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Comorbidity is common among patients with major de- Medical Comorbidity
pression, but in most instances it may be of little rele-vance. Nonetheless, it is a complex issue because of its Clinical trials of antidepressants generally exclude patients relation to treatment response, and few studies have who have significant medical illness, yet depression with attempted to address this. Most have examined comorbid- medical comorbidity is the norm rather than the exception ity after the fact in secondary analyses. In this article, I among patients who are seen in most clinical settings. The focus on whether comorbidity influences depression treat- treatment of depression in medically ill patients is chal- ment response among patients who are primarily diag- lenging. Recognition, compliance, differential diagnosis, nosed as suffering from major depression. At least three side effects, and tolerance of drug regimens can compli- comorbidities are believed to influence treatment re- cate the treatment of depression among patients who are sponse: medical, anxiety, and personality disorders. medically ill. Before the introduction of selective seroto- Whether studies find that these factors predict worseoutcomes in patients with major depression appears to nin reuptake inhibitors (SSRIs), it was generally believed depend on the nature and severity of the medical illness, that medically ill depressed patients did not tolerate or the study setting, and the study design. The best designed respond well to antidepressant treatment. studies reported the least effects of these factors on reported that nortriptyline was contraindicated in treatment outcome. Clinically, this suggests that these 90% of medically ill depressed patients. He also noted that factors should not be seen as impediments to treatment. 80% of potentially eligible patients were unable to com- Biol Psychiatry 2003;53:701–706 2003 Society of Bio- plete a trial of nortriptyline. In a retrospective review reported that only 40% of medically illdepressed patients responded to treatment and that 32% Key Words: Comorbidity, medical, treatment, anxiety,
could not tolerate treatment. Both these studies were conducted before the advent of SSRIs and led to anihilistic perception regarding the use of antidepressants in Introduction
the medically ill. This perception may not be warranted.
A recent Cochrane report on the use of antidepressants Comorbidity is common among patients with major in the medically ill addresses the issue of whether antide- depression, but in most instances it may be of little pressants are effective in this population relevance. Nonetheless, it is a complex issue because of its This review analyzed all relevant randomized trials relation to treatment response, and few studies have that compared any antidepressant drug with placebo or no attempted to address this. Most available studies examined treatment in patients diagnosed with depression and a comorbidity after the fact in secondary analyses. In this specified physical disorder. This review included 18 stud- article, I focus on whether comorbidity influences depres- ies, covering 838 patients with a range of medical condi- sion treatment response among patients who are diagnosed tions (cancer in two studies, diabetes in one, head injury in primarily as suffering from major depression. It is impor- one, heart disease in one, HIV in five, lung disease in one, tant to keep in mind that depression secondary to other multiple sclerosis in one, renal disease in one, stroke in diseases may not have the same response pattern. At least three, combined disorders in two). Six studies used SSRIs, three comorbidities are believed to influence treatment three used atypical antidepressants, and the reminder used response: medical, anxiety, and personality disorders. I tricyclic antidepressants (TCA). The key finding was that briefly review the available information on whether the patients treated with antidepressants were more likely to presence of these three categories of comorbidity influ- improve than those who were given placebo or no treat- ence treatment response among patients with a primary ment. The finding that about four patients would need to be treated with antidepressants to produce one recoveryfrom depression that would not have occurred had they From the Department of Psychiatry and Behavioral Sciences, Duke University been given placebo or no treatment is similar to that seen Medical Center, Durham, North Carolina.
Address reprint requests to Ranga R. Krishnan, M.D., Department of Psychiatry and in trials of depressed patients without medical problems.
Behavioral Sciences, Duke University Medical Center, Box 3950, Durham NC The other interesting finding was that antidepressants were Received May 3, 2002; revised August 26, 2002; accepted October 2, 2002.
well tolerated by patients; about 10 patients would need to be treated with antidepressants to produce one dropoutfrom treatment, which would not have occurred had theybeen given placebo. By inferencefrom this review, one can conclude that medical comor-bidity is not a major factor in treatment response.
