英文小说>2426Review article
Interferon-induced depression:Strategies in treatment
Gregory M.Asnis a,*,Richard De La Garza II b
a
Albert Einstein College of Medicine,Montefiore Medical Center,Anxiety and Depression Program,111E.210th Street,Bronx,NY,United States
b
University of California Los Angeles,Department of Psychiatry and Biobehavioral Sciences,740Westwood Boulevard,
Suite A8-148,Los Angeles,CA 90024,United States
Accepted 1March 2005Available online 19May 2005
Abstract
美式英语音标
Interferon (IFN)is a pro-inflammatory cytokine that is widely ud for the treatment of a number of disorders including viral infections,hematological proliferative disorders,and skin malignancies.Unfortunately,IFN frequently induced depression and has led to compromid tolerability with lowering of the do of IFN and even discontinuation of treatment.Thus,it is imperative to diagno IFN-induced depression early,evaluate whether this depression is associated with IFN-induced anemia or thyroid dysfunction,which can be corrected,and if necessary treat with antidepressants.IFN-induced depression is highly responsive to antidepressants with benefits occurring frequently at relatively low dos and after only a few weeks.Although SSRIs have mainly been studied,non-SSRIs appear to be effective also.Antidepressants have a number of risks and side effects that must be considered and may enter into the decision as to which antidepressant to choo.If IFN induces a depression in a patient with a bipolar disorder history,antidepressant treatment must include a mood stabilizer.In the ca of vulnerable patients (e.g.,tho who have significant depressive symptoms prior to IFN or who have had an IFN-induced depression in the past)prophylactic antidepressant treatment appears to decrea the likelihood of having an IFN-induced depression.On the basis of known and effective treatment strategies,IFN-induced depression should not be an obstacle for continued treatment in most patient populations.
D 2005Published by Elvier Inc.
Keywords:Antidepressant;Depression;Interferon;Serotonin
Contents 1.Introduction ..........................................................8092.IFN-induced depression ....................................................8093.Ruling out depression due to a general 8094.Antidepressants as treatment for IFN-induced depression ...................................8105.Choosing the best treatment for IFN-induced depression ...................................8116.Considering antidepressant side-effects ............................................8117.Future antidepressant treatments for IFN-induced depression .................................8138.Bipolar depression—a special problem ............................................8149.
Other non-antidepressant practical issues ..........
.................................
815
0278-5846/$-e front matter D 2005Published by Elvier Inc.doi:10.1016/j.pnpbp.2005.03.006
Abbreviations:5-HT,5-hydroxytryptophan (rotonin);ALT,alanine aminotransfera;CHC,chronic hepatitis C;CRH,corticotrophin releasing hormone;HIV ,human immunodeficiency virus;HPA,axis,hyp
othalamic pituitary adrenal axis;IFN,interferon;MDD,major depressive disorder;MAOI,monoamine oxida inhibitor;NSAID,non-steroidal anti-inflammatory drug;SCID,structured clinical interview for DSM-IV;SSRI,lective rotonin reuptake inhibitor;SJS,Steven’s Johnson Syndrome;TCA,tricyclic antidepressant;TNF-a ,tumor necrosis factor-a .*Corresponding author.Tel.:+17189204287;fax:+17188824735.E-mail address: (G.M.Asnis).Progress in Neuro-Psychopharmacology &Biological Psychiatry 29(2005)808–
818
/locate/pnpbp
10.Preventative(pre-ont)versus restorative(post-ont)antidepressant treatment strategies (815)
11.Conclusions (816)
References (816)
1.Introduction
Interferon(IFN)is a pro-inflammatory cytokine that impacts immune system functioning resulting in marked anti-viral,anti-cancer,and immunomodulatory effects.IFN is approved by the FDA for a numb
er of disorders including multiple sclerosis,malignant melanoma,chronic myelogenous leukemia,and is the only approved treatment for chronic hepatitis C(CHC)(Piper et al.,2001).In spite of its efficacy,IFN induces a number of neurotoxic effects including depression which compromis its tolerability among patients.In the past,IFN-induced depression has been one of the main reasons for clinicians lowering the do and/or discontinuing IFN treatment(Trask et al., 2000;Zdilar et al.,2000).The actions can cau a remission of the depressive episode,but are frequently associated with the failure in achieving the anti-cancer, anti-viral,and immunomodulatory properties produced by IFN.It is now clear that IFN-induced depression can be proactively treated by a number of diver antidepressants, increasing the likelihood of abatement of depressive symptoms and continuation of IFN treatment.Further-more,recent data suggests that pretreatment with anti-depressants can prevent the ont of IFN-induced depression,and this may be especially relevant for vulnerable populations.This review scrutinizes evidence for treatment versus prevention of IFN-induced depression, and offers advice when to u each strategy.Furthermore, recommendations for specific antidepressants to be ud and precautions are discusd.高一数学
