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 REVIEW ARTICLE

The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations for the management of patients with mood disorders and select comorbid medical conditions

Rajamannar Ramasubbu, MD, FRCPC, MSc

Department of Psychiatry and Clinical Neurosciences, University of Calgary, Hotchkiss Brain Institute, Calgary, Alberta, Canada

Valerie H. Taylor, MD, PhD, FRCPC

Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

Zainab Samaan, MD, PhD, FRCPC

Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada

Sanjeev Sockalingham, MD, FRCPC

Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

Madeline Li, MD, PhD, FRCPC

Department of Psychiatry, Psychosocial Oncology and Palliative Care, University Health Network, University of Toronto, Toronto, Ontario, Canada

Scott Patten, MD, PhD

Department of Community Health Sciences, University of Calgary, Hotchkiss Brain Institute, Calgary, Alberta, Canada

Gary Rodin, MD, FRCPC

Department of Psychiatry, Psychosocial Oncology and Palliative Care, University Health Network, University of Toronto, Toronto, Ontario, Canada

Ayal Schaffer, MD, FRCPC

Mood and Anxiety Disorders Program, Sunnybrook Health Sciences Centre, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

Serge Beaulieu, MD, PhD, FRCPC

Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, Québec, Canada

Roger S. McIntyre, MD, FRCPC

Mood Disorders Psychopharmacology Unit, University Health Network, Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, Ontario, Canada

BACKGROUND: Medical comorbidity in patients with mood disorders has become an increasingly important clinical and global public health issue. Several specific medical conditions are associated with an increased risk of mood disorders, and conversely, mood disorders are associated with increased morbidity and mortality in patients with specific medical disorders.

METHODS: To help understand the bidirectional relationship and to provide an evidence-based framework to guide the treatment of mood disorders that are comorbid with medical illness, we have reviewed relevant articles and reviews published in English-language databases (to April 2011) on the links between mood disorders and several common medical conditions, evaluating the efficacy and safety of pharmacologic and psychosocial treatments. The medical disorders most commonly encountered in adult populations (ie, cardiovascular disease, cerebrovascular disease, cancer, human immunodeficiency virus, hepatitis C virus, migraine, multiple sclerosis, epilepsy, and osteoporosis) were chosen as the focus of this review.

RESULTS: Emerging evidence suggests that depression comorbid with several medical disorders is treatable and failure to treat depression in medically ill patients may have a negative effect on medical outcomes.

CONCLUSIONS: This review summarizes the available evidence and provides treatment recommendations for the management of comorbid depression in medically ill patients.

KEYWORDS: bipolar disorder, cancer, cerebrovascular disease, comorbidity, coronary heart disease, epilepsy, HCV, HIV, major depressive disorder, migraine, multiple sclerosis, osteoporosis

ANNALS OF CLINICAL PSYCHIATRY 2012;24(1):91-109

  INTRODUCTION

Mood disorders are a multisystem group of disorders that can adversely affect a variety of end organ systems. Conversely, diseases of several organ systems increase the risk of mood disorders. This article reviews the available evidence on the bidirectional comorbid relationships between mood disorders and several common medical conditions, evaluates the evidence of efficacy and safety of pharmacologic and psychosocial treatments, and provides recommendations regarding the management of patients with these comorbid conditions. The medical conditions chosen as the focus of this review are among the more commonly encountered medical disorders in clinical practice and include cardiovascular disease (CVD), cerebrovascular disease, cancer, human immunodeficiency virus (HIV), hepatitis C virus (HCV), migraine, multiple sclerosis (MS), epilepsy, and osteoporosis.

Cardiovascular disease

Mood disorders are overrepresented in patients with CVD, and up to 20% of patients with CVD also meet criteria for major depressive disorder (MDD) or bipolar disorder (BD).1,2 As a consequence, a significant amount of research has been focused on understanding this association. Since the late 1990s, there have been >100 narrative reviews of this literature, as well as numerous meta-analyses examining the role of mood disorders on cardiovascular morbidity and mortality.3,4 Despite differences in samples, duration of follow-up, and assessment of depression and depressive symptoms, these studies have demonstrated relatively consistent results. Less research has focused on BD and CVD, but the results of studies examining mortality and hospitalization indicate that patients with BD have higher mortality from cardiac disorders than the general population.5 As a result of these findings, several clinical guidelines recommend that screening for mood disorders be considered in patients with CVD, and conversely, that screening for CVD occur in patients experiencing mood changes, highlighting the bidirectional nature of this association.6-9

These recommendations are not without controversy, however, in part because of equivocal outcomes in interventional studies. In the past decade, 3 large studies have not shown a positive effect of MDD treatment on medical endpoints.10-12 Despite these negative findings, meta-analyses have concluded that psychosocial interventions are associated with significant reductions in mortality and cardiac morbidity,13,14 although mortality benefits may differ by sex.5 A systematic review published in the Journal of the American Medical Association examining the effects of MDD treatment in CVD patients identified 4 efficacy studies of antidepressant medications that met search inclusion criteria; these included studies using fluoxetine,16 sertraline,17 citalopram,18 and mirtazapine.19 In the fluoxetine study,16 Strik et al compared the efficacy and safety of fluoxetine administered to patients after their first myocardial infarction (MI) and found a trend toward antidepressant efficacy. The Sertraline Antidepressant Heart Attack Randomized Trial (N = 369)17 tested the efficacy and safety of sertraline in patients with MDD. Here the investigators conducted a randomized study of MDD in patients with unstable ischemic heart disease and found no difference in cardiovascular adverse events between the drug and placebo groups after 16 weeks of therapy. The Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy Trial (N = 284)18 compared citalopram to placebo and compared short-term interpersonal psychotherapy plus clinical management to clinical management alone in patients with coronary artery disease; the results showed antidepressant efficacy and no evidence of harm. However, in the Myocardial Infarction and Depression–Intervention Trial,19 which used mirtazapine, the drug showed superiority to placebo on some but not all depression scales. Further complicating the picture is the outcome of a systematic review that did not find evidence for or against the recommendations that MDD be evaluated or that screening for MDD be considered part of standard care in patients with CVD.20

A number of factors support an association between mood disorders and CVD. From a behavioral perspective, patients with MDD or BD are more likely to engage in unhealthy behaviors, such as smoking or having a sedentary lifestyle, that increase the risk of CVD.21 When diagnosed with heart disease, having a mood disorder is associated with lack of medical adherence to pharmacologic treatments or interventions such as exercise.22,23 Patients with a mood disorder also have a lower frequency of hospitalization for heart disease and lesser exposure to cardiac treatment.24 Although not always consistent, several studies in depressed patients with coronary artery disease also have reported reduced heart rate variability (suggesting increased sympathetic activity and/or reduced vagal activity)25 and hypothalamic-pituitary-adrenal (HPA) axis dysfunction,26 increased plasma platelet factor 4 and β-thromboglobulin (suggesting enhanced platelet activation),27,28 impaired vascular function,29 and increased C-reactive protein, interleukin (IL) 6, intercellular adhesion molecule-1, and fibrinogen levels (suggesting an increased innate inflammatory response).30,31

Treatment recommendations. The nature of the association between mood disorders and CVD has not been fully elucidated, and research is needed to determine the effectiveness and efficacy of various treatment outcomes. The evidence we do have, however, supports adoption of the following recommendations:

  1. Routine screening for depression in patients with CVD in various settings, including hospitals, physicians’ offices, and cardiac rehabilitation centers (level 2).

  2. Selective serotonin reuptake inhibitors (SSRIs) and noradrenergic and specific serotonergic antidepressants have been shown to be beneficial in treating depression after a cardiac event with no worsening of cardiac events (level 2).

  3. There is first-line evidence that patients with CVD who are receiving treatment for MDD should be carefully monitored for adherence to their medical care, drug efficacy, and safety with respect to both their cardiovascular and mental health (level 1).

  4. The use of psychotherapeutic techniques such as cognitive-behavioral therapy (CBT), interpersonal therapy (IPT), or problem-solving therapy is beneficial alone or in combination with medication for mild to moderate depression (level 2).

  5. There are no systematic studies evaluating electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS). ECT can be performed safely in most patients with underlying cardiac conditions, with the caveat that appropriate cardiac treatments are administered at the time of neuromodulation treatment (level 3).

Cerebrovascular disease

Stroke represents a major public health problem worldwide. It is the third leading cause of mortality in patients age ≥50 and the sixth leading cause of burden of disease worldwide.32,33 An association between depression and stroke has long been recognized, but only in the last 20 to 25 years have studies examined the comorbid relationship between the two. Depression following stroke is often termed post-stroke depression (PSD), although the validity of this entity as a specific type of secondary depression remains controversial.34

Epidemiology of comorbidity. There is robust evidence that stroke increases the risk of depression35 and that depression increases the risk of vascular disease.22,36 Mania is relatively rare following stroke, and although 2 cases of secondary mania post-stroke were reported in a cohort of 309 stroke patients,37 other large-scale studies did not find a single case of mania.34,38

PSD negatively influences stroke recovery by impairing physical and cognitive functions,39,40 and it increases both the risk of medical mortality41 and death by suicide.42 Since 1990, 9 prospective studies have shown evidence for an association between antecedent depression and stroke, supporting the bidirectional relationship between these 2 disorders.43 Larson et al reported a relative risk of 2.67 for stroke in patients who had depressive disorder, which was higher than the relative risk reported in other studies using broadly defined depressive symptoms, suggesting a dose-response relationship between depression and stroke.44

Etiologic mechanisms of comorbidity. Several lines of evidence suggest that PSD may be influenced by physical factors such as cerebral ischemia and stroke lesions, psychosocial factors such as stress related to physical and cognitive impairment associated with stroke,45 and genetic factors linked to serotonin transporter polymorphisms.46,47 Cerebral ischemia also leads to alterations in proinflammatory cytokines and stroke lesions that may cause depletion in monoamines, increased HPA activity, and disruption in emotional neural circuits.48,49 There is also evidence that personal and family history of depression increases the risk of PSD.50,51 Conversely, depression might contribute to illness onset and progression of vascular diseases with stroke outcome by increasing platelet activation and adhesions, HPA activity, heart rate variability, sympathetic activity, proinflammatory cytokines, and insulin resistance.43

Efficacy of interventions in the treatment and prevention of depression in stroke. Several randomized control trials (RCTs) have examined the safety and efficacy of pharmacologic and psychotherapeutic interventions in PSD. A recent Cochrane systematic review of 13 RCTs of pharmacotherapy interventions found a small but significant effect of pharmacotherapy on achieving remission and reducing depression or depressive symptoms after stroke.52 The results of that review also found evidence of increased adverse events associated with antidepressant treatment. Based on these results, the authors did not recommend routine use of antidepressants in PSD. Another meta-analytic review of 16 RCTs involving a total of 1,320 patients disputed this finding, concluding that antidepressant treatment was effective in patients with PSD.53 Based on the data available from RCTs of SSRIs, citalopram was found to be safe and effective,54 the effect of fluoxetine and sertraline on PSD was either inconclusive or negative,55-58 and among the tricyclic antidepressants (TCAs), nortriptyline was found to be effective.56,59 Methylphenidate treatment also showed small improvements in activities of daily living (ADLs) over the course of treatment.60 Regarding psychotherapeutic interventions, no benefit was noted in 4 trials of psychotherapy involving counseling or specific psychotherapy compared with standard care in the treatment of depression associated with stroke.52 However, a Cochrane review did note that problem-solving therapy and motivational interviewing seem to have benefit in preventing depression in stroke patients.61 Regarding antidepressant treatment in the prophylaxis of depression, a Cochrane review showed negative results, whereas 2 other meta-analytic reviews and one recent RCT showed evidence for efficacy in preventing depression.62-64

Treatment recommendations. The available evidence supports adoption of the following recommendations:

  1. Only nortriptyline treatment has level 1 evidence56,59 in terms of efficacy for the treatment of PSD. Given the risk of delirium65 and safety concerns in patients with concomitant cardiac disease, it is recommended as a second-line treatment.

  2. Although citalopram has level 2 evidence,54 it is recommended as first-line treatment because of its safety in cardiac and elderly patients, whereas other treatments with level 2 evidence, such as amitriptyline and trazodone, should be considered third-line treatments due to side effects and efficacy only in subgroups.66-68

  3. Paroxetine and fluoxetine should be avoided, as they are potent inhibitors of cytochrome P450 and interact with several cardiac medications.69 Typical or atypical antipsychotics may increase the risk of stroke in elderly individuals, and caution should be exercised in using antipsychotics as add-on treatment for resistant depression or BD70 (level 2).

  4. There is inadequate evidence at present to support the use of psychotherapy as monotherapy in the treatment of PSD. However, structured psychological therapies such as problem-solving therapy and motivational interviewing in combination with antidepressants may have a role in the treatment of MDD resistant to first-line antidepressants and in relapse prevention. However, controlled studies for these combination treatments are needed.

  5. Because of a lack of adequate evidence, the routine use of antidepressants in stroke patients to prevent depression and improve stroke recovery is not recommended at the present time. More research is needed to examine the benefits of pharmacologic preventive intervention for the entire stroke population.

  6. ECT, repetitive TMS, and treatment with psychostimulants60,71,72 have only level 3 evidence and are recommended as third-line treatment for patients with treatment-resistant PSD.

Cancer

Cancer is associated with distress at all points in the disease trajectory. Psychological concerns contributing to such distress include uncertainty about the future, loss of autonomy and sense of control with increasing disability, perceived alterations in the life trajectory, existential concerns, and fear of dying.73 Adding to the burden of disease are the functional limitations in occupational and recreational activities, family role functioning, and ADLs that may be associated with cancer. In a substantial minority of individuals with cancer, mood disorders such as MDD, dysthymia, minor depression, and adjustment disorder with depressed mood may develop.

