Current Psychiatry

After reading “Is she being abused or ‘acting out’” (Cases That Test Your Skills, Current Psychiatry, December 2007), I wonder if oxcarbazepine might have been the culprit behind Ms. L’s delusions that her caretaker was abusing her. There is some evidence that oxcarbazepine can contribute to delirium, and the timing of her allegations shortly after starting oxcarbazepine makes me think that perhaps the drug contributed to her delusions. Clearly the patient improved when taking risperidone, but I wonder what would happen if she had been switched to a different mood stabilizer.

Susan Rose, PhD
Portland, OR

After reading “Is she being abused or ‘acting out’” (Cases That Test Your Skills, Current Psychiatry, December 2007), I wonder if oxcarbazepine might have been the culprit behind Ms. L’s delusions that her caretaker was abusing her. There is some evidence that oxcarbazepine can contribute to delirium, and the timing of her allegations shortly after starting oxcarbazepine makes me think that perhaps the drug contributed to her delusions. Clearly the patient improved when taking risperidone, but I wonder what would happen if she had been switched to a different mood stabilizer.

Susan Rose, PhD
Portland, OR

After reading “Is she being abused or ‘acting out’” (Cases That Test Your Skills, Current Psychiatry, December 2007), I wonder if oxcarbazepine might have been the culprit behind Ms. L’s delusions that her caretaker was abusing her. There is some evidence that oxcarbazepine can contribute to delirium, and the timing of her allegations shortly after starting oxcarbazepine makes me think that perhaps the drug contributed to her delusions. Clearly the patient improved when taking risperidone, but I wonder what would happen if she had been switched to a different mood stabilizer.

Susan Rose, PhD
Portland, OR

In “Modafinil: Not just for sleep disorders?” (Current Psychiatry, November 2007) the authors reviewed evidence-based studies of off-label use of modafinil in several psychiatric disorders. Two double-blind studies that were not cited in the article assessed the effect of modafinil in healthy volunteers.^1,2 Modafinil improved vigilance, decreased fatigue, and induced a general sense of well-being, but these volunteers overestimated their cognitive and physical capacities. The study’s authors postulated that the self-perception of enhanced vigilance might distort the cognitive appraisal of one’s actual cognitive and physical capacities.

There is a similarity between the effects of modafinil in healthy volunteers and the reported improved vigilance, decreased fatigue, and global improvement of symptoms in patients with major depressive disorder (MDD). The extent and role of distorted self-appraisal—which paradoxically might be positive—in depression has yet to be explored. Also, the parameters of modafinil discontinuation in remitted MDD and the possible outcome of this discontinuation on the sense of well-being and fatigue needs to be determined.

Unlike patients with MDD, those with bipolar disorder (BD) have trait-dependent impairment of verbal memory and executive functions during euthymic states between episodes.³ Patients in the depressive phase of BD might exhibit cognitive impairments different from those found in MDD patients. Studies assessing the effect of modafinil on the mood of depressed BD patients also need to evaluate its effect on cognitive impairments.

Modafinil improved set shifting in schizophrenia, sustained attention in attention-deficit/hyperactivity disorder, and short memory span in both disorders. Set shifting has been linked to norepinephrine and sustained attention and short memory span to dopamine. These neurocognitive correlates provide further information about modafinil’s pharma cologic actions.

Michel J. Calache, MD
Marion, IN

In “Modafinil: Not just for sleep disorders?” (Current Psychiatry, November 2007) the authors reviewed evidence-based studies of off-label use of modafinil in several psychiatric disorders. Two double-blind studies that were not cited in the article assessed the effect of modafinil in healthy volunteers.^1,2 Modafinil improved vigilance, decreased fatigue, and induced a general sense of well-being, but these volunteers overestimated their cognitive and physical capacities. The study’s authors postulated that the self-perception of enhanced vigilance might distort the cognitive appraisal of one’s actual cognitive and physical capacities.

There is a similarity between the effects of modafinil in healthy volunteers and the reported improved vigilance, decreased fatigue, and global improvement of symptoms in patients with major depressive disorder (MDD). The extent and role of distorted self-appraisal—which paradoxically might be positive—in depression has yet to be explored. Also, the parameters of modafinil discontinuation in remitted MDD and the possible outcome of this discontinuation on the sense of well-being and fatigue needs to be determined.

Unlike patients with MDD, those with bipolar disorder (BD) have trait-dependent impairment of verbal memory and executive functions during euthymic states between episodes.³ Patients in the depressive phase of BD might exhibit cognitive impairments different from those found in MDD patients. Studies assessing the effect of modafinil on the mood of depressed BD patients also need to evaluate its effect on cognitive impairments.

Modafinil improved set shifting in schizophrenia, sustained attention in attention-deficit/hyperactivity disorder, and short memory span in both disorders. Set shifting has been linked to norepinephrine and sustained attention and short memory span to dopamine. These neurocognitive correlates provide further information about modafinil’s pharma cologic actions.

Michel J. Calache, MD
Marion, IN

In “Modafinil: Not just for sleep disorders?” (Current Psychiatry, November 2007) the authors reviewed evidence-based studies of off-label use of modafinil in several psychiatric disorders. Two double-blind studies that were not cited in the article assessed the effect of modafinil in healthy volunteers.^1,2 Modafinil improved vigilance, decreased fatigue, and induced a general sense of well-being, but these volunteers overestimated their cognitive and physical capacities. The study’s authors postulated that the self-perception of enhanced vigilance might distort the cognitive appraisal of one’s actual cognitive and physical capacities.

There is a similarity between the effects of modafinil in healthy volunteers and the reported improved vigilance, decreased fatigue, and global improvement of symptoms in patients with major depressive disorder (MDD). The extent and role of distorted self-appraisal—which paradoxically might be positive—in depression has yet to be explored. Also, the parameters of modafinil discontinuation in remitted MDD and the possible outcome of this discontinuation on the sense of well-being and fatigue needs to be determined.

Unlike patients with MDD, those with bipolar disorder (BD) have trait-dependent impairment of verbal memory and executive functions during euthymic states between episodes.³ Patients in the depressive phase of BD might exhibit cognitive impairments different from those found in MDD patients. Studies assessing the effect of modafinil on the mood of depressed BD patients also need to evaluate its effect on cognitive impairments.

Modafinil improved set shifting in schizophrenia, sustained attention in attention-deficit/hyperactivity disorder, and short memory span in both disorders. Set shifting has been linked to norepinephrine and sustained attention and short memory span to dopamine. These neurocognitive correlates provide further information about modafinil’s pharma cologic actions.

Michel J. Calache, MD
Marion, IN

Dr. Henry Nasrallah’s editorial on polypharmacy (“Innovative polypharmacy: When dopamine blockade is not enough.” From the Editor, Current Psychiatry, November 2007) was thought provoking. The available medication databases are very good at detecting pharmacokinetic drug-drug interactions but poor at informing clinicians about pharmacodynamic drug-drug interactions. The receptor profile of a drug is its unique signature. One can argue that combining 2 drugs with 2 different receptor specificity and potency profiles is akin to creating a designer drug with a unique receptor profile that is different from the sum of its parts.

Neurotransmitter receptor selectivity is an in vitro myth. Due to the well-known interactions among serotonergic, dopaminergic, adrenergic, cholinergic, and many other pathways, it is almost impossible to expect a selective drug to affect 1 pathway without affecting others. The so-called selective serotonin reuptake inhibitors may bind selectively to receptors in vitro, but other pathways will be affected in the dynamic, interactive brain. A change in 1 neurotransmitter pathway will lead to changes in many—if not all—others.

The complexity of interactions among the different neurotransmitter systems makes oversimplification the rule, not the exception. Given that the human mind is capable of manipulating very limited variables concomitantly, artificial intelligence will be needed to try to predict the pharmacodynamic interactions of multiple agents through neurochemical network modeling, similar to programs used to predict the weather.

Last, I offer a defense of speculation and prescribing based on good theoretical proposals, such as the ones made by Dr. Nasrallah. Good research starts with a good hypothesis. Clinical studies in humans and research using animal brains will lag years—maybe decades—behind theory because of the complexity of pharmacodynamic interactions.

The obsession with double-blind, randomized, controlled studies in psychopharmacologic literature has resulted in a false dichotomy between the theoretical and experimental, with respect heaped on the experimental and contempt for the theoretical. Drug-drug pharmacodynamic interactions are more suited for theory-based computer modeling programs, which may drive innovative polypharmacotherapy research as much as—if not more than—clinical studies.

Numan Gharaibeh, MD
Principal psychiatrist
Greater Danbury Mental Health Authority
Danbury, CT

Dr. Henry Nasrallah’s editorial on polypharmacy (“Innovative polypharmacy: When dopamine blockade is not enough.” From the Editor, Current Psychiatry, November 2007) was thought provoking. The available medication databases are very good at detecting pharmacokinetic drug-drug interactions but poor at informing clinicians about pharmacodynamic drug-drug interactions. The receptor profile of a drug is its unique signature. One can argue that combining 2 drugs with 2 different receptor specificity and potency profiles is akin to creating a designer drug with a unique receptor profile that is different from the sum of its parts.

Neurotransmitter receptor selectivity is an in vitro myth. Due to the well-known interactions among serotonergic, dopaminergic, adrenergic, cholinergic, and many other pathways, it is almost impossible to expect a selective drug to affect 1 pathway without affecting others. The so-called selective serotonin reuptake inhibitors may bind selectively to receptors in vitro, but other pathways will be affected in the dynamic, interactive brain. A change in 1 neurotransmitter pathway will lead to changes in many—if not all—others.

The complexity of interactions among the different neurotransmitter systems makes oversimplification the rule, not the exception. Given that the human mind is capable of manipulating very limited variables concomitantly, artificial intelligence will be needed to try to predict the pharmacodynamic interactions of multiple agents through neurochemical network modeling, similar to programs used to predict the weather.

Last, I offer a defense of speculation and prescribing based on good theoretical proposals, such as the ones made by Dr. Nasrallah. Good research starts with a good hypothesis. Clinical studies in humans and research using animal brains will lag years—maybe decades—behind theory because of the complexity of pharmacodynamic interactions.

The obsession with double-blind, randomized, controlled studies in psychopharmacologic literature has resulted in a false dichotomy between the theoretical and experimental, with respect heaped on the experimental and contempt for the theoretical. Drug-drug pharmacodynamic interactions are more suited for theory-based computer modeling programs, which may drive innovative polypharmacotherapy research as much as—if not more than—clinical studies.

Numan Gharaibeh, MD
Principal psychiatrist
Greater Danbury Mental Health Authority
Danbury, CT

Dr. Henry Nasrallah’s editorial on polypharmacy (“Innovative polypharmacy: When dopamine blockade is not enough.” From the Editor, Current Psychiatry, November 2007) was thought provoking. The available medication databases are very good at detecting pharmacokinetic drug-drug interactions but poor at informing clinicians about pharmacodynamic drug-drug interactions. The receptor profile of a drug is its unique signature. One can argue that combining 2 drugs with 2 different receptor specificity and potency profiles is akin to creating a designer drug with a unique receptor profile that is different from the sum of its parts.

Neurotransmitter receptor selectivity is an in vitro myth. Due to the well-known interactions among serotonergic, dopaminergic, adrenergic, cholinergic, and many other pathways, it is almost impossible to expect a selective drug to affect 1 pathway without affecting others. The so-called selective serotonin reuptake inhibitors may bind selectively to receptors in vitro, but other pathways will be affected in the dynamic, interactive brain. A change in 1 neurotransmitter pathway will lead to changes in many—if not all—others.

The complexity of interactions among the different neurotransmitter systems makes oversimplification the rule, not the exception. Given that the human mind is capable of manipulating very limited variables concomitantly, artificial intelligence will be needed to try to predict the pharmacodynamic interactions of multiple agents through neurochemical network modeling, similar to programs used to predict the weather.

Last, I offer a defense of speculation and prescribing based on good theoretical proposals, such as the ones made by Dr. Nasrallah. Good research starts with a good hypothesis. Clinical studies in humans and research using animal brains will lag years—maybe decades—behind theory because of the complexity of pharmacodynamic interactions.

The obsession with double-blind, randomized, controlled studies in psychopharmacologic literature has resulted in a false dichotomy between the theoretical and experimental, with respect heaped on the experimental and contempt for the theoretical. Drug-drug pharmacodynamic interactions are more suited for theory-based computer modeling programs, which may drive innovative polypharmacotherapy research as much as—if not more than—clinical studies.

Numan Gharaibeh, MD
Principal psychiatrist
Greater Danbury Mental Health Authority
Danbury, CT

In “The#1 question to ask inpatients” (Pearls, Current Psychiatry, October 2007), Dr. Kenneth Lakritz encouraged clinicians to ask patients about the quality of their treatment in the hospital. If the patient’s response is negative, the clinician could consider various personality disorders, including borderline personality disorder, when a patient describes “hospital staff split into idealized and rejected components.”

Before exploring characterologic issues, determine if the patient has a valid concern about the quality of care, perhaps in regard to select staff only. Relying solely on the approach described in this article could worsen the therapeutic relationship.

Robert Barris, MD
Flushing, NY

Dr. Lakritz’s article regarding the diagnostic helpfulness of a hospitalized patient’s response to the question, “How are they treating you here at the hospital?” was interesting and useful. However, I would like to clarify a sentence regarding patients with substance abuse disorders.

The article states, “Patients with substance abuse disorders will respond by discussing the timing and adequacy of their opioid and benzodiazepine prescriptions.” The same response could be given by a patient whose pain is undertreated, which often happens with short-acting opioids. Hydrocodone, oxycodone, or codeine often don’t ease pain for as long as assumed. Actual pain relief may be 2 to 3 hours at most, when the typical order is for 4 to 6 hours “as needed for pain.”

Because a patient might be in significant pain after 2 to 3 hours and the next dose isn’t due for another 1 to 4 hours, he or she understandably might be preoccupied with the timing and dose of pain medications. This behavior could make these patients appear to be substance abusers.

The difference between these 2 groups is evident when the pain is adequately treated and the demanding behavior disappears. In patients abusing opiates, the dose always needs to be a little higher. This phenomenon is known as pseudoaddiction. I realize that Dr. Lakritz had limited space to make his point. However, in recent years considerable time and effort has been expended to improve pain treatment.

Michael Newberry, MD
Vail, CO

Dr. Lakritz Responds

I agree with the points made by Drs. Barris and Newberry: neglectful or abusive hospital staff and undertreated pain are all too common, as is the tendency to label unhappy patients as “difficult” or character disordered. Perhaps I should have emphasized that a “positive” answer to my favorite question doesn’t establish a diagnosis, but rather should guide a more thorough investigation of the patient’s circumstances.

Kenneth Lakritz, MD
Lahey Clinic Medical Center
Burlington, MA

In “The#1 question to ask inpatients” (Pearls, Current Psychiatry, October 2007), Dr. Kenneth Lakritz encouraged clinicians to ask patients about the quality of their treatment in the hospital. If the patient’s response is negative, the clinician could consider various personality disorders, including borderline personality disorder, when a patient describes “hospital staff split into idealized and rejected components.”

Before exploring characterologic issues, determine if the patient has a valid concern about the quality of care, perhaps in regard to select staff only. Relying solely on the approach described in this article could worsen the therapeutic relationship.

Robert Barris, MD
Flushing, NY

Dr. Lakritz’s article regarding the diagnostic helpfulness of a hospitalized patient’s response to the question, “How are they treating you here at the hospital?” was interesting and useful. However, I would like to clarify a sentence regarding patients with substance abuse disorders.

The article states, “Patients with substance abuse disorders will respond by discussing the timing and adequacy of their opioid and benzodiazepine prescriptions.” The same response could be given by a patient whose pain is undertreated, which often happens with short-acting opioids. Hydrocodone, oxycodone, or codeine often don’t ease pain for as long as assumed. Actual pain relief may be 2 to 3 hours at most, when the typical order is for 4 to 6 hours “as needed for pain.”

Because a patient might be in significant pain after 2 to 3 hours and the next dose isn’t due for another 1 to 4 hours, he or she understandably might be preoccupied with the timing and dose of pain medications. This behavior could make these patients appear to be substance abusers.

The difference between these 2 groups is evident when the pain is adequately treated and the demanding behavior disappears. In patients abusing opiates, the dose always needs to be a little higher. This phenomenon is known as pseudoaddiction. I realize that Dr. Lakritz had limited space to make his point. However, in recent years considerable time and effort has been expended to improve pain treatment.

Michael Newberry, MD
Vail, CO

Dr. Lakritz Responds

I agree with the points made by Drs. Barris and Newberry: neglectful or abusive hospital staff and undertreated pain are all too common, as is the tendency to label unhappy patients as “difficult” or character disordered. Perhaps I should have emphasized that a “positive” answer to my favorite question doesn’t establish a diagnosis, but rather should guide a more thorough investigation of the patient’s circumstances.

Kenneth Lakritz, MD
Lahey Clinic Medical Center
Burlington, MA

In “The#1 question to ask inpatients” (Pearls, Current Psychiatry, October 2007), Dr. Kenneth Lakritz encouraged clinicians to ask patients about the quality of their treatment in the hospital. If the patient’s response is negative, the clinician could consider various personality disorders, including borderline personality disorder, when a patient describes “hospital staff split into idealized and rejected components.”

Before exploring characterologic issues, determine if the patient has a valid concern about the quality of care, perhaps in regard to select staff only. Relying solely on the approach described in this article could worsen the therapeutic relationship.

Robert Barris, MD
Flushing, NY

Dr. Lakritz’s article regarding the diagnostic helpfulness of a hospitalized patient’s response to the question, “How are they treating you here at the hospital?” was interesting and useful. However, I would like to clarify a sentence regarding patients with substance abuse disorders.

The article states, “Patients with substance abuse disorders will respond by discussing the timing and adequacy of their opioid and benzodiazepine prescriptions.” The same response could be given by a patient whose pain is undertreated, which often happens with short-acting opioids. Hydrocodone, oxycodone, or codeine often don’t ease pain for as long as assumed. Actual pain relief may be 2 to 3 hours at most, when the typical order is for 4 to 6 hours “as needed for pain.”

Because a patient might be in significant pain after 2 to 3 hours and the next dose isn’t due for another 1 to 4 hours, he or she understandably might be preoccupied with the timing and dose of pain medications. This behavior could make these patients appear to be substance abusers.

The difference between these 2 groups is evident when the pain is adequately treated and the demanding behavior disappears. In patients abusing opiates, the dose always needs to be a little higher. This phenomenon is known as pseudoaddiction. I realize that Dr. Lakritz had limited space to make his point. However, in recent years considerable time and effort has been expended to improve pain treatment.

