Case-Based Review

History: From sociable to sullen

Julie, a Hispanic/Native American, was adopted by a Caucasian couple when she was 6 weeks old. Before age 12, she had no psychiatric problems and was medically healthy though slightly overweight.

At age 12, Julie started having episodes of brooding depression, verbal and physical aggression, and impulsive suicidal behavior. She also began suffering intermittent migraines and having trouble falling asleep. She insisted on sleeping with her parents or with a nightlight in her room.

Once a sociable girl who enjoyed being in the middle school chorus and band, Julie suddenly became sullen and defiant. She dropped out of afterschool activities and stopped socializing with peers except for her best friend, Sheila, age 12, and Mark, age 13, an “almost boyfriend” who lived next door.

Julie also started arguing with her mother, often yelling and screaming when approached with minor requests. Sometimes, Julie hit and pushed her. A psychiatrist diagnosed the 12-year-old with major depressive disorder and prescribed fluoxetine, dosage unknown.

Soon after Julie’s symptoms surfaced, her adoptive father, a sales representative, was laid off. He found work in another state; the family left an ethnically diverse city for a predominantly Caucasian rural area. There, Julie completed middle school and her freshman year of high school, and lost contact with Sheila and Mark.

Midway through her freshman year, Julie tried to induce vomiting after eating so that she would lose weight and “fit in better with the other girls.” She stopped this at the end of the school year.

The following fall, 5 weeks into her sophomore year, she dropped out of high school and was ultimately enrolled in home school.

Treatment: 4 hospitalizations in 3 years

Between ages 12 and 15, Julie was hospitalized four times for outbursts of violence with impulsive self-harm. She “overdosed” on eight aceta-minophen/diphenhydramine tablets on one occasion and superficially cut her forearm on another. During these episodes, she said, she heard voices telling her to harm her mother and herself.

During this period, Julie was diagnosed as having schizophrenia, major depressive disorder, attention-deficit/hyperactivity disorder (ADHD), and oppositional defiant disorder (ODD). Numerous antidepressant and mood stabilizer regimens produced no lasting improvement, though her angry and violent episodes became less frequent.

poll here

The authors’ observations

Although Julie’s psychotic symptoms might suggest an evolving disorder such as schizophrenia, no clear pattern supports this diagnosis. Also:

• Onset at age 12 is unusual. Schizophrenia typically begins in late teens to early adulthood.
  
• Julie showed no premorbid personality problems—found in up to one-third of patients with chronic schizophrenia—and no premorbid adjustment difficulties resulting from negative symptoms, cognitive deficits, or poor social function.¹
  

Julie’s angry behaviors and refusal to stay in school suggest ODD, but this disorder generally presents without self-harm or other impulsive behaviors and occurs apart from psychosis or mood disorder episodes.¹ Her low mood, withdrawal from activities, and suicidal actions may suggest major depressive disorder with psychotic features, but this diagnosis does not explain the sudden dramatic transformation in her baseline personality.

Julie’s birth parents’ mental health history would offer crucial information, but this was not available.

Continued history: ‘I left my body’

Shortly after her 15th birthday, Julie broke down and told her parents that 3 years earlier, four boys had gang-raped her while she was “on a first date” with one of them at a school football game. She said one attacker held a knife to her throat, and they threatened to kill her friend Sheila if anyone was told. Julie said she felt so terrorized that “I left my body and watched what was happening.”

After the rape, Julie went home, showered, and went to bed. She said she felt “emotionally numb” for 2 months, during which she threw herself into schoolwork, stopped attending after-school events, and began arguing with her parents. She developed nightmares of the trauma and, eventually, auditory command hallucinations. When stressed, she has “out of body” feelings lasting several minutes.

The parents, though angry at Julie‘s attackers, did not seek legal counsel or report the rape to authorities because they felt too much time had passed. They sought support from a counselor, who referred their daughter to a male psychiatrist for medication management. Julie, now age 16, preferred to be treated by a woman, so her care was transferred to our clinic.

Based on clinical observations, Julie gets along well with her father. She complains that her mother is overprotective yet Julie cannot bear to be separated from her for even a couple hours. She resents her mother’s overinvolvement but relies on it for emotional regulation. Her mother has been treated for major depressive disorder, generalized anxiety disorder, and alcohol dependence. These were in sustained remission when Julie presented to us.

 

At presentation, we diagnosed Julie as having chronic posttraumatic stress disorder (PTSD), recurrent major depressive disorder, and eating disorder not otherwise specified. At 5 feet, 7 inches and 190 pounds, her body mass index is 30 kg/m², indicating clinical obesity. She has been taking duloxetine, 60 mg/d, extended release dextroamphetamine, 20 mg/d, aripiprazole, 20 mg/d, and amitriptyline, 10 mg/d nightly. She also has been taking sumatriptan, 100 mg as needed, for migraines.

poll here

The authors’ observations

After a life-threatening sexual assault, Julie suddenly became irritable and hostile. She could not keep relationships, yet she feared being alone. She impulsively hurt herself, experienced nightmares, and systematically avoided school activities. These behaviors suggest PTSD,¹ which is prevalent among sexual assault victims (Box 1). For 3 years, however, psychiatrists kept missing the diagnosis as Julie kept her shame a secret.

Julie tells us that she re-experiences trauma-related dysphoria when exposed to cues, such as the anniversary of the rape. She endorses avoidance symptoms, including feelings of estrangement from her family and friends. She shuns thoughts, feelings, places, and conversations associated with the trauma, which partly explains her refusal to stay in school. She reports arousal symptoms, including difficulty falling and staying asleep and fears of harm if left alone, even during the day. At night she has rituals for checking windows and doors to ensure they are locked.

Julie’s decision to hide her trauma was understandable given her age and developmental phase. For a teenager trying to separate from her parents and fit in at school, the humiliation was overwhelming. She lacked the cognitive tools to process and describe her experience. She was assaulted while on a date, normally a positive rite of passage. Further, as a young Hispanic/Native American, Julie feared disappointing her Caucasian parents by not fitting in at school.

When a previously well-adjusted teenager presents with sudden-onset behavioral problems, ask about past or recent trauma. Watch for contextual, developmental, and sociocultural factors that may prevent the youth from disclosing embarrassing events.

Also question the diagnosis if several adequate medication trials have failed. Check for comorbidities, lack of adherence, or other circumstances that can hamper response to treatment.

Box 1

Factors that may signal ptsd

American Psychiatric Association (APA) practice guidelines for treating PTSD list several factors to consider if you suspect this diagnosis:⁵

Impulsive and episodic aggression can result from an anticipatory bias that increases readiness for “fight, flight, or freeze.” For Julie, this turned previously comfortable interactions into dissonance and conflict.

Self-injurious and suicidal behaviors often occur when trauma creates stigma, shame, or guilt. Julie felt these emotions while trying to establish herself in a new community and school. Her obesity and ethnic background further set her apart from peers. She also left behind friends who provided emotional support outside the home and helped her differentiate from her mother.

Trauma during early adolescence can impair age-appropriate development, making it difficult to develop a stable self-image, consolidate and integrate the personality, and form relationships. At age 16, poor self-image and maladaptive coping strategies were an enduring pattern in Julie’s life.

Psychiatric comorbidities. Many patients with PTSD develop psychiatric comorbidities that exaggerate symptoms, making the disorder more difficult to detect and treat. Julie’s depression increased her avoidance tendencies and rein-forced her isolation. Difficulty concentrating—misdiagnosed as ADHD—deterred her from engaging in school. Dissociative symptoms related to PTSD impaired her reality testing, diminishing her ability to interact with others.

Treatment: Medication change

We continued extended-release dextroamphetamine, 20 mg/d, as Julie felt the medication helped her focus on her schoolwork. We also:

• weaned her off aripiprazole, which was not helping her symptoms
  
• stopped amitriptyline and duloxetine because of her history of impulsive overdose and to reduce side-effect risk from polypharmacy
  
• titrated fluoxetine to 40 mg/d to treat her ongoing chronic depression and added trazodone, 50 mg/d as needed, to help her sleep
  
• stopped sumatriptan, as the headaches remitted after Julie’s eyes were tested and eyeglasses prescribed.
  

Initially, we managed Julie’s medications while she received psychotherapy from her counselor, but she eventually shifted her entire care to us. We then began seeing her weekly for psychoeducation and supportive therapy.

 

poll here

The authors’ observations

Medication. APA treatment guidelines support using SSRIs to treat all three PTSD symptom clusters—re-experiencing, avoidance, and hyperarousal—as well as coexisting depression. Evidence also supports use of the tricyclics amitriptyline and imipramine and some monoamine oxidase inhibitors (MAOIs).^6-10 Dietary restrictions associated with MAOIs, however, can pose a problem for teenagers.

Benzodiazepines can decrease anxiety and improve sleep, but they can be addictive and their efficacy in treating PTSD has not been established. Alpha-2-adrenergic agonists such as prazosin and clonidine may decrease hyperarousal and trauma-related nightmares.^11,12

Obtain informed parental consent before starting a child or adolescent on an antidepressant. These medications contain a black-box warning that the drug may increase suicide risk in youths.

Psychotherapy. Varying levels of evidence support psychotherapy models in PTSD (Box 2). Julie can benefit from psychoeducation, supportive therapy, psychodynamic psychotherapy, and cautious re-exposure to trauma where possible.

Psychoeducation provided a safe starting point for Julie’s therapy, engaged her parents and select school counselors and teachers, and helped her understand PTSD’s effects. This allowed us to teach stress reduction and coping strategies.

Supportive techniques helped Julie contain painful affects. She could then network with community resources such as AlaTeen and a peer support group via a local Native American mental health program. This approach helped us gain Julie’s trust, and we anticipate more in-depth work with time.

Trauma re-exposure helps some patients but worsens others’ symptoms. For Julie, trauma re-exposure has been minimal because of the many other issues she was facing.

Developing a trusting relationship over time is crucial to successful trauma re-exposure. Re-exposure should be gradual to keep affective arousal moderate. This will minimize dissociation and affective flooding, which can frustrate treatment.

Cognitive-behavioral therapy (CBT) might help Julie understand the automatic thoughts of failure and defeat that flood her when she is stressed. CBT could help her master her feelings and lay a foundation for improved coping.

Psychodynamic psychotherapy may be started later to help Julie verbalize feelings and modulate how she expresses affect. This model could promote her development, improve her self-image, and treat her depression.

Box 2

Follow-up: Back to school

After 2 months under our care, Julie begins to show improvement. Because of her progress and the fact that her parents drive 45 minutes each way to get to our clinic, we reduce visit frequency from weekly to biweekly.

Julie now attends school 2 hours daily, is earning additional credits through home study, and plans to graduate early and attend community college. Her depression has lifted, and she continues to take fluoxetine, 40 mg/d and extended-release dextroamphetamine, 20 mg/d. She still struggles with social isolation, failure to reach age-appropriate developmental milestones, and a poor body image.

Related resources

• American Psychiatric Association. Practice guideline for treating acute stress disorder and posttraumatic stress disorder. www.psych.org/psych_pract/treatg/pg/PTSD-PG-PartsA-B-C-New.pdf
  
• National Center for Post-Traumatic Stress Disorder. Information on obtaining Impact of Events Scale and Davidson Trauma Scale. www.ncptsd.va.gov/publications/assessment/adult_self_report.html
  

Drug brand names

• Amitriptyline • Elavil
  
• Aripiprazole • Abilify
  
• Clonidine • Catapres
  
• Dextroamphetamine (extended-release) • Adderall XR
  
• Duloxetine • Cymbalta
  
• Fluoxetine • Prozac
  
• Imipramine • Tofranil
  
• Phenelzine • Nardil
  
• Prazosin • Minipress
  
• Sumatriptan • Imitrex
  
• Trazodone • Desyrel
  

Disclosure

Dr. Matthews is an American Psychiatric Association Bristol-Myers Squibb Co. fellow in public and community psychiatry.

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

Acknowledgements

The authors thank Larry Schwartz, MD, for his help in preparing this article for publication.

History: From sociable to sullen

Julie, a Hispanic/Native American, was adopted by a Caucasian couple when she was 6 weeks old. Before age 12, she had no psychiatric problems and was medically healthy though slightly overweight.

At age 12, Julie started having episodes of brooding depression, verbal and physical aggression, and impulsive suicidal behavior. She also began suffering intermittent migraines and having trouble falling asleep. She insisted on sleeping with her parents or with a nightlight in her room.

Once a sociable girl who enjoyed being in the middle school chorus and band, Julie suddenly became sullen and defiant. She dropped out of afterschool activities and stopped socializing with peers except for her best friend, Sheila, age 12, and Mark, age 13, an “almost boyfriend” who lived next door.

Julie also started arguing with her mother, often yelling and screaming when approached with minor requests. Sometimes, Julie hit and pushed her. A psychiatrist diagnosed the 12-year-old with major depressive disorder and prescribed fluoxetine, dosage unknown.

Soon after Julie’s symptoms surfaced, her adoptive father, a sales representative, was laid off. He found work in another state; the family left an ethnically diverse city for a predominantly Caucasian rural area. There, Julie completed middle school and her freshman year of high school, and lost contact with Sheila and Mark.

Midway through her freshman year, Julie tried to induce vomiting after eating so that she would lose weight and “fit in better with the other girls.” She stopped this at the end of the school year.

The following fall, 5 weeks into her sophomore year, she dropped out of high school and was ultimately enrolled in home school.

Treatment: 4 hospitalizations in 3 years

Between ages 12 and 15, Julie was hospitalized four times for outbursts of violence with impulsive self-harm. She “overdosed” on eight aceta-minophen/diphenhydramine tablets on one occasion and superficially cut her forearm on another. During these episodes, she said, she heard voices telling her to harm her mother and herself.

During this period, Julie was diagnosed as having schizophrenia, major depressive disorder, attention-deficit/hyperactivity disorder (ADHD), and oppositional defiant disorder (ODD). Numerous antidepressant and mood stabilizer regimens produced no lasting improvement, though her angry and violent episodes became less frequent.

poll here

The authors’ observations

Although Julie’s psychotic symptoms might suggest an evolving disorder such as schizophrenia, no clear pattern supports this diagnosis. Also:

• Onset at age 12 is unusual. Schizophrenia typically begins in late teens to early adulthood.
  
• Julie showed no premorbid personality problems—found in up to one-third of patients with chronic schizophrenia—and no premorbid adjustment difficulties resulting from negative symptoms, cognitive deficits, or poor social function.¹
  

Julie’s angry behaviors and refusal to stay in school suggest ODD, but this disorder generally presents without self-harm or other impulsive behaviors and occurs apart from psychosis or mood disorder episodes.¹ Her low mood, withdrawal from activities, and suicidal actions may suggest major depressive disorder with psychotic features, but this diagnosis does not explain the sudden dramatic transformation in her baseline personality.

Julie’s birth parents’ mental health history would offer crucial information, but this was not available.

Continued history: ‘I left my body’

Shortly after her 15th birthday, Julie broke down and told her parents that 3 years earlier, four boys had gang-raped her while she was “on a first date” with one of them at a school football game. She said one attacker held a knife to her throat, and they threatened to kill her friend Sheila if anyone was told. Julie said she felt so terrorized that “I left my body and watched what was happening.”

After the rape, Julie went home, showered, and went to bed. She said she felt “emotionally numb” for 2 months, during which she threw herself into schoolwork, stopped attending after-school events, and began arguing with her parents. She developed nightmares of the trauma and, eventually, auditory command hallucinations. When stressed, she has “out of body” feelings lasting several minutes.

The parents, though angry at Julie‘s attackers, did not seek legal counsel or report the rape to authorities because they felt too much time had passed. They sought support from a counselor, who referred their daughter to a male psychiatrist for medication management. Julie, now age 16, preferred to be treated by a woman, so her care was transferred to our clinic.

Based on clinical observations, Julie gets along well with her father. She complains that her mother is overprotective yet Julie cannot bear to be separated from her for even a couple hours. She resents her mother’s overinvolvement but relies on it for emotional regulation. Her mother has been treated for major depressive disorder, generalized anxiety disorder, and alcohol dependence. These were in sustained remission when Julie presented to us.

 

At presentation, we diagnosed Julie as having chronic posttraumatic stress disorder (PTSD), recurrent major depressive disorder, and eating disorder not otherwise specified. At 5 feet, 7 inches and 190 pounds, her body mass index is 30 kg/m², indicating clinical obesity. She has been taking duloxetine, 60 mg/d, extended release dextroamphetamine, 20 mg/d, aripiprazole, 20 mg/d, and amitriptyline, 10 mg/d nightly. She also has been taking sumatriptan, 100 mg as needed, for migraines.

poll here

The authors’ observations

After a life-threatening sexual assault, Julie suddenly became irritable and hostile. She could not keep relationships, yet she feared being alone. She impulsively hurt herself, experienced nightmares, and systematically avoided school activities. These behaviors suggest PTSD,¹ which is prevalent among sexual assault victims (Box 1). For 3 years, however, psychiatrists kept missing the diagnosis as Julie kept her shame a secret.

Julie tells us that she re-experiences trauma-related dysphoria when exposed to cues, such as the anniversary of the rape. She endorses avoidance symptoms, including feelings of estrangement from her family and friends. She shuns thoughts, feelings, places, and conversations associated with the trauma, which partly explains her refusal to stay in school. She reports arousal symptoms, including difficulty falling and staying asleep and fears of harm if left alone, even during the day. At night she has rituals for checking windows and doors to ensure they are locked.

Julie’s decision to hide her trauma was understandable given her age and developmental phase. For a teenager trying to separate from her parents and fit in at school, the humiliation was overwhelming. She lacked the cognitive tools to process and describe her experience. She was assaulted while on a date, normally a positive rite of passage. Further, as a young Hispanic/Native American, Julie feared disappointing her Caucasian parents by not fitting in at school.

When a previously well-adjusted teenager presents with sudden-onset behavioral problems, ask about past or recent trauma. Watch for contextual, developmental, and sociocultural factors that may prevent the youth from disclosing embarrassing events.

Also question the diagnosis if several adequate medication trials have failed. Check for comorbidities, lack of adherence, or other circumstances that can hamper response to treatment.

Box 1

Factors that may signal ptsd

American Psychiatric Association (APA) practice guidelines for treating PTSD list several factors to consider if you suspect this diagnosis:⁵

Impulsive and episodic aggression can result from an anticipatory bias that increases readiness for “fight, flight, or freeze.” For Julie, this turned previously comfortable interactions into dissonance and conflict.

Self-injurious and suicidal behaviors often occur when trauma creates stigma, shame, or guilt. Julie felt these emotions while trying to establish herself in a new community and school. Her obesity and ethnic background further set her apart from peers. She also left behind friends who provided emotional support outside the home and helped her differentiate from her mother.

Trauma during early adolescence can impair age-appropriate development, making it difficult to develop a stable self-image, consolidate and integrate the personality, and form relationships. At age 16, poor self-image and maladaptive coping strategies were an enduring pattern in Julie’s life.

Psychiatric comorbidities. Many patients with PTSD develop psychiatric comorbidities that exaggerate symptoms, making the disorder more difficult to detect and treat. Julie’s depression increased her avoidance tendencies and rein-forced her isolation. Difficulty concentrating—misdiagnosed as ADHD—deterred her from engaging in school. Dissociative symptoms related to PTSD impaired her reality testing, diminishing her ability to interact with others.

Treatment: Medication change

We continued extended-release dextroamphetamine, 20 mg/d, as Julie felt the medication helped her focus on her schoolwork. We also:

• weaned her off aripiprazole, which was not helping her symptoms
  
• stopped amitriptyline and duloxetine because of her history of impulsive overdose and to reduce side-effect risk from polypharmacy
  
• titrated fluoxetine to 40 mg/d to treat her ongoing chronic depression and added trazodone, 50 mg/d as needed, to help her sleep
  
• stopped sumatriptan, as the headaches remitted after Julie’s eyes were tested and eyeglasses prescribed.
  

Initially, we managed Julie’s medications while she received psychotherapy from her counselor, but she eventually shifted her entire care to us. We then began seeing her weekly for psychoeducation and supportive therapy.

 

poll here

The authors’ observations

Medication. APA treatment guidelines support using SSRIs to treat all three PTSD symptom clusters—re-experiencing, avoidance, and hyperarousal—as well as coexisting depression. Evidence also supports use of the tricyclics amitriptyline and imipramine and some monoamine oxidase inhibitors (MAOIs).^6-10 Dietary restrictions associated with MAOIs, however, can pose a problem for teenagers.

Benzodiazepines can decrease anxiety and improve sleep, but they can be addictive and their efficacy in treating PTSD has not been established. Alpha-2-adrenergic agonists such as prazosin and clonidine may decrease hyperarousal and trauma-related nightmares.^11,12

Obtain informed parental consent before starting a child or adolescent on an antidepressant. These medications contain a black-box warning that the drug may increase suicide risk in youths.

Psychotherapy. Varying levels of evidence support psychotherapy models in PTSD (Box 2). Julie can benefit from psychoeducation, supportive therapy, psychodynamic psychotherapy, and cautious re-exposure to trauma where possible.

Psychoeducation provided a safe starting point for Julie’s therapy, engaged her parents and select school counselors and teachers, and helped her understand PTSD’s effects. This allowed us to teach stress reduction and coping strategies.

Supportive techniques helped Julie contain painful affects. She could then network with community resources such as AlaTeen and a peer support group via a local Native American mental health program. This approach helped us gain Julie’s trust, and we anticipate more in-depth work with time.

Trauma re-exposure helps some patients but worsens others’ symptoms. For Julie, trauma re-exposure has been minimal because of the many other issues she was facing.

Developing a trusting relationship over time is crucial to successful trauma re-exposure. Re-exposure should be gradual to keep affective arousal moderate. This will minimize dissociation and affective flooding, which can frustrate treatment.

Cognitive-behavioral therapy (CBT) might help Julie understand the automatic thoughts of failure and defeat that flood her when she is stressed. CBT could help her master her feelings and lay a foundation for improved coping.

Psychodynamic psychotherapy may be started later to help Julie verbalize feelings and modulate how she expresses affect. This model could promote her development, improve her self-image, and treat her depression.

Box 2

Follow-up: Back to school

After 2 months under our care, Julie begins to show improvement. Because of her progress and the fact that her parents drive 45 minutes each way to get to our clinic, we reduce visit frequency from weekly to biweekly.

Julie now attends school 2 hours daily, is earning additional credits through home study, and plans to graduate early and attend community college. Her depression has lifted, and she continues to take fluoxetine, 40 mg/d and extended-release dextroamphetamine, 20 mg/d. She still struggles with social isolation, failure to reach age-appropriate developmental milestones, and a poor body image.

Related resources

• American Psychiatric Association. Practice guideline for treating acute stress disorder and posttraumatic stress disorder. www.psych.org/psych_pract/treatg/pg/PTSD-PG-PartsA-B-C-New.pdf
  
• National Center for Post-Traumatic Stress Disorder. Information on obtaining Impact of Events Scale and Davidson Trauma Scale. www.ncptsd.va.gov/publications/assessment/adult_self_report.html
  

Drug brand names

• Amitriptyline • Elavil
  
• Aripiprazole • Abilify
  
• Clonidine • Catapres
  
• Dextroamphetamine (extended-release) • Adderall XR
  
• Duloxetine • Cymbalta
  
• Fluoxetine • Prozac
  
• Imipramine • Tofranil
  
• Phenelzine • Nardil
  
• Prazosin • Minipress
  
• Sumatriptan • Imitrex
  
• Trazodone • Desyrel
  

Disclosure

Dr. Matthews is an American Psychiatric Association Bristol-Myers Squibb Co. fellow in public and community psychiatry.

