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Antidepressants for depression in medical illness, types of mental disorders - Reviews

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Major depressive disorder (MDD) is highly prevalent in medically ill subjects and is associated with increased morbidity and mortality in that population. Mount Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. It is the policy of Mount Sinai School of Medicine to ensure fair balance, independence, objectivity, and scientific rigor in all its sponsored activities.
For decades, there has been a controversy over whether depression in medically ill individuals is a distinct diagnostic entity from major depressive disorder (MDD).
Multiple studies have reported a significantly higher prevalence of depression in the medically ill compared to the general population. Other studies have analyzed the impact of overall medical illness on the prevalence of MDD.
In some studies, antidepressant drugs have been reported to be more efficacious than placebo in patients with MDD and comorbid medical illness, while in other studies the antidepressant treatment did not separate from placebo.
Earlier studies46 of tricyclic antidepressants (TCAs) reported low rates of improvement of depressive symptoms in MDD subjects with comorbid medical illness. Several studies48-58 have been published in the last decade comparing the outcome of antidepressant treatment in MDD subjects with and without medical illness. Only two studies52,58 compared antidepressant treatment for prevention of MDD relapse in subjects with and without comorbid medical illness.
In conclusion, MDD subjects with comorbid medical illness achieve lower rates of antidepressant treatment response and remission in the acute phase of MDD treatment, and higher rates of depressive relapse in the continuation phase, compared to MDD without medical illness.
The efficacy of psychostimulants as a treatment of depression in medically ill subjects is supported by retrospective analyses59-62 and by open-design prospective studies with very few patients.63,64 The few double-blind controlled studies on psychostimulant treatment for depression associated with medical conditions are varied in their design. Interestingly, psychostimulants have not shown antidepressant efficacy in depression subjects with Parkinson’s disease. Specific antidepressant treatments have also been proposed for depressed subjects with chronic pain.
Medications with dual serotonin and norepinephrine reuptake inhibition appear to have good activity in pain. The studies reviewed here suggest that although usual antidepressant treatments are effective in subjects with MDD and comorbid medical illness, this comorbidity is associated with lower rates of recovery and remission of depressive symptoms, as well as higher rates of relapse during continued treatment, compared with depressed subjects with no medical comorbidity.
ABSTRACT: Depression in the elderly significantly affects patients, families, and communities.
Depression is the most common mental health problem in the elderly[1] and is associated with a significant burden of illness that affects patients, their families, and communities and takes an economic toll as well. Because of our aging population, it is expected that the num­ber of seniors suffering from depression will increase.
There is also often a tendency for people to see their symptoms as part of the normal aging process, which they are not. The Geriatric Depression Scale (GDS) is a well-validated screening tool for depression in the elderly that comes in two common formats: the 30-item (long form) and 15-item (short-form) self-rating scale. The CCSD relies on an interview with a family member or caregiver as well as with the patient, and is validated for use with nondemented and demented depressed elderly.
TreatmentThe current Canadian practice guidelines for the treatment of depression in the elderly were developed by the Canadian Coalition for Seniors’ Mental Health (CCSMH) in 2006.[1] They were created by experts in the field, are evidence-based, and include both pharmacological and nonpharmacological strategies. Note that most depression studies have been conducted on younger populations, and when mixed-aged groups have been studied older adults have been underrepresented. If older adults are unresponsive to low doses of antidepressants, higher doses may be required to achieve a therapeutic effect. Choice of antidepressantFortunately there are several antidepressants that have been shown to be efficacious in elderly patients being treated for a major depressive episode without psychotic features.
The selective serotonin reuptake inhibitors (SSRIs) and the newer antidepressants buproprion, mirtazapine, moclobemide, and venlafaxine (a selective norepinephrine reuptake inhibitor or SNRI) are all relatively safe in the elderly. It is important to check sodium levels 1 month after starting treatment on SSRIs, especially in patients taking other medications with a propensity to cause hyponatremia, such as diuretics. Of the SSRIs, fluoxetine is generally not recommended for use in the elderly because of its long half-life and prolonged side effects. Many medical conditions seen in the elderly, such as dementia, Parkinson disease, and cardiovascular problems can be worsened by a tricyclic antidepressant. Also, it is recommended that an ECG and postural blood pressure reading be obtained before starting a patient on a tricyclic antidepressant and after increasing the dose.[1] Tricyclic antidepressant blood levels should be monitored since tricyclics are associated with more toxicity and since blood levels can be high despite low doses because some patients can be slow metabolizers.
