Current Psychiatry

Psychiatrists often have to deal with “ethically challenged” entities or individuals. This can be of concern because, ultimately, unethical policies or behavior can harm our patients. However, psychiatrists recognize that what may appear to be unethical to them may not be considered as such by nonpsychiatrists.

Ethics (from Ethos, which means customs) is defined as the standards and rules of conduct that govern a set of human actions by a specific group, profession, or culture. Thus, there are medical ethics, corporate ethics, Christian ethics, student ethics, fishing ethics, etc. Ethics is, therefore, not an absolute standard and may exist only “in the eye of the beholder.” For example, psychiatry as a medical specialty has its own rigorous ethical code that other medical specialties do not uphold (such as prohibiting socializing with patients).

Who are the entities whose ethical transgressions may affect psychiatrists’ work? Consider the following examples:

Insurance companies. Some of their business practices outrage psychiatrists, including:

• vehemently opposing parity for psychiatric brain disorders with other medical disorders
• refusing to cover preexisting conditions
• the preauthorization farce, which costs psychiatrists a large amount of uncompensated time and effort (essentially an unfunded mandate)
• low reimbursement rate for psychiatric care and a bias against coverage for psychotherapy
• forcing stable patients to switch to a cheaper medication that may not work as well, thus potentially destabilizing the patient.

Pharmaceutical companies. Because of intense scrutiny by regulatory and compliance bodies, pharmaceutical companies have largely discontinued questionable practices such as:

• not publishing unfavorable drug data
• minimizing serious side effects such as obesity and diabetes until after their drug is widely used.

However, some companies continue to disconcert psychiatrists and trigger their umbrage by:

• abandoning psychiatric drug development despite the tremendous unmet need and shifting resources to more profitable therapeutic areas
• direct-to-consumer advertising that disrupts the doctor-patient relationship and undermines psychiatrists’ clinical judgment.

The FDA. This key government agency plays an important role in protecting the public, but its policies occasionally spawn ethical dilemmas.

For example, why does it insist that new psychiatric medications be indicated for a DSM “diagnosis” instead of common “symptoms” such as agitation, depression, delusions, hallucinations, anxiety, or impulsivity? DSM diagnoses are arbitrary, committee-created constructs that may change drastically from edition to edition. There is extensive evidence for overlapping symptoms of many psychiatric “diagnoses,” which implies that a drug approved and deemed safe and effective for 1 psychiatric syndrome (eg, psychosis, depression) can help other disorders that share symptoms.

Why doesn’t the FDA channel the billions of dollars in penalties they have imposed on pharmaceutical companies to the National Institutes of Health (NIH) instead of to the government’s general fund? These valuable funds are being siphoned from research; ethically, from a public health perspective, they should be kept in research. These billions can help one of the NIH institutes such the National Institute of Mental Health (NIMH) establish a psychiatric drug development section to translate biologic discoveries into novel treatments. No such capability exists at the NIMH due to lack of funds.

Legislators. There generally is considerable cynicism about the ethical conduct of politicians, but from psychiatry’s point of view, consider the following:

• Why not use the force of law to enforce parity in insurance coverage?
• Why are legislators willing to appropriate funds to build prisons but not long-term psychiatric hospitals? Is it ethical to criminalize mental illness and incarcerate persons with brain disorders side-by-side with hardened criminals instead of providing them with a dignified and safe medical facility?
• Why don’t legislators fix the broken public mental health system that is underfunded, ineffective, and too bureaucratic for patients and families to navigate?

The media. Although significant improvement has taken place in portraying mental illness compared with a few decades ago, the following unacceptable patterns continue:

• depicting the mentally ill as dangerous killers and “psychos”
• continuing to mock mental illness and addictions as character frailties rather than view them as legitimate illnesses
• failing to expose the injustices that afflict persons with psychiatric brain disorders, including stigma, neglect of physical health needs, inadequate treatment resources (such as availability of inpatient psychiatric beds), or imprisonment in lieu of hospitalization.

Communities. It is regrettable that the negative attitude toward mental illness still is intense enough to perpetuate the vociferous “not in my backyard” (NIMBY) opposition to mental health clinics, residential facilities, or halfway houses. Although the NIMBY syndrome is driven by lack of education and/or understanding of mental illness, ignorance is a poor excuse for ethical shortcomings.

Non-psychiatric physicians. It is quite disheartening to see how prejudiced some internists and surgeons can be toward mentally ill individuals. Most developed a distorted view of psychiatry from being trained decades ago, before the momentous neuroscience advances in psychiatry. But more worrisome are the barriers mentally ill persons face in health care^1-4 that lead to underutilization of routine primary care⁵ and underdiagnosis of serious health conditions.^2,6 Psychiatric patients are less likely to undergo coronary revascularization procedures after a myocardial infarction⁷ or to be properly treated for chronic conditions such as arthritis.⁸ Limited or inadequate medical care has led to early mortality.^9,10 But there is good news from the U.S. Department of Veterans Affairs, where psychiatric patients with diabetes receive as good care as veterans without mental illness¹¹ and have no barriers to nutrition and exercise counseling.¹²

What about our own ethical conduct?

Finally, perhaps psychiatrists should think twice before throwing stones because we, too, may live in ethical “glass houses.” Although we try to adhere to our ethical standards, some of us occasionally may commit ethical peccadilloes, such as:

• continuing to use haloperidol, a 45-year-old drug that has been shown to be neurotoxic in >20 studies over the past decade¹³
• ignoring tier I evidence-based treatments and using unproven modalities that may delay illness resolution
• not regularly monitoring patients for metabolic complications of antipsychotics¹⁴
• not using depot antipsychotics for patients who exhibit violent behavior each time they relapse due to nonadherence
• requiring a drug company representative to bring lunch to the entire clinic staff in return for access to the prescriber.

The quandary with ethics is that they can be too nuanced, enabling almost anyone who breaches an ethical boundary to find a justification. The most unambiguous ethical standards have long been moved from a moral philosophy to codified and legally enforced laws (robbery, assault, rape, homicide, etc.). Psychiatry deals with many groups that have their own version of an “ethics compass.” We psychiatrists have our own ethics standards, which we always aspire to uphold. However, are we so ethically infallible that we can smugly throw stones at people who live in ethical “glass houses?” Doesn’t our ethical “brick house” have glass windows?

Psychiatrists often have to deal with “ethically challenged” entities or individuals. This can be of concern because, ultimately, unethical policies or behavior can harm our patients. However, psychiatrists recognize that what may appear to be unethical to them may not be considered as such by nonpsychiatrists.

Ethics (from Ethos, which means customs) is defined as the standards and rules of conduct that govern a set of human actions by a specific group, profession, or culture. Thus, there are medical ethics, corporate ethics, Christian ethics, student ethics, fishing ethics, etc. Ethics is, therefore, not an absolute standard and may exist only “in the eye of the beholder.” For example, psychiatry as a medical specialty has its own rigorous ethical code that other medical specialties do not uphold (such as prohibiting socializing with patients).

Who are the entities whose ethical transgressions may affect psychiatrists’ work? Consider the following examples:

Insurance companies. Some of their business practices outrage psychiatrists, including:

• vehemently opposing parity for psychiatric brain disorders with other medical disorders
• refusing to cover preexisting conditions
• the preauthorization farce, which costs psychiatrists a large amount of uncompensated time and effort (essentially an unfunded mandate)
• low reimbursement rate for psychiatric care and a bias against coverage for psychotherapy
• forcing stable patients to switch to a cheaper medication that may not work as well, thus potentially destabilizing the patient.

Pharmaceutical companies. Because of intense scrutiny by regulatory and compliance bodies, pharmaceutical companies have largely discontinued questionable practices such as:

• not publishing unfavorable drug data
• minimizing serious side effects such as obesity and diabetes until after their drug is widely used.

However, some companies continue to disconcert psychiatrists and trigger their umbrage by:

• abandoning psychiatric drug development despite the tremendous unmet need and shifting resources to more profitable therapeutic areas
• direct-to-consumer advertising that disrupts the doctor-patient relationship and undermines psychiatrists’ clinical judgment.

The FDA. This key government agency plays an important role in protecting the public, but its policies occasionally spawn ethical dilemmas.

For example, why does it insist that new psychiatric medications be indicated for a DSM “diagnosis” instead of common “symptoms” such as agitation, depression, delusions, hallucinations, anxiety, or impulsivity? DSM diagnoses are arbitrary, committee-created constructs that may change drastically from edition to edition. There is extensive evidence for overlapping symptoms of many psychiatric “diagnoses,” which implies that a drug approved and deemed safe and effective for 1 psychiatric syndrome (eg, psychosis, depression) can help other disorders that share symptoms.

Why doesn’t the FDA channel the billions of dollars in penalties they have imposed on pharmaceutical companies to the National Institutes of Health (NIH) instead of to the government’s general fund? These valuable funds are being siphoned from research; ethically, from a public health perspective, they should be kept in research. These billions can help one of the NIH institutes such the National Institute of Mental Health (NIMH) establish a psychiatric drug development section to translate biologic discoveries into novel treatments. No such capability exists at the NIMH due to lack of funds.

Legislators. There generally is considerable cynicism about the ethical conduct of politicians, but from psychiatry’s point of view, consider the following:

• Why not use the force of law to enforce parity in insurance coverage?
• Why are legislators willing to appropriate funds to build prisons but not long-term psychiatric hospitals? Is it ethical to criminalize mental illness and incarcerate persons with brain disorders side-by-side with hardened criminals instead of providing them with a dignified and safe medical facility?
• Why don’t legislators fix the broken public mental health system that is underfunded, ineffective, and too bureaucratic for patients and families to navigate?

The media. Although significant improvement has taken place in portraying mental illness compared with a few decades ago, the following unacceptable patterns continue:

• depicting the mentally ill as dangerous killers and “psychos”
• continuing to mock mental illness and addictions as character frailties rather than view them as legitimate illnesses
• failing to expose the injustices that afflict persons with psychiatric brain disorders, including stigma, neglect of physical health needs, inadequate treatment resources (such as availability of inpatient psychiatric beds), or imprisonment in lieu of hospitalization.

Communities. It is regrettable that the negative attitude toward mental illness still is intense enough to perpetuate the vociferous “not in my backyard” (NIMBY) opposition to mental health clinics, residential facilities, or halfway houses. Although the NIMBY syndrome is driven by lack of education and/or understanding of mental illness, ignorance is a poor excuse for ethical shortcomings.

Non-psychiatric physicians. It is quite disheartening to see how prejudiced some internists and surgeons can be toward mentally ill individuals. Most developed a distorted view of psychiatry from being trained decades ago, before the momentous neuroscience advances in psychiatry. But more worrisome are the barriers mentally ill persons face in health care^1-4 that lead to underutilization of routine primary care⁵ and underdiagnosis of serious health conditions.^2,6 Psychiatric patients are less likely to undergo coronary revascularization procedures after a myocardial infarction⁷ or to be properly treated for chronic conditions such as arthritis.⁸ Limited or inadequate medical care has led to early mortality.^9,10 But there is good news from the U.S. Department of Veterans Affairs, where psychiatric patients with diabetes receive as good care as veterans without mental illness¹¹ and have no barriers to nutrition and exercise counseling.¹²

What about our own ethical conduct?

Finally, perhaps psychiatrists should think twice before throwing stones because we, too, may live in ethical “glass houses.” Although we try to adhere to our ethical standards, some of us occasionally may commit ethical peccadilloes, such as:

• continuing to use haloperidol, a 45-year-old drug that has been shown to be neurotoxic in >20 studies over the past decade¹³
• ignoring tier I evidence-based treatments and using unproven modalities that may delay illness resolution
• not regularly monitoring patients for metabolic complications of antipsychotics¹⁴
• not using depot antipsychotics for patients who exhibit violent behavior each time they relapse due to nonadherence
• requiring a drug company representative to bring lunch to the entire clinic staff in return for access to the prescriber.

The quandary with ethics is that they can be too nuanced, enabling almost anyone who breaches an ethical boundary to find a justification. The most unambiguous ethical standards have long been moved from a moral philosophy to codified and legally enforced laws (robbery, assault, rape, homicide, etc.). Psychiatry deals with many groups that have their own version of an “ethics compass.” We psychiatrists have our own ethics standards, which we always aspire to uphold. However, are we so ethically infallible that we can smugly throw stones at people who live in ethical “glass houses?” Doesn’t our ethical “brick house” have glass windows?

Psychiatrists often have to deal with “ethically challenged” entities or individuals. This can be of concern because, ultimately, unethical policies or behavior can harm our patients. However, psychiatrists recognize that what may appear to be unethical to them may not be considered as such by nonpsychiatrists.

Ethics (from Ethos, which means customs) is defined as the standards and rules of conduct that govern a set of human actions by a specific group, profession, or culture. Thus, there are medical ethics, corporate ethics, Christian ethics, student ethics, fishing ethics, etc. Ethics is, therefore, not an absolute standard and may exist only “in the eye of the beholder.” For example, psychiatry as a medical specialty has its own rigorous ethical code that other medical specialties do not uphold (such as prohibiting socializing with patients).

Who are the entities whose ethical transgressions may affect psychiatrists’ work? Consider the following examples:

Insurance companies. Some of their business practices outrage psychiatrists, including:

• vehemently opposing parity for psychiatric brain disorders with other medical disorders
• refusing to cover preexisting conditions
• the preauthorization farce, which costs psychiatrists a large amount of uncompensated time and effort (essentially an unfunded mandate)
• low reimbursement rate for psychiatric care and a bias against coverage for psychotherapy
• forcing stable patients to switch to a cheaper medication that may not work as well, thus potentially destabilizing the patient.

Pharmaceutical companies. Because of intense scrutiny by regulatory and compliance bodies, pharmaceutical companies have largely discontinued questionable practices such as:

• not publishing unfavorable drug data
• minimizing serious side effects such as obesity and diabetes until after their drug is widely used.

However, some companies continue to disconcert psychiatrists and trigger their umbrage by:

• abandoning psychiatric drug development despite the tremendous unmet need and shifting resources to more profitable therapeutic areas
• direct-to-consumer advertising that disrupts the doctor-patient relationship and undermines psychiatrists’ clinical judgment.

The FDA. This key government agency plays an important role in protecting the public, but its policies occasionally spawn ethical dilemmas.

For example, why does it insist that new psychiatric medications be indicated for a DSM “diagnosis” instead of common “symptoms” such as agitation, depression, delusions, hallucinations, anxiety, or impulsivity? DSM diagnoses are arbitrary, committee-created constructs that may change drastically from edition to edition. There is extensive evidence for overlapping symptoms of many psychiatric “diagnoses,” which implies that a drug approved and deemed safe and effective for 1 psychiatric syndrome (eg, psychosis, depression) can help other disorders that share symptoms.

Why doesn’t the FDA channel the billions of dollars in penalties they have imposed on pharmaceutical companies to the National Institutes of Health (NIH) instead of to the government’s general fund? These valuable funds are being siphoned from research; ethically, from a public health perspective, they should be kept in research. These billions can help one of the NIH institutes such the National Institute of Mental Health (NIMH) establish a psychiatric drug development section to translate biologic discoveries into novel treatments. No such capability exists at the NIMH due to lack of funds.

Legislators. There generally is considerable cynicism about the ethical conduct of politicians, but from psychiatry’s point of view, consider the following:

• Why not use the force of law to enforce parity in insurance coverage?
• Why are legislators willing to appropriate funds to build prisons but not long-term psychiatric hospitals? Is it ethical to criminalize mental illness and incarcerate persons with brain disorders side-by-side with hardened criminals instead of providing them with a dignified and safe medical facility?
• Why don’t legislators fix the broken public mental health system that is underfunded, ineffective, and too bureaucratic for patients and families to navigate?

The media. Although significant improvement has taken place in portraying mental illness compared with a few decades ago, the following unacceptable patterns continue:

• depicting the mentally ill as dangerous killers and “psychos”
• continuing to mock mental illness and addictions as character frailties rather than view them as legitimate illnesses
• failing to expose the injustices that afflict persons with psychiatric brain disorders, including stigma, neglect of physical health needs, inadequate treatment resources (such as availability of inpatient psychiatric beds), or imprisonment in lieu of hospitalization.

Communities. It is regrettable that the negative attitude toward mental illness still is intense enough to perpetuate the vociferous “not in my backyard” (NIMBY) opposition to mental health clinics, residential facilities, or halfway houses. Although the NIMBY syndrome is driven by lack of education and/or understanding of mental illness, ignorance is a poor excuse for ethical shortcomings.