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

Acknowledgements

The authors thank Larry Schwartz, MD, for his help in preparing this article for publication.

History: From sociable to sullen

Julie, a Hispanic/Native American, was adopted by a Caucasian couple when she was 6 weeks old. Before age 12, she had no psychiatric problems and was medically healthy though slightly overweight.

At age 12, Julie started having episodes of brooding depression, verbal and physical aggression, and impulsive suicidal behavior. She also began suffering intermittent migraines and having trouble falling asleep. She insisted on sleeping with her parents or with a nightlight in her room.

Once a sociable girl who enjoyed being in the middle school chorus and band, Julie suddenly became sullen and defiant. She dropped out of afterschool activities and stopped socializing with peers except for her best friend, Sheila, age 12, and Mark, age 13, an “almost boyfriend” who lived next door.

Julie also started arguing with her mother, often yelling and screaming when approached with minor requests. Sometimes, Julie hit and pushed her. A psychiatrist diagnosed the 12-year-old with major depressive disorder and prescribed fluoxetine, dosage unknown.

Soon after Julie’s symptoms surfaced, her adoptive father, a sales representative, was laid off. He found work in another state; the family left an ethnically diverse city for a predominantly Caucasian rural area. There, Julie completed middle school and her freshman year of high school, and lost contact with Sheila and Mark.

Midway through her freshman year, Julie tried to induce vomiting after eating so that she would lose weight and “fit in better with the other girls.” She stopped this at the end of the school year.

The following fall, 5 weeks into her sophomore year, she dropped out of high school and was ultimately enrolled in home school.

Treatment: 4 hospitalizations in 3 years

Between ages 12 and 15, Julie was hospitalized four times for outbursts of violence with impulsive self-harm. She “overdosed” on eight aceta-minophen/diphenhydramine tablets on one occasion and superficially cut her forearm on another. During these episodes, she said, she heard voices telling her to harm her mother and herself.

During this period, Julie was diagnosed as having schizophrenia, major depressive disorder, attention-deficit/hyperactivity disorder (ADHD), and oppositional defiant disorder (ODD). Numerous antidepressant and mood stabilizer regimens produced no lasting improvement, though her angry and violent episodes became less frequent.

poll here

The authors’ observations

Although Julie’s psychotic symptoms might suggest an evolving disorder such as schizophrenia, no clear pattern supports this diagnosis. Also:

• Onset at age 12 is unusual. Schizophrenia typically begins in late teens to early adulthood.
  
• Julie showed no premorbid personality problems—found in up to one-third of patients with chronic schizophrenia—and no premorbid adjustment difficulties resulting from negative symptoms, cognitive deficits, or poor social function.¹
  

Julie’s angry behaviors and refusal to stay in school suggest ODD, but this disorder generally presents without self-harm or other impulsive behaviors and occurs apart from psychosis or mood disorder episodes.¹ Her low mood, withdrawal from activities, and suicidal actions may suggest major depressive disorder with psychotic features, but this diagnosis does not explain the sudden dramatic transformation in her baseline personality.

Julie’s birth parents’ mental health history would offer crucial information, but this was not available.

Continued history: ‘I left my body’

Shortly after her 15th birthday, Julie broke down and told her parents that 3 years earlier, four boys had gang-raped her while she was “on a first date” with one of them at a school football game. She said one attacker held a knife to her throat, and they threatened to kill her friend Sheila if anyone was told. Julie said she felt so terrorized that “I left my body and watched what was happening.”

After the rape, Julie went home, showered, and went to bed. She said she felt “emotionally numb” for 2 months, during which she threw herself into schoolwork, stopped attending after-school events, and began arguing with her parents. She developed nightmares of the trauma and, eventually, auditory command hallucinations. When stressed, she has “out of body” feelings lasting several minutes.

The parents, though angry at Julie‘s attackers, did not seek legal counsel or report the rape to authorities because they felt too much time had passed. They sought support from a counselor, who referred their daughter to a male psychiatrist for medication management. Julie, now age 16, preferred to be treated by a woman, so her care was transferred to our clinic.

Based on clinical observations, Julie gets along well with her father. She complains that her mother is overprotective yet Julie cannot bear to be separated from her for even a couple hours. She resents her mother’s overinvolvement but relies on it for emotional regulation. Her mother has been treated for major depressive disorder, generalized anxiety disorder, and alcohol dependence. These were in sustained remission when Julie presented to us.

 

At presentation, we diagnosed Julie as having chronic posttraumatic stress disorder (PTSD), recurrent major depressive disorder, and eating disorder not otherwise specified. At 5 feet, 7 inches and 190 pounds, her body mass index is 30 kg/m², indicating clinical obesity. She has been taking duloxetine, 60 mg/d, extended release dextroamphetamine, 20 mg/d, aripiprazole, 20 mg/d, and amitriptyline, 10 mg/d nightly. She also has been taking sumatriptan, 100 mg as needed, for migraines.

poll here

The authors’ observations

After a life-threatening sexual assault, Julie suddenly became irritable and hostile. She could not keep relationships, yet she feared being alone. She impulsively hurt herself, experienced nightmares, and systematically avoided school activities. These behaviors suggest PTSD,¹ which is prevalent among sexual assault victims (Box 1). For 3 years, however, psychiatrists kept missing the diagnosis as Julie kept her shame a secret.

Julie tells us that she re-experiences trauma-related dysphoria when exposed to cues, such as the anniversary of the rape. She endorses avoidance symptoms, including feelings of estrangement from her family and friends. She shuns thoughts, feelings, places, and conversations associated with the trauma, which partly explains her refusal to stay in school. She reports arousal symptoms, including difficulty falling and staying asleep and fears of harm if left alone, even during the day. At night she has rituals for checking windows and doors to ensure they are locked.

Julie’s decision to hide her trauma was understandable given her age and developmental phase. For a teenager trying to separate from her parents and fit in at school, the humiliation was overwhelming. She lacked the cognitive tools to process and describe her experience. She was assaulted while on a date, normally a positive rite of passage. Further, as a young Hispanic/Native American, Julie feared disappointing her Caucasian parents by not fitting in at school.

When a previously well-adjusted teenager presents with sudden-onset behavioral problems, ask about past or recent trauma. Watch for contextual, developmental, and sociocultural factors that may prevent the youth from disclosing embarrassing events.

Also question the diagnosis if several adequate medication trials have failed. Check for comorbidities, lack of adherence, or other circumstances that can hamper response to treatment.

Box 1

Factors that may signal ptsd

American Psychiatric Association (APA) practice guidelines for treating PTSD list several factors to consider if you suspect this diagnosis:⁵

Impulsive and episodic aggression can result from an anticipatory bias that increases readiness for “fight, flight, or freeze.” For Julie, this turned previously comfortable interactions into dissonance and conflict.

Self-injurious and suicidal behaviors often occur when trauma creates stigma, shame, or guilt. Julie felt these emotions while trying to establish herself in a new community and school. Her obesity and ethnic background further set her apart from peers. She also left behind friends who provided emotional support outside the home and helped her differentiate from her mother.

Trauma during early adolescence can impair age-appropriate development, making it difficult to develop a stable self-image, consolidate and integrate the personality, and form relationships. At age 16, poor self-image and maladaptive coping strategies were an enduring pattern in Julie’s life.

Psychiatric comorbidities. Many patients with PTSD develop psychiatric comorbidities that exaggerate symptoms, making the disorder more difficult to detect and treat. Julie’s depression increased her avoidance tendencies and rein-forced her isolation. Difficulty concentrating—misdiagnosed as ADHD—deterred her from engaging in school. Dissociative symptoms related to PTSD impaired her reality testing, diminishing her ability to interact with others.

Treatment: Medication change

We continued extended-release dextroamphetamine, 20 mg/d, as Julie felt the medication helped her focus on her schoolwork. We also:

• weaned her off aripiprazole, which was not helping her symptoms
  
• stopped amitriptyline and duloxetine because of her history of impulsive overdose and to reduce side-effect risk from polypharmacy
  
• titrated fluoxetine to 40 mg/d to treat her ongoing chronic depression and added trazodone, 50 mg/d as needed, to help her sleep
  
• stopped sumatriptan, as the headaches remitted after Julie’s eyes were tested and eyeglasses prescribed.
  

Initially, we managed Julie’s medications while she received psychotherapy from her counselor, but she eventually shifted her entire care to us. We then began seeing her weekly for psychoeducation and supportive therapy.

 

poll here

The authors’ observations

Medication. APA treatment guidelines support using SSRIs to treat all three PTSD symptom clusters—re-experiencing, avoidance, and hyperarousal—as well as coexisting depression. Evidence also supports use of the tricyclics amitriptyline and imipramine and some monoamine oxidase inhibitors (MAOIs).^6-10 Dietary restrictions associated with MAOIs, however, can pose a problem for teenagers.

Benzodiazepines can decrease anxiety and improve sleep, but they can be addictive and their efficacy in treating PTSD has not been established. Alpha-2-adrenergic agonists such as prazosin and clonidine may decrease hyperarousal and trauma-related nightmares.^11,12

Obtain informed parental consent before starting a child or adolescent on an antidepressant. These medications contain a black-box warning that the drug may increase suicide risk in youths.

Psychotherapy. Varying levels of evidence support psychotherapy models in PTSD (Box 2). Julie can benefit from psychoeducation, supportive therapy, psychodynamic psychotherapy, and cautious re-exposure to trauma where possible.

Psychoeducation provided a safe starting point for Julie’s therapy, engaged her parents and select school counselors and teachers, and helped her understand PTSD’s effects. This allowed us to teach stress reduction and coping strategies.

Supportive techniques helped Julie contain painful affects. She could then network with community resources such as AlaTeen and a peer support group via a local Native American mental health program. This approach helped us gain Julie’s trust, and we anticipate more in-depth work with time.

Trauma re-exposure helps some patients but worsens others’ symptoms. For Julie, trauma re-exposure has been minimal because of the many other issues she was facing.

Developing a trusting relationship over time is crucial to successful trauma re-exposure. Re-exposure should be gradual to keep affective arousal moderate. This will minimize dissociation and affective flooding, which can frustrate treatment.

Cognitive-behavioral therapy (CBT) might help Julie understand the automatic thoughts of failure and defeat that flood her when she is stressed. CBT could help her master her feelings and lay a foundation for improved coping.

Psychodynamic psychotherapy may be started later to help Julie verbalize feelings and modulate how she expresses affect. This model could promote her development, improve her self-image, and treat her depression.

Box 2

Follow-up: Back to school

After 2 months under our care, Julie begins to show improvement. Because of her progress and the fact that her parents drive 45 minutes each way to get to our clinic, we reduce visit frequency from weekly to biweekly.

Julie now attends school 2 hours daily, is earning additional credits through home study, and plans to graduate early and attend community college. Her depression has lifted, and she continues to take fluoxetine, 40 mg/d and extended-release dextroamphetamine, 20 mg/d. She still struggles with social isolation, failure to reach age-appropriate developmental milestones, and a poor body image.

Related resources

• American Psychiatric Association. Practice guideline for treating acute stress disorder and posttraumatic stress disorder. www.psych.org/psych_pract/treatg/pg/PTSD-PG-PartsA-B-C-New.pdf
  
• National Center for Post-Traumatic Stress Disorder. Information on obtaining Impact of Events Scale and Davidson Trauma Scale. www.ncptsd.va.gov/publications/assessment/adult_self_report.html
  

Drug brand names

• Amitriptyline • Elavil
  
• Aripiprazole • Abilify
  
• Clonidine • Catapres
  
• Dextroamphetamine (extended-release) • Adderall XR
  
• Duloxetine • Cymbalta
  
• Fluoxetine • Prozac
  
• Imipramine • Tofranil
  
• Phenelzine • Nardil
  
• Prazosin • Minipress
  
• Sumatriptan • Imitrex
  
• Trazodone • Desyrel
  

Disclosure

Dr. Matthews is an American Psychiatric Association Bristol-Myers Squibb Co. fellow in public and community psychiatry.

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

Acknowledgements

The authors thank Larry Schwartz, MD, for his help in preparing this article for publication.

History: A tortured past

Ms. A, age 46, is referred to us by her primary care physician for a psychiatric evaluation. The patient endorses longstanding depression but has never seen a psychiatrist. She also reports that she was raped several years ago.

Ms. A meets DSM-IV-TR criteria for major depressive disorder, recurrent moderate; and posttraumatic stress disorder (PTSD). She complains of depressed mood, lack of energy, poor concentration and memory, anxiety, feelings of hopelessness and worthlessness, insomnia, and poor appetite. She has nightmares, flashbacks of her rape, and decreased interest in activities. She says she tries to avoid thoughts associated with her rape, feels detached from others, is easily startled, and at times is irritable.

Approximately 8 years ago—shortly after she started taking bupropion, 150 mg/d, to help her quit smoking—Ms. A suffered her first seizure-like episode. A neurologist diagnosed her with epilepsy based on EEG findings. He started her on carbamazepine, 200 mg bid, and titrated the dosage to 900 mg/d. After 2 years, however, her spells continued. Usually, she would black out for a few minutes and forget what she was doing. During some spells she would jerk her hands and feet, stare into space, repeat words over and over, and/or fumble with her hands.

After changing health insurance plans, Ms. A saw another neurologist who switched her to divalproex, 250 mg bid. She began having nausea, vomiting, and alopecia, so she stopped taking divalproex after 2 weeks. The neurologist switched her to topiramate, 25 mg bid, and titrated the dosage to 400 mg/d over 8 weeks with no side effects but minimal response. Reducing topiramate to 200 mg/d and adding phenytoin, 300 mg/d, produced little improvement.

Ms. A says these spells now come once or twice daily. She denies aura, loss of consciousness, tongue biting, or incontinence during seizures.

Medical history. Ms. A has undergone posterior fossa decompression for Arnold-Chiari type I malformation, right nephrectomy for renal cell carcinoma, a complete hysterectomy, an appendectomy, and bilateral breast implants. She has also had venous angiomas with head and neck pain.

Ms. A is frustrated over her lack of independence, her limited social life, and her inability to drive because of her seizure disorder. Once employed full-time for 12 years in a doctor’s office, she now gets by on disability benefits, which she finds degrading. She feels hopeless and helpless, as antiepileptics have not worked.

poll here

The authors’ observations

Ms. A complained of depression, sleep problems secondary to depression and PTSD, poor appetite, underlying anxiety, and decreased concentration, energy, and interest. We decided to address these symptoms with mirtazapine. Because she is thin (126 lb, body mass index 19.2 kg/m²), potential for weight gain with mirtazapine was not a concern.

We gauged Ms. A’s response to mirtazapine and her seizure history at our next visit, during which we customarily continue taking the patient’s history.

Treatment: Marriage by force?

Ms. A begins taking mirtazapine, 15 mg/d. At her next appointment the following week, she says she has stopped it because it has increased her appetite, which she fears will cause weight gain. She says her seizures, which usually occur at home, have continued with the same frequency.

Upon exploring her history further, we discover that Ms. A’s father was rarely around, and when he was he physically abused her. As a child she struggled with dyslexia, for which she received special education. She became pregnant while finishing high school and feels her mother forced her to marry her first husband.

Ms. A added that her three former husbands were physically and/or emotionally abusive toward her. About 10 years ago, she says, her third husband raped her.

We begin to suspect that Ms. A might not have epilepsy because of the seizures’ distinct nature, her vague symptoms, minimal or no response to antiepileptics, and comorbid mood and anxiety disorders. We refer her to another neurologist for video EEG (VEEG). She reluctantly agrees to the test, unwilling to believe that her seizures might have a psychiatric cause.

poll here

The authors’ observations

Recurrent seizures characteristic of epilepsy can significantly impair quality of life. Although the diagnosis often is straightforward, distinguishing epilepsy from psychogenic nonepileptic seizures (PNES) can be difficult.

PNES are sudden, episodic changes in behavior, perception, thinking, or feeling. These changes resemble epileptic events but are not prompted by abnormal brain electrical discharges as measured by EEG.¹

Formerly called pseudoseizures, PNES can have a physiologic or psychological cause (Table 1). They often are a somatic response to unbearable past events and/or current psychological tension or conflict. Most patients with PNES cite domestic abuse or family conflicts as key stressors.²

 

Few systematic studies have addressed how life events contribute to PNES. Associated life events—described mostly in case reports—fall into three general categories:

• childhood and adult trauma
  
• bereavement or loss
  
• acute or situational stressors.³
  

PNES diagnosis has become progressively refined over the last three decades. VEEG is used to diagnose PNES. Neuropsychological evaluation and VEEG are used together if PNES is believed to coexist with epilepsy or psychiatric disorders.^4,5

Table 1

Physiologic and psychological causes of nonepileptic seizures

Physiologic
Autonomic disorders
Cerebrovascular disease
Cardiac disorders
Vasovagal syncope
Ischemic heart disease
Valvular heart disease
Arrythmias
Drug toxicity
Endocrine disturbance
Metabolic disorders
Migraines
Paroxysmal movement disorder
Sleep disorder
Psychological
Anxiety disorders
Conversion disorder
Dissociative disorder
Factitious disorder
Malingering
Victim of physical, emotional, or sexual abuse
Posttraumatic stress disorder
Psychotic disorder
Somatoform disorder
Substance abuse/dependence

Continued treatment: Wasted years

Two weeks after our referral, Ms. A reports that the neurologist discontinued topiramate and phenytoin after VEEG showed no epileptic activity.

Ms. A now realizes she does not have epilepsy. She is angry that her first neurologist had misdiag-nosed her, effectively sentencing her to 8 years of needless dependency and disability.

We prescribe escitalopram, starting at 10 mg/d and titrating to 20 mg/d, to address Ms. A’s depressive/PTSD symptoms. We also refer her to a psychotherapist, who schedules twice-weekly supportive psychotherapy sessions. The therapist plans to teach her coping techniques and provide ego support and encouragement.

Ms. A’s psychotherapy progresses slowly at first, but by the fourth session she sets goals, which include getting off disability as soon as possible. With careful ego strengthening, she resumes driving and searches for a job. During one session, she tells her therapist she has long wanted to become a nurse, so she is encouraged to see a nursing school counselor for advice on selecting prerequisite nursing classes.

The authors’ observations

As with Ms. A, an erroneous epilepsy diagnosis can cause physical, psychosocial, and socioeconomic grief for the patient and can lead to needless restrictions, unemployment or underemployment, and dependence on disability benefits. After the misdiagnosis, Ms. A lost control of her future and considered her life a burden, leading to depression and anxiety. Her seizures caused most of her physical and psychological disturbances and diminished her overall function.

PNES are often mistaken for epileptic seizures, and 26% of seizure patients experience both.⁶ In a study of 50 patients, between 5% and 20% of patients evaluated for epilepsy and 10% to 40% of patients referred to comprehensive epilepsy centers were later found to have PNES.⁷

Like Ms. A, many patients with undiagnosed PNES receive antiepileptics to treat apparent epilepsy. These medications can cause troublesome side effects—from GI problems, to respiratory arrest in patients with pseudostatus, to potential teratogenicity.

In addition, comorbid epilepsy often goes undetected in patients with PNES. This could lead to inadequate treatment, increasing the patient’s morbidity and mortality risk.⁸

poll here

The authors’ observations

Patient history. Take a thorough history for patients with a history of seizures.

Too often, doctors assume a previous epilepsy diagnosis is correct, especially if rendered by a neurologist. In the United Kingdom, 20% to 31% of epilepsy diagnoses are incorrect because of incomplete history and misinterpreted EEG findings.⁸ When taking a patient’s seizure history, clinicians often do not get:

• a detailed history of seizures or seizurelike events, including onset, frequency, observations from family or friends, and seizure duration
  
• information on whether the patient remembers seizure details; has had prespell aura or loss of consciousness, or cries during the spells
  
• history of physical and/or sexual abuse.
  

Multiple daily seizures, repeated hospitalizations or emergency room visits, minimal response to antiepileptics, and no history of injury after seizures could suggest nonepileptic seizures. Seizures may be psychogenic if the patient was sexually abused, has a comorbid psychiatric disorder, or suffers attacks only when alone or only in public (Table 2).

Refer patients with features that may suggest PNES to a neurologist for VEEG to confirm or rule out epilepsy, because roughly one-quarter of seizure patients can have both.

Table 2

Patient features that suggest nonepileptic seizures

Comorbid psychiatric disorder(s)
Events occur only in presence of others or only when alone
Lack of concern or excessive emotional response to seizures
Minimal or no response to antiepileptics
Multiple daily seizures
No history of injury resulting from seizures
Normal neurologic history and examination
Repeated hospitalizations or emergency room visits
Unremarkable EEG and MRI findings
Victim of sexual abuse

Finding psychological causes. Psychological investigations become paramount after physiologic causes for nonepileptic seizures are ruled out.

The Minnesota Multiphasic Personality Inventory (MMPI) is often used to discriminate PNES from epilepsy. Wilkus et al⁹ reported significant differences in scores of MMPI hypochondriasis, hysteria, and schizophrenia scales among patients with PNES and epilepsy. Patients with PNES may have higher MMPI hypochondriasis, hysteria, schizophrenia, and psychopathic deviate scores than do patients with epilepsy.

 

Other authors, however, have found more variable MMPI results when using the test to distinguish PNES from epilepsy. Thus, the MMPI may provide supportive data for PNES diagnosis but is not a definitive tool.

Explaining the findings. Getting the patient to accept that the epilepsy is “in your head” is crucial to engaging him or her in treatment. The clinician needs to be honest with the patient while projecting a positive approach to the diagnosis. Tell the patient that not having epilepsy is “good news,” that antiepileptics are not needed, and that he or she can gain better control once stress or emotional issues are resolved.¹⁰

Follow-up: A learning experience

Within 4 months of her last seizure, Ms. A showed dramatic improvement. She began driving, working part-time and enrolled in nursing school. Her disability benefits program provided tuition assistance.

Ms. A has now been seizure-free for 1 year. Motivated and determined, she is taking up to 8 credit hours per semester and earning As and Bs but at times is anxious and fears failure. She needs much support and encouragement. Multiple therapy techniques—including direct teaching, admiring her progress, offering support, explaining, and ego strengthening—have produced good results. She is still taking escitalopram, 20 mg/d, and sees her therapist every 2 weeks.

Related resources

• Adetunji B, Mathews M, Williams A, Verma S. Psychogenic or epileptic seizures? How to clinch the diagnosis. Current Psychiatry 2004;3(11):25-35.
  
• Privitera MD. EEGs and epilepsy: When seizures mimic psychiatric illness. Current Psychiatry 2002;1(9):14-21.
  

Drug brand names

• Bupropion • Wellbutrin, Zyban
  
• Carbamazepine • Tegretol
  
• Divalproex sodium • Depakote
  
• Escitalopram • Lexapro
  
• Mirtazapine • Remeron
  
• Phenytoin • Dilantin
  
• Topiramate • Topamax
  

Disclosure

Dr. Khan is a speaker for Pfizer and Wyeth.

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

History: A tortured past

Ms. A, age 46, is referred to us by her primary care physician for a psychiatric evaluation. The patient endorses longstanding depression but has never seen a psychiatrist. She also reports that she was raped several years ago.