Given the side effect profile and high rates of drug-drug interactions, monoamine oxidase inhibitors (MAOIs) are not considered first- or even second-line agents for depression in the elderly. DosingOnce an antidepressant is selected for an older patient, the starting dose should be half that prescribed for a younger adult[1] in order to minimize side effects.
It is also important at each visit to monitor for any worsening of depression, emergence of agitation or anxiety, as well as for suicide risk, especially in the early stages of treatment. Treatment to remissionAccording to the current CCSMH guidelines, if there is no improvement in depressive symptoms after 4 weeks or insufficient improvement in symptoms after 8 weeks on the maximum recommended or tolerated dose of an antidepressant, then the antidepressant should be changed.
Cross-titrating can be done—weaning the patient off the old antidepressant while introducing the new one—although caution is needed to ensure that there are no interactions between the two antidepressants. Stopping some medications suddenly (particularly ven­lafaxine and paroxetine) can lead to a withdrawal syndrome that includes anxiety, insomnia, and flu-like symptoms. If there is significant improvement but not full remission after 4 weeks on the optimized antidepressant, the recommendation is to wait another 4 weeks and then consider add-on treatment if remission is still not achieved.[1] Add-on options include either an antidepressant of a different class, another agent such as lithium, or psychotherapy such as cognitive-behavioral therapy or interpersonal therapy. Newer pharmacological approachesSince the CCSMH guidelines document was published in 2006, newer antidepressant agents have become available including duloxetine and desvenlafaxine, both SNRIs.
Atypical antipsychotics used as add-on therapy in the treatment of depression shows some promise. The latest 2009 CANMAT national practice guidelines for the treatment of major depressive disorder in adults[28] recommend the use of atypical antipsychotic agents such as rispiridone, olan­zapine, and aripiprazole as first-line add-on agents in the treatment of depression, while quetiapine is recommended as a second-line add-on agent owing to fewer studies. Nonetheless, atypical antipsychotics may prove to be an effective treatment for severe or refractory depression in the elderly who fail to respond fully to other medications.
Together, these strategies can help promote the safe use of antidepressants in the elderly. AcknowledgmentsI would like to thank Dr Martha Donnelly for her encouragement and support in the preparation of this manuscript. Although many antidepressants have established efficacy and tolerability in depression associated with medical conditions, current research shows that physicians prescribe antidepressants less frequently and in lower doses for medically ill MDD subjects compared to other depressed patients.

Iosifescu is director of neurophysiology studies in the Depression Clinical and Research Program at Massachusetts General Hospital, and assistant professor of psychiatry at Harvard Medical School, both in Boston, Massachusetts. Fraguas is a research fellow in psychiatry at Massachusetts General Hospital and Harvard Medical School, and chief of the consultation group of the Institute of Psychiatry at the Hospital das Clinicas of the University of Sao Paulo School of Medicine in Brazil. This is a significant association that impacts the prognosis of both medical and psychiatric treatments. This article will review studies reporting a high incidence of depression in patients with a variety of medical illnesses. Koenig and colleagues31,32 identified the presence of severe medical illness as a risk factor for depression. Such mixed results have been reported in randomized, placebo-controlled studies of antidepressants in subjects with MDD and a variety of comorbid medical illnesses (eg, MI,36,37 stroke,38-41 diabetes,42,43 and cancer44,45). These studies differ in design, diagnosis of depression, ratings of medical illness, and antidepressant treatment utilized. Six out of the nine studies48,50,51,53,54,56 reported lower treatment response in MDD subjects with comorbid medical illness (Figure 1). Both studies included subjects with MDD in remission after acute antidepressant treatment, and both studies used the CIRS to rate the severity and the total burden of all comorbid illnesses.
Glassman AH, O’Connor CM, Califf RM, et al, for the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) Group. Small GW, Birkett M, Meyers BS, Koran LM, Bystritsky A, Nemeroff CB, for the Fluoxetine Collaborative Study Group.