Epidemiology and comorbidity. The reported prevalence of clinically significant depression in cancer patients has varied widely depending on the cancer type, demographics of the population studied, stage of cancer, diagnostic criteria and strategy applied, timing and method of assessment, measurement tools used, and diagnostic thresholds.74,75 Overall, it is estimated that 10% to 25% of cancer patients have clinically significant depressive symptoms,76,77 with a higher prevalence toward the end of life78 and in cancers with poorer prognoses, such as pancreatic and oropharyngeal cancer.79,80 These overall rates of depression in cancer are approximately 2 to 4 times that found in the general population.81 Depression in patients with cancer has been associated with reduced quality of life,82 an elevated rate of suicide and a desire for hastened death,76,83 poorer treatment compliance,84 greater physical distress,85 and more prolonged hospital stays.86 It has also been shown to be an independent risk factor for mortality87-89 and has been reported by some to be associated with increased resistance and slower response rates to antidepressant medication and higher rates of depressive relapse.

Etiology. Psychosocial factors that increase the risk of depression in cancer patients include younger age, personal or family history of depression, less social support, greater attachment anxiety, poor communication with medical caregivers, greater illness intrusiveness, and maladaptive coping strategies.91 There is little evidence that psychosocial factors or depression increase the incidence of cancer or the risk of disease progression,80,92 although recent work is beginning to explore plausible biological mechanisms by which this could occur.93

Immune-activated systemic inflammation is a proposed shared biologic mechanism mediating the bidirectional relationship between depression and cancer. This has been supported by mounting evidence that tumor cell burden and treatment-induced tissue destruction results in the release of proinflammatory cytokines that alter neurotransmitter and neuroendocrine function, leading to behavioral changes termed sickness behavior.94

Effectiveness of treatment for depression in cancer. There have been 4 systematic reviews of pharmacologic treatment for depression in cancer, which have provided mixed evidence for effectiveness.95-98 Jacobsen et al identified 9 RCTs, in which 13 of 26 depression outcomes (total observer and self-report measures combined across all follow-up assessments) revealed significant treatment effects.95 Six RCTs were identified by Williams and Dale, of which only 2 demonstrated reductions in caseness for MDD, although 5 found reductions in depressive symptoms.96 In a systematic review limited to studies reported to June 2005, in which clinically significant depression was an inclusion criterion, Rodin et al identified only 3 of 7 RCTs in which a significant reduction of depressive symptoms was reported.97 Ng et al98 extended this review to February 2010, identifying only 3 of 8 RCTs with positive findings for effectiveness. This review also reported on 5 open-label studies that demonstrated the efficacy of methylphenidate in treating depression in cancer patients, although there were no controlled trials of this intervention for depression98 (TABLE 1).104-128

Evidence for the effectiveness of psychosocial interventions for depression in cancer is considerably larger but similarly mixed, in part because of significant variation in demographic, disease, and treatment characteristics in the populations studied and methodological differences in inclusion criteria, outcome assessments, and duration of follow-up. Jacobsen et al comprehensively reviewed 9 systematic reviews and 4 meta-analyses99 of the effects of interventions such as psychoeducation, problem-solving therapy, CBT, IPT, supportive-expressive psychotherapy, and relaxation therapies for depression in cancer. Based on 9 of 13 publications, they reached positive conclusions about the efficacy of psychosocial interventions. Only 3 RCTs of psychosocial interventions to treat depression in cancer patients demonstrated reductions in caseness for depression.96 Only 50% of psychosocial intervention studies limited to clinically significant depression demonstrated reductions in depressive symptoms,97 and a meta-analysis yielded a negligible effect size (Cohen’s d = .19).100 Although controversy persists regarding the overall efficacy of psychosocial interventions in cancer,101,102 Jacobsen99 has proposed deriving specific clinically relevant recommendations based on the number of RCTs that demonstrate efficacy in managing depression per intervention type and patient disease or treatment status (TABLE 2).129-153

Treatment recommendations. The available evidence supports adoption of the following recommendations:

  1. It is difficult to derive clinically relevant first-line treatment recommendations based on the current RCT literature for pharmacologic treatment of depression in cancer. Level 1 evidence is available only for paroxetine in depression prevention trials, but caution should be used based on its strong inhibition of cytochrome P450 2D6103 and its relatively pronounced anticholinergic side effects. At present, there is no evidence that any particular antidepressant is more efficacious than others in the management of depression in cancer.

  2. First-line treatment recommendations for specific psychosocial interventions in depressed cancer patients are similarly difficult to derive, because the evidence does not support the superiority of 1 treatment modality over another. The use of a psychotherapeutic interventions has been shown to be helpful, with choice guided by patient characteristics.


TABLE 1

Evidence for efficacy of pharmacologic interventions in preventing or relieving depression in cancer patients

Medication Positive trials Negative trials Level of evidence
Antidepressants
Paroxetine Pezzella et al, 2001107
Morrow et al, 2003104
Musselman et al, 2001105
Roscoe et al, 2005106
Musselman et al, 2006108 1
Fluoxetine Navari et al, 2007109 Razavi et al, 1996110
Holland et al, 1998111
Fisch et al, 2003112
2
Citalopram Lydiatt et al, 2008113   2
Mianserin Costa et al, 1985114
van Heeringen et al, 1996115
Tarrier et al, 1984116 1
Desipramine   Holland et al, 1998111
Musselman et al, 2006108
Negative evidence
Amitriptyline Pezzella et al, 2001107   2
Mirtazapine Ersoy et al, 2008117
Kim et al, 2008118
  3
Bupropion Moss et al, 2006119   3
Anxiolytics
Alprazolam Holland et al, 1991120 Wald et al, 1993121 2
Steroids
Prednisone Bruera et al, 1985122   2
Stimulants
Methylphenidate Fernandez et al, 1987123
Homsi et al, 2001124
Macleod, 1998125
Olin et al, 1996126
Natenshon, 1956127
  3
Mazindol   Bruera et al, 1986128 Negative evidence

TABLE 2

Evidence for efficacy of psychosocial interventions to prevent or relieve depression in cancer patients

Patient or treatment status RCT evidence Level of evidence
Relaxation techniques
Newly diagnosed patients Arakawa et al, 1997129
Bindemann et al, 1991130
Edgar et al, 2001131
1
Undergoing surgery Fawzy et al, 1990132
Petersen et al, 2002133
1
Undergoing chemotherapy Ando et al, 2009134
Burish et al, 1987135
Burish et al, 1981136
Jacobsen et al, 2002137
Mantovani et al,1996138
1
Undergoing radiotherapy Decker et al, 1992139
Evans et al, 1995140
Pruitt et al, 1993141
1
Completion of active treatment Simpson et al, 2001142 2
Terminal phase of illness Liossi et al, 2001143 2
Psychoeducation
Newly diagnosed patients McQuellon et al, 1998144 2
Undergoing surgery McArdle et al, 1996145 2
Undergoing chemotherapy Rawl et al, 2002146 2
Supportive-expressive therapies
Undergoing surgery Watson et al, 1988147 2
Undergoing chemotherapy Mantovani et al, 1996138 2
Undergoing radiotherapy Evans et al, 1995140 2
Patients with metastatic disease Kissane et al, 2007148
Edelman et al, 1999149
Goodwin et al, 2001150
1
Cognitive-behavioral therapies
Undergoing chemotherapy Pitceathly et al, 2009151
Marchioro et al, 1996152
1
Patients with metastatic disease Savard et al, 2006153
Edelman et al, 1999149
1
Human immunodeficiency virus and hepatitis C virus

Human immunodeficiency virus. Approximately 33 million people are infected with HIV globally, and the prevalence rate is 0.6% in North America.154 Furthermore, nearly 50% of HIV-infected patients have a comorbid psychiatric disorder such as a depressive or anxiety disorder, which is often unrecognized in this patient population.155,156

The high degree of comorbidity between depression and HIV has a significant impact on treatment outcomes. Depression and other factors, such as substance use and poor social support, have deleterious effects on adherence to highly active antiretroviral therapy (HAART) in HIV-infected patients and can potentially influence HIV illness outcomes.157,158 In a study of 765 HIV-seropositive women, depression severity and chronicity was associated with decreased CD4+ cell counts and survival.159 Although a retrospective study of 1,713 HIV-infected patients showed an improvement in HAART adherence with antidepressant treatment, the relationship between depression treatment and HIV adherence is less clear.160

The presentation of depression in HIV is further complicated by common somatic symptoms related to HIV infection itself, resulting in sleep disturbance, fatigue, impaired concentration, and loss of appetite. Although there is considerable overlap between somatic symptoms of depression and HIV, studies have shown improvement in both affective and somatic symptoms with antidepressant treatment.161,162

ETIOLOGY OF DEPRESSION IN HIV. Depression in the context of HIV infection can be conceptualized as primary or secondary in nature and can complicate the diagnosis of depression in this patient population. As stated above, depression in HIV often is associated with somatic symptoms related to HIV illness itself, and symptomatic HIV disease is associated with an increased risk of depression compared with controls.163 Harbingers for depression secondary to HIV include the absence of a family history of depression and central nervous system involvement of HIV.

Depression can influence immune activity in HIV and the course of infection. A decline in natural killer cell functioning and numbers has been associated with depression in HIV patients.164 In a study of HIV-infected women, depression resulted in increased activated CD8 lymphocytes and viral load.165 Psychosocial factors such as stigma associated with HIV and interpersonal losses may also contribute to the development of depression in HIV-infected patients.

Treatment with specific HAART, such as efavirenz, a nonnucleoside reverse transcriptase inhibitor, can also induce depressive symptoms—specifically, sadness and suicidal ideation—in up to 19.3% and 9.2% of patients, respectively.166 These changes have been linked to increased proinflammatory cytokines (interleukin-1 and tumor necrosis factor α) in rat studies with efavirenz, which are attenuated by paroxetine treatment.167 Given the high prevalence of depression in HIV and potential responsiveness to treatment, assessment and subsequent treatment of depression in HIV is important to HIV illness outcomes.

TREATMENT OF DEPRESSION IN HIV. Pharmacologic management of depression in patients with HIV has been an emerging focus over the last 20 years. A recent meta-analysis of all published RCTs for antidepressant medications among HIV-positive individuals demonstrated a moderate effect size (0.57) in this patient population.168 Heterogeneity across studies in this meta-analysis was associated with high placebo response (>33%).

The available evidence supports adoption of the following recommendations:

  1. Despite initial studies demonstrating the efficacy of TCAs for depression in this population, the side effects of TCAs, such as dry mouth, constipation, heart palpitations, headache, and insomnia, have led to higher dropout rates compared with other agents.169 These adverse effects often are compounded by the side effects from HAART regimens and somatic symptoms that are prevalent in HIV-infected patients; therefore, TCAs should be used only after SSRIs have failed to demonstrate efficacy or tolerability (level 2).

  2. Stimulant agents such as dextroamphetamine and methylphenidate have been shown in 2 RCTs to be effective in treating depression in HIV-positive patients.170,171 In a recent trial, modafinil failed to show a significant change in depressive symptoms in patients with HIV, although it was effective in reducing fatigue172 (level 2).

  3. Because of the improved tolerability of SSRIs, more recent RCTs have predominantly focused on these agents in the treatment of depression in HIV-positive individuals. Fluoxetine and paroxetine have shown efficacy in the treatment of depressive symptoms compared with placebo and TCA control treatments, respectively.173,174 Evidence from open-label studies support the use of sertraline and citalopram in treating depression in patients with comorbid HIV.175,176 Escitalopram and citalopram may be preferred in this patient population due to their limited drug-drug interactions with HAART177 (level 1).

  4. In addition to pharmacotherapy, psychosocial interventions have been studied in the treatment of depression in HIV-positive patients. Although trials have focused predominantly on CBT, supportive psychotherapy and psychoeducational groups have demonstrated efficacy comparable to CBT group interventions.162,178,179 Moreover, IPT has demonstrated efficacy in treating depression in HIV patients and was superior to supportive psychotherapy and CBT in 2 studies.162,180 Therefore, evidence exists for the use of a range of psychosocial interventions in managing depression in the context of HIV (level 2).

Hepatitis C virus. Approximately 140 million people worldwide are infected with HCV, which is primarily transmitted through intravenous drug use.181 Following acute HCV infection, up to 85% of individuals will develop chronic HCV infection, which will eventually lead to liver cirrhosis in 20% of patients over 20 years.182,183

HCV is associated with high rates of lifetime psychiatric comorbidity, with substance use disorders, mood disorders, and anxiety disorders occurring at high rates in these patients.184

ETIOLOGY OF DEPRESSION IN HEPATITIS C. A paucity of research has examined potential mechanisms of depression in untreated patients with HCV. However, studies have explored the etiology of interferon (IFN)-α–induced depression (IFN-MDD) on treatment in HCV patients. Research studies purport abnormal serotonin metabolism as a potential mechanism for IFN-MDD. IFN-α activates indoleamine 2,3-dioxygenase, a catabolizing enzyme for tryptophan (TRP), resulting in decreased TRP and serotonin (5-HT) levels and increased neurotoxic metabolites, specifically kynurenine and quinolinic acid.185 Treatment with paroxetine did not alter levels of kynurenine or quinolinic acid or attenuate behavioral symptoms secondary to IFN-α-mediated TRP depletion.186 In addition, proinflammatory cytokines, specifically IL-1, IL-2, IL-6, and IL-10, are increased with IFN-α treatment and have been linked to increased depressive symptoms.185,187

EVIDENCE FOR TREATMENT OF DEPRESSION IN HCV. The available evidence regarding treatment of depression in HCV is as follows:

  1. Open trials of citalopram and escitalopram have shown a significant reduction in depressive symptoms in patients with HCV, and both agents were well tolerated188,189 (level 3).

