Introduction
Many patients with chronic coronary heart disease (CHD) have clinically significant depression: a costly, disease-accelerating comorbidity that is associated with compromised health-related quality of life and reduced quality-adjusted life years (QALYs). Depression is also associated with an increased risk of recurrent acute coronary syndrome (ACS) events, doubled all-cause mortality, and larger healthcare costs. Many of these patients also have clinically significant anxiety and stress. Given these observational data, many advisory and professional societies have suggested screening patients with CHD for negative emotions and providing comprehensive treatment if clinical levels of distress are detected.
The overarching goal of this chapter is to provide cardiologists with the state-of-the-art evidence for the aforementioned assertions and provide practical advice on screening, counseling, and treating depression, anxiety, and stress in patients with CHD. We begin by providing an overview of the professional guidelines and advisories on this topic. We then discuss the evidence on the epidemiology, screening, and treatment of these negative emotions in CHD patients. We end by providing some context for the current debates among scientists, practitioners, and professional organizations on the usefulness of managing negative emotions in CHD patients.
Few cardiologists and other healthcare providers have implemented the recommendations to screen all patients with CHD for depression, anxiety, and stress, and treat these conditions if they are found. The top barriers in the implementation of these recommendations include lack of time to assess and manage depression, insufficient depression education networks, and lack of evidence from randomized controlled trials (RCTs) to support these recommendations. Yet, mandatory universal screening of depression in patients with CHD (or any patient) is recommended. As of 2014, the National Quality Forum introduced universal depression screening as a quality metric for all patients with a health encounter ; successful depression management at 6 and 12 months are quality metrics that will take effect in the near future. Thus, in the United States, patients with CHD will soon require screening for depression, and, if they are found to have clinically impairing depression, they will need to be followed up. With these changes looming in the United States and many other parts of the world, we provide an overview of the science, tools, and controversies on this topic.
Professional Society Guidelines/Advisories/Statements
Depression
The strength of observational findings linking depression to CHD outcomes has led many professional societies to advise routine depression screening for CHD patients and referral for treatment if indicated. However, it is important to note that there are no RCTs on this subject to inform these recommendations. Furthermore, although RCTs have shown that treatment can improve depression in some instances, it has not been clearly shown to lead to improved CHD outcomes.
American Heart Association
In 2008, the American Heart Association (AHA) issued a science advisory endorsed by the American Psychiatric Association (APA) that recommended administering a depression screening questionnaire to ACS patients and referring those who screen positive to a professional qualified to diagnose and manage depression according to the algorithm in Fig. 26.1 . Boxes 26.1 and 26.2 detail the recommended screening questionnaires. The United States Preventative Services Task Force (USPSTF) and AHA/APA guidelines recommend the Patient Health Questionnaire-2 (PHQ-2) yes/no version as the initial screen, as it has been validated as more sensitive and easier to administer than the PHQ-2 multiple choice screening questionnaire. This advisory effectively expanded the scope of the previous year’s release of evidence-based guidelines for cardiovascular disease prevention in women, which suggested that screening women at risk of CHD for depression and referring/treating when indicated was a class IIa (weight of evidence/opinion is in favor of usefulness/efficacy), level B (limited evidence from single randomized trial or other randomized studies) recommendation. The 2008 AHA advisory did specifically note that, at the time of its issuance, there was no direct evidence linking the treatment of depression with improved cardiac outcomes.
Over the past 2 weeks, how often have you been bothered by any of the following problems?
- 1.
Little interest or pleasure in doing things.
- 2.
Feeling down, depressed, or hopeless.
- 3.
Trouble falling asleep, staying asleep, or sleeping too much.
- 4.
Feeling tired or having little energy.
- 5.
Poor appetite or overeating.
- 6.
Feeling bad about yourself, feeling that you are a failure, or feeling that you have let yourself or your family down.
- 7.
Trouble concentrating on things such as reading the newspaper or watching television.
- 8.
Moving or speaking so slowly that other people could have noticed. Or being so fidgety or restless that you have been moving around a lot more than usual.
- 9.
Thinking that you would be better off dead or that you want to hurt yourself in some way.
During the past month, have you often been bothered by:
- 1.
Feeling down, depressed, or hopeless? (yes/no)
- 2.
