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The phenomenology and treatment of interferon-induced depression
Abstract
Interferon (IFN)-alpha, IFN-beta, and IFN-gamma are currently available for the treatment of malignancies, viral infections (e.g., hepatitis C virus), multiple sclerosis (MS), and skin conditions. In addition to their therapeutic effects, IFNs commonly cause various side effects. Most common among the side effects of IFN are "flu-like" symptoms such as chills, fever, and muscle soreness. However, IFN can also cause significant neuropsychiatric side effects, particularly symptoms of depression. A literature search was conducted in order to summarize current information on (1) the frequency, characteristics, and risk factors of IFN-induced depression, (2) possible biochemical mechanisms associated with IFN-induced depression, and (3) the treatment strategies for IFN-induced depression. Review of the literature suggests that symptoms of depression induced by IFN therapy, in particular IFN-alpha therapy, are common and can limit the treatment utility, often necessitating discontinuation of IFN therapy or the use of psychopharmacologic agents. Depression is also a suspected side effect of therapy with IFN-beta and IFN-gamma; however, the association has not been as convincingly confirmed. Importantly, IFNs affect neurochemical pathways putatively involved in the etiology of depression. While these depressive side effects usually resolve after the completion of IFN therapy, they can persist or reappear with dose escalations. It is recommended that health care providers, patients and their families be informed about the potential risk of the psychiatric disturbances that can occur with IFN-alpha therapy. Screening and monitoring, ideally using symptom rating scales for depression, and early antidepressant treatment intervention appear necessary to optimize IFN therapy for the majority of patients.
... To target pro-inflammatory cytokines and their signaling path-ways showed as a novel approach to treat and manage depressive disorders suggested by these findings (Figure 1.3) [Raison et al., 2006]. [Loftis and Hauser, 2004]. In the animal model, antidepressant-like effects can be produced by blocking pro-inflammatory cytokine-mediated signaling [Krishnan and Nestler, 2008]. ...
... IFN-α is widely applied for malignancies, including malignant melanoma and renal cell carcinoma as well as chronic viral infections (e.g., hepatitis C virus) and myeloproliferative disorders. IFN-β is a standard treatment for relapsing multiple sclerosis (MS), and IFN-γ therapy is currently applied for chronic granulomatous disease and skin lesions [Loftis and Hauser, 2004]. In addition to their therapeutic effects, IFNs induce some toxicities, including symptoms associated with depression such as fatigue, insomnia, irritability, loss of appetite as well as cognitive changes. ...
Background: Major depressive disorder (MDD) is a heterogeneous psychiatric illness manifested by symptoms such as depressed mood, a feeling of weakness, and diminished interest in daily activities. MDD is one of the leading psychiatric diseases but it lacks biological markers for diagnosis. Currently, MDD is diagnosed by evaluation of some structured questions asked a qualified psychiatrist or self-answered; sometimes abnormal behavior delineated by family members or relatives. Any established quantitative test is unavailable to diagnose depression, it is anticipated that the current study may be helpful to diagnose and manage MDD in a better way. Objective: The study aimed to investigate the serum levels of pro-inflammatory cytokine IFN-γ in patients with MDD and healthy controls and make a comparison between them. After that, we focused on the diagnostic performance of the altered parameters. Eventually, we tried to find out the association between serum levels of pro-inflammatory cytokine IFN-γ with the severity of the disease to make out the result more reliable.
... Decreased infiltration of immune cells may also contribute to slower wound healing associated with MA use [41]. Peripheral inflammation is known to play a role in mental health as we and others have described [1,7,42,43]. Inflammation-induced mental dysfunction is most clearly observed in conditions such as cancer or hepatitis, where patients are treated with a pro-inflammatory mediator such as interferon-α [42,[44][45][46], and, more recently, in the context of substance use disorders [1,47,48]. ...
... Peripheral inflammation is known to play a role in mental health as we and others have described [1,7,42,43]. Inflammation-induced mental dysfunction is most clearly observed in conditions such as cancer or hepatitis, where patients are treated with a pro-inflammatory mediator such as interferon-α [42,[44][45][46], and, more recently, in the context of substance use disorders [1,47,48]. Thus, reduced CCL3 may lead to slower wound healing, thereby resulting in persistent infection and a prolonged period of inflammatory signaling, which may result in ongoing symptoms of depression, anxiety and memory impairment. ...
Background:
Methamphetamine (MA) abuse causes immune dysfunction and neuropsychiatric impairment. The mechanisms underlying these deficits remain unidentified.
Methods:
The effects of MA on anxiety-like behavior and immune function were investigated in mice selectively bred to voluntarily consume high amounts of MA [i.e., MA high drinking (MAHDR) mice]. MA (or saline) was administered to mice using a chronic (14-day), binge-like model. Performance in the elevated zero maze (EZM) was determined 5 days after the last MA dose to examine anxiety-like behavior. Cytokine and chemokine expressions were measured in the hippocampus using quantitative polymerase chain reaction (qPCR). Human studies were also conducted to evaluate symptoms of anxiety using the General Anxiety Disorder-7 Scale in adults with and without a history of MA dependence. Plasma samples collected from human research participants were used for confirmatory analysis of murine qPCR results using an enzyme-linked immunosorbent assay.
Results:
During early remission from MA, MAHDR mice exhibited increased anxiety-like behavior on the EZM and reduced expression of chemokine (C-C motif) ligand 3 (ccl3) in the hippocampus relative to saline-treated mice. Human adults actively dependent on MA and those in early remission had elevated symptoms of anxiety as well as reductions in plasma levels of CCL3, relative to adults with no history of MA abuse.
Conclusions:
The results highlight the complex effects of MA on immune and behavioral function and suggest that alterations in CCL3 signaling may contribute to the mood impairments observed during remission from MA addiction.
... It is possible that the frequency of major depression and related symptoms observed before antiviral treatment reflect, at least in part, the clinical background of the patients. It is well documented in the literature that the frequency of depression and depressive symptoms increases over the course of interferon based treatment [39][40][41], but returns to baseline levels after the cessation of treatment, indicating the reversibility of these symptoms, observations confirmed by this study. Recently Huckans et al. also reported increased symptoms of depression during interferon therapy in a cohort of 33 HCV infected patients, which decreased or remitted following treatment discontinuation [42]. ...
... It is notable that hemolytic anemia induced by ribavirin is common during antiviral treatment, contributing to the somatic effects of depression. An American study with 32 patients concluded that interferon exacerbates somatic depressive symptoms [39]. However, the major limitation of this study pertains to the fact that the data were not controlled for anemia, and only US war veterans were included in the study, which is possibly not a representative sample of the population infected with HCV. ...
Background
Chronic hepatitis C virus (HCV) infection is associated with impairment of cognitive function and mood disorders. Our aim was to evaluate the impact of sustained virological response (SVR) on cognitive function and mood disorders. MethodA prospective exploratory one arm study was conducted. Adult clinically compensated HVC patients were consecutively recruited before treatment with interferon and ribavirin for 24 to 48 weeks, according to HCV genotype. Clinical, neurocognitive and mood assessments using the PRIME-MD and BDI instruments were performed at baseline, right after half of the expected treatment has been reached and 6 months after the end of antiviral treatment. Exclusion criteria were the use of illicit psychotropic substances, mental confusion, hepatic encephalopathy, hepatocellular carcinoma, severe anemia, untreated hypothyroidism, Addison syndrome and major depression before treatment. ResultsThirty six patients were enrolled and 21 completed HCV treatment (n = 16 with SVR and n = 5 without). Regardless of the viral clearance at the end of treatment, there was a significant improvement in the immediate verbal episodic memory (p = 0.010), delayed verbal episodic memory (p = 0.007), selective attention (p < 0.001) and phonemic fluency (p = 0.043). Patients with SVR displayed significant improvement in immediate (p = 0.045) and delayed verbal episodic memory (p = 0.040) compared to baseline. The baseline frequency of depression was 9.5%, which rose to 52.4% during treatment, and returned to 9.5% 6 months after the end of treatment, without significant difference between patients with and without SVR. Depressive symptoms were observed in 19.1% before treatment, 62% during (p = 0.016) and 28.6% 6 months after the end of treatment (p = 0.719). Conclusions
Eradication of HCV infection improved cognitive performance but did not affect the frequency of depressive symptoms at least in the short range.
... For instance, administering interferon as a treatment for hepatitis C can trigger or exacerbate psoriasis while also commonly causing depression as a side effect. [7][8] Conversely, reports suggest that certain psoriasis treatments, such as tumor necrosis factor (TNF) inhibitors [9][10] or an interleukin-12 and 23 inhibitor, [11] can improve mood symptoms. discomfort associated with psoriatic lesions can profoundly impact self-image and quality of life. ...
Psoriasis is a chronic inflammatory skin condition that can severely diminish a patient's quality of life. Beyond the physical manifestations, psoriasis has been linked to an increased risk of psychological comorbidities like depression. This review aims to synthesize the available evidence examining the relationship between psoriasis and depression. Methods: A comprehensive literature search across multiple electronic databases (PubMed, PsycINFO, Embase) was conducted to identify relevant studies exploring the association between psoriasis and depressive symptoms or disorders. Both observational studies and intervention trials were included. Results: Numerous cross-sectional and longitudinal studies consistently report a higher prevalence of depression among individuals with psoriasis compared to the general population. The risk and severity of depressive symptoms appear positively correlated with the extent of psoriasis lesions and degree of psychosocial impairment. Potential underlying mechanisms discussed include psychosocial factors (stigma, low self-esteem), biological factors (inflammatory processes, cytokine dysregulation), and shared genetic predisposition. However, the causal direction remains unclear. Limited intervention data suggests effective psoriasis treatment may help alleviate coexisting depressive symptoms. Conclusion: This review highlights the substantial psychological burden associated with psoriasis, underscoring the importance of routine screening and appropriate management of depressive disorders in this patient population. An integrated multidisciplinary approach combining dermatological treatment with psychological interventions may enhance overall well-being and quality of life.
... Interferons have been investigated for use in other types of cancer, with mixed results. While they can induce tumor cell death and stimulate immune responses, they can also have significant side effects, such as flu-like symptoms and depression [19]. Interleukin-2 (IL-2) plays a critical role in priming tumorinfiltrating lymphocytes for the treatment of cancers such as non-small cell lung cancer and metastatic melanoma [20,21]. ...
Purpose of Review
This review aims to synthesize the latest advances in immunotherapeutic cancer treatment approaches and spotlight groundbreaking discoveries and clinical trial outcomes.
Recent Findings
Immunotherapy represents a promising and transformative strategy for treating a variety of hematological malignancies and solid tumors. This therapeutic approach strives to bolster the body's inherent defense mechanisms to elicit enduring, specific, and individualized anti-tumor responses by harnessing the immune system's ability to identify and eradicate cancer cells. Various modes of immunotherapy—including monoclonal antibodies, immune checkpoint inhibitors, cancer vaccines, adoptive T-cell therapies, and oncolytic viruses—have achieved considerable success in clinical trials and patient results.
Summary
Despite notable successes, challenges persist in the broader adoption of immunotherapy. Issues such as resistance mechanisms, tumor heterogeneity, and the complexity of the tumor microenvironment can weaken immune responses and constrain the efficacy of treatments. The current review is dedicated to understanding these obstacles and devising comprehensive strategies to surmount resistance and secure sustained responses.
... Yakın zamanda yapılan başka bir çalışmada, NLR ile intihar davranışı arasında önemli bir ilişki bulunmuştur (Velasco et al., 2020). Majör depresyonun C Reaktif Protein (CRP), Tümör Nekroz Faktörü-alfa (TNF-alfa), Interleukin-6 (IL-6) ve Interleukin-1 (IL-1) gibi inflamatuar belirteçlerle ilişkili olabileceği gösterilmiş olmasına rağmen, bu belirteçlerin etiyolojideki rolü henüz tam olarak aydınlatılamamıştır (Cepeda MS, 2016;Loftis JM, 2004). Bu noktada elde edilen veriler ışığında inflamatuar sitokinlerin rolü ve hücre yüzeyindeki ACE-2 reseptörlerinin varlığı, COVID-19 ve depresyon arasındaki ortak patofizyolojik mekanizmada önemli bir yere sahip olduğu düşünülebilir (da Silva Lopes et al., 2021). ...
... Yakın zamanda yapılan başka bir çalışmada, NLR ile intihar davranışı arasında önemli bir ilişki bulunmuştur (Velasco et al., 2020). Majör depresyonun C Reaktif Protein (CRP), Tümör Nekroz Faktörü-alfa (TNF-alfa), Interleukin-6 (IL-6) ve Interleukin-1 (IL-1) gibi inflamatuar belirteçlerle ilişkili olabileceği gösterilmiş olmasına rağmen, bu belirteçlerin etiyolojideki rolü henüz tam olarak aydınlatılamamıştır (Cepeda MS, 2016;Loftis JM, 2004). Bu noktada elde edilen veriler ışığında inflamatuar sitokinlerin rolü ve hücre yüzeyindeki ACE-2 reseptörlerinin varlığı, COVID-19 ve depresyon arasındaki ortak patofizyolojik mekanizmada önemli bir yere sahip olduğu düşünülebilir (da Silva Lopes et al., 2021). ...
... Yakın zamanda yapılan başka bir çalışmada, NLR ile intihar davranışı arasında önemli bir ilişki bulunmuştur (Velasco et al., 2020). Majör depresyonun C Reaktif Protein (CRP), Tümör Nekroz Faktörü-alfa (TNF-alfa), Interleukin-6 (IL-6) ve Interleukin-1 (IL-1) gibi inflamatuar belirteçlerle ilişkili olabileceği gösterilmiş olmasına rağmen, bu belirteçlerin etiyolojideki rolü henüz tam olarak aydınlatılamamıştır (Cepeda MS, 2016;Loftis JM, 2004). Bu noktada elde edilen veriler ışığında inflamatuar sitokinlerin rolü ve hücre yüzeyindeki ACE-2 reseptörlerinin varlığı, COVID-19 ve depresyon arasındaki ortak patofizyolojik mekanizmada önemli bir yere sahip olduğu düşünülebilir (da Silva Lopes et al., 2021). ...
... Since then, interferons have been investigated for use in other types of cancer, with mixed results. While they can induce tumor cell death and stimulate immune responses, they can also have significant side effects, such as flu-like symptoms and depression (10). Despite these challenges, interferons remain an important part of the cancer immunotherapy arsenal and are being explored in combination with other immunotherapeutic agents to enhance their efficacy. ...
Chimeric antigen receptor (CAR) T cell therapy represents a major breakthrough in cancer care since the approval of tisagenlecleucel by the Food and Drug Administration in 2017 for the treatment of pediatric and young adult patients with relapsed or refractory acute lymphocytic leukemia. As of April 2023, six CAR T cell therapies have been approved, demonstrating unprecedented efficacy in patients with B-cell malignancies and multiple myeloma. However, adverse events such as cytokine release syndrome and immune effector cell-associated neurotoxicity pose significant challenges to CAR T cell therapy. The severity of these adverse events correlates with the pretreatment tumor burden, where a higher tumor burden results in more severe consequences. This observation is supported by the application of CD19-targeted CAR T cell therapy in autoimmune diseases including systemic lupus erythematosus and antisynthetase syndrome. These results indicate that initiating CAR T cell therapy early at low tumor burden or using debulking strategy prior to CAR T cell infusion may reduce the severity of adverse events. In addition, CAR T cell therapy is expensive and has limited effectiveness against solid tumors. In this article, we review the critical steps that led to this groundbreaking therapy and explore ongoing efforts to overcome these challenges. With the promise of more effective and safer CAR T cell therapies in development, we are optimistic that a broader range of cancer patients will benefit from this revolutionary therapy in the foreseeable future.
