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The Deadly Duo

José R. Maldonado, MD | October 1, 2010
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The Case

A 29-year-old man with a history of depression and possible psychosis was found unconscious and unresponsive at home and was brought to the emergency department. He was tachycardic, hypertensive, and unresponsive to painful stimuli. His electrocardiogram revealed tachycardia, QT prolongation, QRS widening, and a nonspecific intraventricular conduction delay, all evidence of potentially dangerous heart rhythms. He was intubated for airway protection and given activated charcoal through a nasogastric tube to treat a presumed drug overdose. He was also treated with a bicarbonate drip, which can help suppress overdose-related arrhythmias.

Further history obtained from the paramedics revealed that the patient had been prescribed amitriptyline (a tricyclic antidepressant) and risperidone (an antipsychotic medication) by his primary care physician to treat his psychiatric conditions. Empty bottles of both were found on the floor near the patient at his home, and it was presumed that he had overdosed on the medications as a suicide attempt. The patient survived the episode without any life-threatening arrhythmias and was transferred to an inpatient psychiatric ward once he was stabilized.

The Commentary

The delivery of mental health care by primary care physicians is likely a necessary component of health care in the United States. Mental health disorders are incredibly common: up to 26% of Americans have psychiatric disorders in a given year and 6% have a serious mental illness that significantly impairs their life.(1,2) The data suggest that many patients with psychiatric disorders are cared for by primary care providers (internists, generalists, NPs, etc.), not psychiatrists.(3,4) In one epidemiologic survey, specialists in mental and addictive disorders provided treatment to 5.9% of the US population, while 6.4% of the population sought mental health services from general medical physicians.(5)

Although this case does not reveal the specifics of how the patient's primary care physician delivered care, it highlights some of the most significant challenges of a system in which primary care providers deliver a majority of the care for patients with mental health disorders. Any physician treating patients for a psychiatric disorder must be able to (i) recognize an impending suicide attempt, (ii) understand proper dosing and the time necessary for psychiatric medications to take effect, and (iii) possess a full understanding of the unique drug–drug interactions or adverse effects of psychoactive medications. When such knowledge is not top-of-mind, it can lead to major errors, some of which may have occurred in this case. Although the exact error (or errors) made in this case is not obvious, the case provides an opportunity to explore the potential hazards when non-psychiatrists manage patients with psychiatric diseases.

Specifically, a primary care physician prescribed psychiatric medications for a patient with depression and possible psychosis. Although primary care providers care for patients with many different psychiatric disorders, major depressive disorder is one of the most common. In fact, approximately 5% to 10% of primary care patients meet DSM-IV criteria for major depression, 3% to 5% for dysthymia (a form of mild chronic depression), and 10% for minor depression.(6) Consequently, most antidepressant medications are prescribed by non-psychiatric physicians. In 2005, 169.9 million outpatient prescriptions for antidepressants were dispensed in the United States.(7) Among prescribers, the top medical specialties included psychiatry (29.3%), general practice (22.6%), family practice (20.5%), internal medicine (10.0%), and others (17.6%).(7) This trend is similar to that reported in other countries. For example, general practitioners prescribe 86% of antidepressants in Australia.(8) Not only is antidepressant prescribing common in primary care, it is increasing. According to one study, antidepressants were prescribed in 2.6% of all primary care visits (~6 million visits) in 1989 and 7.1% (~20.5 million visits) in 2000.(9) Incredibly, antidepressants have become the most prescribed medications in the United States, with more prescriptions than those to treat high blood pressure, high cholesterol, or headaches.(10)

Given that most antidepressants are prescribed by non-psychiatrists, these providers must be aware of potential errors in managing both psychiatric illnesses and the medications used to treat these illnesses.

Recognize and Respond to an Impending Suicide Attempt

In the present case, the patient appeared to have attempted suicide by overdosing on his prescribed medications. Primary care providers may be in a unique position to recognize an impending suicide attempt due to their frequent interactions with patients. A review of 40 studies found that more than 75% of patients who committed suicide had contact with primary care providers within a year of their death, compared with one-third who had contact with mental health professionals.(11) Similarly, twice as many suicide patients had contact with primary care providers as mental health services in the month before their suicide (45% versus 20%). An AHCPR Panel (12) recommended that more severely depressed patients be seen weekly and those with less severe illness every 10 to 14 days during the initial 6 to 8 weeks of pharmacotherapy. This schedule was thought to improve patient adherence, facilitate dosage adjustment, and permit more careful monitoring.(13)