is that they did not include both healthyand medically ill patients with depression. Thus, it cannotbe definitively stated that, under the same trial conditions,medical comorbidity does not influence treatment re-sponse. Steffens recently studied this issue in a naturalisticmanner Thirty-one elderly patientswith unipolar major depression (DSM-IV) who wereenrolled in Duke’s Mental Health Clinical Research Cen- Figure 1. Cumulative remission for depressed patients starting ter for the Study of Depression in Later Life were prescribed bupropion SR or IR, alone or in combinationwith other antidepressant agents, for 12 weeks. Montgom- disease and other forms of dementia, stroke, Parkinson’s ery–Asberg Depression Rating Scale (MADRS; disease, and multiple sclerosis); subjects with current or recent histories of substance abuse were also excluded. At Impression (CGI) severity scores were used to define baseline, subjects received standardized clinical assess- response. Seventy-four percent of the sample responded to ments including the MADRS and Cumulative Illness treatment. Fifty-three percent (16 of 30) achieved a partial or complete remission of major depression at week 12.
viewer administered the Duke Depression Evaluation Response rates did not differ between those with high concluded that geriatric patients with high and low med- instrument that includes the Centers for Epidemiologic ical comorbidity responded well to bupropion and bupro- portions of the National Institute of Mental Health Diag- We recently evaluated the effect of sertraline in patients nostic Interview Schedule (DIS). The interview consists of with major depression and comorbid vascular disease questions that screen for DSM-IV diagnoses including major depression, bipolar disorder, generalized anxiety three groups: 1) patients with a current diagnosis of disorder, and panic disorder. Clinical assessments were hypertension only, 2) patients with a current or past history repeated every 3 months and when contact was clinically of cardiovascular illness but no hypertension, and 3) patients with no hypertension or comorbid vascular illness.
Subjects in the study were treated as clinically indi- Sertraline treatment yielded similar levels of response in cated, using antidepressant medications, electroconvulsive all three groups (response criterion: CGI much or very therapy (ECT), and individual and group cognitive– be- much improved) at treatment end point on a completer analysis (hypertension: 86%; vascular disease: 89%; no vascular disease: 77%). Both our study and that of The results of the study demonstrated that the cumula- tive remission rate was slightly greater among patients however, and the medical comorbidity evaluated was without medical illness than among those with mild restricted to vascular disease in our study. We therefore medical illness (CIRS Ͼ 5; see Remission was evaluated the role of medical factors in a large sample of defined as MADRS score less than 8; when adjusted for elderly patients who were treated using a staged approach.
age, however, this variable was not significant. In sum- The sample consisted of 259 subjects enrolled in the mary, the results of these three studies, in consonant to the National Institute of Mental Health–sponsored Mental Health Clinical Research Center for the Study of Depres- medical comorbidity has only a modest and insignificant sion in Later Life (Conte Center). The subjects were Ն 60 effect on antidepressant treatment response; however, this years and met DSM-IV criteria for major depression at may not be the case for other medical conditions and needs baseline. Exclusions included other major psychiatric to be further evaluated. Whether studies find that medical illness (e.g., schizophrenia, schizoaffective disorder, bipo- disorders predict worse outcome in patients with major lar disorder) or major neurologic illness (e.g., Alzheimer’s depression appears to depend on the nature and severity of the medical illness, the study setting, and the study design.
described earlier, no difference in treatment response was The best designed studies reported the least effect of found among paroxetine, sertraline, and fluoxetine medical illness on depression treatment outcome. Clini- cally, this suggests that medical illness should not be seen venlafaxine in patients with anxiety and depression. A pooled analysis was conducted of six short-term trials ofvenlafaxine measuring anxiety in anxious-depressed pa-tients using the HAM-D, anxiety/somatization factor and Anxiety Disorder
psychic anxiety item scores. Treatment with venlafaxine Anxiety disorder is also common among patients with resulted in a significant improvement in depression scores in patients who were anxious at baseline compared with quency of diagnostic comorbidity in major depressive disorder (MDD). At the time of the evaluation, 64.1% of Data from eight randomized, double-blind, placebo- the patients met criteria for at least 1 of the 23 Axis I controlled clinical trials comparing mirtazapine to placebo disorders, and more than one third had two or more in patients with high anxiety and depression were reported disorders. Anxiety disorders were the most frequent co- morbid disorders (56.8%), and social phobia was the most demonstrated a statistically significant reduction in the frequent individual disorder. Among depressed patients, sum of anxiety and agitation compared with placebo- the more severe the depression, the more likely the treated patients. In general, the drug was effective in presence of anxiety symptoms. It is assumed that anxiety treating both anxiety and depression, and anxiety did not symptoms affect treatment response. This has been eval- uated in a number of studies. reported that All these studies primarily classified patients on the people with