Efficacy of SSRIs and newer antidepressants in severe depression: comparison with TCAs.

BACKGROUND: The significant morbidity and mortality associated with severe depression and its psychotic or melancholic subtypes necessitate effective and well-tolerated therapy. This review evaluates antidepressant treatments for patients with severe depression. DATA SOURCES: Comparative clinical trials conducted on patients with severe depression were found by an English-language MEDLINE search (1985 to present). Additional studies were identified in article bibliographies. Search terms included depressive disorders, depression and severe, hospitalized, melancholic or melancholia, psychotic, and endogenous. STUDY FINDINGS: Evidence for efficacy of SSRIs in severe or melancholic depression comes from a small but growing number of controlled studies with adequate samples, as well as meta-analyses and retrospective subgroup analysis of premarketing trials. In studies that defined response as a 50% or greater reduction in Hamilton Rating Scale for Depression (HAM-D) scores, response rates ranged from 53% to 64% for SSRIs and 43% to 70% for TCAs. In separate trials on severe depression, venlafaxine and mirtazapine were both more effective than placebo and an active comparator. Nefazodone and bupropion were each found to be more effective than placebo in studies of severe depression. Venlafaxine and mirtazapine have been found to be more effective than fluoxetine. CONCLUSION: SSRIs and TCAs are comparably effective for the treatment of severe or melancholic depression. SSRIs and other newer agents appear to be better tolerated than TCAs, specifically lacking adverse anticholinergic and cardiovascular effects that may limit the use of TCAs. Emerging data with venlafaxine and mirtazapine in severely depressed patients with or without melancholia support the efficacy of these treatments. Nefazodone and bupropion were found to be effective in hospitalized depressed patients. Electroconvulsive therapy (ECT) or combined antidepressant therapy may be useful in some patients with severe depression. Patients with severe psychotic depression may respond better to an antipsychotic-antidepressant combination.     

Major Depression and Heart Disease: Treatment Trials

Cardiac disease and depression affect a significant number of individuals every year, and developing effective treatment for depression in cardiac disease could have a substantial impact on public health. Several studies have shown that depression increases cardiac morbidity and mortality and total costs of care and is associated with a poor psychosocial outcome. Psychopharmacological treatment trials have shown that tricyclic antidepressants have antiarrhythmic effects, prolong cardiac conduction, and cause orthostatic hypotension, but do not impair left ventricular function, even in patients with underlying left ventricular impairment. Tricyclic antidepressants are efficacious in treating depression but have a higher rate of cardiovascular complications than other antidepressants, with orthostatic hypotension being the most common complication. Recent small clinical trials with bupropion and selective serotonin reuptake inhibitors (SSRIs) indicate that they are efficacious and have a more benign cardiovascular side-effect profile, although large studies need to be performed to establish their safety and efficacy. Most psychosocial studies have focused on cardiac patients in general and not specifically on depressed cardiac patients. Studies of cardiac patients have shown that stress, social isolation, and lower income and educational levels are associated with a poorer cardiac outcome. A large meta-analysis of randomized, controlled trials of psychosocial interventions in nondepressed cardiac patients found that a diverse array of psychosocial interventions decreased morbidity and mortality. However, one recent psychosocial treatment trial of post-myocardial infarction (MI) patients has shown increased mortality in women in the intervention arm of the trial. There have been several recent studies showing that mental stress induces cardiac ischemia, that mental stress-induced cardiac ischemia is associated with a higher rate of adverse cardiac events than exercise-induced ischemia, and that with stress management training, patients show significant reductions in ischemic responses to mental stress. Currently, there are two large studies underway examining pharmacological and psychotherapeutic treatment of post-MI depressed and/or socially isolated patients. These large clinical trials are needed to determine if effective treatment of depression can modify the increased risk for mortality and morbidity associated with depression in cardiac disease. Hopefully, the development of effective treatment for depressed cardiac patients will decrease their morbidity and mortality and enhance their overall quality and enjoyment of life.     

The Impact of Depression in Heart Disease

Depression and heart disease affect millions of people worldwide. Studies have shown that depression is a significant risk factor for new heart disease and that it increases morbidity and mortality in established heart disease. Many hypothesized and studied mechanisms have linked depression and heart disease, including serotonergic pathway and platelet dysfunction, inflammation, autonomic nervous system and hypothalamic-pituitary-adrenal axis imbalance, and psychosocial factors. Although the treatment of depression in cardiac patients has been shown to be safe and modestly efficacious, it has yet to translate into reduced cardiovascular morbidity and mortality. Understanding the impact and mechanisms behind the association of depression and heart disease may allow for the development of treatments aimed at altering the devastating consequences caused by these comorbid illnesses.     

