Placebo-controlled Trials Of Antidepressants Research Articles

Treatment of Major Depressive Disorder and Dysthymic Disorder With Antidepressants in Patients With Comorbid Opiate Use Disorders Enrolled in Methadone Maintenance Therapy

Depression and opiate-use disorders (abuse, dependence) often co-occur, each condition complicating the course and outcome of the other. It has been recommended that clinicians prescribe antidepressant therapy for mood symptoms in patients with active substance-use disorders, but whether antidepressants are effective in this specific population is not entirely clear. Therefore, the aim of this study was to examine the efficacy of antidepressants in patients with unipolar major depressive disorder (MDD) and/or dysthymic disorder (DD) with comorbid opiate-use disorders currently in methadone maintenance treatment (MMT). Medline/PubMed publication databases were searched for randomized, double-blind, placebo-controlled trials of antidepressants used as monotherapy for the treatment of MDD/DD in patients with comorbid opiate-use disorders currently in MMT. The search was limited to articles published between January 1, 1980, and June 30, 2010 (inclusive). Four manuscripts were found eligible for inclusion in our analysis (n = 317 patients). We found no statistically significant difference in response rates between antidepressant and placebo therapy in trials of MDD/DD patients with comorbid opiate-use disorders currently in MMT (risk ratio for response, 1.182; 95% CI: 0.822-1.700; P = 0.366). These results show no difference in the depressive outcome of patients with comorbid opiate-use disorders on MMT whether they are on medication or placebo. Future studies examining the effectiveness of antidepressants while controlling for several variables such as psychosocial treatment and assessing the specific classes of antidepressants are needed.

Does the frequency of follow-up assessments affect clinical trial outcome? A meta-analysis and meta-regression of placebo-controlled randomized trials

The number and temporal distribution of follow-up assessments during a clinical trial is a critical factor which may influence the outcome as well as the overall cost of a trial. Therefore, we aimed to examine whether the overall and differential frequency of study observations during the course of a clinical trial affects the risk ratio (RR) of responding to antidepressants vs. placebo, specifically in trials for major depressive disorder (MDD). Medline/Pubmed publication databases were searched for randomized, double-blind, placebo-controlled trials of antidepressants for adults with MDD (1 January 1980-11 May 2010). A total of 142 manuscripts involving 256 drug-placebo comparison were pooled (n=38 860). We found that higher overall frequency (OF, frequency of assessments during the entire trial) and higher late frequency (LF, frequency of assessments after the first 3 wk of the trial), but not higher early frequency (EF, frequency of assessments during the first 3 wk of the trial), of follow-up visits predicted a significantly greater RR of responding to antidepressant vs. placebo (coefficient=0.213, p=0.014; coefficient=0.238, p=0.003; and coefficient=0.021, p=0.755, respectively, for OF, LF and EF). None of the measures of frequency examined (OF, EF, LF) significantly predicted the RR of discontinuing antidepressant vs. placebo. These findings suggest that increasing the number of follow-up visits, specifically after the third week rather than within the first 3 wk of the trial, may be an effective approach to improve the likelihood of success in placebo-controlled clinical trials for MDD.

Antidepressants for Major Depressive Disorder and Dysthymic Disorder in Patients With Comorbid Alcohol Use Disorders

Mood and alcohol use disorders are often co-occurring, each condition complicating the course and outcome of the other. The aim of this study was to examine the efficacy of antidepressants in patients with unipolar major depressive disorder (MDD) and/or dysthymic disorder with comorbid alcohol use disorders and to compare antidepressant and placebo response rates between depressed patients with or without comorbid alcohol use disorders. MEDLINE/PubMed publication databases were searched for randomized, double-blind, placebo-controlled trials of antidepressants used as monotherapy for the acute-phase treatment of MDD and/or dysthymic disorder in patients with or without alcohol use disorders. The search term placebo was cross-referenced with each of the antidepressants approved by the US, Canadian, or European Union drug regulatory agencies for the treatment of MDD and/or dysthymic disorder. 195 articles were found eligible for inclusion in our analysis, 11 of which focused on the treatment of MDD/dysthymic disorder in patients with comorbid alcohol use disorders. The search was limited to articles published between January 1, 1980, and March 15, 2009 (inclusive). We found that antidepressant therapy was more effective than placebo in patients with comorbid alcohol use disorders (risk ratio of response = 1.336; P = .021). However, this was not the case when selective serotonin reuptake inhibitor (SSRI) antidepressants were examined alone (P > .05). There was no significant difference in the relative efficacy of antidepressants (versus placebo) when comparing studies in MDD/dysthymic disorder patients with or without alcohol use disorders (P = .973). Meta-regression analyses yielded no significant differences in the risk ratio of responding to antidepressants versus placebo in trials with comorbid alcohol use disorders, whether antidepressants were used alone or adjunctively to psychotherapy, whether they were used in patients actively drinking or recently sober, or whether they were used in pure MDD or in combined MDD and dysthymic disorder populations. These results support the utility of certain antidepressants (tricyclics, nefazodone) in treating depression in patients with comorbid alcohol use disorders. More data on the use of newer antidepressants, including the SSRIs, for this select patient population are needed.

