Have your patients asked you about smartphone apps? If they haven’t yet, they may soon, as interest in apps for mental health continues to expand. There are now >10,000 mental health–related smartphone apps.¹ The rapid rise of these apps is partly due to their potential to transform a patient’s smartphone into a monitoring and therapeutic platform, capable of capturing mental health symptoms in real time and delivering on-the-go therapy. Setting aside questions about the potential of mobile health, 2 urgent questions remain for the busy psychiatrist in clinical practice: What is the current evidence base for mental health apps, and what should you tell your patients about them?

For most apps, evidence of efficacy is limited

While the evidence base for mental health smartphone apps continues to expand, for many of these apps, there is no evidence of effectiveness. The growing consensus is that most commercially available apps are not evidence-based and some are even dangerous. For example, researchers who examined >700 mindfulness apps on the iTunes and Google Play stores found that only 4% provided acceptable mindfulness training and education.² Another study of 58 apps that claimed to offer sobriety assessments found that none had ever been formally evaluated.³ Evidence-based reviews of suicide prevention apps have identified potentially harmful apps,⁴ and studies evaluating apps for bipolar disorder⁵ and depression⁶ have yielded similar results—few have any evidence supporting their use, and some offer dangerous and harmful advice. For example, researchers found that one app for bipolar disorder advised patients who are experiencing a manic episode to drink alcohol.⁵ Currently, the vast majority of commercially available apps are not appropriate for clinical care. This finding is not unique to mental health; similar findings have been reported for apps for cancer.⁷ The bottom line is that the apps that your patients are finding, and perhaps already using, may not be useful or effective.

However, early studies have demonstrated efficacy of some apps for several conditions, including schizophrenia,⁸ depression,⁹ anxiety disorders,¹⁰ and suicidal ideation.¹¹ Although many of the apps evaluated in these studies are not available to the public, or still require large-scale assessment before they are ready for mainstream clinical care, this research demonstrates that mental health apps can help improve treatment outcomes. As this research develops, a wave of evidence-based and effective mental health apps may be available in the near future.

Although it is unknown how many patients are presently using mental health apps, there is strong anecdotal evidence that an increasing number of patients who use these apps and other forms of digital technology are finding some benefits. In many cases, patients may actually be ahead of the research. For example, one study that conducted an online survey of patients with schizophrenia noted that some patients are using their smartphones to play music to help block auditory hallucinations.¹²

Why online reviews are of limited use

As this evidence continues to mature, and with an ever-growing number of mental health apps available on commercial marketplaces, busy psychiatrists need to navigate this complex space. Even psychiatrists who decide to not use apps as part of care still need to be knowledgeable about them, because patients are likely to ask about the benefits of using apps, and they will expect an informed response. How would you reply if your patient asked you about a new mood-tracking app he or she recently heard about? On what would you base your recommendation and opinion?

Reading online app reviews for guidance is not a good solution. A recent study found little relationship between the star ratings of health apps and the quality of those apps,¹³ which suggests that a 5-star rating on the app store is of limited use.

Unlike medications whose ingredients do not change over time, or manualized psychotherapies that use specific protocols, mental health apps are dynamic and constantly changing.¹⁴ Think of how often the apps on your smartphone update. Thus, the version of a mental health app that your patient downloads today may be very different from the version that received a favorable user review last month. And just as there is no single medication or therapy that is ideal for every patient, neither is there a single “best” app for all patients with the same disorder. Picking an app is a personal decision that cannot be made based on a single score or numeric rating. Furthermore, the validity of app rating systems is unclear. One study found a wide variation in the interrater reliability of measures used to evaluate apps from sources that included PsyberGuide, the Anxiety and Depression Association of America, and the research literature. Quality measures such as effectiveness, ease of use, and performance had relatively poor interrater reliability.¹⁵ This means that, for example, an app that one patient finds “easy to use” may be difficult to use for another. Thus, providing patients with suggestions based on an app’s ratings may result in providing information that sounds useful, but often is misleading.

One possible solution is a risk-based and personalized assessment approach to evaluating mental health apps. Although it does not offer scoring or recommendations of specific apps, the American Psychiatric Association (APA) App Evaluation Model (Figure) provides a framework to guide discussion and informed decision-making about apps. (The authors of this article helped create this model, but receive no compensation for that volunteer work.) The pyramid shape reflects the hierarchical nature of the model. To begin the process, start at the base of the pyramid and work upward.

Ground. First, consider the context of the app by determining basic facts, such as who made it, how much it costs, and its technology requirements. This ground layer establishes the credibility of the app’s creator by questioning his or her reputation, ability to update the app, and funding sources. Understanding the app’s business model also will help you determine whether the app will stand the test of time: Will it continue to exist next month or next year, or will a lack of reliable funding lead the vendor to abandon it?

Risk. The next layer assesses the risk, privacy, and security features of the app. Many mental health apps actively aim to avoid falling under the jurisdiction of U.S. federal health care privacy rules, such as the Health Insurance Portability and Accountability Act of 1996, so there is no guarantee that sensitive data supplied to an app will be protected. The true cost of a “free” app often is your patient’s personal mental health information, which the app’s developer may accumulate and sell for profit. Thus, it is wise to check the privacy policy to learn where your patient’s data goes. Furthermore, patients and psychiatrists must be vigilant that malware-infected apps can be uploaded to the app store, which can further compromise privacy.¹⁶ You may be surprised to learn that many apps lack a privacy policy, which means there are no protections for personal information or safeguards against the misuse of mental health data.¹⁷ Checking that an app at least promises to digitally protect mental health data through encryption and secure storage also is a good step.

The goal of considering these factors is not to create a score, but rather to be aware of them and consider them in the context of the specific app, patient, and clinical situation. Doing so helps determine whether the app meets the appropriate risk, privacy, and security standards for your patient.

Evidence. The next layer of the evaluation framework is evidence. The goal is to seek an app with clinical evidence of effectiveness. Simply put, if a patient is going to use an app, he should use one that works. An app without formal evidence may be effective, but it is important to make sure the patient is aware that these claims have not been verified. Many apps claim that they offer cognitive-behavioral therapy or mindfulness therapy, but few deliver on such claims.¹⁸ It is wise to try an app before recommending it to a patient to ensure that it does what it claims it does, and does not offer dangerous or harmful recommendations.

Ease of use. Across all health apps, there is growing recognition that most downloaded apps are never used. Patient engagement with mental health apps appears to rapidly decline over the first week of use.¹⁹ There also is emerging evidence that many apps are not user-friendly. A recent study of several common mood-tracking apps found that patients with depression had difficulty entering and accessing their data.²⁰ Because many psychiatric disorders are chronic or last at least several months, it is especially important to consider how engaging and usable the app will be for your patient. Usability varies from patient to patient, so it is best to check directly with your patient regarding his comfort with apps and mobile technology. Offering check-ins and support to help patients keep on track with apps may be critical for successful outcomes.

Interoperability. The final layer of the model is data sharing and interoperability. It is important to determine if the data collected or generated by the app are available to you, the patient, the treatment team, and others involved in the patient’s care. As mental health treatment moves toward integrated care, apps that fragment care (by not sharing information) impede care. Check if the app can share data with an electronic medical record, or if there is a plan to review and act on data from the app as part of your patient’s treatment plan.

More information about the APA App Evaluation Model, including additional factors to consider within each layer, is available from the APA for free at https://www.psychiatry.org/psychiatrists/practice/mental-health-apps/app-evaluation-model. For a sample of factors to consider when evaluating a mental health app, see the Table.

A reasonable strategy

Although the APA App Evaluation Model does not endorse any particular app, it can help guide more informed decision-making. As the evidence on mental health apps continues to evolve, it will become easier to make definitive statements on what constitutes a useful app. For now, the best strategy when discussing mental health apps with patients is to combine the use of this model with your clinical judgment.

Have your patients asked you about smartphone apps? If they haven’t yet, they may soon, as interest in apps for mental health continues to expand. There are now >10,000 mental health–related smartphone apps.¹ The rapid rise of these apps is partly due to their potential to transform a patient’s smartphone into a monitoring and therapeutic platform, capable of capturing mental health symptoms in real time and delivering on-the-go therapy. Setting aside questions about the potential of mobile health, 2 urgent questions remain for the busy psychiatrist in clinical practice: What is the current evidence base for mental health apps, and what should you tell your patients about them?

For most apps, evidence of efficacy is limited

While the evidence base for mental health smartphone apps continues to expand, for many of these apps, there is no evidence of effectiveness. The growing consensus is that most commercially available apps are not evidence-based and some are even dangerous. For example, researchers who examined >700 mindfulness apps on the iTunes and Google Play stores found that only 4% provided acceptable mindfulness training and education.² Another study of 58 apps that claimed to offer sobriety assessments found that none had ever been formally evaluated.³ Evidence-based reviews of suicide prevention apps have identified potentially harmful apps,⁴ and studies evaluating apps for bipolar disorder⁵ and depression⁶ have yielded similar results—few have any evidence supporting their use, and some offer dangerous and harmful advice. For example, researchers found that one app for bipolar disorder advised patients who are experiencing a manic episode to drink alcohol.⁵ Currently, the vast majority of commercially available apps are not appropriate for clinical care. This finding is not unique to mental health; similar findings have been reported for apps for cancer.⁷ The bottom line is that the apps that your patients are finding, and perhaps already using, may not be useful or effective.

However, early studies have demonstrated efficacy of some apps for several conditions, including schizophrenia,⁸ depression,⁹ anxiety disorders,¹⁰ and suicidal ideation.¹¹ Although many of the apps evaluated in these studies are not available to the public, or still require large-scale assessment before they are ready for mainstream clinical care, this research demonstrates that mental health apps can help improve treatment outcomes. As this research develops, a wave of evidence-based and effective mental health apps may be available in the near future.

Although it is unknown how many patients are presently using mental health apps, there is strong anecdotal evidence that an increasing number of patients who use these apps and other forms of digital technology are finding some benefits. In many cases, patients may actually be ahead of the research. For example, one study that conducted an online survey of patients with schizophrenia noted that some patients are using their smartphones to play music to help block auditory hallucinations.¹²

Why online reviews are of limited use

As this evidence continues to mature, and with an ever-growing number of mental health apps available on commercial marketplaces, busy psychiatrists need to navigate this complex space. Even psychiatrists who decide to not use apps as part of care still need to be knowledgeable about them, because patients are likely to ask about the benefits of using apps, and they will expect an informed response. How would you reply if your patient asked you about a new mood-tracking app he or she recently heard about? On what would you base your recommendation and opinion?

Reading online app reviews for guidance is not a good solution. A recent study found little relationship between the star ratings of health apps and the quality of those apps,¹³ which suggests that a 5-star rating on the app store is of limited use.

Unlike medications whose ingredients do not change over time, or manualized psychotherapies that use specific protocols, mental health apps are dynamic and constantly changing.¹⁴ Think of how often the apps on your smartphone update. Thus, the version of a mental health app that your patient downloads today may be very different from the version that received a favorable user review last month. And just as there is no single medication or therapy that is ideal for every patient, neither is there a single “best” app for all patients with the same disorder. Picking an app is a personal decision that cannot be made based on a single score or numeric rating. Furthermore, the validity of app rating systems is unclear. One study found a wide variation in the interrater reliability of measures used to evaluate apps from sources that included PsyberGuide, the Anxiety and Depression Association of America, and the research literature. Quality measures such as effectiveness, ease of use, and performance had relatively poor interrater reliability.¹⁵ This means that, for example, an app that one patient finds “easy to use” may be difficult to use for another. Thus, providing patients with suggestions based on an app’s ratings may result in providing information that sounds useful, but often is misleading.

One possible solution is a risk-based and personalized assessment approach to evaluating mental health apps. Although it does not offer scoring or recommendations of specific apps, the American Psychiatric Association (APA) App Evaluation Model (Figure) provides a framework to guide discussion and informed decision-making about apps. (The authors of this article helped create this model, but receive no compensation for that volunteer work.) The pyramid shape reflects the hierarchical nature of the model. To begin the process, start at the base of the pyramid and work upward.

Ground. First, consider the context of the app by determining basic facts, such as who made it, how much it costs, and its technology requirements. This ground layer establishes the credibility of the app’s creator by questioning his or her reputation, ability to update the app, and funding sources. Understanding the app’s business model also will help you determine whether the app will stand the test of time: Will it continue to exist next month or next year, or will a lack of reliable funding lead the vendor to abandon it?

Risk. The next layer assesses the risk, privacy, and security features of the app. Many mental health apps actively aim to avoid falling under the jurisdiction of U.S. federal health care privacy rules, such as the Health Insurance Portability and Accountability Act of 1996, so there is no guarantee that sensitive data supplied to an app will be protected. The true cost of a “free” app often is your patient’s personal mental health information, which the app’s developer may accumulate and sell for profit. Thus, it is wise to check the privacy policy to learn where your patient’s data goes. Furthermore, patients and psychiatrists must be vigilant that malware-infected apps can be uploaded to the app store, which can further compromise privacy.¹⁶ You may be surprised to learn that many apps lack a privacy policy, which means there are no protections for personal information or safeguards against the misuse of mental health data.¹⁷ Checking that an app at least promises to digitally protect mental health data through encryption and secure storage also is a good step.

The goal of considering these factors is not to create a score, but rather to be aware of them and consider them in the context of the specific app, patient, and clinical situation. Doing so helps determine whether the app meets the appropriate risk, privacy, and security standards for your patient.

Evidence. The next layer of the evaluation framework is evidence. The goal is to seek an app with clinical evidence of effectiveness. Simply put, if a patient is going to use an app, he should use one that works. An app without formal evidence may be effective, but it is important to make sure the patient is aware that these claims have not been verified. Many apps claim that they offer cognitive-behavioral therapy or mindfulness therapy, but few deliver on such claims.¹⁸ It is wise to try an app before recommending it to a patient to ensure that it does what it claims it does, and does not offer dangerous or harmful recommendations.

Ease of use. Across all health apps, there is growing recognition that most downloaded apps are never used. Patient engagement with mental health apps appears to rapidly decline over the first week of use.¹⁹ There also is emerging evidence that many apps are not user-friendly. A recent study of several common mood-tracking apps found that patients with depression had difficulty entering and accessing their data.²⁰ Because many psychiatric disorders are chronic or last at least several months, it is especially important to consider how engaging and usable the app will be for your patient. Usability varies from patient to patient, so it is best to check directly with your patient regarding his comfort with apps and mobile technology. Offering check-ins and support to help patients keep on track with apps may be critical for successful outcomes.

Interoperability. The final layer of the model is data sharing and interoperability. It is important to determine if the data collected or generated by the app are available to you, the patient, the treatment team, and others involved in the patient’s care. As mental health treatment moves toward integrated care, apps that fragment care (by not sharing information) impede care. Check if the app can share data with an electronic medical record, or if there is a plan to review and act on data from the app as part of your patient’s treatment plan.

More information about the APA App Evaluation Model, including additional factors to consider within each layer, is available from the APA for free at https://www.psychiatry.org/psychiatrists/practice/mental-health-apps/app-evaluation-model. For a sample of factors to consider when evaluating a mental health app, see the Table.

A reasonable strategy

Although the APA App Evaluation Model does not endorse any particular app, it can help guide more informed decision-making. As the evidence on mental health apps continues to evolve, it will become easier to make definitive statements on what constitutes a useful app. For now, the best strategy when discussing mental health apps with patients is to combine the use of this model with your clinical judgment.

Have your patients asked you about smartphone apps? If they haven’t yet, they may soon, as interest in apps for mental health continues to expand. There are now >10,000 mental health–related smartphone apps.¹ The rapid rise of these apps is partly due to their potential to transform a patient’s smartphone into a monitoring and therapeutic platform, capable of capturing mental health symptoms in real time and delivering on-the-go therapy. Setting aside questions about the potential of mobile health, 2 urgent questions remain for the busy psychiatrist in clinical practice: What is the current evidence base for mental health apps, and what should you tell your patients about them?

For most apps, evidence of efficacy is limited

While the evidence base for mental health smartphone apps continues to expand, for many of these apps, there is no evidence of effectiveness. The growing consensus is that most commercially available apps are not evidence-based and some are even dangerous. For example, researchers who examined >700 mindfulness apps on the iTunes and Google Play stores found that only 4% provided acceptable mindfulness training and education.² Another study of 58 apps that claimed to offer sobriety assessments found that none had ever been formally evaluated.³ Evidence-based reviews of suicide prevention apps have identified potentially harmful apps,⁴ and studies evaluating apps for bipolar disorder⁵ and depression⁶ have yielded similar results—few have any evidence supporting their use, and some offer dangerous and harmful advice. For example, researchers found that one app for bipolar disorder advised patients who are experiencing a manic episode to drink alcohol.⁵ Currently, the vast majority of commercially available apps are not appropriate for clinical care. This finding is not unique to mental health; similar findings have been reported for apps for cancer.⁷ The bottom line is that the apps that your patients are finding, and perhaps already using, may not be useful or effective.

However, early studies have demonstrated efficacy of some apps for several conditions, including schizophrenia,⁸ depression,⁹ anxiety disorders,¹⁰ and suicidal ideation.¹¹ Although many of the apps evaluated in these studies are not available to the public, or still require large-scale assessment before they are ready for mainstream clinical care, this research demonstrates that mental health apps can help improve treatment outcomes. As this research develops, a wave of evidence-based and effective mental health apps may be available in the near future.

Although it is unknown how many patients are presently using mental health apps, there is strong anecdotal evidence that an increasing number of patients who use these apps and other forms of digital technology are finding some benefits. In many cases, patients may actually be ahead of the research. For example, one study that conducted an online survey of patients with schizophrenia noted that some patients are using their smartphones to play music to help block auditory hallucinations.¹²

Why online reviews are of limited use

As this evidence continues to mature, and with an ever-growing number of mental health apps available on commercial marketplaces, busy psychiatrists need to navigate this complex space. Even psychiatrists who decide to not use apps as part of care still need to be knowledgeable about them, because patients are likely to ask about the benefits of using apps, and they will expect an informed response. How would you reply if your patient asked you about a new mood-tracking app he or she recently heard about? On what would you base your recommendation and opinion?

Reading online app reviews for guidance is not a good solution. A recent study found little relationship between the star ratings of health apps and the quality of those apps,¹³ which suggests that a 5-star rating on the app store is of limited use.

Unlike medications whose ingredients do not change over time, or manualized psychotherapies that use specific protocols, mental health apps are dynamic and constantly changing.¹⁴ Think of how often the apps on your smartphone update. Thus, the version of a mental health app that your patient downloads today may be very different from the version that received a favorable user review last month. And just as there is no single medication or therapy that is ideal for every patient, neither is there a single “best” app for all patients with the same disorder. Picking an app is a personal decision that cannot be made based on a single score or numeric rating. Furthermore, the validity of app rating systems is unclear. One study found a wide variation in the interrater reliability of measures used to evaluate apps from sources that included PsyberGuide, the Anxiety and Depression Association of America, and the research literature. Quality measures such as effectiveness, ease of use, and performance had relatively poor interrater reliability.¹⁵ This means that, for example, an app that one patient finds “easy to use” may be difficult to use for another. Thus, providing patients with suggestions based on an app’s ratings may result in providing information that sounds useful, but often is misleading.

One possible solution is a risk-based and personalized assessment approach to evaluating mental health apps. Although it does not offer scoring or recommendations of specific apps, the American Psychiatric Association (APA) App Evaluation Model (Figure) provides a framework to guide discussion and informed decision-making about apps. (The authors of this article helped create this model, but receive no compensation for that volunteer work.) The pyramid shape reflects the hierarchical nature of the model. To begin the process, start at the base of the pyramid and work upward.

Ground. First, consider the context of the app by determining basic facts, such as who made it, how much it costs, and its technology requirements. This ground layer establishes the credibility of the app’s creator by questioning his or her reputation, ability to update the app, and funding sources. Understanding the app’s business model also will help you determine whether the app will stand the test of time: Will it continue to exist next month or next year, or will a lack of reliable funding lead the vendor to abandon it?

Risk. The next layer assesses the risk, privacy, and security features of the app. Many mental health apps actively aim to avoid falling under the jurisdiction of U.S. federal health care privacy rules, such as the Health Insurance Portability and Accountability Act of 1996, so there is no guarantee that sensitive data supplied to an app will be protected. The true cost of a “free” app often is your patient’s personal mental health information, which the app’s developer may accumulate and sell for profit. Thus, it is wise to check the privacy policy to learn where your patient’s data goes. Furthermore, patients and psychiatrists must be vigilant that malware-infected apps can be uploaded to the app store, which can further compromise privacy.¹⁶ You may be surprised to learn that many apps lack a privacy policy, which means there are no protections for personal information or safeguards against the misuse of mental health data.¹⁷ Checking that an app at least promises to digitally protect mental health data through encryption and secure storage also is a good step.

The goal of considering these factors is not to create a score, but rather to be aware of them and consider them in the context of the specific app, patient, and clinical situation. Doing so helps determine whether the app meets the appropriate risk, privacy, and security standards for your patient.