Depression in the medically ill: Management considerations

This article reviews the management of depression in three medical conditions associated with a high frequency of depression: coronary artery disease (CAD), cancer, and human immunodeficiency virus (HIV) infection. Major depression significantly increases mortality in patients with CAD. This effect of depression may be mediated by a decrease in heart rate variability. Tricyclic antidepressants (TCAs) possess Type 1A antiarrhythmic activity, which may increase the risk of sudden death. Initial data suggest that tricyclic antidepressants also may decrease heart rate variability. Antidepressant therapy is effective and can improve quality of life for patients with cancer or HIV infection. Strong social support or psychosocial interventions that improve coping skills may positively affect outcome in HIV infection and cancer. Selective serotonin reuptake inhibitors(SSRIs) and new agents may be well suited for use in depressed patients with medical illnesses because they lack the significant adverse anticholinergic and cardiovascular effects of TCAs and other classes of antidepressants. Depression and Anxiety 4:199–208, 1996/1997.© 1997 Wiley-Liss, Inc.     

Cardiovascular health and depression

Research has shown that depression increases the likelihood that otherwise healthy people will develop ischemic heart disease (IHD) and worsens the prognosis of patients who already have IHD. Moreover, concerns about safety (e.g., cardiac side effects, drug-drug interactions) have caused physicians to be hesitant about using antidepressant agents in patients with IHD. This article is based on a recent roundtable of experts who met to discuss risk, diagnosis, and treatment options for depression in patients with IHD. This article reviews clinical and epidemiological studies that have described a link between depression and the subsequent development of IHD and have examined the role of depression as a predictor of cardiac events in patients with existing IHD. The article addresses the issue of whether depression can be safely and efficaciously treated both in patients with stable IHD and in those with acute coronary syndromes. The authors discuss safety issues related to the potential for interactions between antidepressants and cardiovascular medications, the use of nonpharmacologic treatment options such as psychosocial interventions, and the effect of antidepressant therapy on quality of life in patients with IHD. The article concludes with practical clinical guidance concerning the management of depression in patients who have recently experienced myocardial infarction.     

Omega-3 fatty acids, homocysteine, and the increased risk of cardiovascular mortality in major depressive disorder

Depression is associated with elevated rates of cardiovascular morbidity and mortality. This elevation seems to be due to a significantly increased risk of coronary artery disease and myocardial infarction and, once the ischemic heart disease is established, sudden cardiac death. Recent data suggest that the increased rates of cardiovascular disease in patients with depression may be the result of one or more still-unrecognized underlying physiological factors that predispose a patient to both depression and cardiovascular disease. Two possibly related factors that may have a causal relation with both depressive disorders and cardiovascular disease are an omega-3 fatty acid deficiency and elevated homocysteine levels. We present the available data connecting cardiovascular disease, depression, omega-3 fatty acids, and homocysteine. In addition, we suggest research strategies and some preliminary treatment recommendations that may reduce the increased risk of cardiovascular mortality in patients with major depressive disorder.     

SSRIs vs. TCAs in the treatment of panic disorder: a meta-analysis

OBJECTIVE: To compare the short-term efficacy of selective serotonin reuptake inhibitors (SSRIs) vs. tricyclic antidepressants (TCAs) in the treatment of panic disorder (PD) a meta-analysis was conducted. METHOD: Included were 43 studies (34 randomized, nine open), pertaining to 53 treatment conditions, 2367 patients at pretest and 1804 at post-test. Outcome was measured with the proportion of patients becoming panic-free, and with pre/post Cohen's d effect sizes, calculated for four clinical variables: panic, agoraphobia, depression, and general anxiety. RESULTS: There were no differences between SSRIs and TCAs on any of the effect sizes, indicating that both groups of antidepressants are equally effective in reducing panic symptoms, agoraphobic avoidance, depressive symptomatology and general anxiety. Also the percentage of patients free of panic attacks at post-test did not differ. The number of drop-outs, however, was significantly lower in the group of patients treated with SSRIs (18%) vs. TCAs (31%). CONCLUSION: SSRIs and TCAs are equal in efficacy in the treatment of panic disorder, but SSRIs are tolerated better.     

Adverse cardiovascular events in antidepressant trials involving high-risk patients: a systematic review of randomized trials.

