Evidence-Based Reviews

Sexual trauma may cause or exacerbate posttraumatic stress disorder (PTSD).^{See "Traumatized Troops: How to treat combat-related PTSD"). Two recommended questions (Box) for men and women can help you start discussing MST.}

Use compassion and sensitivity, recognizing the stigma of sexual assault while fastidiously preserving confidentiality. Establish a comfortable environment for disclosure, be nonjudgmental, and maintain good eye contact as you gradually introduce the questions.

Box

Recommended treatment

Comprehensive MST management includes assessing for PTSD, major depression, and substance abuse. When a veteran screens positive for MST, validation and empathy are first-line treatment. Provide MST education, assess health status, and ask them about their support systems.

Sexual trauma survivors often suffer low selfesteem, self-blame, anger, difficulties with interpersonal relationships, and sexual dysfunction. “PTSD flare-ups” can occur during medical encounters and clinical procedures. Evaluate MST survivors regularly for re-victimization, as they may be at risk to be sexually abused again outside the military.⁵

Referral. Consider referring veterans to a local VA facility, which all have a “military sexual trauma coordinator” to help veterans obtain treatment. Other VA resources include referrals to the women veterans program manager or mental health clinic.

Veterans living in the community can be referred to readjustment counseling service offices, which have sexual trauma counselors on staff. This may be an option for the veteran who does not want to obtain mental health services from the VA.

Related resources

• Street A, Stafford J. Military sexual trauma: Issues in caring for veterans. National Center for Posttraumatic Stress Disorder. http://www.ncptsd.org//war/military_sexual_trauma.html.
  

Sexual trauma may cause or exacerbate posttraumatic stress disorder (PTSD).^{See "Traumatized Troops: How to treat combat-related PTSD"). Two recommended questions (Box) for men and women can help you start discussing MST.}

Use compassion and sensitivity, recognizing the stigma of sexual assault while fastidiously preserving confidentiality. Establish a comfortable environment for disclosure, be nonjudgmental, and maintain good eye contact as you gradually introduce the questions.

Box

Recommended treatment

Comprehensive MST management includes assessing for PTSD, major depression, and substance abuse. When a veteran screens positive for MST, validation and empathy are first-line treatment. Provide MST education, assess health status, and ask them about their support systems.

Sexual trauma survivors often suffer low selfesteem, self-blame, anger, difficulties with interpersonal relationships, and sexual dysfunction. “PTSD flare-ups” can occur during medical encounters and clinical procedures. Evaluate MST survivors regularly for re-victimization, as they may be at risk to be sexually abused again outside the military.⁵

Referral. Consider referring veterans to a local VA facility, which all have a “military sexual trauma coordinator” to help veterans obtain treatment. Other VA resources include referrals to the women veterans program manager or mental health clinic.

Veterans living in the community can be referred to readjustment counseling service offices, which have sexual trauma counselors on staff. This may be an option for the veteran who does not want to obtain mental health services from the VA.

Related resources

• Street A, Stafford J. Military sexual trauma: Issues in caring for veterans. National Center for Posttraumatic Stress Disorder. http://www.ncptsd.org//war/military_sexual_trauma.html.
  

Sexual trauma may cause or exacerbate posttraumatic stress disorder (PTSD).^{See "Traumatized Troops: How to treat combat-related PTSD"). Two recommended questions (Box) for men and women can help you start discussing MST.}

Use compassion and sensitivity, recognizing the stigma of sexual assault while fastidiously preserving confidentiality. Establish a comfortable environment for disclosure, be nonjudgmental, and maintain good eye contact as you gradually introduce the questions.

Box

Recommended treatment

Comprehensive MST management includes assessing for PTSD, major depression, and substance abuse. When a veteran screens positive for MST, validation and empathy are first-line treatment. Provide MST education, assess health status, and ask them about their support systems.

Sexual trauma survivors often suffer low selfesteem, self-blame, anger, difficulties with interpersonal relationships, and sexual dysfunction. “PTSD flare-ups” can occur during medical encounters and clinical procedures. Evaluate MST survivors regularly for re-victimization, as they may be at risk to be sexually abused again outside the military.⁵

Referral. Consider referring veterans to a local VA facility, which all have a “military sexual trauma coordinator” to help veterans obtain treatment. Other VA resources include referrals to the women veterans program manager or mental health clinic.

Veterans living in the community can be referred to readjustment counseling service offices, which have sexual trauma counselors on staff. This may be an option for the veteran who does not want to obtain mental health services from the VA.

Related resources

• Street A, Stafford J. Military sexual trauma: Issues in caring for veterans. National Center for Posttraumatic Stress Disorder. http://www.ncptsd.org//war/military_sexual_trauma.html.
  

Thousands of U.S. troops are seeking mental health care after being deployed in Iraq. Among 222,000 Army and Marine Iraq veterans, 35% sought treatment in the year after returning home—many for posttraumatic stress disorder (PTSD).^{In a related article, we discuss the diagnosis and treatment of military sexual trauma, a form of PTSD.}

Persistent pathology

The greater the intensity of an Iraq/Afghanistan veteran’s combat experiences (“firefights”), the more likely the soldier is to develop PTSD.^{Traumatic brain injury: Choosing medications for neurobehavioral symptoms”). Sexual trauma also may cause or exacerbate PTSD.Military sexual trauma: How to identify and treat a unique form of PTSD”).}

Table 1

3 domains of posttraumatic stress disorder symptoms

Domain	Symptoms
Re-experiencing	Recurrent, intrusive, distressing recollections or dreams of traumatic event Acting or feeling as if the event were recurring Intense psychological distress or physiologic reactions when exposed to internal or external cues
Avoidance and numbing	Efforts to avoid thoughts, feelings, or conversations about the trauma or activities, places, or people that arouse recollections Inability to recall an important aspect of the trauma Markedly less interest or participation in significant activities Feeling detached or estranged from others Restricted range of affect Sense of a foreshortened future
Increased arousal	Difficulty falling or staying asleep Irritability or angry outbursts Difficulty concentrating Hypervigilance Exaggerated startle response
Source: DSM-IV-TR

FigurePTSD screen for war veterans

Source: U.S. Department of Veterans Affairs. Afghan & Iraq Post-Deployment Screen, Attachment B. Screening for risk factors associated with development of post-traumatic stress disorder (PTSD)

Cognitive therapy

Psychotherapy is the cornerstone of PTSD treatment; skilled therapists may achieve greater efficacy and more-durable results than medications do. Evidence strongly supports cognitive behavioral therapy—including exposure therapy, anxiety management, and cognitive therapy.^{U.S. troops returning home: Are you prepared? Current Psychiatry 2006;5(1):12-22.}

• U.S. Department of Veterans Affairs. Seamless Transition Home. http://www.seamlesstransition.va.gov. Accessed March 13, 2006.

• American Psychiatric Association. Practice guideline for the treatment of acute stress disorder and posttraumatic stress disorder. http://www.psych.org/psych_pract/treatg/pg/PTSD-PG-PartsA-B-C-New.pdf.

Drug brand names

• Carbamazepine • Carbatrol
• Fluoxetine • Prozac
• Lamotrigine • Lamictal
• Lithium • Lithobid, others
• Mirtazapine • Remeron
• Paroxetine • Paxil
• Prazosin • Minipress
• Sertraline • Zoloft
• Trazodone • Desyrel
• Temazepam • Restoril
• Valproic acid • Divalproex, others
• Venlafaxine • Effexor
• Zolpidem • Ambien

Disclosures

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. Drs. Lineberry, Bostwick, and Rundell served on active duty in the U.S. Air Force. Dr. Ramaswamy is staff psychiatrist, Omaha Veterans Administration. and Director of Psychopharmacology Research, Creighton University, Omaha, NE.

Thousands of U.S. troops are seeking mental health care after being deployed in Iraq. Among 222,000 Army and Marine Iraq veterans, 35% sought treatment in the year after returning home—many for posttraumatic stress disorder (PTSD).^{In a related article, we discuss the diagnosis and treatment of military sexual trauma, a form of PTSD.}

Persistent pathology

The greater the intensity of an Iraq/Afghanistan veteran’s combat experiences (“firefights”), the more likely the soldier is to develop PTSD.^{Traumatic brain injury: Choosing medications for neurobehavioral symptoms”). Sexual trauma also may cause or exacerbate PTSD.Military sexual trauma: How to identify and treat a unique form of PTSD”).}

Table 1

3 domains of posttraumatic stress disorder symptoms

Domain	Symptoms
Re-experiencing	Recurrent, intrusive, distressing recollections or dreams of traumatic event Acting or feeling as if the event were recurring Intense psychological distress or physiologic reactions when exposed to internal or external cues
Avoidance and numbing	Efforts to avoid thoughts, feelings, or conversations about the trauma or activities, places, or people that arouse recollections Inability to recall an important aspect of the trauma Markedly less interest or participation in significant activities Feeling detached or estranged from others Restricted range of affect Sense of a foreshortened future
Increased arousal	Difficulty falling or staying asleep Irritability or angry outbursts Difficulty concentrating Hypervigilance Exaggerated startle response
Source: DSM-IV-TR

FigurePTSD screen for war veterans

Source: U.S. Department of Veterans Affairs. Afghan & Iraq Post-Deployment Screen, Attachment B. Screening for risk factors associated with development of post-traumatic stress disorder (PTSD)

Cognitive therapy

Psychotherapy is the cornerstone of PTSD treatment; skilled therapists may achieve greater efficacy and more-durable results than medications do. Evidence strongly supports cognitive behavioral therapy—including exposure therapy, anxiety management, and cognitive therapy.^{U.S. troops returning home: Are you prepared? Current Psychiatry 2006;5(1):12-22.}

• U.S. Department of Veterans Affairs. Seamless Transition Home. http://www.seamlesstransition.va.gov. Accessed March 13, 2006.

• American Psychiatric Association. Practice guideline for the treatment of acute stress disorder and posttraumatic stress disorder. http://www.psych.org/psych_pract/treatg/pg/PTSD-PG-PartsA-B-C-New.pdf.