Evidence. The next layer of the evaluation framework is evidence. The goal is to seek an app with clinical evidence of effectiveness. Simply put, if a patient is going to use an app, he should use one that works. An app without formal evidence may be effective, but it is important to make sure the patient is aware that these claims have not been verified. Many apps claim that they offer cognitive-behavioral therapy or mindfulness therapy, but few deliver on such claims.¹⁸ It is wise to try an app before recommending it to a patient to ensure that it does what it claims it does, and does not offer dangerous or harmful recommendations.

Ease of use. Across all health apps, there is growing recognition that most downloaded apps are never used. Patient engagement with mental health apps appears to rapidly decline over the first week of use.¹⁹ There also is emerging evidence that many apps are not user-friendly. A recent study of several common mood-tracking apps found that patients with depression had difficulty entering and accessing their data.²⁰ Because many psychiatric disorders are chronic or last at least several months, it is especially important to consider how engaging and usable the app will be for your patient. Usability varies from patient to patient, so it is best to check directly with your patient regarding his comfort with apps and mobile technology. Offering check-ins and support to help patients keep on track with apps may be critical for successful outcomes.

Interoperability. The final layer of the model is data sharing and interoperability. It is important to determine if the data collected or generated by the app are available to you, the patient, the treatment team, and others involved in the patient’s care. As mental health treatment moves toward integrated care, apps that fragment care (by not sharing information) impede care. Check if the app can share data with an electronic medical record, or if there is a plan to review and act on data from the app as part of your patient’s treatment plan.

More information about the APA App Evaluation Model, including additional factors to consider within each layer, is available from the APA for free at https://www.psychiatry.org/psychiatrists/practice/mental-health-apps/app-evaluation-model. For a sample of factors to consider when evaluating a mental health app, see the Table.

A reasonable strategy

Although the APA App Evaluation Model does not endorse any particular app, it can help guide more informed decision-making. As the evidence on mental health apps continues to evolve, it will become easier to make definitive statements on what constitutes a useful app. For now, the best strategy when discussing mental health apps with patients is to combine the use of this model with your clinical judgment.

The emergence of treatment-resistant depression (TRD) poses a great clinical and public health challenge. There is no clear consensus on criteria to define TRD. The criteria range from failure to respond to 4 weeks of a single antidepressant to failure to respond to a single trial of electroconvulsive therapy (ECT).¹

Neuromodulatory treatments for depression involve electrical stimulation of the brain through invasive or noninvasive methods. In this article, we discuss criteria for defining TRD, and compare the advantages and disadvantages of 4 neuromodulatory treatment options—ECT, vagus nerve stimulation (VNS), repetitive transcranial magnetic stimulation (rTMS), and deep brain stimulation (DBS)—for patients with depression who fail to respond to appropriate pharmacologic interventions (Table 1). Most of the studies we discuss selected patients who had severe depression and had not responded to numerous treatment trials.

Defining treatment resistance

Thase and Rush² suggested progressive stages for categorizing TRD, ranging from Stage I (failure of at least 1 adequate trial of antidepressants) to Stage V (failure of adequate treatment with 2 selective serotonin reuptake inhibitors [SSRIs], a tricyclic antidepressant, a monoamine oxidase inhibitor, and a course of bilateral ECT). The Massachusetts General Hospital Staging Model suggested a quantitative scale to help characterize the degree of treatment resistance in which a higher score corresponds to a higher level of resistance.³ For every failed 6-week trial with adequate dose of an antidepressant, the patient is given a score of 1. The patient receives an extra .5 point for failure to respond to optimization of the dosage and augmentation with another medication. The patient also is given 3 points for failure to respond to ECT. Souery et al^4,5 proposed a model in which they defined TRD as a failure to respond after ≥1 adequate antidepressant trials of ≥12 weeks.

Treatment resistance often is the result of inadequate treatment of depressive symptoms. Inadequate treatment includes an inadequate dose of antidepressants and/or an inadequate duration of treatment. Treatment of depression also is often complicated by medical (cardiovascular, neurologic, endocrine disorders) and psychiatric (substance abuse disorders, personality disorders) comorbidities (Table 2). Patients with such comorbidities are at increased risk of mortality, and have lower response rates and increased morbidity.⁶

Electroconvulsive therapy

ECT involves the application of electric current to induce a self-limiting seizure. It affects multiple brain functions to produce its antidepressant effects. Patients with depression have a reduced concentration of γ-aminobutyric acid (GABA) in their plasma, CSF, and cortex. ECT increases GABAergic transmission in cortical circuits as demonstrated by increased levels of GABA in the occipital cortex, which may be responsible for ECT’s antidepressant effects.⁷ Sensitization of the 5-HT1A receptors and increased dopamine receptor binding in the striatum also have been associated with the antidepressant action of ECT.⁸ The antidepressant effects of ECT also can be attributed to increased neuroplasticity, as evidenced by increased neuro­trophic factors and cell proliferation in animal models.⁹ Dysfunction of the HPA axis has long been associated with depressive disorders; ECT improves this dysfunction, as evidenced by normalization of the dexamethasone suppression test in patients who receive ECT.⁷

The results of neuroimaging studies exploring the effects of ECT vary widely based on the specific neuroimaging method, population, and statistical methods used to assess the changes. Some of the most consistent findings include reduced glucose metabolism in the frontal brain regions; reduced glucose metabolism in the hippocampus and medial temporal lobes; and reduction in functional connectivity in the anterior cingulate, parietal, medical frontal, and dorsolateral prefrontal cortex (DLPFC).¹⁰

Randomized control trials (RCTs) have established the superiority of ECT over pharmacotherapy and sham ECT. Compared with other neuromodulatory treatments, ECT has higher remission rates. On average, the remission rate among patients receiving ECT whose depression did not respond to pharmacotherapy is approximately 48%; this increases to 64.9% among patients who previously had responded to a medication.¹¹

Some earlier trials found bilateral ECT to be more effective than unilateral ECT.¹² Recent studies suggest that high-dose unilateral ECT (6 times the seizure threshold) is as effective as bilateral ECT.¹³ Studies have shown no significant differences in efficacy or treatment outcomes between twice- and thrice-weekly ECT regimens. Some studies suggest that twice-weekly ECT may be associated with a lower risk of short-term cognitive impairment compared with thrice-weekly ECT.¹⁴

In highly refractory cases, the effects of ECT can be augmented by using pre-treatment strategies such as hyperventilation, which may increase the duration of the seizure, and remifentanil, which helps reduce the anticonvulsant effect of agents used for anesthesia.¹⁵ Advanced age, psychotic features, resistance to pharmacotherapy, and comorbid personality disorders predict poor response to ECT.¹⁶

Adverse effects. Concerns about cognitive deficits secondary to ECT may curtail its use. Retrograde and anterograde amnesia are the most common deficits observed acutely after ECT.¹² Other commonly affected cognitive functions include processing speed, attention/working memory, verbal and visual episodic memory, spatial problem solving, and executive functioning. The specific patterns of these deficits (in terms of duration and severity) vary between studies. In general, high-dose, thrice-weekly ECT and bilateral ECT are associated with greater cognitive deficits, whereas twice-weekly ECT and unilateral ECT are associated with a lower risk of cognitive adverse effects.¹² A recent meta-analysis by Semkovska and McLoughlin¹⁷ found that most cognitive deficits seen after ECT are limited to the first 3 days after treatment. The authors of this meta-analysis concluded that these impairments improve over time and approach baseline 2 weeks after treatment. In fact, some of these impairments (processing speed, working memory, anterograde memory, and some aspects of executive function) improved beyond baseline after 15 days of treatment.¹⁷ The need for anesthesia and associated potential adverse effects also are a cause of concern with ECT.

Combining ECT with medication. Several patient-specific factors, including medication regimen and comorbid medical conditions, need to be considered before using ECT in combination with pharmacotherapy. Although most antipsychotics are safe to use with ECT, concomitant use of agents with higher antihistaminic properties may increase the risk of delirium. The risk of delirium also is increased with the use of anticonvulsants and mood stabilizers (eg, lithium) because these agents increase the seizure threshold. The potential for drug interactions may affect the choice of the anesthetic agents. Also, SSRIs and serotonin-norepinephrine reuptake inhibitors can increase the duration of induced seizures.¹⁸

Vagus nerve stimulation

VNS, in which an implanted device stimulates the vagus nerve with electrical impulses, initially was used to reduce the frequency of seizures in patients with epilepsy and treatment-resistant partial onset seizures.¹⁹ VNS was FDA-approved for TRD in July 2005.²⁰ One VNS system, the NCP System, consists of an implantable, multi-programmable generator, known as a pulse generator, that is subcutaneously placed in the anterior chest wall during an outpatient surgical procedure. Separate bipolar nerve-stimulating electrodes are surgically wrapped around the left cervical vagus nerve, and then connected to the generator via a tunneling procedure. A telemetric wand is subsequently linked to a portable computer and used to adjust stimulation parameters.^21,22

Support for using VNS for TRD came from a multitude of investigations and observations. Harden et al²³ and Elger et al²⁴ prospectively evaluated epileptic patients with standard depression symptom severity rating scales. They found that VNS was associated with statistically significant improvements in mood that were not related to reductions in seizures.^23,24

The mechanism of action of VNS is not clear. Earlier researchers had found evidence that VNS affected brain regions associated with norepinephrine²⁵ and serotonin systems²⁶; both of these neuro­transmitters have been implicated in the pathophysiology of depression. Positron emission tomography studies conducted during VNS treatment of epilepsy showed metabolic changes in cortical and subcortical areas of the brain, including the amygdala, hippocampus, and cingulate gyrus, all structures implicated in the pathophysiology of mood disorders.²⁷

Most studies conducted to evaluate the efficacy of VNS have been observational, looking at depression ratings before and after treatment with VNS. The short-term studies measured the difference in depression rating scales at baseline and after 10 weeks of treatment. In most of these studies, treatment with VNS resulted in a statistically significant drop in depression rating scales scores, such as on the Hamilton Depression Rating Scale (HAM-D). Based on the study design and number of study participants, response rates have varied from 13%²⁸ to 40%,²⁹ whereas remission rates have varied from 15.3%³⁰ to 28%.³¹ More than one-half of the reduction in symptoms occurred after 6 weeks of treatment.³⁰ In longer-term follow-up studies, the antidepressant effect generally was sustained over time. Response rates remained essentially unchanged, but the remission rates increased to approximately 29%.²⁹ Only 1 RCT has compared patients with controls; it found no significant differences in the response or remission rates between active VNS and sham VNS.³² In this study, all patients had VNS implanted, but in the control group, the VNS was never turned on.³² In a meta-analysis conducted by Martin and Martín-Sánchez,³³ 31.8% (95% confidence interval [CI], 23.2% to 41.8%; P < .001) of patients treated with VNS had a significant reduction in HAM-D scores. The response rate in patients with TRD ranged from 27% to 37% and the remission rate was approximately 13%. In studies that followed patients over longer periods, both the remission and response rates increased over time.³⁴

Recent evidence suggests that the effectiveness of VNS may depend on the stimulation level. A multi-center double-blind study randomized patients to receive either a low (0.25 mA current, 130-millisecond pulse width), medium (0.5e1.0 mA, 250 millisecond), or high (1.25e1.5 mA, 250 millisecond) dose of VNS.³⁵ Although all dose levels were associated with improvement in symptoms, a statistically significant durability in response was associated with the medium- and high-dose treatments.

Adverse effects. VNS has no major adverse effects on cognitive functioning, and some studies have found improvement in executive functioning that corresponded to improvement in depressive symptoms.³⁰ VNS also may result in improved sleep patterns as evidenced by EEG changes.³¹ The most commonly reported adverse effects include pain in the incision site, hoarseness of voice, throat pain, and neck pain.³⁶

rTMS is a noninvasive technique that uses high-intensity magnetic impulses to stimulate cortical neurons. A magnetic field is produced when current passes through a coil, which in turn causes electrical stimulation in the cortical neurons that results in transient changes in the excitability of the cortical neurons.³⁷ Although many stimulation parameters exist for TMS, high-frequency stimulation to the left prefrontal cortex (HFL-rTMS) and low-frequency stimulation to the right prefrontal cortex (LFR-rTMS) have been shown most efficacious for treating depression.³⁸ High-frequency (5 Hz to 20 Hz) stimulation using rTMS increases cortical neuron excitability, whereas low-frequency (approximately 1 Hz) is associated with reduced cortical neuron excitability.³⁹ The choice of targeting the DLPFC stems from a large body of functional neuroimaging studies that have shown reduction in activity/blood flow in the left DLPFC and abnormal activity/blood flow in the right DLPFC.⁴⁰

There is no dearth of RCTs evaluating the efficacy of rTMS vs sham rTMS (where no magnetic stimulation was provided). In a meta-analysis of 8 RCTs, low-frequency rTMS applied to the right DLPFC was associated with a remission rate of approximately 34.6%, compared with a 9.7% remission rate with sham rTMS.⁴¹ A response rate of approximately 38.2% was observed with HFL-rTMS, compared with a response rate of 15.1% for sham rTMS.⁴¹

Gaynes et al⁴² conducted a meta-analysis to determine the efficacy of rTMS in TRD. They found that for patients with TRD, rTMs produced a response rate of 29% and a remission rate of 30%. In long-term, naturalistic, observational studies, the response rates and remission rates were much higher (58% and 37.1%, respectively).⁴³ Over a 1-year follow-up, almost two-thirds of patients continued to meet criteria for response to treatment.⁴⁴ Trials comparing HFL-rTMS and LFR-rTMS have found no significant differences in efficacy.⁴⁵

Advanced age, psychotic symptoms, and a longer duration of the current depressive episode predict poor response to rTMS. Also, imaging studies have shown that a lower metabolism in cerebellar, temporal, anterior cingulate, and occipital parts of the brain correlate with better response to HFL-rTMS.^46,47

Adverse effects. The major adverse effect associated with rTMS is the risk of inducing seizures, which is more commonly associated with high-frequency rTMS. Other common adverse effects include headache, facial muscle twitching, and tinnitus.³⁷

Deep brain stimulation

DBS is an invasive stereotactic surgical procedure. It involves unilateral or bilateral placement of electrodes at neuroanatomical locations to deliver continuous stimulation from a subcutaneously implanted pulse generator.⁴⁸ In the past, destructive surgical procedures were used to treat intractable depression. Surgeries such as anterior cingulotomy, anterior capsulotomy, subcaudate tractotomy, and limbic leucotomy have been shown to effectively reduce depressive symptoms.⁴⁹ The advantages of DBS over destructive procedures include the fact that DBS is reversible and that the stimulation levels can easily be adjusted, and the treatment can easily be stopped or restarted.

There is no consensus on the optimal anatomic locations for the electrode implantation in DBS. Electrodes have been implanted in the subcallosal cingulate gyrus, inferior thalamic peduncle, ventral capsule/ventral striatum, superolateral branch of the medial forebrain bundle (MFB), and nucleus accumbens.

The choice of anatomic locations stems from the large body of neuroimaging literature characterizing functional changes associated with acute depression and response to treatment. The electrode placement targets “nodes” that form an integral part of the affected neural circuits that are responsible for regulating depressive symptoms.⁵⁰ Increased metabolic activity and blood flow to the subgenual cingulate gyrus and reduction in the blood flow to the DLPFC and the striatum have been associated with active depressed states. Response to antidepressant treatment has been associated with reversal of these findings.⁵¹ Functional magnetic resonance imaging studies have consistently shown increased activity in the amygdala in response to negative stimuli among patients with depression.

Regardless of the site of electrode placement, studies have reported symptomatic improvement among patients with depression who are treated with DBS. In 2 case reports, the electrode was implanted in the inferior thalamic peduncle.^52,53 Each study had 1 participant, and each patient remitted.^52,53

Placement of the electrodes in the nucleus accumbens resulted in a response rate of 45% in 1 study,⁵⁴ whereas in a different study, all patients reported improvement in anhedonia.⁵⁵ A response rate of 71% and a remission rate of 35% were observed in a study in which the electrode was implanted in the ventral capsule/ventral striatum area.⁵⁶

Berlim et al⁵⁷ published a systematic review and exploratory meta-analysis of studies in which the electrode had been implanted in the subgenual cingulate cortex. At 12 months, the response rate was 39.9% (95% CI, 28.4% to 52.8%), and 26.3% (95% CI, 13% to 45.9%) of patients achieved remission. The most significant drop in depression scores was observed 3 to 6 months after the surgery. No significant change in scores was observed between 6 to 12 months after surgery.⁵⁷

The MFB, specifically the superolateral branch, is emerging as an exciting new target for electrode placement in DBS. Schlaepfer et al⁵⁸ studied the effects of electrodes implanted bilaterally in the superolateral branch of the MFB. They observed an almost 50% reduction in symptoms by Day 7, and at the last follow-up visit (12 to 33 weeks) 4 of the 6 patients had achieved remission.⁵⁸ In a recent systematic review, Gálvez et al⁵⁹ found most studies had high response/remission rates without any significant adverse effects. In a recent study of DBS targeting the MFB, 3 of 4 patients had a >50% reduction in Montgomery-Åsberg Depression Rating Scale scores at the end of first week. Although 1 patient withdrew, 2 of the other 3 patients continued to report a >80% reduction in depressive symptoms, even at Week 26.⁶⁰

Accurate localization of target areas (white matter tracts) and subsequent electrode placement might be an important factor governing treatment response. Riva-Posse et al⁶¹ found that clinical response was seen when the electrodes stimulated 3 specific white matter bundles. Interestingly, nonresponders were converted to responders simply by changing the position of the electrodes to include these white matter tracts.⁶¹

Adverse effects. The most common adverse effects noted during studies of DBS include pain at the site of implantation and wound infection. Other adverse effects include lead fracture, transient dysphagia, and other hardware-related problems.⁴⁹

In the absence of head-to-head trials, it is difficult to establish a hierarchal algorithm for use of the 4 neuromodulatory treatments discussed in the article. If we were to base our decision solely on the current literature, ECT by far has the most evidence and highest remission rates.¹¹ We can reduce the risk of cognitive deficits by using twice-weekly instead of thrice-weekly ECT, or by using unilateral instead of bilateral ECT.¹² Another strategy for reducing adverse effects associated with long-term maintenance ECT is by using it in combination with VNS. ECT and VNS can be used safely concomitantly; ECT can be used to treat acutely worsening depression, and VNS for maintaining the antidepressant effect.⁶²

Aside from ECT, rTMS is the only other treatment that has evidence from RCTs. Although the remission rates are not as high as ECT, its preferable adverse effects profile, noninvasive nature, and comparative low cost (compared with surgical procedures) make it a favorable choice. The Canadian Network for Mood and Anxiety Treatment guidelines suggest rTMS as the first-line treatment for patients who do not respond to pharmacologic treatments.⁶³ ECT can be considered second-line treatment unless the patient has acute suicidal ideation, catatonia, psychotic features, greater treatment resistance, or physical deterioration, in which case ECT should be tried before TMS.⁶³

Among the invasive options, VNS has more evidence and is FDA-approved for TRD. However, DBS has shown great promise in early studies, with remission rates as high as 35%.⁵⁶ DBS has the advantage of being reversible, and the amount of stimulation can be adjusted easily. Despite early promise, more research is needed before DBS can be widely used in clinical settings.

The emergence of treatment-resistant depression (TRD) poses a great clinical and public health challenge. There is no clear consensus on criteria to define TRD. The criteria range from failure to respond to 4 weeks of a single antidepressant to failure to respond to a single trial of electroconvulsive therapy (ECT).¹

Neuromodulatory treatments for depression involve electrical stimulation of the brain through invasive or noninvasive methods. In this article, we discuss criteria for defining TRD, and compare the advantages and disadvantages of 4 neuromodulatory treatment options—ECT, vagus nerve stimulation (VNS), repetitive transcranial magnetic stimulation (rTMS), and deep brain stimulation (DBS)—for patients with depression who fail to respond to appropriate pharmacologic interventions (Table 1). Most of the studies we discuss selected patients who had severe depression and had not responded to numerous treatment trials.

Defining treatment resistance

Thase and Rush² suggested progressive stages for categorizing TRD, ranging from Stage I (failure of at least 1 adequate trial of antidepressants) to Stage V (failure of adequate treatment with 2 selective serotonin reuptake inhibitors [SSRIs], a tricyclic antidepressant, a monoamine oxidase inhibitor, and a course of bilateral ECT). The Massachusetts General Hospital Staging Model suggested a quantitative scale to help characterize the degree of treatment resistance in which a higher score corresponds to a higher level of resistance.³ For every failed 6-week trial with adequate dose of an antidepressant, the patient is given a score of 1. The patient receives an extra .5 point for failure to respond to optimization of the dosage and augmentation with another medication. The patient also is given 3 points for failure to respond to ECT. Souery et al^4,5 proposed a model in which they defined TRD as a failure to respond after ≥1 adequate antidepressant trials of ≥12 weeks.