ellen2.IFN-induced depression
IFN-induced depression is more appropriately designated a substance-induced mood disorder with d
epressive fea-tures,yet for the purpo of this review we will consider only tho cas that coincide with the full criteria of a major depressive disorder(MDD).In contrast to a sub-stance-induced mood disorder with depressive features, MDD must not only have a persistent depresd mood or loss of interest or pleasure,but must be of at least2weeks in duration with at least5associated ,low energy,disturbances in sleep or appetite)(American Psychiatric Association,2000).By assuring that a diagnosis of IFN-induced depression coincides with criteria for MDD, we substantiate that the obrved syndrome is of significant verity and not just a fleeting experience.Another reason to focus on MDD criteria is that most clinical rearch and knowledge of efficacy of antidepressants in depression have focud exclusively on MDD.With this definition in mind,it is notable that the prevalence rate of IFN-induced depression is approximately23%to45%(Otsubo et al., 1997;Muslman et al.,2001;Bonaccorso et al.,2002a,b; Haur et al.,2002;Horikawa et al.,2003).
Determining that IFN-induced depressive disorder sat-isfies the criteria of a MDD necessitates a careful interview to asss the required symptoms for the diagnosis.Many studies,particularly tho conducted by physicians outside of psychiatry,have relied on lf-rating questionnaires, including specific depression rating scales such as the Zung Depression Rating Scale(Zung et al.,1965)and th
圣诞的英文e Beck Depression Inventory(Beck et al.,1961),each with suggested cut-offs for a MDD diagnosis.High scores on the questionnaires do not insure an accurate asssment since they do not include the necessary timeframe or symptoms for a MDD diagnosis.Using a structured inter-view guide such as the Structured Clinical Interview for DSM-IV(SCID)(First et al.,1995)will not only help diagno a MDD,but will also detect other co-morbid illness or prior psychiatric disorders that might influence treatment planning.
3.Ruling out depression due to a general medical condition
In considering IFN-induced depression,it is important to rule out the possibility that other physiological caus (general medical conditions)may be the source of the depression and to determine whether this disorder requires isolated treatment.
IFN can affect the hematological system and thyroid gland causing symptoms that appear similar to a MDD and/ or may contribute to the precipitation of MDD.IFN,as well as ribavirin(a co-treatment for CHC)(Plosker and Keating, 2004),decreas red blood cells via a hemolytic process and suppression of erythropoietin frequently leading to anemia. With the combination therapy of IFN+ribavirin,54% experienced reductions of hemoglobin of3g/dl or more from baline,while8–9%h
ad reductions of hemoglobin to <10g/dl(Maddrey,1999;Sulkowski et al.,2004).Such anemia can be associated with anhedonia,fatigue,dyspnea, headaches,cognitive dysfunction and compromis of functional capacity leading to reduced quality of life (Pockros et al.,2004).This symptomatic picture is important to understand becau aggressive treatment with erythropoietin leads to improvement of anemia with an accompanying improvement in quality of life measures (Pockros et al.,2004).Thus,if the depression is associated with IFN-induced anemia,treatment with erythropoietin may lead to an improvement of the symptoms.If depression
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remains,and/or the associated depression is vere,anti-depressant treatment should be initiated.look after
IFN,particularly IFN-a,is known to induce thyroid dysfunction in approximately12%of patients(Dalgard et al.,2002).This appears to be predominantly due to an autoimmune phenomenon with accompanying thyroid ,thyroid peroxida autoantibodies). Clinically,hypothyroidism is most common and Graves’Dia with hyperthyroidism is less frequently obrved. The association of thyroid disorders,particularly hypo-thyroidism with depressio
n(as well as anxiety)is well known(Jackson,1998).Since both IFN-induced depression and IFN-induced thyroid disorders frequently develop over a similar time frame,usually during the first12weeks of treatment(Dalgard et al.,2002;Haur et al.,2002; Horikawa et al.,2003),a careful evaluation of thyroid functioning is indicated if depression aris.In patients with thyroid disorders who have an accompanying depressive symptomatology,treatment of the thyroid disorder alone frequently leads to a remission of the depression(Jackson, 1998).Antidepressants can be initiated if the depression continues in spite of a thyroid correction or if the depression is too vere at any point in time.
