Current Psychiatry

The larger mosaic

Dr. Nasrallah paints a frightening vision in his April editorial. There are many schools of thought in psychiatry, including biological, psychodynamic, cognitive behavioral, relational, and humanistic approaches. All of these reflect a piece of the larger mosaic that makes us human and contributes to our mental health. Psychiatry is the only medical specialty where well and broadly trained clinicians can treat patients on any or all of these levels in an integrated fashion.

The desire to redefine psychiatry as the treatment of strictly neurologically based conditions may work well for illness such as schizophrenia or bipolar I disorder, but it does a disservice to patients with anxiety, depression, trauma, etc., who can benefit from an integrative approach that may include medication and a neuroscience perspective but does not deny the healing power of approaches that work with the subjective side of mental life.

David Aftergood, MD
Private Practice
White Plains, NY

Same goal, different method

I agree with Dr. Nasrallah that psychiatry is ready for creative destruction. We differ in the best way to achieve that goal. It is not enough to revolutionize current diagnostic schemes or the disastrously dysfunctional mental health bureaucracy. My suggestion is to get psychiatry out of the pocket of pharmaceutical manufacturers who support academic psychiatry and its publications. The April 2012 issue of Current Psychiatry has 78 pages; one-half are drug advertising. If we want to revolutionize our profession I suggest we wean ourselves from our dependency on pharmaceutical manufacturers’ support, and advocate for the elimination of direct-to-consumer advertising.

Carl Hammerschlag, MD
Chief of Community Mental Health
Gesundheit! Institute
Phoenix, AZ

Dr. Nasrallah responds

I thank my colleagues for their comments on my editorial, whether supportive or dismissive. Editorials represent my opinion, sometimes critical, sometimes aspirational, but always intended to provoke healthy discourse with Current Psychiatry ’s readers. My intent in this editorial was to urge psychiatrists to continuously question what we do and whether we can practice our art differently, better, or in a more scientifically valid manner.

Regarding the issue of laboratory testing to confirm a clinical diagnosis—which many were hoping would be part of DSM-5—I have no doubt that this will become a reality in the not-too-distant future. Testing will include a mix of blood, cerebrospinal fluid, neurophysiological, or neuroimaging tests—structural, functional, spectroscopic, and diffusion tensor imaging MRI. If this sounds unlikely right now, that’s what most people thought about our ability to land on the moon a mere decade before it happened.

When it comes to the future of psychiatry, I uphold 1 mantra: yes we can and yes we will!

Henry A. Nasrallah, MD
Editor-in-Chief

The larger mosaic

Dr. Nasrallah paints a frightening vision in his April editorial. There are many schools of thought in psychiatry, including biological, psychodynamic, cognitive behavioral, relational, and humanistic approaches. All of these reflect a piece of the larger mosaic that makes us human and contributes to our mental health. Psychiatry is the only medical specialty where well and broadly trained clinicians can treat patients on any or all of these levels in an integrated fashion.

The desire to redefine psychiatry as the treatment of strictly neurologically based conditions may work well for illness such as schizophrenia or bipolar I disorder, but it does a disservice to patients with anxiety, depression, trauma, etc., who can benefit from an integrative approach that may include medication and a neuroscience perspective but does not deny the healing power of approaches that work with the subjective side of mental life.

David Aftergood, MD
Private Practice
White Plains, NY

Same goal, different method

I agree with Dr. Nasrallah that psychiatry is ready for creative destruction. We differ in the best way to achieve that goal. It is not enough to revolutionize current diagnostic schemes or the disastrously dysfunctional mental health bureaucracy. My suggestion is to get psychiatry out of the pocket of pharmaceutical manufacturers who support academic psychiatry and its publications. The April 2012 issue of Current Psychiatry has 78 pages; one-half are drug advertising. If we want to revolutionize our profession I suggest we wean ourselves from our dependency on pharmaceutical manufacturers’ support, and advocate for the elimination of direct-to-consumer advertising.

Carl Hammerschlag, MD
Chief of Community Mental Health
Gesundheit! Institute
Phoenix, AZ

Dr. Nasrallah responds

I thank my colleagues for their comments on my editorial, whether supportive or dismissive. Editorials represent my opinion, sometimes critical, sometimes aspirational, but always intended to provoke healthy discourse with Current Psychiatry ’s readers. My intent in this editorial was to urge psychiatrists to continuously question what we do and whether we can practice our art differently, better, or in a more scientifically valid manner.

Regarding the issue of laboratory testing to confirm a clinical diagnosis—which many were hoping would be part of DSM-5—I have no doubt that this will become a reality in the not-too-distant future. Testing will include a mix of blood, cerebrospinal fluid, neurophysiological, or neuroimaging tests—structural, functional, spectroscopic, and diffusion tensor imaging MRI. If this sounds unlikely right now, that’s what most people thought about our ability to land on the moon a mere decade before it happened.

When it comes to the future of psychiatry, I uphold 1 mantra: yes we can and yes we will!

Henry A. Nasrallah, MD
Editor-in-Chief

The larger mosaic

Dr. Nasrallah paints a frightening vision in his April editorial. There are many schools of thought in psychiatry, including biological, psychodynamic, cognitive behavioral, relational, and humanistic approaches. All of these reflect a piece of the larger mosaic that makes us human and contributes to our mental health. Psychiatry is the only medical specialty where well and broadly trained clinicians can treat patients on any or all of these levels in an integrated fashion.

The desire to redefine psychiatry as the treatment of strictly neurologically based conditions may work well for illness such as schizophrenia or bipolar I disorder, but it does a disservice to patients with anxiety, depression, trauma, etc., who can benefit from an integrative approach that may include medication and a neuroscience perspective but does not deny the healing power of approaches that work with the subjective side of mental life.

David Aftergood, MD
Private Practice
White Plains, NY

Same goal, different method

I agree with Dr. Nasrallah that psychiatry is ready for creative destruction. We differ in the best way to achieve that goal. It is not enough to revolutionize current diagnostic schemes or the disastrously dysfunctional mental health bureaucracy. My suggestion is to get psychiatry out of the pocket of pharmaceutical manufacturers who support academic psychiatry and its publications. The April 2012 issue of Current Psychiatry has 78 pages; one-half are drug advertising. If we want to revolutionize our profession I suggest we wean ourselves from our dependency on pharmaceutical manufacturers’ support, and advocate for the elimination of direct-to-consumer advertising.

Carl Hammerschlag, MD
Chief of Community Mental Health
Gesundheit! Institute
Phoenix, AZ

Dr. Nasrallah responds

I thank my colleagues for their comments on my editorial, whether supportive or dismissive. Editorials represent my opinion, sometimes critical, sometimes aspirational, but always intended to provoke healthy discourse with Current Psychiatry ’s readers. My intent in this editorial was to urge psychiatrists to continuously question what we do and whether we can practice our art differently, better, or in a more scientifically valid manner.

Regarding the issue of laboratory testing to confirm a clinical diagnosis—which many were hoping would be part of DSM-5—I have no doubt that this will become a reality in the not-too-distant future. Testing will include a mix of blood, cerebrospinal fluid, neurophysiological, or neuroimaging tests—structural, functional, spectroscopic, and diffusion tensor imaging MRI. If this sounds unlikely right now, that’s what most people thought about our ability to land on the moon a mere decade before it happened.

When it comes to the future of psychiatry, I uphold 1 mantra: yes we can and yes we will!

Henry A. Nasrallah, MD
Editor-in-Chief

Depression treatment seems to be in a “funk” these days. Armchair critics, some of whom have never treated a depressed patient, are flooding the media and Internet with allegations that antidepressants—which have helped patients for decades—are no better than placebo.

Several major pharmaceutical companies have pared down or shut down their CNS discovery, research, and development operations. There is a lack of new antidepressants with novel mechanisms of action, and the proportion of refractory or treatment-resistant depression (TRD) seems to be growing. In short, the status of clinical depression seems rather depressing.

Yet nothing can be further from the truth! A vibrant set of innovative, even radical, solutions for TRD are on the horizon. Here are some of the paradigm shifts in the neurobiology and therapeutics of major depression that gradually are toppling decades-old tenets and creeds related to this serious psychiatric disorder:

From genes vs environment to gene × environment interaction. For decades, it was assumed that some people have “endogenous” depression due to genetic determinants, while others are afflicted with “exogenous” depression caused by stressful life events. The new model shows that the environment interacts with genes to produce depression, and that having only risk genes or only environmental stress does not necessarily lead to depression.¹

From ‘chemical imbalance’ to ‘inflammatory process.’ Evidence is accumulating that inflammation may be underpinning depression,² and studies show levels of inflammatory cytokines and interleukins rise during a depressive episode and decline when the depression remits.

From ‘neurotransmitters’ to ‘neuroplasticity and neurotropic factors.’ Current treatments were developed to increase neurotransmitter activity in the brain, but new research reveals that depression is associated with a significant drop in neurotropic factors such as brain derived neurotropic factor (BDNF) or fibroblast growth factor with a concomitant decline in hippocampal neurogenesis.³

From serotonin, norepinephrine, and dopamine to glutamate. Over the past few years, glutamate pathways and the glutamate N-methyl-D-aspartate (NMDA) receptor have emerged as possibly of central importance to the neurobiology of depression.⁴ The link between the strong therapeutic effects of antagonizing the NMDA receptor in depression and the increase in BDNF and neuroplasticity has emerged as a fresh model of depression.

From pills to intravenous infusions. Studies have shown that a single infusion of the NMDA receptor antagonist ketamine produces a very robust response, including full remission, in treatment–resistant unipolar or bipolar depression within 1 to 2 hours!⁵ The mechanism of action has been attributed to a surge of BDNF and immediate neuroplastic changes⁴ following NMDA receptor blockade. This abrupt reversal of severe depression, like turning on a switch, is a total and pleasant surprise.

From monotherapy to augmentation strategies. The rather imprudent notion that a single medication can be effective in a heterogeneous spectrum of disorders such as depression gradually is yielding to intelligent polypharmacy, using evidence-based augmentation strategies that might include lithium, thyroid hormone, another antidepressant (particularly mirtazapine), atypical antipsychotics, anti-inflammatory agents (including omega-3 fatty acids), antioxidants (especially N-acetylcysteine), L-methylfolate, and exercise.

