This approach aims to predict susceptibility to illnesses, ensure accurate diagnoses, and optimize therapeutic responses. Factors such as genetic variations, clinical symptomatology, biomarkers, and environmental influences are pivotal in customizing treatment plans. For instance, a study demonstrated that personalized therapeutic plans significantly improved the quality of life and reduced psychological symptoms in patients with advanced colonic cancer requiring palliative care101.

The development of novel pharmacological agents is also crucial, particularly for populations with specific needs. Recent advancements have introduced rapid-acting antidepressants targeting non-traditional pathways, offering hope for treatment-resistant cases. For example, esketamine nasal spray has been approved as a standalone therapy for adults with treatment-resistant depression, providing an alternative for patients who cannot tolerate or do not respond to oral antidepressants102.

In conclusion, bridging the gap between physical and psychiatric care through personalized treatment strategies and the development of novel, safe pharmacological options holds promise for improving patient outcomes across various populations.

Conflict of interests: AC and AF wish to disclose that in the last five years they have received lectures and advisory board honoraria or have engaged in clinical trial activities with the following companies, all of which are unrelated to this article. In particular, AC: Angelini, GlaxoSmithKline, Italfarmaco, Lundbeck, Janssen, Mylan, Neuraxpharm, Otsuka, Pfizer, Recordati, Sanofi Aventis, Viatris; AF: Angelini, Aspen, Biogen, Boehringer Ingelheim, Janssen, Lundbeck, Neuraxpharm, Otsuka, Pfizer, Recordati, Viatris. The other authors have no conflict of interests to declare.

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