  2. Two randomized placebo-controlled trials involving paroxetine pretreatment in HCV-infected patients failed to reduce the incidence of IFN-MDD compared with the placebo group190,191 (level 2).

  3. Trials involving amantadine have failed to demonstrate a significant effect on IFN-MDD and are limited by poor tolerability192,193 (level 2).

  4. Treatment of IFN-MDD with fluoxetine, sertraline, venlafaxine, bupropion, mirtazapine, nortriptyline, and imipramine is supported by anecdotal and case series evidence194-199 (level 3).

  5. Limited research exists for psychosocial interventions either alone or in combination with pharmacotherapy in treating depression in HCV-infected patients. These interventions may be of benefit but further research is needed (level 3).

TREATMENT RECOMMENDATIONS FOR DEPRESSION IN HCV. Because of lack of evidence, there are no first-line or second-line treatment recommendations for the management of depression in HCV and IFN-MDD.

Migraine

Migraine is a primary headache disorder characterized by recurrent episodes of headache associated with gastrointestinal, neurologic, and autonomic symptoms.200 Migraine and MDD have long been noted to co-occur, and most studies suggest the frequency of this phenomenon is greater than can be explained by chance.201 Several clinical and epidemiologic studies have consistently reported a positive correlation between depression and migraine.202-211 Such studies demonstrated a higher risk for depression among individuals with migraine and a higher risk for migraine among depressed patients. A bidirectional relationship also was observed,202 with migraine predicting first onset of depression and depression predicting first onset of migraine; these observations were further confirmed by several subsequent studies.204,205,212 A review of studies carried out since the introduction of the explicit and widely accepted diagnostic criteria for primary headache disorders, including migraine, by the International Classification Committee of Headache Disorders (first edition in 1988, followed by a revised edition in 2004) suggested that the specificity of the migraine-depression association remains unclear, and the authors concluded no difference was demonstrated between patients with migraine and those with tension headache in terms of prevalence of psychopathology.213 A more recent study that investigated migraine prevalence in cases of recurrent depression in comparison to psychiatrically healthy controls reported a significant association between depression and headache in general; however, among individuals with headache, migraine with aura had the strongest association with depression (odds ratio [OR] 5.63; 95% confidence interval [CI], 3.94 to 9.0).211

Etiologic mechanisms. Several studies have attempted to explore the mechanisms behind the association between migraine and depression; however, such mechanisms remain unclear. Causal and noncausal interpretations have been proposed. Studies on biological markers such as dexamethasone suppression,214 tyramine conjugation,215 and [3H]-imipramine platelet binding216 suggest shared mechanisms between migraine and depression. The observations of TCA and monoamine oxidase inhibitor (MAOI) antidepressant efficacy in both disorders, along with evidence suggesting a dysfunction in the serotonergic and noradrenergic neurotransmitter systems, might further provide an understanding of the common mechanisms underpinning this comorbidity.217-219 More recently, with the expansion of genetic studies, migraine and depression were reported to be independently associated with a functional genetic variant.220,221

Evidence and treatment recommendations. The available evidence supports adoption of the following recommendations:

  1. Individuals with depression should be screened for migraine using standardized and validated questionnaires that range from a simple 3-item questionnaire (the ID Migraine) 222 or a more detailed questionnaire that can distinguish different subtypes of migraine, such as the Structured Migraine Interview questionnaire.223

  2. Somatic treatments such as TMS or vagus nerve stimulation (VNS) have shown promise in the treatment of depression and migraine (level 3).

  3. Psychotherapeutic approaches, including patient education, CBT, and biofeedback, have a role in both conditions. Evidence-based literature is seldom available to support such effectiveness for comorbid depression and migraine (level 3).

  4. There are no RCTs available to establish efficacy of antidepressant treatment in individuals with both migraine and depression. Amitriptyline and, to a lesser extent, SSRIs and serotonin-norepinephrine reuptake inhibitor (SNRIs), have all shown a significant effect on migraine treatment in case control and observational studies (levels 2 and 3).224

  5. TABLE 3 shows the most commonly used medications for the prophylactic treatment of migraine that overlaps greatly with the treatment of depression.

  6. Although SSRIs are the first-line treatment for depression,225 in the presence of migraine, SSRIs may exacerbate migraine headaches (level 2).

  7. Combination therapy is recommended to control the symptoms of migraine in depressed individuals. Such combination therapy may include anticonvulsants such as valproate, beta blockers, or calcium channel blockers (level 1).


TABLE 3

Evidence for migraine prophylactic treatment

Drug group Level of Evidence Comments
Antidepressants
Amitriptyline 1 Most commonly used
Citalopram 2 Tested in subjects with migraine and depression
Escitalopram 2 Tested in migraine without depression
Fluoxetine 2 May worsen headache
Sertraline 3 May worsen headache
Paroxetine 3 May worsen headache
Bupropion 3
Mirtazapine 4 Individual case reports
Venlafaxine 1
Duloxetine 3
Antiepileptics
Gabapentin 2
Lamotrigine 3
Topiramate 1 May worsen depression
Valproate 1 First-line migraine prophylaxis
Beta blockers
Propranolol 1
Calcium channel blockers
Verapamil 2
Multiple sclerosis

MS has been historically regarded as a demyelinating disease, but axonal damage has been increasingly implicated, especially in the progression of disability.226 According to an atlas produced by the World Health Organization, the prevalence of MS in Canada is 132.5 per 100,000,227 one of the highest in the world. MDD is an important issue for individuals with MS.228

Epidemiology of comorbidity. Epidemiologic studies indicate that the annual prevalence of MDD is 16%229 and the lifetime prevalence may be as high as 50%.230-232 These prevalence estimates are approximately 3 times higher than corresponding general population frequencies and may contribute to the high suicide rates reported in MS.233-236 Approximately 1% of men and 0.5% of women with MS die by suicide during the first 10 years after diagnosis.234 Female sex, being under the age of 35, experiencing high stress, and having a family history of MDD may all be associated with high MDD prevalence in this population.

Etiologic mechanisms of comorbidity. The etiology of MDD in MS is complex and poorly understood. Presumably it is at least partially related to the neurologic impact of MS, because lesion location and regional cerebrospinal fluid volume are correlated with major depression.237 However, bidirectional effects (an effect of major depression on MS course or outcome) also may be important. For example, treatment of depression may improve medication adherence238 and may even be associated with favorable immunologic changes.239

Treatment guidelines. Diagnosing depression can be complicated in the context of MS. Pseudobulbar affective changes, which are common in MS,240 can superficially resemble depressive episodes. Also, irritability is believed to be a common manifestation of major depression in individuals with MS, often overshadowing symptoms of sadness and anhedonia, whereas symptoms such as fatigue and cognitive dysfunction are found in both illnesses. These symptoms often occur with increased intensity or with a change in quality contributing to the diagnosis of MDD in people with MS.241

Current evidence supports adoption of the following recommendations:

  1. The literature of treatment studies is small but has generally reported positive outcomes.228 In addition to a few uncontrolled studies,242-244 3 controlled trials of antidepressant medication for the treatment of depressive disorders have been published.245-247 These studies evaluated desipramine, sertraline, and paroxetine, respectively. A meta-analysis has confirmed the positive impact of antidepressant treatment in MS when data from all 3 studies are combined.248 Use of antidepressants in this population should strongly be considered (level 2).

  2. A meta-analysis found that psychotherapies emphasizing coping strategies are more effective than those focusing on insight249 (level 2).

  3. Due to issues with fatigue, orthostatic hypotension, balance, cognitive issues, and bladder problems, antidepressants with significant sedating or anticholinergic side effects should be avoided (level 3).

  4. The prevalence of BD is markedly elevated in MS,232,250 suggesting that people with MS should be monitored for hypomanic and manic symptoms while they are being treated with antidepressant medications (level 4).

Epilepsy

Epilepsy is a chronic neurologic disorder that often manifests with recurrent seizures caused by excessive and disorderly electrical discharge of nerve tissue.251 Approximately 5% of the general population will have epilepsy in their lifetime,252 and depression is the most common comorbid psychiatric disorder associated with this seizure disorder. Comorbid BD has been reported, but the frequency of BD is less common than is unipolar depression.253

Epidemiology of comorbidity. The available epidemiologic data suggest that the relationship between depression and epilepsy is bidirectional in nature. The lifetime prevalence of depression in individuals with epilepsy ranges from 6% to 50%, exceeding rates found in the general population.254 Depression that is temporally related to seizure occurrence (preictal, ictal, and postictal depression) generally resolves with adequate control of epilepsy but can still be quite debilitating. Interictal depression, the most common seizure-related depression in epilepsy, impacts between 30% and 70% of those with epilepsy, presents with chronic symptoms with endogenous features, and is associated with severe impairment in ADLs and social functioning.255 In addition to the evidence supporting an increased risk of depression onset and progression with epilepsy, a few population-based studies have shown that the history of depression increases the likelihood of having seizure 3- to 6-fold, even after controlling for pharmacologic treatment for depression.256,257 This impacts outcome, as comorbid depression is one of several risk factors associated with increased suicide in patients with epilepsy, and has a mortality rate 10 times higher than that of the general population.254 Depression increases the experience of burden from seizures and affects all domains of quality of life even after controlling for seizure frequency, severity, and other psychosocial variables.254

Etiologic mechanisms of comorbidity. Seizure focus in temporal and frontal lobe epilepsy has been frequently associated with depression. Complex partial seizures (temporal lobe epilepsy) with auras of psychological symptoms (depersonalization, forced thinking, déjà vu, fear, depression, pleasure, illusions, hallucinations, and amnesias) are more commonly associated with MDD than are seizures without auras or with auras of motor and sensory symptoms258 suggesting that depression in epilepsy may result from disturbances in the limbic system. The findings of increased density of 5-HT2 receptors in mesiotemporal and prefrontal areas and decreased binding of 5-HT1A receptors in patients with epilepsy may also play a role in the development of depression in patients with epilepsy.259,260 In addition to biological factors, psychosocial factors such as poor adjustment to epilepsy, stigma, discrimination, loss of driving privileges, limited job opportunities because of seizure precautions, change of jobs, and lack of social and family support may also contribute to stress and depression in these vulnerable patients.254 Approximately 50% of epileptic patients with depression also have a family history of psychiatric disorder, indicating a shared vulnerability.261 Antiepileptic drugs (AEDs) that have adverse effects on mood and cognition may also contribute to depression comorbidity, and phenobarbitone, primidone, topiramate, tiagabine, and vigabatrin can all exert negative effects on mood. The potential depressogenic effect of these AEDs may be related to potentiation of the gamma-aminobutyric acid (GABA) system, folate deficiency, forced normalization, and polytherapy.262 Conversely, AEDs such as lamotrigine, carbamazepine, and valproate, which potentiate serotonin neurotransmission, have antidepressant properties.263

Several lines of evidence suggest that common pathogenic mechanisms are related to the comorbid association between epilepsy and depression. The diminished serotonergic and noradrenergic functions implicated in the pathogenesis of depression have also been shown to facilitate the kindling process of seizure foci,264 while other putative common pathogenic mechanisms include dysregulation in HPA axis, glutamate, and GABAergic system.265,266 Animal studies have shown that increased interleukin-1 beta (IL-1beta) signaling in the hippocampus associated with status epilepticus may lead to dysregulation in HPA axis and raphe-hippocampal serotonergic neurotransmission, causing depression,267 while the use of antidepressants with proconvulsant properties (bupropion, maprotiline, and amoxapine) may exacerbate seizure problems and should be used only after careful clinical consideration.268,269

The increased comorbidity of BD with epilepsy also may be related to underlying common neurobiological mechanisms between these 2 disorders.270 The kindling process has been implicated in both the recurrence of seizures and the episodic nature of BD, and changes in second messenger systems (G-protein, phosphatidylinositol, protein kinase C, myristoylated alanine-rich C kinase substrate, calcium activity) have been reported in both conditions. Alternatively, antikindling, calcium antagonism, and potassium outward current modulation have been suggested as the basis for antiepileptic and mood-stabilizing effects of AEDs.270,271

Evidence of treatment efficacy and safety.

  1. With respect to antidepressants, only 1 published randomized, placebo-controlled, double-blind study examined the efficacy and safety of antidepressants in this population. It showed that mianserin or amitriptyline can be used in patients with epilepsy272 (level 2).

  2. No controlled data are available to evaluate the safety and efficacy of first-line antidepressants (SSRIs, SNRIs) in depression associated with epilepsy. In 2 open, uncontrolled studies, citalopram was found to be effective in the treatment of interictal depression (level 3).273,274 In one of these 2 studies, citalopram was associated with reduction in seizure frequency.274 Some authors have recommended the use of escitalopram based on its low potential for P450 enzyme pharmacokinetic interactions with AEDs275 (level 4).

  3. Sertraline in the dose range of 50 to 200 mg and venlafaxine in the dose range of 75 to 225 mg have also been recommended by experts based on their clinical experience254 (level 4).

  4. In a secondary analysis of a randomized, double-blind, placebo-controlled study, lamotrigine treatment has been shown to improve depressive symptoms independent of seizure reduction in patients with generalized seizure.276 In an open-label, multicenter study involving epileptic patients age ≥50, lamotrigine add-on treatment for epilepsy showed efficacy in the reduction of depressive symptoms277 (level 3).

