Current Psychiatry

Consider these common human tales:

• A prominent politician who made his reputation combating prostitution loses his job after being discovered to have consorted with many "escorts." He believed he would never be caught.
• A sociopathic man charms a young woman and convinces her he will love her forever. She is infatuated with him. He dumps her a month later.
• A gambler is "convinced" his next bet will win back his previous losses and ends up losing his shirt again.
• Voters elect a politician who promises to solve all their problems but are disillusioned a few years later when things have barely changed.
• A woman with severe chronic fibromyalgia seeks the help of a shaman in her village in Haiti. He pain amazingly disappears for a few days before recurring.

The human brain has been both blessed and cursed during its evolutionary journey by developing the capacity for self-deception. Unlike other living things, humans are capable of massive self-deception—as these tales show.

Advantage: survival

Self-deception's upside is obvious, with established survival value. Hope, optimism, and self-confidence in dark times are antidotes to capitulation, despair, and inaction. Infatuation helps perpetuate the human species, and "eternal love" leads to other obligatory self-deceptions such as "till death do us part." Sometimes self-deception helps communities survive by promoting altruism, charity, and compassion for strangers.

For us in the health professions—especially psychiatry—self-deception's benefits for patients are well recognized: a remarkable healing capacity, an almost magical placebo effect from drug therapy or psychotherapy, and the advantages of positive transference toward the physician. Without self-deception, our patients could not respond to support and reassurance or resist hopelessness and the urge to give up and end their lives.

Disadvantage: suffering

But self-deception has a serious downside as well, from hubris and arrogance that end badly to blind faith and gullibility that lead to joining cults and "drinking the Kool-Aid," from unshakable belief in astrology or fanatical pursuit of a cause to believing in nothing and wasting one's life with nihilism.

The biology of self-deception also may represent the foundation of psychopathology, such as:

• unremitting panic and anxiety associated with a firm belief in impending doom
• bizarre, fixed, false beliefs of schizophrenia
• grandiose delusions of bipolar mania
• melancholia's profound and inconsolable sorrow, futility, and worthlessness
• pervasive belief in one's repulsiveness by attractive women with dysmorphic body disorder
• distorted conviction of obesity in skin-and-bones teenagers with anorexia nervosa
• unshakable parasitosis of a delusional disorder
• tortured and agonizing obsessions to perform meaningless rituals.

Psychiatric disorders are extremes of self-deception gone awry across complex neural pathways, encompassing emotions, thoughts, behavior, and cognitions. Human adaptation to stress or serious illness is often enhanced by the blissful escape of self-deception, but its curse can destroy lives and cause untold suffering.

So, are nonhuman creatures spared the double-edged sword of self-deception? If so, then why do dogs have unshakable loyalty, even when their owners abuse them? Maybe self-deception is not uniquely human after all.

Consider these common human tales:

• A prominent politician who made his reputation combating prostitution loses his job after being discovered to have consorted with many "escorts." He believed he would never be caught.
• A sociopathic man charms a young woman and convinces her he will love her forever. She is infatuated with him. He dumps her a month later.
• A gambler is "convinced" his next bet will win back his previous losses and ends up losing his shirt again.
• Voters elect a politician who promises to solve all their problems but are disillusioned a few years later when things have barely changed.
• A woman with severe chronic fibromyalgia seeks the help of a shaman in her village in Haiti. He pain amazingly disappears for a few days before recurring.

The human brain has been both blessed and cursed during its evolutionary journey by developing the capacity for self-deception. Unlike other living things, humans are capable of massive self-deception—as these tales show.

Advantage: survival

Self-deception's upside is obvious, with established survival value. Hope, optimism, and self-confidence in dark times are antidotes to capitulation, despair, and inaction. Infatuation helps perpetuate the human species, and "eternal love" leads to other obligatory self-deceptions such as "till death do us part." Sometimes self-deception helps communities survive by promoting altruism, charity, and compassion for strangers.

For us in the health professions—especially psychiatry—self-deception's benefits for patients are well recognized: a remarkable healing capacity, an almost magical placebo effect from drug therapy or psychotherapy, and the advantages of positive transference toward the physician. Without self-deception, our patients could not respond to support and reassurance or resist hopelessness and the urge to give up and end their lives.

Disadvantage: suffering

But self-deception has a serious downside as well, from hubris and arrogance that end badly to blind faith and gullibility that lead to joining cults and "drinking the Kool-Aid," from unshakable belief in astrology or fanatical pursuit of a cause to believing in nothing and wasting one's life with nihilism.

The biology of self-deception also may represent the foundation of psychopathology, such as:

• unremitting panic and anxiety associated with a firm belief in impending doom
• bizarre, fixed, false beliefs of schizophrenia
• grandiose delusions of bipolar mania
• melancholia's profound and inconsolable sorrow, futility, and worthlessness
• pervasive belief in one's repulsiveness by attractive women with dysmorphic body disorder
• distorted conviction of obesity in skin-and-bones teenagers with anorexia nervosa
• unshakable parasitosis of a delusional disorder
• tortured and agonizing obsessions to perform meaningless rituals.

Psychiatric disorders are extremes of self-deception gone awry across complex neural pathways, encompassing emotions, thoughts, behavior, and cognitions. Human adaptation to stress or serious illness is often enhanced by the blissful escape of self-deception, but its curse can destroy lives and cause untold suffering.

So, are nonhuman creatures spared the double-edged sword of self-deception? If so, then why do dogs have unshakable loyalty, even when their owners abuse them? Maybe self-deception is not uniquely human after all.

Consider these common human tales:

• A prominent politician who made his reputation combating prostitution loses his job after being discovered to have consorted with many "escorts." He believed he would never be caught.
• A sociopathic man charms a young woman and convinces her he will love her forever. She is infatuated with him. He dumps her a month later.
• A gambler is "convinced" his next bet will win back his previous losses and ends up losing his shirt again.
• Voters elect a politician who promises to solve all their problems but are disillusioned a few years later when things have barely changed.
• A woman with severe chronic fibromyalgia seeks the help of a shaman in her village in Haiti. He pain amazingly disappears for a few days before recurring.

The human brain has been both blessed and cursed during its evolutionary journey by developing the capacity for self-deception. Unlike other living things, humans are capable of massive self-deception—as these tales show.

Advantage: survival

Self-deception's upside is obvious, with established survival value. Hope, optimism, and self-confidence in dark times are antidotes to capitulation, despair, and inaction. Infatuation helps perpetuate the human species, and "eternal love" leads to other obligatory self-deceptions such as "till death do us part." Sometimes self-deception helps communities survive by promoting altruism, charity, and compassion for strangers.

For us in the health professions—especially psychiatry—self-deception's benefits for patients are well recognized: a remarkable healing capacity, an almost magical placebo effect from drug therapy or psychotherapy, and the advantages of positive transference toward the physician. Without self-deception, our patients could not respond to support and reassurance or resist hopelessness and the urge to give up and end their lives.

Disadvantage: suffering

But self-deception has a serious downside as well, from hubris and arrogance that end badly to blind faith and gullibility that lead to joining cults and "drinking the Kool-Aid," from unshakable belief in astrology or fanatical pursuit of a cause to believing in nothing and wasting one's life with nihilism.

The biology of self-deception also may represent the foundation of psychopathology, such as:

• unremitting panic and anxiety associated with a firm belief in impending doom
• bizarre, fixed, false beliefs of schizophrenia
• grandiose delusions of bipolar mania
• melancholia's profound and inconsolable sorrow, futility, and worthlessness
• pervasive belief in one's repulsiveness by attractive women with dysmorphic body disorder
• distorted conviction of obesity in skin-and-bones teenagers with anorexia nervosa
• unshakable parasitosis of a delusional disorder
• tortured and agonizing obsessions to perform meaningless rituals.

Psychiatric disorders are extremes of self-deception gone awry across complex neural pathways, encompassing emotions, thoughts, behavior, and cognitions. Human adaptation to stress or serious illness is often enhanced by the blissful escape of self-deception, but its curse can destroy lives and cause untold suffering.

So, are nonhuman creatures spared the double-edged sword of self-deception? If so, then why do dogs have unshakable loyalty, even when their owners abuse them? Maybe self-deception is not uniquely human after all.

CASE: ’I’m not crazy’

Ms. S, age 55, presents for treatment because she is feeling depressed and anxious. Her symptoms include decreased concentration, intermittent irritability, hoarding, and difficulty starting and completing tasks. She also has chronic sleep difficulties that often keep her awake until dawn.

Fatigue, lack of focus, and poor comprehension and motivation have left her unemployed. She and her teenage daughter live with Ms. S’s elderly mother. Ms. S feels tremendous guilt because she cannot be the mother and daughter she wants to be.

Initially, I (PK) diagnose Ms. S with major depressive disorder and prescribe sertraline, 100 mg/d, which improves her mood and energy. However, her inability to stay organized results in her being “let go” from job training.

Ms. S reports similar difficulties in school as a child. I determine that she meets DSM-IV-TR criteria for attention-deficit/hyperactivity disorder (ADHD). Adding methylphenidate, 10 mg bid, improves her concentration and ability to complete tasks. It also reduces the impulsivity that has disrupted her relationships.

Despite a strong desire to normalize her sleep schedule, Ms. S continues to have difficulty falling asleep, so I add melatonin, 3 to 6 mg at bedtime. Her sleeping pattern is improved, but still variable. She also tries quetiapine, 25 mg at bedtime, but soon discontinues it due to intolerance.

As our rapport strengthens, Ms. S reveals that she has had multiple encounters with aliens beginning at age 3. Although she has not had an “alien experience” for about 5 years, she does not feel safe sleeping at night and instead sleeps during the day. Her efforts to stay awake at night strain her relationship with her mother.

The authors’ observations

Approximately 1% of the U.S. population report alien abduction experiences (AAE)—an umbrella term that includes alleged contact with aliens ranging from sightings to abductions.¹ Patients rarely report AAE to mental health professionals. In our society, claiming to be an “abductee” implies that one might be insane. A survey of 398 Canadian students that assessed attitudes, beliefs, and experiences regarding alien abductions found that 79% of respondents believed they would have mostly negative consequences—such as being laughed at or socially isolated—if they claimed to have encountered aliens.¹

Persons who have AAE may attend support groups of fellow “abductees” to accumulate behavior-consonant information (hearing other people’s abduction stories) and reduce dissonance by being surrounded by others who share a questionable belief.² A survey of “abductees” found that 88% report at least some positive aspects of the experience, such as a sense of importance or feeling as though they were chosen to bridge communication between extraterrestrials and humans.³

• high levels of psychic energy
  
• self-sufficiency
  
• resourcefulness
  
• a tendency to question authority and to be exposed to situational conflicts.¹
  

After Ms. S reveals her alien experiences, I reassure her in a nonjudgmental manner that we will explore her experiences and determine ways to help her cope with them.

HISTORY: Terrifying experiences

Ms. S elaborates on her alien experiences, relating a particularly terrifying example from her teen years. She was lying awake in bed, looking at the ceiling, where she saw a jeweled spider with a drill. As the spider descended from the ceiling and spread its legs, she recalled a noise like a dentist’s drill. As the spider neared her face, it grew larger and larger. Terrified, Ms. S was unable to scream for help or move anything except her eyes as the spider clamped its legs around her head and bored into her skull. She reported that although she could feel the drill go in, it wasn’t painful.

Other experiences included giving birth, undergoing examinations or probes, and communicating with aliens. Although she is very distressed by most memories, she feels she benefited from others. For example, as a child, Ms. S’s math skills improved dramatically after an AAE episode; she believes this was a gift from the aliens. Ms. S’s AAE memories are as vivid to her as memories of her college graduation. She had been reluctant to discuss these events with anyone outside her family out of fear of being perceived as “crazy.”

Ms. S says she was a shy child who had difficulty making friends. She was plagued with fatigue and worry about family members. She believed that aliens might attack her sisters and felt obligated to stay awake at night to protect them. Aside from alien experiences, Ms. S reports a happy childhood.

She has always been an avid reader. At age 8 or 9, after reading a book on alien abduction, she concluded that she had been abducted. Later, she joined a group of professed alien abductees. She feels accepted and validated by this group and has a forum for discussing her experiences without fear of ridicule or rejection.

Ms. S remains frightened by things that remind her of aliens. Although she wrote a summary of her alien experiences, she cannot draw a picture of an alien, and thoughts or images of the prototypical “grey” alien trigger panic. She also feels somewhat “different,” nervous, and distant from others.

The authors’ observations

Reviewing AAE literature led me to consider several diagnoses, including:

• psychosis
  
• seizures
  
• false memory (sexual abuse, trauma)
  
• narcolepsy
  
• sleep paralysis.
  

Electroencephalography (during drowsiness) revealed abnormal activity (occurrences of widely scattered bursts of nonspecific, round, sharply contoured slow waves in the left frontal region) only in the F7 electrode. In the absence of clinical symptoms and when found in a single lead, this is considered a normal variant.

Diagnostic testing ruled out hallucinosis related to seizures. I also ruled out false memory related to sexual abuse or trauma, which is commonly found in patients who present with AAE.

Collaborative information from relatives did not uncover a history of psychosis. She and family members reported, however, that Ms. S’s father and 1 sister had periodic sleep disturbances with associated hallucinations. I began to suspect sleep paralysis.

The authors’ observations

Full-body paralysis normally accompanies rapid eye movement (REM) sleep, which occurs several times a night.⁴ Sleep paralysis is a transient state that occurs when an individual becomes conscious of this immobility, typically while falling asleep or awakening.⁵ These experiences can be accompanied by hypnagogic (while falling asleep) or hypnopompic (while awakening) hallucinations. An estimated 30% of the population has had at least one sleep paralysis episode.⁶ In one study, 5% of sleep paralysis patients had episodes that were accompanied by hallucinations.⁷

Although individuals cannot make gross body movements during sleep paralysis, they can open their eyes and are able to report events that occurred around them during the episode.⁸ Patients interpret sleep paralysis experiences in subjective terms. Common descriptions include intense fear, breathing difficulties, feeling of bodily pressure—especially on the chest—and sensations of floating, flying, or falling (Table 1).^7,9

During sleep paralysis episodes, individuals typically sense a threatening presence.⁶ Patients have reported beastly and demonic figures of doom: devils, demons, witches, aliens, and even cinematic villains such as Darth Vader and Freddy Kruger.⁶ Others have described this presence in terms of alien visitations or abductions.

Table 1

4 types of sleep paralysis-related hallucinations

A Harvard University study of 11 individuals who reported alien abductions found that all participants experienced a similar sequence of events:

• They suspected abduction after sleep episodes characterized by awakening, full-body paralysis, intense fear, and a feeling of a presence. Several reported tactile or visual sensations strikingly similar to descriptions of sleep paralysis, such as levitating, being touched, and seeing shadowy figures.
  
• They sought explanations for what they perceived as anomalous experiences.
  
• They “recovered” abduction memories in therapy (with the help of techniques such as hypnosis) or spontaneously (after reading books or seeing movies or television shows depicting similar episodes).⁴
  

• an absence of organic or psychiatric dysfunction
  
• a familial pattern of sleep disturbances
  
• the temporal pattern and description of her symptoms (Table 2).¹¹
  

Table 2

Diagnostic criteria for sleep paralysis

TREATMENT: Reassurance, therapy

Effective treatment for Ms. S required helping her to understand that an organic condition was the foundation of her experiences. I began by conveying the sleep paralysis diagnosis and my understanding of the occupational and personal consequences that this condition had had for her. I explained the physiology of sleep paralysis and that memories or hallucinations (dreamlike mentation) are preserved in an extremely vivid fashion because her eyes are open. I acknowledged the realistic character of her experiences and the resulting symptoms of posttraumatic stress disorder (PTSD).