Efficacy of Antidepressants for Dysthymia

The authors sought to determine the efficacy of antidepressants in dysthymic disorder and to compare antidepressant and placebo response rates between major depressive disorder (MDD) and dysthymic disorder. PubMed/MEDLINE databases were searched for double-blind, randomized, placebo-controlled trials of antidepressants used as monotherapy for treatment of MDD or dysthymic disorder. We defined antidepressants as those with a letter of approval by the US, Canadian, or European Union drug regulatory agencies for treatment of MDD or dysthymic disorder, which included the following: amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, trimipramine, protriptyline, dothiepin, doxepin, lofepramine, amoxapine, maprotiline, amineptine, nomifensine, bupropion, phenelzine, tranylcypromine, isocarboxazid, moclobemide, brofaromine, fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, zimelidine, tianeptine, ritanserin, trazodone, nefazodone, agomelatine, venlafaxine, desvenlafaxine, duloxetine, milnacipran, reboxetine, mirtazapine, and mianserin. Eligible studies were identified by cross-referencing the search term placebo with each of the above-mentioned agents. The search was limited to articles published between January 1, 1980, and November 20, 2009 (inclusive). To expand our database, we also reviewed the reference lists of the identified studies. We selected randomized, double-blind, placebo-controlled trials of antidepressants for either MDD or dysthymic disorder according to preset criteria relating to comorbidities, patient age, drug formulation, study duration, diagnostic criteria, choice of assessment scales, and whether or not the study reported original data. Final selection of articles was determined by consensus among the authors. A total of 194 studies were found that were eligible for inclusion in our analysis. Of these, 177 focused on the treatment of MDD and 17 on the treatment of dysthymic disorder. We found that antidepressant therapy was significantly more effective than placebo in dysthymic disorder (risk ratio = 1.75; 95% CI, 1.49-2.04; P < .0001), while placebo response rates in dysthymic disorder trials were significantly lower compared to MDD trials (29.9% vs 37.9%, respectively; P = .042). Meta-regression suggested a statistically significant difference in the risk ratio of responding to antidepressants versus placebo when comparing studies either on dysthymic disorder or on MDD, suggesting a greater risk ratio for response in favor of antidepressant therapy versus placebo in patients with dysthymic disorder versus MDD (coefficient of -0.113; P = .007). These results support the utility of antidepressants for dysthymic disorder. In fact, the margin of efficacy of antidepressants for dysthymic disorder was larger than for MDD. Future studies providing longer-term data on the treatment of dysthymic disorder with antidepressants are essential.

Antidepressants for major depressive disorder in patients with a co-morbid axis-III disorder

The objective of this study is to assess whether the antidepressants are effective in treating major depressive disorder (MDD) in patients with a co-morbid axis-III disorder, and to compare the relative efficacy (vs. placebo) of antidepressants between these patients and those enrolled in general MDD trials. Medline/Pubmed publication databases were searched. We selected for randomized, double-blind, placebo-controlled trials of antidepressants for MDD, whether conducted in a general population, or in populations with an axis-III disorder. Antidepressants were more effective than placebo in patients with axis-III disorders overall [risk ratio for response (RR)=1.42, P<0.0001], as well as specifically for post-stroke (RR=1.43, P=0.04), human-immunodeficiency virus positive or acquired immunodeficiency syndrome (RR=1.66, P=0.005), but not cancer patients (RR=1.26, P=0.19). There was a trend for higher placebo response rates in studies, which did (41.2%) versus those which did not (37.7%) select for axis-III disorders (P=0.06), and significantly higher antidepressant response rates in studies which did (57.4%) versus those which did not (53.5%) select for axis-III disorders (P=0.01). Antidepressants are effective for MDD in patients who present with co-morbid axis-III disorders and as effective (vs. placebo) in this population as they are in the general MDD population. Higher general response rates observed in the co-morbid MDD population are intriguing, and require replication.