  5. The combination of TCAs and SSRIs has been suggested for resistant depression in patients with epilepsy278 (level 4).

  6. There are no published controlled data available on the efficacy of psychosocial interventions in the treatment of depression associated with epilepsy. Several psychosocial interventions, such as relaxation therapy, CBT, and biofeedback, and educational interventions have been used to reduce depression and seizure frequency and improve quality of life, but a Cochrane systematic review of these studies found no reliable evidence to support the use of these interventions.279 Two open, controlled trials, however, found CBT to be effective in reducing depression among patients with epilepsy280,281 (level 3).

Treatment recommendations. Current evidence supports adoption of the following recommendations:

  1. Because depression is more highly prevalent in patients with recurrent seizures than in seizure-free patients, the first step in the effective treatment of comorbid depression with epilepsy is to control the seizures with AEDs.

  2. Seizure-free patients also are at risk in special situations. Even after the postsurgical control of seizures, patients who underwent anterotemporal lobectomy were at greater risk of depression.282 The appearance of depression in patients with better seizure control with AEDs (forced normalization) has been reported.283

  3. Anticonvulsants with potential depressogenic properties or increased suicidal risks (GABAergic AEDS with no serotonin reuptake inhibition) such as phenobarbitone, primidone, tiagabine, vigabatrin, felbamate, and topiramate should be avoided, if possible. If the onset of depression is temporally related to the initiation or upward titration of dose of these AEDs, then lowering the dose or switching to anticonvulsants with mood-stabilizing properties such as lamotrigine, valproic acid, and carbamazepine has been recommended (level 4).254 If potential depressogenic AEDs produce the best seizure control, the depressive episodes triggered by these AEDs can be symptomatically treated with antidepressants.254

  4. Selection of antidepressants: SSRIs with minimal P450 enzyme pharmacokinetic interactions, including citalopram, escitalopram, and sertraline, that can be used safely in combination with AEDs are recommended as second-line treatment since these medications have only level 3 evidence.273,274,284 However in the absence of first-line treatment recommendations, these medications should be considered the preferred choice. Switching to venlafaxine (75 to 225 mg) can be tried as third-line treatment if SSRI treatment fails.254 The antidepressants with the strongest proconvulsive properties, such as bupropion, maprotiline, and amoxapine, should be avoided. TCAs and MAOI antidepressants are considered only in the treatment of resistant depression; otherwise, treatment with TCAs should be avoided because of drug interactions, which result in decreases in epileptic threshold. Polypharmacy of antidepressants, higher doses of antidepressants, and rapid titration should be avoided to prevent decreases in the seizure threshold.

  5. Lamotrigine as monotherapy or add-on treatment can be considered as second-line treatment for unipolar depression associated with epilepsy (level 3). Evidence for BD depression comorbid with epilepsy is not available.

  6. Other considerations for resistant depression include the following:

CBT in combination with SSRIs can be tried in patients who fail to improve with SSRI monotherapy.

Supplementation with folate can be considered, as folate deficiency associated with the use of AEDs may contribute to depression.262

ECT can be considered for resistant depression associated with epilepsy, as it has both anticonvulsive and antidepressant effects.285,286 Similarly, VNS can be considered to treat both resistant MDD and BD depression associated with controlled or intractable epilepsy.287,288

Osteoporosis

Osteoporosis is a chronic disease that affects approximately 26% of women age ≥65.289,290 A 50-year-old woman has approximately a 40% chance of sustaining an osteoporotic fracture291,292 and a 14-year-old girl has a 17% chance of sustaining a hip fracture at some point in her lifetime.293 One of the few illnesses with a greater disease burden than low bone-mineral density (BMD) is MDD; it has been projected that MDD will be the greatest cause of disability worldwide by 2020.294 This is not simply attributed to psychiatric morbidity, and in fact, MDD has been linked to a host of physical illnesses, mitigated to a large extent by side effects of pharmacotherapy.295 Recent evidence highlights the fact that impaired bone health may soon be joining this growing list.

Epidemiology of comorbidity. The possibility of an association between SSRI use and low BMD has sparked a recent rise in studies investigating the clinical implications of antidepressant treatment on bone health. A number of large population-based studies have found associations between depression and bone density, specifically mediated by SSRI use.296-299 Not all studies investigating the association between SSRI use and BMD have found that SSRI use is associated with reduced bone density, and 3 small studies have demonstrated no connection.300-302 Chronic use of mood stabilizers also may adversely affect bone density, although the relationship has not been fully elucidated. Bone homeostasis is a complicated and active process requiring parathyroid hormones, adequate serum calcium through intestinal absorption and renal reabsorption, and vitamin D. Putative mechanisms of bone loss include liver induction causing increased vitamin D breakdown, calcitonin deficiency, and effects on calcium absorption. Studies show decreased BMD with the use of benzodiazepines, carbamazepine, valproate, gabapentin, and oxcarbazepine.303,304 Lithium is less likely than some other medications to affect BMD in terms of bone turnover, but it causes increases in parathyroid hormone and affects renal calcium reabsorption, which leads to decreased mineral density.305

Etiologic mechanisms of comorbidity. A functional role for 5-HT in bone was first documented in 2001, when Bliziotes and colleagues demonstrated the presence of neurotransmitters, receptors, and transporters in osteoblasts and osteoclasts.306-308 This work provided evidence of the role of serotonin in bone metabolism and a mechanism through which SSRIs may influence bone health.306

Depression also has been linked to decreased BMD in some,300-302,309 but not all,310-312 studies. Several clinical studies examining BMD in depressed medication users and nonusers demonstrated that pharmacologic treatment may independently impact bone health, while physiologic and hormonal changes associated with depressive symptoms may magnify the adverse side effects of SSRIs.297-299,313,314 Therefore, it is possible that depression, in combination with pharmacotherapy, may have an additive negative effect on BMD.

Depression has been hypothesized to influence bone through inflammation, physical inactivity, falls, hypercortisolism, or hypogonadism. Another interesting and potentially modifiable link between bone and depression is vitamin D status. Decreased outdoor exposure associated with a mood disorder may result in lower vitamin D levels, but the few epidemiologic studies of vitamin D and depression have produced inconsistent results and generally have had substantial methodologic limitations. Recent findings from a randomized trial315 suggest that high doses of supplemental vitamin D may improve mild depressive symptoms, but important questions regarding its efficacy in more severe depression remain.316

Treatment recommendations. Current evidence supports adoption of the following recommendations:

  1. The vastly growing body of research on mood disorders and their effect on bone health suggests that this relationship is complex, and interpreting these findings has proved to be challenging. Patients age >40 with long-term SSRI exposure (>2 years) should be routinely screened for bone density via dual-energy X-ray absorptiometry (level 2).

  2. The data related to long-term use of some mood stabilizers are more definitive, however, and we know that exposure is directly related to decreased BMD. Patients receiving long-term exposure to these medications should be routinely screened for bone density (level 1).

  3. For adults age >50 who are at moderate risk of vitamin D deficiency, supplementation with 800 to 1000 IU (20 to 25 mcg) of vitamin D3 daily is recommended317 (level 2).

  CONCLUSIONS

Mood disorders are highly prevalent in patients with chronic medical conditions. Comorbid depression significantly increases disability, morbidity, and mortality in medically ill patients. This review summarizes the comorbid bidirectional relationship between mood disorders and several common medical conditions and provides evidence-based treatment recommendations. The most important message from the literature on treatment of depression in patients with comorbid medical conditions is that depression in medically ill patients is treatable. Failing to provide appropriate treatment to a medically ill patient with clinically diagnosed depression may adversely affect medical outcomes. Given the paucity of randomized controlled trials in this area, future studies are needed to examine the effect of treatment interventions on prevention and treatment of comorbid depression as well as medical outcomes.

DISCLOSURES: Dr. Ramasubbu receives grant/research support from AstraZeneca (investigator initiated grant). Dr. Taylor receives grant/research support from Bristol-Myers Squibb and Novartis, is a consultant to Bristol-Myers Squibb and Eli Lilly and Company, and is a speaker for Bristol-Myers Squibb, Eli Lilly and Company, Lundbeck, and Pfizer. Dr. Sockalingham is a speaker for Hoffman-Roche Canada. Dr. Schaffer receives grant/research support from Pfizer Canada and the Canadian Institutes of Health Research (CIHR); is a consultant to AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, and Lundbeck; and is a speaker for AstraZeneca, Bristol-Myers Squibb, and Eli Lilly and Company. Dr. Beaulieu receives grant/research support from AstraZeneca, Biovail, Bristol-Myers Squibb, the CIHR, Eli Lilly and Company, Fonds de recherche du Québec, Janssen-Ortho, Lundbeck, Merck-Frosst, Novartis, the National Alliance for Research on Schizophrenia and Depression, Pfizer Servier, Revue Santé mentale au Québec, and the Stanley Foundation; is a consultant to AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Janssen-Ortho, Lundbeck, Oryx, Schering-Plough Merck, Wyeth Pfizer; and is a speaker for AstraZeneca, Biovail, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Janssen-Ortho, Lundbeck, Organon, Oryx, and Wyeth Pfizer. Dr. McIntyre is on advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Janssen-Ortho, Lundbeck, Merck, Pfizer, and Shire; is on speakers bureaus for AstraZeneca, Eli Lilly and Company, Janssen-Ortho, Lundbeck, Merck, Otsuka, and Pfizer; is involved in CME activities with AstraZeneca, Bristol-Myers Squibb, CME Outfitters, Eli Lilly and Company, Lundbeck, Merck, Otsuka, Pfizer, and the Physicians’ Postgraduate Press; and receives research grants from AstraZeneca, Eli Lilly and Company, Forest, Janssen-Ortho, Lundbeck, Pfizer, Sepracor, and Shire. Drs. Samaan, Li, Patten, and Rodin report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

