Jack J. Chen, PharmD, BCPS, CGP, FCPhA
Several sessions at the American Society of Health-System Pharmacists 37th Midyear Clinical Meeting focused on immunomodulation. One of these sessions, planned in cooperation with ASHP Section of Clinical Specialists and Scientists, was composed of a series of presentations by 5 distinguished speakers, including Julie A. Dopheide, PharmD, BCPP, School of Pharmacy, University of Southern California, Los Angeles; Michael J. Owens, PhD, School of Medicine, Emory University, Atlanta, Georgia; Dale R. Grothe, PharmD, BCPP, Global Medical Affairs, Wyeth Pharmaceuticals, St. Davids, Pennsylvania; Jacquelyn L. Bainbridge, PharmD, University of Colorado Health Sciences Center, Denver; and Toya M. Bowles, PharmD, BCPP, University of Florida Health Sciences Center, Gainesville.
Neuroscience, psychiatry, and immunology are rapidly growing fields of knowledge in medicine. One area in which these fields overlap is the biology of cytokines. Cytokines are a diverse group of proteins (eg, interferons, tumor necrosis factor, and interleukins) that act as signals between cells of the immune system and play a critical role in mediating immune and inflammatory responses. Although the links between the cellular and hormonal process and behavioral targets remain highly complex, emerging research supports the role of neural concepts involving intracellular signaling pathways of the immune system and endocrine mechanisms affecting human behavior.
According to Dr. Dopheide, the clinical evidence that links mood disorders and endocrine and immune system function "includes the high incidence of mood disorders in immune-mediated illnesses such as multiple sclerosis (60%), rheumatoid arthritis, systemic lupus erythematosus (50%), and acquired immune deficiency syndrome (25%)." Additional clinical evidence is provided by the finding that there is a greater incidence of depression in patients receiving immunomodulating therapy with cytokines (eg, for conditions such as cancer, hepatitis C, multiple sclerosis, and rheumatoid arthritis) compared with similar patients not receiving immunomodulating treatment.
A well-known phenomenon that occurs in acute infections and trauma is the cytokine-mediated "sickness behavior," which manifests as increased sleep, decreased appetite, and decreased sexual drive. For acute processes, this behavior is adaptive and allows the body to mobilize necessary resources for the healing process. However, in chronic disease states, in which there is sustained cytokine elevation or augmentation with cytokine pharmacotherapy, the sickness behavior becomes maladaptive. Although the mechanisms responsible for the beneficial effects of interferons are known, the underlying mechanisms responsible for the sickness behavior and other adverse psychiatric effects have not been elucidated. Since exogenously administered cytokines such as interferon cannot cross the intact blood-brain barrier, several peripheral or indirect central mechanisms involving neurochemical and endocrine effects have been proposed. One proposed mechanism relates to cytokine stimulation of the adrenocorticotropic hormone/cortisol axis, which is believed to result in increases in serum cortisol levels. In patients with major depression, hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is a consistent observation. Additionally, major depression is associated with increased production of proinflammatory cytokines, such as interleukin (IL)-1beta, IL-6, and interferon-gamma. Reductions in serum tryptophan levels have also been observed after administration of interferons, and associated reductions in serotonin may be responsible for depressive symptoms.
The pharmacologic management of chronic iatrogenic psychiatric symptoms consists of introducing antidepressant agents such as tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs). Since interferon-induced neuropsychiatric side effects are a common cause of dose limitation or treatment discontinuation, successful management of the iatrogenic symptoms not only improves quality of life but also allows treatment to be completed or continued. The effect of psychopharmacologic agents on cytokine production is another area for future examination. Currently, the number of studies addressing this issue is limited.
Dr. Owens presented data demonstrating the relationship between corticotropin-releasing factor (CRF) dysregulation and mood disorders. This dysregulation appears to be normalized by current antidepressants. However, the recent development of selective, small-molecule CRF1 receptor antagonists, which block the effects of CRF both in vitro and in vivo, suggest that these novel compounds may be effective in the treatment of affective and anxiety disorders. Early evidence indicates that these agents possess anxiolytic and antidepressant activity in animal behavioral models. Dr. Owen reinforced that the HPA hyperactivity observed consistently in patients with major depression is supported by studies demonstrating enlarged adrenal glands, enlarged pituitary glands, increased levels of CRF in cerebrospinal fluid, and increased levels of cortisol in cerebrospinal fluid, plasma, and urine. Further promoting this state of HPA hyperactivity is the development of glucocorticoid receptor (GR) resistance to feedback inhibition by endogenous glucocorticoids. Several mechanisms for GR resistance have been investigated, including cytokine-induced inhibition of GR activation. Although elevations in cerebrospinal fluid levels of CRF are not correlated to severity of depressive symptoms, this marker appears to correlate to the risk of relapse.