Ms. A meets DSM-IV-TR criteria for major depressive disorder, recurrent moderate; and posttraumatic stress disorder (PTSD). She complains of depressed mood, lack of energy, poor concentration and memory, anxiety, feelings of hopelessness and worthlessness, insomnia, and poor appetite. She has nightmares, flashbacks of her rape, and decreased interest in activities. She says she tries to avoid thoughts associated with her rape, feels detached from others, is easily startled, and at times is irritable.

Approximately 8 years ago—shortly after she started taking bupropion, 150 mg/d, to help her quit smoking—Ms. A suffered her first seizure-like episode. A neurologist diagnosed her with epilepsy based on EEG findings. He started her on carbamazepine, 200 mg bid, and titrated the dosage to 900 mg/d. After 2 years, however, her spells continued. Usually, she would black out for a few minutes and forget what she was doing. During some spells she would jerk her hands and feet, stare into space, repeat words over and over, and/or fumble with her hands.

After changing health insurance plans, Ms. A saw another neurologist who switched her to divalproex, 250 mg bid. She began having nausea, vomiting, and alopecia, so she stopped taking divalproex after 2 weeks. The neurologist switched her to topiramate, 25 mg bid, and titrated the dosage to 400 mg/d over 8 weeks with no side effects but minimal response. Reducing topiramate to 200 mg/d and adding phenytoin, 300 mg/d, produced little improvement.

Ms. A says these spells now come once or twice daily. She denies aura, loss of consciousness, tongue biting, or incontinence during seizures.

Medical history. Ms. A has undergone posterior fossa decompression for Arnold-Chiari type I malformation, right nephrectomy for renal cell carcinoma, a complete hysterectomy, an appendectomy, and bilateral breast implants. She has also had venous angiomas with head and neck pain.

Ms. A is frustrated over her lack of independence, her limited social life, and her inability to drive because of her seizure disorder. Once employed full-time for 12 years in a doctor’s office, she now gets by on disability benefits, which she finds degrading. She feels hopeless and helpless, as antiepileptics have not worked.

poll here

The authors’ observations

Ms. A complained of depression, sleep problems secondary to depression and PTSD, poor appetite, underlying anxiety, and decreased concentration, energy, and interest. We decided to address these symptoms with mirtazapine. Because she is thin (126 lb, body mass index 19.2 kg/m²), potential for weight gain with mirtazapine was not a concern.

We gauged Ms. A’s response to mirtazapine and her seizure history at our next visit, during which we customarily continue taking the patient’s history.

Treatment: Marriage by force?

Ms. A begins taking mirtazapine, 15 mg/d. At her next appointment the following week, she says she has stopped it because it has increased her appetite, which she fears will cause weight gain. She says her seizures, which usually occur at home, have continued with the same frequency.

Upon exploring her history further, we discover that Ms. A’s father was rarely around, and when he was he physically abused her. As a child she struggled with dyslexia, for which she received special education. She became pregnant while finishing high school and feels her mother forced her to marry her first husband.

Ms. A added that her three former husbands were physically and/or emotionally abusive toward her. About 10 years ago, she says, her third husband raped her.

We begin to suspect that Ms. A might not have epilepsy because of the seizures’ distinct nature, her vague symptoms, minimal or no response to antiepileptics, and comorbid mood and anxiety disorders. We refer her to another neurologist for video EEG (VEEG). She reluctantly agrees to the test, unwilling to believe that her seizures might have a psychiatric cause.

poll here

The authors’ observations

Recurrent seizures characteristic of epilepsy can significantly impair quality of life. Although the diagnosis often is straightforward, distinguishing epilepsy from psychogenic nonepileptic seizures (PNES) can be difficult.

PNES are sudden, episodic changes in behavior, perception, thinking, or feeling. These changes resemble epileptic events but are not prompted by abnormal brain electrical discharges as measured by EEG.¹

Formerly called pseudoseizures, PNES can have a physiologic or psychological cause (Table 1). They often are a somatic response to unbearable past events and/or current psychological tension or conflict. Most patients with PNES cite domestic abuse or family conflicts as key stressors.²

 

Few systematic studies have addressed how life events contribute to PNES. Associated life events—described mostly in case reports—fall into three general categories:

• childhood and adult trauma
  
• bereavement or loss
  
• acute or situational stressors.³
  

PNES diagnosis has become progressively refined over the last three decades. VEEG is used to diagnose PNES. Neuropsychological evaluation and VEEG are used together if PNES is believed to coexist with epilepsy or psychiatric disorders.^4,5

Table 1

Physiologic and psychological causes of nonepileptic seizures

Physiologic
Autonomic disorders
Cerebrovascular disease
Cardiac disorders
Vasovagal syncope
Ischemic heart disease
Valvular heart disease
Arrythmias
Drug toxicity
Endocrine disturbance
Metabolic disorders
Migraines
Paroxysmal movement disorder
Sleep disorder
Psychological
Anxiety disorders
Conversion disorder
Dissociative disorder
Factitious disorder
Malingering
Victim of physical, emotional, or sexual abuse
Posttraumatic stress disorder
Psychotic disorder
Somatoform disorder
Substance abuse/dependence

Continued treatment: Wasted years

Two weeks after our referral, Ms. A reports that the neurologist discontinued topiramate and phenytoin after VEEG showed no epileptic activity.

Ms. A now realizes she does not have epilepsy. She is angry that her first neurologist had misdiag-nosed her, effectively sentencing her to 8 years of needless dependency and disability.

We prescribe escitalopram, starting at 10 mg/d and titrating to 20 mg/d, to address Ms. A’s depressive/PTSD symptoms. We also refer her to a psychotherapist, who schedules twice-weekly supportive psychotherapy sessions. The therapist plans to teach her coping techniques and provide ego support and encouragement.

Ms. A’s psychotherapy progresses slowly at first, but by the fourth session she sets goals, which include getting off disability as soon as possible. With careful ego strengthening, she resumes driving and searches for a job. During one session, she tells her therapist she has long wanted to become a nurse, so she is encouraged to see a nursing school counselor for advice on selecting prerequisite nursing classes.

The authors’ observations

As with Ms. A, an erroneous epilepsy diagnosis can cause physical, psychosocial, and socioeconomic grief for the patient and can lead to needless restrictions, unemployment or underemployment, and dependence on disability benefits. After the misdiagnosis, Ms. A lost control of her future and considered her life a burden, leading to depression and anxiety. Her seizures caused most of her physical and psychological disturbances and diminished her overall function.

PNES are often mistaken for epileptic seizures, and 26% of seizure patients experience both.⁶ In a study of 50 patients, between 5% and 20% of patients evaluated for epilepsy and 10% to 40% of patients referred to comprehensive epilepsy centers were later found to have PNES.⁷

Like Ms. A, many patients with undiagnosed PNES receive antiepileptics to treat apparent epilepsy. These medications can cause troublesome side effects—from GI problems, to respiratory arrest in patients with pseudostatus, to potential teratogenicity.

In addition, comorbid epilepsy often goes undetected in patients with PNES. This could lead to inadequate treatment, increasing the patient’s morbidity and mortality risk.⁸

poll here

The authors’ observations

Patient history. Take a thorough history for patients with a history of seizures.

Too often, doctors assume a previous epilepsy diagnosis is correct, especially if rendered by a neurologist. In the United Kingdom, 20% to 31% of epilepsy diagnoses are incorrect because of incomplete history and misinterpreted EEG findings.⁸ When taking a patient’s seizure history, clinicians often do not get:

• a detailed history of seizures or seizurelike events, including onset, frequency, observations from family or friends, and seizure duration
  
• information on whether the patient remembers seizure details; has had prespell aura or loss of consciousness, or cries during the spells
  
• history of physical and/or sexual abuse.
  

Multiple daily seizures, repeated hospitalizations or emergency room visits, minimal response to antiepileptics, and no history of injury after seizures could suggest nonepileptic seizures. Seizures may be psychogenic if the patient was sexually abused, has a comorbid psychiatric disorder, or suffers attacks only when alone or only in public (Table 2).

Refer patients with features that may suggest PNES to a neurologist for VEEG to confirm or rule out epilepsy, because roughly one-quarter of seizure patients can have both.

Table 2

Patient features that suggest nonepileptic seizures

Comorbid psychiatric disorder(s)
Events occur only in presence of others or only when alone
Lack of concern or excessive emotional response to seizures
Minimal or no response to antiepileptics
Multiple daily seizures
No history of injury resulting from seizures
Normal neurologic history and examination
Repeated hospitalizations or emergency room visits
Unremarkable EEG and MRI findings
Victim of sexual abuse

Finding psychological causes. Psychological investigations become paramount after physiologic causes for nonepileptic seizures are ruled out.

The Minnesota Multiphasic Personality Inventory (MMPI) is often used to discriminate PNES from epilepsy. Wilkus et al⁹ reported significant differences in scores of MMPI hypochondriasis, hysteria, and schizophrenia scales among patients with PNES and epilepsy. Patients with PNES may have higher MMPI hypochondriasis, hysteria, schizophrenia, and psychopathic deviate scores than do patients with epilepsy.

 

Other authors, however, have found more variable MMPI results when using the test to distinguish PNES from epilepsy. Thus, the MMPI may provide supportive data for PNES diagnosis but is not a definitive tool.

Explaining the findings. Getting the patient to accept that the epilepsy is “in your head” is crucial to engaging him or her in treatment. The clinician needs to be honest with the patient while projecting a positive approach to the diagnosis. Tell the patient that not having epilepsy is “good news,” that antiepileptics are not needed, and that he or she can gain better control once stress or emotional issues are resolved.¹⁰

Follow-up: A learning experience

Within 4 months of her last seizure, Ms. A showed dramatic improvement. She began driving, working part-time and enrolled in nursing school. Her disability benefits program provided tuition assistance.

Ms. A has now been seizure-free for 1 year. Motivated and determined, she is taking up to 8 credit hours per semester and earning As and Bs but at times is anxious and fears failure. She needs much support and encouragement. Multiple therapy techniques—including direct teaching, admiring her progress, offering support, explaining, and ego strengthening—have produced good results. She is still taking escitalopram, 20 mg/d, and sees her therapist every 2 weeks.

Related resources

• Adetunji B, Mathews M, Williams A, Verma S. Psychogenic or epileptic seizures? How to clinch the diagnosis. Current Psychiatry 2004;3(11):25-35.
  
• Privitera MD. EEGs and epilepsy: When seizures mimic psychiatric illness. Current Psychiatry 2002;1(9):14-21.
  

Drug brand names

• Bupropion • Wellbutrin, Zyban
  
• Carbamazepine • Tegretol
  
• Divalproex sodium • Depakote
  
• Escitalopram • Lexapro
  
• Mirtazapine • Remeron
  
• Phenytoin • Dilantin
  
• Topiramate • Topamax
  

Disclosure

Dr. Khan is a speaker for Pfizer and Wyeth.

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

History: A tortured past

Ms. A, age 46, is referred to us by her primary care physician for a psychiatric evaluation. The patient endorses longstanding depression but has never seen a psychiatrist. She also reports that she was raped several years ago.

Ms. A meets DSM-IV-TR criteria for major depressive disorder, recurrent moderate; and posttraumatic stress disorder (PTSD). She complains of depressed mood, lack of energy, poor concentration and memory, anxiety, feelings of hopelessness and worthlessness, insomnia, and poor appetite. She has nightmares, flashbacks of her rape, and decreased interest in activities. She says she tries to avoid thoughts associated with her rape, feels detached from others, is easily startled, and at times is irritable.

Approximately 8 years ago—shortly after she started taking bupropion, 150 mg/d, to help her quit smoking—Ms. A suffered her first seizure-like episode. A neurologist diagnosed her with epilepsy based on EEG findings. He started her on carbamazepine, 200 mg bid, and titrated the dosage to 900 mg/d. After 2 years, however, her spells continued. Usually, she would black out for a few minutes and forget what she was doing. During some spells she would jerk her hands and feet, stare into space, repeat words over and over, and/or fumble with her hands.

After changing health insurance plans, Ms. A saw another neurologist who switched her to divalproex, 250 mg bid. She began having nausea, vomiting, and alopecia, so she stopped taking divalproex after 2 weeks. The neurologist switched her to topiramate, 25 mg bid, and titrated the dosage to 400 mg/d over 8 weeks with no side effects but minimal response. Reducing topiramate to 200 mg/d and adding phenytoin, 300 mg/d, produced little improvement.

Ms. A says these spells now come once or twice daily. She denies aura, loss of consciousness, tongue biting, or incontinence during seizures.

Medical history. Ms. A has undergone posterior fossa decompression for Arnold-Chiari type I malformation, right nephrectomy for renal cell carcinoma, a complete hysterectomy, an appendectomy, and bilateral breast implants. She has also had venous angiomas with head and neck pain.

Ms. A is frustrated over her lack of independence, her limited social life, and her inability to drive because of her seizure disorder. Once employed full-time for 12 years in a doctor’s office, she now gets by on disability benefits, which she finds degrading. She feels hopeless and helpless, as antiepileptics have not worked.

poll here

The authors’ observations

Ms. A complained of depression, sleep problems secondary to depression and PTSD, poor appetite, underlying anxiety, and decreased concentration, energy, and interest. We decided to address these symptoms with mirtazapine. Because she is thin (126 lb, body mass index 19.2 kg/m²), potential for weight gain with mirtazapine was not a concern.

We gauged Ms. A’s response to mirtazapine and her seizure history at our next visit, during which we customarily continue taking the patient’s history.

Treatment: Marriage by force?

Ms. A begins taking mirtazapine, 15 mg/d. At her next appointment the following week, she says she has stopped it because it has increased her appetite, which she fears will cause weight gain. She says her seizures, which usually occur at home, have continued with the same frequency.

Upon exploring her history further, we discover that Ms. A’s father was rarely around, and when he was he physically abused her. As a child she struggled with dyslexia, for which she received special education. She became pregnant while finishing high school and feels her mother forced her to marry her first husband.

Ms. A added that her three former husbands were physically and/or emotionally abusive toward her. About 10 years ago, she says, her third husband raped her.

We begin to suspect that Ms. A might not have epilepsy because of the seizures’ distinct nature, her vague symptoms, minimal or no response to antiepileptics, and comorbid mood and anxiety disorders. We refer her to another neurologist for video EEG (VEEG). She reluctantly agrees to the test, unwilling to believe that her seizures might have a psychiatric cause.

poll here

The authors’ observations

Recurrent seizures characteristic of epilepsy can significantly impair quality of life. Although the diagnosis often is straightforward, distinguishing epilepsy from psychogenic nonepileptic seizures (PNES) can be difficult.

PNES are sudden, episodic changes in behavior, perception, thinking, or feeling. These changes resemble epileptic events but are not prompted by abnormal brain electrical discharges as measured by EEG.¹

Formerly called pseudoseizures, PNES can have a physiologic or psychological cause (Table 1). They often are a somatic response to unbearable past events and/or current psychological tension or conflict. Most patients with PNES cite domestic abuse or family conflicts as key stressors.²

 

Few systematic studies have addressed how life events contribute to PNES. Associated life events—described mostly in case reports—fall into three general categories:

• childhood and adult trauma
  
• bereavement or loss
  
• acute or situational stressors.³
  

PNES diagnosis has become progressively refined over the last three decades. VEEG is used to diagnose PNES. Neuropsychological evaluation and VEEG are used together if PNES is believed to coexist with epilepsy or psychiatric disorders.^4,5

Table 1

Physiologic and psychological causes of nonepileptic seizures

Physiologic
Autonomic disorders
Cerebrovascular disease
Cardiac disorders
Vasovagal syncope
Ischemic heart disease
Valvular heart disease
Arrythmias
Drug toxicity
Endocrine disturbance
Metabolic disorders
Migraines
Paroxysmal movement disorder
Sleep disorder
Psychological
Anxiety disorders
Conversion disorder
Dissociative disorder
Factitious disorder
Malingering
Victim of physical, emotional, or sexual abuse
Posttraumatic stress disorder
Psychotic disorder
Somatoform disorder
Substance abuse/dependence

Continued treatment: Wasted years

Two weeks after our referral, Ms. A reports that the neurologist discontinued topiramate and phenytoin after VEEG showed no epileptic activity.

Ms. A now realizes she does not have epilepsy. She is angry that her first neurologist had misdiag-nosed her, effectively sentencing her to 8 years of needless dependency and disability.

We prescribe escitalopram, starting at 10 mg/d and titrating to 20 mg/d, to address Ms. A’s depressive/PTSD symptoms. We also refer her to a psychotherapist, who schedules twice-weekly supportive psychotherapy sessions. The therapist plans to teach her coping techniques and provide ego support and encouragement.

Ms. A’s psychotherapy progresses slowly at first, but by the fourth session she sets goals, which include getting off disability as soon as possible. With careful ego strengthening, she resumes driving and searches for a job. During one session, she tells her therapist she has long wanted to become a nurse, so she is encouraged to see a nursing school counselor for advice on selecting prerequisite nursing classes.

The authors’ observations

As with Ms. A, an erroneous epilepsy diagnosis can cause physical, psychosocial, and socioeconomic grief for the patient and can lead to needless restrictions, unemployment or underemployment, and dependence on disability benefits. After the misdiagnosis, Ms. A lost control of her future and considered her life a burden, leading to depression and anxiety. Her seizures caused most of her physical and psychological disturbances and diminished her overall function.

PNES are often mistaken for epileptic seizures, and 26% of seizure patients experience both.⁶ In a study of 50 patients, between 5% and 20% of patients evaluated for epilepsy and 10% to 40% of patients referred to comprehensive epilepsy centers were later found to have PNES.⁷

Like Ms. A, many patients with undiagnosed PNES receive antiepileptics to treat apparent epilepsy. These medications can cause troublesome side effects—from GI problems, to respiratory arrest in patients with pseudostatus, to potential teratogenicity.

In addition, comorbid epilepsy often goes undetected in patients with PNES. This could lead to inadequate treatment, increasing the patient’s morbidity and mortality risk.⁸

poll here

The authors’ observations

Patient history. Take a thorough history for patients with a history of seizures.

Too often, doctors assume a previous epilepsy diagnosis is correct, especially if rendered by a neurologist. In the United Kingdom, 20% to 31% of epilepsy diagnoses are incorrect because of incomplete history and misinterpreted EEG findings.⁸ When taking a patient’s seizure history, clinicians often do not get:

• a detailed history of seizures or seizurelike events, including onset, frequency, observations from family or friends, and seizure duration
  
• information on whether the patient remembers seizure details; has had prespell aura or loss of consciousness, or cries during the spells
  
• history of physical and/or sexual abuse.
  

Multiple daily seizures, repeated hospitalizations or emergency room visits, minimal response to antiepileptics, and no history of injury after seizures could suggest nonepileptic seizures. Seizures may be psychogenic if the patient was sexually abused, has a comorbid psychiatric disorder, or suffers attacks only when alone or only in public (Table 2).

Refer patients with features that may suggest PNES to a neurologist for VEEG to confirm or rule out epilepsy, because roughly one-quarter of seizure patients can have both.

Table 2

Patient features that suggest nonepileptic seizures

Comorbid psychiatric disorder(s)
Events occur only in presence of others or only when alone
Lack of concern or excessive emotional response to seizures
Minimal or no response to antiepileptics
Multiple daily seizures
No history of injury resulting from seizures
Normal neurologic history and examination
Repeated hospitalizations or emergency room visits
Unremarkable EEG and MRI findings
Victim of sexual abuse

Finding psychological causes. Psychological investigations become paramount after physiologic causes for nonepileptic seizures are ruled out.

The Minnesota Multiphasic Personality Inventory (MMPI) is often used to discriminate PNES from epilepsy. Wilkus et al⁹ reported significant differences in scores of MMPI hypochondriasis, hysteria, and schizophrenia scales among patients with PNES and epilepsy. Patients with PNES may have higher MMPI hypochondriasis, hysteria, schizophrenia, and psychopathic deviate scores than do patients with epilepsy.

 

Other authors, however, have found more variable MMPI results when using the test to distinguish PNES from epilepsy. Thus, the MMPI may provide supportive data for PNES diagnosis but is not a definitive tool.

Explaining the findings. Getting the patient to accept that the epilepsy is “in your head” is crucial to engaging him or her in treatment. The clinician needs to be honest with the patient while projecting a positive approach to the diagnosis. Tell the patient that not having epilepsy is “good news,” that antiepileptics are not needed, and that he or she can gain better control once stress or emotional issues are resolved.¹⁰

Follow-up: A learning experience

Within 4 months of her last seizure, Ms. A showed dramatic improvement. She began driving, working part-time and enrolled in nursing school. Her disability benefits program provided tuition assistance.

Ms. A has now been seizure-free for 1 year. Motivated and determined, she is taking up to 8 credit hours per semester and earning As and Bs but at times is anxious and fears failure. She needs much support and encouragement. Multiple therapy techniques—including direct teaching, admiring her progress, offering support, explaining, and ego strengthening—have produced good results. She is still taking escitalopram, 20 mg/d, and sees her therapist every 2 weeks.

Related resources

• Adetunji B, Mathews M, Williams A, Verma S. Psychogenic or epileptic seizures? How to clinch the diagnosis. Current Psychiatry 2004;3(11):25-35.
  
• Privitera MD. EEGs and epilepsy: When seizures mimic psychiatric illness. Current Psychiatry 2002;1(9):14-21.
  

Drug brand names

• Bupropion • Wellbutrin, Zyban
  
• Carbamazepine • Tegretol
  
• Divalproex sodium • Depakote
  
• Escitalopram • Lexapro
  
• Mirtazapine • Remeron
  
• Phenytoin • Dilantin
  
• Topiramate • Topamax
  

Disclosure

Dr. Khan is a speaker for Pfizer and Wyeth.

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

History: impulsive and distractible

For 2 years Mark, age 11, has been treated for attention-deficit/hyperactivity disorder (ADHD). His initial symptoms included inattention, hyperactivity, distractibility, short attention span, failure to follow instructions, poor organization, and intruding on others. He often picks fights with his 7-year-old brother, mildly injuring him on one occasion. His teacher recently punished him for roaming the classroom and distracting his classmates.

None of Mark’s symptoms suggest mania. His family has no history of mood disorders, but his father has been diagnosed with substance dependence.

Mark’s psychiatrist had prescribed an extended-release amphetamine salts preparation, 10 mg/d. Soon after, Mark began experiencing stomachaches, insomnia, facial flushing, and headaches. The dosage was reduced to 5 mg/d, but Mark stopped taking the medication after less than 3 weeks. Cognitive-behavioral therapy and classroom modifications were then tried for 11 months, but Mark’s behavior worsened. His symptoms now include inattention, distractibility, excessive talking, restlessness, and impulsivity.

The authors’ observations

Children and adolescents often present with excessive talking, distractibility, increased activity or restlessness, and loss of normal functioning. Distinguishing these ADHD symptoms from those of bipolar, disruptive, learning, movement, anxiety, substance-related or other mental disorders can be challenging.^{How to reduce mania risk when prescribing stimulants,” October 2005, at www.currentpsychiatry.com.)}

Pediatric bipolar disorder often goes undetected because DSM-IV-TR criteria—established for adults—may not apply to youths. Children are more likely to present with a mixed mood state, less-distinct periods between episodes, grandiosity, irritability, and a chronic, continuous course.² By contrast, bipolar adults often present with a sudden classic manic episode, elation, and euphoria.² Adults also usually have relatively stable periods between episodes and tend to have comorbid substance dependence, panic, or eating disorders.