Non-psychiatric physicians. It is quite disheartening to see how prejudiced some internists and surgeons can be toward mentally ill individuals. Most developed a distorted view of psychiatry from being trained decades ago, before the momentous neuroscience advances in psychiatry. But more worrisome are the barriers mentally ill persons face in health care^1-4 that lead to underutilization of routine primary care⁵ and underdiagnosis of serious health conditions.^2,6 Psychiatric patients are less likely to undergo coronary revascularization procedures after a myocardial infarction⁷ or to be properly treated for chronic conditions such as arthritis.⁸ Limited or inadequate medical care has led to early mortality.^9,10 But there is good news from the U.S. Department of Veterans Affairs, where psychiatric patients with diabetes receive as good care as veterans without mental illness¹¹ and have no barriers to nutrition and exercise counseling.¹²

What about our own ethical conduct?

Finally, perhaps psychiatrists should think twice before throwing stones because we, too, may live in ethical “glass houses.” Although we try to adhere to our ethical standards, some of us occasionally may commit ethical peccadilloes, such as:

• continuing to use haloperidol, a 45-year-old drug that has been shown to be neurotoxic in >20 studies over the past decade¹³
• ignoring tier I evidence-based treatments and using unproven modalities that may delay illness resolution
• not regularly monitoring patients for metabolic complications of antipsychotics¹⁴
• not using depot antipsychotics for patients who exhibit violent behavior each time they relapse due to nonadherence
• requiring a drug company representative to bring lunch to the entire clinic staff in return for access to the prescriber.

The quandary with ethics is that they can be too nuanced, enabling almost anyone who breaches an ethical boundary to find a justification. The most unambiguous ethical standards have long been moved from a moral philosophy to codified and legally enforced laws (robbery, assault, rape, homicide, etc.). Psychiatry deals with many groups that have their own version of an “ethics compass.” We psychiatrists have our own ethics standards, which we always aspire to uphold. However, are we so ethically infallible that we can smugly throw stones at people who live in ethical “glass houses?” Doesn’t our ethical “brick house” have glass windows?

Approximately one-half of patients with major depressive disorder (MDD) will have partial or nonresponse to first-line antidepressant monotherapy, despite receiving an adequate dosage and sufficient duration of treatment.¹ This has led to the definition of treatment-resistant depression (TRD) as a depressive episode that has shown insufficient response to ≥1 trial of an antidepressant that has demonstrated efficacy in clinical trials.¹ Depressed patients should be treated to full remission because absence of complete remission is associated with:

• a more recurrent and chronic illness course^2,3
• increased medical and psychiatric comorbidities
• greater functional burden
• increased social and economic costs linked with impaired social functioning.⁴

Clinicians need to properly identify MDD and treatment resistance to guide optimal treatment choices. Additional tools are necessary to accurately identify, document, and communicate about symptoms commonly experienced by depressed patients but not fully characterized by DSM-IV-TR MDD criteria.⁵ Finally, in many cases, trait or situational factors might obfuscate accurate diagnosis and the natural course of illness, and tools that can be implemented practically will help identify patients with MDD.

Our group has created and implemented 2 clinician-administered tools—the SAFER Interview and the Antidepressant Treatment Response Questionnaire (ATRQ)—to enrich the qualitative assessment of MDD and treatment resistance.

SAFER: Assessing the diagnosis, symptom severity

The SAFER interview refines the diagnosis of depressed patients by assessing the state vs trait nature of the symptoms, their assessability, their face and ecological validity, and if they pass the rule of the 3 Ps: pervasiveness, persistence, and pathological nature of the current MDD episode (Table 1 and Table 2).⁶ This reliable assessment of the patient’s diagnosis and symptom severity is made in a way that reflects the illness in a real-world setting.

Clinical application of SAFER. Implementing SAFER in clinical settings promotes a personalized, dimensional approach by taking into account a varying degree of symptom severity in depressed patients, in contrast to relying on symptom lists as found in the DSM-IV-TR. Using the SAFER interview deepens the typical psychiatric diagnostic process, allows for a more precise understanding of the patient’s situation, and may help clinicians select effective treatments that target specific symptoms, thus resulting in more rapid alleviation of MDD.⁶

Table 1

The SAFER interview: Assessing depression in a real-world setting

Table 2

The SAFER criteria: Rule of the 3 Ps

CASE REPORT: Worsening symptoms

Ms. Y, age 53, has been depressed for 30 years. She hardly remembers a time in her life when she felt good for more than a few days. However, 2 months ago she noted her symptoms got worse. She presents with many MDD symptoms as assessed by the Hamilton Depression Rating Scale, eg, ongoing depressive mood, feelings of guilt, major sleep disturbances, and work impairments.

Using SAFER to evaluate Ms. Y, a clinician would ask: Does she have symptoms that are present primarily during an episode of acute illness? Does the episode constitute a measurable exacerbation of preexisting symptoms? This clinical vignette illustrates the importance of the first SAFER criterion, state vs trait nature of the symptoms. Ms. Y is a SAFER “pass”—meaning consistent with a major depressive episode—because exacerbation of preexisting symptoms is measurable. However, if her symptoms represented a chronic, long-standing trait, she would be a SAFER “fail” based on this criterion, and her symptoms likely would not improve during a brief pharmacologic intervention. For such patients, SAFER would have oriented the clinician toward alternative therapies such as psychotherapy or a combination of longer, more complex pharmacologic treatment and psychotherapy.

By helping clinicians refine MDD diagnoses, SAFER draws attention to specific depression entities (eg, MDD or dysthymia) and directs them toward appropriate guidelines, treatment algorithms, and precautions (eg, when treated with pharmacotherapy, dysthymic patients are particularly sensitive to unwanted effects and adherence is a serious issue).⁷ The SAFER interview also can help identify when what appears to be a depressive episode clearly is precipitated by situational factors, and is more likely to be influenced by changes in the patient’s life than by treatment. For such patients, first consider nonpharmacologic interventions to avoid unnecessary medication exposure.

ATRQ: Efficacy and adequacy

The ATRQ examines the efficacy (improvement from 0% [not improved at all] to 100% [completely improved]), and adequacy (adequate duration and dose) of any antidepressant treatment in a step-by-step procedure.^1,8,9 For a copy of the ATRQ, click here.

While conducting the interview, clinicians ask about treatment adherence to each medication trial. A treatment-resistant patient may go through many types of trials, from monotherapy to combination to augmentation.¹⁰ For each trial, the ATRQ systematically reviews 4 strategies to enhance treatment response:

• increasing the initial antidepressant dosage¹¹
• combining the initial antidepressant with another antidepressant, typically from another class¹²
• augmenting the initial antidepressant with a nonantidepressant¹²
• switching from the initial antidepressant to another antidepressant.¹³

These strategies also are applied in cases of lost sustained antidepressant efficacy or depressive relapse/recurrence, although empirical evidence supporting these strategies is lacking, with the possible exception of dose increase.^14,15

In the convention our group adopted, an adequate antidepressant trial must be ≥6 weeks in total length, with a dose within an adequate range as specified in the medication’s package insert. In addition, for the purposes of conducting TRD trials, we have considered a patient treatment-resistant if response to adequate dose and duration is <50%. On the ATRQ, 50% improvement refers to 50% symptom reduction from baseline without achieving remission. In an initial clinical trial that lasts ≥6 weeks, any dose increase (for ≥4 weeks) represents optimization and is not considered a new or separate trial, whereas augmentation or combination therapy (for ≥3 weeks) or a switch to another antidepressant (for ≥6 weeks) are considered new trials/treatments.

Decision tree for ATRQ. Because antidepressant treatment always is constrained by personal (eg, adherence, insurance coverage, etc.) and clinical (eg, contraindications due to comorbid conditions, side effects, etc.) considerations, we propose a decision tree to help clinicians determine the number of failed antidepressant trials their patient experienced (Figure). Although this tree does not represent all treatment scenarios, we hope it could help clinicians implement TRD treatment strategies because it highlights proper assessment of treatment duration, dosage, and changes before applying a TRD diagnosis.

The ATRQ meticulously examines patients’ antidepressant history to identify:

• pseudo-resistance, to guide adequate dosing and/or duration, and
• resistance, to propose next-step treatment.

Pseudo-resistance refers to treatment failures that can be attributed to factors such as inadequate treatment dosing or duration, atypical pharmacokinetics that reduce agents’ effectiveness, patient nonadherence (eg, due to adverse effects), or misdiagnosis of the primary disorder (ie, other mood disorders or depressive subsets such as dysthymia or minor depression mistreated as unipolar depression).^16,17 Studies show that many patients with MDD referred to specialty settings are undertreated and receive inadequate antidepressant doses,¹⁸ which suggests that many referrals for TRD are in fact pseudo-resistance.¹⁹ Despite the lack of consensus on criteria for TRD,¹ standardization of what constitutes treatment adequacy during antidepressant trials (eg, adherence, dose, duration) is indispensable.

Clinical application of the ATRQ. Because TRD may require specific interventions, we first need to properly identify treatment resistance. Also, systematic use of a classification system enhances the ability of clinicians and patients to provide meaningful descriptions of antidepressant resistance.

In clinical practice, choice of treatment strategy is based on factors that include partial or nonresponse, tolerability, avoiding withdrawal symptoms, the need to target side effects of a current antidepressant by administering another drug, cost, avoiding drug-drug interactions, and patient preference. Because a treatment-resistant patient may go through many types of trials, it is essential to obtain information about all treatments to determine the number of failed clinical trials a patient may have had for the current MDD episode and lifetime episodes. The importance of asking about adherence to each trial cannot be overemphasized.

Figure: Using the Massachusetts General Hospital Antidepressant Treatment History Questionnaire: A decision tree

CASE REPORT: Limited improvement

Mr. T, age 45, reported that his current depressive episode started several years ago. The first antidepressant trial he received, sertraline, 100 mg/d for 3 months, resulted in 0% improvement. Next he received citalopram, 20 mg/d, for 1 month, without any improvement. The next trial, venlafaxine, 75 mg/d, for 7 weeks, resulted in a 30% response. More recently Mr. B tried duloxetine, up to 90 mg/d, for 2 years with an 80% improvement during the first 3 months and then a decrease of response to <40%. He then received aripiprazole, 10 mg/d, in combination with duloxetine for approximately 4 weeks with no response.

Using the ATRQ to evaluate Mr. B, a clinician would consider the sertraline trial as a failed trial. The citalopram treatment would not be considered an adequate trial because it was too short. The venlafaxine course wouldn’t count as an adequate trial because the dosage was too low. The trial with duloxetine would count as a response (80% improvement) followed by a “poop out” or tachyphylaxis (40% improvement). The fifth trial with the combination of duloxetine and aripiprazole would count as a failed trial. The ATRQ highlights which drugs have been used for too short a duration or at too low a dosage. In Mr. B’s case, using the ATRQ revealed that of 5 trials, only 2 showed antidepressant resistance.

The ATRQ and decision tree are meant to provide clinicians with user-friendly tools to more precisely determine the number of failed antidepressant trials a patient experienced. By assessing if an antidepressant trial had an adequate dose and duration, the ATRQ can help suggest the next treatment options. For example, if a trial was inadequate in dose and/or duration but the patient tolerated the medication, then optimizing treatment with the current drug would be a logical next step. If a patient does not respond to an adequate trial, clinicians have several options, such as switching to another antidepressant, using a combination of medications or an augmentation strategy, or increasing the dose of the original antidepressant.

Limitations of the ATRQ. Historical rating of treatment is not as accurate as a prospective trial. Another limitation of the ATRQ is that the minimum effective dose is accepted as adequate; many clinicians would suggest that such a dose is inadequate. Also, the duration specified for augmentation, dose increase, and monotherapy are based on expert consensus¹ rather than systematic research. Nonetheless, this method of documenting prior trials and treatment adequacy is an important advance.

The ATRQ lacks a place to indicate discontinuation due to intolerance. Knowing if adverse events caused treatment nonadherence or discontinuation is relevant to selecting treatment.

The ATRQ considers only pharmacotherapy and electroconvulsive therapy. Comprehensive assessment of treatment resistance requires asking about depression-specific, evidence-based psychotherapies, including cognitive-behavioral therapy and interpersonal therapy. Another precaution is that the ATRQ and SAFER should be used in conjunction with structured or semi-structured clinical interviews and other clinical tools to rule out other primary diagnoses (eg, bipolar disorder, posttraumatic stress disorder, obsessive-compulsive disorder, or surreptitious substance abuse).²⁰

Using SAFER and ATRQ allows clinicians to make a proper MDD diagnosis with an accurate, reliable assessment of symptom severity and a precise count of antidepressant trials of adequate duration and dose. SAFER helps differentiate MDD from other depressive disorders and can be used to separate MDD from a similar presentation of a reaction to external circumstances that may remit if these circumstances change.

These 2 clinical tools focus on MDD and TRD. Compared with treatment resistance in MDD, treatment resistance in other forms of depression, such as minor depressive disorder or dysthymia, has been inadequately researched^21,22 and should be addressed in large studies. However, to help patients achieve remission of depressive disorders—especially MDD—clinicians should use patient information gathered via measurement-based care in combination with algorithm recommendations.²³ Persistence of clinical care of MDD is essential because several treatment steps might be necessary for some patients to achieve remission. Throughout treatment, patients’ symptoms, adverse events secondary to ongoing treatment, and medication adherence should be assessed with appropriate tools. ATRQ and SAFER offer a clinician support in assessing treatment resistance history and a patient’s likelihood to respond to pharmacologic treatment.

Related Resources

• Desseilles M, Witte J, Chang TE, et al. Assessing the adequacy of past antidepressant trials: a clinician’s guide to the Antidepressant Treatment Response Questionnaire (ATRQ). J Clin Psychiatry. 2011;72(8):1152-1154.
• Targum SD, Pollack MH, Fava M. Redefining affective disorders: relevance for drug development. CNS Neurosci Ther. 2008;14(1):2-9.
• Depression Clinical and Research Program. www.massgeneral.org/psychiatry/services/dcrp_home.aspx.

Drug Brand Names

• Aripiprazole • Abilify
• Citalopram • Celexa
• Duloxetine • Cymbalta
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosures

Dr. Desseilles was supported by the National Funds for Scientific Research of Belgium. Additional support came from the Belgian American Educational Foundation.

Dr. Fava receives grant/research support from, is a consultant to, and/or is a speaker for Abbott Laboratories, Adamed, Advanced Meeting Partners, Affectis Pharmaceuticals, Alkermes, Amarin Pharma, American Psychiatric Association, American Society of Clinical Psychopharmacology, Aspect Medical Systems, AstraZeneca, Auspex Pharmaceuticals, Bayer, Belvoir Media Group, Best Practice Project Management, BioMarin, BioResearch, Biovail, Boehringer Ingelheim, BrainCells, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Clinical Trials Solutions, Clintara, CME Institute/Physicians Postgraduate Press, CNS Response, Compellis Pharmaceuticals, Covance, Covidien, Cypress Pharmaceutical, DiagnoSearch Life Sciences, Dainippon Sumitomo Pharma, Dov Pharmaceuticals, Edgemont Pharmaceuticals, Eisai, Eli Lilly and Company, EnVivo Pharmaceuticals, ePharmaSolutions, EPIX Pharmaceuticals, Euthymics Bioscience, Fabre-Kramer Pharmaceuticals, Forest Pharmaceuticals, Ganeden Biotech, GenOmind, GlaxoSmithKline, Grünenthal GmbH, Icon Clinical Research, Imedex, i3 Innovus/Ingenix, Janssen Pharmaceutica, Johnson & Johnson Pharmaceutical Research & Development, Knoll Pharmaceuticals, Labopharm, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Lundbeck, MedAvante, Merck, MGH Psychiatry Academy/Primedia, MGH Psychiatry Academy/Reed Elsevier, MSI Methylation Sciences, National Alliance for Research on Schizophrenia & Depression, National Center for Complementary and Alternative Medicine, National Institute of Drug Abuse, National Institute of Mental Health, Naurex, Neuronetics, NextWave Pharmaceuticals, Novartis, Nutrition 21, Orexigen Therapeutics, Organon Pharmaceuticals, Otsuka Pharmaceuticals, PamLab, Pfizer, PharmaStar, Pharmavite®, PharmoRx Therapeutics, Photothera, Precision Human Biolaboratory, Prexa Pharmaceuticals, Puretech Ventures, PsychoGenics, Psylin Neurosciences, RCT Logic, Rexahn Pharmaceuticals, Ridge Diagnostics, Roche Pharmaceuticals, sanofi-aventis US, Schering-Plough, Sepracor, Servier Laboratories, Shire, Solvay Pharmaceuticals, Somaxon Pharmaceuticals, Somerset Pharmaceuticals, Sunovion Pharmaceuticals, Supernus Pharmaceuticals, Synthelabo, Takeda Pharmaceutical, Tal Medical, Tetragenex Pharmaceuticals, Transcept Pharmaceuticals, TransForm Pharmaceuticals, United BioSource, Vanda Pharmaceuticals, and Wyeth-Ayerst Laboratories.