A number of animal studies have demonstrated that chronic administration of tricyclic antidepressants enhances GR translocation and function and/or upregulates GR protein and mRNA within the brain and attenuates glucocorticoid hypersecretion. Studies evaluating the effect of SSRIs on GR are inconsistent but demonstrate a greater effect on upregulating mineralocorticoid receptors (which may also contribute to increased glucocorticoid-mediated negative feedback of the HPA axis). In addition to promoting changes in GR activity, chronic therapy with the currently available antidepressants also results in plastic changes within the central nervous system (CNS) related to activity of CRF, GRs, neurotrophic factors (eg, brain-derived neurotrophic factor [BDNF]), and transcription factors (eg, cyclic AMP response element-binding protein). The mechanism by which antidepressants exert these plastic changes remains unknown.
Dr. Groethe pointed out the paucity of double-blind, randomized, controlled trials evaluating the efficacy and safety of antidepressant agents for the management of depression in patients receiving immunomodulating therapy. However, recognizing that currently available antidepressants not only enhance the activities of monoamines (eg, serotonin and norepinephrine) but also enhance BDNF activity, reduce hypercortisolemia and GR resistance, and enhance neuronal growth and survival, he expressed optimism that recognition of these novel antidepressant mechanisms have opened the door for the development of a wide variety of agents with theoretical applications in mood disorders. These agents include CRF1 receptor antagonists, phosphodiesterase (PDE) type 4 inhibitors (eg, rolipram), BDNF facilitators, and GR modulators.
Dr. Groethe also highlighted that, in addition to dysfunctions in the turnover of monoamines and the hyperactivity of the HPA axis, there is a third concept in models of major depression: activation of the inflammatory response system. Proinflammatory cytokines have been implicated in the pathophysiology of major depression. Antidepressants (eg, tricyclic agents, SSRIs, serotonin-norepinephrine reuptake inhibitors) have been demonstrated to attenuate the activity of proinflammatory cytokines via enhanced IL-10 production and associated suppression of the interferon-gamma/IL-10 ratio). IL-10 suppresses proinflammatory cytokines (eg, interferon-gamma, IL-1, IL-6). This suggests that antidepressants may exert beneficial effects via negative immunoregulatory effects.
Depressive symptoms are common in chronic immune disorders. Mechanisms involve the activation of the inflammatory response system (eg, cytokines), HPA axis hyperactivity, CRF hypersecretion, and GR dysfunction. Findings that demonstrate direct effects of antidepressants on GR indicate that these agents, in addition to acting as monoamine enhancers, may resolve depressive symptoms through endocrine-mediated mechanisms. The discovery of the intersection between cytokines, the HPA axis, and major depression provides an exciting research venue on the neural-immune axis. There is no doubt this new research will present an opportunity for the development of novel neuropharmacologic interventions in the field of psychiatry.
Multiple Sclerosis (MS)
Dr. Bainbridge and Dr. Bowles wrapped up the session with an overview of MS, with a focus on immunomodulating agents and the management of MS symptoms. MS is an inflammatory disease of the CNS; onset occurs between the ages of 20 and 40 years. The course of MS is generally characterized by acute exacerbations of neurologic symptoms followed by a series of relapses and remissions. These exacerbations often result in permanent neurologic deficits. Although MS is not a fatal disease, disease progression often results in functional disability and reduced quality of life. The pathogenesis of MS remains unknown; however, several hypotheses have been proposed, including an autoimmune mechanism. In the autoimmune proposal, T cells in the peripheral circulation are activated by unknown antigens and cross the blood-brain barrier into the CNS. In the CNS, the T cells stimulate production of proinflammatory cytokines that go on to cause demyelination with subsequent neurologic dysfunction.
The neurologic presentation of MS includes oculomotor disturbances, tremor, ataxia, spasticity, fatigue, sensory disturbances, pain syndromes, bladder or bowel dysfunction, and psychiatric disorders. There is as yet no cure for MS. Treatment includes slowing the disease progression with immunomodulators, attenuating acute exacerbations with high-dose corticosteroids, and providing symptomatic relief with nonpharmacologic and pharmacologic therapy. Dr. Bainbridge reviewed the disease-modifying agents, including 2 interferon beta-1a products (Avonex and Rebif), interferon beta-1b (Betaseron), glatiramer acetate (Copaxone), and mitoxantrone (Novantrone).