From pharmacotherapy to neuromodulation. Because they disseminate to all organs and not just the brain, medications can cause undesirable side effects. Neuromodulation is used to treat depression by stimulating specific brain regions. Electroconvulsive therapy has a tarnished image but well established efficacy in severe depression. Repetitive transcranial magnetic stimulation and vagus nerve stimulation are FDA-approved for treating depression, while other forms of neuromodulation, such as cranial electrical stimulation, epidural cortical stimulation, focused ultrasound, low field magnetic stimulation, magnetic seizure therapy, near infrared light therapy, and transcranial direct current stimulation, still are in development.⁶ Deep brain stimulation (DBS) has been shown in several recent studies to reverse TRD,^7,8 especially when stimulating the subgenual anterior cingulated region. In the future, DBS may become as commonly used in depression as it currently is in Parkinson’s disease.

A remarkable transformation is underway to reinvent the causes and treatments of depression that will reignite optimism about what psychiatry can do and eliminate the disability associated with major depression. Our patients can hardly wait.

Depression treatment seems to be in a “funk” these days. Armchair critics, some of whom have never treated a depressed patient, are flooding the media and Internet with allegations that antidepressants—which have helped patients for decades—are no better than placebo.

Several major pharmaceutical companies have pared down or shut down their CNS discovery, research, and development operations. There is a lack of new antidepressants with novel mechanisms of action, and the proportion of refractory or treatment-resistant depression (TRD) seems to be growing. In short, the status of clinical depression seems rather depressing.

Yet nothing can be further from the truth! A vibrant set of innovative, even radical, solutions for TRD are on the horizon. Here are some of the paradigm shifts in the neurobiology and therapeutics of major depression that gradually are toppling decades-old tenets and creeds related to this serious psychiatric disorder:

From genes vs environment to gene × environment interaction. For decades, it was assumed that some people have “endogenous” depression due to genetic determinants, while others are afflicted with “exogenous” depression caused by stressful life events. The new model shows that the environment interacts with genes to produce depression, and that having only risk genes or only environmental stress does not necessarily lead to depression.¹

From ‘chemical imbalance’ to ‘inflammatory process.’ Evidence is accumulating that inflammation may be underpinning depression,² and studies show levels of inflammatory cytokines and interleukins rise during a depressive episode and decline when the depression remits.

From ‘neurotransmitters’ to ‘neuroplasticity and neurotropic factors.’ Current treatments were developed to increase neurotransmitter activity in the brain, but new research reveals that depression is associated with a significant drop in neurotropic factors such as brain derived neurotropic factor (BDNF) or fibroblast growth factor with a concomitant decline in hippocampal neurogenesis.³

From serotonin, norepinephrine, and dopamine to glutamate. Over the past few years, glutamate pathways and the glutamate N-methyl-D-aspartate (NMDA) receptor have emerged as possibly of central importance to the neurobiology of depression.⁴ The link between the strong therapeutic effects of antagonizing the NMDA receptor in depression and the increase in BDNF and neuroplasticity has emerged as a fresh model of depression.

From pills to intravenous infusions. Studies have shown that a single infusion of the NMDA receptor antagonist ketamine produces a very robust response, including full remission, in treatment–resistant unipolar or bipolar depression within 1 to 2 hours!⁵ The mechanism of action has been attributed to a surge of BDNF and immediate neuroplastic changes⁴ following NMDA receptor blockade. This abrupt reversal of severe depression, like turning on a switch, is a total and pleasant surprise.

From monotherapy to augmentation strategies. The rather imprudent notion that a single medication can be effective in a heterogeneous spectrum of disorders such as depression gradually is yielding to intelligent polypharmacy, using evidence-based augmentation strategies that might include lithium, thyroid hormone, another antidepressant (particularly mirtazapine), atypical antipsychotics, anti-inflammatory agents (including omega-3 fatty acids), antioxidants (especially N-acetylcysteine), L-methylfolate, and exercise.

From pharmacotherapy to neuromodulation. Because they disseminate to all organs and not just the brain, medications can cause undesirable side effects. Neuromodulation is used to treat depression by stimulating specific brain regions. Electroconvulsive therapy has a tarnished image but well established efficacy in severe depression. Repetitive transcranial magnetic stimulation and vagus nerve stimulation are FDA-approved for treating depression, while other forms of neuromodulation, such as cranial electrical stimulation, epidural cortical stimulation, focused ultrasound, low field magnetic stimulation, magnetic seizure therapy, near infrared light therapy, and transcranial direct current stimulation, still are in development.⁶ Deep brain stimulation (DBS) has been shown in several recent studies to reverse TRD,^7,8 especially when stimulating the subgenual anterior cingulated region. In the future, DBS may become as commonly used in depression as it currently is in Parkinson’s disease.

A remarkable transformation is underway to reinvent the causes and treatments of depression that will reignite optimism about what psychiatry can do and eliminate the disability associated with major depression. Our patients can hardly wait.

Depression treatment seems to be in a “funk” these days. Armchair critics, some of whom have never treated a depressed patient, are flooding the media and Internet with allegations that antidepressants—which have helped patients for decades—are no better than placebo.

Several major pharmaceutical companies have pared down or shut down their CNS discovery, research, and development operations. There is a lack of new antidepressants with novel mechanisms of action, and the proportion of refractory or treatment-resistant depression (TRD) seems to be growing. In short, the status of clinical depression seems rather depressing.

Yet nothing can be further from the truth! A vibrant set of innovative, even radical, solutions for TRD are on the horizon. Here are some of the paradigm shifts in the neurobiology and therapeutics of major depression that gradually are toppling decades-old tenets and creeds related to this serious psychiatric disorder:

From genes vs environment to gene × environment interaction. For decades, it was assumed that some people have “endogenous” depression due to genetic determinants, while others are afflicted with “exogenous” depression caused by stressful life events. The new model shows that the environment interacts with genes to produce depression, and that having only risk genes or only environmental stress does not necessarily lead to depression.¹

From ‘chemical imbalance’ to ‘inflammatory process.’ Evidence is accumulating that inflammation may be underpinning depression,² and studies show levels of inflammatory cytokines and interleukins rise during a depressive episode and decline when the depression remits.

From ‘neurotransmitters’ to ‘neuroplasticity and neurotropic factors.’ Current treatments were developed to increase neurotransmitter activity in the brain, but new research reveals that depression is associated with a significant drop in neurotropic factors such as brain derived neurotropic factor (BDNF) or fibroblast growth factor with a concomitant decline in hippocampal neurogenesis.³

From serotonin, norepinephrine, and dopamine to glutamate. Over the past few years, glutamate pathways and the glutamate N-methyl-D-aspartate (NMDA) receptor have emerged as possibly of central importance to the neurobiology of depression.⁴ The link between the strong therapeutic effects of antagonizing the NMDA receptor in depression and the increase in BDNF and neuroplasticity has emerged as a fresh model of depression.

From pills to intravenous infusions. Studies have shown that a single infusion of the NMDA receptor antagonist ketamine produces a very robust response, including full remission, in treatment–resistant unipolar or bipolar depression within 1 to 2 hours!⁵ The mechanism of action has been attributed to a surge of BDNF and immediate neuroplastic changes⁴ following NMDA receptor blockade. This abrupt reversal of severe depression, like turning on a switch, is a total and pleasant surprise.

From monotherapy to augmentation strategies. The rather imprudent notion that a single medication can be effective in a heterogeneous spectrum of disorders such as depression gradually is yielding to intelligent polypharmacy, using evidence-based augmentation strategies that might include lithium, thyroid hormone, another antidepressant (particularly mirtazapine), atypical antipsychotics, anti-inflammatory agents (including omega-3 fatty acids), antioxidants (especially N-acetylcysteine), L-methylfolate, and exercise.

From pharmacotherapy to neuromodulation. Because they disseminate to all organs and not just the brain, medications can cause undesirable side effects. Neuromodulation is used to treat depression by stimulating specific brain regions. Electroconvulsive therapy has a tarnished image but well established efficacy in severe depression. Repetitive transcranial magnetic stimulation and vagus nerve stimulation are FDA-approved for treating depression, while other forms of neuromodulation, such as cranial electrical stimulation, epidural cortical stimulation, focused ultrasound, low field magnetic stimulation, magnetic seizure therapy, near infrared light therapy, and transcranial direct current stimulation, still are in development.⁶ Deep brain stimulation (DBS) has been shown in several recent studies to reverse TRD,^7,8 especially when stimulating the subgenual anterior cingulated region. In the future, DBS may become as commonly used in depression as it currently is in Parkinson’s disease.

A remarkable transformation is underway to reinvent the causes and treatments of depression that will reignite optimism about what psychiatry can do and eliminate the disability associated with major depression. Our patients can hardly wait.

Discuss this article at www.facebook.com/CurrentPsychiatry

Many psychiatric and medical illnesses—as well as normal reactions to stressors—have symptoms that overlap with those of depressive disorders, including outwardly sad or dysphoric appearance, irritability, apathy or amotivation, fatigue, difficulty making decisions, social withdrawal, and sleep disturbances. This cluster of symptoms forms a readily observable behavioral phenotype that clinicians may label as depression before considering a broader differential diagnosis.

To better understand what other conditions belong in the differential diagnosis, we reviewed a sample of 100 consecutive medical/surgical inpatients referred to our consultation-liaison psychiatry practice for evaluation of “depression.” Ultimately, only 29 of these patients received a depression diagnosis. Many of the other diagnoses given in our sample required attention during inpatient medical or surgical care because they were potentially life-threatening if left unaddressed—such as delirium—or they interfered with managing the primary medical or surgical condition for which the patient was hospitalized.

Hurried or uncertain primary care clinicians frequently use “depression” as a catch-all term when requesting psychiatric consultation for patients who seem depressed. A wide range of conditions can mimic depression, and the art of psychosomatic psychiatry includes considering protean possibilities when assessing a patient. We identified 7 diagnoses that mimic major depression and developed our “8 D” differential to help clinicians properly diagnose “depressed” patients who have something other than a depressive disorder. Although our sample consisted of hospitalized patients, these mimics of depression may be found among patients referred from other clinical settings for evaluation of possible depression.

