Current Psychiatry

Hazardous polypharmacy

I am writing to compliment Dr. Henry A. Nasrallah for having the guts to write “Polypharmacy subtypes” (From the Editor, Current Psychiatry, April 2011, p. 10-12). I try hard to have patients on no more than 4 medications, 1 from each class if indicated. In California, what Dr. Nasrallah described as ridiculous and hazardous is all too rampant. I have inherited patients taking as many as 7 psychotropics and the initial evaluation of these patients usually begins with families stating that they are angry about their loved ones being “doped up to the point of being zombies.” When I am finally able to get a good history of symptoms, I typically find that patients do not meet DSM-IV-TR criteria for some diagnoses. I then wean them off the medications, see what symptoms emerge, and then “reinvent the wheel” with their medication regimens. I was verbally reprimanded by the medical director at 1 job because he thought a patient was “doing well” on 7 medications despite the fact he was oversedated. I also have inherited patients on medications that interacted with other medications and were causing medical problems.

Problems with polypharmacy in California are, as I said, rampant.

Terry Roh, MD
Child and Adult Psychiatrist
Lutheran Social Services of Southern California
Big Bear Lake, CA

Ketamine and glutamate

I enjoyed the article “Glutamate: New hope for schizophrenia treatment” (Current Psychiatry, April 2011, p. 68-74) by Drs. Kantrowitz and Javitt. However, perhaps due to my own ignorance of the subject, I remain puzzled about their suggestion that the glutamatergic model of schizophrenia is supported by evidence showing that agonists at presynaptic mGluR2/3 receptors reverse the psychotomimetic effects of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. Indeed, one would think that action of glutamatergic agonists at presynaptic autoreceptors would reduce glutamatergic activity and therefore mimic, rather than block, the effects of the antagonist ketamine.

Scott Mendelson, MD, PhD
Psychiatrist
Roseburg VA Hospital
Roseburg, OR

The authors respond

Thank you for your interest. We agree that this is a paradoxical effect of glutamate that is based largely upon the work of Bita Moghaddam, PhD, John Krystal, MD, and others. The basic finding is that blocking postsynaptic NMDA receptors leads to a rebound increase in presynaptic glutamate release that is pathological. Dr. Moghaddam showed that treatment with mGluR2/3 agonists reversed dopaminergic abnormalities and cognitive deficits induced by NMDAR antagonists in rodents.¹ Dr. Krystal showed that the presynaptic glutamate release antagonist lamotrigine blocked psychotomimetic effects of ketamine in normal human volunteers.² These findings have led to the hypothesis that blocking presynaptic glutamate may restore balance between glutamate and GABA systems, particularly in frontal brain regions. This theory also was supported by 1 successful clinical trial of a mGluR2/3 agonist,³ although replication studies are ongoing. When interpreting these findings, it is important to keep in mind that glutamate acts at several receptor types in addition to NMDA, and it is the balance between these receptors, as well as the balance between excitatory glutamatergic vs inhibitory GABAergic neurotransmission, that may be critical in psychosis.

Joshua T. Kantrowitz, MD
Assistant Professor
Department of Psychiatry
Columbia College of Physicians and Surgeons
New York, NY
Schizophrenia Research Center
Nathan Kline Institute for Psychiatric Research
Orangeburg, NY

Daniel C. Javitt, MD, PhD
Director, Schizophrenia Research
Nathan Kline Institute for Psychiatric Research
Orangeburg, NY
Professor of Psychiatry and Neuroscience
New York University School of Medicine
New York, NY

Hazardous polypharmacy

I am writing to compliment Dr. Henry A. Nasrallah for having the guts to write “Polypharmacy subtypes” (From the Editor, Current Psychiatry, April 2011, p. 10-12). I try hard to have patients on no more than 4 medications, 1 from each class if indicated. In California, what Dr. Nasrallah described as ridiculous and hazardous is all too rampant. I have inherited patients taking as many as 7 psychotropics and the initial evaluation of these patients usually begins with families stating that they are angry about their loved ones being “doped up to the point of being zombies.” When I am finally able to get a good history of symptoms, I typically find that patients do not meet DSM-IV-TR criteria for some diagnoses. I then wean them off the medications, see what symptoms emerge, and then “reinvent the wheel” with their medication regimens. I was verbally reprimanded by the medical director at 1 job because he thought a patient was “doing well” on 7 medications despite the fact he was oversedated. I also have inherited patients on medications that interacted with other medications and were causing medical problems.

Problems with polypharmacy in California are, as I said, rampant.

Terry Roh, MD
Child and Adult Psychiatrist
Lutheran Social Services of Southern California
Big Bear Lake, CA

Ketamine and glutamate

I enjoyed the article “Glutamate: New hope for schizophrenia treatment” (Current Psychiatry, April 2011, p. 68-74) by Drs. Kantrowitz and Javitt. However, perhaps due to my own ignorance of the subject, I remain puzzled about their suggestion that the glutamatergic model of schizophrenia is supported by evidence showing that agonists at presynaptic mGluR2/3 receptors reverse the psychotomimetic effects of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. Indeed, one would think that action of glutamatergic agonists at presynaptic autoreceptors would reduce glutamatergic activity and therefore mimic, rather than block, the effects of the antagonist ketamine.

Scott Mendelson, MD, PhD
Psychiatrist
Roseburg VA Hospital
Roseburg, OR

The authors respond

Thank you for your interest. We agree that this is a paradoxical effect of glutamate that is based largely upon the work of Bita Moghaddam, PhD, John Krystal, MD, and others. The basic finding is that blocking postsynaptic NMDA receptors leads to a rebound increase in presynaptic glutamate release that is pathological. Dr. Moghaddam showed that treatment with mGluR2/3 agonists reversed dopaminergic abnormalities and cognitive deficits induced by NMDAR antagonists in rodents.¹ Dr. Krystal showed that the presynaptic glutamate release antagonist lamotrigine blocked psychotomimetic effects of ketamine in normal human volunteers.² These findings have led to the hypothesis that blocking presynaptic glutamate may restore balance between glutamate and GABA systems, particularly in frontal brain regions. This theory also was supported by 1 successful clinical trial of a mGluR2/3 agonist,³ although replication studies are ongoing. When interpreting these findings, it is important to keep in mind that glutamate acts at several receptor types in addition to NMDA, and it is the balance between these receptors, as well as the balance between excitatory glutamatergic vs inhibitory GABAergic neurotransmission, that may be critical in psychosis.

Joshua T. Kantrowitz, MD
Assistant Professor
Department of Psychiatry
Columbia College of Physicians and Surgeons
New York, NY
Schizophrenia Research Center
Nathan Kline Institute for Psychiatric Research
Orangeburg, NY

Daniel C. Javitt, MD, PhD
Director, Schizophrenia Research
Nathan Kline Institute for Psychiatric Research
Orangeburg, NY
Professor of Psychiatry and Neuroscience
New York University School of Medicine
New York, NY

Hazardous polypharmacy

I am writing to compliment Dr. Henry A. Nasrallah for having the guts to write “Polypharmacy subtypes” (From the Editor, Current Psychiatry, April 2011, p. 10-12). I try hard to have patients on no more than 4 medications, 1 from each class if indicated. In California, what Dr. Nasrallah described as ridiculous and hazardous is all too rampant. I have inherited patients taking as many as 7 psychotropics and the initial evaluation of these patients usually begins with families stating that they are angry about their loved ones being “doped up to the point of being zombies.” When I am finally able to get a good history of symptoms, I typically find that patients do not meet DSM-IV-TR criteria for some diagnoses. I then wean them off the medications, see what symptoms emerge, and then “reinvent the wheel” with their medication regimens. I was verbally reprimanded by the medical director at 1 job because he thought a patient was “doing well” on 7 medications despite the fact he was oversedated. I also have inherited patients on medications that interacted with other medications and were causing medical problems.

Problems with polypharmacy in California are, as I said, rampant.

Terry Roh, MD
Child and Adult Psychiatrist
Lutheran Social Services of Southern California
Big Bear Lake, CA

Ketamine and glutamate

I enjoyed the article “Glutamate: New hope for schizophrenia treatment” (Current Psychiatry, April 2011, p. 68-74) by Drs. Kantrowitz and Javitt. However, perhaps due to my own ignorance of the subject, I remain puzzled about their suggestion that the glutamatergic model of schizophrenia is supported by evidence showing that agonists at presynaptic mGluR2/3 receptors reverse the psychotomimetic effects of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. Indeed, one would think that action of glutamatergic agonists at presynaptic autoreceptors would reduce glutamatergic activity and therefore mimic, rather than block, the effects of the antagonist ketamine.

Scott Mendelson, MD, PhD
Psychiatrist
Roseburg VA Hospital
Roseburg, OR

The authors respond

Thank you for your interest. We agree that this is a paradoxical effect of glutamate that is based largely upon the work of Bita Moghaddam, PhD, John Krystal, MD, and others. The basic finding is that blocking postsynaptic NMDA receptors leads to a rebound increase in presynaptic glutamate release that is pathological. Dr. Moghaddam showed that treatment with mGluR2/3 agonists reversed dopaminergic abnormalities and cognitive deficits induced by NMDAR antagonists in rodents.¹ Dr. Krystal showed that the presynaptic glutamate release antagonist lamotrigine blocked psychotomimetic effects of ketamine in normal human volunteers.² These findings have led to the hypothesis that blocking presynaptic glutamate may restore balance between glutamate and GABA systems, particularly in frontal brain regions. This theory also was supported by 1 successful clinical trial of a mGluR2/3 agonist,³ although replication studies are ongoing. When interpreting these findings, it is important to keep in mind that glutamate acts at several receptor types in addition to NMDA, and it is the balance between these receptors, as well as the balance between excitatory glutamatergic vs inhibitory GABAergic neurotransmission, that may be critical in psychosis.

Joshua T. Kantrowitz, MD
Assistant Professor
Department of Psychiatry
Columbia College of Physicians and Surgeons
New York, NY
Schizophrenia Research Center
Nathan Kline Institute for Psychiatric Research
Orangeburg, NY

Daniel C. Javitt, MD, PhD
Director, Schizophrenia Research
Nathan Kline Institute for Psychiatric Research
Orangeburg, NY
Professor of Psychiatry and Neuroscience
New York University School of Medicine
New York, NY

Post hoc ergo propter hoc—”after this, therefore because of this”—suggests that 2 distinct events linked temporally are related causally. Clinicians often apply this dictum when monitoring effects of psychotropics. Because of stigma associated with psychiatric medications, and the readiness with which many practitioners blame them for unexpected results, it is important to develop a rational approach to evaluating outcomes—particularly adverse ones—after administering psychotropic agents.

Consider a geriatric patient admitted to the hospital for a urinary tract infection. He becomes verbally aggressive and is given IV haloperidol. Five minutes later he strikes a nurse and receives lorazepam. Twenty minutes later, he is lying calmly in his bed. The nursing staff and primary team conclude that the patient’s agitation worsened because of the antipsychotic and responded to the benzodiazepine; the physician documents in the patient’s chart that he had an adverse reaction to haloperidol.

In light of what we know about psychotropic medications’ mechanism of action, a more plausible explanation is that whatever caused the patient to become agitated (delirium) resulted in physical aggression. Haloperidol simply did not have enough time to exert its effect before the patient hit the nurse. It also would be wrong to automatically conclude that the last intervention (a benzodiazepine) produced the beneficial outcome. Was it the lorazepam, the haloperidol finally “kicking in,” or a combination of both? Perhaps it was none of the above but rather a worsening infection or irregular waxing and waning of delirium that was the culprit.

To avoid incorrectly attributing negative outcomes to medications, we suggest asking yourself 3 questions:

1. Is the negative outcome a potential consequence of the underlying condition?

Consider the possibility that the medication did not cause the adverse event but merely failed to adequately treat the underlying problem. A teenager who attempts suicide 2 weeks after starting an antidepressant may be exhibiting symptoms related to depression rather than behavior caused by the medication.

2. Are other medical conditions or medications responsible for the negative outcome?

Weigh the relative likelihood that these factors are contributing to your patient’s presentation. In a surgical patient who is overly somnolent after receiving an anxiolytic, consider the possibility that a narcotic or worsening hypoxia are contributing to her somnolence.

3. Is the negative outcome likely to have occurred spontaneously?

Consider the possibility of coincidence. Lithium might not be causing declining renal function in an older patient. A dosing adjustment based on the patient’s current renal function may be a better harm-reduction strategy than discontinuing a potentially useful medication.

Careful evaluation of these potential confounding factors will greatly reduce the likelihood of falsely identifying psychotropic medications as responsible for negative outcomes. After this, but not always because of this.

Disclosure

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

Post hoc ergo propter hoc—”after this, therefore because of this”—suggests that 2 distinct events linked temporally are related causally. Clinicians often apply this dictum when monitoring effects of psychotropics. Because of stigma associated with psychiatric medications, and the readiness with which many practitioners blame them for unexpected results, it is important to develop a rational approach to evaluating outcomes—particularly adverse ones—after administering psychotropic agents.

Consider a geriatric patient admitted to the hospital for a urinary tract infection. He becomes verbally aggressive and is given IV haloperidol. Five minutes later he strikes a nurse and receives lorazepam. Twenty minutes later, he is lying calmly in his bed. The nursing staff and primary team conclude that the patient’s agitation worsened because of the antipsychotic and responded to the benzodiazepine; the physician documents in the patient’s chart that he had an adverse reaction to haloperidol.