... Interferon-α therapy. Some of the earliest work on inflammation and psychiatric disorders began with the observation that many patients treated with interferon alpha (IFN-α) therapy report depressed mood and other depressive symptoms, which develop into clinically significant depression in up to 40% of patients (Loftis & Hauser 2004). IFN-α elicits a strong inflammatory response and, when administered repeatedly, provides an excellent model for the effects of chronic inflammation on mood, neural function, and behavior. ...
Research conducted over the past several decades has revolutionized our understanding of the role of the immune system in neural and psychological development and function across the life span. Our goal in this review is to introduce this dynamic area of research to a psychological audience and highlight its relevance for clinical psychology. We begin by introducing the basic physiology of immune-to-brain signaling and the neuroimmune network, focusing on inflammation. Drawing from preclinical and clinical research, we then examine effects of immune activation on key psychological domains, including positive and negative valence systems, social processes, cognition, and arousal (fatigue, sleep), as well as links with psychological disorders (depression, posttraumatic stress disorder, anxiety, schizophrenia). We also consider psychosocial stress as a critical modulator of neuroimmune activity and focus on early life adversity. Finally, we highlight psychosocial and mind–body interventions that influence the immune system and may promote neuroimmune resilience.
Expected final online publication date for the Annual Review of Clinical Psychology, Volume 19 is May 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... Depression was a well-described major side effects of earlier interferon (IFN)-ribavirin based HCV antiviral treatments, with some studies showing more than 20% of those treated developed depression [9]. This led to those with current or past psychiatric illness often not being prescribed IFN therapy [10]. ...
Background
Depression is common in people living with HIV-HCV, with biological and psychosocial mechanisms at play. Direct acting antivirals (DAA) result in high rates of sustained virologic response (SVR), with minimal side-effects. We assessed the impact of SVR on presence of depressive symptoms in the HIV-HCV co-infected population in Canada during the second-generation DAA era (2013-2020).
Methods
We used data from the Canadian Co-infection Cohort (CCC), a multicentre prospective cohort of people with a HIV and HCV co-infection, and its associated sub-study on food security. Since depression screening was performed only in the sub-study, we predicted Center for Epidemiologic Studies Depression Scale-10 classes in the CCC using a random forest classifier and corrected for misclassification. We included participants who achieved SVR and fit a segmented modified Poisson model using an interrupted time series design, adjusting for time-varying confounders.
Results
We included 470 participants; 58% had predicted depressive symptoms at baseline. The median follow-up was 2.4 years (IQR: 1.0-4.5.) pre-SVR and 1.4 years (IQR: 0.6-2.5) post-SVR. The pre-SVR trend suggested depressive symptoms changed little over time, with no immediate level change at SVR. However, post-SVR trends showed a reduction of 5% per year (risk ratio: 0.95 (95%CI: 0.94-0.96)) in the prevalence of depressive symptoms.
Conclusions
In the DAA era, predicted depressive symptoms declined over time following SVR. These improvements reflect possible changes in biological pathways and/or better general health. If such improvements in depression symptoms are durable, this provides an additional reason for treatment and early cure of HCV.
... IFN-based treatment regimens were long (lasting 1 year) with weekly injections and had low response rates (on average 30%) and many unpleasant side effects including serious neuropsychiatric outcomes such as mild to severe depression [5,6]. Up to 35% of patients treated with IFN-ribavirin based regimens developed depression [7,8]. Due to these side effects, IFN treatment was relatively contraindicated for patients with current or past major psychiatric illness. ...
Background
Psychiatric illness was a major barrier for HCV treatment during the Interferon (IFN) treatment era due to neuropsychiatric side effects. While direct acting antivirals (DAA) are better tolerated, patient-level barriers persist. We aimed to assess the effect of depressive symptoms on time to HCV treatment initiation among HIV–HCV co-infected persons during the IFN (2003–2011) and second-generation DAA (2013–2020) eras.
Methods
We used data from the Canadian Co-infection Cohort, a multicentre prospective cohort, and its associated sub-study on Food Security (FS). We predicted Center for Epidemiologic Studies Depression Scale-10 (CES-D-10) classes for depressive symptoms indicative of a depression risk using a random forest classifier and corrected for misclassification using predictive value-based record-level correction. We used marginal structural Cox proportional hazards models with inverse weighting for competing risks (death) to assess the effect of depressive symptoms on treatment initiation among HCV RNA-positive participants.
Results
We included 590 and 1127 participants in the IFN and DAA eras. The treatment initiation rate increased from 9 (95% confidence interval (CI): 7–10) to 21 (95% CI: 19–22) per 100 person-years from the IFN to DAA era. Treatment initiation was lower among those with depressive symptoms compared to those without in the IFN era (hazard ratio: 0.81 (95% CI: 0.69–0.95)) and was higher in the DAA era (1.19 (95% CI: 1.10–1.27)).
Conclusion
Depressive symptoms no longer appear to be a barrier to HCV treatment initiation in the co-infected population in the DAA era. The higher rate of treatment initiation in individuals with depressive symptoms suggests those previously unable to tolerate IFN are now accessing treatment.
... Clinically, cytokine-mediated depression has certainly resulted from cytokine administration when used as treatments in cancer and viral infections [224][225][226][227][228]. Increased levels of IL-6 and other cytokines have been found in the cerebrospinal fluid and brains of patients with NP-SLE [229]. ...
To date, CNS disease and neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) have been understudied compared to end-organ failure and peripheral pathology. In this review, we focus on a specific mouse model of lupus and the ways in which this model reflects some of the most common manifestations and potential mechanisms of human NP-SLE. The mouse MRL lymphoproliferation strain (a.k.a. MRL/lpr) spontaneously develops the hallmark serological markers and peripheral pathologies typifying lupus in addition to displaying the cognitive and affective dysfunction characteristic of NP-SLE, which may be among the earliest symptoms of lupus. We suggest that although NP-SLE may share common mechanisms with peripheral organ pathology in lupus, especially in the latter stages of the disease, the immunologically privileged nature of the CNS indicates that early manifestations of particularly mood disorders maybe derived from some unique mechanisms. These include altered cytokine profiles that can activate astrocytes, microglia, and alter neuronal function before dysregulation of the blood-brain barrier and development of clinical autoantibody titres.
... The rates of those experiencing mild depression symptoms were found to be 17.1% for those with low disability and 71.1% for those with high disability (29). In our study, a significant positive correlation was found between increased disability scores and anxiety and depression, (30,31). A systematic literature review study investigating the relationship between depression and IFN treatment, which was published in 2017, shows that the relationship has not been clearly demonstrated, but the presence of a history of depression in the past is a risk factor for developing depression in the first six months of IFN treatment (9). ...
Abstract
Objective: The most common psychiatric comorbidities with multiple sclerosis are depression and anxiety. The Beck Depression Inventory (BDI) and Hamilton Anxiety Scale (HAM-A) are validated tests that are easy to administer and interpret, and are widely used to determine depression and anxiety, respectively. The aim of our study is to examine the association of depression and anxiety levels via the BDI and HAM-A with disease duration, disability, and treatments in patients with Multiple sclerosis (MS).
Materials and Methods: One hundred sixty-three MS patients who gave consent were included in the study. The BDI for depression and HAM-A scales for anxiety were applied. MS patients were analyzed in two subgroups: Relapsing-Remitting and progressive groups. Disability was evaluated with the Expanded Disability Status Scale (EDSS).
Results: A total of 163 patients, including 116 women and 47 men, had a mean age of 38.50±9.63 years, and the mean duration of MS diagnosis was 7.49±6.18 years. The rate of anxiety was 82.2% and depression was 33.7% according to HAM-A and BDI scale, respectively. In subgroup analysis, it was observed that anxiety and depression scores of RRMS patients were significantly lower than progressive subtypes. Anxiety and depression scores of patients with EDSS ≤3 were found to be significantly lower than those with EDSS >3. We found that disease modifying treatments did not have a significant effect on anxiety and depression scores.
Conclusion: In our study, it was observed that depression and anxiety were closely related to MS type and disability. The appropriate treatment of accompanying depression and anxiety is crucial for the management of the MS disease process.
Keywords: Multiple sclerosis, depression, anxiety, Beck Depression Inventory, Hamilton Anxiety Scale
... Results revealed that potential risk factors for increased depression during IFN-a therapy were age, weeks since diagnosis, weeks on treatment, dose rate, and the cumulative dose. However, none of these correlations approached significance (Loftis et al., 2004). ...
Background Depression is a common mental health problem observed frequently in general medical setting. Aim The aim of this study was to identify possible demographic and clinical risk factors for depressive disorders among patients attending outpatient clinics of Assiut University Hospitals. Methods A cross-sectional study was conducted during a 1-year period from 1 June 2006 to 31 May 2007; 2304 patients aged 15 years and above were screened for depression using the Beck Depression Inventory. Patients who scored 4 or more were further evaluated through a psychiatric sheet especially prepared for the present work. Psychiatric diagnosis of patients was based on the Diagnostic and Statistical Manual of Mental Disorders, 4th ed.-text revision criteria. Medical/surgical diagnoses were confirmed by appropriate investigations, and information about the possible risk factors were obtained. Patients were also screened using the suicidality sheet and scored using the Sheehan Disability Scale. Results Depression was found in 202 patients, representing 8.8% of the entire sample. Depression was significantly higher among female patients, highly educated and literate individuals, nonworking male patients and among divorced/widowed/separated individuals. Patients with malignancy, disfiguring conditions, autoimmune conditions, renal diseases, and hepatic diseases were at a higher risk of developing depressive disorders. Patients with two or more medical/surgical conditions were at a high risk of developing depressive disorders (25.9 and 17.1%, respectively). Depressive disorders were significantly high among patients on dialysis (42.9%), radiotherapy (40%), chemotherapy (38.5%), steroids (28.9%), interferon (25%), and digoxin (21.9%). Depressive disorders were more prevalent among patients with a duration of medical illness of 24 months or more. The degree of impairment is significantly higher among patients with moderate and severe depression, particularly in patients having severe depression with psychotic features. Suicidality is significantly higher among patients with severe depression, particularly among patients having severe depression with psychotic features. Conclusion Patients attending outpatient clinics might be at a high risk for depressive disorders, especially those with certain medical conditions, with more than two medical diseases, and receiving specific treatment modalities. These patients need close psychiatric attention for early detection of depressive disorders and proper management.
... However, we did not find elevated depression prevalence among those on antiviral medication, contradicting findings from previous studies [26][27][28][29][30][31][32][33][34][35][36][37]. Given the cross-sectional nature of this study, it is possible that medication-induced depression led to changes in medication status, such as discontinuation of the offending medication [51,52]. A few studies have examined the relationship between medication-induced depression and adherence to medication among patients with viral hepatitis. ...
Asian Americans are disproportionately affected by chronic hepatitis B (CHB), with incidence and mortality rates well above those experienced by non-Hispanic white populations. The goal of this study was to examine the association between depression and modifiable lifestyle behaviors among Asian Americans with CHB, with a comparison between those on hepatitis medication and those not on medication. In total, 313 Asian Americans with CHB were recruited through outpatient clinics and community-based organizations to participate in an in-person baseline assessment. We collected data on participants’ sociodemographic characteristics, health-related behaviors, depression symptoms, and modifiable lifestyle behaviors. Bivariate analyses (two sample t-test and chi-square test of independence) and multivariable logistic regression were conducted. We found a high prevalence of depression among individuals living with CHB (41.81% among those not on antiviral medication and 39.71% among those on medication). Multivariate logistic regression results showed that Chinese ethnicity (vs. Vietnamese) and lack of physical activity were significantly associated with a higher risk of mild/severe depression, regardless of medication status. However, the protective effect of physical activity was strong for those on antiviral medication. Furthermore, being employed was significantly associated with a lower risk for depression among Asian Americans on medication, while younger age and being currently married were significantly associated with lower risk of depression among those not on medication. Our findings highlight the significance of physical activity among Asian Americans with CHB, especially for those on antiviral medication. Future prospective research efforts are needed to better identify the potential behavioral mechanisms of depression and provide insights for the psychopharmacological management in this vulnerable population.
... The most supportive evidence of the influence of inflammation on depression is the development of depressive symptoms in patients who were given IFN-α therapy in order to treat Hepatitis C. Among these patients a substantial amount (~20-40%) developed depression (100). In follow-ups these individuals have shown to be prone to relapse into new depressive episodes (101) -hypothetically triggered by major stressful events or major infections. ...
... In fact, many nonimmune effects of IFN administration in patients have been reported, such as skin rash, flu-like symptoms, nephropathy, gastrointestinal discomfort, endocrine disorders, autoimmune diseases, and mental disorders. [210][211][212][213][214][215] Additionally, it has been revealed that IFNs participate in the regulation of cell cycle, cell differentiation, angiogenesis, and cancer development and progression. ...
Interferons (IFNs) are a large family of pleiotropic cytokines that regulate both innate and adaptive immunity and show anti-cancer effects in various cancer types. Moreover, it was revealed that IFN signaling plays critical roles in the success of cancer therapy strategies, thereby enhancing their therapeutic effects. However, IFNs have minimal or even adverse effects on cancer eradication, and mediate cancer immune escape in some instances. Thus, IFNs have a double-edged effect on the cancer immune response. Recent studies suggest that IFNs regulate each step of the cancer immunity-cycle, consisting of cancer antigen release, presentation of antigens and activation of T cells, trafficking and infiltration of effector T cells into the tumor microenvironment, and recognition and killing of cancer cells, which contributes to our understanding of the mechanisms of IFNs in regulating cancer immunity. In this review, we focus on IFNs and cancer immunity and elaborate on the roles of IFNs in regulating the cancer-immunity cycle.
... Sickness is mediated by pro-inflammatory cytokines that stimulate the HPA axis and inhibit the central serotonin function, such as interleukin-1α (IL-1α), TNF-α, and IL-6 [118]. The incidence of depression is about 30% as an unintended consequence of recombinant interferons [119]. In animals, suppressing signaling mediated by pro-inflammatory cytokine causes antidepressant-like results [120]. ...
The emergence of mental disorders is associated with several risk factors including genetic and environmental susceptibility. A group of nutrients serves an especially important role in a number of essential neurodevelopmental processes through brain areas promoting the high degree of brain metabolism during early life, although almost all nutrients are needed. These include macronutrients and micronutrients (e.g., iron, magnesium, zinc, copper, selenium). Numerous nutritional psychiatry trials have been performed to examine the correlation of many individual nutrients with mental health, such as essential trace elements. The increased accumulation or lack of such components will facilitate an alternative metabolic pathway that can lead to many diseases and conditions of neurodevelopment. Mental functions have biochemical bases, so the impairment of such neurochemical mechanisms due to lack of trace elements can have mental effects. In psychological conditions such as depression, anxiety, schizophrenia, and autism, scientific studies demonstrate the putative role of trace element deficiency. Therefore, given the critical roles played by essential trace elements in the neurodevelopment and mental health, the effect of these elements’ intake on the modulation of psychological functioning is reviewed.