The perils of misdiagnosis

Depression is common among patients hospitalized with medical or surgical conditions. DSM-IV-TR diagnostic criteria for a major depressive episode (MDE) include the presence of low mood and/or anhedonia, plus ≥4 other depressive symptoms for ≥2 weeks.¹ Growing evidence suggests that the relationship between depression and morbidity and mortality in medical illness is bidirectional, and nonpsychiatrists are becoming increasingly aware of major depression’s serious impact on their patients’ physical health.^2-5

Although improving nonpsychiatrists’ recognition of depression in medically ill patients is laudable, it comes with a high false-positive rate. In a study of primary care outpatients, Berardi et al found that 45% of patients labeled “depressed” did not meet ICD-10 criteria for major depression, but >25% of those patients were prescribed an antidepressant.⁶ In a large retrospective study, Boland et al found that approximately 40% of patients referred to an inpatient psychiatric consultation service for depression did not meet criteria for a depressive illness, and primary medical services often confused organic syndromes such as delirium and dementia with depression.⁷ Similarly, Clarke et al found that 26% of medical and surgical inpatients referred to psychiatry with “depression” had another diagnosis—commonly delirium—that better accounted for their symptoms.⁸

What is the harm in overdiagnosing depression? Missing a serious or life-threatening diagnosis is a primary concern. For example, unrecognized delirium, which frequently was misdiagnosed as depression in the Berardi,⁶ Boland,⁷ and Clarke⁸ studies, is associated with myriad difficulties, including higher morbidity and mortality.⁹ Substance use disorders, which also commonly masquerade as depression, frequently are comorbid with medical illness. Delays in appropriate treatment of withdrawal syndromes—particularly of alcohol and sedative/hypnotic medications—are risk factors for increased mortality in these illnesses.¹⁰

Inappropriate, potentially harmful interventions are another concern. Many patients diagnosed with depression are prescribed antidepressants, but this is not always a benign intervention. Smith et al found that >10% of adult medical inpatients referred to a psychiatry consultation service who were started on an antidepressant had an adverse drug reaction severe enough to warrant discontinuing the medication.¹¹ Antidepressant side effects relevant to medically ill patients include hyponatremia, serotonin syndrome, and exacerbation of delirium.¹²

Polypharmacy in medically ill patients increases the risk for serious drug-drug interactions. For example, serotonergic antidepressants can increase the risk for serotonin syndrome when combined with the analgesic tramadol, which has serotonergic activity,¹³ or the antibiotic linezolid, which is a reversible monoamine oxidase inhibitor.¹⁴ Many antidepressants—including paroxetine, fluoxetine, bupropion, sertraline, and duloxetine—are moderate to strong inhibitors of cytochrome P450 2D6 and therefore affect metabolism of many medications, including several beta blockers and antiarrhythmics, as well as the anti-estrogen tamoxifen. In the case of tamoxifen, which is a prodrug converted to active form by 2D6, concomitant use of a 2D6 inhibitor can substantially reduce the medication’s in vivo efficacy and lead to higher morbidity and mortality in breast cancer patients.¹⁵ As with any treatment, a decision to prescribe antidepressants needs to carefully be weighed in light of individual risks and benefits. This analysis starts by ensuring that an antidepressant is indicated.

Another concern is failing to recognize immediate human suffering for what it is. Hospitals and doctors’ offices are places of pain and loss as patients encounter morbidity and mortality in themselves and their loved ones. Rushing to pathologize the psychological or social manifestations of this pain can be invalidating to patients and may impair the doctor-patient relationship.

The 8 Ds

To determine what these “depression lookalike” syndromes could be, we identified 100 consecutive consultations to our adult inpatient psychiatry consultation-liaison team with a question of “depression.” We reviewed each patient’s chart, and recorded the diagnosis the psychiatrist gave to explain the patient’s depressed appearance. Data were recorded without patient identifiers, and the Mayo Clinic institutional review board (IRB) determined this study was exempt from IRB review.

Our sample included 45 men and 55 women with an average age of 48 (range: 18 to 91). On evaluation, 3 patients were given no psychiatric diagnosis, 29 were categorized as depressed, and 68 fell into one of 7 other “D” categories we describe below.

Depressed. These patients met criteria for a MDE in the context of major depressive disorder (MDD) or bipolar disorder, dysthymic disorder, mood disorder due to a general medical condition, substance-induced mood disorder, or depressive disorder not otherwise specified.

Demoralized. Patients who had difficulty adjusting to or coping with illness, and received a DSM-IV-TR diagnosis of adjustment disorder with the illness as the inciting stressor were placed in this category. Consistent with adjustment disorder criteria, these patients did not have depressive symptoms of sufficient intensity or duration to meet criteria for MDD or another primary mood disorder.

Difficult. For these patients, the primary issue was a breakdown in the therapeutic alliance with their treatment team. They received DSM-IV-TR diagnoses of personality disorder, noncompliance with treatment, or adult antisocial behavior.

Drugged. Patients in this category appeared depressed as a result of illicit substance use or misuse of alcohol or pharmaceuticals. DSM-IV-TR diagnoses included substance intoxication or withdrawal and substance abuse or dependence.

Delirious. This group consisted of patients with acute disruption in attention and level of consciousness that met DSM-IV-TR criteria for delirium. Patients whose delirious appearance was the result of illicit substance use or pharmaceutical misuse were categorized as “Drugged” rather than “Delirious.”

Disaffiliated. Patients in this category had dysphoria not commensurate with a full-blown mood disorder but attributable to grief from losing a major relationship to death, separation, or divorce. These patients received a DSM-IV-TR diagnosis of bereavement or a partner relational problem.

Delusional. These patients demonstrated amotivation and affective blunting as a result of a primary psychotic disorder such as schizophrenia. In preparation for emergent surgery, these patients had been prevented from taking anything orally, including antipsychotics, and their antipsychotics had not been restarted, which precipitated a gradual return of psychotic symptoms in the days after surgery.

Dulled. Two patients in our sample had irreversible cognitive deficits that explained their withdrawal and blunted affect; 1 had dementia and the other had mental retardation.

Managing the other Ds

In our sample, the most commonly misdiagnosed patients were those having difficulty adjusting to illness (Demoralized) or to other life events (Disaffiliated) (Table 1). In these cases, misdiagnosis has substantial treatment implications because these patients are better served by acute, illness-specific interventions that bolster coping skills, rather than pharmacotherapy or psychotherapy that targets entrenched depressive symptoms. For these patients, psychiatrists may “prescribe” interventions such as visits with a chaplain or other spiritual advisor, telephone calls or visits from family, friends, and other social supports, participation in physical or occupational therapy to improve adaptive functioning, or connecting with other patients in similar situations. Often, the key with these patients is to identify ways they have managed previous stressors and creatively use those resources to adapt to their new situation.

A second large group in our sample consisted of patients actively or passively fighting with their treatment team—the Difficult (Table 2). The treatment team or the patient’s caregivers and loved ones often are more distressed by the “difficult” patient’s symptoms than the patient, who may instead focus on his or her disappointment with caregivers who are unable to meet the patient’s unreasonable expectations. These challenges typically can be addressed by clarifying the salient issues for both the patient and team and establishing a liaison between patient and team to improve communication among all parties. Multidisciplinary care conferences can be an excellent way to ensure that the care team provides the patient with consistent communication and care.

A third group had potentially life-threatening conditions such as substance abuse/withdrawal or delirium as the cause of their “depressive” symptoms—the Drugged and the Delirious (Table 3). Recognizing an organic etiology of mood or behavioral symptoms is important because managing the underlying problem is the primary treatment strategy, not psychopharmacologic or psychotherapeutic intervention. Early identification and appropriate management of these patients could prevent further deterioration, improve medical outcomes, and shorten length of hospital stay.

A final group of patients was those whose chronic psychiatric and cognitive issues may go unrecognized or unappreciated until they interfere with the patient’s medical care—the Delusional and the Dulled (Table 2). In these cases, the correct diagnosis often hinges on obtaining a thorough history through collateral sources. The consulting psychiatrist can be crucial in co-managing these patients by establishing a liaison with outpatient providers, suggesting in-hospital management strategies such as alternate routes of administration of antipsychotics for patients with psychotic disorders, and connecting patients with outpatient supports after hospitalization. Continuity between inpatient and outpatient management is necessary to ensure a successful medical and psychiatric outcome.

Our 8 Ds are limited to the subset of patients referred by their medical teams with a question of depression. These referrals may have been motivated by a variety of patient, family, and team factors above and beyond the categories discussed in this article, and therefore may not accurately represent all patients who present with depressive symptoms in an inpatient setting. However, we hope that providing a mnemonic that suggests an extensive differential for a depressed phenotype may improve identification and management of these issues.

Table 1

Psychological crises that may look like depression

Table 2

Differentiating patients with social challenges from those with depression

Table 3

Substance abuse and delirium can mimic depression

Related Resources

• Stern TA, Fricchione GL, Cassem NH, et al, eds. Massachusetts General Hospital handbook of general hospital psychiatry, 6th ed. Philadelphia, PA: Saunders Elsevier; 2010.
• Levenson JL, ed. The American Psychiatric Publishing textbook of psychosomatic medicine. 2nd ed. Arlington, VA: American Psychiatric Publishing, Inc.; 2011.
• Academy of Psychosomatic Medicine. www.apm.org.
• Caplan JP, Stern TA. Mnemonics in a mnutshell: 32 aids to psychiatric diagnosis. Current Psychiatry. 2008;7(10):27-33.

Drug Brand Names

• Bupropion • Wellbutrin, Zyban
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Linezolid • Zyvox
• Paroxetine • Paxil
• Sertraline • Zoloft
• Tamoxifen • Nolvadex
• Tramadol • Ultracet

Disclosures

Dr. Bostwick reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Rackley receives research/grant support from the Maternal and Child Health Bureau, Health Resources and Services Administration, U.S. Department of Health and Human Services, for a Collaborative Office Rounds program with primary care pediatricians.

Discuss this article at www.facebook.com/CurrentPsychiatry

Many psychiatric and medical illnesses—as well as normal reactions to stressors—have symptoms that overlap with those of depressive disorders, including outwardly sad or dysphoric appearance, irritability, apathy or amotivation, fatigue, difficulty making decisions, social withdrawal, and sleep disturbances. This cluster of symptoms forms a readily observable behavioral phenotype that clinicians may label as depression before considering a broader differential diagnosis.

To better understand what other conditions belong in the differential diagnosis, we reviewed a sample of 100 consecutive medical/surgical inpatients referred to our consultation-liaison psychiatry practice for evaluation of “depression.” Ultimately, only 29 of these patients received a depression diagnosis. Many of the other diagnoses given in our sample required attention during inpatient medical or surgical care because they were potentially life-threatening if left unaddressed—such as delirium—or they interfered with managing the primary medical or surgical condition for which the patient was hospitalized.

Hurried or uncertain primary care clinicians frequently use “depression” as a catch-all term when requesting psychiatric consultation for patients who seem depressed. A wide range of conditions can mimic depression, and the art of psychosomatic psychiatry includes considering protean possibilities when assessing a patient. We identified 7 diagnoses that mimic major depression and developed our “8 D” differential to help clinicians properly diagnose “depressed” patients who have something other than a depressive disorder. Although our sample consisted of hospitalized patients, these mimics of depression may be found among patients referred from other clinical settings for evaluation of possible depression.