Drug brand names

• Carbamazepine • Carbatrol
• Fluoxetine • Prozac
• Lamotrigine • Lamictal
• Lithium • Lithobid, others
• Mirtazapine • Remeron
• Paroxetine • Paxil
• Prazosin • Minipress
• Sertraline • Zoloft
• Trazodone • Desyrel
• Temazepam • Restoril
• Valproic acid • Divalproex, others
• Venlafaxine • Effexor
• Zolpidem • Ambien

Disclosures

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. Drs. Lineberry, Bostwick, and Rundell served on active duty in the U.S. Air Force. Dr. Ramaswamy is staff psychiatrist, Omaha Veterans Administration. and Director of Psychopharmacology Research, Creighton University, Omaha, NE.

Thousands of U.S. troops are seeking mental health care after being deployed in Iraq. Among 222,000 Army and Marine Iraq veterans, 35% sought treatment in the year after returning home—many for posttraumatic stress disorder (PTSD).^{In a related article, we discuss the diagnosis and treatment of military sexual trauma, a form of PTSD.}

Persistent pathology

The greater the intensity of an Iraq/Afghanistan veteran’s combat experiences (“firefights”), the more likely the soldier is to develop PTSD.^{Traumatic brain injury: Choosing medications for neurobehavioral symptoms”). Sexual trauma also may cause or exacerbate PTSD.Military sexual trauma: How to identify and treat a unique form of PTSD”).}

Table 1

3 domains of posttraumatic stress disorder symptoms

Domain	Symptoms
Re-experiencing	Recurrent, intrusive, distressing recollections or dreams of traumatic event Acting or feeling as if the event were recurring Intense psychological distress or physiologic reactions when exposed to internal or external cues
Avoidance and numbing	Efforts to avoid thoughts, feelings, or conversations about the trauma or activities, places, or people that arouse recollections Inability to recall an important aspect of the trauma Markedly less interest or participation in significant activities Feeling detached or estranged from others Restricted range of affect Sense of a foreshortened future
Increased arousal	Difficulty falling or staying asleep Irritability or angry outbursts Difficulty concentrating Hypervigilance Exaggerated startle response
Source: DSM-IV-TR

FigurePTSD screen for war veterans

Source: U.S. Department of Veterans Affairs. Afghan & Iraq Post-Deployment Screen, Attachment B. Screening for risk factors associated with development of post-traumatic stress disorder (PTSD)

Cognitive therapy

Psychotherapy is the cornerstone of PTSD treatment; skilled therapists may achieve greater efficacy and more-durable results than medications do. Evidence strongly supports cognitive behavioral therapy—including exposure therapy, anxiety management, and cognitive therapy.^{U.S. troops returning home: Are you prepared? Current Psychiatry 2006;5(1):12-22.}

• U.S. Department of Veterans Affairs. Seamless Transition Home. http://www.seamlesstransition.va.gov. Accessed March 13, 2006.

• American Psychiatric Association. Practice guideline for the treatment of acute stress disorder and posttraumatic stress disorder. http://www.psych.org/psych_pract/treatg/pg/PTSD-PG-PartsA-B-C-New.pdf.

Drug brand names

• Carbamazepine • Carbatrol
• Fluoxetine • Prozac
• Lamotrigine • Lamictal
• Lithium • Lithobid, others
• Mirtazapine • Remeron
• Paroxetine • Paxil
• Prazosin • Minipress
• Sertraline • Zoloft
• Trazodone • Desyrel
• Temazepam • Restoril
• Valproic acid • Divalproex, others
• Venlafaxine • Effexor
• Zolpidem • Ambien

Disclosures

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. Drs. Lineberry, Bostwick, and Rundell served on active duty in the U.S. Air Force. Dr. Ramaswamy is staff psychiatrist, Omaha Veterans Administration. and Director of Psychopharmacology Research, Creighton University, Omaha, NE.

Autism’s repetitive behaviors and restricted interests interfere with adaptive functioning, social interactions, and learning. No medications are FDA-approved for autistic disorder, but some selective serotonin reuptake inhibitors (SSRIs) and atypical antipsychotics and an anticonvulsant have reduced repetitive behaviors in controlled trials. We discuss how that evidence shapes our approach to patients with or without a comorbid family history of bipolar disorder.

Evidence for SSRIs

Repetitive behaviors and restricted interests are autism’s third core domain, as defined by DSM-IVTR criteria.¹ For an autistic disorder diagnosis, a patient must show at least one of these behaviors:

• encompassing preoccupations with stereotyped or restricted patterns of interest
• inflexible routines or rituals
• stereotyped, repetitive motor mannerisms
• or persistent preoccupation with parts of objects.

As in obsessive-compulsive disorder (OCD), rituals and restricted interests are thought to decrease anxiety in autism, whereas self-stimulatory behaviors and stereotypy may regulate arousal. The behaviors persist^2,3 but may change across the lifespan.

Because SSRIs improve OCD’s repetitive behaviors, clinicians have also used them to treat autism’s repetitive behaviors, though without supporting data. Recently, however, fluoxetine and fluvoxamine have shown efficacy for autism’s repetitive behaviors in randomized, controlled trials. Results indicate:

• In children, fluoxetine is probably better-tolerated than available dosing forms of fluvoxamine.
• In adults, fluvoxamine is well-tolerated and can improve repetitive behavior.

SSRIs and suicidal ideation in autism. The increased risk of suicidality reported with SSRIs when treating depression and OCD has not been seen in children with autism. But because fewer children with autism have been treated with SSRIs, we recommend that you try to assess suicidal ideation during SSRI treatment in those able to express such concerns (Box). Starting with low SSRI dosages (Table 1) and increasing slowly may help prevent behavioral activation, a possible risk factor for suicidality.

Box

Table 1

4 drugs with evidence of benefit for autism’s repetitive behaviors*

Medication	Suggested target daily dosage
Fluoxetine7	Children: Start at 2.5 mg/d; maximum 20 mg/d
	Adults: Start at 10 to 20 mg/d; maximum 60 mg/d
Fluvoxamine10	Children: Not first-line; start at 12.5 mg/d; maximum 150 to200 mg/d
	Adults: Start at 25 mg/d; maximum 300 mg/d
Risperidone13,16	Children: Start at 0.25 mg/d; maximum 3 mg/d
	Adults: Start at 2 mg/d; maximum 4 mg/d
Valproate20	Children: Start at 125 mg (sprinkles); titrate to clinical effect and blood levels of 50 of 120 mcg/mL
	Adults: Start at 250 mg; increase by 250mg/week to clinical effect and blood levels of 50 to 120 mcg/mL
*Data from randomized, placebo-controlled trials

Fluoxetine. In the first open-label study of fluoxetine in children and adults with autistic disorder, global functioning improved significantly in 15 of 23 patients, as measured by the Clinical Global Impressions (CGI) scale.⁴ Autism symptoms also improved in follow-up, open-label trials, but these did not target repetitive behaviors specifically.^5,6

Our group conducted the first randomized, placebo-controlled study of fluoxetine’s effect on repetitive behaviors in children with autism.⁷ We measured obsessions and compulsions in 45 children, ages 5 to 16, with the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). This 10-item, clinician-rated questionnaire uses a 5-point scale to rate repetitive behaviors by time spent, distress, interference, resistance, and control.

Using a crossover design—two 8-week phases of active or placebo treatment separated by a 4-week washout—we started liquid fluoxetine at 2.5 mg/d and slowly increased the dosage to clinical effect or a maximum of 0.8 mg/kg/day. Mean final dosage was 9.9 (±4.35) mg/d.

Repetitive behaviors improved, even though we used relatively low dosages to avoid side effects. The mean baseline CY-BOCS compulsion score of 13.15 dropped to 11.6 with fluoxetine and to 12.9 with placebo. Fluoxetine’s effect size was moderate to large, and we found no suicidal ideation with this SSRI.

 

Fluvoxamine. Repetitive behaviors did not change—as measured with the CY-BOCS—when 18 children with autism received fluvoxamine, 1.5 mg/kg/day, in a 10-week prospective, open-label trial.⁸ Most patients (72%) reported at least one side effect, and 3 discontinued the SSRI because of behavioral activation. Ten completed the trial. Likewise in a randomized trial, children who received fluvoxamine experienced troublesome side effects and limited benefit.⁹

Compared with outcomes in children, fluvoxamine has shown greater efficacy in adults. In a 12-week, double-blind, placebo-controlled trial of 30 adults with autism, 8 of 15 treated with fluvoxamine (50 mg/d initially and titrated to 300 mg/d) were rated as responders, compared with none of 15 receiving placebo.

Repetitive behaviors and adaptive functioning improved significantly with fluvoxamine, as measured with the Yale-Brown Obsessive Compulsive Scale (YBOCS) and Vineland Adaptive Behavior Scale, respectively.¹⁰ The SSRI was well-tolerated, with only mild nausea and sedation reported.

Thus, fluvoxamine may be useful for treating repetitive behaviors but probably is not a first choice for children with autism. Results might be more favorable in children if fluvoxamine were available in doses <12.5 mg.

Citalopram. Open-label data support using citalopram in autism.¹¹ In a retrospective chart review, 10 of 15 children (73%) were reported “much improved” with citalopram (mean dosage 16.9 mg/d [+/-12.1]), but the review did not specifically address repetitive behaviors. Two patients stopped taking the SSRI because of side effects; agitation, aggressiveness, sedation, and lip dyskinesia were reported.

The National Institutes of Health is sponsoring a multicenter trial of citalopram (starting dosage 2.5 mg/d, up to 20 mg/d) for repetitive behaviors in 144 children with autism, Results are expected in 2007 (see Related resources).

Escitalopram. Some early, open-label evidence suggests that escitalopram may be well-tolerated in autism, but its efficacy for treating repetitive behaviors has not been studied.

Sertraline. One of three reported open-label studies of sertraline in patients with autism measured repetitive behaviors.¹² In this study, 42 adults with autism spectrum disorder were treated for 12 weeks with sertraline, 50 to 200 mg/d. One-half were rated “much improved”—mostly in aggressive and repetitive behaviors—with the CGI improvement scale. Sertraline was well-tolerated, although 3 patients dropped out because of persistent agitation.

No randomized trials have examined sertraline in autism.

Clinical recommendations

Family history of bipolar disorder guides our treatment of patients with an autism spectrum disorder and disabling repetitive behaviors (Algorithm).

Algorithm Suggested medications to treat repetitive behaviors in autism

*Risperidone has the most evidence of efficacy, but aripiprazole may be useful for patients with weight-gain problems.
†For children, controlled data support using liquid fluoxetine, starting at 2.5 mg/d.Without bipolar history. SSRIs are usually first-line therapy (although patients with significant irritability and aggression may be an exception and require an atypical antipsychotic first).