... Major depressive disorder (MDD), also known as depression, is a mental disorder characterized by at least two weeks of pervasive low mood. The leading cause of MDD is believed to be a combination of genetic and environmental factors [1][2][3][4][5][6][7], with about 40% of the risk related to genetics [4]. ...
Activation of PPARD has been shown to inhibit depressive behaviors and enhances neurogenesis. However, whether PPARD is involved in the pathological development of major depressive disorder (MDD) is largely unknown. To explore the potential connection between PPARD and MDD, we first conducted a literature-based data mining to construct a PPARD-driven MDD regulating network. Then, we tested the PPARD expression changes in MDD patients from 18 independent MDD RNA expression datasets, followed by coexpression analysis, multiple linear regression analysis, and a heterogeneity analysis to study the influential factors for PPARD expression levels. Our results showed that overexpression of PPARD could inhibit inflammatory cytokine signaling pathways and the ROS and glutamate pathways that have been shown to play important roles in the pathological development of MDD. However, PPARD could also activate nitric oxide formation and ceramide synthesis, which was implicated as promoters in the pathogenesis of MDD, indicating the complexity of the relationship between PPARD and MDD. PPARG presented significant within- and between-study variations in the 18 MDD datasets (p value = 0.97), which were significantly associated with the population region (country) and sample source (p < 2.67e - 5). Our results suggested that PPARD could be a potential regulator rather than a biomarker in the pathological development of MDD. This study may add new insights into the understanding of the PPARD-MDD relationship.
... Increasing evidence suggests that inflammation is one of the mechanisms underlying these disorders (Raison et al., 2006;Dantzer et al., 2008). In one study, about 30% of human patients who underwent interferon therapy developed depression-like disorders (Loftis and Hauser, 2004). Furthermore, several cases of depression have been suggested to be accompanied by inflammation (Maes et al., 1995). ...
Myeloid differentiation primary response 88 (MyD88) is an adapter protein of the toll-like receptor (TLR) family that regulates innate immune function. Here, we identified a novel role of MyD88 in regulating stress response. MyD88 deficiency decreased immobility time in the forced swim test without affecting locomotor activity in mice. Immobilization stress-induced production of serum corticosterone was also completely inhibited by MyD88 deficiency. Stress induced decrease in glucocorticoid receptor in the hippocampus. On the other hand, stress exposure in MyD88 deficient mice did not cause decrease in its level in the hippocampus. Furthermore, immobilization stress-induced reduction of brain-derived neurotrophic factor (BDNF) levels in the hippocampus was ameliorated by MyD88 deficiency. These results suggest that MyD88 deficiency attenuates depression-like behavior by regulating corticosterone and BDNF levels. Overall, these results indicate the key role of MyD88 in regulating stress response in mice.
... In line with this finding, CSF IL-6 (i.e., IFN-β2) level was increased in a geriatric depression group compared with a non-depression group in an earlier V-plex ® assay (Kern et al., 2014). Remarkably, exogenous IFN-α and IFN-β used for hepatitis C treatment have been reported to induce depressive states as a side effect (Loftis and Hauser, 2004;Machado et al., 2017); this is partially in accordance with our data, since CSF IFN-α2 and IFN-λ1 levels showed no significant differences between our patients and controls. Two multiplex immunoassays (Luminex ® and V-plex ® ) reported CSF cytokine levels (Maxeiner et al., 2014; Haroon et al., 2016) in patients with affective/mood disorder; however, levels for healthy controls were not reported. ...
Aim: Accumulating evidence suggests that neural inflammation plays an important role in psychiatric disorders. We aimed to identify inflammatory cytokines involved in the pathophysiology of such disorders by quantifying them in cerebrospinal fluid (CSF) samples from a large sample of patients with major psychiatric disorders and healthy controls.
Methods: The subjects included 94 patients with schizophrenia, 68 with bipolar disorder, 104 with major depressive disorder, and 118 healthy controls, matched for age, sex, and ethnicity (Japanese). Lumbar puncture was performed to collect these CSF samples. A multiplex immunoassay was then performed to measure CSF cytokine levels using magnetic on-bead antibody conjugation for 19 inflammatory cytokines.
Results: CSF interferon-β level was significantly higher in total psychiatric patients than in healthy controls (corrected p = 0.000029). In diagnostic group comparisons, CSF interferon-β level was significantly higher in patients with schizophrenia, or bipolar disorder (corrected p = 0.000047 or 0.0034) than in healthy controls.
Conclusion: We present novel evidence that CSF IFN-β level showed prominent statistical differences between psychiatric groups and healthy controls. This suggests IFN-β as the most important player among the 19 cytokines tested here in the inflammation-related pathophysiology of major psychiatric disorders.
... Prospective experimental studies have relied on 1 of 3 paradigms to induce inflammation: vaccination, endotoxin injection and interferon treatment. 14 Research findings have indicated potential pathomech anisms by which inflammation is connected to depression: altered neuroplasticity (as an effect of decreased expression of brainderived neuroprotective hormone 15 ), altered dopa minergic system, 16 sustained activation of the hypothalamicpituitary-adrenal axis, 17 altered serotonin system 18 and altered glutamate neurotransmission. 19 Immunotherapy with interferonα facilitates an opportunity for the prospective observation of the occurrence of depressive symptoms. ...
Background:
Tryptophan metabolism via the kynurenine pathway is considered the link between the immune and endocrine systems. Dysregulation of serotonergic transmission can stem from the direct influence of interferon-α on the activity of serotonergic receptors 5-HT1A and 5-HT2A, and from its indirect effect on tryptophan metabolism. Induction of the kynurenine pathway increases the concentration of neurotoxic kynurenine metabolites, and the activity of kynurenine derivatives is linked to the onset of depression. The aim of our study was to evaluate the relationships between depressive symptoms and kynurenine, tryptophan, anthranilic acid and kynurenic acid concentrations, indolamine 2,3-dioxygenase (IDO) activity and tryptophan availability to the brain.
Methods:
The study followed a prospective longitudinal cohort design. We evaluated 101 patients with chronic hepatitis C who were treated with pegylated interferon-α2a, and 40 controls who were awaiting treatment. We evaluated the relationships between total score on the Montgomery-Åsberg Depression Rating Scale and kynurenine, tryptophan, anthranilic acid and kynurenic acid concentrations, IDO activity and tryptophan availability to the brain. A logistic regression model was adapted for the diagnosis of major depressive disorder at each time point, taking into account changes in parameters of the kynurenine pathway between a given time point and the baseline measurement.
Results:
Of the treated patients, 44% fulfilled the criteria for major depressive disorder at least once during the 24 weeks of treatment. Anthranilic acid concentrations were significantly increased compared to baseline for all time points except week 2. Tryptophan availability showed a significant decrease (β = -0.09, p = 0.01) only in week 12 of treatment. Over time, kynurenine, tryptophan and anthranilic acid concentrations, as well as IDO activity and tryptophan availability to the brain, were significantly associated with total score on the Montgomery-Åsberg Depression Rating Scale. A logistic regression model revealed that participants with decreased tryptophan availability to the brain at 12 weeks of treatment and participants with increased anthranilic acid concentrations at week 24 of treatment were at increased risk for diagnosis of major depressive disorder (odds ratios 2.92 and 3.59, respectively).
Limitations:
This study had an open-label design in a population receiving naturalistic treatment.
Conclusion:
The present study provides the first direct evidence of the role of anthranilic acid in the pathogenesis of inflammation-induced major depressive disorder during treatment for hepatitis C with pegylated interferon-α2a.
... In addition to the role of BDNF signaling, several studies have reported an association between MDD and a pro-inflammatory signaling through cytokines such as interferon (IFN)-α, TNF-α , IL-6, and IL-1β (154). Depression is a common side effect in a subset of individuals treated with recombinant interferons (155). Mice deficient in IL-6 and TNF-α receptors, show antidepressant-like behavioral phenotypes, and the blocking of IL-1β receptor reverses the anti-neurogenic and anhedonic effects of chronic stress (151). ...
The innate immune system in the central nervous system (CNS) is mainly represented by specialized tissue‐resident macrophages, called microglia. In the past years, various species‐, host‐ and tissue‐specific as well as environmental factors were recognized that essentially affect microglial properties and functions in the healthy and diseased brain. Host microbiota are mostly residing in the gut and contribute to microglial activation states, for example, via short‐chain fatty acids (SCFAs) or aryl hydrocarbon receptor (AhR) ligands. Thereby, the gut microorganisms are deemed to influence numerous CNS diseases mediated by microglia. In this review, we summarize recent findings of the interaction between the host microbiota and the CNS in health and disease, where we specifically highlight the resident gut microbiota as a crucial environmental factor for microglial function as what we coin “the microbiota‐microglia axis."
... Multiple studies have demonstrated that the exogenous administration of inflammatory cytokines induced the development of MDD symptoms. Therefore, this pathway is of interest for the development of novel theraputics (Kraus et al., 2005;Loftis and Hauser, 2004). While various inflammatory cytokines have been found to influence MDD, increased levels of IL-6 have been consistently identified to be implicated with MDD associated inflammation (Berk et al., 2013;Alvarez-Mon et al., 2019). ...
Recent studies suggest that microbiome derived 3(3,4-dihydroxy-phenyl) propionic acid (DHCA) attenuates IL-6 cytokine production through downregulation of the epigenetic modifier DNA Methyltransferase 1 (DNMT1) expression and inhibition of DNA methylation at the 5′—C—phosphate—G—3′ (CpG)-rich IL6 sequence introns 1 and 3 in a mouse model of depression. In this study, we extended the investigation of DHCA epigenetic mechanisms in IL-6 expression in human peripheral blood mononuclear cells (PBMC). Using Lucia Luciferase reporter gene system we identified CpG-rich sequences in which of methylation is influenced by DHCA similar to what observed in response to treatment with the DNA methylation inhibitor 5-aza-2′-deoxycytidine. Correlation study showed that DNA methylation at select CpG motifs in the IL-6 promoter correlates with IL-6 gene expression. Our study suggests that DHCA is effective in reducing IL-6 expression in human PBMCs, in part, by regulation of methylation in the IL-6 promoter region.
... Several studies demonstrated that inflammatory cytokines affect the brain directly or indirectly, increasing the depression risk [3,[46][47][48][49][50]. ...
There is growing evidence of the association between inflammation and stress-related disorders including depression. The positive correlation between the increased levels of inflammatory cytokines observed in patients with other diseases and the byproduct of the depressive symptoms may be caused by chronic stress. Increased neuroinflammatory responses are capable of activating microglia and astrocytes, which leads to release pro-inflammatory cytokines. Moreover, elevated levels of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1, and IL-6 are causally related to various aspects of depression such as the behavioral symptomatology. Eventually, these elevated cytokines aggravate and propagate neuroinflammation, impairing brain functions. Thus, activated astrocytes and microglia may be potential mediators in neuroinflammatory processes contributing to the development of depression.
... Low level of glucocorticoids could attenuate its immunosuppressant effects and facilitate predominant of cytokines action as humoral mediators of innate or adaptive immunity. The action of cytokines in mood are widely documented [42,43]. Data in the literature suggest that inflammatory innate immune responses might contribute to the development of depression, in part through complex interactions with stress-responsive pathways involving the neuroendocrine and autonomic nervous systems. ...
... 7 Plusieurs études suggèrent un rôle de l'inflammation dans les troubles affectifs. Des travaux ont notamment montré que l'administration de cytokines pro-infammatoires, comme l'interféron alpha, donné pour traiter des pathologies comme l'hépatite chronique, la leucémie…, peut provoquer des symptômes dépressifs (Pavol et al., 1995 ;Krausr et al., 2005 ;Loftis et Hauser, 2004 ;Asnis et La Garza, 2006). La prévalence de dépression chez des patients traités avec du TNFα augmente de 5 à 10 % (Krishnadas and Cavanagh, 2012), comparé à des sujets non traités. ...
Le traitement de la dépression reste insatisfaisant. Avec un tiers des patients ne répondant à aucun traitement proposé, un délai d’action long, et des effets secondaires non négligeables, la nécessité de développer de nouvelles stratégies thérapeutiques devient urgente. La luminothérapie, traitement de choix de la dépression saisonnière, a été montrée depuis une trentaine d’années comme présentant également un intérêt pour le traitement des dépressions non saisonnières, unipolaires comme bipolaires. Cependant, les mécanismes d’actions sous-tendant l’effet antidépresseur de la lumière restent mal connus. L’objectif de ce travail de thèse est de comprendre, à l’aide d’un modèle original de dépression, les mécanismes neurobiologiques à l’origine de l’effet antidépresseur de la lumière. Nous avons pour cela développé un modèle de dépression combinant stress par la nage forcée et isolation sociale. Nos résultats montrent que ce protocole induit chez les animaux des comportements pseudo-dépressifs stables et résistants à des traitements classiques (escitalopram) mais également à la kétamine, utilisée récemment en étude clinique pour traiter certains patients réfractaires. Si la lumière seule à forte irradiance (Bright light stimulation, BLS, 1000 lux, une heure par jour) n’a pas d’effet antidépresseur, nous avons démontré dans notre modèle de dépression résistante que la BLS permettait de potentialiser la réponse antidépressive d’une combinaison de kétamine et de scopolamine (utilisée récemment comme d’antidépresseur potentiel) à des doses sous-efficaces. Cet effet est modulé par la sérotonine. En effet, la déplétion en tryptophane, précurseur de la sérotonine, bloque l’effet antidépresseur de cette combinaison. De manière intéressante, nous avons découvert que l’effet potentialisateur de la lumière met en jeu les astrocytes de l’habénula latérale. Ces données suggèrent que la lumière associée à la kétamine et la scopolamine, ciblerait les astrocytes afin de rétablir une activité normale dans l’habénula latérale, désinhibant les centres monoaminergiques, menant ainsi à une réponse antidépressive. Ce travail a permis de mieux comprendre les mécanismes à l’origine de la potentialisation de l’effet antidépresseur par la lumière et pourrait aider à optimiser les stratégies thérapeutiques chez les patients déprimés résistants aux traitements incluant la kétamine
... Third, individuals who have a high level of interleukin 6 (IL-6) in childhood are at greater risk of developing depression later in life. Finally, general clinical practice has shown that therapeutic cytokines such as interferon gamma are associated with the adverse effects of depressive mood [48]. Several pro-inflammatory cytokines have been found to be involved in depression including IL-1 β, IL-6, interferon-α, and TNF-α [3]. ...