In light of what we know about psychotropic medications’ mechanism of action, a more plausible explanation is that whatever caused the patient to become agitated (delirium) resulted in physical aggression. Haloperidol simply did not have enough time to exert its effect before the patient hit the nurse. It also would be wrong to automatically conclude that the last intervention (a benzodiazepine) produced the beneficial outcome. Was it the lorazepam, the haloperidol finally “kicking in,” or a combination of both? Perhaps it was none of the above but rather a worsening infection or irregular waxing and waning of delirium that was the culprit.

To avoid incorrectly attributing negative outcomes to medications, we suggest asking yourself 3 questions:

1. Is the negative outcome a potential consequence of the underlying condition?

Consider the possibility that the medication did not cause the adverse event but merely failed to adequately treat the underlying problem. A teenager who attempts suicide 2 weeks after starting an antidepressant may be exhibiting symptoms related to depression rather than behavior caused by the medication.

2. Are other medical conditions or medications responsible for the negative outcome?

Weigh the relative likelihood that these factors are contributing to your patient’s presentation. In a surgical patient who is overly somnolent after receiving an anxiolytic, consider the possibility that a narcotic or worsening hypoxia are contributing to her somnolence.

3. Is the negative outcome likely to have occurred spontaneously?

Consider the possibility of coincidence. Lithium might not be causing declining renal function in an older patient. A dosing adjustment based on the patient’s current renal function may be a better harm-reduction strategy than discontinuing a potentially useful medication.

Careful evaluation of these potential confounding factors will greatly reduce the likelihood of falsely identifying psychotropic medications as responsible for negative outcomes. After this, but not always because of this.

Disclosure

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

Post hoc ergo propter hoc—”after this, therefore because of this”—suggests that 2 distinct events linked temporally are related causally. Clinicians often apply this dictum when monitoring effects of psychotropics. Because of stigma associated with psychiatric medications, and the readiness with which many practitioners blame them for unexpected results, it is important to develop a rational approach to evaluating outcomes—particularly adverse ones—after administering psychotropic agents.

Consider a geriatric patient admitted to the hospital for a urinary tract infection. He becomes verbally aggressive and is given IV haloperidol. Five minutes later he strikes a nurse and receives lorazepam. Twenty minutes later, he is lying calmly in his bed. The nursing staff and primary team conclude that the patient’s agitation worsened because of the antipsychotic and responded to the benzodiazepine; the physician documents in the patient’s chart that he had an adverse reaction to haloperidol.

In light of what we know about psychotropic medications’ mechanism of action, a more plausible explanation is that whatever caused the patient to become agitated (delirium) resulted in physical aggression. Haloperidol simply did not have enough time to exert its effect before the patient hit the nurse. It also would be wrong to automatically conclude that the last intervention (a benzodiazepine) produced the beneficial outcome. Was it the lorazepam, the haloperidol finally “kicking in,” or a combination of both? Perhaps it was none of the above but rather a worsening infection or irregular waxing and waning of delirium that was the culprit.

To avoid incorrectly attributing negative outcomes to medications, we suggest asking yourself 3 questions:

1. Is the negative outcome a potential consequence of the underlying condition?

Consider the possibility that the medication did not cause the adverse event but merely failed to adequately treat the underlying problem. A teenager who attempts suicide 2 weeks after starting an antidepressant may be exhibiting symptoms related to depression rather than behavior caused by the medication.

2. Are other medical conditions or medications responsible for the negative outcome?

Weigh the relative likelihood that these factors are contributing to your patient’s presentation. In a surgical patient who is overly somnolent after receiving an anxiolytic, consider the possibility that a narcotic or worsening hypoxia are contributing to her somnolence.

3. Is the negative outcome likely to have occurred spontaneously?

Consider the possibility of coincidence. Lithium might not be causing declining renal function in an older patient. A dosing adjustment based on the patient’s current renal function may be a better harm-reduction strategy than discontinuing a potentially useful medication.

Careful evaluation of these potential confounding factors will greatly reduce the likelihood of falsely identifying psychotropic medications as responsible for negative outcomes. After this, but not always because of this.

Disclosure

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

Many individuals think of postpartum depression as an episode of major depressive disorder within 4 weeks of delivery; however, postpartum depressive symptoms also can occur in the context of bipolar I disorder (BD I) or bipolar II disorder (BD II). Despite the high prevalence of postpartum hypomania (9% to 20%), clinicians often fail to screen for symptoms of mania or hypomania.¹ Determining if your patient’s postpartum depressive episode is caused by BD is essential when formulating an appropriate treatment plan that protects the mother and child.

Postpartum depression literature offers little guidance on the recognition and management of postpartum bipolar disorder.² For example, there is scant evidence on pharmacologic or psychotherapeutic treatment of postpartum bipolar depression, and no studies have evaluated the use of screening instruments such as the Edinburgh Postnatal Depression Scale to detect bipolar disorder.

Misdiagnosis of postpartum depression is more likely in cases of subtle bipolarity—BD II and BD not otherwise specified—than in BD I because:³

• physicians often fail to ask postpartum patients about hypomanic symptoms such as feelings of elation, being overly talkative, racing thoughts, and decreased need for sleep
• DSM-IV-TR does not recognize hypomania with a postpartum onset specifier
• hypomania symptoms overlap normal feelings of elation and sleep disturbance following childbirth.

Clues to postpartum bipolar disorder include:

• hypomania: persistently elevated, expansive, or irritable mood
• depression onset immediately after delivery
• atypical features such as hypersomnia, leaden paralysis, and increased appetite
• racing thoughts
• concomitant psychotic symptoms
• history of BD in a first-degree relative
• antidepressants “misadventures” (rapid response; loss of response; induction of mania, hypomania, or depressive mixed episodes; and poor response).

Treatment strategies

Avoid antidepressants. Bipolar depression does not respond to antidepressants as well as unipolar depression. Moreover, antidepressants can induce mania, hypomania, or mixed states, and can increase mood cycle frequency.

Administer mood stabilizers such as lithium or lamotrigine, or atypical antipsychotics such as quetiapine.

In breast-feeding women the benefits of treatment should be balanced carefully against the risk of infant exposure to medications. Lamotrigine should be used cautiously because of concerns of skin rash and higher-than-expected drug levels in the infant. In light of recent data showing no significant adverse clinical or behavioral effects in infants, breast-feeding while taking lithium should be considered in carefully selected women. The preliminary evidence supporting the use of quetiapine during breast-feeding appears promising; however, data on the safety of atypical antipsychotics in lactating women are limited.

Promote sleep. Sleep disruption can be a symptom of as well as a trigger for postpartum bipolar depression. In women with BD, the benefits of breast-feeding should be balanced carefully against the potential for the deleterious effects of sleep deprivation in triggering mood episodes. Women should consider using a breast pump allowing others to assist with feeding or supplementing breast milk with formula to help get uninterrupted sleep.³

Disclosure

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

Many individuals think of postpartum depression as an episode of major depressive disorder within 4 weeks of delivery; however, postpartum depressive symptoms also can occur in the context of bipolar I disorder (BD I) or bipolar II disorder (BD II). Despite the high prevalence of postpartum hypomania (9% to 20%), clinicians often fail to screen for symptoms of mania or hypomania.¹ Determining if your patient’s postpartum depressive episode is caused by BD is essential when formulating an appropriate treatment plan that protects the mother and child.

Postpartum depression literature offers little guidance on the recognition and management of postpartum bipolar disorder.² For example, there is scant evidence on pharmacologic or psychotherapeutic treatment of postpartum bipolar depression, and no studies have evaluated the use of screening instruments such as the Edinburgh Postnatal Depression Scale to detect bipolar disorder.

Misdiagnosis of postpartum depression is more likely in cases of subtle bipolarity—BD II and BD not otherwise specified—than in BD I because:³

• physicians often fail to ask postpartum patients about hypomanic symptoms such as feelings of elation, being overly talkative, racing thoughts, and decreased need for sleep
• DSM-IV-TR does not recognize hypomania with a postpartum onset specifier
• hypomania symptoms overlap normal feelings of elation and sleep disturbance following childbirth.

Clues to postpartum bipolar disorder include:

• hypomania: persistently elevated, expansive, or irritable mood
• depression onset immediately after delivery
• atypical features such as hypersomnia, leaden paralysis, and increased appetite
• racing thoughts
• concomitant psychotic symptoms
• history of BD in a first-degree relative
• antidepressants “misadventures” (rapid response; loss of response; induction of mania, hypomania, or depressive mixed episodes; and poor response).

Treatment strategies

Avoid antidepressants. Bipolar depression does not respond to antidepressants as well as unipolar depression. Moreover, antidepressants can induce mania, hypomania, or mixed states, and can increase mood cycle frequency.

Administer mood stabilizers such as lithium or lamotrigine, or atypical antipsychotics such as quetiapine.

In breast-feeding women the benefits of treatment should be balanced carefully against the risk of infant exposure to medications. Lamotrigine should be used cautiously because of concerns of skin rash and higher-than-expected drug levels in the infant. In light of recent data showing no significant adverse clinical or behavioral effects in infants, breast-feeding while taking lithium should be considered in carefully selected women. The preliminary evidence supporting the use of quetiapine during breast-feeding appears promising; however, data on the safety of atypical antipsychotics in lactating women are limited.

Promote sleep. Sleep disruption can be a symptom of as well as a trigger for postpartum bipolar depression. In women with BD, the benefits of breast-feeding should be balanced carefully against the potential for the deleterious effects of sleep deprivation in triggering mood episodes. Women should consider using a breast pump allowing others to assist with feeding or supplementing breast milk with formula to help get uninterrupted sleep.³

Disclosure

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

Many individuals think of postpartum depression as an episode of major depressive disorder within 4 weeks of delivery; however, postpartum depressive symptoms also can occur in the context of bipolar I disorder (BD I) or bipolar II disorder (BD II). Despite the high prevalence of postpartum hypomania (9% to 20%), clinicians often fail to screen for symptoms of mania or hypomania.¹ Determining if your patient’s postpartum depressive episode is caused by BD is essential when formulating an appropriate treatment plan that protects the mother and child.

Postpartum depression literature offers little guidance on the recognition and management of postpartum bipolar disorder.² For example, there is scant evidence on pharmacologic or psychotherapeutic treatment of postpartum bipolar depression, and no studies have evaluated the use of screening instruments such as the Edinburgh Postnatal Depression Scale to detect bipolar disorder.

Misdiagnosis of postpartum depression is more likely in cases of subtle bipolarity—BD II and BD not otherwise specified—than in BD I because:³

• physicians often fail to ask postpartum patients about hypomanic symptoms such as feelings of elation, being overly talkative, racing thoughts, and decreased need for sleep
• DSM-IV-TR does not recognize hypomania with a postpartum onset specifier
• hypomania symptoms overlap normal feelings of elation and sleep disturbance following childbirth.

Clues to postpartum bipolar disorder include:

• hypomania: persistently elevated, expansive, or irritable mood
• depression onset immediately after delivery
• atypical features such as hypersomnia, leaden paralysis, and increased appetite
• racing thoughts
• concomitant psychotic symptoms
• history of BD in a first-degree relative
• antidepressants “misadventures” (rapid response; loss of response; induction of mania, hypomania, or depressive mixed episodes; and poor response).

Treatment strategies

Avoid antidepressants. Bipolar depression does not respond to antidepressants as well as unipolar depression. Moreover, antidepressants can induce mania, hypomania, or mixed states, and can increase mood cycle frequency.

Administer mood stabilizers such as lithium or lamotrigine, or atypical antipsychotics such as quetiapine.

In breast-feeding women the benefits of treatment should be balanced carefully against the risk of infant exposure to medications. Lamotrigine should be used cautiously because of concerns of skin rash and higher-than-expected drug levels in the infant. In light of recent data showing no significant adverse clinical or behavioral effects in infants, breast-feeding while taking lithium should be considered in carefully selected women. The preliminary evidence supporting the use of quetiapine during breast-feeding appears promising; however, data on the safety of atypical antipsychotics in lactating women are limited.

Promote sleep. Sleep disruption can be a symptom of as well as a trigger for postpartum bipolar depression. In women with BD, the benefits of breast-feeding should be balanced carefully against the potential for the deleterious effects of sleep deprivation in triggering mood episodes. Women should consider using a breast pump allowing others to assist with feeding or supplementing breast milk with formula to help get uninterrupted sleep.³

Disclosure

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

Adequate adherence to antipsychotics is critical for most patients with a chronic psychotic disorder. Therefore, appraisal of medication adherence—also called compliance in the older literature—is crucial at all visits.

Medication adherence is both an attitude and a behavior,¹ and you need to assess both. Without some motivation to take medications (ie, a positive drug attitude), adherence is unlikely. On the other hand, motivation alone does not guarantee compliance behavior, and you need to assess barriers to adherence even in motivated patients.

To arrive at a clinical estimate of adherence to antipsychotics, ask yourself:

A What is my patient’s Attitude toward antipsychotics?