Little interest or pleasure in doing things? (yes/no)
The AHA/American College of Cardiology (ACC) released secondary prevention guidelines for CHD patients in 2011 that provide a class IIa, level B recommendation that patients with recent myocardial infarction (MI) or coronary artery bypass graft (CABG) be screened for depression. These guidelines acknowledged that treating depression has not been shown to improve CHD outcomes but issued a class IIb, level C recommendation for treating depression with the logic that it may have clinical benefits other than improved CHD outcomes.
In 2014, the AHA issued a scientific statement formally recognizing depression as a risk factor for poor post-ACS outcomes, including all-cause mortality, cardiac mortality, and composite endpoints (cardiac or all-cause mortality and nonfatal cardiac events). This conclusion was based on a systematic review that identified prospective studies showing a strong and consistent observational association between depression and CHD outcomes, a lack of other explanations for this association, and the existence of a plausible biologic mechanism to account for this association.
American Academy of Family Practitioners
In 2009, the American Academy of Family Practitioners (AAFP) published guidelines for the detection and management of post-MI depression. It issued four specific guidelines based on review of published evidence. First, it recommended using any standardized symptom checklist to screen post-MI patients for depression during the index hospitalization and at regular intervals thereafter. Second, it recommended treating post-MI depression in order to improve symptoms. These recommendations were issued as level A with the specific note that they were based on RCTs showing improvement in depression outcomes but not cardiac outcomes, “though the evidence does not yet exclude the possibility of a small benefit.” The third and fourth recommendations suggested selective serotonin reuptake inhibitors (SSRIs) (level A) and/or psychotherapy (level B) for treating depression.
European Societies
The European Guidelines on Cardiovascular Disease Prevention in Clinical Practice are issued by a task force of the European Society of Cardiology and other societies. In 2012, the guidelines stated that depression contributes to both incident CHD and poor CHD outcomes. The guidelines made class IIa, level B recommendations that depression be assessed by a clinical interview or standardized questionnaire, and that tailored clinical management for depression be considered with the goal of improving CHD outcomes and enhancing quality of life.
The British healthcare system, via the National Institute of Health and Care Excellence (NICE), endorses depression screening in CHD patients and referral for treatment if depression is detected.
Anxiety
European Societies
The 2012 European prevention guidelines also state that anxiety contributes to both incident CHD and poor CHD outcomes. The guidelines included anxiety in the class IIa, level B recommendations, suggesting that anxiety be screened for via clinical interview or standardized questionnaire and tailored clinical management should be given, with the goal of improving CHD outcomes and enhancing quality of life.
Stress
European Societies
The 2012 guidelines also state that stress at work and in family life increases the risk of both incident CHD and poor CHD outcomes. The guidelines provide a class IIa, level B recommendation to screen and provide tailored clinical management for stress, with the goal of improving CHD outcomes and enhancing quality of life.
Both stress and anxiety have not been the focus of guidelines or consensus statements; however, interest in this topic seems to be increasing.
Epidemiology
Depression
Depression is the leading cause of “years of life lived with disability” worldwide and significantly compromises quality of life and life expectancy when it coexists with a chronic medical disorder. This is particularly true for CHD, as depression has been associated with an increased risk of developing CHD and worse outcomes among CHD patients. Large epidemiologic studies have convincingly demonstrated that depression is a predictor for occurrence and recurrence of CHD. Depressive symptoms alone also predict CHD risk, but stronger effect sizes have been observed for major depressive disorder (MDD) compared with depressive mood, suggesting a dose-response relationship.
Depression and Incident Coronary Heart Disease
In many studies with varied cohorts, depressive symptoms were associated with an increased risk of developing CHD. Depressive symptoms confer a relative risk of CHD ranging from 0.98 to 3.5 in different studies and a combined overall risk ranging from 1.6 to 5.4 compared with nondepressed patients in systematic reviews. MDD is associated with an even greater risk of incident MI with an odds ratio of approximately 4.5. The risk associated with depressive symptoms or clinical depression is perhaps even greater than that associated with traditional cardiovascular risk factors, as seen in Fig. 26.2 .
Depression among Patients with Coronary Heart Disease
Depression is one of the more frequently encountered chronic diseases among general medical patients, with a prevalence ranging from approximately 5% to 15%. Depression is even more prevalent among CHD patients ( Fig. 26.3 ). As many as 20% of CHD patients meet the diagnostic criteria for MDD by The Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria and 30% to 50% have significant patient-reported depressive symptoms. The increased prevalence of depression extends past the immediate post-MI period. Importantly, both clinically diagnosed depression and depressive symptoms predict increased cardiac risk. Approximately 7 million Americans living with CHD also have clinically significant depression, and half a million new such cases are added to this public health burden annually.