    REFERENCES

  1. Thombs BD, Bass EB, Ford DE, et al. Prevalence of depression in survivors of acute myocardial infarction. J Gen Intern Med. 2006;21:30–38.
  2. Rudisch B, Nemeroff CB. Epidemiology of comorbid coronary artery disease and depression. Biol Psychiatry. 2003;54:227–240.
  3. Rugulies R. Depression as a predictor for coronary heart disease. a review and meta-analysis.  Am J Prev Med. 2002;23:51–61.
  4. Nicholson A, Kuper H, Hemingway H. Depression as an aetiologic and prognostic factor in coronary heart disease: a meta-analysis of 6362 events among 146 538 participants in 54 observational studies. Eur Heart J. 2006;27:2763–2774.
  5. Laursen TM, Munk-Olsen T, Nordentoft M, et al. Increased mortality among patients admitted with major psychiatric disorders: a register-based study comparing mortality in unipolar depressive disorder, bipolar affective disorder, schizoaffective disorder, and schizophrenia. J Clin Psychiatry. 2007;68:899–907.
  6. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction; A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004;44:E1–E211.
  7. Anderson JL, Adams CD, Antman EM, et al; American College of Cardiology; American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction); American College of Emergency Physicians; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons; American Association of Cardiovascular and Pulmonary Rehabilitation; Society for Academic Emergency Medicine. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation. 2007;116:e148–e304.
  8. Gibbons RJ, Abrams J, Chatterjee K, et al; American College of Cardiology; American Heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina). ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina). J Am Coll Cardiol. 2003;41:159–168.
  9. Lichtman JH, Bigger JT Jr, Blumenthal JA, et al; American Heart Association Prevention Committee of the Council on Cardiovascular Nursing; American Heart Association Council on Clinical Cardiology; American Heart Association Council on Epidemiology and Prevention; American Heart Association Interdisciplinary Council on Quality of Care and Outcomes Research; American Psychiatric Association. Depression and coronary heart disease: recommendations for screening referral, and treatment: a science advisory from the American Heart Association Prevention Committee of the Council on Cardiovascular Nursing, Council on Clinical Cardiology, Council on Epidemiology and Prevention, and Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Psychiatric Association. Circulation. 2008;118:1768–1775.
  10. Frasure-Smith N, Lespérance F, Prince RH, et al. Randomised trial of home-based psychosocial nursing intervention for patients recovering from myocardial infarction. Lancet. 1997;350:473–479.
  11. Jones DA, West RR. Psychological rehabilitation after myocardial infarction: multicentre randomised controlled trial. BMJ. 1996;313:1517–1521.
  12. Saab PG, Bang H, Williams RB, et al. The impact of cognitive behavioral group training on event-free survival in patients with myocardial infarction: the ENRICHD experience. J Psychosom Res. 2009;67:45–56.
  13. Linden W, Stossel C, Maurice J. Psychosocial interventions for patients with coronary artery disease: a meta-analysis. Arch Intern Med. 1996;156:745–752.
  14. Dusseldorp E, van Elderen T, Maes S, et al. A meta-analysis of psychoeducational programs for coronary heart disease patients. Health Psychol. 1999;18:506–519.
  15. Linden W, Phillips MJ, Leclerc J. Psychological treatment of cardiac patients: a meta-analysis. Eur Heart J. 2007;28:2972–2984.
  16. Strik JJ, Honig A, Lousberg R, et al. 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. Psychosom Med. 2000;62:783–789.
  17. Glassman AH, O’Connor CM, Califf RM, et al; Sertraline Antidepressant Heart Attack Randomized Trial (SADHEART) Group. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA. 2002;288:701–709.
  18. Lespérance F, Frasure-Smith N, Koszycki D, et al; CREATE Investigators. Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. JAMA. 2007;297:367–379.
  19. Honig A, Kuyper AM, Schene AH, et al; MIND-IT investigators. Treatment of post-myocardial infarction depressive disorder: a randomized placebo-controlled trial with mirtazapine. Psychosom Med. 2007;69:606–613.
  20. Thombs BD, de Jonge P, Coyne JC, et al. Depression screening and patient outcomes in cardiovascular care: a systematic review. JAMA. 2008;300:2161–2171.
  21. Carney RM, Freedland KE, Miller GE, et al. Depression as a risk factor for cardiac mortality and morbidity: a review of potential mechanisms. J Psychosom Res. 2002;53:897–902.
  22. Thomas AJ, Kalaria RN, O’Brien JT. Depression and vascular disease: what is the relationship? J Affect Disord. 2004;79:81–95.
  23. Everson-Rose SA, Lewis TT. Psychosocial factors and cardiovascular diseases. Annu Rev Public Health. 2005;26:469–500.
  24. Laursen TM, Munk-Olsen T, Agerbo E, et al. Somatic hospital contacts, invasive cardiac procedures, and mortality from heart disease in patients with severe mental disorder. Arch Gen Psychiatry. 2009;66:713–720.
  25. Carney RM, Blumenthal JA, Stein PK, et al. Depression, heart rate variability, and acute myocardial infarction. Circulation. 2001;104:2024–2028.
  26. Taylor CB, Conrad A, Wilhelm FH, et al. Psychophysiological and cortisol responses to psychological stress in depressed and nondepressed older men and women with elevated cardiovascular disease risk. Psychosom Med. 2006;68:538–546.
  27. Pollock BG, Laghrissi-Thode F, Wagner WR. Evaluation of platelet activation in depressed patients with ischemic heart disease after paroxetine or nortriptyline treatment. J Clin Psychopharmacol. 2000;20:137–140.
  28. Serebruany VL, Glassman AH, Malinin AI, et al. Enhanced platelet/endothelial activation in depressed patients with acute coronary syndromes: evidence from recent clinical trials. Blood Coagul Fibrinolysis. 2003;14:563–567.
  29. Sherwood A, Hinderliter AL, Watkins LL, et al. Impaired endothelial function in coronary heart disease patients with depressive symptomatology. J Am Coll Cardiol. 2005;46:656–659.
  30. Lespérance F, Frasure-Smith N, Théroux P, et al. The association between major depression and levels of soluble intercellular adhesion molecule 1, interleukin-6, and C-reactive protein in patients with recent acute coronary syndromes. Am J Psychiatry. 2004;161:271–277.
  31. Empana JP, Sykes DH, Luc G, et al; PRIME Study Group. Contributions of depressive mood and circulating inflammatory markers to coronary heart disease in healthy European men: the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation. 2005;111:2299–2305.
  32. Robinson RG, Spalletta G. Poststroke depression: a review. Can J Psychiatry. 2010;55:341–349.
  33.  World Health Organization The global burden of disease: 2004 update. http://www.who.int/healthinfo/global_burden_disease/2004_report_update/en/index.html. Geneva Switzerland: World Health Organization; 2008. Accessed July 16, 2009.
  34. House A, Dennis M, Mogridge L, et al. Mood disorders in the year after first stroke. Br J Psychiatry. 1991;158:83–92.
  35. Robinson RG. Poststroke depression: prevalence diagnosis, treatment, and disease progression. Biol Psychiatry. 2003;54:376–387.
  36. Ramasubbu R. Relationship between depression and cerebrovascular disease: conceptual issues. J Affect Disord. 2000;57:1–11.
  37. Robinson RG. Post stroke mania: prevalence and clinical symptoms. In: Robinson RG. The clinical neuropsychiatry of stroke: cognitive behavioral, and emotional disorders following vascular brain injury.  Cambridge, United Kingdom: Cambridge University Press; 1998:303-312.
  38. Burvill PW, Johnson GA, Jamrozik KD, et al. Prevalence of depression after stroke: the Perth Community Stroke Study. Br J Psychiatry. 1995;166:320–327.
  39. Parikh RM, Robinson RG, Lipsey JR, et al. The impact of poststroke depression on recovery in activities of daily living over a 2-year follow-up. Arch Neurol. 1990;47:785–789.
  40. Robinson RG, Bolla-Wilson K, Kaplan E, et al. Depression influences intellectual impairment in stroke patients. Br J Psychiatry. 1986;148:541–547.
  41. Morris PL, Robinson RG, Samuels J. Depression introversion and mortality following stroke. Aust N Z J Psychiatry. 1993;27:443–449.
  42. Stenager EN, Madsen C, Stenager E, et al. Suicide in patients with stroke: epidemiological study. BMJ. 1998;316:1206.
  43. Ramasubbu R, Patten SB. Effect of depression on stroke morbidity and mortality. Can J Psychiatry. 2003;48:250–257.
  44. Larson SL, Owens PL, Ford D, et al. Depressive disorder, dysthymia, and risk of stroke: thirteen-year follow-up from the Baltimore epidemiologic catchment area study. Stroke. 2001;32:1979–1983.
  45. Whyte EM, Mulsant BH. Post stroke depression: epidemiology pathophysiology, and biological treatment. Biol Psychiatry. 2002;52:253–264.
  46. Ramasubbu R, Tobias R, Bech-Hansen NT. Extended evaluation of serotonin transporter gene functional polymorphisms in subjects with post-stroke depression. Can J Psychiatry. 2008;53:197–201.
  47. Kohen R, Cain KC, Mitchell PH, et al. Association of serotonin transporter gene polymorphisms with poststroke depression. Arch Gen Psychiatry. 2008;65:1296–1302.
  48. Spalletta G, Bossù P, Ciaramella A, et al. The etiology of poststroke depression: a review of the literature and a new hypothesis involving inflammatory cytokines. Mol Psychiatry. 2006;11:984–991.
  49. Robinson RG. Mechanisms of post stroke depression. In: Robinson RG. The clinical neuropsychiatry of stroke: cognitive behavioral, and emotional disorders following vascular brain injury.  Cambridge, United Kingdom: Cambridge University Press; 1998:254-281.
  50. Eastwood MR, Rifat SL, Nobbs H, et al. Mood disorder following cerebrovascular accident. Br J Psychiatry. 1989;154:195–200.
  51. Tenev VT, Robinson RG, Jorge RE. Is family history of depression a risk factor for poststroke depression? Meta-analysis. Am J Geriatr Psychiatry. 2009;17:276–280.
  52. Hackett ML, Anderson CS, House A, et al. Interventions for treating depression after stroke. Cochrane Database Syst Rev. 2008; CD003437.
  53. Chen Y, Guo JJ, Zhan S, et al. Treatment effects of antidepressants in patients with post-stroke depression: a meta-analysis. Ann Pharmacother. 2006;40:2115–2122.
  54. Anderson G, Vestergaard K, Lauritzen L. Effective treatment of post-stroke depression with the selective serotonin reuptake inhibitor citalopram. Stroke. 1994;25:1099–1104.
  55. Wiart L, Petit H, Joseph PA, et al. Fluoxetine in early poststroke depression: a double-blind placebo-controlled study. Stroke. 2000;31:1829–1832.
  56. Robinson RG, Schultz SK, Castillo C, et al. Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: a placebo-controlled, double-blind study. Am J Psychiatry. 2000;157:351–359.
  57. Fruehwald S, Gatterbauer E, Rehak P, et al. Early fluoxetine treatment of post-stroke depression--a three-month double-blind placebo-controlled study with an open-label long-term follow up. J Neurol. 2003;250:347–351.
  58. Murray V, von Arbin M, Bartfai A, et al. Double-blind comparison of sertraline and placebo in stroke patients with minor depression and less severe major depression. J Clin Psychiatry. 2005;66:708–716.
  59. Lipsey JR, Robinson RG, Pearlson GD, et al. Nortriptyline treatment of post-stroke depression: a double-blind study. Lancet. 1984;1:297–300.
  60. Grade C, Redford B, Chrostowski J, et al. Methylphenidate in early poststroke recovery: a double-blind, placebo-controlled study. Arch Phys Med Rehabil. 1998;79:1047–1050.
  61. Hackett ML, Anderson CS, House A, et al. Interventions for preventing depression after stroke. Cochrane Database Syst Rev. 2008;CD003689.
  62. Chen Y, Patel NC, Guo JJ, et al. Antidepressant prophylaxis for poststroke depression: a meta-analysis. Int Clin Psychopharmacol. 2007;22:159–166.
  63. Yi ZM, Liu F, Zhai SD. Fluoxetine for the prophylaxis of poststroke depression in patients with stroke: a meta-analysis. Int J Clin Pract. 2010;64:1310–1317.
  64. Robinson RG, Jorge RE, Moser DJ, et al. Escitalopram and problem-solving therapy for prevention of poststroke depression: a randomized controlled trial. JAMA. 2008;299:2391–2400.
  65. Fullerton AG, Agerholm M. Side-effects of nortriptyline treatment for poststroke depression. Lancet. 1984;323:519–520.
  66. Jiang B, Lu W, Song X-W, et al. The effect of post stroke depression interventions on the recovery of neurological function. Modern Rehabilitation. 2001;5:29–30.
  67. Rampello L, Alvano A, Chiechio S, et al. An evaluation of efficacy and safety of reboxetine in elderly patients affected by “retarded” post-stroke depression. A random, placebo-controlled study. Arch Gerontol Geriatr.  2005;40:275–285.
  68. Reding MJ, Orto LA, Winter SW, et al. Antidepressant therapy after stroke. A double-blind trial. Arch Neurol.  1986;43:763–765.
  69. DeVane CL, Markowitz JS. Avoiding psychotropic drug interactions in the cardiovascular patient. Bull Menninger Clin. 2000;64:49–59.
  70. Sacchetti E, Turrina C, Valsecchi P. Cerebrovascular accidents in elderly people treated with antipsychotic drugs: a systematic review. Drug Saf. 2010;33:273–288.
  71. Murray GB, Shea V, Conn DR. Electroconvulsive therapy for post-stroke depression. J Clin Psychiatry. 1987;47:258–260.
  72. Jorge RE, Robinson RG, Tateno A, et al. Repetitive transcranial magnetic stimulation as treatment of poststroke depression: a preliminary study. Biol Psychiatry. 2004;55:398–405.