The perils of misdiagnosis

Depression is common among patients hospitalized with medical or surgical conditions. DSM-IV-TR diagnostic criteria for a major depressive episode (MDE) include the presence of low mood and/or anhedonia, plus ≥4 other depressive symptoms for ≥2 weeks.¹ Growing evidence suggests that the relationship between depression and morbidity and mortality in medical illness is bidirectional, and nonpsychiatrists are becoming increasingly aware of major depression’s serious impact on their patients’ physical health.^2-5

Although improving nonpsychiatrists’ recognition of depression in medically ill patients is laudable, it comes with a high false-positive rate. In a study of primary care outpatients, Berardi et al found that 45% of patients labeled “depressed” did not meet ICD-10 criteria for major depression, but >25% of those patients were prescribed an antidepressant.⁶ In a large retrospective study, Boland et al found that approximately 40% of patients referred to an inpatient psychiatric consultation service for depression did not meet criteria for a depressive illness, and primary medical services often confused organic syndromes such as delirium and dementia with depression.⁷ Similarly, Clarke et al found that 26% of medical and surgical inpatients referred to psychiatry with “depression” had another diagnosis—commonly delirium—that better accounted for their symptoms.⁸

What is the harm in overdiagnosing depression? Missing a serious or life-threatening diagnosis is a primary concern. For example, unrecognized delirium, which frequently was misdiagnosed as depression in the Berardi,⁶ Boland,⁷ and Clarke⁸ studies, is associated with myriad difficulties, including higher morbidity and mortality.⁹ Substance use disorders, which also commonly masquerade as depression, frequently are comorbid with medical illness. Delays in appropriate treatment of withdrawal syndromes—particularly of alcohol and sedative/hypnotic medications—are risk factors for increased mortality in these illnesses.¹⁰

Inappropriate, potentially harmful interventions are another concern. Many patients diagnosed with depression are prescribed antidepressants, but this is not always a benign intervention. Smith et al found that >10% of adult medical inpatients referred to a psychiatry consultation service who were started on an antidepressant had an adverse drug reaction severe enough to warrant discontinuing the medication.¹¹ Antidepressant side effects relevant to medically ill patients include hyponatremia, serotonin syndrome, and exacerbation of delirium.¹²

Polypharmacy in medically ill patients increases the risk for serious drug-drug interactions. For example, serotonergic antidepressants can increase the risk for serotonin syndrome when combined with the analgesic tramadol, which has serotonergic activity,¹³ or the antibiotic linezolid, which is a reversible monoamine oxidase inhibitor.¹⁴ Many antidepressants—including paroxetine, fluoxetine, bupropion, sertraline, and duloxetine—are moderate to strong inhibitors of cytochrome P450 2D6 and therefore affect metabolism of many medications, including several beta blockers and antiarrhythmics, as well as the anti-estrogen tamoxifen. In the case of tamoxifen, which is a prodrug converted to active form by 2D6, concomitant use of a 2D6 inhibitor can substantially reduce the medication’s in vivo efficacy and lead to higher morbidity and mortality in breast cancer patients.¹⁵ As with any treatment, a decision to prescribe antidepressants needs to carefully be weighed in light of individual risks and benefits. This analysis starts by ensuring that an antidepressant is indicated.

Another concern is failing to recognize immediate human suffering for what it is. Hospitals and doctors’ offices are places of pain and loss as patients encounter morbidity and mortality in themselves and their loved ones. Rushing to pathologize the psychological or social manifestations of this pain can be invalidating to patients and may impair the doctor-patient relationship.

The 8 Ds

To determine what these “depression lookalike” syndromes could be, we identified 100 consecutive consultations to our adult inpatient psychiatry consultation-liaison team with a question of “depression.” We reviewed each patient’s chart, and recorded the diagnosis the psychiatrist gave to explain the patient’s depressed appearance. Data were recorded without patient identifiers, and the Mayo Clinic institutional review board (IRB) determined this study was exempt from IRB review.

Our sample included 45 men and 55 women with an average age of 48 (range: 18 to 91). On evaluation, 3 patients were given no psychiatric diagnosis, 29 were categorized as depressed, and 68 fell into one of 7 other “D” categories we describe below.

Depressed. These patients met criteria for a MDE in the context of major depressive disorder (MDD) or bipolar disorder, dysthymic disorder, mood disorder due to a general medical condition, substance-induced mood disorder, or depressive disorder not otherwise specified.

Demoralized. Patients who had difficulty adjusting to or coping with illness, and received a DSM-IV-TR diagnosis of adjustment disorder with the illness as the inciting stressor were placed in this category. Consistent with adjustment disorder criteria, these patients did not have depressive symptoms of sufficient intensity or duration to meet criteria for MDD or another primary mood disorder.

Difficult. For these patients, the primary issue was a breakdown in the therapeutic alliance with their treatment team. They received DSM-IV-TR diagnoses of personality disorder, noncompliance with treatment, or adult antisocial behavior.

Drugged. Patients in this category appeared depressed as a result of illicit substance use or misuse of alcohol or pharmaceuticals. DSM-IV-TR diagnoses included substance intoxication or withdrawal and substance abuse or dependence.

Delirious. This group consisted of patients with acute disruption in attention and level of consciousness that met DSM-IV-TR criteria for delirium. Patients whose delirious appearance was the result of illicit substance use or pharmaceutical misuse were categorized as “Drugged” rather than “Delirious.”

Disaffiliated. Patients in this category had dysphoria not commensurate with a full-blown mood disorder but attributable to grief from losing a major relationship to death, separation, or divorce. These patients received a DSM-IV-TR diagnosis of bereavement or a partner relational problem.

Delusional. These patients demonstrated amotivation and affective blunting as a result of a primary psychotic disorder such as schizophrenia. In preparation for emergent surgery, these patients had been prevented from taking anything orally, including antipsychotics, and their antipsychotics had not been restarted, which precipitated a gradual return of psychotic symptoms in the days after surgery.

Dulled. Two patients in our sample had irreversible cognitive deficits that explained their withdrawal and blunted affect; 1 had dementia and the other had mental retardation.

Managing the other Ds

In our sample, the most commonly misdiagnosed patients were those having difficulty adjusting to illness (Demoralized) or to other life events (Disaffiliated) (Table 1). In these cases, misdiagnosis has substantial treatment implications because these patients are better served by acute, illness-specific interventions that bolster coping skills, rather than pharmacotherapy or psychotherapy that targets entrenched depressive symptoms. For these patients, psychiatrists may “prescribe” interventions such as visits with a chaplain or other spiritual advisor, telephone calls or visits from family, friends, and other social supports, participation in physical or occupational therapy to improve adaptive functioning, or connecting with other patients in similar situations. Often, the key with these patients is to identify ways they have managed previous stressors and creatively use those resources to adapt to their new situation.

A second large group in our sample consisted of patients actively or passively fighting with their treatment team—the Difficult (Table 2). The treatment team or the patient’s caregivers and loved ones often are more distressed by the “difficult” patient’s symptoms than the patient, who may instead focus on his or her disappointment with caregivers who are unable to meet the patient’s unreasonable expectations. These challenges typically can be addressed by clarifying the salient issues for both the patient and team and establishing a liaison between patient and team to improve communication among all parties. Multidisciplinary care conferences can be an excellent way to ensure that the care team provides the patient with consistent communication and care.

A third group had potentially life-threatening conditions such as substance abuse/withdrawal or delirium as the cause of their “depressive” symptoms—the Drugged and the Delirious (Table 3). Recognizing an organic etiology of mood or behavioral symptoms is important because managing the underlying problem is the primary treatment strategy, not psychopharmacologic or psychotherapeutic intervention. Early identification and appropriate management of these patients could prevent further deterioration, improve medical outcomes, and shorten length of hospital stay.

A final group of patients was those whose chronic psychiatric and cognitive issues may go unrecognized or unappreciated until they interfere with the patient’s medical care—the Delusional and the Dulled (Table 2). In these cases, the correct diagnosis often hinges on obtaining a thorough history through collateral sources. The consulting psychiatrist can be crucial in co-managing these patients by establishing a liaison with outpatient providers, suggesting in-hospital management strategies such as alternate routes of administration of antipsychotics for patients with psychotic disorders, and connecting patients with outpatient supports after hospitalization. Continuity between inpatient and outpatient management is necessary to ensure a successful medical and psychiatric outcome.

Our 8 Ds are limited to the subset of patients referred by their medical teams with a question of depression. These referrals may have been motivated by a variety of patient, family, and team factors above and beyond the categories discussed in this article, and therefore may not accurately represent all patients who present with depressive symptoms in an inpatient setting. However, we hope that providing a mnemonic that suggests an extensive differential for a depressed phenotype may improve identification and management of these issues.

Table 1

Psychological crises that may look like depression

Table 2

Differentiating patients with social challenges from those with depression

Table 3

Substance abuse and delirium can mimic depression

Related Resources

• Stern TA, Fricchione GL, Cassem NH, et al, eds. Massachusetts General Hospital handbook of general hospital psychiatry, 6th ed. Philadelphia, PA: Saunders Elsevier; 2010.
• Levenson JL, ed. The American Psychiatric Publishing textbook of psychosomatic medicine. 2nd ed. Arlington, VA: American Psychiatric Publishing, Inc.; 2011.
• Academy of Psychosomatic Medicine. www.apm.org.
• Caplan JP, Stern TA. Mnemonics in a mnutshell: 32 aids to psychiatric diagnosis. Current Psychiatry. 2008;7(10):27-33.

Drug Brand Names

• Bupropion • Wellbutrin, Zyban
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Linezolid • Zyvox
• Paroxetine • Paxil
• Sertraline • Zoloft
• Tamoxifen • Nolvadex
• Tramadol • Ultracet

Disclosures

Dr. Bostwick reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Rackley receives research/grant support from the Maternal and Child Health Bureau, Health Resources and Services Administration, U.S. Department of Health and Human Services, for a Collaborative Office Rounds program with primary care pediatricians.

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Many psychiatric and medical illnesses—as well as normal reactions to stressors—have symptoms that overlap with those of depressive disorders, including outwardly sad or dysphoric appearance, irritability, apathy or amotivation, fatigue, difficulty making decisions, social withdrawal, and sleep disturbances. This cluster of symptoms forms a readily observable behavioral phenotype that clinicians may label as depression before considering a broader differential diagnosis.

To better understand what other conditions belong in the differential diagnosis, we reviewed a sample of 100 consecutive medical/surgical inpatients referred to our consultation-liaison psychiatry practice for evaluation of “depression.” Ultimately, only 29 of these patients received a depression diagnosis. Many of the other diagnoses given in our sample required attention during inpatient medical or surgical care because they were potentially life-threatening if left unaddressed—such as delirium—or they interfered with managing the primary medical or surgical condition for which the patient was hospitalized.