Prognosis Associated with Depression in Patients with Coronary Heart Disease
Compared with nondepressed post-MI patients, depressed post-MI patients have more medical comorbidities and cardiac complications and higher mortality rates. Observational studies show that ACS patients with depressive symptoms are at a two-fold higher risk of MI recurrence. As seen in Fig. 26.4 , depressive symptoms in CHD patients are at par with conventional CHD prognostic factors for predicting death and CHD recurrence.
The AHA formally recognizes depression as a risk factor for poor outcomes among ACS patients based on its systematic literature review showing depression is a risk factor for all-cause mortality, cardiac mortality, and composite endpoints (cardiac or all-cause mortality and nonfatal cardiac events) after ACS. Others have argued, however, that depression may be a risk marker rather than a risk factor because there is no trial evidence that treating depression alters the prognosis, making it more analogous to high-density lipoprotein or C-reactive protein (CRP).
Impact of Depression on Health-Related Quality of Life
Depression is more strongly associated with health-related quality of life and health status than a single health condition such as angina, arthritis, asthma, or diabetes. Depression clearly predicts impoverished health-related quality of life independent of traditional predictors of quality of life, specifically among patients with stable CHD and those with a recent ACS. In several studies of multiple predictors of quality of life in CHD patients, depression was the most important even when other predictors such as demographic and social variables, severity of disease, ejection fraction, and ischemia were assessed. Recent ACS patients with a history of depression have twice the rate of angina, triple the physical limitations, and almost triple the risk of diminished health-related quality of life. There have been calls to improve quality of life in post-ACS patients, rather than continuing to focus on extending life of diminished quality. Some suggest that treating depression could answer this call.
Costs Associated with Depression
Depression has long been associated with high costs of medical utilization, many lost days of productivity, and reduced work performance. Patients who have a chronic medical condition, such as CHD, with depression have significantly more ambulatory visits, emergency room visits, days in bed due to illness, and functional disability. Annual healthcare costs were almost 41% higher and 5-year healthcare costs were almost 53% higher in depressed post-MI patients compared with nondepressed post-MI patients.
Anxiety
Anxiety disorders are highly prevalent, with nearly 20% of Americans suffering from any anxiety disorder — a rate that is likely mirrored in CHD patients. Some prospective studies have shown an increased risk of cardiovascular events among patients with anxiety symptoms and suggest that the increased risk exists even with simple phobias and nonclinical anxiety levels with a graded-response relationship.
Stress
The literature relating stress and CHD is equivocal, perhaps due to differing definitions and conceptualizations of what constitutes “stress,” as well as which CHD outcomes have been examined. However, recent studies have indicated that stress is associated with incident CHD. Self-reported individual stressors are associated with incident CHD with risk ratios in excess of 1.6. A meta-analysis of six prospective observational cohort studies showed that patient self-reported stress was associated with incident CHD at 6 months, with an aggregate relative risk of 1.27 (95% confidence interval [CI] 1.12–1.45).
Specific stressors such as social isolation, stress at work, and marital problems have also been individually associated with incident CHD with risk ratios of approximately 1.5 in individual studies. Meta-analyses have shown that job strain and loneliness/isolation also increase the risk of incident CHD. Not only is perceived stress a risk factor for CHD, but the perception that stress is affecting one’s health is also a risk factor.
Stress may also be associated with, poor prognosis in established CHD patients, although the evidence is limited. Financial and job strains are examples of stressors that are related to recurrent CHD-related events.
Biologic Mechanisms
Depression
Many biologic mechanisms have been proposed to explain the association between depression and incident and recurrent CHD ( Fig. 26.5 and Fig. 26.6 ). Dysregulations of several physiologic systems in depression are implicated in the depression–CHD link, including platelet reactivity, inflammation, autonomic imbalance, sleep architecture disruption, circadian rhythm disruption, anabolic/catabolic hormonal imbalance, and others. However, the evidence remains equivocal regarding the specific biologic dysregulations responsible for the link between depression and CHD. Although many promising mechanisms are briefly reviewed hereafter, there is little direct human evidence that any of these are causally involved in the pathogenesis of CHD in depression. A recent review of animal studies suggests that most of these mechanisms are plausible, but human experiments and trials are required to conclusively implicate a biologic mechanism in the depression–ACS recurrence association.