If you reach the maximal SSRI dosage without a desired effect, consider adding an atypical (risperidone has the strongest supporting data) or valproate. If behavioral activation symptoms emerge and a lower dosage does not ameliorate them or reduces the clinical effect, consider switching to an atypical or valproate.

With bipolar history. Consider starting with an atypical or valproate; augment with an SSRI if needed.

Monitor for side effects with each medication (Table 2).

Table 2

Medication side effects and recommended monitoring

Medication	Side effects	Recommended monitoring
Fluoxetine	Anxiety, insomnia, GI disturbance, appetite and weight changes, mania/hypomania activation, suicidal ideation	Observe closely when starting treatment and while increasing dosage
Fluvoxamine	Somnolence, nervousness, insomnia, agitation, GI disturbance, suicidal ideation	Observe closely when starting treatment and while increasing dosage
Risperidone	Drowsiness, weight gain, hyperglycemia, GI disturbance, extrapyramidal symptoms, neuroleptic malignant syndrome	Obtain metabolic profile, including serum glucose and lipids
		Monitor for weight gain and clinical signs of extrapyramidal symptoms
Valproate	Rash, headaches, weight gain, ataxia, alopecia, GI disturbance, hyperammonemic encephalopathy, sedation, thrombocytopenia, polycystic ovary syndrome, pancreatitis, liver failure, teratogenic effects	CBC with platelets, liver function tests, valproate levels
		Therapeutic blood levels: 50 to 120 mcg/mL

Evidence for atypical antipsychotics

Atypicals have been used in autistic disorder to treat irritability and impulsive aggression. Risperidone also has been shown to reduce repetitive behaviors in a controlled trial.¹³ No evidence or only open-label trials support the use of other atypicals in patients with autism.

Risperidone’s side effects may include metabolic syndrome. No studies have examined lipid profiles and insulin resistance after risperidone treatment in patients with autism, but weight gain has been reported in the Research Units on Pediatric Psychopharmacology (RUPP) trial andothers.^13-15 Carefully assess the risk-benefit ratio when you consider using risperidone to treat repetitive behaviors in patients with autism.

Atypical antipsychotics also may increase dyskinesia risk, although extrapyramidal symptoms (EPS) have not been reported in studies of patients with autism and repetitive behaviors. Because EPS could develop after clinical trials are completed, long-term naturalistic studies are needed to address this concern.

 

Risperidone. The double-blind, placebo-controlled RUPP trial examined risperidone’s efficacy in treating autism’s core symptoms (primarily irritability) in 101 children.¹³ Mean dosages after 8 weeks and during a 16-week open-label extension for 63 children were 2 and 2.1 mg/d, respectively.

Repetitive behavior—as measured with the CY-BOCS, using RUPP trial data¹⁶—improved significantly with risperidone compared with placebo. During the 8-week controlled trial, CY-BOCS scores improved from 15.51 (SD±2.73) to 11.65 (SD±4.02) in the risperidone group, compared with 15.18 (SD±3.88) to 14.21 (SD±4.81) in the placebo group. This response was maintained through the open-label trial.

Side effects included weight gain, fatigue, drowsiness, and drooling. No children receiving risperidone dropped out because of side effects. No EPS were reported, based on weekly Abnormal Involuntary Movement scale and Simpson-Angus scale scores.

Olanzapine. Only open-label studies have examined olanzapine in autism, and one systematically measured repetitive behaviors.¹⁷ Eight children with autism or other pervasive developmental disorders were given olanzapine, mean dosage 7.8 (±4.7) mg/d at the end of the 12-week trial.

Repetitive behaviors did not change significantly, as measured with YBOCS. Seven of eight patients completed the trial. Mean weight for the group after 12 weeks was 156±55 lbs, compared with 137±56 lbs at baseline.

Quetiapine. No data support using quetiapine for autism’s repetitive behaviors. Quetiapine, 100 to 350 mg/d (1.6 to 5.2 mg/kg/day) was poorly tolerated in a 16-week open-label safety and efficacy trial among 6 mentally retarded boys with autistic disorder. Side effects included a possible seizure, behavioral activation, increased appetite, and weight gain (0.9 to 8.2 kg). Two patients completed the trial.¹⁸

Ziprasidone. Small open-label studies and anecdotal reports of ziprasidone in autism have not examined this drug’s effect on repetitive behaviors.

Aripiprazole. Anecdotal information suggests that clinicians are using this medication to treat patients with autism, but no supporting data exist.

Evidence for valproate

Preliminary trials by our group suggest that valproate may reduce repetitive behaviors in autism. In a retrospective, open-label study, 14 patients (mean age 17) with autism spectrum disorder received divalproex sodium (mean 768±582 mg/d) for a mean 11 months. Ten patients (71%) showed sustained improvement in function, as measured by the CGI-improvement scale, and valproate was generally well-tolerated.¹⁹

We then measured valproate’s effect on repetitive behaviors in an 8-week, double-blind, placebo-controlled study of 13 patients (mean age 9) with autism spectrum disorder. Repetitive behaviors improved significantly compared with placebo, as measured by the CY-BOCS, in those who received divalproex (mean 833.93±326.21 mg/d).²⁰

Further studies are needed to replicate this finding. Although it is too early to make general recommendations, valproate may be a reasonable choice for children with autism and epilepsy or affective instability.

Related resources

• Hollander E, Phillips AT, Yeh CC. Targeted treatments for symptom domains in child and adolescent autism. Lancet 2003;362:732-4.
• Hollander E (ed). Autism spectrum disorders. New York: Marcel Decker; 2003.
• National Institute of Health multicenter study of citalopram for repetitive behaviors in autism. http://www.clinicaltrials.gov/ct/show/nct00086645?order=2

Drug brand names

• Aripiprazole • Abilify
• Citalopram • Celexa
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Valproic acid • Depakote, Depakene
• Ziprasidone • Geodon

Disclosures

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

Dr. Hollander receives research/grant support from and is a consultant to Abbott Laboratories. He also receives support from the National Institutes of Health (STAART Center) to investigate orphan drug status for fluoxetine in treating autism symptoms.

Autism’s repetitive behaviors and restricted interests interfere with adaptive functioning, social interactions, and learning. No medications are FDA-approved for autistic disorder, but some selective serotonin reuptake inhibitors (SSRIs) and atypical antipsychotics and an anticonvulsant have reduced repetitive behaviors in controlled trials. We discuss how that evidence shapes our approach to patients with or without a comorbid family history of bipolar disorder.

Evidence for SSRIs

Repetitive behaviors and restricted interests are autism’s third core domain, as defined by DSM-IVTR criteria.¹ For an autistic disorder diagnosis, a patient must show at least one of these behaviors:

• encompassing preoccupations with stereotyped or restricted patterns of interest
• inflexible routines or rituals
• stereotyped, repetitive motor mannerisms
• or persistent preoccupation with parts of objects.

As in obsessive-compulsive disorder (OCD), rituals and restricted interests are thought to decrease anxiety in autism, whereas self-stimulatory behaviors and stereotypy may regulate arousal. The behaviors persist^2,3 but may change across the lifespan.

Because SSRIs improve OCD’s repetitive behaviors, clinicians have also used them to treat autism’s repetitive behaviors, though without supporting data. Recently, however, fluoxetine and fluvoxamine have shown efficacy for autism’s repetitive behaviors in randomized, controlled trials. Results indicate:

• In children, fluoxetine is probably better-tolerated than available dosing forms of fluvoxamine.
• In adults, fluvoxamine is well-tolerated and can improve repetitive behavior.

SSRIs and suicidal ideation in autism. The increased risk of suicidality reported with SSRIs when treating depression and OCD has not been seen in children with autism. But because fewer children with autism have been treated with SSRIs, we recommend that you try to assess suicidal ideation during SSRI treatment in those able to express such concerns (Box). Starting with low SSRI dosages (Table 1) and increasing slowly may help prevent behavioral activation, a possible risk factor for suicidality.

Box

Table 1

4 drugs with evidence of benefit for autism’s repetitive behaviors*

Medication	Suggested target daily dosage
Fluoxetine7	Children: Start at 2.5 mg/d; maximum 20 mg/d
	Adults: Start at 10 to 20 mg/d; maximum 60 mg/d
Fluvoxamine10	Children: Not first-line; start at 12.5 mg/d; maximum 150 to200 mg/d
	Adults: Start at 25 mg/d; maximum 300 mg/d
Risperidone13,16	Children: Start at 0.25 mg/d; maximum 3 mg/d
	Adults: Start at 2 mg/d; maximum 4 mg/d
Valproate20	Children: Start at 125 mg (sprinkles); titrate to clinical effect and blood levels of 50 of 120 mcg/mL
	Adults: Start at 250 mg; increase by 250mg/week to clinical effect and blood levels of 50 to 120 mcg/mL
*Data from randomized, placebo-controlled trials

Fluoxetine. In the first open-label study of fluoxetine in children and adults with autistic disorder, global functioning improved significantly in 15 of 23 patients, as measured by the Clinical Global Impressions (CGI) scale.⁴ Autism symptoms also improved in follow-up, open-label trials, but these did not target repetitive behaviors specifically.^5,6

Our group conducted the first randomized, placebo-controlled study of fluoxetine’s effect on repetitive behaviors in children with autism.⁷ We measured obsessions and compulsions in 45 children, ages 5 to 16, with the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). This 10-item, clinician-rated questionnaire uses a 5-point scale to rate repetitive behaviors by time spent, distress, interference, resistance, and control.

Using a crossover design—two 8-week phases of active or placebo treatment separated by a 4-week washout—we started liquid fluoxetine at 2.5 mg/d and slowly increased the dosage to clinical effect or a maximum of 0.8 mg/kg/day. Mean final dosage was 9.9 (±4.35) mg/d.

Repetitive behaviors improved, even though we used relatively low dosages to avoid side effects. The mean baseline CY-BOCS compulsion score of 13.15 dropped to 11.6 with fluoxetine and to 12.9 with placebo. Fluoxetine’s effect size was moderate to large, and we found no suicidal ideation with this SSRI.