Hurried or uncertain primary care clinicians frequently use “depression” as a catch-all term when requesting psychiatric consultation for patients who seem depressed. A wide range of conditions can mimic depression, and the art of psychosomatic psychiatry includes considering protean possibilities when assessing a patient. We identified 7 diagnoses that mimic major depression and developed our “8 D” differential to help clinicians properly diagnose “depressed” patients who have something other than a depressive disorder. Although our sample consisted of hospitalized patients, these mimics of depression may be found among patients referred from other clinical settings for evaluation of possible depression.

The perils of misdiagnosis

Depression is common among patients hospitalized with medical or surgical conditions. DSM-IV-TR diagnostic criteria for a major depressive episode (MDE) include the presence of low mood and/or anhedonia, plus ≥4 other depressive symptoms for ≥2 weeks.¹ Growing evidence suggests that the relationship between depression and morbidity and mortality in medical illness is bidirectional, and nonpsychiatrists are becoming increasingly aware of major depression’s serious impact on their patients’ physical health.^2-5

Although improving nonpsychiatrists’ recognition of depression in medically ill patients is laudable, it comes with a high false-positive rate. In a study of primary care outpatients, Berardi et al found that 45% of patients labeled “depressed” did not meet ICD-10 criteria for major depression, but >25% of those patients were prescribed an antidepressant.⁶ In a large retrospective study, Boland et al found that approximately 40% of patients referred to an inpatient psychiatric consultation service for depression did not meet criteria for a depressive illness, and primary medical services often confused organic syndromes such as delirium and dementia with depression.⁷ Similarly, Clarke et al found that 26% of medical and surgical inpatients referred to psychiatry with “depression” had another diagnosis—commonly delirium—that better accounted for their symptoms.⁸

What is the harm in overdiagnosing depression? Missing a serious or life-threatening diagnosis is a primary concern. For example, unrecognized delirium, which frequently was misdiagnosed as depression in the Berardi,⁶ Boland,⁷ and Clarke⁸ studies, is associated with myriad difficulties, including higher morbidity and mortality.⁹ Substance use disorders, which also commonly masquerade as depression, frequently are comorbid with medical illness. Delays in appropriate treatment of withdrawal syndromes—particularly of alcohol and sedative/hypnotic medications—are risk factors for increased mortality in these illnesses.¹⁰

Inappropriate, potentially harmful interventions are another concern. Many patients diagnosed with depression are prescribed antidepressants, but this is not always a benign intervention. Smith et al found that >10% of adult medical inpatients referred to a psychiatry consultation service who were started on an antidepressant had an adverse drug reaction severe enough to warrant discontinuing the medication.¹¹ Antidepressant side effects relevant to medically ill patients include hyponatremia, serotonin syndrome, and exacerbation of delirium.¹²

Polypharmacy in medically ill patients increases the risk for serious drug-drug interactions. For example, serotonergic antidepressants can increase the risk for serotonin syndrome when combined with the analgesic tramadol, which has serotonergic activity,¹³ or the antibiotic linezolid, which is a reversible monoamine oxidase inhibitor.¹⁴ Many antidepressants—including paroxetine, fluoxetine, bupropion, sertraline, and duloxetine—are moderate to strong inhibitors of cytochrome P450 2D6 and therefore affect metabolism of many medications, including several beta blockers and antiarrhythmics, as well as the anti-estrogen tamoxifen. In the case of tamoxifen, which is a prodrug converted to active form by 2D6, concomitant use of a 2D6 inhibitor can substantially reduce the medication’s in vivo efficacy and lead to higher morbidity and mortality in breast cancer patients.¹⁵ As with any treatment, a decision to prescribe antidepressants needs to carefully be weighed in light of individual risks and benefits. This analysis starts by ensuring that an antidepressant is indicated.

Another concern is failing to recognize immediate human suffering for what it is. Hospitals and doctors’ offices are places of pain and loss as patients encounter morbidity and mortality in themselves and their loved ones. Rushing to pathologize the psychological or social manifestations of this pain can be invalidating to patients and may impair the doctor-patient relationship.

The 8 Ds

To determine what these “depression lookalike” syndromes could be, we identified 100 consecutive consultations to our adult inpatient psychiatry consultation-liaison team with a question of “depression.” We reviewed each patient’s chart, and recorded the diagnosis the psychiatrist gave to explain the patient’s depressed appearance. Data were recorded without patient identifiers, and the Mayo Clinic institutional review board (IRB) determined this study was exempt from IRB review.

Our sample included 45 men and 55 women with an average age of 48 (range: 18 to 91). On evaluation, 3 patients were given no psychiatric diagnosis, 29 were categorized as depressed, and 68 fell into one of 7 other “D” categories we describe below.

Depressed. These patients met criteria for a MDE in the context of major depressive disorder (MDD) or bipolar disorder, dysthymic disorder, mood disorder due to a general medical condition, substance-induced mood disorder, or depressive disorder not otherwise specified.

Demoralized. Patients who had difficulty adjusting to or coping with illness, and received a DSM-IV-TR diagnosis of adjustment disorder with the illness as the inciting stressor were placed in this category. Consistent with adjustment disorder criteria, these patients did not have depressive symptoms of sufficient intensity or duration to meet criteria for MDD or another primary mood disorder.

Difficult. For these patients, the primary issue was a breakdown in the therapeutic alliance with their treatment team. They received DSM-IV-TR diagnoses of personality disorder, noncompliance with treatment, or adult antisocial behavior.

Drugged. Patients in this category appeared depressed as a result of illicit substance use or misuse of alcohol or pharmaceuticals. DSM-IV-TR diagnoses included substance intoxication or withdrawal and substance abuse or dependence.

Delirious. This group consisted of patients with acute disruption in attention and level of consciousness that met DSM-IV-TR criteria for delirium. Patients whose delirious appearance was the result of illicit substance use or pharmaceutical misuse were categorized as “Drugged” rather than “Delirious.”

Disaffiliated. Patients in this category had dysphoria not commensurate with a full-blown mood disorder but attributable to grief from losing a major relationship to death, separation, or divorce. These patients received a DSM-IV-TR diagnosis of bereavement or a partner relational problem.

Delusional. These patients demonstrated amotivation and affective blunting as a result of a primary psychotic disorder such as schizophrenia. In preparation for emergent surgery, these patients had been prevented from taking anything orally, including antipsychotics, and their antipsychotics had not been restarted, which precipitated a gradual return of psychotic symptoms in the days after surgery.

Dulled. Two patients in our sample had irreversible cognitive deficits that explained their withdrawal and blunted affect; 1 had dementia and the other had mental retardation.

Managing the other Ds

In our sample, the most commonly misdiagnosed patients were those having difficulty adjusting to illness (Demoralized) or to other life events (Disaffiliated) (Table 1). In these cases, misdiagnosis has substantial treatment implications because these patients are better served by acute, illness-specific interventions that bolster coping skills, rather than pharmacotherapy or psychotherapy that targets entrenched depressive symptoms. For these patients, psychiatrists may “prescribe” interventions such as visits with a chaplain or other spiritual advisor, telephone calls or visits from family, friends, and other social supports, participation in physical or occupational therapy to improve adaptive functioning, or connecting with other patients in similar situations. Often, the key with these patients is to identify ways they have managed previous stressors and creatively use those resources to adapt to their new situation.

A second large group in our sample consisted of patients actively or passively fighting with their treatment team—the Difficult (Table 2). The treatment team or the patient’s caregivers and loved ones often are more distressed by the “difficult” patient’s symptoms than the patient, who may instead focus on his or her disappointment with caregivers who are unable to meet the patient’s unreasonable expectations. These challenges typically can be addressed by clarifying the salient issues for both the patient and team and establishing a liaison between patient and team to improve communication among all parties. Multidisciplinary care conferences can be an excellent way to ensure that the care team provides the patient with consistent communication and care.

A third group had potentially life-threatening conditions such as substance abuse/withdrawal or delirium as the cause of their “depressive” symptoms—the Drugged and the Delirious (Table 3). Recognizing an organic etiology of mood or behavioral symptoms is important because managing the underlying problem is the primary treatment strategy, not psychopharmacologic or psychotherapeutic intervention. Early identification and appropriate management of these patients could prevent further deterioration, improve medical outcomes, and shorten length of hospital stay.

A final group of patients was those whose chronic psychiatric and cognitive issues may go unrecognized or unappreciated until they interfere with the patient’s medical care—the Delusional and the Dulled (Table 2). In these cases, the correct diagnosis often hinges on obtaining a thorough history through collateral sources. The consulting psychiatrist can be crucial in co-managing these patients by establishing a liaison with outpatient providers, suggesting in-hospital management strategies such as alternate routes of administration of antipsychotics for patients with psychotic disorders, and connecting patients with outpatient supports after hospitalization. Continuity between inpatient and outpatient management is necessary to ensure a successful medical and psychiatric outcome.

Our 8 Ds are limited to the subset of patients referred by their medical teams with a question of depression. These referrals may have been motivated by a variety of patient, family, and team factors above and beyond the categories discussed in this article, and therefore may not accurately represent all patients who present with depressive symptoms in an inpatient setting. However, we hope that providing a mnemonic that suggests an extensive differential for a depressed phenotype may improve identification and management of these issues.

Table 1

Psychological crises that may look like depression

Table 2

Differentiating patients with social challenges from those with depression

Table 3

Substance abuse and delirium can mimic depression

Related Resources

• Stern TA, Fricchione GL, Cassem NH, et al, eds. Massachusetts General Hospital handbook of general hospital psychiatry, 6th ed. Philadelphia, PA: Saunders Elsevier; 2010.
• Levenson JL, ed. The American Psychiatric Publishing textbook of psychosomatic medicine. 2nd ed. Arlington, VA: American Psychiatric Publishing, Inc.; 2011.
• Academy of Psychosomatic Medicine. www.apm.org.
• Caplan JP, Stern TA. Mnemonics in a mnutshell: 32 aids to psychiatric diagnosis. Current Psychiatry. 2008;7(10):27-33.

Drug Brand Names

• Bupropion • Wellbutrin, Zyban
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Linezolid • Zyvox
• Paroxetine • Paxil
• Sertraline • Zoloft
• Tamoxifen • Nolvadex
• Tramadol • Ultracet

Disclosures

Dr. Bostwick reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Rackley receives research/grant support from the Maternal and Child Health Bureau, Health Resources and Services Administration, U.S. Department of Health and Human Services, for a Collaborative Office Rounds program with primary care pediatricians.