Platelet Reactivity
Several case-controlled studies have demonstrated platelet hyperreactivity in CHD patients, and CHD patients with MDD have exhibited higher levels of platelet factor 4 and β-thromboglobulin (β-TG)—markers of platelet aggregation—and platelet/endothelial cell adhesion molecule-1 when compared with CHD patients without MDD.
Inflammation
Elevated levels of inflammatory biomarkers, including CRP, soluble intercellular adhesion molecule 1 (sICAM1), soluble vascular cell adhesion molecule-1, and tumor necrosis factor-α, are associated with an increased risk of cardiovascular events in patients with known CHD. Several cross-sectional studies have linked depression to chronic inflammation—as measured by CRP or sICAM1 levels—both in otherwise healthy participants and in post-ACS patients shortly after the index event. Proinflammatory cytokines may contribute to coronary atherosclerosis.
Autonomic Dysregulation
Autonomic dysregulation is characterized by increased activation of the sympathetic nervous system (SNS), which usually acts in concert with a reduced activation of the parasympathetic nervous system (PNS). Excess SNS activity produces many effects that contribute to CHD: high blood pressure, increased myocardial oxygen demand, platelet activation, increased myocyte apoptosis, and arrhythmias. Both elevated SNS activity and reduced PNS activity have been implicated in depression and CHD recurrence. Furthermore, CHD patients with depressive symptoms have been shown to have greater SNS activity as measured by higher norepinephrine excretion levels compared with CHD patients without depressive symptoms.
Sleep Architecture Disruption
Depression and sleep architecture disruption are closely linked, although the specific dysregulated polysomnographic parameters are unclear. Studies have shown that reduced rapid eye movement (REM) latency—the time from sleep onset to the first occurrence of REM—is the most frequently reported sleep dysregulation that distinguishes MDD patients from individuals without MDD. REM sleep is characterized by pronounced surges of SNS, which may be of sufficient magnitude to stimulate thrombotic processes, to increase hemodynamic stress on vessel walls conducive to plaque rupture, and to alter cardiac electrophysiologic properties. These autonomic surges may be responsible for cardiac events witnessed during REM sleep in humans. Importantly, this REM-induced cardiac sympathetic dominance is enhanced in individuals with a recent MI. Additionally, the total sleep time is consistently decreased in depressed patients and those prone to depressive episodes. Although there is a lack of prospective epidemiologic studies on the dimensions of sleep architecture and CHD recurrence, there is epidemiologic evidence that short sleep duration is predictive of ACS.
Circadian Rhythm Disruption
Endogenous circadian rhythms regulate daily variations in most of the hormonal, physiologic, and psychologic variables implicated in depression and ACS. The systems with the most prominent variations are thermoregulation and melatonin secretion. There is evidence that the majority of cardiovascular events, including MIs, show a marked circadian rhythmicity with a peak incidence between 6:00 and 2:00. However, in depressed patients, who often have circadian dysregulation, most MIs occur between 10:00 and 6:00. Thus, circadian rhythm disruption in depressed patients may help elucidate some of the pathways by which these patients are at an increased risk of recurrent cardiovascular events.
Hypothalamic-Pituitary-Adrenal Axis
The hypothalamic-pituitary-adrenal (HPA) axis, the major stress axis through which cortisol is released by the adrenal gland when stimulated by adrenocorticotropin (ACTH), has been studied extensively in depressed patients. Depressed patients exhibit elevated circulating plasma levels of ACTH and cortisol, elevated urinary cortisol concentration, and altered circadian rhythm of cortisol. Prospective studies among acute MI patients have shown that very high levels of cortisol (> 2000 nmol/L) predict mortality.
Anxiety
The neurobiology underlying anxiety has not been examined or elucidated as extensively as that of depression, but some biologic alterations have been identified, such as markers of platelet reactivity, inflammation, autonomic dysregulation, and HPA system hyperactivity.
Platelet Reactivity
Panic disorder patients, like depressed patients, have been observed to have elevated plasma platelet factor 4 and β-TG concentrations.
Inflammation
Inflammatory markers, including CRP and fibrinogen, are elevated among patients with anxiety with a dose-response relationship such that increased levels of inflammatory markers are associated with higher levels of anxiety.