Expect a positive drug attitude if the medication is perceived as warranted, potentially effective, and tolerable. Inquire about prior experience with medications and psychiatrists, including unpleasant somatic experiences, periods of coercion, specific benefits, and fears. Remember that the perceived harm from—vs the perceived need for—medications is judged from the patient’s point of view, not the clinician’s. For example, some patients are motivated to take an antipsychotic because it helps them sleep. Make note if motivation is intrinsic or extrinsic. You might start by asking, “Why do you think taking this medication is a good idea?”

Figure: Attitude, Barriers, and Compliance behavior

B Are there Barriers for a motivated patient to implement optimal adherence?

Ask, “What gets in the way of taking your medication?” Identifying barriers for the motivated patient forces you to look at the individual’s real-life situation. Can the patient afford the co-pay? Is the family against the patient taking an antipsychotic? Does the patient lack a routine that would help him or her remember to take pills? Is the patient too ashamed of the stigma of taking psychiatric medications? Does the patient have cognitive impairment that leads to forgetting to take pills?

C What is my best quantitative estimate of Compliance behavior?

Ask your patient, “In the last 7 days, how many pills have you missed?” Inquire also about names of pills and dosages, number of pills prescribed, and how they are taken to get a sense of your patient’s routines and cognitive competence. This is the time to get collateral information, such as when the last prescription was filled. After collecting this information, you should be able to estimate a patient’s level of adherence (eg, almost 100%, partial 50% to 75%, none). Be aware that both clinicians and patients overestimate actual adherence.

Disclosures

Drs. Kontos and Querques report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Freudenreich receives grant/research support from Pfizer Inc. He is a consultant to Transcept Pharmaceuticals, Inc. and Beacon Health Strategies, LLC and a speaker for Reed Medical Education.

Adequate adherence to antipsychotics is critical for most patients with a chronic psychotic disorder. Therefore, appraisal of medication adherence—also called compliance in the older literature—is crucial at all visits.

Medication adherence is both an attitude and a behavior,¹ and you need to assess both. Without some motivation to take medications (ie, a positive drug attitude), adherence is unlikely. On the other hand, motivation alone does not guarantee compliance behavior, and you need to assess barriers to adherence even in motivated patients.

To arrive at a clinical estimate of adherence to antipsychotics, ask yourself:

A What is my patient’s Attitude toward antipsychotics?

Expect a positive drug attitude if the medication is perceived as warranted, potentially effective, and tolerable. Inquire about prior experience with medications and psychiatrists, including unpleasant somatic experiences, periods of coercion, specific benefits, and fears. Remember that the perceived harm from—vs the perceived need for—medications is judged from the patient’s point of view, not the clinician’s. For example, some patients are motivated to take an antipsychotic because it helps them sleep. Make note if motivation is intrinsic or extrinsic. You might start by asking, “Why do you think taking this medication is a good idea?”

Figure: Attitude, Barriers, and Compliance behavior

B Are there Barriers for a motivated patient to implement optimal adherence?

Ask, “What gets in the way of taking your medication?” Identifying barriers for the motivated patient forces you to look at the individual’s real-life situation. Can the patient afford the co-pay? Is the family against the patient taking an antipsychotic? Does the patient lack a routine that would help him or her remember to take pills? Is the patient too ashamed of the stigma of taking psychiatric medications? Does the patient have cognitive impairment that leads to forgetting to take pills?

C What is my best quantitative estimate of Compliance behavior?

Ask your patient, “In the last 7 days, how many pills have you missed?” Inquire also about names of pills and dosages, number of pills prescribed, and how they are taken to get a sense of your patient’s routines and cognitive competence. This is the time to get collateral information, such as when the last prescription was filled. After collecting this information, you should be able to estimate a patient’s level of adherence (eg, almost 100%, partial 50% to 75%, none). Be aware that both clinicians and patients overestimate actual adherence.

Disclosures

Drs. Kontos and Querques report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Freudenreich receives grant/research support from Pfizer Inc. He is a consultant to Transcept Pharmaceuticals, Inc. and Beacon Health Strategies, LLC and a speaker for Reed Medical Education.

Adequate adherence to antipsychotics is critical for most patients with a chronic psychotic disorder. Therefore, appraisal of medication adherence—also called compliance in the older literature—is crucial at all visits.

Medication adherence is both an attitude and a behavior,¹ and you need to assess both. Without some motivation to take medications (ie, a positive drug attitude), adherence is unlikely. On the other hand, motivation alone does not guarantee compliance behavior, and you need to assess barriers to adherence even in motivated patients.

To arrive at a clinical estimate of adherence to antipsychotics, ask yourself:

A What is my patient’s Attitude toward antipsychotics?

Expect a positive drug attitude if the medication is perceived as warranted, potentially effective, and tolerable. Inquire about prior experience with medications and psychiatrists, including unpleasant somatic experiences, periods of coercion, specific benefits, and fears. Remember that the perceived harm from—vs the perceived need for—medications is judged from the patient’s point of view, not the clinician’s. For example, some patients are motivated to take an antipsychotic because it helps them sleep. Make note if motivation is intrinsic or extrinsic. You might start by asking, “Why do you think taking this medication is a good idea?”

Figure: Attitude, Barriers, and Compliance behavior

B Are there Barriers for a motivated patient to implement optimal adherence?

Ask, “What gets in the way of taking your medication?” Identifying barriers for the motivated patient forces you to look at the individual’s real-life situation. Can the patient afford the co-pay? Is the family against the patient taking an antipsychotic? Does the patient lack a routine that would help him or her remember to take pills? Is the patient too ashamed of the stigma of taking psychiatric medications? Does the patient have cognitive impairment that leads to forgetting to take pills?

C What is my best quantitative estimate of Compliance behavior?

Ask your patient, “In the last 7 days, how many pills have you missed?” Inquire also about names of pills and dosages, number of pills prescribed, and how they are taken to get a sense of your patient’s routines and cognitive competence. This is the time to get collateral information, such as when the last prescription was filled. After collecting this information, you should be able to estimate a patient’s level of adherence (eg, almost 100%, partial 50% to 75%, none). Be aware that both clinicians and patients overestimate actual adherence.

Disclosures

Drs. Kontos and Querques report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Freudenreich receives grant/research support from Pfizer Inc. He is a consultant to Transcept Pharmaceuticals, Inc. and Beacon Health Strategies, LLC and a speaker for Reed Medical Education.

Everybody loves progress. People feel uplifted by the notion of progress, by the dynamic feeling it evokes of “moving forward,” of achieving new milestones and reaching new heights. Progress implies improvement in the human condition and an upgrade in quality of life. In medical disciplines such as psychiatry, it connotes less suffering, better treatments, more hope, improved social and vocational functioning, and full restoration of wellness.

But let’s be realistic. Overall evolution of psychiatry is not as “progressive” as we like to believe. Yes, there are thrilling breakthroughs in basic neuroscience research and understanding brain structure and function at the cellular and molecular levels. However, in many other areas of psychiatric practice, I feel we have moved backward since I began my career 3 decades ago. Egress, not progress, appears to be the state of psychiatry. In a tango-like fashion, psychiatry seems to take 1 step forward on 1 level (science and discovery) and 2 steps back on another level (practice realities). As an optimistic person, it pains me to admit that we have moved backward in several aspects of psychiatry:

• The discovery of chlorpromazine, the first antipsychotic, was a miraculous event for our field, but was it “progress” for our patients? Their symptoms improved partially but they developed serious side effects and remained functionally disabled throughout their lives. Patients were “freed” from locked hospital wards, then hurled into a poorly prepared and under-resourced community mental health care system, resulting in revolving door relapses, extensive drug abuse, rampant stigma, abject poverty, physical neglect, early death, homelessness, and for many psychiatric patients, incarceration in jails and prisons, an environment more restrictive than the reviled asylums. Our patients who were medically ill individuals cared for by doctors, nurses, and other health professionals are now lowly felons. It seems that those unfortunate enough to suffer from a psychotic brain disorder are destined to be further punished for it, a great injustice in the name of “progress.”
• Insurance hassles for serious mental illness did not exist in the asylum era. If an individual developed a psychotic disorder, he or she was admitted to the nearest state hospital without hesitation and provided medical and psychosocial care, even if the stay lasted months or years. Now, the same patient cannot afford psychiatric hospitalization even if he or she has “health insurance” (a euphemism for “restricted health coverage”). Equality of psychiatric disorders with other medical and surgical disorders remains a farce, and the lack of parity for mental illness has deprived millions of patients from adequate care. How many victims of mental illness have suffered or died in the name of “progress” in the health insurance industry?
• Who is the “genius” who stipulated that a psychotic, bipolar, suicidal, or homicidal patient could be effectively treated after 3 to 4 days of hospitalization? How did patients become widgets on an assembly line? Medical students and residents on inpatient wards no longer have the rewarding experience or witnessing full improvement in their patients. Is it progress when a patient with schizophrenia or severe depression is discharged after barely 30% to 40% improvement in symptoms? No wonder relapse, suicide, and homicide rates are very high in the 3 weeks after discharge. Long-term hospitals, the last refuge for severely disabled patients who cannot care for themselves, now are rare. Is that progress?
• Why are psychiatrists shackled by more legal constraints than physicians in other medical specialties? Why should lawyers and judges tell us how to practice medicine and who, when, and how to treat? Legal progress sounds like an oxymoron to me.
• Why is the public mental health system so broken in every state? Why is it so ineffective, chaotic, underfunded, hard to navigate, and demedicalized? Why have psychiatrists—the traditional leaders in mental health—been marginalized to sign prescriptions instead of being executives and policy-setters for mental illness? Respiratory and physical therapists have important roles but the pulmonologist or the orthopedist runs the clinic. Why is it not so in public psychiatry? This is not progress, but a travesty.
• Why is psychiatry now referred to as “behavioral health”? Who decided to fix the name of psychiatric care when the original term is much more comprehensive, factual, and inclusive and uses medical terminology (iatros = “healer” or “medicine”). It is not progress to reduce to “behavior” psychiatric illnesses that involve a broad spectrum of pathologies, including thought disorders, mood disorders, perceptual disorders, cognitive disorders, pain, addictions, and many general medical conditions that manifest with psychiatric signs and symptoms. Redefining psychiatric care with inaccurate terminology certainly is not progress.
• Why are pharmaceutical companies, the only source of drug development, abandoning CNS research? Is it because cardiovascular, oncologic, and GI drugs are more profitable and less “challenging” to develop? Is it progress to turn away from the most critical medical frontier, the human brain, and its diseases? At a time when 80% of psychiatric disorders have no approved medication, it is inexcusable to shirk from discovering drugs that trigger hope for recovery for patients with untreatable mental illness.

Ogden Nash once wrote: “Progress might have been all right once, but it has gone on too long.” I will add to that for psychiatry, progress isn’t what it used to be.

Everybody loves progress. People feel uplifted by the notion of progress, by the dynamic feeling it evokes of “moving forward,” of achieving new milestones and reaching new heights. Progress implies improvement in the human condition and an upgrade in quality of life. In medical disciplines such as psychiatry, it connotes less suffering, better treatments, more hope, improved social and vocational functioning, and full restoration of wellness.

But let’s be realistic. Overall evolution of psychiatry is not as “progressive” as we like to believe. Yes, there are thrilling breakthroughs in basic neuroscience research and understanding brain structure and function at the cellular and molecular levels. However, in many other areas of psychiatric practice, I feel we have moved backward since I began my career 3 decades ago. Egress, not progress, appears to be the state of psychiatry. In a tango-like fashion, psychiatry seems to take 1 step forward on 1 level (science and discovery) and 2 steps back on another level (practice realities). As an optimistic person, it pains me to admit that we have moved backward in several aspects of psychiatry:

• The discovery of chlorpromazine, the first antipsychotic, was a miraculous event for our field, but was it “progress” for our patients? Their symptoms improved partially but they developed serious side effects and remained functionally disabled throughout their lives. Patients were “freed” from locked hospital wards, then hurled into a poorly prepared and under-resourced community mental health care system, resulting in revolving door relapses, extensive drug abuse, rampant stigma, abject poverty, physical neglect, early death, homelessness, and for many psychiatric patients, incarceration in jails and prisons, an environment more restrictive than the reviled asylums. Our patients who were medically ill individuals cared for by doctors, nurses, and other health professionals are now lowly felons. It seems that those unfortunate enough to suffer from a psychotic brain disorder are destined to be further punished for it, a great injustice in the name of “progress.”
• Insurance hassles for serious mental illness did not exist in the asylum era. If an individual developed a psychotic disorder, he or she was admitted to the nearest state hospital without hesitation and provided medical and psychosocial care, even if the stay lasted months or years. Now, the same patient cannot afford psychiatric hospitalization even if he or she has “health insurance” (a euphemism for “restricted health coverage”). Equality of psychiatric disorders with other medical and surgical disorders remains a farce, and the lack of parity for mental illness has deprived millions of patients from adequate care. How many victims of mental illness have suffered or died in the name of “progress” in the health insurance industry?
• Who is the “genius” who stipulated that a psychotic, bipolar, suicidal, or homicidal patient could be effectively treated after 3 to 4 days of hospitalization? How did patients become widgets on an assembly line? Medical students and residents on inpatient wards no longer have the rewarding experience or witnessing full improvement in their patients. Is it progress when a patient with schizophrenia or severe depression is discharged after barely 30% to 40% improvement in symptoms? No wonder relapse, suicide, and homicide rates are very high in the 3 weeks after discharge. Long-term hospitals, the last refuge for severely disabled patients who cannot care for themselves, now are rare. Is that progress?
• Why are psychiatrists shackled by more legal constraints than physicians in other medical specialties? Why should lawyers and judges tell us how to practice medicine and who, when, and how to treat? Legal progress sounds like an oxymoron to me.
• Why is the public mental health system so broken in every state? Why is it so ineffective, chaotic, underfunded, hard to navigate, and demedicalized? Why have psychiatrists—the traditional leaders in mental health—been marginalized to sign prescriptions instead of being executives and policy-setters for mental illness? Respiratory and physical therapists have important roles but the pulmonologist or the orthopedist runs the clinic. Why is it not so in public psychiatry? This is not progress, but a travesty.
• Why is psychiatry now referred to as “behavioral health”? Who decided to fix the name of psychiatric care when the original term is much more comprehensive, factual, and inclusive and uses medical terminology (iatros = “healer” or “medicine”). It is not progress to reduce to “behavior” psychiatric illnesses that involve a broad spectrum of pathologies, including thought disorders, mood disorders, perceptual disorders, cognitive disorders, pain, addictions, and many general medical conditions that manifest with psychiatric signs and symptoms. Redefining psychiatric care with inaccurate terminology certainly is not progress.
• Why are pharmaceutical companies, the only source of drug development, abandoning CNS research? Is it because cardiovascular, oncologic, and GI drugs are more profitable and less “challenging” to develop? Is it progress to turn away from the most critical medical frontier, the human brain, and its diseases? At a time when 80% of psychiatric disorders have no approved medication, it is inexcusable to shirk from discovering drugs that trigger hope for recovery for patients with untreatable mental illness.