Over the past year, Dr. Mischoulon has received research support from the Bowman Family Foundation, FisherWallace, Ganeden, and Nordic Naturals. He has received honoraria for speaking from Nordic Naturals. He has received royalties from Lippincott Williams & Wilkins for the book Natural medications for psychiatric disorders: Considering the alternatives. No payment has exceeded $10,000.

Dr. Freeman has received research support from Eli Lilly and Company, Forest Laboratories, and GlaxoSmithKline, and served on a one-time advisory board to Bristol-Myers Squibb.

Acknowledgment

The authors acknowledge Janet Witte, MD, MPH, Trina E. Chang, MD, MPH, Nadia Iovieno, MD, PhD, Christina Dording, MD, Heidi Ashih, MD, PhD, Maren Nyer, PhD, and Marasha-Fiona De Jong, MD from the Clinical Trials Network and Institute at Massachusetts General Hospital, Boston, MA.

Approximately one-half of patients with major depressive disorder (MDD) will have partial or nonresponse to first-line antidepressant monotherapy, despite receiving an adequate dosage and sufficient duration of treatment.¹ This has led to the definition of treatment-resistant depression (TRD) as a depressive episode that has shown insufficient response to ≥1 trial of an antidepressant that has demonstrated efficacy in clinical trials.¹ Depressed patients should be treated to full remission because absence of complete remission is associated with:

• a more recurrent and chronic illness course^2,3
• increased medical and psychiatric comorbidities
• greater functional burden
• increased social and economic costs linked with impaired social functioning.⁴

Clinicians need to properly identify MDD and treatment resistance to guide optimal treatment choices. Additional tools are necessary to accurately identify, document, and communicate about symptoms commonly experienced by depressed patients but not fully characterized by DSM-IV-TR MDD criteria.⁵ Finally, in many cases, trait or situational factors might obfuscate accurate diagnosis and the natural course of illness, and tools that can be implemented practically will help identify patients with MDD.

Our group has created and implemented 2 clinician-administered tools—the SAFER Interview and the Antidepressant Treatment Response Questionnaire (ATRQ)—to enrich the qualitative assessment of MDD and treatment resistance.

SAFER: Assessing the diagnosis, symptom severity

The SAFER interview refines the diagnosis of depressed patients by assessing the state vs trait nature of the symptoms, their assessability, their face and ecological validity, and if they pass the rule of the 3 Ps: pervasiveness, persistence, and pathological nature of the current MDD episode (Table 1 and Table 2).⁶ This reliable assessment of the patient’s diagnosis and symptom severity is made in a way that reflects the illness in a real-world setting.

Clinical application of SAFER. Implementing SAFER in clinical settings promotes a personalized, dimensional approach by taking into account a varying degree of symptom severity in depressed patients, in contrast to relying on symptom lists as found in the DSM-IV-TR. Using the SAFER interview deepens the typical psychiatric diagnostic process, allows for a more precise understanding of the patient’s situation, and may help clinicians select effective treatments that target specific symptoms, thus resulting in more rapid alleviation of MDD.⁶

Table 1

The SAFER interview: Assessing depression in a real-world setting

Table 2

The SAFER criteria: Rule of the 3 Ps

CASE REPORT: Worsening symptoms

Ms. Y, age 53, has been depressed for 30 years. She hardly remembers a time in her life when she felt good for more than a few days. However, 2 months ago she noted her symptoms got worse. She presents with many MDD symptoms as assessed by the Hamilton Depression Rating Scale, eg, ongoing depressive mood, feelings of guilt, major sleep disturbances, and work impairments.

Using SAFER to evaluate Ms. Y, a clinician would ask: Does she have symptoms that are present primarily during an episode of acute illness? Does the episode constitute a measurable exacerbation of preexisting symptoms? This clinical vignette illustrates the importance of the first SAFER criterion, state vs trait nature of the symptoms. Ms. Y is a SAFER “pass”—meaning consistent with a major depressive episode—because exacerbation of preexisting symptoms is measurable. However, if her symptoms represented a chronic, long-standing trait, she would be a SAFER “fail” based on this criterion, and her symptoms likely would not improve during a brief pharmacologic intervention. For such patients, SAFER would have oriented the clinician toward alternative therapies such as psychotherapy or a combination of longer, more complex pharmacologic treatment and psychotherapy.

By helping clinicians refine MDD diagnoses, SAFER draws attention to specific depression entities (eg, MDD or dysthymia) and directs them toward appropriate guidelines, treatment algorithms, and precautions (eg, when treated with pharmacotherapy, dysthymic patients are particularly sensitive to unwanted effects and adherence is a serious issue).⁷ The SAFER interview also can help identify when what appears to be a depressive episode clearly is precipitated by situational factors, and is more likely to be influenced by changes in the patient’s life than by treatment. For such patients, first consider nonpharmacologic interventions to avoid unnecessary medication exposure.

ATRQ: Efficacy and adequacy

The ATRQ examines the efficacy (improvement from 0% [not improved at all] to 100% [completely improved]), and adequacy (adequate duration and dose) of any antidepressant treatment in a step-by-step procedure.^1,8,9 For a copy of the ATRQ, click here.

While conducting the interview, clinicians ask about treatment adherence to each medication trial. A treatment-resistant patient may go through many types of trials, from monotherapy to combination to augmentation.¹⁰ For each trial, the ATRQ systematically reviews 4 strategies to enhance treatment response:

• increasing the initial antidepressant dosage¹¹
• combining the initial antidepressant with another antidepressant, typically from another class¹²
• augmenting the initial antidepressant with a nonantidepressant¹²
• switching from the initial antidepressant to another antidepressant.¹³

These strategies also are applied in cases of lost sustained antidepressant efficacy or depressive relapse/recurrence, although empirical evidence supporting these strategies is lacking, with the possible exception of dose increase.^14,15

In the convention our group adopted, an adequate antidepressant trial must be ≥6 weeks in total length, with a dose within an adequate range as specified in the medication’s package insert. In addition, for the purposes of conducting TRD trials, we have considered a patient treatment-resistant if response to adequate dose and duration is <50%. On the ATRQ, 50% improvement refers to 50% symptom reduction from baseline without achieving remission. In an initial clinical trial that lasts ≥6 weeks, any dose increase (for ≥4 weeks) represents optimization and is not considered a new or separate trial, whereas augmentation or combination therapy (for ≥3 weeks) or a switch to another antidepressant (for ≥6 weeks) are considered new trials/treatments.

Decision tree for ATRQ. Because antidepressant treatment always is constrained by personal (eg, adherence, insurance coverage, etc.) and clinical (eg, contraindications due to comorbid conditions, side effects, etc.) considerations, we propose a decision tree to help clinicians determine the number of failed antidepressant trials their patient experienced (Figure). Although this tree does not represent all treatment scenarios, we hope it could help clinicians implement TRD treatment strategies because it highlights proper assessment of treatment duration, dosage, and changes before applying a TRD diagnosis.

The ATRQ meticulously examines patients’ antidepressant history to identify:

• pseudo-resistance, to guide adequate dosing and/or duration, and
• resistance, to propose next-step treatment.

Pseudo-resistance refers to treatment failures that can be attributed to factors such as inadequate treatment dosing or duration, atypical pharmacokinetics that reduce agents’ effectiveness, patient nonadherence (eg, due to adverse effects), or misdiagnosis of the primary disorder (ie, other mood disorders or depressive subsets such as dysthymia or minor depression mistreated as unipolar depression).^16,17 Studies show that many patients with MDD referred to specialty settings are undertreated and receive inadequate antidepressant doses,¹⁸ which suggests that many referrals for TRD are in fact pseudo-resistance.¹⁹ Despite the lack of consensus on criteria for TRD,¹ standardization of what constitutes treatment adequacy during antidepressant trials (eg, adherence, dose, duration) is indispensable.

Clinical application of the ATRQ. Because TRD may require specific interventions, we first need to properly identify treatment resistance. Also, systematic use of a classification system enhances the ability of clinicians and patients to provide meaningful descriptions of antidepressant resistance.

In clinical practice, choice of treatment strategy is based on factors that include partial or nonresponse, tolerability, avoiding withdrawal symptoms, the need to target side effects of a current antidepressant by administering another drug, cost, avoiding drug-drug interactions, and patient preference. Because a treatment-resistant patient may go through many types of trials, it is essential to obtain information about all treatments to determine the number of failed clinical trials a patient may have had for the current MDD episode and lifetime episodes. The importance of asking about adherence to each trial cannot be overemphasized.

Figure: Using the Massachusetts General Hospital Antidepressant Treatment History Questionnaire: A decision tree

CASE REPORT: Limited improvement

Mr. T, age 45, reported that his current depressive episode started several years ago. The first antidepressant trial he received, sertraline, 100 mg/d for 3 months, resulted in 0% improvement. Next he received citalopram, 20 mg/d, for 1 month, without any improvement. The next trial, venlafaxine, 75 mg/d, for 7 weeks, resulted in a 30% response. More recently Mr. B tried duloxetine, up to 90 mg/d, for 2 years with an 80% improvement during the first 3 months and then a decrease of response to <40%. He then received aripiprazole, 10 mg/d, in combination with duloxetine for approximately 4 weeks with no response.

Using the ATRQ to evaluate Mr. B, a clinician would consider the sertraline trial as a failed trial. The citalopram treatment would not be considered an adequate trial because it was too short. The venlafaxine course wouldn’t count as an adequate trial because the dosage was too low. The trial with duloxetine would count as a response (80% improvement) followed by a “poop out” or tachyphylaxis (40% improvement). The fifth trial with the combination of duloxetine and aripiprazole would count as a failed trial. The ATRQ highlights which drugs have been used for too short a duration or at too low a dosage. In Mr. B’s case, using the ATRQ revealed that of 5 trials, only 2 showed antidepressant resistance.

The ATRQ and decision tree are meant to provide clinicians with user-friendly tools to more precisely determine the number of failed antidepressant trials a patient experienced. By assessing if an antidepressant trial had an adequate dose and duration, the ATRQ can help suggest the next treatment options. For example, if a trial was inadequate in dose and/or duration but the patient tolerated the medication, then optimizing treatment with the current drug would be a logical next step. If a patient does not respond to an adequate trial, clinicians have several options, such as switching to another antidepressant, using a combination of medications or an augmentation strategy, or increasing the dose of the original antidepressant.

Limitations of the ATRQ. Historical rating of treatment is not as accurate as a prospective trial. Another limitation of the ATRQ is that the minimum effective dose is accepted as adequate; many clinicians would suggest that such a dose is inadequate. Also, the duration specified for augmentation, dose increase, and monotherapy are based on expert consensus¹ rather than systematic research. Nonetheless, this method of documenting prior trials and treatment adequacy is an important advance.

The ATRQ lacks a place to indicate discontinuation due to intolerance. Knowing if adverse events caused treatment nonadherence or discontinuation is relevant to selecting treatment.

The ATRQ considers only pharmacotherapy and electroconvulsive therapy. Comprehensive assessment of treatment resistance requires asking about depression-specific, evidence-based psychotherapies, including cognitive-behavioral therapy and interpersonal therapy. Another precaution is that the ATRQ and SAFER should be used in conjunction with structured or semi-structured clinical interviews and other clinical tools to rule out other primary diagnoses (eg, bipolar disorder, posttraumatic stress disorder, obsessive-compulsive disorder, or surreptitious substance abuse).²⁰

Using SAFER and ATRQ allows clinicians to make a proper MDD diagnosis with an accurate, reliable assessment of symptom severity and a precise count of antidepressant trials of adequate duration and dose. SAFER helps differentiate MDD from other depressive disorders and can be used to separate MDD from a similar presentation of a reaction to external circumstances that may remit if these circumstances change.

These 2 clinical tools focus on MDD and TRD. Compared with treatment resistance in MDD, treatment resistance in other forms of depression, such as minor depressive disorder or dysthymia, has been inadequately researched^21,22 and should be addressed in large studies. However, to help patients achieve remission of depressive disorders—especially MDD—clinicians should use patient information gathered via measurement-based care in combination with algorithm recommendations.²³ Persistence of clinical care of MDD is essential because several treatment steps might be necessary for some patients to achieve remission. Throughout treatment, patients’ symptoms, adverse events secondary to ongoing treatment, and medication adherence should be assessed with appropriate tools. ATRQ and SAFER offer a clinician support in assessing treatment resistance history and a patient’s likelihood to respond to pharmacologic treatment.

Related Resources

• Desseilles M, Witte J, Chang TE, et al. Assessing the adequacy of past antidepressant trials: a clinician’s guide to the Antidepressant Treatment Response Questionnaire (ATRQ). J Clin Psychiatry. 2011;72(8):1152-1154.
• Targum SD, Pollack MH, Fava M. Redefining affective disorders: relevance for drug development. CNS Neurosci Ther. 2008;14(1):2-9.
• Depression Clinical and Research Program. www.massgeneral.org/psychiatry/services/dcrp_home.aspx.

Drug Brand Names

• Aripiprazole • Abilify
• Citalopram • Celexa
• Duloxetine • Cymbalta
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosures

Dr. Desseilles was supported by the National Funds for Scientific Research of Belgium. Additional support came from the Belgian American Educational Foundation.

Dr. Fava receives grant/research support from, is a consultant to, and/or is a speaker for Abbott Laboratories, Adamed, Advanced Meeting Partners, Affectis Pharmaceuticals, Alkermes, Amarin Pharma, American Psychiatric Association, American Society of Clinical Psychopharmacology, Aspect Medical Systems, AstraZeneca, Auspex Pharmaceuticals, Bayer, Belvoir Media Group, Best Practice Project Management, BioMarin, BioResearch, Biovail, Boehringer Ingelheim, BrainCells, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Clinical Trials Solutions, Clintara, CME Institute/Physicians Postgraduate Press, CNS Response, Compellis Pharmaceuticals, Covance, Covidien, Cypress Pharmaceutical, DiagnoSearch Life Sciences, Dainippon Sumitomo Pharma, Dov Pharmaceuticals, Edgemont Pharmaceuticals, Eisai, Eli Lilly and Company, EnVivo Pharmaceuticals, ePharmaSolutions, EPIX Pharmaceuticals, Euthymics Bioscience, Fabre-Kramer Pharmaceuticals, Forest Pharmaceuticals, Ganeden Biotech, GenOmind, GlaxoSmithKline, Grünenthal GmbH, Icon Clinical Research, Imedex, i3 Innovus/Ingenix, Janssen Pharmaceutica, Johnson & Johnson Pharmaceutical Research & Development, Knoll Pharmaceuticals, Labopharm, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Lundbeck, MedAvante, Merck, MGH Psychiatry Academy/Primedia, MGH Psychiatry Academy/Reed Elsevier, MSI Methylation Sciences, National Alliance for Research on Schizophrenia & Depression, National Center for Complementary and Alternative Medicine, National Institute of Drug Abuse, National Institute of Mental Health, Naurex, Neuronetics, NextWave Pharmaceuticals, Novartis, Nutrition 21, Orexigen Therapeutics, Organon Pharmaceuticals, Otsuka Pharmaceuticals, PamLab, Pfizer, PharmaStar, Pharmavite®, PharmoRx Therapeutics, Photothera, Precision Human Biolaboratory, Prexa Pharmaceuticals, Puretech Ventures, PsychoGenics, Psylin Neurosciences, RCT Logic, Rexahn Pharmaceuticals, Ridge Diagnostics, Roche Pharmaceuticals, sanofi-aventis US, Schering-Plough, Sepracor, Servier Laboratories, Shire, Solvay Pharmaceuticals, Somaxon Pharmaceuticals, Somerset Pharmaceuticals, Sunovion Pharmaceuticals, Supernus Pharmaceuticals, Synthelabo, Takeda Pharmaceutical, Tal Medical, Tetragenex Pharmaceuticals, Transcept Pharmaceuticals, TransForm Pharmaceuticals, United BioSource, Vanda Pharmaceuticals, and Wyeth-Ayerst Laboratories.

Over the past year, Dr. Mischoulon has received research support from the Bowman Family Foundation, FisherWallace, Ganeden, and Nordic Naturals. He has received honoraria for speaking from Nordic Naturals. He has received royalties from Lippincott Williams & Wilkins for the book Natural medications for psychiatric disorders: Considering the alternatives. No payment has exceeded $10,000.

Dr. Freeman has received research support from Eli Lilly and Company, Forest Laboratories, and GlaxoSmithKline, and served on a one-time advisory board to Bristol-Myers Squibb.