I refer Ms. S to a therapist for psychotherapy. The therapist begins by using trauma informed techniques to address Ms. S’s PTSD. As she improves, her therapy evolves into a combination of narrative and supportive psychotherapy, and then family systems therapy to address issues with her daughter and mother.

In a follow-up visit 1 year after beginning treatment, Ms. S cites multiple improvements, with no recurrence of sleep paralysis episodes. She continues to take sertraline, which relieves her depression and anxiety, and methylphenidate to improve her attention and concentration. She has taken on more responsibility at home, cleaning, preparing meals, helping her daughter choose a college, and attending to her mother’s health issues. Ms. S still has difficulties with her sleep patterns, and her new psychiatrist is exploring the possibility of a bipolar component to her mood disorder.

The authors’ observations

Like other traumas, AAE can induce symptoms of acute or chronic PTSD. The various psychoses, personality disorders, and dissociative disorders that could account for abduction experiences are characterized by delusions, so conduct ongoing assessment for these conditions in patients who report AAE. However, evidence suggests that serious psychopathology is no more common among “abductees” than among the general population.¹²

Persons reporting AAE exhibit physiologic reactivity as profound as that of survivors of combat or sexual assault.¹³ This reactivity confirms that the emotional power of the memory is as evocative and problematic as the physiologic reactions attributable to genuine (documented) traumatic events. Because patients have difficulty differentiating these hallucinations from actual events, they experience emotional pain and suffering. Fifty-seven percent of sleep paralysis patients who report AAE attempt suicide.¹⁴

There are no FDA-approved medications for treating sleep paralysis. Pharmacotherapy can be used to address psychiatric symptoms such as the depression and anxiety Ms. S exhibited.

Related resources

• American Academy of Sleep Medicine. International classification of sleep disorders, revised: diagnostic and coding manual. Chicago, IL: American Academy of Sleep Medicine; 2001:166-9.
  
• Cheyne JA. Sleep paralysis and associated hypnagogic and hypnopompic experiences. http://watarts.uwaterloo.ca/~acheyne/S_P.html.
  

• Methylphenidate • Ritalin
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  

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

CASE: ’I’m not crazy’

Ms. S, age 55, presents for treatment because she is feeling depressed and anxious. Her symptoms include decreased concentration, intermittent irritability, hoarding, and difficulty starting and completing tasks. She also has chronic sleep difficulties that often keep her awake until dawn.

Fatigue, lack of focus, and poor comprehension and motivation have left her unemployed. She and her teenage daughter live with Ms. S’s elderly mother. Ms. S feels tremendous guilt because she cannot be the mother and daughter she wants to be.

Initially, I (PK) diagnose Ms. S with major depressive disorder and prescribe sertraline, 100 mg/d, which improves her mood and energy. However, her inability to stay organized results in her being “let go” from job training.

Ms. S reports similar difficulties in school as a child. I determine that she meets DSM-IV-TR criteria for attention-deficit/hyperactivity disorder (ADHD). Adding methylphenidate, 10 mg bid, improves her concentration and ability to complete tasks. It also reduces the impulsivity that has disrupted her relationships.

Despite a strong desire to normalize her sleep schedule, Ms. S continues to have difficulty falling asleep, so I add melatonin, 3 to 6 mg at bedtime. Her sleeping pattern is improved, but still variable. She also tries quetiapine, 25 mg at bedtime, but soon discontinues it due to intolerance.

As our rapport strengthens, Ms. S reveals that she has had multiple encounters with aliens beginning at age 3. Although she has not had an “alien experience” for about 5 years, she does not feel safe sleeping at night and instead sleeps during the day. Her efforts to stay awake at night strain her relationship with her mother.

The authors’ observations

Approximately 1% of the U.S. population report alien abduction experiences (AAE)—an umbrella term that includes alleged contact with aliens ranging from sightings to abductions.¹ Patients rarely report AAE to mental health professionals. In our society, claiming to be an “abductee” implies that one might be insane. A survey of 398 Canadian students that assessed attitudes, beliefs, and experiences regarding alien abductions found that 79% of respondents believed they would have mostly negative consequences—such as being laughed at or socially isolated—if they claimed to have encountered aliens.¹

Persons who have AAE may attend support groups of fellow “abductees” to accumulate behavior-consonant information (hearing other people’s abduction stories) and reduce dissonance by being surrounded by others who share a questionable belief.² A survey of “abductees” found that 88% report at least some positive aspects of the experience, such as a sense of importance or feeling as though they were chosen to bridge communication between extraterrestrials and humans.³

• high levels of psychic energy
  
• self-sufficiency
  
• resourcefulness
  
• a tendency to question authority and to be exposed to situational conflicts.¹
  

After Ms. S reveals her alien experiences, I reassure her in a nonjudgmental manner that we will explore her experiences and determine ways to help her cope with them.

HISTORY: Terrifying experiences

Ms. S elaborates on her alien experiences, relating a particularly terrifying example from her teen years. She was lying awake in bed, looking at the ceiling, where she saw a jeweled spider with a drill. As the spider descended from the ceiling and spread its legs, she recalled a noise like a dentist’s drill. As the spider neared her face, it grew larger and larger. Terrified, Ms. S was unable to scream for help or move anything except her eyes as the spider clamped its legs around her head and bored into her skull. She reported that although she could feel the drill go in, it wasn’t painful.

Other experiences included giving birth, undergoing examinations or probes, and communicating with aliens. Although she is very distressed by most memories, she feels she benefited from others. For example, as a child, Ms. S’s math skills improved dramatically after an AAE episode; she believes this was a gift from the aliens. Ms. S’s AAE memories are as vivid to her as memories of her college graduation. She had been reluctant to discuss these events with anyone outside her family out of fear of being perceived as “crazy.”

Ms. S says she was a shy child who had difficulty making friends. She was plagued with fatigue and worry about family members. She believed that aliens might attack her sisters and felt obligated to stay awake at night to protect them. Aside from alien experiences, Ms. S reports a happy childhood.

She has always been an avid reader. At age 8 or 9, after reading a book on alien abduction, she concluded that she had been abducted. Later, she joined a group of professed alien abductees. She feels accepted and validated by this group and has a forum for discussing her experiences without fear of ridicule or rejection.

Ms. S remains frightened by things that remind her of aliens. Although she wrote a summary of her alien experiences, she cannot draw a picture of an alien, and thoughts or images of the prototypical “grey” alien trigger panic. She also feels somewhat “different,” nervous, and distant from others.

The authors’ observations

Reviewing AAE literature led me to consider several diagnoses, including:

• psychosis
  
• seizures
  
• false memory (sexual abuse, trauma)
  
• narcolepsy
  
• sleep paralysis.
  

Electroencephalography (during drowsiness) revealed abnormal activity (occurrences of widely scattered bursts of nonspecific, round, sharply contoured slow waves in the left frontal region) only in the F7 electrode. In the absence of clinical symptoms and when found in a single lead, this is considered a normal variant.

Diagnostic testing ruled out hallucinosis related to seizures. I also ruled out false memory related to sexual abuse or trauma, which is commonly found in patients who present with AAE.

Collaborative information from relatives did not uncover a history of psychosis. She and family members reported, however, that Ms. S’s father and 1 sister had periodic sleep disturbances with associated hallucinations. I began to suspect sleep paralysis.

The authors’ observations

Full-body paralysis normally accompanies rapid eye movement (REM) sleep, which occurs several times a night.⁴ Sleep paralysis is a transient state that occurs when an individual becomes conscious of this immobility, typically while falling asleep or awakening.⁵ These experiences can be accompanied by hypnagogic (while falling asleep) or hypnopompic (while awakening) hallucinations. An estimated 30% of the population has had at least one sleep paralysis episode.⁶ In one study, 5% of sleep paralysis patients had episodes that were accompanied by hallucinations.⁷

Although individuals cannot make gross body movements during sleep paralysis, they can open their eyes and are able to report events that occurred around them during the episode.⁸ Patients interpret sleep paralysis experiences in subjective terms. Common descriptions include intense fear, breathing difficulties, feeling of bodily pressure—especially on the chest—and sensations of floating, flying, or falling (Table 1).^7,9

During sleep paralysis episodes, individuals typically sense a threatening presence.⁶ Patients have reported beastly and demonic figures of doom: devils, demons, witches, aliens, and even cinematic villains such as Darth Vader and Freddy Kruger.⁶ Others have described this presence in terms of alien visitations or abductions.

Table 1

4 types of sleep paralysis-related hallucinations

A Harvard University study of 11 individuals who reported alien abductions found that all participants experienced a similar sequence of events:

• They suspected abduction after sleep episodes characterized by awakening, full-body paralysis, intense fear, and a feeling of a presence. Several reported tactile or visual sensations strikingly similar to descriptions of sleep paralysis, such as levitating, being touched, and seeing shadowy figures.
  
• They sought explanations for what they perceived as anomalous experiences.
  
• They “recovered” abduction memories in therapy (with the help of techniques such as hypnosis) or spontaneously (after reading books or seeing movies or television shows depicting similar episodes).⁴
  

• an absence of organic or psychiatric dysfunction
  
• a familial pattern of sleep disturbances
  
• the temporal pattern and description of her symptoms (Table 2).¹¹
  

Table 2

Diagnostic criteria for sleep paralysis

TREATMENT: Reassurance, therapy

Effective treatment for Ms. S required helping her to understand that an organic condition was the foundation of her experiences. I began by conveying the sleep paralysis diagnosis and my understanding of the occupational and personal consequences that this condition had had for her. I explained the physiology of sleep paralysis and that memories or hallucinations (dreamlike mentation) are preserved in an extremely vivid fashion because her eyes are open. I acknowledged the realistic character of her experiences and the resulting symptoms of posttraumatic stress disorder (PTSD).

I refer Ms. S to a therapist for psychotherapy. The therapist begins by using trauma informed techniques to address Ms. S’s PTSD. As she improves, her therapy evolves into a combination of narrative and supportive psychotherapy, and then family systems therapy to address issues with her daughter and mother.

In a follow-up visit 1 year after beginning treatment, Ms. S cites multiple improvements, with no recurrence of sleep paralysis episodes. She continues to take sertraline, which relieves her depression and anxiety, and methylphenidate to improve her attention and concentration. She has taken on more responsibility at home, cleaning, preparing meals, helping her daughter choose a college, and attending to her mother’s health issues. Ms. S still has difficulties with her sleep patterns, and her new psychiatrist is exploring the possibility of a bipolar component to her mood disorder.

The authors’ observations

Like other traumas, AAE can induce symptoms of acute or chronic PTSD. The various psychoses, personality disorders, and dissociative disorders that could account for abduction experiences are characterized by delusions, so conduct ongoing assessment for these conditions in patients who report AAE. However, evidence suggests that serious psychopathology is no more common among “abductees” than among the general population.¹²

Persons reporting AAE exhibit physiologic reactivity as profound as that of survivors of combat or sexual assault.¹³ This reactivity confirms that the emotional power of the memory is as evocative and problematic as the physiologic reactions attributable to genuine (documented) traumatic events. Because patients have difficulty differentiating these hallucinations from actual events, they experience emotional pain and suffering. Fifty-seven percent of sleep paralysis patients who report AAE attempt suicide.¹⁴

There are no FDA-approved medications for treating sleep paralysis. Pharmacotherapy can be used to address psychiatric symptoms such as the depression and anxiety Ms. S exhibited.

Related resources

• American Academy of Sleep Medicine. International classification of sleep disorders, revised: diagnostic and coding manual. Chicago, IL: American Academy of Sleep Medicine; 2001:166-9.
  
• Cheyne JA. Sleep paralysis and associated hypnagogic and hypnopompic experiences. http://watarts.uwaterloo.ca/~acheyne/S_P.html.
  

• Methylphenidate • Ritalin
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  

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

CASE: ’I’m not crazy’

Ms. S, age 55, presents for treatment because she is feeling depressed and anxious. Her symptoms include decreased concentration, intermittent irritability, hoarding, and difficulty starting and completing tasks. She also has chronic sleep difficulties that often keep her awake until dawn.

Fatigue, lack of focus, and poor comprehension and motivation have left her unemployed. She and her teenage daughter live with Ms. S’s elderly mother. Ms. S feels tremendous guilt because she cannot be the mother and daughter she wants to be.

Initially, I (PK) diagnose Ms. S with major depressive disorder and prescribe sertraline, 100 mg/d, which improves her mood and energy. However, her inability to stay organized results in her being “let go” from job training.

Ms. S reports similar difficulties in school as a child. I determine that she meets DSM-IV-TR criteria for attention-deficit/hyperactivity disorder (ADHD). Adding methylphenidate, 10 mg bid, improves her concentration and ability to complete tasks. It also reduces the impulsivity that has disrupted her relationships.

Despite a strong desire to normalize her sleep schedule, Ms. S continues to have difficulty falling asleep, so I add melatonin, 3 to 6 mg at bedtime. Her sleeping pattern is improved, but still variable. She also tries quetiapine, 25 mg at bedtime, but soon discontinues it due to intolerance.

As our rapport strengthens, Ms. S reveals that she has had multiple encounters with aliens beginning at age 3. Although she has not had an “alien experience” for about 5 years, she does not feel safe sleeping at night and instead sleeps during the day. Her efforts to stay awake at night strain her relationship with her mother.

The authors’ observations

Approximately 1% of the U.S. population report alien abduction experiences (AAE)—an umbrella term that includes alleged contact with aliens ranging from sightings to abductions.¹ Patients rarely report AAE to mental health professionals. In our society, claiming to be an “abductee” implies that one might be insane. A survey of 398 Canadian students that assessed attitudes, beliefs, and experiences regarding alien abductions found that 79% of respondents believed they would have mostly negative consequences—such as being laughed at or socially isolated—if they claimed to have encountered aliens.¹

Persons who have AAE may attend support groups of fellow “abductees” to accumulate behavior-consonant information (hearing other people’s abduction stories) and reduce dissonance by being surrounded by others who share a questionable belief.² A survey of “abductees” found that 88% report at least some positive aspects of the experience, such as a sense of importance or feeling as though they were chosen to bridge communication between extraterrestrials and humans.³

• high levels of psychic energy
  
• self-sufficiency
  
• resourcefulness
  
• a tendency to question authority and to be exposed to situational conflicts.¹
  

After Ms. S reveals her alien experiences, I reassure her in a nonjudgmental manner that we will explore her experiences and determine ways to help her cope with them.

HISTORY: Terrifying experiences

Ms. S elaborates on her alien experiences, relating a particularly terrifying example from her teen years. She was lying awake in bed, looking at the ceiling, where she saw a jeweled spider with a drill. As the spider descended from the ceiling and spread its legs, she recalled a noise like a dentist’s drill. As the spider neared her face, it grew larger and larger. Terrified, Ms. S was unable to scream for help or move anything except her eyes as the spider clamped its legs around her head and bored into her skull. She reported that although she could feel the drill go in, it wasn’t painful.