Michael Newberry, MD
Vail, CO

Dr. Lakritz Responds

I agree with the points made by Drs. Barris and Newberry: neglectful or abusive hospital staff and undertreated pain are all too common, as is the tendency to label unhappy patients as “difficult” or character disordered. Perhaps I should have emphasized that a “positive” answer to my favorite question doesn’t establish a diagnosis, but rather should guide a more thorough investigation of the patient’s circumstances.

Kenneth Lakritz, MD
Lahey Clinic Medical Center
Burlington, MA

Might it resolve to spend far more money on innovative research and development than on marketing?

Making New Year’s resolutions is a time-honored tradition. Whether we resolve to lose a few pounds, exercise regularly, or quit a harmful habit, we all partake in self-improvement as the new year dawns.

What would a large corporation resolve to do in the new year? We can only imagine, but a corporation that discovers and manufactures CNS pharmaceuticals might resolve to:

1. Test new drugs in patients who resemble “real world” patients, not just in patients with no medical problems, no substance abuse, and no history of treatment resistance.

2. Develop drugs with new mechanisms, not just another “me too” agent.

3. Publish all data (positive and negative), not just favorable results.

4. Develop drugs for children, rather than following the tradition of developing drugs for adults and then waiting many years (during which practitioners use those drugs off-label in children) before finally conducting trials to secure FDA approval of pediatric indications.

5. Conduct studies to guide practitioners about the safety of new drugs in pregnant women with mental illness.

6. Spend far more money on innovative research and development than on marketing.

7. Kick the habit of direct-to-consumer marketing, so that physicians can prescribe the best agent in their clinical judgment, not the drug the patient demands because she saw it on TV.

8. Accelerate the discovery of pharmacogenomic biomarkers to help match drug and patient, maximize efficacy, and minimize serious side effects.

9. Be more transparent about the fact that many clinical trials are being conducted in developing countries because U.S.-based trials have become too expensive and pose other “disadvantages” (such as a higher placebo response rate and more side effect complaints).

10. Establish mutually beneficial partnerships with the National Institutes of Health and academic research institutes to translate neurobiological discoveries into new and physiology-driven pharmacotherapeutic interventions.

11. Pool grants with competitors so that continuing medical education (CME) programs are no longer sponsored by a single company and are designed without real or perceived influence by an industry sponsor.

12. Better inform the public about the pharmaceutical industry’s positive aspects, such as being the only U.S. industry that: a) develops new medications for disabling psychiatric disorders; b) donates billions of dollars worth of drug samples to indigent or uninsured community patients; and c) provides hundreds of thousands of well-paying jobs for scientists, managers, and sales representatives.

13. Remind the world that hundreds of disabling and fatal diseases still have no available treatments, and a huge financial investment and years of basic and clinic research are needed to discover the needed treatments for them.

14. Justify the high cost of new drugs by demonstrating how profits are ploughed into discovering new drugs (in other words, show convincingly that the pharmaceutical industry works for the public good, not just for shareholders).

15. Stop buying lunches for doctors who attend speaker programs, and instead make donations to their designated charities.

I cannot vouch that this fictional account of a pharmaceutical company’s New Year’s resolutions reflects reality. But if it does, I wonder if such resolutions—like those of almost all of us—would falter soon after the new year starts… .

Might it resolve to spend far more money on innovative research and development than on marketing?

Making New Year’s resolutions is a time-honored tradition. Whether we resolve to lose a few pounds, exercise regularly, or quit a harmful habit, we all partake in self-improvement as the new year dawns.

What would a large corporation resolve to do in the new year? We can only imagine, but a corporation that discovers and manufactures CNS pharmaceuticals might resolve to:

1. Test new drugs in patients who resemble “real world” patients, not just in patients with no medical problems, no substance abuse, and no history of treatment resistance.

2. Develop drugs with new mechanisms, not just another “me too” agent.

3. Publish all data (positive and negative), not just favorable results.

4. Develop drugs for children, rather than following the tradition of developing drugs for adults and then waiting many years (during which practitioners use those drugs off-label in children) before finally conducting trials to secure FDA approval of pediatric indications.

5. Conduct studies to guide practitioners about the safety of new drugs in pregnant women with mental illness.

6. Spend far more money on innovative research and development than on marketing.

7. Kick the habit of direct-to-consumer marketing, so that physicians can prescribe the best agent in their clinical judgment, not the drug the patient demands because she saw it on TV.

8. Accelerate the discovery of pharmacogenomic biomarkers to help match drug and patient, maximize efficacy, and minimize serious side effects.

9. Be more transparent about the fact that many clinical trials are being conducted in developing countries because U.S.-based trials have become too expensive and pose other “disadvantages” (such as a higher placebo response rate and more side effect complaints).

10. Establish mutually beneficial partnerships with the National Institutes of Health and academic research institutes to translate neurobiological discoveries into new and physiology-driven pharmacotherapeutic interventions.

11. Pool grants with competitors so that continuing medical education (CME) programs are no longer sponsored by a single company and are designed without real or perceived influence by an industry sponsor.

12. Better inform the public about the pharmaceutical industry’s positive aspects, such as being the only U.S. industry that: a) develops new medications for disabling psychiatric disorders; b) donates billions of dollars worth of drug samples to indigent or uninsured community patients; and c) provides hundreds of thousands of well-paying jobs for scientists, managers, and sales representatives.

13. Remind the world that hundreds of disabling and fatal diseases still have no available treatments, and a huge financial investment and years of basic and clinic research are needed to discover the needed treatments for them.

14. Justify the high cost of new drugs by demonstrating how profits are ploughed into discovering new drugs (in other words, show convincingly that the pharmaceutical industry works for the public good, not just for shareholders).

15. Stop buying lunches for doctors who attend speaker programs, and instead make donations to their designated charities.

I cannot vouch that this fictional account of a pharmaceutical company’s New Year’s resolutions reflects reality. But if it does, I wonder if such resolutions—like those of almost all of us—would falter soon after the new year starts… .

Might it resolve to spend far more money on innovative research and development than on marketing?

Making New Year’s resolutions is a time-honored tradition. Whether we resolve to lose a few pounds, exercise regularly, or quit a harmful habit, we all partake in self-improvement as the new year dawns.

What would a large corporation resolve to do in the new year? We can only imagine, but a corporation that discovers and manufactures CNS pharmaceuticals might resolve to:

1. Test new drugs in patients who resemble “real world” patients, not just in patients with no medical problems, no substance abuse, and no history of treatment resistance.

2. Develop drugs with new mechanisms, not just another “me too” agent.

3. Publish all data (positive and negative), not just favorable results.

4. Develop drugs for children, rather than following the tradition of developing drugs for adults and then waiting many years (during which practitioners use those drugs off-label in children) before finally conducting trials to secure FDA approval of pediatric indications.

5. Conduct studies to guide practitioners about the safety of new drugs in pregnant women with mental illness.

6. Spend far more money on innovative research and development than on marketing.

7. Kick the habit of direct-to-consumer marketing, so that physicians can prescribe the best agent in their clinical judgment, not the drug the patient demands because she saw it on TV.

8. Accelerate the discovery of pharmacogenomic biomarkers to help match drug and patient, maximize efficacy, and minimize serious side effects.

9. Be more transparent about the fact that many clinical trials are being conducted in developing countries because U.S.-based trials have become too expensive and pose other “disadvantages” (such as a higher placebo response rate and more side effect complaints).

10. Establish mutually beneficial partnerships with the National Institutes of Health and academic research institutes to translate neurobiological discoveries into new and physiology-driven pharmacotherapeutic interventions.

11. Pool grants with competitors so that continuing medical education (CME) programs are no longer sponsored by a single company and are designed without real or perceived influence by an industry sponsor.

12. Better inform the public about the pharmaceutical industry’s positive aspects, such as being the only U.S. industry that: a) develops new medications for disabling psychiatric disorders; b) donates billions of dollars worth of drug samples to indigent or uninsured community patients; and c) provides hundreds of thousands of well-paying jobs for scientists, managers, and sales representatives.

13. Remind the world that hundreds of disabling and fatal diseases still have no available treatments, and a huge financial investment and years of basic and clinic research are needed to discover the needed treatments for them.

14. Justify the high cost of new drugs by demonstrating how profits are ploughed into discovering new drugs (in other words, show convincingly that the pharmaceutical industry works for the public good, not just for shareholders).

15. Stop buying lunches for doctors who attend speaker programs, and instead make donations to their designated charities.

I cannot vouch that this fictional account of a pharmaceutical company’s New Year’s resolutions reflects reality. But if it does, I wonder if such resolutions—like those of almost all of us—would falter soon after the new year starts… .

CASE: The man from Betelgeuse

Mr. F, age 33, has been hospitalized repeatedly for psychotic episodes after abuse of dextromethorphan in cold medications.

Approximately 1 week before presenting to us, Mr. F stormed out of his house after his father, with whom he lived, confronted him about spending his allowance on cold medications. He spent the week living on the streets, abusing dextromethorphan whenever he could get it.

One night, Mr. F approached a police officer at an accident scene and exclaimed, “Dude, I’m from the planet Betelgeuse.” He appeared disorganized as police questioned him, and officers transported him to the county hospital’s psychiatric emergency service.

At presentation, Mr. F is at times silly, irritable, and sleepy, and chants incantations during the intake interview. Alternately, he hears Jesus Christ and aliens from Betelgeuse telling him “everything is going to be cool” and voices of aliens threatening to abduct him.

We admit Mr. F to the inpatient psychiatric unit, start risperidone at 2 mg nightly, and titrate it to 6 mg nightly over 3 days, after which he is significantly more organized with reduced auditory hallucinations. At discharge 6 days later, he still occasionally hears Jesus but has partial insight into his obsession with aliens and no paranoid delusions. We continue risperidone, 6 mg nightly, and refer him to an outpatient mental health program. He visits the clinic once but avoids the attending psychiatrist.

Five days later, Mr. F begins hallucinating at home and his father brings him back to the emergency psychiatry unit. At presentation, the patient claims to be an agent of Satan and waves his arms wildly while performing “black magic.” He believes he is damned and that previous messages he thought came from Jesus and extraterrestrials were instead from the devil.

Mr. F’s father reports that over the weekend his son ingested 6 boxes of cold medicine—each with 16 tablets containing 30 mg of dextromethorphan. Peeling skin on the lower part of Mr. F’s forehead, the bridge of his nose, and under his eyes suggests chronic cold tablet abuse. We re-admit the patient after extended urine drug screen shows traces of chlorpheniramine.

The authors’ observations

Routine urine drug screens based on radio-immunoassay detect many substances, but an extended or comprehensive urine drug screen based on gas chromatography-mass spectrometry is needed to detect dextromethorphan.¹ Tertiary hospitals and reference laboratories usually offer these tests.

An extended urine screen will not detect dextromethorphan 24 hours after use because the agent has a 3- to 11-hour half-life. The test can, however, detect other active cold preparation compounds with longer half-lives, such as chlorpheniramine.

If extended urine screening is not available, clinical findings discussed later in this article can confirm recent cold medication abuse. Blood testing can reveal dextromethorphan levels, but a 3- to 6-mL sample may be needed.

HISTORY: ‘Sick’ at 16

Mr. F began abusing dextromethorphan at age 16, when friends would “turn him on” to 8-ounce bottles of cough syrup every other week. He later tried marijuana, cocaine, phencyclidine, methamphetamine, morphine, and LSD. Soon after graduating from high school, he stopped using substances and remained clean for several years.

Mr. F worked as a restaurant manager for about 4 months but found the job stressful and constantly argued with staff. He resumed abusing cough syrup to relieve his stress but soon became hooked on its dissociative and hallucinogenic effects. One night he ingested enough cough syrup to remain “high” until the next morning. He was hallucinating when he reported to work that day and was fired.

Since then, Mr. F’s cold medication abuse has escalated from biweekly to almost daily at presentation. He switched to tablets because the syrup induced cold symptoms and he finds the “buzz” from the tablets easier to control.

He typically dresses in black (in keeping with his satanic obsessions) and wears a long black overcoat with several pockets, that allows him to carry boxes of cold capsules, books, and other items.

Mr. F’s father has repeatedly tried to stop his son’s cold tablet abuse by cutting off his allowance. Dextromethorphan-containing cold medications are inexpensive, however—a box of 16 30-mg tablets costs as little as $1.50. Also, Mr. F often would get money for cold capsules by going to malls and participating in market research surveys.

In the past year, Mr. F was hospitalized 6 times after dextromethorphan-induced psychotic decompensations. He has been unemployed for more than 5 years, has not been in a serious romantic relationship since college, and depends on his father for financial support. He is not abusing other substances.

The authors’ observations

As many as 80% of patients with schizophrenia also have a substance abuse disorder.² Access to psychoactive substances, kindling associated with schizophrenia, and attempts to stop hallucinations with alcohol or illicit drugs may explain this high prevalence.² Also, genetic or phenotypic vulnerability in schizophrenia might alter the mesolimbic dopamine system that moderates reward.

Compared with patients with schizophrenia who are substance-free, comorbid substance abuse in schizophrenia increases:

• severity of psychotic symptoms
  
• likelihood of emergency service use
  
• risk of suicide, illness, injury, hospitalization, or incarceration.³
  

Mr. F responded well to risperidone when he wasn’t abusing cold tablets. After his last hospitalization, we referred him to a comprehensive outpatient program that could have addressed his cold medicine abuse and reintegrated him into the workplace. He avoided seeing the clinic psychiatrist, however, after promising his case manager that he would stop abusing dextromethorphan.

TREATMENT: Back to Betelgeuse

Upon re-admission, we restart risperidone, 6 mg nightly. Mr. F shows extreme somnolence caused by massive cold capsule use and is minimally cooperative with the psychiatrist’s follow-up interview. Over 36 hours, he awakens only for meals and medication and to use the bathroom. Once the somnolence passes, he cannot fall asleep at night.

Six days after admission, Mr. F is organized and hears voices mostly from Jesus with some demonic delusions. Extended urine drug screen taken 3 days after admission shows traces of chlorpheniramine but no dextromethorphan.

By day 7, Mr. F is nearly free of delusions and is discharged the next day. We continue risperidone, 6 mg nightly, to prevent the “voices,” and add diphenhydramine, 50 mg nightly, to regulate his sleep. We arrange follow-up care at an outpatient clinic, but Mr. F again avoids the clinic psychiatrist.

The authors’ observations

Mr. F’s “robo” binge triggered a profound and prolonged psychotic decompensation.

Dextrorphan—a pharmacologically active metabolite of dextromethorphan— might have disrupted cortical and sub-cortical glutamatergic neurotransmission,⁶ leading to florid psychosis and delayed recovery. Induction of the cytochrome P-450 2D6 isoenzyme, which metabolizes dextromethorphan, also could have prolonged Mr. F’s psychosis (Box 1).^7-11

RELAPSE: Return visits

Three weeks after discharge, Mr. F fights with police officers after they find him hallucinating in the streets. Police charge him with disorderly conduct and resisting arrest and bring him back to the psychiatric ER. We again resolve his auditory hallucinations with risperidone, 6 mg nightly. After 8 days we discharge him to police, who then transport him to jail and later release him on bail.

Six months later, Mr. F is hospitalized twice in 2 months after dextromethorphan-induced decompensations. He recovers quickly both times but lacks insight into his mental illness and his “robo” problem.

The authors’ observations

Dextromethorphan, known by many street names (Box 2), is contained in more than 100 OTC preparations, and is sold on the Internet in powder form.

• Most people do not know that dextromethorphan-laced medications are dangerous if misused.
  
• These preparations can be purchased at many stores or snatched from the medicine chest.
  
• Several Web sites describe how to “safely” abuse dextromethorphan.¹³
  

medical consequences

Many dextromethorphan-laced preparations contain other active compounds—such as pseudoephedrine, acetaminophen, chlorpheniramine, guaifenesin, or bromide—that can cause serious adverse effects at above-normal doses. Abuse of medications containing both chlorpheniramine and dextromethorphan leads to hallucinogenic euphoria and dissociation, followed by hours of intense somnolence.

Dextromethorphan can cause serotonin syndrome when taken with serotonergic drugs such as amphetamines, cocaine, monoamine oxidase inhibitors, or selective serotonin reuptake inhibitors. Symptoms include tachycardia, hypertension, diaphoresis, mydriasis, myoclonus, agitation, and seizures.

Box 2

The authors’ observations

Physical and psychiatric symptoms, patient history, and collateral information together can confirm dextromethorphan abuse in patients who present with mainly visual and tactile hallucinations. The signs are easy to miss in patients with schizophrenia because schizophrenia is believed to be causing the psychosis.

Psychiatric/physical symptoms. Psychiatric symptoms of “robo” intoxication include euphoria, altered time perception, disorientation, and tactile, visual and auditory hallucinations.⁷ Physical symptoms include excitation, nystagmus, tachycardia, hypertension, hyperthermia, vomiting, urinary retention, drowsiness, and rash. Extreme dextromethorphan withdrawal can cause dysphoria, insomnia, vomiting, diaphoresis, abdominal pain, and diarrhea.⁷

Also watch for dermatitis on the forehead, nose, or cheeks, which can result from chronic abuse of preparations containing dextromethorphan plus bromide or chlorpheniramine.

Patient history. Has the patient abused dextromethorphan before? If so, how often? When was he last treated for decompensation after cold medication abuse?

Also check for abuse of other substances, and ask teenage patients if their friends use cold preparations recreationally.

Collateral information. Ask family members to search the patient’s room for supplies of cold medicine and for empty boxes and capsule cards, check the medicine chest regularly to see if cold medications are missing, and check the patient’s jacket or coat pockets for cold tablets or cough syrup.

Treating ‘robo’ abuse

Convincing the patient and family that dextromethorphan abuse can cause severe harm is critical to promoting a positive outcome. Referral to a substance abuse rehabilitation program or 12-step group can help.

Related resources

• U.S. Department of Justice, National Drug Intelligence Center. Intelligence bulletin: DXM (dextromethorphan). www.usdoj.gov/ndic/pubs11/11563/index.htm.
  
• Partnership for a Drug-Free America. Resource for parents. www.drugfree.org/Parent. Click on “Cough Medicine Abuse” under “Special Drug Reports.”
  
• U.S. Food and Drug Administraton. FDA warns against abuse of dextromethorphan (DXM). www.fda.gov, enter “dextromethorphan” in search field.
  

• Risperidone • Risperdal
  

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

CASE: The man from Betelgeuse

Mr. F, age 33, has been hospitalized repeatedly for psychotic episodes after abuse of dextromethorphan in cold medications.

Approximately 1 week before presenting to us, Mr. F stormed out of his house after his father, with whom he lived, confronted him about spending his allowance on cold medications. He spent the week living on the streets, abusing dextromethorphan whenever he could get it.