Acknowledgment

The authors acknowledge Janet Witte, MD, MPH, Trina E. Chang, MD, MPH, Nadia Iovieno, MD, PhD, Christina Dording, MD, Heidi Ashih, MD, PhD, Maren Nyer, PhD, and Marasha-Fiona De Jong, MD from the Clinical Trials Network and Institute at Massachusetts General Hospital, Boston, MA.

Approximately one-half of patients with major depressive disorder (MDD) will have partial or nonresponse to first-line antidepressant monotherapy, despite receiving an adequate dosage and sufficient duration of treatment.¹ This has led to the definition of treatment-resistant depression (TRD) as a depressive episode that has shown insufficient response to ≥1 trial of an antidepressant that has demonstrated efficacy in clinical trials.¹ Depressed patients should be treated to full remission because absence of complete remission is associated with:

• a more recurrent and chronic illness course^2,3
• increased medical and psychiatric comorbidities
• greater functional burden
• increased social and economic costs linked with impaired social functioning.⁴

Clinicians need to properly identify MDD and treatment resistance to guide optimal treatment choices. Additional tools are necessary to accurately identify, document, and communicate about symptoms commonly experienced by depressed patients but not fully characterized by DSM-IV-TR MDD criteria.⁵ Finally, in many cases, trait or situational factors might obfuscate accurate diagnosis and the natural course of illness, and tools that can be implemented practically will help identify patients with MDD.

Our group has created and implemented 2 clinician-administered tools—the SAFER Interview and the Antidepressant Treatment Response Questionnaire (ATRQ)—to enrich the qualitative assessment of MDD and treatment resistance.

SAFER: Assessing the diagnosis, symptom severity

The SAFER interview refines the diagnosis of depressed patients by assessing the state vs trait nature of the symptoms, their assessability, their face and ecological validity, and if they pass the rule of the 3 Ps: pervasiveness, persistence, and pathological nature of the current MDD episode (Table 1 and Table 2).⁶ This reliable assessment of the patient’s diagnosis and symptom severity is made in a way that reflects the illness in a real-world setting.

Clinical application of SAFER. Implementing SAFER in clinical settings promotes a personalized, dimensional approach by taking into account a varying degree of symptom severity in depressed patients, in contrast to relying on symptom lists as found in the DSM-IV-TR. Using the SAFER interview deepens the typical psychiatric diagnostic process, allows for a more precise understanding of the patient’s situation, and may help clinicians select effective treatments that target specific symptoms, thus resulting in more rapid alleviation of MDD.⁶

Table 1

The SAFER interview: Assessing depression in a real-world setting

Table 2

The SAFER criteria: Rule of the 3 Ps

CASE REPORT: Worsening symptoms

Ms. Y, age 53, has been depressed for 30 years. She hardly remembers a time in her life when she felt good for more than a few days. However, 2 months ago she noted her symptoms got worse. She presents with many MDD symptoms as assessed by the Hamilton Depression Rating Scale, eg, ongoing depressive mood, feelings of guilt, major sleep disturbances, and work impairments.

Using SAFER to evaluate Ms. Y, a clinician would ask: Does she have symptoms that are present primarily during an episode of acute illness? Does the episode constitute a measurable exacerbation of preexisting symptoms? This clinical vignette illustrates the importance of the first SAFER criterion, state vs trait nature of the symptoms. Ms. Y is a SAFER “pass”—meaning consistent with a major depressive episode—because exacerbation of preexisting symptoms is measurable. However, if her symptoms represented a chronic, long-standing trait, she would be a SAFER “fail” based on this criterion, and her symptoms likely would not improve during a brief pharmacologic intervention. For such patients, SAFER would have oriented the clinician toward alternative therapies such as psychotherapy or a combination of longer, more complex pharmacologic treatment and psychotherapy.

By helping clinicians refine MDD diagnoses, SAFER draws attention to specific depression entities (eg, MDD or dysthymia) and directs them toward appropriate guidelines, treatment algorithms, and precautions (eg, when treated with pharmacotherapy, dysthymic patients are particularly sensitive to unwanted effects and adherence is a serious issue).⁷ The SAFER interview also can help identify when what appears to be a depressive episode clearly is precipitated by situational factors, and is more likely to be influenced by changes in the patient’s life than by treatment. For such patients, first consider nonpharmacologic interventions to avoid unnecessary medication exposure.

ATRQ: Efficacy and adequacy

The ATRQ examines the efficacy (improvement from 0% [not improved at all] to 100% [completely improved]), and adequacy (adequate duration and dose) of any antidepressant treatment in a step-by-step procedure.^1,8,9 For a copy of the ATRQ, click here.

While conducting the interview, clinicians ask about treatment adherence to each medication trial. A treatment-resistant patient may go through many types of trials, from monotherapy to combination to augmentation.¹⁰ For each trial, the ATRQ systematically reviews 4 strategies to enhance treatment response:

• increasing the initial antidepressant dosage¹¹
• combining the initial antidepressant with another antidepressant, typically from another class¹²
• augmenting the initial antidepressant with a nonantidepressant¹²
• switching from the initial antidepressant to another antidepressant.¹³

These strategies also are applied in cases of lost sustained antidepressant efficacy or depressive relapse/recurrence, although empirical evidence supporting these strategies is lacking, with the possible exception of dose increase.^14,15

In the convention our group adopted, an adequate antidepressant trial must be ≥6 weeks in total length, with a dose within an adequate range as specified in the medication’s package insert. In addition, for the purposes of conducting TRD trials, we have considered a patient treatment-resistant if response to adequate dose and duration is <50%. On the ATRQ, 50% improvement refers to 50% symptom reduction from baseline without achieving remission. In an initial clinical trial that lasts ≥6 weeks, any dose increase (for ≥4 weeks) represents optimization and is not considered a new or separate trial, whereas augmentation or combination therapy (for ≥3 weeks) or a switch to another antidepressant (for ≥6 weeks) are considered new trials/treatments.

Decision tree for ATRQ. Because antidepressant treatment always is constrained by personal (eg, adherence, insurance coverage, etc.) and clinical (eg, contraindications due to comorbid conditions, side effects, etc.) considerations, we propose a decision tree to help clinicians determine the number of failed antidepressant trials their patient experienced (Figure). Although this tree does not represent all treatment scenarios, we hope it could help clinicians implement TRD treatment strategies because it highlights proper assessment of treatment duration, dosage, and changes before applying a TRD diagnosis.

The ATRQ meticulously examines patients’ antidepressant history to identify:

• pseudo-resistance, to guide adequate dosing and/or duration, and
• resistance, to propose next-step treatment.

Pseudo-resistance refers to treatment failures that can be attributed to factors such as inadequate treatment dosing or duration, atypical pharmacokinetics that reduce agents’ effectiveness, patient nonadherence (eg, due to adverse effects), or misdiagnosis of the primary disorder (ie, other mood disorders or depressive subsets such as dysthymia or minor depression mistreated as unipolar depression).^16,17 Studies show that many patients with MDD referred to specialty settings are undertreated and receive inadequate antidepressant doses,¹⁸ which suggests that many referrals for TRD are in fact pseudo-resistance.¹⁹ Despite the lack of consensus on criteria for TRD,¹ standardization of what constitutes treatment adequacy during antidepressant trials (eg, adherence, dose, duration) is indispensable.

Clinical application of the ATRQ. Because TRD may require specific interventions, we first need to properly identify treatment resistance. Also, systematic use of a classification system enhances the ability of clinicians and patients to provide meaningful descriptions of antidepressant resistance.

In clinical practice, choice of treatment strategy is based on factors that include partial or nonresponse, tolerability, avoiding withdrawal symptoms, the need to target side effects of a current antidepressant by administering another drug, cost, avoiding drug-drug interactions, and patient preference. Because a treatment-resistant patient may go through many types of trials, it is essential to obtain information about all treatments to determine the number of failed clinical trials a patient may have had for the current MDD episode and lifetime episodes. The importance of asking about adherence to each trial cannot be overemphasized.

Figure: Using the Massachusetts General Hospital Antidepressant Treatment History Questionnaire: A decision tree

CASE REPORT: Limited improvement

Mr. T, age 45, reported that his current depressive episode started several years ago. The first antidepressant trial he received, sertraline, 100 mg/d for 3 months, resulted in 0% improvement. Next he received citalopram, 20 mg/d, for 1 month, without any improvement. The next trial, venlafaxine, 75 mg/d, for 7 weeks, resulted in a 30% response. More recently Mr. B tried duloxetine, up to 90 mg/d, for 2 years with an 80% improvement during the first 3 months and then a decrease of response to <40%. He then received aripiprazole, 10 mg/d, in combination with duloxetine for approximately 4 weeks with no response.

Using the ATRQ to evaluate Mr. B, a clinician would consider the sertraline trial as a failed trial. The citalopram treatment would not be considered an adequate trial because it was too short. The venlafaxine course wouldn’t count as an adequate trial because the dosage was too low. The trial with duloxetine would count as a response (80% improvement) followed by a “poop out” or tachyphylaxis (40% improvement). The fifth trial with the combination of duloxetine and aripiprazole would count as a failed trial. The ATRQ highlights which drugs have been used for too short a duration or at too low a dosage. In Mr. B’s case, using the ATRQ revealed that of 5 trials, only 2 showed antidepressant resistance.

The ATRQ and decision tree are meant to provide clinicians with user-friendly tools to more precisely determine the number of failed antidepressant trials a patient experienced. By assessing if an antidepressant trial had an adequate dose and duration, the ATRQ can help suggest the next treatment options. For example, if a trial was inadequate in dose and/or duration but the patient tolerated the medication, then optimizing treatment with the current drug would be a logical next step. If a patient does not respond to an adequate trial, clinicians have several options, such as switching to another antidepressant, using a combination of medications or an augmentation strategy, or increasing the dose of the original antidepressant.

Limitations of the ATRQ. Historical rating of treatment is not as accurate as a prospective trial. Another limitation of the ATRQ is that the minimum effective dose is accepted as adequate; many clinicians would suggest that such a dose is inadequate. Also, the duration specified for augmentation, dose increase, and monotherapy are based on expert consensus¹ rather than systematic research. Nonetheless, this method of documenting prior trials and treatment adequacy is an important advance.

The ATRQ lacks a place to indicate discontinuation due to intolerance. Knowing if adverse events caused treatment nonadherence or discontinuation is relevant to selecting treatment.

The ATRQ considers only pharmacotherapy and electroconvulsive therapy. Comprehensive assessment of treatment resistance requires asking about depression-specific, evidence-based psychotherapies, including cognitive-behavioral therapy and interpersonal therapy. Another precaution is that the ATRQ and SAFER should be used in conjunction with structured or semi-structured clinical interviews and other clinical tools to rule out other primary diagnoses (eg, bipolar disorder, posttraumatic stress disorder, obsessive-compulsive disorder, or surreptitious substance abuse).²⁰

Using SAFER and ATRQ allows clinicians to make a proper MDD diagnosis with an accurate, reliable assessment of symptom severity and a precise count of antidepressant trials of adequate duration and dose. SAFER helps differentiate MDD from other depressive disorders and can be used to separate MDD from a similar presentation of a reaction to external circumstances that may remit if these circumstances change.

These 2 clinical tools focus on MDD and TRD. Compared with treatment resistance in MDD, treatment resistance in other forms of depression, such as minor depressive disorder or dysthymia, has been inadequately researched^21,22 and should be addressed in large studies. However, to help patients achieve remission of depressive disorders—especially MDD—clinicians should use patient information gathered via measurement-based care in combination with algorithm recommendations.²³ Persistence of clinical care of MDD is essential because several treatment steps might be necessary for some patients to achieve remission. Throughout treatment, patients’ symptoms, adverse events secondary to ongoing treatment, and medication adherence should be assessed with appropriate tools. ATRQ and SAFER offer a clinician support in assessing treatment resistance history and a patient’s likelihood to respond to pharmacologic treatment.

Related Resources

• Desseilles M, Witte J, Chang TE, et al. Assessing the adequacy of past antidepressant trials: a clinician’s guide to the Antidepressant Treatment Response Questionnaire (ATRQ). J Clin Psychiatry. 2011;72(8):1152-1154.
• Targum SD, Pollack MH, Fava M. Redefining affective disorders: relevance for drug development. CNS Neurosci Ther. 2008;14(1):2-9.
• Depression Clinical and Research Program. www.massgeneral.org/psychiatry/services/dcrp_home.aspx.

Drug Brand Names

• Aripiprazole • Abilify
• Citalopram • Celexa
• Duloxetine • Cymbalta
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosures

Dr. Desseilles was supported by the National Funds for Scientific Research of Belgium. Additional support came from the Belgian American Educational Foundation.

Dr. Fava receives grant/research support from, is a consultant to, and/or is a speaker for Abbott Laboratories, Adamed, Advanced Meeting Partners, Affectis Pharmaceuticals, Alkermes, Amarin Pharma, American Psychiatric Association, American Society of Clinical Psychopharmacology, Aspect Medical Systems, AstraZeneca, Auspex Pharmaceuticals, Bayer, Belvoir Media Group, Best Practice Project Management, BioMarin, BioResearch, Biovail, Boehringer Ingelheim, BrainCells, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Clinical Trials Solutions, Clintara, CME Institute/Physicians Postgraduate Press, CNS Response, Compellis Pharmaceuticals, Covance, Covidien, Cypress Pharmaceutical, DiagnoSearch Life Sciences, Dainippon Sumitomo Pharma, Dov Pharmaceuticals, Edgemont Pharmaceuticals, Eisai, Eli Lilly and Company, EnVivo Pharmaceuticals, ePharmaSolutions, EPIX Pharmaceuticals, Euthymics Bioscience, Fabre-Kramer Pharmaceuticals, Forest Pharmaceuticals, Ganeden Biotech, GenOmind, GlaxoSmithKline, Grünenthal GmbH, Icon Clinical Research, Imedex, i3 Innovus/Ingenix, Janssen Pharmaceutica, Johnson & Johnson Pharmaceutical Research & Development, Knoll Pharmaceuticals, Labopharm, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Lundbeck, MedAvante, Merck, MGH Psychiatry Academy/Primedia, MGH Psychiatry Academy/Reed Elsevier, MSI Methylation Sciences, National Alliance for Research on Schizophrenia & Depression, National Center for Complementary and Alternative Medicine, National Institute of Drug Abuse, National Institute of Mental Health, Naurex, Neuronetics, NextWave Pharmaceuticals, Novartis, Nutrition 21, Orexigen Therapeutics, Organon Pharmaceuticals, Otsuka Pharmaceuticals, PamLab, Pfizer, PharmaStar, Pharmavite®, PharmoRx Therapeutics, Photothera, Precision Human Biolaboratory, Prexa Pharmaceuticals, Puretech Ventures, PsychoGenics, Psylin Neurosciences, RCT Logic, Rexahn Pharmaceuticals, Ridge Diagnostics, Roche Pharmaceuticals, sanofi-aventis US, Schering-Plough, Sepracor, Servier Laboratories, Shire, Solvay Pharmaceuticals, Somaxon Pharmaceuticals, Somerset Pharmaceuticals, Sunovion Pharmaceuticals, Supernus Pharmaceuticals, Synthelabo, Takeda Pharmaceutical, Tal Medical, Tetragenex Pharmaceuticals, Transcept Pharmaceuticals, TransForm Pharmaceuticals, United BioSource, Vanda Pharmaceuticals, and Wyeth-Ayerst Laboratories.

Over the past year, Dr. Mischoulon has received research support from the Bowman Family Foundation, FisherWallace, Ganeden, and Nordic Naturals. He has received honoraria for speaking from Nordic Naturals. He has received royalties from Lippincott Williams & Wilkins for the book Natural medications for psychiatric disorders: Considering the alternatives. No payment has exceeded $10,000.

Dr. Freeman has received research support from Eli Lilly and Company, Forest Laboratories, and GlaxoSmithKline, and served on a one-time advisory board to Bristol-Myers Squibb.

Acknowledgment

The authors acknowledge Janet Witte, MD, MPH, Trina E. Chang, MD, MPH, Nadia Iovieno, MD, PhD, Christina Dording, MD, Heidi Ashih, MD, PhD, Maren Nyer, PhD, and Marasha-Fiona De Jong, MD from the Clinical Trials Network and Institute at Massachusetts General Hospital, Boston, MA.