OBJECTIVE: To examine whether selective serotonin reuptake inhibitor (SSRI) antidepressants were associated with an increased or decreased risk of cardiovascular adverse events (AEs). METHODS: We conducted a systematic review of randomized controlled trials published between 1967 and May 2005 that treated patients with cardiac disease, diabetes mellitus, stroke, geriatric age, nicotine dependence, alcoholism, HIV infection, and obesity. We defined serious AEs as death due to a cardiovascular cause, heart failure, stroke, transient ischemic attack, and myocardial infarction. Nonserious AEs were defined as palpitations, chest pain, angina, arrhythmia, hypertension, hypotension-syncope, and unspecified cardiovascular or neurologic events. Adverse event rates were calculated in 4 groups: SSRIs, tricyclic antidepressants (TCAs), other active therapies, and placebo. RESULTS: Stroke and cardiac patients were the highest-risk groups for cardiovascular AEs. We were unable to detect differences in odds between SSRI and placebo for both serious (odds ratio [OR] 0.69; 95% confidence interval [CI], 0.39 to 1.21) and nonserious (OR 1.18; 95% CI, 0.90 to 1.57) cardiovascular AEs. There was a significant decrease in the odds of nonserious cardiovascular AEs (OR 0.46; 95% CI, 0.24 to 0.86, P = 0.02) for patients receiving SSRIs, compared with TCAs. Over one-half of the selected trials did not report the presence or absence of cardiovascular events. CONCLUSIONS: This systematic review of antidepressant trials in high-risk patients did not determine whether SSRIs are associated with a greater or lesser risk of cardiovascular AEs. Reasons for this conclusion include the rarity of serious AEs, the lack of large trials in these patients, and a lack of adequate reporting of AEs in published trials. Further trials assessing the risk of cardiovascular AEs and better trial reporting are needed.     

Treatment of affective disorders in cardiac disease

Patients with cardiovascular disease (CVD) commonly have syndromal major depression, and depression has been associated with an increased risk of morbidity and mortality. Prevalence of depression is between 17% and 47% in CVD patients. Pharmacologic and psychotherapeutic interventions have long been studied, and in general are safe and somewhat efficacious in decreasing depressive symptoms in patients with CVD. The impact on cardiac outcomes remains unclear. The evidence from randomized controlled clinical trials indicates that antidepressants, especially selective serotonin uptake inhibitors, are overwhelmingly safe, and likely to be effective in the treatment of depression in patients with CVD. This review describes the prevalence of depression in patients with CVD, the physiological links between depression and CVD, the treatment options for affective disorders, and the clinical trials that demonstrate efficacy and safety of antidepressant medications and psychotherapy in this patient population. Great progress has been made in understanding potential mediators between major depressive disorder and CVD—both health behaviors and shared biological risks such as inflammation.     

Tricyclic antidepressants in depressed patients with cardiac conduction disease

The observation that fatalities from tricyclic antidepressant (TCA) overdose are associated with heart block and/or arrhythmias has led to concern about the cardiovascular effects of TCAs. Contrary to expectations, studies have shown TCAs to be relatively safe in patients without heart disease. However, it is unclear whether these drugs are also safe in patients with heart disease. This prospective study compared the risk of cardiovascular complication at therapeutic plasma concentrations of TCAs in 196 depressed patients, 155 with normal electrocardiograms and 41 with either prolonged PR interval and/or bundle-branch block. The prevalence of second-degree atrioventricular block was significantly greater in patients with preexisting bundle-branch block (9%) than in patients with normal electrocardiograms (0.7%). Orthostatic hypotension occurred significantly more frequently with imipramine than with nortriptyline, and in patients with heart disease.     

Is There a High-Risk Subtype of Depression in Patients with Coronary Heart Disease?

Depression is a risk factor for cardiac morbidity and mortality in patients with coronary heart disease, especially in those with a recent history of acute coronary syndrome. To improve risk stratification and treatment planning, it would be useful to identify the characteristics or subtypes of depression that are associated with the highest risk of cardiac events. This paper reviews the evidence concerning several putative depression subtypes and symptom patterns that may be associated with a high risk of morbidity and mortality in cardiac patients, including single-episode major depressive disorder, depression that emerges after a cardiac event, somatic symptoms of depression, and treatment-resistant depression.     

The place for the tricyclic antidepressants in the treatment of depression.