The mechanism underlying depression, anxiety, and stress-related psychiatric disorders is far from understood. The utilization of animal models of anxiety and stress can improve our knowledge of the pathology of these disorders as well as aiding in the identification of pharmacological therapeutic targets. The involvement of inflammation in the pathology of stress-related disorders is widely acknowledged. This study was therefore undertaken to assess depressive and anxiety-like behavior as well as neuroinflammation in acute-isolated rats. The study design comprised two main groups:1) rats in acute isolation (one rat per cage) and 2) standard housing (two rats per cage). Within ten days of acute isolation, we carried behavioral tests including Sucrose Neophobia (SNP), Sucrose Preference Test (SPT), Open field (OPF), and a Forced swim test (FST). In a separate set of experiments, we examined the molecular changes after five days of isolations, we examined the mRNA expression of Toll-like receptors (TLRs) and inflammatory markers in the hippocampal brain region. We found that acute social isolation did not have profound functional effects and the behavioral analysis revealed similarities between the isolated and standard housed rats. However, the molecular studies showed a significant increase in TLRs. An increase in Interleukin 6 (IL-6) and Tumor necrosis factor-alpha (TNF-alpha) was observed in the hippocampus of isolated rats but not the control rats. The results suggest that acute environmental isolation does not significantly affect depressive and anxiety-like behavior but does contribute to upregulations in neuroinflammatory responses. This indicates the initiation of neuronal insults following exposure to short-term isolation.
... IFN-γ-induced depression has been less studied than that of depression induced by IFN-α, whose mechanisms are well documented [41][42][43][44][45][46][47]. However, there are some reports of cases in which patients receiving IFN-γ therapy have exhibited mood disorders and depression [42]. ...
Changes in cytokine levels in major depression and during treatment have been reported in adults. However, few studies have examined cytokine levels in an adolescent sample despite this being a common age of onset. Methods . We measured proinflammatory (IL-2, IFN- γ , IL-1 β , TNF- α , IL-6, IL-12, and IL-15) and anti-inflammatory (IL-4, IL-5, IL-13, IL-1Ra, and IL-10) cytokine serum levels in 22 adolescents with major depression and 18 healthy volunteers. Cytokines were measured by multiplex bead-based immunoassays at baseline, and 4 and 8 weeks after commencement of fluoxetine administration in the clinical group. Results . Compared to healthy volunteers, adolescents with major depression at baseline showed significant increases in all pro- and anti-inflammatory cytokines, except IL-1Ra and IL-10. Significant changes were observed in fluoxetine treatment compared to baseline: proinflammatory cytokines IFN- γ , IL-1 β , TNF- α , IL-6, IL-12, and IL-15 were decreased only at week 4 whereas IL-2 was increased only at week 8; anti-inflammatory cytokines IL-4 and IL-5 were increased at week 8 while IL-1Ra was reduced only at week 4. There were no significant correlations between cytokine levels and symptomatic improvement in HDRS. Discussion . The results suggest a significant interplay between cytokine levels, the depressive state, and the stage of treatment with an SSRI. To the best of our knowledge, this is the first report in depressed adolescents with elevated IL-12, IL-13, and IL-15 levels. Further studies are necessary to clarify the role and mechanisms of altered cytokine levels in the pathogenesis and physiopathology of major depressive disorder.
... Indeed, studies on the effects of interferon treatment of patients with various conditions (e.g., hepatitis C, multiple sclerosis) have clearly demonstrated the impact of this cytokine on symptoms such as depression, fatigue, and cognition. The effects of interferon can occur rapidly and be demonstrated by new approaches to brain imaging (45)(46)(47)(48). One study that investigated the role of interferon with depression and fatigue in SLE failed to find an association of these symptoms with the interferon signature (49), although more current approaches for gene expression analysis may reveal associations with different transcriptional modules (50,51). ...
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that varies markedly in severity and can be difficult to both diagnose and treat (1, 2). Many manifestations of SLE result from well‐defined immune mechanisms that drive systemic as well as local inflammation. If not adequately controlled, these manifestations can lead to organ injury and dysfunction (3). Other manifestations of SLE are vague in origin and have an uncertain relationship to inflammation.
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... Recently, numerous studies indicate that inflammation plays important roles in the development of depression. Depression often occurs in hepatitis C or cancer patients treated with interferon alpha (IFN-?) ( Loftis and Hauser, 2004). Subjects with depression are asso- ciated with increased levels of IL-1? and inflammasomes in the brain ( Singhal et al., 2014). ...
Background:
Numerous studies indicate that inflammation plays important roles in the development of depression. Astrocytes are crucial regulators of immune response in the central nervous system, and strongly activated by pro-inflammatory cytokines. We hypothesized that inhibition of activated astrocytes contributed to ameliorate depressive-like symptoms.
Methods:
This study evaluated the antidepressant-like effect of inhibition of activated astrocytes, by a well-established astrocyte inactivator fluorocitrate (FC), on a lipopolysaccharide (LPS)-induced model of depression. Forced swim test (FST), tail suspension test (TST) and sucrose preference test were used to assess depressive-like behaviors. The expression of fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and neuroinflammation were determined in the hippocampus and cortex.
Results:
The results demonstrated that LPS increased immobility time in the TST and FST, reduced sucrose preference as well. LPS also enhanced the expression of IL-1β, TNF-α, iNOS and GFAP, accompanying with decreased expression of BDNF in the hippocampus and cortex. Inhibition of activated astrocytes by FC significantly prevented LPS- induced alteration in the FST, TST and sucrose preference test. Moreover, in the hippocampus and cortex, inhibition of activated astrocytes by FC significantly attenuated increases of neuroinflammation and GFAP whereas reversed decrease of BDNF in LPS- challenged depression.
Conclusions:
Taken together, the results suggest that inhibition of activated astrocytes ameliorates LPS-induced depressive-like behavior, providing the first evidence that inhibition of activated astrocytes might represent a novel therapeutic target for depression.
... Over the last years, research attempting to elucidate the mechanisms involved in the serious collateral effects associated to this agent, namely cognitive disorders and depression has increased. IFN induces changes in the endocrine function (hypothalamic-pituitary-adrenal axis) and in neurotransmission activity (especially serotonin and dopamine) (32)(33)(34). ...
Literature on depression and obesity describes the relevance of the hypothalamic pituitary adrenal axis dysfunction, sympathetic nervous system (SNS) activation, and inflammatory processes as well as the interaction of genetic and environmental factors. Recent investigation in obesity highlights the involvement of several regulation systems, particularly in white adipose tissue. The hypothalamic pituitary adrenal axis, gonadal, growth hormone, leptin, sympathetic nervous system and adrenergic, dopaminergic, and serotoninergic central pathways, all seem interconnected and involved in obesity. From another perspective, the role of psychosocial chronic stressors, determining poor mental and physical health, is well documented. Empirical data can support biologically conceivable theories describing how perceptions of the external social environment are transduced into cellular inflammation and depression. Although in neurobiological models of depression, stress responses are associated with neuroendocrine and neuro-inflammatory processes, concerning similar pathways to those described in obesity, an integrating model is still lacking. The aim of this mini-review is to offer a reflexion on the interplay between the neuroendocrine dysfunctions related to chronic stress and the nature of the shared biologic mechanisms in the pathophysiology of both clinical entities, depression and obesity. We highlight dysfunctional answers of mind body systems that are usually activated to promote regulation and adaptation. Stress response, as a mediator between different level phenomena, may undertake the role of a plausible link between psychological and biological determinants of disease. Depression and obesity are major public health issues, urging for new insights and novel interventions and this discussion points to the need of a more in-depth approach.
... For instance, sleep impairment in depressed patients is associated with increased levels of IL-6 and the soluble forms of intercellular adhesion type 1 molecules in plasma (76) and with the activation in blood cells of nuclear factor-κB (NF-κB), the principal transcription factor involved in initiation of the inflammatory response (77). In other studies, about 50% of the patients chronically administered IFNα developed symptoms of depression, which further supports the role of inflammation in DD pathogenesis (78,79). ...
Depressive disorders (DDs) are one of the most widespread forms of psychiatric pathology. According to the World Health Organization, about 350 million people in the world are affected by this condition. Family and twin studies have demonstrated that the contribution of genetic factors to the risk of the onset of DDs is quite large. Various methodological approaches (analysis of candidate genes, genome-wide association analysis, genome-wide sequencing) have been used, and a large number of the associations between genes and different clinical DD variants and DD subphenotypes have been published. However, in most cases, these associations have not been confirmed in replication studies, and only a small number of genes have been proven to be associated with DD development risk. To ascertain the role of genetic factors in DD pathogenesis, further investigations of the relevant conditions are required. Special consideration should be given to the polygenic characteristics noted in whole-genome studies of the heritability of the disorder without a pronounced effect of the major gene. These observations accentuate the relevance of the analysis of gene-interaction roles in DD development and progression. It is important that association studies of the inherited variants of the genome should be supported by analysis of dynamic changes during DD progression. Epigenetic changes that cause modifications of a gene's functional state without changing its coding sequence are of primary interest. However, the opportunities for studying changes in the epigenome, transcriptome, and proteome during DD are limited by the nature of the disease and the need for brain tissue analysis, which is possible only postmortem. Therefore, any association studies between DD pathogenesis and epigenetic factors must be supplemented through the use of different animal models of depression. A threefold approach comprising the combination of gene association studies, assessment of the epigenetic state in DD patients, and analysis of different “omic” changes in animal depression models will make it possible to evaluate the contribution of genetic, epigenetic, and environmental factors to the development of different forms of depression and to help develop ways to decrease the risk of depression and improve the treatment of DD.
... peg IFN in combination with ribavirin is the currently recommended treatment for 70-80% of genotype 2 or 3 and is also used for 40-50% of genotype 1 patients with HCV infection, and conventional interferon were used for other patients (6,7). peg IFN and ribavirin are successful antiviral treatment for numerous adverse effects, including fatigue, mood disorders, anxiety, irritability, emotional lability, agitation, apathy, anhedonia, anorexia, retardation, sleep disturbance, sexual dysfunction and cognitive deficits have been reported during and after the treatment of hepatitis C (8)(9)(10). Various studies have reported psychiatric side effects in ~84.5% of patients during treatment with peg IFN and in 42.6% of patients at 6 months after completion of treatment (7,11). ...
An estimated 185 million people worldwide are infected with hepatitis C virus (HCV). Combination therapy with pegylated interferon-α (peg IFN) and ribavirin is the first line of treatment against the psychiatric side effects, including mood disorders, anxiety and irritability. In the present study, all of the studies electronically published between 2000 and 2016 were retrieved using databases including Scopus, PubMed, Institute for Scientific Information, Science Direct and Google Scholar. All of the articles were independently evaluated by two reviewers and the results were compared, followed by removal of duplicate, irrelevant and re-published studies after reviewing. The studies were assessed based on the heterogeneity of their results using the Cochrane test and I² analysis. All groups included neuropsychiatric side effects, fatigue was reported at the highest rate in 60.41% [95% confidence interval (CI)=39.18-81.64%] and insomnia was reported at a lower rate in 16.28% of cases (95% CI=6.59-25.98%). In conclusion, the present meta-analysis indicated that treatment with peg IFN + ribavirin or interferon only is associated with a wide range of neuropsychiatric side effects, including fatigue, mood disorders, anxiety, irritability, emotional ability and agitation.
... The rate of treatment response (SVR) was high in the overall sample (88 percent), with no differences between men and women. For both men and women, the severity of depressive symptoms was high at the beginning of treatment and remitted after exposure to treatment, as reported in prior studies (Huckans et al. 2015;Loftis and Hauser 2004) and confirming the transient depressogenic nature of IFN-α. Our findings also indicated that women were more likely to present with MDD at week 24 when compared to men (no differences were found in the remaining time points, however). ...
In this prospective study conducted from October 2013 to June 2015 in Brighton, England, we examined differences between men and women in new-onset major depressive disorder (MDD) during interferon-alpha-based (IFN-α) therapy for hepatitis C virus (HCV). We included 155 HCV-infected patients (47 women), eligible to receive HCV therapy, including direct-acting antivirals. The Semi-Structured Clinical Interview (SCID-I) was used to assess MDD. Severity of depressive symptoms was assessed using the Hamilton Depression Rating Scale. Patients were assessed at baseline, during treatment and six months after treatment completion. A significant increase in depressive symptoms was observed in the total sample from baseline to week 4, and a significant decrease was observed from end of treatment (week 24) to the sustained virological response (SVR) endpoint at six months post-treatment. Women were more likely to have a MDD at week 24. In both men and women, neuro-vegetative and mood-cognitive syndromes increased significantly at the early stage of treatment but remitted by the end of HCV therapy. Proportions with SVR was similar among females and males (91.5% vs. 87%). Under an inflammatory condition, boosted by interferon-based treatments, these results suggest that female gender is not associated with increased vulnerability for developing depression during IFN-α therapy.
... Medical conditions associated with chronic inflammatory and immunological abnormalities, including obesity, diabetes, rheumatoid arthritis, and MS are risk factors for depression (Mezuk et al., 2008;Faith et al., 2011;Matcham et al., 2013;Feinstein et al., 2014). Almost one-half of non-depressed hepatitis C and cancer patients treated with interferon develop depressive symptoms associated with increased serum IL-6 levels (one of the more reliable peripheral biomarkers in major depression) (Loftis and Hauser, 2004), while significantly higher circulating concentrations of TNF-α and IL-6 were reported in depressed subjects compared with controls (Dowlati et al., 2010). Intravenous administration in healthy male volunteers of low-dose endotoxin not only induces a significant increase in peripheral blood concentrations of TNF-α, IL-6, and IL-10 but also results, with some delay, in a selective increase of IL-6 in CSF (Engler et al., 2017). ...
Inflammation is a complex biological response fundamental to how the body deals with injury and infection to eliminate the initial cause of cell injury and effect repair. Unlike a normally beneficial acute inflammatory response, chronic inflammation can lead to tissue damage and ultimately its destruction, and often results from an inappropriate immune response. Inflammation in the nervous system (“neuroinflammation”), especially when prolonged, can be particularly injurious. While inflammation per se may not cause disease, it contributes importantly to disease pathogenesis across both the peripheral (neuropathic pain, fibromyalgia) and central [e.g., Alzheimer disease, Parkinson disease, multiple sclerosis, motor neuron disease, ischemia and traumatic brain injury, depression, and autism spectrum disorder] nervous systems. The existence of extensive lines of communication between the nervous system and immune system represents a fundamental principle underlying neuroinflammation. Immune cell-derived inflammatory molecules are critical for regulation of host responses to inflammation. Although these mediators can originate from various non-neuronal cells, important sources in the above neuropathologies appear to be microglia and mast cells, together with astrocytes and possibly also oligodendrocytes. Understanding neuroinflammation also requires an appreciation that non-neuronal cell—cell interactions, between both glia and mast cells and glia themselves, are an integral part of the inflammation process. Within this context the mast cell occupies a key niche in orchestrating the inflammatory process, from initiation to prolongation. This review will describe the current state of knowledge concerning the biology of neuroinflammation, emphasizing mast cell-glia and glia-glia interactions, then conclude with a consideration of how a cell's endogenous mechanisms might be leveraged to provide a therapeutic strategy to target neuroinflammation.
... In particular, the combination of pegylated interferon (peg IFN) and ribavirin, which is an anti-viral medication, has been considered standard therapy for these patients (2). However, this combination therapy is associated with various side effects and some patients cannot tolerate treatment (1,11). Serious side effects include neuropsychiatric complications such as depression. ...