Discuss this article at www.facebook.com/CurrentPsychiatry

Work on the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)—scheduled to be published in May 2013—has been ongoing for more than a decade. Momentous advances in genetics and brain imaging since publication of DSM-IV in 1994 have generated optimism that an improved understanding of the neurobiologic underpinnings of psychiatric disorders might lead to a paradigm shift from the current descriptive classification system to a more scientific etiopathophysiological system similar to that used by other medical specialities.¹

Some fear that any changes to our current classification system may be premature and could make an already complex system even more unwieldy.² Scores of articles about the content and process of DSM-5 and several critiques and commentaries on the topic have been published. The American Psychiatric Association (APA) has made the DSM-5 process transparent by posting frequent updates to the DSM-5 Development Web site (www.dsm5.org), seeking feedback from the psychiatric community and the public, and presenting progress reports by members of the DSM-5 Task Force at scientific meetings.

There have been few discussions on the implications of DSM-5 from the practicing clinician’s vantage point, which I seek to present in this series of articles, the remainder of which will be published here, at CurrentPsychiatry.com. In this article, I:

• provide a brief history of psychiatric classification, focusing on the origins and evolution of the DSM system
• summarize the limitations of DSM-IV
• note the challenges and tensions in the construction of DSM-5
• review the DSM-5 process
• outline its current status
• discuss the organization and content of future articles in this series.

Although I am a member of the DSM-5 Psychotic Disorders Work Group, I am solely responsible for the content and any opinions that I offer in this article and series. All details of DSM-5 that I discuss are publicly available at www.dsm5.org. I’ve been a clinician and clinical researcher for >25 years, and my opinions are colored by the need for clarity, rigor, clinical relevance, and a disdain for overly speculative thinking.

Evolution of DSM

A nosological system (system of classification of disease) enables clinicians to provide specific treatments for medical causes of human disease and/or disability with precise and predictable effects and guide patients and families about the likely course and outcome. Such classification systems also are used by:

• researchers, to learn more about the nature of the conditions being classified and develop better treatments for them
• health care systems, to provide optimal health care and track its appropriate provision
• insurance companies, to provide appropriate reimbursement for health care
• health product developers, including pharmaceutical companies, to develop health care products and promote their appropriate utilization
• government agencies, to determine health priorities and apportionment of health care resources
• public health agencies, to track the distribution of health and disease in communities around the world.

An ideal classification system would meet all constituents’ needs while perfectly mapping natural disease entities with distinct etiology and pathophysiology (validity), consistently allow all users to reach the same diagnosis (reliability), and provide clinicians with clear guidance about treatment and likely course for each of the entities (utility), with the list of entities being mutually exclusive and collectively exhaustive (coverage).

The current nosological system for psychiatric disorders originated in the late 19^th and early 20^th centuries and culminated in the first edition of the Diagnostic and Statistical Manual of Mental Disorders³ released in 1952 and a section related to mental disorders (section V) in the sixth revision of the International Classification of Disease (ICD).⁴ Whereas DSM focuses exclusively on mental disorders, the ICD is a general medical classification system that began covering mental disorders with its sixth revision in 1949. In subsequent revisions (ICD-7 through -10 and DSM-II through -IV), substantial changes in diagnostic criteria have been made, although the systems’ basic structure has been retained. Table 1 describes major changes from DSM-I through DSM-IV-TR.^3,5-9 DSM and ICD both are being revised; DSM-5 is scheduled to be released in 2013 and ICD-11 is to be finalized by 2016.

Table 1

Conceptual development of DSM-I to DSM-IV-TR

What do clinicians need?

Similar to ICD-10, DSM-IV is marked by considerable complexity, variable validity, limited clinical and research utility, and problems of burgeoning comorbidity.¹⁰ Efforts to revise DSM seek to address these limitations. From a clinician’s perspective, the most challenging aspects of DSM-IV derive from its complexity—which makes clinical application difficult—and its limited clinical utility, which is exemplified by artificial comorbidity,¹¹ frequent use of “not otherwise specified” (NOS), and relative treatment nonspecificity with reference to diagnosis.

As clinicians, we want a nosological system that is easy to use, can guide treatment decisions, provides useful information about likely disease course and outcomes, and allows us to easily communicate about disease nature with patients, families, payers, and health care administrators. Additionally, although good validity and reliability are desirable for clinicians, adequate coverage of psychiatric disease—the listed conditions should be collectively exhaustive and mutually exclusive—is particularly valued. Finally, we want a diagnostic system that allows us to explain the reasoning behind psychiatric diagnoses and related treatment in lay terms to patients and their families.

DSM-5 development to date

DSM-5 development has been a collaborative effort led by the APA and involves the National Institute of Mental Health, the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, and the World Health Organization (WHO). Between 1999 and 2002, 3 work conferences resulted in a series of white papers that identified gaps and research needs.¹ Between 2003 and 2008, the American Psychiatric Institute for Research and Education, the National Institute of Health, and the WHO organized 13 international conferences to review a wide range of nosologic issues; the proceedings have been compiled into 13 monographs (11 published and 2 in press) and >125 scientific articles that serve as key reference sources for the DSM-5 process. For a continually updated list of these publications, see www.dsm5.org/Research.

In 2006, DSM-5 Task Force Chair David J. Kupfer, MD and Vice Chair Darrel A. Regier, MD, MPH were appointed and began selecting members of the DSM-5 Task Force, a process that was completed in 2007. Members of the 13 diagnostic area Work Groups (Table 2) were selected and the Work Groups were constituted in 2008. All 168 Task Force and Work Group members were vetted to ensure that they met standards of minimum conflict of interest and broad representation. Membership includes diverse professional representation from academia and mental health; 75% of members are from the United States. Six cross-cutting study groups have deliberated on a range of common issues, including:

• spectrum disorders
• lifespan and development
• gender and cross-cultural
• psychiatric/general medicine interface
• impairment and disability assessment
• diagnostic measurement and assessment.

Additionally, >300 external advisors with special expertise have participated in the process. Since 2008, each of the Work Groups has conducted extensive literature reviews of all assigned disorders, evaluated what works and what doesn’t work in DSM-IV-TR, assessed new research developments and clinical issues that have arisen since publication of DSM-IV-TR in 1994, and developed research plans to investigate critical issues utilizing systematic reviews and secondary data analyses. Based on these analyses, each Work Group proposed draft diagnostic criteria for its disorders, using a strict protocol for criteria revisions such as addition or deletion of disorders and changes to existing diagnostic criteria. These draft diagnostic criteria were first presented on www.dsm5.org in late 2009 through early 2010. Based on input from other Work Groups, the Task Force, several external groups, and the public, the Work Groups revised these criteria and prioritized necessary field trials to evaluate key recommendations. Phase I of the field trials began in 2010.¹² Results of these field trials are being compiled and analyzed.

The DSM-5 Work Groups have met via teleconference 1 to 2 times a month and in-person twice a year, with significant communication between meetings. Work Group chairs are members of the Task Force, which has equally frequent meetings. Reports of DSM-5 deliberations have been presented at hundreds of professional meetings and described in >200 scientific publications. Comprehensive information and ongoing updates on DSM-5 and a list of publications and meetings are provided at www.dsm5.org.

Public input has been sought and the Work Groups have received and processed >10,000 comments. In 2010, the APA Board of Trustees appointed a Scientific Review Committee to evaluate the scientific merit and clinical impact of the Work Group recommendations and comment on the strength of the evidence advanced in support of each proposed revision. In 2011, the Board of Trustees appointed a Clinical and Public Health Committee to evaluate the clinical utility and public health significance of the proposed revisions. The APA and WHO have shared information and assessments in an effort to harmonize diagnostic criteria between DSM-5 and ICD-11.

Initial hopes that DSM-5 could represent a paradigm shift toward an etiopathophysiological classification of psychiatric disorders have been tempered by recognition of the limitations of our current neurobiologic understanding of psychiatric disorders. Therefore, the focus for DSM-5 has shifted from validity enhancements to improved clinical utility while building a framework that better lends itself to a future etiopathophysiological nosology.^13-18 Whereas dimensional assessments are likely to be added across various diagnostic categories, a primarily categorical nosology will be retained and the proposed criterion changes are relatively modest. The results of our enhanced knowledge about the neurobiologic underpinnings of psychiatric disorders will not be reflected in diagnostic criteria, but in the significant revisions to the DSM text.

Our DSM-5 series

Subsequent articles in this series—which will be published here, at CurrentPsychiatry.com—will discuss specific proposed DSM-5 changes in 13 groups of disorders (Table 2) and their clinical implications. These articles also will address the relationship of DSM to ICD, issues with dimensional classification, and the importance of and challenges in precise diagnostic measurement.

Table 2

DSM-5 Work Groups

Related Resources

• American Psychiatric Association. DSM-5 Development. www.dsm5.org.
• Black DW, Zimmerman M. Redefining personality disorders: Proposed revisions for DSM-5. Current Psychiatry. 2011;10(9):26-38.

Disclosure

Dr. Tandon is a member of the DSM-5 Psychotic Disorders Work Group. He reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Work on the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)—scheduled to be published in May 2013—has been ongoing for more than a decade. Momentous advances in genetics and brain imaging since publication of DSM-IV in 1994 have generated optimism that an improved understanding of the neurobiologic underpinnings of psychiatric disorders might lead to a paradigm shift from the current descriptive classification system to a more scientific etiopathophysiological system similar to that used by other medical specialities.¹

Some fear that any changes to our current classification system may be premature and could make an already complex system even more unwieldy.² Scores of articles about the content and process of DSM-5 and several critiques and commentaries on the topic have been published. The American Psychiatric Association (APA) has made the DSM-5 process transparent by posting frequent updates to the DSM-5 Development Web site (www.dsm5.org), seeking feedback from the psychiatric community and the public, and presenting progress reports by members of the DSM-5 Task Force at scientific meetings.

There have been few discussions on the implications of DSM-5 from the practicing clinician’s vantage point, which I seek to present in this series of articles, the remainder of which will be published here, at CurrentPsychiatry.com. In this article, I:

• provide a brief history of psychiatric classification, focusing on the origins and evolution of the DSM system
• summarize the limitations of DSM-IV
• note the challenges and tensions in the construction of DSM-5
• review the DSM-5 process
• outline its current status
• discuss the organization and content of future articles in this series.

Although I am a member of the DSM-5 Psychotic Disorders Work Group, I am solely responsible for the content and any opinions that I offer in this article and series. All details of DSM-5 that I discuss are publicly available at www.dsm5.org. I’ve been a clinician and clinical researcher for >25 years, and my opinions are colored by the need for clarity, rigor, clinical relevance, and a disdain for overly speculative thinking.

Evolution of DSM

A nosological system (system of classification of disease) enables clinicians to provide specific treatments for medical causes of human disease and/or disability with precise and predictable effects and guide patients and families about the likely course and outcome. Such classification systems also are used by:

• researchers, to learn more about the nature of the conditions being classified and develop better treatments for them
• health care systems, to provide optimal health care and track its appropriate provision
• insurance companies, to provide appropriate reimbursement for health care
• health product developers, including pharmaceutical companies, to develop health care products and promote their appropriate utilization
• government agencies, to determine health priorities and apportionment of health care resources
• public health agencies, to track the distribution of health and disease in communities around the world.

An ideal classification system would meet all constituents’ needs while perfectly mapping natural disease entities with distinct etiology and pathophysiology (validity), consistently allow all users to reach the same diagnosis (reliability), and provide clinicians with clear guidance about treatment and likely course for each of the entities (utility), with the list of entities being mutually exclusive and collectively exhaustive (coverage).

The current nosological system for psychiatric disorders originated in the late 19^th and early 20^th centuries and culminated in the first edition of the Diagnostic and Statistical Manual of Mental Disorders³ released in 1952 and a section related to mental disorders (section V) in the sixth revision of the International Classification of Disease (ICD).⁴ Whereas DSM focuses exclusively on mental disorders, the ICD is a general medical classification system that began covering mental disorders with its sixth revision in 1949. In subsequent revisions (ICD-7 through -10 and DSM-II through -IV), substantial changes in diagnostic criteria have been made, although the systems’ basic structure has been retained. Table 1 describes major changes from DSM-I through DSM-IV-TR.^3,5-9 DSM and ICD both are being revised; DSM-5 is scheduled to be released in 2013 and ICD-11 is to be finalized by 2016.

Table 1

Conceptual development of DSM-I to DSM-IV-TR

What do clinicians need?

Similar to ICD-10, DSM-IV is marked by considerable complexity, variable validity, limited clinical and research utility, and problems of burgeoning comorbidity.¹⁰ Efforts to revise DSM seek to address these limitations. From a clinician’s perspective, the most challenging aspects of DSM-IV derive from its complexity—which makes clinical application difficult—and its limited clinical utility, which is exemplified by artificial comorbidity,¹¹ frequent use of “not otherwise specified” (NOS), and relative treatment nonspecificity with reference to diagnosis.

As clinicians, we want a nosological system that is easy to use, can guide treatment decisions, provides useful information about likely disease course and outcomes, and allows us to easily communicate about disease nature with patients, families, payers, and health care administrators. Additionally, although good validity and reliability are desirable for clinicians, adequate coverage of psychiatric disease—the listed conditions should be collectively exhaustive and mutually exclusive—is particularly valued. Finally, we want a diagnostic system that allows us to explain the reasoning behind psychiatric diagnoses and related treatment in lay terms to patients and their families.

DSM-5 development to date

DSM-5 development has been a collaborative effort led by the APA and involves the National Institute of Mental Health, the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, and the World Health Organization (WHO). Between 1999 and 2002, 3 work conferences resulted in a series of white papers that identified gaps and research needs.¹ Between 2003 and 2008, the American Psychiatric Institute for Research and Education, the National Institute of Health, and the WHO organized 13 international conferences to review a wide range of nosologic issues; the proceedings have been compiled into 13 monographs (11 published and 2 in press) and >125 scientific articles that serve as key reference sources for the DSM-5 process. For a continually updated list of these publications, see www.dsm5.org/Research.

In 2006, DSM-5 Task Force Chair David J. Kupfer, MD and Vice Chair Darrel A. Regier, MD, MPH were appointed and began selecting members of the DSM-5 Task Force, a process that was completed in 2007. Members of the 13 diagnostic area Work Groups (Table 2) were selected and the Work Groups were constituted in 2008. All 168 Task Force and Work Group members were vetted to ensure that they met standards of minimum conflict of interest and broad representation. Membership includes diverse professional representation from academia and mental health; 75% of members are from the United States. Six cross-cutting study groups have deliberated on a range of common issues, including:

• spectrum disorders
• lifespan and development
• gender and cross-cultural
• psychiatric/general medicine interface
• impairment and disability assessment
• diagnostic measurement and assessment.

Additionally, >300 external advisors with special expertise have participated in the process. Since 2008, each of the Work Groups has conducted extensive literature reviews of all assigned disorders, evaluated what works and what doesn’t work in DSM-IV-TR, assessed new research developments and clinical issues that have arisen since publication of DSM-IV-TR in 1994, and developed research plans to investigate critical issues utilizing systematic reviews and secondary data analyses. Based on these analyses, each Work Group proposed draft diagnostic criteria for its disorders, using a strict protocol for criteria revisions such as addition or deletion of disorders and changes to existing diagnostic criteria. These draft diagnostic criteria were first presented on www.dsm5.org in late 2009 through early 2010. Based on input from other Work Groups, the Task Force, several external groups, and the public, the Work Groups revised these criteria and prioritized necessary field trials to evaluate key recommendations. Phase I of the field trials began in 2010.¹² Results of these field trials are being compiled and analyzed.

The DSM-5 Work Groups have met via teleconference 1 to 2 times a month and in-person twice a year, with significant communication between meetings. Work Group chairs are members of the Task Force, which has equally frequent meetings. Reports of DSM-5 deliberations have been presented at hundreds of professional meetings and described in >200 scientific publications. Comprehensive information and ongoing updates on DSM-5 and a list of publications and meetings are provided at www.dsm5.org.

Public input has been sought and the Work Groups have received and processed >10,000 comments. In 2010, the APA Board of Trustees appointed a Scientific Review Committee to evaluate the scientific merit and clinical impact of the Work Group recommendations and comment on the strength of the evidence advanced in support of each proposed revision. In 2011, the Board of Trustees appointed a Clinical and Public Health Committee to evaluate the clinical utility and public health significance of the proposed revisions. The APA and WHO have shared information and assessments in an effort to harmonize diagnostic criteria between DSM-5 and ICD-11.

Initial hopes that DSM-5 could represent a paradigm shift toward an etiopathophysiological classification of psychiatric disorders have been tempered by recognition of the limitations of our current neurobiologic understanding of psychiatric disorders. Therefore, the focus for DSM-5 has shifted from validity enhancements to improved clinical utility while building a framework that better lends itself to a future etiopathophysiological nosology.^13-18 Whereas dimensional assessments are likely to be added across various diagnostic categories, a primarily categorical nosology will be retained and the proposed criterion changes are relatively modest. The results of our enhanced knowledge about the neurobiologic underpinnings of psychiatric disorders will not be reflected in diagnostic criteria, but in the significant revisions to the DSM text.