In reference to the “antipsychiatry” editorial by Dr. Henry A. Nasrallah (“The antipsychiatry movement: Who and why,” From the Editor, Current Psychiatry, December 2011, p. 4-6, 53): many years ago, when I was working at Chestnut Lodge, the family of a hospitalized patient asked Dr. Thomas Szasz to evaluate—as a consultant and “antipsychiatrist”—what should be done for this patient. Contrary to the family’s expectations, Dr. Szasz’s opinion was that the patient needed psychiatric treatment and hospitalization.

As a resident at Yale University, I knew Dr. Theodore Lidz very well. It is true that at a time of limited biological knowledge, he emphasized family dynamics as contributing to severe psychopathology, but he did not—to my knowledge—object to electroconvulsive therapy for a particular catatonic patient. His being demonized as an “antipsychiatrist” offends me because it misrepresents him.

John S. Kafka, MD
Private Practice
Washington, DC

In reference to the “antipsychiatry” editorial by Dr. Henry A. Nasrallah (“The antipsychiatry movement: Who and why,” From the Editor, Current Psychiatry, December 2011, p. 4-6, 53): many years ago, when I was working at Chestnut Lodge, the family of a hospitalized patient asked Dr. Thomas Szasz to evaluate—as a consultant and “antipsychiatrist”—what should be done for this patient. Contrary to the family’s expectations, Dr. Szasz’s opinion was that the patient needed psychiatric treatment and hospitalization.

As a resident at Yale University, I knew Dr. Theodore Lidz very well. It is true that at a time of limited biological knowledge, he emphasized family dynamics as contributing to severe psychopathology, but he did not—to my knowledge—object to electroconvulsive therapy for a particular catatonic patient. His being demonized as an “antipsychiatrist” offends me because it misrepresents him.

John S. Kafka, MD
Private Practice
Washington, DC

In reference to the “antipsychiatry” editorial by Dr. Henry A. Nasrallah (“The antipsychiatry movement: Who and why,” From the Editor, Current Psychiatry, December 2011, p. 4-6, 53): many years ago, when I was working at Chestnut Lodge, the family of a hospitalized patient asked Dr. Thomas Szasz to evaluate—as a consultant and “antipsychiatrist”—what should be done for this patient. Contrary to the family’s expectations, Dr. Szasz’s opinion was that the patient needed psychiatric treatment and hospitalization.

As a resident at Yale University, I knew Dr. Theodore Lidz very well. It is true that at a time of limited biological knowledge, he emphasized family dynamics as contributing to severe psychopathology, but he did not—to my knowledge—object to electroconvulsive therapy for a particular catatonic patient. His being demonized as an “antipsychiatrist” offends me because it misrepresents him.

John S. Kafka, MD
Private Practice
Washington, DC

Recently, when The Dr. Oz Show’s Dr. Mehmet Oz turned to his television audience to ask if anyone had heard of transcranial magnetic stimulation (TMS) after a demonstration of its effectiveness in treatment-resistant depression (TRD), no one in the audience raised their hands.

I wonder why Drs. Desseilles, Fava, Mischoulon, and Freeman did not discuss TMS as an important choice for TRD in their article (“Personalizing depression treatment: 2 clinical tools,” Current Psychiatry, March 2012, p. 26-33). Harvard Medical School has done trials of TMS and McLean Hospital has created a positive video on TMS.

Andrew Krompier, MD
Private Practice
San Ramon, CA

Recently, when The Dr. Oz Show’s Dr. Mehmet Oz turned to his television audience to ask if anyone had heard of transcranial magnetic stimulation (TMS) after a demonstration of its effectiveness in treatment-resistant depression (TRD), no one in the audience raised their hands.

I wonder why Drs. Desseilles, Fava, Mischoulon, and Freeman did not discuss TMS as an important choice for TRD in their article (“Personalizing depression treatment: 2 clinical tools,” Current Psychiatry, March 2012, p. 26-33). Harvard Medical School has done trials of TMS and McLean Hospital has created a positive video on TMS.

Andrew Krompier, MD
Private Practice
San Ramon, CA

Recently, when The Dr. Oz Show’s Dr. Mehmet Oz turned to his television audience to ask if anyone had heard of transcranial magnetic stimulation (TMS) after a demonstration of its effectiveness in treatment-resistant depression (TRD), no one in the audience raised their hands.

I wonder why Drs. Desseilles, Fava, Mischoulon, and Freeman did not discuss TMS as an important choice for TRD in their article (“Personalizing depression treatment: 2 clinical tools,” Current Psychiatry, March 2012, p. 26-33). Harvard Medical School has done trials of TMS and McLean Hospital has created a positive video on TMS.

Andrew Krompier, MD
Private Practice
San Ramon, CA

CASE: New-onset seizures

Ms. R, age 33, is referred by her neurologist for treatment of depressive symptoms that have intensified after she was diagnosed with epilepsy 1 year ago. She has a history of bulimia and ongoing anxiety and depression. She also has long-standing neuropathic pain in her left lateral shin and ankle that started after her foot was amputated in a lawn mower accident at age 5. Ms. R says she didn’t take pain medication until age 24, when her pain specialist prescribed tramadol, 300 to 400 mg/d, which she continues to take.

Ms. R’s first seizure occurred 1 year ago. Despite trials of several antiepileptics, her seizures persist; she is taking lamotrigine, 200 mg/d, when she presents for treatment. She has no history of brain injuries or strokes to explain her epilepsy. An MRI and 3 electroencephalograms show no signs of focal, potentially epileptogenic lesions.

Ms. R reports worsening depressive symptoms—particularly impaired attention and concentration—over several months that interfere with her housekeeping and ability to finish simple tasks at work. She says she drinks alcohol occasionally, but denies substance abuse. We initiate venlafaxine, titrated to 300 mg/d, because Ms. R has a history of intolerable side effects with fluoxetine (gastrointestinal distress) and citalopram (weight gain).

The authors’ observations

Tramadol, a centrally acting synthetic analgesic, consists of 2 enantiomers that act as weak agonists at μ-opioid receptors while also inhibiting serotonin and norepinephrine reuptake.¹ Euphoria associated with μ receptor activation often is considered a “high.” Most abused opioids are prototypical μ agonists. When opioids are injected or inhaled, drug levels in the brain rise rapidly, causing a “rush”—a brief, intense, pleasurable sensation—followed by a longer-lasting high. Tolerance and physical dependence occur when opioids are used chronically.

Despite tramadol’s μ-opioid activity, the FDA approved it as an unscheduled analgesic in 1994 based on several human studies.² Experience with tramadol has confirmed it has low abuse potential, yet human laboratory data—and some epidemiologic data—show that repeated use can lead to physical dependence. Although tramadol is considered a relatively weak opioid, human studies suggest that it possesses μ-agonist activity. The Drug Abuse Warning Network reported >15,000 emergency department (ED) visits for nonmedical tramadol use in 2009, which was more than the number of ED visits for codeine products (7,958) or propoxyphene products (9,526), but much fewer than visits for hydrocodone (86,258) or oxycodone (148,449) products.³

The recommended tramadol dose is 50 to 100 mg every 4 to 6 hours (maximum 400 mg/d). Adverse effects range from dysphoria, constipation, and nausea to agitation, seizures, respiratory depression, and coma.⁴ Tramadol withdrawal is similar to opioid withdrawal, and is characterized by anxiety, restlessness, insomnia, yawning, rhinorrhea, lacrimation, diaphoresis, tremor, muscle spasms, vomiting, diarrhea, and tachycardia. Rarely, psychomotor agitation and confusion may occur.⁵

Tramadol and seizures

At clinically appropriate doses, tramadol slightly suppresses seizure severity,⁶ but higher doses can induce seizures.^7-12 This paradox is explained by tramadol’s effect on γ-aminobutyric acid (GABA) receptors. Although at clinical doses tramadol does not affect GABA, which could precipitate seizures, at higher doses it has been shown to have an inhibitory effect on GABA receptors.^13,14 No prospective studies have assessed how often tramadol-induced seizures occur. Case reports^12,15 suggest that seizures are more likely with acute tramadol intoxication, in patients with a history of alcohol abuse, or with pharmacologic regimens that include other medications that may cause seizures. Tramadol-induced seizures are generalized tonic-clonic in nature, and typically occur within 24 hours of the last dose.¹⁶

HISTORY: Worsening seizures

Two months after she presents for psychiatric evaluation, Ms. R experiences 6 generalized convulsions lasting from 15 minutes to 1 hour with no identifiable precipitant. Because oxcarbazepine and lamotrigine have failed to suppress her seizures, her neurologist adds phenytoin, 200 mg/d, and increases lamotrigine from 200 to 300 mg/d. Her depression continues to worsen. She reports severe insomnia, anhedonia, restlessness, and hopelessness, so we add sertraline, 50 mg/d, to venlafaxine. Ms. R says the seizures are terrifying and she cannot work. She moves in with her parents because she is unable to care for herself.

During a psychiatric appointment, Ms. R confesses that for 2 years her pain has been so unbearable that she has been buying extra tramadol from Internet retailers and taking 600 to 800 mg/d in addition to the prescribed 400 mg/d.

The authors’ observations

Ms. R had a history of chronic pain Table 1¹⁷ and developed seizures after escalating her tramadol use. After her first epilepsy attack, she did not tell her physicians she was taking additional tramadol nor did she stop taking it. Treatment with several antiepileptics was unsuccessful. Her seizures persisted as long as her tramadol addiction continued.

Table 1

DSM-IV-TR criteria for pain disorder

Spiller et al¹⁸ reported the lowest daily tramadol dose associated with seizures is 500 mg/d, although Talaie et al¹⁶ observed seizures at doses as low as 100 mg/d. Additionally, seizure risk may increase through tramadol’s interactions with several medications, including tricyclic antidepressants, selective serotonin reuptake inhibitors, phenothiazines, fluoroquinolone antibiotics, meperidine, clozapine, buspirone, bupropion, phenylephrine, guaifenesin, tripelennamine, thioridazine, theophylline, and acetaminophen, butalbital, and caffeine combination (Table 2).¹⁹ Transdermal selegiline is contraindicated with tramadol. For Ms. R, the sertraline and venlafaxine she was taking may have augmented tramadol’s seizure potential.

Table 2

Tramadol: Major drug-drug interactions

It is important to avoid polypharmacy in patients taking tramadol.²⁰ Most psychiatrists are aware of the risk of serotonin syndrome with antidepressants, but may be less likely to attribute serotonergic additive effects from other medication classes such as analgesics. Recognizing tramadol’s potential to contribute to serotonin syndrome—especially in light of concomitant usage with other serotonergic medications such as antidepressants—is essential.