Bipolar Phenomenology: Have We Learned All We Can Learn?

Bipolar Phenomenology: Have We Learned All We Can Learn?

Placebo-Controlled, Antidepressant Clinical Trials Cannot Be Shortened to Less Than 4 Weeks’ Duration

In double-blind, randomized, placebo-controlled clinical trials for major depressive disorder (MDD), the impact of study duration on outcome has not been adequately studied. Our aim was to examine whether placebo-controlled antidepressant trials in MDD could be shortened to less than 4 weeks. In order to accomplish this, we examined the relationship between a "positive" or "negative" finding early on (weeks 1-4), and outcome at end point. MEDLINE/PubMed publication databases were searched for randomized, double-blind, placebo-controlled trials of antidepressants for adults with MDD published between January 1, 1980, and July 1, 2009 (inclusive). One hundred seventy-five articles were found eligible. We obtained required measures during the required time points for 101 articles (57.7%). Final inclusion of articles was determined by consensus among the authors. One hundred eighty-two drug-placebo comparisons from 104 clinical trials were pooled (29,213 patients). The strength of the relationship between early and end point outcome increased progressively. However, only at week 4 did the diagnostic odds ratio (27.44) indicate strong concordance between early and end point outcome. The specificity of early outcome as a predictor of end point outcome did not vary substantially from visit to visit (0.91-0.92), while the sensitivity increased proportionally with each visit (from 0.17 to 0.72). The present analysis suggests that antidepressant clinical trials cannot be shortened to less than 4 weeks' duration, primarily due to the increased risk of erroneously concluding that an effective treatment is ineffective. Four weeks is the minimum adequate length of a trial in order to reliably detect drug versus placebo differences.

Antidepressant drug effects and depression severity: a patient-level meta-analysis.

Antidepressant medications represent the best established treatment for major depressive disorder, but there is little evidence that they have a specific pharmacological effect relative to pill placebo for patients with less severe depression. To estimate the relative benefit of medication vs placebo across a wide range of initial symptom severity in patients diagnosed with depression. PubMed, PsycINFO, and the Cochrane Library databases were searched from January 1980 through March 2009, along with references from meta-analyses and reviews. Randomized placebo-controlled trials of antidepressants approved by the Food and Drug Administration in the treatment of major or minor depressive disorder were selected. Studies were included if their authors provided the requisite original data, they comprised adult outpatients, they included a medication vs placebo comparison for at least 6 weeks, they did not exclude patients on the basis of a placebo washout period, and they used the Hamilton Depression Rating Scale (HDRS). Data from 6 studies (718 patients) were included. Individual patient-level data were obtained from study authors. Medication vs placebo differences varied substantially as a function of baseline severity. Among patients with HDRS scores below 23, Cohen d effect sizes for the difference between medication and placebo were estimated to be less than 0.20 (a standard definition of a small effect). Estimates of the magnitude of the superiority of medication over placebo increased with increases in baseline depression severity and crossed the threshold defined by the National Institute for Clinical Excellence for a clinically significant difference at a baseline HDRS score of 25. The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial.