One night, Mr. F approached a police officer at an accident scene and exclaimed, “Dude, I’m from the planet Betelgeuse.” He appeared disorganized as police questioned him, and officers transported him to the county hospital’s psychiatric emergency service.

At presentation, Mr. F is at times silly, irritable, and sleepy, and chants incantations during the intake interview. Alternately, he hears Jesus Christ and aliens from Betelgeuse telling him “everything is going to be cool” and voices of aliens threatening to abduct him.

We admit Mr. F to the inpatient psychiatric unit, start risperidone at 2 mg nightly, and titrate it to 6 mg nightly over 3 days, after which he is significantly more organized with reduced auditory hallucinations. At discharge 6 days later, he still occasionally hears Jesus but has partial insight into his obsession with aliens and no paranoid delusions. We continue risperidone, 6 mg nightly, and refer him to an outpatient mental health program. He visits the clinic once but avoids the attending psychiatrist.

Five days later, Mr. F begins hallucinating at home and his father brings him back to the emergency psychiatry unit. At presentation, the patient claims to be an agent of Satan and waves his arms wildly while performing “black magic.” He believes he is damned and that previous messages he thought came from Jesus and extraterrestrials were instead from the devil.

Mr. F’s father reports that over the weekend his son ingested 6 boxes of cold medicine—each with 16 tablets containing 30 mg of dextromethorphan. Peeling skin on the lower part of Mr. F’s forehead, the bridge of his nose, and under his eyes suggests chronic cold tablet abuse. We re-admit the patient after extended urine drug screen shows traces of chlorpheniramine.

The authors’ observations

Routine urine drug screens based on radio-immunoassay detect many substances, but an extended or comprehensive urine drug screen based on gas chromatography-mass spectrometry is needed to detect dextromethorphan.¹ Tertiary hospitals and reference laboratories usually offer these tests.

An extended urine screen will not detect dextromethorphan 24 hours after use because the agent has a 3- to 11-hour half-life. The test can, however, detect other active cold preparation compounds with longer half-lives, such as chlorpheniramine.

If extended urine screening is not available, clinical findings discussed later in this article can confirm recent cold medication abuse. Blood testing can reveal dextromethorphan levels, but a 3- to 6-mL sample may be needed.

HISTORY: ‘Sick’ at 16

Mr. F began abusing dextromethorphan at age 16, when friends would “turn him on” to 8-ounce bottles of cough syrup every other week. He later tried marijuana, cocaine, phencyclidine, methamphetamine, morphine, and LSD. Soon after graduating from high school, he stopped using substances and remained clean for several years.

Mr. F worked as a restaurant manager for about 4 months but found the job stressful and constantly argued with staff. He resumed abusing cough syrup to relieve his stress but soon became hooked on its dissociative and hallucinogenic effects. One night he ingested enough cough syrup to remain “high” until the next morning. He was hallucinating when he reported to work that day and was fired.

Since then, Mr. F’s cold medication abuse has escalated from biweekly to almost daily at presentation. He switched to tablets because the syrup induced cold symptoms and he finds the “buzz” from the tablets easier to control.

He typically dresses in black (in keeping with his satanic obsessions) and wears a long black overcoat with several pockets, that allows him to carry boxes of cold capsules, books, and other items.

Mr. F’s father has repeatedly tried to stop his son’s cold tablet abuse by cutting off his allowance. Dextromethorphan-containing cold medications are inexpensive, however—a box of 16 30-mg tablets costs as little as $1.50. Also, Mr. F often would get money for cold capsules by going to malls and participating in market research surveys.

In the past year, Mr. F was hospitalized 6 times after dextromethorphan-induced psychotic decompensations. He has been unemployed for more than 5 years, has not been in a serious romantic relationship since college, and depends on his father for financial support. He is not abusing other substances.

The authors’ observations

As many as 80% of patients with schizophrenia also have a substance abuse disorder.² Access to psychoactive substances, kindling associated with schizophrenia, and attempts to stop hallucinations with alcohol or illicit drugs may explain this high prevalence.² Also, genetic or phenotypic vulnerability in schizophrenia might alter the mesolimbic dopamine system that moderates reward.

Compared with patients with schizophrenia who are substance-free, comorbid substance abuse in schizophrenia increases:

• severity of psychotic symptoms
  
• likelihood of emergency service use
  
• risk of suicide, illness, injury, hospitalization, or incarceration.³
  

Mr. F responded well to risperidone when he wasn’t abusing cold tablets. After his last hospitalization, we referred him to a comprehensive outpatient program that could have addressed his cold medicine abuse and reintegrated him into the workplace. He avoided seeing the clinic psychiatrist, however, after promising his case manager that he would stop abusing dextromethorphan.

TREATMENT: Back to Betelgeuse

Upon re-admission, we restart risperidone, 6 mg nightly. Mr. F shows extreme somnolence caused by massive cold capsule use and is minimally cooperative with the psychiatrist’s follow-up interview. Over 36 hours, he awakens only for meals and medication and to use the bathroom. Once the somnolence passes, he cannot fall asleep at night.

Six days after admission, Mr. F is organized and hears voices mostly from Jesus with some demonic delusions. Extended urine drug screen taken 3 days after admission shows traces of chlorpheniramine but no dextromethorphan.

By day 7, Mr. F is nearly free of delusions and is discharged the next day. We continue risperidone, 6 mg nightly, to prevent the “voices,” and add diphenhydramine, 50 mg nightly, to regulate his sleep. We arrange follow-up care at an outpatient clinic, but Mr. F again avoids the clinic psychiatrist.

The authors’ observations

Mr. F’s “robo” binge triggered a profound and prolonged psychotic decompensation.

Dextrorphan—a pharmacologically active metabolite of dextromethorphan— might have disrupted cortical and sub-cortical glutamatergic neurotransmission,⁶ leading to florid psychosis and delayed recovery. Induction of the cytochrome P-450 2D6 isoenzyme, which metabolizes dextromethorphan, also could have prolonged Mr. F’s psychosis (Box 1).^7-11

RELAPSE: Return visits

Three weeks after discharge, Mr. F fights with police officers after they find him hallucinating in the streets. Police charge him with disorderly conduct and resisting arrest and bring him back to the psychiatric ER. We again resolve his auditory hallucinations with risperidone, 6 mg nightly. After 8 days we discharge him to police, who then transport him to jail and later release him on bail.

Six months later, Mr. F is hospitalized twice in 2 months after dextromethorphan-induced decompensations. He recovers quickly both times but lacks insight into his mental illness and his “robo” problem.

The authors’ observations

Dextromethorphan, known by many street names (Box 2), is contained in more than 100 OTC preparations, and is sold on the Internet in powder form.

• Most people do not know that dextromethorphan-laced medications are dangerous if misused.
  
• These preparations can be purchased at many stores or snatched from the medicine chest.
  
• Several Web sites describe how to “safely” abuse dextromethorphan.¹³
  

medical consequences

Many dextromethorphan-laced preparations contain other active compounds—such as pseudoephedrine, acetaminophen, chlorpheniramine, guaifenesin, or bromide—that can cause serious adverse effects at above-normal doses. Abuse of medications containing both chlorpheniramine and dextromethorphan leads to hallucinogenic euphoria and dissociation, followed by hours of intense somnolence.

Dextromethorphan can cause serotonin syndrome when taken with serotonergic drugs such as amphetamines, cocaine, monoamine oxidase inhibitors, or selective serotonin reuptake inhibitors. Symptoms include tachycardia, hypertension, diaphoresis, mydriasis, myoclonus, agitation, and seizures.

Box 2

The authors’ observations

Physical and psychiatric symptoms, patient history, and collateral information together can confirm dextromethorphan abuse in patients who present with mainly visual and tactile hallucinations. The signs are easy to miss in patients with schizophrenia because schizophrenia is believed to be causing the psychosis.

Psychiatric/physical symptoms. Psychiatric symptoms of “robo” intoxication include euphoria, altered time perception, disorientation, and tactile, visual and auditory hallucinations.⁷ Physical symptoms include excitation, nystagmus, tachycardia, hypertension, hyperthermia, vomiting, urinary retention, drowsiness, and rash. Extreme dextromethorphan withdrawal can cause dysphoria, insomnia, vomiting, diaphoresis, abdominal pain, and diarrhea.⁷

Also watch for dermatitis on the forehead, nose, or cheeks, which can result from chronic abuse of preparations containing dextromethorphan plus bromide or chlorpheniramine.

Patient history. Has the patient abused dextromethorphan before? If so, how often? When was he last treated for decompensation after cold medication abuse?

Also check for abuse of other substances, and ask teenage patients if their friends use cold preparations recreationally.

Collateral information. Ask family members to search the patient’s room for supplies of cold medicine and for empty boxes and capsule cards, check the medicine chest regularly to see if cold medications are missing, and check the patient’s jacket or coat pockets for cold tablets or cough syrup.

Treating ‘robo’ abuse

Convincing the patient and family that dextromethorphan abuse can cause severe harm is critical to promoting a positive outcome. Referral to a substance abuse rehabilitation program or 12-step group can help.

Related resources

• U.S. Department of Justice, National Drug Intelligence Center. Intelligence bulletin: DXM (dextromethorphan). www.usdoj.gov/ndic/pubs11/11563/index.htm.
  
• Partnership for a Drug-Free America. Resource for parents. www.drugfree.org/Parent. Click on “Cough Medicine Abuse” under “Special Drug Reports.”
  
• U.S. Food and Drug Administraton. FDA warns against abuse of dextromethorphan (DXM). www.fda.gov, enter “dextromethorphan” in search field.
  

• Risperidone • Risperdal
  

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

CASE: The man from Betelgeuse

Mr. F, age 33, has been hospitalized repeatedly for psychotic episodes after abuse of dextromethorphan in cold medications.

Approximately 1 week before presenting to us, Mr. F stormed out of his house after his father, with whom he lived, confronted him about spending his allowance on cold medications. He spent the week living on the streets, abusing dextromethorphan whenever he could get it.

One night, Mr. F approached a police officer at an accident scene and exclaimed, “Dude, I’m from the planet Betelgeuse.” He appeared disorganized as police questioned him, and officers transported him to the county hospital’s psychiatric emergency service.

At presentation, Mr. F is at times silly, irritable, and sleepy, and chants incantations during the intake interview. Alternately, he hears Jesus Christ and aliens from Betelgeuse telling him “everything is going to be cool” and voices of aliens threatening to abduct him.

We admit Mr. F to the inpatient psychiatric unit, start risperidone at 2 mg nightly, and titrate it to 6 mg nightly over 3 days, after which he is significantly more organized with reduced auditory hallucinations. At discharge 6 days later, he still occasionally hears Jesus but has partial insight into his obsession with aliens and no paranoid delusions. We continue risperidone, 6 mg nightly, and refer him to an outpatient mental health program. He visits the clinic once but avoids the attending psychiatrist.

Five days later, Mr. F begins hallucinating at home and his father brings him back to the emergency psychiatry unit. At presentation, the patient claims to be an agent of Satan and waves his arms wildly while performing “black magic.” He believes he is damned and that previous messages he thought came from Jesus and extraterrestrials were instead from the devil.

Mr. F’s father reports that over the weekend his son ingested 6 boxes of cold medicine—each with 16 tablets containing 30 mg of dextromethorphan. Peeling skin on the lower part of Mr. F’s forehead, the bridge of his nose, and under his eyes suggests chronic cold tablet abuse. We re-admit the patient after extended urine drug screen shows traces of chlorpheniramine.

The authors’ observations

Routine urine drug screens based on radio-immunoassay detect many substances, but an extended or comprehensive urine drug screen based on gas chromatography-mass spectrometry is needed to detect dextromethorphan.¹ Tertiary hospitals and reference laboratories usually offer these tests.

An extended urine screen will not detect dextromethorphan 24 hours after use because the agent has a 3- to 11-hour half-life. The test can, however, detect other active cold preparation compounds with longer half-lives, such as chlorpheniramine.

If extended urine screening is not available, clinical findings discussed later in this article can confirm recent cold medication abuse. Blood testing can reveal dextromethorphan levels, but a 3- to 6-mL sample may be needed.

HISTORY: ‘Sick’ at 16

Mr. F began abusing dextromethorphan at age 16, when friends would “turn him on” to 8-ounce bottles of cough syrup every other week. He later tried marijuana, cocaine, phencyclidine, methamphetamine, morphine, and LSD. Soon after graduating from high school, he stopped using substances and remained clean for several years.

Mr. F worked as a restaurant manager for about 4 months but found the job stressful and constantly argued with staff. He resumed abusing cough syrup to relieve his stress but soon became hooked on its dissociative and hallucinogenic effects. One night he ingested enough cough syrup to remain “high” until the next morning. He was hallucinating when he reported to work that day and was fired.

Since then, Mr. F’s cold medication abuse has escalated from biweekly to almost daily at presentation. He switched to tablets because the syrup induced cold symptoms and he finds the “buzz” from the tablets easier to control.

He typically dresses in black (in keeping with his satanic obsessions) and wears a long black overcoat with several pockets, that allows him to carry boxes of cold capsules, books, and other items.

Mr. F’s father has repeatedly tried to stop his son’s cold tablet abuse by cutting off his allowance. Dextromethorphan-containing cold medications are inexpensive, however—a box of 16 30-mg tablets costs as little as $1.50. Also, Mr. F often would get money for cold capsules by going to malls and participating in market research surveys.

In the past year, Mr. F was hospitalized 6 times after dextromethorphan-induced psychotic decompensations. He has been unemployed for more than 5 years, has not been in a serious romantic relationship since college, and depends on his father for financial support. He is not abusing other substances.

The authors’ observations

As many as 80% of patients with schizophrenia also have a substance abuse disorder.² Access to psychoactive substances, kindling associated with schizophrenia, and attempts to stop hallucinations with alcohol or illicit drugs may explain this high prevalence.² Also, genetic or phenotypic vulnerability in schizophrenia might alter the mesolimbic dopamine system that moderates reward.

Compared with patients with schizophrenia who are substance-free, comorbid substance abuse in schizophrenia increases:

• severity of psychotic symptoms
  
• likelihood of emergency service use
  
• risk of suicide, illness, injury, hospitalization, or incarceration.³
  

Mr. F responded well to risperidone when he wasn’t abusing cold tablets. After his last hospitalization, we referred him to a comprehensive outpatient program that could have addressed his cold medicine abuse and reintegrated him into the workplace. He avoided seeing the clinic psychiatrist, however, after promising his case manager that he would stop abusing dextromethorphan.

TREATMENT: Back to Betelgeuse

Upon re-admission, we restart risperidone, 6 mg nightly. Mr. F shows extreme somnolence caused by massive cold capsule use and is minimally cooperative with the psychiatrist’s follow-up interview. Over 36 hours, he awakens only for meals and medication and to use the bathroom. Once the somnolence passes, he cannot fall asleep at night.

Six days after admission, Mr. F is organized and hears voices mostly from Jesus with some demonic delusions. Extended urine drug screen taken 3 days after admission shows traces of chlorpheniramine but no dextromethorphan.

By day 7, Mr. F is nearly free of delusions and is discharged the next day. We continue risperidone, 6 mg nightly, to prevent the “voices,” and add diphenhydramine, 50 mg nightly, to regulate his sleep. We arrange follow-up care at an outpatient clinic, but Mr. F again avoids the clinic psychiatrist.

The authors’ observations

Mr. F’s “robo” binge triggered a profound and prolonged psychotic decompensation.

Dextrorphan—a pharmacologically active metabolite of dextromethorphan— might have disrupted cortical and sub-cortical glutamatergic neurotransmission,⁶ leading to florid psychosis and delayed recovery. Induction of the cytochrome P-450 2D6 isoenzyme, which metabolizes dextromethorphan, also could have prolonged Mr. F’s psychosis (Box 1).^7-11

RELAPSE: Return visits

Three weeks after discharge, Mr. F fights with police officers after they find him hallucinating in the streets. Police charge him with disorderly conduct and resisting arrest and bring him back to the psychiatric ER. We again resolve his auditory hallucinations with risperidone, 6 mg nightly. After 8 days we discharge him to police, who then transport him to jail and later release him on bail.

Six months later, Mr. F is hospitalized twice in 2 months after dextromethorphan-induced decompensations. He recovers quickly both times but lacks insight into his mental illness and his “robo” problem.

The authors’ observations

Dextromethorphan, known by many street names (Box 2), is contained in more than 100 OTC preparations, and is sold on the Internet in powder form.

• Most people do not know that dextromethorphan-laced medications are dangerous if misused.
  
• These preparations can be purchased at many stores or snatched from the medicine chest.
  
• Several Web sites describe how to “safely” abuse dextromethorphan.¹³
  

medical consequences

Many dextromethorphan-laced preparations contain other active compounds—such as pseudoephedrine, acetaminophen, chlorpheniramine, guaifenesin, or bromide—that can cause serious adverse effects at above-normal doses. Abuse of medications containing both chlorpheniramine and dextromethorphan leads to hallucinogenic euphoria and dissociation, followed by hours of intense somnolence.

Dextromethorphan can cause serotonin syndrome when taken with serotonergic drugs such as amphetamines, cocaine, monoamine oxidase inhibitors, or selective serotonin reuptake inhibitors. Symptoms include tachycardia, hypertension, diaphoresis, mydriasis, myoclonus, agitation, and seizures.

Box 2

The authors’ observations

Physical and psychiatric symptoms, patient history, and collateral information together can confirm dextromethorphan abuse in patients who present with mainly visual and tactile hallucinations. The signs are easy to miss in patients with schizophrenia because schizophrenia is believed to be causing the psychosis.

Psychiatric/physical symptoms. Psychiatric symptoms of “robo” intoxication include euphoria, altered time perception, disorientation, and tactile, visual and auditory hallucinations.⁷ Physical symptoms include excitation, nystagmus, tachycardia, hypertension, hyperthermia, vomiting, urinary retention, drowsiness, and rash. Extreme dextromethorphan withdrawal can cause dysphoria, insomnia, vomiting, diaphoresis, abdominal pain, and diarrhea.⁷

Also watch for dermatitis on the forehead, nose, or cheeks, which can result from chronic abuse of preparations containing dextromethorphan plus bromide or chlorpheniramine.

Patient history. Has the patient abused dextromethorphan before? If so, how often? When was he last treated for decompensation after cold medication abuse?

Also check for abuse of other substances, and ask teenage patients if their friends use cold preparations recreationally.

Collateral information. Ask family members to search the patient’s room for supplies of cold medicine and for empty boxes and capsule cards, check the medicine chest regularly to see if cold medications are missing, and check the patient’s jacket or coat pockets for cold tablets or cough syrup.

Treating ‘robo’ abuse

Convincing the patient and family that dextromethorphan abuse can cause severe harm is critical to promoting a positive outcome. Referral to a substance abuse rehabilitation program or 12-step group can help.