4.Antidepressants as treatment for IFN-induced depression
A number of ca studies have found that antidepressants from veral drug class are effective in the treatment of IFN-induced depression.Most of the ca studies have focud predominantly on lective rotonin re-uptake inhibitors(SSRIs)such as rtraline(Gleason and Yates, 1999;Schramm et al.,2000),fluoxetine(Levenson and Fallon,1993),paroxetine(Gleason and Yates,1999)and citalopram(Farah,2002).The reports also specified efficacy for various tricyclic antidepressants(TCAs), including nortriptyline(Goldman,1994)and imipramine (Gleason and Yates,1999),which are predominantly norepinephrine reuptake inhibitors.Additional compounds inclu
de a rotonergic and noradrenergic receptor modu-lator,mirtazapine(Russo et al.,2003),and the norepinephr-ine and dopamine reuptake inhibitor bupropion(Malek-Ahmadi and Ghandour,2004).A large open-label treatment study evaluated citalopram in13in39HCV patients who developed an IFN-induced depression.An impressive number who developed depression(9of11patients)that were administered citalopram responded to the treatment. One depresd patient requested fluoxetine and responded and another patient who failed to respond to citalopram in the past was treated with bupropion and responded(Haur et al.,2002).A similar open-label study of paroxetine in14 CHC patients who developed IFN-induced depression was conducted and revealed that11of14patients(78.6%) significantly improved and were able to continue their antiviral therapy without do reduction(Kraus et al.,2002).
Since IFN-induced depression is so prevalent,another strategy that others have investigated is whether prophylactic antidepressant treatment reduces or prevents its occurrence.Supporting investigation of this strategy is experimental data demonstrating that cytokine-induced depression(‘‘sickness behavior’’)in animals could be prevented with pretreatment with antidepressants(Yir-miya,1996).Furthermore,in patients with recurrent MDD who have a non-iatrogenic relapsing depressive disorder, depressive episodes can be frequently prevented with prop
kickhylactic antidepressant treatment(Frank et al.,1990). Of interest,a ca report by Haur et al.(2000)showed that pretreatment with fluoxetine prevented the development of IFN-induced depression in a patient who had previously developed a vere depression during IFN treatment. Subquently,Muslman et al.(2001)published a pla-cebo-controlled trial assaying the ability of paroxetine to prevent IFN-induced depression.In that study,patients with malignant melanoma were randomized to treatment with paroxetine or placebo(n=20each),starting2weeks before, and continuing12weeks during,IFN treatment.Symptoms consistent with a diagnosis of MDD developed in2of18 patients(11%)in the paroxetine group and9of20(45%)in the placebo group.Moreover,vere depression necessi-tated the discontinuation of IFN treatment in1of20 patients(5%)in the paroxetine group,compared with7of 20(35%)in the placebo group.Further analys demon-strated that neurovegetative and somatic symptoms of IFN treatment,such as anorexia,pain,and fatigue,appeared within2weeks from the beginning of treatment,whereas symptoms of depresd mood,anxiety,and cognitive dysfunction appeared later,especially in patients who met DSM-IV criteria for MDD.In addition,antidepressant treatment reduced the occurrence of depression,anxiety and cognitive symptoms and failed to affect the ont of neurovegetative symptoms.The results led to the suggestion that there might be two different IFN-induced symptom constellations(a mood/cognitive syndrome ver-sus a neurovegetative syndrome),with distinct underlying biochemical dysfunctions and responsivity to antidepres-sants(Capuron et al.,2002).