 

Fluvoxamine. Repetitive behaviors did not change—as measured with the CY-BOCS—when 18 children with autism received fluvoxamine, 1.5 mg/kg/day, in a 10-week prospective, open-label trial.⁸ Most patients (72%) reported at least one side effect, and 3 discontinued the SSRI because of behavioral activation. Ten completed the trial. Likewise in a randomized trial, children who received fluvoxamine experienced troublesome side effects and limited benefit.⁹

Compared with outcomes in children, fluvoxamine has shown greater efficacy in adults. In a 12-week, double-blind, placebo-controlled trial of 30 adults with autism, 8 of 15 treated with fluvoxamine (50 mg/d initially and titrated to 300 mg/d) were rated as responders, compared with none of 15 receiving placebo.

Repetitive behaviors and adaptive functioning improved significantly with fluvoxamine, as measured with the Yale-Brown Obsessive Compulsive Scale (YBOCS) and Vineland Adaptive Behavior Scale, respectively.¹⁰ The SSRI was well-tolerated, with only mild nausea and sedation reported.

Thus, fluvoxamine may be useful for treating repetitive behaviors but probably is not a first choice for children with autism. Results might be more favorable in children if fluvoxamine were available in doses <12.5 mg.

Citalopram. Open-label data support using citalopram in autism.¹¹ In a retrospective chart review, 10 of 15 children (73%) were reported “much improved” with citalopram (mean dosage 16.9 mg/d [+/-12.1]), but the review did not specifically address repetitive behaviors. Two patients stopped taking the SSRI because of side effects; agitation, aggressiveness, sedation, and lip dyskinesia were reported.

The National Institutes of Health is sponsoring a multicenter trial of citalopram (starting dosage 2.5 mg/d, up to 20 mg/d) for repetitive behaviors in 144 children with autism, Results are expected in 2007 (see Related resources).

Escitalopram. Some early, open-label evidence suggests that escitalopram may be well-tolerated in autism, but its efficacy for treating repetitive behaviors has not been studied.

Sertraline. One of three reported open-label studies of sertraline in patients with autism measured repetitive behaviors.¹² In this study, 42 adults with autism spectrum disorder were treated for 12 weeks with sertraline, 50 to 200 mg/d. One-half were rated “much improved”—mostly in aggressive and repetitive behaviors—with the CGI improvement scale. Sertraline was well-tolerated, although 3 patients dropped out because of persistent agitation.

No randomized trials have examined sertraline in autism.

Clinical recommendations

Family history of bipolar disorder guides our treatment of patients with an autism spectrum disorder and disabling repetitive behaviors (Algorithm).

Algorithm Suggested medications to treat repetitive behaviors in autism

*Risperidone has the most evidence of efficacy, but aripiprazole may be useful for patients with weight-gain problems.
†For children, controlled data support using liquid fluoxetine, starting at 2.5 mg/d.Without bipolar history. SSRIs are usually first-line therapy (although patients with significant irritability and aggression may be an exception and require an atypical antipsychotic first).

If you reach the maximal SSRI dosage without a desired effect, consider adding an atypical (risperidone has the strongest supporting data) or valproate. If behavioral activation symptoms emerge and a lower dosage does not ameliorate them or reduces the clinical effect, consider switching to an atypical or valproate.

With bipolar history. Consider starting with an atypical or valproate; augment with an SSRI if needed.

Monitor for side effects with each medication (Table 2).

Table 2

Medication side effects and recommended monitoring

Medication	Side effects	Recommended monitoring
Fluoxetine	Anxiety, insomnia, GI disturbance, appetite and weight changes, mania/hypomania activation, suicidal ideation	Observe closely when starting treatment and while increasing dosage
Fluvoxamine	Somnolence, nervousness, insomnia, agitation, GI disturbance, suicidal ideation	Observe closely when starting treatment and while increasing dosage
Risperidone	Drowsiness, weight gain, hyperglycemia, GI disturbance, extrapyramidal symptoms, neuroleptic malignant syndrome	Obtain metabolic profile, including serum glucose and lipids
		Monitor for weight gain and clinical signs of extrapyramidal symptoms
Valproate	Rash, headaches, weight gain, ataxia, alopecia, GI disturbance, hyperammonemic encephalopathy, sedation, thrombocytopenia, polycystic ovary syndrome, pancreatitis, liver failure, teratogenic effects	CBC with platelets, liver function tests, valproate levels
		Therapeutic blood levels: 50 to 120 mcg/mL

Evidence for atypical antipsychotics

Atypicals have been used in autistic disorder to treat irritability and impulsive aggression. Risperidone also has been shown to reduce repetitive behaviors in a controlled trial.¹³ No evidence or only open-label trials support the use of other atypicals in patients with autism.

Risperidone’s side effects may include metabolic syndrome. No studies have examined lipid profiles and insulin resistance after risperidone treatment in patients with autism, but weight gain has been reported in the Research Units on Pediatric Psychopharmacology (RUPP) trial andothers.^13-15 Carefully assess the risk-benefit ratio when you consider using risperidone to treat repetitive behaviors in patients with autism.

Atypical antipsychotics also may increase dyskinesia risk, although extrapyramidal symptoms (EPS) have not been reported in studies of patients with autism and repetitive behaviors. Because EPS could develop after clinical trials are completed, long-term naturalistic studies are needed to address this concern.

 

Risperidone. The double-blind, placebo-controlled RUPP trial examined risperidone’s efficacy in treating autism’s core symptoms (primarily irritability) in 101 children.¹³ Mean dosages after 8 weeks and during a 16-week open-label extension for 63 children were 2 and 2.1 mg/d, respectively.

Repetitive behavior—as measured with the CY-BOCS, using RUPP trial data¹⁶—improved significantly with risperidone compared with placebo. During the 8-week controlled trial, CY-BOCS scores improved from 15.51 (SD±2.73) to 11.65 (SD±4.02) in the risperidone group, compared with 15.18 (SD±3.88) to 14.21 (SD±4.81) in the placebo group. This response was maintained through the open-label trial.

Side effects included weight gain, fatigue, drowsiness, and drooling. No children receiving risperidone dropped out because of side effects. No EPS were reported, based on weekly Abnormal Involuntary Movement scale and Simpson-Angus scale scores.

Olanzapine. Only open-label studies have examined olanzapine in autism, and one systematically measured repetitive behaviors.¹⁷ Eight children with autism or other pervasive developmental disorders were given olanzapine, mean dosage 7.8 (±4.7) mg/d at the end of the 12-week trial.

Repetitive behaviors did not change significantly, as measured with YBOCS. Seven of eight patients completed the trial. Mean weight for the group after 12 weeks was 156±55 lbs, compared with 137±56 lbs at baseline.

Quetiapine. No data support using quetiapine for autism’s repetitive behaviors. Quetiapine, 100 to 350 mg/d (1.6 to 5.2 mg/kg/day) was poorly tolerated in a 16-week open-label safety and efficacy trial among 6 mentally retarded boys with autistic disorder. Side effects included a possible seizure, behavioral activation, increased appetite, and weight gain (0.9 to 8.2 kg). Two patients completed the trial.¹⁸

Ziprasidone. Small open-label studies and anecdotal reports of ziprasidone in autism have not examined this drug’s effect on repetitive behaviors.

Aripiprazole. Anecdotal information suggests that clinicians are using this medication to treat patients with autism, but no supporting data exist.

Evidence for valproate

Preliminary trials by our group suggest that valproate may reduce repetitive behaviors in autism. In a retrospective, open-label study, 14 patients (mean age 17) with autism spectrum disorder received divalproex sodium (mean 768±582 mg/d) for a mean 11 months. Ten patients (71%) showed sustained improvement in function, as measured by the CGI-improvement scale, and valproate was generally well-tolerated.¹⁹

We then measured valproate’s effect on repetitive behaviors in an 8-week, double-blind, placebo-controlled study of 13 patients (mean age 9) with autism spectrum disorder. Repetitive behaviors improved significantly compared with placebo, as measured by the CY-BOCS, in those who received divalproex (mean 833.93±326.21 mg/d).²⁰

Further studies are needed to replicate this finding. Although it is too early to make general recommendations, valproate may be a reasonable choice for children with autism and epilepsy or affective instability.

Related resources

• Hollander E, Phillips AT, Yeh CC. Targeted treatments for symptom domains in child and adolescent autism. Lancet 2003;362:732-4.
• Hollander E (ed). Autism spectrum disorders. New York: Marcel Decker; 2003.
• National Institute of Health multicenter study of citalopram for repetitive behaviors in autism. http://www.clinicaltrials.gov/ct/show/nct00086645?order=2

Drug brand names

• Aripiprazole • Abilify
• Citalopram • Celexa
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Valproic acid • Depakote, Depakene
• Ziprasidone • Geodon

Disclosures

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

Dr. Hollander receives research/grant support from and is a consultant to Abbott Laboratories. He also receives support from the National Institutes of Health (STAART Center) to investigate orphan drug status for fluoxetine in treating autism symptoms.

Autism’s repetitive behaviors and restricted interests interfere with adaptive functioning, social interactions, and learning. No medications are FDA-approved for autistic disorder, but some selective serotonin reuptake inhibitors (SSRIs) and atypical antipsychotics and an anticonvulsant have reduced repetitive behaviors in controlled trials. We discuss how that evidence shapes our approach to patients with or without a comorbid family history of bipolar disorder.

Evidence for SSRIs

Repetitive behaviors and restricted interests are autism’s third core domain, as defined by DSM-IVTR criteria.¹ For an autistic disorder diagnosis, a patient must show at least one of these behaviors:

• encompassing preoccupations with stereotyped or restricted patterns of interest
• inflexible routines or rituals
• stereotyped, repetitive motor mannerisms
• or persistent preoccupation with parts of objects.

As in obsessive-compulsive disorder (OCD), rituals and restricted interests are thought to decrease anxiety in autism, whereas self-stimulatory behaviors and stereotypy may regulate arousal. The behaviors persist^2,3 but may change across the lifespan.

Because SSRIs improve OCD’s repetitive behaviors, clinicians have also used them to treat autism’s repetitive behaviors, though without supporting data. Recently, however, fluoxetine and fluvoxamine have shown efficacy for autism’s repetitive behaviors in randomized, controlled trials. Results indicate:

• In children, fluoxetine is probably better-tolerated than available dosing forms of fluvoxamine.
• In adults, fluvoxamine is well-tolerated and can improve repetitive behavior.