Other experiences included giving birth, undergoing examinations or probes, and communicating with aliens. Although she is very distressed by most memories, she feels she benefited from others. For example, as a child, Ms. S’s math skills improved dramatically after an AAE episode; she believes this was a gift from the aliens. Ms. S’s AAE memories are as vivid to her as memories of her college graduation. She had been reluctant to discuss these events with anyone outside her family out of fear of being perceived as “crazy.”

Ms. S says she was a shy child who had difficulty making friends. She was plagued with fatigue and worry about family members. She believed that aliens might attack her sisters and felt obligated to stay awake at night to protect them. Aside from alien experiences, Ms. S reports a happy childhood.

She has always been an avid reader. At age 8 or 9, after reading a book on alien abduction, she concluded that she had been abducted. Later, she joined a group of professed alien abductees. She feels accepted and validated by this group and has a forum for discussing her experiences without fear of ridicule or rejection.

Ms. S remains frightened by things that remind her of aliens. Although she wrote a summary of her alien experiences, she cannot draw a picture of an alien, and thoughts or images of the prototypical “grey” alien trigger panic. She also feels somewhat “different,” nervous, and distant from others.

The authors’ observations

Reviewing AAE literature led me to consider several diagnoses, including:

• psychosis
  
• seizures
  
• false memory (sexual abuse, trauma)
  
• narcolepsy
  
• sleep paralysis.
  

Electroencephalography (during drowsiness) revealed abnormal activity (occurrences of widely scattered bursts of nonspecific, round, sharply contoured slow waves in the left frontal region) only in the F7 electrode. In the absence of clinical symptoms and when found in a single lead, this is considered a normal variant.

Diagnostic testing ruled out hallucinosis related to seizures. I also ruled out false memory related to sexual abuse or trauma, which is commonly found in patients who present with AAE.

Collaborative information from relatives did not uncover a history of psychosis. She and family members reported, however, that Ms. S’s father and 1 sister had periodic sleep disturbances with associated hallucinations. I began to suspect sleep paralysis.

The authors’ observations

Full-body paralysis normally accompanies rapid eye movement (REM) sleep, which occurs several times a night.⁴ Sleep paralysis is a transient state that occurs when an individual becomes conscious of this immobility, typically while falling asleep or awakening.⁵ These experiences can be accompanied by hypnagogic (while falling asleep) or hypnopompic (while awakening) hallucinations. An estimated 30% of the population has had at least one sleep paralysis episode.⁶ In one study, 5% of sleep paralysis patients had episodes that were accompanied by hallucinations.⁷

Although individuals cannot make gross body movements during sleep paralysis, they can open their eyes and are able to report events that occurred around them during the episode.⁸ Patients interpret sleep paralysis experiences in subjective terms. Common descriptions include intense fear, breathing difficulties, feeling of bodily pressure—especially on the chest—and sensations of floating, flying, or falling (Table 1).^7,9

During sleep paralysis episodes, individuals typically sense a threatening presence.⁶ Patients have reported beastly and demonic figures of doom: devils, demons, witches, aliens, and even cinematic villains such as Darth Vader and Freddy Kruger.⁶ Others have described this presence in terms of alien visitations or abductions.

Table 1

4 types of sleep paralysis-related hallucinations

A Harvard University study of 11 individuals who reported alien abductions found that all participants experienced a similar sequence of events:

• They suspected abduction after sleep episodes characterized by awakening, full-body paralysis, intense fear, and a feeling of a presence. Several reported tactile or visual sensations strikingly similar to descriptions of sleep paralysis, such as levitating, being touched, and seeing shadowy figures.
  
• They sought explanations for what they perceived as anomalous experiences.
  
• They “recovered” abduction memories in therapy (with the help of techniques such as hypnosis) or spontaneously (after reading books or seeing movies or television shows depicting similar episodes).⁴
  

• an absence of organic or psychiatric dysfunction
  
• a familial pattern of sleep disturbances
  
• the temporal pattern and description of her symptoms (Table 2).¹¹
  

Table 2

Diagnostic criteria for sleep paralysis

TREATMENT: Reassurance, therapy

Effective treatment for Ms. S required helping her to understand that an organic condition was the foundation of her experiences. I began by conveying the sleep paralysis diagnosis and my understanding of the occupational and personal consequences that this condition had had for her. I explained the physiology of sleep paralysis and that memories or hallucinations (dreamlike mentation) are preserved in an extremely vivid fashion because her eyes are open. I acknowledged the realistic character of her experiences and the resulting symptoms of posttraumatic stress disorder (PTSD).

I refer Ms. S to a therapist for psychotherapy. The therapist begins by using trauma informed techniques to address Ms. S’s PTSD. As she improves, her therapy evolves into a combination of narrative and supportive psychotherapy, and then family systems therapy to address issues with her daughter and mother.

In a follow-up visit 1 year after beginning treatment, Ms. S cites multiple improvements, with no recurrence of sleep paralysis episodes. She continues to take sertraline, which relieves her depression and anxiety, and methylphenidate to improve her attention and concentration. She has taken on more responsibility at home, cleaning, preparing meals, helping her daughter choose a college, and attending to her mother’s health issues. Ms. S still has difficulties with her sleep patterns, and her new psychiatrist is exploring the possibility of a bipolar component to her mood disorder.

The authors’ observations

Like other traumas, AAE can induce symptoms of acute or chronic PTSD. The various psychoses, personality disorders, and dissociative disorders that could account for abduction experiences are characterized by delusions, so conduct ongoing assessment for these conditions in patients who report AAE. However, evidence suggests that serious psychopathology is no more common among “abductees” than among the general population.¹²

Persons reporting AAE exhibit physiologic reactivity as profound as that of survivors of combat or sexual assault.¹³ This reactivity confirms that the emotional power of the memory is as evocative and problematic as the physiologic reactions attributable to genuine (documented) traumatic events. Because patients have difficulty differentiating these hallucinations from actual events, they experience emotional pain and suffering. Fifty-seven percent of sleep paralysis patients who report AAE attempt suicide.¹⁴

There are no FDA-approved medications for treating sleep paralysis. Pharmacotherapy can be used to address psychiatric symptoms such as the depression and anxiety Ms. S exhibited.

Related resources

• American Academy of Sleep Medicine. International classification of sleep disorders, revised: diagnostic and coding manual. Chicago, IL: American Academy of Sleep Medicine; 2001:166-9.
  
• Cheyne JA. Sleep paralysis and associated hypnagogic and hypnopompic experiences. http://watarts.uwaterloo.ca/~acheyne/S_P.html.
  

• Methylphenidate • Ritalin
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  

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

Psychiatric emergency rooms (ERs) often are the first stop for patients experiencing severe psychiatric symptoms. Following these strategies can help as you assess and treat a variety of patients and create a modicum of calm out of the chaos.

‘Heal’ borderlines

Although patients diagnosed with borderline personality disorder often present treatment challenges, a supportive psychotherapeutic approach based on empathic listening often can be helpful. Allowing these patients to feel understood in the midst of an interpersonal crisis may be enough to help them navigate their predicament in a healthier way.

Beware of shift changes

Patients arriving during a staff shift change might not receive the time and attention necessary for a comprehensive psychiatric evaluation. Resist pressure to speed up the workflow, and do not leave patients waiting to be seen by the oncoming shift. Working only by the clock may result in a rushed and inadequate assessment and a suboptimal treatment plan.

Sleeping it off

Patients often arrive intoxicated and might not be able to adequately participate in a psychiatric assessment. Talk to intoxicated patients briefly, get an adequate medical history, ensure their safety and monitoring, and then let them sleep in the ER. Re-evaluation in the morning often yields dramatically different mental status findings.

Be familiar with social services

Although some ERs employ staff members who specialize in coordinating social services, be familiar with available homeless shelters, travelers’ aid societies, halfway houses, and safe homes. Armed with this information, you can refer to appropriate agencies patients with problems that are more social than psychiatric.

Know your staff

Psychiatric ERs are staffed by a variety of mental health professionals, and individual team members’ experience, training, and knowledge can vary greatly. It is your responsibility to be familiar with the strengths and weaknesses of these workers to guard against having to repeat tasks.

Feed your patients

Providing patients with food is a straight-forward way to demonstrate you care about their needs and want to help. Though it is important that patients do not view psychiatric ERs as places to come to get a hot meal, generously dispensing food often helps lay the groundwork for a therapeutic relationship.

Be generous with thiamine

Many ER patients are undernourished or abuse alcohol and therefore are at risk for thiamine deficiency. The sequelae of thiamine deficiency, including Wernicke’s encephalopathy and Korsakoff’s syndrome, are serious and in some cases irreversible.

Psychiatric emergency rooms (ERs) often are the first stop for patients experiencing severe psychiatric symptoms. Following these strategies can help as you assess and treat a variety of patients and create a modicum of calm out of the chaos.

‘Heal’ borderlines

Although patients diagnosed with borderline personality disorder often present treatment challenges, a supportive psychotherapeutic approach based on empathic listening often can be helpful. Allowing these patients to feel understood in the midst of an interpersonal crisis may be enough to help them navigate their predicament in a healthier way.

Beware of shift changes

Patients arriving during a staff shift change might not receive the time and attention necessary for a comprehensive psychiatric evaluation. Resist pressure to speed up the workflow, and do not leave patients waiting to be seen by the oncoming shift. Working only by the clock may result in a rushed and inadequate assessment and a suboptimal treatment plan.

Sleeping it off

Patients often arrive intoxicated and might not be able to adequately participate in a psychiatric assessment. Talk to intoxicated patients briefly, get an adequate medical history, ensure their safety and monitoring, and then let them sleep in the ER. Re-evaluation in the morning often yields dramatically different mental status findings.

Be familiar with social services

Although some ERs employ staff members who specialize in coordinating social services, be familiar with available homeless shelters, travelers’ aid societies, halfway houses, and safe homes. Armed with this information, you can refer to appropriate agencies patients with problems that are more social than psychiatric.

Know your staff

Psychiatric ERs are staffed by a variety of mental health professionals, and individual team members’ experience, training, and knowledge can vary greatly. It is your responsibility to be familiar with the strengths and weaknesses of these workers to guard against having to repeat tasks.

Feed your patients

Providing patients with food is a straight-forward way to demonstrate you care about their needs and want to help. Though it is important that patients do not view psychiatric ERs as places to come to get a hot meal, generously dispensing food often helps lay the groundwork for a therapeutic relationship.

Be generous with thiamine

Many ER patients are undernourished or abuse alcohol and therefore are at risk for thiamine deficiency. The sequelae of thiamine deficiency, including Wernicke’s encephalopathy and Korsakoff’s syndrome, are serious and in some cases irreversible.

Psychiatric emergency rooms (ERs) often are the first stop for patients experiencing severe psychiatric symptoms. Following these strategies can help as you assess and treat a variety of patients and create a modicum of calm out of the chaos.

‘Heal’ borderlines

Although patients diagnosed with borderline personality disorder often present treatment challenges, a supportive psychotherapeutic approach based on empathic listening often can be helpful. Allowing these patients to feel understood in the midst of an interpersonal crisis may be enough to help them navigate their predicament in a healthier way.

Beware of shift changes

Patients arriving during a staff shift change might not receive the time and attention necessary for a comprehensive psychiatric evaluation. Resist pressure to speed up the workflow, and do not leave patients waiting to be seen by the oncoming shift. Working only by the clock may result in a rushed and inadequate assessment and a suboptimal treatment plan.

Sleeping it off

Patients often arrive intoxicated and might not be able to adequately participate in a psychiatric assessment. Talk to intoxicated patients briefly, get an adequate medical history, ensure their safety and monitoring, and then let them sleep in the ER. Re-evaluation in the morning often yields dramatically different mental status findings.

Be familiar with social services

Although some ERs employ staff members who specialize in coordinating social services, be familiar with available homeless shelters, travelers’ aid societies, halfway houses, and safe homes. Armed with this information, you can refer to appropriate agencies patients with problems that are more social than psychiatric.

Know your staff

Psychiatric ERs are staffed by a variety of mental health professionals, and individual team members’ experience, training, and knowledge can vary greatly. It is your responsibility to be familiar with the strengths and weaknesses of these workers to guard against having to repeat tasks.

Feed your patients

Providing patients with food is a straight-forward way to demonstrate you care about their needs and want to help. Though it is important that patients do not view psychiatric ERs as places to come to get a hot meal, generously dispensing food often helps lay the groundwork for a therapeutic relationship.

Be generous with thiamine

Many ER patients are undernourished or abuse alcohol and therefore are at risk for thiamine deficiency. The sequelae of thiamine deficiency, including Wernicke’s encephalopathy and Korsakoff’s syndrome, are serious and in some cases irreversible.

Ms. G, age 28, presents to a tertiary care hospital with altered mental status. Six weeks ago she started taking phentermine, 37.5 mg/d, to lose weight. Her body mass index is 24 kg/m² (normal range), and she obtained the stimulant agent via the Internet. Her family reports Ms. G was very busy in the past week, staying up until 2 AM cleaning. They say she also was irritable with her 5-year-old son.

Two days ago, Ms. G complained of fatigue and nausea without emesis. She went to bed early and did not awaken the next morning. Her sister found her in bed, minimally responsive to verbal stimuli, and brought her to the hospital.

Patients have used phentermine as a weight-reducing agent since the FDA approved this amphetamine-like compound in 1960.¹ Phentermine’s mechanism of action is thought to involve dopaminergic, noradrenergic, and serotonergic effects.² Stimulation of norepinephrine (NE) release is its most potent effect, followed by NE reuptake inhibition, stimulation of dopamine (DA) release, DA reuptake inhibition, stimulation of serotonin (5-HT) release, and 5-HT reuptake inhibition (weak).³

Because phentermine could in theory cause serotonin syndrome,⁴ its use is contraindicated with monoamine oxidase inhibitors (MAOIs) and not recommended with selective serotonin reuptake inhibitors (SSRIs).⁵ One case report describes an interaction between fluoxetine and phentermine that appears consistent with serotonin syndrome.⁶ We are aware of no case reports of serotonin syndrome caused by phentermine alone.

This article reports the case of Ms. G, who presented with probable serotonin syndrome associated with phentermine use and subsequently developed a rapid-onset, superimposed neuroleptic malignant syndrome (NMS). We hypothesize that phentermine use may increase NMS risk through adverse drug events and discuss potential pathophysiologic mechanisms and treatment implications.

Serotonin syndrome vs NMS

Serotonin syndrome is an infrequent and potentially life-threatening adverse drug reaction that presumably results from excess serotonin activity (Box 1).^7-10 NMS also is an infrequent and potentially life-threatening neurologic emergency (Box 2).^11-18 Similarities between disorders of increased serotonergic activity and disorders of low dopaminergic activity (Table 1) suggest both may result from an imbalance between the serotonergic and dopaminergic systems, which have reciprocal relationships in the CNS.¹⁹

Differentiating between serotonin syndrome and NMS is further complicated when both antipsychotics and serotonergic agents may be implicated.²⁰ Clinical trials are not feasible because NMS and serotonin syndrome rarely occur.