Mark’s symptoms still suggest ADHD. His inattention started before age 7, and his teacher is mostly concerned about his hyperactive, impulsive, and disruptive behavior. Mark’s mother, teacher, and psychiatrist feel confident that the ADHD diagnosis is correct, so we decide against comprehensive reassessment or prescribing a mood stabilizer. Mark’s mother opts to try the nonstimulant ADHD medication atomoxetine rather than a different stimulant.

Treatment: a moving experience

Mark’s psychiatrist prescribes atomoxetine, 18 mg/d for 4 days, then increases the dosage to 25 mg/d after finding that the boy could tolerate the medication.

Two weeks after starting atomoxetine, Mark becomes agitated and activated, and voices suicidal thoughts on one occasion. Without warning, while his mother is driving him to school, he opens the door of the moving vehicle and tries to jump out. His mother stops him by calling his name, yelling “No,” and slamming on the brakes. Mark tells her that he is “bad” and wants to die. She has no idea what prompted this behavior.

Mark also has become more oppositional and defiant, and his temper tantrums and destruction of household items are more frequent. He continues to behave aggressively toward his younger brother, often breaking some of his favorite toys. Mark also shows elevated and expansive mood, irritability, pressured speech, inflated self-esteem, and psychomotor agitation—symptoms consistent with a manic episode. At one visit, Mark tells his psychia trist, “I feel great! I can do anything.”

The authors’ observations

Mark, who had been diagnosed as having ADHD, began showing manic activation and suicidal thinking 2 weeks after starting atomoxetine. Whether he showed de novo suicidal behavior or reckless behavior associated with mania is unclear.

Atomoxetine-induced mania is not a new finding.^2,5 During clinical trials, 2% of patients reported mood swings and 8% reported irritability. Subsequent experience indicates the risk of mood destabilization may be as high as 33%.⁵

Atomoxetine, a nonstimulant medication indicated for treating pediatric and adult ADHD, is a potent norepinephrine reuptake inhibitor. Reanalysis of the atomoxetine clinical trial database showed a slightly but statistically significant higher risk of suicidal behavior and thoughts in children and adolescents compared with placebo.⁶ No deaths from suicide were reported. The FDA subsequently ordered a black box warning on atomoxetine’s label instructing physicians, patients, and families to watch closely for suicidality symptoms with atomoxetine use.

Atomoxetine is safe and effective for pediatric ADHD, provided youths are properly monitored. Be careful, however, when prescribing atomoxetine to youths with a personal or family history of mood disorder.

FDA also is reviewing data on all drugs indicated for treating ADHD to determine whether they cause suicidality, new-onset mental disorders, or other psychiatric adverse events.⁷

Assessing medication risk

All youths being treated for a mood disorder and/or ADHD must be assessed for suicide risk, but how to most effectively perform this assessment is unclear. Organizations representing pediatrics and child and adolescent psychiatry have not yet incorporated FDA’s medication guidelines regarding pediatric suicidality—released earlier this year—into their guidelines (Table 1). As a result, most physicians follow pediatric patients less frequently than FDA now advises.

 

Atomoxetine’s receptor profile resembles that of antidepressants, which also are labeled with a black box warning describing increased suicidality risk when used in children and adolescents. Risk of suicidal behavior is highest within 10 days of starting antidepressants, and a significant risk remains throughout the first month. The suicidality rate appears to drop after that time.^9,10

Follow FDA patient monitoring guidelines for antidepressants when prescribing atomoxetine to youths—particularly given the prospective labeling change. Atomoxetine’s manufacturer is expected to release a patient monitoring guideline unique to this drug.

Table 1

FDA guidelines for monitoring pediatric antidepressant use

After starting an antidepressant, patients should see their doctor:
Once weekly for 4 weeks Every 2 weeks for the next month At the end of the 12th week taking the drug More often if problems or questions arise
Source: Reference 8

Suicidality: finding other causes

Suicidality is more prevalent in bipolar disorder than in other mental disorders,^2,4 and ADHD and mania often co-exist (Box 1).^11,12 Mania induced by medication might explain suicidality or other behavior changes in some youths, but activation, mania, behavior change, or suicidality can result from the primary or comorbid disorder rather than the medication.

No deaths by suicide were reported among the FDA-reviewed studies of antidepressant use in children and adolescents. Fatal suicidal behavior has been reported in adolescents not treated with medications.¹⁴

FDA cites 12 features that point to suicide risk in youths (Box 2).^8-10 Seven features suggest both ADHD and mania, which overlap to the point of diagnostic distraction.

Box 1

Box 2

The authors’ observations

Consider a broad differential diagnosis when evaluating inattention, hyperactivity, and impulsivity in children. Family medical history, corroborative clinical interviews, past and current behavioral rating scores, and psychological testing can help confirm an ADHD diagnosis (Table 2).

A careful patient interview, watching for diagnostic clues, taking a confirmatory history, and attention to key symptoms can help you discern ADHD from mania. Rule out unexplored diagnoses such as substance abuse, disturbed relationships, medical illness, and other mental disorders. Having the family and teachers track the youth’s longitudinal mood, energy, sleep, and actions may confirm a mood disorder.

Elated mood or grandiosity indicate mania. Irritable hyperactivity is seen more frequently in mania, whereas general hyperactivity tends to be present in ADHD. Childhood depression often heralds bipolar disorder.

Suspected medication-induced suicidality may call for stopping the offending agent, but determining whether a mental disorder or medication is causing suicidal thoughts can be difficult.

Try stopping the suspected offending drug first. If the youth remains suicidal after 1 week, a thorough biopsychosocial reassessment may guide future options including inpatient care, intensive outpatient psychotherapy, monitoring, and cautious use of antidepressant and/or antimanic medications.

Suicide risk requires clinician vigilance. As we learn from the FDA’s warnings, each treatment episode confers new risk and underscores the importance of watching for risk factors that may predict suicide (Table 3).

Table 2

What to include in an ADHD evaluation

Histories: psychosocial, developmental, medical, educational, substance use and/or family
Clinical interviews with the child or adolescent. Corroborative interviews with parents, guardians, teachers, others
Rating scales assessing past behavior: Instruments completed by multiple sources such as the youth, family members or guardian, former teachers, others
Rating scales of current behavior: Instruments completed by youth, parents or guardian, former teachers, siblings, significant others
Psychological testing: Psychoeducational evaluation, personality inventory, intelligence assessment, and/or a continuous performance test. ADHD diagnosis remains clinical, and no evaluation should rely too heavily on “objective tests” for a definitive diagnosis

Table 3

Risk factors that may predict suicide in youths

Older (pubertal) age
Male gender
Mania
Mixed mood state
Psychosis
Victim of sexual or physical abuse
Co-occurring disruptive disorders
Comorbid substance abuse
Impulsivity
Easy access to means, such as firearms, lethal toxins, or medications
Lack of family support
Acute stressors
Family history of suicide
Source: Adapted from reference 2.

Continued treatment: no more medication

Mark’s psychiatrist immediately stops atomoxetine. The boy’s mother, a psychiatric nurse, declines a trial of divalproex because she fears drug toxicity. Mark’s suicidality and agitation resolve over 1 week, and he returns to baseline function, leading us to believe his mania was medication-induced.

 

One year later, Mark takes no medications. He is behaving well at school and made the honor roll this fall. His teacher reports that Mark is “smart, well liked, but talks excessively,” though she says his talking is “not as out of control” as it was a year ago.

Mark recently began playing soccer as an outlet for his hyperactivity. He has not been penalized on the soccer field but is occasionally “over the edge,” pushing and shoving other players. When frustrated at home he has short outbursts, slams doors, and yells at his brother without being physically aggressive.

Mark’s office visits are infrequent, but he recently asked his mother to take him to his psychiatrist and counselor. His mother realizes he may soon need medication, but she wants to wait.

Related resources

• U.S. Food and Drug Administration. List of drugs receiving a boxed warning, other product labeling changes, and a medication guide pertaining to pediatric suicidality. www.fda.gov/cder/drug/antidepressants/MDD_alldruglist.pdf.
• Eli Lilly and Co. Questions and answers about the Strattera (atomoxetine) label change: a guide for patients and parents. www.strattera.com/1_5_news/Q&A_Strattera_label_update.pdf.
• U.S. Food and Drug Administration. Public health advisory: Suicidal thinking in children and adolescents being treated with Strattera (atomoxetine).www.fda.gov/cder/drug/advisory/atomoxetine.htm.
• Mann JJ, Apter A, Bertolote J, et al. Suicide prevention strategies: a systematic review. JAMA 2005;294(16):2064-74.

Drug brand names

• Divalproex sodium • Depakote
• Mixed amphetamine salts • Adderall XR
• Atomoxetine • Strattera

Disclosure

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

History: impulsive and distractible

For 2 years Mark, age 11, has been treated for attention-deficit/hyperactivity disorder (ADHD). His initial symptoms included inattention, hyperactivity, distractibility, short attention span, failure to follow instructions, poor organization, and intruding on others. He often picks fights with his 7-year-old brother, mildly injuring him on one occasion. His teacher recently punished him for roaming the classroom and distracting his classmates.

None of Mark’s symptoms suggest mania. His family has no history of mood disorders, but his father has been diagnosed with substance dependence.

Mark’s psychiatrist had prescribed an extended-release amphetamine salts preparation, 10 mg/d. Soon after, Mark began experiencing stomachaches, insomnia, facial flushing, and headaches. The dosage was reduced to 5 mg/d, but Mark stopped taking the medication after less than 3 weeks. Cognitive-behavioral therapy and classroom modifications were then tried for 11 months, but Mark’s behavior worsened. His symptoms now include inattention, distractibility, excessive talking, restlessness, and impulsivity.

The authors’ observations

Children and adolescents often present with excessive talking, distractibility, increased activity or restlessness, and loss of normal functioning. Distinguishing these ADHD symptoms from those of bipolar, disruptive, learning, movement, anxiety, substance-related or other mental disorders can be challenging.^{How to reduce mania risk when prescribing stimulants,” October 2005, at www.currentpsychiatry.com.)}

Pediatric bipolar disorder often goes undetected because DSM-IV-TR criteria—established for adults—may not apply to youths. Children are more likely to present with a mixed mood state, less-distinct periods between episodes, grandiosity, irritability, and a chronic, continuous course.² By contrast, bipolar adults often present with a sudden classic manic episode, elation, and euphoria.² Adults also usually have relatively stable periods between episodes and tend to have comorbid substance dependence, panic, or eating disorders.

Mark’s symptoms still suggest ADHD. His inattention started before age 7, and his teacher is mostly concerned about his hyperactive, impulsive, and disruptive behavior. Mark’s mother, teacher, and psychiatrist feel confident that the ADHD diagnosis is correct, so we decide against comprehensive reassessment or prescribing a mood stabilizer. Mark’s mother opts to try the nonstimulant ADHD medication atomoxetine rather than a different stimulant.

Treatment: a moving experience

Mark’s psychiatrist prescribes atomoxetine, 18 mg/d for 4 days, then increases the dosage to 25 mg/d after finding that the boy could tolerate the medication.

Two weeks after starting atomoxetine, Mark becomes agitated and activated, and voices suicidal thoughts on one occasion. Without warning, while his mother is driving him to school, he opens the door of the moving vehicle and tries to jump out. His mother stops him by calling his name, yelling “No,” and slamming on the brakes. Mark tells her that he is “bad” and wants to die. She has no idea what prompted this behavior.

Mark also has become more oppositional and defiant, and his temper tantrums and destruction of household items are more frequent. He continues to behave aggressively toward his younger brother, often breaking some of his favorite toys. Mark also shows elevated and expansive mood, irritability, pressured speech, inflated self-esteem, and psychomotor agitation—symptoms consistent with a manic episode. At one visit, Mark tells his psychia trist, “I feel great! I can do anything.”

The authors’ observations

Mark, who had been diagnosed as having ADHD, began showing manic activation and suicidal thinking 2 weeks after starting atomoxetine. Whether he showed de novo suicidal behavior or reckless behavior associated with mania is unclear.

Atomoxetine-induced mania is not a new finding.^2,5 During clinical trials, 2% of patients reported mood swings and 8% reported irritability. Subsequent experience indicates the risk of mood destabilization may be as high as 33%.⁵

Atomoxetine, a nonstimulant medication indicated for treating pediatric and adult ADHD, is a potent norepinephrine reuptake inhibitor. Reanalysis of the atomoxetine clinical trial database showed a slightly but statistically significant higher risk of suicidal behavior and thoughts in children and adolescents compared with placebo.⁶ No deaths from suicide were reported. The FDA subsequently ordered a black box warning on atomoxetine’s label instructing physicians, patients, and families to watch closely for suicidality symptoms with atomoxetine use.

Atomoxetine is safe and effective for pediatric ADHD, provided youths are properly monitored. Be careful, however, when prescribing atomoxetine to youths with a personal or family history of mood disorder.

FDA also is reviewing data on all drugs indicated for treating ADHD to determine whether they cause suicidality, new-onset mental disorders, or other psychiatric adverse events.⁷

Assessing medication risk

All youths being treated for a mood disorder and/or ADHD must be assessed for suicide risk, but how to most effectively perform this assessment is unclear. Organizations representing pediatrics and child and adolescent psychiatry have not yet incorporated FDA’s medication guidelines regarding pediatric suicidality—released earlier this year—into their guidelines (Table 1). As a result, most physicians follow pediatric patients less frequently than FDA now advises.

 

Atomoxetine’s receptor profile resembles that of antidepressants, which also are labeled with a black box warning describing increased suicidality risk when used in children and adolescents. Risk of suicidal behavior is highest within 10 days of starting antidepressants, and a significant risk remains throughout the first month. The suicidality rate appears to drop after that time.^9,10

Follow FDA patient monitoring guidelines for antidepressants when prescribing atomoxetine to youths—particularly given the prospective labeling change. Atomoxetine’s manufacturer is expected to release a patient monitoring guideline unique to this drug.

Table 1

FDA guidelines for monitoring pediatric antidepressant use

After starting an antidepressant, patients should see their doctor:
Once weekly for 4 weeks Every 2 weeks for the next month At the end of the 12th week taking the drug More often if problems or questions arise
Source: Reference 8

Suicidality: finding other causes

Suicidality is more prevalent in bipolar disorder than in other mental disorders,^2,4 and ADHD and mania often co-exist (Box 1).^11,12 Mania induced by medication might explain suicidality or other behavior changes in some youths, but activation, mania, behavior change, or suicidality can result from the primary or comorbid disorder rather than the medication.

No deaths by suicide were reported among the FDA-reviewed studies of antidepressant use in children and adolescents. Fatal suicidal behavior has been reported in adolescents not treated with medications.¹⁴

FDA cites 12 features that point to suicide risk in youths (Box 2).^8-10 Seven features suggest both ADHD and mania, which overlap to the point of diagnostic distraction.

Box 1

Box 2

The authors’ observations

Consider a broad differential diagnosis when evaluating inattention, hyperactivity, and impulsivity in children. Family medical history, corroborative clinical interviews, past and current behavioral rating scores, and psychological testing can help confirm an ADHD diagnosis (Table 2).

A careful patient interview, watching for diagnostic clues, taking a confirmatory history, and attention to key symptoms can help you discern ADHD from mania. Rule out unexplored diagnoses such as substance abuse, disturbed relationships, medical illness, and other mental disorders. Having the family and teachers track the youth’s longitudinal mood, energy, sleep, and actions may confirm a mood disorder.

Elated mood or grandiosity indicate mania. Irritable hyperactivity is seen more frequently in mania, whereas general hyperactivity tends to be present in ADHD. Childhood depression often heralds bipolar disorder.

Suspected medication-induced suicidality may call for stopping the offending agent, but determining whether a mental disorder or medication is causing suicidal thoughts can be difficult.

Try stopping the suspected offending drug first. If the youth remains suicidal after 1 week, a thorough biopsychosocial reassessment may guide future options including inpatient care, intensive outpatient psychotherapy, monitoring, and cautious use of antidepressant and/or antimanic medications.

Suicide risk requires clinician vigilance. As we learn from the FDA’s warnings, each treatment episode confers new risk and underscores the importance of watching for risk factors that may predict suicide (Table 3).

Table 2

What to include in an ADHD evaluation

Histories: psychosocial, developmental, medical, educational, substance use and/or family
Clinical interviews with the child or adolescent. Corroborative interviews with parents, guardians, teachers, others
Rating scales assessing past behavior: Instruments completed by multiple sources such as the youth, family members or guardian, former teachers, others
Rating scales of current behavior: Instruments completed by youth, parents or guardian, former teachers, siblings, significant others
Psychological testing: Psychoeducational evaluation, personality inventory, intelligence assessment, and/or a continuous performance test. ADHD diagnosis remains clinical, and no evaluation should rely too heavily on “objective tests” for a definitive diagnosis

Table 3

Risk factors that may predict suicide in youths

Older (pubertal) age
Male gender
Mania
Mixed mood state
Psychosis
Victim of sexual or physical abuse
Co-occurring disruptive disorders
Comorbid substance abuse
Impulsivity
Easy access to means, such as firearms, lethal toxins, or medications
Lack of family support
Acute stressors
Family history of suicide
Source: Adapted from reference 2.

Continued treatment: no more medication

Mark’s psychiatrist immediately stops atomoxetine. The boy’s mother, a psychiatric nurse, declines a trial of divalproex because she fears drug toxicity. Mark’s suicidality and agitation resolve over 1 week, and he returns to baseline function, leading us to believe his mania was medication-induced.

 

One year later, Mark takes no medications. He is behaving well at school and made the honor roll this fall. His teacher reports that Mark is “smart, well liked, but talks excessively,” though she says his talking is “not as out of control” as it was a year ago.

Mark recently began playing soccer as an outlet for his hyperactivity. He has not been penalized on the soccer field but is occasionally “over the edge,” pushing and shoving other players. When frustrated at home he has short outbursts, slams doors, and yells at his brother without being physically aggressive.

Mark’s office visits are infrequent, but he recently asked his mother to take him to his psychiatrist and counselor. His mother realizes he may soon need medication, but she wants to wait.

Related resources

• U.S. Food and Drug Administration. List of drugs receiving a boxed warning, other product labeling changes, and a medication guide pertaining to pediatric suicidality. www.fda.gov/cder/drug/antidepressants/MDD_alldruglist.pdf.
• Eli Lilly and Co. Questions and answers about the Strattera (atomoxetine) label change: a guide for patients and parents. www.strattera.com/1_5_news/Q&A_Strattera_label_update.pdf.
• U.S. Food and Drug Administration. Public health advisory: Suicidal thinking in children and adolescents being treated with Strattera (atomoxetine).www.fda.gov/cder/drug/advisory/atomoxetine.htm.
• Mann JJ, Apter A, Bertolote J, et al. Suicide prevention strategies: a systematic review. JAMA 2005;294(16):2064-74.

Drug brand names

• Divalproex sodium • Depakote
• Mixed amphetamine salts • Adderall XR
• Atomoxetine • Strattera

Disclosure

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

History: impulsive and distractible

For 2 years Mark, age 11, has been treated for attention-deficit/hyperactivity disorder (ADHD). His initial symptoms included inattention, hyperactivity, distractibility, short attention span, failure to follow instructions, poor organization, and intruding on others. He often picks fights with his 7-year-old brother, mildly injuring him on one occasion. His teacher recently punished him for roaming the classroom and distracting his classmates.

None of Mark’s symptoms suggest mania. His family has no history of mood disorders, but his father has been diagnosed with substance dependence.

Mark’s psychiatrist had prescribed an extended-release amphetamine salts preparation, 10 mg/d. Soon after, Mark began experiencing stomachaches, insomnia, facial flushing, and headaches. The dosage was reduced to 5 mg/d, but Mark stopped taking the medication after less than 3 weeks. Cognitive-behavioral therapy and classroom modifications were then tried for 11 months, but Mark’s behavior worsened. His symptoms now include inattention, distractibility, excessive talking, restlessness, and impulsivity.

The authors’ observations

Children and adolescents often present with excessive talking, distractibility, increased activity or restlessness, and loss of normal functioning. Distinguishing these ADHD symptoms from those of bipolar, disruptive, learning, movement, anxiety, substance-related or other mental disorders can be challenging.^{How to reduce mania risk when prescribing stimulants,” October 2005, at www.currentpsychiatry.com.)}

Pediatric bipolar disorder often goes undetected because DSM-IV-TR criteria—established for adults—may not apply to youths. Children are more likely to present with a mixed mood state, less-distinct periods between episodes, grandiosity, irritability, and a chronic, continuous course.² By contrast, bipolar adults often present with a sudden classic manic episode, elation, and euphoria.² Adults also usually have relatively stable periods between episodes and tend to have comorbid substance dependence, panic, or eating disorders.

Mark’s symptoms still suggest ADHD. His inattention started before age 7, and his teacher is mostly concerned about his hyperactive, impulsive, and disruptive behavior. Mark’s mother, teacher, and psychiatrist feel confident that the ADHD diagnosis is correct, so we decide against comprehensive reassessment or prescribing a mood stabilizer. Mark’s mother opts to try the nonstimulant ADHD medication atomoxetine rather than a different stimulant.

Treatment: a moving experience

Mark’s psychiatrist prescribes atomoxetine, 18 mg/d for 4 days, then increases the dosage to 25 mg/d after finding that the boy could tolerate the medication.

Two weeks after starting atomoxetine, Mark becomes agitated and activated, and voices suicidal thoughts on one occasion. Without warning, while his mother is driving him to school, he opens the door of the moving vehicle and tries to jump out. His mother stops him by calling his name, yelling “No,” and slamming on the brakes. Mark tells her that he is “bad” and wants to die. She has no idea what prompted this behavior.

Mark also has become more oppositional and defiant, and his temper tantrums and destruction of household items are more frequent. He continues to behave aggressively toward his younger brother, often breaking some of his favorite toys. Mark also shows elevated and expansive mood, irritability, pressured speech, inflated self-esteem, and psychomotor agitation—symptoms consistent with a manic episode. At one visit, Mark tells his psychia trist, “I feel great! I can do anything.”

The authors’ observations

Mark, who had been diagnosed as having ADHD, began showing manic activation and suicidal thinking 2 weeks after starting atomoxetine. Whether he showed de novo suicidal behavior or reckless behavior associated with mania is unclear.

Atomoxetine-induced mania is not a new finding.^2,5 During clinical trials, 2% of patients reported mood swings and 8% reported irritability. Subsequent experience indicates the risk of mood destabilization may be as high as 33%.⁵

Atomoxetine, a nonstimulant medication indicated for treating pediatric and adult ADHD, is a potent norepinephrine reuptake inhibitor. Reanalysis of the atomoxetine clinical trial database showed a slightly but statistically significant higher risk of suicidal behavior and thoughts in children and adolescents compared with placebo.⁶ No deaths from suicide were reported. The FDA subsequently ordered a black box warning on atomoxetine’s label instructing physicians, patients, and families to watch closely for suicidality symptoms with atomoxetine use.

Atomoxetine is safe and effective for pediatric ADHD, provided youths are properly monitored. Be careful, however, when prescribing atomoxetine to youths with a personal or family history of mood disorder.