SSRIs and suicidal ideation in autism. The increased risk of suicidality reported with SSRIs when treating depression and OCD has not been seen in children with autism. But because fewer children with autism have been treated with SSRIs, we recommend that you try to assess suicidal ideation during SSRI treatment in those able to express such concerns (Box). Starting with low SSRI dosages (Table 1) and increasing slowly may help prevent behavioral activation, a possible risk factor for suicidality.

Box

Table 1

4 drugs with evidence of benefit for autism’s repetitive behaviors*

Medication	Suggested target daily dosage
Fluoxetine7	Children: Start at 2.5 mg/d; maximum 20 mg/d
	Adults: Start at 10 to 20 mg/d; maximum 60 mg/d
Fluvoxamine10	Children: Not first-line; start at 12.5 mg/d; maximum 150 to200 mg/d
	Adults: Start at 25 mg/d; maximum 300 mg/d
Risperidone13,16	Children: Start at 0.25 mg/d; maximum 3 mg/d
	Adults: Start at 2 mg/d; maximum 4 mg/d
Valproate20	Children: Start at 125 mg (sprinkles); titrate to clinical effect and blood levels of 50 of 120 mcg/mL
	Adults: Start at 250 mg; increase by 250mg/week to clinical effect and blood levels of 50 to 120 mcg/mL
*Data from randomized, placebo-controlled trials

Fluoxetine. In the first open-label study of fluoxetine in children and adults with autistic disorder, global functioning improved significantly in 15 of 23 patients, as measured by the Clinical Global Impressions (CGI) scale.⁴ Autism symptoms also improved in follow-up, open-label trials, but these did not target repetitive behaviors specifically.^5,6

Our group conducted the first randomized, placebo-controlled study of fluoxetine’s effect on repetitive behaviors in children with autism.⁷ We measured obsessions and compulsions in 45 children, ages 5 to 16, with the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). This 10-item, clinician-rated questionnaire uses a 5-point scale to rate repetitive behaviors by time spent, distress, interference, resistance, and control.

Using a crossover design—two 8-week phases of active or placebo treatment separated by a 4-week washout—we started liquid fluoxetine at 2.5 mg/d and slowly increased the dosage to clinical effect or a maximum of 0.8 mg/kg/day. Mean final dosage was 9.9 (±4.35) mg/d.

Repetitive behaviors improved, even though we used relatively low dosages to avoid side effects. The mean baseline CY-BOCS compulsion score of 13.15 dropped to 11.6 with fluoxetine and to 12.9 with placebo. Fluoxetine’s effect size was moderate to large, and we found no suicidal ideation with this SSRI.

 

Fluvoxamine. Repetitive behaviors did not change—as measured with the CY-BOCS—when 18 children with autism received fluvoxamine, 1.5 mg/kg/day, in a 10-week prospective, open-label trial.⁸ Most patients (72%) reported at least one side effect, and 3 discontinued the SSRI because of behavioral activation. Ten completed the trial. Likewise in a randomized trial, children who received fluvoxamine experienced troublesome side effects and limited benefit.⁹

Compared with outcomes in children, fluvoxamine has shown greater efficacy in adults. In a 12-week, double-blind, placebo-controlled trial of 30 adults with autism, 8 of 15 treated with fluvoxamine (50 mg/d initially and titrated to 300 mg/d) were rated as responders, compared with none of 15 receiving placebo.

Repetitive behaviors and adaptive functioning improved significantly with fluvoxamine, as measured with the Yale-Brown Obsessive Compulsive Scale (YBOCS) and Vineland Adaptive Behavior Scale, respectively.¹⁰ The SSRI was well-tolerated, with only mild nausea and sedation reported.

Thus, fluvoxamine may be useful for treating repetitive behaviors but probably is not a first choice for children with autism. Results might be more favorable in children if fluvoxamine were available in doses <12.5 mg.

Citalopram. Open-label data support using citalopram in autism.¹¹ In a retrospective chart review, 10 of 15 children (73%) were reported “much improved” with citalopram (mean dosage 16.9 mg/d [+/-12.1]), but the review did not specifically address repetitive behaviors. Two patients stopped taking the SSRI because of side effects; agitation, aggressiveness, sedation, and lip dyskinesia were reported.

The National Institutes of Health is sponsoring a multicenter trial of citalopram (starting dosage 2.5 mg/d, up to 20 mg/d) for repetitive behaviors in 144 children with autism, Results are expected in 2007 (see Related resources).

Escitalopram. Some early, open-label evidence suggests that escitalopram may be well-tolerated in autism, but its efficacy for treating repetitive behaviors has not been studied.

Sertraline. One of three reported open-label studies of sertraline in patients with autism measured repetitive behaviors.¹² In this study, 42 adults with autism spectrum disorder were treated for 12 weeks with sertraline, 50 to 200 mg/d. One-half were rated “much improved”—mostly in aggressive and repetitive behaviors—with the CGI improvement scale. Sertraline was well-tolerated, although 3 patients dropped out because of persistent agitation.

No randomized trials have examined sertraline in autism.

Clinical recommendations

Family history of bipolar disorder guides our treatment of patients with an autism spectrum disorder and disabling repetitive behaviors (Algorithm).

Algorithm Suggested medications to treat repetitive behaviors in autism

*Risperidone has the most evidence of efficacy, but aripiprazole may be useful for patients with weight-gain problems.
†For children, controlled data support using liquid fluoxetine, starting at 2.5 mg/d.Without bipolar history. SSRIs are usually first-line therapy (although patients with significant irritability and aggression may be an exception and require an atypical antipsychotic first).

If you reach the maximal SSRI dosage without a desired effect, consider adding an atypical (risperidone has the strongest supporting data) or valproate. If behavioral activation symptoms emerge and a lower dosage does not ameliorate them or reduces the clinical effect, consider switching to an atypical or valproate.

With bipolar history. Consider starting with an atypical or valproate; augment with an SSRI if needed.

Monitor for side effects with each medication (Table 2).

Table 2

Medication side effects and recommended monitoring

Medication	Side effects	Recommended monitoring
Fluoxetine	Anxiety, insomnia, GI disturbance, appetite and weight changes, mania/hypomania activation, suicidal ideation	Observe closely when starting treatment and while increasing dosage
Fluvoxamine	Somnolence, nervousness, insomnia, agitation, GI disturbance, suicidal ideation	Observe closely when starting treatment and while increasing dosage
Risperidone	Drowsiness, weight gain, hyperglycemia, GI disturbance, extrapyramidal symptoms, neuroleptic malignant syndrome	Obtain metabolic profile, including serum glucose and lipids
		Monitor for weight gain and clinical signs of extrapyramidal symptoms
Valproate	Rash, headaches, weight gain, ataxia, alopecia, GI disturbance, hyperammonemic encephalopathy, sedation, thrombocytopenia, polycystic ovary syndrome, pancreatitis, liver failure, teratogenic effects	CBC with platelets, liver function tests, valproate levels
		Therapeutic blood levels: 50 to 120 mcg/mL

Evidence for atypical antipsychotics

Atypicals have been used in autistic disorder to treat irritability and impulsive aggression. Risperidone also has been shown to reduce repetitive behaviors in a controlled trial.¹³ No evidence or only open-label trials support the use of other atypicals in patients with autism.

Risperidone’s side effects may include metabolic syndrome. No studies have examined lipid profiles and insulin resistance after risperidone treatment in patients with autism, but weight gain has been reported in the Research Units on Pediatric Psychopharmacology (RUPP) trial andothers.^13-15 Carefully assess the risk-benefit ratio when you consider using risperidone to treat repetitive behaviors in patients with autism.

Atypical antipsychotics also may increase dyskinesia risk, although extrapyramidal symptoms (EPS) have not been reported in studies of patients with autism and repetitive behaviors. Because EPS could develop after clinical trials are completed, long-term naturalistic studies are needed to address this concern.

 

Risperidone. The double-blind, placebo-controlled RUPP trial examined risperidone’s efficacy in treating autism’s core symptoms (primarily irritability) in 101 children.¹³ Mean dosages after 8 weeks and during a 16-week open-label extension for 63 children were 2 and 2.1 mg/d, respectively.

Repetitive behavior—as measured with the CY-BOCS, using RUPP trial data¹⁶—improved significantly with risperidone compared with placebo. During the 8-week controlled trial, CY-BOCS scores improved from 15.51 (SD±2.73) to 11.65 (SD±4.02) in the risperidone group, compared with 15.18 (SD±3.88) to 14.21 (SD±4.81) in the placebo group. This response was maintained through the open-label trial.

Side effects included weight gain, fatigue, drowsiness, and drooling. No children receiving risperidone dropped out because of side effects. No EPS were reported, based on weekly Abnormal Involuntary Movement scale and Simpson-Angus scale scores.

Olanzapine. Only open-label studies have examined olanzapine in autism, and one systematically measured repetitive behaviors.¹⁷ Eight children with autism or other pervasive developmental disorders were given olanzapine, mean dosage 7.8 (±4.7) mg/d at the end of the 12-week trial.

Repetitive behaviors did not change significantly, as measured with YBOCS. Seven of eight patients completed the trial. Mean weight for the group after 12 weeks was 156±55 lbs, compared with 137±56 lbs at baseline.

Quetiapine. No data support using quetiapine for autism’s repetitive behaviors. Quetiapine, 100 to 350 mg/d (1.6 to 5.2 mg/kg/day) was poorly tolerated in a 16-week open-label safety and efficacy trial among 6 mentally retarded boys with autistic disorder. Side effects included a possible seizure, behavioral activation, increased appetite, and weight gain (0.9 to 8.2 kg). Two patients completed the trial.¹⁸

Ziprasidone. Small open-label studies and anecdotal reports of ziprasidone in autism have not examined this drug’s effect on repetitive behaviors.

Aripiprazole. Anecdotal information suggests that clinicians are using this medication to treat patients with autism, but no supporting data exist.

Evidence for valproate

Preliminary trials by our group suggest that valproate may reduce repetitive behaviors in autism. In a retrospective, open-label study, 14 patients (mean age 17) with autism spectrum disorder received divalproex sodium (mean 768±582 mg/d) for a mean 11 months. Ten patients (71%) showed sustained improvement in function, as measured by the CGI-improvement scale, and valproate was generally well-tolerated.¹⁹

We then measured valproate’s effect on repetitive behaviors in an 8-week, double-blind, placebo-controlled study of 13 patients (mean age 9) with autism spectrum disorder. Repetitive behaviors improved significantly compared with placebo, as measured by the CY-BOCS, in those who received divalproex (mean 833.93±326.21 mg/d).²⁰

Further studies are needed to replicate this finding. Although it is too early to make general recommendations, valproate may be a reasonable choice for children with autism and epilepsy or affective instability.