Treatment resistance often is the result of inadequate treatment of depressive symptoms. Inadequate treatment includes an inadequate dose of antidepressants and/or an inadequate duration of treatment. Treatment of depression also is often complicated by medical (cardiovascular, neurologic, endocrine disorders) and psychiatric (substance abuse disorders, personality disorders) comorbidities (Table 2). Patients with such comorbidities are at increased risk of mortality, and have lower response rates and increased morbidity.⁶

Electroconvulsive therapy

ECT involves the application of electric current to induce a self-limiting seizure. It affects multiple brain functions to produce its antidepressant effects. Patients with depression have a reduced concentration of γ-aminobutyric acid (GABA) in their plasma, CSF, and cortex. ECT increases GABAergic transmission in cortical circuits as demonstrated by increased levels of GABA in the occipital cortex, which may be responsible for ECT’s antidepressant effects.⁷ Sensitization of the 5-HT1A receptors and increased dopamine receptor binding in the striatum also have been associated with the antidepressant action of ECT.⁸ The antidepressant effects of ECT also can be attributed to increased neuroplasticity, as evidenced by increased neuro­trophic factors and cell proliferation in animal models.⁹ Dysfunction of the HPA axis has long been associated with depressive disorders; ECT improves this dysfunction, as evidenced by normalization of the dexamethasone suppression test in patients who receive ECT.⁷

The results of neuroimaging studies exploring the effects of ECT vary widely based on the specific neuroimaging method, population, and statistical methods used to assess the changes. Some of the most consistent findings include reduced glucose metabolism in the frontal brain regions; reduced glucose metabolism in the hippocampus and medial temporal lobes; and reduction in functional connectivity in the anterior cingulate, parietal, medical frontal, and dorsolateral prefrontal cortex (DLPFC).¹⁰

Randomized control trials (RCTs) have established the superiority of ECT over pharmacotherapy and sham ECT. Compared with other neuromodulatory treatments, ECT has higher remission rates. On average, the remission rate among patients receiving ECT whose depression did not respond to pharmacotherapy is approximately 48%; this increases to 64.9% among patients who previously had responded to a medication.¹¹

Some earlier trials found bilateral ECT to be more effective than unilateral ECT.¹² Recent studies suggest that high-dose unilateral ECT (6 times the seizure threshold) is as effective as bilateral ECT.¹³ Studies have shown no significant differences in efficacy or treatment outcomes between twice- and thrice-weekly ECT regimens. Some studies suggest that twice-weekly ECT may be associated with a lower risk of short-term cognitive impairment compared with thrice-weekly ECT.¹⁴

In highly refractory cases, the effects of ECT can be augmented by using pre-treatment strategies such as hyperventilation, which may increase the duration of the seizure, and remifentanil, which helps reduce the anticonvulsant effect of agents used for anesthesia.¹⁵ Advanced age, psychotic features, resistance to pharmacotherapy, and comorbid personality disorders predict poor response to ECT.¹⁶

Adverse effects. Concerns about cognitive deficits secondary to ECT may curtail its use. Retrograde and anterograde amnesia are the most common deficits observed acutely after ECT.¹² Other commonly affected cognitive functions include processing speed, attention/working memory, verbal and visual episodic memory, spatial problem solving, and executive functioning. The specific patterns of these deficits (in terms of duration and severity) vary between studies. In general, high-dose, thrice-weekly ECT and bilateral ECT are associated with greater cognitive deficits, whereas twice-weekly ECT and unilateral ECT are associated with a lower risk of cognitive adverse effects.¹² A recent meta-analysis by Semkovska and McLoughlin¹⁷ found that most cognitive deficits seen after ECT are limited to the first 3 days after treatment. The authors of this meta-analysis concluded that these impairments improve over time and approach baseline 2 weeks after treatment. In fact, some of these impairments (processing speed, working memory, anterograde memory, and some aspects of executive function) improved beyond baseline after 15 days of treatment.¹⁷ The need for anesthesia and associated potential adverse effects also are a cause of concern with ECT.

Combining ECT with medication. Several patient-specific factors, including medication regimen and comorbid medical conditions, need to be considered before using ECT in combination with pharmacotherapy. Although most antipsychotics are safe to use with ECT, concomitant use of agents with higher antihistaminic properties may increase the risk of delirium. The risk of delirium also is increased with the use of anticonvulsants and mood stabilizers (eg, lithium) because these agents increase the seizure threshold. The potential for drug interactions may affect the choice of the anesthetic agents. Also, SSRIs and serotonin-norepinephrine reuptake inhibitors can increase the duration of induced seizures.¹⁸

Vagus nerve stimulation

VNS, in which an implanted device stimulates the vagus nerve with electrical impulses, initially was used to reduce the frequency of seizures in patients with epilepsy and treatment-resistant partial onset seizures.¹⁹ VNS was FDA-approved for TRD in July 2005.²⁰ One VNS system, the NCP System, consists of an implantable, multi-programmable generator, known as a pulse generator, that is subcutaneously placed in the anterior chest wall during an outpatient surgical procedure. Separate bipolar nerve-stimulating electrodes are surgically wrapped around the left cervical vagus nerve, and then connected to the generator via a tunneling procedure. A telemetric wand is subsequently linked to a portable computer and used to adjust stimulation parameters.^21,22

Support for using VNS for TRD came from a multitude of investigations and observations. Harden et al²³ and Elger et al²⁴ prospectively evaluated epileptic patients with standard depression symptom severity rating scales. They found that VNS was associated with statistically significant improvements in mood that were not related to reductions in seizures.^23,24

The mechanism of action of VNS is not clear. Earlier researchers had found evidence that VNS affected brain regions associated with norepinephrine²⁵ and serotonin systems²⁶; both of these neuro­transmitters have been implicated in the pathophysiology of depression. Positron emission tomography studies conducted during VNS treatment of epilepsy showed metabolic changes in cortical and subcortical areas of the brain, including the amygdala, hippocampus, and cingulate gyrus, all structures implicated in the pathophysiology of mood disorders.²⁷

Most studies conducted to evaluate the efficacy of VNS have been observational, looking at depression ratings before and after treatment with VNS. The short-term studies measured the difference in depression rating scales at baseline and after 10 weeks of treatment. In most of these studies, treatment with VNS resulted in a statistically significant drop in depression rating scales scores, such as on the Hamilton Depression Rating Scale (HAM-D). Based on the study design and number of study participants, response rates have varied from 13%²⁸ to 40%,²⁹ whereas remission rates have varied from 15.3%³⁰ to 28%.³¹ More than one-half of the reduction in symptoms occurred after 6 weeks of treatment.³⁰ In longer-term follow-up studies, the antidepressant effect generally was sustained over time. Response rates remained essentially unchanged, but the remission rates increased to approximately 29%.²⁹ Only 1 RCT has compared patients with controls; it found no significant differences in the response or remission rates between active VNS and sham VNS.³² In this study, all patients had VNS implanted, but in the control group, the VNS was never turned on.³² In a meta-analysis conducted by Martin and Martín-Sánchez,³³ 31.8% (95% confidence interval [CI], 23.2% to 41.8%; P < .001) of patients treated with VNS had a significant reduction in HAM-D scores. The response rate in patients with TRD ranged from 27% to 37% and the remission rate was approximately 13%. In studies that followed patients over longer periods, both the remission and response rates increased over time.³⁴

Recent evidence suggests that the effectiveness of VNS may depend on the stimulation level. A multi-center double-blind study randomized patients to receive either a low (0.25 mA current, 130-millisecond pulse width), medium (0.5e1.0 mA, 250 millisecond), or high (1.25e1.5 mA, 250 millisecond) dose of VNS.³⁵ Although all dose levels were associated with improvement in symptoms, a statistically significant durability in response was associated with the medium- and high-dose treatments.

Adverse effects. VNS has no major adverse effects on cognitive functioning, and some studies have found improvement in executive functioning that corresponded to improvement in depressive symptoms.³⁰ VNS also may result in improved sleep patterns as evidenced by EEG changes.³¹ The most commonly reported adverse effects include pain in the incision site, hoarseness of voice, throat pain, and neck pain.³⁶

rTMS is a noninvasive technique that uses high-intensity magnetic impulses to stimulate cortical neurons. A magnetic field is produced when current passes through a coil, which in turn causes electrical stimulation in the cortical neurons that results in transient changes in the excitability of the cortical neurons.³⁷ Although many stimulation parameters exist for TMS, high-frequency stimulation to the left prefrontal cortex (HFL-rTMS) and low-frequency stimulation to the right prefrontal cortex (LFR-rTMS) have been shown most efficacious for treating depression.³⁸ High-frequency (5 Hz to 20 Hz) stimulation using rTMS increases cortical neuron excitability, whereas low-frequency (approximately 1 Hz) is associated with reduced cortical neuron excitability.³⁹ The choice of targeting the DLPFC stems from a large body of functional neuroimaging studies that have shown reduction in activity/blood flow in the left DLPFC and abnormal activity/blood flow in the right DLPFC.⁴⁰

There is no dearth of RCTs evaluating the efficacy of rTMS vs sham rTMS (where no magnetic stimulation was provided). In a meta-analysis of 8 RCTs, low-frequency rTMS applied to the right DLPFC was associated with a remission rate of approximately 34.6%, compared with a 9.7% remission rate with sham rTMS.⁴¹ A response rate of approximately 38.2% was observed with HFL-rTMS, compared with a response rate of 15.1% for sham rTMS.⁴¹

Gaynes et al⁴² conducted a meta-analysis to determine the efficacy of rTMS in TRD. They found that for patients with TRD, rTMs produced a response rate of 29% and a remission rate of 30%. In long-term, naturalistic, observational studies, the response rates and remission rates were much higher (58% and 37.1%, respectively).⁴³ Over a 1-year follow-up, almost two-thirds of patients continued to meet criteria for response to treatment.⁴⁴ Trials comparing HFL-rTMS and LFR-rTMS have found no significant differences in efficacy.⁴⁵

Advanced age, psychotic symptoms, and a longer duration of the current depressive episode predict poor response to rTMS. Also, imaging studies have shown that a lower metabolism in cerebellar, temporal, anterior cingulate, and occipital parts of the brain correlate with better response to HFL-rTMS.^46,47

Adverse effects. The major adverse effect associated with rTMS is the risk of inducing seizures, which is more commonly associated with high-frequency rTMS. Other common adverse effects include headache, facial muscle twitching, and tinnitus.³⁷

Deep brain stimulation

DBS is an invasive stereotactic surgical procedure. It involves unilateral or bilateral placement of electrodes at neuroanatomical locations to deliver continuous stimulation from a subcutaneously implanted pulse generator.⁴⁸ In the past, destructive surgical procedures were used to treat intractable depression. Surgeries such as anterior cingulotomy, anterior capsulotomy, subcaudate tractotomy, and limbic leucotomy have been shown to effectively reduce depressive symptoms.⁴⁹ The advantages of DBS over destructive procedures include the fact that DBS is reversible and that the stimulation levels can easily be adjusted, and the treatment can easily be stopped or restarted.

There is no consensus on the optimal anatomic locations for the electrode implantation in DBS. Electrodes have been implanted in the subcallosal cingulate gyrus, inferior thalamic peduncle, ventral capsule/ventral striatum, superolateral branch of the medial forebrain bundle (MFB), and nucleus accumbens.

The choice of anatomic locations stems from the large body of neuroimaging literature characterizing functional changes associated with acute depression and response to treatment. The electrode placement targets “nodes” that form an integral part of the affected neural circuits that are responsible for regulating depressive symptoms.⁵⁰ Increased metabolic activity and blood flow to the subgenual cingulate gyrus and reduction in the blood flow to the DLPFC and the striatum have been associated with active depressed states. Response to antidepressant treatment has been associated with reversal of these findings.⁵¹ Functional magnetic resonance imaging studies have consistently shown increased activity in the amygdala in response to negative stimuli among patients with depression.

Regardless of the site of electrode placement, studies have reported symptomatic improvement among patients with depression who are treated with DBS. In 2 case reports, the electrode was implanted in the inferior thalamic peduncle.^52,53 Each study had 1 participant, and each patient remitted.^52,53

Placement of the electrodes in the nucleus accumbens resulted in a response rate of 45% in 1 study,⁵⁴ whereas in a different study, all patients reported improvement in anhedonia.⁵⁵ A response rate of 71% and a remission rate of 35% were observed in a study in which the electrode was implanted in the ventral capsule/ventral striatum area.⁵⁶

Berlim et al⁵⁷ published a systematic review and exploratory meta-analysis of studies in which the electrode had been implanted in the subgenual cingulate cortex. At 12 months, the response rate was 39.9% (95% CI, 28.4% to 52.8%), and 26.3% (95% CI, 13% to 45.9%) of patients achieved remission. The most significant drop in depression scores was observed 3 to 6 months after the surgery. No significant change in scores was observed between 6 to 12 months after surgery.⁵⁷

The MFB, specifically the superolateral branch, is emerging as an exciting new target for electrode placement in DBS. Schlaepfer et al⁵⁸ studied the effects of electrodes implanted bilaterally in the superolateral branch of the MFB. They observed an almost 50% reduction in symptoms by Day 7, and at the last follow-up visit (12 to 33 weeks) 4 of the 6 patients had achieved remission.⁵⁸ In a recent systematic review, Gálvez et al⁵⁹ found most studies had high response/remission rates without any significant adverse effects. In a recent study of DBS targeting the MFB, 3 of 4 patients had a >50% reduction in Montgomery-Åsberg Depression Rating Scale scores at the end of first week. Although 1 patient withdrew, 2 of the other 3 patients continued to report a >80% reduction in depressive symptoms, even at Week 26.⁶⁰

Accurate localization of target areas (white matter tracts) and subsequent electrode placement might be an important factor governing treatment response. Riva-Posse et al⁶¹ found that clinical response was seen when the electrodes stimulated 3 specific white matter bundles. Interestingly, nonresponders were converted to responders simply by changing the position of the electrodes to include these white matter tracts.⁶¹

Adverse effects. The most common adverse effects noted during studies of DBS include pain at the site of implantation and wound infection. Other adverse effects include lead fracture, transient dysphagia, and other hardware-related problems.⁴⁹

In the absence of head-to-head trials, it is difficult to establish a hierarchal algorithm for use of the 4 neuromodulatory treatments discussed in the article. If we were to base our decision solely on the current literature, ECT by far has the most evidence and highest remission rates.¹¹ We can reduce the risk of cognitive deficits by using twice-weekly instead of thrice-weekly ECT, or by using unilateral instead of bilateral ECT.¹² Another strategy for reducing adverse effects associated with long-term maintenance ECT is by using it in combination with VNS. ECT and VNS can be used safely concomitantly; ECT can be used to treat acutely worsening depression, and VNS for maintaining the antidepressant effect.⁶²

Aside from ECT, rTMS is the only other treatment that has evidence from RCTs. Although the remission rates are not as high as ECT, its preferable adverse effects profile, noninvasive nature, and comparative low cost (compared with surgical procedures) make it a favorable choice. The Canadian Network for Mood and Anxiety Treatment guidelines suggest rTMS as the first-line treatment for patients who do not respond to pharmacologic treatments.⁶³ ECT can be considered second-line treatment unless the patient has acute suicidal ideation, catatonia, psychotic features, greater treatment resistance, or physical deterioration, in which case ECT should be tried before TMS.⁶³

Among the invasive options, VNS has more evidence and is FDA-approved for TRD. However, DBS has shown great promise in early studies, with remission rates as high as 35%.⁵⁶ DBS has the advantage of being reversible, and the amount of stimulation can be adjusted easily. Despite early promise, more research is needed before DBS can be widely used in clinical settings.

The emergence of treatment-resistant depression (TRD) poses a great clinical and public health challenge. There is no clear consensus on criteria to define TRD. The criteria range from failure to respond to 4 weeks of a single antidepressant to failure to respond to a single trial of electroconvulsive therapy (ECT).¹

Neuromodulatory treatments for depression involve electrical stimulation of the brain through invasive or noninvasive methods. In this article, we discuss criteria for defining TRD, and compare the advantages and disadvantages of 4 neuromodulatory treatment options—ECT, vagus nerve stimulation (VNS), repetitive transcranial magnetic stimulation (rTMS), and deep brain stimulation (DBS)—for patients with depression who fail to respond to appropriate pharmacologic interventions (Table 1). Most of the studies we discuss selected patients who had severe depression and had not responded to numerous treatment trials.

Defining treatment resistance

Thase and Rush² suggested progressive stages for categorizing TRD, ranging from Stage I (failure of at least 1 adequate trial of antidepressants) to Stage V (failure of adequate treatment with 2 selective serotonin reuptake inhibitors [SSRIs], a tricyclic antidepressant, a monoamine oxidase inhibitor, and a course of bilateral ECT). The Massachusetts General Hospital Staging Model suggested a quantitative scale to help characterize the degree of treatment resistance in which a higher score corresponds to a higher level of resistance.³ For every failed 6-week trial with adequate dose of an antidepressant, the patient is given a score of 1. The patient receives an extra .5 point for failure to respond to optimization of the dosage and augmentation with another medication. The patient also is given 3 points for failure to respond to ECT. Souery et al^4,5 proposed a model in which they defined TRD as a failure to respond after ≥1 adequate antidepressant trials of ≥12 weeks.

Treatment resistance often is the result of inadequate treatment of depressive symptoms. Inadequate treatment includes an inadequate dose of antidepressants and/or an inadequate duration of treatment. Treatment of depression also is often complicated by medical (cardiovascular, neurologic, endocrine disorders) and psychiatric (substance abuse disorders, personality disorders) comorbidities (Table 2). Patients with such comorbidities are at increased risk of mortality, and have lower response rates and increased morbidity.⁶

Electroconvulsive therapy

ECT involves the application of electric current to induce a self-limiting seizure. It affects multiple brain functions to produce its antidepressant effects. Patients with depression have a reduced concentration of γ-aminobutyric acid (GABA) in their plasma, CSF, and cortex. ECT increases GABAergic transmission in cortical circuits as demonstrated by increased levels of GABA in the occipital cortex, which may be responsible for ECT’s antidepressant effects.⁷ Sensitization of the 5-HT1A receptors and increased dopamine receptor binding in the striatum also have been associated with the antidepressant action of ECT.⁸ The antidepressant effects of ECT also can be attributed to increased neuroplasticity, as evidenced by increased neuro­trophic factors and cell proliferation in animal models.⁹ Dysfunction of the HPA axis has long been associated with depressive disorders; ECT improves this dysfunction, as evidenced by normalization of the dexamethasone suppression test in patients who receive ECT.⁷

The results of neuroimaging studies exploring the effects of ECT vary widely based on the specific neuroimaging method, population, and statistical methods used to assess the changes. Some of the most consistent findings include reduced glucose metabolism in the frontal brain regions; reduced glucose metabolism in the hippocampus and medial temporal lobes; and reduction in functional connectivity in the anterior cingulate, parietal, medical frontal, and dorsolateral prefrontal cortex (DLPFC).¹⁰

Randomized control trials (RCTs) have established the superiority of ECT over pharmacotherapy and sham ECT. Compared with other neuromodulatory treatments, ECT has higher remission rates. On average, the remission rate among patients receiving ECT whose depression did not respond to pharmacotherapy is approximately 48%; this increases to 64.9% among patients who previously had responded to a medication.¹¹

Some earlier trials found bilateral ECT to be more effective than unilateral ECT.¹² Recent studies suggest that high-dose unilateral ECT (6 times the seizure threshold) is as effective as bilateral ECT.¹³ Studies have shown no significant differences in efficacy or treatment outcomes between twice- and thrice-weekly ECT regimens. Some studies suggest that twice-weekly ECT may be associated with a lower risk of short-term cognitive impairment compared with thrice-weekly ECT.¹⁴

In highly refractory cases, the effects of ECT can be augmented by using pre-treatment strategies such as hyperventilation, which may increase the duration of the seizure, and remifentanil, which helps reduce the anticonvulsant effect of agents used for anesthesia.¹⁵ Advanced age, psychotic features, resistance to pharmacotherapy, and comorbid personality disorders predict poor response to ECT.¹⁶

Adverse effects. Concerns about cognitive deficits secondary to ECT may curtail its use. Retrograde and anterograde amnesia are the most common deficits observed acutely after ECT.¹² Other commonly affected cognitive functions include processing speed, attention/working memory, verbal and visual episodic memory, spatial problem solving, and executive functioning. The specific patterns of these deficits (in terms of duration and severity) vary between studies. In general, high-dose, thrice-weekly ECT and bilateral ECT are associated with greater cognitive deficits, whereas twice-weekly ECT and unilateral ECT are associated with a lower risk of cognitive adverse effects.¹² A recent meta-analysis by Semkovska and McLoughlin¹⁷ found that most cognitive deficits seen after ECT are limited to the first 3 days after treatment. The authors of this meta-analysis concluded that these impairments improve over time and approach baseline 2 weeks after treatment. In fact, some of these impairments (processing speed, working memory, anterograde memory, and some aspects of executive function) improved beyond baseline after 15 days of treatment.¹⁷ The need for anesthesia and associated potential adverse effects also are a cause of concern with ECT.