Awareness of predisposing and precipitating factors can help identify patients in need of screening with tools such as the Geriatric Depression Scale. However, it is necessary first to identify and diagnose depression, which can be challenging in this population owing to communication difficulties caused by hearing or cognitive impairment, other comorbidities with physical symptoms similar to those of depression, and the stigma associated with mental illness that can limit the self-reporting of depressive symptoms. Depression in the elderly still goes undertreated and untreated, owing in part to some of these issues. It is also important to minimize drug-drug interactions, especially given the number of medications elderly pa­tients are often taking.
In choosing an antidepressant it is recommended that selection be based on the best side effect profile and lowest risk of drug-drug interactions. They have lower anticholinergic effects than older antidepressants and are thus well tolerated by patients with cardiovascular disease.
Increased side effects from antidepressant use in the elderly are thought to be due to changes in hepatic metabolism with aging, concurrent medical conditions, and drug-drug interactions. Thus, it is important to schedule regular follow-up visits to monitor treatment response while assessing for side effects and titrating accordingly.
For example, if fluoxetine is being discontinued, then a wash-out period of several weeks is recommended because of the drug’s long half-life.
If a second antidepressant is added, monitor for the emergence of serotonin syndrome, which can arise if both medications are serotonergic. However, the CANMAT recommendations are based on studies of younger adults and are not intended for the elderly. Atypical antipsychotics at the lowest doses for symptom control are also recommended for the treatment of psychotic symptoms associated with depression. Besides medications, other therapies for depression that might be considered include various forms of psychotherapy and neurostimulation, with electroconvulsive therapy still being the gold standard for severe or psychotic depression. National guidelines for seniors’ mental health: The assessment and treatment of depression.
However, treatment nonresponse and depressive relapse are more common in medically ill MDD subjects than in depressed individuals with no medical illness. Credits will be calculated by the MSSM OCME and provided for the journal upon completion of agenda.
This article reviews studies comparing the outcome of antidepressant treatment in subjects with major depressive disorder (MDD) with and without comorbid medical illness. However, the importance of this comorbidity is related to the negative impact that the presence of one condition has on the course of the other condition.6 In a number of studies,7-13 the presence of depression was predictive of poor medical outcome and of increased mortality. In a meta-analysis of 42 studies,29 the odds of depression in the diabetes group were twice that of the nondiabetes group. In a study of 2,554 subjects, Wells and colleagues33 found the 6-month prevalence of depression increased from 6% to 9% when comorbid medical illness was present, and the lifetime prevalence increased from 9% to 13%. These mixed efficacy results are consistent with the following reports showing that depression with comorbid medical illness is more refractory to antidepressant treatment. The three other studies49,55,57 reported no difference in treatment outcome in subjects with and without medical comorbidity.
One study used nortriptyline,52 and the other used fluoxetine58 for prevention of depressive relapse. Differentiation of primary affective illness from situational, symptomatic, and secondary depressions. Even minimal symptoms of depression increase mortality risk after acute myocardial infarction. Patients with depression are less likely to follow recommendations to reduce cardiac risk during recovery from a myocardial infarction. A comparative study into the one year cumulative incidence of depression after stroke and myocardial infarction. Prevalence and predictors of depression and anxiety-related disorders during the year after heart transplantation. Relationship of depression to increased risk of mortality and rehospitalization in patients with congestive heart failure. Prevalence and correlates of depressive symptoms in a community sample of people suffering from heart failure. Major depressive disorder in hospitalized medically ill patients: an examination of young and elderly male veterans. How the medical comorbidity of depressed patients differs across health care settings: results from the Medical Outcomes Study. Cognitive and somatic symptoms of depression are associated with medical comorbidity in patients after acute myocardial infarction. Efficacy and safety of fluoxetine in the treatment of patients with major depression after first myocardial infarction: findings from a double-blind, placebo-controlled trial.

Effective treatment of post-stroke depression with the selective serotonin reuptake inhibitor citalopram. Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: a placebo-controlled, double-blind study. Early fluoxetine treatment of post-stroke depression—a three-month double-blind placebo-controlled study with an open-label long-term follow up.