IFN-induced depression appears to be a depressive disorder that is unusually responsive to antidepressant treatment.Not only is treatment effective in approxi-mately80%of patients,but respon occurs at relatively small dos with a rapid ont of action.Most reports detail respons at4weeks and not uncommonly,as early as2weeks(Kraus et al.,2002).This incread nsitivity apparent in IFN-induced-depression may be related to a short duration of illness when treatment is usually initiated and the mild to moderate verity of illness in most cas.It is also possible that IFN-induced depression is unusually placebo responsive.Since none of the current studies on antidepressant treatment of IFN-induced depression has been placebo-controlled,this cannot be answered yet.
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5.Choosing the best treatment for IFN-induced depression
Selecting antidepressants for the treatment of IFN-induced depression should be bad on a number of factors. Firstly,antidepressants should be chon that appear to be the most successful and best tolerated in the treatment of IFN-induced depression.This is particularly important since the
u of antidepressants for IFN-induced depression has not garnered FDA approval and thus its u is‘‘off label’’. Therefore,the choice of any particular antidepressant should be backed by the supporting clinical literature.Furthermore, antidepressants can be chon bad on specific side effect profiles,many times utilizing a side effect of most likely benefit to the clinical situation(described below).Lastly,the choice of antidepressants may partially depend upon possible drug–drug interactions.
In using antidepressants in patients receiving IFN, particularly tho with CHC,one must address whether liver dia might alter the pharmacokinetics of the medication presumably due to a reduced ability to metab-olize and eliminate the antidepressant.This action would increa the half-life of the drug and increa clinical caution regarding side effects and toxicity.Prior studies have suggested that patients with vere liver dia had elevated citalopram blood levels(Baumann and Larn, 1995).Recently,Gleason et al.(2004)assd the efficacy of an8-week treatment cour of citalopram in CHC patients with MDD and reported that citalopram blood levels were comparable(the levels were non-significantly lower)in depresd patients without liver dia versus normal controls.Therefore,they suggested that antidepres-sants are well-tolerated and safe,at least in patients without vere liver dia(liver enzymes less than2.5times above the normal range).Clinic
ally,gastroenterologists support the safety of antidepressant administration and u it in patients with liver dia.When using antidepressants in this population,we recommend a somewhat slower titration schedule as with any medical illness due to possible nsitivity to psychotropic medications and frequent con-current systemic symptoms.
Most of the clinical literature on the u of antidepres-sants in IFN-induced depression has focud mainly on SSRIs.This is partly due to the widespread u of SSRIs during the last decade,their well-established efficacy,and a benign safety profile.For example,SSRIs have minimal cardiovascular side effects and are very safe in terms of overdo attempts in contrast to the prior generation of antidepressants(TCAs and monoamine oxida inhibitors: MAOIs).It is quite likely that non-SSRIs may be equally effective in treating IFN-induced depression,as has been suggested by numerous ca reports.Even if a rotonin(5-HT)dysfunction is central to IFN-induced depression, antidepressants that predominantly effect non-5-HT path-ways still impact5-HT system functioning via known interactions in specific brain regions(Lucki and O’Leary,2004).For example,patients with MDD who have evidence of5-HT or norepinephrine dysfunction usually have an abnormality in both neurotransmitter systems,suggesting this interrelationship(Asnis et al.,1992).SSRIs are effective not only as antidepressants,but also posss significant anti-anxiety properties.In fact,some SSRIs are F
DA-approved for anxiety disorders,including generalized anxiety disorder and panic disorder(Brawman-Mintzer and Yonkers,2004). This may be an important consideration in the treatment of patients currently undergoing IFN treatment.For example, pre-treatment with a SSRI prevented the ont of anxiety in a majority of melanoma patients who might have experi-enced IFN-induced anxiety symptoms(Muslman et al., 2001;Capuron et al.,2002).Antidepressants from other drug class may also posss anxiolytic properties,but only venlafaxine,a dual neurotransmitter re-uptake inhibitor,has been extensively studied and is also markedly anxiolytic(it is also FDA-approved for generalized anxiety disorder) (Gelenberg et al.,2000).Bupropion may have an energizing effect with anxiogenic qualities(American Psychiatric Association,1993)and may therefore be problematic in IFN-induced depression with marked anxiety.As most clinicians know very well,irritability and anger are prominent symptoms(in50%of patients)that occur during IFN treatment(Capuron et al.,2002),and may require the most immediate attention in order for IFN treatment to be successful.Anger and irritability appear to be related to5-HT dysfunction and SSRIs have also been reported to be beneficial for the symptoms(Fava,1998).