Related resources

• U.S. Department of Justice, National Drug Intelligence Center. Intelligence bulletin: DXM (dextromethorphan). www.usdoj.gov/ndic/pubs11/11563/index.htm.
  
• Partnership for a Drug-Free America. Resource for parents. www.drugfree.org/Parent. Click on “Cough Medicine Abuse” under “Special Drug Reports.”
  
• U.S. Food and Drug Administraton. FDA warns against abuse of dextromethorphan (DXM). www.fda.gov, enter “dextromethorphan” in search field.
  

• Risperidone • Risperdal
  

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

Diagnosis and treatment of neuroleptic malignant syndrome (NMS) are controversial because this potentially life-threatening syndrome is rare and its presentation varies. These factors make it difficult to evaluate treatments in controlled clinical trials, and data about the relative efficacy of specific interventions are scarce. It may be possible, however, to develop rational treatment guidelines using empiric clinical data.^1,2

This article examines the evidence related to 6 controversial aspects of NMS diagnosis and treatment:

• most-reliable risk factors
• NMS as a spectrum disorder
• what causes NMS
• NMS triggered by first-generation vs second-generation antipsychotics
• first-line interventions
• restarting antipsychotics after an NMS episode.

1. Are there reliable risk factors for NMS?

In small case-controlled studies, agitation, dehydration, and exhaustion were the most consistently found systemic factors believed to predispose patients taking antipsychotics to NMS (Table 1).^3-5 Catatonia and organic brain syndromes may be separate risk factors.^1,6

Preliminary studies also have implicated dopamine receptor abnormalities caused by genetic polymorphisms or effects of low serum iron.^1,7,8 Pharmacologic studies have suggested that higher doses, rapid titration, and IM injections of antipsychotics are associated with increased NMS risk.^3,5 Some studies suggest that 15% to 20% of NMS patients have a history of NMS episodes.^1,2 In addition, high-potency first-generation antipsychotics (FGAs)—especially haloperidol—are assumed to carry higher risk than low-potency drugs and second-generation antipsychotics (SGAs), although this hypothesis remains difficult to prove.^9-11

These risk factors, however, are not practical for estimating NMS risk in a given patient because they are relatively common compared with the low risk of NMS occurrence. For the vast majority of patients with psychotic symptoms, the benefits of properly indicated antipsychotic pharmacotherapy will outweigh the risks.

Table 1

*For individual patients, these common risk factors must be weighted again the benefits of antipsychotic therapy FGAs: first-generation antipsychotics; SGAs:second-generation antipsychotics; NMS: neuroleptic malignant syndromeSource: References 1-5

2. Is NMS related to parkinsonism, catatonia, or malignant hyperthermia?

Parkinsonsim. Some researchers have described NMS as an extreme parkinsonian crisis resulting from overwhelming blockade of dopamine pathways in the brain.^1,2,12 In this view, NMS resembles the parkinsonian-hyperthermia syndrome that can occur in Parkinson's disease patients following abrupt discontinuation or loss of efficacy of dopaminergic therapy, which can be treated by reinstituting dopaminergic agents.¹³ Evidence to support this view includes:

• Parkinsonian signs are a cardinal feature of NMS.
• Withdrawal of dopamine agonists precipitates the syndrome.
• All triggering drugs are dopamine receptor antagonists.
• Risks of NMS correlates with drugs' dopamine receptor affinity.
• Dopaminergic agonists may be an effective treatment.
• Lesions in dopaminergic pathways produce a similar syndrome.
• Patients with NMS have demonstrated low cerebrospinal fluid concentrations of the dopamine metabolite homovanillic acid.¹⁴

Catatonia. Fink et al¹⁵ and others^16-18 have persuasively argued that NMS represents a form of drug-induced malignant catatonia. Evidence supporting this includes:

• The 2 disorders share neuropsychiatric symptoms.
• Catalonic signs are common in NMS.¹⁹
• Malignant catatonia and NMS share physiologic and labratory signs.²⁰
• Reintroduction of antipsychotics can acutely worsen both conditions.
• Benzodiazepines and electroconvulsive therapy (ECT) are effective treatments for both disorders.^15-18

Lee²¹ examined the relationship between catatonic features and treatment response of 14 NMS patients. Most patients with catatonic symptoms responded to benzodiazepines, whereas none of those did who had an extrapyramidal-hyperthermic presentation without catatonia. Lee concluded that NMS is heterogeneous and may occur in catatonic and noncatatonic forms that differ in treatment response.

• similar clinical signs of rigidity, hyperthermia, and hypermetabolism
• similar psychologic and labratory signs, such as rhabdomyolysis
• hyperthermia in both responding to dantrolene.

Although the 2 are similar in presentation, malignant hyperthermia occurs intraoperatively and reflects a pharmacogenetic disorder of calcium regulation in skeletal muscle. Additionally, rigidity in malignant hyperthermia does not respond to peripheral-acting muscle relaxants.^1,22 Evidence suggests that patients who have previously experienced an NMS episodes are not at risk for malignant hyperthermia.²²

3. What is the pathophysiology of NMS?

NMS pathophysiology is complex and likely involves interplay between multiple central and systemic pathways and neurotransmitters. As described above, compelling evidence suggests that dopamine blockade plays a central role.¹²

Dopamine blockade in the hypothalamus is believed to contribute to thermoregulatory failure, and blockade in the nigrostriatal system likely contributes to muscle rigidity and hypermetabolism. The loss of dopaminergic input to the anterior cingulate-medial orbitofrontal circuit and the lateral orbitofrontal circuit likely con-tributes to the mental status changes and catatonic features seen in NMS.¹²

Some researchers have proposed competing or complementary hypotheses, however. For example, Gurrera²³ proposed that patients who are prone to developing NMS have a vulnerability to a hyperactive and dysregulated sympathetic nervous system, and this trait—together with dopamine system disruption induced by dopamine-blocking agents—produces NMS. Other investigators have implicated serotonin, norepinephrine, gamma-aminobutyric acid and glutaminergic mechanisms.^1,12,24,25

4. Are FGAs or SGAs more likely to cause NMS?

NMS is assumed to occur less frequently in patients treated with SGAs than in those receiving FGAs, although this hypothesisis unproven. Isolated reports of NMS have been associated with nearly every SGA.^9-11 It is difficult to prove FGA vs SGA liabilities because:

• NMS is rare.
• Dosing practices may be more conser-vative now than in the past.
• Most clinicians are aware of the earlysigns of NMS.

In an epidemiological study of a large database, Stubner et al²⁶ found that patients receiving SGAs had a lower risk of NMS than those treated with haloperidol.²⁶ In this study, the overall rate of NMS was 0.02%.

NMS hotline data. We recently examined which medication classes were implicated in 111 NMS cases reported to the Neuroleptic Malignant Syndrome Information Service hotline (1-888-NMS-TEMP) between 1997 and 2006 (Figure). We included only cases of definite or probable NMS (as diagnosed by hotline consultants) in which a single antipsychotic was administered. Slightly more cases were attributed to FGAs (51%) than SGAs (45%). The remaining cases were attributed to neuroleptics used in medical settings (such as promethazineor prochlorperazine). Because they are now prescribed less often, FGAs accounted for a disproportionate number of NMS cases reported to the hotline. Haloperidol accounted for the majority of FGA cases and 44% of all cases. If we had excluded haloperidol and compared the NMS risk of SGAs to only intermediate- or low-potency FGAs, the relative advantage of SGAs would have been lost. On the other hand, it is clear that SGAs still carry a risk for NMS. Analyses suggest that the SGA-associated classic features of NMS—fever, muscle rigidity, and autonomic and mental status changes—are retained in patients receiving SGAs, although some may not develop the severe rigidity and extreme temperatures common in patients receiving FGAs.^9-11 The milder clinical characteristics associated with SGAs may reflect more conservative prescribing patterns or increased awareness and earlier recognition of NMS, which would prevent fulminant presentations.

5. What is the evidence for specific NMS treatments?

NMS is rare, its presentation varies, and its progression is unpredictable. These factors make it difficult to evaluate treatments in controlled clinical trials, and data about the relative efficacy of specific interventions are scarce.

Even so, the notion that NMS represents an extreme variant of drug-induced parkinsonism or catatonia suggests that specific NMS treatments could be based on symptom severity or stage of presentation. We propose a treatment guideline basedon theoretical mechanisms and anecdotal data (Algorithm).^2,27-29

Support. After immediate withdrawal of the offending medication, supportive therapy is the cornerstone of NMS treatment.^1,2,27

For patients presenting with mild signs and symptoms, supportive care and careful clinical monitoring may be sufficient. Extreme hyperthermia demands volume resuscitation and cooling measures, intensive medical care, and careful monitoring for complications.

Treatment. Despite a lack of consensus on drug treatments for uncomplicated NMS, approximately 40% of patients with acute NMS receive pharmacologic treatments.²

Lorazepam, 1 to 2 mg parenterally, is a reasonable first-line therapy for NMS, especially in individuals with catatonic features.^{4,15-18,21,30,31} Some investigators recommend higher doses.¹⁵ Benzodiazepines are preferred if sedation is required in agitated NMS patients.^4,15-18

Dopaminergic agents such as bromocriptine and amantadine enhance dopaminergic transmission to reverse parkinsonian symptoms and have been reported to reduce time to recovery and halve mortality rates when used alone or in conjunction with other treatments.^13,27,32,33 Rapid discontinuation of these agents can result in rebound symptoms, although this may be true for any specific drug treatment of NMS.^1,31,32

Dantrolene uncouples excitation-contraction coupling by enhancing calcium sequestration in sarcoplasmic reticulumin skeletal muscle and has been used to treat NMS hypermetabolic symptoms. Some reviews found improvement in up to 80% of NMS patients treated with dantrolene monotherapy.^27,32-35 Compared with supportive care, time to recovery may be reduced—and mortality decreased by almost one-half—when dantrolene is used alone or in combination with other medications.

Not all case reports have shown that dantrolene, benzodiazepines, ordopaminergic agonists are effective in treating NMS.^31,36 In our opinion, only advanced NMS cases—with extreme temperature elevations, severe rigidity, and evidence of systemic hypermetabolism—benefit from dantrolene treatment.^1,2

ECT has been used successfully to reduce mortality from NMS and other catatonic-spectrum disorders. It is usually employed after supportive therapy and psychopharmacologic interventions fail.^{2,15,16,27,37} ECT for acute NMS typically consists of a series of 6 to 10 treatments with bilateral electrode placement. Daily ECT may be needed initially.¹⁵

6. Are antipsychotics contraindicated following an NMS episode?

The rate of NMS recurrence on retreatment with an antipsychotic has varied.38 We estimate that up to 30% of patients may be at risk of NMS recurrence when rechallenged with an antipsychotic.1 By following proper precautions (Table 2), however, you can safely treat most patients who require continued antipsychotic therapy.^1,2 When you restart treatment, a lower-potency antipsychotic from a different chemical class may be a safer option than retrying the triggering agent, according to retrospective analyses of limited available data. A patient who develops NMS on a FGA might benefit from an SGA trial, although some risk of recurrence remains.^1,10

Current Psychiatry 2007;6(8):89-95.
Drug brand names

• Amantadine • Symmetrel
• Bromocriptine • Parlodel
• Chlorpromazine • Thorazine
• Dantrolene • Dantrium
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Lorazepam • Ativan
• Loxapine • Loxitane
• Perphenazine • Trilafon
• Prochlorperazine • Compazine, Compro
• Promethazine • Phenergan
• Thioridazine • Mellaril

Disclosure

Dr. Strawn is an American Psychiatric Institute for Research and Education (APIRE)/Janssen Scholar.

Dr. Keck has received research support from or served as a consultant to Abbott Laboratories, American Diabetes Association, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly and Company, Janssen Pharmaceutica, National Institute of Mental Health, National Institute of Drug Abuse, Pfizer, Stanley Medical Research Institute, and UCB Pharma.

Dr. Caroff has received research support from Bristol-Myers Squibb, Ortho-McNeil Neurologics, and Pfizer.

Diagnosis and treatment of neuroleptic malignant syndrome (NMS) are controversial because this potentially life-threatening syndrome is rare and its presentation varies. These factors make it difficult to evaluate treatments in controlled clinical trials, and data about the relative efficacy of specific interventions are scarce. It may be possible, however, to develop rational treatment guidelines using empiric clinical data.^1,2

This article examines the evidence related to 6 controversial aspects of NMS diagnosis and treatment:

• most-reliable risk factors
• NMS as a spectrum disorder
• what causes NMS
• NMS triggered by first-generation vs second-generation antipsychotics
• first-line interventions
• restarting antipsychotics after an NMS episode.

1. Are there reliable risk factors for NMS?

In small case-controlled studies, agitation, dehydration, and exhaustion were the most consistently found systemic factors believed to predispose patients taking antipsychotics to NMS (Table 1).^3-5 Catatonia and organic brain syndromes may be separate risk factors.^1,6

Preliminary studies also have implicated dopamine receptor abnormalities caused by genetic polymorphisms or effects of low serum iron.^1,7,8 Pharmacologic studies have suggested that higher doses, rapid titration, and IM injections of antipsychotics are associated with increased NMS risk.^3,5 Some studies suggest that 15% to 20% of NMS patients have a history of NMS episodes.^1,2 In addition, high-potency first-generation antipsychotics (FGAs)—especially haloperidol—are assumed to carry higher risk than low-potency drugs and second-generation antipsychotics (SGAs), although this hypothesis remains difficult to prove.^9-11

These risk factors, however, are not practical for estimating NMS risk in a given patient because they are relatively common compared with the low risk of NMS occurrence. For the vast majority of patients with psychotic symptoms, the benefits of properly indicated antipsychotic pharmacotherapy will outweigh the risks.

Table 1

*For individual patients, these common risk factors must be weighted again the benefits of antipsychotic therapy FGAs: first-generation antipsychotics; SGAs:second-generation antipsychotics; NMS: neuroleptic malignant syndromeSource: References 1-5

2. Is NMS related to parkinsonism, catatonia, or malignant hyperthermia?

Parkinsonsim. Some researchers have described NMS as an extreme parkinsonian crisis resulting from overwhelming blockade of dopamine pathways in the brain.^1,2,12 In this view, NMS resembles the parkinsonian-hyperthermia syndrome that can occur in Parkinson's disease patients following abrupt discontinuation or loss of efficacy of dopaminergic therapy, which can be treated by reinstituting dopaminergic agents.¹³ Evidence to support this view includes:

• Parkinsonian signs are a cardinal feature of NMS.
• Withdrawal of dopamine agonists precipitates the syndrome.
• All triggering drugs are dopamine receptor antagonists.
• Risks of NMS correlates with drugs' dopamine receptor affinity.
• Dopaminergic agonists may be an effective treatment.
• Lesions in dopaminergic pathways produce a similar syndrome.
• Patients with NMS have demonstrated low cerebrospinal fluid concentrations of the dopamine metabolite homovanillic acid.¹⁴

Catatonia. Fink et al¹⁵ and others^16-18 have persuasively argued that NMS represents a form of drug-induced malignant catatonia. Evidence supporting this includes:

• The 2 disorders share neuropsychiatric symptoms.
• Catalonic signs are common in NMS.¹⁹
• Malignant catatonia and NMS share physiologic and labratory signs.²⁰
• Reintroduction of antipsychotics can acutely worsen both conditions.
• Benzodiazepines and electroconvulsive therapy (ECT) are effective treatments for both disorders.^15-18

Lee²¹ examined the relationship between catatonic features and treatment response of 14 NMS patients. Most patients with catatonic symptoms responded to benzodiazepines, whereas none of those did who had an extrapyramidal-hyperthermic presentation without catatonia. Lee concluded that NMS is heterogeneous and may occur in catatonic and noncatatonic forms that differ in treatment response.

• similar clinical signs of rigidity, hyperthermia, and hypermetabolism
• similar psychologic and labratory signs, such as rhabdomyolysis
• hyperthermia in both responding to dantrolene.

Although the 2 are similar in presentation, malignant hyperthermia occurs intraoperatively and reflects a pharmacogenetic disorder of calcium regulation in skeletal muscle. Additionally, rigidity in malignant hyperthermia does not respond to peripheral-acting muscle relaxants.^1,22 Evidence suggests that patients who have previously experienced an NMS episodes are not at risk for malignant hyperthermia.²²

3. What is the pathophysiology of NMS?

NMS pathophysiology is complex and likely involves interplay between multiple central and systemic pathways and neurotransmitters. As described above, compelling evidence suggests that dopamine blockade plays a central role.¹²

Dopamine blockade in the hypothalamus is believed to contribute to thermoregulatory failure, and blockade in the nigrostriatal system likely contributes to muscle rigidity and hypermetabolism. The loss of dopaminergic input to the anterior cingulate-medial orbitofrontal circuit and the lateral orbitofrontal circuit likely con-tributes to the mental status changes and catatonic features seen in NMS.¹²

Some researchers have proposed competing or complementary hypotheses, however. For example, Gurrera²³ proposed that patients who are prone to developing NMS have a vulnerability to a hyperactive and dysregulated sympathetic nervous system, and this trait—together with dopamine system disruption induced by dopamine-blocking agents—produces NMS. Other investigators have implicated serotonin, norepinephrine, gamma-aminobutyric acid and glutaminergic mechanisms.^1,12,24,25

4. Are FGAs or SGAs more likely to cause NMS?

NMS is assumed to occur less frequently in patients treated with SGAs than in those receiving FGAs, although this hypothesisis unproven. Isolated reports of NMS have been associated with nearly every SGA.^9-11 It is difficult to prove FGA vs SGA liabilities because:

• NMS is rare.
• Dosing practices may be more conser-vative now than in the past.
• Most clinicians are aware of the earlysigns of NMS.

In an epidemiological study of a large database, Stubner et al²⁶ found that patients receiving SGAs had a lower risk of NMS than those treated with haloperidol.²⁶ In this study, the overall rate of NMS was 0.02%.

NMS hotline data. We recently examined which medication classes were implicated in 111 NMS cases reported to the Neuroleptic Malignant Syndrome Information Service hotline (1-888-NMS-TEMP) between 1997 and 2006 (Figure). We included only cases of definite or probable NMS (as diagnosed by hotline consultants) in which a single antipsychotic was administered. Slightly more cases were attributed to FGAs (51%) than SGAs (45%). The remaining cases were attributed to neuroleptics used in medical settings (such as promethazineor prochlorperazine). Because they are now prescribed less often, FGAs accounted for a disproportionate number of NMS cases reported to the hotline. Haloperidol accounted for the majority of FGA cases and 44% of all cases. If we had excluded haloperidol and compared the NMS risk of SGAs to only intermediate- or low-potency FGAs, the relative advantage of SGAs would have been lost. On the other hand, it is clear that SGAs still carry a risk for NMS. Analyses suggest that the SGA-associated classic features of NMS—fever, muscle rigidity, and autonomic and mental status changes—are retained in patients receiving SGAs, although some may not develop the severe rigidity and extreme temperatures common in patients receiving FGAs.^9-11 The milder clinical characteristics associated with SGAs may reflect more conservative prescribing patterns or increased awareness and earlier recognition of NMS, which would prevent fulminant presentations.