What patient behaviors should primary care doctors be looking for in their depressed patients to indicate impending suicidal behavior? It appears that symptoms of anxiety may predominate prior to suicide attempts. In one study, 79% of patients had severe or extreme anxiety and/or agitation in the week before suicide.(14) Self-reported anxiety symptoms were associated with a twofold increased likelihood of reporting suicidality after controlling for confounding factors (demographics, depressive symptoms, and diagnoses).(15)

Prior research also has identified other patient features that may predict suicidal behavior. The strongest single factor predictive of suicide is prior history of attempted suicide.(16) In addition, other major predictors in the patient's history are a depressed mood, recent loss of an interpersonal relationship, insomnia, recent abuse of alcohol or illicit substances, and feelings of hopelessness or helplessness.(17) In fact, in at least one group of patients, hopelessness was 1.3 times more important than depression in explaining suicidal ideation.(18)

In this case, we are not given enough information regarding the patient's mood or behaviors prior to his presumed suicide attempt (or whether he saw the prescribing physician), but it is possible there was an opportunity to intervene. While patients may be reluctant to communicate their intent to commit suicide, patients with suicidal ideation will generally tell their physicians about such thoughts when asked.(19) Primary care providers should be aware of the above predictors and be vigilant when seeing patients with depression. If there is an acute concern for suicidality, the patient should be seen immediately by a psychiatrist and potentially admitted to the hospital. Even if no overt signs of suicidal behavior are present but the patient with depression has some of the predictors, it's important that the patient be referred to see a psychiatrist within a few days.

Understand Time to Effect and Dosing

In managing patients with depression, it is also important for primary care providers to recognize that it can take substantial time for antidepressant medications to take effect and that the frustration of waiting can induce or exacerbate suicidal tendencies; therefore, it is important to carefully monitor these patients until effective dosing has been established. In general, it takes 10 to 14 days to notice any effect from antidepressant medications, and up to 6 to 8 weeks for the full effect to become evident. If there is no response by 8 to 12 weeks at a maximum therapeutic dose, the patient should be given a trial of another antidepressant (either of the same or different class) or should be referred to a psychiatrist.(20)

Related to this, physicians must become familiar with appropriate dosing for different antidepressant agents. In general, the major mistakes in prescribing tricyclic antidepressants (TCAs) involve prescribing doses that are not high enough. One study suggested that only one-third of non-psychiatric patients on TCAs had a therapeutic dose or plasma level.(21) Conversely, a major mistake in prescribing selective serotonin reuptake inhibitors (SSRIs) is overprescribing and not recognizing that increasing the dose may simply worsen side effects and not have a therapeutic benefit. It is not clear from the case whether there were issues with recognizing the expected onset of the medications or with dosing, but these are relatively common prescribing errors in this setting.

Understand the Complex Effect Profiles of Psychoactive Medications

Last, primary care physicians may not be familiar with adverse effect profiles of psychoactive medications, particularly drug–drug interactions. The patient in this case was taking a TCA and an antipsychotic medication. Although each class of medication can have adverse effects in standard doses, the effects may be more severe when taken in combination. Tricyclic antidepressant agents were the third leading cause of toxic exposures reported to Poison Control centers in 2004 after analgesics and sedatives.(22) TCAs owe their lethality to the fact that the therapeutic dose is perilously close to the lethal dose. Data suggest that 3 to 5 times the therapeutic dose (about a 2-week supply) is potentially lethal in an overdose, especially when combined with alcohol or other central nervous system depressant agents. Of note, fatality before reaching a health care facility occurs in approximately 70% of patients attempting suicide with TCAs. Yet only 2% to 3% of TCA overdose cases that reach a health care facility result in death.(23) Factors that increase the risk of toxicity include advancing age, cardiac status, and concomitant use of other drugs.(24)

The most dreaded toxicity of TCAs derives from their multiple effects on the cardiac conduction system, including prolongation of intervals, ST and T-wave changes, and even degrees of heart block. These changes may lead to increased cardiac morbidity and mortality in one of four scenarios: (i) when administered to a patient with pre-existing cardiac problems (e.g., bundle-branch block, third-degree AV block); (ii) when ingested in an overdose; (iii) when administered along with other agents that also affect cardiac conduction (e.g., type I antiarrhytmic drugs); or (iv) when administered with medications that impair their metabolism (e.g., antipsychotic agents), as in this case.