depression who were anxious responded basis of the anxiety subscale of the HAM-D. They did not poorly to amitriptyline compared with other depressed specifically address the issue of whether the anxiety was patients. Another study reported that neurotic symptoms part of depression or as part of another anxiety disorder. In general, these studies would have excluded patients with The data with regard to the SSRIs appears to be primary anxiety disorders. The data are modest in terms of whether the presence of an anxiety disorder can influence randomized, double-blind clinical trials comparing fluox- etine with placebo or TCAs in patients with major depres- response in patients with major depression and comorbid sion. On the basis of the anxiety/somatization factor within anxiety disorder who were treated with fluvoxamine. The the 21-item Hamilton Rating Scale for Depression (HAM- mean number of comorbid anxiety disorders per patient D), patients were characterized as anxious (score Ն 7) or was 2.1 Ϯ 1.1. Fluvoxamine was shown to be effective in nonanxious (score Ͻ 7). Fluoxetine was significantly (p Յ treating outpatients with major depression with comorbid .05) more effective than placebo in treating both anxious anxiety disorder. This study was limited by the small and nonanxious major depression. Fluoxetine was also number of subjects and by the fact that a number of studies more effective than placebo in reducing the anxiety/ have not shown a clear antidepressant effect for fluvox- The effect of anxiety on treatment response to sertraline efficacy of venalfaxine on patients with concomitant was evaluated in a study of chronic depression generalized anxiety disorder and depression. Ninety-two In this study, patients diagnosed with chronic patients meeting DSM-IV criteria for MDD who also had major or double depression were randomized to 12 weeks comorbid generalized anxiety disorder were compared of double-blind treatment with either sertraline or imipra- with 276 noncomorbid patients. Patients received ven- mine in a 2:1 ratio. A high-anxiety subgroup was opera- lafaxine XR (75–225 mg/day), fluoxetine (20 – 60 mg/ tionally defined by a HAM-D anxiety/somatization factor day), or placebo for 12 weeks. Onset of efficacy was score Ն 7. Of the total sample, 209 were treated with slower in comorbid than in noncomorbid patients. Re- imipramine and 426 with sertraline. Thirty-six percent of sponse, defined as Ͼ 50% decrease in symptom score on the population met criteria for the high-anxiety subgroup.
the HAM-D, was achieved in 66% of the comorbid Patients with significant concurrent anxiety symptoms patients in the venlafaxine XR group at week 12. This were more likely to respond by 12 weeks (66.4%) than response was higher than that seen with fluoxetine (52%) those without significant anxiety symptoms (54.2%).
There was no significant difference in response rates for In contrast to these reports, a study in primary care sertraline versus imipramine. In a comparison of SSRIs patients reported that anxiety can predict persistence of among patients with anxious depression classified as depression at baseline, 43 had coexisting anxiety disorder Table 1. Personality Disorder and Treatment Response (38 with social phobia). The risk for persistent depression at 12 months was 44% greater among those with coexist-ing anxiety; this may largely reflect the type of anxiety disorder that coexists with major depression. A recent more effective than desipramine for depression in the context of obsessive– compulsive disorder. This is consis- tent with data showing that SSRIs are more effective than drugs that primarily work through a norepinephrine mech- anism. Given that SSRIs are effective for posttraumatic stress disorder, social phobia, obsessive– compulsive dis-order, panic disorder, and generalized anxiety disorder, itis not surprising that these drugs are effective in treatingdepression in the context of anxiety disorders. Nonethe- medication treatment, three showed no difference, and two less, randomized trials evaluating whether the response showed worse outcome for patients with personality dis- rate is altered by the presence of each of these anxiety orders (one with desipramine and one with maprotoline; The largest study (Hirshfield 1998), with more The data with psychotherapy may be significantly than 600 patients, used sertraline and showed no differ- ence between patients with and without significant per- higher levels of anxiety predicted poor response to treat- sonality pathology. reported that cluster B ment. Additional studies are needed to evaluate whether factors affected treatment response, with patients with treatment response is different with specific comorbid high reward dependence responding better to clomipra- anxiety disorder such as obsessive– compulsive disorder mine than to desipramine. In his review of these studies, Mulder’s appropriate conclusion is as follows: “Whetheror not personality pathology significantly worsens out-come in patients with major depression appears to depend Personality Traits and Disorders
on study design, since the rate of personality pathology Personality traits have long been considered important in varies markedly depending on how it is measured. In the treatment outcome of depression. The study of person- addition, depressed patients with personality pathology ality traits and disorders is complex, and a variety of appear less likely to receive adequate treatment in uncon- methods has been used, including dimensional measures, trolled studies. Finally, studies rarely control for depres- such as neuroticism and the Tridimensional Personality sion characteristics (e.g., chronicity, severity) that may Questionnaire (TPQ) (Newman et al 2000), and categori- influence outcome and be related to personality pathology.