Ogden Nash once wrote: “Progress might have been all right once, but it has gone on too long.” I will add to that for psychiatry, progress isn’t what it used to be.

Everybody loves progress. People feel uplifted by the notion of progress, by the dynamic feeling it evokes of “moving forward,” of achieving new milestones and reaching new heights. Progress implies improvement in the human condition and an upgrade in quality of life. In medical disciplines such as psychiatry, it connotes less suffering, better treatments, more hope, improved social and vocational functioning, and full restoration of wellness.

But let’s be realistic. Overall evolution of psychiatry is not as “progressive” as we like to believe. Yes, there are thrilling breakthroughs in basic neuroscience research and understanding brain structure and function at the cellular and molecular levels. However, in many other areas of psychiatric practice, I feel we have moved backward since I began my career 3 decades ago. Egress, not progress, appears to be the state of psychiatry. In a tango-like fashion, psychiatry seems to take 1 step forward on 1 level (science and discovery) and 2 steps back on another level (practice realities). As an optimistic person, it pains me to admit that we have moved backward in several aspects of psychiatry:

• The discovery of chlorpromazine, the first antipsychotic, was a miraculous event for our field, but was it “progress” for our patients? Their symptoms improved partially but they developed serious side effects and remained functionally disabled throughout their lives. Patients were “freed” from locked hospital wards, then hurled into a poorly prepared and under-resourced community mental health care system, resulting in revolving door relapses, extensive drug abuse, rampant stigma, abject poverty, physical neglect, early death, homelessness, and for many psychiatric patients, incarceration in jails and prisons, an environment more restrictive than the reviled asylums. Our patients who were medically ill individuals cared for by doctors, nurses, and other health professionals are now lowly felons. It seems that those unfortunate enough to suffer from a psychotic brain disorder are destined to be further punished for it, a great injustice in the name of “progress.”
• Insurance hassles for serious mental illness did not exist in the asylum era. If an individual developed a psychotic disorder, he or she was admitted to the nearest state hospital without hesitation and provided medical and psychosocial care, even if the stay lasted months or years. Now, the same patient cannot afford psychiatric hospitalization even if he or she has “health insurance” (a euphemism for “restricted health coverage”). Equality of psychiatric disorders with other medical and surgical disorders remains a farce, and the lack of parity for mental illness has deprived millions of patients from adequate care. How many victims of mental illness have suffered or died in the name of “progress” in the health insurance industry?
• Who is the “genius” who stipulated that a psychotic, bipolar, suicidal, or homicidal patient could be effectively treated after 3 to 4 days of hospitalization? How did patients become widgets on an assembly line? Medical students and residents on inpatient wards no longer have the rewarding experience or witnessing full improvement in their patients. Is it progress when a patient with schizophrenia or severe depression is discharged after barely 30% to 40% improvement in symptoms? No wonder relapse, suicide, and homicide rates are very high in the 3 weeks after discharge. Long-term hospitals, the last refuge for severely disabled patients who cannot care for themselves, now are rare. Is that progress?
• Why are psychiatrists shackled by more legal constraints than physicians in other medical specialties? Why should lawyers and judges tell us how to practice medicine and who, when, and how to treat? Legal progress sounds like an oxymoron to me.
• Why is the public mental health system so broken in every state? Why is it so ineffective, chaotic, underfunded, hard to navigate, and demedicalized? Why have psychiatrists—the traditional leaders in mental health—been marginalized to sign prescriptions instead of being executives and policy-setters for mental illness? Respiratory and physical therapists have important roles but the pulmonologist or the orthopedist runs the clinic. Why is it not so in public psychiatry? This is not progress, but a travesty.
• Why is psychiatry now referred to as “behavioral health”? Who decided to fix the name of psychiatric care when the original term is much more comprehensive, factual, and inclusive and uses medical terminology (iatros = “healer” or “medicine”). It is not progress to reduce to “behavior” psychiatric illnesses that involve a broad spectrum of pathologies, including thought disorders, mood disorders, perceptual disorders, cognitive disorders, pain, addictions, and many general medical conditions that manifest with psychiatric signs and symptoms. Redefining psychiatric care with inaccurate terminology certainly is not progress.
• Why are pharmaceutical companies, the only source of drug development, abandoning CNS research? Is it because cardiovascular, oncologic, and GI drugs are more profitable and less “challenging” to develop? Is it progress to turn away from the most critical medical frontier, the human brain, and its diseases? At a time when 80% of psychiatric disorders have no approved medication, it is inexcusable to shirk from discovering drugs that trigger hope for recovery for patients with untreatable mental illness.

Ogden Nash once wrote: “Progress might have been all right once, but it has gone on too long.” I will add to that for psychiatry, progress isn’t what it used to be.

Discuss this article at www.facebook.com/CurrentPsychiatry

Most clinical trials of major depressive disorder (MDD) have focused on diagnosis and treatment of adults, but many younger and older patients also suffer from this condition. The prevalence of MDD is estimated to be 2% in children and 6% in adolescents.¹ Up to 25% of adults age >60 experience MDD, dysthymic disorder, or “minor” depression.²

Although diagnosis and treatment of depression is similar regardless of a patient’s age, younger and older patients may not exhibit typical depressive symptoms (Table 1).^1,2 For example, older adults may be more likely to report a lack of emotions than depressed mood. Vigilance for these types of distinct clinical manifestations can improve early recognition and treatment. In addition, evidence suggests there are differences in MDD treatment for younger and older patients.

This article reviews common challenges in recognizing and treating MDD in children, adolescents, and older adults.

Table 1

Major depressive disorder: Age-related differences

Varying clinical features

Children/adolescents. The clinical presentation of MDD in children and adolescents is similar to that of adults. Children usually display anxiety, irritability, temper tantrums, and somatic complaints before verbally expressing depressive feelings. Psychotic depression in children manifests more often as auditory hallucinations than delusions.¹

Younger vs middle-age adults. Researchers who evaluated baseline clinical and sociodemographic information of 1,498 patients enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study found that the presentation of depressive symptoms in young adult patients (age 18 to 35) differed from those of middle-age (age 36 to 50) patients.³ Younger patients were more likely to be irritable, complain of weight gain and hypersomnia, and have a negative view of life and the future. They also were more likely to report previous suicide attempts and endorse symptoms consistent with generalized anxiety disorder, social phobia, panic disorder, and drug abuse. Middle-age patients had more depressive episodes, deceased libido, and middle insomnia, and more frequently reported gastrointestinal symptoms such as diarrhea or constipation.³

Older adults. In our experience, typical MDD mood symptoms often are absent in older patients. Frequently, we see somatic complaints, motor restlessness, or psychomotor retardation; these symptoms may be attributable to a concurrent medical illness. This in turn may worsen the physical illness, leading to social isolation and considerable medical morbidity.⁴

Pain plays an important role in depression, particularly in older adults. Chronic pain affects up to 65% of older adults who live in the community and up to 80% of those who are institutionalized.⁵ The most common causes of pain in these patients are osteoarthritis, osteoporosis, fibromyalgia, degenerative disk disease, lumbar spinal stenosis, and scoliosis. In addition, neuropathic pain, such as post-herpetic neuralgia and peripheral neuropathy, and injuries resulting from falls often cause long-lasting pain.⁶

The presence of pain tends to negatively affect recognizing and treating depression. Regardless of their age, when a patient presents with pain or depression, investigate and consider treating both conditions.⁷

Memory decline is likely to be depressed older adults’ chief complaint, and when objectively tested these patients often show cognitive impairment.⁸ Whether depressive symptoms in this age group are a reaction to early cognitive deficits or are an early symptom of neurodegeneration remains controversial.⁹ Some case-control studies have found a link between a history of depression and Alzheimer’s disease (AD).^10,11 In general, older patients whose first episode of depression occurs in late life have a higher relative risk of developing some form of dementia; research suggests that 50% of late-life MDD patients will develop dementia within 5 years.¹²

Researchers have considered the possibility that mild cognitive impairment (MCI) and dementia are a continuum of depression. In 1 study, 29 patients with MCI and 31 with MCI and MDD were assessed annually for an average of 4.3 years.¹³ Thirty-six patients with MCI (60%) progressed to AD. Presence of depression at the time of MCI diagnosis did not predict conversion to AD but persistence of depression for 2 to 3 years and the presence of melancholic features were associated with higher risk for AD.

Alexopoulos et al¹⁴ proposed the “vascular hypothesis theory” that cerebrovascular disease can predispose patients, particularly older adults, to depressive symptoms (Table 2).¹⁴ Whether vascular depression is a subtype of MDD remains controversial.

Table 2

Features of vascular depression

Course and prognosis

MDD has been characterized as a self-limited disease, with an average duration of 6 to 9 months. However, newer prospective studies suggest that a substantial number of patients recover more slowly or do not ever fully recover.¹⁵ Several factors, such as genetic/biologic vulnerability and psychosocial factors, influence the courses, prognosis, and risk of relapse/recurrence of MDD in all age groups.

Children and adolescents. The typical duration of a major depressive episode for clinically referred children and adolescents is 8 to 13 months.^1,16 Approximately 90% of these patients’ major depressive episodes remit by 2 years, but up to 10% persist.^1,16 Within 5 years of MDD onset, up to 70% of children and adolescents will experience a recurrence,¹⁷ a rate comparable to adults.

Anxiety disorders, panic disorders, phobias, substance abuse, conduct and oppositional disorders, and attention-deficit/hyperactivity disorder occur 2 to 6 times more frequently in children and adolescents with MDD.^18,19 Children with MDD who have significant psychiatric and psychosocial comorbidity experience poorer outcomes.¹⁸

Older adults. Despite optimal treatment conditions, ≥50% of older patients fail to respond adequately to first-line antidepressant pharmacotherapy.²⁰ Treatment-resistant MDD in older patients increases:

• nonadherence to treatment for comorbid medical disorders
• disability and cognitive impairment
• burden on caregivers
• risk for early mortality, including suicide.²⁰

Differences in treatment

Although MDD often is recurrent, episodic, and in some patients chronic, in general earlier treatment and quicker response lead to better outcomes. A large, naturalistic German study of 795 inpatients with major depression found that early improvement (20% reduction in Hamilton Depression Rating Scale-21 score within the first 2 weeks) with antidepressant therapy may predict later response and remission.²¹

Regardless of a patient’s age, MDD treatment should begin with education. All patients should be involved in their treatment. Encourage patients to become familiar with their triggers and stressors, improve their coping skills, and adopt a healthy lifestyle, which includes a nutritious diet, frequent exercise, and adequate sleep. As maintenance treatment we recommend that patients participate in frequent socialization and activities (Table 3). Refer patients to self-help books, online help guides, and handouts from sources such as National Institute of Mental Health.^22,23 Encourage patients to have patience and perseverance, and guide them through each step of recovery.

In addition to lifestyle modification, other treatment options for depression include pharmacotherapy, interpersonal psychotherapy, cognitive-behavioral therapy (CBT), and electroconvulsive therapy (ECT). All these modalities are effective for acute and maintenance treatment and should be considered when determining the best approach for each patient.

The effectiveness of antidepressants in general is comparable among and within classes.² Base your initial selection on the patient’s previous response to antidepressants and the medication’s side effects profile and cost.

The benefits of exercise for all patients cannot be underestimated.²⁴ Prescribe 20 to 30 minutes of daily exercise as part of recommended lifestyle changes. Writing “daily exercise” on a prescription pad can effectively remind patients that exercise needs to be taken as seriously as medication compliance.