The Cost of Restricting Knowledge

Although clinicians lack evidence-based treatments for mental illness in perinatal women, this does not constitute “operating in a vast sea of ignorance.”1 In the relative absence of clinical studies, clinicians rely upon community-based standards of care that emerge from clinical experience, descriptive/observational studies, guidelines of professional associations, and the adaptation of scientific evidence from other populations. While these sources are less robust than the gold standard of research, randomized placebo-controlled trials (RCT), findings from these sources still provide credible treatment rationales. This state of affairs prompts a more substantive question: What prevents randomized, placebo-controlled trials in perinatal women? Like perinatal women, children constitute a vulnerable population requiring special protections, yet placebo-controlled trials of antidepressants among children appear in the literature today.2 We acknowledge the dual requirement to protect the fetus and the mother, and recognize that the ethical considerations complicating perinatal research are inescapable. However, the lack of robust research with perinatal women blinds us to the unknown risks or benefits of treatment and the lack of treatment to both mother and child over time. Nevertheless, funding agencies and regulatory boards continue to disqualify research with perinatal women that incorporates a placebo arm. Might we be, as Alta Charo provocatively asks, “Protecting [Women] to Death?”3 Ethicists, investigators, and clinicians have suggested that a framework for ethical decision-making in perinatal research would give all stakeholders an important tool to address this inequity in research.4 Such a framework has already been suggested for decision-making in the clinical setting.5 In this risk-benefit model for the treatment of schizophrenia in perinatal women, clinician and patient together carefully consider interventions by incorporating the values of both parties about treatment alternatives and possible outcomes. Collaboratively, those involved decide upon an integrative choice of treatment that is open to revision as necessary. However, this promising clinical model does not address the additional ethical considerations of perinatal research; therefore, we propose an equally collaborative development of a set of guidelines to aid all stakeholders in optimizing the risk-benefit ratio in the design and ethical conduct of RCTs. One approach towards the development of such guidelines is to invite investigators, decision-makers in regulatory and funding agencies, legal experts, community health providers, research participants, patients and their partners to describe their experiences, values, and beliefs regarding perinatal mental health research. A preliminary investigation of the concerns of prominent perinatal mental health investigators has already identified issues related to informed consent, inclusion/exclusion criteria, randomization, and the therapeutic misconception as important targets to address in a more inclusive group of stakeholders. Subsequently, a bioethical analysis of the issues and prospective solutions would generate guidelines and, in turn, an algorithm useful for weighing the risks and benefits as they are understood by all of the stakeholders. We recognize that excluding perinatal women and their unborn children from research disadvantages them across all medical treatments, so mental health guidelines for this population could stimulate the development of similar decision-making frameworks for other populations and conditions. We invite your comments.

The Ethics of Randomized Placebo-Controlled Trials of Antidepressants With Pregnant Women

To determine whether placebo-controlled randomized clinical trials of antidepressant medications with pregnant participants are ethically justified. We searched PUBMED, PsychINFO, and Cochrane databases for articles related to the ethical justification of randomized placebo-controlled trials involving pregnant women and for all research articles for the treatment of depression during pregnancy, using the keys words depression, antidepressive agents, pregnancy, clinical trials, placebo, and ethics. We based our ethical framework on current literature on the ethics of maternal-fetal medicine and research and the requirements of argument-based ethics. We selected studies in which maternal, fetal, and neonatal health outcomes associated with antidepressant exposure were reported. We integrated evidence-based reasoning and argument-based ethics to address four questions to determine whether what is known as normative equipoise (evidence-based reasoning requires uncertainty about which clinical management is superior) exists: 1) Is there evidence of efficacy of antidepressant use during pregnancy? 2) Is there documented causality of serious, far-reaching, and irreversible clinical harm to the fetal or neonatal patient? 3) Is there documented causality of serious, far-reaching, and irreversible harm to depressed pregnant women in a placebo arm? 4) Are there no or only rare documented occurrences of less serious injury to the fetal or neonatal patient? Evidence-based answers to these questions support the judgment that normative equipoise exists with respect to randomized placebo-controlled trials of antidepressants with pregnant participants. Randomized placebo-controlled trials of antidepressant medications during pregnancy are ethically justified. Well-conducted and ethically justified trials of antidepressants should improve the quality of care provided to depressed pregnant women and thus address a major public health problem.

Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD

Substantial and highly variable placebo response rates represent a major obstacle to antidepressant development in major depressive disorder (MDD). However, whether the likelihood of receiving active treatment or placebo, a proxy of the degree of expectation of improvement, may itself influence clinical trial outcome is unclear. The goal of this work was to examine whether the probability of receiving placebo influences clinical trial outcome antidepressant MDD trials. Medline/Pubmed publication databases were searched for randomized, double-blind, placebo-controlled trials of antidepressants for adults with MDD. 146 manuscripts involving 182 clinical trials were pooled ( n = 36,385). Pooled response rates for drug and placebo were 53.8% and 37.3%. A meta-regression (random-effects) established that the probability of receiving placebo, year of publication, and baseline severity were independent predictors of the risk ratio of responding to antidepressants versus placebo. Specifically, a greater probability of receiving placebo, greater baseline severity and an earlier year of publication predicted greater antidepressant-placebo “efficacy separation”. Fixed versus flexible dose design, trial duration and population age did not influence clinical trial outcome.

Antidepressants and suicide symptoms: compelling new insights from the FDA’s analysis of individual patient level data

In May 2007 the Food and Drug Administration (FDA) ordered that all antidepressant drugs carry an expanded black-box warning incorporating information about an increased risk of suicidal symptoms in young...