Combining ECT with medication. Several patient-specific factors, including medication regimen and comorbid medical conditions, need to be considered before using ECT in combination with pharmacotherapy. Although most antipsychotics are safe to use with ECT, concomitant use of agents with higher antihistaminic properties may increase the risk of delirium. The risk of delirium also is increased with the use of anticonvulsants and mood stabilizers (eg, lithium) because these agents increase the seizure threshold. The potential for drug interactions may affect the choice of the anesthetic agents. Also, SSRIs and serotonin-norepinephrine reuptake inhibitors can increase the duration of induced seizures.¹⁸

Vagus nerve stimulation

VNS, in which an implanted device stimulates the vagus nerve with electrical impulses, initially was used to reduce the frequency of seizures in patients with epilepsy and treatment-resistant partial onset seizures.¹⁹ VNS was FDA-approved for TRD in July 2005.²⁰ One VNS system, the NCP System, consists of an implantable, multi-programmable generator, known as a pulse generator, that is subcutaneously placed in the anterior chest wall during an outpatient surgical procedure. Separate bipolar nerve-stimulating electrodes are surgically wrapped around the left cervical vagus nerve, and then connected to the generator via a tunneling procedure. A telemetric wand is subsequently linked to a portable computer and used to adjust stimulation parameters.^21,22

Support for using VNS for TRD came from a multitude of investigations and observations. Harden et al²³ and Elger et al²⁴ prospectively evaluated epileptic patients with standard depression symptom severity rating scales. They found that VNS was associated with statistically significant improvements in mood that were not related to reductions in seizures.^23,24

The mechanism of action of VNS is not clear. Earlier researchers had found evidence that VNS affected brain regions associated with norepinephrine²⁵ and serotonin systems²⁶; both of these neuro­transmitters have been implicated in the pathophysiology of depression. Positron emission tomography studies conducted during VNS treatment of epilepsy showed metabolic changes in cortical and subcortical areas of the brain, including the amygdala, hippocampus, and cingulate gyrus, all structures implicated in the pathophysiology of mood disorders.²⁷

Most studies conducted to evaluate the efficacy of VNS have been observational, looking at depression ratings before and after treatment with VNS. The short-term studies measured the difference in depression rating scales at baseline and after 10 weeks of treatment. In most of these studies, treatment with VNS resulted in a statistically significant drop in depression rating scales scores, such as on the Hamilton Depression Rating Scale (HAM-D). Based on the study design and number of study participants, response rates have varied from 13%²⁸ to 40%,²⁹ whereas remission rates have varied from 15.3%³⁰ to 28%.³¹ More than one-half of the reduction in symptoms occurred after 6 weeks of treatment.³⁰ In longer-term follow-up studies, the antidepressant effect generally was sustained over time. Response rates remained essentially unchanged, but the remission rates increased to approximately 29%.²⁹ Only 1 RCT has compared patients with controls; it found no significant differences in the response or remission rates between active VNS and sham VNS.³² In this study, all patients had VNS implanted, but in the control group, the VNS was never turned on.³² In a meta-analysis conducted by Martin and Martín-Sánchez,³³ 31.8% (95% confidence interval [CI], 23.2% to 41.8%; P < .001) of patients treated with VNS had a significant reduction in HAM-D scores. The response rate in patients with TRD ranged from 27% to 37% and the remission rate was approximately 13%. In studies that followed patients over longer periods, both the remission and response rates increased over time.³⁴

Recent evidence suggests that the effectiveness of VNS may depend on the stimulation level. A multi-center double-blind study randomized patients to receive either a low (0.25 mA current, 130-millisecond pulse width), medium (0.5e1.0 mA, 250 millisecond), or high (1.25e1.5 mA, 250 millisecond) dose of VNS.³⁵ Although all dose levels were associated with improvement in symptoms, a statistically significant durability in response was associated with the medium- and high-dose treatments.

Adverse effects. VNS has no major adverse effects on cognitive functioning, and some studies have found improvement in executive functioning that corresponded to improvement in depressive symptoms.³⁰ VNS also may result in improved sleep patterns as evidenced by EEG changes.³¹ The most commonly reported adverse effects include pain in the incision site, hoarseness of voice, throat pain, and neck pain.³⁶

rTMS is a noninvasive technique that uses high-intensity magnetic impulses to stimulate cortical neurons. A magnetic field is produced when current passes through a coil, which in turn causes electrical stimulation in the cortical neurons that results in transient changes in the excitability of the cortical neurons.³⁷ Although many stimulation parameters exist for TMS, high-frequency stimulation to the left prefrontal cortex (HFL-rTMS) and low-frequency stimulation to the right prefrontal cortex (LFR-rTMS) have been shown most efficacious for treating depression.³⁸ High-frequency (5 Hz to 20 Hz) stimulation using rTMS increases cortical neuron excitability, whereas low-frequency (approximately 1 Hz) is associated with reduced cortical neuron excitability.³⁹ The choice of targeting the DLPFC stems from a large body of functional neuroimaging studies that have shown reduction in activity/blood flow in the left DLPFC and abnormal activity/blood flow in the right DLPFC.⁴⁰

There is no dearth of RCTs evaluating the efficacy of rTMS vs sham rTMS (where no magnetic stimulation was provided). In a meta-analysis of 8 RCTs, low-frequency rTMS applied to the right DLPFC was associated with a remission rate of approximately 34.6%, compared with a 9.7% remission rate with sham rTMS.⁴¹ A response rate of approximately 38.2% was observed with HFL-rTMS, compared with a response rate of 15.1% for sham rTMS.⁴¹

Gaynes et al⁴² conducted a meta-analysis to determine the efficacy of rTMS in TRD. They found that for patients with TRD, rTMs produced a response rate of 29% and a remission rate of 30%. In long-term, naturalistic, observational studies, the response rates and remission rates were much higher (58% and 37.1%, respectively).⁴³ Over a 1-year follow-up, almost two-thirds of patients continued to meet criteria for response to treatment.⁴⁴ Trials comparing HFL-rTMS and LFR-rTMS have found no significant differences in efficacy.⁴⁵

Advanced age, psychotic symptoms, and a longer duration of the current depressive episode predict poor response to rTMS. Also, imaging studies have shown that a lower metabolism in cerebellar, temporal, anterior cingulate, and occipital parts of the brain correlate with better response to HFL-rTMS.^46,47

Adverse effects. The major adverse effect associated with rTMS is the risk of inducing seizures, which is more commonly associated with high-frequency rTMS. Other common adverse effects include headache, facial muscle twitching, and tinnitus.³⁷

Deep brain stimulation

DBS is an invasive stereotactic surgical procedure. It involves unilateral or bilateral placement of electrodes at neuroanatomical locations to deliver continuous stimulation from a subcutaneously implanted pulse generator.⁴⁸ In the past, destructive surgical procedures were used to treat intractable depression. Surgeries such as anterior cingulotomy, anterior capsulotomy, subcaudate tractotomy, and limbic leucotomy have been shown to effectively reduce depressive symptoms.⁴⁹ The advantages of DBS over destructive procedures include the fact that DBS is reversible and that the stimulation levels can easily be adjusted, and the treatment can easily be stopped or restarted.

There is no consensus on the optimal anatomic locations for the electrode implantation in DBS. Electrodes have been implanted in the subcallosal cingulate gyrus, inferior thalamic peduncle, ventral capsule/ventral striatum, superolateral branch of the medial forebrain bundle (MFB), and nucleus accumbens.

The choice of anatomic locations stems from the large body of neuroimaging literature characterizing functional changes associated with acute depression and response to treatment. The electrode placement targets “nodes” that form an integral part of the affected neural circuits that are responsible for regulating depressive symptoms.⁵⁰ Increased metabolic activity and blood flow to the subgenual cingulate gyrus and reduction in the blood flow to the DLPFC and the striatum have been associated with active depressed states. Response to antidepressant treatment has been associated with reversal of these findings.⁵¹ Functional magnetic resonance imaging studies have consistently shown increased activity in the amygdala in response to negative stimuli among patients with depression.

Regardless of the site of electrode placement, studies have reported symptomatic improvement among patients with depression who are treated with DBS. In 2 case reports, the electrode was implanted in the inferior thalamic peduncle.^52,53 Each study had 1 participant, and each patient remitted.^52,53

Placement of the electrodes in the nucleus accumbens resulted in a response rate of 45% in 1 study,⁵⁴ whereas in a different study, all patients reported improvement in anhedonia.⁵⁵ A response rate of 71% and a remission rate of 35% were observed in a study in which the electrode was implanted in the ventral capsule/ventral striatum area.⁵⁶

Berlim et al⁵⁷ published a systematic review and exploratory meta-analysis of studies in which the electrode had been implanted in the subgenual cingulate cortex. At 12 months, the response rate was 39.9% (95% CI, 28.4% to 52.8%), and 26.3% (95% CI, 13% to 45.9%) of patients achieved remission. The most significant drop in depression scores was observed 3 to 6 months after the surgery. No significant change in scores was observed between 6 to 12 months after surgery.⁵⁷

The MFB, specifically the superolateral branch, is emerging as an exciting new target for electrode placement in DBS. Schlaepfer et al⁵⁸ studied the effects of electrodes implanted bilaterally in the superolateral branch of the MFB. They observed an almost 50% reduction in symptoms by Day 7, and at the last follow-up visit (12 to 33 weeks) 4 of the 6 patients had achieved remission.⁵⁸ In a recent systematic review, Gálvez et al⁵⁹ found most studies had high response/remission rates without any significant adverse effects. In a recent study of DBS targeting the MFB, 3 of 4 patients had a >50% reduction in Montgomery-Åsberg Depression Rating Scale scores at the end of first week. Although 1 patient withdrew, 2 of the other 3 patients continued to report a >80% reduction in depressive symptoms, even at Week 26.⁶⁰

Accurate localization of target areas (white matter tracts) and subsequent electrode placement might be an important factor governing treatment response. Riva-Posse et al⁶¹ found that clinical response was seen when the electrodes stimulated 3 specific white matter bundles. Interestingly, nonresponders were converted to responders simply by changing the position of the electrodes to include these white matter tracts.⁶¹

Adverse effects. The most common adverse effects noted during studies of DBS include pain at the site of implantation and wound infection. Other adverse effects include lead fracture, transient dysphagia, and other hardware-related problems.⁴⁹

In the absence of head-to-head trials, it is difficult to establish a hierarchal algorithm for use of the 4 neuromodulatory treatments discussed in the article. If we were to base our decision solely on the current literature, ECT by far has the most evidence and highest remission rates.¹¹ We can reduce the risk of cognitive deficits by using twice-weekly instead of thrice-weekly ECT, or by using unilateral instead of bilateral ECT.¹² Another strategy for reducing adverse effects associated with long-term maintenance ECT is by using it in combination with VNS. ECT and VNS can be used safely concomitantly; ECT can be used to treat acutely worsening depression, and VNS for maintaining the antidepressant effect.⁶²

Aside from ECT, rTMS is the only other treatment that has evidence from RCTs. Although the remission rates are not as high as ECT, its preferable adverse effects profile, noninvasive nature, and comparative low cost (compared with surgical procedures) make it a favorable choice. The Canadian Network for Mood and Anxiety Treatment guidelines suggest rTMS as the first-line treatment for patients who do not respond to pharmacologic treatments.⁶³ ECT can be considered second-line treatment unless the patient has acute suicidal ideation, catatonia, psychotic features, greater treatment resistance, or physical deterioration, in which case ECT should be tried before TMS.⁶³

Among the invasive options, VNS has more evidence and is FDA-approved for TRD. However, DBS has shown great promise in early studies, with remission rates as high as 35%.⁵⁶ DBS has the advantage of being reversible, and the amount of stimulation can be adjusted easily. Despite early promise, more research is needed before DBS can be widely used in clinical settings.

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a label variation for Neulasta® (pegfilgrastim) to include the Neulasta® Onpro® Kit.

The Neulasta Onpro Kit is an on-body injector (OBI) delivery system for Neulasta, which is approved in the European Union to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukemia and myelodysplastic syndromes).

The Neulasta Onpro Kit includes a specifically designed Neulasta pre-filled syringe along with a single-use OBI. The small, lightweight OBI is applied to a patient’s skin on the same day of chemotherapy.

The OBI is intended to facilitate timed delivery of the correct dose of Neulasta and eliminate the need for patients to return to a healthcare setting the day after they receive chemotherapy.

The CHMP’s opinion on the Neulasta Onpro Kit will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, the centralized marketing authorization of Neulasta will be updated to include information on the Neulasta Onpro Kit in the drug’s label.

This change will be valid throughout the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions about Neulasta’s label on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a label variation for Neulasta® (pegfilgrastim) to include the Neulasta® Onpro® Kit.

The Neulasta Onpro Kit is an on-body injector (OBI) delivery system for Neulasta, which is approved in the European Union to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukemia and myelodysplastic syndromes).

The Neulasta Onpro Kit includes a specifically designed Neulasta pre-filled syringe along with a single-use OBI. The small, lightweight OBI is applied to a patient’s skin on the same day of chemotherapy.

The OBI is intended to facilitate timed delivery of the correct dose of Neulasta and eliminate the need for patients to return to a healthcare setting the day after they receive chemotherapy.

The CHMP’s opinion on the Neulasta Onpro Kit will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, the centralized marketing authorization of Neulasta will be updated to include information on the Neulasta Onpro Kit in the drug’s label.

This change will be valid throughout the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions about Neulasta’s label on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

Photo from Amgen

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a label variation for Neulasta® (pegfilgrastim) to include the Neulasta® Onpro® Kit.

The Neulasta Onpro Kit is an on-body injector (OBI) delivery system for Neulasta, which is approved in the European Union to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukemia and myelodysplastic syndromes).

The Neulasta Onpro Kit includes a specifically designed Neulasta pre-filled syringe along with a single-use OBI. The small, lightweight OBI is applied to a patient’s skin on the same day of chemotherapy.

The OBI is intended to facilitate timed delivery of the correct dose of Neulasta and eliminate the need for patients to return to a healthcare setting the day after they receive chemotherapy.

The CHMP’s opinion on the Neulasta Onpro Kit will be reviewed by the European Commission (EC).

If the EC agrees with the CHMP, the centralized marketing authorization of Neulasta will be updated to include information on the Neulasta Onpro Kit in the drug’s label.

This change will be valid throughout the European Union. Norway, Iceland, and Liechtenstein will make corresponding decisions about Neulasta’s label on the basis of the EC’s decision.

The EC typically makes a decision within 67 days of the CHMP’s recommendation.

In recent years, the pace of the development of novel new treatments for brain disorders in both psychiatry and neurology, including psychiatric disorders, has been the subject of much worry and hand-wringing.¹

Some major pharmaceutical companies have stopped research programs in neuropsychiatry to focus on other, “easier” therapeutic areas where they think the biology is better understood and therefore drug development is more feasible.

However, I am now more optimistic than I have been in many years that we are on the verge of a promising era of pharmacotherapy that will usher in far better prevention, diagnosis, and management of neuropsychiatric disorders, and a better outcome for our patients. Why the optimism? There is a series of converging trends that justify it.

Funding for basic neuroscience research. Governments all over the world have woken up to the fact that brain disorders will account for the largest economic impact unless new treatments are developed. This has spurred multiple initiatives to better understand the underlying neurobiologic mechanisms of the brain in health and disease.²

Renewed enthusiasm for brain disorders from small pharmaceutical and mid-size biotechnology companies. While some of the larger pharmaceutical companies have withdrawn from pursuing new treatments for psychiatric disorders due to the need to satisfy “shareholders,” small and nimble biotechnology companies have stepped up, seeing an opportunity in a field that is not overcrowded and still has an extensive unmet need. These companies are developing truly novel treatments and approaches that can differentiate from current treatments. These include:

• rapid-acting antidepressants
• targeting specific symptom domains of psychiatric disorders, such as cognition, apathy, or anhedonia, that currently have no adequate or effective treatment
• novel therapeutic targets in a range of indications
• nonpharmacologic approaches.

Leading companies in this space include Allergan and Blackthorn Therapeutics. These companies and others have publicly discussed their commitment to developing new treatments for psychiatric disorders.

But large pharmaceutical companies should not be discounted. Examples of advances by larger companies include the recent FDA “breakthrough designation” for the development of balovaptan by Roche, a medication with the potential to improve “core social interaction and communication” in patients with autism, and the work Johnson & Johnson is conducting with S-ketamine for depression and acutely suicidal patients.

New scientific breakthroughs in areas such as synthetic biology, gene editing, nanotechnology, pluripotent cells, understanding the impact of the microbiome, and many other fields will dramatically accelerate the pace of scientific progress, allowing new treatment approaches not previously imagined.

New technologies. An array of new technologies—such as biosensors, artificial intelligence and machine learning, augmented and virtual reality, and other digital health tools—will impact every step of the “patient journey.” These will enable earlier detection and diagnosis, ongoing real-time assessment of symptoms, and more objective assessments, and they will facilitate the delivery of, and assessment of adherence to, treatments such as pharmacotherapy, neuro­modulation, video games, apps, or a combination of these modalities.

Until recently, the idea of a video game or augmented reality glasses being viewed as serious and validated treatment modalities would have been considered science fiction. New ways of assessing patients—including voice, typing, activity on smartphones, diurnal rhythm, etc.—have the potential to dramatically improve the information clinicians will have about patient functioning in the real world. Another area where new technologies may eventually have a huge impact is in facilitating the prediction of suicide attempts.³

New digital therapeutics companies. It is no coincidence that the digital therapeutics companies that have been making the news and obtaining FDA approvals, such as Proteus Digital Health, Pear Therapeutics, Akili, and Click Therapeutics, are all addressing brain disorders.

Patient empowerment. With these new tools, the patient can become a true partner in the therapeutic alliance more than ever before. Patients can have an active role in diagnosis and be active participants in many new treatment modalities. There will be many new ways for patients to share their data to improve their care and to advance the science of these tools. Utilizing blockchain protocols, patients will have more control over how and with whom their data is shared, and even be compensated for it.

This may all seem like a medical “brave new world,” and perhaps a long way away. However, I believe these changes are happening at an exponential rate. It is hard to believe that common technological tools such as Google Maps, Gmail, and the smartphone first became available only a few years ago. The merging of biology and technology will have profound effects, and will be recognized as the momentous scientific achievement of the early 21st century.

Unlike clunky technologies such as electronic medical records, which have in fact made the clinician–patient experience worse, I believe that the technologies I describe above will enhance and augment the clinician–patient relationship. As health care practitioners, we need to be open to new technologies and ways of assessing and treating our patients while making sure our clinical insights and experience inform the development of these new technologies.

Let’s buckle up. Life in psychiatry is going to get more interesting than ever!

In recent years, the pace of the development of novel new treatments for brain disorders in both psychiatry and neurology, including psychiatric disorders, has been the subject of much worry and hand-wringing.¹

Some major pharmaceutical companies have stopped research programs in neuropsychiatry to focus on other, “easier” therapeutic areas where they think the biology is better understood and therefore drug development is more feasible.

However, I am now more optimistic than I have been in many years that we are on the verge of a promising era of pharmacotherapy that will usher in far better prevention, diagnosis, and management of neuropsychiatric disorders, and a better outcome for our patients. Why the optimism? There is a series of converging trends that justify it.

Funding for basic neuroscience research. Governments all over the world have woken up to the fact that brain disorders will account for the largest economic impact unless new treatments are developed. This has spurred multiple initiatives to better understand the underlying neurobiologic mechanisms of the brain in health and disease.²

Renewed enthusiasm for brain disorders from small pharmaceutical and mid-size biotechnology companies. While some of the larger pharmaceutical companies have withdrawn from pursuing new treatments for psychiatric disorders due to the need to satisfy “shareholders,” small and nimble biotechnology companies have stepped up, seeing an opportunity in a field that is not overcrowded and still has an extensive unmet need. These companies are developing truly novel treatments and approaches that can differentiate from current treatments. These include:

• rapid-acting antidepressants
• targeting specific symptom domains of psychiatric disorders, such as cognition, apathy, or anhedonia, that currently have no adequate or effective treatment
• novel therapeutic targets in a range of indications
• nonpharmacologic approaches.

Leading companies in this space include Allergan and Blackthorn Therapeutics. These companies and others have publicly discussed their commitment to developing new treatments for psychiatric disorders.

But large pharmaceutical companies should not be discounted. Examples of advances by larger companies include the recent FDA “breakthrough designation” for the development of balovaptan by Roche, a medication with the potential to improve “core social interaction and communication” in patients with autism, and the work Johnson & Johnson is conducting with S-ketamine for depression and acutely suicidal patients.

New scientific breakthroughs in areas such as synthetic biology, gene editing, nanotechnology, pluripotent cells, understanding the impact of the microbiome, and many other fields will dramatically accelerate the pace of scientific progress, allowing new treatment approaches not previously imagined.

New technologies. An array of new technologies—such as biosensors, artificial intelligence and machine learning, augmented and virtual reality, and other digital health tools—will impact every step of the “patient journey.” These will enable earlier detection and diagnosis, ongoing real-time assessment of symptoms, and more objective assessments, and they will facilitate the delivery of, and assessment of adherence to, treatments such as pharmacotherapy, neuro­modulation, video games, apps, or a combination of these modalities.

Until recently, the idea of a video game or augmented reality glasses being viewed as serious and validated treatment modalities would have been considered science fiction. New ways of assessing patients—including voice, typing, activity on smartphones, diurnal rhythm, etc.—have the potential to dramatically improve the information clinicians will have about patient functioning in the real world. Another area where new technologies may eventually have a huge impact is in facilitating the prediction of suicide attempts.³

New digital therapeutics companies. It is no coincidence that the digital therapeutics companies that have been making the news and obtaining FDA approvals, such as Proteus Digital Health, Pear Therapeutics, Akili, and Click Therapeutics, are all addressing brain disorders.