Autonomic Dysregulation
Increased anxiety has been associated with an increased risk of hypertension in prospective cohort studies, which suggests SNS hyperactivity. However, further research is needed to clarify this association.
Hypothalamic-Pituitary-Adrenal Axis
Similar to depressed patients, patients with post-traumatic stress disorder (PTSD), a specific anxiety disorder, exhibit HPA system hyperactivity. Corticotropin-releasing factor concentrations are increased in the cerebrospinal fluid of patients with anxiety and/or PTSD. Panic disorder patients do not seem to have consistent HPA system alterations, and there are insufficient data on HPA axis function in patients with other specific anxiety disorders.
Stress
Similar to depression and anxiety, the mechanism linking stress with CHD outcomes is likely multifactorial and includes platelet reactivity, inflammation, autonomic dysregulation, and increased HPA axis activity. Because an acute response to stress is transient hypertension, it has been hypothesized that a response to chronic stress is persistent hypertension.
Additionally, acute cardiac events may be triggered by acute emotional stress. A meta-analysis showed that ACS that is preceded by anger, stress, or depressed mood in the past 24 hours has a pooled relative risk of nearly 2.5. The risk may increase further with high-intensity emotional stressors such as death of a significant person or a diagnosis of cancer. Similarly, Takotsubo (or stress) cardiomyopathy, a transient dysfunction of the left ventricle, has been shown to be associated with both acute and former or chronic psychiatric diagnoses. Up to 42.3% of Takotsubo patients had a psychiatric illness, and approximately half of these were affective disorders.
Behavioral Mechanisms
Depression
Depression is associated with cardiac risk factors such as smoking, obesity, and sedentary lifestyle. Depression may also influence post-ACS outcomes through its effects on a patient’s behaviors with regard to adherence to prescribed medications and primary or secondary prevention recommendations. In addition, there may be disparities in the way the healthcare system behaves toward depressed patients, and these differences (e.g., the treatment they receive) may lead to worse outcomes. Although it is now widely accepted that post-ACS depression is associated with a poor medical prognosis, there remains a gap in our knowledge about which behavioral mechanisms underlie this association. See Fig. 26.6 for a schematic of the interplay between behavioral and biologic mechanisms underlying the association between depression and cardiovascular disease.
Adherence
Poor adherence to behaviors recommended for managing medical illnesses is well-established as an important factor in determining outcomes for a range of diseases. For example, treatment adherence accounted for 26% of the difference in outcomes among high adherers compared with low adherers in a meta-analysis. Nonadherence to cardiovascular medications such as aspirin, statins, and β-blockers after ACS is clearly linked with poor medical outcomes, including cardiac outcomes, mortality, and composite endpoints with hazard ratios (HRs) between 3 and 3.8.
Prior research shows that depression is associated with poor adherence among patients with a number of chronic medical illnesses, including ACS. Patients with persistent depressive symptoms after ACS are less likely to adhere to secondary CHD prevention behaviors, such as exercising regularly and quitting smoking. Although there are a number of potential behavioral mechanisms linking depression and post-ACS outcomes, poor medication adherence specifically represents the most promising and best-supported mechanism explaining this association. In an outpatient population of CHD patients, nearly 15% of those with MDD reported not taking their medication as prescribed, compared with 5% of those without depression. In a post-ACS population, 42% of persistently depressed patients took their prescribed aspirin less than 75% of the time, whereas only approximately 11% of nondepressed patients demonstrated this level of nonadherence.
Stigma
Finally, as a result of the cognitive, affective, and social characteristics of mental illnesses, patients with depression can be stigmatized by their illness, which may lead to lower rates of treatment for cardiac disease or poorer communication about secondary prevention behaviors. For example, individuals with comorbid mental disorders are less likely to undergo coronary revascularization procedures than those without mental disorders. Additionally, patients with depression tend to have flat affect and be less engaging; therefore they may be most susceptible to such physician bias.
Anxiety
Much less is known about the association of anxiety with medication adherence or with adherence to secondary CHD prevention behaviors. Some studies indicate that anxious patients, in general, are more adherent, particularly when their anxiety takes the form of generalized anxiety disorder. However, other anxious patients with phobic or panic symptoms may be less likely to adhere. But, relatively little empiric evidence exists to strongly support any of these small-study findings and conjectures.