Examining the Evidence on Augmentation with Atypical Antipsychotics

There is mounting evidence to suggest that the efficacy of all available antidepressants when used as monotherapy to treat major depressive disorder (MDD) is, at best, modest. For example, a meta-analysis of all double-blind placebo-controlled studies of antidepressants published since 1980 revealed response rates of 53% for antidepressants versus 36% for placebo (difference in response rate of 16.8%) (Slide 1). To make matters worse, if one is to assume that “negative trials” (ie, trials which do not demonstrate the superiority of a drug over placebo) are less likely to be published than “positive trials” (trials which demonstrate the superiority of a drug versus placebo), it is quite possible that the margin of efficacy of antidepressants when compared to placebo is ≤16.8%. Thus, if one were to include all unpublished along with published double-blind, placebo-controlled trials of antidepressants for MDD, this efficacy margin could be ≤10%.

The persistence of the placebo response in antidepressant clinical trials

Our objective was to assess the persistence of the placebo response during at least 12 weeks of continued placebo administration in depressed patients who have responded to 6–8 weeks of acute placebo treatment. We identified 8 placebo-controlled antidepressant trials with a total of 3063 depressed patients in which, after acute phase placebo treatment, placebo was continued for more than 12 weeks. The number of patients entering the continuation phase and percentages relapsing during this phase were determined. Based on the total number of patients entering the continuation phase 79% of placebo responders remained well (did not meet relapse criteria) during this phase compared to 93% of antidepressant responders. Although significantly more patients on placebo than on antidepressants relapsed in the continuation phase, 4 out of 5 placebo responders stayed well. The widely held belief that the placebo response in depression is short-lived appears to be based largely on intuition and perhaps wishful thinking.

Efficacy and Safety of Antidepressants for Treatment of Depression in Alzheimer's Disease: A Metaanalysis

Depression in patients with Alzheimer's disease (AD) is common (15% to 63%) and is associated with significant morbidity and increased mortality. Our objective was to quantitatively summarize the data on the efficacy and safety of antidepressant treatment for depression complicating AD. We performed a metaanalysis of randomized, double-blind, placebo-controlled trials of antidepressants with a database search of the English literature (up to 2006) and a manual search of references in the retrieved articles. We extracted the proportion of subjects who responded and remitted, experienced adverse events (AEs), discontinued treatment due to AEs, or discontinued treatment for any reason. Cognition scores were also extracted. We included 5 studies, which involved 82 subjects treated with antidepressants and 83 subjects who received placebo treatment. Antidepressants were superior to placebo for both treatment response (odds ratio [OR] 2.32; 95% confidence interval [CI], 1.04 to 5.16) and remission of depression (OR 2.75; 95% CI, 1.13 to 6.65). There were no significant differences between the 2 groups for change in cognition (weighted mean difference -0.71, 95% CI, -3.20 to 1.79), overall dropouts (OR 0.70; 95% CI, 0.29 to 1.66) or dropout due to AEs (OR 1.41; 95% CI 0.36 to 5.54). The numbers needed to treat for one additional AD patient to respond to antidepressant treatment were 5 (95% CI, 3 to 59) and 5 (95% CI, 2 to 24) for remission of depression. Antidepressant treatment for depression in AD is efficacious, with rates of discontinuation that are comparable to placebo. Nonetheless, clinicians must be vigilant regarding the potential side effects of antidepressants in this population.

Therapeutic effect of follow-up assessments on antidepressant and placebo response rates in antidepressant efficacy trials

It remains unclear how much various factors contribute to the placebo response. To estimate the therapeutic impact of follow-up assessments on placebo response in antidepressant trials. Double-blind, placebo-controlled antidepressant trials that reported weekly changes in Hamilton Rating Scale for Depression (HRSD) scores over 6 weeks were selected. Included studies (n=41) were divided into those that conducted four, five or six follow-up assessments. Reductions in HRSD scores as a function of the different follow-up schedules were compared. An extra follow-up visit at week 3 was associated with a 0.86 further reduction in HRSD score; an extra visit at week 5 was associated with a 0.67 further reduction. These effects represented approximately 34-44% of the placebo response that occurred over these time frames. Two additional visits were associated with twice the reduction in HRSD score than one, suggesting that the therapeutic impact of assessment visits is cumulative and proportional. A comparable therapeutic effect was also found in participants receiving active medication. Follow-up assessments in antidepressant treatment trials incur a significant therapeutic effect for participants on placebo, and this represents about 40% of the placebo response.