  73. Lo C, Li M, Rodin G. The assessment and treatment of distress in cancer patients: overview and future directions. Minerva Psichiatr. 2008;49:129–143.
  74. Massie MJ. Prevalence of depression in patients with cancer. J Natl Cancer Inst Monogr. 2004:57-71.
  75. Brintzenhofe-Szoc KM, Levin TT, Li Y, et al. Mixed anxiety/depression symptoms in a large cancer cohort: prevalence by cancer type. Psychosomatics. 2009;50:383–391.
  76. Rodin G, Zimmermann C, Rydall A, et al. The desire for hastened death in patients with metastatic cancer. J Pain Symptom Manage. 2007;33:661–675.
  77. Pirl WF. Evidence report on the occurrence assessment, and treatment of depression in cancer patients. J Natl Cancer Inst Monogr. 2004;32:32–39.
  78. Lo C, Zimmermann C, Rydall A, et al. Longitudinal study of depressive symptoms in patients with metastatic gastrointestinal and lung cancer. J Clin Oncol. 2010;28:3084–3089.
  79. Benton T, Staab J, Evans DL. Medical comorbidity in depressive disorders. Ann Clin Psychiatry. 2007;19:289–303.
  80. Clarke DM, Currie KC. Depression anxiety and their relationship with chronic diseases: a review of the epidemiology, risk and treatment evidence. Med J Aust. 2009;190:S54–S60.
  81. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289:3095–3105.
  82. Grassi L, Indelli M, Marzola M, et al. Depressive symptoms and quality of life in home-care-assisted cancer patients. J Pain Symptom Manage. 1996;12:300–307.
  83. Chochinov HM, Wilson KG, Enns M, et al. Depression, hopelessness, and suicidal ideation. Psychosomatics. 1998;39:366–370.
  84. Colleoni M, Mandala M, Peruzzotti G, et al. Depression and degree of acceptance of adjuvant cytotoxic drugs. Lancet. 2000;356:1326–1327.
  85. Chen ML, Chang HK. Physical symptom profiles of depressed and nondepressed patients with cancer. Palliat Med. 2004;18:712–718.
  86. Prieto JM, Blanch J, Atala J, et al. Psychiatric morbidity and impact on hospital length of stay among hematologic cancer patients receiving stem-cell transplantation. J Clin Oncol. 2002;20:1907–1917.
  87. Pinquart M, Duberstein PR. Depression and cancer mortality: a meta-analysis. Psychol Med. 2010;40:1797–1810.
  88. Satin JR, Linden W, Phillips MJ. Depression as a predictor of disease progression and mortality in cancer patients: a meta-analysis. Cancer. 2009;115:5349–5361.
  89. Lloyd-Williams M, Shiels C, Taylor F, et al. Depression—an independent predictor of early death in patients with advanced cancer. J Affect Disord. 2009;113:127–132.
  90. Iosifescu DV. Treating depression in the medically ill. Psychiatr Clin North Am. 2007;30:77–90.
  91. Li M, Boquiren V, Lo C, et al. Depression and anxiety in supportive oncology. In: Davis MP, Feyer P, Ortner P, et al, eds. Supportive oncology. Philadelphia, PA: Saunders; 2011:528–538.
  92. Garssen B. Psychological factors and cancer development: evidence after 30 years of research. Clin Psychol Rev. 2004;24:315–338.
  93. Nausheen B, Carr NJ, Peveler RC, et al. Relationship between loneliness and proangiogenic cytokines in newly diagnosed tumors of colon and rectum. Psychosom Med. 2010;72:912–916.
  94. Miller AH, Ancoli-Israel S, Bower JE, et al. Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer. J Clin Oncol. 2008;26:971–982.
  95. Jacobsen PB, Donovan KA, Swaine AN, et al. Management of anxiety and depression in adult cancer patients: toward an evidence-based approach. In: Chang AE, Ganz PA, Kinsella TJ, et al, eds. Oncology: an evidence-based approach. New York, NY: Springer-Verlag; 2006:1552-1579.
  96. Williams S, Dale J. The effectiveness of treatment for depression/depressive symptoms in adults with cancer: a systematic review. Br J Cancer. 2006;94:372–390.
  97. Rodin G, Lloyd N, Katz M, et al. The treatment of depression in cancer patients: a systematic review. Support Care Cancer. 2007;15:123–136.
  98. Ng CG, Boks MP, Zainal NZ, et al. The prevalence and pharmacotherapy of depression in cancer patients. J Affect Disord. 2010;131:1–7.
  99. Jacobsen PB, Jim HS. Psychosocial interventions for anxiety and depression in adult cancer patients: achievements and challenges. CA Cancer J Clin. 2008;58:214–230.
  100. Sheard T, Maguire P. The effect of psychological interventions on anxiety and depression in cancer patients: results of two meta-analyses. Br J Cancer. 1999;80:1770–1780.
  101. Andrykowski MA, Manne SL. Are psychological interventions effective and accepted by cancer patients? I. Standards and levels of evidence. Ann Behav Med.  2006;32:93–97.
  102. Lepore SJ, Coyne JC. Psychological interventions for distress in cancer patients: a review of reviews. Ann Behav Med. 2006;32:85–92.
  103. Hiemke C, Hartter S. Pharmacokinetics of selective serotonin reuptake inhibitors. Pharmacol Ther. 2000;85:11–28.
  104. Morrow GR, Hickok JT, Roscoe JA, et al. Differential effects of paroxetine on fatigue and depression: a randomized, double-blind trial from the University of Rochester Cancer Center Community Clinical Oncology Program. J Clin Oncol. 2003;21:4635–4641.
  105. Musselman DL, Lawson DH, Gumnick JF, et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med. 2001;344:961–966.
  106. Roscoe JA, Morrow GR, Hickok JT, et al. Effect of paroxetine hydrochloride (Paxil) on fatigue and depression in breast cancer patients receiving chemotherapy. Breast Cancer Res Treat. 2005;89:243–249.
  107. Pezzella G, Moslinger-Gehmayr R, Contu A. Treatment of depression in patients with breast cancer: a comparison between paroxetine and amitriptyline. Breast Cancer Res Treat. 2001;70:1–10.
  108. Musselman DL, Somerset WI, Guo Y, et al. A double-blind, multicenter, parallel-group study of paroxetine, desipramine, or placebo in breast cancer patients (stages I, II, III, and IV) with major depression. J Clin Psychiatry. 2006;67:288–296.
  109. Navari RM, Brenner MC, Wilson MN. Treatment of depressive symptoms in patients with early stage breast cancer undergoing adjuvant therapy. Breast Cancer Res Treat. 2008;112:197–201.
  110. Razavi D, Allilaire JF, Smith M, et al. The effect of fluoxetine on anxiety and depression symptoms in cancer patients. Acta Psychiatr Scand. 1996;94:205–210.
  111. Holland JC, Romano SJ, Heiligenstein JH, et al. A controlled trial of fluoxetine and desipramine in depressed women with advanced cancer. Psychooncology. 1998;7:291–300.
  112. Fisch MJ, Loehrer PJ, Kristeller J, et al. Fluoxetine versus placebo in advanced cancer outpatients: a double-blinded trial of the Hoosier Oncology Group. J Clin Oncol. 2003;21:1937–1943.
  113. Lydiatt WM, Denman D, McNeilly DP, et al. A randomized, placebo-controlled trial of citalopram for the prevention of major depression during treatment for head and neck cancer. Arch Otolaryngol Head Neck Surg. 2008;134:528–535.
  114. Costa D, Mogos I, Toma T. Efficacy and safety of mianserin in the treatment of depression of women with cancer. Acta Psychiatr Scand. 1985; 320:85–92.
  115. van Heeringen K, Zivkov M. Pharmacological treatment of depression in cancer patients. A placebo-controlled study of mianserin. Br J Psychiatry.  1996;169:440–443.
  116. Tarrier N, Maguire P. Treatment of psychological distress following mastectomy: an initial report. Behav Res Ther. 1984;22:81–84.
  117. Ersoy MA, Noyan AM, Elbi H. An open-label long-term naturalistic study of mirtazapine treatment for depression in cancer patients. Clin Drug Investig. 2008;28:113–120.
  118. Kim SW, Shin IS, Kim JM, et al. Effectiveness of mirtazapine for nausea and insomnia in cancer patients with depression. Psychiatry Clin Neurosci. 2008;62:75–83.
  119. Moss EL, Simpson JS, Pelletier G, et al. An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners. Psychooncology. 2006;15:259–267.
  120. Holland JC, Morrow GR, Schmale A, et al. A randomized clinical trial of alprazolam versus progressive muscle relaxation in cancer patients with anxiety and depressive symptoms. J Clin Oncol. 1991;9:1004–1011.
  121. Wald TG, Kathol RG, Noyes R Jr, et al. Rapid relief of anxiety in cancer patients with both alprazolam and placebo. Psychosomatics. 1993;34:324–332.
  122. Bruera E, Roca E, Cedaro L, et al. Action of oral methylprednisolone in terminal cancer patients: a prospective randomized double-blind study. Cancer Treat Rep. 1985;69:751–754.
  123. Fernandez F, Adams F, Holmes VF, et al. Methylphenidate for depressive disorders in cancer patients. An alternative to standard antidepressants.  Psychosomatics. 1987;28:455–461.
  124. Homsi J, Nelson KA, Sarhill N, et al. A phase II study of methylphenidate for depression in advanced cancer. Am J Hosp Palliat Care. 2001;18:403–407.
  125. Macleod AD. Methylphenidate in terminal depression. J Pain Symptom Manage. 1998;16:193–198.
  126. Olin J, Masand P. Psychostimulants for depression in hospitalized cancer patients. Psychosomatics. 1996;37:57–62.
  127. Natenshon AL. Clinical evaluation of Ritalin. Dis Nerv Syst. 1956;17:392–396.
  128. Bruera E, Carraro S, Roca E, et al. Double-blind evaluation of the effects of mazindol on pain, depression, anxiety, appetite, and activity in terminal cancer patients. Cancer Treat Rep. 1986;70:295–298.
  129. Arakawa S. Relaxation to reduce nausea vomiting, and anxiety induced by chemotherapy in Japanese patients. Cancer Nurs. 1997;20:342–349.
  130. Bindemann S, Soukop M, Kaye SB. Randomised controlled study of relaxation training. Eur J Cancer. 1991;27:170–174.
  131. Edgar L, Rosberger Z, Collet JP. Lessons learned: Outcomes and methodology of a coping skills intervention trial comparing individual and group formats for patients with cancer. Int J Psychiatry Med. 2001;31:289–304.
  132. Fawzy FI, Kemeny ME, Fawzy NW, et al. A structured psychiatric intervention for cancer patients. II. Changes over time in immunological measures. Arch Gen Psychiatry.  1990;47:729–735.
  133. Petersen RW, Quinlivan JA. Preventing anxiety and depression in gynaecological cancer: a randomised controlled trial. BJOG. 2002;109:386–394.
  134. Ando M, Morita T, Akechi T, et al. The efficacy of mindfulness-based meditation therapy on anxiety, depression, and spirituality in Japanese patients with cancer. J Palliat Med. 2009;12:1091–1094.
  135. Burish TG, Carey MP, Krozely MG, et al. Conditioned side effects induced by cancer chemotherapy: prevention through behavioral treatment. J Consult Clin Psychol. 1987;55:42–48.
  136. Burish TG, Lyles JN. Effectiveness of relaxation training in reducing adverse reactions to cancer chemotherapy. J Behav Med. 1981;4:65–78.
  137. Jacobsen PB, Meade CD, Stein KD, et al. Efficacy and costs of two forms of stress management training for cancer patients undergoing chemotherapy. J Clin Oncol. 2002;20:2851–2862.
  138. Mantovani G, Astara G, Lampis B, et al. Evaluation by multidimensional instruments of health-related quality of life of elderly cancer patients undergoing three different “psychosocial” treatment approaches. A randomized clinical trial. Support Care Cancer.  1996;4:129–140.
  139. Decker TW, Cline-Elsen J, Gallagher M. Relaxation therapy as an adjunct in radiation oncology. J Clin Psychol. 1992;48:388–393.
  140. Evans RL, Connis RT. Comparison of brief group therapies for depressed cancer patients receiving radiation treatment. Public Health Rep. 1995;110:306–311.
  141. Pruitt BT, Waligora-Serafin B, McMahon T, et al. An educational intervention for newly-diagnosed cancer patients undergoing radiotherapy. Psychooncology. 1993;2:55–62.
  142. Simpson JS, Carlson LE, Trew ME. Effect of group therapy for breast cancer on healthcare utilization. Cancer Pract. 2001;9:19–26.
  143. Liossi C, White P. Efficacy of clinical hypnosis in the enhancement of quality of life of terminally ill cancer patients. Contemp Hypn. 2001;18:145–160.
  144. McQuellon RP, Wells M, Hoffman S, et al. Reducing distress in cancer patients with an orientation program. Psychooncology. 1998;7:207–217.
  145. McArdle JM, George WD, McArdle CS, et al. Psychological support for patients undergoing breast cancer surgery: a randomised study. BMJ (Clinical research ed). 1996;312:813–816.
  146. Rawl SM, Given BA, Given CW, et al. Intervention to improve psychological functioning for newly diagnosed patients with cancer. Oncol Nurs Forum. 2002;29:967–975.
  147. Watson M, Denton S, Baum M, et al. Counselling breast cancer patients: a specialist nurse service. Couns Psychol Quart. 1988;1:25–34.
  148. Kissane DW, Grabsch B, Clarke DM, et al. Supportive-expressive group therapy for women with metastatic breast cancer: survival and psychosocial outcome from a randomized controlled trial. Psychooncology. 2007;16:277–286.
  149. Edelman S, Bell DR, Kidman AD. A group cognitive behaviour therapy programme with metastatic breast cancer patients. Psychooncology. 1999;8:295–305.
  150. Goodwin PJ, Leszcz M, Ennis M, et al. The effect of group psychosocial support on survival in metastatic breast cancer. N Engl J Med. 2001;345:1719–1726.
  151. Pitceathly C, Maguire P, Fletcher I, et al. Can a brief psychological intervention prevent anxiety or depressive disorders in cancer patients? A randomised controlled trial. Ann Oncol. 2009;20:928–934.
  152. Marchioro G, Azzarello G, Checchin F, et al. The impact of a psychological intervention on quality of life in non-metastatic breast cancer. Eur J Cancer. 1996;32A:1612–1615.
  153. Savard J, Simard S, Giguere I, et al. Randomized clinical trial on cognitive therapy for depression in women with metastatic breast cancer: psychological and immunological effects. Palliat Support Care. 2006;4:219–237.