Patient empowerment. With these new tools, the patient can become a true partner in the therapeutic alliance more than ever before. Patients can have an active role in diagnosis and be active participants in many new treatment modalities. There will be many new ways for patients to share their data to improve their care and to advance the science of these tools. Utilizing blockchain protocols, patients will have more control over how and with whom their data is shared, and even be compensated for it.

This may all seem like a medical “brave new world,” and perhaps a long way away. However, I believe these changes are happening at an exponential rate. It is hard to believe that common technological tools such as Google Maps, Gmail, and the smartphone first became available only a few years ago. The merging of biology and technology will have profound effects, and will be recognized as the momentous scientific achievement of the early 21st century.

Unlike clunky technologies such as electronic medical records, which have in fact made the clinician–patient experience worse, I believe that the technologies I describe above will enhance and augment the clinician–patient relationship. As health care practitioners, we need to be open to new technologies and ways of assessing and treating our patients while making sure our clinical insights and experience inform the development of these new technologies.

Let’s buckle up. Life in psychiatry is going to get more interesting than ever!

In recent years, the pace of the development of novel new treatments for brain disorders in both psychiatry and neurology, including psychiatric disorders, has been the subject of much worry and hand-wringing.¹

Some major pharmaceutical companies have stopped research programs in neuropsychiatry to focus on other, “easier” therapeutic areas where they think the biology is better understood and therefore drug development is more feasible.

However, I am now more optimistic than I have been in many years that we are on the verge of a promising era of pharmacotherapy that will usher in far better prevention, diagnosis, and management of neuropsychiatric disorders, and a better outcome for our patients. Why the optimism? There is a series of converging trends that justify it.

Funding for basic neuroscience research. Governments all over the world have woken up to the fact that brain disorders will account for the largest economic impact unless new treatments are developed. This has spurred multiple initiatives to better understand the underlying neurobiologic mechanisms of the brain in health and disease.²

Renewed enthusiasm for brain disorders from small pharmaceutical and mid-size biotechnology companies. While some of the larger pharmaceutical companies have withdrawn from pursuing new treatments for psychiatric disorders due to the need to satisfy “shareholders,” small and nimble biotechnology companies have stepped up, seeing an opportunity in a field that is not overcrowded and still has an extensive unmet need. These companies are developing truly novel treatments and approaches that can differentiate from current treatments. These include:

• rapid-acting antidepressants
• targeting specific symptom domains of psychiatric disorders, such as cognition, apathy, or anhedonia, that currently have no adequate or effective treatment
• novel therapeutic targets in a range of indications
• nonpharmacologic approaches.

Leading companies in this space include Allergan and Blackthorn Therapeutics. These companies and others have publicly discussed their commitment to developing new treatments for psychiatric disorders.

But large pharmaceutical companies should not be discounted. Examples of advances by larger companies include the recent FDA “breakthrough designation” for the development of balovaptan by Roche, a medication with the potential to improve “core social interaction and communication” in patients with autism, and the work Johnson & Johnson is conducting with S-ketamine for depression and acutely suicidal patients.

New scientific breakthroughs in areas such as synthetic biology, gene editing, nanotechnology, pluripotent cells, understanding the impact of the microbiome, and many other fields will dramatically accelerate the pace of scientific progress, allowing new treatment approaches not previously imagined.

New technologies. An array of new technologies—such as biosensors, artificial intelligence and machine learning, augmented and virtual reality, and other digital health tools—will impact every step of the “patient journey.” These will enable earlier detection and diagnosis, ongoing real-time assessment of symptoms, and more objective assessments, and they will facilitate the delivery of, and assessment of adherence to, treatments such as pharmacotherapy, neuro­modulation, video games, apps, or a combination of these modalities.

Until recently, the idea of a video game or augmented reality glasses being viewed as serious and validated treatment modalities would have been considered science fiction. New ways of assessing patients—including voice, typing, activity on smartphones, diurnal rhythm, etc.—have the potential to dramatically improve the information clinicians will have about patient functioning in the real world. Another area where new technologies may eventually have a huge impact is in facilitating the prediction of suicide attempts.³

New digital therapeutics companies. It is no coincidence that the digital therapeutics companies that have been making the news and obtaining FDA approvals, such as Proteus Digital Health, Pear Therapeutics, Akili, and Click Therapeutics, are all addressing brain disorders.

Patient empowerment. With these new tools, the patient can become a true partner in the therapeutic alliance more than ever before. Patients can have an active role in diagnosis and be active participants in many new treatment modalities. There will be many new ways for patients to share their data to improve their care and to advance the science of these tools. Utilizing blockchain protocols, patients will have more control over how and with whom their data is shared, and even be compensated for it.

This may all seem like a medical “brave new world,” and perhaps a long way away. However, I believe these changes are happening at an exponential rate. It is hard to believe that common technological tools such as Google Maps, Gmail, and the smartphone first became available only a few years ago. The merging of biology and technology will have profound effects, and will be recognized as the momentous scientific achievement of the early 21st century.

Unlike clunky technologies such as electronic medical records, which have in fact made the clinician–patient experience worse, I believe that the technologies I describe above will enhance and augment the clinician–patient relationship. As health care practitioners, we need to be open to new technologies and ways of assessing and treating our patients while making sure our clinical insights and experience inform the development of these new technologies.

Let’s buckle up. Life in psychiatry is going to get more interesting than ever!

“It is beyond a doubt that all our knowledge begins with experience.”
- Immanuel Kant

Medicine, a highly experiential profession, is constantly evolving. The consistency of change and the psychiatrist’s inherent wonder offers a paradoxical sense of comfort and conundrum.

As students, we look to our predecessors, associations, and peers to master concepts both concrete and abstract. And once we achieve competence at understanding mechanisms, applying biopsychosocial formulations, and effectively teaching what we’ve learned—everything changes!

We journey through a new era of medicine together. With burgeoning technology, intense politics, and confounding social media, we are undergoing new applications, hurdles to health care, and personal exposure to extremes that have never been experienced before. The landscape of psychiatric practice is changing. Its transformation inherently challenges our existing practices and standards.

It wasn’t too long ago that classroom fodder included how to deal with seeing your patient at a cocktail party. Contemporary discussions are more likely to address the patient who follows you on Twitter (and whom you follow back). Long ago are the days of educating students through a didactic model. Learning now occurs in collaborative group settings with a focus on the practical and hands-on experience. Budding psychiatrists are interested these days in talking about setting up their own apps, establishing a start-up company for health care, working on policy reform, and innovating new approaches to achieve social justice.

A history of challenge and change

Developing variables and expectations in this Millennial Age makes it an exciting time for psychiatrists to explore, adapt, and lead into the future. Fortunately, the field has had ample practice with challenge and changes. Social constructs of how individuals with mental illness were treated altered with William Battie, an English physician whose 1758 Treatise on Madness called for treatments to be utilized on rich and poor mental patients alike in asylums.¹ Remember the days of chaining patients to bedposts on psychiatric wards? Of course not! Such archaic practices thankfully disappeared, due in large part to French physician Philippe Pinel. Patient care has evolved to encompass empathy, rights, and dignity.²

German physician Johann Christian Reil, who coined the term “psychiatry” more than 200 years ago, asserted that mental illness should be treated by the most highly qualified physicians.³ Such thinking seems obvious in 2018, but before Reil, the mental and physical states were seen as unrelated.

Modern psychiatry has certainly come a long way.⁴ We recognize mental health as being essential to overall health. Medications have evolved beyond lithium, chlorpromazine, and fluoxetine. We now have quarterly injectable antipsychotics and pills that patients can swallow and actually be monitored by their clinicians!⁴

The American Psychiatric Association (APA) has published multiple iterations of the Diagnostic and Statistical Manual of Mental Disorders since its inception in 1968.⁵ And with those revisions have come changes that most contemporary colleagues could only describe as self-evident—such as the declassification of homosexuality as a mental disorder in 1973.

Despite these advances and the advent of the Mental Health Parity Act of 2008, experience has shown us that some things have seen little progress. Reil, who saw a nexus between mental and physical health, launched an anti-stigma campaign more than 200 years ago. This begs a question to colleagues: How far have we come? Or better yet, capitalizing on our knowledge, experience, and hopes: What else can we do?

The essential interaction between mental, chemical, and physical domains has given rise to psychiatry and its many subspecialties. Among them is forensic psychiatry, which deals with the overlap of mental health and legal matters.⁶

While often recognized for its relation to criminology, forensic psychiatry encompasses the entirety of legal mental health matters.⁷ These are things that the daily practitioner faces on a routine basis.

My mentor, Dr. Douglas Mossman, author of Current Psychiatry’s Malpractice Rx department, passed away on January 4, 2018. Dr. Mossman emphasized to his trainees that above all else, understanding forensic matters simply makes one a better psychiatrist. Legal matters and psychiatry go hand-in-hand. Involuntary hospitalization, Health Insurance Portability and Accountability Act violations, licensure boards, telepsychiatry, guardianship, and informed consent are just a few areas that psychiatrists interface with routinely.

A new department for a new era

The world is changing very rapidly, and we face new dilemmas in the midst of trying to uphold our duties to patients and the profession. There are emerging domains that psychiatrists will experience for the first time—leaving us with more questions than direction. And that is the impetus for this new department, Psychiatry 2.0.

The ever-evolving Internet opens doors for psychiatrists to access and educate a larger audience. It also provides a tool for psychiatrists to keep a web-based presence, something essential for competitive business practices to stay relevant. We are languishing in a political climate that challenges our sense of duty to the public, which often is in contrast with the ethical principles of our association. Technology also poses problems, whether it’s tracking our patients through the pills they ingest, following them on an app, or relying on data from wearable devices in lieu of a patient’s report. All of this suggests a potential for progress as well as problems.

The goal of Psychiatry 2.0 is to experience new challenges together. As Department Editor, I will cover an array of cutting-edge and controversial topics. Continuing with Dr. Mossman’s teachings—that forensic understanding enhances the clinical practice—this department will routinely combine evidence-based information with legal concepts.

Each article in Psychiatry 2.0 will be divided into 3 parts, focusing on a clinician’s dilemma, a duty, and a discussion. The dilemma will be relatable to the clinician in everyday practice. A practical and evidence-based approach will be taken to expound upon our duty as physicians. And finally, there will be discussion about where the field is going, and how it will likely change. In its quarterly publication, Psychiatry 2.0 will explore a diverse range of topics, including technology, social media, stigma, social justice, and politics.

In my role as Department Editor, I find myself already reflecting on the experience, wisdom, compassion, encouragement, and legacy of Dr. Mossman. A distinguished psychiatrist, gifted musician, and inspiring mentor and academician, Dr. Mossman embodied knowledge, creativity, and devotion.

Among Dr. Mossman’s many accolades, including more than 180 authored publications, he was recipient of the Guttmacher Award (2008, the APA) and Golden Apple (2017, the American Academy of Psychiatry and Law). Dr. Mossman was further known to many as a mentor and friend. He was generous with his experiences as a highly accomplished physician and thoughtful in his teachings and publications, leaving an enduring legacy.

Remembering Dr. Mossman’s sage voice and articulate writings will be essential to moving forward in this modern age of psychiatry, as we experience new dilemmas and opportunities.

“It is beyond a doubt that all our knowledge begins with experience.”
- Immanuel Kant

Medicine, a highly experiential profession, is constantly evolving. The consistency of change and the psychiatrist’s inherent wonder offers a paradoxical sense of comfort and conundrum.

As students, we look to our predecessors, associations, and peers to master concepts both concrete and abstract. And once we achieve competence at understanding mechanisms, applying biopsychosocial formulations, and effectively teaching what we’ve learned—everything changes!

We journey through a new era of medicine together. With burgeoning technology, intense politics, and confounding social media, we are undergoing new applications, hurdles to health care, and personal exposure to extremes that have never been experienced before. The landscape of psychiatric practice is changing. Its transformation inherently challenges our existing practices and standards.

It wasn’t too long ago that classroom fodder included how to deal with seeing your patient at a cocktail party. Contemporary discussions are more likely to address the patient who follows you on Twitter (and whom you follow back). Long ago are the days of educating students through a didactic model. Learning now occurs in collaborative group settings with a focus on the practical and hands-on experience. Budding psychiatrists are interested these days in talking about setting up their own apps, establishing a start-up company for health care, working on policy reform, and innovating new approaches to achieve social justice.

A history of challenge and change

Developing variables and expectations in this Millennial Age makes it an exciting time for psychiatrists to explore, adapt, and lead into the future. Fortunately, the field has had ample practice with challenge and changes. Social constructs of how individuals with mental illness were treated altered with William Battie, an English physician whose 1758 Treatise on Madness called for treatments to be utilized on rich and poor mental patients alike in asylums.¹ Remember the days of chaining patients to bedposts on psychiatric wards? Of course not! Such archaic practices thankfully disappeared, due in large part to French physician Philippe Pinel. Patient care has evolved to encompass empathy, rights, and dignity.²

German physician Johann Christian Reil, who coined the term “psychiatry” more than 200 years ago, asserted that mental illness should be treated by the most highly qualified physicians.³ Such thinking seems obvious in 2018, but before Reil, the mental and physical states were seen as unrelated.

Modern psychiatry has certainly come a long way.⁴ We recognize mental health as being essential to overall health. Medications have evolved beyond lithium, chlorpromazine, and fluoxetine. We now have quarterly injectable antipsychotics and pills that patients can swallow and actually be monitored by their clinicians!⁴

The American Psychiatric Association (APA) has published multiple iterations of the Diagnostic and Statistical Manual of Mental Disorders since its inception in 1968.⁵ And with those revisions have come changes that most contemporary colleagues could only describe as self-evident—such as the declassification of homosexuality as a mental disorder in 1973.

Despite these advances and the advent of the Mental Health Parity Act of 2008, experience has shown us that some things have seen little progress. Reil, who saw a nexus between mental and physical health, launched an anti-stigma campaign more than 200 years ago. This begs a question to colleagues: How far have we come? Or better yet, capitalizing on our knowledge, experience, and hopes: What else can we do?

The essential interaction between mental, chemical, and physical domains has given rise to psychiatry and its many subspecialties. Among them is forensic psychiatry, which deals with the overlap of mental health and legal matters.⁶

While often recognized for its relation to criminology, forensic psychiatry encompasses the entirety of legal mental health matters.⁷ These are things that the daily practitioner faces on a routine basis.

My mentor, Dr. Douglas Mossman, author of Current Psychiatry’s Malpractice Rx department, passed away on January 4, 2018. Dr. Mossman emphasized to his trainees that above all else, understanding forensic matters simply makes one a better psychiatrist. Legal matters and psychiatry go hand-in-hand. Involuntary hospitalization, Health Insurance Portability and Accountability Act violations, licensure boards, telepsychiatry, guardianship, and informed consent are just a few areas that psychiatrists interface with routinely.

A new department for a new era

The world is changing very rapidly, and we face new dilemmas in the midst of trying to uphold our duties to patients and the profession. There are emerging domains that psychiatrists will experience for the first time—leaving us with more questions than direction. And that is the impetus for this new department, Psychiatry 2.0.

The ever-evolving Internet opens doors for psychiatrists to access and educate a larger audience. It also provides a tool for psychiatrists to keep a web-based presence, something essential for competitive business practices to stay relevant. We are languishing in a political climate that challenges our sense of duty to the public, which often is in contrast with the ethical principles of our association. Technology also poses problems, whether it’s tracking our patients through the pills they ingest, following them on an app, or relying on data from wearable devices in lieu of a patient’s report. All of this suggests a potential for progress as well as problems.

The goal of Psychiatry 2.0 is to experience new challenges together. As Department Editor, I will cover an array of cutting-edge and controversial topics. Continuing with Dr. Mossman’s teachings—that forensic understanding enhances the clinical practice—this department will routinely combine evidence-based information with legal concepts.

Each article in Psychiatry 2.0 will be divided into 3 parts, focusing on a clinician’s dilemma, a duty, and a discussion. The dilemma will be relatable to the clinician in everyday practice. A practical and evidence-based approach will be taken to expound upon our duty as physicians. And finally, there will be discussion about where the field is going, and how it will likely change. In its quarterly publication, Psychiatry 2.0 will explore a diverse range of topics, including technology, social media, stigma, social justice, and politics.

In my role as Department Editor, I find myself already reflecting on the experience, wisdom, compassion, encouragement, and legacy of Dr. Mossman. A distinguished psychiatrist, gifted musician, and inspiring mentor and academician, Dr. Mossman embodied knowledge, creativity, and devotion.

Among Dr. Mossman’s many accolades, including more than 180 authored publications, he was recipient of the Guttmacher Award (2008, the APA) and Golden Apple (2017, the American Academy of Psychiatry and Law). Dr. Mossman was further known to many as a mentor and friend. He was generous with his experiences as a highly accomplished physician and thoughtful in his teachings and publications, leaving an enduring legacy.

Remembering Dr. Mossman’s sage voice and articulate writings will be essential to moving forward in this modern age of psychiatry, as we experience new dilemmas and opportunities.

“It is beyond a doubt that all our knowledge begins with experience.”
- Immanuel Kant

Medicine, a highly experiential profession, is constantly evolving. The consistency of change and the psychiatrist’s inherent wonder offers a paradoxical sense of comfort and conundrum.

As students, we look to our predecessors, associations, and peers to master concepts both concrete and abstract. And once we achieve competence at understanding mechanisms, applying biopsychosocial formulations, and effectively teaching what we’ve learned—everything changes!

We journey through a new era of medicine together. With burgeoning technology, intense politics, and confounding social media, we are undergoing new applications, hurdles to health care, and personal exposure to extremes that have never been experienced before. The landscape of psychiatric practice is changing. Its transformation inherently challenges our existing practices and standards.

It wasn’t too long ago that classroom fodder included how to deal with seeing your patient at a cocktail party. Contemporary discussions are more likely to address the patient who follows you on Twitter (and whom you follow back). Long ago are the days of educating students through a didactic model. Learning now occurs in collaborative group settings with a focus on the practical and hands-on experience. Budding psychiatrists are interested these days in talking about setting up their own apps, establishing a start-up company for health care, working on policy reform, and innovating new approaches to achieve social justice.

A history of challenge and change

Developing variables and expectations in this Millennial Age makes it an exciting time for psychiatrists to explore, adapt, and lead into the future. Fortunately, the field has had ample practice with challenge and changes. Social constructs of how individuals with mental illness were treated altered with William Battie, an English physician whose 1758 Treatise on Madness called for treatments to be utilized on rich and poor mental patients alike in asylums.¹ Remember the days of chaining patients to bedposts on psychiatric wards? Of course not! Such archaic practices thankfully disappeared, due in large part to French physician Philippe Pinel. Patient care has evolved to encompass empathy, rights, and dignity.²

German physician Johann Christian Reil, who coined the term “psychiatry” more than 200 years ago, asserted that mental illness should be treated by the most highly qualified physicians.³ Such thinking seems obvious in 2018, but before Reil, the mental and physical states were seen as unrelated.

Modern psychiatry has certainly come a long way.⁴ We recognize mental health as being essential to overall health. Medications have evolved beyond lithium, chlorpromazine, and fluoxetine. We now have quarterly injectable antipsychotics and pills that patients can swallow and actually be monitored by their clinicians!⁴

The American Psychiatric Association (APA) has published multiple iterations of the Diagnostic and Statistical Manual of Mental Disorders since its inception in 1968.⁵ And with those revisions have come changes that most contemporary colleagues could only describe as self-evident—such as the declassification of homosexuality as a mental disorder in 1973.

Despite these advances and the advent of the Mental Health Parity Act of 2008, experience has shown us that some things have seen little progress. Reil, who saw a nexus between mental and physical health, launched an anti-stigma campaign more than 200 years ago. This begs a question to colleagues: How far have we come? Or better yet, capitalizing on our knowledge, experience, and hopes: What else can we do?

The essential interaction between mental, chemical, and physical domains has given rise to psychiatry and its many subspecialties. Among them is forensic psychiatry, which deals with the overlap of mental health and legal matters.⁶

While often recognized for its relation to criminology, forensic psychiatry encompasses the entirety of legal mental health matters.⁷ These are things that the daily practitioner faces on a routine basis.

My mentor, Dr. Douglas Mossman, author of Current Psychiatry’s Malpractice Rx department, passed away on January 4, 2018. Dr. Mossman emphasized to his trainees that above all else, understanding forensic matters simply makes one a better psychiatrist. Legal matters and psychiatry go hand-in-hand. Involuntary hospitalization, Health Insurance Portability and Accountability Act violations, licensure boards, telepsychiatry, guardianship, and informed consent are just a few areas that psychiatrists interface with routinely.

A new department for a new era

The world is changing very rapidly, and we face new dilemmas in the midst of trying to uphold our duties to patients and the profession. There are emerging domains that psychiatrists will experience for the first time—leaving us with more questions than direction. And that is the impetus for this new department, Psychiatry 2.0.