Interferon (IFN) has various side effects, including psychiatric symptoms. Event-related potentials are used as an electrophysiologic index of cognitive disorders. Auditory event-related potentials (P300) are often used in conditions in which cognitive ability is affected. In this study, we evaluated the association between P300, used to assess cognitive impairment, and neuropsychological side effects of IFN treatment in patients with chronic hepatitis C. Subjects were 20 patients with chronic hepatitis C; 13 patients were treated with peg IFN-α2b and ribavirin (riba group), and 7 patients were treated with peg IFN-α2a (alone group). P300 was performed on all patients before treatment and after 1 week, 4 weeks, 2 months, and 3 months of treatment. In addition, 10 patients of them completed the self-rating depression scale (SDS). P300 latency was significantly prolonged at all points of measurement during IFN treatment. No correlation between the change of SDS score and the change rate of P300 latency was shown. Six patients with neuropsychological symptom had a significantly increased change rate of P300 latency compared with patients without neuropsychological symptoms (P < 0.05). Based on P300 findings, this study suggests that patients with chronic hepatitis C treated with IFN may experience significant cognitive impairment.
... Changes in the levels of certain cytokines, such as increased levels of interleukin (IL)-6 and IL-8, may be associated with depression during IFN-based treatment [63]. The opioid and the noradrenaline system may also be involved in depression symptoms during IFN-based treatment, while RBV is reported to enhance this phenomenon [64][65]. Drug-induced depression might enhance the psychosocial problems in this group of patients. ...
Hereditary bleeding disorders include a group of diseases with abnormalities of coagulation. Prior to 1990, infection with hepatitis C virus (HCV) was mainly transmitted via pooled plasma products as a treatment for hereditary bleeding disorders. Anti-HCV positivity in these patients may be as high as >70% in some areas, while some of them have also been coinfected with human immunodeficiency virus. Since about 20% of HCV-infected patients clear the infection naturally, chronic HCV infection represents a significant health problem in this group of patients. Mortality due to chronic HCV infection is estimated to be >10 times higher in patients with hemophilia than in the general population, and is mainly due to liver cirrhosis and hepatocellular carcinoma. The antiviral treatment of HCV in patients with hereditary bleeding disorders is not different from that of any other infected patients. Nevertheless, many patients with hereditary bleeding disorders have declined (Peg)interferon-based treatment because of side effects. In recent years, multiple orally administrated direct-acting antivirals (DAAs) have been approved for HCV treatment. Unfortunately, there is not much experience from treating these patients with DAA regimens, as major studies and real-life data did not include adequate numbers of patients with inherited hemorrhagic disorders. However, the available data indicate that DAAs have an excellent safety profile with a sustained virological response rate of >90%.
Background
Depression is a prevalent psychiatric disorder with high long‐term morbidities, recurrences, and mortalities. Despite extensive research efforts spanning decades, the cellular and molecular mechanisms of depression remain largely unknown. What's more, about one third of patients do not have effective anti‐depressant therapies, so there is an urgent need to uncover more mechanisms to guide the development of novel therapeutic strategies. Adenosine triphosphate (ATP) plays an important role in maintaining ion gradients essential for neuronal activities, as well as in the transport and release of neurotransmitters. Additionally, ATP could also participate in signaling pathways following the activation of postsynaptic receptors. By searching the website PubMed for articles about “ATP and depression” especially focusing on the role of extracellular ATP (eATP) in depression in the last 5 years, we found that numerous studies have implied that the insufficient ATP release from astrocytes could lead to depression and exogenous supply of eATP or endogenously stimulating the release of ATP from astrocytes could alleviate depression, highlighting the potential therapeutic role of eATP in alleviating depression.
Aim
Currently, there are few reviews discussing the relationship between eATP and depression. Therefore, the aim of our review is to conclude the role of eATP in depression, especially focusing on the evidence and mechanisms of eATP in alleviating depression.
Conclusion
We will provide insights into the prospects of leveraging eATP as a novel avenue for the treatment of depression.
We present a computational model that elucidates the interplay between inflammation, serotonin levels, and brain activity. The model delineates how inflammation impacts extracellular serotonin, while cerebral activity reciprocally influences serotonin concentration. Understanding the reciprocal interplay between the immune system and brain dynamics is important, as unabated inflammation can lead to relapsing depression. The model predicts dynamics within the prefrontal cortex (PFC) and subcallosal cingulate cortex (SCC), mirroring patterns observed in depressive conditions. It also accommodates pharmaceutical interventions that encompass anti-inflammatory and antidepressant agents, concurrently evaluating their efficacy with regard to the severity of depressive symptoms.
Background: Physicians generally prescribe disease-modifying drugs (DMDs) to reduce the frequency and severity of relapses in multiple sclerosis (MS). The frequency and severity of side effects are important factors that can affect drug choice. The main purpose of this analysis was to evaluate the side effects of different types of first-line injectable DMDs and determine which drug has more complications, and which drug has the most drug discontinuation rates due to severe side effects. Methods: Four groups of injectable DMDs were compared in 386 relapsing-remitting MS (RRMS) patients in the range of 15-60 years who were controlled with these drugs for at least two years (2017-2019) and had the Expanded Disability Status Scale (EDSS) from 0 to 5 without underlying heart and liver diseases. Eventually, the frequency of side effects was determined for each group, and the collected data were compared in each treatment group. Results: In the present study, 31% of patients had no complications. Most of the reported complications (68.25%) were mild in severity, and only 15.5% of the patients discontinued their therapy. Conclusion: The findings recommend that the side effects of different DMDs used for RRMS should be studied more comprehensively in clinical and post-marketing trials. Additionally, physicians should take note of these side effects of DMDs in their prescriptions to increase patients’ adherence to therapy.
In einer Perspektive der psychischen und somatischen Komorbidität werden folgende Krankheiten der Leber und der Bauchspeicheldrüse betrachtet: Virus-Hepatitis C, alkoholische Fettleberhepatitis, nicht-alkoholische Fettleberhepatitis, Endstadien chronischer Lebererkrankungen mit Zirrhose sowie Pankreaskarzinom. Der Einfluss vorbestehender affektiver und Stress-bezogener Störungen auf die Entwicklung spezifischer hepatischer Erkrankungsrisiken ist vielschichtig zu beurteilen. Patienten mit Virus-Hepatitis C und alkoholischer Fettleberhepatitis akquirieren ihre Erkrankungen häufig in einem psychosozialen Risikokontext, der per se mit erhöhten Raten vorbestehender psychischer, sowohl affektiver als auch Substanz-bezogener Störungen assoziiert ist. Auch bei Personen mit nicht-alkoholischer Fettleberhepatitis ist ein pathologisches Essverhalten häufig ebenfalls auf dem Boden affektiver und Stress-bezogener Einflüsse zu untersuchen. Das signifikant erhöhte Niveau von Depression und Angst vor der Diagnose eines Pankreaskarzinoms ist am ehesten als eine zentralnervös vermittelte Prodromalmanifestation eines klinisch noch okkulten kanzerogenen Prozesses zu verstehen. Resultate aus empirischen Studien zur Psychotherapie und Pharmakotherapie koexistenter affektiver und Stress-bezogener Symptome bei den diversen hepatischen Krankheiten werden referiert.
Background and Objective
Interferon-alpha (IFN-α) is an important treatment modality for the hepatitis C virus (HCV). However, treatment with IFN-α is often associated with cognitive difficulties in HCV patients. Thus, this systematic review was performed to assess the effects of IFN-α on cognitive functioning in patients suffering from HCV.
Methods
Relevant literature was identified by performing a comprehensive literature search in major databases including PubMed, clinicaltrials.gov, and Cochrane Central using a combination of suitable keywords. We retrieved studies that were published from the starting of each database until August 2021.
Results
Out of 210 articles, 73 studies were selected after removing the duplicates. In the first pass, 60 articles were excluded. Out of 13 full-text articles, only 5 articles qualified for qualitative analyses in the second pass. We observed conflicting results concerned with the use of IFN-α and the risk of neurocognitive impairment in HCV patients.
Conclusion
In conclusion, we have observed conflicting results regarding the impact of INF-α treatment on the cognitive functioning of patients suffering from HCV. Thus, there is an urgent need for an extensive study to evaluate the exact association between INF-α therapy and cognitive functioning in HCV patients.
Major depression (MD) is the most common psychiatric disorder, predicted to affect around 264 million people worldwide. Although the etiology of depression remains elusive, the interplay between genetics and environmental factors, such as early life events, stress, exposure to drugs and health problems appears to underlie its development. Whereas depression is twice more prevalent in women than in men, most preclinical studies are performed in male rodents. In fact, females’ physiology and reproductive experience are associated with changes to brain, behavior and endocrine profiles that may influence both stress, an important precipitating factor for depression, and response to treatment. These specificities emphasize the need to choose the most suitable models and readouts in order to better understand the pathophysiological mechanisms of depression in females.
With this review, we aim to provide an overview of female animal models of depression highlighting the major differences between models, regarding behavioral, physiological, and molecular readouts, but also the major gaps in research, attending to the role of etiological factors, protocol variability and sex.
The interaction between major depressive disorder (MDD) and other medical conditions is increasingly recognized as an important factor for clinical management and for biomarker development. Many common medical conditions have a bidirectional epidemiologic relationship with MDD that may have roots in shared pathophysiologic, environmental, and psychosocial factors. Furthermore, depression is increasingly recognized as a systemic disease. Understanding this relationship is challenging because of the immense variability between patients with MDD and also within other medical disorders themselves. This includes not only specific symptoms, but also disease severity, duration, disability, and treatment resistance.
Major depressive disorder (MDD) is a common condition that afflicts the general population across a broad spectrum of ages and social backgrounds. MDD has been identified by the World Health Organization as a leading cause of disability worldwide.
Approximately 30% of patients are poor responsive to standard of care (SOC) treatment and novel therapeutic approaches are warranted.
Since chronic inflammation, as it is often observed in certain cancers, type 2 diabetes, psoriasis and chronic arthritis, are accompanied by depression, it has been suggested that immunoinflammatory processes may be involved in the pathogenesis of MDD.
Cytokines are a group of glycoproteins secreted from lymphoid and non-lymphoid cells that orchestrate immune responses. It has been suggested that a dysregulated production of cytokines may be implicated in the pathogenesis and maintenance of MDD. On the basis of their functions, cytokines can be subdivided in pro-inflammatory and anti-inflammatory cytokines. Since abnormal blood and cerebrospinal fluid of both pro and anti-inflammatory cytokines are altered in MDD, it has been suggested that abnormal cytokine homeostasis may be implicated in the pathogenesis of MDD and possibly to induction of therapeutic resistance.
We review current data that indicate that cytokines may represent a useful tool to identify MDD patients that may benefit from tailored immunotherapeutic approaches and may represent a potential tailored therapeutic target.
The aim of this study was to evaluate the changes in hematologic inflammatory markers such as neutrophil /lymphocyte ratio (NLR), platelet/ lymphocyte ratio (PLR), red cell distribution width (RDW) and mean platelet volume (MPV) in patients with diagnosis of Major Depressive Disorder (MDD). Seventy-five patients between the ages of 18 and 75 who were not currently undergoing any psychiatric treatment and diagnosed having the first episode of MDD according to DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) criteria in the outpatient clinic of the Department of Psychiatry of the Erzurum Regional Training and Research Hospital between June 2016 and September 2016 were included in the study. The control group was selected from relatives of the hospital employees. Fifty-seven volunteers with similar sociodemographic characteristics and body mass indices selected from relatives of the hospital staff who had not any psychiatric and other clinical conditions were included as a control group. Sociodemographic form, Structured Clinical Interview for DSM IV Axis I Disorders (SCID I), Hamilton Depression Rating Scale (HDRS) and Clinical Global Impression Scale (CGI-S) were applied to the patients. Sociodemographic form and SCID I were applied to the control group. There was not any significant difference between groups in terms of hematologic parameters like hemoglobin, he-matocrit, leukocyte count, platelet count, lymphocyte count and neutrophil count. Although there was no significant difference between groups in terms of NLR, PLR and RDW, there existed significant difference between groups in terms of MPV. In the patient group HDRS and CGI-S were not significantly correlated with NLR, PLR, RDW and MPV. As a conclusion; we found increased MPV in MDD group compared with the control group. Further studies are needed to reveal the relationship between depression and inflammatory markers.
A phase I-II trial was initiated to investigate the effects of a combination of alpha- and gamma-interferon in 12 patients with malignant carcinoid tumors. All patients were treated with alpha-interferon at a dose of 5-10 MU, 3-5 times weekly for a median of 22 months and had stable or progressive disease. Gamma-interferon was added at a daily dose of 0.5 MU subcutaneously. After 3 months of treatment 4 patients showed progressive biochemical disease while 8 patients had continuous stable biochemical disease. The dose was escalated to 1 MU daily in 8 patients while 3 continued at lower dose levels. Gamma-interferon was withdrawn from one patient due to mental depression. At 6 months there was 1 partial response, 3 patients with progressive and 7 with stable disease. Half of the patients experienced increased fatigue during the study. Other adverse reactions were skin lesions and myalgia. The combination therapy demonstrated subjective improvement in half of the patients, but lacked antitumoral effects.
Recombinant human interferon-alpha (r-IFN-alpha) is often successfully used in the treatment of patients with chronic viral hepatitis B and C. Thyroid dysfunction has been reported to occur with variable frequency during r-IFN-alpha therapy especially in patients with preexisting thyroid autoimmunity. We have prospectively evaluated the effect of r-IFN-alpha on various aspects of thyroid function in patients with HCV chronic hepatitis.
Thirty-two patients with HCV chronic active hepatitis were studied prospectively before and during r-IFN-alpha therapy. Serum TSH, FT4, FT3, and thyroid receptor (TSR) and thyroid peroxidase (TPO) antibodies, and the iodide-perchlorate discharge test (I-C10(4)) to detect subtle defects in the thyroid organification of iodide were carried out during the study. Thyroid radioactive iodine uptakes (RAIU) were obtained in patients who developed thyrotoxicosis.
All patients were clinically and biochemically euthyroid prior to r-IFN-alpha therapy with negative I-C10(4) discharge tests. Four patients became thyrotoxic, 3 secondary to destructive or inflammatory thyroiditis with a low thyroid RAIU, and 1 patient developed hypothyroidism. The I-C10(4) discharge test became positive in 7 of the 32 patients studied prospectively; 5 of these patients did not develop other evidence of thyroid dysfunction and did not have positive TPO antibodies. In these 5 patients the test became negative after r-IFN-alpha was discontinued. Appropriate therapy of the patients with thyrotoxicosis (methylprednisolone for 3 patients with destructive thyroiditis and methimazole for 1 patient with hyperthyroidism) or with hypothyroidism (L-thyroxine) was successful.
Thyroid dysfunction, especially destructive or silent thyroiditis resulting in thyrotoxicosis, is not infrequently observed in patients receiving r-IFN-alpha therapy for chronic active hepatitis. Although underlying autoimmune thyroid disease appears to predispose patients to develop thyroid dysfunction, other patients become thyrotoxic or hypothyroid in the absence of baseline positive TPO-Ab. Subtle defects in the thyroidal organification of iodine as determined by the I-C10(4) discharge test, in the absence of autoimmune thyroid disease, was observed in 5 patients who remained euthyroid, suggesting that r-IFN-alpha directly reduces the intrathyroidal organification of iodine.