5. What is the evidence for specific NMS treatments?

NMS is rare, its presentation varies, and its progression is unpredictable. These factors make it difficult to evaluate treatments in controlled clinical trials, and data about the relative efficacy of specific interventions are scarce.

Even so, the notion that NMS represents an extreme variant of drug-induced parkinsonism or catatonia suggests that specific NMS treatments could be based on symptom severity or stage of presentation. We propose a treatment guideline basedon theoretical mechanisms and anecdotal data (Algorithm).^2,27-29

Support. After immediate withdrawal of the offending medication, supportive therapy is the cornerstone of NMS treatment.^1,2,27

For patients presenting with mild signs and symptoms, supportive care and careful clinical monitoring may be sufficient. Extreme hyperthermia demands volume resuscitation and cooling measures, intensive medical care, and careful monitoring for complications.

Treatment. Despite a lack of consensus on drug treatments for uncomplicated NMS, approximately 40% of patients with acute NMS receive pharmacologic treatments.²

Lorazepam, 1 to 2 mg parenterally, is a reasonable first-line therapy for NMS, especially in individuals with catatonic features.^{4,15-18,21,30,31} Some investigators recommend higher doses.¹⁵ Benzodiazepines are preferred if sedation is required in agitated NMS patients.^4,15-18

Dopaminergic agents such as bromocriptine and amantadine enhance dopaminergic transmission to reverse parkinsonian symptoms and have been reported to reduce time to recovery and halve mortality rates when used alone or in conjunction with other treatments.^13,27,32,33 Rapid discontinuation of these agents can result in rebound symptoms, although this may be true for any specific drug treatment of NMS.^1,31,32

Dantrolene uncouples excitation-contraction coupling by enhancing calcium sequestration in sarcoplasmic reticulumin skeletal muscle and has been used to treat NMS hypermetabolic symptoms. Some reviews found improvement in up to 80% of NMS patients treated with dantrolene monotherapy.^27,32-35 Compared with supportive care, time to recovery may be reduced—and mortality decreased by almost one-half—when dantrolene is used alone or in combination with other medications.

Not all case reports have shown that dantrolene, benzodiazepines, ordopaminergic agonists are effective in treating NMS.^31,36 In our opinion, only advanced NMS cases—with extreme temperature elevations, severe rigidity, and evidence of systemic hypermetabolism—benefit from dantrolene treatment.^1,2

ECT has been used successfully to reduce mortality from NMS and other catatonic-spectrum disorders. It is usually employed after supportive therapy and psychopharmacologic interventions fail.^{2,15,16,27,37} ECT for acute NMS typically consists of a series of 6 to 10 treatments with bilateral electrode placement. Daily ECT may be needed initially.¹⁵

6. Are antipsychotics contraindicated following an NMS episode?

The rate of NMS recurrence on retreatment with an antipsychotic has varied.38 We estimate that up to 30% of patients may be at risk of NMS recurrence when rechallenged with an antipsychotic.1 By following proper precautions (Table 2), however, you can safely treat most patients who require continued antipsychotic therapy.^1,2 When you restart treatment, a lower-potency antipsychotic from a different chemical class may be a safer option than retrying the triggering agent, according to retrospective analyses of limited available data. A patient who develops NMS on a FGA might benefit from an SGA trial, although some risk of recurrence remains.^1,10

Current Psychiatry 2007;6(8):89-95.
Drug brand names

• Amantadine • Symmetrel
• Bromocriptine • Parlodel
• Chlorpromazine • Thorazine
• Dantrolene • Dantrium
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Lorazepam • Ativan
• Loxapine • Loxitane
• Perphenazine • Trilafon
• Prochlorperazine • Compazine, Compro
• Promethazine • Phenergan
• Thioridazine • Mellaril

Disclosure

Dr. Strawn is an American Psychiatric Institute for Research and Education (APIRE)/Janssen Scholar.

Dr. Keck has received research support from or served as a consultant to Abbott Laboratories, American Diabetes Association, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly and Company, Janssen Pharmaceutica, National Institute of Mental Health, National Institute of Drug Abuse, Pfizer, Stanley Medical Research Institute, and UCB Pharma.

Dr. Caroff has received research support from Bristol-Myers Squibb, Ortho-McNeil Neurologics, and Pfizer.

Diagnosis and treatment of neuroleptic malignant syndrome (NMS) are controversial because this potentially life-threatening syndrome is rare and its presentation varies. These factors make it difficult to evaluate treatments in controlled clinical trials, and data about the relative efficacy of specific interventions are scarce. It may be possible, however, to develop rational treatment guidelines using empiric clinical data.^1,2

This article examines the evidence related to 6 controversial aspects of NMS diagnosis and treatment:

• most-reliable risk factors
• NMS as a spectrum disorder
• what causes NMS
• NMS triggered by first-generation vs second-generation antipsychotics
• first-line interventions
• restarting antipsychotics after an NMS episode.

1. Are there reliable risk factors for NMS?

In small case-controlled studies, agitation, dehydration, and exhaustion were the most consistently found systemic factors believed to predispose patients taking antipsychotics to NMS (Table 1).^3-5 Catatonia and organic brain syndromes may be separate risk factors.^1,6

Preliminary studies also have implicated dopamine receptor abnormalities caused by genetic polymorphisms or effects of low serum iron.^1,7,8 Pharmacologic studies have suggested that higher doses, rapid titration, and IM injections of antipsychotics are associated with increased NMS risk.^3,5 Some studies suggest that 15% to 20% of NMS patients have a history of NMS episodes.^1,2 In addition, high-potency first-generation antipsychotics (FGAs)—especially haloperidol—are assumed to carry higher risk than low-potency drugs and second-generation antipsychotics (SGAs), although this hypothesis remains difficult to prove.^9-11

These risk factors, however, are not practical for estimating NMS risk in a given patient because they are relatively common compared with the low risk of NMS occurrence. For the vast majority of patients with psychotic symptoms, the benefits of properly indicated antipsychotic pharmacotherapy will outweigh the risks.

Table 1

*For individual patients, these common risk factors must be weighted again the benefits of antipsychotic therapy FGAs: first-generation antipsychotics; SGAs:second-generation antipsychotics; NMS: neuroleptic malignant syndromeSource: References 1-5

2. Is NMS related to parkinsonism, catatonia, or malignant hyperthermia?

Parkinsonsim. Some researchers have described NMS as an extreme parkinsonian crisis resulting from overwhelming blockade of dopamine pathways in the brain.^1,2,12 In this view, NMS resembles the parkinsonian-hyperthermia syndrome that can occur in Parkinson's disease patients following abrupt discontinuation or loss of efficacy of dopaminergic therapy, which can be treated by reinstituting dopaminergic agents.¹³ Evidence to support this view includes:

• Parkinsonian signs are a cardinal feature of NMS.
• Withdrawal of dopamine agonists precipitates the syndrome.
• All triggering drugs are dopamine receptor antagonists.
• Risks of NMS correlates with drugs' dopamine receptor affinity.
• Dopaminergic agonists may be an effective treatment.
• Lesions in dopaminergic pathways produce a similar syndrome.
• Patients with NMS have demonstrated low cerebrospinal fluid concentrations of the dopamine metabolite homovanillic acid.¹⁴

Catatonia. Fink et al¹⁵ and others^16-18 have persuasively argued that NMS represents a form of drug-induced malignant catatonia. Evidence supporting this includes:

• The 2 disorders share neuropsychiatric symptoms.
• Catalonic signs are common in NMS.¹⁹
• Malignant catatonia and NMS share physiologic and labratory signs.²⁰
• Reintroduction of antipsychotics can acutely worsen both conditions.
• Benzodiazepines and electroconvulsive therapy (ECT) are effective treatments for both disorders.^15-18

Lee²¹ examined the relationship between catatonic features and treatment response of 14 NMS patients. Most patients with catatonic symptoms responded to benzodiazepines, whereas none of those did who had an extrapyramidal-hyperthermic presentation without catatonia. Lee concluded that NMS is heterogeneous and may occur in catatonic and noncatatonic forms that differ in treatment response.

• similar clinical signs of rigidity, hyperthermia, and hypermetabolism
• similar psychologic and labratory signs, such as rhabdomyolysis
• hyperthermia in both responding to dantrolene.

Although the 2 are similar in presentation, malignant hyperthermia occurs intraoperatively and reflects a pharmacogenetic disorder of calcium regulation in skeletal muscle. Additionally, rigidity in malignant hyperthermia does not respond to peripheral-acting muscle relaxants.^1,22 Evidence suggests that patients who have previously experienced an NMS episodes are not at risk for malignant hyperthermia.²²

3. What is the pathophysiology of NMS?

NMS pathophysiology is complex and likely involves interplay between multiple central and systemic pathways and neurotransmitters. As described above, compelling evidence suggests that dopamine blockade plays a central role.¹²

Dopamine blockade in the hypothalamus is believed to contribute to thermoregulatory failure, and blockade in the nigrostriatal system likely contributes to muscle rigidity and hypermetabolism. The loss of dopaminergic input to the anterior cingulate-medial orbitofrontal circuit and the lateral orbitofrontal circuit likely con-tributes to the mental status changes and catatonic features seen in NMS.¹²

Some researchers have proposed competing or complementary hypotheses, however. For example, Gurrera²³ proposed that patients who are prone to developing NMS have a vulnerability to a hyperactive and dysregulated sympathetic nervous system, and this trait—together with dopamine system disruption induced by dopamine-blocking agents—produces NMS. Other investigators have implicated serotonin, norepinephrine, gamma-aminobutyric acid and glutaminergic mechanisms.^1,12,24,25

4. Are FGAs or SGAs more likely to cause NMS?

NMS is assumed to occur less frequently in patients treated with SGAs than in those receiving FGAs, although this hypothesisis unproven. Isolated reports of NMS have been associated with nearly every SGA.^9-11 It is difficult to prove FGA vs SGA liabilities because:

• NMS is rare.
• Dosing practices may be more conser-vative now than in the past.
• Most clinicians are aware of the earlysigns of NMS.

In an epidemiological study of a large database, Stubner et al²⁶ found that patients receiving SGAs had a lower risk of NMS than those treated with haloperidol.²⁶ In this study, the overall rate of NMS was 0.02%.

NMS hotline data. We recently examined which medication classes were implicated in 111 NMS cases reported to the Neuroleptic Malignant Syndrome Information Service hotline (1-888-NMS-TEMP) between 1997 and 2006 (Figure). We included only cases of definite or probable NMS (as diagnosed by hotline consultants) in which a single antipsychotic was administered. Slightly more cases were attributed to FGAs (51%) than SGAs (45%). The remaining cases were attributed to neuroleptics used in medical settings (such as promethazineor prochlorperazine). Because they are now prescribed less often, FGAs accounted for a disproportionate number of NMS cases reported to the hotline. Haloperidol accounted for the majority of FGA cases and 44% of all cases. If we had excluded haloperidol and compared the NMS risk of SGAs to only intermediate- or low-potency FGAs, the relative advantage of SGAs would have been lost. On the other hand, it is clear that SGAs still carry a risk for NMS. Analyses suggest that the SGA-associated classic features of NMS—fever, muscle rigidity, and autonomic and mental status changes—are retained in patients receiving SGAs, although some may not develop the severe rigidity and extreme temperatures common in patients receiving FGAs.^9-11 The milder clinical characteristics associated with SGAs may reflect more conservative prescribing patterns or increased awareness and earlier recognition of NMS, which would prevent fulminant presentations.

5. What is the evidence for specific NMS treatments?

NMS is rare, its presentation varies, and its progression is unpredictable. These factors make it difficult to evaluate treatments in controlled clinical trials, and data about the relative efficacy of specific interventions are scarce.

Even so, the notion that NMS represents an extreme variant of drug-induced parkinsonism or catatonia suggests that specific NMS treatments could be based on symptom severity or stage of presentation. We propose a treatment guideline basedon theoretical mechanisms and anecdotal data (Algorithm).^2,27-29

Support. After immediate withdrawal of the offending medication, supportive therapy is the cornerstone of NMS treatment.^1,2,27

For patients presenting with mild signs and symptoms, supportive care and careful clinical monitoring may be sufficient. Extreme hyperthermia demands volume resuscitation and cooling measures, intensive medical care, and careful monitoring for complications.

Treatment. Despite a lack of consensus on drug treatments for uncomplicated NMS, approximately 40% of patients with acute NMS receive pharmacologic treatments.²

Lorazepam, 1 to 2 mg parenterally, is a reasonable first-line therapy for NMS, especially in individuals with catatonic features.^{4,15-18,21,30,31} Some investigators recommend higher doses.¹⁵ Benzodiazepines are preferred if sedation is required in agitated NMS patients.^4,15-18

Dopaminergic agents such as bromocriptine and amantadine enhance dopaminergic transmission to reverse parkinsonian symptoms and have been reported to reduce time to recovery and halve mortality rates when used alone or in conjunction with other treatments.^13,27,32,33 Rapid discontinuation of these agents can result in rebound symptoms, although this may be true for any specific drug treatment of NMS.^1,31,32

Dantrolene uncouples excitation-contraction coupling by enhancing calcium sequestration in sarcoplasmic reticulumin skeletal muscle and has been used to treat NMS hypermetabolic symptoms. Some reviews found improvement in up to 80% of NMS patients treated with dantrolene monotherapy.^27,32-35 Compared with supportive care, time to recovery may be reduced—and mortality decreased by almost one-half—when dantrolene is used alone or in combination with other medications.

Not all case reports have shown that dantrolene, benzodiazepines, ordopaminergic agonists are effective in treating NMS.^31,36 In our opinion, only advanced NMS cases—with extreme temperature elevations, severe rigidity, and evidence of systemic hypermetabolism—benefit from dantrolene treatment.^1,2

ECT has been used successfully to reduce mortality from NMS and other catatonic-spectrum disorders. It is usually employed after supportive therapy and psychopharmacologic interventions fail.^{2,15,16,27,37} ECT for acute NMS typically consists of a series of 6 to 10 treatments with bilateral electrode placement. Daily ECT may be needed initially.¹⁵

6. Are antipsychotics contraindicated following an NMS episode?

The rate of NMS recurrence on retreatment with an antipsychotic has varied.38 We estimate that up to 30% of patients may be at risk of NMS recurrence when rechallenged with an antipsychotic.1 By following proper precautions (Table 2), however, you can safely treat most patients who require continued antipsychotic therapy.^1,2 When you restart treatment, a lower-potency antipsychotic from a different chemical class may be a safer option than retrying the triggering agent, according to retrospective analyses of limited available data. A patient who develops NMS on a FGA might benefit from an SGA trial, although some risk of recurrence remains.^1,10

Current Psychiatry 2007;6(8):89-95.
Drug brand names

• Amantadine • Symmetrel
• Bromocriptine • Parlodel
• Chlorpromazine • Thorazine
• Dantrolene • Dantrium
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Lorazepam • Ativan
• Loxapine • Loxitane
• Perphenazine • Trilafon
• Prochlorperazine • Compazine, Compro
• Promethazine • Phenergan
• Thioridazine • Mellaril

Disclosure

Dr. Strawn is an American Psychiatric Institute for Research and Education (APIRE)/Janssen Scholar.

Dr. Keck has received research support from or served as a consultant to Abbott Laboratories, American Diabetes Association, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly and Company, Janssen Pharmaceutica, National Institute of Mental Health, National Institute of Drug Abuse, Pfizer, Stanley Medical Research Institute, and UCB Pharma.

Dr. Caroff has received research support from Bristol-Myers Squibb, Ortho-McNeil Neurologics, and Pfizer.

Accurate and early diagnosis of Alzheimer’s disease (AD) is evolving, and—although not yet definitive—is no longer one of exclusion. With a careful in-office work-up and routine assessment tools, you can accurately identify >90% of patients with late-onset AD.¹

AD is by far the most common cause of dementia in older patients. To help you make the diagnosis, this state-of-the-art article discusses:

• AD’s clinical presentation and course
  
• the role of neuropsychological tests for assessing cognitive and functional status
  
• neuropsychiatric and medical findings that differentiate AD from other dementia causes
  
• indications for structural neuroimaging with CT or MRI.
  

Presentation and course

Variability. AD’s gradual onset and progression are characterized by prominent memory loss, anomia, constructional apraxia, anosognosia, and personality changes with affect deregulation, behavioral disturbance, and distorted perception.¹ Amnesia—particularly deficits in anterograde episodic memory—is the most common presentation, but the disease course is heterogeneous and may be affected by:

• patient age at onset
  
• illness severity at diagnosis
  
• comorbid medical and neuropsychiatric illnesses
  
• premorbid cerebral reserves (amount of brain damage a person can sustain before reaching a threshold for the clinical expression of dementia).^1-3
  

Mild AD. An individual or close companion may notice increased forgetfulness and word-finding difficulties, a tendency to lose or misplace things, repeated questioning, and some disorientation. Motor skills are intact.

Severe AD. An individual with late-stage disease has severe impairment and can be bedridden, incontinent, and unable to under-stand or speak. Full-time care is required.

Staging informs treatment. In clinical trials, patients with mild-to-moderate AD consistently show small improvements in cognitive and global function when treated with acetylcholinesterase inhibitors (AChEIs) such as donepezil, rivastigmine, and galantamine.⁴ Donepezil also is approved for use in severe AD.

Memantine is indicated for symptomatic treatment of moderate-to-severe AD. It differs in mechanism of action from the AChEIs and is thought to inhibit cytotoxic overstimulation of glutamatergic neurons.⁴ For moderately advanced AD, memantine appears to be beneficial alone or in combination with AChEIs.

Dementia assessment

Clinical assessment has low sensitivity for early-phase AD and compromised specificity in advanced stages, where all dementia subtypes are similar and comorbidities may confuse the picture. Promising surrogate biomarkers and other diagnostic tools are being developed (Box 1),^5-8 but definitive AD diagnosis still requires post-mortem histopathologic examination of the cerebral cortex.

Box 2

In typical cases, the history guides the physical/neurologic examination. Advancing age and family history are confirmed risk factors for AD; others may include:

• female gender (after age 80)
  
• cardiovascular disease (such as cerebral infarcts, hypertension, elevated cholesterol/homocysteine, smoking, and diabetes mellitus)
  
• history of head trauma, especially with loss of consciousness.
  