Tramadol toxicity appears to be caused by monoamine uptake inhibition rather than its opioid effects.²¹ The most frequent pharmacokinetic drug-drug interactions that lead to side effects such as serotonin syndrome or seizures involve several isoenzymes of the hepatic cytochrome P450 (CYP). The isoenzymes CYP2D6 (substrates—eg, amitriptyline, tramadol, and venlafaxine; inhibitors—eg, fluoxetine and duloxetine) and CYP3A4 (substrates—eg, carbamazepine, oxycodone, and venlafaxine; inductors—eg, carbamazepine; inhibitors, eg—grapefruit juice) are most important clinically.²²

Ms. R readily obtained tramadol from Internet retailers. In a 2004 report, a Google search yielded 2,150,000 sources for acquiring tramadol, most of which did not require a prescription.²³ Chronic pain patients have a higher prevalence of substance abuse than the general population.²⁴ Because Ms. R did not have a documented substance abuse history, none of her physicians screened her for drug abuse, although toxicology screening wouldn’t have helped because the tramadol had been prescribed. We didn’t think to directly ask Ms. R about medication misuse, but if we had, she might have revealed it sooner.

OUTCOME: Seizure free

With Ms. R’s permission, we speak to her neurologist, who agrees that excess tramadol likely induced her seizures. The seizures stop after Ms. R discontinues tramadol. After 3 months without seizures, phenytoin is discontinued and lamotrigine is tapered to 200 mg/d. Ms. R participates in a pain rehabilitation program and continues to take venlafaxine, 300 mg/d, and sertraline, 50 mg/d. Her mood improves and she returns to work. Her pain is managed by non-steroidal anti-inflammatory drugs because she decides to decrease her activity level. Ms. R also is trying alternative medicine modalities such as acupuncture and acupressure.

Related Resource

• Clark MR, Treisman GJ. Chronic pain and addiction. Basel, Switzerland: Karger; 2011.

Drug Brand Names

• Acetaminophen, butalbital, and caffeine • Fioricet
• Amitriptyline • Elavil
• Bupropion • Wellbutrin
• Buspirone • Buspar
• Carbamazepine • Tegretol, Carbatrol
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Desipramine • Norpramin
• Doxepin • Adapin, Silenor
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Guaifenesin • Tenex
• Haloperidol • Haldol
• Imipramine • Tofranil
• Ketamine • Ketalar
• Lamotrigine • Lamictal
• Linezolid • Zyvox
• Meperidine • Demerol
• Mirtazapine • Remeron
• Nortriptyline • Aventyl
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Oxycodone • Percolone, OxyContin
• Paroxetine • Paxil
• Phenylephrine • Lusonal
• Phenytoin • Dilantin
• Propoxyphene • Darvon
• Risperidone • Risperdal
• Selegiline • Eldepryl, EMSAM
• Sertraline • Zoloft
• Theophylline • Aerolate
• Thioridazine • Mellaril
• Tramadol • Ultram
• Tripelennamine • Pyribenzamine
• Venlafaxine • Effexor

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufactur-ers of competing products.

CASE: New-onset seizures

Ms. R, age 33, is referred by her neurologist for treatment of depressive symptoms that have intensified after she was diagnosed with epilepsy 1 year ago. She has a history of bulimia and ongoing anxiety and depression. She also has long-standing neuropathic pain in her left lateral shin and ankle that started after her foot was amputated in a lawn mower accident at age 5. Ms. R says she didn’t take pain medication until age 24, when her pain specialist prescribed tramadol, 300 to 400 mg/d, which she continues to take.

Ms. R’s first seizure occurred 1 year ago. Despite trials of several antiepileptics, her seizures persist; she is taking lamotrigine, 200 mg/d, when she presents for treatment. She has no history of brain injuries or strokes to explain her epilepsy. An MRI and 3 electroencephalograms show no signs of focal, potentially epileptogenic lesions.

Ms. R reports worsening depressive symptoms—particularly impaired attention and concentration—over several months that interfere with her housekeeping and ability to finish simple tasks at work. She says she drinks alcohol occasionally, but denies substance abuse. We initiate venlafaxine, titrated to 300 mg/d, because Ms. R has a history of intolerable side effects with fluoxetine (gastrointestinal distress) and citalopram (weight gain).

The authors’ observations

Tramadol, a centrally acting synthetic analgesic, consists of 2 enantiomers that act as weak agonists at μ-opioid receptors while also inhibiting serotonin and norepinephrine reuptake.¹ Euphoria associated with μ receptor activation often is considered a “high.” Most abused opioids are prototypical μ agonists. When opioids are injected or inhaled, drug levels in the brain rise rapidly, causing a “rush”—a brief, intense, pleasurable sensation—followed by a longer-lasting high. Tolerance and physical dependence occur when opioids are used chronically.

Despite tramadol’s μ-opioid activity, the FDA approved it as an unscheduled analgesic in 1994 based on several human studies.² Experience with tramadol has confirmed it has low abuse potential, yet human laboratory data—and some epidemiologic data—show that repeated use can lead to physical dependence. Although tramadol is considered a relatively weak opioid, human studies suggest that it possesses μ-agonist activity. The Drug Abuse Warning Network reported >15,000 emergency department (ED) visits for nonmedical tramadol use in 2009, which was more than the number of ED visits for codeine products (7,958) or propoxyphene products (9,526), but much fewer than visits for hydrocodone (86,258) or oxycodone (148,449) products.³

The recommended tramadol dose is 50 to 100 mg every 4 to 6 hours (maximum 400 mg/d). Adverse effects range from dysphoria, constipation, and nausea to agitation, seizures, respiratory depression, and coma.⁴ Tramadol withdrawal is similar to opioid withdrawal, and is characterized by anxiety, restlessness, insomnia, yawning, rhinorrhea, lacrimation, diaphoresis, tremor, muscle spasms, vomiting, diarrhea, and tachycardia. Rarely, psychomotor agitation and confusion may occur.⁵

Tramadol and seizures

At clinically appropriate doses, tramadol slightly suppresses seizure severity,⁶ but higher doses can induce seizures.^7-12 This paradox is explained by tramadol’s effect on γ-aminobutyric acid (GABA) receptors. Although at clinical doses tramadol does not affect GABA, which could precipitate seizures, at higher doses it has been shown to have an inhibitory effect on GABA receptors.^13,14 No prospective studies have assessed how often tramadol-induced seizures occur. Case reports^12,15 suggest that seizures are more likely with acute tramadol intoxication, in patients with a history of alcohol abuse, or with pharmacologic regimens that include other medications that may cause seizures. Tramadol-induced seizures are generalized tonic-clonic in nature, and typically occur within 24 hours of the last dose.¹⁶

HISTORY: Worsening seizures

Two months after she presents for psychiatric evaluation, Ms. R experiences 6 generalized convulsions lasting from 15 minutes to 1 hour with no identifiable precipitant. Because oxcarbazepine and lamotrigine have failed to suppress her seizures, her neurologist adds phenytoin, 200 mg/d, and increases lamotrigine from 200 to 300 mg/d. Her depression continues to worsen. She reports severe insomnia, anhedonia, restlessness, and hopelessness, so we add sertraline, 50 mg/d, to venlafaxine. Ms. R says the seizures are terrifying and she cannot work. She moves in with her parents because she is unable to care for herself.

During a psychiatric appointment, Ms. R confesses that for 2 years her pain has been so unbearable that she has been buying extra tramadol from Internet retailers and taking 600 to 800 mg/d in addition to the prescribed 400 mg/d.

The authors’ observations

Ms. R had a history of chronic pain Table 1¹⁷ and developed seizures after escalating her tramadol use. After her first epilepsy attack, she did not tell her physicians she was taking additional tramadol nor did she stop taking it. Treatment with several antiepileptics was unsuccessful. Her seizures persisted as long as her tramadol addiction continued.

Table 1

DSM-IV-TR criteria for pain disorder

Spiller et al¹⁸ reported the lowest daily tramadol dose associated with seizures is 500 mg/d, although Talaie et al¹⁶ observed seizures at doses as low as 100 mg/d. Additionally, seizure risk may increase through tramadol’s interactions with several medications, including tricyclic antidepressants, selective serotonin reuptake inhibitors, phenothiazines, fluoroquinolone antibiotics, meperidine, clozapine, buspirone, bupropion, phenylephrine, guaifenesin, tripelennamine, thioridazine, theophylline, and acetaminophen, butalbital, and caffeine combination (Table 2).¹⁹ Transdermal selegiline is contraindicated with tramadol. For Ms. R, the sertraline and venlafaxine she was taking may have augmented tramadol’s seizure potential.

Table 2

Tramadol: Major drug-drug interactions

It is important to avoid polypharmacy in patients taking tramadol.²⁰ Most psychiatrists are aware of the risk of serotonin syndrome with antidepressants, but may be less likely to attribute serotonergic additive effects from other medication classes such as analgesics. Recognizing tramadol’s potential to contribute to serotonin syndrome—especially in light of concomitant usage with other serotonergic medications such as antidepressants—is essential.

Tramadol toxicity appears to be caused by monoamine uptake inhibition rather than its opioid effects.²¹ The most frequent pharmacokinetic drug-drug interactions that lead to side effects such as serotonin syndrome or seizures involve several isoenzymes of the hepatic cytochrome P450 (CYP). The isoenzymes CYP2D6 (substrates—eg, amitriptyline, tramadol, and venlafaxine; inhibitors—eg, fluoxetine and duloxetine) and CYP3A4 (substrates—eg, carbamazepine, oxycodone, and venlafaxine; inductors—eg, carbamazepine; inhibitors, eg—grapefruit juice) are most important clinically.²²

Ms. R readily obtained tramadol from Internet retailers. In a 2004 report, a Google search yielded 2,150,000 sources for acquiring tramadol, most of which did not require a prescription.²³ Chronic pain patients have a higher prevalence of substance abuse than the general population.²⁴ Because Ms. R did not have a documented substance abuse history, none of her physicians screened her for drug abuse, although toxicology screening wouldn’t have helped because the tramadol had been prescribed. We didn’t think to directly ask Ms. R about medication misuse, but if we had, she might have revealed it sooner.