This study examined the efficacy of an 8-week telephone-administered cognitive-behavioral therapy (CBT) for the treatment of depressive symptomatology in multiple sclerosis (MS) patients. The treatment, Coping with MS (CMS), included a patient workbook designed to structure the treatment, provide visual aids, and help with homework assignments. Thirty-two patients with MS, who scored at least 15 on the Profile of Mood States Depression-Dejection scale, were randomly assigned to either the telephone CMS or to a usual-care control (UCC) condition. Depressive symptomatology decreased significantly in the CMS condition compared with the UCC condition. Furthermore, adherence to interferon beta-1a, a disease-modifying medication for the treatment of MS, was significantly better at the 4-month follow-up among patients who received CMS as compared with those in the UCC condition.
OBJECTIVE: Neuropsychiatric symptoms are commonly associated with chronic hepatitis C virus infection, its sequelae, and its treatment. In particular, interferon, a primary component of treatment for chronic hepatitis C, has been strongly associated with depressive symptoms. This review summarizes current knowledge about the etiology, course, and treatment of neuropsychiatric problems associated with hepatitis C and interferon alpha (IFN-α) treatment. METHOD: Studies were identified by computerized searches, and further references were obtained from bibliographies of the reviewed articles. RESULTS: Chronic infection with the hepatitis C virus is a common and growing problem, often affecting persons with psychiatric and substance use problems. Although changes in cognition, mood, and personality have been described in association with hepatitis C and with IFN-α treatment, there has been little systematic study of these changes. CONCLUSIONS: Psychiatrists should become familiar with the clinical spectrum associated with hepatitis C virus infection as well as the neuropsychiatric symptoms related to hepatitis C and IFN-α treatment. More studies are necessary to define the neuropsychiatric syndromes associated with this population and to find possible effective treatments. Furthermore, research is needed so that patients with psychiatric problems are not excluded from effective treatments for this growing medical problem.
• Data on 24-hour urinary levels of catecholamines and metabolites were determined in 114 depressed patients. For each patient, a D-type score was calculated, using a discriminant function equation that was previously derived using data from an independent group of depressed patients. Of all measures, D-type scores provided the highest sensitivity and specificity for separating bipolar/schizoaffective-depressed patients from all remaining patients or from those patients with unipolar nonendogenous depressions. Using Research Diagnostic Criteria (RDC), bipolar I patients demonstrated significantly lower D-type scores than did all other RDC depressive subtypes, including bipolar II disorders. Similar findings were observed using the Clinical Inventory for the Diagnosis and Classification of Affective Disorders (CIDCAD) system: bipolar/schizoaffective patients demonstrated significantly lower D-type scores than all remaining subtypes, including diagnostically unclassifiable, probable bipolar patients (a category somewhat akin to RDC bipolar II disorder). Data pointed to the heterogeneity of bipolar disorders. Catecholamine and metabolite data in this study were compared with recent studies of others.
Depression is a suspected side effect of multiple sclerosis (MS) treatment with interferon β-1a. However, this has not been confirmed by rigorous studies. Several psychological symptom rating scales were completed during the PRISMS clinical trial of subcutaneous interferon β-1a (Rebif®) for relapsing - remitting MS. We conducted an analysis of these data in order to determine whether symptom elevations were associated with treatment. The PRISMS clinical trial included 560 subjects from 22 centres in nine countries. There were two active treatment arms (44 mcg × 3 and 22 mcg × 3 subcutaneously three times per week) and a placebo group. Two hundred and sixty-seven of these subjects were enrolled at English speaking study centres, where psychiatric symptom ratings were obtained at baseline, 6, 12, 18 and 24 months using the Center for Epidemiological Studies Depression Rating Scale (CES-D), the General Health Questionnaire (GHQ) and the Beck Hopelessness Scale (BHS). After randomization, the groups completing these scales were similar in terms of age, gender, EDSS, duration of illness and employment status. Median CES-D scores in the high dose, low dose and placebo groups at baseline were also similar: 8.0, 7.0 and 8.0, respectively. After 6 months of treatment, the median change in CES-D score was zero in all three groups. The proportion of subjects exceeding the traditional CES-D cut-point for clinically significant depression (>15) after 6 months of treatment was strongly associated with pre-treatment depression (RR 2.9, 95% C.I.: 1.8 - 4.7), but not with treatment group (chi-square=1.64, d.f.=2, P=0.44). The results were comparable at 12, 18 and 24 months and when ratings from the other scales were evaluated. This analysis confirms that depression is common in persons with MS: the incidence of CES-D depression in the first 6 months of follow-up was 15.6%. However, no evidence of increased depressive symptomatology was observed in association with interferon b-1a (Rebif®).
In this report, we investigated the relationship between depressive symptoms and plasma interferon (IFN)-α-like immunoreactivity, cyclic GMP (cGMP) and soluble interleukin-2 receptor (sIL-2R) levels during IFN therapy. An altered mood state was observed in 5 of 26 patients. IFN-α-like immunoreactivity in the depressed group tended to be elevated. cGMP levels of depressed patients were significantly greater than those of control subjects before and 6 weeks after IFN therapy. However, sIL-2R levels were not different between the two groups. These results suggest that a number of patients suffered from depression during IFN therapy and that patients had greater concentrations of cGMP levels.Copyright © 1997 S. Karger AG, Basel
Interferon-α (IFN-α) is used clinically in the treatment of several pathologies such as hepatitis C and various cancers. The positive therapeutic potential is however often limited by negative secondary effects which include major depression, one of the cardinal symptoms of which is anhedonia which has been operationalised as a decreased sensitivity to rewards (inability to experience pleasure). Previous studies have demonstrated the existence of anhedonia in rats following an acute injection of IFN-α at doses corresponding to those used in clinical applications. If this previously demonstrated anhedonia is indeed part of a depression syndrome in rats, this behavioural symptom should be reversible by the administration of antidepressants. The objective of the present experiment was to determine whether two commonly used antidepressants (desipramine and fluoxetine) were effective in ameliorating IFN-α-induced anhedonia in rats. The experiment consisted of two phases. In the first, the effects of daily systemic injections of 104 units/kg of IFN-α (or vehicle) were evaluated with the three-bottle (1%, 8%, and 32%) sucrose-consumption test. In the second phase of the experiment, in addition to continued injections of IFN-α, different groups received daily injections of desipramine (7.5 mg/kg ip), fluoxetine (7.5 mg/kg ip), or vehicle. The IFN-α injections during Phase 1 resulted in clear anhedonia, as expressed by increased consumption of the 32% solution and decreased consumption of 1% over the 33 days of this phase. After 15 days of antidepressant treatments, 32% sucrose consumption returned to baseline values. We have therefore confirmed that IFN-α-induced anhedonia is susceptible to reversal following chronic antidepressant treatment and thus it may appear timely to consider the prophylactic use of such in particular patients prescribed IFN in the clinic.
The effect of recombinant human α-interferon on plasma corticosterone concentrations was investigated in adult male rats. Intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration of α-interferon (10–104 U i.p., and 1–103 U i.c.v.) decreased basal plasma corticosterone concentrations. This effect was evident at both the peak and nadir in the circadian rhythm of hypothalamo-pituitary-adrenocortical secretory activity. The same inhibitory effect was obtained with intra-paraventricular nucleus administration of the cytokine. Furthermore, α-inteferon attenuated the effects of stressors such as handling, 1 min of forced swimming, and sound stress in a novel environment. The effect of α-interferon (102 U i.c.v.) was blocked by prior injection of the opioid receptor antagonist, naloxone (1 mg/kg i.p.). Similarly, the effect of 103 U α-interferon administered i.p. was blocked by i.c.v. injection of naloxone (1 μg/kg), or of the μ1-specific receptor antagonist, naloxonazine (1 μg). The selective δ-opioid receptor antagonist, naltrindole (1 μg i.c.v.) and the κ-opioid receptor antagonist, nor-binaltorphimine (1 μg i.c.v.) both failed to prevent the inhibitory effect of α-interferon (103 U i.p.) on adrenocortical secretion. The results obtained provide further evidence for a neuromodulatory effect of α-interferon and that this effect is mediated by central opioid receptors of the μ1-subtype, δ- and κ-opioid receptors not being involved.
The aim of this study was to assess the incidence of fatal, life-threatening side effects and the de novo appearance of non-hepatic morbidity during interferon alfa therapy for chronic viral hepatitis. The relationship of these adverse events to actual total dose and duration of interferon was also evaluated.
We conducted a retrospective study at 73 Italian centers of 11,241 consecutive patients with chronic viral hepatitis who underwent interferon alfa treatment.
Five patients died during interferon therapy due to liver failure (n = 4) or complications arising from sepsis. Life-threatening side effects were observed in eight patients: two cases where depression developed and led to a suicide attempt and six patients with bone marrow suppression (granulocytes < 500/mm3 or platelets < 25,000/mm3). These symptoms and signs completely disappeared after interferon withdrawal. During interferon treatment, 131 patients developed the following de novo non-hepatic disorders: symptomatic thyroid disease (n = 71), impotence (n = 5), systemic autoimmune disease (n = 5), immune-mediated dermatologic disease (n = 14), diabetes mellitus (n = 10), cardiovascular disease (n = 7), psychosis n = 10), seizures (n = 4), peripheral neuropathy (n = 3) and hemolytic anemia (n = 2). Most of these complications are reversible or can be ameliorated. Fatal or life-threatening side effects were not related to actual total dose or duration of interferon alfa, while the majority of patients with de novo non-hepatic morbidity received medium/high doses (> 200 million units) of interferon alfa or were treated for periods longer than 16 weeks (68% and 80%, respectively).
Treatment with interferon alfa may have fatal or life-threatening side effects, their incidence in this study being low (0.04% and 0.07%, respectively) and perhaps no different than in untreated patients with chronic viral hepatitis. Moreover de novo non-hepatic morbidity occurred in 1.2% of patients, and the dose and duration of interferon therapy seem important in determining the frequency of this complication. The development of clinically-overt thyroid disease was most common.
Interferon-a (IFN-α) has potential dose-limiting neurotoxic side effects when used in cancer therapy. The nature of this neurotoxicity is speculative, and there is no definitive treatment. Because animal studies suggest that IFN-α acts at opioid receptor sites, we gave naltrexone, a long-acting opioid antagonist, to 9 patients who had hematological malignancies and who suffered from IFN-α side effects. Seven of these patients experienced complete or moderate relief of side effects. Five of the patients tested before and during naltrexone treatment showed improvement of cognitive functioning. Two patients could not tolerate naltrexone side effects. This study suggests an intervention against IFN-α side effects and provides support for the role of opioid receptor interaction in IFN-α neurotoxicity.
BACKGROUND
The use of a high dose regimen of interferon-alpha-2b (IFN) has recently been demonstrated to benefit patients with resected high risk melanoma. The incidence of melanoma is rising rapidly, and the use of this regimen is becoming increasingly common. IFN has been associated with numerous psychiatric side effects.METHODS
The authors describe four melanoma patients treated with adjuvant IFN who developed a manic-depressive syndrome or mood instability with therapy, and they review the literature on mania and the mixed affective syndromes associated with IFN.RESULTSThe authors suggest that IFN may induce a mixed affective instability, and that patients risk developing hypomania or mania as IFN doses fluctuate or as IFN-induced depression is treated with antidepressants alone. Mania is particularly associated with dose reductions or pauses in IFN treatment. The risk of mood fluctuation continues after treatment with IFN stops, and patients should be monitored for 6 months following completion of therapy. Gabapentin appeared effective as monotherapy for acute mania, as an antianxiety agent, as a hypnotic, and as a mood stabilizer in these individual cases.CONCLUSIONS
Mania and mood instability can occur in patients being treated with IFN therapy for melanoma. In this study, gabapentin was an effective mood-stabilizing agent for these patients. Cancer 2000;89:356–62. © 2000 American Cancer Society.
Interferons have been shown to be potential anti-cancer agents and to inhibit tumor cell growth in culture. The in vivo mechanism of the anti-proliferative effect may be direct or indirect through the immune system; however, in vitro a primary mechanism of cytotoxicity is through the depletion of tryptophan. In particular, interferon-gamma (IFN-gamma) induces an enzyme of tryptophan catabolism, indoleamine 2,3-dioxygenase (IDO), which is responsible for conversion of tryptophan and other indole derivatives to kynurenine. The inhibitory effect of interferon on many intracellular parasites such as Toxoplasma gondii and Chlamydia trachomatis is by the same mechanism. Elevated kynurenine levels have been found in humans in a number of diseases and after interferon treatment, and the enzyme is induced in rodents after administration of interferon inducers, or influenza virus. IDO induction also occurs in vivo during rejection of allogeneic tumors, indicating a possible role for this enzyme in the tumor rejection process. The gene for IDO has been cloned and shown to be differentially regulated by IFN-alpha and IFN-gamma. IDO induction has been correlated with induction of GTP-cyclohydrolase, the key enzyme in pteridine biosynthesis. A direct role for IDO in pteridine synthesis has not been shown, and this parallel induction may reflect coordinate regulation of genes induced by IFN-gamma. A possible role for IDO in O2-radical scavenging and in inflammation is discussed.
The acute effects of interferon alpha-2a (3 x 10 IU im) on catecholamine and immunoreactive beta endorphin plasma levels, cortisol serum levels and lymphocyte beta 2-adrenoceptor density were evaluated in ten healthy volunteers. Interferon induced a significant increase in plasma norepinephrine; there was an increased norepinephrine standing response, too. On the contrary, epinephrine standing response was reduced by interferon. Lymphocyte beta 2-adrenoceptors decreased significantly after interferon administration; dissociation constant of binding was unchanged. Cortisol serum levels increased significantly with respect to control test, whereas immunoreactive beta endorphin did not change. These results support the hypothesis of functional relationships between neuroendocrine and immune systems; moreover they may be useful in clinical trials given the administration of interferon alpha in an increasing number of diseases.
Data on 24-hour urinary levels of catecholamines and metabolites were determined in 114 depressed patients. For each patient, a D-type score was calculated, using a discriminant function equation that was previously derived using data from an independent group of depressed patients. Of all measures, D-type scores provided the highest sensitivity and specificity for separating bipolar/schizoaffective-depressed patients from all remaining patients or from those patients with unipolar nonendogenous depressions. Using Research Diagnostic Criteria (RDC), bipolar I patients demonstrated significantly lower D-type scores than did all other RDC depressive subtypes, including bipolar II disorders. Similar findings were observed using the Clinical Inventory for the Diagnosis and Classification of Affective Disorders (CIDCAD) system: bipolar/schizoaffective patients demonstrated significantly lower D-type scores than all remaining subtypes, including diagnostically unclassifiable, probable bipolar patients (a category somewhat akin to RDC bipolar II disorder). Data pointed to the heterogeneity of bipolar disorders. Catecholamine and metabolite data in this study were compared with recent studies of others.
Ten (17%) of 58 patients with chronic viral hepatitis treated with a four- to 12-month course of recombinant human interferon alfa developed psychiatric side effects. The psychiatric side effects fell into three categories: an organic personality syndrome characterized by irritability and short temper; an organic affective syndrome marked by extreme emotional lability, depression, and tearfulness; and a delirium marked by clouding of consciousness, agitation, paranoia, and suicidal potential. These psychiatric side effects appeared after one to three months of therapy, usually improved within three to four days of decreasing the dose of interferon alfa, and invariably resolved once therapy was stopped. The organic personality and affective syndromes tended to occur in patients who received the highest dose of interferon alfa, who had relatively mild hepatitis, and who lost weight during interferon treatment. Delirium tended to occur in patients with severe hepatitis who had previous evidence of organic brain injury or dysfunction or previous drug and alcohol abuse. Failure to recognize these side effects quickly and to treat them with supportive therapy and modification of the dose of interferon alfa could result in limitation of therapy and serious personal and interpersonal consequences.