Early and accurate diagnosis of AD is challenging in patients with mixed dementias, comorbid neurologic diseases, or atypical features. Patients with these presentations may require referral to an expert clinician, extensive workup, or longitudinal follow-up before the diagnosis becomes clear.

Neuropsychological testing. Most mental status tests examine orientation, attention/concentration, learning, memory, language, and constructional praxis. The Folstein Mini-Mental State Examination (MMSE)⁹ is the most widely used and well-validated mental status test. A score of 10 to 20 on the MMSE is generally considered as moderate AD, and 10 Other mental status testing options include:

• Blessed Information-Memory-Concentration (BIMC)
  
• Blessed Orientation-Memory-Concentration (BOMC)
  
• Short Test of Mental Status (STMS)
  
• Saint Louis University Mental Status (SLUMS).^11,12
  

Reversible causes. If the patient is generally healthy, a core of laboratory tests is recommended in the diagnostic workup (Table 1).^6,15 Other options include:

• CSF examination for atypical presentations, such as unusually rapid symptom progression, altered consciousness, or other neurologic manifestations
  
• EEG to differentiate delirium, seizure disorders, encephalopathies, or a rapidly progressing dementia such as CreutzfeldtJakob disease.
  

Because delirium may be the initial presentation of AD or reversible causes, re-evaluate patients for dementia after delirium clears.

Neuroimaging. Structural neuroimaging with a noncontrast CT or MRI is appropriate in the initial evaluation of patients with dementia.¹⁷ More routinely, it is used to exclude rare but potentially correctable dementia causes, such as space-occupying lesions.¹⁸ Hippocampal and entorhinal volume are measured most often in discriminating AD from non-demented aging and other dementias.¹⁹

Positron emission tomography (PET) using fluorine-18-labeled deoxyglucose (FDG) may help differentiate characteristic patterns of cerebral hypometabolism in the temporoparietal lobes in AD from fronto-temporal dementia (FTD) and other less common dementias, particularly during the earliest stages of the disease.¹⁹ Medi-care reimbursement for brain PET is limited to differentiating FTD from AD.

Table 1

Recommended lab tests for Alzheimer’s disease workup

Detecting causes of potentially reversible cognitive impairment

Diagnostic criteria

NINCDS-ADRDA. Neuropsychological AD assessment criteria developed by the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) classify AD as probable, possible, or definite:

Possible AD is considered when a patient has an atypical onset, presentation, or course and other secondary illnesses capable of producing dementia are not believed to be the cause.

Definite AD requires histopathologic evidence of AD in addition to fulfilling criteria for probable AD.20

DSM-IV-TR. Similar but broader DSM-IVTR criteria describe an insidious progressive cognitive decline that affects recent memory and ≥1 other cognitive domain (apraxia, aphasia, agnosia, or executive functioning). This cognitive decline impairs social and occupational function, represents a change from a higher level, and is not due to other causes such as delirium.²¹

NINCDS-ADRDA and DSM-IV-TR criteria have comparable sensitivity and specificity for clinical AD diagnosis. Neither requires neuropathologic or genetic assessment (Box 3).^15,17,22-²⁴ Neuroimaging and other tests may be required to rule out other brain diseases that may cause dementia.

Other causes of dementia

Mild cognitive impairment (MCI) may represent a prodromal state for the earliest clinical manifestations of dementia. Symptoms include memory complaints but generally preserved activities of daily living.

Originally introduced to define a progressive, single-symptom amnestic syndrome, MCI has evolved into a classification of amnestic and non-amnestic MCI with single or multiple domains.²⁵ Amnestic MCI is the most specifically correlated with AD.²⁶ Neurobiologic similarities between amnestic MCI and clinically diagnosed AD include:

• neuropsychiatric symptoms, such as apathy, mood disturbance, irritability and anxiety
  
• over-representation of the APOE ε4 allele
  
• volumetric loss in the entorhinal cortex and hippocampus as measured by MRI
  
• Glucose hypometabolism in AD-typical regions as measured by FDG-PET
  
• neuronal loss in vulnerable brain regions.²⁶
  

Parkinson’s disease (PD) and DLB may represent a clinicopathologic continuum, and substantial overlap exists among AD, DLB, and PD in underlying disease process and clinical presentation.^15,29 Hallucinations, depression, delusions, and delusional misidentification are seen more often in patients with DLB than AD.¹⁵

Vascular dementia (VaD) was once thought to account for 15% to 20% of dementing illnesses, but discrete VaD is now viewed as much less common. Whatever the underlying vasculopathy, vascular lesions often co-exist with other causes of dementia—usually AD (in 77% of presumed VaD cases).³⁰

Compared with AD, patients with VaD have a more subcortical dementia with difficulty retrieving words, organizing and solving complex problems, “absent-mindedness,” and psychomotor slowing with relatively preserved language skills. VaD is thought to have a more abrupt onset than AD and “stepladder” deterioration.

Frontotemporal dementia (FTD)—such as Pick’s disease—is associated with focal atrophy of the frontal and/or temporal lobes. Mean onset is age 52 to 56, and FTD is less common than AD, VaD, or DLB.

FTD often presents with gradual personality changes (with inappropriate responses or activities) or language changes (with severe naming difficulty and problems with word meaning).³¹ Features that may help differentiate FTD from AD include:

• disinhibition/apathy with personality change
  
• affect disregulation
  
• behavioral disturbance (frontal type) and expressive/receptive language changes (semantic or primary progressive aphasia) with relatively mild memory loss.^32,33
  

Other neurodegenerative diseases that might present with dementia include PD, Huntington’s disease, progressive supra-nuclear palsy, corticobasal degeneration, and Creutzfeldt-Jakob disease.³³

Box 3

• Morris JC. Dementia update 2005. Alzheimer Dis Assoc Disord 2005;19:100-17.
  
• Boeve BF. A review of the non-Alzheimer dementias. J Clin Psychiatry 2006;67(12)1985-2001.
  
• Medscape. Alzheimer’s disease resource center. www.medscape.com/resource/alzheimers.
  

• Donepezil • Aricept
  
• Memantine • Namenda
  
• Galantamine • Razadyne
  
• Rivastigmine • Exelon
  

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

Dr. Grossberg receives grant/research support from Abbott Laboratories, Bristol-Myers Squibb, Forest Laboratories, Eli Lilly and Company, Novartis, Pfizer Inc., Wyeth, Elan, Myriad, Ono Pharmaceutical, and the Alzheimer’s Disease Cooperative Study Consortium. He is a consultant to Bristol-Myers Squibb, Forest Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, Novartis, AstraZeneca, Wyeth, Pfizer Inc., Takeda, and Sepracor.

Accurate and early diagnosis of Alzheimer’s disease (AD) is evolving, and—although not yet definitive—is no longer one of exclusion. With a careful in-office work-up and routine assessment tools, you can accurately identify >90% of patients with late-onset AD.¹

AD is by far the most common cause of dementia in older patients. To help you make the diagnosis, this state-of-the-art article discusses:

• AD’s clinical presentation and course
  
• the role of neuropsychological tests for assessing cognitive and functional status
  
• neuropsychiatric and medical findings that differentiate AD from other dementia causes
  
• indications for structural neuroimaging with CT or MRI.
  

Presentation and course

Variability. AD’s gradual onset and progression are characterized by prominent memory loss, anomia, constructional apraxia, anosognosia, and personality changes with affect deregulation, behavioral disturbance, and distorted perception.¹ Amnesia—particularly deficits in anterograde episodic memory—is the most common presentation, but the disease course is heterogeneous and may be affected by:

• patient age at onset
  
• illness severity at diagnosis
  
• comorbid medical and neuropsychiatric illnesses
  
• premorbid cerebral reserves (amount of brain damage a person can sustain before reaching a threshold for the clinical expression of dementia).^1-3
  

Mild AD. An individual or close companion may notice increased forgetfulness and word-finding difficulties, a tendency to lose or misplace things, repeated questioning, and some disorientation. Motor skills are intact.

Severe AD. An individual with late-stage disease has severe impairment and can be bedridden, incontinent, and unable to under-stand or speak. Full-time care is required.

Staging informs treatment. In clinical trials, patients with mild-to-moderate AD consistently show small improvements in cognitive and global function when treated with acetylcholinesterase inhibitors (AChEIs) such as donepezil, rivastigmine, and galantamine.⁴ Donepezil also is approved for use in severe AD.

Memantine is indicated for symptomatic treatment of moderate-to-severe AD. It differs in mechanism of action from the AChEIs and is thought to inhibit cytotoxic overstimulation of glutamatergic neurons.⁴ For moderately advanced AD, memantine appears to be beneficial alone or in combination with AChEIs.

Dementia assessment

Clinical assessment has low sensitivity for early-phase AD and compromised specificity in advanced stages, where all dementia subtypes are similar and comorbidities may confuse the picture. Promising surrogate biomarkers and other diagnostic tools are being developed (Box 1),^5-8 but definitive AD diagnosis still requires post-mortem histopathologic examination of the cerebral cortex.

Box 2

In typical cases, the history guides the physical/neurologic examination. Advancing age and family history are confirmed risk factors for AD; others may include:

• female gender (after age 80)
  
• cardiovascular disease (such as cerebral infarcts, hypertension, elevated cholesterol/homocysteine, smoking, and diabetes mellitus)
  
• history of head trauma, especially with loss of consciousness.
  

Early and accurate diagnosis of AD is challenging in patients with mixed dementias, comorbid neurologic diseases, or atypical features. Patients with these presentations may require referral to an expert clinician, extensive workup, or longitudinal follow-up before the diagnosis becomes clear.

Neuropsychological testing. Most mental status tests examine orientation, attention/concentration, learning, memory, language, and constructional praxis. The Folstein Mini-Mental State Examination (MMSE)⁹ is the most widely used and well-validated mental status test. A score of 10 to 20 on the MMSE is generally considered as moderate AD, and 10 Other mental status testing options include:

• Blessed Information-Memory-Concentration (BIMC)
  
• Blessed Orientation-Memory-Concentration (BOMC)
  
• Short Test of Mental Status (STMS)
  
• Saint Louis University Mental Status (SLUMS).^11,12
  

Reversible causes. If the patient is generally healthy, a core of laboratory tests is recommended in the diagnostic workup (Table 1).^6,15 Other options include:

• CSF examination for atypical presentations, such as unusually rapid symptom progression, altered consciousness, or other neurologic manifestations
  
• EEG to differentiate delirium, seizure disorders, encephalopathies, or a rapidly progressing dementia such as CreutzfeldtJakob disease.
  

Because delirium may be the initial presentation of AD or reversible causes, re-evaluate patients for dementia after delirium clears.

Neuroimaging. Structural neuroimaging with a noncontrast CT or MRI is appropriate in the initial evaluation of patients with dementia.¹⁷ More routinely, it is used to exclude rare but potentially correctable dementia causes, such as space-occupying lesions.¹⁸ Hippocampal and entorhinal volume are measured most often in discriminating AD from non-demented aging and other dementias.¹⁹

Positron emission tomography (PET) using fluorine-18-labeled deoxyglucose (FDG) may help differentiate characteristic patterns of cerebral hypometabolism in the temporoparietal lobes in AD from fronto-temporal dementia (FTD) and other less common dementias, particularly during the earliest stages of the disease.¹⁹ Medi-care reimbursement for brain PET is limited to differentiating FTD from AD.

Table 1

Recommended lab tests for Alzheimer’s disease workup

Detecting causes of potentially reversible cognitive impairment

Diagnostic criteria

NINCDS-ADRDA. Neuropsychological AD assessment criteria developed by the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) classify AD as probable, possible, or definite:

Possible AD is considered when a patient has an atypical onset, presentation, or course and other secondary illnesses capable of producing dementia are not believed to be the cause.

Definite AD requires histopathologic evidence of AD in addition to fulfilling criteria for probable AD.20

DSM-IV-TR. Similar but broader DSM-IVTR criteria describe an insidious progressive cognitive decline that affects recent memory and ≥1 other cognitive domain (apraxia, aphasia, agnosia, or executive functioning). This cognitive decline impairs social and occupational function, represents a change from a higher level, and is not due to other causes such as delirium.²¹

NINCDS-ADRDA and DSM-IV-TR criteria have comparable sensitivity and specificity for clinical AD diagnosis. Neither requires neuropathologic or genetic assessment (Box 3).^15,17,22-²⁴ Neuroimaging and other tests may be required to rule out other brain diseases that may cause dementia.

Other causes of dementia

Mild cognitive impairment (MCI) may represent a prodromal state for the earliest clinical manifestations of dementia. Symptoms include memory complaints but generally preserved activities of daily living.

Originally introduced to define a progressive, single-symptom amnestic syndrome, MCI has evolved into a classification of amnestic and non-amnestic MCI with single or multiple domains.²⁵ Amnestic MCI is the most specifically correlated with AD.²⁶ Neurobiologic similarities between amnestic MCI and clinically diagnosed AD include:

• neuropsychiatric symptoms, such as apathy, mood disturbance, irritability and anxiety
  
• over-representation of the APOE ε4 allele
  
• volumetric loss in the entorhinal cortex and hippocampus as measured by MRI
  
• Glucose hypometabolism in AD-typical regions as measured by FDG-PET
  
• neuronal loss in vulnerable brain regions.²⁶
  

Parkinson’s disease (PD) and DLB may represent a clinicopathologic continuum, and substantial overlap exists among AD, DLB, and PD in underlying disease process and clinical presentation.^15,29 Hallucinations, depression, delusions, and delusional misidentification are seen more often in patients with DLB than AD.¹⁵

Vascular dementia (VaD) was once thought to account for 15% to 20% of dementing illnesses, but discrete VaD is now viewed as much less common. Whatever the underlying vasculopathy, vascular lesions often co-exist with other causes of dementia—usually AD (in 77% of presumed VaD cases).³⁰

Compared with AD, patients with VaD have a more subcortical dementia with difficulty retrieving words, organizing and solving complex problems, “absent-mindedness,” and psychomotor slowing with relatively preserved language skills. VaD is thought to have a more abrupt onset than AD and “stepladder” deterioration.

Frontotemporal dementia (FTD)—such as Pick’s disease—is associated with focal atrophy of the frontal and/or temporal lobes. Mean onset is age 52 to 56, and FTD is less common than AD, VaD, or DLB.

FTD often presents with gradual personality changes (with inappropriate responses or activities) or language changes (with severe naming difficulty and problems with word meaning).³¹ Features that may help differentiate FTD from AD include:

• disinhibition/apathy with personality change
  
• affect disregulation
  
• behavioral disturbance (frontal type) and expressive/receptive language changes (semantic or primary progressive aphasia) with relatively mild memory loss.^32,33
  

Other neurodegenerative diseases that might present with dementia include PD, Huntington’s disease, progressive supra-nuclear palsy, corticobasal degeneration, and Creutzfeldt-Jakob disease.³³

Box 3

• Morris JC. Dementia update 2005. Alzheimer Dis Assoc Disord 2005;19:100-17.
  
• Boeve BF. A review of the non-Alzheimer dementias. J Clin Psychiatry 2006;67(12)1985-2001.
  
• Medscape. Alzheimer’s disease resource center. www.medscape.com/resource/alzheimers.
  

• Donepezil • Aricept
  
• Memantine • Namenda
  
• Galantamine • Razadyne
  
• Rivastigmine • Exelon
  

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

Dr. Grossberg receives grant/research support from Abbott Laboratories, Bristol-Myers Squibb, Forest Laboratories, Eli Lilly and Company, Novartis, Pfizer Inc., Wyeth, Elan, Myriad, Ono Pharmaceutical, and the Alzheimer’s Disease Cooperative Study Consortium. He is a consultant to Bristol-Myers Squibb, Forest Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, Novartis, AstraZeneca, Wyeth, Pfizer Inc., Takeda, and Sepracor.

Accurate and early diagnosis of Alzheimer’s disease (AD) is evolving, and—although not yet definitive—is no longer one of exclusion. With a careful in-office work-up and routine assessment tools, you can accurately identify >90% of patients with late-onset AD.¹

AD is by far the most common cause of dementia in older patients. To help you make the diagnosis, this state-of-the-art article discusses:

• AD’s clinical presentation and course
  
• the role of neuropsychological tests for assessing cognitive and functional status
  
• neuropsychiatric and medical findings that differentiate AD from other dementia causes
  
• indications for structural neuroimaging with CT or MRI.
  

Presentation and course

Variability. AD’s gradual onset and progression are characterized by prominent memory loss, anomia, constructional apraxia, anosognosia, and personality changes with affect deregulation, behavioral disturbance, and distorted perception.¹ Amnesia—particularly deficits in anterograde episodic memory—is the most common presentation, but the disease course is heterogeneous and may be affected by:

• patient age at onset
  
• illness severity at diagnosis
  
• comorbid medical and neuropsychiatric illnesses
  
• premorbid cerebral reserves (amount of brain damage a person can sustain before reaching a threshold for the clinical expression of dementia).^1-3
  

Mild AD. An individual or close companion may notice increased forgetfulness and word-finding difficulties, a tendency to lose or misplace things, repeated questioning, and some disorientation. Motor skills are intact.

Severe AD. An individual with late-stage disease has severe impairment and can be bedridden, incontinent, and unable to under-stand or speak. Full-time care is required.

Staging informs treatment. In clinical trials, patients with mild-to-moderate AD consistently show small improvements in cognitive and global function when treated with acetylcholinesterase inhibitors (AChEIs) such as donepezil, rivastigmine, and galantamine.⁴ Donepezil also is approved for use in severe AD.

Memantine is indicated for symptomatic treatment of moderate-to-severe AD. It differs in mechanism of action from the AChEIs and is thought to inhibit cytotoxic overstimulation of glutamatergic neurons.⁴ For moderately advanced AD, memantine appears to be beneficial alone or in combination with AChEIs.

Dementia assessment

Clinical assessment has low sensitivity for early-phase AD and compromised specificity in advanced stages, where all dementia subtypes are similar and comorbidities may confuse the picture. Promising surrogate biomarkers and other diagnostic tools are being developed (Box 1),^5-8 but definitive AD diagnosis still requires post-mortem histopathologic examination of the cerebral cortex.

Box 2

In typical cases, the history guides the physical/neurologic examination. Advancing age and family history are confirmed risk factors for AD; others may include:

• female gender (after age 80)
  
• cardiovascular disease (such as cerebral infarcts, hypertension, elevated cholesterol/homocysteine, smoking, and diabetes mellitus)
  
• history of head trauma, especially with loss of consciousness.
  

Early and accurate diagnosis of AD is challenging in patients with mixed dementias, comorbid neurologic diseases, or atypical features. Patients with these presentations may require referral to an expert clinician, extensive workup, or longitudinal follow-up before the diagnosis becomes clear.