Children and adolescents. For mild depression, supportive therapy seems to be as effective as CBT and medications.²⁵ A randomized controlled trial of 439 depressed adolescents found that CBT plus fluoxetine conferred quicker benefit, but in the long run may not be any more efficacious than pharmacotherapy alone.²⁵ Researchers also found that CBT plus fluoxetine was no more effective than pharmacotherapy alone for adolescents with moderate to severe depression.²⁵

Older adults. Compared with younger patients, geriatric patients typically require lower antidepressant dosages to achieve a specific blood level, but the blood levels at which antidepressants are most effective appear to be similar.² Older patients also may be more likely to relapse and less likely to achieve full response to antidepressants than younger patients.² In older adults, amitriptyline, imipramine, and doxepin are not preferred because these agents may cause orthostatic hypotension and urinary retention.² A depressed older adult who experiences weight loss might benefit from an antidepressant that improves appetite, such as mirtazapine.²⁶ Some research suggests that maintenance antidepressant therapy in older patients experiencing a first-time episode of MDD should continue for up to 2 years.²⁷

A meta-analysis of 12 studies of CBT in depressed adults age ≥60 with chronic pain found that CBT was effective at improving self-reported pain but had no significant effect on depressive symptoms, physical function, or medication use.⁶ ECT often is prescribed for depressed older adults because its safety and efficacy for these patients has been well documented.²⁸ Other neuromodulation therapies include vagus nerve, repetitive transcranial magnetic stimulation, and deep brain stimulation, but none of these treatments have been extensively evaluated in older patients.

Table 3

Avoiding reoccurrence of depression—a ‘prescription’ for patients

Related Resource

• American Psychiatric Association. Treatment of patients with major depressive disorder. 3rd ed. www.psychiatryonline.com/pracGuide/pracGuideChapToc_7.aspx.

Drug Brand Names

• Amitriptyline • Elavil
• Doxepin • Aponal, Silenor
• Fluoxetine • Prozac
• Imipramine • Tofranil
• Mirtazapine • Remeron

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Most clinical trials of major depressive disorder (MDD) have focused on diagnosis and treatment of adults, but many younger and older patients also suffer from this condition. The prevalence of MDD is estimated to be 2% in children and 6% in adolescents.¹ Up to 25% of adults age >60 experience MDD, dysthymic disorder, or “minor” depression.²

Although diagnosis and treatment of depression is similar regardless of a patient’s age, younger and older patients may not exhibit typical depressive symptoms (Table 1).^1,2 For example, older adults may be more likely to report a lack of emotions than depressed mood. Vigilance for these types of distinct clinical manifestations can improve early recognition and treatment. In addition, evidence suggests there are differences in MDD treatment for younger and older patients.

This article reviews common challenges in recognizing and treating MDD in children, adolescents, and older adults.

Table 1

Major depressive disorder: Age-related differences

Varying clinical features

Children/adolescents. The clinical presentation of MDD in children and adolescents is similar to that of adults. Children usually display anxiety, irritability, temper tantrums, and somatic complaints before verbally expressing depressive feelings. Psychotic depression in children manifests more often as auditory hallucinations than delusions.¹

Younger vs middle-age adults. Researchers who evaluated baseline clinical and sociodemographic information of 1,498 patients enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study found that the presentation of depressive symptoms in young adult patients (age 18 to 35) differed from those of middle-age (age 36 to 50) patients.³ Younger patients were more likely to be irritable, complain of weight gain and hypersomnia, and have a negative view of life and the future. They also were more likely to report previous suicide attempts and endorse symptoms consistent with generalized anxiety disorder, social phobia, panic disorder, and drug abuse. Middle-age patients had more depressive episodes, deceased libido, and middle insomnia, and more frequently reported gastrointestinal symptoms such as diarrhea or constipation.³

Older adults. In our experience, typical MDD mood symptoms often are absent in older patients. Frequently, we see somatic complaints, motor restlessness, or psychomotor retardation; these symptoms may be attributable to a concurrent medical illness. This in turn may worsen the physical illness, leading to social isolation and considerable medical morbidity.⁴

Pain plays an important role in depression, particularly in older adults. Chronic pain affects up to 65% of older adults who live in the community and up to 80% of those who are institutionalized.⁵ The most common causes of pain in these patients are osteoarthritis, osteoporosis, fibromyalgia, degenerative disk disease, lumbar spinal stenosis, and scoliosis. In addition, neuropathic pain, such as post-herpetic neuralgia and peripheral neuropathy, and injuries resulting from falls often cause long-lasting pain.⁶

The presence of pain tends to negatively affect recognizing and treating depression. Regardless of their age, when a patient presents with pain or depression, investigate and consider treating both conditions.⁷

Memory decline is likely to be depressed older adults’ chief complaint, and when objectively tested these patients often show cognitive impairment.⁸ Whether depressive symptoms in this age group are a reaction to early cognitive deficits or are an early symptom of neurodegeneration remains controversial.⁹ Some case-control studies have found a link between a history of depression and Alzheimer’s disease (AD).^10,11 In general, older patients whose first episode of depression occurs in late life have a higher relative risk of developing some form of dementia; research suggests that 50% of late-life MDD patients will develop dementia within 5 years.¹²

Researchers have considered the possibility that mild cognitive impairment (MCI) and dementia are a continuum of depression. In 1 study, 29 patients with MCI and 31 with MCI and MDD were assessed annually for an average of 4.3 years.¹³ Thirty-six patients with MCI (60%) progressed to AD. Presence of depression at the time of MCI diagnosis did not predict conversion to AD but persistence of depression for 2 to 3 years and the presence of melancholic features were associated with higher risk for AD.

Alexopoulos et al¹⁴ proposed the “vascular hypothesis theory” that cerebrovascular disease can predispose patients, particularly older adults, to depressive symptoms (Table 2).¹⁴ Whether vascular depression is a subtype of MDD remains controversial.

Table 2

Features of vascular depression

Course and prognosis

MDD has been characterized as a self-limited disease, with an average duration of 6 to 9 months. However, newer prospective studies suggest that a substantial number of patients recover more slowly or do not ever fully recover.¹⁵ Several factors, such as genetic/biologic vulnerability and psychosocial factors, influence the courses, prognosis, and risk of relapse/recurrence of MDD in all age groups.

Children and adolescents. The typical duration of a major depressive episode for clinically referred children and adolescents is 8 to 13 months.^1,16 Approximately 90% of these patients’ major depressive episodes remit by 2 years, but up to 10% persist.^1,16 Within 5 years of MDD onset, up to 70% of children and adolescents will experience a recurrence,¹⁷ a rate comparable to adults.

Anxiety disorders, panic disorders, phobias, substance abuse, conduct and oppositional disorders, and attention-deficit/hyperactivity disorder occur 2 to 6 times more frequently in children and adolescents with MDD.^18,19 Children with MDD who have significant psychiatric and psychosocial comorbidity experience poorer outcomes.¹⁸

Older adults. Despite optimal treatment conditions, ≥50% of older patients fail to respond adequately to first-line antidepressant pharmacotherapy.²⁰ Treatment-resistant MDD in older patients increases:

• nonadherence to treatment for comorbid medical disorders
• disability and cognitive impairment
• burden on caregivers
• risk for early mortality, including suicide.²⁰

Differences in treatment

Although MDD often is recurrent, episodic, and in some patients chronic, in general earlier treatment and quicker response lead to better outcomes. A large, naturalistic German study of 795 inpatients with major depression found that early improvement (20% reduction in Hamilton Depression Rating Scale-21 score within the first 2 weeks) with antidepressant therapy may predict later response and remission.²¹

Regardless of a patient’s age, MDD treatment should begin with education. All patients should be involved in their treatment. Encourage patients to become familiar with their triggers and stressors, improve their coping skills, and adopt a healthy lifestyle, which includes a nutritious diet, frequent exercise, and adequate sleep. As maintenance treatment we recommend that patients participate in frequent socialization and activities (Table 3). Refer patients to self-help books, online help guides, and handouts from sources such as National Institute of Mental Health.^22,23 Encourage patients to have patience and perseverance, and guide them through each step of recovery.

In addition to lifestyle modification, other treatment options for depression include pharmacotherapy, interpersonal psychotherapy, cognitive-behavioral therapy (CBT), and electroconvulsive therapy (ECT). All these modalities are effective for acute and maintenance treatment and should be considered when determining the best approach for each patient.

The effectiveness of antidepressants in general is comparable among and within classes.² Base your initial selection on the patient’s previous response to antidepressants and the medication’s side effects profile and cost.

The benefits of exercise for all patients cannot be underestimated.²⁴ Prescribe 20 to 30 minutes of daily exercise as part of recommended lifestyle changes. Writing “daily exercise” on a prescription pad can effectively remind patients that exercise needs to be taken as seriously as medication compliance.

Children and adolescents. For mild depression, supportive therapy seems to be as effective as CBT and medications.²⁵ A randomized controlled trial of 439 depressed adolescents found that CBT plus fluoxetine conferred quicker benefit, but in the long run may not be any more efficacious than pharmacotherapy alone.²⁵ Researchers also found that CBT plus fluoxetine was no more effective than pharmacotherapy alone for adolescents with moderate to severe depression.²⁵

Older adults. Compared with younger patients, geriatric patients typically require lower antidepressant dosages to achieve a specific blood level, but the blood levels at which antidepressants are most effective appear to be similar.² Older patients also may be more likely to relapse and less likely to achieve full response to antidepressants than younger patients.² In older adults, amitriptyline, imipramine, and doxepin are not preferred because these agents may cause orthostatic hypotension and urinary retention.² A depressed older adult who experiences weight loss might benefit from an antidepressant that improves appetite, such as mirtazapine.²⁶ Some research suggests that maintenance antidepressant therapy in older patients experiencing a first-time episode of MDD should continue for up to 2 years.²⁷

A meta-analysis of 12 studies of CBT in depressed adults age ≥60 with chronic pain found that CBT was effective at improving self-reported pain but had no significant effect on depressive symptoms, physical function, or medication use.⁶ ECT often is prescribed for depressed older adults because its safety and efficacy for these patients has been well documented.²⁸ Other neuromodulation therapies include vagus nerve, repetitive transcranial magnetic stimulation, and deep brain stimulation, but none of these treatments have been extensively evaluated in older patients.

Table 3

Avoiding reoccurrence of depression—a ‘prescription’ for patients

Related Resource

• American Psychiatric Association. Treatment of patients with major depressive disorder. 3rd ed. www.psychiatryonline.com/pracGuide/pracGuideChapToc_7.aspx.

Drug Brand Names

• Amitriptyline • Elavil
• Doxepin • Aponal, Silenor
• Fluoxetine • Prozac
• Imipramine • Tofranil
• Mirtazapine • Remeron

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Most clinical trials of major depressive disorder (MDD) have focused on diagnosis and treatment of adults, but many younger and older patients also suffer from this condition. The prevalence of MDD is estimated to be 2% in children and 6% in adolescents.¹ Up to 25% of adults age >60 experience MDD, dysthymic disorder, or “minor” depression.²

Although diagnosis and treatment of depression is similar regardless of a patient’s age, younger and older patients may not exhibit typical depressive symptoms (Table 1).^1,2 For example, older adults may be more likely to report a lack of emotions than depressed mood. Vigilance for these types of distinct clinical manifestations can improve early recognition and treatment. In addition, evidence suggests there are differences in MDD treatment for younger and older patients.

This article reviews common challenges in recognizing and treating MDD in children, adolescents, and older adults.

Table 1

Major depressive disorder: Age-related differences

Varying clinical features

Children/adolescents. The clinical presentation of MDD in children and adolescents is similar to that of adults. Children usually display anxiety, irritability, temper tantrums, and somatic complaints before verbally expressing depressive feelings. Psychotic depression in children manifests more often as auditory hallucinations than delusions.¹

Younger vs middle-age adults. Researchers who evaluated baseline clinical and sociodemographic information of 1,498 patients enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study found that the presentation of depressive symptoms in young adult patients (age 18 to 35) differed from those of middle-age (age 36 to 50) patients.³ Younger patients were more likely to be irritable, complain of weight gain and hypersomnia, and have a negative view of life and the future. They also were more likely to report previous suicide attempts and endorse symptoms consistent with generalized anxiety disorder, social phobia, panic disorder, and drug abuse. Middle-age patients had more depressive episodes, deceased libido, and middle insomnia, and more frequently reported gastrointestinal symptoms such as diarrhea or constipation.³

Older adults. In our experience, typical MDD mood symptoms often are absent in older patients. Frequently, we see somatic complaints, motor restlessness, or psychomotor retardation; these symptoms may be attributable to a concurrent medical illness. This in turn may worsen the physical illness, leading to social isolation and considerable medical morbidity.⁴

Pain plays an important role in depression, particularly in older adults. Chronic pain affects up to 65% of older adults who live in the community and up to 80% of those who are institutionalized.⁵ The most common causes of pain in these patients are osteoarthritis, osteoporosis, fibromyalgia, degenerative disk disease, lumbar spinal stenosis, and scoliosis. In addition, neuropathic pain, such as post-herpetic neuralgia and peripheral neuropathy, and injuries resulting from falls often cause long-lasting pain.⁶

The presence of pain tends to negatively affect recognizing and treating depression. Regardless of their age, when a patient presents with pain or depression, investigate and consider treating both conditions.⁷

Memory decline is likely to be depressed older adults’ chief complaint, and when objectively tested these patients often show cognitive impairment.⁸ Whether depressive symptoms in this age group are a reaction to early cognitive deficits or are an early symptom of neurodegeneration remains controversial.⁹ Some case-control studies have found a link between a history of depression and Alzheimer’s disease (AD).^10,11 In general, older patients whose first episode of depression occurs in late life have a higher relative risk of developing some form of dementia; research suggests that 50% of late-life MDD patients will develop dementia within 5 years.¹²

Researchers have considered the possibility that mild cognitive impairment (MCI) and dementia are a continuum of depression. In 1 study, 29 patients with MCI and 31 with MCI and MDD were assessed annually for an average of 4.3 years.¹³ Thirty-six patients with MCI (60%) progressed to AD. Presence of depression at the time of MCI diagnosis did not predict conversion to AD but persistence of depression for 2 to 3 years and the presence of melancholic features were associated with higher risk for AD.