Interferon-alpha (IFN-alpha) has potential dose-limiting neurotoxic side effects when used in cancer therapy. The nature of this neurotoxicity is speculative, and there is no definitive treatment. Because animal studies suggest that IFN-alpha acts at opioid receptor sites, we gave naltrexone, a long-acting opioid antagonist, to 9 patients who had hematological malignancies and who suffered from IFN-alpha side effects. Seven of these patients experienced complete or moderate relief of side effects. Five of the patients tested before and during naltrexone treatment showed improvement of cognitive functioning. Two patients could not tolerate naltrexone side effects. This study suggests an intervention against IFN-alpha side effects and provides support for the role of opioid receptor interaction in IFN-alpha neurotoxicity.
We evaluated the neuropsychological and personality profiles of 25 patients with chronic myelogenous leukemia treated with interferon alfa (IFN-alpha). This group of persons performed well below expectation on tests of cognitive speed, verbal memory, and executive functions. Personality changes included depression, increased somatic concern, and stress reactions. A control group of leukemia patients not treated with IFN-alpha had significantly better cognitive speed and mood. The pattern of cognitive and personality changes in patients receiving IFN-alpha is highly suggestive of frontal-subcortical brain dysfunction.
Alpha-interferon (alpha-IFN) treatment in humans induces anorexic effects. However, the mechanisms and sites of action are unknown. Rats implanted with an intracerebroventricular (i.c.v.) cannula for local injection, and semi-microelectrodes in the lateral hypothalamic (LH) area for neuronal recording were used. The animals were kept in metabolic cages, and food and water intake was measured daily at 7:00 and 19:00 hr for 35 days, including: 5 days before the experiment; 10 days during daily alpha-IFN application (either i.p. 1500 I.U./gbw, or i.c.v. 1500 and 150 I.U./animal) and/or a vehicle control group; and 20 days post drug treatment. The unitary activity recording from the LH area was made before (30 min), during (10 min) and after (200 min) the alpha-IFN applications. alpha-IFN elicited a reversible dose-related decrease of both food intake and body weight. This decrease in food intake following alpha-IFN injections was correlated with a depression of LH neuronal electrical activity. Since direct brain application (i.c.v.) and systemic (i.p.) alpha-IFN treatment elicited identical responses, it is possible to assume that alpha-IFN suppresses food intake by a direct action on CNS sites including the LH neurons.
We evaluated the effect of recombinant interferon gamma (rIFN-gamma) on survival and toxicity in small-cell lung cancer (SCLC) patients in complete remission (CR).
One hundred patients in CR following treatment with six cycles of combination chemotherapy, thoracic radiotherapy (TRT), and prophylactic cranial irradiation (PCI) were studied. All patients had been enrolled onto a cooperative group trial (North Central Cancer Treatment Group [NCCTG] 86-20-51). Patients received observation only or rIFN-gamma at a dose of 4 x 10(6) U subcutaneously per day for 6 months.
Six patients (12%) did not comply with rIFN-gamma treatment. Substantial nonhematologic toxicities consisting of chills, myalgia, lethargy, and alteration of mood-personality were observed. No patient experienced life-threatening or fatal toxicity. The median times to progression for rIFN-gamma treatment or observation were 6.9 and 8.1 months (P = .54). The median survival times were 13.3 and 18.8 months, respectively (P = .43). Approximately 70% of all patients relapsed within 2 years.
Time to progression and survival were inferior in patients treated with rIFN-gamma compared with randomized control subjects, although this difference was not statistically significant. These data indicate that rIFN-gamma treatment is not associated with a 33% improvement in survival (P = .04). Because of the high rate of relapse, SCLC patients in CR are an ideal group in which to evaluate novel and minimally toxic agents.
We report on two attempted suicides and one successful suicide during or shortly after alfa-interferon therapy for chronic viral hepatitis. While on therapy, all three patients developed a psychiatric disorder leading to their suicidal behavior. In a survey of 15 European hospitals, three cases of attempted and two of successful suicide during alfa-interferon therapy for chronic viral hepatitis, were additionally reported. None of the patients had a psychiatric history. Alfa-interferon is known to lead to neuropsychiatric symptoms, and our observations strongly suggest that these mental disorders could lead to suicidal behavior. Therefore it is important that physicians, patients and their families are informed about the potential risk of the emotional and psychiatric disturbances that can occur during alfa-interferon therapy.
In our earlier studies we have demonstrated that recombinant human interferon-alpha 2A (rHu-IFN-alpha 2A) inhibits hypothalamo-pituitary-adrenocortical (HPA) secretion following both peripheral and central administration. Furthermore, this effect is antagonized by mu-opioid receptor antagonists, suggesting transduction by this subtype of opioid receptors. In the present studies, we demonstrate that this effect is also observed with the hybrid recombinant preparation, rHu-IFN-alpha A/D, and a leucocyte-derived rat IFN-alpha preparation. The inhibitory effects on HPA activity were observed after intraperitoneal (i.p.) injections of rHu-IFN-alpha 2A (10(3) U), rHu-IFN-alpha A/D (10(4) U), and of Rat-IFN-alpha (1 and 10 U). Similar effects were observed with intracerebroventricular (i.c.v.) administration of all three IFN-alpha preparations. No increases in plasma concentrations of corticosterone were observed with doses of rHu-IFN-alpha A/D up to 10(6) U (i.p.) or 7 x 10(5) U (i.c.v.), but increases were found following i.c.v. administration of high doses of Rat-IFN-alpha (10(3) and 5 x 10(3) U). The inhibitory effects of all of the IFN-alpha preparations tested were antagonized by naloxone, but the stimulatory effects of 5 x 10(3) U Rat-IFN-alpha were not. Injections of rHu-IFN-alpha 2A (10(4) U i.p.) to urethane-anesthetized rats decreased the electrical activity of the majority of hypothalamic paraventricular nucleus neurons tested, including putative corticotropin-releasing factor-secreting neurons antidromically identified as projecting to the median eminence. These electrophysiological data suggest that the decreases in HPA activity evoked by IFN-alpha are mediated by a rapid inhibitory effect at the level of the corticotropin-releasing factor-secreting neurons. The sensitivity of many central nervous system effects of IFN-alpha to mu-receptor antagonists strongly suggests that the cytokine serves as an endogenous opioid agonist arising from the immune system. In support of this hypothesis we have shown that SH-SY5Y human neuroblastoma cells, differentiated with retinoic acid treatment to express predominantly mu-receptors, are sensitive to rHu-IFN-alpha 2A in vitro. This sensitivity took the form of a dose-dependent inhibition of forskolin-stimulated adenylyl cyclase activity. The data yielded an IC50 (95% confidence intervals) value of 7.93 (5.70-11.04) nM for this effect. Neither undifferentiated SH-SY5Y cells nor NG108-15 mouse neuroblastoma x rat glioma hybrid cells (expressing delta-receptors) were affected by rHu-IFN-alpha 2A.(ABSTRACT TRUNCATED AT 400 WORDS)
We studied the psychiatric side effect of interferon (IFN) therapy to the patients with chronic hepatitis type C (n = 48) using Cornell Medical Index (CMI) and Self-Depression Scale (CMI). No patients in this study showed any overt psychiatric diseases by IFN treatment. However, scores of SDS were more increased in the patients treated with IFN-alpha (32.7 +/- 7.4 to 38.9 +/- 8.4, n = 26, p < 0.001) than in those treated with IFN-beta (33.7 +/- 9.8 to 36.0 +/- 12.4, n = 18, not significant), suggesting subclinical psychiatric abnormalities caused by IFN therapy. We should take care of psychiatric side effects on treatment of IFN, especially IFN-alpha, for chronic hepatitis. Further studies are needed.
The brain has been known to produce high levels of interferon-alpha (IFN-alpha) during viral infections. We investigated the central and peripheral mechanisms of the brain IFN-alpha-induced suppression of natural killer (NK) cytotoxicity in the rat. The activity of NK cells in the spleen and the peripheral blood decreased 30-120 min after intracerebroventricular (icv) injection of recombinant human IFN-alpha of > 1,000 U but not after its intraperitoneal injection. This effect was antagonized by pretreatment with icv naltrexone (NLTX). Splenic denervation was observed to completely abolish the IFN-alpha-induced suppression of NK activity, whereas bilateral adrenalectomy did not. Furthermore, this immunosuppression was blocked by an icv injection of an antagonist of corticotropin-releasing factor (CRF), alpha-helical CRF-(9-41). The icv injection of CRF resulted in reduced NK activity, which was not affected by NLTX. The results suggest that brain IFN-alpha activates the CRF system through central opioid receptors and thereby suppresses the NK cytotoxicity predominantly through splenic sympathetic innervation.
The effect of recombinant human alpha-interferon on plasma corticosterone concentrations was investigated in adult male rats. Intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration of alpha-interferon (10-10(4) U i.p., and 1-10(3) U i.c.v.) decreased basal plasma corticosterone concentrations. This effect was evident at both the peak and nadir in the circadian rhythm of hypothalamo-pituitary-adrenocortical secretory activity. The same inhibitory effect was obtained with intra-paraventricular nucleus administration of the cytokine. Furthermore, alpha-interferon attenuated the effects of stressors such as handling, 1 min of forced swimming, and sound stress in a novel environment. The effect of alpha-interferon (10(2) U i.c.v.) was blocked by prior injection of the opioid receptor antagonist, naloxone (1 mg/kg i.p.). Similarly, the effect of 10(3) U alpha-interferon administered i.p. was blocked by i.c.v. injection of naloxone (1 microgram/kg), or of the mu 1-specific receptor antagonist, naloxonazine (1 microgram). The selective delta-opioid receptor antagonist, naltrindole (1 microgram i.c.v.) and the kappa-opioid receptor antagonist, nor-binaltorphimine (1 microgram i.c.v.) both failed to prevent the inhibitory effect of alpha-interferon (10(3) U i.p.) on adrenocortical secretion. The results obtained provide further evidence for a neuromodulatory effect of alpha-interferon and that this effect is mediated by central opioid receptors of the mu 1-subtype, delta- and kappa-opioid receptors not being involved.
This paper addresses the current literature related to investigations of the link between exercise treatments and depression, anxiety and other mood states. Results from these investigations are supportive of the anti-depressant, anti-anxiety and mood enhancing effects of exercise programs. There were considered to be, however, a number of potential methodological problems in many of the research studies; the nature of these were considered. Finally, some possible directions for future research are outlined.
Interferon-alpha is the only approved and effective treatment for hepatitis C. Psychiatric side effects are common and have frequently required a decrease in dose or discontinuation of therapy. We here report a case of interferon-alpha-induced depression in a 40-yr-old man with hepatitis C successfully treated with the antidepressant fluoxetine, which allowed completion of interferon treatment.
To determine which patients are prone to side effects from interferon beta-1b and which side effects are most troublesome, we studied 72 patients with clinically definite MS who were started on interferon beta-1b after its release and found that the side effects significantly associated with treatment included skin reactions, flu-like symptoms, fatigue, leukopenia, new or worsened depression, and new or worsened headache. Of these, only fatigue and depression were significantly associated with discontinuance of therapy. Moreover, the course of disease before initiation of treatment also had a significant impact on the likelihood of discontinuing medication. Thus, despite an apparently similar therapeutic benefit (as judged by the similarly reduced attack rate in each group), patients with a secondary chronic progressive course were more likely to discontinue treatment (63%) than patients with either a relapsing/progressive course (18%) or a remitting/relapsing course (7%). Indeed, in the final regression equation, the only factors significantly related (r = 0.875) to the discontinuance of therapy were fatigue (p < 0.0001), a fatigue-depression interaction (p < 0.0001), and a chronic progressive course of disease (p<0.0001). Thus, if future clinical trials are to provide useful information on the value of interferon beta-1b in progressive MS, the side effects of fatigue and depression will need to be ameliorated to limit the drop-out rate from such trials.
The number of patients treated with interferon (IFN) has increased markedly in Japan since 1992, when the Health and Welfare Ministry approved the use of IFN for treating chronic active hepatitis C. It is important to identify and treat depression, which is one of the psychiatric complications of IFN therapy and often leads to discontinuation of the therapy, in patients with chronic hepatitis C. In this study we prospectively investigated the incidence of depression during IFN therapy in patients with chronic active hepatitis C. The psychiatric status of 85 patients (53 men, 32 women; mean age 49.1 years) with chronic active hepatitis C who began receiving IFN at Showa University Hospital was assessed before and 2, 4, 12 and 24 weeks after the start of IFN therapy, using the major depressive episode diagnostic criteria listed in the DSM-III-R and the Hamilton Depression Scale HDS). All of the patients provided informed consent prior to participation in this study. IFN therapy was discontinued in 5 cases (5.9%) because of physical side effects and in 4 cases (4.7%) because of depression. Two, 11, 14, 25 and 16 patients were diagnosed as having major depressive episodes before and 2, 4, 12 and 24 weeks after the start of IFN therapy, respectively. The number of patients who were asymptomatic before the start of IFN therapy but were diagnosed as having a major depressive episode at least once during IFN therapy was 31 (31/83 = 37.3%). The mean HDS scores at 2, 4, 12 and 24 weeks (5.4, 6.0, 8.8 and 6.6) were significantly higher than that before the start of IFN therapy (3.0). The patients whose first diagnosed major depressive episodes occurred more than 4 weeks after the start of IFN therapy tended to be more severely depressed than those in whom it occurred less than 4 weeks after the start of IFN therapy. Compared to the 47 patients who completed 24 weeks of IFN therapy without experiencing depression, the 31 patients who were diagnosed as experiencing major depressive episodes during IFN therapy had significantly higher neuroticism scores determined using the Eysenck Personality Questionnaire, showed a more severely depressed mood and experienced more severe sleep disturbances before the start of IFN therapy. The latter group of patients also tended to have comorbid chronic physical disorders such as hypertension or diabetes mellitus and the histories of mental disorders before the IFN therapy; however these differences were not statistically significant. There were no differences between the two groups in patient age or sex, the severity of hepatitis before the IFN therapy, the type of IFN used in the therapy or the efficacy of IFN in the treatment of the hepatitis C. Our results indicate that the decision as to whether to treat chronic active hepatitis C with IFN should be made carefully and that early intervention and careful monitoring of depression are required during IFN therapy in the treatment of chronic active hepatitis C.