The ever-evolving Internet opens doors for psychiatrists to access and educate a larger audience. It also provides a tool for psychiatrists to keep a web-based presence, something essential for competitive business practices to stay relevant. We are languishing in a political climate that challenges our sense of duty to the public, which often is in contrast with the ethical principles of our association. Technology also poses problems, whether it’s tracking our patients through the pills they ingest, following them on an app, or relying on data from wearable devices in lieu of a patient’s report. All of this suggests a potential for progress as well as problems.

The goal of Psychiatry 2.0 is to experience new challenges together. As Department Editor, I will cover an array of cutting-edge and controversial topics. Continuing with Dr. Mossman’s teachings—that forensic understanding enhances the clinical practice—this department will routinely combine evidence-based information with legal concepts.

Each article in Psychiatry 2.0 will be divided into 3 parts, focusing on a clinician’s dilemma, a duty, and a discussion. The dilemma will be relatable to the clinician in everyday practice. A practical and evidence-based approach will be taken to expound upon our duty as physicians. And finally, there will be discussion about where the field is going, and how it will likely change. In its quarterly publication, Psychiatry 2.0 will explore a diverse range of topics, including technology, social media, stigma, social justice, and politics.

In my role as Department Editor, I find myself already reflecting on the experience, wisdom, compassion, encouragement, and legacy of Dr. Mossman. A distinguished psychiatrist, gifted musician, and inspiring mentor and academician, Dr. Mossman embodied knowledge, creativity, and devotion.

Among Dr. Mossman’s many accolades, including more than 180 authored publications, he was recipient of the Guttmacher Award (2008, the APA) and Golden Apple (2017, the American Academy of Psychiatry and Law). Dr. Mossman was further known to many as a mentor and friend. He was generous with his experiences as a highly accomplished physician and thoughtful in his teachings and publications, leaving an enduring legacy.

Remembering Dr. Mossman’s sage voice and articulate writings will be essential to moving forward in this modern age of psychiatry, as we experience new dilemmas and opportunities.

Ms. E, age 23, presents to your office for a routine visit for management of bipolar I disorder and posttraumatic stress disorder with comorbid type 2 diabetes mellitus. She currently is taking risperidone, 3 mg/d, lamotrigine, 200 mg/d, metformin, 2,000 mg/d, medroxyprogesterone, 150 mg every 3 months, and prazosin, 8 mg/d. Her mood has been stabilized for the last 3 years with this medication regimen.

Ms. E has a history of self-discontinuing medication when adverse events occur. She has been hospitalized twice for psychosis and suicide attempts. Past psychotropic medications that have been discontinued due to adverse effects include ziprasidone (mild abnormal lip movement), olanzapine (ineffective and drowsy), valproic acid (tremor and abdominal discomfort), lithium (rash), and aripiprazole (increased fasting blood sugar and labile mood).

At her appointment today, Ms. E says she is concerned because she has been experiencing galactorrhea for the past 4 weeks. Her prolactin level is 14.4 ng/mL; a normal level for a woman who is not pregnant is <25 ng/mL. However, a repeat prolactin level is obtained, and is found to be elevated at 38 ng/mL.

Prolactin, a polypeptide hormone that is secreted from the pituitary gland, has many functions, including involvement in the synthesis and maintenance of breast milk production, in reproductive behavior, and in luteal function.^1,2 Hyperprolactinemia—an elevated prolactin level—is a common endocrinologic disorder of the hypothalamic–pituitary–axis.³ Children, adolescents, premenopausal women, and women in the perinatal period are more vulnerable to medication-induced hyperprolactinemia.⁴ If not asymptomatic, patients with hyperprolactinemia may experience amenorrhea, galactorrhea, hypogonadism, sexual dysfunction, or infertility.^1,4 Chronic hyperprolactinemia may increase the risk for long-term complications, such as decreased bone mineral density and osteoporosis, although available evidence has conflicting findings.¹

Hyperprolactinemia is diagnosed by a prolactin concentration above the upper reference range.³ Various hormones and neurotransmitters can impact inhibition or stimulation of prolactin release.⁵ For example, dopamine tonically inhibits prolactin release and synthesis, whereas estrogen stimulates prolactin secretion.^1,5 Prolactin also can be elevated under several physiologic and pathologic conditions, such as during stressful situations, meals, or sexual activity.^1,5 A prolactin level >250 ng/mL is usually indicative of a prolactinoma; however, some medications, such as strong D2 receptor antagonists (eg, risperidone, haloperidol), can cause significant elevation without evidence of prolactinoma.³ In the absence of a tumor, medications are often identified as the cause of hyperprolactinemia.³ According to the Endocrinology Society clinical practice guideline, medication-induced elevated prolactin levels are typically between 25 to 100 ng/mL.³

Medication-induced hyperprolactinemia

Antipsychotics, antidepressants, hormonal preparations, antihypertensives, and gastrointestinal agents have been associated with hyperprolactinemia (Table 1^1,3,5-11). These medication classes increase prolactin by decreasing dopamine, which facilitates disinhibition of prolactin synthesis and release, or increasing prolactin stimulating hormones, such as serotonin or estrogen.⁵

Antipsychotics are the most common medication-related cause of hyperprolactinemia.³ Typical antipsychotics are more likely to cause hyperprolactinemia than atypical antipsychotics; the incidence among patients taking typical antipsychotics is 40% to 90%.³ Atypical antipsychotics, except risperidone and paliperidone, are considered to cause less endocrinologic effects than typical antipsychotics through various mechanisms: serotonergic receptor antagonism, fast dissociation from D2 receptors, D2 receptor partial agonism, and preferential binding of D3 vs D2 receptors.^1,5 By having transient D2 receptor association, clozapine and quetiapine are considered to have less risk of hyperprolactinemia compared with other atypical antipsychotics.^1,5 Aripiprazole, brexpiprazole, and cariprazine are partial D2 receptor agonists, and cariprazine is the only agent that exhibits preferential binding to D3 receptors.^12,13 Based on limited data, brexpiprazole and cariprazine may have prolactin-sparing properties given their partial D2 receptor agonism.^12,13 However, one study found increased prolactin levels in some patients after treatment with brexpiprazole, 4 mg/d.¹⁴ Similarly, another study found that cariprazine could increase prolactin levels as much as 4.1 ng/mL, depending on the dose.¹⁵ Except for aripiprazole, brexpiprazole, cariprazine, and clozapine, all other atypical antipsychotics marketed in the United States have a standard warning in the package insert regarding prolactin elevations.^1,16,17

Because antidepressants are less well-studied as a cause of medication-induced hyperprolactinemia, drawing definitive conclusions regarding incidence rates is limited, but the incidence seems to be fairly low.^6,18 A French pharmacovigilance study found that of 182,836 spontaneous adverse drug events reported between 1985 and 2009, there were 159 reports of selective serotonin reuptake inhibitors (SSRIs) inducing hyper­prolactinemia.⁶ Fluoxetine and paroxetine represented about one-half of the cases; however, there were also cases associated with citalopram, escitalopram, sertraline, fluvoxamine, milnacipran, and venlafaxine. In comparison, there were only 11 reports of hyperprolactinemia associated with tricyclic antidepressants or monoamine oxidase inhibitors. Although patients were not always symptomatic, the most commonly reported symptoms were galactorrhea (55%), gynecomastia (29%), amenorrhea (11%), mastodynia (11%), and sexual disorders (4%).⁶ Another study of 5,920 patients treated with fluoxetine found mastodynia in 0.25%, gynecomastia in 0.08%, and galactorrhea in 0.07% of patients.¹⁸ Symptoms occurred in an extremely low percentage of patients, and the study is >20 years old.¹⁸

Mirtazapine and bupropion have been found to be prolactin-neutral.⁵ Bupropion also has been reported to decrease prolactin levels, potentially via its ability to block dopamine reuptake.¹⁹

Managing medication-induced hyperprolactinemia

Screening for and identifying clinically significant hyperprolactinemia is critical, because adverse effects of medications can lead to nonadherence and clinical decompensation.²⁰ Patients must be informed of potential symptoms of hyperprolactinemia, and clinicians should inquire about such symptoms at each visit. Routine monitoring of prolactin levels in asymptomatic patients is not necessary, because the Endocrine Society Clinical Practice Guideline does not recommend treating patients with asymptomatic medication-induced hyperprolactinemia.³

In patients who report hyperprolactinemia symptoms, clinicians should review the patient’s prescribed medications and past medical history (eg, chronic renal failure, hypothyroidism) for potential causes or exacerbations, and address these factors accordingly.³ Order a measurement of prolactin level. A patient with a prolactin level >100 ng/mL should be referred to Endocrinology to rule out prolactinoma.¹

If a patient’s prolactin level is between 25 and 100 ng/mL, review the patient’s medications (Table 1^1,3,5-11), because prolactin levels within this range usually signal a medication-induced cause.³ For patients with antipsychotic-induced hyperprolactinemia, there are several management strategies (Table 2^{1,3,4,9,16,17,21-27}):

• Watch and wait may be warranted when the patient is experiencing mild hyperprolactinemia symptoms.
• Discontinue. If the patient can be maintained without an antipsychotic, discontinuing the antipsychotic would be a first-line option.³
• Reduce the dose. Reducing the antipsychotic dose may be the preferred strategy for patients with moderate to severe hyperprolactinemia symptoms who responded to the antipsychotic and do not wish to start adjunctive therapy.⁴
• Switching to a prolactin-sparing antipsychotic may help normalize prolactin levels and may be preferred when the risk of relapse is low.³ Dopamine agonists can treat medication-induced hyperprolactinemia, but may worsen psychiatric symptoms.^28,29 Therefore, this may be the preferred strategy if the offending medication cannot be discontinued or switched, or if the patient has a comorbid prolactinoma.

Less data exist on managing hyperprolactinemia that is induced by a medication other than an antipsychotic; however, it seems reasonable that the same strategies could be implemented. Specifically, for SSRI–induced hyperprolactinemia, if clinically appropriate, switching to or adding an alternative antidepressant that may be prolactin-sparing, such as mirtazapine or bupropion, could be attempted.⁸ One study found that fluoxetine-induced galactorrhea ceased within 10 days of discontinuing the medication.³⁰

CASE CONTINUED

Because Ms. E has been on the same medication regimen for 3 years and recently developed galactorrhea, it seems unlikely that her hyperprolactinemia is medication-induced. However, a tumor-related cause is less likely because the prolactin level is <100 ng/mL. Based on the literature, the only possible medication-induced cause of her galactorrhea is risperidone. Ms. E agrees to a trial of adjunctive oral aripiprazole, 5 mg/d, with close monitoring of her type 2 diabetes mellitus. Because of the long elimination half-life of aripiprazole, 1 month is required to monitor for improvement in galactorrhea. Ms. E is advised to use breast pads as a nonpharmacologic strategy in the interim. After 1 month of treatment, Ms. E denies galactorrhea symptoms and no longer requires the use of breast pads.

Ms. E, age 23, presents to your office for a routine visit for management of bipolar I disorder and posttraumatic stress disorder with comorbid type 2 diabetes mellitus. She currently is taking risperidone, 3 mg/d, lamotrigine, 200 mg/d, metformin, 2,000 mg/d, medroxyprogesterone, 150 mg every 3 months, and prazosin, 8 mg/d. Her mood has been stabilized for the last 3 years with this medication regimen.

Ms. E has a history of self-discontinuing medication when adverse events occur. She has been hospitalized twice for psychosis and suicide attempts. Past psychotropic medications that have been discontinued due to adverse effects include ziprasidone (mild abnormal lip movement), olanzapine (ineffective and drowsy), valproic acid (tremor and abdominal discomfort), lithium (rash), and aripiprazole (increased fasting blood sugar and labile mood).

At her appointment today, Ms. E says she is concerned because she has been experiencing galactorrhea for the past 4 weeks. Her prolactin level is 14.4 ng/mL; a normal level for a woman who is not pregnant is <25 ng/mL. However, a repeat prolactin level is obtained, and is found to be elevated at 38 ng/mL.

Prolactin, a polypeptide hormone that is secreted from the pituitary gland, has many functions, including involvement in the synthesis and maintenance of breast milk production, in reproductive behavior, and in luteal function.^1,2 Hyperprolactinemia—an elevated prolactin level—is a common endocrinologic disorder of the hypothalamic–pituitary–axis.³ Children, adolescents, premenopausal women, and women in the perinatal period are more vulnerable to medication-induced hyperprolactinemia.⁴ If not asymptomatic, patients with hyperprolactinemia may experience amenorrhea, galactorrhea, hypogonadism, sexual dysfunction, or infertility.^1,4 Chronic hyperprolactinemia may increase the risk for long-term complications, such as decreased bone mineral density and osteoporosis, although available evidence has conflicting findings.¹

Hyperprolactinemia is diagnosed by a prolactin concentration above the upper reference range.³ Various hormones and neurotransmitters can impact inhibition or stimulation of prolactin release.⁵ For example, dopamine tonically inhibits prolactin release and synthesis, whereas estrogen stimulates prolactin secretion.^1,5 Prolactin also can be elevated under several physiologic and pathologic conditions, such as during stressful situations, meals, or sexual activity.^1,5 A prolactin level >250 ng/mL is usually indicative of a prolactinoma; however, some medications, such as strong D2 receptor antagonists (eg, risperidone, haloperidol), can cause significant elevation without evidence of prolactinoma.³ In the absence of a tumor, medications are often identified as the cause of hyperprolactinemia.³ According to the Endocrinology Society clinical practice guideline, medication-induced elevated prolactin levels are typically between 25 to 100 ng/mL.³

Medication-induced hyperprolactinemia

Antipsychotics, antidepressants, hormonal preparations, antihypertensives, and gastrointestinal agents have been associated with hyperprolactinemia (Table 1^1,3,5-11). These medication classes increase prolactin by decreasing dopamine, which facilitates disinhibition of prolactin synthesis and release, or increasing prolactin stimulating hormones, such as serotonin or estrogen.⁵

Antipsychotics are the most common medication-related cause of hyperprolactinemia.³ Typical antipsychotics are more likely to cause hyperprolactinemia than atypical antipsychotics; the incidence among patients taking typical antipsychotics is 40% to 90%.³ Atypical antipsychotics, except risperidone and paliperidone, are considered to cause less endocrinologic effects than typical antipsychotics through various mechanisms: serotonergic receptor antagonism, fast dissociation from D2 receptors, D2 receptor partial agonism, and preferential binding of D3 vs D2 receptors.^1,5 By having transient D2 receptor association, clozapine and quetiapine are considered to have less risk of hyperprolactinemia compared with other atypical antipsychotics.^1,5 Aripiprazole, brexpiprazole, and cariprazine are partial D2 receptor agonists, and cariprazine is the only agent that exhibits preferential binding to D3 receptors.^12,13 Based on limited data, brexpiprazole and cariprazine may have prolactin-sparing properties given their partial D2 receptor agonism.^12,13 However, one study found increased prolactin levels in some patients after treatment with brexpiprazole, 4 mg/d.¹⁴ Similarly, another study found that cariprazine could increase prolactin levels as much as 4.1 ng/mL, depending on the dose.¹⁵ Except for aripiprazole, brexpiprazole, cariprazine, and clozapine, all other atypical antipsychotics marketed in the United States have a standard warning in the package insert regarding prolactin elevations.^1,16,17

Because antidepressants are less well-studied as a cause of medication-induced hyperprolactinemia, drawing definitive conclusions regarding incidence rates is limited, but the incidence seems to be fairly low.^6,18 A French pharmacovigilance study found that of 182,836 spontaneous adverse drug events reported between 1985 and 2009, there were 159 reports of selective serotonin reuptake inhibitors (SSRIs) inducing hyper­prolactinemia.⁶ Fluoxetine and paroxetine represented about one-half of the cases; however, there were also cases associated with citalopram, escitalopram, sertraline, fluvoxamine, milnacipran, and venlafaxine. In comparison, there were only 11 reports of hyperprolactinemia associated with tricyclic antidepressants or monoamine oxidase inhibitors. Although patients were not always symptomatic, the most commonly reported symptoms were galactorrhea (55%), gynecomastia (29%), amenorrhea (11%), mastodynia (11%), and sexual disorders (4%).⁶ Another study of 5,920 patients treated with fluoxetine found mastodynia in 0.25%, gynecomastia in 0.08%, and galactorrhea in 0.07% of patients.¹⁸ Symptoms occurred in an extremely low percentage of patients, and the study is >20 years old.¹⁸

Mirtazapine and bupropion have been found to be prolactin-neutral.⁵ Bupropion also has been reported to decrease prolactin levels, potentially via its ability to block dopamine reuptake.¹⁹

Managing medication-induced hyperprolactinemia

Screening for and identifying clinically significant hyperprolactinemia is critical, because adverse effects of medications can lead to nonadherence and clinical decompensation.²⁰ Patients must be informed of potential symptoms of hyperprolactinemia, and clinicians should inquire about such symptoms at each visit. Routine monitoring of prolactin levels in asymptomatic patients is not necessary, because the Endocrine Society Clinical Practice Guideline does not recommend treating patients with asymptomatic medication-induced hyperprolactinemia.³

In patients who report hyperprolactinemia symptoms, clinicians should review the patient’s prescribed medications and past medical history (eg, chronic renal failure, hypothyroidism) for potential causes or exacerbations, and address these factors accordingly.³ Order a measurement of prolactin level. A patient with a prolactin level >100 ng/mL should be referred to Endocrinology to rule out prolactinoma.¹

If a patient’s prolactin level is between 25 and 100 ng/mL, review the patient’s medications (Table 1^1,3,5-11), because prolactin levels within this range usually signal a medication-induced cause.³ For patients with antipsychotic-induced hyperprolactinemia, there are several management strategies (Table 2^{1,3,4,9,16,17,21-27}):

• Watch and wait may be warranted when the patient is experiencing mild hyperprolactinemia symptoms.
• Discontinue. If the patient can be maintained without an antipsychotic, discontinuing the antipsychotic would be a first-line option.³
• Reduce the dose. Reducing the antipsychotic dose may be the preferred strategy for patients with moderate to severe hyperprolactinemia symptoms who responded to the antipsychotic and do not wish to start adjunctive therapy.⁴
• Switching to a prolactin-sparing antipsychotic may help normalize prolactin levels and may be preferred when the risk of relapse is low.³ Dopamine agonists can treat medication-induced hyperprolactinemia, but may worsen psychiatric symptoms.^28,29 Therefore, this may be the preferred strategy if the offending medication cannot be discontinued or switched, or if the patient has a comorbid prolactinoma.

Less data exist on managing hyperprolactinemia that is induced by a medication other than an antipsychotic; however, it seems reasonable that the same strategies could be implemented. Specifically, for SSRI–induced hyperprolactinemia, if clinically appropriate, switching to or adding an alternative antidepressant that may be prolactin-sparing, such as mirtazapine or bupropion, could be attempted.⁸ One study found that fluoxetine-induced galactorrhea ceased within 10 days of discontinuing the medication.³⁰

CASE CONTINUED

Because Ms. E has been on the same medication regimen for 3 years and recently developed galactorrhea, it seems unlikely that her hyperprolactinemia is medication-induced. However, a tumor-related cause is less likely because the prolactin level is <100 ng/mL. Based on the literature, the only possible medication-induced cause of her galactorrhea is risperidone. Ms. E agrees to a trial of adjunctive oral aripiprazole, 5 mg/d, with close monitoring of her type 2 diabetes mellitus. Because of the long elimination half-life of aripiprazole, 1 month is required to monitor for improvement in galactorrhea. Ms. E is advised to use breast pads as a nonpharmacologic strategy in the interim. After 1 month of treatment, Ms. E denies galactorrhea symptoms and no longer requires the use of breast pads.

Ms. E, age 23, presents to your office for a routine visit for management of bipolar I disorder and posttraumatic stress disorder with comorbid type 2 diabetes mellitus. She currently is taking risperidone, 3 mg/d, lamotrigine, 200 mg/d, metformin, 2,000 mg/d, medroxyprogesterone, 150 mg every 3 months, and prazosin, 8 mg/d. Her mood has been stabilized for the last 3 years with this medication regimen.

Ms. E has a history of self-discontinuing medication when adverse events occur. She has been hospitalized twice for psychosis and suicide attempts. Past psychotropic medications that have been discontinued due to adverse effects include ziprasidone (mild abnormal lip movement), olanzapine (ineffective and drowsy), valproic acid (tremor and abdominal discomfort), lithium (rash), and aripiprazole (increased fasting blood sugar and labile mood).

At her appointment today, Ms. E says she is concerned because she has been experiencing galactorrhea for the past 4 weeks. Her prolactin level is 14.4 ng/mL; a normal level for a woman who is not pregnant is <25 ng/mL. However, a repeat prolactin level is obtained, and is found to be elevated at 38 ng/mL.