Immunomodulators (ie, interferons and glatiramer) are effective in patients with relapsing-remitting MS and reduce the frequency of acute exacerbations. In addition, magnetic resonance imaging scans suggest that these agents can decrease myelin destruction and attenuate lesion burden in MS. Recent clinical studies, such as Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) and Effect of Early Interferon Treatment on Conversion to Definite Multiple Sclerosis (ETOMS), confirm these benefits. Dr. Bainbridge highlighted the clinical evidence that supports early initiation of disease-modifying agents in all patients with a diagnosis of relapsing-remitting MS and noted that therapy should continue except in the presence of contraindications or lack of clinical benefit. Selection of disease-modifying products and compliance with therapy can be enhanced by knowledge of product dosing frequency, route of administration, storage, and side-effect profile (Table).
Table. Multiple Sclerosis Immunomodulators
|Storage||Refrigeration; Room temperature (up to 30 days)||Refrigeration||Refrigeration; room temperature (up to 7 days)||Refrigerate; room temperature (up to 7 days)|
|Route of administration||IM||SC||SC||SC|
|Frequency of administration||Once weekly||Thrice weekly||Every other day||Daily|
IM = intramuscularly; SC = subcutaneously
Common side effects of the interferons include flu-like symptoms, fever, chills, sweating, muscle aches, fatigue, depression, and injection-site reactions. Less common side effects include leucopenia, anemia, thrombocytopenia, increased hepatic enzymes, spontaneous abortion, and development of neutralizing antibodies. The common side effects of glatiramer acetate include dizziness, flushing, and injection-site reactions. For all these products, rotating the site of injection is recommended to minimize skin reactions. Dr. Bainbridge noted that the interferon beta-1b (Betaseron) and interferon beta-1a (Rebif) products appear to be associated with a greater frequency of injection-site reactions compared with the interferon beta-1a (Avonex) and glatiramer acetate products.
The chemotherapeutic agent mitoxantrone is useful for reducing disability and frequency of relapses in secondary progressive MS, progressive-relapsing MS, and worsening relapsing-remitting MS. The standard dosage is 12 mg/m2 administered every 3 months. To minimize the risk of cardiotoxicity, the recommended maximum cumulative dose is 140 mg/m2.
Fatigue, cognitive impairment, mood disorders, and pain are common symptoms of MS. Autonomic dysfunction, such as bladder or bowel incontinence, is also common. Dr. Bowles noted that the treatment of these symptoms can be complex and difficult and that most treatment options are based on anecdotal data with a paucity of evidence-based data in the MS population. Fatigue may present itself upon exertion, in the afternoon or early evening, or with increased temperatures. Both Dr. Bainbridge and Dr. Bowles emphasized that the fever induced by interferon products is not benign and can significantly exacerbate fatigue symptoms. Therefore, antipyretic premedication is encouraged. Nonpharmacologic management of fatigue includes cooling measures (eg, cooling vests) and avoidance of fever and heat extremes. Dr. Bowles commented that pharmacologic management consists of amantadine followed by modafinil and pemoline. The usefulness of other agents such as SSRIs is predicated on anecdotal information.
Cognitive impairment is a major cause of disability in patients with MS and can be exacerbated by concurrent fatigue, depression, and interferon therapy. Currently, no effective pharmacologic agents are approved as symptomatic therapy for cognitive impairment in MS. However, the results of uncontrolled trials suggest that cholinesterase inhibitors (eg, donepezil) may be beneficial.
Mood disorders occur frequently in patients with MS. Symptoms of depression can also be exacerbated by concurrent interferon or corticosteroid therapy and comorbid cognitive impairment, fatigue, and pain. In addition to psychotherapy, pharmacologic agents are beneficial. The tricyclic antidepressants have been utilized; however, side effects of sedation and anticholinergic properties are problematic and may worsen symptoms of MS. Case reports suggest that SSRIs are effective and well tolerated for management of depression in patients with MS.
Pain symptoms also occur frequently in patients with MS. Acute pain conditions include trigeminal neuralgia, painful optic neuritis, and Lhermitte's syndrome. Chronic pain conditions such as limb dysesthesias, joint pain, and other musculoskeletal or mechanical pain problems develop as a function of spasticity and deconditioning associated with MS. Pharmacologic, surgical, rehabilitative, and psychological interventions may be helpful.
Dr. Bowles emphasized that each of these symptoms may wax and wane with the disease progression, and periodic assessment is recommended. Clinicians should also be vigilant for drug-disease interactions that can exacerbate symptoms, and management can be optimized with the appropriate selection of drugs that benefit multiple comorbidities.
In summary, MS is a chronic immune disorder associated with significant functional disability and reduced quality of life. Clinical and neuroimaging data support the early initiation of immunomodulating therapies to improve functionality and to slow disease progression. The treatment of comorbid, symptomatic conditions (eg, cognitive impairment, fatigue, mood disorders, and pain) constitutes another significant aspect of care for patients with MS and can be a challenge to manage. Further clinical research is needed to develop a more rigorous evidence-based approach for the symptomatic treatment of MS.
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