Effects of nortriptyline on depression and glycemic control in diabetes: results of a double-blind, placebo-controlled trial.
Fluoxetine for depression in diabetes: a randomized double-blind placebo-controlled trial. 12-month outcome of patients with major depression and comorbid psychiatric or medical illness (compound depression). Impact of physical illness on quality of life and antidepressant response in geriatric major depression. Comorbid medical illness and relapse of major depressive disorder in the continuation phase of treatment.
Treatment of depression with methylphenidate in patients difficult to wean from mechanical ventilation in the intensive care unit.
Effects of dextroamphetamine on depression and fatigue in men with HIV: a double-blind, placebo-controlled trial. Effects of methylphenidate in HIV-related depression: a comparative trial with desipramine.
A randomized, double-blind, placebo-controlled trial of psychostimulants for the treatment of fatigue in ambulatory patients with human immunodeficiency virus disease. Efficacy of venlafaxine for the long term treatment of chronic pain with associated major depressive disorder.
Duloxetine in the treatment of depression: a double-blind placebo-controlled comparison with paroxetine. Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial. After diagnosis, regular follow-up and active medication management are crucial to maximize treatment and remission. Nonetheless, in recent years there is an increasing body of literature specific to the elderly (as referenced below), which helps guide the clinician in the appropriate prescription and use of antidepressants in this patient population. For a list of commonly used antidepressants and associated doses for older adults, see the accompanying Table. Identification followed by a thorough assessment can help guide the selection of an appropriate antidepressant medication. Physicians treating depression in the medically ill should be prepared to use common strategies utilized for treatment-resistant depression (eg, dose increases, augmentation, or switching of antidepressants).
MDD subjects with medical illness tend to have lower improvement of depressive symptoms and higher rates of depressive relapse with antidepressant treatment compared to MDD subjects without medical illness.
In the study by Iosifescu and colleagues,58 higher medical comorbidity (measured by the CIRS score) was predictive of higher rates of relapse (Figure 2), as well as increases in self-reported symptoms of depression, anxiety, and anger. Selection of an antidepressant medication should be based on the best side effect profile and the lowest risk of drug-drug interaction.
There are several factors to consider when selecting, adjusting, and changing antidepressants in the elderly. In addition, this article reviews the limited data for specific antidepressant treatment strategies for MDD subjects with medical illness. Alexopoulos and colleagues52 reported no significant relationship between medical comorbidity (CIRS score) and MDD relapse or recurrence. It concludes with clinical strategies recommended in light of the literature reviewed: an increased index of suspicion for depression in medically ill subjects, and more aggressive antidepressant treatment in depressed subjects with medical comorbidity. In cases of severe, psychotic, or refractory depression in the elderly, electroconvulsive therapy is recommended.
Self-rated depression scales and screening for major depression in the older hospitalized patient with medical illness. The association of depression and mortality in elderly persons: A case for multiple, independent pathways. National guidelines for seniors’ mental health: The assessment of suicide risk and prevention of suicide. Development and validation of a geriatric depression screening scale: a preliminary report. Pharmacological and psychological treatments for depressed older patients: A meta-analysis and overview of recent findings.
Feasibility and effectiveness of treatments for depression in elderly medical inpatients: A systematic review. Antidepressant pharmacotherapy in the treatment of depression in the very old: A randomized, placebo-controlled trial.
The safety and tolerability of duloxetine in depressed elderly patients with and without medical comorbidity. Time to response for duloxetine 60 mg once daily versus placebo in elderly patients with major depressive disorder. Methylphenidate for the treatment of depressive symptoms, including fatigue and apathy, in medically ill older adults and terminally ill adults.
Efficacy and safety of adjunctive aripiprazole in major depressive disorder in older adult patients: A pooled subpopulation analysis. Placebo-controlled study of relapse prevention with risperidone augmentation in older patients with resistant depression. Canadian Network for Mood and Anxiety Treatments (CANMAT) clinical guidelines for the management of major depressive disorder in adults. Risk of death with atypical antipsychotic drug treatment for dementia: Meta-analysis of randomized placebo-controlled trials.

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