  154.  UNAIDS. UNAIDS report on the global AIDS epidemic. 2010. http://www.unaids.org/globalreport/global_report.htm. Accessed May 19, 2011.
  155. Brown GR, Rundell JR, McManis SE, et al. Prevalence of psychiatric disorders in early stages of HIV infection. Psychosom Med. 1992;54:588–601.
  156. Dew MA, Becker JT, Sanchez J, et al. Prevalence and predictors of depressive, anxiety and substance use disorders in HIV-infected and uninfected men: a longitudinal evaluation. Psychol Med. 1997;27:395–409.
  157. Avants SK, Margolin A, Warburton LA, et al. Predictors of nonadherence to HIV-related medication regimens during methadone stabilization. Am J Addict. 2001;10:69–78.
  158. Tucker JS, Burnam MA, Sherbourne CD, et al. Substance use and mental health correlates of nonadherence to antiretroviral medications in a sample of patients with human immunodeficiency virus infection. Am J Med. 2003;114:573–580.
  159. Ickovics JR, Hamburger ME, Vlahov D, et al. Mortality, CD4 cell count decline, and depressive symptoms among HIV-seropositive women: longitudinal analysis from the HIV Epidemiology Research Study. JAMA. 2001;285:1466–1474.
  160. Yun LW, Maravi M, Kobayashi JS, et al. Antidepressant treatment improves adherence to antiretroviral therapy among depressed HIV-infected patients. J Acquir Immune Defic Syndr. 2005;38:432–438.
  161. Ferrando SJ, Goldman JD, Charness WE. Selective serotonin reuptake inhibitor treatment of depression in symptomatic HIV infection and AIDS. Improvements in affective and somatic symptoms. Gen Hosp Psych.  1997;19:89–97.
  162. Markowitz JC, Kocsis JH, Fishman B, et al. Treatment of depressive symptoms in human immunodeficiency virus-positive patients. Arch Gen Psychiatry. 1998;55:452–457.
  163. Atkinson JH, Heaton RK, Patterson TL, et al. Two-year prospective study of major depressive disorder in HIV-infected men. J Affect Disord. 2008;108:225–234.
  164. Alciati A, Gallo L, Monforte AD, et al. Major depression-related immunological changes and combination antiretroviral therapy in HIV-seropositive patients. Hum Psychopharmacol. 2007;22:33–40.
  165. Evans DL, Ten Have TR, Douglas SD, et al. Association of depression with viral load, CD8 T lymphocytes, and natural killer cells in women with HIV infection. Am J Psychiatry. 2002;159:1752–1759.
  166. Lochet P, Peyriere H, Lotthe A, et al. Long-term assessment of neuropsychiatric adverse reactions associated with efavirenz. HIV Med. 2003;4:62–66.
  167. O’Mahony SM, Myint AM, Steinbusch H, et al. Efavirenz induces depressive-like behaviour, increased stress response and changes in the immune response in rats. Neuroimmunomodulation. 2005;12:293–298.
  168. Himelhoch S, Medoff DR. Efficacy of antidepressant medication among HIV-positive individuals with depression: a systematic review and meta-analysis. AIDS Patient Care STDS. 2005;19:813–822.
  169. Rabkin JG, Rabkin R, Harrison W, et al. Effect of imipramine on mood and enumerative measures of immune status in depressed patients with HIV illness. Am J Psychiatry. 1994;151:516–523.
  170. Fernandez F, Levy JK, Samley HR, et al. Effects of methylphenidate in HIV-related depression: a comparative trial with desipramine. Int J Psychiatry Med. 1995;25:53–67.
  171. Wagner GJ, Rabkin R. Effects of dextroamphetamine on depression and fatigue in men with HIV: a double-blind placebo-controlled trial. J Clin Psychiatry. 2000;61:436–440.
  172. Rabkin JG, McElhiney MC, Rabkin R, et al. Modafinil treatment for fatigue in HIV/AIDS: a randomized placebo-controlled study. J Clin Psychiatry. 2010;71:707–715.
  173. Elliott AJ, Uldall KK, Bergam K, et al. Randomized, placebo-controlled trial of paroxetine versus imipramine in depressed HIV-positive outpatients. Am J Psychiatry. 1998;155:367–372.
  174. Schwartz JA, McDaniel JS. Double-blind comparison of fluoxetine and desipramine in the treatment of depressed women with advanced HIV disease: a pilot study. Depress Anxiety. 1999;9:70–74.
  175. Currier MB, Molina G, Kato M. Citalopram treatment of major depressive disorder in Hispanic HIV and AIDS patients: a prospective study. Psychosomatics. 2004;45:210–216.
  176. Rabkin JG, Wagner G, Rabkin R. Effects of sertraline on mood and immune status in patients with major depression and HIV illness: an open trial. J Clin Psychiatry. 1994;55:433–439.
  177. Gutierrez MM, Rosenberg J, Abramowitz W. An evaluation of the potential for pharmacokinetic interaction between escitalopram and the cytochrome P450 3A4 inhibitor ritonavir. Clin Ther. 2003;25:1200–1210.
  178. Chesney MA, Chambers DB, Taylor JM, et al. Coping effectiveness training for men living with HIV: results from a randomized clinical trial testing a group-based intervention. Psychosom Med. 2003;65:1038–1046.
  179. Kelly JA, Murphy DA, Bahr GR, et al. Outcome of cognitive-behavioral and support group brief therapies for depressed, HIV-infected persons. Am J Psychiatry. 1993;150:1679–1686.
  180. Markowitz JC, Klerman GL, Clougherty KF, et al. Individual psychotherapies for depressed HIV-positive patients. Am J Psychiatry. 1995;152:1504–1509.
  181. Hepatitis C. global prevalence Wkly Epidemiol Rec. 1997;72:341–344.
  182. Sherman M, Shafran S, Burak K, et al. Management of chronic hepatitis C: consensus guidelines. Can J Gastroenterol. 2007;21(suppl C):25C–34C.
  183. Strader DB, Wright T, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C. Hepatology. 2004;39:1147–1171.
  184. el-Serag HB, Kunik M, Richardson P, et al. Psychiatric disorders among veterans with hepatitis C infection. Gastroenterology. 2002;123:476–482.
  185. Wichers MC, Koek GH, Robaeys G, et al. IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity. Mol Psychiatry. 2005;10:538–544.
  186. Capuron L, Pagnoni G, Demetrashvili M, et al. Anterior cingulate activation and error processing during interferon-alpha treatment. Biol Psychiatry. 2005;58:190–196.
  187. Wichers MC, Kenis G, Koek GH, et al. Interferon-alpha-induced depressive symptoms are related to changes in the cytokine network but not to cortisol. J Psychosom Res. 2007;62:207–214.
  188. Gleason OC, Yates WR, Isbell MD, et al. An open-label trial of citalopram for major depression in patients with hepatitis C. J Clin Psychiatry. 2002;63:194–198.
  189. Gleason OC, Yates WR, Philipsen MA. Major depressive disorder in hepatitis C: an open-label trial of escitalopram. Prim Care Companion J Clin Psychiatry. 2005;7:225–230.
  190. Morasco BJ, Rifai MA, Loftis JM, et al. A randomized trial of paroxetine to prevent interferon-alpha-induced depression in patients with hepatitis C. J Affect Disord. 2007;103:83–90.
  191. Raison CL, Woolwine BJ, Demetrashvili MF, et al. Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C. Aliment Pharmacol Ther. 2007;25:1163–1174.
  192. Kronenberger B, Berg T, Herrmann E, et al. Efficacy of amantadine on quality of life in patients with chronic hepatitis C treated with interferon-alpha and ribavirin: results from a randomized, placebo-controlled, double-blind trial. Eur J Gastroenterol Hepatol. 2007;19:639–646.
  193. Quarantini LC, Miranda-Scippa A, Schinoni MI, et al. Effect of amantadine on depressive symptoms in chronic hepatitis C patients treated with pegylated interferon: a randomized, controlled pilot study. Clin Neuropharmacol. 2006;29:138–143.
  194. Schramm TM, Lawford BR, Macdonald GA, et al. Sertraline treatment of interferon-alfa-induced depressive disorder. Med J Aust. 2000;173:359–361.
  195. Kalyoncu OA, Tan D, Mirsal H, et al. Major depressive disorder with psychotic features induced by interferon-alpha treatment for hepatitis C in a polydrug abuser. J Psychopharmacol. 2005;19:102–105.
  196. Levenson JL, Fallon HJ. Fluoxetine treatment of depression caused by interferon-alpha. Am J Gastroenterol. 1993;88:760–761.
  197. Goldman SL. Successful treatment of interferon-alfa-induced depression treated with nortriptyline (letter). Psychosomatics. 1994;35:412–413.
  198. Gleason OC, Yates WR. Five cases of interferon-alpha-induced depression treated with antidepressant therapy. Psychosomatics. 1999;40:510–512.
  199. Malek-Ahmadi P, Ghandour E. Bupropion for treatment of interferon-induced depression. Ann Pharmacother. 2004;38:1202–1205.
  200.  ICHD-II. The International Classification of Headache Disorders. 2nd ed. Cephalalgia. 2004;24:8–160.
  201. Merikangas KR, Stevens DE. Comorbidity of migraine and psychiatric disorders. Neurol Clin. 1997;15:115–123.
  202. Breslau N, Davis G, Schultz L, et al. Migraine and major depression: a longitudinal study. Headache. 1994;34:387–393.
  203. Breslau N. Psychiatric comorbidity in migraine. Cephalalgia. 1998;18(suppl 22):56–58.
  204. Breslau N, Lipton R, Stewart W, et al. Comorbidity of migraine and depression. Investigating potential etiology and prognosis. Neurology.  2003;60:1308–1312.
  205. Merikangas KR, Stevens DE, Angst J. Psychopathology and headache syndromes in the community. Headache. 1994;34:S17–S22.
  206. Merikangas KR, Angst J, Isler H. Migraine and psychopathology. Results of the Zurich cohort study of young adults. Arch Gen Psychiatry.  1990;47:849–853.
  207. Merikangas KR, Risch NJ, Merikangas JR, et al. Migraine and depression: association and familial transmission. J Psychiatr Res. 1988;22:119–129.
  208. Lipton R, Hamelsky S, Kolodner K, et al. Migraine, quality of life, and depression. Neurology. 2000;55:629–635.
  209. Breslau N, Davis GC. Migraine physical health and psychiatric disorder: a prospective epidemiologic study in young adults. J Psychiatr Res. 1993;27:211–221.
  210. Stewart WF, Shechter A, Liberman J. Physician consultation for headache pain and history of panic: results from a population-based study. Am J Med. 1992;92:35–40.
  211. Samaan Z, Farmer A, Craddock N, et al. Migraine in recurrent depression: case-control study. Br J Psychiatry. 2009;194:350–354.
  212. Breslau N, Schultz L, Stewart W, et al. Headache and major depression: is the association specific to migraine?  Neurology. 2000;54:308–313.
  213. Radat F, Swendsen J. Psychiatric comorbidity in migraine: a review. Cephalalgia. 2005;25:165–178.
  214. Ziegler DK, Hassanein RS, Kodanaz A, et al. Circadian rhythms of plasma cortisol in migraine. J Neurol Neurosurg Psychiatry. 1979;42:741–748.
  215. Merikangas KR, Stevens DE, Merikangas JR, et al. Tyramine conjugation deficit in migraine, tension-type headache, and depression. Biol Psychiatry. 1995;38:730–736.
  216. Jarman J, Davies P, Fernandez M, et al. Platelet [3H]imipramine binding in migraine and tension headache in relation to depression. J Psychiatr Res. 1991;25:205–211.
  217. D’Andrea G, Welch K, Riddle J, et al. Platelet serotonin metabolism and ultrastructure in migraine. Arch Neurol. 1989;46:1187–1189.
  218. Meltzer H, Lowy M. The serotonin hypothesis of depression. In: Meltzer H ed. Psychopharmacology: the third generation of progress. New York, NY: Raven Press; 1987:513-526.
  219. Buchsbaum MS, Coursey RD, Murphy DL. The biochemical high-risk paradigm: behavioural and familial correlates of low platelets monoamine oxidase activity. Science. 1976;194:339–341.
  220. Rubino E, Ferrero M, Rainero I, et al. Association of the C677T polymorphism in the MTHFR gene with migraine: a meta-analysis. Cephalalgia. 2009;29:818–825.
  221. Samaan Z, Farmer A. Migraine and depression: connecting the dots. Mind and Brain The Journal of Psychiatry. 2010;1:55–64.
  222. Lipton RB, Dodick D, Sadovsky R, et al. A self-administered screener for migraine in primary care: The ID Migraine validation study. Neurology. 2003;61:375–382.
  223. Samaan Z, MacGregor EA, Dowson A, et al. Diagnosing migraine in research and clinical settings: development and validation of the Structured Migraine Interview (SMI). BMC Neurol. 2010;10:7.
  224. Lampl C, Schweiger C. Antidepressants for migraine prophylaxis. European Neurological Journal. 2010;2:83–87.
  225. Olfoson M, Marcus SC, Druss B, et al. National trends in the outpatient treatment of depression. JAMA. 2002;287:203–209.
  226. Murray TJ. Diagnosis and treatment of multiple sclerosis. BMJ. 2006;332:525–527.
  227.  World Health Organization, Atlas of multiple sclerosis resources in the world 2008 Geneva Switzerland: World Health Organization; 2008.
  228. Goldman Consensus Group. The Goldman Consensus statement on depression in multiple sclerosis. Mult Scler. 2005;11:328–337.
  229. Patten SB, Beck CA, Williams JV, et al. Major depression in multiple sclerosis: a population-based perspective. Neurology. 2003;61:1524–1527.
  230. Minden SL, Orav J, Reich P. Depression in multiple sclerosis. Gen Hosp Psychiatry. 1987;9:426–434.
  231. Sadovnick AD, Remick RA, Allen J, et al. Depression and multiple sclerosis. Neurology. 1996;46:628–632.
  232. Joffe RT, Lippert GP, Gray TA, et al. Mood disorder and multiple sclerosis. Arch Neurol. 1987;44:376–378.
  233. Sadovnick AD, Eisen K, Ebers GC, et al. Cause of death in patients attending multiple sclerosis clinics. Neurology. 1991;41:1193–1196.
  234. Bronnum-Hansen H, Stenager E, Nylev Stenager E, et al. Suicide among Danes with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2005;76:1457–1459.
  235. Koch-Henriksen N, Bronnum-Hansen H, Stenager E. Underlying cause of death in Danish patients with multiple sclerosis: results from the Danish Multiple Sclerosis Registry. J Neurol Neurosurg Psychiatry. 1998;65:56–59.
  236. Stenager EN, Stenager E, Koch-Henriksen N, et al. Suicide and multiple sclerosis: an epidemiological investigation. J Neurol Neurosurg Psychiatry. 1992;55:542–545.