Alexopoulos et al¹⁴ proposed the “vascular hypothesis theory” that cerebrovascular disease can predispose patients, particularly older adults, to depressive symptoms (Table 2).¹⁴ Whether vascular depression is a subtype of MDD remains controversial.

Table 2

Features of vascular depression

Course and prognosis

MDD has been characterized as a self-limited disease, with an average duration of 6 to 9 months. However, newer prospective studies suggest that a substantial number of patients recover more slowly or do not ever fully recover.¹⁵ Several factors, such as genetic/biologic vulnerability and psychosocial factors, influence the courses, prognosis, and risk of relapse/recurrence of MDD in all age groups.

Children and adolescents. The typical duration of a major depressive episode for clinically referred children and adolescents is 8 to 13 months.^1,16 Approximately 90% of these patients’ major depressive episodes remit by 2 years, but up to 10% persist.^1,16 Within 5 years of MDD onset, up to 70% of children and adolescents will experience a recurrence,¹⁷ a rate comparable to adults.

Anxiety disorders, panic disorders, phobias, substance abuse, conduct and oppositional disorders, and attention-deficit/hyperactivity disorder occur 2 to 6 times more frequently in children and adolescents with MDD.^18,19 Children with MDD who have significant psychiatric and psychosocial comorbidity experience poorer outcomes.¹⁸

Older adults. Despite optimal treatment conditions, ≥50% of older patients fail to respond adequately to first-line antidepressant pharmacotherapy.²⁰ Treatment-resistant MDD in older patients increases:

• nonadherence to treatment for comorbid medical disorders
• disability and cognitive impairment
• burden on caregivers
• risk for early mortality, including suicide.²⁰

Differences in treatment

Although MDD often is recurrent, episodic, and in some patients chronic, in general earlier treatment and quicker response lead to better outcomes. A large, naturalistic German study of 795 inpatients with major depression found that early improvement (20% reduction in Hamilton Depression Rating Scale-21 score within the first 2 weeks) with antidepressant therapy may predict later response and remission.²¹

Regardless of a patient’s age, MDD treatment should begin with education. All patients should be involved in their treatment. Encourage patients to become familiar with their triggers and stressors, improve their coping skills, and adopt a healthy lifestyle, which includes a nutritious diet, frequent exercise, and adequate sleep. As maintenance treatment we recommend that patients participate in frequent socialization and activities (Table 3). Refer patients to self-help books, online help guides, and handouts from sources such as National Institute of Mental Health.^22,23 Encourage patients to have patience and perseverance, and guide them through each step of recovery.

In addition to lifestyle modification, other treatment options for depression include pharmacotherapy, interpersonal psychotherapy, cognitive-behavioral therapy (CBT), and electroconvulsive therapy (ECT). All these modalities are effective for acute and maintenance treatment and should be considered when determining the best approach for each patient.

The effectiveness of antidepressants in general is comparable among and within classes.² Base your initial selection on the patient’s previous response to antidepressants and the medication’s side effects profile and cost.

The benefits of exercise for all patients cannot be underestimated.²⁴ Prescribe 20 to 30 minutes of daily exercise as part of recommended lifestyle changes. Writing “daily exercise” on a prescription pad can effectively remind patients that exercise needs to be taken as seriously as medication compliance.

Children and adolescents. For mild depression, supportive therapy seems to be as effective as CBT and medications.²⁵ A randomized controlled trial of 439 depressed adolescents found that CBT plus fluoxetine conferred quicker benefit, but in the long run may not be any more efficacious than pharmacotherapy alone.²⁵ Researchers also found that CBT plus fluoxetine was no more effective than pharmacotherapy alone for adolescents with moderate to severe depression.²⁵

Older adults. Compared with younger patients, geriatric patients typically require lower antidepressant dosages to achieve a specific blood level, but the blood levels at which antidepressants are most effective appear to be similar.² Older patients also may be more likely to relapse and less likely to achieve full response to antidepressants than younger patients.² In older adults, amitriptyline, imipramine, and doxepin are not preferred because these agents may cause orthostatic hypotension and urinary retention.² A depressed older adult who experiences weight loss might benefit from an antidepressant that improves appetite, such as mirtazapine.²⁶ Some research suggests that maintenance antidepressant therapy in older patients experiencing a first-time episode of MDD should continue for up to 2 years.²⁷

A meta-analysis of 12 studies of CBT in depressed adults age ≥60 with chronic pain found that CBT was effective at improving self-reported pain but had no significant effect on depressive symptoms, physical function, or medication use.⁶ ECT often is prescribed for depressed older adults because its safety and efficacy for these patients has been well documented.²⁸ Other neuromodulation therapies include vagus nerve, repetitive transcranial magnetic stimulation, and deep brain stimulation, but none of these treatments have been extensively evaluated in older patients.

Table 3

Avoiding reoccurrence of depression—a ‘prescription’ for patients

Related Resource

• American Psychiatric Association. Treatment of patients with major depressive disorder. 3rd ed. www.psychiatryonline.com/pracGuide/pracGuideChapToc_7.aspx.

Drug Brand Names

• Amitriptyline • Elavil
• Doxepin • Aponal, Silenor
• Fluoxetine • Prozac
• Imipramine • Tofranil
• Mirtazapine • Remeron

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Patients with treatment-resistant schizophrenia can be broadly defined to include any persons with residual symptoms that cause distress or impairment despite several treatment attempts. Unfortunately, this definition may include most of our patients with schizophrenia.

Clinical trial data on treatment-resistant schizophrenia can be contradictory, leaving “N of 1” empirical treatment trials for individual patients as the current state of the art. This article presents data from clinical trials for pharmacologic and nonpharmacologic options and offers recommendations to try to help our treatment-resistant patients.

Defining treatment resistance

Research reports regarding treatment-resistant or treatment-refractory schizophrenia have relied on operational criteria such as that found in the pivotal study for clozapine¹:

• at least 3 periods of treatment in the preceding 5 years with neuroleptic agents from at least 2 different chemical classes at dosages equivalent to ≥1000 mg/d of chlorpromazine for 6 weeks, each without significant symptomatic relief, and
• no period of good functioning within the preceding 5 years.¹ In that study, patients also underwent a prospective treatment trial with what we now know are high doses of haloperidol (up to 60 mg/d or higher) and benztropine mesylate (6 mg/d) for a period of 6 weeks to confirm lack of drug responsiveness. Other studies have more relaxed criteria, such as:
• persistent positive symptoms—hallucinations, delusions, or marked thought disorder—after at least 6 contiguous weeks of past or present treatment, with ≥1 typical antipsychotics at doses of ≥600 mg/d in chlorpromazine equivalents
• a poor level of functioning over the past 2 years, as defined by the lack of competitive employment or enrollment in an academic or vocational program and not having age-expected interpersonal relations with someone outside the biologic family with whom ongoing regular contacts were maintained.²

In this study, no prospective period of treatment to confirm lack of drug responsiveness was required.

The most clinically relevant definition of treatment resistance depends on the patient’s individual circumstances. For some patients, targeting positive symptoms is a high priority; for others it may be negative and cognitive symptoms; for others, it may be excitement. Moreover, families may complain of symptoms or behavior that are of little or no concern to your patient.

Although we desire treatment response and remission for our patients, definitions for remission and functional recovery are in flux. Proposed criteria define symptomatic remission as 6-month maintenance of simultaneous ratings of mild or less on delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms.^3,4 Emsley et al⁴ note that reported remission rates vary widely across studies (17% to 88%) and that patients in remission do better than their non-remitted counterparts in several other outcome domains. Also, patients move in and out of remission over time. Predictors of remission include:

• early treatment response
• baseline symptom severity
• subjective well-being.⁴

Recovery is a more complex construct than remission and includes social outcomes. Although recovery lacks a standard definition, it is the implied goal of treatment. Anything short of recovery can be viewed as inadequate. If we set the bar at this height, many or most of the patients we treat for schizophrenia could be considered treatment-resistant.

Confounding factors

Before concluding that a patient is treatment-resistant, address medication adherence and possible substance use. Partial or nonadherence with antipsychotic treatment is common—approximately one-half of patients are nonadherent⁵—and associated with relapse and re-hospitalization.⁶ In addition, an estimated one-half of all individuals with schizophrenia also use substances.⁷

Be aware of the optimal dose for any particular antipsychotic and factors that can interfere with achieving adequate plasma levels. This means acknowledging that dosing ranges established during registration studies may not reflect the needs of day-to-day clinical practice.⁸ Pharmacokinetic interactions with other medications, such as carbamazepine or rifampin, can induce liver enzymes and result in subtherapeutic antipsychotic levels. Cigarette smoking also may have this effect. Lowered clozapine or olanzapine plasma levels have been observed in patients who resume smoking after being discharged from a non-smoking inpatient environment. Some antipsychotics, such as ziprasidone and lurasidone, must be taken with food in order to have sufficient bioavailability.⁹

What does a patient want?

Patients with schizophrenia often have limited insight into their psychotic symptoms.¹⁰ Savvy clinicians will attempt to leverage a patient’s insight into ancillary symptoms—such as impaired sleep, anxiety, and dysphoria—to encourage a therapeutic alliance and therefore adherence. If patients feel their concerns are not addressed, they may consider treatment inadequate even though the intensity of their hallucinations and delusions may have decreased.

Which antipsychotic is best?

Meta-analyses of randomized controlled trials (RCTs) of antipsychotic treatment for schizophrenia found that, although individual response will vary, clozapine generally has better efficacy that other antipsychotics.^11-13 Olanzapine, risperidone, and amisulpride (which is not available in the United States) appear to be more efficacious than first-generation antipsychotics. Other second-generation antipsychotics do not consistently show greater efficacy than first-generation antipsychotics, although their tolerability profiles vary greatly.^11-13

Antipsychotic monotherapy. More than 25 RCTs have focused on antipsychotic monotherapy for treatment-resistant patients; for a bibliography of these studies, click here. For the most part, clozapine has consistently demonstrated superiority over comparators. Because not all patients with schizophrenia can tolerate clozapine or are willing to have their blood monitored as required, other second-generation antipsychotics have been suggested as possible substitutes. Olanzapine has established superior efficacy to first-generation antipsychotics^11-13 and perhaps comparable efficacy to clozapine in some studies.^2,14-17 Risperidone appeared to be comparable to clozapine in some studies,^18,19 whereas clozapine’s superiority was evident in others.^14,20,21 Although an RCT found comparable efficacy for ziprasidone vs clozapine,²² patients enrolled in this study may not have been treatment-resistant regarding efficacy but instead could not tolerate prior treatments. Enrolling patients on the basis of poor efficacy and/or poor tolerability to their prior antipsychotic regimen also has complicated the interpretation of studies comparing olanzapine with clozapine¹⁶ and risperidone with clozapine.¹⁸

Antipsychotic combinations. Combinations of antipsychotics are used commonly when treating chronic schizophrenia.²³ Of the approximately 20 RCTs of antipsychotic combination therapy, most tested clozapine combined with other second-generation antipsychotics, such as risperidone. For a bibliography of these studies, click here. Only 5 studies support a combination approach (Table 1).

Table 1

Antipsychotic combinations: Few studies support efficacy

What about augmentation?

Adjunctive non-antipsychotics also are commonly used when treating patients with chronic schizophrenia. For example, lithium and anticonvulsants are used in approximately one-half of all inpatients with schizophrenia in facilities operated by the State of New York Office of Mental Health.^24,25 The evidence base for these agents as adjuncts to antipsychotics generally is weak.²⁶ Specifically, early reports of benefit with adjunctive lithium have been negated by later studies. Similarly, large trials of adjunctive valproate and lamotrigine have failed to replicate early and promising efficacy signals from smaller trials, although the larger studies did not specifically target treatment-resistant schizophrenia.

Among mood stabilizers, lamotrigine may be the most promising for treatment-resistant schizophrenia. In a meta-analysis of clinical trials examining schizophrenia patients receiving clozapine (N=161) who were randomized to receive adjunctive lamotrigine or adjunctive placebo, lamotrigine was superior to placebo in total score for psychosis symptoms and scores for positive and negative symptoms.²⁷

More than 125 published RCTs have studied a wide variety of adjunctive agents other than lithium or anticonvulsants for treating persistent schizophrenia symptoms (Table 2).