Stress
Stress may also be linked to poor CHD outcomes through behavioral mechanisms. For example, poor health behaviors that develop as a response to stress may result in obesity, hyperglycemia, and dyslipidemia — all of which are known cardiovascular risk factors. Studies have attributed a portion of the effect of stress on CHD to the increased risk of metabolic syndrome among patients with high levels of perceived stress.
Treatment Options
Depression
Treatment for depression may include psychotherapy, physical activity, or antidepressant drugs ( Fig. 26.7 ).
Psychotherapy
Three types of psychotherapy have been shown to be effective in ameliorating depression. Psychotherapy can be as effective as medication in treating depression and may be preferred in patients who cannot tolerate or do not want to take antidepressants. Many depressed patients may respond better to a combination of antidepressants and psychotherapy, specifically cognitive behavioral therapy (CBT), than either treatment alone.
The most frequently used type of psychotherapy is CBT, which modifies thoughts and behaviors to decrease depressive symptoms. The second type of psychotherapy is interpersonal therapy, which focuses on interpersonal situations such as conflicts or role transitions. These two therapies were found to have only modest improvements in depression in recent RCTs of CHD patients, although a recent trial of CABG patients showed good treatment effects for CBT. Another study of CHD patients showed that 12 to 16 sessions of CBT over a period of 12 weeks helped achieve remission of depression.
Finally, problem-solving therapy teaches patients to improve their abilities to solve everyday problems, and, when used in a patient preference design (in which patients are educated about the benefits and limitations of each therapy and then choose for themselves if they prefer problem-solving therapy and/or pharmacotherapy), improves depression in CHD patients. Importantly, these psychotherapies can now be provided over the telephone, which is both cost effective and removes barriers to treatments for patients with mobility or transportation issues.
Physical Activity
For patients with mild depressive symptoms, exercise can remediate depressive symptoms. Exercise can improve both depressive symptoms and cardiovascular fitness. The specific exercise regimen prescribed should be tailored to the cardiac condition and exercise capacity of each individual patient.
Antidepressant Drugs
Depression can be treated with a variety of antidepressant drugs, including SSRIs, tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs). Patients initiated on antidepressants should be closely monitored for the first 2 months of treatment and regularly thereafter to ensure adherence, detect adverse effects, and monitor suicidal risk.
Tailored drug selection is critical among CHD patients, as antidepressants have been associated (but not tested in active comparator trials) with both increased and decreased cardiac risk. Cardiologists should manage pharmacotherapy with careful consideration of each individual patient’s cardiovascular disease and risk profile. Certain antidepressants may be associated with increased risk for arrhythmias, orthostatic hypotension, or hypertensive crisis, especially when combined with certain cardiovascular medications. Please see Tables 26.1, 26.2, and 26.3 for detailed information about antidepressant drug classes and individual drug cardiovascular side effects, potential interactions with cardiac medications, and pharmacokinetic interactions, respectively.
| Class | Cardiovascular Side Effects | Likely Mechanism of Side Effect | Other Effects and Benefits |
|---|---|---|---|
| Tricyclic and related cyclic antidepressants | Orthostatic hypotension | Postsynaptic α 1 -receptor blockade | |
| Nortriptyline (Pamelor) | Lowest incidence of orthostatic hypotension with nortriptyline | ||
| Imipramine (Tofranil) | |||
| Amitriptyline (Elavil) | |||
| Desipramine (Norpramin) | Tachycardia | Secondary to hypotension | |
| Clomipramine (Anafranil) | |||
| Doxepin (Sinequan) | Decreased heart rate variability | Postsynaptic cholinergic-receptor blockade | Urinary retention, dry mouth, constipation, confusion, exacerbation of narrow-angle glaucoma |
| Trimipramine (Surmontil) | |||
| Protriptyline (Vivactil) | Slowing of intraventricular conduction | Quinidine-like effects | Avoid in patients with bifascicular block, left bundle branch block, QTc > 44 msec, or QRS > 11 msec |