  237. Feinstein A, Roy P, Lobaugh N, et al. Structural brain abnormalities in multiple sclerosis patients with major depression. Neurology. 2004;62:586–590.
  238. Mohr DC, Goodkin DE, Likosky W, et al. Treatment of depression improves adherence to interferon beta-1b therapy for multiple sclerosis. Arch Neurol. 1997;54:531–533.
  239. Mohr DC, Goodkin DE, Islar J, et al. Treatment of depression is associated with suppression of nonspecific and antigen-specific T(H)1 responses in multiple sclerosis. Arch Neurol. 2001;58:1081–1086.
  240. Feinstein A, Feinstein K, Gray T, et al. Prevalence and neurobehavioral correlates of pathological laughing and crying in multiple sclerosis. Arch Neurol. 1997;54:1116–1121.
  241. Patten S. Diagnosing depression in MS in the face of overlapping symptoms. Int MS J. 2010;17:3–5.
  242. Barak Y, Ur E, Achiron A. Moclobemide treatment in multiple sclerosis patients with comorbid depression: an open-label safety trial. J Neuropsychiatry Clin Neurosci. 1999;11:271–273.
  243. Benedetti F, Campori E, Colombo C, et al. Fluvoxamine treatment of major depression associated with multiple sclerosis. J Neuropsychiatry Clin Neurosci. 2004;16:364–366.
  244. Scott TF, Nussbaum P, McConnell H, et al. Measurement of treatment response to sertraline in depressed multiple sclerosis patients using the Carroll scale. Neurol Res. 1995;17:421–422.
  245. Ehde DM, Kraft GH, Chwastiak L, et al. Efficacy of paroxetine in treating major depressive disorder in persons with multiple sclerosis. Gen Hosp Psychiatry. 2008;30:40–48.
  246. Schiffer RB, Wineman NM. Antidepressant pharmacotherapy of depression associated with multiple sclerosis. Am J Psychiatry. 1990;147:1493–1497.
  247. Mohr DC, Boudewyn AC, Goodkin DE, et al. Comparative outcomes for individual cognitive-behavior therapy, supportive-expressive group psychotherapy, and sertraline for the treatment of depression in multiple sclerosis. J Consult Clin Psychol. 2001;69:942–949.
  248. Patten SB. Antidepressant treatment for major depression in multiple sclerosis: the evolving efficacy literature. International Journal of MS Care. 2009;11:174–179.
  249. Mohr DC, Goodkin DE. Treatment of depression in multiple sclerosis: review and meta-analysis. Clinical Psychology: Science and Practice. 1999;6:1–9.
  250. Schiffer RB, Wineman NM, Weitkamp LR. Association between bipolar affective disorder and multiple sclerosis. Am J Psychiatry. 1986;143:94–95.
  251. Fisher RS, van Emde Boas W, Blume W, et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia. 2005;46:470–472.
  252. Sander JW. The epidemiology of epilepsy revisited. Curr Opin Neurol. 2003;16:165–170.
  253. Mula M, Schmitz B, Jauch R, et al. On the prevalence of bipolar disorder in epilepsy. Epilepsy Behav. 2008;13:658–661.
  254. Kanner AM. Depression in epilepsy: prevalence clinical semiology, pathogenic mechanisms, and treatment. Biol Psychiatry. 2003;54:388–398.
  255. Mendez MF, Doss RC, Taylor JL, et al. Depression in epilepsy. Relationship to seizures and anticonvulsant therapy. J Nerv Ment Dis.  1993;181:444–447.
  256. Hesdorffer DC, Hauser WA, Annegers JF, et al. Major depression is a risk factor for seizures in older adults. Ann Neurol. 2000;47:246–249.
  257. Forsgren L, Nyström L. An incident case-referent study of epileptic seizures in adults. Epilepsy Res. 1990;6:66–81.
  258. Mendez MF, Engebrit B, Doss R, et al. The relationship of epileptic auras and psychological attributes. J Neuropsychiatry Clin Neurosci. 1996;8:287–292.
  259. Gilliam FG, Santos J, Vahle V, et al. Depression in epilepsy: ignoring clinical expression of neuronal network dysfunction?  Epilepsia. 2004;45(suppl 2):28–33.
  260. Kanner AM. Depression in epilepsy: a complex relation with unexpected consequences. Curr Opin Neurol. 2008;21:190–194.
  261. Robertson MM, Trimble MR. Depressive illness in patients with epilepsy: a review. Epilepsia. 1983;24(suppl 2):S109–S116.
  262. Mula M, Sander JW. Negative effects of antiepileptic drugs on mood in patients with epilepsy. Drug Saf. 2007;30:555–567.
  263. Kalinin VV. Suicidality and antiepileptic drugs: is there a link?  Drug Saf. 2007;30:123–142.
  264. Jobe PC, Mishra PK, Adams-Curtis LE, et al. The genetically epilepsy-prone rat (GEPR). Ital J Neurol Sci. 1995;16:91–99.
  265. Kanner AM. Depression and epilepsy: do glucocorticoids and glutamate explain their relationship?  Curr Neurol Neurosci Rep. 2009;9:307–312.
  266. Kanner AM. Mood disorder and epilepsy: a neurobiologic perspective of their relationship. Dialogues Clin Neurosci. 2008;10:39–45.
  267. Pineda E, Shin D, Sankar R, et al. Comorbidity between epilepsy and depression: experimental evidence for the involvement of serotonergic, glucocorticoid, and neuroinflammatory mechanisms. Epilepsia. 2010;51(suppl 3):110–114.
  268. Pisani F, Spina E, Oteri G. Antidepressant drugs and seizure susceptibility: from in vitro data to clinical practice. Epilepsia. 1999;40(suppl 10):S48–S56.
  269. Ruffmann C, Bogliun G, Beghi E. Epileptogenic drugs: a systematic review. Expert Rev Neurother. 2006;6:575–589.
  270. Mula M. The clinical spectrum of bipolar symptoms in epilepsy: a critical reappraisal. Postgrad Med. 2010;122:17–23.
  271. Mazza M, Di Nicola M, Della Marca G, et al. Bipolar disorder and epilepsy: a bidirectional relation? Neurobiological underpinnings, current hypotheses, and future research directions. Neuroscientist. 2007;13:392–404.
  272. Robertson MM, Trimble MR. The treatment of depression in patients with epilepsy. A double-blind trial. J Affect Disord.  1985;9:127–136.
  273. Hovorka J, Herman E, Nemcová II. Treatment of interictal depression with citalopram in patients with epilepsy. Epilepsy Behav. 2000;1:444–447.
  274. Specchio LM, Iudice A, Specchio N, et al. Citalopram as treatment of depression in patients with epilepsy. Clin Neuropharmacol. 2004;27:133–136.
  275. DeVane CL. Metabolism and pharmacokinetics of selective serotonin reuptake inhibitors. Cell Mol Neurobiol. 1999;19:443–466.
  276. Ettinger AB, Kustra RP, Hammer AE. Effect of lamotrigine on depressive symptoms in adult patients with epilepsy. Epilepsy Behav. 2007;10:148–154.
  277. Fakhoury TA, Miller JM, Hammer AE, et al. Effects of lamotrigine on mood in older adults with epilepsy and comorbid depressive symptoms: an open-label, multicentre, prospective study. Drugs Aging. 2008;25:955–962.
  278. Blumer D, Montouris G, Hermann B. Psychiatric morbidity in seizure patients on a neurodiagnostic monitoring unit. J Neuropsychiatry Clin Neurosci. 1995;7:445–456.
  279. Ramaratnam S, Baker GA, Goldstein LH. Psychological treatments for epilepsy. Cochrane Database Syst Rev. 2008;(3):CD002029.
  280. Davis GR, Armstrong HE Jr, Donovan DM, et al. Cognitive-behavioral treatment of depressed affect among epileptics: preliminary findings. J Clin Psychol. 1984;40:930–935.
  281. Martinovic Z, Simonovic P, Djokic R. Preventing depression in adolescents with epilepsy. Epilepsy Behav. 2006;9:619–624.
  282. Savard G, Andermann LF, Reutens D, et al. Epilepsy, surgical treatment and postoperative psychiatric complications: a re-evaluation of the evidence. In: Trimble MR, Schmidt B, eds. Forced normalization and alternative psychosis of epilepsy. Petersfield, United Kingdom: Wrightson Biomedical; 1998:179-192.
  283. Robertson MM. Forced normalization and the aetiology of depression in epilepsy. In: Trimble MR Schmidt B, eds. Forced normalization and alternative psychosis of epilepsy. Petersfield, United Kingdom: Wrightson Biomedical; 1998:143-167.
  284. Kanner AM, Kozak AM, Frey M. The use of sertraline in patients with epilepsy: is it safe?  Epilepsy Behav. 2000;1:100–105.
  285. Sackeim HA. The anticonvulsant hypothesis of the mechanisms of action of ECT: current status. J ECT. 1999;15:5–26.
  286. Coffey CE, Lucke J, Weiner RD, et al. Seizure threshold in electroconvulsive therapy (ECT) II. The anticonvulsant effect of ECT. Biol Psychiatry.  1995;37:777–788.
  287. randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. The Vagus Nerve Stimulation Study Group. Neurology. 1995;45:224–230.
  288. George MS, Rush AJ, Marangell LB, et al. A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biol Psychiatry. 2005;58:364–373.
  289. Sawka AM, Thabane L, Papaioannou A, et al. The number of Canadian men and women needed to be screened to detect a case of osteoporosis: a population based study from the Canadian Multicentre Osteoporosis Study (CaMos). J Bone Miner Res. 2004;19:S368.
  290. Looker AC, Melton LJ 3rd, Harris TB, et al. Prevalence and trends in low femur bone density among older US adults: NHANES 2005-2006 compared with NHANES III. J Bone Miner Res. 2010;25:64–71.
  291. Doherty DA, Sanders KM, Kotowicz MA, et al. Lifetime and five-year age-specific risks of first and subsequent osteoporotic fractures in postmenopausal women. Osteoporos Int. 2001;12:16–23.
  292. Cummings SR, Black DM, Rubin SM. Lifetime risks of hip Colles’, or vertebral fracture and coronary heart disease among white postmenopausal women. Arch Intern Med. 1989;149:2445–2448.
  293. Melton LJ 3rd, Chrischilles EA, Cooper C, et al. Perspective. How many women have osteoporosis? J Bone Miner Res. 1992;7:1005–1010.
  294.  World Health Organization. The world health report 2001: mental health: new understanding new hope. Geneva, Switzerland: World Health Organization; 2001.
  295. Taylor V, McKinnon MC, Macdonald K, et al. Adults with mood disorders have an increased risk profile for cardiovascular disease within the first two years of treatment. Can J Psychiatry. 2010;55:362–368.
  296. Ziere G, Dieleman JP, van der Cammen TJ, et al. Selective serotonin reuptake inhibiting antidepressants are associated with an increased risk of nonvertebral fractures. J Clin Psychopharmacol. 2008;28:411–417.
  297. Diem SJ, Blackwell TL, Stone KL, et al. Use of antidepressants and rates of hip bone loss in older women: the study of osteoporotic fractures. Arch Intern Med. 2007;167:1240–1245.
  298. Richards JB, Papaioannou A, Adachi JD, et al. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med. 2007;167:188–194.
  299. Cauley JA, Fullman RL, Stone KL, et al. Factors associated with the lumbar spine and proximal femur bone mineral density in older men. Osteoporos Int. 2005;16:1525–1537.
  300. Michelson D, Stratakis C, Hill L, et al. Bone mineral density in women with depression. N Eng J Med. 1996;335:1176–1181.
  301. Eskandari F, Martinez PE, Torvik S, et al. Low bone mass in premenopausal women with depression. Arch Intern Med. 2007;167:2329–2336.
  302. Petronijevic M, Petronijevic N, Ivkovic M, et al. Low bone mineral density and high bone metabolism turnover in premenopausal women with unipolar depression. Bone. 2008;42:582–590.
  303. Kinjo M, Setoguchi S, Schneeweiss S, et al. Bone mineral density in subjects using central nervous system-active medications. Am J Med. 2005;118:1414.
  304. Bolton JM, Targownik LE, Leung S, et al. Risk of low bone mineral density associated with psychotropic medications and mental disorders in postmenopausal women. J Clin Psychopharmacol. 2011;31:56–60.
  305. Plenge P, Rafaelsen OJ. Lithium effects on calcium magnesium and phosphate in man: effects on balance, bone mineral content, faecal and urinary excretion. Acta Psychiatr Scand. 1982;66:361–373.
  306. Bliziotes MM, Eshleman AJ, Zhang XW, et al. Neurotransmitter action in osteoblasts: expression of a functional system for serotonin receptor activation and reuptake. Bone. 2001;29:477–486.
  307. Battaglino R, Fu J, Spate U, et al. Serotonin regulates osteoclast differentiation through its transporter. J Bone Miner Res. 2004;19:1420–1431.
  308. Warden SJ, Bliziotes MM, Wiren KM, et al. Neural regulation of bone and the skeletal effects of serotonin (5-hydroxytryptamine). Mol Cell Endocrinol. 2005;242:1–9.
  309. Cizza G, Ravn P, Chrousos GP, et al. Depression: a major, unrecognized risk factor for osteoporosis?  Trends Endocrinol Metab. 2001;12:198–203.
  310. Spangler L, Scholes D, Brunner RL, et al. Depressive symptoms, bone loss, and fractures in postmenopausal women. J Gen Intern Med. 2008;23:567–574.
  311. Reginster JY, Deroisy R, Paul I, et al. Depressive vulnerability is not an independent risk factor for osteoporosis in postmenopausal women. Maturitas. 1999;33:133–137.
  312. Whitson HE, Sanders L, Pieper CF, et al. Depressive symptomatology and fracture risk in community-dwelling older men and women. Aging Clin Exp Res. 2008;20:585–592.
  313. Liu B, Anderson G, Mittmann N, et al. Use of selective serotonin reuptake inhibitors or tricyclic antidepressants and risk of hip fractures in elderly people. Lancet. 1998;351:1303–1307.
  314. Haney EM, Chan BK, Diem SJ, et al. Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men. Arch Intern Med. 2007; 67:1246–1251.
  315. Jorde R, Sneve M, Figenschau Y, et al. Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. J Intern Med. 2008;264:599–609.
  316. Howland RH. Vitamin D and depression. J Psychosoc Nurs Ment Health Serv. 2011;49:15–18.
  317. Papaioannou A, Morin S, Cheung AM, et al. 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. CMAJ. 2010;182:1864–1873.

CORRESPONDENCE: Rajamannar Ramasubbu, MD, FRCPC, MSc, Associate Professor, Department of Psychiatry and Clinical Neurosciences, University of Calgary Mental Health Centre for Research and Education, TRW Building, Room #4D64, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6 Canada E-MAIL: rramasub@ucalgary.ca