Box 1

Signs and symptoms of NMS vs serotonin syndrome

CASE CONTINUED: Fever follows haloperidol

Initial workup. Ms. G has no significant medical or psychiatric history. She has no history of seizures, head trauma, changes in mental status, recent travel, tick bites, or mosquito bites. Family history is relevant only for a maternal aunt with a history of 1 seizure. Ms. G is employed and lives with her husband and son. She is not taking other medications, herbal supplements, or vitamins and does not use tobacco, alcohol, caffeine, or illicit drugs.

On admission, she is somnolent and arousable only to painful stimuli. Temperature is 36.7°C, blood pressure 89/58 mm Hg, heart rate 73 bpm, and respirations 21/minute. She does not talk but is cooperative to physical examination, which is otherwise unremarkable.

Neurologic exam also is unremarkable, with no evidence of meningeal irritation, abnormal reflexes, or muscle tone. Serum ammonia (51 µmol/L; normal range 7 to 42 µmol/L) is slightly elevated. Liver function tests, electrolytes, blood urea nitrogen, creatinine, complete blood counts, urinalysis, urine culture, and blood cultures are unremarkable. Ethanol, salicylate, and acetaminophen levels are negative. Evaluation reveals a positive urine drug screen only for amphetamines, attributed to use of phentermine. Chest radiography and head CT are unremarkable.

Electroencephalography (EEG) 17 hours after admission reveals left anterior temporal spikes suggestive of seizure activity lasting 50 seconds. The patient is described as stuporous but arousable during EEG, and diffuse delta slow waves are superimposed on an alpha rhythm with intermittent diffuse delta bursts. Brain MRI is unremarkable.

Despite no clinical evidence of seizure, Ms. G is transferred to the cardiac telemetry ward to monitor for potential side effects from IV phenytoin loading, at which time (24 hours after admission) she is found to have intermittent sinus tachycardia ≤140 bpm.

Antipsychotic therapy. Thirty hours after admission—after phenytoin loading and normalized EEG—Ms. G shows periodic episodes of sudden startling, with repetitive leg shaking. Continuous ankle clonus is present bilaterally. She complains of severe paresthesias in her legs and is unable to urinate on her own.

NMS signs emerge. Forty-eight hours after admission, Ms. G becomes febrile (38.3°C) and shows tachycardia, with heart rate consistently >130 bpm. Her vital signs did not normalize before the fever developed. She remains somnolent and continues to have spastic lower leg and ankle clonus. She shows no seizure activity on video EEG monitoring during later episodes of repetitive leg shaking, approximately 60 hours after admission.

Ms. G receives empiric vancomycin, ceftriaxone, ampicillin, and acyclovir for possible infectious encephalitis, and lumbar puncture is done emergently. Further laboratory tests reveal creatine kinase (CK) elevation (17,282 U/L, from 270 on admission), leukocytosis (white blood cell count 16.1K/mm³, from 7.2K on admission), and elevated transaminases (AST 199 U/L, up from 21 on admission; ALT 84 U/L, up from 19 on admission).

She is transferred to the ICU with a preliminary diagnosis of NMS. Again, continuous EEG monitoring does not show seizure activity. CSF specimen is negative for infection (negative cultures, negative herpes simplex virus PCR, protein 31 mg/dl, glucose 75 mg/dl). She is started on dantrolene, bromocriptine, and levodopa but shows no initial improvement.

Intubation. On hospital day 8, the patient is intubated to protect her airway and placed in a pentobarbital coma for 2 days, with no improvement. On hospital day 9, cyproheptadine, 24 mg/d, is added for possible serotonin syndrome, and continued for 9 days.

On day 11, the addition of IV diazepam, 10 mg per hour, is followed by gradual improvement in rigidity. Ms. G remains on continuous EEG, with no evidence of seizure activity before diazepam was added or after it is tapered off by day 23.

Discharge. Ms. G is extubated on hospital day 18. On day 23 she can follow commands but is not fully oriented, and levodopa, phenytoin, bromocriptine, and dantrolene are tapered off. She is discharged to a rehabilitation facility, where she again requires phenytoin for a witnessed seizure, attributed to anticonvulsant withdrawal.

On follow-up phone interviews 4 and 18 months after hospitalization, Ms. G says she remains seizure-free without taking anticonvulsants. She reports a subjective, interval improvement in cognitive function, which has since returned to baseline.

Evidence for serotonin syndrome

This case involves a young woman with a several-week history of phentermine use for weight reduction who presented with confusion, sedation, mutism, and nausea. She was initially found to have an abnormal EEG, for which she was loaded with the anticonvulsant phenytoin. However, she continued to exhibit altered mental status, myoclonus, and hyperreflexia along with autonomic dysregulation—such as urinary retention and tachycardia—despite a negative EEG on continuous monitoring.

On retrospective review, we believe she likely was experiencing serotonin toxicity from phentermine. She later developed NMS within several hours of receiving the antipsychotic haloperidol.

Even though phentermine is thought to have a relatively weak serotonergic effect,³ it has been shown to markedly increase serotonin efflux in the rat hypothalamus (to a greater degree than the SSRI fluoxetine).²³ Although Ms. G did not report having consumed foods or supplements that could have interfered with phentermine’s metabolism, such use could have contributed to or prolonged a serotonin syndrome.²⁰ Phentermine misuse also cannot be ruled out.

Excess phentermine or concomitant use of other serotonergic agents may have precipitated serotonin syndrome. Ms. G’s hyperactivity a few days before she complained of fatigue and somnolence may represent:

• a sign of phentermine intoxication or overuse
  
• a harbinger of serotonin syndrome, because these symptoms were followed by overt serotonin syndrome signs such as confusion, disorientation, myoclonus, and autonomic dysfunction.
  

Evidence for NMS

Ms. G received haloperidol because her agitation obstructed urgent evaluation. After several doses, she rapidly developed signs and symptoms highly consistent with NMS. Onset was rapid compared with the typically described, more insidious NMS evolution of 24 to 72 hours, however.²⁵ Rapid NMS onset may have been precipitated in 2 ways:

• dopaminergic (phentermine) withdrawal combined with dopamine antagonist challenge (haloperidol)^25,26
  
• background serotonin syndrome caused by amphetamine (phentermine) predisposing the patient to develop NMS.²⁷
  

Treatment strategy

Because serotonin syndrome and NMS share many clinical findings, differentiating between the 2 syndromes may be difficult, especially when the patient’s medication history does not implicate a specific agent. A detailed history and physical may help distinguish the syndromes. Clonus may be particularly specific and is important in the diagnosis of serotonin syndrome.³² If you are unable to differentiate between serotonin syndrome and NMS in a patient with this acute neurotoxic abnormal behavior syndrome,³³ consider a common treatment strategy (Table 2).^19,25

In Ms. G’s case, she probably should not have received bromocriptine for NMS,²⁰ given the potential role of serotonin syndrome in precipitating her symptoms.

Case reports support our hypotheses of an increased predilection for NMS with dopaminergic withdrawal or serotonin syndrome. Growing evidence supports the use of chlorpromazine for serotonin syndrome,³⁴ but consider its use contraindicated in patients with NMS.

Table 2

Serotonin syndrome or NMS?
When in doubt, follow 4 management principles

• Carbone JR. The neuroleptic malignant and serotonin syndromes. Emerg Med Clin North Am 2000;18:317-25.
  
• Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol 1999;13:100-9.
  
• Neuroleptic Malignant Syndrome Information Service (NMSIS). www.nmsis.org. NMS hotline for medical professionals (toll-free 888-667-8367) handles calls on NMS, serotonin syndrome, heat stroke, malignant catatonia, and other drug-induced heat-related disorders.
  

• Acyclovir • Zovirax
  
• Ampicillin • various
  
• Bromocriptine • Parlodel
  
• Ceftriaxone • Rocephin
  
• Chlorpromazine • Thorazine
  
• Cyproheptadine • Periactin
  
• Dantrolene • Dantrium
  
• Diazepam • Valium
  
• Dextroamphetamine • Dexedrine
  
• Fluoxetine • Prozac
  
• Haloperidol • Haldol
  
• Levodopa • various
  
• Methysergide • Sansert
  
• Pentobarbital • Nembutal
  
• Phentermine • various
  
• Phenytoin • Dilantin
  
• Propranolol • Inderal
  
• Vancomycin • various
  

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

Ms. G, age 28, presents to a tertiary care hospital with altered mental status. Six weeks ago she started taking phentermine, 37.5 mg/d, to lose weight. Her body mass index is 24 kg/m² (normal range), and she obtained the stimulant agent via the Internet. Her family reports Ms. G was very busy in the past week, staying up until 2 AM cleaning. They say she also was irritable with her 5-year-old son.

Two days ago, Ms. G complained of fatigue and nausea without emesis. She went to bed early and did not awaken the next morning. Her sister found her in bed, minimally responsive to verbal stimuli, and brought her to the hospital.

Patients have used phentermine as a weight-reducing agent since the FDA approved this amphetamine-like compound in 1960.¹ Phentermine’s mechanism of action is thought to involve dopaminergic, noradrenergic, and serotonergic effects.² Stimulation of norepinephrine (NE) release is its most potent effect, followed by NE reuptake inhibition, stimulation of dopamine (DA) release, DA reuptake inhibition, stimulation of serotonin (5-HT) release, and 5-HT reuptake inhibition (weak).³

Because phentermine could in theory cause serotonin syndrome,⁴ its use is contraindicated with monoamine oxidase inhibitors (MAOIs) and not recommended with selective serotonin reuptake inhibitors (SSRIs).⁵ One case report describes an interaction between fluoxetine and phentermine that appears consistent with serotonin syndrome.⁶ We are aware of no case reports of serotonin syndrome caused by phentermine alone.

This article reports the case of Ms. G, who presented with probable serotonin syndrome associated with phentermine use and subsequently developed a rapid-onset, superimposed neuroleptic malignant syndrome (NMS). We hypothesize that phentermine use may increase NMS risk through adverse drug events and discuss potential pathophysiologic mechanisms and treatment implications.

Serotonin syndrome vs NMS

Serotonin syndrome is an infrequent and potentially life-threatening adverse drug reaction that presumably results from excess serotonin activity (Box 1).^7-10 NMS also is an infrequent and potentially life-threatening neurologic emergency (Box 2).^11-18 Similarities between disorders of increased serotonergic activity and disorders of low dopaminergic activity (Table 1) suggest both may result from an imbalance between the serotonergic and dopaminergic systems, which have reciprocal relationships in the CNS.¹⁹

Differentiating between serotonin syndrome and NMS is further complicated when both antipsychotics and serotonergic agents may be implicated.²⁰ Clinical trials are not feasible because NMS and serotonin syndrome rarely occur.

Box 1

Signs and symptoms of NMS vs serotonin syndrome

CASE CONTINUED: Fever follows haloperidol

Initial workup. Ms. G has no significant medical or psychiatric history. She has no history of seizures, head trauma, changes in mental status, recent travel, tick bites, or mosquito bites. Family history is relevant only for a maternal aunt with a history of 1 seizure. Ms. G is employed and lives with her husband and son. She is not taking other medications, herbal supplements, or vitamins and does not use tobacco, alcohol, caffeine, or illicit drugs.

On admission, she is somnolent and arousable only to painful stimuli. Temperature is 36.7°C, blood pressure 89/58 mm Hg, heart rate 73 bpm, and respirations 21/minute. She does not talk but is cooperative to physical examination, which is otherwise unremarkable.

Neurologic exam also is unremarkable, with no evidence of meningeal irritation, abnormal reflexes, or muscle tone. Serum ammonia (51 µmol/L; normal range 7 to 42 µmol/L) is slightly elevated. Liver function tests, electrolytes, blood urea nitrogen, creatinine, complete blood counts, urinalysis, urine culture, and blood cultures are unremarkable. Ethanol, salicylate, and acetaminophen levels are negative. Evaluation reveals a positive urine drug screen only for amphetamines, attributed to use of phentermine. Chest radiography and head CT are unremarkable.

Electroencephalography (EEG) 17 hours after admission reveals left anterior temporal spikes suggestive of seizure activity lasting 50 seconds. The patient is described as stuporous but arousable during EEG, and diffuse delta slow waves are superimposed on an alpha rhythm with intermittent diffuse delta bursts. Brain MRI is unremarkable.

Despite no clinical evidence of seizure, Ms. G is transferred to the cardiac telemetry ward to monitor for potential side effects from IV phenytoin loading, at which time (24 hours after admission) she is found to have intermittent sinus tachycardia ≤140 bpm.

Antipsychotic therapy. Thirty hours after admission—after phenytoin loading and normalized EEG—Ms. G shows periodic episodes of sudden startling, with repetitive leg shaking. Continuous ankle clonus is present bilaterally. She complains of severe paresthesias in her legs and is unable to urinate on her own.

NMS signs emerge. Forty-eight hours after admission, Ms. G becomes febrile (38.3°C) and shows tachycardia, with heart rate consistently >130 bpm. Her vital signs did not normalize before the fever developed. She remains somnolent and continues to have spastic lower leg and ankle clonus. She shows no seizure activity on video EEG monitoring during later episodes of repetitive leg shaking, approximately 60 hours after admission.

Ms. G receives empiric vancomycin, ceftriaxone, ampicillin, and acyclovir for possible infectious encephalitis, and lumbar puncture is done emergently. Further laboratory tests reveal creatine kinase (CK) elevation (17,282 U/L, from 270 on admission), leukocytosis (white blood cell count 16.1K/mm³, from 7.2K on admission), and elevated transaminases (AST 199 U/L, up from 21 on admission; ALT 84 U/L, up from 19 on admission).

She is transferred to the ICU with a preliminary diagnosis of NMS. Again, continuous EEG monitoring does not show seizure activity. CSF specimen is negative for infection (negative cultures, negative herpes simplex virus PCR, protein 31 mg/dl, glucose 75 mg/dl). She is started on dantrolene, bromocriptine, and levodopa but shows no initial improvement.

Intubation. On hospital day 8, the patient is intubated to protect her airway and placed in a pentobarbital coma for 2 days, with no improvement. On hospital day 9, cyproheptadine, 24 mg/d, is added for possible serotonin syndrome, and continued for 9 days.

On day 11, the addition of IV diazepam, 10 mg per hour, is followed by gradual improvement in rigidity. Ms. G remains on continuous EEG, with no evidence of seizure activity before diazepam was added or after it is tapered off by day 23.

Discharge. Ms. G is extubated on hospital day 18. On day 23 she can follow commands but is not fully oriented, and levodopa, phenytoin, bromocriptine, and dantrolene are tapered off. She is discharged to a rehabilitation facility, where she again requires phenytoin for a witnessed seizure, attributed to anticonvulsant withdrawal.

On follow-up phone interviews 4 and 18 months after hospitalization, Ms. G says she remains seizure-free without taking anticonvulsants. She reports a subjective, interval improvement in cognitive function, which has since returned to baseline.

Evidence for serotonin syndrome

This case involves a young woman with a several-week history of phentermine use for weight reduction who presented with confusion, sedation, mutism, and nausea. She was initially found to have an abnormal EEG, for which she was loaded with the anticonvulsant phenytoin. However, she continued to exhibit altered mental status, myoclonus, and hyperreflexia along with autonomic dysregulation—such as urinary retention and tachycardia—despite a negative EEG on continuous monitoring.

On retrospective review, we believe she likely was experiencing serotonin toxicity from phentermine. She later developed NMS within several hours of receiving the antipsychotic haloperidol.