| Monoamine oxidase inhibitors | Orthostatic hypotension | Inhibition of metabolism of serotonin and catecholamines | Fatal in overdose |
| Phenelzine (Nardil) | Hypertensive crisis | Requires adherence to tyramine-free diet and avoidance of other antidepressants and sympathomimetics | |
| Tranylcypromine (Parnate) | |||
| Isocarboxazid (Marplan) | |||
| SSRIs | Postsynaptic serotonin-receptor blockade | Fatal in overdose | |
| Typical side effects: nausea, insomnia, sexual dysfunction, nervousness | |||
| Fluoxetine (Prozac) | Sinus bradycardia | Unknown | Requires 8 weeks for complete washout |
| Inhibitor of CYP IID6 and CYP IIIA4 enzymes | |||
| Also FDA approved for treatment of adult and pediatric OCD, bulimia, pediatric depression | |||
| Paroxetine (Paxil) | Clinically insignificant decreases in heart rate | Unknown | Inhibitor of CYP IID6 enzyme |
| Also FDA indicated for treatment of social phobia, panic disorder, OCD, GAD | |||
| Sertraline (Zoloft) | None known | In high doses, inhibitor of CYP IID6 enzyme | |
| Also FDA indicated for treatment of panic disorder, adult and pediatric OCD, PTSD | |||
| Fluvoxamine (Luvox) | None known | Potent inhibitor of multiple CYP enzymes | |
| Also FDA approved for treatment of adult and pediatric OCD | |||
| Citalopram (Celexa) | None known | ||
| Escitalopram (Lexapro) | None known | SSRI with most selective binding to serotonin transporter | |
| Venlafaxine (Effexor) | Arrhythmia or cardiac block in overdose | Unknown | No significant inhibition of CYP enzymes |
| Decreased HRV | Also FDA indicated for treatment of GAD | ||
| Increased diastolic blood pressure in doses > 300 mg/day | Presynaptic inhibition of norepinephrine reuptake | Side-effect profile similar to that of SSRIs | |
| Presynaptic α 2 -receptor antagonist | |||
| Mirtazapine (Remeron) | None known | Postsynaptic histamine 1 receptor blockade | Very sedating in low doses |
| Weight gain | |||
| Minimal sexual side effects | |||
| No significant inhibition of CYP enzymes | |||
| Dopamine and norepinephrine reuptake inhibitor | |||
| Bupropion (Wellbutrin, Zyban) | Significant increases in blood pressure in patients with preexisting hypertension (rare) | Presynaptic inhibition of norepinephrine reuptake | No significant inhibition of CYP enzymes Minimal sexual side effects Not proven effective in the treatment of anxiety disorders |
| FDA indicated for treatment of nicotine dependence | |||
| Atypical serotonergic agents | |||
| Trazodone (Desyrel) | Orthostatic hypotension | Postsynaptic α 1 receptor blockade | Sedation, confusion, dizziness |
| Cardiac arrhythmias rare | Unknown | Rare cases of priapism | |
| Nefazodone (Serzone) | Sinus bradycardia | Unknown | Similar side-effect profile as trazodone (except without priapism) |
| Minimal sexual side effects | |||
| Potent inhibitor of multiple CYP enzymes | |||
| Liver failure rare | |||
| Psychostimulants | |||
| Dextroamphetamine (Dexedrine) | Rarely increases blood pressure or tachycardia in therapeutic doses | Release of dopamine and catecholamines | Avoid in patients with hyperthyroidism, severe hypertension, severe angina, tachyarrhythmias |
| Methylphenidate (Ritalin) | |||
| Benzodiazepines | Allosteric alteration of GABA A receptors | Rapid relief of anxiety symptoms | |
| Alprazolam (Xanax) | |||
| Clonazepam (Klonopin) | |||
| Lorazepam (Ativan) | Hypotension | Muscle relaxation of GABA A spinal cord receptors | Can cause fatigue, ataxia, drowsiness, amnesia, and behavioral dyscontrol |
| Oxazepam (Serax) | Relatively safe in overdose | ||
| Physiologic and psychological dependence and withdrawal symptoms if dosage not gradually tapered | |||
| Partial 5-HT 1A receptor agonist | |||
| Buspirone (BuSpar) | None known | FDA approved for treatment of GADNonaddictive | |
| Omega 1 receptor agonist | |||
| Zolpidem (Ambien) | None known | Potentiation of GABA A receptor | Sedating |
| Nonaddictive | |||
| Zaleplon (Sonata) | None known | ||
| Lithium | Sinus node dysfunction | Unknown | Narrow therapeutic index (1.6–1.2 mmol/L) |
| Sinoatrial block | Many medications alter lithium plasma levels ∗ | ||
| T-wave inversion or flattening, particularly in patients > 60 years | Fatal in overdose | ||
| Arrhythmias and sudden death in patients with cardiac disease | Mood stabilizer for patients with bipolar disorder | ||
| Yearly ECG in patients > 50 years |
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