Neuropsychological testing. Most mental status tests examine orientation, attention/concentration, learning, memory, language, and constructional praxis. The Folstein Mini-Mental State Examination (MMSE)⁹ is the most widely used and well-validated mental status test. A score of 10 to 20 on the MMSE is generally considered as moderate AD, and 10 Other mental status testing options include:

• Blessed Information-Memory-Concentration (BIMC)
  
• Blessed Orientation-Memory-Concentration (BOMC)
  
• Short Test of Mental Status (STMS)
  
• Saint Louis University Mental Status (SLUMS).^11,12
  

Reversible causes. If the patient is generally healthy, a core of laboratory tests is recommended in the diagnostic workup (Table 1).^6,15 Other options include:

• CSF examination for atypical presentations, such as unusually rapid symptom progression, altered consciousness, or other neurologic manifestations
  
• EEG to differentiate delirium, seizure disorders, encephalopathies, or a rapidly progressing dementia such as CreutzfeldtJakob disease.
  

Because delirium may be the initial presentation of AD or reversible causes, re-evaluate patients for dementia after delirium clears.

Neuroimaging. Structural neuroimaging with a noncontrast CT or MRI is appropriate in the initial evaluation of patients with dementia.¹⁷ More routinely, it is used to exclude rare but potentially correctable dementia causes, such as space-occupying lesions.¹⁸ Hippocampal and entorhinal volume are measured most often in discriminating AD from non-demented aging and other dementias.¹⁹

Positron emission tomography (PET) using fluorine-18-labeled deoxyglucose (FDG) may help differentiate characteristic patterns of cerebral hypometabolism in the temporoparietal lobes in AD from fronto-temporal dementia (FTD) and other less common dementias, particularly during the earliest stages of the disease.¹⁹ Medi-care reimbursement for brain PET is limited to differentiating FTD from AD.

Table 1

Recommended lab tests for Alzheimer’s disease workup

Detecting causes of potentially reversible cognitive impairment

Diagnostic criteria

NINCDS-ADRDA. Neuropsychological AD assessment criteria developed by the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) classify AD as probable, possible, or definite:

Possible AD is considered when a patient has an atypical onset, presentation, or course and other secondary illnesses capable of producing dementia are not believed to be the cause.

Definite AD requires histopathologic evidence of AD in addition to fulfilling criteria for probable AD.20

DSM-IV-TR. Similar but broader DSM-IVTR criteria describe an insidious progressive cognitive decline that affects recent memory and ≥1 other cognitive domain (apraxia, aphasia, agnosia, or executive functioning). This cognitive decline impairs social and occupational function, represents a change from a higher level, and is not due to other causes such as delirium.²¹

NINCDS-ADRDA and DSM-IV-TR criteria have comparable sensitivity and specificity for clinical AD diagnosis. Neither requires neuropathologic or genetic assessment (Box 3).^15,17,22-²⁴ Neuroimaging and other tests may be required to rule out other brain diseases that may cause dementia.

Other causes of dementia

Mild cognitive impairment (MCI) may represent a prodromal state for the earliest clinical manifestations of dementia. Symptoms include memory complaints but generally preserved activities of daily living.

Originally introduced to define a progressive, single-symptom amnestic syndrome, MCI has evolved into a classification of amnestic and non-amnestic MCI with single or multiple domains.²⁵ Amnestic MCI is the most specifically correlated with AD.²⁶ Neurobiologic similarities between amnestic MCI and clinically diagnosed AD include:

• neuropsychiatric symptoms, such as apathy, mood disturbance, irritability and anxiety
  
• over-representation of the APOE ε4 allele
  
• volumetric loss in the entorhinal cortex and hippocampus as measured by MRI
  
• Glucose hypometabolism in AD-typical regions as measured by FDG-PET
  
• neuronal loss in vulnerable brain regions.²⁶
  

Parkinson’s disease (PD) and DLB may represent a clinicopathologic continuum, and substantial overlap exists among AD, DLB, and PD in underlying disease process and clinical presentation.^15,29 Hallucinations, depression, delusions, and delusional misidentification are seen more often in patients with DLB than AD.¹⁵

Vascular dementia (VaD) was once thought to account for 15% to 20% of dementing illnesses, but discrete VaD is now viewed as much less common. Whatever the underlying vasculopathy, vascular lesions often co-exist with other causes of dementia—usually AD (in 77% of presumed VaD cases).³⁰

Compared with AD, patients with VaD have a more subcortical dementia with difficulty retrieving words, organizing and solving complex problems, “absent-mindedness,” and psychomotor slowing with relatively preserved language skills. VaD is thought to have a more abrupt onset than AD and “stepladder” deterioration.

Frontotemporal dementia (FTD)—such as Pick’s disease—is associated with focal atrophy of the frontal and/or temporal lobes. Mean onset is age 52 to 56, and FTD is less common than AD, VaD, or DLB.

FTD often presents with gradual personality changes (with inappropriate responses or activities) or language changes (with severe naming difficulty and problems with word meaning).³¹ Features that may help differentiate FTD from AD include:

• disinhibition/apathy with personality change
  
• affect disregulation
  
• behavioral disturbance (frontal type) and expressive/receptive language changes (semantic or primary progressive aphasia) with relatively mild memory loss.^32,33
  

Other neurodegenerative diseases that might present with dementia include PD, Huntington’s disease, progressive supra-nuclear palsy, corticobasal degeneration, and Creutzfeldt-Jakob disease.³³

Box 3

• Morris JC. Dementia update 2005. Alzheimer Dis Assoc Disord 2005;19:100-17.
  
• Boeve BF. A review of the non-Alzheimer dementias. J Clin Psychiatry 2006;67(12)1985-2001.
  
• Medscape. Alzheimer’s disease resource center. www.medscape.com/resource/alzheimers.
  

• Donepezil • Aricept
  
• Memantine • Namenda
  
• Galantamine • Razadyne
  
• Rivastigmine • Exelon
  

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

Dr. Grossberg receives grant/research support from Abbott Laboratories, Bristol-Myers Squibb, Forest Laboratories, Eli Lilly and Company, Novartis, Pfizer Inc., Wyeth, Elan, Myriad, Ono Pharmaceutical, and the Alzheimer’s Disease Cooperative Study Consortium. He is a consultant to Bristol-Myers Squibb, Forest Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, Novartis, AstraZeneca, Wyeth, Pfizer Inc., Takeda, and Sepracor.

All phases of bipolar disorder can be difficult to treat, and patients remain symptomatic on average about half the time.¹ Not all bipolar patients who experience continued illness and disability are treatment-resistant (Box 1), but when symptoms persist you may ask yourself: Was treatment suboptimal or simply ineffective?

Patients with severe symptoms may be satisfied with a substantial decrease in symptoms, but any residual symptoms cause ongoing distress and lower the threshold for recurrences.² Finding the right combination of therapies for your patient is key to achieving an enduring response.

Future studies may tell us which treatments to combine and in what sequence for complex bipolar disorder, but—since most published studies exclude complex and comorbid cases—for now we must rely on limited controlled data and clinical experience. Using those resources, we offer comprehensive, practical recommendations for trouble-shooting (Box 2)^3-6 and getting better results when bipolar disorder does not respond to standard treatment.

Box 1

Mania

When a patient with mania does not respond as expected, the next step depends on which antimanic agent you prescribed:

Lithium can take a month to become fully effective for mania, which is why a benzodiazepine or antipsychotic is often added acutely to reduce agitation. Do not mistake neurotoxic interactions between lithium and antipsychotics for increased mania.

Although data vary on lithium’s optimal serum level, adjust to approximately 0.8 to 1 mEq/L, if tolerated, when lower levels are not effective. Children and young adolescents may need higher serum levels (such as 1.5 mEq/L) because the difference between serum and brain lithium levels is greater in younger patients than in adults.

Consider the dosing schedule. Because lithium’s elimination half-life with repeated dosing is 24 hours, most adults can take any formulation once daily—which improves adherence and reduces adverse effects. Children eliminate lithium more rapidly and need more frequent dosing.

High loading doses result in more rapid control of agitation, probably as a result of sedation. In our experience, however, rapidly sedating patients may interfere with long-term adherence.

Carbamazepine, other anticonvulsants. Because they less sedating, carbamazepine and other anticonvulsants might not appear to be rapidly effective for bipolar mania. If you wait up to a month, however, any antimanic effect will be obvious.

Antipsychotics are rapidly effective for mania. Higher doses work faster but produce more side effects. After an acute response, some patients can be maintained on a second-generation antipsychotic (SGA), but others do better on a standard mood stabilizer such as lithium or valproate.

Calcium channel blockers. Verapamil has been effective mostly for lithium-responsive mania in 27 of 30 studies. Nimodipine has been useful for more complex bipolar syndromes in a few studies using patients as their own controls.

To be effective for bipolar disorder, however, calcium channel blockers require frequent, high dosing (such as verapamil, 120 mg 4 times daily, or nimodipine, 60 to 120 mg 6 times daily), which makes adherence difficult.

Box 2

• consider augmentation first when a patient has had a partial response to a given medication
  
• switch when a patient cannot tolerate or shows no response to a therapeutic dose of a given medication.
  

Switching among anticonvulsants can be useful because their actions and side effects differ. Clozapine in a wide range of doses can be very effective for refractory mania,¹¹ but its use is difficult to monitor in highly agitated manic patients.

Other options. Electroconvulsive therapy (ECT) is the most effective treatment for mania, producing higher response rates than any antimanic drug.¹² In a study of repetitive transcranial magnetic stimulation (rTMS), 8 of 9 patients with mania refractory to mood stabilizers had a sustained response after 1 month of right-sided rTMS treatment.¹³ Conversely, left-sided rTMS can aggravate mania.

Bipolar depression

Continuing controversy about the best way to treat bipolar depression makes it difficult to know if treatment has been suboptimal or a patient is treatment-resistant.

Antidepressants. No antidepressant is approved (or recommended) as monotherapy for bipolar depression, and most experts recommend against prescribing antidepressants without concomitant mood stabilizers. Even so:

• Clinicians prescribing monotherapy for bipolar disorder choose antidepressants twice as often as mood stabilizers.
  
• Antidepressants are prescribed more frequently in combination with mood stabilizers than as monotherapy, although empiric trials have shown most antidepressants are not effective for bipolar depression.¹⁴
  

Antipsychotics. Quetiapine¹⁶ and a combination of olanzapine and fluoxetine¹⁷ are approved for treating bipolar depression. The studies supporting this indication lasted only 8 weeks, however, and excluded patients with the kinds of complicated and comorbid mood disorders commonly seen in clinical practice.

Many patients dropped out before the studies were completed, and “screen fails” (patients with the diagnosis who were not enrolled in the study) were not reported. In addition, “remitted” patients remained symptomatic.

Therefore, FDA approval of this indication does not guarantee these medications’ long-term efficacy or safety for bipolar depression or that they are useful in patients with complex forms of bipolar depression.

Recommended approach. Treatment resistance of bipolar depression to multiple mood stabilizers—with or without an antidepressant—or to an antipsychotic may manifest as lack of response, partial response, or initial good response followed by relapse or recurrence. Sometimes depression improves but irritability or mood lability worsen.

No reliable controlled studies have addressed complex refractory bipolar depression, but clinical experience suggests 1 approach for all of these responses:

Reconsider possible hypothyroidism. A low-normal T4—especially if decreased over time—and a mid-range or high-normal TSH—especially if increased—may indicate that subclinical hypothyroidism is inhibiting a response to mood stabilizers and antidepressants.¹⁸

Stop the antidepressant. If your patient is taking an antidepressant, it may be ineffective, creating mixed dysphoric hypomania, and/or driving another recurrence of depression. This is especially likely if the patient shows an initial prompt antidepressant response, but depression returns with irritability, insomnia, restlessness, or other subtle symptoms of dysphoric hypomania.

Withdraw the antidepressant gradually; for example, you might reduce the dose by 10% every few weeks so that the agent is discontinued across several months. Discontinuing an antidepressant too rapidly—even if it does not seem to be having any effect—can cause rebound depression that creates the mistaken impression that the antidepressant is needed.

Combine mood stabilizers. If a single mood stabilizer does not at least eliminate mood lability and other symptoms of activation, add a second agent. The combination of lithium and carbamazepine helps some depressed patients.²⁰ Patients with considerable mood instability or psychotic symptoms may benefit from an adjunct antipsychotic.

Introduce mood stabilizers gradually. These medications may work more rapidly against mixed manic symptoms than they do against depression, especially when the dose is raised too quickly. The result is rapid control of irritability, hyperactivity, agitation, and related symptoms but an apparent increase in depression as mixed elements of elevated mood and energy are filtered out.

Add an antidepressant? If gradual adjustment of mood stabilizers eliminates mixed symptoms and mood fluctuations but the patient is still depressed, cautiously add an antidepressant. Antidepressants may be less likely to destabilize mood after all mixed elements have been treated completely.

Box 3

Treat seasonal symptoms. Many bipolar patients are most likely to be depressed in winter, and seasonal affective disorder is common in patients with a bipolar mood disorder. Their depression may respond to artificial bright light, usually given in the morning. Light therapy can help normalize the sleep-wake cycle, although it also can induce hypomania.

Other options. ECT is the most reliably effective treatment for bipolar depression. Because it treats both poles of the mood disorder, ECT also can be a useful maintenance treatment. A comparison of rTMS and placebo in 23 bipolar depressed patients failed to find any benefit of active treatment.³²

Table

What now? Treatment options for refractory bipolar depression

Rapid and ultradian cycling

No controlled studies have compared single-drug or combination therapies for rapid and ultradian cycling (Box 3).³³ Thus, our recommendations for treating patients with cycling who have not responded to initial interventions are based on case series and clinical experience.

Reassess thyroid function. As many as 70% of patients with rapid cycling have subclinical hypothyroidism that contributes to mood instability.³⁴ Thyroid replacement is indicated for any degree of hypothyroidism—even if medically unimportant—in patients with refractory mood disorders.

Slowly withdraw antidepressants. Most patients with rapid cycling are taking antidepressants. If your patient is experiencing depressive symptoms while taking an antidepressant, this means the antidepressant is not working and there is little point in continuing it. For patients being withdrawn from multiple antidepressants, rotate dose decrements to help you monitor the effect of each reduction.

Other options to consider in combination with mood stabilizers:

• an antipsychotic, especially in the presence of psychotic symptoms, when mixed symptoms are present
  
• clozapine, which can be a highly effective adjunct for refractory mood cycling and mixed states³⁶ (but is a later adjunct because of required monitoring, common adverse effects, and risk of interactions with carbamazepine and benzodiazepines)
  
• nimodipine, which has empiric support for complex mood cycling³⁷ and is well-tolerated with fewer interactions than other mood stabilizers (but cost and need for frequent dosing make it a second-line adjunct)
  
• supraphysiologic doses of thyroxine (≤0.4 mg/d, with T4 levels in the hyperthyroid range), which can improve response to mood-stabilizing regimens³⁴ (but risks of inducing hyperthyroidism make this intervention third-line).
  

Related resources

• Dubovsky SL. Clinical guide to psychotropic medications. New York: WW Norton; 2005.
  
• Dubovsky SL. Treatment of bipolar depression. Psychiatr Clin North Am 2005;28:349-70.
  
• Phillip Long, MD. Internet Mental Health. Online psychiatric diagnosis for the two-thirds of individuals with mental illness who do not seek treatment. www.mentalhealth.com/dis/p20-md02.html.
  

• Bupropion • Wellbutrin
  
• Carbamazepine • Tegretol
  
• Clonazepam • Klonopin
  
• Clozapine • Clozaril
  
• Fluoxetine • Prozac
  
• Gabapentin • Neurontin
  
• Lamotrigine • Lamictal
  
• Levetiracetam • Keppra
  
• Lithium • Lithobid, others
  
• Lorazepam • Ativan
  
• Memantine • Namenda
  
• Methylphenidate • Concerta, Ritalin, others
  
• Modafinil • Provigil
  
• Nimodipine • Nimotop
  
• Olanzapine/fluoxetine • Symbyax
  
• Oxcarbazepine • Trileptal
  
• Paroxetine • Paxil
  
• Pramipexole • Mirapex
  
• Pregabalin • Lyrica
  
• Quetiapine • Seroquel
  
• Riluzole • Rilutek
  
• Selegiline • Eldepryl
  
• Topiramate • Topamax
  
• Tranylcypromine • Parnate
  
• Valproate • Depakene, Depakote
  
• Venlafaxine • Effexor
  
• Verapamil • Calan, Isoptin, others
  
• Zonisamide • Zonegran
  

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

Dr. Dubovsky receives research/grant support from Eli Lilly and Company, Organon, Pfizer, UCB Pharma, anhd Forest Laboratories. He is a consultant to Oganon and Biovail Pharmaceuticals.

All phases of bipolar disorder can be difficult to treat, and patients remain symptomatic on average about half the time.¹ Not all bipolar patients who experience continued illness and disability are treatment-resistant (Box 1), but when symptoms persist you may ask yourself: Was treatment suboptimal or simply ineffective?

Patients with severe symptoms may be satisfied with a substantial decrease in symptoms, but any residual symptoms cause ongoing distress and lower the threshold for recurrences.² Finding the right combination of therapies for your patient is key to achieving an enduring response.

Future studies may tell us which treatments to combine and in what sequence for complex bipolar disorder, but—since most published studies exclude complex and comorbid cases—for now we must rely on limited controlled data and clinical experience. Using those resources, we offer comprehensive, practical recommendations for trouble-shooting (Box 2)^3-6 and getting better results when bipolar disorder does not respond to standard treatment.

Box 1

Mania

When a patient with mania does not respond as expected, the next step depends on which antimanic agent you prescribed:

Lithium can take a month to become fully effective for mania, which is why a benzodiazepine or antipsychotic is often added acutely to reduce agitation. Do not mistake neurotoxic interactions between lithium and antipsychotics for increased mania.

Although data vary on lithium’s optimal serum level, adjust to approximately 0.8 to 1 mEq/L, if tolerated, when lower levels are not effective. Children and young adolescents may need higher serum levels (such as 1.5 mEq/L) because the difference between serum and brain lithium levels is greater in younger patients than in adults.

Consider the dosing schedule. Because lithium’s elimination half-life with repeated dosing is 24 hours, most adults can take any formulation once daily—which improves adherence and reduces adverse effects. Children eliminate lithium more rapidly and need more frequent dosing.

High loading doses result in more rapid control of agitation, probably as a result of sedation. In our experience, however, rapidly sedating patients may interfere with long-term adherence.

Carbamazepine, other anticonvulsants. Because they less sedating, carbamazepine and other anticonvulsants might not appear to be rapidly effective for bipolar mania. If you wait up to a month, however, any antimanic effect will be obvious.