Our DSM-5 series

Subsequent articles in this series—which will be published here, at CurrentPsychiatry.com—will discuss specific proposed DSM-5 changes in 13 groups of disorders (Table 2) and their clinical implications. These articles also will address the relationship of DSM to ICD, issues with dimensional classification, and the importance of and challenges in precise diagnostic measurement.

Table 2

DSM-5 Work Groups

Related Resources

• American Psychiatric Association. DSM-5 Development. www.dsm5.org.
• Black DW, Zimmerman M. Redefining personality disorders: Proposed revisions for DSM-5. Current Psychiatry. 2011;10(9):26-38.

Disclosure

Dr. Tandon is a member of the DSM-5 Psychotic Disorders Work Group. He reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Work on the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)—scheduled to be published in May 2013—has been ongoing for more than a decade. Momentous advances in genetics and brain imaging since publication of DSM-IV in 1994 have generated optimism that an improved understanding of the neurobiologic underpinnings of psychiatric disorders might lead to a paradigm shift from the current descriptive classification system to a more scientific etiopathophysiological system similar to that used by other medical specialities.¹

Some fear that any changes to our current classification system may be premature and could make an already complex system even more unwieldy.² Scores of articles about the content and process of DSM-5 and several critiques and commentaries on the topic have been published. The American Psychiatric Association (APA) has made the DSM-5 process transparent by posting frequent updates to the DSM-5 Development Web site (www.dsm5.org), seeking feedback from the psychiatric community and the public, and presenting progress reports by members of the DSM-5 Task Force at scientific meetings.

There have been few discussions on the implications of DSM-5 from the practicing clinician’s vantage point, which I seek to present in this series of articles, the remainder of which will be published here, at CurrentPsychiatry.com. In this article, I:

• provide a brief history of psychiatric classification, focusing on the origins and evolution of the DSM system
• summarize the limitations of DSM-IV
• note the challenges and tensions in the construction of DSM-5
• review the DSM-5 process
• outline its current status
• discuss the organization and content of future articles in this series.

Although I am a member of the DSM-5 Psychotic Disorders Work Group, I am solely responsible for the content and any opinions that I offer in this article and series. All details of DSM-5 that I discuss are publicly available at www.dsm5.org. I’ve been a clinician and clinical researcher for >25 years, and my opinions are colored by the need for clarity, rigor, clinical relevance, and a disdain for overly speculative thinking.

Evolution of DSM

A nosological system (system of classification of disease) enables clinicians to provide specific treatments for medical causes of human disease and/or disability with precise and predictable effects and guide patients and families about the likely course and outcome. Such classification systems also are used by:

• researchers, to learn more about the nature of the conditions being classified and develop better treatments for them
• health care systems, to provide optimal health care and track its appropriate provision
• insurance companies, to provide appropriate reimbursement for health care
• health product developers, including pharmaceutical companies, to develop health care products and promote their appropriate utilization
• government agencies, to determine health priorities and apportionment of health care resources
• public health agencies, to track the distribution of health and disease in communities around the world.

An ideal classification system would meet all constituents’ needs while perfectly mapping natural disease entities with distinct etiology and pathophysiology (validity), consistently allow all users to reach the same diagnosis (reliability), and provide clinicians with clear guidance about treatment and likely course for each of the entities (utility), with the list of entities being mutually exclusive and collectively exhaustive (coverage).

The current nosological system for psychiatric disorders originated in the late 19^th and early 20^th centuries and culminated in the first edition of the Diagnostic and Statistical Manual of Mental Disorders³ released in 1952 and a section related to mental disorders (section V) in the sixth revision of the International Classification of Disease (ICD).⁴ Whereas DSM focuses exclusively on mental disorders, the ICD is a general medical classification system that began covering mental disorders with its sixth revision in 1949. In subsequent revisions (ICD-7 through -10 and DSM-II through -IV), substantial changes in diagnostic criteria have been made, although the systems’ basic structure has been retained. Table 1 describes major changes from DSM-I through DSM-IV-TR.^3,5-9 DSM and ICD both are being revised; DSM-5 is scheduled to be released in 2013 and ICD-11 is to be finalized by 2016.

Table 1

Conceptual development of DSM-I to DSM-IV-TR

What do clinicians need?

Similar to ICD-10, DSM-IV is marked by considerable complexity, variable validity, limited clinical and research utility, and problems of burgeoning comorbidity.¹⁰ Efforts to revise DSM seek to address these limitations. From a clinician’s perspective, the most challenging aspects of DSM-IV derive from its complexity—which makes clinical application difficult—and its limited clinical utility, which is exemplified by artificial comorbidity,¹¹ frequent use of “not otherwise specified” (NOS), and relative treatment nonspecificity with reference to diagnosis.

As clinicians, we want a nosological system that is easy to use, can guide treatment decisions, provides useful information about likely disease course and outcomes, and allows us to easily communicate about disease nature with patients, families, payers, and health care administrators. Additionally, although good validity and reliability are desirable for clinicians, adequate coverage of psychiatric disease—the listed conditions should be collectively exhaustive and mutually exclusive—is particularly valued. Finally, we want a diagnostic system that allows us to explain the reasoning behind psychiatric diagnoses and related treatment in lay terms to patients and their families.

DSM-5 development to date

DSM-5 development has been a collaborative effort led by the APA and involves the National Institute of Mental Health, the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, and the World Health Organization (WHO). Between 1999 and 2002, 3 work conferences resulted in a series of white papers that identified gaps and research needs.¹ Between 2003 and 2008, the American Psychiatric Institute for Research and Education, the National Institute of Health, and the WHO organized 13 international conferences to review a wide range of nosologic issues; the proceedings have been compiled into 13 monographs (11 published and 2 in press) and >125 scientific articles that serve as key reference sources for the DSM-5 process. For a continually updated list of these publications, see www.dsm5.org/Research.

In 2006, DSM-5 Task Force Chair David J. Kupfer, MD and Vice Chair Darrel A. Regier, MD, MPH were appointed and began selecting members of the DSM-5 Task Force, a process that was completed in 2007. Members of the 13 diagnostic area Work Groups (Table 2) were selected and the Work Groups were constituted in 2008. All 168 Task Force and Work Group members were vetted to ensure that they met standards of minimum conflict of interest and broad representation. Membership includes diverse professional representation from academia and mental health; 75% of members are from the United States. Six cross-cutting study groups have deliberated on a range of common issues, including:

• spectrum disorders
• lifespan and development
• gender and cross-cultural
• psychiatric/general medicine interface
• impairment and disability assessment
• diagnostic measurement and assessment.

Additionally, >300 external advisors with special expertise have participated in the process. Since 2008, each of the Work Groups has conducted extensive literature reviews of all assigned disorders, evaluated what works and what doesn’t work in DSM-IV-TR, assessed new research developments and clinical issues that have arisen since publication of DSM-IV-TR in 1994, and developed research plans to investigate critical issues utilizing systematic reviews and secondary data analyses. Based on these analyses, each Work Group proposed draft diagnostic criteria for its disorders, using a strict protocol for criteria revisions such as addition or deletion of disorders and changes to existing diagnostic criteria. These draft diagnostic criteria were first presented on www.dsm5.org in late 2009 through early 2010. Based on input from other Work Groups, the Task Force, several external groups, and the public, the Work Groups revised these criteria and prioritized necessary field trials to evaluate key recommendations. Phase I of the field trials began in 2010.¹² Results of these field trials are being compiled and analyzed.

The DSM-5 Work Groups have met via teleconference 1 to 2 times a month and in-person twice a year, with significant communication between meetings. Work Group chairs are members of the Task Force, which has equally frequent meetings. Reports of DSM-5 deliberations have been presented at hundreds of professional meetings and described in >200 scientific publications. Comprehensive information and ongoing updates on DSM-5 and a list of publications and meetings are provided at www.dsm5.org.

Public input has been sought and the Work Groups have received and processed >10,000 comments. In 2010, the APA Board of Trustees appointed a Scientific Review Committee to evaluate the scientific merit and clinical impact of the Work Group recommendations and comment on the strength of the evidence advanced in support of each proposed revision. In 2011, the Board of Trustees appointed a Clinical and Public Health Committee to evaluate the clinical utility and public health significance of the proposed revisions. The APA and WHO have shared information and assessments in an effort to harmonize diagnostic criteria between DSM-5 and ICD-11.

Initial hopes that DSM-5 could represent a paradigm shift toward an etiopathophysiological classification of psychiatric disorders have been tempered by recognition of the limitations of our current neurobiologic understanding of psychiatric disorders. Therefore, the focus for DSM-5 has shifted from validity enhancements to improved clinical utility while building a framework that better lends itself to a future etiopathophysiological nosology.^13-18 Whereas dimensional assessments are likely to be added across various diagnostic categories, a primarily categorical nosology will be retained and the proposed criterion changes are relatively modest. The results of our enhanced knowledge about the neurobiologic underpinnings of psychiatric disorders will not be reflected in diagnostic criteria, but in the significant revisions to the DSM text.

Our DSM-5 series

Subsequent articles in this series—which will be published here, at CurrentPsychiatry.com—will discuss specific proposed DSM-5 changes in 13 groups of disorders (Table 2) and their clinical implications. These articles also will address the relationship of DSM to ICD, issues with dimensional classification, and the importance of and challenges in precise diagnostic measurement.

Table 2

DSM-5 Work Groups

Related Resources

• American Psychiatric Association. DSM-5 Development. www.dsm5.org.
• Black DW, Zimmerman M. Redefining personality disorders: Proposed revisions for DSM-5. Current Psychiatry. 2011;10(9):26-38.

Disclosure

Dr. Tandon is a member of the DSM-5 Psychotic Disorders Work Group. He reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Patients who complain of unpleasant paresthesias present a challenge to psychiatrists who need to differentiate between what could be psychotropic side effects from restless legs syndrome (RLS). Reconizing the differences between the 2 conditions can guide intervention. A previously unknown RLS diagnosis may shed light on a patient’s comorbid sleep disturbances and insomnia.

Signs that suggest RLS

Symptoms consistent with akathisia temporally related to initiating an antipsychotic or antidepressant should not be considered RLS-induced. In less clear cases, subtleties of the symptoms can help you decide.

RLS often presents as discomfort in the legs that patients describe as creeping, crawling, pulling, or itching; movement typically relieves this discomfort. Feelings of akathisia also have been described as an inner restlessness and a need to get up and move to relieve the tension. However, RLS has the following defining characteristics:

• occurs specifically in the lower extremities
• has a circadian rhythm and is worse at night
• can be accompanied by paresthesias and myoclonic jerks while awake.¹

Other factors that support an RLS diagnosis are a family history of RLS,¹ positive response to dopaminergic drugs,¹ and low ferritin levels. Also consider conditions that put patients at risk for RLS, including end stage renal disease, diabetes mellitus, multiple sclerosis, Parkinson’s disease, anemia, rheumatic disease, venous insufficiency, and pregnancy.

3 substances that can worsen RLS

Ask patients about their intake of caffeine, nicotine, and alcohol. Use of these substances is common among psychiatric patients and can worsen RLS symptoms. Making a connection between these substances and RLS symptoms can help motivate patients to temper their use.

In addition to mimicking the subjective experience of RLS, many psychotropics, including antidepressants, neuroleptics, and antihistamines,^2-4 can worsen RLS symptoms in patients with a known RLS diagnosis.

The next step

RLS is a clinical diagnosis that’s usually made based on a patient’s medical history. Polysomnography is not necessary to make an RLS diagnosis but may be helpful if a patient is treatment-resistant or to monitor periodic leg movement disorders. Serum ferritin levels should be checked because normal hemoglobin levels do not rule out iron deficiency.

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Patients who complain of unpleasant paresthesias present a challenge to psychiatrists who need to differentiate between what could be psychotropic side effects from restless legs syndrome (RLS). Reconizing the differences between the 2 conditions can guide intervention. A previously unknown RLS diagnosis may shed light on a patient’s comorbid sleep disturbances and insomnia.

Signs that suggest RLS

Symptoms consistent with akathisia temporally related to initiating an antipsychotic or antidepressant should not be considered RLS-induced. In less clear cases, subtleties of the symptoms can help you decide.

RLS often presents as discomfort in the legs that patients describe as creeping, crawling, pulling, or itching; movement typically relieves this discomfort. Feelings of akathisia also have been described as an inner restlessness and a need to get up and move to relieve the tension. However, RLS has the following defining characteristics:

• occurs specifically in the lower extremities
• has a circadian rhythm and is worse at night
• can be accompanied by paresthesias and myoclonic jerks while awake.¹

Other factors that support an RLS diagnosis are a family history of RLS,¹ positive response to dopaminergic drugs,¹ and low ferritin levels. Also consider conditions that put patients at risk for RLS, including end stage renal disease, diabetes mellitus, multiple sclerosis, Parkinson’s disease, anemia, rheumatic disease, venous insufficiency, and pregnancy.

3 substances that can worsen RLS

Ask patients about their intake of caffeine, nicotine, and alcohol. Use of these substances is common among psychiatric patients and can worsen RLS symptoms. Making a connection between these substances and RLS symptoms can help motivate patients to temper their use.

In addition to mimicking the subjective experience of RLS, many psychotropics, including antidepressants, neuroleptics, and antihistamines,^2-4 can worsen RLS symptoms in patients with a known RLS diagnosis.

The next step

RLS is a clinical diagnosis that’s usually made based on a patient’s medical history. Polysomnography is not necessary to make an RLS diagnosis but may be helpful if a patient is treatment-resistant or to monitor periodic leg movement disorders. Serum ferritin levels should be checked because normal hemoglobin levels do not rule out iron deficiency.

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Patients who complain of unpleasant paresthesias present a challenge to psychiatrists who need to differentiate between what could be psychotropic side effects from restless legs syndrome (RLS). Reconizing the differences between the 2 conditions can guide intervention. A previously unknown RLS diagnosis may shed light on a patient’s comorbid sleep disturbances and insomnia.

Signs that suggest RLS

Symptoms consistent with akathisia temporally related to initiating an antipsychotic or antidepressant should not be considered RLS-induced. In less clear cases, subtleties of the symptoms can help you decide.

RLS often presents as discomfort in the legs that patients describe as creeping, crawling, pulling, or itching; movement typically relieves this discomfort. Feelings of akathisia also have been described as an inner restlessness and a need to get up and move to relieve the tension. However, RLS has the following defining characteristics:

• occurs specifically in the lower extremities
• has a circadian rhythm and is worse at night
• can be accompanied by paresthesias and myoclonic jerks while awake.¹

Other factors that support an RLS diagnosis are a family history of RLS,¹ positive response to dopaminergic drugs,¹ and low ferritin levels. Also consider conditions that put patients at risk for RLS, including end stage renal disease, diabetes mellitus, multiple sclerosis, Parkinson’s disease, anemia, rheumatic disease, venous insufficiency, and pregnancy.

3 substances that can worsen RLS

Ask patients about their intake of caffeine, nicotine, and alcohol. Use of these substances is common among psychiatric patients and can worsen RLS symptoms. Making a connection between these substances and RLS symptoms can help motivate patients to temper their use.

In addition to mimicking the subjective experience of RLS, many psychotropics, including antidepressants, neuroleptics, and antihistamines,^2-4 can worsen RLS symptoms in patients with a known RLS diagnosis.

The next step

RLS is a clinical diagnosis that’s usually made based on a patient’s medical history. Polysomnography is not necessary to make an RLS diagnosis but may be helpful if a patient is treatment-resistant or to monitor periodic leg movement disorders. Serum ferritin levels should be checked because normal hemoglobin levels do not rule out iron deficiency.

Disclosure

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

Perinatal psychopathology is a common and undertreated problem with wide-ranging consequences for both mother and child.^1-4 Women at risk for psychopathology are more likely to engage in unhealthy behaviors such as smoking and substance abuse and have difficulty engaging in treatment and attending psychiatric and obstetrics appointments.⁵ In addition, many of these women have trouble attaching to and caring for their infants and struggle with everyday stressors during pregnancy and postpartum.⁶

Routine prenatal screening for mental illness coupled with non-judgmental, collaborative, and individualized care delivered by a multidisciplinary team is critical for treatment engagement and adherence. Providers should be aware of risk factors for perinatal psychiatric illness—including a history of mental illness, stressful life events, and interpersonal conflict—and should be versed in current treatment guidelines.