Thus,it is very likely that a clinician would be inclined to u SSRIs in IFN-induced depression.Nonetheless,there are certain risks and side effects with this class of medications(as well
as other antidepressants)that the clinician should keep in mind.The considerations will likely impact the choice of antidepressant to be ud for treatment.
6.Considering antidepressant side-effects
It has become clear that SSRIs are associated with an incread tendency to bleed culminating in mild prenta-tions such as bruising,to more rious conquences such as gastrointestinal hemorrhages(Weinrieb et al.,2003).The hematological effects result from depriving platelet intra-cellular5-HT,which is necessary for clot formation (Serebruany et al.,2001).Since CHC with cirrhosis and many other conditions being treated with ,chronic myelogenous leukemia)are frequently associated with reduced platelet numbers,and IFN itlf is frequently associated with thrombocytopenia(Fried,2002),care must be taken in subjects who are to be treated with SSRIs.A retrospective chart review of patients with melanoma being treated with IFN revealed7cas with retinopathy including cotton wool spots with retinal hemorrhage.Six of the7 cas were concurrently on paroxetine suggesting that this
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class of compounds may increa the vulnerability of IFN-related retinal hemorrhage(Hejny et al.,2001).Another factor is that patients treated with IFN frequently take NSAIDs(or aspirin)for IFN-induced flu-like symptoms. Anti-inflammatory medications alone increa the like-lihood of a bleed,which has been shown to be an additive risk to that pod by SSRIs(de Jong et al.,2003).The combined u of NSAIDs,SSRIs,and IFN may further increa the risk of bleeding.If a patient is particularly vulnerable to a bleed,such as having thrombocytopenia, being on anticoagulants,or prence of ulcers,non-SSRIs might be considered for the treatment of IFN-induced depression since they have fewer effects on platelet functioning(Dalton et al.,2003).There are other risks and side effects of SSRIs that are shared by most antidepressants that will also be reviewed.Some of the might influence the class of antidepressants chon for treatment.
Antidepressants,including SSRIs,can induce hypo-manic/manic episodes particularly in patients with a history of bipolar disorder(Post et al.,2003;Ghaemi et al.,2003; Silverstone and Silverstone,2004)and in patients who have a non-bipolar depression(Ramasubbu,2001).The precip-itation of a hypomanic/manic episode is also en as part of IFN therapy(Crone et al.,2004)and therefore the combination of IFN and antidepressants may increa the likelihood of this event(Asnis et al.,2004b).It is imperative that clinicians asss each prospective IFN patient for a personal histor
y(and perhaps also a family history)of bipolar disorder prior to initiating antidepressant therapy, becau monotherapy with antidepressants should be considered a contraindication in the cas.Of the antidepressants,SSRIs,norepinephrine and rotonin reup-take ,venlafaxine)and dopamine and norepinephrine reuptake ,bupropion)are less likely to induce a hypomanic/manic episode,as compared to TCAs and MAOIs(Ghaemi et al.,2003;Post et al.,2003). Goodwin and Ghaemi(1998)have suggested that parox-etine and bupropion,in particular,may be the safest choices.
A patient with a bipolar disorder history may po special treatment challenges for IFN therapy,which will be commented on later.
We would be remiss if we failed to mention the SSRI controversy where it has been reported that the drugs may be associated with a slight but significant incread risk of suicidal behavior in depresd children and adolescents (Newman,2004).This obrvation has led the FDA and other regulatory agencies to mandate that this information be listed as a warning in package inrts to increa the vigilance of both clinicians and patients to this rare,but potentially rious adver event.Although the regulatory agencies have not found such an association in adults, careful monitoring of all patients to be treated with SSRIs is recommended.