Antipsychotics are rapidly effective for mania. Higher doses work faster but produce more side effects. After an acute response, some patients can be maintained on a second-generation antipsychotic (SGA), but others do better on a standard mood stabilizer such as lithium or valproate.

Calcium channel blockers. Verapamil has been effective mostly for lithium-responsive mania in 27 of 30 studies. Nimodipine has been useful for more complex bipolar syndromes in a few studies using patients as their own controls.

To be effective for bipolar disorder, however, calcium channel blockers require frequent, high dosing (such as verapamil, 120 mg 4 times daily, or nimodipine, 60 to 120 mg 6 times daily), which makes adherence difficult.

Box 2

• consider augmentation first when a patient has had a partial response to a given medication
  
• switch when a patient cannot tolerate or shows no response to a therapeutic dose of a given medication.
  

Switching among anticonvulsants can be useful because their actions and side effects differ. Clozapine in a wide range of doses can be very effective for refractory mania,¹¹ but its use is difficult to monitor in highly agitated manic patients.

Other options. Electroconvulsive therapy (ECT) is the most effective treatment for mania, producing higher response rates than any antimanic drug.¹² In a study of repetitive transcranial magnetic stimulation (rTMS), 8 of 9 patients with mania refractory to mood stabilizers had a sustained response after 1 month of right-sided rTMS treatment.¹³ Conversely, left-sided rTMS can aggravate mania.

Bipolar depression

Continuing controversy about the best way to treat bipolar depression makes it difficult to know if treatment has been suboptimal or a patient is treatment-resistant.

Antidepressants. No antidepressant is approved (or recommended) as monotherapy for bipolar depression, and most experts recommend against prescribing antidepressants without concomitant mood stabilizers. Even so:

• Clinicians prescribing monotherapy for bipolar disorder choose antidepressants twice as often as mood stabilizers.
  
• Antidepressants are prescribed more frequently in combination with mood stabilizers than as monotherapy, although empiric trials have shown most antidepressants are not effective for bipolar depression.¹⁴
  

Antipsychotics. Quetiapine¹⁶ and a combination of olanzapine and fluoxetine¹⁷ are approved for treating bipolar depression. The studies supporting this indication lasted only 8 weeks, however, and excluded patients with the kinds of complicated and comorbid mood disorders commonly seen in clinical practice.

Many patients dropped out before the studies were completed, and “screen fails” (patients with the diagnosis who were not enrolled in the study) were not reported. In addition, “remitted” patients remained symptomatic.

Therefore, FDA approval of this indication does not guarantee these medications’ long-term efficacy or safety for bipolar depression or that they are useful in patients with complex forms of bipolar depression.

Recommended approach. Treatment resistance of bipolar depression to multiple mood stabilizers—with or without an antidepressant—or to an antipsychotic may manifest as lack of response, partial response, or initial good response followed by relapse or recurrence. Sometimes depression improves but irritability or mood lability worsen.

No reliable controlled studies have addressed complex refractory bipolar depression, but clinical experience suggests 1 approach for all of these responses:

Reconsider possible hypothyroidism. A low-normal T4—especially if decreased over time—and a mid-range or high-normal TSH—especially if increased—may indicate that subclinical hypothyroidism is inhibiting a response to mood stabilizers and antidepressants.¹⁸

Stop the antidepressant. If your patient is taking an antidepressant, it may be ineffective, creating mixed dysphoric hypomania, and/or driving another recurrence of depression. This is especially likely if the patient shows an initial prompt antidepressant response, but depression returns with irritability, insomnia, restlessness, or other subtle symptoms of dysphoric hypomania.

Withdraw the antidepressant gradually; for example, you might reduce the dose by 10% every few weeks so that the agent is discontinued across several months. Discontinuing an antidepressant too rapidly—even if it does not seem to be having any effect—can cause rebound depression that creates the mistaken impression that the antidepressant is needed.

Combine mood stabilizers. If a single mood stabilizer does not at least eliminate mood lability and other symptoms of activation, add a second agent. The combination of lithium and carbamazepine helps some depressed patients.²⁰ Patients with considerable mood instability or psychotic symptoms may benefit from an adjunct antipsychotic.

Introduce mood stabilizers gradually. These medications may work more rapidly against mixed manic symptoms than they do against depression, especially when the dose is raised too quickly. The result is rapid control of irritability, hyperactivity, agitation, and related symptoms but an apparent increase in depression as mixed elements of elevated mood and energy are filtered out.

Add an antidepressant? If gradual adjustment of mood stabilizers eliminates mixed symptoms and mood fluctuations but the patient is still depressed, cautiously add an antidepressant. Antidepressants may be less likely to destabilize mood after all mixed elements have been treated completely.

Box 3

Treat seasonal symptoms. Many bipolar patients are most likely to be depressed in winter, and seasonal affective disorder is common in patients with a bipolar mood disorder. Their depression may respond to artificial bright light, usually given in the morning. Light therapy can help normalize the sleep-wake cycle, although it also can induce hypomania.

Other options. ECT is the most reliably effective treatment for bipolar depression. Because it treats both poles of the mood disorder, ECT also can be a useful maintenance treatment. A comparison of rTMS and placebo in 23 bipolar depressed patients failed to find any benefit of active treatment.³²

Table

What now? Treatment options for refractory bipolar depression

Rapid and ultradian cycling

No controlled studies have compared single-drug or combination therapies for rapid and ultradian cycling (Box 3).³³ Thus, our recommendations for treating patients with cycling who have not responded to initial interventions are based on case series and clinical experience.

Reassess thyroid function. As many as 70% of patients with rapid cycling have subclinical hypothyroidism that contributes to mood instability.³⁴ Thyroid replacement is indicated for any degree of hypothyroidism—even if medically unimportant—in patients with refractory mood disorders.

Slowly withdraw antidepressants. Most patients with rapid cycling are taking antidepressants. If your patient is experiencing depressive symptoms while taking an antidepressant, this means the antidepressant is not working and there is little point in continuing it. For patients being withdrawn from multiple antidepressants, rotate dose decrements to help you monitor the effect of each reduction.

Other options to consider in combination with mood stabilizers:

• an antipsychotic, especially in the presence of psychotic symptoms, when mixed symptoms are present
  
• clozapine, which can be a highly effective adjunct for refractory mood cycling and mixed states³⁶ (but is a later adjunct because of required monitoring, common adverse effects, and risk of interactions with carbamazepine and benzodiazepines)
  
• nimodipine, which has empiric support for complex mood cycling³⁷ and is well-tolerated with fewer interactions than other mood stabilizers (but cost and need for frequent dosing make it a second-line adjunct)
  
• supraphysiologic doses of thyroxine (≤0.4 mg/d, with T4 levels in the hyperthyroid range), which can improve response to mood-stabilizing regimens³⁴ (but risks of inducing hyperthyroidism make this intervention third-line).
  

Related resources

• Dubovsky SL. Clinical guide to psychotropic medications. New York: WW Norton; 2005.
  
• Dubovsky SL. Treatment of bipolar depression. Psychiatr Clin North Am 2005;28:349-70.
  
• Phillip Long, MD. Internet Mental Health. Online psychiatric diagnosis for the two-thirds of individuals with mental illness who do not seek treatment. www.mentalhealth.com/dis/p20-md02.html.
  

• Bupropion • Wellbutrin
  
• Carbamazepine • Tegretol
  
• Clonazepam • Klonopin
  
• Clozapine • Clozaril
  
• Fluoxetine • Prozac
  
• Gabapentin • Neurontin
  
• Lamotrigine • Lamictal
  
• Levetiracetam • Keppra
  
• Lithium • Lithobid, others
  
• Lorazepam • Ativan
  
• Memantine • Namenda
  
• Methylphenidate • Concerta, Ritalin, others
  
• Modafinil • Provigil
  
• Nimodipine • Nimotop
  
• Olanzapine/fluoxetine • Symbyax
  
• Oxcarbazepine • Trileptal
  
• Paroxetine • Paxil
  
• Pramipexole • Mirapex
  
• Pregabalin • Lyrica
  
• Quetiapine • Seroquel
  
• Riluzole • Rilutek
  
• Selegiline • Eldepryl
  
• Topiramate • Topamax
  
• Tranylcypromine • Parnate
  
• Valproate • Depakene, Depakote
  
• Venlafaxine • Effexor
  
• Verapamil • Calan, Isoptin, others
  
• Zonisamide • Zonegran
  

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

Dr. Dubovsky receives research/grant support from Eli Lilly and Company, Organon, Pfizer, UCB Pharma, anhd Forest Laboratories. He is a consultant to Oganon and Biovail Pharmaceuticals.

All phases of bipolar disorder can be difficult to treat, and patients remain symptomatic on average about half the time.¹ Not all bipolar patients who experience continued illness and disability are treatment-resistant (Box 1), but when symptoms persist you may ask yourself: Was treatment suboptimal or simply ineffective?

Patients with severe symptoms may be satisfied with a substantial decrease in symptoms, but any residual symptoms cause ongoing distress and lower the threshold for recurrences.² Finding the right combination of therapies for your patient is key to achieving an enduring response.

Future studies may tell us which treatments to combine and in what sequence for complex bipolar disorder, but—since most published studies exclude complex and comorbid cases—for now we must rely on limited controlled data and clinical experience. Using those resources, we offer comprehensive, practical recommendations for trouble-shooting (Box 2)^3-6 and getting better results when bipolar disorder does not respond to standard treatment.

Box 1

Mania

When a patient with mania does not respond as expected, the next step depends on which antimanic agent you prescribed:

Lithium can take a month to become fully effective for mania, which is why a benzodiazepine or antipsychotic is often added acutely to reduce agitation. Do not mistake neurotoxic interactions between lithium and antipsychotics for increased mania.

Although data vary on lithium’s optimal serum level, adjust to approximately 0.8 to 1 mEq/L, if tolerated, when lower levels are not effective. Children and young adolescents may need higher serum levels (such as 1.5 mEq/L) because the difference between serum and brain lithium levels is greater in younger patients than in adults.

Consider the dosing schedule. Because lithium’s elimination half-life with repeated dosing is 24 hours, most adults can take any formulation once daily—which improves adherence and reduces adverse effects. Children eliminate lithium more rapidly and need more frequent dosing.

High loading doses result in more rapid control of agitation, probably as a result of sedation. In our experience, however, rapidly sedating patients may interfere with long-term adherence.

Carbamazepine, other anticonvulsants. Because they less sedating, carbamazepine and other anticonvulsants might not appear to be rapidly effective for bipolar mania. If you wait up to a month, however, any antimanic effect will be obvious.

Antipsychotics are rapidly effective for mania. Higher doses work faster but produce more side effects. After an acute response, some patients can be maintained on a second-generation antipsychotic (SGA), but others do better on a standard mood stabilizer such as lithium or valproate.

Calcium channel blockers. Verapamil has been effective mostly for lithium-responsive mania in 27 of 30 studies. Nimodipine has been useful for more complex bipolar syndromes in a few studies using patients as their own controls.

To be effective for bipolar disorder, however, calcium channel blockers require frequent, high dosing (such as verapamil, 120 mg 4 times daily, or nimodipine, 60 to 120 mg 6 times daily), which makes adherence difficult.

Box 2

• consider augmentation first when a patient has had a partial response to a given medication
  
• switch when a patient cannot tolerate or shows no response to a therapeutic dose of a given medication.
  

Switching among anticonvulsants can be useful because their actions and side effects differ. Clozapine in a wide range of doses can be very effective for refractory mania,¹¹ but its use is difficult to monitor in highly agitated manic patients.

Other options. Electroconvulsive therapy (ECT) is the most effective treatment for mania, producing higher response rates than any antimanic drug.¹² In a study of repetitive transcranial magnetic stimulation (rTMS), 8 of 9 patients with mania refractory to mood stabilizers had a sustained response after 1 month of right-sided rTMS treatment.¹³ Conversely, left-sided rTMS can aggravate mania.

Bipolar depression

Continuing controversy about the best way to treat bipolar depression makes it difficult to know if treatment has been suboptimal or a patient is treatment-resistant.

Antidepressants. No antidepressant is approved (or recommended) as monotherapy for bipolar depression, and most experts recommend against prescribing antidepressants without concomitant mood stabilizers. Even so:

• Clinicians prescribing monotherapy for bipolar disorder choose antidepressants twice as often as mood stabilizers.
  
• Antidepressants are prescribed more frequently in combination with mood stabilizers than as monotherapy, although empiric trials have shown most antidepressants are not effective for bipolar depression.¹⁴
  

Antipsychotics. Quetiapine¹⁶ and a combination of olanzapine and fluoxetine¹⁷ are approved for treating bipolar depression. The studies supporting this indication lasted only 8 weeks, however, and excluded patients with the kinds of complicated and comorbid mood disorders commonly seen in clinical practice.

Many patients dropped out before the studies were completed, and “screen fails” (patients with the diagnosis who were not enrolled in the study) were not reported. In addition, “remitted” patients remained symptomatic.

Therefore, FDA approval of this indication does not guarantee these medications’ long-term efficacy or safety for bipolar depression or that they are useful in patients with complex forms of bipolar depression.

Recommended approach. Treatment resistance of bipolar depression to multiple mood stabilizers—with or without an antidepressant—or to an antipsychotic may manifest as lack of response, partial response, or initial good response followed by relapse or recurrence. Sometimes depression improves but irritability or mood lability worsen.

No reliable controlled studies have addressed complex refractory bipolar depression, but clinical experience suggests 1 approach for all of these responses:

Reconsider possible hypothyroidism. A low-normal T4—especially if decreased over time—and a mid-range or high-normal TSH—especially if increased—may indicate that subclinical hypothyroidism is inhibiting a response to mood stabilizers and antidepressants.¹⁸

Stop the antidepressant. If your patient is taking an antidepressant, it may be ineffective, creating mixed dysphoric hypomania, and/or driving another recurrence of depression. This is especially likely if the patient shows an initial prompt antidepressant response, but depression returns with irritability, insomnia, restlessness, or other subtle symptoms of dysphoric hypomania.

Withdraw the antidepressant gradually; for example, you might reduce the dose by 10% every few weeks so that the agent is discontinued across several months. Discontinuing an antidepressant too rapidly—even if it does not seem to be having any effect—can cause rebound depression that creates the mistaken impression that the antidepressant is needed.

Combine mood stabilizers. If a single mood stabilizer does not at least eliminate mood lability and other symptoms of activation, add a second agent. The combination of lithium and carbamazepine helps some depressed patients.²⁰ Patients with considerable mood instability or psychotic symptoms may benefit from an adjunct antipsychotic.

Introduce mood stabilizers gradually. These medications may work more rapidly against mixed manic symptoms than they do against depression, especially when the dose is raised too quickly. The result is rapid control of irritability, hyperactivity, agitation, and related symptoms but an apparent increase in depression as mixed elements of elevated mood and energy are filtered out.

Add an antidepressant? If gradual adjustment of mood stabilizers eliminates mixed symptoms and mood fluctuations but the patient is still depressed, cautiously add an antidepressant. Antidepressants may be less likely to destabilize mood after all mixed elements have been treated completely.

Box 3

Treat seasonal symptoms. Many bipolar patients are most likely to be depressed in winter, and seasonal affective disorder is common in patients with a bipolar mood disorder. Their depression may respond to artificial bright light, usually given in the morning. Light therapy can help normalize the sleep-wake cycle, although it also can induce hypomania.

Other options. ECT is the most reliably effective treatment for bipolar depression. Because it treats both poles of the mood disorder, ECT also can be a useful maintenance treatment. A comparison of rTMS and placebo in 23 bipolar depressed patients failed to find any benefit of active treatment.³²

Table

What now? Treatment options for refractory bipolar depression

Rapid and ultradian cycling

No controlled studies have compared single-drug or combination therapies for rapid and ultradian cycling (Box 3).³³ Thus, our recommendations for treating patients with cycling who have not responded to initial interventions are based on case series and clinical experience.

Reassess thyroid function. As many as 70% of patients with rapid cycling have subclinical hypothyroidism that contributes to mood instability.³⁴ Thyroid replacement is indicated for any degree of hypothyroidism—even if medically unimportant—in patients with refractory mood disorders.

Slowly withdraw antidepressants. Most patients with rapid cycling are taking antidepressants. If your patient is experiencing depressive symptoms while taking an antidepressant, this means the antidepressant is not working and there is little point in continuing it. For patients being withdrawn from multiple antidepressants, rotate dose decrements to help you monitor the effect of each reduction.

Other options to consider in combination with mood stabilizers:

• an antipsychotic, especially in the presence of psychotic symptoms, when mixed symptoms are present
  
• clozapine, which can be a highly effective adjunct for refractory mood cycling and mixed states³⁶ (but is a later adjunct because of required monitoring, common adverse effects, and risk of interactions with carbamazepine and benzodiazepines)
  
• nimodipine, which has empiric support for complex mood cycling³⁷ and is well-tolerated with fewer interactions than other mood stabilizers (but cost and need for frequent dosing make it a second-line adjunct)
  
• supraphysiologic doses of thyroxine (≤0.4 mg/d, with T4 levels in the hyperthyroid range), which can improve response to mood-stabilizing regimens³⁴ (but risks of inducing hyperthyroidism make this intervention third-line).
  

Related resources

• Dubovsky SL. Clinical guide to psychotropic medications. New York: WW Norton; 2005.
  
• Dubovsky SL. Treatment of bipolar depression. Psychiatr Clin North Am 2005;28:349-70.
  
• Phillip Long, MD. Internet Mental Health. Online psychiatric diagnosis for the two-thirds of individuals with mental illness who do not seek treatment. www.mentalhealth.com/dis/p20-md02.html.
  

• Bupropion • Wellbutrin
  
• Carbamazepine • Tegretol
  
• Clonazepam • Klonopin
  
• Clozapine • Clozaril
  
• Fluoxetine • Prozac
  
• Gabapentin • Neurontin
  
• Lamotrigine • Lamictal
  
• Levetiracetam • Keppra
  
• Lithium • Lithobid, others
  
• Lorazepam • Ativan
  
• Memantine • Namenda
  
• Methylphenidate • Concerta, Ritalin, others
  
• Modafinil • Provigil
  
• Nimodipine • Nimotop
  
• Olanzapine/fluoxetine • Symbyax
  
• Oxcarbazepine • Trileptal
  
• Paroxetine • Paxil
  
• Pramipexole • Mirapex
  
• Pregabalin • Lyrica
  
• Quetiapine • Seroquel
  
• Riluzole • Rilutek
  
• Selegiline • Eldepryl
  
• Topiramate • Topamax
  
• Tranylcypromine • Parnate
  
• Valproate • Depakene, Depakote
  
• Venlafaxine • Effexor
  
• Verapamil • Calan, Isoptin, others
  
• Zonisamide • Zonegran