FDA also is reviewing data on all drugs indicated for treating ADHD to determine whether they cause suicidality, new-onset mental disorders, or other psychiatric adverse events.⁷

Assessing medication risk

All youths being treated for a mood disorder and/or ADHD must be assessed for suicide risk, but how to most effectively perform this assessment is unclear. Organizations representing pediatrics and child and adolescent psychiatry have not yet incorporated FDA’s medication guidelines regarding pediatric suicidality—released earlier this year—into their guidelines (Table 1). As a result, most physicians follow pediatric patients less frequently than FDA now advises.

 

Atomoxetine’s receptor profile resembles that of antidepressants, which also are labeled with a black box warning describing increased suicidality risk when used in children and adolescents. Risk of suicidal behavior is highest within 10 days of starting antidepressants, and a significant risk remains throughout the first month. The suicidality rate appears to drop after that time.^9,10

Follow FDA patient monitoring guidelines for antidepressants when prescribing atomoxetine to youths—particularly given the prospective labeling change. Atomoxetine’s manufacturer is expected to release a patient monitoring guideline unique to this drug.

Table 1

FDA guidelines for monitoring pediatric antidepressant use

After starting an antidepressant, patients should see their doctor:
Once weekly for 4 weeks Every 2 weeks for the next month At the end of the 12th week taking the drug More often if problems or questions arise
Source: Reference 8

Suicidality: finding other causes

Suicidality is more prevalent in bipolar disorder than in other mental disorders,^2,4 and ADHD and mania often co-exist (Box 1).^11,12 Mania induced by medication might explain suicidality or other behavior changes in some youths, but activation, mania, behavior change, or suicidality can result from the primary or comorbid disorder rather than the medication.

No deaths by suicide were reported among the FDA-reviewed studies of antidepressant use in children and adolescents. Fatal suicidal behavior has been reported in adolescents not treated with medications.¹⁴

FDA cites 12 features that point to suicide risk in youths (Box 2).^8-10 Seven features suggest both ADHD and mania, which overlap to the point of diagnostic distraction.

Box 1

Box 2

The authors’ observations

Consider a broad differential diagnosis when evaluating inattention, hyperactivity, and impulsivity in children. Family medical history, corroborative clinical interviews, past and current behavioral rating scores, and psychological testing can help confirm an ADHD diagnosis (Table 2).

A careful patient interview, watching for diagnostic clues, taking a confirmatory history, and attention to key symptoms can help you discern ADHD from mania. Rule out unexplored diagnoses such as substance abuse, disturbed relationships, medical illness, and other mental disorders. Having the family and teachers track the youth’s longitudinal mood, energy, sleep, and actions may confirm a mood disorder.

Elated mood or grandiosity indicate mania. Irritable hyperactivity is seen more frequently in mania, whereas general hyperactivity tends to be present in ADHD. Childhood depression often heralds bipolar disorder.

Suspected medication-induced suicidality may call for stopping the offending agent, but determining whether a mental disorder or medication is causing suicidal thoughts can be difficult.

Try stopping the suspected offending drug first. If the youth remains suicidal after 1 week, a thorough biopsychosocial reassessment may guide future options including inpatient care, intensive outpatient psychotherapy, monitoring, and cautious use of antidepressant and/or antimanic medications.

Suicide risk requires clinician vigilance. As we learn from the FDA’s warnings, each treatment episode confers new risk and underscores the importance of watching for risk factors that may predict suicide (Table 3).

Table 2

What to include in an ADHD evaluation

Histories: psychosocial, developmental, medical, educational, substance use and/or family
Clinical interviews with the child or adolescent. Corroborative interviews with parents, guardians, teachers, others
Rating scales assessing past behavior: Instruments completed by multiple sources such as the youth, family members or guardian, former teachers, others
Rating scales of current behavior: Instruments completed by youth, parents or guardian, former teachers, siblings, significant others
Psychological testing: Psychoeducational evaluation, personality inventory, intelligence assessment, and/or a continuous performance test. ADHD diagnosis remains clinical, and no evaluation should rely too heavily on “objective tests” for a definitive diagnosis

Table 3

Risk factors that may predict suicide in youths

Older (pubertal) age
Male gender
Mania
Mixed mood state
Psychosis
Victim of sexual or physical abuse
Co-occurring disruptive disorders
Comorbid substance abuse
Impulsivity
Easy access to means, such as firearms, lethal toxins, or medications
Lack of family support
Acute stressors
Family history of suicide
Source: Adapted from reference 2.

Continued treatment: no more medication

Mark’s psychiatrist immediately stops atomoxetine. The boy’s mother, a psychiatric nurse, declines a trial of divalproex because she fears drug toxicity. Mark’s suicidality and agitation resolve over 1 week, and he returns to baseline function, leading us to believe his mania was medication-induced.

 

One year later, Mark takes no medications. He is behaving well at school and made the honor roll this fall. His teacher reports that Mark is “smart, well liked, but talks excessively,” though she says his talking is “not as out of control” as it was a year ago.

Mark recently began playing soccer as an outlet for his hyperactivity. He has not been penalized on the soccer field but is occasionally “over the edge,” pushing and shoving other players. When frustrated at home he has short outbursts, slams doors, and yells at his brother without being physically aggressive.

Mark’s office visits are infrequent, but he recently asked his mother to take him to his psychiatrist and counselor. His mother realizes he may soon need medication, but she wants to wait.

Related resources

• U.S. Food and Drug Administration. List of drugs receiving a boxed warning, other product labeling changes, and a medication guide pertaining to pediatric suicidality. www.fda.gov/cder/drug/antidepressants/MDD_alldruglist.pdf.
• Eli Lilly and Co. Questions and answers about the Strattera (atomoxetine) label change: a guide for patients and parents. www.strattera.com/1_5_news/Q&A_Strattera_label_update.pdf.
• U.S. Food and Drug Administration. Public health advisory: Suicidal thinking in children and adolescents being treated with Strattera (atomoxetine).www.fda.gov/cder/drug/advisory/atomoxetine.htm.
• Mann JJ, Apter A, Bertolote J, et al. Suicide prevention strategies: a systematic review. JAMA 2005;294(16):2064-74.

Drug brand names

• Divalproex sodium • Depakote
• Mixed amphetamine salts • Adderall XR
• Atomoxetine • Strattera

Disclosure

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

Presentation: ‘they’re stalking me’

Ms. P, age 30, fears she is being stalked and is too terrified to be home alone. Worried, her ex-boyfriend calls police, who bring her to the emergency room

At the ER, Ms. P reports that surveillance cameras have been planted inside her house, that men often stand on her roof and watch her go to her car, and that men constantly are stalking her. She also hears voices and reports frightening peripheral visions of “outsiders.” The ER doctor consults the psychiatry service and orders laboratory tests, but all results—including urine drug screen findings—are negative.

Ms. P says she has been sleeping 3 to 4 hours nightly. She acknowledges depressed mood and decreased appetite, leading to a 10-lb weight loss over 1 month. She says she has felt depressed off and on for several years but has received no treatment for her mood symptoms. We admit her to the psychiatric unit to treat her acute-onset psychosis.

Lately, Ms. P’s life has been difficult. A college sophomore, she is failing all her classes. She was recently fired from her job as a case manager because of inappropriate behavior, such as buying gifts for the children she was managing and taking them for hair-cuts without their parents’ permission. Several months ago, she broke up with her boyfriend of 6 years. In addition to these stressors, she recently moved into an apartment and for the first time was living on her own.

Medical history. Ms. P has no major medical problems. Her mother has battled alcohol and drug dependence and depression but to Ms. P’s knowledge has never experienced psychosis. Ms. P, who admits that she binge drinks once or twice monthly, meets DSM-IV-TR criteria for alcohol abuse disorder. She denies using illicit drugs but admits that she regularly takes “energy pills” purchased over the Internet because she cannot wake up without them.

Physical exam is normal, but Ms. P’s body mass index (BMI) is 18 kg/m², slightly below normal (height: 5 feet 8 inches; weight: 117.5 lb).

The authors’ observations

We diagnosed Ms. P as having recurrent and severe major depressive disorder with psychotic features because of her longstanding depressive symptoms. We considered substance-induced psychosis, but her urine drug screen is negative.

Treatment at this point should address both the paranoid delusions and depressive symptoms.

Treatment: starved for energy

We start haloperidol, 1 mg nightly, to treat Ms. P’s paranoid delusions, and mirtazapine, 15 mg nightly, to improve her sleep. We choose mirtazapine—which can increase appetite and lead to weight gain—because Ms. P is underweight. We also choose haloperidol because Ms. P is unemployed and cannot afford a second-generation antipsychotic.

Shortly afterward, we interview Ms. P’s ex-boyfriend. He tells us that she has been using diet pills regularly for 3 to 4 years, and that her chronic use has been escalating by the month. Lately, he says, she has been “popping the pills like candy.”

When we ask Ms. P about her diet pill use, she says she had mainly been using Xenadrine, an over-the-counter weight-loss supplement. Five months ago, she also started taking prescription phentermine, which she purchases over the Internet. She says that before her hospitalization, she was taking three phentermine tablets daily to boost her energy.

According to her ex-boyfriend, Ms. P began showing signs of psychosis 3 to 4 weeks after starting phentermine, and Ms. P notes that her initial paranoia and gustatory hallucinations have worsened. She now fears her bathroom is rigged with cameras. She showers with her swimsuit on.

We change Ms. P’s diagnosis to diet pill-induced psychosis. Because she had discarded the pill packaging before admission, we could not examine it for dosing information or ingredients.

The authors’ observations

Differentiating drug-induced psychosis from other psychoses often is difficult. Mood disorder with psychosis, schizophrenia, and substance-induced psychosis have similar characteristics (Table).

Ms. P has no personal or family history of psychosis that would suggest a thought disorder. She had good pre-morbid functioning (going to college, steady employment, long-term relationship with boyfriend) before her psychosis onset. She did, however, have a personal and family history of depression and was confronting many stressors (losing her job, failing grades at school, breaking up with her longtime boyfriend) that would suggest a primary mood disorder with psychosis.

We suspected an eating disorder and asked Ms. P more than once about her eating habits, but she insists she does not take the pills to lose weight. Also, her ex-boyfriend believes she is eating normally. Her low BMI and suspected obsession with weight loss could have signaled anorexia nervosa, but no other signs were present and her history does not support the diagnosis.

 

Table

Three causes of psychosis—and different characteristics of each presentation

Characteristic	Mood disorder with psychosis	Schizophrenia	Substance-induced psychosis
Acute onset	x	-	x
Delusions	x	x	x
Disorganized or catatonic behavior	x	x	x
Family history of psychosis	x	x	_
Good premorbid function	x	_	x
Hallucinations	x	x	x
Negative symptoms	x	x	x
Personal history of psychosis	x	x	_
Prodromal and residual symptoms	_	x	_

Relapse: cameras ‘off’ for 1 week

Five days after admission, we discharge Ms. P as her psychosis has improved significantly.

Later that day at the outpatient clinic, Ms. P requests a medication change, voicing fears about haloperidol’s long term side effects and mirtazapine-induced weight gain. Risperidone, 2 mg nightly, and citalopram, 20 mg/d, are started instead.

One week later, Ms. P’s parents again bring her to the ER after police find her sitting in her car, confused and paranoid. She complains that cameras have been set up in her car, and she responds to voices when alone.

On the way to the ER, Ms. P tries to jump from the moving car. She assaults her mother as she stops her from jumping.

Blood pressure is 155/92, heart rate is 82 beats per minute, respiratory rate is 18 breaths per minute, and temperature is 96°F.

On interview, Ms. P admits that she stopped risperidone and citalopram and restarted Xenadrine and phentermine. She also reports orthostasis from risperidone. We again admit her to the acute-care psychiatric unit and restart haloperidol, 1 mg/d, and citalopram, 20 mg/d.

The authors’ observations

Although we knew Ms. P was abusing diet pills, we could have easily ruled out drug-induced psychosis based on her three negative urine drug screens.

The clinical course of Ms. P’s psychosis, however, closely followed her diet pill use—emerging soon after starting phentermine and remitting soon after stopping it. Also:

• she was taking 2 to 3 times the recommended dosage of phentermine for several months. Phentermine is indicated for short-term (a few weeks) treatment of exogenous obesity (BMI ≥27 kg/m² in persons with hypertension, diabetes, or hyperlipidemia; BMI ≥30 kg/m² in persons without these risk factors)¹
  
• her BMI was below normal
  
• her psychosis remains in remission without use of an antipsychotic.
  

These factors, combined with the potentiating effects of these stimulating agents, apparently led to psychosis.

Stimulant medications such as amphetamines and stimulant drugs such as cocaine can produce psychotic symptoms including paranoid delusions, hallucinations, and bizarre behavior. Farrell and colleagues⁵ found that cannabis and psychostimulants increase the risk of psychosis.

Genetic load could have influenced Ms. P’s response to diet pills, but we have no information to support a genetic predisposition. Also, we saw no clear family history of a formal thought disorder.

The authors’ observations

Urine drug screens can pick up the main drug classes and often their derivatives, but this testing method is limited.²

Urine tests employ assays with semi-quantitative results. A urine sample may contain an abused substance but at levels below the cutoff. Also, because no correlation exists between cutoff levels and drug effect, a patient can have drug-induced symptoms but a negative urine drug screen. This makes detecting a suspected but unknown drug of abuse extremely difficult.

A routine urine screen can detect phentermine and other stimulants, but the phentermine level needed for a positive assay is 50 times that of pure amphetamine.² Ms. P’s last urine drug screen showed an amphetamine level just under the cutoff.

Use of cocaine—undetectable in urine 3 to 4 days after use—could be considered when drug-induced psychosis is suspected. Ms. P’s psychosis correlated with her phentermine relapse, however, and both she and her ex-boyfriend denied that she uses street drugs.

Obtain specific drug levels when you suspect medication abuse. Request gas chromatography or mass spectrometry to provide a quantitative result and confirm medication abuse.^2,3 These tests would have been appropriate for Ms. P once her ex-boyfriend revealed the diet pill abuse.

Detecting diet pill abuse

Use of weight-loss supplements and appetite suppressants is alarmingly common (Box). Many patients suffer adverse effects from diet pills but do not tell their doctors they are using them because they:

• fear the physician will scold them for circumventing his or her advice by obtaining medications online
  
• sense that obtaining diet pills over the Internet might be illegal
  
• do not realize the doctor needs to know about nonprescription drug use
  
• or fear the physician will tell them to stop taking the drug.
  

On the other hand, physicians often do not ask about diet pill use. They may perceive OTC appetite suppressants and weight-loss agents as harmless, or—as with Ms. P—may not suspect diet pill use because the patient is not overweight.

Rapid or unexplained weight loss, hypertension, tachycardia, tremors, psychomotor agitation, and hyperalertness could signal diet pill abuse. Emotional lability, such as euphoria during a high and fatigue and dysphoria during withdrawal, also could be indicative. Collateral information from family members or significant others can narrow the differential diagnosis.

 

Cognitive-behavioral therapy (CBT) can help Ms. P, who claimed she used diet pills to boost her energy. CBT would challenge her unrealistically high goals, teach and explain the consequences of drug use, and offer support to reinforce abstinence from diet pills. Educating patients about potential adverse drug effects also is essential.

Box

Conclusion: back to baseline

After 10 weeks, Ms. P’s condition returns to baseline. She starts a new job and abstains from diet pills. Her thought process and cognition improve significantly, and she reports no depressive symptoms at her most-recent visit. She maintains her weight at 139 lb. BMI is 21.1kg/m² (normal).

Haloperidol is slowly tapered across 2 weeks with no return of psychosis. Although Ms. P wants to stop haloperidol, we taper instead to guard against psychotic relapse. She continues to take citalopram, 20 mg/d, to prevent depressive symptom re-emergence and is receiving supportive psychotherapy to aid her relapse prevention.

Related resources

• Supplement Research Foundation. Supplement reviews. www.tsrf.com/supplements.htm
  
• Devan GS. Phentermine and Psychosis. Br J Psychiatry 1990;156:442-3.
  
• Cleare AJ. Phentermine, psychosis, and family history. J Clin Psychopharmacol 1996;16:470-1.
  
• Hoffman BF. Diet pill psychosis. CMAJ 1977;116:351-5.
  

Drug brand names

• Citalopram • Celexa
  
• Haloperidol • Haldol
  
• Mirtazapine • Remeron
  
• Phenteramine • Adipex
  
• Risperidone • Risperdal
  

Disclosure

Dr. Khan is a speaker for Pfizer and Wyeth Pharmaceuticals.

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

Presentation: ‘they’re stalking me’

Ms. P, age 30, fears she is being stalked and is too terrified to be home alone. Worried, her ex-boyfriend calls police, who bring her to the emergency room

At the ER, Ms. P reports that surveillance cameras have been planted inside her house, that men often stand on her roof and watch her go to her car, and that men constantly are stalking her. She also hears voices and reports frightening peripheral visions of “outsiders.” The ER doctor consults the psychiatry service and orders laboratory tests, but all results—including urine drug screen findings—are negative.

Ms. P says she has been sleeping 3 to 4 hours nightly. She acknowledges depressed mood and decreased appetite, leading to a 10-lb weight loss over 1 month. She says she has felt depressed off and on for several years but has received no treatment for her mood symptoms. We admit her to the psychiatric unit to treat her acute-onset psychosis.

Lately, Ms. P’s life has been difficult. A college sophomore, she is failing all her classes. She was recently fired from her job as a case manager because of inappropriate behavior, such as buying gifts for the children she was managing and taking them for hair-cuts without their parents’ permission. Several months ago, she broke up with her boyfriend of 6 years. In addition to these stressors, she recently moved into an apartment and for the first time was living on her own.

Medical history. Ms. P has no major medical problems. Her mother has battled alcohol and drug dependence and depression but to Ms. P’s knowledge has never experienced psychosis. Ms. P, who admits that she binge drinks once or twice monthly, meets DSM-IV-TR criteria for alcohol abuse disorder. She denies using illicit drugs but admits that she regularly takes “energy pills” purchased over the Internet because she cannot wake up without them.

Physical exam is normal, but Ms. P’s body mass index (BMI) is 18 kg/m², slightly below normal (height: 5 feet 8 inches; weight: 117.5 lb).

The authors’ observations

We diagnosed Ms. P as having recurrent and severe major depressive disorder with psychotic features because of her longstanding depressive symptoms. We considered substance-induced psychosis, but her urine drug screen is negative.

Treatment at this point should address both the paranoid delusions and depressive symptoms.

Treatment: starved for energy

We start haloperidol, 1 mg nightly, to treat Ms. P’s paranoid delusions, and mirtazapine, 15 mg nightly, to improve her sleep. We choose mirtazapine—which can increase appetite and lead to weight gain—because Ms. P is underweight. We also choose haloperidol because Ms. P is unemployed and cannot afford a second-generation antipsychotic.

Shortly afterward, we interview Ms. P’s ex-boyfriend. He tells us that she has been using diet pills regularly for 3 to 4 years, and that her chronic use has been escalating by the month. Lately, he says, she has been “popping the pills like candy.”

When we ask Ms. P about her diet pill use, she says she had mainly been using Xenadrine, an over-the-counter weight-loss supplement. Five months ago, she also started taking prescription phentermine, which she purchases over the Internet. She says that before her hospitalization, she was taking three phentermine tablets daily to boost her energy.

According to her ex-boyfriend, Ms. P began showing signs of psychosis 3 to 4 weeks after starting phentermine, and Ms. P notes that her initial paranoia and gustatory hallucinations have worsened. She now fears her bathroom is rigged with cameras. She showers with her swimsuit on.

We change Ms. P’s diagnosis to diet pill-induced psychosis. Because she had discarded the pill packaging before admission, we could not examine it for dosing information or ingredients.

The authors’ observations

Differentiating drug-induced psychosis from other psychoses often is difficult. Mood disorder with psychosis, schizophrenia, and substance-induced psychosis have similar characteristics (Table).

Ms. P has no personal or family history of psychosis that would suggest a thought disorder. She had good pre-morbid functioning (going to college, steady employment, long-term relationship with boyfriend) before her psychosis onset. She did, however, have a personal and family history of depression and was confronting many stressors (losing her job, failing grades at school, breaking up with her longtime boyfriend) that would suggest a primary mood disorder with psychosis.

We suspected an eating disorder and asked Ms. P more than once about her eating habits, but she insists she does not take the pills to lose weight. Also, her ex-boyfriend believes she is eating normally. Her low BMI and suspected obsession with weight loss could have signaled anorexia nervosa, but no other signs were present and her history does not support the diagnosis.

 

Table

Three causes of psychosis—and different characteristics of each presentation

Characteristic	Mood disorder with psychosis	Schizophrenia	Substance-induced psychosis
Acute onset	x	-	x
Delusions	x	x	x
Disorganized or catatonic behavior	x	x	x
Family history of psychosis	x	x	_
Good premorbid function	x	_	x
Hallucinations	x	x	x
Negative symptoms	x	x	x
Personal history of psychosis	x	x	_
Prodromal and residual symptoms	_	x	_

Relapse: cameras ‘off’ for 1 week

Five days after admission, we discharge Ms. P as her psychosis has improved significantly.

Later that day at the outpatient clinic, Ms. P requests a medication change, voicing fears about haloperidol’s long term side effects and mirtazapine-induced weight gain. Risperidone, 2 mg nightly, and citalopram, 20 mg/d, are started instead.

One week later, Ms. P’s parents again bring her to the ER after police find her sitting in her car, confused and paranoid. She complains that cameras have been set up in her car, and she responds to voices when alone.

On the way to the ER, Ms. P tries to jump from the moving car. She assaults her mother as she stops her from jumping.

Blood pressure is 155/92, heart rate is 82 beats per minute, respiratory rate is 18 breaths per minute, and temperature is 96°F.

On interview, Ms. P admits that she stopped risperidone and citalopram and restarted Xenadrine and phentermine. She also reports orthostasis from risperidone. We again admit her to the acute-care psychiatric unit and restart haloperidol, 1 mg/d, and citalopram, 20 mg/d.

The authors’ observations

Although we knew Ms. P was abusing diet pills, we could have easily ruled out drug-induced psychosis based on her three negative urine drug screens.

The clinical course of Ms. P’s psychosis, however, closely followed her diet pill use—emerging soon after starting phentermine and remitting soon after stopping it. Also:

• she was taking 2 to 3 times the recommended dosage of phentermine for several months. Phentermine is indicated for short-term (a few weeks) treatment of exogenous obesity (BMI ≥27 kg/m² in persons with hypertension, diabetes, or hyperlipidemia; BMI ≥30 kg/m² in persons without these risk factors)¹
  
• her BMI was below normal
  
• her psychosis remains in remission without use of an antipsychotic.
  

These factors, combined with the potentiating effects of these stimulating agents, apparently led to psychosis.

Stimulant medications such as amphetamines and stimulant drugs such as cocaine can produce psychotic symptoms including paranoid delusions, hallucinations, and bizarre behavior. Farrell and colleagues⁵ found that cannabis and psychostimulants increase the risk of psychosis.

Genetic load could have influenced Ms. P’s response to diet pills, but we have no information to support a genetic predisposition. Also, we saw no clear family history of a formal thought disorder.

The authors’ observations

Urine drug screens can pick up the main drug classes and often their derivatives, but this testing method is limited.²

Urine tests employ assays with semi-quantitative results. A urine sample may contain an abused substance but at levels below the cutoff. Also, because no correlation exists between cutoff levels and drug effect, a patient can have drug-induced symptoms but a negative urine drug screen. This makes detecting a suspected but unknown drug of abuse extremely difficult.