OBJECTIVE: The new generation antidepressants have been an important advance in the treatment of depression. Since their introduction, their use has become widespread and the role of the older tricyclic antidepressants (TCAs) has been suggested only as a second-line choice. This assumption is questioned and the role of the TCAs as a first-line treatment for severe depression is discussed. METHOD: The relevant literature concerning the efficacy, tolerability and safety of the antidepressant drugs is reviewed, particularly those studies which compare the newer antidepressant agents with the TCAs. RESULTS: The newer agents are equally as efficient as the tricyclics in the treatment of mild to moderate depression. There are indications that the TCAs are more efficacious for severe depression. The tolerability of the drugs appear about equivalent in terms of discontinuation rates; however, the side effects are different and clinicians need to be mindful of drug interactions and the potential of the serotonin syndrome with the selective serotonin re-uptake inhibitors (SSRIs), problems not found with the TCAs. The TCAs are potentially lethal in overdose; however, appropriate clinical management appears to be a more important issue than the toxicity of the medication. CONCLUSIONS: The newer antidepressant agents are important advances in the treatment of depression. However, the TCAs still have an important place as the first-line treatment for patients with severe (melancholic/endogenous) depression.     

Depression as a risk factor for cardiac mortality and morbidity: a review of potential mechanisms

Depression increases the risk of cardiac mortality and morbidity in patients with coronary heart disease (CHD), but the mechanisms that underlie this association remain unclear. This review considers the evidence for several behavioral and physiological mechanisms that might explain how depression increases the risk for incident coronary disease and for subsequent cardiac morbidity and mortality. The candidate mechanisms include: (1). antidepressant cardiotoxicity; (2). association of depression with cardiac risk factors such as cigarette smoking, hypertension, diabetes, and reduced functional capacity; (3). association of depression with greater coronary disease severity; (4). nonadherence to cardiac prevention and treatment regimens; (5). lower heart rate variability (HRV) reflecting altered cardiac autonomic tone; (6). increased platelet aggregation; and (7). inflammatory processes. Despite recent advances in our understanding of these potential mechanisms, further research is needed to determine how depression increases risk for cardiac morbidity and mortality.     

Pharmacotherapy for depression in patients with myocardial ischemia

The comorbidity of depression and heart diseases is an important but still devaluated clinical problem. Mood disorders in those ill with cardiac ischaemic disease significantly worsen the predictive mortality and quality of life. It may be predicted that adequate therapy of depression could have a positive effect on the long term course of IHD. Careful analysis of indications and contradictions as well as the application of new generation drugs allows for safe therapy. Evident benefits of appropriate treatment of depression in this group of patients, deny the old thesis on the damage of antidepressive drugs on the cardio-vascular system.     

Antidepressants in the treatment of fibromyalgia

Fibromyalgia syndrome is a chronic disease of widespread and debilitating pain whose cause is unknown and whose risk factors are poorly understood. It is often comorbid with rheumatoid and other pain disorders as well as psychiatric disorders such as anxiety and depression. Although they are not officially approved for this indication, antiepileptics and antidepressants are often used to treat fibromyalgia. The tricyclic antidepressants (TCAs), particularly amitriptyline, are among the most common treatment strategies. Because of the poor tolerability of the tricyclics, the newer antidepressants have been widely tested in fibromyalgia. The selective serotonin reuptake inhibitors (SSRIs) and the reversible monoamine oxidase inhibitors do not seem to be particularly helpful. The serotonin and norepinephrine reuptake inhibitors (SNRIs), duloxetine and milnacipran, on the other hand, have been shown in placebo-controlled trials to offer significant relief to patients suffering from fibromyalgia. Although no direct comparative studies have been performed, these compounds appear to be as effective as the TCAs but much better tolerated. The effectiveness of the SNRIs as well as other dual acting antidepressants, such as mirtazapine, but not the SSRIs, implies that a dysfunction of both serotonin and norepinephrine neurotransmission probably exists in fibromyalgia. The effectiveness of antidepressants appears to be independent of their effect on comorbid depression.     

Antidepressant drugs and cardiovascular pathology: a clinical overview of effectiveness and safety

Objective: To review data examining the relationships between depression, antidepressants and cardiovascular disease. Method: Structured searches of PubMed, Medline and Embase conducted in March 2008. Results: Depression and cardiovascular disease are closely associated clinical entities. Depression appears both to cause and worsen cardiovascular disease. Cardiovascular disease is in turn associated with a high incidence of depression. Depression is associated with increased mortality in cardiovascular disease, and after myocardial infarction (MI) and stroke. Many antidepressants have cardiotoxic properties. Tricyclic drugs are highly cardiotoxic in overdose and may induce cardiovascular disease and worsen outcome in established cardiovascular disease. Reboxetine, duloxetine and venlafaxine are known to increase blood pressure. Other antidepressants have neutral or beneficial effects in various cardiovascular disorders. Conclusion: Sertraline, fluoxetine, citalopram, bupropion and mirtazapine appear to be safe to use after MI; the use of sertraline, and response to citalopram and mirtazapine may improve mortality. Paroxetine and citalopram appear to be safe to use in patients with established coronary artery disease. Limited data suggest that a variety of antidepressants are effective and safe to use after stroke.     