OUTCOME: Seizure free

With Ms. R’s permission, we speak to her neurologist, who agrees that excess tramadol likely induced her seizures. The seizures stop after Ms. R discontinues tramadol. After 3 months without seizures, phenytoin is discontinued and lamotrigine is tapered to 200 mg/d. Ms. R participates in a pain rehabilitation program and continues to take venlafaxine, 300 mg/d, and sertraline, 50 mg/d. Her mood improves and she returns to work. Her pain is managed by non-steroidal anti-inflammatory drugs because she decides to decrease her activity level. Ms. R also is trying alternative medicine modalities such as acupuncture and acupressure.

Related Resource

• Clark MR, Treisman GJ. Chronic pain and addiction. Basel, Switzerland: Karger; 2011.

Drug Brand Names

• Acetaminophen, butalbital, and caffeine • Fioricet
• Amitriptyline • Elavil
• Bupropion • Wellbutrin
• Buspirone • Buspar
• Carbamazepine • Tegretol, Carbatrol
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Desipramine • Norpramin
• Doxepin • Adapin, Silenor
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Guaifenesin • Tenex
• Haloperidol • Haldol
• Imipramine • Tofranil
• Ketamine • Ketalar
• Lamotrigine • Lamictal
• Linezolid • Zyvox
• Meperidine • Demerol
• Mirtazapine • Remeron
• Nortriptyline • Aventyl
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Oxycodone • Percolone, OxyContin
• Paroxetine • Paxil
• Phenylephrine • Lusonal
• Phenytoin • Dilantin
• Propoxyphene • Darvon
• Risperidone • Risperdal
• Selegiline • Eldepryl, EMSAM
• Sertraline • Zoloft
• Theophylline • Aerolate
• Thioridazine • Mellaril
• Tramadol • Ultram
• Tripelennamine • Pyribenzamine
• Venlafaxine • Effexor

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufactur-ers of competing products.

CASE: New-onset seizures

Ms. R, age 33, is referred by her neurologist for treatment of depressive symptoms that have intensified after she was diagnosed with epilepsy 1 year ago. She has a history of bulimia and ongoing anxiety and depression. She also has long-standing neuropathic pain in her left lateral shin and ankle that started after her foot was amputated in a lawn mower accident at age 5. Ms. R says she didn’t take pain medication until age 24, when her pain specialist prescribed tramadol, 300 to 400 mg/d, which she continues to take.

Ms. R’s first seizure occurred 1 year ago. Despite trials of several antiepileptics, her seizures persist; she is taking lamotrigine, 200 mg/d, when she presents for treatment. She has no history of brain injuries or strokes to explain her epilepsy. An MRI and 3 electroencephalograms show no signs of focal, potentially epileptogenic lesions.

Ms. R reports worsening depressive symptoms—particularly impaired attention and concentration—over several months that interfere with her housekeeping and ability to finish simple tasks at work. She says she drinks alcohol occasionally, but denies substance abuse. We initiate venlafaxine, titrated to 300 mg/d, because Ms. R has a history of intolerable side effects with fluoxetine (gastrointestinal distress) and citalopram (weight gain).

The authors’ observations

Tramadol, a centrally acting synthetic analgesic, consists of 2 enantiomers that act as weak agonists at μ-opioid receptors while also inhibiting serotonin and norepinephrine reuptake.¹ Euphoria associated with μ receptor activation often is considered a “high.” Most abused opioids are prototypical μ agonists. When opioids are injected or inhaled, drug levels in the brain rise rapidly, causing a “rush”—a brief, intense, pleasurable sensation—followed by a longer-lasting high. Tolerance and physical dependence occur when opioids are used chronically.

Despite tramadol’s μ-opioid activity, the FDA approved it as an unscheduled analgesic in 1994 based on several human studies.² Experience with tramadol has confirmed it has low abuse potential, yet human laboratory data—and some epidemiologic data—show that repeated use can lead to physical dependence. Although tramadol is considered a relatively weak opioid, human studies suggest that it possesses μ-agonist activity. The Drug Abuse Warning Network reported >15,000 emergency department (ED) visits for nonmedical tramadol use in 2009, which was more than the number of ED visits for codeine products (7,958) or propoxyphene products (9,526), but much fewer than visits for hydrocodone (86,258) or oxycodone (148,449) products.³

The recommended tramadol dose is 50 to 100 mg every 4 to 6 hours (maximum 400 mg/d). Adverse effects range from dysphoria, constipation, and nausea to agitation, seizures, respiratory depression, and coma.⁴ Tramadol withdrawal is similar to opioid withdrawal, and is characterized by anxiety, restlessness, insomnia, yawning, rhinorrhea, lacrimation, diaphoresis, tremor, muscle spasms, vomiting, diarrhea, and tachycardia. Rarely, psychomotor agitation and confusion may occur.⁵

Tramadol and seizures

At clinically appropriate doses, tramadol slightly suppresses seizure severity,⁶ but higher doses can induce seizures.^7-12 This paradox is explained by tramadol’s effect on γ-aminobutyric acid (GABA) receptors. Although at clinical doses tramadol does not affect GABA, which could precipitate seizures, at higher doses it has been shown to have an inhibitory effect on GABA receptors.^13,14 No prospective studies have assessed how often tramadol-induced seizures occur. Case reports^12,15 suggest that seizures are more likely with acute tramadol intoxication, in patients with a history of alcohol abuse, or with pharmacologic regimens that include other medications that may cause seizures. Tramadol-induced seizures are generalized tonic-clonic in nature, and typically occur within 24 hours of the last dose.¹⁶

HISTORY: Worsening seizures

Two months after she presents for psychiatric evaluation, Ms. R experiences 6 generalized convulsions lasting from 15 minutes to 1 hour with no identifiable precipitant. Because oxcarbazepine and lamotrigine have failed to suppress her seizures, her neurologist adds phenytoin, 200 mg/d, and increases lamotrigine from 200 to 300 mg/d. Her depression continues to worsen. She reports severe insomnia, anhedonia, restlessness, and hopelessness, so we add sertraline, 50 mg/d, to venlafaxine. Ms. R says the seizures are terrifying and she cannot work. She moves in with her parents because she is unable to care for herself.

During a psychiatric appointment, Ms. R confesses that for 2 years her pain has been so unbearable that she has been buying extra tramadol from Internet retailers and taking 600 to 800 mg/d in addition to the prescribed 400 mg/d.

The authors’ observations

Ms. R had a history of chronic pain Table 1¹⁷ and developed seizures after escalating her tramadol use. After her first epilepsy attack, she did not tell her physicians she was taking additional tramadol nor did she stop taking it. Treatment with several antiepileptics was unsuccessful. Her seizures persisted as long as her tramadol addiction continued.

Table 1

DSM-IV-TR criteria for pain disorder

Spiller et al¹⁸ reported the lowest daily tramadol dose associated with seizures is 500 mg/d, although Talaie et al¹⁶ observed seizures at doses as low as 100 mg/d. Additionally, seizure risk may increase through tramadol’s interactions with several medications, including tricyclic antidepressants, selective serotonin reuptake inhibitors, phenothiazines, fluoroquinolone antibiotics, meperidine, clozapine, buspirone, bupropion, phenylephrine, guaifenesin, tripelennamine, thioridazine, theophylline, and acetaminophen, butalbital, and caffeine combination (Table 2).¹⁹ Transdermal selegiline is contraindicated with tramadol. For Ms. R, the sertraline and venlafaxine she was taking may have augmented tramadol’s seizure potential.

Table 2

Tramadol: Major drug-drug interactions

It is important to avoid polypharmacy in patients taking tramadol.²⁰ Most psychiatrists are aware of the risk of serotonin syndrome with antidepressants, but may be less likely to attribute serotonergic additive effects from other medication classes such as analgesics. Recognizing tramadol’s potential to contribute to serotonin syndrome—especially in light of concomitant usage with other serotonergic medications such as antidepressants—is essential.

Tramadol toxicity appears to be caused by monoamine uptake inhibition rather than its opioid effects.²¹ The most frequent pharmacokinetic drug-drug interactions that lead to side effects such as serotonin syndrome or seizures involve several isoenzymes of the hepatic cytochrome P450 (CYP). The isoenzymes CYP2D6 (substrates—eg, amitriptyline, tramadol, and venlafaxine; inhibitors—eg, fluoxetine and duloxetine) and CYP3A4 (substrates—eg, carbamazepine, oxycodone, and venlafaxine; inductors—eg, carbamazepine; inhibitors, eg—grapefruit juice) are most important clinically.²²

Ms. R readily obtained tramadol from Internet retailers. In a 2004 report, a Google search yielded 2,150,000 sources for acquiring tramadol, most of which did not require a prescription.²³ Chronic pain patients have a higher prevalence of substance abuse than the general population.²⁴ Because Ms. R did not have a documented substance abuse history, none of her physicians screened her for drug abuse, although toxicology screening wouldn’t have helped because the tramadol had been prescribed. We didn’t think to directly ask Ms. R about medication misuse, but if we had, she might have revealed it sooner.

OUTCOME: Seizure free

With Ms. R’s permission, we speak to her neurologist, who agrees that excess tramadol likely induced her seizures. The seizures stop after Ms. R discontinues tramadol. After 3 months without seizures, phenytoin is discontinued and lamotrigine is tapered to 200 mg/d. Ms. R participates in a pain rehabilitation program and continues to take venlafaxine, 300 mg/d, and sertraline, 50 mg/d. Her mood improves and she returns to work. Her pain is managed by non-steroidal anti-inflammatory drugs because she decides to decrease her activity level. Ms. R also is trying alternative medicine modalities such as acupuncture and acupressure.

Related Resource

• Clark MR, Treisman GJ. Chronic pain and addiction. Basel, Switzerland: Karger; 2011.

Drug Brand Names

• Acetaminophen, butalbital, and caffeine • Fioricet
• Amitriptyline • Elavil
• Bupropion • Wellbutrin
• Buspirone • Buspar
• Carbamazepine • Tegretol, Carbatrol
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Desipramine • Norpramin
• Doxepin • Adapin, Silenor
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Guaifenesin • Tenex
• Haloperidol • Haldol
• Imipramine • Tofranil
• Ketamine • Ketalar
• Lamotrigine • Lamictal
• Linezolid • Zyvox
• Meperidine • Demerol
• Mirtazapine • Remeron
• Nortriptyline • Aventyl
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Oxycodone • Percolone, OxyContin
• Paroxetine • Paxil
• Phenylephrine • Lusonal
• Phenytoin • Dilantin
• Propoxyphene • Darvon
• Risperidone • Risperdal
• Selegiline • Eldepryl, EMSAM
• Sertraline • Zoloft
• Theophylline • Aerolate
• Thioridazine • Mellaril
• Tramadol • Ultram
• Tripelennamine • Pyribenzamine
• Venlafaxine • Effexor

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufactur-ers of competing products.