cal measures such as DSM-based personality disorder Overall, the best designed studies reported the least effect scales. recently evaluated these studies in of personality pathology on depression treatment outcome.
an excellent review. To summarize the results based on his Clinically, this suggests that comorbid personality pathol- review, neuroticism generally predicted poor long-term ogy should not be seen as an impediment to good response. The studies of shorter duration care were more equivocal, with most not showing a relationship to short-term outcome. Studies with the TPQ were done at a latertime point and were better designed. The TPQ measures novelty seeking, which reflects differences in the behav-ioral activation system; harm avoidance, which reflects Comorbidity as generally seen in the context of major differences in the behavioral inhibition system; and reward depression appears to be only a minor factor determining dependence, which reflects differences in the behavioral treatment response. Medical comorbidity has a modest and maintenance system. The largest study, by Nelson and insignificant effect on short-term treatment response to Clonninger (1997), showed that reward dependence pre- SSRIs and other, more recently introduced medications.
The nihilistic assumption that antidepressants are not The categorical assessment studies were highly varied effective based on early studies with TCAs is not war- in that a variety of methods was used. Seven studies used ranted. In fact, even in patients with significant medical both a standardized assessment and standardized treatment problems, antidepressants are effective. Severity of anxi- (sertraline, TCAs, ECT). Of the five studies that used ety symptoms does not appear to have a major differential effect on somatic treatment response, especially for the sive and major depressive disorders. Arch Gen Psychiatry SSRIs and other newer antidepressants, although it may for psychotherapy. Anxiety disorders are well treated with Joyce PR, Mulder RT, Cloninger CR (1994): Temperament SSRIs, and thus the findings that these drugs work well for predicts clomipramine and desipramine response in major depression in the context of anxiety disorders is not depression. J Affect Disord 30:35– 46.
surprising. At least for comorbid generalized anxiety and Koenig HG, Goli V, Shelp F, Kudler HS, Cohen HJ, Meador KG, depression, the presence of comorbidity does not affect Blazer DG (1989): Antidepressant use in elderly medicalinpatients: Lesions from an attempted clinical trial. J Gen treatment response. Personality disorder also does not appear to have a major effect on treatment response.
Krishnan KR, Doraiswamy PM, Clary CM (2001): Clinical and Although intuitively it is likely that severe personality treatment response characteristics of late-life depression as- disorder is likely to reduce treatment response, this has yet sociated with vascular disease: A pooled analysis of two to be studied. Neuroticism appears to be a predictor of multicenter trials with sertraline. Prog Neuropsychopharma- col Biol Psychiatry 25:347–361.
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major depression and response to fluoxetine treatment. Psy- Newman JR, Ewing SE, McColl RD, Borus JS, Nierenberg AA, chother Psychosom 62:160 –167.
Pava J, Fava M (2000): Tridemensional Personality Question- Fava M, Rosenbaum JF, Hoog SL, Tepner RG, Koop JB, Nilsson naire and treatment response in major depressive disorder: a ME (2000): Fluoxetine versus sertraline and paroxetine in negative study. J Affect Dis 57:241–247.
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Paykel ES (1972): Depressive typologies and response to ami- triptyline. Br J Psychiatry 120:147–156.
Fawcett J, Barkin RL (1998): A meta-analysis of eight random- ized, double-blind, controlled clinical trials of mirtazapine for Peselow ED, Fieve RR, DiFiglia C (1992): Personality traits and the treatment of patients with major depression and symptoms response to desipramine. J Affect Disord 24:209 –216.
of anxiety. J Clin Psychiatry 59:123–127.
Popkin MK, Callies AL, Mackenzie TB (1985): The outcome of Feske U, Frank E, Kupfer DJ, Shear MK, Weaver E (1998): antidepressant use in the medically ill. Arch Gen Psychiatry Anxiety as a predictor of response to interpersonal psycho- therapy for recurrent major depression: An exploratory inves- Radloff LS (1977): The CES-D scale: A self-report depression tigation. Depress Anxiety 8:135–141.
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