Although SSRIs are substantially safer than TCAs in overdose, they too have important toxicities, particularly when taken in large doses or with other medications. SSRI-related side effects include increased depression or suicidality (25), excessive activation (including causing or worsening anxiety), apathy or anhedonia, headache, gastrointestinal distress, sedation, insomnia, and sexual dysfunction. There is evidence suggesting that SSRIs can decrease intraplatelet serotonin concentrations, impairing platelet aggregation and leading to an increased risk of bleeding. The increased bleeding risk can manifest as easy bruising, epistaxis (nosebleeds), need for transfusions with surgery, and upper gastrointestinal bleeding, particularly in patients concomitantly taking NSAIDS.(26-29)

With improved understanding of antidepressant metabolism has come an increased awareness of the contribution of pharmacokinetic drug interactions to the toxicity profile of antidepressant drugs. Some SSRIs (e.g., fluoxetine, paroxetine, fluvoxamine, nefazodone) have potent inhibitory effects on P-450 isoenzymes, the liver enzymes responsible for metabolizing or breaking down drugs. Thus, SSRIs have the potential to alter the metabolism of co-administered prescription and over-the-counter drugs, which may be a source of considerable toxicity.(30,31) SSRIs may significantly increase the blood levels of various pharmacologic agents requiring hepatic metabolism (e.g., TCAs, antipsychotics, digitoxin, beta-blockers, benzodiazepines, Ca-channel blockers, and antiarrhythmic agents) or impede the therapeutic effects of certain agents, by preventing prodrugs from being effectively metabolized. Physicians must be mindful of the potential significant drug–drug interactions of prescribed psychotropic agents. They may alter the metabolism of other prescribed medications, or add to potential side effects increasing the likelihood of occurrence and the severity of the same when they do occur—such as the cardiac conduction problems illustrated by this case.

Proactively Refer to Psychiatrists

Although many primary care providers do a wonderful job of caring for psychiatric illness and non-psychiatrists can safely dispense many psychoactive medications, both the patient population and the medications can be complex, and errors do occur. It is essential that primary care providers are aware of the common pitfalls and errors, can recognize danger signs, and have a low threshold for psychiatric referral. Situations that merit referral to psychiatrists include: when the first-line drug cannot be tolerated or produces no benefit; there are signs of severe depression with possible thought disorder (e.g., psychosis, disorganized thinking) or suicidal ideation; the patient is interested in understanding the depression or initiating psychotherapy; and in cases of treatment-resistant patients (e.g., failing more than 2 adequate antidepressant medication trials).(20,32)

Take-Home Points

This case illustrates several key points to consider when treating patients with psychiatric medications:

  • Antidepressant agents have become the most commonly prescribed drugs in the United States, and their use by primary care providers has tripled over the last 10 years.
  • Primary care providers may be in a unique position to recognize an impending suicide attempt: twice as many suicide patients contacted their primary care providers compared to mental health providers in the month before their suicide.
  • The major predictors of suicide include a history of suicide attempts, anxiety, depressed mood, recent loss of an interpersonal relationship, abuse of alcohol or illicit substances, feelings of hopelessness or helplessness, insomnia, anhedonia, medical illness, and impulsive behavior.
  • It can take substantial time for antidepressant medications to take effect; therefore, these patients should be carefully monitored until effective dosing has been established.
  • Tricyclic antidepressants are commonly underdosed by primary care doctors but have substantial side effects, including multiple cardiac toxicities.
  • Although SSRIs are substantially safer than TCAs in overdose, they too have important side effects including worsening depression or suicidality, apathy or anhedonia, headache, gastrointestinal distress, sedation, insomnia, sexual dysfunction, bleeding, and significant drug–drug interactions.
  • Because of potential drug–drug interactions, co-prescribing of multiple psychiatric agents must be done with care and may best be done in consultation with a psychiatrist.

José R. Maldonado, MD

Associate Professor of Psychiatry & Medicine

Chief, Medical & Forensic Psychiatry Section

Medical Director, Psychosomatic Medicine Service Stanford University School of Medicine


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This project was funded under contract number 75Q80119C00004 from the Agency for Healthcare Research and Quality (AHRQ), U.S. Department of Health and Human Services. The authors are solely responsible for this report’s contents, findings, and conclusions, which do not necessarily represent the views of AHRQ. Readers should not interpret any statement in this report as an official position of AHRQ or of the U.S. Department of Health and Human Services. None of the authors has any affiliation or financial involvement that conflicts with the material presented in this report. View AHRQ Disclaimers
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