Treatment of severe depression with the selective serotonin reuptake inhibitors

The selective serotonin reuptake inhibitors (SSRIs) are recognized as effective as and better tolerated than older antidepressant therapies and have become the drugs of choice in the treatment of mild to moderate depression. However, there is a clinical impression that the SSRIs are less effective than older therapies in the severely depressed patient. A limited number of trials have attempted to address this issue. This review assesses 16 controlled studies of SSRIs in severe depression. The findings from a majority of studies found the SSRIs to be superior to placebo and as effective as but better tolerated than the tricyclic antidepressants (TCAs) in severely depressed patients. Although future studies are needed to corroborate and elaborate on these data, studies still support the use of SSRIs in this patient population. Depression and Anxiety 4:182–189, 1996/1997. © 1997 Wiley-Liss, Inc.     

New approaches to the treatment of refractory depression

Although the majority of patients with depression respond well to their initial pharmacologic treatment, as many as 30% to 45% fail to achieve an adequate response. In addition to the more traditional lithium and thyroid hormone augmentation strategies, a number of new pharmacotherapeutic approaches are currently being used to help manage refractory depression, including the addition of another agent or a switch to another antidepressant. Augmentation and switching strategies are often selected in order to obtain a different neurochemical effect (e.g., adding a relatively noradrenergic agent to a relatively serotonergic antidepressant). In particular, several studies have suggested that depressed patients refractory to treatment with selective serotonin reuptake inhibitors (SSRIs) may show a good response to newer agents that have a pharmacologic profile distinct from the SSRIs. Furthermore, preliminary studies have shown that the addition of SSRIs to either noradrenergic drugs such as the tricyclic antidepressants (TCAs) or dopaminergic agents may be efficacious, even though concerns about drug-drug interactions and tricyclic cardiac toxicity have limited the use of TCA-SSRI combinations. The introduction of reboxetine, a relatively selective norepinephrine reuptake inhibitor, may increase the use of the latter therapeutic approach because of its improved safety profile compared with the TCAs. The review of treatment options for refractory depression that follows will outline the advantages, disadvantages, and level of support for a number of new treatment strategies.     

SSRI efficacy-finding the right dose

The selective serotonin reuptake inhibitors (SSRIs) are a class of effective, well-tolerated antidepressants. They have a number of benefits compared with the tricyclic antidepressants (TCAs) including improved safety in overdose, reduced side-effect burden, and uncomplicated dosing regimens. To avoid the potential for troublesome side effects with TCAs, doses should be gradually increased over several weeks. Dose titration can be associated with several drawbacks such as patients discontinuing therapy due to a prolonged time to therapeutic response, additional visits to a prescribing healthcare provider, or additional hospitalizations. In contrast, the SSRIs typically do not require dose titration since many patients find the initial dose effective. The ability to prescribe an initial optimum therapeutic dose while avoiding dose-related side effects is important in the treatment of major depression. With this in mind, the authors consider the recommended dose ranges for the five SSRIs: citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.     

Depression and pain: An appraisal of cost effectiveness and cost utility of antidepressants

BackgroundAlthough depression and chronic pain frequently co-occur, there is a lack of clarity in the literature regarding the cost-effectiveness and cost-utility of antidepressants in the presence of these two conditions. From the perspective of healthcare provider, the current study aims to compare the cost-effectiveness and cost-utility of antidepressants in a national cohort of depressed patients with and without comorbid pain conditions.MethodsAdult patients prescribed with antidepressants for depression were identified from the National Health Insurance Research Database in Taiwan (n = 96,501). By using remission as effectiveness measure and quality-adjusted life years (QALYs) as utility measure, the cost-effectiveness and cost-utility were compared across selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs), as well as by the presence of comorbid painful physical symptoms (PPS).ResultsSSRIs dominated SNRIs in both the cost-effectiveness and cost-utility regardless of comorbid PPS. In comparison with TCAs, SSRIs were likely to be the cost-effective option for patients without PPS. In patients with PPS, the cost-utility advantage for SSRIs over TCAs varied with threshold willingness-to-pay levels. Comorbid PPS may be considered an effect modifier of the cost-utility comparisons between SSRIs and TCAs.ConclusionsFor depressed patients without PPS, SSRIs are likely to be cost-effective in improving remission rates and QALYs compared to TCAs and SNRIs. However, to improve cost-utility in those with comorbid PPS, people need to choose between SSRIs and TCAs according to threshold willingness-to-pay levels. Future research is warranted to clarify the impacts of different pain conditions on the economic evaluations of pharmacological treatments in patients with depression.