可爱英文名字
Antidepressants can induce xual dysfunction in as many as50%of patients(American Psychiatric Associ-ation,1993;Piazza et al.,1997)and may worn organically-induced xual dysfunction.If xual dys-function is already prent as a result of IFN treatment (IFN is known to cau xual dysfunction in over20% of patients)(Piazza et al.,1997),the u of an antidepressant that spares xual functioning should be considered.Options include bupropion,nefazodone,and mirtazapine(American Psychiatric Association,1993; Dording et al.,2002).In addition,bupropion and mirtazapine have been reported to improve compromid xual functioning produced by other antidepressants when added to the treatment(Dording et al.,2002; Clayton et al.,2004).
Insomnia may be another factor for consideration in lecting antidepressants.Insomnia is commonly induced by IFN(in45%of patients)either as a direct central nervous system effect,or as part of IFN-induced depression(Capuron et al.,2002).SSRIs(but also MAOIs,as well as dual neurotransmitter re-uptake inhibitors)frequently cau insomnia as a side effect or exacerbate it when already prent.When insomnia is vere,consideration should be given to dating TCAs like imipramine and amitriptyline as well as mirtazapine and nefazodone,which treat the depression and also improve existing insomnia(American Psychiatric Associ-ation,1993;Dording et al.,2002).Alternatively,anti-depressants can be ud and if insomnia persists,a non-benzodiazepine
hypnotic like zolpidem can be adminis-tered as needed(Asnis et al.,1999).Some investigators have expresd concern with the u of hypnotics,even non-benzodiazepines in patients undergoing IFN treatment since the individuals are more likely than not to have a history of drug abu(particularly CHC patients)(Dording et al.,2002).Trazodone,mirtazipine and dating TCAs at small dos can also be helpful in antidepressant-induced insomnia(Dording et al.,2002)or insomnia condary to IFN treatment.
Somatic pain may also influence the choice of antidepressant.One of the toxic effects of IFN is somatic pain,which can be experienced as joint pain,headaches, and total body pain with over55%experiencing pain symptoms(Capuron et al.,2002).Although the literature on antidepressants and pain is inconclusive,recent data suggests that antidepressants that potentiate5-HT and norepinephrine are more effective for pain than antide-pressants that potentiate only5-HT(Lynch,2001).One recently FDA-approved dual neurotransmitter re-uptake inhibitor(norepinephrine and5-HT),duloxetine,appears particularly effective for somatic pain in MDD with pain symptoms responding prior to the ont of any anti-depressant effects(Wohlreich et al.,2004).In fact,the anti-pain effects of duloxetine have been highlighted by its recent approval for the treatment of pain due to diabetic neuropathy,a neurological condition devoid of depression (Pres
korn,2004).Thus,if vere pain is prominent in patients with IFN-induced depression,duloxetine or other non-SSRIs should be considered.
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Gastrointestinal symptoms,particularly naua and vom-iting,are frequent side effects of antidepressants and may impact antidepressant choice(American Psychiatric Asso-ciation,1993;Dording et al.,2002).This can be a limiting factor since one of the toxic effects of IFN is naua and other gastrointestinal symptoms,which have been reported in as many as50%of patients(Capuron et al.,2002). Although all antidepressants can induce the effects, mirtazapine(which blocks the5-HT3receptor)(Stahl, 2000)appears to be less of a problem.Some new preparations of existing medications such as paroxetine controlled relea avoids gastric absorption and is mainly absorbed in the small intestine where there are fewer5-HT3 receptors,resulting in fewer incidences of naua(Bang and Keating,2004).
Weight gain is a common side effect of most antidepressants.With most treatment populations,this side effect is problematic for cosmetic,but also health reasons.In populations being treated with IFN,
over35% of patients experience anorexia and weight loss(Capuron et al.,2002)and therefore the patients would probably benefit from this antidepressant-induced side effect. Mirtazapine may produce the maximal effect on weight gain(Dording et al.,2002;Stahl,2000).Nonetheless, there are many patients being treated with IFN that will not lo weight due to this treatment and would find antidepressant-induced weight gain a significant problem. Bupropion may be considered here since it may have the fewest effects on appetite and weight gain(Dording et al., 2002;Stahl,2000).