Even though phentermine is thought to have a relatively weak serotonergic effect,³ it has been shown to markedly increase serotonin efflux in the rat hypothalamus (to a greater degree than the SSRI fluoxetine).²³ Although Ms. G did not report having consumed foods or supplements that could have interfered with phentermine’s metabolism, such use could have contributed to or prolonged a serotonin syndrome.²⁰ Phentermine misuse also cannot be ruled out.

Excess phentermine or concomitant use of other serotonergic agents may have precipitated serotonin syndrome. Ms. G’s hyperactivity a few days before she complained of fatigue and somnolence may represent:

• a sign of phentermine intoxication or overuse
  
• a harbinger of serotonin syndrome, because these symptoms were followed by overt serotonin syndrome signs such as confusion, disorientation, myoclonus, and autonomic dysfunction.
  

Evidence for NMS

Ms. G received haloperidol because her agitation obstructed urgent evaluation. After several doses, she rapidly developed signs and symptoms highly consistent with NMS. Onset was rapid compared with the typically described, more insidious NMS evolution of 24 to 72 hours, however.²⁵ Rapid NMS onset may have been precipitated in 2 ways:

• dopaminergic (phentermine) withdrawal combined with dopamine antagonist challenge (haloperidol)^25,26
  
• background serotonin syndrome caused by amphetamine (phentermine) predisposing the patient to develop NMS.²⁷
  

Treatment strategy

Because serotonin syndrome and NMS share many clinical findings, differentiating between the 2 syndromes may be difficult, especially when the patient’s medication history does not implicate a specific agent. A detailed history and physical may help distinguish the syndromes. Clonus may be particularly specific and is important in the diagnosis of serotonin syndrome.³² If you are unable to differentiate between serotonin syndrome and NMS in a patient with this acute neurotoxic abnormal behavior syndrome,³³ consider a common treatment strategy (Table 2).^19,25

In Ms. G’s case, she probably should not have received bromocriptine for NMS,²⁰ given the potential role of serotonin syndrome in precipitating her symptoms.

Case reports support our hypotheses of an increased predilection for NMS with dopaminergic withdrawal or serotonin syndrome. Growing evidence supports the use of chlorpromazine for serotonin syndrome,³⁴ but consider its use contraindicated in patients with NMS.

Table 2

Serotonin syndrome or NMS?
When in doubt, follow 4 management principles

• Carbone JR. The neuroleptic malignant and serotonin syndromes. Emerg Med Clin North Am 2000;18:317-25.
  
• Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol 1999;13:100-9.
  
• Neuroleptic Malignant Syndrome Information Service (NMSIS). www.nmsis.org. NMS hotline for medical professionals (toll-free 888-667-8367) handles calls on NMS, serotonin syndrome, heat stroke, malignant catatonia, and other drug-induced heat-related disorders.
  

• Acyclovir • Zovirax
  
• Ampicillin • various
  
• Bromocriptine • Parlodel
  
• Ceftriaxone • Rocephin
  
• Chlorpromazine • Thorazine
  
• Cyproheptadine • Periactin
  
• Dantrolene • Dantrium
  
• Diazepam • Valium
  
• Dextroamphetamine • Dexedrine
  
• Fluoxetine • Prozac
  
• Haloperidol • Haldol
  
• Levodopa • various
  
• Methysergide • Sansert
  
• Pentobarbital • Nembutal
  
• Phentermine • various
  
• Phenytoin • Dilantin
  
• Propranolol • Inderal
  
• Vancomycin • various
  

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

Ms. G, age 28, presents to a tertiary care hospital with altered mental status. Six weeks ago she started taking phentermine, 37.5 mg/d, to lose weight. Her body mass index is 24 kg/m² (normal range), and she obtained the stimulant agent via the Internet. Her family reports Ms. G was very busy in the past week, staying up until 2 AM cleaning. They say she also was irritable with her 5-year-old son.

Two days ago, Ms. G complained of fatigue and nausea without emesis. She went to bed early and did not awaken the next morning. Her sister found her in bed, minimally responsive to verbal stimuli, and brought her to the hospital.

Patients have used phentermine as a weight-reducing agent since the FDA approved this amphetamine-like compound in 1960.¹ Phentermine’s mechanism of action is thought to involve dopaminergic, noradrenergic, and serotonergic effects.² Stimulation of norepinephrine (NE) release is its most potent effect, followed by NE reuptake inhibition, stimulation of dopamine (DA) release, DA reuptake inhibition, stimulation of serotonin (5-HT) release, and 5-HT reuptake inhibition (weak).³

Because phentermine could in theory cause serotonin syndrome,⁴ its use is contraindicated with monoamine oxidase inhibitors (MAOIs) and not recommended with selective serotonin reuptake inhibitors (SSRIs).⁵ One case report describes an interaction between fluoxetine and phentermine that appears consistent with serotonin syndrome.⁶ We are aware of no case reports of serotonin syndrome caused by phentermine alone.

This article reports the case of Ms. G, who presented with probable serotonin syndrome associated with phentermine use and subsequently developed a rapid-onset, superimposed neuroleptic malignant syndrome (NMS). We hypothesize that phentermine use may increase NMS risk through adverse drug events and discuss potential pathophysiologic mechanisms and treatment implications.

Serotonin syndrome vs NMS

Serotonin syndrome is an infrequent and potentially life-threatening adverse drug reaction that presumably results from excess serotonin activity (Box 1).^7-10 NMS also is an infrequent and potentially life-threatening neurologic emergency (Box 2).^11-18 Similarities between disorders of increased serotonergic activity and disorders of low dopaminergic activity (Table 1) suggest both may result from an imbalance between the serotonergic and dopaminergic systems, which have reciprocal relationships in the CNS.¹⁹

Differentiating between serotonin syndrome and NMS is further complicated when both antipsychotics and serotonergic agents may be implicated.²⁰ Clinical trials are not feasible because NMS and serotonin syndrome rarely occur.

Box 1

Signs and symptoms of NMS vs serotonin syndrome

CASE CONTINUED: Fever follows haloperidol

Initial workup. Ms. G has no significant medical or psychiatric history. She has no history of seizures, head trauma, changes in mental status, recent travel, tick bites, or mosquito bites. Family history is relevant only for a maternal aunt with a history of 1 seizure. Ms. G is employed and lives with her husband and son. She is not taking other medications, herbal supplements, or vitamins and does not use tobacco, alcohol, caffeine, or illicit drugs.

On admission, she is somnolent and arousable only to painful stimuli. Temperature is 36.7°C, blood pressure 89/58 mm Hg, heart rate 73 bpm, and respirations 21/minute. She does not talk but is cooperative to physical examination, which is otherwise unremarkable.

Neurologic exam also is unremarkable, with no evidence of meningeal irritation, abnormal reflexes, or muscle tone. Serum ammonia (51 µmol/L; normal range 7 to 42 µmol/L) is slightly elevated. Liver function tests, electrolytes, blood urea nitrogen, creatinine, complete blood counts, urinalysis, urine culture, and blood cultures are unremarkable. Ethanol, salicylate, and acetaminophen levels are negative. Evaluation reveals a positive urine drug screen only for amphetamines, attributed to use of phentermine. Chest radiography and head CT are unremarkable.

Electroencephalography (EEG) 17 hours after admission reveals left anterior temporal spikes suggestive of seizure activity lasting 50 seconds. The patient is described as stuporous but arousable during EEG, and diffuse delta slow waves are superimposed on an alpha rhythm with intermittent diffuse delta bursts. Brain MRI is unremarkable.

Despite no clinical evidence of seizure, Ms. G is transferred to the cardiac telemetry ward to monitor for potential side effects from IV phenytoin loading, at which time (24 hours after admission) she is found to have intermittent sinus tachycardia ≤140 bpm.

Antipsychotic therapy. Thirty hours after admission—after phenytoin loading and normalized EEG—Ms. G shows periodic episodes of sudden startling, with repetitive leg shaking. Continuous ankle clonus is present bilaterally. She complains of severe paresthesias in her legs and is unable to urinate on her own.

NMS signs emerge. Forty-eight hours after admission, Ms. G becomes febrile (38.3°C) and shows tachycardia, with heart rate consistently >130 bpm. Her vital signs did not normalize before the fever developed. She remains somnolent and continues to have spastic lower leg and ankle clonus. She shows no seizure activity on video EEG monitoring during later episodes of repetitive leg shaking, approximately 60 hours after admission.

Ms. G receives empiric vancomycin, ceftriaxone, ampicillin, and acyclovir for possible infectious encephalitis, and lumbar puncture is done emergently. Further laboratory tests reveal creatine kinase (CK) elevation (17,282 U/L, from 270 on admission), leukocytosis (white blood cell count 16.1K/mm³, from 7.2K on admission), and elevated transaminases (AST 199 U/L, up from 21 on admission; ALT 84 U/L, up from 19 on admission).

She is transferred to the ICU with a preliminary diagnosis of NMS. Again, continuous EEG monitoring does not show seizure activity. CSF specimen is negative for infection (negative cultures, negative herpes simplex virus PCR, protein 31 mg/dl, glucose 75 mg/dl). She is started on dantrolene, bromocriptine, and levodopa but shows no initial improvement.

Intubation. On hospital day 8, the patient is intubated to protect her airway and placed in a pentobarbital coma for 2 days, with no improvement. On hospital day 9, cyproheptadine, 24 mg/d, is added for possible serotonin syndrome, and continued for 9 days.

On day 11, the addition of IV diazepam, 10 mg per hour, is followed by gradual improvement in rigidity. Ms. G remains on continuous EEG, with no evidence of seizure activity before diazepam was added or after it is tapered off by day 23.

Discharge. Ms. G is extubated on hospital day 18. On day 23 she can follow commands but is not fully oriented, and levodopa, phenytoin, bromocriptine, and dantrolene are tapered off. She is discharged to a rehabilitation facility, where she again requires phenytoin for a witnessed seizure, attributed to anticonvulsant withdrawal.

On follow-up phone interviews 4 and 18 months after hospitalization, Ms. G says she remains seizure-free without taking anticonvulsants. She reports a subjective, interval improvement in cognitive function, which has since returned to baseline.

Evidence for serotonin syndrome

This case involves a young woman with a several-week history of phentermine use for weight reduction who presented with confusion, sedation, mutism, and nausea. She was initially found to have an abnormal EEG, for which she was loaded with the anticonvulsant phenytoin. However, she continued to exhibit altered mental status, myoclonus, and hyperreflexia along with autonomic dysregulation—such as urinary retention and tachycardia—despite a negative EEG on continuous monitoring.

On retrospective review, we believe she likely was experiencing serotonin toxicity from phentermine. She later developed NMS within several hours of receiving the antipsychotic haloperidol.

Even though phentermine is thought to have a relatively weak serotonergic effect,³ it has been shown to markedly increase serotonin efflux in the rat hypothalamus (to a greater degree than the SSRI fluoxetine).²³ Although Ms. G did not report having consumed foods or supplements that could have interfered with phentermine’s metabolism, such use could have contributed to or prolonged a serotonin syndrome.²⁰ Phentermine misuse also cannot be ruled out.

Excess phentermine or concomitant use of other serotonergic agents may have precipitated serotonin syndrome. Ms. G’s hyperactivity a few days before she complained of fatigue and somnolence may represent:

• a sign of phentermine intoxication or overuse
  
• a harbinger of serotonin syndrome, because these symptoms were followed by overt serotonin syndrome signs such as confusion, disorientation, myoclonus, and autonomic dysfunction.
  

Evidence for NMS

Ms. G received haloperidol because her agitation obstructed urgent evaluation. After several doses, she rapidly developed signs and symptoms highly consistent with NMS. Onset was rapid compared with the typically described, more insidious NMS evolution of 24 to 72 hours, however.²⁵ Rapid NMS onset may have been precipitated in 2 ways:

• dopaminergic (phentermine) withdrawal combined with dopamine antagonist challenge (haloperidol)^25,26
  
• background serotonin syndrome caused by amphetamine (phentermine) predisposing the patient to develop NMS.²⁷
  

Treatment strategy

Because serotonin syndrome and NMS share many clinical findings, differentiating between the 2 syndromes may be difficult, especially when the patient’s medication history does not implicate a specific agent. A detailed history and physical may help distinguish the syndromes. Clonus may be particularly specific and is important in the diagnosis of serotonin syndrome.³² If you are unable to differentiate between serotonin syndrome and NMS in a patient with this acute neurotoxic abnormal behavior syndrome,³³ consider a common treatment strategy (Table 2).^19,25

In Ms. G’s case, she probably should not have received bromocriptine for NMS,²⁰ given the potential role of serotonin syndrome in precipitating her symptoms.

Case reports support our hypotheses of an increased predilection for NMS with dopaminergic withdrawal or serotonin syndrome. Growing evidence supports the use of chlorpromazine for serotonin syndrome,³⁴ but consider its use contraindicated in patients with NMS.

Table 2

Serotonin syndrome or NMS?
When in doubt, follow 4 management principles

• Carbone JR. The neuroleptic malignant and serotonin syndromes. Emerg Med Clin North Am 2000;18:317-25.
  
• Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol 1999;13:100-9.
  
• Neuroleptic Malignant Syndrome Information Service (NMSIS). www.nmsis.org. NMS hotline for medical professionals (toll-free 888-667-8367) handles calls on NMS, serotonin syndrome, heat stroke, malignant catatonia, and other drug-induced heat-related disorders.
  

• Acyclovir • Zovirax
  
• Ampicillin • various
  
• Bromocriptine • Parlodel
  
• Ceftriaxone • Rocephin
  
• Chlorpromazine • Thorazine
  
• Cyproheptadine • Periactin
  
• Dantrolene • Dantrium
  
• Diazepam • Valium
  
• Dextroamphetamine • Dexedrine
  
• Fluoxetine • Prozac
  
• Haloperidol • Haldol
  
• Levodopa • various
  
• Methysergide • Sansert
  
• Pentobarbital • Nembutal
  
• Phentermine • various
  
• Phenytoin • Dilantin
  
• Propranolol • Inderal
  
• Vancomycin • various
  

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

In a perfect world, every treatment decision would fall under the protective umbrella of evidence-based medicine. The reality is that up to 30% of schizophrenia patients respond poorly to antipsychotic monotherapy,¹ and addressing their chronic debilitating illness requires clinicians to step outside the realm of evidence.

This does not have to be a blind step, however. Guided by logic, you can apply knowledge of receptor binding profiles, adverse effects, and kinetic considerations when choosing antipsychotic polypharmacy. This article offers evidence to answer 2 questions:

• What clinical evidence and/or pharmacologic rationale support using >1 antipsychotic?
  
• When might it be appropriate to use 2 antipsychotics in patients with treatment-resistant psychosis?
  

Antipsychotic polypharmacy defined

“Polypharmacy” can carry a negative connotation, but not all forms are bad. In some circumstances, antipsychotic polypharmacy may be necessary to provide optimum benefit and prevent harm to the patient and/or staff.

Short-term polypharmacy often occurs when switching patients from 1 antipsychotic to another. This “crossover phase” is justified to provide a smooth transition between the 2 agents, as abrupt antipsychotic discontinuation may cause a rebound worsening of psychosis. Other short-term antipsychotic polypharmacy strategies may be necessary in inpatient settings, particularly for a patient who is acutely psychotic or aggressive.