A routine urine screen can detect phentermine and other stimulants, but the phentermine level needed for a positive assay is 50 times that of pure amphetamine.² Ms. P’s last urine drug screen showed an amphetamine level just under the cutoff.

Use of cocaine—undetectable in urine 3 to 4 days after use—could be considered when drug-induced psychosis is suspected. Ms. P’s psychosis correlated with her phentermine relapse, however, and both she and her ex-boyfriend denied that she uses street drugs.

Obtain specific drug levels when you suspect medication abuse. Request gas chromatography or mass spectrometry to provide a quantitative result and confirm medication abuse.^2,3 These tests would have been appropriate for Ms. P once her ex-boyfriend revealed the diet pill abuse.

Detecting diet pill abuse

Use of weight-loss supplements and appetite suppressants is alarmingly common (Box). Many patients suffer adverse effects from diet pills but do not tell their doctors they are using them because they:

• fear the physician will scold them for circumventing his or her advice by obtaining medications online
  
• sense that obtaining diet pills over the Internet might be illegal
  
• do not realize the doctor needs to know about nonprescription drug use
  
• or fear the physician will tell them to stop taking the drug.
  

On the other hand, physicians often do not ask about diet pill use. They may perceive OTC appetite suppressants and weight-loss agents as harmless, or—as with Ms. P—may not suspect diet pill use because the patient is not overweight.

Rapid or unexplained weight loss, hypertension, tachycardia, tremors, psychomotor agitation, and hyperalertness could signal diet pill abuse. Emotional lability, such as euphoria during a high and fatigue and dysphoria during withdrawal, also could be indicative. Collateral information from family members or significant others can narrow the differential diagnosis.

 

Cognitive-behavioral therapy (CBT) can help Ms. P, who claimed she used diet pills to boost her energy. CBT would challenge her unrealistically high goals, teach and explain the consequences of drug use, and offer support to reinforce abstinence from diet pills. Educating patients about potential adverse drug effects also is essential.

Box

Conclusion: back to baseline

After 10 weeks, Ms. P’s condition returns to baseline. She starts a new job and abstains from diet pills. Her thought process and cognition improve significantly, and she reports no depressive symptoms at her most-recent visit. She maintains her weight at 139 lb. BMI is 21.1kg/m² (normal).

Haloperidol is slowly tapered across 2 weeks with no return of psychosis. Although Ms. P wants to stop haloperidol, we taper instead to guard against psychotic relapse. She continues to take citalopram, 20 mg/d, to prevent depressive symptom re-emergence and is receiving supportive psychotherapy to aid her relapse prevention.

Related resources

• Supplement Research Foundation. Supplement reviews. www.tsrf.com/supplements.htm
  
• Devan GS. Phentermine and Psychosis. Br J Psychiatry 1990;156:442-3.
  
• Cleare AJ. Phentermine, psychosis, and family history. J Clin Psychopharmacol 1996;16:470-1.
  
• Hoffman BF. Diet pill psychosis. CMAJ 1977;116:351-5.
  

Drug brand names

• Citalopram • Celexa
  
• Haloperidol • Haldol
  
• Mirtazapine • Remeron
  
• Phenteramine • Adipex
  
• Risperidone • Risperdal
  

Disclosure

Dr. Khan is a speaker for Pfizer and Wyeth Pharmaceuticals.

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

Presentation: ‘they’re stalking me’

Ms. P, age 30, fears she is being stalked and is too terrified to be home alone. Worried, her ex-boyfriend calls police, who bring her to the emergency room

At the ER, Ms. P reports that surveillance cameras have been planted inside her house, that men often stand on her roof and watch her go to her car, and that men constantly are stalking her. She also hears voices and reports frightening peripheral visions of “outsiders.” The ER doctor consults the psychiatry service and orders laboratory tests, but all results—including urine drug screen findings—are negative.

Ms. P says she has been sleeping 3 to 4 hours nightly. She acknowledges depressed mood and decreased appetite, leading to a 10-lb weight loss over 1 month. She says she has felt depressed off and on for several years but has received no treatment for her mood symptoms. We admit her to the psychiatric unit to treat her acute-onset psychosis.

Lately, Ms. P’s life has been difficult. A college sophomore, she is failing all her classes. She was recently fired from her job as a case manager because of inappropriate behavior, such as buying gifts for the children she was managing and taking them for hair-cuts without their parents’ permission. Several months ago, she broke up with her boyfriend of 6 years. In addition to these stressors, she recently moved into an apartment and for the first time was living on her own.

Medical history. Ms. P has no major medical problems. Her mother has battled alcohol and drug dependence and depression but to Ms. P’s knowledge has never experienced psychosis. Ms. P, who admits that she binge drinks once or twice monthly, meets DSM-IV-TR criteria for alcohol abuse disorder. She denies using illicit drugs but admits that she regularly takes “energy pills” purchased over the Internet because she cannot wake up without them.

Physical exam is normal, but Ms. P’s body mass index (BMI) is 18 kg/m², slightly below normal (height: 5 feet 8 inches; weight: 117.5 lb).

The authors’ observations

We diagnosed Ms. P as having recurrent and severe major depressive disorder with psychotic features because of her longstanding depressive symptoms. We considered substance-induced psychosis, but her urine drug screen is negative.

Treatment at this point should address both the paranoid delusions and depressive symptoms.

Treatment: starved for energy

We start haloperidol, 1 mg nightly, to treat Ms. P’s paranoid delusions, and mirtazapine, 15 mg nightly, to improve her sleep. We choose mirtazapine—which can increase appetite and lead to weight gain—because Ms. P is underweight. We also choose haloperidol because Ms. P is unemployed and cannot afford a second-generation antipsychotic.

Shortly afterward, we interview Ms. P’s ex-boyfriend. He tells us that she has been using diet pills regularly for 3 to 4 years, and that her chronic use has been escalating by the month. Lately, he says, she has been “popping the pills like candy.”

When we ask Ms. P about her diet pill use, she says she had mainly been using Xenadrine, an over-the-counter weight-loss supplement. Five months ago, she also started taking prescription phentermine, which she purchases over the Internet. She says that before her hospitalization, she was taking three phentermine tablets daily to boost her energy.

According to her ex-boyfriend, Ms. P began showing signs of psychosis 3 to 4 weeks after starting phentermine, and Ms. P notes that her initial paranoia and gustatory hallucinations have worsened. She now fears her bathroom is rigged with cameras. She showers with her swimsuit on.

We change Ms. P’s diagnosis to diet pill-induced psychosis. Because she had discarded the pill packaging before admission, we could not examine it for dosing information or ingredients.

The authors’ observations

Differentiating drug-induced psychosis from other psychoses often is difficult. Mood disorder with psychosis, schizophrenia, and substance-induced psychosis have similar characteristics (Table).

Ms. P has no personal or family history of psychosis that would suggest a thought disorder. She had good pre-morbid functioning (going to college, steady employment, long-term relationship with boyfriend) before her psychosis onset. She did, however, have a personal and family history of depression and was confronting many stressors (losing her job, failing grades at school, breaking up with her longtime boyfriend) that would suggest a primary mood disorder with psychosis.

We suspected an eating disorder and asked Ms. P more than once about her eating habits, but she insists she does not take the pills to lose weight. Also, her ex-boyfriend believes she is eating normally. Her low BMI and suspected obsession with weight loss could have signaled anorexia nervosa, but no other signs were present and her history does not support the diagnosis.

 

Table

Three causes of psychosis—and different characteristics of each presentation

Characteristic	Mood disorder with psychosis	Schizophrenia	Substance-induced psychosis
Acute onset	x	-	x
Delusions	x	x	x
Disorganized or catatonic behavior	x	x	x
Family history of psychosis	x	x	_
Good premorbid function	x	_	x
Hallucinations	x	x	x
Negative symptoms	x	x	x
Personal history of psychosis	x	x	_
Prodromal and residual symptoms	_	x	_

Relapse: cameras ‘off’ for 1 week

Five days after admission, we discharge Ms. P as her psychosis has improved significantly.

Later that day at the outpatient clinic, Ms. P requests a medication change, voicing fears about haloperidol’s long term side effects and mirtazapine-induced weight gain. Risperidone, 2 mg nightly, and citalopram, 20 mg/d, are started instead.

One week later, Ms. P’s parents again bring her to the ER after police find her sitting in her car, confused and paranoid. She complains that cameras have been set up in her car, and she responds to voices when alone.

On the way to the ER, Ms. P tries to jump from the moving car. She assaults her mother as she stops her from jumping.

Blood pressure is 155/92, heart rate is 82 beats per minute, respiratory rate is 18 breaths per minute, and temperature is 96°F.

On interview, Ms. P admits that she stopped risperidone and citalopram and restarted Xenadrine and phentermine. She also reports orthostasis from risperidone. We again admit her to the acute-care psychiatric unit and restart haloperidol, 1 mg/d, and citalopram, 20 mg/d.

The authors’ observations

Although we knew Ms. P was abusing diet pills, we could have easily ruled out drug-induced psychosis based on her three negative urine drug screens.

The clinical course of Ms. P’s psychosis, however, closely followed her diet pill use—emerging soon after starting phentermine and remitting soon after stopping it. Also:

• she was taking 2 to 3 times the recommended dosage of phentermine for several months. Phentermine is indicated for short-term (a few weeks) treatment of exogenous obesity (BMI ≥27 kg/m² in persons with hypertension, diabetes, or hyperlipidemia; BMI ≥30 kg/m² in persons without these risk factors)¹
  
• her BMI was below normal
  
• her psychosis remains in remission without use of an antipsychotic.
  

These factors, combined with the potentiating effects of these stimulating agents, apparently led to psychosis.

Stimulant medications such as amphetamines and stimulant drugs such as cocaine can produce psychotic symptoms including paranoid delusions, hallucinations, and bizarre behavior. Farrell and colleagues⁵ found that cannabis and psychostimulants increase the risk of psychosis.

Genetic load could have influenced Ms. P’s response to diet pills, but we have no information to support a genetic predisposition. Also, we saw no clear family history of a formal thought disorder.

The authors’ observations

Urine drug screens can pick up the main drug classes and often their derivatives, but this testing method is limited.²

Urine tests employ assays with semi-quantitative results. A urine sample may contain an abused substance but at levels below the cutoff. Also, because no correlation exists between cutoff levels and drug effect, a patient can have drug-induced symptoms but a negative urine drug screen. This makes detecting a suspected but unknown drug of abuse extremely difficult.

A routine urine screen can detect phentermine and other stimulants, but the phentermine level needed for a positive assay is 50 times that of pure amphetamine.² Ms. P’s last urine drug screen showed an amphetamine level just under the cutoff.

Use of cocaine—undetectable in urine 3 to 4 days after use—could be considered when drug-induced psychosis is suspected. Ms. P’s psychosis correlated with her phentermine relapse, however, and both she and her ex-boyfriend denied that she uses street drugs.

Obtain specific drug levels when you suspect medication abuse. Request gas chromatography or mass spectrometry to provide a quantitative result and confirm medication abuse.^2,3 These tests would have been appropriate for Ms. P once her ex-boyfriend revealed the diet pill abuse.

Detecting diet pill abuse

Use of weight-loss supplements and appetite suppressants is alarmingly common (Box). Many patients suffer adverse effects from diet pills but do not tell their doctors they are using them because they:

• fear the physician will scold them for circumventing his or her advice by obtaining medications online
  
• sense that obtaining diet pills over the Internet might be illegal
  
• do not realize the doctor needs to know about nonprescription drug use
  
• or fear the physician will tell them to stop taking the drug.
  

On the other hand, physicians often do not ask about diet pill use. They may perceive OTC appetite suppressants and weight-loss agents as harmless, or—as with Ms. P—may not suspect diet pill use because the patient is not overweight.

Rapid or unexplained weight loss, hypertension, tachycardia, tremors, psychomotor agitation, and hyperalertness could signal diet pill abuse. Emotional lability, such as euphoria during a high and fatigue and dysphoria during withdrawal, also could be indicative. Collateral information from family members or significant others can narrow the differential diagnosis.

 

Cognitive-behavioral therapy (CBT) can help Ms. P, who claimed she used diet pills to boost her energy. CBT would challenge her unrealistically high goals, teach and explain the consequences of drug use, and offer support to reinforce abstinence from diet pills. Educating patients about potential adverse drug effects also is essential.

Box

Conclusion: back to baseline

After 10 weeks, Ms. P’s condition returns to baseline. She starts a new job and abstains from diet pills. Her thought process and cognition improve significantly, and she reports no depressive symptoms at her most-recent visit. She maintains her weight at 139 lb. BMI is 21.1kg/m² (normal).

Haloperidol is slowly tapered across 2 weeks with no return of psychosis. Although Ms. P wants to stop haloperidol, we taper instead to guard against psychotic relapse. She continues to take citalopram, 20 mg/d, to prevent depressive symptom re-emergence and is receiving supportive psychotherapy to aid her relapse prevention.

Related resources

• Supplement Research Foundation. Supplement reviews. www.tsrf.com/supplements.htm
  
• Devan GS. Phentermine and Psychosis. Br J Psychiatry 1990;156:442-3.
  
• Cleare AJ. Phentermine, psychosis, and family history. J Clin Psychopharmacol 1996;16:470-1.
  
• Hoffman BF. Diet pill psychosis. CMAJ 1977;116:351-5.
  

Drug brand names

• Citalopram • Celexa
  
• Haloperidol • Haldol
  
• Mirtazapine • Remeron
  
• Phenteramine • Adipex
  
• Risperidone • Risperdal
  

Disclosure

Dr. Khan is a speaker for Pfizer and Wyeth Pharmaceuticals.

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

History: Depressed and dropping out

Ms. Q, age 23, presented 6 years ago with a profound anergic depression with suicidal thinking and social withdrawal. This caused her to drop out of high school for approximately 4 months. She also gained 30 lbs across 3 months, further diminishing her low self-image.

At the time, Ms. Q was diagnosed as having unipolar depression. Fluoxetine, 20 mg/d titrated to 40 mg/d, resolved her symptoms before she started college the following year.

Three years later, while continuing on fluoxetine at the same dosage, Ms. Q experienced dysphoric mania, with irritability, grandiosity, and impaired judgment. She was behaving promiscuously during this episode but was not using alcohol or other substances.

After a subsequent manic episode, she was diagnosed with bipolar type I affective disorder. Haloperidol, 10 mg/d for 2 weeks, resolved her mania. She was then maintained on fluoxetine, 50 mg/d, but was not given a mood stabilizer or antipsychotic.

Two years later, I was called in to consult on Ms. Q’s case. She was euthymic and stable at that time but 2 months earlier had experienced a euphoric manic episode characterized by 5 days of racing thoughts, lack of sleep, and manic motoric acceleration. She had stopped seeing her psychiatrist near college and admitted that she needed to work with someone more experienced than her primary care physician in addressing psychiatric symptoms.

When Ms. Q was age 4, her maternal aunt committed suicide via gas poisoning. Also, her paternal grandmother committed suicide before she was born, and her mother had been treated for dysthymia. She has no significant medical history.

Addressing Ms. Q’s bipolar affective disorder poses a clinical challenge. Controlling her mania is a priority but I also need to continue treating her depression, given her significant family history of affective disturbance.

Dr. Schneider’s observations

To address Ms. Q’s mania, I added controlled-release lithium, 900 mg/d, yielding a blood level of 0.9 mEq/L. Ms. Q was not rapid cycling, was taking her fluoxetine as prescribed, and was not abusing alcohol or drugs, so she seemed an appropriate candidate for lithium treatment.

To manage her depression, I cautiously continued fluoxetine, 40 mg/d. The antidepressant had not obviously destabilized her illness, and Ms. Q felt that it allowed her to work and maintain a social life.

Treatment: Cruising and cycling

After 8 months of stability, Ms. Q developed a sudden dysphoric hypomanic episode, with depressed mood, increased energy, racing thoughts, and inability to sleep. She had some insight into her condition and sought consultation with me.

Ms. Q’s parents reported that she had been taking lithium and fluoxetine as prescribed, was taking no other medications, was not using alcohol or drugs, and experienced no unusual stressors, change in diet, or other lifestyle changes. Having her symptoms re-emerge despite faithful medication adherence made Ms. Q extremely anxious and bewildered her and her parents.

Ms. Q later recalled that her parents had taken her on a coastal cruise to Mexico the week before her cycling episode, and that her symptoms emerged while on ship. She began to experience initial and mid-cycle insomnia and was unusually irritable over minor annoyances.

Having seen Ms. Q immediately after the cruise, I added olanzapine, 5 mg nightly for 5 days, to prevent a full-blown manic episode. About 6 days later, she said she was excessively tired, but her insomnia and irritability had ceased. I stopped olanzapine and returned Ms. Q to her previous regimen.

Dr. Schneider’s observations

Ms. Q appeared to have sustained an unexpected relapse into hypomania despite treatment adherence. At this point, I was concerned that:

• fluoxetine might have destabilized her illness
  
• her lithium level decreased without explanation
  
• or she had a “breakthrough” relapse while on medication.
  

Upon returning home, however, Ms. Q’s lithium blood level was 0.8 mEq/L, consistent with prior levels. Also, she had remained stable for 8 months while taking fluoxetine.

Follow-up: A ‘sickening’ discovery

At follow up approximately 1 week later, Ms. Q reported that she had continuously worn scopolamine patches throughout the 8-day cruise to prevent motion sickness. She had forgotten to mention this, however, during our emergency consultation. She had experienced some mydriasis and dry mouth during the cruise but did not remove the patch for fear of seasickness.

On further questioning, Ms. Q said she knew the patch was designed to be used for 2 to 3 days maximum, but added she was responding well to its effects and foresaw no problems with extended use.

Dr. Schneider’s observations

This case illustrates the potentially destabilizing effects of a seemingly innocuous concomitant medication in patients with bipolar disorder.

 

Scopolamine, indicated for preventing nausea and vomiting associated with motion sickness, is a centrally acting belladonna alkaloid with primary anticholinergic activity. The agent is thought to block transmission from the vestibular nuclei to higher brain centers and from the reticular formation to the brain’s so-called “vomiting centers.”

The transdermal agent can cause drowsiness, dryness of secretory areas, and impaired motor function. It has no known direct pharmacokinetic interaction with lithium. Use for >5 consecutive days can cause anticholinergic delirium-like states, especially in older patients.

For Ms. Q, scopolamine’s direct anticholinergic action may have destabilized an affective disorder in remission. The putative mechanism of anticholinergic-induced psychosis, delirium, mania, and depression has not been well explained and may differ among these states. The serotonergic and cholinergic systems, however, are assumed to be in a type of balance. Cholinergic deficiencies—as seen in dementia or with medications that have anticholinergic potential—may increase sensitivity to serotonergic tone, thus contributing to Ms. Q’s switch to mania.¹

Dr. Schneider’s observations

Ask the patient at each office visit if he or she is concomitantly using an over-the-counter (OTC) medication or a prescription agent from another physician. As with scopolamine, diet pills and oral contraceptives can also destabilize mood or cause depression. Often patients neglect to tell their psychiatrists they started taking an antibiotic, antihypertensive, or other medication since their last visit.

Undetected use of herbal supplements also is a burgeoning clinical problem. Most physicians do not routinely ask patients whether they are using a nonprescription medication, and some clinicians know little about these products’ side effects or interactions with other drugs. Adverse events associated with herbal agents (Table) are difficult to interpret because the purity and amounts of active compounds vary widely.

Table

Mood destabilization, other effects reported after herbal supplement use

Herbal supplement	Common use(s)	Adverse effects in psychiatric patients
Dehydroepiandrosterone (DHEA)	Alzheimer’s dementia treatment, body muscle-fat ratio enhancement, stress relief, sexual enhancer	Acute mania when taken with other psychotropics;2 patients with history of affective disorder can exhibit mania when taking DHEA3
Gingko biloba	Cognitive/memory enhancement	Nausea, diarrhea, bleeding in patients taking psychotropics4,5
		Massive purpura after concomitant gingko plus citalopram or venlafaxine (clinical experience)
Ginseng	Stimulant, also purportedly an aphrodisiac	Ginseng-induced mania in two patients with depressive disorders6,7
Horny goat weed	Purported sexual enhancer for men	New-onset hypomania in 66-year-old man after ingesting compound for 2 weeks8
St. John’s wort	Primary or secondary antidepressant	Multiple cases of mania induction, affective destabilization attributed to presumed cytotoxic effects9

Diet pills. Use of prescription and OTC anorectics is common among weight-conscious Americans.

Appetite suppressants have been reported to cause depression during use or withdrawal,¹⁰ but large epidemiologic studies have not determined which diet pills are most associated with depressive symptoms.

Oral contraceptives. Mood changes are an ongoing, noticeable side effect of oral contraceptives¹¹ regardless of whether the patient is taking a psychotropic. Depression is a frequently cited reason for oral contraceptive discontinuation.¹²

The literature is mixed on how oral contraceptives stabilize or destabilize mood and affect. Hormone-induced mood changes may be caused by:

• estrogen-induced B6 deficiency and subsequent decrease in serotonin and gamma-aminobutyric acid (GABA) because of lower affinity for pyridoxal phosphatate¹³
  
• progesterone or estrogen-mediated augmentation of GABA-induced glutamate suppression
  
• progesterone-mediated increase in mono-amine oxidase activity, leading to lower serotonin concentrations.¹⁴
  

Related resources

• Physicians’ Desk Reference supplements for over-the-counter medications and nutraceuticals. www.pdr.net/pdrnet/librarian (click on “PDRbookstore”).
  
• Farley D. How to get the most benefits with the fewest risks. Web MD. http://my.webmd.com/content/article/6/1680_51630.htm.
  

Drug Brand Names

• Fluoxetine • Prozac
  
• Haloperdiol • Haldol
  
• Lithium • Eskalith, others
  
• Olanzapine • Zyprexa
  
• Scopolamine • Transderm Scop
  

Disclosures

Dr. Schneider is a consultant to and speaker for Bristol-Myers Squibb Co., Forest Pharmaceuticals, and Wyeth Pharmaceuticals. He holds research grants from the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD), the Stanley Medical Research Institute, and the Alzheimer’s Association (Ronald Reagan Research Award).

History: Depressed and dropping out

Ms. Q, age 23, presented 6 years ago with a profound anergic depression with suicidal thinking and social withdrawal. This caused her to drop out of high school for approximately 4 months. She also gained 30 lbs across 3 months, further diminishing her low self-image.

At the time, Ms. Q was diagnosed as having unipolar depression. Fluoxetine, 20 mg/d titrated to 40 mg/d, resolved her symptoms before she started college the following year.

Three years later, while continuing on fluoxetine at the same dosage, Ms. Q experienced dysphoric mania, with irritability, grandiosity, and impaired judgment. She was behaving promiscuously during this episode but was not using alcohol or other substances.

After a subsequent manic episode, she was diagnosed with bipolar type I affective disorder. Haloperidol, 10 mg/d for 2 weeks, resolved her mania. She was then maintained on fluoxetine, 50 mg/d, but was not given a mood stabilizer or antipsychotic.

Two years later, I was called in to consult on Ms. Q’s case. She was euthymic and stable at that time but 2 months earlier had experienced a euphoric manic episode characterized by 5 days of racing thoughts, lack of sleep, and manic motoric acceleration. She had stopped seeing her psychiatrist near college and admitted that she needed to work with someone more experienced than her primary care physician in addressing psychiatric symptoms.