Related resources

• Hollander E, Phillips AT, Yeh CC. Targeted treatments for symptom domains in child and adolescent autism. Lancet 2003;362:732-4.
• Hollander E (ed). Autism spectrum disorders. New York: Marcel Decker; 2003.
• National Institute of Health multicenter study of citalopram for repetitive behaviors in autism. http://www.clinicaltrials.gov/ct/show/nct00086645?order=2

Drug brand names

• Aripiprazole • Abilify
• Citalopram • Celexa
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Valproic acid • Depakote, Depakene
• Ziprasidone • Geodon

Disclosures

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

Dr. Hollander receives research/grant support from and is a consultant to Abbott Laboratories. He also receives support from the National Institutes of Health (STAART Center) to investigate orphan drug status for fluoxetine in treating autism symptoms.

Untreated depression can have serious consequences, but many pregnant women resist taking antidepressants because they overestimate the risk of birth defects.^{Paroxetine in pregnancy”). Further study is needed to define the risks of teratogenesis with paroxetine compared with other antidepressants.}

Third-trimester exposure

In a recent meta-analysis, infants exposed to SSRIs in utero showed an increased risk for prematurity (OR; 2.03) and low birth weight (OR; 2.37).¹⁵ Other studies, however, showed no differences in these risks in SSRI-exposed infants or attributed the results to untreated maternal depression or smoking.¹⁶

A Medline search across the last 20 years¹⁷ found 26 case reports, three prospective controlled cohort studies, and other records of >400 women who received fluoxetine, sertraline, or paroxetine in the third trimester. The authors found the evidence “ambiguous” as to the cause of adverse events and concluded that the risk of not treating major depression with adequate SSRI therapy at that stage of pregnancy “most likely” outweighs the risk of harm to infants.

Transient neonatal complications. Thirty percent of neonates exposed to SSRIs in the third trimester experience transient adaptation problems, which peak 48 hours after birth¹⁸ (Table 3). Symptoms may include initial lack of crying, increased muscle tonus, flush, irritability, jitteriness, hypothermia, abnormal breathing, and disrupted sleep and motor activity.^2,19,20

Transient neonatal symptoms from SSRI exposure are thought to be a serotonin withdrawal syndrome or serotonin overstimulation.²¹ The syndrome is usually mild, self-limited, and requires only supportive treatments. All antidepressants’ labels warn of these effects.

Table 3

Neonatal SSRI withdrawal: Symptoms, causes, and treatment

Symptoms	Initial lack of crying
	Increased muscle tonus
	Irritability, jitteriness
	Abnormal breathing pattern
	Disrupted sleep and motor activity
Hypotheses of cause	Serotonin overstimulation or withdrawal
Treatment	Close observation
	Supportive measures

Pulmonary hypertension. An increased risk of persistent pulmonary hypertension of the newborn (PPHN) has been shown in infants exposed to SSRIs after 20 weeks’ gestation. A retrospective case-control study concluded that the absolute risk of PPHN with SSRIs is relatively low (6 to 12 cases per 1,000 pregnancies).²²

Recommendation. Some authors have recommended tapering antidepressants in the third trimester, but the risk of postpartum depression appears to outweigh any potential benefit from discontinuation. Because birth timing is unpredictable, some women whose antidepressants are tapered off could be without medication for a long time.

Thus, we recommend:

• continuing SSRIs during late pregnancy
  
• monitoring the newborn for 48 hours for transient neonatal adaptation symptoms or PPHN.^2,17,18
  

Long-term effects of SSRI exposure

Do SSRIs during pregnancy have long-term effects on infants’ neurodevelopment? Study results are mixed. For example:

• A prospective, controlled, cohort trial found no adverse effects on IQ, language, or behavioral development in children ages 15 months to 6 years whose mothers took tricyclic antidepressants (N=46) or fluoxetine (N=40) during pregnancy, compared with 36 unexposed controls.²³
  
• Another prospective study showed lower Bayley Psychomotor Developmental Index scores in 31 SSRI-exposed infants compared with 13 infants born to depressed mothers not on antidepressants. Reduced body control, coordination, and fine motor skills might suggest possible subtle effects of SSRIs on motor development in exposed infants, the authors concluded.²⁴
  

Case continued: A healthy delivery

Ms. P’s depression improves a few weeks after she restarts an SSRI. She delivers a healthy term baby with Apgar score of 7. The baby initially does not cry, awakens easily, and shows mild irritability. His mother’s SSRI use, her severe depression during part of the pregnancy, or some other factor may have caused his mild neonatal complications.

Nursing staff carefully observe the infant for 2 days in the newborn nursery, and his irritability fades away. Ms. P decides to continue taking antidepressants to care for herself and the baby.

Weighing treatment options

For each woman with a history of depression who is pregnant or intends to conceive, we recommend a risk-benefit analysis of her depression severity and need for an antidepressant:

Mild depression (BDI 25,26

Moderate to severe depression (history of recurrent depressive episodes, hospitalization, or suicidality). Strongly consider medication. If your patient is taking an SSRI, counsel her about:

• the 70% risk of depression relapse if she stops the medication, even for the first trimester
  
• risks of untreated depression during pregnancy (poor self-care, preterm labor, birth complications, and increased risk for poor stress adaptations in children).
  

If she refuses antidepressant treatment, monitor her for suicidal tendencies, deteriorating social function, psychosis, and inability to comply with prenatal care during the pregnancy and postpartum.

Choosing an SSRI. No one SSRI is the safest choice for all women, especially when data on breast-feeding come into play.

• Fluoxetine has been studied more than other SSRIs during pregnancy; most evidence is reassuring, except for transient neonatal complications. With its long half-life, fluoxetine is not recommended during breastfeeding because it may accumulate in infant sera.
  
• Sertraline has shown low umbilical cord to maternal serum ratios in small samples and has reassuring breast-feeding data.
  
• Citalopram, compared with sertraline, has been studied more in pregnancy but has a higher fetal-to-maternal serum ratio (as does escitalopram). These SSRIs are usually second-line for starting a new antidepressant during pregnancy but could be first-line if they have worked well for a patient or she has had adverse effects with fluoxetine or sertraline.
  

 

You may need to increase SSRI dosages as pregnancy progresses. Increased metabolism and weight gain during pregnancy can lower SSRI serum levels, allowing depressive symptoms to re-emerge in the third trimester. Counsel the patient to continue taking the antidepressant for at least 12 months postpartum, then re-evaluate the need for medication based on her history.

Paroxetine precautions. If your patient is taking paroxetine and wishes to become pregnant, consider switching to another SSRI (using a slow cross-taper) unless paroxetine has been the only effective medication (Table 4). When discussing risks of any SSRI, explain that the baseline risk for congenital malformations is 3%. Paroxetine might increase this risk by 1% and other SSRIs by less.

If a woman becomes pregnant while taking paroxetine, often the time when cardiac defects occur is passed or will be before you slowly taper the medication to avoid withdrawal. If the patient’s depression has been severe, the risk of shifting her to an untested SSRI is probably higher than the possible 1% increased risk of fetal malformation. If she has taken paroxetine during the first-trimester, refer for ultrasound to monitor for cardiac anomalies.

Table 4

Recommendations for managing paroxetine risk during pregnancy

Patient status	Recommendation
Taking paroxetine and planning pregnancy	Advise of possible 1% increase in risk of fetal malformation
	Switch to another SSRI unless paroxetine has been the only successful therapy for depression
	If stopping paroxetine, slowly taper to avoid withdrawal symptoms
Taking paroxetine and is pregnant	Advise of possible 1% increase in risk of fetal malformation
	Continue paroxetine; a slow taper probably could not be completed before the first-trimester period associated with increased risk of fetal cardiac defects
	If any paroxetine exposure in first trimester, order ultrasound to monitor for fetal malformations

Related resources

• California Teratogen Information Service (CTIS). Pediatric department, University of California San Diego Medical Center. www.otispregnancy.org/ctis.html
  
• MGH Center for Women’s Mental Health, Massachusetts General Hospital. Psychiatric disorders during pregnancy and postpartum. www.womensmentalhealth.com
  
• MOTHERISK Web site. Teratogen information and updates on reproductive risk research. The Hospital for Sick Children, University of Toronto. www.motherisk.org
  

Drug brand names

• Citalopram • Celexa
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  

Disclosures

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

Untreated depression can have serious consequences, but many pregnant women resist taking antidepressants because they overestimate the risk of birth defects.^{Paroxetine in pregnancy”). Further study is needed to define the risks of teratogenesis with paroxetine compared with other antidepressants.}

Third-trimester exposure

In a recent meta-analysis, infants exposed to SSRIs in utero showed an increased risk for prematurity (OR; 2.03) and low birth weight (OR; 2.37).¹⁵ Other studies, however, showed no differences in these risks in SSRI-exposed infants or attributed the results to untreated maternal depression or smoking.¹⁶

A Medline search across the last 20 years¹⁷ found 26 case reports, three prospective controlled cohort studies, and other records of >400 women who received fluoxetine, sertraline, or paroxetine in the third trimester. The authors found the evidence “ambiguous” as to the cause of adverse events and concluded that the risk of not treating major depression with adequate SSRI therapy at that stage of pregnancy “most likely” outweighs the risk of harm to infants.

Transient neonatal complications. Thirty percent of neonates exposed to SSRIs in the third trimester experience transient adaptation problems, which peak 48 hours after birth¹⁸ (Table 3). Symptoms may include initial lack of crying, increased muscle tonus, flush, irritability, jitteriness, hypothermia, abnormal breathing, and disrupted sleep and motor activity.^2,19,20

Transient neonatal symptoms from SSRI exposure are thought to be a serotonin withdrawal syndrome or serotonin overstimulation.²¹ The syndrome is usually mild, self-limited, and requires only supportive treatments. All antidepressants’ labels warn of these effects.