The use of a first-generation antipsychotic (FGA) to lead in a second-generation antipsychotic (SGA) is a justifiable treatment strategy. In addition, sedative antipsychotics such as quetiapine often are used during initial treatment of acutely ill patients and subsequently withdrawn.

Box

Experience-based treatment?

Antipsychotic polypharmacy is prevalent (reported in up to 25% of outpatients and 50% of inpatients with schizophrenia),^2-7 costly for patients and insurers,⁸ and likely to be associated with increased risk of adverse effects and drug-drug interactions. Despite what is known, a wide gap exists between the science and clinical practice of combination antipsychotic therapy in schizophrenia (Table 1).

Clinical trials. The efficacy and safety of antipsychotic combinations in schizophrenia (with options including FGA + FGA, FGA + SGA, and SGA + SGA) has not been studied adequately in well-controlled, systematic trials. Four short-term—6 to 26 weeks—randomized, double-blind, controlled studies^9-12 have examined antipsychotic polypharmacy (clozapine + risperidone) in patients with schizophrenia:

• In 3 studies,^9,11,12 adding risperidone to clozapine did not significantly improve positive or negative symptoms.
  
• In all 4 studies, clozapine + risperidone was associated with increased sedation, akathisia, hyperprolactinemia, and elevated fasting blood glucose.
  

Mortality risk? Two independent, longitudinal cohort studies have found antipsychotic polypharmacy to be a statistically significant predictor of reduced survival.^21,22 Although these studies have identified a possible association, additional research is required to determine whether increased mortality in schizophrenia is attributable to the disorder, comorbid medical conditions, antipsychotic medications, or a complex interaction of factors.

Treatment guidelines—such as the Texas Medication Algorithm Project’s updated treatment algorithm for schizophrenia²³—reflect the paucity of controlled studies of antipsychotic combinations. The expert consensus panel that developed the TMAP algorithm recommends clozapine augmentation with an FGA or SGA, or electroconvulsive therapy after adequate trials of antipsychotic monotherapy, including clozapine. The panel recommends reserving other antipsychotic combinations as a last-line strategy (see Related Resources).

Table 1

Take-home points about antipsychotic polypharmacy

‘Sensible’ pharmacology

Despite the lack of supporting evidence, many clinicians apparently are using antipsychotic polypharmacy for schizophrenia patients with treatment-resistant psychosis. Moreover, reports that up to one-fourth of outpatients and one-half of inpatients may receive antipsychotic polypharmacy^2-7 suggest that this approach is not being reserved for treatment-resistant psychosis. Rather, it is being used in non-treatment-refractory schizophrenia patients as well—a practice Stahl labeled a “dirty little secret.”²⁴

Before you consider using antipsychotic polypharmacy for a schizophrenia patient, we suggest that you answer a series of questions to rationalize your decision (Table 2). These questions seem intuitive, but they represent appropriate clinical practice and may support the use of multiple antipsychotics in selected patients.

Which combination? If you determine that a patient is an appropriate candidate for antipsychotic polypharmacy, think about the pharmacologic profiles of available agents. Administering 2 antipsychotics may augment pharmacologic activity, provide an additive effect, or worsen your patient’s symptoms.

Although data from well-controlled studies of clozapine + risperidone do not support its efficacy,^9-12 this combination is rational from a pharmacologic perspective. Clozapine shows a lower D2 receptor occupancy (16% to 68%) than that of risperidone (63% to 89%),²⁵ so risperidone’s additional D2 receptor occupancy may enhance a patient’s response to clozapine. Table 3 lists other potentially “sensible” antipsychoticantipsychotic combinations.

Table 2

Questions to consider before initiating antipsychotic polypharmacy

Theoretically beneficial antipsychotic combinations

Safety/tolerability

Reduced dosages. Combining antipsychotics may allow you to increase treatment efficacy and improve patient tolerability. Lower dosages of 2 antipsychotics may cause fewer side effects than a high dosage of 1 antipsychotic.

For example, case reports and retrospective studies^26,27 suggest that adding aripiprazole to clozapine may improve antipsychotic efficacy and reduce metabolic adverse events in treatment-resistant patients. In these cases, clozapine dosages were lower than those usually used in patients with schizophrenia.

Metabolic effects. Carefully weigh the propensity of some antipsychotics to induce weight gain, hyperlipidemia, or glucose dysregulation if you plan to use these agents as part of a polypharmacy regimen. Among SGAs, clozapine and olanzapine are associated with the highest risks of metabolic adverse effects, followed by quetiapine and risperidone. Aripiprazole and ziprasidone are less likely than other SGAs to cause these effects.²⁸

A recent study found a higher incidence of metabolic syndrome in patients receiving antipsychotic polypharmacy. The increased incidence was linked to demographics and clinical risk factors, however, and was not independently associated with the use of multiple antipsychotics.²⁹

Because evidence is scarce and inconclusive, the risk of metabolic adverse events is unknown when antipsychotics are combined. Exercise caution when combining antipsychotics—particularly those known to cause adverse metabolic effects—in case the risk is additive.

Tardive dyskinesia (TD). SGAs are associated with a lower incidence of TD compared with FGAs, but adding an FGA to an SGA may increase the patient’s TD risk.³⁰ Also assess patients regularly (as often as weekly during acute treatment and every 6 to 12 months during maintenance treatment)³¹ for extrapyramidal symptoms, including akathisia. Administer appropriate rating scales (such as the Abnormal Involuntary Movements Scale [AIMS], Barnes Akathisia Rating Scale [BARS], or Simpson-Angus Rating Scale [SARS]), and treat these adverse events as clinically indicated.

Other adverse effects. The concurrent use of 2 antipsychotics may amplify side effects that are generally considered mild, such as sedation. For example, risperidone and ziprasidone are considered to cause low to moderate sedation. This combination may result in an additive sedative effect that could negatively impact the patient’s psychosocial functioning.

Anticholinergic effects may also be potentiated, especially if a particular combination of antipsychotics warrants anticholinergic medication use for extrapyramidal symptoms.

Related resources

• Texas Medication Algorithm Project (TMAP). Schizophrenia antipsychotic treatment algorithm. www.dshs.state.tx.us/mhprograms/TIMA.shtm.
  
• Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, 2nd ed. Am J Psychiatry 2004;161(suppl):1-56.
  

• Aripiprazole • Abilify
  
• Clozapine • Clozaril
  
• Haloperidol • Haldol
  
• Lamotrigine • Lamictal
  
• Loxapine • Loxitane
  
• Olanzapine • Zyprexa
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Valproic acid • Depakene
  
• Ziprasidone • Geodon
  

Dr. Gibson reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. He receives research support from the PhRMA Foundation.

Dr. Patel receives grant support from Takeda Pharmaceuticals and is a consultant for Eli Lilly and Company and Shire Pharmaceuticals.

Dr. Lauriello receives grant support from Eli Lilly and Company and serves as a consultant to Eli Lilly and Company and Vanda Pharmaceuticals.

Dr. Buckley receives grant support from AstraZeneca, National Institute of Mental Health, Pfizer Inc., Solvay, and Wyeth and is a consultant for AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Janssen Pharmaceutica, Lundbeck, Pfizer Inc., Solvay, and Wyeth. He receives honoraria from Bristol Myers-Squibb, Janssen Pharmaceutica, Lundbeck, and Pfizer Inc.

In a perfect world, every treatment decision would fall under the protective umbrella of evidence-based medicine. The reality is that up to 30% of schizophrenia patients respond poorly to antipsychotic monotherapy,¹ and addressing their chronic debilitating illness requires clinicians to step outside the realm of evidence.

This does not have to be a blind step, however. Guided by logic, you can apply knowledge of receptor binding profiles, adverse effects, and kinetic considerations when choosing antipsychotic polypharmacy. This article offers evidence to answer 2 questions:

• What clinical evidence and/or pharmacologic rationale support using >1 antipsychotic?
  
• When might it be appropriate to use 2 antipsychotics in patients with treatment-resistant psychosis?
  

Antipsychotic polypharmacy defined

“Polypharmacy” can carry a negative connotation, but not all forms are bad. In some circumstances, antipsychotic polypharmacy may be necessary to provide optimum benefit and prevent harm to the patient and/or staff.

Short-term polypharmacy often occurs when switching patients from 1 antipsychotic to another. This “crossover phase” is justified to provide a smooth transition between the 2 agents, as abrupt antipsychotic discontinuation may cause a rebound worsening of psychosis. Other short-term antipsychotic polypharmacy strategies may be necessary in inpatient settings, particularly for a patient who is acutely psychotic or aggressive.

The use of a first-generation antipsychotic (FGA) to lead in a second-generation antipsychotic (SGA) is a justifiable treatment strategy. In addition, sedative antipsychotics such as quetiapine often are used during initial treatment of acutely ill patients and subsequently withdrawn.

Box

Experience-based treatment?

Antipsychotic polypharmacy is prevalent (reported in up to 25% of outpatients and 50% of inpatients with schizophrenia),^2-7 costly for patients and insurers,⁸ and likely to be associated with increased risk of adverse effects and drug-drug interactions. Despite what is known, a wide gap exists between the science and clinical practice of combination antipsychotic therapy in schizophrenia (Table 1).

Clinical trials. The efficacy and safety of antipsychotic combinations in schizophrenia (with options including FGA + FGA, FGA + SGA, and SGA + SGA) has not been studied adequately in well-controlled, systematic trials. Four short-term—6 to 26 weeks—randomized, double-blind, controlled studies^9-12 have examined antipsychotic polypharmacy (clozapine + risperidone) in patients with schizophrenia:

• In 3 studies,^9,11,12 adding risperidone to clozapine did not significantly improve positive or negative symptoms.
  
• In all 4 studies, clozapine + risperidone was associated with increased sedation, akathisia, hyperprolactinemia, and elevated fasting blood glucose.
  

Mortality risk? Two independent, longitudinal cohort studies have found antipsychotic polypharmacy to be a statistically significant predictor of reduced survival.^21,22 Although these studies have identified a possible association, additional research is required to determine whether increased mortality in schizophrenia is attributable to the disorder, comorbid medical conditions, antipsychotic medications, or a complex interaction of factors.

Treatment guidelines—such as the Texas Medication Algorithm Project’s updated treatment algorithm for schizophrenia²³—reflect the paucity of controlled studies of antipsychotic combinations. The expert consensus panel that developed the TMAP algorithm recommends clozapine augmentation with an FGA or SGA, or electroconvulsive therapy after adequate trials of antipsychotic monotherapy, including clozapine. The panel recommends reserving other antipsychotic combinations as a last-line strategy (see Related Resources).

Table 1

Take-home points about antipsychotic polypharmacy

‘Sensible’ pharmacology

Despite the lack of supporting evidence, many clinicians apparently are using antipsychotic polypharmacy for schizophrenia patients with treatment-resistant psychosis. Moreover, reports that up to one-fourth of outpatients and one-half of inpatients may receive antipsychotic polypharmacy^2-7 suggest that this approach is not being reserved for treatment-resistant psychosis. Rather, it is being used in non-treatment-refractory schizophrenia patients as well—a practice Stahl labeled a “dirty little secret.”²⁴

Before you consider using antipsychotic polypharmacy for a schizophrenia patient, we suggest that you answer a series of questions to rationalize your decision (Table 2). These questions seem intuitive, but they represent appropriate clinical practice and may support the use of multiple antipsychotics in selected patients.

Which combination? If you determine that a patient is an appropriate candidate for antipsychotic polypharmacy, think about the pharmacologic profiles of available agents. Administering 2 antipsychotics may augment pharmacologic activity, provide an additive effect, or worsen your patient’s symptoms.

Although data from well-controlled studies of clozapine + risperidone do not support its efficacy,^9-12 this combination is rational from a pharmacologic perspective. Clozapine shows a lower D2 receptor occupancy (16% to 68%) than that of risperidone (63% to 89%),²⁵ so risperidone’s additional D2 receptor occupancy may enhance a patient’s response to clozapine. Table 3 lists other potentially “sensible” antipsychoticantipsychotic combinations.

Table 2

Questions to consider before initiating antipsychotic polypharmacy

Theoretically beneficial antipsychotic combinations

Safety/tolerability

Reduced dosages. Combining antipsychotics may allow you to increase treatment efficacy and improve patient tolerability. Lower dosages of 2 antipsychotics may cause fewer side effects than a high dosage of 1 antipsychotic.

For example, case reports and retrospective studies^26,27 suggest that adding aripiprazole to clozapine may improve antipsychotic efficacy and reduce metabolic adverse events in treatment-resistant patients. In these cases, clozapine dosages were lower than those usually used in patients with schizophrenia.

Metabolic effects. Carefully weigh the propensity of some antipsychotics to induce weight gain, hyperlipidemia, or glucose dysregulation if you plan to use these agents as part of a polypharmacy regimen. Among SGAs, clozapine and olanzapine are associated with the highest risks of metabolic adverse effects, followed by quetiapine and risperidone. Aripiprazole and ziprasidone are less likely than other SGAs to cause these effects.²⁸

A recent study found a higher incidence of metabolic syndrome in patients receiving antipsychotic polypharmacy. The increased incidence was linked to demographics and clinical risk factors, however, and was not independently associated with the use of multiple antipsychotics.²⁹

Because evidence is scarce and inconclusive, the risk of metabolic adverse events is unknown when antipsychotics are combined. Exercise caution when combining antipsychotics—particularly those known to cause adverse metabolic effects—in case the risk is additive.

Tardive dyskinesia (TD). SGAs are associated with a lower incidence of TD compared with FGAs, but adding an FGA to an SGA may increase the patient’s TD risk.³⁰ Also assess patients regularly (as often as weekly during acute treatment and every 6 to 12 months during maintenance treatment)³¹ for extrapyramidal symptoms, including akathisia. Administer appropriate rating scales (such as the Abnormal Involuntary Movements Scale [AIMS], Barnes Akathisia Rating Scale [BARS], or Simpson-Angus Rating Scale [SARS]), and treat these adverse events as clinically indicated.

Other adverse effects. The concurrent use of 2 antipsychotics may amplify side effects that are generally considered mild, such as sedation. For example, risperidone and ziprasidone are considered to cause low to moderate sedation. This combination may result in an additive sedative effect that could negatively impact the patient’s psychosocial functioning.

Anticholinergic effects may also be potentiated, especially if a particular combination of antipsychotics warrants anticholinergic medication use for extrapyramidal symptoms.

Related resources

• Texas Medication Algorithm Project (TMAP). Schizophrenia antipsychotic treatment algorithm. www.dshs.state.tx.us/mhprograms/TIMA.shtm.
  
• Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, 2nd ed. Am J Psychiatry 2004;161(suppl):1-56.
  

• Aripiprazole • Abilify
  
• Clozapine • Clozaril
  
• Haloperidol • Haldol
  
• Lamotrigine • Lamictal
  
• Loxapine • Loxitane
  
• Olanzapine • Zyprexa
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Valproic acid • Depakene
  
• Ziprasidone • Geodon
  

Dr. Gibson reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. He receives research support from the PhRMA Foundation.

Dr. Patel receives grant support from Takeda Pharmaceuticals and is a consultant for Eli Lilly and Company and Shire Pharmaceuticals.

Dr. Lauriello receives grant support from Eli Lilly and Company and serves as a consultant to Eli Lilly and Company and Vanda Pharmaceuticals.