CASE REPORT: Difficulty coping

Ms. A, age 28, is referred to our High Risk Perinatal Team by her obstetrician when she is approximately 6 weeks pregnant. She is single, has 3 other children (age 10, 4, and 2), a history of depression, and chronic pain related to an auto accident 3 years ago. She reports that this pregnancy likely is the result of a sexual assault, but she has decided to keep the baby. Ms. A describes severe depressive symptoms, including insomnia, low appetite, feelings of worthlessness, and thoughts of harming herself. In addition, she has incapacitating panic attacks and constantly worries about her children’s safety when she is not with them. She schedules an appointment with the perinatal team, but does not show up twice.

When our team finally sees Ms. A, she is well into her second trimester and brings her 2 youngest children with her. She says she recently was fired from her job as a cashier because she missed too many days of work, and is applying for Medicaid. Recently, her back and shoulder pain have worsened, and she is running out of her prescription for acetaminophen/hydrocodone. Ms. A’s affect is flat, her mood depressed, and she has difficulty explaining her history because her 2-year-old son interrupts the interview. She has never been in psychotherapy, and is reluctant to take antidepressants. Despite a difficult first visit, she engages with the clinician and agrees to schedule a second appointment.

What complicates pregnancy?

Women are at higher risk for developing depression during puberty, the perinatal period (ie, pregnancy and first year postpartum), and perimenopause.⁷ These times often are fraught with unfamiliar hormonal fluctuations, role transitions, emotional upheaval, and physical changes. However, because these times are expected to be stressful, serious mood changes often go unnoticed by patients and untreated by clinicians.⁸ Women are expected to celebrate, thrive, and “glow” during pregnancy, and those who suffer from depression and anxiety frequently do so in silence. Social stigma surrounding perinatal depression or anxiety leads many women to believe they are alone in their struggle and hesitant to seek help.⁹

Most pregnant women who develop psychiatric illness do not present for treatment.¹⁰ One study found that 86% of pregnant women who screened positive for depression in an obstetrics (OB) setting did not receive treatment.¹¹ Some women are reluctant to take antidepressants out of concern for their infant’s safety,⁸ and psychotherapy or alternative approaches are not available in all areas.¹² Transportation, childcare issues, or ongoing life stressors may prevent women from seeking help (Box 1).⁹

Diagnostic uncertainty among professionals may aggravate undertreatment. Clinicians who are unfamiliar with the presentation of perinatal mental illness may mislabel depressive features—such as irritability, loss of interest in activities, low energy, increased anxiety, difficulty sleeping, or appetite dysregulation—as normative experiences during pregnancy or adjustment after childbirth. Concerned about fetal exposure to potentially teratogenic compounds, clinicians may under-dose otherwise effective medications, which can lead to treatment resistance. Even if treated aggressively, depression in pregnancy may persist because of other factors, such as comorbid anxiety, somatization, pain, substance use/dependence, undiagnosed bipolar illness, or the presence of severe psychosocial stress or trauma.

Maternal suicide and/or harm to the infant—the most severe result of untreated perinatal psychopathology—is rare.¹³ Common negative outcomes of untreated depression or anxiety in pregnant women include inadequate weight gain, preeclampsia, difficulty bonding with their unborn baby, premature labor, and lack of follow through with prenatal care.^14,15 Symptoms become harder to treat when aggravated by psychosocial stressors such as poor social support, ambivalence about the pregnancy, and/or substance abuse.

The key to successful intervention is finding a balance between managing psychiatric concerns, facilitating adequate coping with psychosocial stressors, and, if necessary, aggressively treating pregnancy-related physical illnesses. Successful treatment response depends on early detection and initiating individualized care as soon as possible.

Box 1

Early detection. Women’s health care providers play a fundamental role in guiding decision-making about mental health care, providing referrals, and most important, allowing women to talk about perinatal psychopathology without fear of stigma.

When a woman becomes pregnant, it is critical to determine if she is at risk for developing psychopathology or presents with active illness. Many OB clinics screen for depression several times during pregnancy and early postpartum. The most commonly used screening tool is the Edinburgh Postpartum Depression Scale (EPDS),¹⁶ a 10-item self-report measure that is sensitive to cognitive and affective symptoms of depression. If a woman scores >15 during pregnancy or >13 postpartum, further assessment is indicated.¹⁷ The anxiety subscale (items 5 and 6) of the EPDS has been validated for screening perinatal anxiety using a cut-off score >4.¹⁸ Depression can be quickly assessed using the 2-question Patient Health Questionnaire (PHQ-2) or the 9-question PHQ-9.^19,20 All 3 scales are free and available on the Internet (Table 1).²¹

These screening tools offer clinicians an opportunity to assess for risk factors that may increase the likelihood of illness onset or worsened prognosis (Table 2).^5,22 All women who present with pregnancy-related medical illness, such as preeclampsia or gestational diabetes, should be screened for co-occurring depression or anxiety because psychiatric comorbidity is common.

Individualized care. Have an open mind about the kind of care to offer and collaborate with the patient when discussing treatment options.⁵ Some pregnant women may reject traditional treatments, such as pharmacotherapy or psychotherapy, because of concern about harm to the unborn baby or reluctance to work through past or present conflicts in therapy during a vulnerable time.⁹ Women may assume that medication will be the only treatment offered, or even fear that they will be forced to take antidepressants. Women often do not follow through on mental health referrals, even when they are appropriately screened and identified to be at risk, and an OB nurse explains the risks of untreated psychopathology.¹¹

A multidisciplinary, collaborative care model is vital for positive pregnancy outcomes. Connecting obstetricians and midwives with psychologists, psychiatrists, social workers, and infant mental health specialists to coordinate treatment ensures that at-risk pregnant and postpartum women get the care they need. A nonjudgmental approach is essential to engage pregnant women in care. Assure women that pharmacotherapy is not required when receiving mental health treatment, but is an option they can choose.

Table 1

Screening for psychiatric illness during pregnancy

Treatment choices

Pharmacotherapy. If a woman has only mild symptoms or has been symptom-free for ≥6 months, it may be safe to decrease or discontinue antidepressants during pregnancy or while trying to conceive, but such patients should be monitored closely for signs of relapse.²³ In a study of 201 depressed pregnant women, 68% of those who discontinued medication experienced symptom relapse compared with 26% of those who continued medication.²⁴ If a depressed woman has a history of relapse or severe symptoms, including suicide attempts and inpatient psychiatric admissions, it is recommended that she remain on antidepressants or mood stabilizers, regardless of pregnancy status.²⁵ If medications are necessary during pregnancy— ie, the benefits to the mother outweigh the risks to the unborn baby—the following precautions could help decrease fetal exposure:²³

• keep the medication regimen simple and at the lowest effective dose
• use monotherapy when appropriate
• if possible, do not change medications during pregnancy.

When considering pharmacotherapy, evaluate each woman’s risk for disease exacerbation and consequences for pregnancy and neonatal outcomes, and ask the woman how she views reproductive risk vs disease benefit.

Developing fetuses are exposed to either the effects of the mother’s untreated mental illness or the medication.²⁶ A recent study comparing birth and neonatal outcomes among women with untreated depression vs those taking selective serotonin reuptake inhibitors (SSRIs) found similar adverse outcomes.²⁷ Babies continously exposed to either prenatal depression or SSRIs were more likely to be born prematurely, but partial exposure to either condition did not increase this risk.²⁷ In addition, women who were not taking SSRIs had more depressive symptoms and more trouble functioning, which can interfere with bonding between mother and baby, both in-utero and postpartum.^6,27 Neither SSRIs nor depression exposure increased risk for minor physical anomalies.²⁷

A careful process of informed consent and documentation is essential when prescribing medications during pregnancy. Women should understand the risks of pharmacotherapy as well as the risks of undertreated illness.

Electroconvulsive therapy can safely help pregnant women with treatment-resistant, life-threatening, or psychotic depression.^28,29

Table 2

Risk factors for perinatal psychopathology

Psychotherapy. The American College of Obstetricians and Gynecologists treatment guidelines²² favor psychotherapy over medication for women with mild depressive symptoms and no loss of function, suicidality, or psychotic experiences; pharmacotherapy is suggested for women who have moderate to severely impaired functioning, recurrent depressive symptoms, or suicidal thinking (Table 3).²²

Interpersonal psychotherapy or cognitive-behavioral therapy can be safe and effective during pregnancy.^30,31 Other psychotherapeutic modalities and alternative/complementary treatments offer potential benefit without substantial risk, and could help prevent relapse when discontinuing mood stabilizers or antidepressants after conception (Box 2).^32-35

Table 3

ACOG guidelines for treating depression during pregnancy

Box 2

CASE CONTINUED: Healthy baby boy

Ms. A either doesn’t show up or cancels her weekly appointments about once a month, but seems to be making progress. Her therapist makes accommodations for Ms. A, such as offering childcare in an adjacent room during sessions, conducting brief sessions by phone when Ms. A is unable to come to the clinic, and helping her enroll in the state’s Maternal Infant Health Program. Ms. A’s therapist has referred her to a specialized OB clinic that can manage her pain medication and monitor for signs of abuse and keeps in regular contact with her obstetrician.

At 26 weeks gestation, Ms. A still is reluctant to try psychotropics, so her therapist works with her to integrate psychotherapy with alternative approaches such as mindfulness meditation and yoga. During therapy, Ms. A learns ways to manage her depressive symptoms, improve her social functioning, adjust to role transitions, and work through her traumatic experiences. Ms. A enrolls in a prenatal yoga class with a mindfulness focus, which allows her to interact with other pregnant women at risk for psychopathology and learn new ways to cope with her depressed mood and chronic pain.

Ms. A delivers a healthy boy at 38 weeks gestation. During labor, she uses many of the yoga poses she learned to manage pain, but elects to have an epidural after 30 hours of labor. Her baby tests positive for hydrocodone, which can cause ongoing mild irritability and occasional jitteriness. He is observed in the hospital for signs of withdrawal for 48 hours and then discharged home with his mother. Ms. A starts breast-feeding in the hospital and plans to continue at home.

Ms. A’s therapist continues to stay in touch with her by phone until she schedules another appointment and assists with referrals to other community resources.

Related Resources

• University of Michigan Department of Psychiatry Depression Center Women’s Mental Health and Infants Program. Women and depression. www.psych.med.umich.edu/wimhc.
• Yonkers KA, Wisner KL, Stewart DE, et al. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Gen Hosp Psychiatry. 2009;31(5):403-413.
• Michigan Families Medicaid Project. Year 1 final report. Includes a list of maternal and child health services similar to Michigan’s Maternal Infant Health Program, for all 50 states. http://1.usa.gov/yCzdca.

Drug Brand Name

• Acetaminophen/hydrocodone • Vicodin

Disclosures

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

Perinatal psychopathology is a common and undertreated problem with wide-ranging consequences for both mother and child.^1-4 Women at risk for psychopathology are more likely to engage in unhealthy behaviors such as smoking and substance abuse and have difficulty engaging in treatment and attending psychiatric and obstetrics appointments.⁵ In addition, many of these women have trouble attaching to and caring for their infants and struggle with everyday stressors during pregnancy and postpartum.⁶

Routine prenatal screening for mental illness coupled with non-judgmental, collaborative, and individualized care delivered by a multidisciplinary team is critical for treatment engagement and adherence. Providers should be aware of risk factors for perinatal psychiatric illness—including a history of mental illness, stressful life events, and interpersonal conflict—and should be versed in current treatment guidelines.

CASE REPORT: Difficulty coping

Ms. A, age 28, is referred to our High Risk Perinatal Team by her obstetrician when she is approximately 6 weeks pregnant. She is single, has 3 other children (age 10, 4, and 2), a history of depression, and chronic pain related to an auto accident 3 years ago. She reports that this pregnancy likely is the result of a sexual assault, but she has decided to keep the baby. Ms. A describes severe depressive symptoms, including insomnia, low appetite, feelings of worthlessness, and thoughts of harming herself. In addition, she has incapacitating panic attacks and constantly worries about her children’s safety when she is not with them. She schedules an appointment with the perinatal team, but does not show up twice.

When our team finally sees Ms. A, she is well into her second trimester and brings her 2 youngest children with her. She says she recently was fired from her job as a cashier because she missed too many days of work, and is applying for Medicaid. Recently, her back and shoulder pain have worsened, and she is running out of her prescription for acetaminophen/hydrocodone. Ms. A’s affect is flat, her mood depressed, and she has difficulty explaining her history because her 2-year-old son interrupts the interview. She has never been in psychotherapy, and is reluctant to take antidepressants. Despite a difficult first visit, she engages with the clinician and agrees to schedule a second appointment.

What complicates pregnancy?

Women are at higher risk for developing depression during puberty, the perinatal period (ie, pregnancy and first year postpartum), and perimenopause.⁷ These times often are fraught with unfamiliar hormonal fluctuations, role transitions, emotional upheaval, and physical changes. However, because these times are expected to be stressful, serious mood changes often go unnoticed by patients and untreated by clinicians.⁸ Women are expected to celebrate, thrive, and “glow” during pregnancy, and those who suffer from depression and anxiety frequently do so in silence. Social stigma surrounding perinatal depression or anxiety leads many women to believe they are alone in their struggle and hesitant to seek help.⁹

Most pregnant women who develop psychiatric illness do not present for treatment.¹⁰ One study found that 86% of pregnant women who screened positive for depression in an obstetrics (OB) setting did not receive treatment.¹¹ Some women are reluctant to take antidepressants out of concern for their infant’s safety,⁸ and psychotherapy or alternative approaches are not available in all areas.¹² Transportation, childcare issues, or ongoing life stressors may prevent women from seeking help (Box 1).⁹

Diagnostic uncertainty among professionals may aggravate undertreatment. Clinicians who are unfamiliar with the presentation of perinatal mental illness may mislabel depressive features—such as irritability, loss of interest in activities, low energy, increased anxiety, difficulty sleeping, or appetite dysregulation—as normative experiences during pregnancy or adjustment after childbirth. Concerned about fetal exposure to potentially teratogenic compounds, clinicians may under-dose otherwise effective medications, which can lead to treatment resistance. Even if treated aggressively, depression in pregnancy may persist because of other factors, such as comorbid anxiety, somatization, pain, substance use/dependence, undiagnosed bipolar illness, or the presence of severe psychosocial stress or trauma.

Maternal suicide and/or harm to the infant—the most severe result of untreated perinatal psychopathology—is rare.¹³ Common negative outcomes of untreated depression or anxiety in pregnant women include inadequate weight gain, preeclampsia, difficulty bonding with their unborn baby, premature labor, and lack of follow through with prenatal care.^14,15 Symptoms become harder to treat when aggravated by psychosocial stressors such as poor social support, ambivalence about the pregnancy, and/or substance abuse.

The key to successful intervention is finding a balance between managing psychiatric concerns, facilitating adequate coping with psychosocial stressors, and, if necessary, aggressively treating pregnancy-related physical illnesses. Successful treatment response depends on early detection and initiating individualized care as soon as possible.

Box 1

Early detection. Women’s health care providers play a fundamental role in guiding decision-making about mental health care, providing referrals, and most important, allowing women to talk about perinatal psychopathology without fear of stigma.

When a woman becomes pregnant, it is critical to determine if she is at risk for developing psychopathology or presents with active illness. Many OB clinics screen for depression several times during pregnancy and early postpartum. The most commonly used screening tool is the Edinburgh Postpartum Depression Scale (EPDS),¹⁶ a 10-item self-report measure that is sensitive to cognitive and affective symptoms of depression. If a woman scores >15 during pregnancy or >13 postpartum, further assessment is indicated.¹⁷ The anxiety subscale (items 5 and 6) of the EPDS has been validated for screening perinatal anxiety using a cut-off score >4.¹⁸ Depression can be quickly assessed using the 2-question Patient Health Questionnaire (PHQ-2) or the 9-question PHQ-9.^19,20 All 3 scales are free and available on the Internet (Table 1).²¹

These screening tools offer clinicians an opportunity to assess for risk factors that may increase the likelihood of illness onset or worsened prognosis (Table 2).^5,22 All women who present with pregnancy-related medical illness, such as preeclampsia or gestational diabetes, should be screened for co-occurring depression or anxiety because psychiatric comorbidity is common.

Individualized care. Have an open mind about the kind of care to offer and collaborate with the patient when discussing treatment options.⁵ Some pregnant women may reject traditional treatments, such as pharmacotherapy or psychotherapy, because of concern about harm to the unborn baby or reluctance to work through past or present conflicts in therapy during a vulnerable time.⁹ Women may assume that medication will be the only treatment offered, or even fear that they will be forced to take antidepressants. Women often do not follow through on mental health referrals, even when they are appropriately screened and identified to be at risk, and an OB nurse explains the risks of untreated psychopathology.¹¹

A multidisciplinary, collaborative care model is vital for positive pregnancy outcomes. Connecting obstetricians and midwives with psychologists, psychiatrists, social workers, and infant mental health specialists to coordinate treatment ensures that at-risk pregnant and postpartum women get the care they need. A nonjudgmental approach is essential to engage pregnant women in care. Assure women that pharmacotherapy is not required when receiving mental health treatment, but is an option they can choose.