Fatigue is a frequently occurring side effect with antidepressants.Since fatigue is perhaps the most common neurotoxic effect of IFN,occurring in70–100%of patients(Malik et al.,2001),the addition of antidepres-sants can be problematic.Bupropion is the least dating antidepressant and some have found it to be alerting (American Psychiatric Association,1993;Stahl,2000).In the treatment of depression,the addition of bupropion to antidepressants can result in significant improvement of fatigue(Green,1997)and might be considered in the antidepressant treatment of IFN-induced depression.Psy-chostimulants such as methylphenidate or modafinil may also be beneficial for IFN-induced fatigue,but they have yet to be studied.
心照不宣的反义词Drug–drug interactions can have a role in antidepressant lection since many of the compounds inhibit cyto-chrome P450enzymes and contribute to elevations of a competing drug.For example,TC
As,MAOIs,and some ,paroxetine)significantly affect cytochrome 2D6.In contrast,mirtazapine,venlafaxine,citalopram and escitalopram have minimal effects on this enzyme,while fluvoxamine has a significant effect on cytochrome3A4and 1A2(Preskorn,1997;Owen and Nemeroff,1998;Caccia, 2004).In addition,cytochrome2D6is genetically poly-morphic with people having alleles leading to fast metab-olism and others slow metabolism(Malhotra et al.,2004).Practically,drug–drug interaction issues and pharmacoge-netics may not have major bearing on a general population. One area that the factors may well be important is with antidepressant treatment of IFN-induced depression in patients with CHC with comorbid human immunodefi-ciency dia(HIV).The primary treatment for HIV is protea inhibitors,which can significantly effect cyto-chrome enzymes and metabolism,particularly cytochrome 3A4.Fluvoxamine should be avoided,but escitalopram, which is partially metabolized via3A4,was found to be safe with the u of protea inhibitors(Gutierrez et al.,2003). Another area of concern is administering antidepressants to IFN-induced depression in opiate addicts.The addition of fluvoxamine was found to significantly increa methadone levels,whereas fluoxetine had a more modest effect(Eap et al.,1997).Lastly,administering bupropion to patients on certain HIV drugs such as protea inhibitors and rever transcripta inhibitors can lead to high concentrations of bupropion(metabolism of bupropion to its hydroxy metabolite is blocked via the HIV drugs inhibiting effects on cytochrome2B6),and can result in an incread risk of izures(Park-Wyllie and Antoniou,2003).
7.Future antidepressant treatments for IFN-induced depression
IFN triggers a cascade of neurobiological changes that likely contribute to the development of depression.As reviewed previously(Asnis et al.,2003),IFN stimulates various pro-inflammatory cytokines.The prence of MDD and IFN-induced depression have each been positively associated with elevations in pro-inflammatory cytokines. The cytokines,in turn,affect the hypothalamic–pitui-tary–adrenal(HPA)axis and monoamine regulation. Regarding monoamines,IFN most consistently lowers plasma and brain5-HT,with similar effects on norepinephr-ine and dopamine.It is well documented that deficits in the monoamines are associated with major depression. IFN is also a potent stimulator of the HPA axis resulting in hypercretion of corticotropin releasing hormone(CRH), adrenocorticotropin hormone(ACTH),and cortisol.Acti-vation of the HPA axis has been positively associated with the incidences of IFN-induced depression and MDD. Antidepressants that have been successful for the treatment of MDD and IFN-induced depression have a number of common effects on the cascade of events initiated by IFN. Firstly,antidepressants have been shown to decrea pro-inflammatory cytokines and increa anti-inflammatory cytokines,thus having a major immunoregulatory effect. Secondly,antidepressants dampen the HPA axis by directly effecting steroid receptors.Lastly,antidepressants increa the availability of monoam
ines and this is believed to be a central mechanism for their efficacy.The arch for potential new antidepressants for IFN-induced depression and perhaps MDD are likely to include drugs that dampen
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