Dr. Buckley receives grant support from AstraZeneca, National Institute of Mental Health, Pfizer Inc., Solvay, and Wyeth and is a consultant for AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Janssen Pharmaceutica, Lundbeck, Pfizer Inc., Solvay, and Wyeth. He receives honoraria from Bristol Myers-Squibb, Janssen Pharmaceutica, Lundbeck, and Pfizer Inc.

In a perfect world, every treatment decision would fall under the protective umbrella of evidence-based medicine. The reality is that up to 30% of schizophrenia patients respond poorly to antipsychotic monotherapy,¹ and addressing their chronic debilitating illness requires clinicians to step outside the realm of evidence.

This does not have to be a blind step, however. Guided by logic, you can apply knowledge of receptor binding profiles, adverse effects, and kinetic considerations when choosing antipsychotic polypharmacy. This article offers evidence to answer 2 questions:

• What clinical evidence and/or pharmacologic rationale support using >1 antipsychotic?
  
• When might it be appropriate to use 2 antipsychotics in patients with treatment-resistant psychosis?
  

Antipsychotic polypharmacy defined

“Polypharmacy” can carry a negative connotation, but not all forms are bad. In some circumstances, antipsychotic polypharmacy may be necessary to provide optimum benefit and prevent harm to the patient and/or staff.

Short-term polypharmacy often occurs when switching patients from 1 antipsychotic to another. This “crossover phase” is justified to provide a smooth transition between the 2 agents, as abrupt antipsychotic discontinuation may cause a rebound worsening of psychosis. Other short-term antipsychotic polypharmacy strategies may be necessary in inpatient settings, particularly for a patient who is acutely psychotic or aggressive.

The use of a first-generation antipsychotic (FGA) to lead in a second-generation antipsychotic (SGA) is a justifiable treatment strategy. In addition, sedative antipsychotics such as quetiapine often are used during initial treatment of acutely ill patients and subsequently withdrawn.

Box

Experience-based treatment?

Antipsychotic polypharmacy is prevalent (reported in up to 25% of outpatients and 50% of inpatients with schizophrenia),^2-7 costly for patients and insurers,⁸ and likely to be associated with increased risk of adverse effects and drug-drug interactions. Despite what is known, a wide gap exists between the science and clinical practice of combination antipsychotic therapy in schizophrenia (Table 1).

Clinical trials. The efficacy and safety of antipsychotic combinations in schizophrenia (with options including FGA + FGA, FGA + SGA, and SGA + SGA) has not been studied adequately in well-controlled, systematic trials. Four short-term—6 to 26 weeks—randomized, double-blind, controlled studies^9-12 have examined antipsychotic polypharmacy (clozapine + risperidone) in patients with schizophrenia:

• In 3 studies,^9,11,12 adding risperidone to clozapine did not significantly improve positive or negative symptoms.
  
• In all 4 studies, clozapine + risperidone was associated with increased sedation, akathisia, hyperprolactinemia, and elevated fasting blood glucose.
  

Mortality risk? Two independent, longitudinal cohort studies have found antipsychotic polypharmacy to be a statistically significant predictor of reduced survival.^21,22 Although these studies have identified a possible association, additional research is required to determine whether increased mortality in schizophrenia is attributable to the disorder, comorbid medical conditions, antipsychotic medications, or a complex interaction of factors.

Treatment guidelines—such as the Texas Medication Algorithm Project’s updated treatment algorithm for schizophrenia²³—reflect the paucity of controlled studies of antipsychotic combinations. The expert consensus panel that developed the TMAP algorithm recommends clozapine augmentation with an FGA or SGA, or electroconvulsive therapy after adequate trials of antipsychotic monotherapy, including clozapine. The panel recommends reserving other antipsychotic combinations as a last-line strategy (see Related Resources).

Table 1

Take-home points about antipsychotic polypharmacy

‘Sensible’ pharmacology

Despite the lack of supporting evidence, many clinicians apparently are using antipsychotic polypharmacy for schizophrenia patients with treatment-resistant psychosis. Moreover, reports that up to one-fourth of outpatients and one-half of inpatients may receive antipsychotic polypharmacy^2-7 suggest that this approach is not being reserved for treatment-resistant psychosis. Rather, it is being used in non-treatment-refractory schizophrenia patients as well—a practice Stahl labeled a “dirty little secret.”²⁴

Before you consider using antipsychotic polypharmacy for a schizophrenia patient, we suggest that you answer a series of questions to rationalize your decision (Table 2). These questions seem intuitive, but they represent appropriate clinical practice and may support the use of multiple antipsychotics in selected patients.

Which combination? If you determine that a patient is an appropriate candidate for antipsychotic polypharmacy, think about the pharmacologic profiles of available agents. Administering 2 antipsychotics may augment pharmacologic activity, provide an additive effect, or worsen your patient’s symptoms.

Although data from well-controlled studies of clozapine + risperidone do not support its efficacy,^9-12 this combination is rational from a pharmacologic perspective. Clozapine shows a lower D2 receptor occupancy (16% to 68%) than that of risperidone (63% to 89%),²⁵ so risperidone’s additional D2 receptor occupancy may enhance a patient’s response to clozapine. Table 3 lists other potentially “sensible” antipsychoticantipsychotic combinations.

Table 2

Questions to consider before initiating antipsychotic polypharmacy

Theoretically beneficial antipsychotic combinations

Safety/tolerability

Reduced dosages. Combining antipsychotics may allow you to increase treatment efficacy and improve patient tolerability. Lower dosages of 2 antipsychotics may cause fewer side effects than a high dosage of 1 antipsychotic.

For example, case reports and retrospective studies^26,27 suggest that adding aripiprazole to clozapine may improve antipsychotic efficacy and reduce metabolic adverse events in treatment-resistant patients. In these cases, clozapine dosages were lower than those usually used in patients with schizophrenia.

Metabolic effects. Carefully weigh the propensity of some antipsychotics to induce weight gain, hyperlipidemia, or glucose dysregulation if you plan to use these agents as part of a polypharmacy regimen. Among SGAs, clozapine and olanzapine are associated with the highest risks of metabolic adverse effects, followed by quetiapine and risperidone. Aripiprazole and ziprasidone are less likely than other SGAs to cause these effects.²⁸

A recent study found a higher incidence of metabolic syndrome in patients receiving antipsychotic polypharmacy. The increased incidence was linked to demographics and clinical risk factors, however, and was not independently associated with the use of multiple antipsychotics.²⁹

Because evidence is scarce and inconclusive, the risk of metabolic adverse events is unknown when antipsychotics are combined. Exercise caution when combining antipsychotics—particularly those known to cause adverse metabolic effects—in case the risk is additive.

Tardive dyskinesia (TD). SGAs are associated with a lower incidence of TD compared with FGAs, but adding an FGA to an SGA may increase the patient’s TD risk.³⁰ Also assess patients regularly (as often as weekly during acute treatment and every 6 to 12 months during maintenance treatment)³¹ for extrapyramidal symptoms, including akathisia. Administer appropriate rating scales (such as the Abnormal Involuntary Movements Scale [AIMS], Barnes Akathisia Rating Scale [BARS], or Simpson-Angus Rating Scale [SARS]), and treat these adverse events as clinically indicated.

Other adverse effects. The concurrent use of 2 antipsychotics may amplify side effects that are generally considered mild, such as sedation. For example, risperidone and ziprasidone are considered to cause low to moderate sedation. This combination may result in an additive sedative effect that could negatively impact the patient’s psychosocial functioning.

Anticholinergic effects may also be potentiated, especially if a particular combination of antipsychotics warrants anticholinergic medication use for extrapyramidal symptoms.

Related resources

• Texas Medication Algorithm Project (TMAP). Schizophrenia antipsychotic treatment algorithm. www.dshs.state.tx.us/mhprograms/TIMA.shtm.
  
• Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, 2nd ed. Am J Psychiatry 2004;161(suppl):1-56.
  

• Aripiprazole • Abilify
  
• Clozapine • Clozaril
  
• Haloperidol • Haldol
  
• Lamotrigine • Lamictal
  
• Loxapine • Loxitane
  
• Olanzapine • Zyprexa
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Valproic acid • Depakene
  
• Ziprasidone • Geodon
  

Dr. Gibson reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. He receives research support from the PhRMA Foundation.

Dr. Patel receives grant support from Takeda Pharmaceuticals and is a consultant for Eli Lilly and Company and Shire Pharmaceuticals.

Dr. Lauriello receives grant support from Eli Lilly and Company and serves as a consultant to Eli Lilly and Company and Vanda Pharmaceuticals.

Dr. Buckley receives grant support from AstraZeneca, National Institute of Mental Health, Pfizer Inc., Solvay, and Wyeth and is a consultant for AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Janssen Pharmaceutica, Lundbeck, Pfizer Inc., Solvay, and Wyeth. He receives honoraria from Bristol Myers-Squibb, Janssen Pharmaceutica, Lundbeck, and Pfizer Inc.

Nausea and vomiting in pregnancy (NVP) is a misunderstood disorder associated with stress, anxiety, and depression. Prejudice toward women is thought to have guided the historical psychoanalytic concept of NVP as psychogenic, but this view is being replaced by newer biologic theories.

This article examines the evidence for psychological and organic causes of NVP to inform psychiatrists treating pregnant patients. We review guidelines for pharmacologic treatment of NVP and discuss potentially useful psychotherapies and alternative approaches.

Definitive cause unknown

“Morning sickness” affects 50% to 80% of pregnant women, occurring so commonly that NVP is often considered normal.^1,2 Approximately 0.5% to 2% of women experience the most severe NVP—hyperemesis gravidarum (HG)³—characterized by intractable vomiting, weight loss, and electrolyte imbalance that can lead to hospitalization.

Without modern supportive care, HG can be lethal; although Charlotte Brontë’s death certificate states she died of “phthisis” (tuberculosis), the author of Jane Eyre is popularly believed to have succumbed to HG.^4,5

The search for effective NVP treatments has been disappointing, partly because no cause has been identified. After other conditions that may lead to nausea and vomiting are ruled out (Table 1), NVP medical management is supportive. Correcting dehydration and encouraging dietary and lifestyle changes (Table 2)⁶ are important adjuncts to step-wise pharmacologic treatment recommended by the American College of Obstetrics and Gynecology (Algorithm).⁷

Algorithm Pharmacologic treatment of nausea and vomiting in pregnancy*

Source: Adapted and reprinted with permission from Canadian Family Physician. Levichek Z, Atanackovic G, Oepkes D, et al. Nausea and vomiting of pregnancy. Evidence-based treatment algorithm. Can Fam Physician 2002;48:267-77Table 1

Medical causes of nausea and vomiting in pregnancy

Table 2

Advice for patients: Strategies to manage NVP

Prejudice vs evidence

Psychological factors. Historically, psychological factors have been blamed for NVP, but support comes from a few poorly designed studies or case reports.^3,4

Psychoanalytically, pregnancy and childbirth are significant events in a woman’s life and a rich environment for conflict that could lead to physical expression of symptoms. Freud believed pregnancy and childbirth involve the unconscious substitution of the penis with the child.⁸ Later writers viewed motherhood as woman’s most powerful wish and the primary organizer of her sexual drive and personality.⁸

NVP has been considered a conversion or somatization disorder in which symptoms are a “hysterical” expression of unconscious conflict. A psychoanalytic view contends that women who experience NVP are ambivalent about the pregnancy and seek to reject it.^1,9 Vomiting, in this view, represents an oral abortion attempt.¹⁰ Others claim NVP is a rejection of femininity³ or that symptoms in women with overly attached maternal relationships mask unconscious aggressive feelings toward their mothers.¹¹

Robertson¹¹ proposed an association between NVP and a woman’s view of sexual experiences and her ability to achieve orgasm. He interviewed 100 women and found that 40 of 57 with NVP had “disturbed sexual functioning” or were “frigid” (defined as experiencing coitus as undesirable and unaccompanied by orgasm).

Higgins¹² in 1887 proposed that the cause of NVP “is sexual intercourse, the husband too eager for it and the wife too adverse.” Additionally, NVP and HG have been associated with infantile, childish, immature, and hysterical personalities.^12-14

Psychiatric comorbidities. Attempts have been made to associate NVP with other psychiatric disorders such as depression, bipolar disorder, schizophrenia, and anxiety disorders, including posttraumatic stress disorder (PTSD). No definitive association has been found between NVP and depressive illness, bipolar disorder, or schizophrenia¹⁵ or the use of antidepressants before or during early pregnancy.¹⁶ Studies reporting an association with depression have not established a cause-effect relationship.¹⁷

Seng¹⁸ reported increased NVP risk in women with PTSD. High levels of stress, anxiety, and depression found in women with NVP are thought to result from—rather than cause—NVP’s physical symptoms, however.^3,19,20

Psychosocial stressors have been implicated, with higher NVP rates reported in unmarried women, those with unwanted or unplanned pregnancies, immigrants, and those living in crowded situations.²¹ NVP also is more frequent among women who experience emotionally disturbing events or interpersonal, economic, or occupational difficulties during pregnancy.²² Physical symptoms may provide secondary gain in attention and sympathy and a time-out from stressful home events.¹⁴

These psychosocial theories are poorly supported by data, but some clinicians may still believe NVP has a psychogenic cause. Lennane and Lennane²³ proposed in 1973 that this perception may result from gender bias because:

• most conditions believed to have psychogenic causes affect women more than men
• the belief that NVP is psychogenic has been perpetuated primarily by male authors.

They argued that sexual prejudice may prevent women from receiving necessary symptomatic treatment and impede research into the cause of NVP.²³

Gender bias continues to be found in the diagnosis of women with physical complaints. In 2006, Chiaramonte and Friend²⁴ found strong, consistent gender bias among medical students and residents when evaluating women who reported coronary disease symptoms during stressful life events.

Organic theories

Organic theories view NVP as multifactorial, with contributions from evolution and multiple organ systems. Endocrine, vestibular, gastrointestinal, and CNS contributions have been described, but none have solved NVP’s etiologic mystery.