Table 3

Neonatal SSRI withdrawal: Symptoms, causes, and treatment

Symptoms	Initial lack of crying
	Increased muscle tonus
	Irritability, jitteriness
	Abnormal breathing pattern
	Disrupted sleep and motor activity
Hypotheses of cause	Serotonin overstimulation or withdrawal
Treatment	Close observation
	Supportive measures

Pulmonary hypertension. An increased risk of persistent pulmonary hypertension of the newborn (PPHN) has been shown in infants exposed to SSRIs after 20 weeks’ gestation. A retrospective case-control study concluded that the absolute risk of PPHN with SSRIs is relatively low (6 to 12 cases per 1,000 pregnancies).²²

Recommendation. Some authors have recommended tapering antidepressants in the third trimester, but the risk of postpartum depression appears to outweigh any potential benefit from discontinuation. Because birth timing is unpredictable, some women whose antidepressants are tapered off could be without medication for a long time.

Thus, we recommend:

• continuing SSRIs during late pregnancy
  
• monitoring the newborn for 48 hours for transient neonatal adaptation symptoms or PPHN.^2,17,18
  

Long-term effects of SSRI exposure

Do SSRIs during pregnancy have long-term effects on infants’ neurodevelopment? Study results are mixed. For example:

• A prospective, controlled, cohort trial found no adverse effects on IQ, language, or behavioral development in children ages 15 months to 6 years whose mothers took tricyclic antidepressants (N=46) or fluoxetine (N=40) during pregnancy, compared with 36 unexposed controls.²³
  
• Another prospective study showed lower Bayley Psychomotor Developmental Index scores in 31 SSRI-exposed infants compared with 13 infants born to depressed mothers not on antidepressants. Reduced body control, coordination, and fine motor skills might suggest possible subtle effects of SSRIs on motor development in exposed infants, the authors concluded.²⁴
  

Case continued: A healthy delivery

Ms. P’s depression improves a few weeks after she restarts an SSRI. She delivers a healthy term baby with Apgar score of 7. The baby initially does not cry, awakens easily, and shows mild irritability. His mother’s SSRI use, her severe depression during part of the pregnancy, or some other factor may have caused his mild neonatal complications.

Nursing staff carefully observe the infant for 2 days in the newborn nursery, and his irritability fades away. Ms. P decides to continue taking antidepressants to care for herself and the baby.

Weighing treatment options

For each woman with a history of depression who is pregnant or intends to conceive, we recommend a risk-benefit analysis of her depression severity and need for an antidepressant:

Mild depression (BDI 25,26

Moderate to severe depression (history of recurrent depressive episodes, hospitalization, or suicidality). Strongly consider medication. If your patient is taking an SSRI, counsel her about:

• the 70% risk of depression relapse if she stops the medication, even for the first trimester
  
• risks of untreated depression during pregnancy (poor self-care, preterm labor, birth complications, and increased risk for poor stress adaptations in children).
  

If she refuses antidepressant treatment, monitor her for suicidal tendencies, deteriorating social function, psychosis, and inability to comply with prenatal care during the pregnancy and postpartum.

Choosing an SSRI. No one SSRI is the safest choice for all women, especially when data on breast-feeding come into play.

• Fluoxetine has been studied more than other SSRIs during pregnancy; most evidence is reassuring, except for transient neonatal complications. With its long half-life, fluoxetine is not recommended during breastfeeding because it may accumulate in infant sera.
  
• Sertraline has shown low umbilical cord to maternal serum ratios in small samples and has reassuring breast-feeding data.
  
• Citalopram, compared with sertraline, has been studied more in pregnancy but has a higher fetal-to-maternal serum ratio (as does escitalopram). These SSRIs are usually second-line for starting a new antidepressant during pregnancy but could be first-line if they have worked well for a patient or she has had adverse effects with fluoxetine or sertraline.
  

 

You may need to increase SSRI dosages as pregnancy progresses. Increased metabolism and weight gain during pregnancy can lower SSRI serum levels, allowing depressive symptoms to re-emerge in the third trimester. Counsel the patient to continue taking the antidepressant for at least 12 months postpartum, then re-evaluate the need for medication based on her history.

Paroxetine precautions. If your patient is taking paroxetine and wishes to become pregnant, consider switching to another SSRI (using a slow cross-taper) unless paroxetine has been the only effective medication (Table 4). When discussing risks of any SSRI, explain that the baseline risk for congenital malformations is 3%. Paroxetine might increase this risk by 1% and other SSRIs by less.

If a woman becomes pregnant while taking paroxetine, often the time when cardiac defects occur is passed or will be before you slowly taper the medication to avoid withdrawal. If the patient’s depression has been severe, the risk of shifting her to an untested SSRI is probably higher than the possible 1% increased risk of fetal malformation. If she has taken paroxetine during the first-trimester, refer for ultrasound to monitor for cardiac anomalies.

Table 4

Recommendations for managing paroxetine risk during pregnancy

Patient status	Recommendation
Taking paroxetine and planning pregnancy	Advise of possible 1% increase in risk of fetal malformation
	Switch to another SSRI unless paroxetine has been the only successful therapy for depression
	If stopping paroxetine, slowly taper to avoid withdrawal symptoms
Taking paroxetine and is pregnant	Advise of possible 1% increase in risk of fetal malformation
	Continue paroxetine; a slow taper probably could not be completed before the first-trimester period associated with increased risk of fetal cardiac defects
	If any paroxetine exposure in first trimester, order ultrasound to monitor for fetal malformations

Related resources

• California Teratogen Information Service (CTIS). Pediatric department, University of California San Diego Medical Center. www.otispregnancy.org/ctis.html
  
• MGH Center for Women’s Mental Health, Massachusetts General Hospital. Psychiatric disorders during pregnancy and postpartum. www.womensmentalhealth.com
  
• MOTHERISK Web site. Teratogen information and updates on reproductive risk research. The Hospital for Sick Children, University of Toronto. www.motherisk.org
  

Drug brand names

• Citalopram • Celexa
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  

Disclosures

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

Untreated depression can have serious consequences, but many pregnant women resist taking antidepressants because they overestimate the risk of birth defects.^{Paroxetine in pregnancy”). Further study is needed to define the risks of teratogenesis with paroxetine compared with other antidepressants.}

Third-trimester exposure

In a recent meta-analysis, infants exposed to SSRIs in utero showed an increased risk for prematurity (OR; 2.03) and low birth weight (OR; 2.37).¹⁵ Other studies, however, showed no differences in these risks in SSRI-exposed infants or attributed the results to untreated maternal depression or smoking.¹⁶

A Medline search across the last 20 years¹⁷ found 26 case reports, three prospective controlled cohort studies, and other records of >400 women who received fluoxetine, sertraline, or paroxetine in the third trimester. The authors found the evidence “ambiguous” as to the cause of adverse events and concluded that the risk of not treating major depression with adequate SSRI therapy at that stage of pregnancy “most likely” outweighs the risk of harm to infants.

Transient neonatal complications. Thirty percent of neonates exposed to SSRIs in the third trimester experience transient adaptation problems, which peak 48 hours after birth¹⁸ (Table 3). Symptoms may include initial lack of crying, increased muscle tonus, flush, irritability, jitteriness, hypothermia, abnormal breathing, and disrupted sleep and motor activity.^2,19,20

Transient neonatal symptoms from SSRI exposure are thought to be a serotonin withdrawal syndrome or serotonin overstimulation.²¹ The syndrome is usually mild, self-limited, and requires only supportive treatments. All antidepressants’ labels warn of these effects.

Table 3

Neonatal SSRI withdrawal: Symptoms, causes, and treatment

Symptoms	Initial lack of crying
	Increased muscle tonus
	Irritability, jitteriness
	Abnormal breathing pattern
	Disrupted sleep and motor activity
Hypotheses of cause	Serotonin overstimulation or withdrawal
Treatment	Close observation
	Supportive measures

Pulmonary hypertension. An increased risk of persistent pulmonary hypertension of the newborn (PPHN) has been shown in infants exposed to SSRIs after 20 weeks’ gestation. A retrospective case-control study concluded that the absolute risk of PPHN with SSRIs is relatively low (6 to 12 cases per 1,000 pregnancies).²²

Recommendation. Some authors have recommended tapering antidepressants in the third trimester, but the risk of postpartum depression appears to outweigh any potential benefit from discontinuation. Because birth timing is unpredictable, some women whose antidepressants are tapered off could be without medication for a long time.

Thus, we recommend:

• continuing SSRIs during late pregnancy
  
• monitoring the newborn for 48 hours for transient neonatal adaptation symptoms or PPHN.^2,17,18
  

Long-term effects of SSRI exposure

Do SSRIs during pregnancy have long-term effects on infants’ neurodevelopment? Study results are mixed. For example:

• A prospective, controlled, cohort trial found no adverse effects on IQ, language, or behavioral development in children ages 15 months to 6 years whose mothers took tricyclic antidepressants (N=46) or fluoxetine (N=40) during pregnancy, compared with 36 unexposed controls.²³
  
• Another prospective study showed lower Bayley Psychomotor Developmental Index scores in 31 SSRI-exposed infants compared with 13 infants born to depressed mothers not on antidepressants. Reduced body control, coordination, and fine motor skills might suggest possible subtle effects of SSRIs on motor development in exposed infants, the authors concluded.²⁴
  

Case continued: A healthy delivery

Ms. P’s depression improves a few weeks after she restarts an SSRI. She delivers a healthy term baby with Apgar score of 7. The baby initially does not cry, awakens easily, and shows mild irritability. His mother’s SSRI use, her severe depression during part of the pregnancy, or some other factor may have caused his mild neonatal complications.

Nursing staff carefully observe the infant for 2 days in the newborn nursery, and his irritability fades away. Ms. P decides to continue taking antidepressants to care for herself and the baby.

Weighing treatment options

For each woman with a history of depression who is pregnant or intends to conceive, we recommend a risk-benefit analysis of her depression severity and need for an antidepressant:

Mild depression (BDI 25,26

Moderate to severe depression (history of recurrent depressive episodes, hospitalization, or suicidality). Strongly consider medication. If your patient is taking an SSRI, counsel her about:

• the 70% risk of depression relapse if she stops the medication, even for the first trimester
  
• risks of untreated depression during pregnancy (poor self-care, preterm labor, birth complications, and increased risk for poor stress adaptations in children).
  

If she refuses antidepressant treatment, monitor her for suicidal tendencies, deteriorating social function, psychosis, and inability to comply with prenatal care during the pregnancy and postpartum.

Choosing an SSRI. No one SSRI is the safest choice for all women, especially when data on breast-feeding come into play.