Only some of the approximately 40 RCTs regarding adjunctive antidepressants in patients with chronic schizophrenia focused on patients with ongoing depressive symptoms. For a bibliography of these studies, click here. In a meta-analysis measuring improvement of negative symptoms from 23 trials (N=819),²⁸ the effect size was moderate in favor of antidepressants. Subgroup analysis revealed significant responses for fluoxetine, trazodone, and ritanserin.

More than 50 RCTs have focused on augmenting medications for cognitive dysfunction in chronic schizophrenia. Unfortunately, agents used to treat Alzheimer’s disease have shown disappointing results when tested in patients with schizophrenia, as have agents prescribed for attention-deficit/hyperactivity disorder (methylphenidate, guanfacine, atomoxetine) or agents used to promote alertness (modafinil and armodafinil).

Medications that act on glutamate receptors may offer another potential solution, although not in combination with clozapine.²⁹

Other agents that require further study where ≥2 positive studies have been reported (with ≤2 negative studies) include celecoxib, neurosteroids and hormones, purinergic agents, serotonin 5-HT1A receptor agonists, and serotonin 5-HT3 receptor antagonists.

Table 2

Agents studied as adjuncts to antipsychotics

Therapeutic neuromodulation

More than 10 RCTs of repetitive transcranial magnetic stimulation (rTMS) in patients with refractory symptoms of schizophrenia have been published; the results were mixed. For a bibliography of these studies, click here. In a meta-analysis of 9 trials (n=213),³⁰ prefrontal rTMS for treating negative symptoms demonstrated a small-to-medium effect size. In another meta-analysis³¹ of all prospective studies of rTMS for negative symptoms and for auditory hallucinations and overall positive symptoms in refractory schizophrenia, the effect sizes showed moderate effects.

Fewer controlled trials are available for electroconvulsive therapy,^32,33 but its use with clozapine appears encouraging.³⁴

Psychological and behavioral intervention. Cognitive-behavioral therapy, although labor-intensive, can be helpful even in patients considered treatment-resistant (Table 3). These interventions generally are provided together with pharmacotherapy.

Complementary and alternative therapies. Patients and their families may ask about complementary and alternative therapies, particularly when conventional approaches have not been successful. A meta-analysis of 6 studies (n=828)³⁵ that reviewed adjunctive use of ginkgo in patients with chronic schizophrenia found statistically significant moderate improvement in total and negative symptoms. Negative reports also are available, including a 5-month study of adjunctive megavitamins that did not demonstrate any benefits.³⁶ In a review of 13 RCTs of acupuncture for schizophrenia, Lee et al found the overall methodological quality was too low to draw firm conclusions.³⁷

Table 3

Cognitive-behavioral therapy for schizophrenia

Clinical recommendations

Before declaring a patient with schizophrenia as treatment-resistant, ensure that an adequate trial of medication did take place. This includes consideration of adequate dosing and pharmacokinetic issues. Awareness of potential substance use and/or partial adherence or nonadherence also is critical because these factors can impact treatment response.

When prescribing for a treatment-resistant schizophrenia patient, identify specific target symptoms to better inform medication selection—especially for symptoms that the patient feels are important. For example, consider an antidepressant for patients who have negative or depressive symptoms. Also take into account other patient-centered concerns, such as tolerability issues that may have interfered with adherence and response in the past.

Clozapine remains the medication of choice for treatment-resistant schizophrenia. Despite dozens of RCTs of potential adjunctive agents for treatment-resistant schizophrenia, no single approach has consistently shown efficacy in reducing symptoms, improving cognition, or increasing a patient’s level of function. Individual response can vary, and our search for the “outlier” who does respond to an adjunctive agent can explain our use of these strategies in clinical practice.

Related Resources

• Cochrane Database of Systematic Reviews. www.cochrane.org/reviews. This database contains reviews of additional therapeutic options for patients with treatment-resistant schizophrenia. As of February 23, 2011, 157 reviews were available.
• Citrome L. Treatment-refractory schizophrenia: What it is and what’s been done about it. Neuropsychiatry. 2011. Epub ahead of print.
• Citrome L. Clozapine for schizophrenia. Life-threatening or life-saving treatment? Current Psychiatry. 2009;8(12):56-63.

Drug Brand Names

• Aripiprazole • Abilify
• Armodafinil • Nuvigil
• Atomoxetine • Strattera
• Benztropine mesylate • Cogentin
• Carbamazepine • Tegretol
• Celecoxib • Celebrex
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluoxetine • Prozac
• Guanfacine • Tenex
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid, others
• Lurasidone • Latuda
• Methylphenidate • Ritalin, Methylin, others
• Modafinil • Provigil
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Rifampin • Rifadin
• Risperidone • Risperdal
• Trazodone • Desyrel, Oleptro
• Valproate (Divalproex) • Depakote, Depakote ER
• Ziprasidone • Geodon

Disclosure

No writing assistance or external financial support was used for this article. Dr. Citrome is a consultant for, has received honoraria from, or has conducted clinical research supported by Abbott Laboratories, AstraZeneca Pharmaceuticals, Avanir Pharmaceuticals, Azur Pharma Inc., Barr Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Forest Research Institute, GlaxoSmithKline, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Merck, Novartis, Pfizer Inc., Sunovion, Valeant Pharmaceuticals, and Vanda Pharmaceuticals.

Discuss this article at www.facebook.com/CurrentPsychiatry

Patients with treatment-resistant schizophrenia can be broadly defined to include any persons with residual symptoms that cause distress or impairment despite several treatment attempts. Unfortunately, this definition may include most of our patients with schizophrenia.

Clinical trial data on treatment-resistant schizophrenia can be contradictory, leaving “N of 1” empirical treatment trials for individual patients as the current state of the art. This article presents data from clinical trials for pharmacologic and nonpharmacologic options and offers recommendations to try to help our treatment-resistant patients.

Defining treatment resistance

Research reports regarding treatment-resistant or treatment-refractory schizophrenia have relied on operational criteria such as that found in the pivotal study for clozapine¹:

• at least 3 periods of treatment in the preceding 5 years with neuroleptic agents from at least 2 different chemical classes at dosages equivalent to ≥1000 mg/d of chlorpromazine for 6 weeks, each without significant symptomatic relief, and
• no period of good functioning within the preceding 5 years.¹ In that study, patients also underwent a prospective treatment trial with what we now know are high doses of haloperidol (up to 60 mg/d or higher) and benztropine mesylate (6 mg/d) for a period of 6 weeks to confirm lack of drug responsiveness. Other studies have more relaxed criteria, such as:
• persistent positive symptoms—hallucinations, delusions, or marked thought disorder—after at least 6 contiguous weeks of past or present treatment, with ≥1 typical antipsychotics at doses of ≥600 mg/d in chlorpromazine equivalents
• a poor level of functioning over the past 2 years, as defined by the lack of competitive employment or enrollment in an academic or vocational program and not having age-expected interpersonal relations with someone outside the biologic family with whom ongoing regular contacts were maintained.²

In this study, no prospective period of treatment to confirm lack of drug responsiveness was required.

The most clinically relevant definition of treatment resistance depends on the patient’s individual circumstances. For some patients, targeting positive symptoms is a high priority; for others it may be negative and cognitive symptoms; for others, it may be excitement. Moreover, families may complain of symptoms or behavior that are of little or no concern to your patient.

Although we desire treatment response and remission for our patients, definitions for remission and functional recovery are in flux. Proposed criteria define symptomatic remission as 6-month maintenance of simultaneous ratings of mild or less on delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms.^3,4 Emsley et al⁴ note that reported remission rates vary widely across studies (17% to 88%) and that patients in remission do better than their non-remitted counterparts in several other outcome domains. Also, patients move in and out of remission over time. Predictors of remission include:

• early treatment response
• baseline symptom severity
• subjective well-being.⁴

Recovery is a more complex construct than remission and includes social outcomes. Although recovery lacks a standard definition, it is the implied goal of treatment. Anything short of recovery can be viewed as inadequate. If we set the bar at this height, many or most of the patients we treat for schizophrenia could be considered treatment-resistant.

Confounding factors

Before concluding that a patient is treatment-resistant, address medication adherence and possible substance use. Partial or nonadherence with antipsychotic treatment is common—approximately one-half of patients are nonadherent⁵—and associated with relapse and re-hospitalization.⁶ In addition, an estimated one-half of all individuals with schizophrenia also use substances.⁷

Be aware of the optimal dose for any particular antipsychotic and factors that can interfere with achieving adequate plasma levels. This means acknowledging that dosing ranges established during registration studies may not reflect the needs of day-to-day clinical practice.⁸ Pharmacokinetic interactions with other medications, such as carbamazepine or rifampin, can induce liver enzymes and result in subtherapeutic antipsychotic levels. Cigarette smoking also may have this effect. Lowered clozapine or olanzapine plasma levels have been observed in patients who resume smoking after being discharged from a non-smoking inpatient environment. Some antipsychotics, such as ziprasidone and lurasidone, must be taken with food in order to have sufficient bioavailability.⁹

What does a patient want?

Patients with schizophrenia often have limited insight into their psychotic symptoms.¹⁰ Savvy clinicians will attempt to leverage a patient’s insight into ancillary symptoms—such as impaired sleep, anxiety, and dysphoria—to encourage a therapeutic alliance and therefore adherence. If patients feel their concerns are not addressed, they may consider treatment inadequate even though the intensity of their hallucinations and delusions may have decreased.

Which antipsychotic is best?

Meta-analyses of randomized controlled trials (RCTs) of antipsychotic treatment for schizophrenia found that, although individual response will vary, clozapine generally has better efficacy that other antipsychotics.^11-13 Olanzapine, risperidone, and amisulpride (which is not available in the United States) appear to be more efficacious than first-generation antipsychotics. Other second-generation antipsychotics do not consistently show greater efficacy than first-generation antipsychotics, although their tolerability profiles vary greatly.^11-13

Antipsychotic monotherapy. More than 25 RCTs have focused on antipsychotic monotherapy for treatment-resistant patients; for a bibliography of these studies, click here. For the most part, clozapine has consistently demonstrated superiority over comparators. Because not all patients with schizophrenia can tolerate clozapine or are willing to have their blood monitored as required, other second-generation antipsychotics have been suggested as possible substitutes. Olanzapine has established superior efficacy to first-generation antipsychotics^11-13 and perhaps comparable efficacy to clozapine in some studies.^2,14-17 Risperidone appeared to be comparable to clozapine in some studies,^18,19 whereas clozapine’s superiority was evident in others.^14,20,21 Although an RCT found comparable efficacy for ziprasidone vs clozapine,²² patients enrolled in this study may not have been treatment-resistant regarding efficacy but instead could not tolerate prior treatments. Enrolling patients on the basis of poor efficacy and/or poor tolerability to their prior antipsychotic regimen also has complicated the interpretation of studies comparing olanzapine with clozapine¹⁶ and risperidone with clozapine.¹⁸

Antipsychotic combinations. Combinations of antipsychotics are used commonly when treating chronic schizophrenia.²³ Of the approximately 20 RCTs of antipsychotic combination therapy, most tested clozapine combined with other second-generation antipsychotics, such as risperidone. For a bibliography of these studies, click here. Only 5 studies support a combination approach (Table 1).

Table 1

Antipsychotic combinations: Few studies support efficacy

What about augmentation?

Adjunctive non-antipsychotics also are commonly used when treating patients with chronic schizophrenia. For example, lithium and anticonvulsants are used in approximately one-half of all inpatients with schizophrenia in facilities operated by the State of New York Office of Mental Health.^24,25 The evidence base for these agents as adjuncts to antipsychotics generally is weak.²⁶ Specifically, early reports of benefit with adjunctive lithium have been negated by later studies. Similarly, large trials of adjunctive valproate and lamotrigine have failed to replicate early and promising efficacy signals from smaller trials, although the larger studies did not specifically target treatment-resistant schizophrenia.

Among mood stabilizers, lamotrigine may be the most promising for treatment-resistant schizophrenia. In a meta-analysis of clinical trials examining schizophrenia patients receiving clozapine (N=161) who were randomized to receive adjunctive lamotrigine or adjunctive placebo, lamotrigine was superior to placebo in total score for psychosis symptoms and scores for positive and negative symptoms.²⁷

More than 125 published RCTs have studied a wide variety of adjunctive agents other than lithium or anticonvulsants for treating persistent schizophrenia symptoms (Table 2).

Only some of the approximately 40 RCTs regarding adjunctive antidepressants in patients with chronic schizophrenia focused on patients with ongoing depressive symptoms. For a bibliography of these studies, click here. In a meta-analysis measuring improvement of negative symptoms from 23 trials (N=819),²⁸ the effect size was moderate in favor of antidepressants. Subgroup analysis revealed significant responses for fluoxetine, trazodone, and ritanserin.

More than 50 RCTs have focused on augmenting medications for cognitive dysfunction in chronic schizophrenia. Unfortunately, agents used to treat Alzheimer’s disease have shown disappointing results when tested in patients with schizophrenia, as have agents prescribed for attention-deficit/hyperactivity disorder (methylphenidate, guanfacine, atomoxetine) or agents used to promote alertness (modafinil and armodafinil).

Medications that act on glutamate receptors may offer another potential solution, although not in combination with clozapine.²⁹

Other agents that require further study where ≥2 positive studies have been reported (with ≤2 negative studies) include celecoxib, neurosteroids and hormones, purinergic agents, serotonin 5-HT1A receptor agonists, and serotonin 5-HT3 receptor antagonists.