Evolutionary. NVP may provide an evolutionary advantage by protecting the embryo and mother. This theory states that potential toxins are present in many foods, especially if eaten in large quantities. NVP prevents the pregnant woman from eating very much and harming the embryo. Below-average miscarriage rates are seen in women with NVP.^1,2,25

And because a woman’s immune system is depressed during pregnancy, NVP may be advantageous for the mother by limiting her ingestion of potential toxins.²⁵

Endocrine. Human chorionic gonadotropin (hCG), estrogens, progesterone, and leptin, as well as adrenal cortex insufficiencies have been investigated for a role in NVP. Only hCG has shown clear evidence of an association, and some researchers believe it is the most likely cause of NVP.²⁰

NVP rates are higher in pregnancies with elevated hCG. Molar and multiple-gestation pregnancies—each associated with elevated hCG—are complicated more frequently with the severest form of NVP.^20,26 Conversely, NVP is less common in women who smoke, which is associated with lower hCG.²⁶

During pregnancy, actions of hCG stimulate the thyroid. Hyperstimulation, leading to transient hyperthyroidism, has been implicated in NVP development.^20,26 Symptom severity and the degree of thyroid stimulating hormone (TSH) suppression are closely correlated.²⁶

Elevated hCG levels, hypersensitive TSH receptors, and the presence of a hyperactive hCG isoform have been proposed.²⁰

Gastrointestinal disorders are believed to be involved in the pathogenesis of persistent NVP. Women with NVP usually lack structural or mucosal abnormalities and have normal endoscopic upper GI evaluations. They may, however, have disorders of the stomach’s neuromuscular function. Severe cases of gastric dysrhythmias and abnormalities of gastric tone may lead to gastroparesis.²⁷

Stomach motility in pregnancy is influenced by neurohormonal changes, specifically in estrogen and thyroid hormones. Gastric motility abnormalities—evaluated by electrogastrography (EGG)—have been associated with NVP symptoms and normal EGGs with the absence of symptoms. Some women who had NVP and abnormal EGGs were retested after delivery when symptom-free and found to have normal myoelectric EGG patterns.²⁷

Helicobacter pylori also may be involved in NVP, and at least 1 study found active H pylori infection and HG to be highly correlated. Pregnancy is not believed to predispose to H pylori infection, but active infection compounded by pregnancy’s hormonal changes may exacerbate NVP.²⁸

NVP and motion sickness share many features, suggesting that NVP treatment could be targeted if a vestibular disorder could be discovered.²⁹ Abnormal electroencephalography—particularly generalized slowing—that is not present in asymptomatic pregnant women has been reported in women with NVP.³⁰

CNS contributions. Persistent NVP may be a learned behavior,²⁴ a view based on findings of anticipatory nausea and vomiting in chemotherapy patients. Through conditioning, a pregnant woman may associate her physical symptoms with elements in her life that maintain the cycle of nausea and vomiting.³¹

Treating psychological symptoms

Brief psychotherapy to identify and correct sources of anxiety in pregnancy may alleviate a patient’s nausea and vomiting.³²

• Progressive muscle relaxation training, often combined with guided imagery, can decrease nausea and vomiting associated with chemotherapy and may prevent anticipatory symptoms by decreasing anxiety.
• Systematic desensitization is successful in most chemotherapy patients who try it. In this technique, relaxation is counter-conditioned as a response to stimuli known to elicit symptoms.³¹

Hypnosis allows patients to achieve a physiologic state incompatible with nausea and vomiting³¹ and can terminate vomiting after 1 to 3 sessions.³

Medication. Similar to ondansetron, the antidepressant mirtazapine exhibits an antiemetic effect by blocking the 5-HT3 receptor. In treatment-resistant cases, mirtazapine, 30 mg/d, has been reported to ameliorate NVP symptoms, usually within 24 hours. Patients were able to return to normal diets and discontinue treatment after 6 to 10 days. Mirtazapine appears to be safe during pregnancy, based on animal studies using 17 and 20 times the maximum recommended human dose.³³

For patients with anxiety symptoms, consider other medications—including selective serotonin reuptake inhibitors and benzodiazepines—only after counseling the patient about potential risks and benefits to her and the fetus.³⁴

Alternative treatments. In traditional Indian medicine, a mixture of powdered ginger and honey is given to women with NVP. At least 2 studies demonstrate ginger’s efficacy.³⁵

In traditional Chinese medicine, stimulating the Neiguan point (P6) on the wrist is believed to relieve nausea and vomiting. Although results are inconclusive, studies suggest that P6 stimulation can help control NVP.³⁶ The FDA has approved wristbands that stimulate the P6 site, either electrically or by acupressure (Figure).³⁶

Figure Wristband to manage nausea and vomiting in pregnancy

The FDA-cleared BioBand acupressure wristband may help control nausea and vomiting in pregnancy by stimulating the Neiguan point (P6) on the wrist.
Source: Reference 36Consider thiamine supplementation for women with severe symptoms, as Wernicke’s encephalopathy is a rare complication of prolonged NVP.^19,37

Related resources

• Motherisk Program at The Hospital for Sick Children, Toronto, Ontario, Canada. Website with information on vomiting during pregnancy: www.motherisk.org/women/morningSickness.jsp. Nausea and vomiting of pregnancy (NVP) forum. www.motherisk.org/women/forum.jsp.
• BioBand acupuncture wristband. www.BioBands.com.
• Koren G, Bishai R, eds. Nausea and vomiting of pregnancy: state of the art 2000. Toronto, Ontario, Canada: The Motherisk Program; 2000.

Drug brand names

• Dimenhydrinate • Dramamine
• Doxylamine • Unisom
• Methylprednisolone • Medrol
• Metoclopramide • Reglan
• Mirtazapine • Remeron
• Ondansetron • Zofran
• Promethazine • Phenergan
• Trimethobenzamide • Tigan

Disclosure

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

Nausea and vomiting in pregnancy (NVP) is a misunderstood disorder associated with stress, anxiety, and depression. Prejudice toward women is thought to have guided the historical psychoanalytic concept of NVP as psychogenic, but this view is being replaced by newer biologic theories.

This article examines the evidence for psychological and organic causes of NVP to inform psychiatrists treating pregnant patients. We review guidelines for pharmacologic treatment of NVP and discuss potentially useful psychotherapies and alternative approaches.

Definitive cause unknown

“Morning sickness” affects 50% to 80% of pregnant women, occurring so commonly that NVP is often considered normal.^1,2 Approximately 0.5% to 2% of women experience the most severe NVP—hyperemesis gravidarum (HG)³—characterized by intractable vomiting, weight loss, and electrolyte imbalance that can lead to hospitalization.

Without modern supportive care, HG can be lethal; although Charlotte Brontë’s death certificate states she died of “phthisis” (tuberculosis), the author of Jane Eyre is popularly believed to have succumbed to HG.^4,5

The search for effective NVP treatments has been disappointing, partly because no cause has been identified. After other conditions that may lead to nausea and vomiting are ruled out (Table 1), NVP medical management is supportive. Correcting dehydration and encouraging dietary and lifestyle changes (Table 2)⁶ are important adjuncts to step-wise pharmacologic treatment recommended by the American College of Obstetrics and Gynecology (Algorithm).⁷

Algorithm Pharmacologic treatment of nausea and vomiting in pregnancy*

Source: Adapted and reprinted with permission from Canadian Family Physician. Levichek Z, Atanackovic G, Oepkes D, et al. Nausea and vomiting of pregnancy. Evidence-based treatment algorithm. Can Fam Physician 2002;48:267-77Table 1

Medical causes of nausea and vomiting in pregnancy

Table 2

Advice for patients: Strategies to manage NVP

Prejudice vs evidence

Psychological factors. Historically, psychological factors have been blamed for NVP, but support comes from a few poorly designed studies or case reports.^3,4

Psychoanalytically, pregnancy and childbirth are significant events in a woman’s life and a rich environment for conflict that could lead to physical expression of symptoms. Freud believed pregnancy and childbirth involve the unconscious substitution of the penis with the child.⁸ Later writers viewed motherhood as woman’s most powerful wish and the primary organizer of her sexual drive and personality.⁸

NVP has been considered a conversion or somatization disorder in which symptoms are a “hysterical” expression of unconscious conflict. A psychoanalytic view contends that women who experience NVP are ambivalent about the pregnancy and seek to reject it.^1,9 Vomiting, in this view, represents an oral abortion attempt.¹⁰ Others claim NVP is a rejection of femininity³ or that symptoms in women with overly attached maternal relationships mask unconscious aggressive feelings toward their mothers.¹¹

Robertson¹¹ proposed an association between NVP and a woman’s view of sexual experiences and her ability to achieve orgasm. He interviewed 100 women and found that 40 of 57 with NVP had “disturbed sexual functioning” or were “frigid” (defined as experiencing coitus as undesirable and unaccompanied by orgasm).

Higgins¹² in 1887 proposed that the cause of NVP “is sexual intercourse, the husband too eager for it and the wife too adverse.” Additionally, NVP and HG have been associated with infantile, childish, immature, and hysterical personalities.^12-14

Psychiatric comorbidities. Attempts have been made to associate NVP with other psychiatric disorders such as depression, bipolar disorder, schizophrenia, and anxiety disorders, including posttraumatic stress disorder (PTSD). No definitive association has been found between NVP and depressive illness, bipolar disorder, or schizophrenia¹⁵ or the use of antidepressants before or during early pregnancy.¹⁶ Studies reporting an association with depression have not established a cause-effect relationship.¹⁷

Seng¹⁸ reported increased NVP risk in women with PTSD. High levels of stress, anxiety, and depression found in women with NVP are thought to result from—rather than cause—NVP’s physical symptoms, however.^3,19,20

Psychosocial stressors have been implicated, with higher NVP rates reported in unmarried women, those with unwanted or unplanned pregnancies, immigrants, and those living in crowded situations.²¹ NVP also is more frequent among women who experience emotionally disturbing events or interpersonal, economic, or occupational difficulties during pregnancy.²² Physical symptoms may provide secondary gain in attention and sympathy and a time-out from stressful home events.¹⁴

These psychosocial theories are poorly supported by data, but some clinicians may still believe NVP has a psychogenic cause. Lennane and Lennane²³ proposed in 1973 that this perception may result from gender bias because:

• most conditions believed to have psychogenic causes affect women more than men
• the belief that NVP is psychogenic has been perpetuated primarily by male authors.

They argued that sexual prejudice may prevent women from receiving necessary symptomatic treatment and impede research into the cause of NVP.²³

Gender bias continues to be found in the diagnosis of women with physical complaints. In 2006, Chiaramonte and Friend²⁴ found strong, consistent gender bias among medical students and residents when evaluating women who reported coronary disease symptoms during stressful life events.

Organic theories

Organic theories view NVP as multifactorial, with contributions from evolution and multiple organ systems. Endocrine, vestibular, gastrointestinal, and CNS contributions have been described, but none have solved NVP’s etiologic mystery.

Evolutionary. NVP may provide an evolutionary advantage by protecting the embryo and mother. This theory states that potential toxins are present in many foods, especially if eaten in large quantities. NVP prevents the pregnant woman from eating very much and harming the embryo. Below-average miscarriage rates are seen in women with NVP.^1,2,25

And because a woman’s immune system is depressed during pregnancy, NVP may be advantageous for the mother by limiting her ingestion of potential toxins.²⁵

Endocrine. Human chorionic gonadotropin (hCG), estrogens, progesterone, and leptin, as well as adrenal cortex insufficiencies have been investigated for a role in NVP. Only hCG has shown clear evidence of an association, and some researchers believe it is the most likely cause of NVP.²⁰

NVP rates are higher in pregnancies with elevated hCG. Molar and multiple-gestation pregnancies—each associated with elevated hCG—are complicated more frequently with the severest form of NVP.^20,26 Conversely, NVP is less common in women who smoke, which is associated with lower hCG.²⁶

During pregnancy, actions of hCG stimulate the thyroid. Hyperstimulation, leading to transient hyperthyroidism, has been implicated in NVP development.^20,26 Symptom severity and the degree of thyroid stimulating hormone (TSH) suppression are closely correlated.²⁶

Elevated hCG levels, hypersensitive TSH receptors, and the presence of a hyperactive hCG isoform have been proposed.²⁰

Gastrointestinal disorders are believed to be involved in the pathogenesis of persistent NVP. Women with NVP usually lack structural or mucosal abnormalities and have normal endoscopic upper GI evaluations. They may, however, have disorders of the stomach’s neuromuscular function. Severe cases of gastric dysrhythmias and abnormalities of gastric tone may lead to gastroparesis.²⁷

Stomach motility in pregnancy is influenced by neurohormonal changes, specifically in estrogen and thyroid hormones. Gastric motility abnormalities—evaluated by electrogastrography (EGG)—have been associated with NVP symptoms and normal EGGs with the absence of symptoms. Some women who had NVP and abnormal EGGs were retested after delivery when symptom-free and found to have normal myoelectric EGG patterns.²⁷

Helicobacter pylori also may be involved in NVP, and at least 1 study found active H pylori infection and HG to be highly correlated. Pregnancy is not believed to predispose to H pylori infection, but active infection compounded by pregnancy’s hormonal changes may exacerbate NVP.²⁸

NVP and motion sickness share many features, suggesting that NVP treatment could be targeted if a vestibular disorder could be discovered.²⁹ Abnormal electroencephalography—particularly generalized slowing—that is not present in asymptomatic pregnant women has been reported in women with NVP.³⁰

CNS contributions. Persistent NVP may be a learned behavior,²⁴ a view based on findings of anticipatory nausea and vomiting in chemotherapy patients. Through conditioning, a pregnant woman may associate her physical symptoms with elements in her life that maintain the cycle of nausea and vomiting.³¹

Treating psychological symptoms

Brief psychotherapy to identify and correct sources of anxiety in pregnancy may alleviate a patient’s nausea and vomiting.³²

• Progressive muscle relaxation training, often combined with guided imagery, can decrease nausea and vomiting associated with chemotherapy and may prevent anticipatory symptoms by decreasing anxiety.
• Systematic desensitization is successful in most chemotherapy patients who try it. In this technique, relaxation is counter-conditioned as a response to stimuli known to elicit symptoms.³¹

Hypnosis allows patients to achieve a physiologic state incompatible with nausea and vomiting³¹ and can terminate vomiting after 1 to 3 sessions.³

Medication. Similar to ondansetron, the antidepressant mirtazapine exhibits an antiemetic effect by blocking the 5-HT3 receptor. In treatment-resistant cases, mirtazapine, 30 mg/d, has been reported to ameliorate NVP symptoms, usually within 24 hours. Patients were able to return to normal diets and discontinue treatment after 6 to 10 days. Mirtazapine appears to be safe during pregnancy, based on animal studies using 17 and 20 times the maximum recommended human dose.³³

For patients with anxiety symptoms, consider other medications—including selective serotonin reuptake inhibitors and benzodiazepines—only after counseling the patient about potential risks and benefits to her and the fetus.³⁴

Alternative treatments. In traditional Indian medicine, a mixture of powdered ginger and honey is given to women with NVP. At least 2 studies demonstrate ginger’s efficacy.³⁵

In traditional Chinese medicine, stimulating the Neiguan point (P6) on the wrist is believed to relieve nausea and vomiting. Although results are inconclusive, studies suggest that P6 stimulation can help control NVP.³⁶ The FDA has approved wristbands that stimulate the P6 site, either electrically or by acupressure (Figure).³⁶

Figure Wristband to manage nausea and vomiting in pregnancy

The FDA-cleared BioBand acupressure wristband may help control nausea and vomiting in pregnancy by stimulating the Neiguan point (P6) on the wrist.
Source: Reference 36Consider thiamine supplementation for women with severe symptoms, as Wernicke’s encephalopathy is a rare complication of prolonged NVP.^19,37

Related resources

• Motherisk Program at The Hospital for Sick Children, Toronto, Ontario, Canada. Website with information on vomiting during pregnancy: www.motherisk.org/women/morningSickness.jsp. Nausea and vomiting of pregnancy (NVP) forum. www.motherisk.org/women/forum.jsp.
• BioBand acupuncture wristband. www.BioBands.com.
• Koren G, Bishai R, eds. Nausea and vomiting of pregnancy: state of the art 2000. Toronto, Ontario, Canada: The Motherisk Program; 2000.

Drug brand names

• Dimenhydrinate • Dramamine
• Doxylamine • Unisom
• Methylprednisolone • Medrol
• Metoclopramide • Reglan
• Mirtazapine • Remeron
• Ondansetron • Zofran
• Promethazine • Phenergan
• Trimethobenzamide • Tigan