Fatigue occurs in more than 70% of patients treated with interferon-alpha (IFN-alpha) and is the most problematic toxicity associated with IFN-based immunotherapy. Abundant evidence suggests that immune-mediated endocrine disease occurs during IFN-alpha therapy, which may contribute to the etiology of fatigue. Autoimmune thyroid disease is a well-recognized consequence of IFN-alpha therapy and may be mediated by the induction of IFN-gamma production by lymphocytes. Administration of exogenous IFN-gamma has been associated with upregulation of class II major histocompatibility antigens in the thyroid and the development of thyroiditis. Interferon-alpha also stimulates the production of interleukin-6; both interleukin-6 and IFN-gamma have specific effects on thyrocyte function. There also is evidence suggesting that IFN-alpha initiates a cytokine cascade that effects the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, thus affecting regulation of glucocorticoid and sex steroid hormone secretion, but the clinical significance of these observations has not been established. Although endocrine disease will not explain the occurrence of fatigue symptoms in all patients, there is clear evidence that hormonal deficiency syndromes occur in a relatively large portion of patients receiving systemic IFN-alpha therapy. Most importantly, the possibility of hypothyroidism must be considered; however, diagnosis of hypothyroidism in cancer patients is complicated by the occurrence of the "sick euthyroid syndrome." Clinical recommendations for assessment and treatment of IFN-alpha-induced fatigue are offered. Most importantly, measurements of thyroid-stimulating hormone and antithyroid autoantibodies should be used to evaluate thyroid status. Acknowledging the limitations of current clinical data, adrenal- and gonadal-axis dysfunction also must be considered in patients with IFN-alpha-induced fatigue.
The central nervous system side effects associated with interferon-alpha (IFN-alpha) therapy, including depression and cognitive changes, can compromise otherwise effective immunotherapy. The term "depression" has multiple meanings ranging from a feeling of sadness to a neuropsychiatric disorder with defined diagnostic criteria. A syndrome of mood disturbance with memory impairment, cognitive slowing, and impaired executive function is common with IFN-alpha therapy and is consistent with mild subcortical dementia. Cognitive deficits and mood disorder may occur independently, and in some cases depression is a reactive phenomenon. Risk factors for development of IFN-alpha neurotoxicity include duration of treatment, high-dose therapy, and prior cranial irradiation or neurologic illness. Past or current psychiatric illness also may put the patient at risk. Subtypes of major depression are associated with neuroendocrine and neurochemical alterations that are consistent with the observed activities of IFN-alpha. This may provide insight into the etiology of IFN-alpha neurotoxicity, as well as possible interventions. Assessment of the neuropsychiatric status of patients treated with IFN-alpha should be a standard of care. Possible pharmacologic interventions to decrease the neurotoxicity associated with IFN-alpha therapy include antidepressants, psychostimulants, and opioid antagonists. Preliminary clinical and research experience suggests that it is possible to effectively palliate IFN-alpha toxicity.
Various interferon-alpha (IFN-alpha) preparations, either as individual subtypes or natural mixtures, induce or inhibit expression of several other cytokines, as well as cytokine receptors and chemokines. The cytokines and receptors reportedly affected by IFN-alpha include interleukin-1 (IL-1), IL-2, IL-6, IL-8, IL-1 receptor, IL-1 receptor antagonist, tumor necrosis factor, tumor necrosis factor receptor, and IFN-gamma, all of which may amplify the effects of IFN-alpha treatment. The mechanism by which IFN-alpha induces expression of these cytokines is not clear. Some of the therapeutic and toxic effects associated with IFN-alpha therapy may be caused by the induction or inhibition of other cytokines and their respective cellular effects. Side effects including fever, anorexia, and fatigue can be caused by one or more of the cytokines induced by IFN-alpha. The response of different cell types, normal or malignant, to cytokines can vary. Such variation in cell type-specific responses may contribute to the diverse array of physiologic effects associated with IFN-alpha therapy. Further research is required to systematically uncover how other cytokines, receptors, or cellular factors contribute to the therapeutic and toxic effects of IFN-alpha.
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We report 5 cases of psychiatric side effects in patients treated with alpha interferon for chronic viral C hepatitis. The first case includes depression with suicidal impulses without a suicide attempt; there was a positive rechallenge of interferon. In the second and third cases, depression occurred during interferon therapy, but has not disappeared after interferon withdrawal. In the 4th and 5th cases, depression occurred after interferon withdrawal. Overall, suicide was attempted in 4 cases after interferon withdrawal and was responsible for 2 deaths. The prevalence of suicide attempts during the 6 to 12 months of interferon therapy was 0% compared to 1.3% during the 6 months after interferon therapy (P < 0.05) in 306 patients with chronic hepatitis C treated by interferon in our local area network during the same period.
In conclusion:
a) depression does not always disappear after interferon is discontinued; b) regular psychiatric follow-up is justified during treatment with interferon; c) psychiatric supervision should be continued, even more frequently after interferon withdrawal; d) the increased risk of psychiatric side-effect due to interferon as well as their severity suggest interferon should be administered with caution; e) the role of interferon can only be evaluated in controlled studies including the incidence and predictive value of emotional disorders.
In a previous study, we indicated that human interferon (IFN)-alpha (IFN-alpha, 6 x 10(4) IU/kg, i.v.), but not human IFN-beta or -gamma, prolonged the immobility time of the forced swimming test in mice. In this study, we investigated the mechanism of the effect of human IFN-alpha. None of the mouse IFNs tested (IFN-alpha/beta, IFN-beta, and IFN-gamma, 3 x 10(5) U/kg, i.v.) changed the immobility time or the spontaneous locomotor activity in mice. Indomethacin (10 mg/kg, s.c.), a cyclooxygenase inhibitor, did not affect the increase in the immobility time induced by human IFN-alpha (6 x 10(4) IU/kg, i.v.). However, naloxone (1 mg/kg, s.c.), an opioid receptor antagonist, blocked the increasing caused by human IFN-alpha in the forced swimming test. These results suggest that the increase in the immobility time caused by human IFN-alpha in the forced swimming test might be mediated through opioid receptors, but not mouse IFN receptors.
We report 3 cases of suicide attempts in postoperative patients with renal cancer after alpha interferon withdrawal.
In the first patient, depression occurred during interferon therapy, and remained after interferon withdrawal. A suicide attempt occurred 7 months after interferon withdrawal.
In the second and third patients, depression did not occur during interferon therapy, but suicide attempts occurred 40 days and 7 months after interferon withdrawal, respectively.
Depression does not always dissappear after interferon is discontinued. Psychiatric supervision should be continued even more frequently after interferon withdrawal. The increased risk of psychiatric side effects due to interferon, as well as their severity, suggest that interferon should be administered with caution.
To study prospectively the psychiatric side effects of interferon-alpha in patients with hepatitis C.
Sixty-three consecutive patients at a hepatitis clinic were recruited. All were assessed using a psychiatric interview (SCID) and monitored using a self-reporting psychiatric symptom questionnaire (SCL-90).
Patients on interferon did not suffer a drop in mood or an increase in anxiety or irritability. The subgroup with past depression also did not suffer an increase in depressive symptoms. No patients attempted suicide.
The risk of serious psychiatric symptoms when being treated with interferon-alpha may not be high. Psychiatric illness or the possibility of psychiatric complications should not be used as a reason to refuse this treatment to patients with hepatitis C.
Depressive symptomatology is frequently associated with interleukin (IL)-2 and interferon alfa-2b (INFalpha-2b) therapy in cancer patients. The objective of the present study was to evaluate the depressive and anxiety symptoms induced by IL-2 and/or INFalpha-2b in cancer patients during the first days of cytokine immunotherapy.
The study included 48 patients with renal cell carcinoma or melanoma. Patients were treated either with subcutaneous IL-2, alone (n = 20) or in combination with INFalpha-2b (n = 6); or with INFalpha-2b alone, administered subcutaneously at a low dose (n = 8) or intravenously at a high dose (n = 14). Depressive symptoms were evaluated using the Montgomery and Asberg Depression Rating Scale (MADRS), and anxiety symptoms were evaluated using the Covi scale. Evaluations were performed just before initiation of treatment (day 1) and on days 3 and 5 of treatment.
Patients treated with IL-2 alone or in association with INFalpha-2b had significantly higher MADRS scores after 5 days of cytokine therapy, and patients who received both cytokines had increased scores on day 3. In contrast, patients treated with INFalpha-2b alone did not have varying MADRS scores during the course of treatment. Cytokine therapy had no effect on anxiety, except in patients treated with IL-2 in combination with INFalpha-2b. In these patients, the enhancement in anxiety scores that was observed on day 5 was mainly attributable to increased somatic complaints.
IL-2 and INFalpha-2b have differential effects on mood, and IL-2 therapy induces depressive symptoms early in treatment.
Neuropsychiatric symptoms are commonly associated with chronic hepatitis C virus infection, its sequelae, and its treatment. In particular, interferon, a primary component of treatment for chronic hepatitis C, has been strongly associated with depressive symptoms. This review summarizes current knowledge about the etiology, course, and treatment of neuropsychiatric problems associated with hepatitis C and interferon alpha (IFN-alpha) treatment.
Studies were identified by computerized searches, and further references were obtained from bibliographies of the reviewed articles.
Chronic infection with the hepatitis C virus is a common and growing problem, often affecting persons with psychiatric and substance use problems. Although changes in cognition, mood, and personality have been described in association with hepatitis C and with IFN-alpha treatment, there has been little systematic study of these changes.
Psychiatrists should become familiar with the clinical spectrum associated with hepatitis C virus infection as well as the neuropsychiatric symptoms related to hepatitis C and IFN-alpha treatment. More studies are necessary to define the neuropsychiatric syndromes associated with this population and to find possible effective treatments. Furthermore, research is needed so that patients with psychiatric problems are not excluded from effective treatments for this growing medical problem.
At the doses used for the treatment of chronic viral hepatitis, interferon (IFN)-related side-effects are usually modest, even though in some cases they require the interruption of therapy. Neuropsychiatric disturbances that range from modest depression and irritability to forms of manic-depressive psychosis and attempted or successful suicides are among the most important side-effects. The aim of our study was to determine whether the Minnesota Multiphasic Personality Inventory (MMPI) is a sensitive and reliable test for the early identification of patients at risk of depression before IFN therapy is commenced, and whether it could be useful for the monitoring of these patients during treatment.
We prospectively studied 67 patients with chronic active liver diseases, consecutively enrolled in open studies and treated with r-IFNalpha2. Before starting therapy and after 3 months of treatment, all patients underwent a clinical neurological evaluation and MMPI.
At baseline, the correlation between the clinical evaluation and the score of the depression scale of the MMPI was statistically significant (P< 0.0001). Nine of 14 (64.3%) patients with a baseline score > or = 60/100 showed a depressive mood after 3 months of therapy. Five of 44 patients (11.3%) with a baseline score < 60/100 showed a depression of medium level after 3 months of treatment. This difference was highly significant (P< 0.0001).
According to our results, the MMPI is a reliable and sensitive test for the early identification of patients at risk of depression before and during IFN therapy for chronic viral liver diseases.
We analysed data from a multicentre interferon (IFN) treatment trial to evaluate symptoms in patients with chronic hepatitis C and to identify factors that might predict development of debilitating IFN side-effects. Two hundred and twenty-two patients (120 US, 102 French) received 3 or 5 million units (MU) of IFN-alpha three times weekly (t.i.w.) for 3 months. Those who had detectable hepatitis C virus (HCV) RNA, as detected by the branched DNA signal amplification (bDNA) assay, at 3 months were intensified to daily therapy, while patients who were bDNA negative continued t.i.w. dosing for the subsequent 3 months of treatment. Symptoms were assessed at baseline, and adverse effects were evaluated at 6 months of therapy. Prior to treatment, the most common symptom that interfered with daily functioning was fatigue, occurring in 25% of patients. The frequency of debilitating fatigue, myalgia, arthralgia, headache, the presence of dry eyes and dry mouth, and use of antidepressant medication increased significantly from baseline to 6 months of IFN therapy (all P < 0.01). In multivariate analysis, the development of a debilitating side-effect at 6 months of treatment was associated with the presence of that symptom prior to therapy in all cases. Symptoms and adverse effects varied by gender and country. Compared with patients maintained on t.i.w. dosing, those who were dose intensified to daily IFN reported more debilitating fatigue, malaise, myalgia, arthralgia, fever, nausea, and headache, and the presence of dry mouth (all P < 0.05). In conclusion, patient characteristics, including pretreatment symptoms, gender and nationality, as well as daily IFN dosing are associated with the development of debilitating adverse effects on IFN therapy.
We performed an analysis of toxicity and survival in stage III melanoma patients receiving adjuvant interferon alfa-2b (IFN). This was a retrospective single-arm analysis of 40 patients with stage III melanoma who received (IFN) administered at maximum tolerated doses of 20 mU/m2/day intravenously (i.v.) for 1 month and 10 mU/m2 three times per week subcutaneously (s.c.) for 48 weeks. Toxicity in our series is comparable to that experienced in the Eastern Cooperative Oncology Group (ECOG) 1684 trial, except for higher rates of dose-limiting myelosuppression and hepatotoxicity. All 40 patients experienced constitutional symptoms, but only 14/40 (35%) experienced grade 3 to 4 symptoms. Of the 40 patients, 36 (90%) experienced neurologic symptoms, but only seven (17.5%) experienced grade 3 to 4 neurotoxicity. Two patients stopped treatment because of severe psychiatric symptoms; one patient attempted suicide, and a psychosis developed in another. Thirty-nine (97.5%) patients experienced myelosuppression; 31 (77.5%) developing grade 3 to 4 myelosuppression. Hepatotoxicity was evident in 39 (97.5%) patients, and 26 (65%) experienced grade 3 to 4 hepatotoxicity. Three patients (7.5%) experienced mild renal toxicity. At a median follow-up of 27 months from initiation of therapy, there have been 19 relapses (47.5% disease-free survival [DFS]) and 10 deaths (75% OS) resulting from progression of disease. The DFS compares with the treatment arm in ECOG 1684 at 27 months, but overall survival is higher in our series of patients at the same time point. In a single program setting, IFN can be administered with similar side effects and outcome profiles seen in multi-institutional studies. Modifications in the induction regimen resulted in notably higher hematologic and hepatic toxicities but did not preclude administering further therapy and did not result in increased attrition rate among patients: only nine patients (22.5%) had their treatment stopped as a result of IFN-related toxicity. In comparison, 26% of patients had to have their treatment discontinued because of toxicity in ECOG 1684.
The use of a high dose regimen of interferon-alpha-2b (IFN) has recently been demonstrated to benefit patients with resected high risk melanoma. The incidence of melanoma is rising rapidly, and the use of this regimen is becoming increasingly common. IFN has been associated with numerous psychiatric side effects.
The authors describe four melanoma patients treated with adjuvant IFN who developed a manic-depressive syndrome or mood instability with therapy, and they review the literature on mania and the mixed affective syndromes associated with IFN.
The authors suggest that IFN may induce a mixed affective instability, and that patients risk developing hypomania or mania as IFN doses fluctuate or as IFN-induced depression is treated with antidepressants alone. Mania is particularly associated with dose reductions or pauses in IFN treatment. The risk of mood fluctuation continues after treatment with IFN stops, and patients should be monitored for 6 months following completion of therapy. Gabapentin appeared effective as monotherapy for acute mania, as an antianxiety agent, as a hypnotic, and as a mood stabilizer in these individual cases.
Mania and mood instability can occur in patients being treated with IFN therapy for melanoma. In this study, gabapentin was an effective mood-stabilizing agent for these patients.
Interferon alfa therapy for chronic hepatitis C infection is commonly associated with neuropsychiatric symptoms, including depression. These side effects may necessitate reduction or even cessation of interferon alfa, but there is little information regarding the management of this important problem. We report 10 cases of interferon-alfa-induced depressive disorder treated with the selective serotonin reuptake inhibitor sertraline. All patients obtained rapid symptom relief without the need for reduction or cessation of interferon alfa.