Table 1

Screening for psychiatric illness during pregnancy

Treatment choices

Pharmacotherapy. If a woman has only mild symptoms or has been symptom-free for ≥6 months, it may be safe to decrease or discontinue antidepressants during pregnancy or while trying to conceive, but such patients should be monitored closely for signs of relapse.²³ In a study of 201 depressed pregnant women, 68% of those who discontinued medication experienced symptom relapse compared with 26% of those who continued medication.²⁴ If a depressed woman has a history of relapse or severe symptoms, including suicide attempts and inpatient psychiatric admissions, it is recommended that she remain on antidepressants or mood stabilizers, regardless of pregnancy status.²⁵ If medications are necessary during pregnancy— ie, the benefits to the mother outweigh the risks to the unborn baby—the following precautions could help decrease fetal exposure:²³

• keep the medication regimen simple and at the lowest effective dose
• use monotherapy when appropriate
• if possible, do not change medications during pregnancy.

When considering pharmacotherapy, evaluate each woman’s risk for disease exacerbation and consequences for pregnancy and neonatal outcomes, and ask the woman how she views reproductive risk vs disease benefit.

Developing fetuses are exposed to either the effects of the mother’s untreated mental illness or the medication.²⁶ A recent study comparing birth and neonatal outcomes among women with untreated depression vs those taking selective serotonin reuptake inhibitors (SSRIs) found similar adverse outcomes.²⁷ Babies continously exposed to either prenatal depression or SSRIs were more likely to be born prematurely, but partial exposure to either condition did not increase this risk.²⁷ In addition, women who were not taking SSRIs had more depressive symptoms and more trouble functioning, which can interfere with bonding between mother and baby, both in-utero and postpartum.^6,27 Neither SSRIs nor depression exposure increased risk for minor physical anomalies.²⁷

A careful process of informed consent and documentation is essential when prescribing medications during pregnancy. Women should understand the risks of pharmacotherapy as well as the risks of undertreated illness.

Electroconvulsive therapy can safely help pregnant women with treatment-resistant, life-threatening, or psychotic depression.^28,29

Table 2

Risk factors for perinatal psychopathology

Psychotherapy. The American College of Obstetricians and Gynecologists treatment guidelines²² favor psychotherapy over medication for women with mild depressive symptoms and no loss of function, suicidality, or psychotic experiences; pharmacotherapy is suggested for women who have moderate to severely impaired functioning, recurrent depressive symptoms, or suicidal thinking (Table 3).²²

Interpersonal psychotherapy or cognitive-behavioral therapy can be safe and effective during pregnancy.^30,31 Other psychotherapeutic modalities and alternative/complementary treatments offer potential benefit without substantial risk, and could help prevent relapse when discontinuing mood stabilizers or antidepressants after conception (Box 2).^32-35

Table 3

ACOG guidelines for treating depression during pregnancy

Box 2

CASE CONTINUED: Healthy baby boy

Ms. A either doesn’t show up or cancels her weekly appointments about once a month, but seems to be making progress. Her therapist makes accommodations for Ms. A, such as offering childcare in an adjacent room during sessions, conducting brief sessions by phone when Ms. A is unable to come to the clinic, and helping her enroll in the state’s Maternal Infant Health Program. Ms. A’s therapist has referred her to a specialized OB clinic that can manage her pain medication and monitor for signs of abuse and keeps in regular contact with her obstetrician.

At 26 weeks gestation, Ms. A still is reluctant to try psychotropics, so her therapist works with her to integrate psychotherapy with alternative approaches such as mindfulness meditation and yoga. During therapy, Ms. A learns ways to manage her depressive symptoms, improve her social functioning, adjust to role transitions, and work through her traumatic experiences. Ms. A enrolls in a prenatal yoga class with a mindfulness focus, which allows her to interact with other pregnant women at risk for psychopathology and learn new ways to cope with her depressed mood and chronic pain.

Ms. A delivers a healthy boy at 38 weeks gestation. During labor, she uses many of the yoga poses she learned to manage pain, but elects to have an epidural after 30 hours of labor. Her baby tests positive for hydrocodone, which can cause ongoing mild irritability and occasional jitteriness. He is observed in the hospital for signs of withdrawal for 48 hours and then discharged home with his mother. Ms. A starts breast-feeding in the hospital and plans to continue at home.

Ms. A’s therapist continues to stay in touch with her by phone until she schedules another appointment and assists with referrals to other community resources.

Related Resources

• University of Michigan Department of Psychiatry Depression Center Women’s Mental Health and Infants Program. Women and depression. www.psych.med.umich.edu/wimhc.
• Yonkers KA, Wisner KL, Stewart DE, et al. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Gen Hosp Psychiatry. 2009;31(5):403-413.
• Michigan Families Medicaid Project. Year 1 final report. Includes a list of maternal and child health services similar to Michigan’s Maternal Infant Health Program, for all 50 states. http://1.usa.gov/yCzdca.

Drug Brand Name

• Acetaminophen/hydrocodone • Vicodin

Disclosures

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

Perinatal psychopathology is a common and undertreated problem with wide-ranging consequences for both mother and child.^1-4 Women at risk for psychopathology are more likely to engage in unhealthy behaviors such as smoking and substance abuse and have difficulty engaging in treatment and attending psychiatric and obstetrics appointments.⁵ In addition, many of these women have trouble attaching to and caring for their infants and struggle with everyday stressors during pregnancy and postpartum.⁶

Routine prenatal screening for mental illness coupled with non-judgmental, collaborative, and individualized care delivered by a multidisciplinary team is critical for treatment engagement and adherence. Providers should be aware of risk factors for perinatal psychiatric illness—including a history of mental illness, stressful life events, and interpersonal conflict—and should be versed in current treatment guidelines.

CASE REPORT: Difficulty coping

Ms. A, age 28, is referred to our High Risk Perinatal Team by her obstetrician when she is approximately 6 weeks pregnant. She is single, has 3 other children (age 10, 4, and 2), a history of depression, and chronic pain related to an auto accident 3 years ago. She reports that this pregnancy likely is the result of a sexual assault, but she has decided to keep the baby. Ms. A describes severe depressive symptoms, including insomnia, low appetite, feelings of worthlessness, and thoughts of harming herself. In addition, she has incapacitating panic attacks and constantly worries about her children’s safety when she is not with them. She schedules an appointment with the perinatal team, but does not show up twice.

When our team finally sees Ms. A, she is well into her second trimester and brings her 2 youngest children with her. She says she recently was fired from her job as a cashier because she missed too many days of work, and is applying for Medicaid. Recently, her back and shoulder pain have worsened, and she is running out of her prescription for acetaminophen/hydrocodone. Ms. A’s affect is flat, her mood depressed, and she has difficulty explaining her history because her 2-year-old son interrupts the interview. She has never been in psychotherapy, and is reluctant to take antidepressants. Despite a difficult first visit, she engages with the clinician and agrees to schedule a second appointment.

What complicates pregnancy?

Women are at higher risk for developing depression during puberty, the perinatal period (ie, pregnancy and first year postpartum), and perimenopause.⁷ These times often are fraught with unfamiliar hormonal fluctuations, role transitions, emotional upheaval, and physical changes. However, because these times are expected to be stressful, serious mood changes often go unnoticed by patients and untreated by clinicians.⁸ Women are expected to celebrate, thrive, and “glow” during pregnancy, and those who suffer from depression and anxiety frequently do so in silence. Social stigma surrounding perinatal depression or anxiety leads many women to believe they are alone in their struggle and hesitant to seek help.⁹

Most pregnant women who develop psychiatric illness do not present for treatment.¹⁰ One study found that 86% of pregnant women who screened positive for depression in an obstetrics (OB) setting did not receive treatment.¹¹ Some women are reluctant to take antidepressants out of concern for their infant’s safety,⁸ and psychotherapy or alternative approaches are not available in all areas.¹² Transportation, childcare issues, or ongoing life stressors may prevent women from seeking help (Box 1).⁹

Diagnostic uncertainty among professionals may aggravate undertreatment. Clinicians who are unfamiliar with the presentation of perinatal mental illness may mislabel depressive features—such as irritability, loss of interest in activities, low energy, increased anxiety, difficulty sleeping, or appetite dysregulation—as normative experiences during pregnancy or adjustment after childbirth. Concerned about fetal exposure to potentially teratogenic compounds, clinicians may under-dose otherwise effective medications, which can lead to treatment resistance. Even if treated aggressively, depression in pregnancy may persist because of other factors, such as comorbid anxiety, somatization, pain, substance use/dependence, undiagnosed bipolar illness, or the presence of severe psychosocial stress or trauma.

Maternal suicide and/or harm to the infant—the most severe result of untreated perinatal psychopathology—is rare.¹³ Common negative outcomes of untreated depression or anxiety in pregnant women include inadequate weight gain, preeclampsia, difficulty bonding with their unborn baby, premature labor, and lack of follow through with prenatal care.^14,15 Symptoms become harder to treat when aggravated by psychosocial stressors such as poor social support, ambivalence about the pregnancy, and/or substance abuse.

The key to successful intervention is finding a balance between managing psychiatric concerns, facilitating adequate coping with psychosocial stressors, and, if necessary, aggressively treating pregnancy-related physical illnesses. Successful treatment response depends on early detection and initiating individualized care as soon as possible.

Box 1

Early detection. Women’s health care providers play a fundamental role in guiding decision-making about mental health care, providing referrals, and most important, allowing women to talk about perinatal psychopathology without fear of stigma.

When a woman becomes pregnant, it is critical to determine if she is at risk for developing psychopathology or presents with active illness. Many OB clinics screen for depression several times during pregnancy and early postpartum. The most commonly used screening tool is the Edinburgh Postpartum Depression Scale (EPDS),¹⁶ a 10-item self-report measure that is sensitive to cognitive and affective symptoms of depression. If a woman scores >15 during pregnancy or >13 postpartum, further assessment is indicated.¹⁷ The anxiety subscale (items 5 and 6) of the EPDS has been validated for screening perinatal anxiety using a cut-off score >4.¹⁸ Depression can be quickly assessed using the 2-question Patient Health Questionnaire (PHQ-2) or the 9-question PHQ-9.^19,20 All 3 scales are free and available on the Internet (Table 1).²¹

These screening tools offer clinicians an opportunity to assess for risk factors that may increase the likelihood of illness onset or worsened prognosis (Table 2).^5,22 All women who present with pregnancy-related medical illness, such as preeclampsia or gestational diabetes, should be screened for co-occurring depression or anxiety because psychiatric comorbidity is common.

Individualized care. Have an open mind about the kind of care to offer and collaborate with the patient when discussing treatment options.⁵ Some pregnant women may reject traditional treatments, such as pharmacotherapy or psychotherapy, because of concern about harm to the unborn baby or reluctance to work through past or present conflicts in therapy during a vulnerable time.⁹ Women may assume that medication will be the only treatment offered, or even fear that they will be forced to take antidepressants. Women often do not follow through on mental health referrals, even when they are appropriately screened and identified to be at risk, and an OB nurse explains the risks of untreated psychopathology.¹¹

A multidisciplinary, collaborative care model is vital for positive pregnancy outcomes. Connecting obstetricians and midwives with psychologists, psychiatrists, social workers, and infant mental health specialists to coordinate treatment ensures that at-risk pregnant and postpartum women get the care they need. A nonjudgmental approach is essential to engage pregnant women in care. Assure women that pharmacotherapy is not required when receiving mental health treatment, but is an option they can choose.

Table 1

Screening for psychiatric illness during pregnancy

Treatment choices

Pharmacotherapy. If a woman has only mild symptoms or has been symptom-free for ≥6 months, it may be safe to decrease or discontinue antidepressants during pregnancy or while trying to conceive, but such patients should be monitored closely for signs of relapse.²³ In a study of 201 depressed pregnant women, 68% of those who discontinued medication experienced symptom relapse compared with 26% of those who continued medication.²⁴ If a depressed woman has a history of relapse or severe symptoms, including suicide attempts and inpatient psychiatric admissions, it is recommended that she remain on antidepressants or mood stabilizers, regardless of pregnancy status.²⁵ If medications are necessary during pregnancy— ie, the benefits to the mother outweigh the risks to the unborn baby—the following precautions could help decrease fetal exposure:²³

• keep the medication regimen simple and at the lowest effective dose
• use monotherapy when appropriate
• if possible, do not change medications during pregnancy.

When considering pharmacotherapy, evaluate each woman’s risk for disease exacerbation and consequences for pregnancy and neonatal outcomes, and ask the woman how she views reproductive risk vs disease benefit.

Developing fetuses are exposed to either the effects of the mother’s untreated mental illness or the medication.²⁶ A recent study comparing birth and neonatal outcomes among women with untreated depression vs those taking selective serotonin reuptake inhibitors (SSRIs) found similar adverse outcomes.²⁷ Babies continously exposed to either prenatal depression or SSRIs were more likely to be born prematurely, but partial exposure to either condition did not increase this risk.²⁷ In addition, women who were not taking SSRIs had more depressive symptoms and more trouble functioning, which can interfere with bonding between mother and baby, both in-utero and postpartum.^6,27 Neither SSRIs nor depression exposure increased risk for minor physical anomalies.²⁷

A careful process of informed consent and documentation is essential when prescribing medications during pregnancy. Women should understand the risks of pharmacotherapy as well as the risks of undertreated illness.

Electroconvulsive therapy can safely help pregnant women with treatment-resistant, life-threatening, or psychotic depression.^28,29

Table 2

Risk factors for perinatal psychopathology

Psychotherapy. The American College of Obstetricians and Gynecologists treatment guidelines²² favor psychotherapy over medication for women with mild depressive symptoms and no loss of function, suicidality, or psychotic experiences; pharmacotherapy is suggested for women who have moderate to severely impaired functioning, recurrent depressive symptoms, or suicidal thinking (Table 3).²²

Interpersonal psychotherapy or cognitive-behavioral therapy can be safe and effective during pregnancy.^30,31 Other psychotherapeutic modalities and alternative/complementary treatments offer potential benefit without substantial risk, and could help prevent relapse when discontinuing mood stabilizers or antidepressants after conception (Box 2).^32-35

Table 3

ACOG guidelines for treating depression during pregnancy

Box 2

CASE CONTINUED: Healthy baby boy

Ms. A either doesn’t show up or cancels her weekly appointments about once a month, but seems to be making progress. Her therapist makes accommodations for Ms. A, such as offering childcare in an adjacent room during sessions, conducting brief sessions by phone when Ms. A is unable to come to the clinic, and helping her enroll in the state’s Maternal Infant Health Program. Ms. A’s therapist has referred her to a specialized OB clinic that can manage her pain medication and monitor for signs of abuse and keeps in regular contact with her obstetrician.

At 26 weeks gestation, Ms. A still is reluctant to try psychotropics, so her therapist works with her to integrate psychotherapy with alternative approaches such as mindfulness meditation and yoga. During therapy, Ms. A learns ways to manage her depressive symptoms, improve her social functioning, adjust to role transitions, and work through her traumatic experiences. Ms. A enrolls in a prenatal yoga class with a mindfulness focus, which allows her to interact with other pregnant women at risk for psychopathology and learn new ways to cope with her depressed mood and chronic pain.

Ms. A delivers a healthy boy at 38 weeks gestation. During labor, she uses many of the yoga poses she learned to manage pain, but elects to have an epidural after 30 hours of labor. Her baby tests positive for hydrocodone, which can cause ongoing mild irritability and occasional jitteriness. He is observed in the hospital for signs of withdrawal for 48 hours and then discharged home with his mother. Ms. A starts breast-feeding in the hospital and plans to continue at home.

Ms. A’s therapist continues to stay in touch with her by phone until she schedules another appointment and assists with referrals to other community resources.

Related Resources

• University of Michigan Department of Psychiatry Depression Center Women’s Mental Health and Infants Program. Women and depression. www.psych.med.umich.edu/wimhc.
• Yonkers KA, Wisner KL, Stewart DE, et al. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Gen Hosp Psychiatry. 2009;31(5):403-413.
• Michigan Families Medicaid Project. Year 1 final report. Includes a list of maternal and child health services similar to Michigan’s Maternal Infant Health Program, for all 50 states. http://1.usa.gov/yCzdca.

Drug Brand Name

• Acetaminophen/hydrocodone • Vicodin

Disclosures

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