Prolactin, a polypeptide hormone that is secreted from the pituitary gland, has many functions, including involvement in the synthesis and maintenance of breast milk production, in reproductive behavior, and in luteal function.^1,2 Hyperprolactinemia—an elevated prolactin level—is a common endocrinologic disorder of the hypothalamic–pituitary–axis.³ Children, adolescents, premenopausal women, and women in the perinatal period are more vulnerable to medication-induced hyperprolactinemia.⁴ If not asymptomatic, patients with hyperprolactinemia may experience amenorrhea, galactorrhea, hypogonadism, sexual dysfunction, or infertility.^1,4 Chronic hyperprolactinemia may increase the risk for long-term complications, such as decreased bone mineral density and osteoporosis, although available evidence has conflicting findings.¹

Hyperprolactinemia is diagnosed by a prolactin concentration above the upper reference range.³ Various hormones and neurotransmitters can impact inhibition or stimulation of prolactin release.⁵ For example, dopamine tonically inhibits prolactin release and synthesis, whereas estrogen stimulates prolactin secretion.^1,5 Prolactin also can be elevated under several physiologic and pathologic conditions, such as during stressful situations, meals, or sexual activity.^1,5 A prolactin level >250 ng/mL is usually indicative of a prolactinoma; however, some medications, such as strong D2 receptor antagonists (eg, risperidone, haloperidol), can cause significant elevation without evidence of prolactinoma.³ In the absence of a tumor, medications are often identified as the cause of hyperprolactinemia.³ According to the Endocrinology Society clinical practice guideline, medication-induced elevated prolactin levels are typically between 25 to 100 ng/mL.³

Medication-induced hyperprolactinemia

Antipsychotics, antidepressants, hormonal preparations, antihypertensives, and gastrointestinal agents have been associated with hyperprolactinemia (Table 1^1,3,5-11). These medication classes increase prolactin by decreasing dopamine, which facilitates disinhibition of prolactin synthesis and release, or increasing prolactin stimulating hormones, such as serotonin or estrogen.⁵

Antipsychotics are the most common medication-related cause of hyperprolactinemia.³ Typical antipsychotics are more likely to cause hyperprolactinemia than atypical antipsychotics; the incidence among patients taking typical antipsychotics is 40% to 90%.³ Atypical antipsychotics, except risperidone and paliperidone, are considered to cause less endocrinologic effects than typical antipsychotics through various mechanisms: serotonergic receptor antagonism, fast dissociation from D2 receptors, D2 receptor partial agonism, and preferential binding of D3 vs D2 receptors.^1,5 By having transient D2 receptor association, clozapine and quetiapine are considered to have less risk of hyperprolactinemia compared with other atypical antipsychotics.^1,5 Aripiprazole, brexpiprazole, and cariprazine are partial D2 receptor agonists, and cariprazine is the only agent that exhibits preferential binding to D3 receptors.^12,13 Based on limited data, brexpiprazole and cariprazine may have prolactin-sparing properties given their partial D2 receptor agonism.^12,13 However, one study found increased prolactin levels in some patients after treatment with brexpiprazole, 4 mg/d.¹⁴ Similarly, another study found that cariprazine could increase prolactin levels as much as 4.1 ng/mL, depending on the dose.¹⁵ Except for aripiprazole, brexpiprazole, cariprazine, and clozapine, all other atypical antipsychotics marketed in the United States have a standard warning in the package insert regarding prolactin elevations.^1,16,17

Because antidepressants are less well-studied as a cause of medication-induced hyperprolactinemia, drawing definitive conclusions regarding incidence rates is limited, but the incidence seems to be fairly low.^6,18 A French pharmacovigilance study found that of 182,836 spontaneous adverse drug events reported between 1985 and 2009, there were 159 reports of selective serotonin reuptake inhibitors (SSRIs) inducing hyper­prolactinemia.⁶ Fluoxetine and paroxetine represented about one-half of the cases; however, there were also cases associated with citalopram, escitalopram, sertraline, fluvoxamine, milnacipran, and venlafaxine. In comparison, there were only 11 reports of hyperprolactinemia associated with tricyclic antidepressants or monoamine oxidase inhibitors. Although patients were not always symptomatic, the most commonly reported symptoms were galactorrhea (55%), gynecomastia (29%), amenorrhea (11%), mastodynia (11%), and sexual disorders (4%).⁶ Another study of 5,920 patients treated with fluoxetine found mastodynia in 0.25%, gynecomastia in 0.08%, and galactorrhea in 0.07% of patients.¹⁸ Symptoms occurred in an extremely low percentage of patients, and the study is >20 years old.¹⁸

Mirtazapine and bupropion have been found to be prolactin-neutral.⁵ Bupropion also has been reported to decrease prolactin levels, potentially via its ability to block dopamine reuptake.¹⁹

Managing medication-induced hyperprolactinemia

Screening for and identifying clinically significant hyperprolactinemia is critical, because adverse effects of medications can lead to nonadherence and clinical decompensation.²⁰ Patients must be informed of potential symptoms of hyperprolactinemia, and clinicians should inquire about such symptoms at each visit. Routine monitoring of prolactin levels in asymptomatic patients is not necessary, because the Endocrine Society Clinical Practice Guideline does not recommend treating patients with asymptomatic medication-induced hyperprolactinemia.³

In patients who report hyperprolactinemia symptoms, clinicians should review the patient’s prescribed medications and past medical history (eg, chronic renal failure, hypothyroidism) for potential causes or exacerbations, and address these factors accordingly.³ Order a measurement of prolactin level. A patient with a prolactin level >100 ng/mL should be referred to Endocrinology to rule out prolactinoma.¹

If a patient’s prolactin level is between 25 and 100 ng/mL, review the patient’s medications (Table 1^1,3,5-11), because prolactin levels within this range usually signal a medication-induced cause.³ For patients with antipsychotic-induced hyperprolactinemia, there are several management strategies (Table 2^{1,3,4,9,16,17,21-27}):

• Watch and wait may be warranted when the patient is experiencing mild hyperprolactinemia symptoms.
• Discontinue. If the patient can be maintained without an antipsychotic, discontinuing the antipsychotic would be a first-line option.³
• Reduce the dose. Reducing the antipsychotic dose may be the preferred strategy for patients with moderate to severe hyperprolactinemia symptoms who responded to the antipsychotic and do not wish to start adjunctive therapy.⁴
• Switching to a prolactin-sparing antipsychotic may help normalize prolactin levels and may be preferred when the risk of relapse is low.³ Dopamine agonists can treat medication-induced hyperprolactinemia, but may worsen psychiatric symptoms.^28,29 Therefore, this may be the preferred strategy if the offending medication cannot be discontinued or switched, or if the patient has a comorbid prolactinoma.

Less data exist on managing hyperprolactinemia that is induced by a medication other than an antipsychotic; however, it seems reasonable that the same strategies could be implemented. Specifically, for SSRI–induced hyperprolactinemia, if clinically appropriate, switching to or adding an alternative antidepressant that may be prolactin-sparing, such as mirtazapine or bupropion, could be attempted.⁸ One study found that fluoxetine-induced galactorrhea ceased within 10 days of discontinuing the medication.³⁰

CASE CONTINUED

Because Ms. E has been on the same medication regimen for 3 years and recently developed galactorrhea, it seems unlikely that her hyperprolactinemia is medication-induced. However, a tumor-related cause is less likely because the prolactin level is <100 ng/mL. Based on the literature, the only possible medication-induced cause of her galactorrhea is risperidone. Ms. E agrees to a trial of adjunctive oral aripiprazole, 5 mg/d, with close monitoring of her type 2 diabetes mellitus. Because of the long elimination half-life of aripiprazole, 1 month is required to monitor for improvement in galactorrhea. Ms. E is advised to use breast pads as a nonpharmacologic strategy in the interim. After 1 month of treatment, Ms. E denies galactorrhea symptoms and no longer requires the use of breast pads.

CASE Psychotic and reclusive

Ms. A, age 51, has schizophrenia and has been doing well living at a supervised residential facility. She was stable on haloperidol, 10 mg twice a day, for years but recently became agitated, threatening her roommate and yelling during the night. Ms. A begins to refuse to take her haloperidol. She also refuses to attend several outpatient appointments. As a result, Ms. A is admitted to the psychiatric unit on an involuntary basis.

In the hospital, Ms. A rarely comes out of her room. When she does come out, she usually sits in a chair, talking to herself and occasionally yelling or crying in apparent distress. Ms. A refuses to engage with her treatment team and lies mute in her bed when they attempt to interview her. Her records indicate that previous medication trials have included chlorpromazine, fluphenazine, haloperidol, paliperidone, ziprasidone, and quetiapine. Despite her present decompensation, discussion with the clinicians who had previously treated her reveals that she has done well on haloperidol and thus she is restarted on her outpatient dose.

Over the next week, Ms. A begins to interact more appropriately with nursing staff and can make her needs known; however, conversations are still extremely brief and based primarily around her requests. Although the frequency of her distressed outbursts has decreased, she is still responding to internal stimuli, loudly yelling and crying out at times. After 2 weeks, Ms. A still will not cooperate with her treatment team or social workers. She refuses to talk about planning her discharge, and often remains in bed for long periods during the day.

[polldaddy:9945425]

The authors’ observations

As a class, antipsychotics lead to symptom reduction in approximately 70% of patients.¹ However, the degree of response can vary markedly between individuals; although some patients may experience almost complete resolution of symptoms, others are still markedly impaired, as in Ms. A’s case.

A substantial amount of literature suggests that although the practice is common, use of >1 antipsychotic does not significantly increase efficacy but increases risk of adverse effects, such as type 2 diabetes mellitus, metabolic syndrome, cognitive impairment, and extrapyramidal symptoms.^2-4 One exception is augmentation of clozapine with a second anti­psychotic, which in certain cases appears to offer greater efficacy than clozapine alone.¹ Practice guidelines and evidence generally do not support the use of multiple antipsychotics, but 20% of patients take >1 antipsychotic.^5,6 Although antipsychotic polypharmacy may be appropriate for some patients, current literature suggests it is being done more often than recommended.

Clozapine is considered the most efficacious option for treatment-resistant schizophrenia.⁷ Because of Ms. A’s history of recurrent hospitalizations, her extensive list of trialed medications, and her ongoing symptoms despite a sufficient trial of haloperidol, the treatment team gives serious consideration to switching Ms. A to clozapine. However, Ms. A is not able to tolerate blood draws without significant support from nursing staff, and it is likely she would be unable to tolerate the frequent blood monitoring required of patients receiving clozapine.

Because many of Ms. A’s symptoms were negative or depressive, including hypersomnia, psychomotor retardation, sadness with frequent crying spells, and reduced interest in activities, adding an antidepressant to Ms. A’s medication regimen was considered. A recent systematic review and meta-analysis showed that adding an antidepressant to an antipsychotic in patients with schizophrenia had small but beneficial effects on depressive and negative symptoms and a low risk of adverse effects.⁸ However, Ms. A declined this option.

Ms. A had previously achieved therapeutic blood levels⁹ with oral haloperidol. Data suggest that compared with the oral form, long-acting injectable antipsychotics can both improve compliance and decrease rehospitalization rates.^10-12 Because Ms. A previously had done well with haloperidol decanoate, 200 mg every 2 weeks, achieving a blood level of 16.2 ng/mL, and because she had a partial response to oral haloperidol, we add haloperidol decanoate, 100 mg every 2 weeks, to her regimen, with the intention of transitioning her to all-depot dosing. In addition, the treatment team tries to engage Ms. A in a discussion of potential psychological contributions to her current presentation. They note that Ms. A has her basic needs met on the unit and reports feeling safe there; thus, a fear of discharge may be contributing to her lack of engagement with the team. However, because of her limited communication, it is challenging to investigate this hypothesis or explore other possible psychological issues.

Despite increasing the dosing of haloperidol, Ms. A shows minimal improvement. She continues to stonewall her treatment team, and is unwilling or unable to engage in meaningful conversation. A review of her chart suggests that this hospital course is different from previous ones in which her average stay was a few weeks, and she generally was able to converse with the treatment team, participate in discussions about her care, and make decisions about her desire for discharge.

The team considers if additional factors could be impacting Ms. A’s current presentation. They raise the possibility that she could be going through menopause, and hormonal fluctuations may be contributing to her symptoms. Despite being on the unit for nearly 2 months, Ms. A has not required the use of sanitary products. She also reports to nursing staff that at times she feels flushed and sweaty, but she is afebrile and does not have other signs or symptoms of infection.

[polldaddy:9945428]

The authors’ observations

Evidence suggests that estrogen levels can influence the development and severity of symptoms of schizophrenia (Table 1^13,14). Rates of schizophrenia are lower in women, and women typically have a later onset of illness with less severe symptoms.¹³ Women also have a second peak incidence of schizophrenia between ages 45 and 50, corresponding with the hormonal changes associated with menopause and the associated drop in estrogen.¹⁴ Symptoms also fluctuate with hormonal cycles—women experience worsening symptoms during the premenstrual phase of the menstrual cycle, when estrogen levels are low, and an improvement of symptoms during high-estrogen phases of the cycle.¹⁴ Overall, low levels of estrogen also have been observed in women with schizophrenia relative to controls, although this may be partially attributable to treatment with antipsychotics.¹⁴

Estrogen affects various regions of the brain implicated in schizophrenia and likely imparts its behavioral effects through several different mechanisms. Estrogen can act on cells to directly impact intracellular signaling and to alter gene expression.¹⁵ Although most often thought of as being related to reproductive functions, estrogen receptors can be found in many cortical and subcortical regions of the brain, such as the hippocampus, substantia nigra, and prefrontal cortex. Estrogen receptor expression levels in certain brain regions have been found to be altered in individuals with schizophrenia.¹⁵ Estrogen also enhances neurogenesis and neuroplasticity, playing a role in learning and memory.¹⁶ Particularly relevant, estrogen has been shown to directly impact both the dopaminergic and serotonergic systems.^15,17 In animal models, estrogen has been shown to decrease the behavioral effects induced by dopamine agonists and decrease symptoms of schizophrenia.¹⁸ The underlying molecular mechanisms by which estrogen has these effects are uncertain.

Given estrogen’s potentially protective effects, clinical trials have explored the role of estrogen as an adjuvant to antipsychotics for treating schizophrenia. Studies have shown that estrogen can improve psychotic symptoms in patients with schizophrenia.^19,20 However, because estrogen administration can increase the risk of breast and uterine cancer, researchers are instead investigating selective estrogen receptor modulators (SERMs).¹⁴ These medications have mixed agonist and antagonist effects, with different effects on different tissues. Raloxifene is a SERM that acts as an estrogen agonist in some tissues, but an antagonist in uterine and breast tissue, which may minimize potential deleterious adverse effects (Table 2^21-24). Repeated randomized controlled trials have found promising results for use of raloxifene as an adjunctive treatment in peri- and postmenopausal women with schizophrenia, including those refractory to antipsychotic treatment.^13,25-27

TREATMENT Address symptoms

The treatment team takes steps to address Ms. A’s perimenopausal symptoms. For mild to moderate hot flashes, primary interventions are nonpharmacologic.²⁸ Because Ms. A primarily reports her hot flashes at night, she is given lightweight pajamas and moved to the coolest room on the unit. Both bring some relief, and her hot flashes appear to be less distressing. The treatment team decides to consult Endocrinology to further investigate the feasibility of starting raloxifene (Table 3) because of their experience using this medication to manage osteoporosis.

[polldaddy:9945429]

The authors’ observations

Raloxifene is FDA-approved for treating osteoporosis and preventing invasive breast cancer.²⁹ Because it is an estrogen antagonist in both breast and uterine tissues, raloxifene does not increase the risk of uterine or breast cancer. Large studies have shown rates of cardiovascular events are similar for raloxifene and placebo, and some studies have found that raloxifene treatment is associated with improvement in cardiovascular risk factors, including lower blood pressure, lower low-density lipoprotein cholesterol, and increased high-density lipoprotein cholesterol.²⁹ Raloxifene does, however, increase risk of venous thromboembolism, including deep vein thrombosis and pulmonary embolism, and fatal stroke.^29,30 Overall, the risk remains relatively low, with an absolute risk increase of fatal stroke of 0.7 per 1,000 woman-years (number needed to harm [NNH]: 250) and an absolute risk increase of venous thromboembolic events of 1.88 per 1,000 women-years (NNH: 158).³¹ However, raloxifene may not be appropriate for patients with independent risk factors for these events. Despite this, a large meta-analysis found a 10% decrease in mortality for patients taking raloxifene compared with those receiving placebo.³² Raloxifene also can cause hot flashes, muscle cramps, and flu-like symptoms.²⁹

Diagnosis of menopause and perimenopause is largely clinical, with hormone testing generally recommended for women age <45 in whom the diagnosis may be unclear.²⁸ Thus, Ms. A’s vasomotor symptoms and absence of a menstrual cycle for at least 2 months were diagnostic of perimenopause; a 12-month cessation in menstrual cycles is required for a diagnosis of menopause.²⁸

OUTCOME Improvement with raloxifene

Because Ms. A is at relatively low risk for a thromboembolism or stroke, the benefit of raloxifene is thought to outweigh the risk, and she is started on raloxifene, 60 mg/d. Over the next 2 weeks, Ms. A becomes increasingly interactive, and is seen sitting at a table talking with other patients on multiple occasions. She spends time looking at fashion magazines, and engages in conversation about fashion with staff and other patients. She participates in group therapy for the first time during this hospital stay and begins to talk about discharge. She occasionally smiles and waves at her treatment team and participates more in the daily interview, although these interactions remain limited and on her terms. She maintains this improvement and is transferred to a psychiatric facility in her home county for ongoing care and discharge planning.

CASE Psychotic and reclusive

Ms. A, age 51, has schizophrenia and has been doing well living at a supervised residential facility. She was stable on haloperidol, 10 mg twice a day, for years but recently became agitated, threatening her roommate and yelling during the night. Ms. A begins to refuse to take her haloperidol. She also refuses to attend several outpatient appointments. As a result, Ms. A is admitted to the psychiatric unit on an involuntary basis.

In the hospital, Ms. A rarely comes out of her room. When she does come out, she usually sits in a chair, talking to herself and occasionally yelling or crying in apparent distress. Ms. A refuses to engage with her treatment team and lies mute in her bed when they attempt to interview her. Her records indicate that previous medication trials have included chlorpromazine, fluphenazine, haloperidol, paliperidone, ziprasidone, and quetiapine. Despite her present decompensation, discussion with the clinicians who had previously treated her reveals that she has done well on haloperidol and thus she is restarted on her outpatient dose.

Over the next week, Ms. A begins to interact more appropriately with nursing staff and can make her needs known; however, conversations are still extremely brief and based primarily around her requests. Although the frequency of her distressed outbursts has decreased, she is still responding to internal stimuli, loudly yelling and crying out at times. After 2 weeks, Ms. A still will not cooperate with her treatment team or social workers. She refuses to talk about planning her discharge, and often remains in bed for long periods during the day.

[polldaddy:9945425]

The authors’ observations

As a class, antipsychotics lead to symptom reduction in approximately 70% of patients.¹ However, the degree of response can vary markedly between individuals; although some patients may experience almost complete resolution of symptoms, others are still markedly impaired, as in Ms. A’s case.

A substantial amount of literature suggests that although the practice is common, use of >1 antipsychotic does not significantly increase efficacy but increases risk of adverse effects, such as type 2 diabetes mellitus, metabolic syndrome, cognitive impairment, and extrapyramidal symptoms.^2-4 One exception is augmentation of clozapine with a second anti­psychotic, which in certain cases appears to offer greater efficacy than clozapine alone.¹ Practice guidelines and evidence generally do not support the use of multiple antipsychotics, but 20% of patients take >1 antipsychotic.^5,6 Although antipsychotic polypharmacy may be appropriate for some patients, current literature suggests it is being done more often than recommended.

Clozapine is considered the most efficacious option for treatment-resistant schizophrenia.⁷ Because of Ms. A’s history of recurrent hospitalizations, her extensive list of trialed medications, and her ongoing symptoms despite a sufficient trial of haloperidol, the treatment team gives serious consideration to switching Ms. A to clozapine. However, Ms. A is not able to tolerate blood draws without significant support from nursing staff, and it is likely she would be unable to tolerate the frequent blood monitoring required of patients receiving clozapine.

Because many of Ms. A’s symptoms were negative or depressive, including hypersomnia, psychomotor retardation, sadness with frequent crying spells, and reduced interest in activities, adding an antidepressant to Ms. A’s medication regimen was considered. A recent systematic review and meta-analysis showed that adding an antidepressant to an antipsychotic in patients with schizophrenia had small but beneficial effects on depressive and negative symptoms and a low risk of adverse effects.⁸ However, Ms. A declined this option.

Ms. A had previously achieved therapeutic blood levels⁹ with oral haloperidol. Data suggest that compared with the oral form, long-acting injectable antipsychotics can both improve compliance and decrease rehospitalization rates.^10-12 Because Ms. A previously had done well with haloperidol decanoate, 200 mg every 2 weeks, achieving a blood level of 16.2 ng/mL, and because she had a partial response to oral haloperidol, we add haloperidol decanoate, 100 mg every 2 weeks, to her regimen, with the intention of transitioning her to all-depot dosing. In addition, the treatment team tries to engage Ms. A in a discussion of potential psychological contributions to her current presentation. They note that Ms. A has her basic needs met on the unit and reports feeling safe there; thus, a fear of discharge may be contributing to her lack of engagement with the team. However, because of her limited communication, it is challenging to investigate this hypothesis or explore other possible psychological issues.