Table 2

Agents studied as adjuncts to antipsychotics

Therapeutic neuromodulation

More than 10 RCTs of repetitive transcranial magnetic stimulation (rTMS) in patients with refractory symptoms of schizophrenia have been published; the results were mixed. For a bibliography of these studies, click here. In a meta-analysis of 9 trials (n=213),³⁰ prefrontal rTMS for treating negative symptoms demonstrated a small-to-medium effect size. In another meta-analysis³¹ of all prospective studies of rTMS for negative symptoms and for auditory hallucinations and overall positive symptoms in refractory schizophrenia, the effect sizes showed moderate effects.

Fewer controlled trials are available for electroconvulsive therapy,^32,33 but its use with clozapine appears encouraging.³⁴

Psychological and behavioral intervention. Cognitive-behavioral therapy, although labor-intensive, can be helpful even in patients considered treatment-resistant (Table 3). These interventions generally are provided together with pharmacotherapy.

Complementary and alternative therapies. Patients and their families may ask about complementary and alternative therapies, particularly when conventional approaches have not been successful. A meta-analysis of 6 studies (n=828)³⁵ that reviewed adjunctive use of ginkgo in patients with chronic schizophrenia found statistically significant moderate improvement in total and negative symptoms. Negative reports also are available, including a 5-month study of adjunctive megavitamins that did not demonstrate any benefits.³⁶ In a review of 13 RCTs of acupuncture for schizophrenia, Lee et al found the overall methodological quality was too low to draw firm conclusions.³⁷

Table 3

Cognitive-behavioral therapy for schizophrenia

Clinical recommendations

Before declaring a patient with schizophrenia as treatment-resistant, ensure that an adequate trial of medication did take place. This includes consideration of adequate dosing and pharmacokinetic issues. Awareness of potential substance use and/or partial adherence or nonadherence also is critical because these factors can impact treatment response.

When prescribing for a treatment-resistant schizophrenia patient, identify specific target symptoms to better inform medication selection—especially for symptoms that the patient feels are important. For example, consider an antidepressant for patients who have negative or depressive symptoms. Also take into account other patient-centered concerns, such as tolerability issues that may have interfered with adherence and response in the past.

Clozapine remains the medication of choice for treatment-resistant schizophrenia. Despite dozens of RCTs of potential adjunctive agents for treatment-resistant schizophrenia, no single approach has consistently shown efficacy in reducing symptoms, improving cognition, or increasing a patient’s level of function. Individual response can vary, and our search for the “outlier” who does respond to an adjunctive agent can explain our use of these strategies in clinical practice.

Related Resources

• Cochrane Database of Systematic Reviews. www.cochrane.org/reviews. This database contains reviews of additional therapeutic options for patients with treatment-resistant schizophrenia. As of February 23, 2011, 157 reviews were available.
• Citrome L. Treatment-refractory schizophrenia: What it is and what’s been done about it. Neuropsychiatry. 2011. Epub ahead of print.
• Citrome L. Clozapine for schizophrenia. Life-threatening or life-saving treatment? Current Psychiatry. 2009;8(12):56-63.

Drug Brand Names

• Aripiprazole • Abilify
• Armodafinil • Nuvigil
• Atomoxetine • Strattera
• Benztropine mesylate • Cogentin
• Carbamazepine • Tegretol
• Celecoxib • Celebrex
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluoxetine • Prozac
• Guanfacine • Tenex
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid, others
• Lurasidone • Latuda
• Methylphenidate • Ritalin, Methylin, others
• Modafinil • Provigil
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Rifampin • Rifadin
• Risperidone • Risperdal
• Trazodone • Desyrel, Oleptro
• Valproate (Divalproex) • Depakote, Depakote ER
• Ziprasidone • Geodon

Disclosure

No writing assistance or external financial support was used for this article. Dr. Citrome is a consultant for, has received honoraria from, or has conducted clinical research supported by Abbott Laboratories, AstraZeneca Pharmaceuticals, Avanir Pharmaceuticals, Azur Pharma Inc., Barr Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Forest Research Institute, GlaxoSmithKline, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Merck, Novartis, Pfizer Inc., Sunovion, Valeant Pharmaceuticals, and Vanda Pharmaceuticals.

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Patients with treatment-resistant schizophrenia can be broadly defined to include any persons with residual symptoms that cause distress or impairment despite several treatment attempts. Unfortunately, this definition may include most of our patients with schizophrenia.

Clinical trial data on treatment-resistant schizophrenia can be contradictory, leaving “N of 1” empirical treatment trials for individual patients as the current state of the art. This article presents data from clinical trials for pharmacologic and nonpharmacologic options and offers recommendations to try to help our treatment-resistant patients.

Defining treatment resistance

Research reports regarding treatment-resistant or treatment-refractory schizophrenia have relied on operational criteria such as that found in the pivotal study for clozapine¹:

• at least 3 periods of treatment in the preceding 5 years with neuroleptic agents from at least 2 different chemical classes at dosages equivalent to ≥1000 mg/d of chlorpromazine for 6 weeks, each without significant symptomatic relief, and
• no period of good functioning within the preceding 5 years.¹ In that study, patients also underwent a prospective treatment trial with what we now know are high doses of haloperidol (up to 60 mg/d or higher) and benztropine mesylate (6 mg/d) for a period of 6 weeks to confirm lack of drug responsiveness. Other studies have more relaxed criteria, such as:
• persistent positive symptoms—hallucinations, delusions, or marked thought disorder—after at least 6 contiguous weeks of past or present treatment, with ≥1 typical antipsychotics at doses of ≥600 mg/d in chlorpromazine equivalents
• a poor level of functioning over the past 2 years, as defined by the lack of competitive employment or enrollment in an academic or vocational program and not having age-expected interpersonal relations with someone outside the biologic family with whom ongoing regular contacts were maintained.²

In this study, no prospective period of treatment to confirm lack of drug responsiveness was required.

The most clinically relevant definition of treatment resistance depends on the patient’s individual circumstances. For some patients, targeting positive symptoms is a high priority; for others it may be negative and cognitive symptoms; for others, it may be excitement. Moreover, families may complain of symptoms or behavior that are of little or no concern to your patient.

Although we desire treatment response and remission for our patients, definitions for remission and functional recovery are in flux. Proposed criteria define symptomatic remission as 6-month maintenance of simultaneous ratings of mild or less on delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms.^3,4 Emsley et al⁴ note that reported remission rates vary widely across studies (17% to 88%) and that patients in remission do better than their non-remitted counterparts in several other outcome domains. Also, patients move in and out of remission over time. Predictors of remission include:

• early treatment response
• baseline symptom severity
• subjective well-being.⁴

Recovery is a more complex construct than remission and includes social outcomes. Although recovery lacks a standard definition, it is the implied goal of treatment. Anything short of recovery can be viewed as inadequate. If we set the bar at this height, many or most of the patients we treat for schizophrenia could be considered treatment-resistant.

Confounding factors

Before concluding that a patient is treatment-resistant, address medication adherence and possible substance use. Partial or nonadherence with antipsychotic treatment is common—approximately one-half of patients are nonadherent⁵—and associated with relapse and re-hospitalization.⁶ In addition, an estimated one-half of all individuals with schizophrenia also use substances.⁷

Be aware of the optimal dose for any particular antipsychotic and factors that can interfere with achieving adequate plasma levels. This means acknowledging that dosing ranges established during registration studies may not reflect the needs of day-to-day clinical practice.⁸ Pharmacokinetic interactions with other medications, such as carbamazepine or rifampin, can induce liver enzymes and result in subtherapeutic antipsychotic levels. Cigarette smoking also may have this effect. Lowered clozapine or olanzapine plasma levels have been observed in patients who resume smoking after being discharged from a non-smoking inpatient environment. Some antipsychotics, such as ziprasidone and lurasidone, must be taken with food in order to have sufficient bioavailability.⁹

What does a patient want?

Patients with schizophrenia often have limited insight into their psychotic symptoms.¹⁰ Savvy clinicians will attempt to leverage a patient’s insight into ancillary symptoms—such as impaired sleep, anxiety, and dysphoria—to encourage a therapeutic alliance and therefore adherence. If patients feel their concerns are not addressed, they may consider treatment inadequate even though the intensity of their hallucinations and delusions may have decreased.

Which antipsychotic is best?

Meta-analyses of randomized controlled trials (RCTs) of antipsychotic treatment for schizophrenia found that, although individual response will vary, clozapine generally has better efficacy that other antipsychotics.^11-13 Olanzapine, risperidone, and amisulpride (which is not available in the United States) appear to be more efficacious than first-generation antipsychotics. Other second-generation antipsychotics do not consistently show greater efficacy than first-generation antipsychotics, although their tolerability profiles vary greatly.^11-13

Antipsychotic monotherapy. More than 25 RCTs have focused on antipsychotic monotherapy for treatment-resistant patients; for a bibliography of these studies, click here. For the most part, clozapine has consistently demonstrated superiority over comparators. Because not all patients with schizophrenia can tolerate clozapine or are willing to have their blood monitored as required, other second-generation antipsychotics have been suggested as possible substitutes. Olanzapine has established superior efficacy to first-generation antipsychotics^11-13 and perhaps comparable efficacy to clozapine in some studies.^2,14-17 Risperidone appeared to be comparable to clozapine in some studies,^18,19 whereas clozapine’s superiority was evident in others.^14,20,21 Although an RCT found comparable efficacy for ziprasidone vs clozapine,²² patients enrolled in this study may not have been treatment-resistant regarding efficacy but instead could not tolerate prior treatments. Enrolling patients on the basis of poor efficacy and/or poor tolerability to their prior antipsychotic regimen also has complicated the interpretation of studies comparing olanzapine with clozapine¹⁶ and risperidone with clozapine.¹⁸

Antipsychotic combinations. Combinations of antipsychotics are used commonly when treating chronic schizophrenia.²³ Of the approximately 20 RCTs of antipsychotic combination therapy, most tested clozapine combined with other second-generation antipsychotics, such as risperidone. For a bibliography of these studies, click here. Only 5 studies support a combination approach (Table 1).

Table 1

Antipsychotic combinations: Few studies support efficacy

What about augmentation?

Adjunctive non-antipsychotics also are commonly used when treating patients with chronic schizophrenia. For example, lithium and anticonvulsants are used in approximately one-half of all inpatients with schizophrenia in facilities operated by the State of New York Office of Mental Health.^24,25 The evidence base for these agents as adjuncts to antipsychotics generally is weak.²⁶ Specifically, early reports of benefit with adjunctive lithium have been negated by later studies. Similarly, large trials of adjunctive valproate and lamotrigine have failed to replicate early and promising efficacy signals from smaller trials, although the larger studies did not specifically target treatment-resistant schizophrenia.

Among mood stabilizers, lamotrigine may be the most promising for treatment-resistant schizophrenia. In a meta-analysis of clinical trials examining schizophrenia patients receiving clozapine (N=161) who were randomized to receive adjunctive lamotrigine or adjunctive placebo, lamotrigine was superior to placebo in total score for psychosis symptoms and scores for positive and negative symptoms.²⁷

More than 125 published RCTs have studied a wide variety of adjunctive agents other than lithium or anticonvulsants for treating persistent schizophrenia symptoms (Table 2).

Only some of the approximately 40 RCTs regarding adjunctive antidepressants in patients with chronic schizophrenia focused on patients with ongoing depressive symptoms. For a bibliography of these studies, click here. In a meta-analysis measuring improvement of negative symptoms from 23 trials (N=819),²⁸ the effect size was moderate in favor of antidepressants. Subgroup analysis revealed significant responses for fluoxetine, trazodone, and ritanserin.

More than 50 RCTs have focused on augmenting medications for cognitive dysfunction in chronic schizophrenia. Unfortunately, agents used to treat Alzheimer’s disease have shown disappointing results when tested in patients with schizophrenia, as have agents prescribed for attention-deficit/hyperactivity disorder (methylphenidate, guanfacine, atomoxetine) or agents used to promote alertness (modafinil and armodafinil).

Medications that act on glutamate receptors may offer another potential solution, although not in combination with clozapine.²⁹

Other agents that require further study where ≥2 positive studies have been reported (with ≤2 negative studies) include celecoxib, neurosteroids and hormones, purinergic agents, serotonin 5-HT1A receptor agonists, and serotonin 5-HT3 receptor antagonists.

Table 2

Agents studied as adjuncts to antipsychotics

Therapeutic neuromodulation

More than 10 RCTs of repetitive transcranial magnetic stimulation (rTMS) in patients with refractory symptoms of schizophrenia have been published; the results were mixed. For a bibliography of these studies, click here. In a meta-analysis of 9 trials (n=213),³⁰ prefrontal rTMS for treating negative symptoms demonstrated a small-to-medium effect size. In another meta-analysis³¹ of all prospective studies of rTMS for negative symptoms and for auditory hallucinations and overall positive symptoms in refractory schizophrenia, the effect sizes showed moderate effects.

Fewer controlled trials are available for electroconvulsive therapy,^32,33 but its use with clozapine appears encouraging.³⁴

Psychological and behavioral intervention. Cognitive-behavioral therapy, although labor-intensive, can be helpful even in patients considered treatment-resistant (Table 3). These interventions generally are provided together with pharmacotherapy.