When Ms. Q was age 4, her maternal aunt committed suicide via gas poisoning. Also, her paternal grandmother committed suicide before she was born, and her mother had been treated for dysthymia. She has no significant medical history.

Addressing Ms. Q’s bipolar affective disorder poses a clinical challenge. Controlling her mania is a priority but I also need to continue treating her depression, given her significant family history of affective disturbance.

Dr. Schneider’s observations

To address Ms. Q’s mania, I added controlled-release lithium, 900 mg/d, yielding a blood level of 0.9 mEq/L. Ms. Q was not rapid cycling, was taking her fluoxetine as prescribed, and was not abusing alcohol or drugs, so she seemed an appropriate candidate for lithium treatment.

To manage her depression, I cautiously continued fluoxetine, 40 mg/d. The antidepressant had not obviously destabilized her illness, and Ms. Q felt that it allowed her to work and maintain a social life.

Treatment: Cruising and cycling

After 8 months of stability, Ms. Q developed a sudden dysphoric hypomanic episode, with depressed mood, increased energy, racing thoughts, and inability to sleep. She had some insight into her condition and sought consultation with me.

Ms. Q’s parents reported that she had been taking lithium and fluoxetine as prescribed, was taking no other medications, was not using alcohol or drugs, and experienced no unusual stressors, change in diet, or other lifestyle changes. Having her symptoms re-emerge despite faithful medication adherence made Ms. Q extremely anxious and bewildered her and her parents.

Ms. Q later recalled that her parents had taken her on a coastal cruise to Mexico the week before her cycling episode, and that her symptoms emerged while on ship. She began to experience initial and mid-cycle insomnia and was unusually irritable over minor annoyances.

Having seen Ms. Q immediately after the cruise, I added olanzapine, 5 mg nightly for 5 days, to prevent a full-blown manic episode. About 6 days later, she said she was excessively tired, but her insomnia and irritability had ceased. I stopped olanzapine and returned Ms. Q to her previous regimen.

Dr. Schneider’s observations

Ms. Q appeared to have sustained an unexpected relapse into hypomania despite treatment adherence. At this point, I was concerned that:

• fluoxetine might have destabilized her illness
  
• her lithium level decreased without explanation
  
• or she had a “breakthrough” relapse while on medication.
  

Upon returning home, however, Ms. Q’s lithium blood level was 0.8 mEq/L, consistent with prior levels. Also, she had remained stable for 8 months while taking fluoxetine.

Follow-up: A ‘sickening’ discovery

At follow up approximately 1 week later, Ms. Q reported that she had continuously worn scopolamine patches throughout the 8-day cruise to prevent motion sickness. She had forgotten to mention this, however, during our emergency consultation. She had experienced some mydriasis and dry mouth during the cruise but did not remove the patch for fear of seasickness.

On further questioning, Ms. Q said she knew the patch was designed to be used for 2 to 3 days maximum, but added she was responding well to its effects and foresaw no problems with extended use.

Dr. Schneider’s observations

This case illustrates the potentially destabilizing effects of a seemingly innocuous concomitant medication in patients with bipolar disorder.

 

Scopolamine, indicated for preventing nausea and vomiting associated with motion sickness, is a centrally acting belladonna alkaloid with primary anticholinergic activity. The agent is thought to block transmission from the vestibular nuclei to higher brain centers and from the reticular formation to the brain’s so-called “vomiting centers.”

The transdermal agent can cause drowsiness, dryness of secretory areas, and impaired motor function. It has no known direct pharmacokinetic interaction with lithium. Use for >5 consecutive days can cause anticholinergic delirium-like states, especially in older patients.

For Ms. Q, scopolamine’s direct anticholinergic action may have destabilized an affective disorder in remission. The putative mechanism of anticholinergic-induced psychosis, delirium, mania, and depression has not been well explained and may differ among these states. The serotonergic and cholinergic systems, however, are assumed to be in a type of balance. Cholinergic deficiencies—as seen in dementia or with medications that have anticholinergic potential—may increase sensitivity to serotonergic tone, thus contributing to Ms. Q’s switch to mania.¹

Dr. Schneider’s observations

Ask the patient at each office visit if he or she is concomitantly using an over-the-counter (OTC) medication or a prescription agent from another physician. As with scopolamine, diet pills and oral contraceptives can also destabilize mood or cause depression. Often patients neglect to tell their psychiatrists they started taking an antibiotic, antihypertensive, or other medication since their last visit.

Undetected use of herbal supplements also is a burgeoning clinical problem. Most physicians do not routinely ask patients whether they are using a nonprescription medication, and some clinicians know little about these products’ side effects or interactions with other drugs. Adverse events associated with herbal agents (Table) are difficult to interpret because the purity and amounts of active compounds vary widely.

Table

Mood destabilization, other effects reported after herbal supplement use

Herbal supplement	Common use(s)	Adverse effects in psychiatric patients
Dehydroepiandrosterone (DHEA)	Alzheimer’s dementia treatment, body muscle-fat ratio enhancement, stress relief, sexual enhancer	Acute mania when taken with other psychotropics;2 patients with history of affective disorder can exhibit mania when taking DHEA3
Gingko biloba	Cognitive/memory enhancement	Nausea, diarrhea, bleeding in patients taking psychotropics4,5
		Massive purpura after concomitant gingko plus citalopram or venlafaxine (clinical experience)
Ginseng	Stimulant, also purportedly an aphrodisiac	Ginseng-induced mania in two patients with depressive disorders6,7
Horny goat weed	Purported sexual enhancer for men	New-onset hypomania in 66-year-old man after ingesting compound for 2 weeks8
St. John’s wort	Primary or secondary antidepressant	Multiple cases of mania induction, affective destabilization attributed to presumed cytotoxic effects9

Diet pills. Use of prescription and OTC anorectics is common among weight-conscious Americans.

Appetite suppressants have been reported to cause depression during use or withdrawal,¹⁰ but large epidemiologic studies have not determined which diet pills are most associated with depressive symptoms.

Oral contraceptives. Mood changes are an ongoing, noticeable side effect of oral contraceptives¹¹ regardless of whether the patient is taking a psychotropic. Depression is a frequently cited reason for oral contraceptive discontinuation.¹²

The literature is mixed on how oral contraceptives stabilize or destabilize mood and affect. Hormone-induced mood changes may be caused by:

• estrogen-induced B6 deficiency and subsequent decrease in serotonin and gamma-aminobutyric acid (GABA) because of lower affinity for pyridoxal phosphatate¹³
  
• progesterone or estrogen-mediated augmentation of GABA-induced glutamate suppression
  
• progesterone-mediated increase in mono-amine oxidase activity, leading to lower serotonin concentrations.¹⁴
  

Related resources

• Physicians’ Desk Reference supplements for over-the-counter medications and nutraceuticals. www.pdr.net/pdrnet/librarian (click on “PDRbookstore”).
  
• Farley D. How to get the most benefits with the fewest risks. Web MD. http://my.webmd.com/content/article/6/1680_51630.htm.
  

Drug Brand Names

• Fluoxetine • Prozac
  
• Haloperdiol • Haldol
  
• Lithium • Eskalith, others
  
• Olanzapine • Zyprexa
  
• Scopolamine • Transderm Scop
  

Disclosures

Dr. Schneider is a consultant to and speaker for Bristol-Myers Squibb Co., Forest Pharmaceuticals, and Wyeth Pharmaceuticals. He holds research grants from the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD), the Stanley Medical Research Institute, and the Alzheimer’s Association (Ronald Reagan Research Award).

History: Depressed and dropping out

Ms. Q, age 23, presented 6 years ago with a profound anergic depression with suicidal thinking and social withdrawal. This caused her to drop out of high school for approximately 4 months. She also gained 30 lbs across 3 months, further diminishing her low self-image.

At the time, Ms. Q was diagnosed as having unipolar depression. Fluoxetine, 20 mg/d titrated to 40 mg/d, resolved her symptoms before she started college the following year.

Three years later, while continuing on fluoxetine at the same dosage, Ms. Q experienced dysphoric mania, with irritability, grandiosity, and impaired judgment. She was behaving promiscuously during this episode but was not using alcohol or other substances.

After a subsequent manic episode, she was diagnosed with bipolar type I affective disorder. Haloperidol, 10 mg/d for 2 weeks, resolved her mania. She was then maintained on fluoxetine, 50 mg/d, but was not given a mood stabilizer or antipsychotic.

Two years later, I was called in to consult on Ms. Q’s case. She was euthymic and stable at that time but 2 months earlier had experienced a euphoric manic episode characterized by 5 days of racing thoughts, lack of sleep, and manic motoric acceleration. She had stopped seeing her psychiatrist near college and admitted that she needed to work with someone more experienced than her primary care physician in addressing psychiatric symptoms.

When Ms. Q was age 4, her maternal aunt committed suicide via gas poisoning. Also, her paternal grandmother committed suicide before she was born, and her mother had been treated for dysthymia. She has no significant medical history.

Addressing Ms. Q’s bipolar affective disorder poses a clinical challenge. Controlling her mania is a priority but I also need to continue treating her depression, given her significant family history of affective disturbance.

Dr. Schneider’s observations

To address Ms. Q’s mania, I added controlled-release lithium, 900 mg/d, yielding a blood level of 0.9 mEq/L. Ms. Q was not rapid cycling, was taking her fluoxetine as prescribed, and was not abusing alcohol or drugs, so she seemed an appropriate candidate for lithium treatment.

To manage her depression, I cautiously continued fluoxetine, 40 mg/d. The antidepressant had not obviously destabilized her illness, and Ms. Q felt that it allowed her to work and maintain a social life.

Treatment: Cruising and cycling

After 8 months of stability, Ms. Q developed a sudden dysphoric hypomanic episode, with depressed mood, increased energy, racing thoughts, and inability to sleep. She had some insight into her condition and sought consultation with me.

Ms. Q’s parents reported that she had been taking lithium and fluoxetine as prescribed, was taking no other medications, was not using alcohol or drugs, and experienced no unusual stressors, change in diet, or other lifestyle changes. Having her symptoms re-emerge despite faithful medication adherence made Ms. Q extremely anxious and bewildered her and her parents.

Ms. Q later recalled that her parents had taken her on a coastal cruise to Mexico the week before her cycling episode, and that her symptoms emerged while on ship. She began to experience initial and mid-cycle insomnia and was unusually irritable over minor annoyances.

Having seen Ms. Q immediately after the cruise, I added olanzapine, 5 mg nightly for 5 days, to prevent a full-blown manic episode. About 6 days later, she said she was excessively tired, but her insomnia and irritability had ceased. I stopped olanzapine and returned Ms. Q to her previous regimen.

Dr. Schneider’s observations

Ms. Q appeared to have sustained an unexpected relapse into hypomania despite treatment adherence. At this point, I was concerned that:

• fluoxetine might have destabilized her illness
  
• her lithium level decreased without explanation
  
• or she had a “breakthrough” relapse while on medication.
  

Upon returning home, however, Ms. Q’s lithium blood level was 0.8 mEq/L, consistent with prior levels. Also, she had remained stable for 8 months while taking fluoxetine.

Follow-up: A ‘sickening’ discovery

At follow up approximately 1 week later, Ms. Q reported that she had continuously worn scopolamine patches throughout the 8-day cruise to prevent motion sickness. She had forgotten to mention this, however, during our emergency consultation. She had experienced some mydriasis and dry mouth during the cruise but did not remove the patch for fear of seasickness.

On further questioning, Ms. Q said she knew the patch was designed to be used for 2 to 3 days maximum, but added she was responding well to its effects and foresaw no problems with extended use.

Dr. Schneider’s observations

This case illustrates the potentially destabilizing effects of a seemingly innocuous concomitant medication in patients with bipolar disorder.

 

Scopolamine, indicated for preventing nausea and vomiting associated with motion sickness, is a centrally acting belladonna alkaloid with primary anticholinergic activity. The agent is thought to block transmission from the vestibular nuclei to higher brain centers and from the reticular formation to the brain’s so-called “vomiting centers.”

The transdermal agent can cause drowsiness, dryness of secretory areas, and impaired motor function. It has no known direct pharmacokinetic interaction with lithium. Use for >5 consecutive days can cause anticholinergic delirium-like states, especially in older patients.

For Ms. Q, scopolamine’s direct anticholinergic action may have destabilized an affective disorder in remission. The putative mechanism of anticholinergic-induced psychosis, delirium, mania, and depression has not been well explained and may differ among these states. The serotonergic and cholinergic systems, however, are assumed to be in a type of balance. Cholinergic deficiencies—as seen in dementia or with medications that have anticholinergic potential—may increase sensitivity to serotonergic tone, thus contributing to Ms. Q’s switch to mania.¹

Dr. Schneider’s observations

Ask the patient at each office visit if he or she is concomitantly using an over-the-counter (OTC) medication or a prescription agent from another physician. As with scopolamine, diet pills and oral contraceptives can also destabilize mood or cause depression. Often patients neglect to tell their psychiatrists they started taking an antibiotic, antihypertensive, or other medication since their last visit.

Undetected use of herbal supplements also is a burgeoning clinical problem. Most physicians do not routinely ask patients whether they are using a nonprescription medication, and some clinicians know little about these products’ side effects or interactions with other drugs. Adverse events associated with herbal agents (Table) are difficult to interpret because the purity and amounts of active compounds vary widely.

Table

Mood destabilization, other effects reported after herbal supplement use

Herbal supplement	Common use(s)	Adverse effects in psychiatric patients
Dehydroepiandrosterone (DHEA)	Alzheimer’s dementia treatment, body muscle-fat ratio enhancement, stress relief, sexual enhancer	Acute mania when taken with other psychotropics;2 patients with history of affective disorder can exhibit mania when taking DHEA3
Gingko biloba	Cognitive/memory enhancement	Nausea, diarrhea, bleeding in patients taking psychotropics4,5
		Massive purpura after concomitant gingko plus citalopram or venlafaxine (clinical experience)
Ginseng	Stimulant, also purportedly an aphrodisiac	Ginseng-induced mania in two patients with depressive disorders6,7
Horny goat weed	Purported sexual enhancer for men	New-onset hypomania in 66-year-old man after ingesting compound for 2 weeks8
St. John’s wort	Primary or secondary antidepressant	Multiple cases of mania induction, affective destabilization attributed to presumed cytotoxic effects9

Diet pills. Use of prescription and OTC anorectics is common among weight-conscious Americans.

Appetite suppressants have been reported to cause depression during use or withdrawal,¹⁰ but large epidemiologic studies have not determined which diet pills are most associated with depressive symptoms.

Oral contraceptives. Mood changes are an ongoing, noticeable side effect of oral contraceptives¹¹ regardless of whether the patient is taking a psychotropic. Depression is a frequently cited reason for oral contraceptive discontinuation.¹²

The literature is mixed on how oral contraceptives stabilize or destabilize mood and affect. Hormone-induced mood changes may be caused by:

• estrogen-induced B6 deficiency and subsequent decrease in serotonin and gamma-aminobutyric acid (GABA) because of lower affinity for pyridoxal phosphatate¹³
  
• progesterone or estrogen-mediated augmentation of GABA-induced glutamate suppression
  
• progesterone-mediated increase in mono-amine oxidase activity, leading to lower serotonin concentrations.¹⁴
  

Related resources

• Physicians’ Desk Reference supplements for over-the-counter medications and nutraceuticals. www.pdr.net/pdrnet/librarian (click on “PDRbookstore”).
  
• Farley D. How to get the most benefits with the fewest risks. Web MD. http://my.webmd.com/content/article/6/1680_51630.htm.
  

Drug Brand Names

• Fluoxetine • Prozac
  
• Haloperdiol • Haldol
  
• Lithium • Eskalith, others
  
• Olanzapine • Zyprexa
  
• Scopolamine • Transderm Scop
  

Disclosures

Dr. Schneider is a consultant to and speaker for Bristol-Myers Squibb Co., Forest Pharmaceuticals, and Wyeth Pharmaceuticals. He holds research grants from the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD), the Stanley Medical Research Institute, and the Alzheimer’s Association (Ronald Reagan Research Award).

History: losing his ‘drive’

Mr. D, age 49, has been treated for major depressive disorder for approximately 1 year but reports only occasional minor symptom improvement. At presentation, he had been irritable and lethargic for about 2 weeks and had increased appetite, decreased concentration, and trouble falling asleep at night.

A once-gregarious family man, Mr. D had become apathetic and too tired to enjoy socializing. He denied suicidal thoughts or feelings of worthlessness and hopelessness but feared his fatigue was interfering with his job as a truck driver. He tired after driving only a few hours.

Mr. D had been diagnosed with sleep apnea when he was younger but had no other medical history. He said his erratic work schedule kept him from using his continuous positive airway pressure (CPAP) machine regularly. He was taking no medications and had not seen a primary care physician for more than 2 years because of lack of coverage. He denied past or current substance abuse.

The patient weighed 280 lbs at intake. His body mass index (BMI) was 37.5, indicating clinical obesity.

Because Mr. D lacked health insurance, we enrolled him 1 year ago in a free depression study at a psychiatric outpatient clinic. At intake, he said numerous life stresses—particularly the recent death of his brother in a motor vehicle accident—had left him feeling depressed.

We started Mr. D on citalopram, 20 mg/d, which was the study protocol. Two weeks later, he complained of dry mouth and sedation with minimal symptom improvement. We stopped citalopram and started sertraline, 25 mg/d.

Two weeks later, Mr. D again complained he had “no energy” and was “sleeping all day.” We titrated sertraline to 200 mg/d over 2 months, but his excessive tiredness, increased appetite, and decreased motivation persisted. Mr. D needed routine laboratory tests, so we referred him to a local clinic that charges on a sliding scale. He did not complete the tests, however, for fear of incurring medical expenses.

We tried to improve Mr. D’s mood symptoms by adding lithium—225 mg/d titrated to 675 mg/d over 7 weeks—but his depression and fatigue kept worsening. We tapered him off lithium and sertraline and switched to the monoamine oxidase inhibitor tranylcypromine, 30 mg/d, which was also part of the study protocol. We warned him not to eat pizza, fermented dry sausages, or other foods that could interact adversely with tranylcypromine. After 4 weeks, Mr. D stopped taking the agent, saying he could not follow the dietary restrictions while on the road.

We released Mr. D from the study because of nonresponse. Bupropion, started at 100 mg bid and titrated to 300 mg each morning and 150 mg nightly across 5 months, did not resolve his fatigue. He also started having agitation and “anger problems,” often getting into shouting matches over his CBradio with other truck drivers. We started quetiapine, 25 mg bid, hoping the low dose would calm his mood.

Until now, Mr. D has ignored our requests to undergo routine laboratory testing. We referred him to the local clinic four times over the past year but he has not complied, citing lack of health insurance and financial concerns.

The authors’ observations

Although Mr. D’s symptoms (constantly depressed mood, loss of interest in usual activities) clearly suggest treatment-resistant major depressive disorder, an underlying medical disorder cannot be ruled out, yet he refuses to get needed tests.

Medical comorbidities are more prevalent in patients with mental illness than in the general population.¹ As many as 43% of patients referred to some psychiatry clinics have medical disorders, and almost one-half the diagnoses were missed by the referring physician.²

Compared to patients without psychiatric diagnoses, those with mental illness have more difficulty gaining access to medical care and are less likely to receive and follow guidelines for preventive care. Mental illness symptoms often compromise one’s ability to seek health care or follow a doctor’s orders. For example, a psychotic person may be overly suspicious of doctors, whereas someone with anxiety may seek care inappropriately.^3,4 Also, some studies estimate that 1 in 5 persons with mental illness are uninsured.^1,5,6

Mr. D denies substance abuse, but primary care and behavioral health clinicians often miss substance use disorders.⁷ Accuracy of substance abuse self-reports varies widely; some studies report high accuracy, whereas almost 33% of patients in other studies do not disclose substance abuse.⁸

Testing: stimulating findings

At his next visit, Mr. D reports worsening thirst and increased urination and complains of increased appetite, easy bruising, excessive sleepiness, and apathy. He also reveals that for 2 months he has been taking 2 to 3 fat-burning stimulant capsules a day to stay awake while driving.

 

Alarmed by his elevated blood pressure (177/99 mm Hg) and worsening physical symptoms, Mr. D finally consents to baseline laboratory testing. Blood glucose is 306 mg/dL (normal 70 to 110 mg/dL), and glycosylated hemoglobin is 12% (normal

Mr. D, who now weighs 270 lbs, is diagnosed as having hypertension and type 2 diabetes mellitus. Clinic doctors start him on metformin, 500 mg bid titrated to 1,000 mg bid, and glyburide, 5 mg/d, to control his glucose, and lisinopril, 10 mg/d, to control his hypertension, reduce cardiovascular risk, and preserve renal function. Clinicians also order Mr. D to follow an 1,800-calorie, American Diabetes Association-approved diet. We stop quetiapine and bupropion.

Mr. D’s diabetes and hypertension diagnosis, combined with his habitus and history of easy bruising, suggest Cushing’s syndrome. Doctors rule out this disorder based on a 24-hour free cortisol reading of 59 mg/L and normal dexamethasone suppression. Lab findings suggest he is not taking stimulants away from work.

The authors’ observations

Ideally, Mr. D should have undergone laboratory testing after the initial intake visit, before psychotropics were started. Routine vital signs also should have been taken.

Symptoms of major depressive disorder and early type 2 diabetes are strikingly similar (Table 1). For example, early diabetes symptoms such as fatigue can mimic depression or other medical problems. In one study of 69 diabetic patients who were referred by their primary care doctors to a psychiatric clinic, 57 had not been diagnosed as having diabetes before referral.⁹

Aside from its medical complications, diabetes also doubles the risk of comorbid depression, which can alter diabetes’ course and outcome.¹⁰

Earlier laboratory testing could have uncovered Mr. D’s comorbid stimulant abuse, which also can mimic depression and complicate its treatment.¹¹ Signs of amphetamine withdrawal—such as dysphoric mood, fatigue, insomnia or hypersomnia, increased appetite, and psychomotor retardation—can be mistaken for depression (Table 1).

Patients with Cushing’s syndrome may present with nonspecific complaints of fatigue, decreased energy, apathy, depressed mood, and hypersomnia. A 24-hour free cortisol reading and dexamethasone suppression testing can differentiate Cushing’s syndrome from depression.

Costly, unnecessary care. Missing a medical cause of apparent psychiatric symptoms can lead to unnecessary treatment and needless expense. A complete metabolic profile and urine drug screen—approximately $60—could have saved the nearly $5,000 spent on treating Mr. D’s “resistant” depression ( Table 2).

Psychiatrists need to watch for potential medical problems and for cormorbidities associated with mental illness. Patients with frequent mental distress—defined as ≥ 14 mentally unhealthy days within 30 days—were found to be more likely to smoke, drink heavily, and be physically inactive and obese than were mentally healthy persons. Mentally distressed patients also were more likely to lack health care coverage and to engage in multiple adverse behaviors, increasing their risk for mental and physical illness.¹²

Ensuring proper medical care. Based on our experience with Mr. D, routine vital signs—including BMI, weight, blood pressure, and pulse rate—should be recorded at each visit. At intake, we recommend that psychiatrists:

• find out when the patient last saw a primary health provider other than in the emergency room, and whether the patient is receiving preventive medical care
  
• assess for unhealthy lifestyle habits (smoking, drug use, poor diet) or family history of serious medical illnesses.
  

Mr. D, for example, had not received preventative care for at least 2 to 3 years and had obesity, a family history of diabetes, a sedentary lifestyle, and an unhealthy diet.