Despite increasing the dosing of haloperidol, Ms. A shows minimal improvement. She continues to stonewall her treatment team, and is unwilling or unable to engage in meaningful conversation. A review of her chart suggests that this hospital course is different from previous ones in which her average stay was a few weeks, and she generally was able to converse with the treatment team, participate in discussions about her care, and make decisions about her desire for discharge.

The team considers if additional factors could be impacting Ms. A’s current presentation. They raise the possibility that she could be going through menopause, and hormonal fluctuations may be contributing to her symptoms. Despite being on the unit for nearly 2 months, Ms. A has not required the use of sanitary products. She also reports to nursing staff that at times she feels flushed and sweaty, but she is afebrile and does not have other signs or symptoms of infection.

[polldaddy:9945428]

The authors’ observations

Evidence suggests that estrogen levels can influence the development and severity of symptoms of schizophrenia (Table 1^13,14). Rates of schizophrenia are lower in women, and women typically have a later onset of illness with less severe symptoms.¹³ Women also have a second peak incidence of schizophrenia between ages 45 and 50, corresponding with the hormonal changes associated with menopause and the associated drop in estrogen.¹⁴ Symptoms also fluctuate with hormonal cycles—women experience worsening symptoms during the premenstrual phase of the menstrual cycle, when estrogen levels are low, and an improvement of symptoms during high-estrogen phases of the cycle.¹⁴ Overall, low levels of estrogen also have been observed in women with schizophrenia relative to controls, although this may be partially attributable to treatment with antipsychotics.¹⁴

Estrogen affects various regions of the brain implicated in schizophrenia and likely imparts its behavioral effects through several different mechanisms. Estrogen can act on cells to directly impact intracellular signaling and to alter gene expression.¹⁵ Although most often thought of as being related to reproductive functions, estrogen receptors can be found in many cortical and subcortical regions of the brain, such as the hippocampus, substantia nigra, and prefrontal cortex. Estrogen receptor expression levels in certain brain regions have been found to be altered in individuals with schizophrenia.¹⁵ Estrogen also enhances neurogenesis and neuroplasticity, playing a role in learning and memory.¹⁶ Particularly relevant, estrogen has been shown to directly impact both the dopaminergic and serotonergic systems.^15,17 In animal models, estrogen has been shown to decrease the behavioral effects induced by dopamine agonists and decrease symptoms of schizophrenia.¹⁸ The underlying molecular mechanisms by which estrogen has these effects are uncertain.

Given estrogen’s potentially protective effects, clinical trials have explored the role of estrogen as an adjuvant to antipsychotics for treating schizophrenia. Studies have shown that estrogen can improve psychotic symptoms in patients with schizophrenia.^19,20 However, because estrogen administration can increase the risk of breast and uterine cancer, researchers are instead investigating selective estrogen receptor modulators (SERMs).¹⁴ These medications have mixed agonist and antagonist effects, with different effects on different tissues. Raloxifene is a SERM that acts as an estrogen agonist in some tissues, but an antagonist in uterine and breast tissue, which may minimize potential deleterious adverse effects (Table 2^21-24). Repeated randomized controlled trials have found promising results for use of raloxifene as an adjunctive treatment in peri- and postmenopausal women with schizophrenia, including those refractory to antipsychotic treatment.^13,25-27

TREATMENT Address symptoms

The treatment team takes steps to address Ms. A’s perimenopausal symptoms. For mild to moderate hot flashes, primary interventions are nonpharmacologic.²⁸ Because Ms. A primarily reports her hot flashes at night, she is given lightweight pajamas and moved to the coolest room on the unit. Both bring some relief, and her hot flashes appear to be less distressing. The treatment team decides to consult Endocrinology to further investigate the feasibility of starting raloxifene (Table 3) because of their experience using this medication to manage osteoporosis.

[polldaddy:9945429]

The authors’ observations

Raloxifene is FDA-approved for treating osteoporosis and preventing invasive breast cancer.²⁹ Because it is an estrogen antagonist in both breast and uterine tissues, raloxifene does not increase the risk of uterine or breast cancer. Large studies have shown rates of cardiovascular events are similar for raloxifene and placebo, and some studies have found that raloxifene treatment is associated with improvement in cardiovascular risk factors, including lower blood pressure, lower low-density lipoprotein cholesterol, and increased high-density lipoprotein cholesterol.²⁹ Raloxifene does, however, increase risk of venous thromboembolism, including deep vein thrombosis and pulmonary embolism, and fatal stroke.^29,30 Overall, the risk remains relatively low, with an absolute risk increase of fatal stroke of 0.7 per 1,000 woman-years (number needed to harm [NNH]: 250) and an absolute risk increase of venous thromboembolic events of 1.88 per 1,000 women-years (NNH: 158).³¹ However, raloxifene may not be appropriate for patients with independent risk factors for these events. Despite this, a large meta-analysis found a 10% decrease in mortality for patients taking raloxifene compared with those receiving placebo.³² Raloxifene also can cause hot flashes, muscle cramps, and flu-like symptoms.²⁹

Diagnosis of menopause and perimenopause is largely clinical, with hormone testing generally recommended for women age <45 in whom the diagnosis may be unclear.²⁸ Thus, Ms. A’s vasomotor symptoms and absence of a menstrual cycle for at least 2 months were diagnostic of perimenopause; a 12-month cessation in menstrual cycles is required for a diagnosis of menopause.²⁸

OUTCOME Improvement with raloxifene

Because Ms. A is at relatively low risk for a thromboembolism or stroke, the benefit of raloxifene is thought to outweigh the risk, and she is started on raloxifene, 60 mg/d. Over the next 2 weeks, Ms. A becomes increasingly interactive, and is seen sitting at a table talking with other patients on multiple occasions. She spends time looking at fashion magazines, and engages in conversation about fashion with staff and other patients. She participates in group therapy for the first time during this hospital stay and begins to talk about discharge. She occasionally smiles and waves at her treatment team and participates more in the daily interview, although these interactions remain limited and on her terms. She maintains this improvement and is transferred to a psychiatric facility in her home county for ongoing care and discharge planning.

CASE Psychotic and reclusive

Ms. A, age 51, has schizophrenia and has been doing well living at a supervised residential facility. She was stable on haloperidol, 10 mg twice a day, for years but recently became agitated, threatening her roommate and yelling during the night. Ms. A begins to refuse to take her haloperidol. She also refuses to attend several outpatient appointments. As a result, Ms. A is admitted to the psychiatric unit on an involuntary basis.

In the hospital, Ms. A rarely comes out of her room. When she does come out, she usually sits in a chair, talking to herself and occasionally yelling or crying in apparent distress. Ms. A refuses to engage with her treatment team and lies mute in her bed when they attempt to interview her. Her records indicate that previous medication trials have included chlorpromazine, fluphenazine, haloperidol, paliperidone, ziprasidone, and quetiapine. Despite her present decompensation, discussion with the clinicians who had previously treated her reveals that she has done well on haloperidol and thus she is restarted on her outpatient dose.

Over the next week, Ms. A begins to interact more appropriately with nursing staff and can make her needs known; however, conversations are still extremely brief and based primarily around her requests. Although the frequency of her distressed outbursts has decreased, she is still responding to internal stimuli, loudly yelling and crying out at times. After 2 weeks, Ms. A still will not cooperate with her treatment team or social workers. She refuses to talk about planning her discharge, and often remains in bed for long periods during the day.

[polldaddy:9945425]

The authors’ observations

As a class, antipsychotics lead to symptom reduction in approximately 70% of patients.¹ However, the degree of response can vary markedly between individuals; although some patients may experience almost complete resolution of symptoms, others are still markedly impaired, as in Ms. A’s case.

A substantial amount of literature suggests that although the practice is common, use of >1 antipsychotic does not significantly increase efficacy but increases risk of adverse effects, such as type 2 diabetes mellitus, metabolic syndrome, cognitive impairment, and extrapyramidal symptoms.^2-4 One exception is augmentation of clozapine with a second anti­psychotic, which in certain cases appears to offer greater efficacy than clozapine alone.¹ Practice guidelines and evidence generally do not support the use of multiple antipsychotics, but 20% of patients take >1 antipsychotic.^5,6 Although antipsychotic polypharmacy may be appropriate for some patients, current literature suggests it is being done more often than recommended.

Clozapine is considered the most efficacious option for treatment-resistant schizophrenia.⁷ Because of Ms. A’s history of recurrent hospitalizations, her extensive list of trialed medications, and her ongoing symptoms despite a sufficient trial of haloperidol, the treatment team gives serious consideration to switching Ms. A to clozapine. However, Ms. A is not able to tolerate blood draws without significant support from nursing staff, and it is likely she would be unable to tolerate the frequent blood monitoring required of patients receiving clozapine.

Because many of Ms. A’s symptoms were negative or depressive, including hypersomnia, psychomotor retardation, sadness with frequent crying spells, and reduced interest in activities, adding an antidepressant to Ms. A’s medication regimen was considered. A recent systematic review and meta-analysis showed that adding an antidepressant to an antipsychotic in patients with schizophrenia had small but beneficial effects on depressive and negative symptoms and a low risk of adverse effects.⁸ However, Ms. A declined this option.

Ms. A had previously achieved therapeutic blood levels⁹ with oral haloperidol. Data suggest that compared with the oral form, long-acting injectable antipsychotics can both improve compliance and decrease rehospitalization rates.^10-12 Because Ms. A previously had done well with haloperidol decanoate, 200 mg every 2 weeks, achieving a blood level of 16.2 ng/mL, and because she had a partial response to oral haloperidol, we add haloperidol decanoate, 100 mg every 2 weeks, to her regimen, with the intention of transitioning her to all-depot dosing. In addition, the treatment team tries to engage Ms. A in a discussion of potential psychological contributions to her current presentation. They note that Ms. A has her basic needs met on the unit and reports feeling safe there; thus, a fear of discharge may be contributing to her lack of engagement with the team. However, because of her limited communication, it is challenging to investigate this hypothesis or explore other possible psychological issues.

Despite increasing the dosing of haloperidol, Ms. A shows minimal improvement. She continues to stonewall her treatment team, and is unwilling or unable to engage in meaningful conversation. A review of her chart suggests that this hospital course is different from previous ones in which her average stay was a few weeks, and she generally was able to converse with the treatment team, participate in discussions about her care, and make decisions about her desire for discharge.

The team considers if additional factors could be impacting Ms. A’s current presentation. They raise the possibility that she could be going through menopause, and hormonal fluctuations may be contributing to her symptoms. Despite being on the unit for nearly 2 months, Ms. A has not required the use of sanitary products. She also reports to nursing staff that at times she feels flushed and sweaty, but she is afebrile and does not have other signs or symptoms of infection.

[polldaddy:9945428]

The authors’ observations

Evidence suggests that estrogen levels can influence the development and severity of symptoms of schizophrenia (Table 1^13,14). Rates of schizophrenia are lower in women, and women typically have a later onset of illness with less severe symptoms.¹³ Women also have a second peak incidence of schizophrenia between ages 45 and 50, corresponding with the hormonal changes associated with menopause and the associated drop in estrogen.¹⁴ Symptoms also fluctuate with hormonal cycles—women experience worsening symptoms during the premenstrual phase of the menstrual cycle, when estrogen levels are low, and an improvement of symptoms during high-estrogen phases of the cycle.¹⁴ Overall, low levels of estrogen also have been observed in women with schizophrenia relative to controls, although this may be partially attributable to treatment with antipsychotics.¹⁴

Estrogen affects various regions of the brain implicated in schizophrenia and likely imparts its behavioral effects through several different mechanisms. Estrogen can act on cells to directly impact intracellular signaling and to alter gene expression.¹⁵ Although most often thought of as being related to reproductive functions, estrogen receptors can be found in many cortical and subcortical regions of the brain, such as the hippocampus, substantia nigra, and prefrontal cortex. Estrogen receptor expression levels in certain brain regions have been found to be altered in individuals with schizophrenia.¹⁵ Estrogen also enhances neurogenesis and neuroplasticity, playing a role in learning and memory.¹⁶ Particularly relevant, estrogen has been shown to directly impact both the dopaminergic and serotonergic systems.^15,17 In animal models, estrogen has been shown to decrease the behavioral effects induced by dopamine agonists and decrease symptoms of schizophrenia.¹⁸ The underlying molecular mechanisms by which estrogen has these effects are uncertain.

Given estrogen’s potentially protective effects, clinical trials have explored the role of estrogen as an adjuvant to antipsychotics for treating schizophrenia. Studies have shown that estrogen can improve psychotic symptoms in patients with schizophrenia.^19,20 However, because estrogen administration can increase the risk of breast and uterine cancer, researchers are instead investigating selective estrogen receptor modulators (SERMs).¹⁴ These medications have mixed agonist and antagonist effects, with different effects on different tissues. Raloxifene is a SERM that acts as an estrogen agonist in some tissues, but an antagonist in uterine and breast tissue, which may minimize potential deleterious adverse effects (Table 2^21-24). Repeated randomized controlled trials have found promising results for use of raloxifene as an adjunctive treatment in peri- and postmenopausal women with schizophrenia, including those refractory to antipsychotic treatment.^13,25-27

TREATMENT Address symptoms

The treatment team takes steps to address Ms. A’s perimenopausal symptoms. For mild to moderate hot flashes, primary interventions are nonpharmacologic.²⁸ Because Ms. A primarily reports her hot flashes at night, she is given lightweight pajamas and moved to the coolest room on the unit. Both bring some relief, and her hot flashes appear to be less distressing. The treatment team decides to consult Endocrinology to further investigate the feasibility of starting raloxifene (Table 3) because of their experience using this medication to manage osteoporosis.

[polldaddy:9945429]

The authors’ observations

Raloxifene is FDA-approved for treating osteoporosis and preventing invasive breast cancer.²⁹ Because it is an estrogen antagonist in both breast and uterine tissues, raloxifene does not increase the risk of uterine or breast cancer. Large studies have shown rates of cardiovascular events are similar for raloxifene and placebo, and some studies have found that raloxifene treatment is associated with improvement in cardiovascular risk factors, including lower blood pressure, lower low-density lipoprotein cholesterol, and increased high-density lipoprotein cholesterol.²⁹ Raloxifene does, however, increase risk of venous thromboembolism, including deep vein thrombosis and pulmonary embolism, and fatal stroke.^29,30 Overall, the risk remains relatively low, with an absolute risk increase of fatal stroke of 0.7 per 1,000 woman-years (number needed to harm [NNH]: 250) and an absolute risk increase of venous thromboembolic events of 1.88 per 1,000 women-years (NNH: 158).³¹ However, raloxifene may not be appropriate for patients with independent risk factors for these events. Despite this, a large meta-analysis found a 10% decrease in mortality for patients taking raloxifene compared with those receiving placebo.³² Raloxifene also can cause hot flashes, muscle cramps, and flu-like symptoms.²⁹

Diagnosis of menopause and perimenopause is largely clinical, with hormone testing generally recommended for women age <45 in whom the diagnosis may be unclear.²⁸ Thus, Ms. A’s vasomotor symptoms and absence of a menstrual cycle for at least 2 months were diagnostic of perimenopause; a 12-month cessation in menstrual cycles is required for a diagnosis of menopause.²⁸

OUTCOME Improvement with raloxifene

Because Ms. A is at relatively low risk for a thromboembolism or stroke, the benefit of raloxifene is thought to outweigh the risk, and she is started on raloxifene, 60 mg/d. Over the next 2 weeks, Ms. A becomes increasingly interactive, and is seen sitting at a table talking with other patients on multiple occasions. She spends time looking at fashion magazines, and engages in conversation about fashion with staff and other patients. She participates in group therapy for the first time during this hospital stay and begins to talk about discharge. She occasionally smiles and waves at her treatment team and participates more in the daily interview, although these interactions remain limited and on her terms. She maintains this improvement and is transferred to a psychiatric facility in her home county for ongoing care and discharge planning.

Hospital psychiatrists often are asked whether a patient with comorbid medical and psychiatric illnesses should be admitted to an inpatient psychiatry unit or to a medical unit. Psychiatric units vary widely in their capacity to manage patients’ medical conditions. Medical comorbidity also is associated with longer psychiatric hospitalizations.¹ The decision of where to admit may be particularly challenging when presented with a patient with delirium, which often mimics primary psychiatric illnesses such as depression but will not resolve without treatment of the underlying illness. While diagnosis and treatment of delirium typically occur in the hospital setting, 1 study found that approximately 15% of 199 psychiatric inpatients were delirious and that these patients had hospital stays that were approximately 62% longer than those without delirium.²

When you need to determine whether a patient should be admitted to an inpatient psychiatry unit with a medical consult or vice versa, consider the following 3 Ms and 3 Ps.

Medications. Can medications, including those that are given intravenously or require serum monitoring, be administered on the psychiatric unit? Can the medical unit administer involuntary psychotropics?

Mobility. Does the patient require assistance with mobility? Does the patient pose a fall risk? A physical therapy consult may be helpful.

Monitoring. Suicide risk is the most common indication for patient sitters.³ Would a patient sitter be needed for the patient? On the other hand, can the psychiatry unit manage telemetry, frequent vital signs, or infectious disease precautions?

People. Would the patient benefit from the therapeutic milieu and specialized staff of an inpatient psychiatry unit?

Prognosis. What ongoing medical and psychiatric management is required? What are the medical and psychiatric prognoses?

Placement. To where will the patient be transferred after hospitalization? How does admission to inpatient psychiatry vs medical impact the ultimate disposition?

Help the treatment team make the decision

Determining the ideal patient placement often evokes strong feelings among treatment teams. Psychiatrists can help facilitate the conversation by asking the questions outlined above, and by keep­ing in mind, “What is best for this patient?”

Hospital psychiatrists often are asked whether a patient with comorbid medical and psychiatric illnesses should be admitted to an inpatient psychiatry unit or to a medical unit. Psychiatric units vary widely in their capacity to manage patients’ medical conditions. Medical comorbidity also is associated with longer psychiatric hospitalizations.¹ The decision of where to admit may be particularly challenging when presented with a patient with delirium, which often mimics primary psychiatric illnesses such as depression but will not resolve without treatment of the underlying illness. While diagnosis and treatment of delirium typically occur in the hospital setting, 1 study found that approximately 15% of 199 psychiatric inpatients were delirious and that these patients had hospital stays that were approximately 62% longer than those without delirium.²

When you need to determine whether a patient should be admitted to an inpatient psychiatry unit with a medical consult or vice versa, consider the following 3 Ms and 3 Ps.

Medications. Can medications, including those that are given intravenously or require serum monitoring, be administered on the psychiatric unit? Can the medical unit administer involuntary psychotropics?

Mobility. Does the patient require assistance with mobility? Does the patient pose a fall risk? A physical therapy consult may be helpful.

Monitoring. Suicide risk is the most common indication for patient sitters.³ Would a patient sitter be needed for the patient? On the other hand, can the psychiatry unit manage telemetry, frequent vital signs, or infectious disease precautions?

People. Would the patient benefit from the therapeutic milieu and specialized staff of an inpatient psychiatry unit?

Prognosis. What ongoing medical and psychiatric management is required? What are the medical and psychiatric prognoses?

Placement. To where will the patient be transferred after hospitalization? How does admission to inpatient psychiatry vs medical impact the ultimate disposition?

Help the treatment team make the decision

Determining the ideal patient placement often evokes strong feelings among treatment teams. Psychiatrists can help facilitate the conversation by asking the questions outlined above, and by keep­ing in mind, “What is best for this patient?”

Hospital psychiatrists often are asked whether a patient with comorbid medical and psychiatric illnesses should be admitted to an inpatient psychiatry unit or to a medical unit. Psychiatric units vary widely in their capacity to manage patients’ medical conditions. Medical comorbidity also is associated with longer psychiatric hospitalizations.¹ The decision of where to admit may be particularly challenging when presented with a patient with delirium, which often mimics primary psychiatric illnesses such as depression but will not resolve without treatment of the underlying illness. While diagnosis and treatment of delirium typically occur in the hospital setting, 1 study found that approximately 15% of 199 psychiatric inpatients were delirious and that these patients had hospital stays that were approximately 62% longer than those without delirium.²

When you need to determine whether a patient should be admitted to an inpatient psychiatry unit with a medical consult or vice versa, consider the following 3 Ms and 3 Ps.

Medications. Can medications, including those that are given intravenously or require serum monitoring, be administered on the psychiatric unit? Can the medical unit administer involuntary psychotropics?

Mobility. Does the patient require assistance with mobility? Does the patient pose a fall risk? A physical therapy consult may be helpful.

Monitoring. Suicide risk is the most common indication for patient sitters.³ Would a patient sitter be needed for the patient? On the other hand, can the psychiatry unit manage telemetry, frequent vital signs, or infectious disease precautions?

People. Would the patient benefit from the therapeutic milieu and specialized staff of an inpatient psychiatry unit?

Prognosis. What ongoing medical and psychiatric management is required? What are the medical and psychiatric prognoses?

Placement. To where will the patient be transferred after hospitalization? How does admission to inpatient psychiatry vs medical impact the ultimate disposition?

Help the treatment team make the decision

Determining the ideal patient placement often evokes strong feelings among treatment teams. Psychiatrists can help facilitate the conversation by asking the questions outlined above, and by keep­ing in mind, “What is best for this patient?”