How Can We Know Whether Antidepressants Increase Suicide Risk?

How Can We Know Whether Antidepressants Increase Suicide Risk?

A Meta-Analysis of Early Sustained Response Rates Between Antidepressants and Placebo for the Treatment of Major Depressive Disorder

Pattern analysis suggests that "true" drug response is characterized by clinical improvement that is not subsequently followed by a worsening of symptoms (sustained clinical response). To date, several reports demonstrate that early response rates are equivalent between antidepressant-treated and placebo-treated groups of patients with major depressive disorder, suggesting that patients who demonstrate significant and sustained symptom improvement during the first 2 weeks of treatment are not responding to the antidepressant itself, but to nonspecific, placebo-like factors. To compare early sustained response rates between antidepressant- and placebo-treated adults with major depressive disorder. Medline/Pubmed were searched. No year of publication limits were used. Randomized, double-blind, placebo-controlled antidepressant trials or pooled reports/meta-analyses of such trials reporting early sustained response rates for major depressive disorder. The decision to include studies in the meta-analysis was performed by 2 reviewers. Data were extracted with the use of a precoded form. Analyses were performed on the proportion of patients who achieved a sustained response the first 2 weeks of treatment, as well as the first week of treatment. A random-effects model with fixed drug effects was used to combine the studies and make comparisons of sustained early response rates between antidepressant- and placebo-treated groups. Data from 8 reports involving a total of 7121 major depressive disorder patients (4076 randomized to treatment with an antidepressant and 3045 randomized to placebo) were analyzed. Antidepressant-treated patients were more likely to demonstrate sustained clinical response by 2 weeks (odds ratio 2.06, 95% CI: 1.52-2.8) or 1 week of treatment (odds ratio 1.50, 95% CI: 1.08-2.08) than placebo-treated patients. The results of the present analysis suggest that "true" drug response can occur the first 2 week as well as the first week of treatment of major depressive disorder with conventional antidepressants.

Management of Depression After Stroke

Although depression may affect recovery and outcome after stroke, it is often overlooked or inadequately managed, and there is uncertainty regarding the benefits of antidepressant therapy in this setting. We aimed to assess the effectiveness of antidepressants for the treatment and prevention of depression after stroke. We undertook a systematic review using Cochrane methods of randomized placebo-controlled trials of antidepressants for the treatment or prevention of depressive illness and "abnormal mood" after stroke. Treatment effects on physical and other outcomes were also examined. Outcome data were available for 7 treatment trials including 615 patients and 9 prevention trials including 479 patients. Because of the considerable variation in research design, trial quality, and method of reporting across studies, we did not pool all the outcome data. In the treatment trials, antidepressants reduced mood symptoms but had no clear effect on producing a remission of diagnosable depressive illness. There was no definitive evidence that antidepressants prevent depression or improve recovery after stroke. There is insufficient randomized evidence to support the routine use of antidepressants for the prevention of depression or to improve recovery from stroke. Although antidepressants may improve mood in stroke patients with depression, it is unclear how clinically significant such modest effects are in patients other than those with major depression. There is a pressing need for further research to better define the role of antidepressants in stroke management.

Use of Antidepressants in Older Patients with Co-Morbid Medical Conditions

Advanced age and medical complexity are characteristics not often associated with participation in randomised, placebo-controlled trials of antidepressants. Thus, evidence for the efficacy of antidepressant treatment among typical seniors with somatic illness and advanced age is scant. Furthermore, there appears to be no clear empirically based delineation between depressive symptoms and depressive disorders among very old, physically ill adults. The increasing numbers of antidepressants and adjunctive medications add to the practitioner's perplexity when confronted with a very old, very depressed patient. Nonetheless, a growing body of evidence from antidepressant studies in the context of age-related somatic illnesses allows reasonable inferences to guide diagnosis and treatment. Once the practitioner and patient agree upon an antidepressant trial, the benefits of prescribed medication should be assessed within the first days rather than first weeks of treatment. The patient and practitioner should expect to escalate the antidepressant to the established therapeutic range rather than seek the lowest dose that is effective. Patients who experience no benefit whatsoever within the first weeks of treatment despite being within the therapeutic range should be offered an alternative promptly. With the results of studies of depression in co-morbid disorders and analyses of treatment response trajectory, the practitioner can be assured that advanced age, physical illness and depression need not go hand in hand.