Educate patients about the interplay between physical and mental illness to help them understand the importance of seeing a primary care doctor. Finally, be familiar with local indigent health clinics and their fee scales.

Table 1

Medical symptoms that mimic depression

Symptom	Amphetamine withdrawal	Cushing’s syndrome	Diabetes
Anxiety		×
Dysphoric mood	×
Fatigue	×	×	×
Hypersomnia	×
Increased appetite	×		×
Insomnia	×
Irritability		×	×
Muscle aches and cramps			×
Psychomotor retardation	×
Vivid, unpleasant dreams	×
Weakness		×
Weight gain or loss			×

Table 2

The cost of treating Mr. D’s ‘resistant depression’

Medication/dosage	Start date	Stop date	Approximate cost
Citalopram, 20 mg/d	10/3/03	10/24/03	$58.50
Sertraline, 25 to 200 mg/d	10/24/03	12/24/03	$283.00
Sertraline 150 mg/d, with lithium, 225 to 675 mg/d	12/24/03	2/6/04	$343.00
Tranylcypromine, 10 mg each morning, 20 mg at bedtime	2/27/04	4/20/04	$322.00
Bupropion (sustained release) up to 450 mg/d	5/7/04	8/30/04	$372.00
Bupropion (sustained release), 450 mg/d, plus quetiapine, 25 mg/d	8/30/04	11/8/04	$554.00
Total cost of psychotropics			$1,932.50
Total cost of office visits ($95 X 30 visits)			$2,850.00
TOTAL COST OF TREATMENT			$4,782.50
Source: Walgreens Co. retail prices in Wichita, KS

Follow-up: 30 lbs in 4 months

Mr. D has lost >30 lbs over 4 months, and his blood pressure and serum glucose are normal. BMI is now 32, in the lower range of clinical obesity. He feels more energetic and active, no longer reports excessive sedation and apathy, and has stopped taking stimulants. His depressive symptoms have remitted.

 

Related resources

• WrongDiagnosis.com. Information on differential diagnosis of medical and psychiatric problems. www.wrongdiagnosis.com.
  
• Mauksch LB, Tucker SM, Katon WJ, et al. Mental illness, functional impairment, and patient preferences for collaborative care in an uninsured, primary care population. J Fam Pract 2001;50:41-7.
  
• Glied S, Little SE. The uninsured and the benefits of medical progress. Health Aff (Millwood) 2003;22:210-9.
  

Drug brand names

• Bupropion • Wellbutrin
  
• Citalopram • Celexa
  
• Dexamethasone • Ciprodex, others
  
• Glucophage • Metformin
  
• Glyburide • DiaBeta, others
  
• Lisinopril • Prinivil, Zestril
  
• Lithium • Eskalith, others
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  
• Tranylcypromine •Parnate
  

Disclosure

Dr. Khan is a speaker for Wyeth Pharmaceuticals.

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

History: losing his ‘drive’

Mr. D, age 49, has been treated for major depressive disorder for approximately 1 year but reports only occasional minor symptom improvement. At presentation, he had been irritable and lethargic for about 2 weeks and had increased appetite, decreased concentration, and trouble falling asleep at night.

A once-gregarious family man, Mr. D had become apathetic and too tired to enjoy socializing. He denied suicidal thoughts or feelings of worthlessness and hopelessness but feared his fatigue was interfering with his job as a truck driver. He tired after driving only a few hours.

Mr. D had been diagnosed with sleep apnea when he was younger but had no other medical history. He said his erratic work schedule kept him from using his continuous positive airway pressure (CPAP) machine regularly. He was taking no medications and had not seen a primary care physician for more than 2 years because of lack of coverage. He denied past or current substance abuse.

The patient weighed 280 lbs at intake. His body mass index (BMI) was 37.5, indicating clinical obesity.

Because Mr. D lacked health insurance, we enrolled him 1 year ago in a free depression study at a psychiatric outpatient clinic. At intake, he said numerous life stresses—particularly the recent death of his brother in a motor vehicle accident—had left him feeling depressed.

We started Mr. D on citalopram, 20 mg/d, which was the study protocol. Two weeks later, he complained of dry mouth and sedation with minimal symptom improvement. We stopped citalopram and started sertraline, 25 mg/d.

Two weeks later, Mr. D again complained he had “no energy” and was “sleeping all day.” We titrated sertraline to 200 mg/d over 2 months, but his excessive tiredness, increased appetite, and decreased motivation persisted. Mr. D needed routine laboratory tests, so we referred him to a local clinic that charges on a sliding scale. He did not complete the tests, however, for fear of incurring medical expenses.

We tried to improve Mr. D’s mood symptoms by adding lithium—225 mg/d titrated to 675 mg/d over 7 weeks—but his depression and fatigue kept worsening. We tapered him off lithium and sertraline and switched to the monoamine oxidase inhibitor tranylcypromine, 30 mg/d, which was also part of the study protocol. We warned him not to eat pizza, fermented dry sausages, or other foods that could interact adversely with tranylcypromine. After 4 weeks, Mr. D stopped taking the agent, saying he could not follow the dietary restrictions while on the road.

We released Mr. D from the study because of nonresponse. Bupropion, started at 100 mg bid and titrated to 300 mg each morning and 150 mg nightly across 5 months, did not resolve his fatigue. He also started having agitation and “anger problems,” often getting into shouting matches over his CBradio with other truck drivers. We started quetiapine, 25 mg bid, hoping the low dose would calm his mood.

Until now, Mr. D has ignored our requests to undergo routine laboratory testing. We referred him to the local clinic four times over the past year but he has not complied, citing lack of health insurance and financial concerns.

The authors’ observations

Although Mr. D’s symptoms (constantly depressed mood, loss of interest in usual activities) clearly suggest treatment-resistant major depressive disorder, an underlying medical disorder cannot be ruled out, yet he refuses to get needed tests.

Medical comorbidities are more prevalent in patients with mental illness than in the general population.¹ As many as 43% of patients referred to some psychiatry clinics have medical disorders, and almost one-half the diagnoses were missed by the referring physician.²

Compared to patients without psychiatric diagnoses, those with mental illness have more difficulty gaining access to medical care and are less likely to receive and follow guidelines for preventive care. Mental illness symptoms often compromise one’s ability to seek health care or follow a doctor’s orders. For example, a psychotic person may be overly suspicious of doctors, whereas someone with anxiety may seek care inappropriately.^3,4 Also, some studies estimate that 1 in 5 persons with mental illness are uninsured.^1,5,6

Mr. D denies substance abuse, but primary care and behavioral health clinicians often miss substance use disorders.⁷ Accuracy of substance abuse self-reports varies widely; some studies report high accuracy, whereas almost 33% of patients in other studies do not disclose substance abuse.⁸

Testing: stimulating findings

At his next visit, Mr. D reports worsening thirst and increased urination and complains of increased appetite, easy bruising, excessive sleepiness, and apathy. He also reveals that for 2 months he has been taking 2 to 3 fat-burning stimulant capsules a day to stay awake while driving.

 

Alarmed by his elevated blood pressure (177/99 mm Hg) and worsening physical symptoms, Mr. D finally consents to baseline laboratory testing. Blood glucose is 306 mg/dL (normal 70 to 110 mg/dL), and glycosylated hemoglobin is 12% (normal

Mr. D, who now weighs 270 lbs, is diagnosed as having hypertension and type 2 diabetes mellitus. Clinic doctors start him on metformin, 500 mg bid titrated to 1,000 mg bid, and glyburide, 5 mg/d, to control his glucose, and lisinopril, 10 mg/d, to control his hypertension, reduce cardiovascular risk, and preserve renal function. Clinicians also order Mr. D to follow an 1,800-calorie, American Diabetes Association-approved diet. We stop quetiapine and bupropion.

Mr. D’s diabetes and hypertension diagnosis, combined with his habitus and history of easy bruising, suggest Cushing’s syndrome. Doctors rule out this disorder based on a 24-hour free cortisol reading of 59 mg/L and normal dexamethasone suppression. Lab findings suggest he is not taking stimulants away from work.

The authors’ observations

Ideally, Mr. D should have undergone laboratory testing after the initial intake visit, before psychotropics were started. Routine vital signs also should have been taken.

Symptoms of major depressive disorder and early type 2 diabetes are strikingly similar (Table 1). For example, early diabetes symptoms such as fatigue can mimic depression or other medical problems. In one study of 69 diabetic patients who were referred by their primary care doctors to a psychiatric clinic, 57 had not been diagnosed as having diabetes before referral.⁹

Aside from its medical complications, diabetes also doubles the risk of comorbid depression, which can alter diabetes’ course and outcome.¹⁰

Earlier laboratory testing could have uncovered Mr. D’s comorbid stimulant abuse, which also can mimic depression and complicate its treatment.¹¹ Signs of amphetamine withdrawal—such as dysphoric mood, fatigue, insomnia or hypersomnia, increased appetite, and psychomotor retardation—can be mistaken for depression (Table 1).

Patients with Cushing’s syndrome may present with nonspecific complaints of fatigue, decreased energy, apathy, depressed mood, and hypersomnia. A 24-hour free cortisol reading and dexamethasone suppression testing can differentiate Cushing’s syndrome from depression.

Costly, unnecessary care. Missing a medical cause of apparent psychiatric symptoms can lead to unnecessary treatment and needless expense. A complete metabolic profile and urine drug screen—approximately $60—could have saved the nearly $5,000 spent on treating Mr. D’s “resistant” depression ( Table 2).

Psychiatrists need to watch for potential medical problems and for cormorbidities associated with mental illness. Patients with frequent mental distress—defined as ≥ 14 mentally unhealthy days within 30 days—were found to be more likely to smoke, drink heavily, and be physically inactive and obese than were mentally healthy persons. Mentally distressed patients also were more likely to lack health care coverage and to engage in multiple adverse behaviors, increasing their risk for mental and physical illness.¹²

Ensuring proper medical care. Based on our experience with Mr. D, routine vital signs—including BMI, weight, blood pressure, and pulse rate—should be recorded at each visit. At intake, we recommend that psychiatrists:

• find out when the patient last saw a primary health provider other than in the emergency room, and whether the patient is receiving preventive medical care
  
• assess for unhealthy lifestyle habits (smoking, drug use, poor diet) or family history of serious medical illnesses.
  

Mr. D, for example, had not received preventative care for at least 2 to 3 years and had obesity, a family history of diabetes, a sedentary lifestyle, and an unhealthy diet.

Educate patients about the interplay between physical and mental illness to help them understand the importance of seeing a primary care doctor. Finally, be familiar with local indigent health clinics and their fee scales.

Table 1

Medical symptoms that mimic depression

Symptom	Amphetamine withdrawal	Cushing’s syndrome	Diabetes
Anxiety		×
Dysphoric mood	×
Fatigue	×	×	×
Hypersomnia	×
Increased appetite	×		×
Insomnia	×
Irritability		×	×
Muscle aches and cramps			×
Psychomotor retardation	×
Vivid, unpleasant dreams	×
Weakness		×
Weight gain or loss			×

Table 2

The cost of treating Mr. D’s ‘resistant depression’

Medication/dosage	Start date	Stop date	Approximate cost
Citalopram, 20 mg/d	10/3/03	10/24/03	$58.50
Sertraline, 25 to 200 mg/d	10/24/03	12/24/03	$283.00
Sertraline 150 mg/d, with lithium, 225 to 675 mg/d	12/24/03	2/6/04	$343.00
Tranylcypromine, 10 mg each morning, 20 mg at bedtime	2/27/04	4/20/04	$322.00
Bupropion (sustained release) up to 450 mg/d	5/7/04	8/30/04	$372.00
Bupropion (sustained release), 450 mg/d, plus quetiapine, 25 mg/d	8/30/04	11/8/04	$554.00
Total cost of psychotropics			$1,932.50
Total cost of office visits ($95 X 30 visits)			$2,850.00
TOTAL COST OF TREATMENT			$4,782.50
Source: Walgreens Co. retail prices in Wichita, KS

Follow-up: 30 lbs in 4 months

Mr. D has lost >30 lbs over 4 months, and his blood pressure and serum glucose are normal. BMI is now 32, in the lower range of clinical obesity. He feels more energetic and active, no longer reports excessive sedation and apathy, and has stopped taking stimulants. His depressive symptoms have remitted.

 

Related resources

• WrongDiagnosis.com. Information on differential diagnosis of medical and psychiatric problems. www.wrongdiagnosis.com.
  
• Mauksch LB, Tucker SM, Katon WJ, et al. Mental illness, functional impairment, and patient preferences for collaborative care in an uninsured, primary care population. J Fam Pract 2001;50:41-7.
  
• Glied S, Little SE. The uninsured and the benefits of medical progress. Health Aff (Millwood) 2003;22:210-9.
  

Drug brand names

• Bupropion • Wellbutrin
  
• Citalopram • Celexa
  
• Dexamethasone • Ciprodex, others
  
• Glucophage • Metformin
  
• Glyburide • DiaBeta, others
  
• Lisinopril • Prinivil, Zestril
  
• Lithium • Eskalith, others
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  
• Tranylcypromine •Parnate
  

Disclosure

Dr. Khan is a speaker for Wyeth Pharmaceuticals.

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

History: losing his ‘drive’

Mr. D, age 49, has been treated for major depressive disorder for approximately 1 year but reports only occasional minor symptom improvement. At presentation, he had been irritable and lethargic for about 2 weeks and had increased appetite, decreased concentration, and trouble falling asleep at night.

A once-gregarious family man, Mr. D had become apathetic and too tired to enjoy socializing. He denied suicidal thoughts or feelings of worthlessness and hopelessness but feared his fatigue was interfering with his job as a truck driver. He tired after driving only a few hours.

Mr. D had been diagnosed with sleep apnea when he was younger but had no other medical history. He said his erratic work schedule kept him from using his continuous positive airway pressure (CPAP) machine regularly. He was taking no medications and had not seen a primary care physician for more than 2 years because of lack of coverage. He denied past or current substance abuse.

The patient weighed 280 lbs at intake. His body mass index (BMI) was 37.5, indicating clinical obesity.

Because Mr. D lacked health insurance, we enrolled him 1 year ago in a free depression study at a psychiatric outpatient clinic. At intake, he said numerous life stresses—particularly the recent death of his brother in a motor vehicle accident—had left him feeling depressed.

We started Mr. D on citalopram, 20 mg/d, which was the study protocol. Two weeks later, he complained of dry mouth and sedation with minimal symptom improvement. We stopped citalopram and started sertraline, 25 mg/d.

Two weeks later, Mr. D again complained he had “no energy” and was “sleeping all day.” We titrated sertraline to 200 mg/d over 2 months, but his excessive tiredness, increased appetite, and decreased motivation persisted. Mr. D needed routine laboratory tests, so we referred him to a local clinic that charges on a sliding scale. He did not complete the tests, however, for fear of incurring medical expenses.

We tried to improve Mr. D’s mood symptoms by adding lithium—225 mg/d titrated to 675 mg/d over 7 weeks—but his depression and fatigue kept worsening. We tapered him off lithium and sertraline and switched to the monoamine oxidase inhibitor tranylcypromine, 30 mg/d, which was also part of the study protocol. We warned him not to eat pizza, fermented dry sausages, or other foods that could interact adversely with tranylcypromine. After 4 weeks, Mr. D stopped taking the agent, saying he could not follow the dietary restrictions while on the road.

We released Mr. D from the study because of nonresponse. Bupropion, started at 100 mg bid and titrated to 300 mg each morning and 150 mg nightly across 5 months, did not resolve his fatigue. He also started having agitation and “anger problems,” often getting into shouting matches over his CBradio with other truck drivers. We started quetiapine, 25 mg bid, hoping the low dose would calm his mood.

Until now, Mr. D has ignored our requests to undergo routine laboratory testing. We referred him to the local clinic four times over the past year but he has not complied, citing lack of health insurance and financial concerns.

The authors’ observations

Although Mr. D’s symptoms (constantly depressed mood, loss of interest in usual activities) clearly suggest treatment-resistant major depressive disorder, an underlying medical disorder cannot be ruled out, yet he refuses to get needed tests.

Medical comorbidities are more prevalent in patients with mental illness than in the general population.¹ As many as 43% of patients referred to some psychiatry clinics have medical disorders, and almost one-half the diagnoses were missed by the referring physician.²

Compared to patients without psychiatric diagnoses, those with mental illness have more difficulty gaining access to medical care and are less likely to receive and follow guidelines for preventive care. Mental illness symptoms often compromise one’s ability to seek health care or follow a doctor’s orders. For example, a psychotic person may be overly suspicious of doctors, whereas someone with anxiety may seek care inappropriately.^3,4 Also, some studies estimate that 1 in 5 persons with mental illness are uninsured.^1,5,6

Mr. D denies substance abuse, but primary care and behavioral health clinicians often miss substance use disorders.⁷ Accuracy of substance abuse self-reports varies widely; some studies report high accuracy, whereas almost 33% of patients in other studies do not disclose substance abuse.⁸

Testing: stimulating findings

At his next visit, Mr. D reports worsening thirst and increased urination and complains of increased appetite, easy bruising, excessive sleepiness, and apathy. He also reveals that for 2 months he has been taking 2 to 3 fat-burning stimulant capsules a day to stay awake while driving.

 

Alarmed by his elevated blood pressure (177/99 mm Hg) and worsening physical symptoms, Mr. D finally consents to baseline laboratory testing. Blood glucose is 306 mg/dL (normal 70 to 110 mg/dL), and glycosylated hemoglobin is 12% (normal

Mr. D, who now weighs 270 lbs, is diagnosed as having hypertension and type 2 diabetes mellitus. Clinic doctors start him on metformin, 500 mg bid titrated to 1,000 mg bid, and glyburide, 5 mg/d, to control his glucose, and lisinopril, 10 mg/d, to control his hypertension, reduce cardiovascular risk, and preserve renal function. Clinicians also order Mr. D to follow an 1,800-calorie, American Diabetes Association-approved diet. We stop quetiapine and bupropion.

Mr. D’s diabetes and hypertension diagnosis, combined with his habitus and history of easy bruising, suggest Cushing’s syndrome. Doctors rule out this disorder based on a 24-hour free cortisol reading of 59 mg/L and normal dexamethasone suppression. Lab findings suggest he is not taking stimulants away from work.

The authors’ observations

Ideally, Mr. D should have undergone laboratory testing after the initial intake visit, before psychotropics were started. Routine vital signs also should have been taken.

Symptoms of major depressive disorder and early type 2 diabetes are strikingly similar (Table 1). For example, early diabetes symptoms such as fatigue can mimic depression or other medical problems. In one study of 69 diabetic patients who were referred by their primary care doctors to a psychiatric clinic, 57 had not been diagnosed as having diabetes before referral.⁹

Aside from its medical complications, diabetes also doubles the risk of comorbid depression, which can alter diabetes’ course and outcome.¹⁰

Earlier laboratory testing could have uncovered Mr. D’s comorbid stimulant abuse, which also can mimic depression and complicate its treatment.¹¹ Signs of amphetamine withdrawal—such as dysphoric mood, fatigue, insomnia or hypersomnia, increased appetite, and psychomotor retardation—can be mistaken for depression (Table 1).

Patients with Cushing’s syndrome may present with nonspecific complaints of fatigue, decreased energy, apathy, depressed mood, and hypersomnia. A 24-hour free cortisol reading and dexamethasone suppression testing can differentiate Cushing’s syndrome from depression.

Costly, unnecessary care. Missing a medical cause of apparent psychiatric symptoms can lead to unnecessary treatment and needless expense. A complete metabolic profile and urine drug screen—approximately $60—could have saved the nearly $5,000 spent on treating Mr. D’s “resistant” depression ( Table 2).

Psychiatrists need to watch for potential medical problems and for cormorbidities associated with mental illness. Patients with frequent mental distress—defined as ≥ 14 mentally unhealthy days within 30 days—were found to be more likely to smoke, drink heavily, and be physically inactive and obese than were mentally healthy persons. Mentally distressed patients also were more likely to lack health care coverage and to engage in multiple adverse behaviors, increasing their risk for mental and physical illness.¹²

Ensuring proper medical care. Based on our experience with Mr. D, routine vital signs—including BMI, weight, blood pressure, and pulse rate—should be recorded at each visit. At intake, we recommend that psychiatrists:

• find out when the patient last saw a primary health provider other than in the emergency room, and whether the patient is receiving preventive medical care
  
• assess for unhealthy lifestyle habits (smoking, drug use, poor diet) or family history of serious medical illnesses.
  

Mr. D, for example, had not received preventative care for at least 2 to 3 years and had obesity, a family history of diabetes, a sedentary lifestyle, and an unhealthy diet.

Educate patients about the interplay between physical and mental illness to help them understand the importance of seeing a primary care doctor. Finally, be familiar with local indigent health clinics and their fee scales.

Table 1

Medical symptoms that mimic depression

Symptom	Amphetamine withdrawal	Cushing’s syndrome	Diabetes
Anxiety		×
Dysphoric mood	×
Fatigue	×	×	×
Hypersomnia	×
Increased appetite	×		×
Insomnia	×
Irritability		×	×
Muscle aches and cramps			×
Psychomotor retardation	×
Vivid, unpleasant dreams	×
Weakness		×
Weight gain or loss			×

Table 2

The cost of treating Mr. D’s ‘resistant depression’

Medication/dosage	Start date	Stop date	Approximate cost
Citalopram, 20 mg/d	10/3/03	10/24/03	$58.50
Sertraline, 25 to 200 mg/d	10/24/03	12/24/03	$283.00
Sertraline 150 mg/d, with lithium, 225 to 675 mg/d	12/24/03	2/6/04	$343.00
Tranylcypromine, 10 mg each morning, 20 mg at bedtime	2/27/04	4/20/04	$322.00
Bupropion (sustained release) up to 450 mg/d	5/7/04	8/30/04	$372.00
Bupropion (sustained release), 450 mg/d, plus quetiapine, 25 mg/d	8/30/04	11/8/04	$554.00
Total cost of psychotropics			$1,932.50
Total cost of office visits ($95 X 30 visits)			$2,850.00
TOTAL COST OF TREATMENT			$4,782.50
Source: Walgreens Co. retail prices in Wichita, KS

Follow-up: 30 lbs in 4 months

Mr. D has lost >30 lbs over 4 months, and his blood pressure and serum glucose are normal. BMI is now 32, in the lower range of clinical obesity. He feels more energetic and active, no longer reports excessive sedation and apathy, and has stopped taking stimulants. His depressive symptoms have remitted.

 

Related resources

• WrongDiagnosis.com. Information on differential diagnosis of medical and psychiatric problems. www.wrongdiagnosis.com.
  
• Mauksch LB, Tucker SM, Katon WJ, et al. Mental illness, functional impairment, and patient preferences for collaborative care in an uninsured, primary care population. J Fam Pract 2001;50:41-7.
  
• Glied S, Little SE. The uninsured and the benefits of medical progress. Health Aff (Millwood) 2003;22:210-9.
  

Drug brand names

• Bupropion • Wellbutrin
  
• Citalopram • Celexa
  
• Dexamethasone • Ciprodex, others
  
• Glucophage • Metformin
  
• Glyburide • DiaBeta, others
  
• Lisinopril • Prinivil, Zestril
  
• Lithium • Eskalith, others
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  
• Tranylcypromine •Parnate
  

Disclosure

Dr. Khan is a speaker for Wyeth Pharmaceuticals.

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