• Fluoxetine has been studied more than other SSRIs during pregnancy; most evidence is reassuring, except for transient neonatal complications. With its long half-life, fluoxetine is not recommended during breastfeeding because it may accumulate in infant sera.
  
• Sertraline has shown low umbilical cord to maternal serum ratios in small samples and has reassuring breast-feeding data.
  
• Citalopram, compared with sertraline, has been studied more in pregnancy but has a higher fetal-to-maternal serum ratio (as does escitalopram). These SSRIs are usually second-line for starting a new antidepressant during pregnancy but could be first-line if they have worked well for a patient or she has had adverse effects with fluoxetine or sertraline.
  

 

You may need to increase SSRI dosages as pregnancy progresses. Increased metabolism and weight gain during pregnancy can lower SSRI serum levels, allowing depressive symptoms to re-emerge in the third trimester. Counsel the patient to continue taking the antidepressant for at least 12 months postpartum, then re-evaluate the need for medication based on her history.

Paroxetine precautions. If your patient is taking paroxetine and wishes to become pregnant, consider switching to another SSRI (using a slow cross-taper) unless paroxetine has been the only effective medication (Table 4). When discussing risks of any SSRI, explain that the baseline risk for congenital malformations is 3%. Paroxetine might increase this risk by 1% and other SSRIs by less.

If a woman becomes pregnant while taking paroxetine, often the time when cardiac defects occur is passed or will be before you slowly taper the medication to avoid withdrawal. If the patient’s depression has been severe, the risk of shifting her to an untested SSRI is probably higher than the possible 1% increased risk of fetal malformation. If she has taken paroxetine during the first-trimester, refer for ultrasound to monitor for cardiac anomalies.

Table 4

Recommendations for managing paroxetine risk during pregnancy

Patient status	Recommendation
Taking paroxetine and planning pregnancy	Advise of possible 1% increase in risk of fetal malformation
	Switch to another SSRI unless paroxetine has been the only successful therapy for depression
	If stopping paroxetine, slowly taper to avoid withdrawal symptoms
Taking paroxetine and is pregnant	Advise of possible 1% increase in risk of fetal malformation
	Continue paroxetine; a slow taper probably could not be completed before the first-trimester period associated with increased risk of fetal cardiac defects
	If any paroxetine exposure in first trimester, order ultrasound to monitor for fetal malformations

Related resources

• California Teratogen Information Service (CTIS). Pediatric department, University of California San Diego Medical Center. www.otispregnancy.org/ctis.html
  
• MGH Center for Women’s Mental Health, Massachusetts General Hospital. Psychiatric disorders during pregnancy and postpartum. www.womensmentalhealth.com
  
• MOTHERISK Web site. Teratogen information and updates on reproductive risk research. The Hospital for Sick Children, University of Toronto. www.motherisk.org
  

Drug brand names

• Citalopram • Celexa
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  

Disclosures

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

Have you noticed two curious patterns in off-label prescribing? Psychiatrists avoid agents approved for treating insomnia but prescribe anticonvulsants for a variety of unapproved uses.

Most of us prescribe medications for therapeutic uses not found in FDA-approved labeling. Among 200 psychiatrists surveyed, 65% said they had prescribed off label in the previous month, and only 4% had ever received a patient complaint about the practice.^{Malpractice Verdicts).
Box}

Table 2

Why psychiatrists prescribe off-label

Therapeutic reasons
Patient has a disorder for which no drug is labeled
Patient falls outside of labeled age or demographic group, such as children, older patients, and pregnant women
Patient fails to respond to labeled products
Off-label product may potentiate response to a labeled agent or minimize its adverse effects
Preferences
Manufacturers and respected peers promote use of off-label products as first- or second-line agents18
Practitioner wishes to foster innovative treatments
Patients or families request an off-label drug instead of labeled alternatives
Practitioner avoids using a particular labeled drug or drug class

Informed consent. Failing to obtain informed consent can increase your risk of malpractice litigation if a patient is injured, although state laws generally do not require you to disclose that you are prescribing off label. In our experience, disclosure helps prevent patient confusion and anxiety when materials they receive at the pharmacy or find on the Internet do not list their diagnoses among prescribed medications’ approved indications.

Most state medical practice laws spell out the information required in the patient chart to demonstrate informed consent, defined variously as:

• what a reasonable provider would tell a patient
  
• what a reasonable patient would expect to hear from the provider
  
• what a patient would need to hear before deciding on a treatment course.
  

What the law says

Off-label prescribing is legal, common, necessary, and recognized in some states by statute and by U.S. Supreme Court review.

Court decisions. In a class action suit before the top court (Buckman Company vs. Plaintiff’s Legal Commission, 2001), 5,000 plaintiffs claimed damages from orthopedic screws and plates that were FDA-approved for use in long bones but not for use in the spine. A unanimous court held that such off-label use is an accepted and necessary offshoot of FDA regulatory function and does not interfere with the practice of medicine.

The courts also have determined that off-label use does not mean “experimental” and itself is not a risk. Off-label use may be consistent with the standard of care and does not categorically indicate negligence (though a practitioner who prescribes negligently—such as prescribing a drug to which a patient is known to be allergic—may be found liable).

Drug manufacturers’ risk. The courts recognize that patients receive prescription drugs from doctors, not directly from the manufacturers. The law thus provides some immunity to manufacturers if your patient is injured by a drug you prescribe off-label. The learned-intermediary rule says anufacturers must warn you adequately of a drug’s foreseeable risks, and you then assume the responsibility to warn the patient.

The courts recognize exceptions, though, and have required manufacturers to warn patients directly about vaccines given in mass immunizations, drugs withdrawn from the market, drugs advertised directly to consumers, and other risks.

Related resources

• BMJ Publishing Group. Clinical evidence. Summary of what is known—and not known—about more than 200 medical disorders and 2,000 treatments. www.clinicalevidence.com.
  
• Cochrane Library of evidence-based clinical reviews. www.cochrane.org.
  
• Agency for Health Care Research and Quality. Draft comparative effectiveness review of off-label use of atypical antipsychotic drugs. http://effectivehealthcare.ahrq.gov/synthesize/reports/draft.cfm.
  

Drug brand names

• Amitriptyline • Elavil, others
  
• Carbamazepine • Carbetrol; Epitol; Equetro; Tegretol
  
• Gabapentin • Gabarone; Neurontin
  
• Lamotrigine • Lamictal
  
• Trazodone • Desyrel; Trialodine
  
• Valproate • Depakote; Depakene
  

Disclosures

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

Dr. McCall receives research support from GlaxoSmithKline, Sanofi-Aventis, Sepracor, Takeda, and Wyeth, is an advisor to King Pharmaceuticals and Sepracor, and is a speaker for GlaxoSmtihKline, Sepracor, and Wyeth.

Have you noticed two curious patterns in off-label prescribing? Psychiatrists avoid agents approved for treating insomnia but prescribe anticonvulsants for a variety of unapproved uses.

Most of us prescribe medications for therapeutic uses not found in FDA-approved labeling. Among 200 psychiatrists surveyed, 65% said they had prescribed off label in the previous month, and only 4% had ever received a patient complaint about the practice.^{Malpractice Verdicts).
Box}

Table 2

Why psychiatrists prescribe off-label

Therapeutic reasons
Patient has a disorder for which no drug is labeled
Patient falls outside of labeled age or demographic group, such as children, older patients, and pregnant women
Patient fails to respond to labeled products
Off-label product may potentiate response to a labeled agent or minimize its adverse effects
Preferences
Manufacturers and respected peers promote use of off-label products as first- or second-line agents18
Practitioner wishes to foster innovative treatments
Patients or families request an off-label drug instead of labeled alternatives
Practitioner avoids using a particular labeled drug or drug class

Informed consent. Failing to obtain informed consent can increase your risk of malpractice litigation if a patient is injured, although state laws generally do not require you to disclose that you are prescribing off label. In our experience, disclosure helps prevent patient confusion and anxiety when materials they receive at the pharmacy or find on the Internet do not list their diagnoses among prescribed medications’ approved indications.

Most state medical practice laws spell out the information required in the patient chart to demonstrate informed consent, defined variously as:

• what a reasonable provider would tell a patient
  
• what a reasonable patient would expect to hear from the provider
  
• what a patient would need to hear before deciding on a treatment course.
  

What the law says

Off-label prescribing is legal, common, necessary, and recognized in some states by statute and by U.S. Supreme Court review.

Court decisions. In a class action suit before the top court (Buckman Company vs. Plaintiff’s Legal Commission, 2001), 5,000 plaintiffs claimed damages from orthopedic screws and plates that were FDA-approved for use in long bones but not for use in the spine. A unanimous court held that such off-label use is an accepted and necessary offshoot of FDA regulatory function and does not interfere with the practice of medicine.

The courts also have determined that off-label use does not mean “experimental” and itself is not a risk. Off-label use may be consistent with the standard of care and does not categorically indicate negligence (though a practitioner who prescribes negligently—such as prescribing a drug to which a patient is known to be allergic—may be found liable).

Drug manufacturers’ risk. The courts recognize that patients receive prescription drugs from doctors, not directly from the manufacturers. The law thus provides some immunity to manufacturers if your patient is injured by a drug you prescribe off-label. The learned-intermediary rule says anufacturers must warn you adequately of a drug’s foreseeable risks, and you then assume the responsibility to warn the patient.

The courts recognize exceptions, though, and have required manufacturers to warn patients directly about vaccines given in mass immunizations, drugs withdrawn from the market, drugs advertised directly to consumers, and other risks.

Related resources

• BMJ Publishing Group. Clinical evidence. Summary of what is known—and not known—about more than 200 medical disorders and 2,000 treatments. www.clinicalevidence.com.
  
• Cochrane Library of evidence-based clinical reviews. www.cochrane.org.
  
• Agency for Health Care Research and Quality. Draft comparative effectiveness review of off-label use of atypical antipsychotic drugs. http://effectivehealthcare.ahrq.gov/synthesize/reports/draft.cfm.
  

Drug brand names

• Amitriptyline • Elavil, others
  
• Carbamazepine • Carbetrol; Epitol; Equetro; Tegretol
  
• Gabapentin • Gabarone; Neurontin
  
• Lamotrigine • Lamictal
  
• Trazodone • Desyrel; Trialodine
  
• Valproate • Depakote; Depakene
  

Disclosures

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

Dr. McCall receives research support from GlaxoSmithKline, Sanofi-Aventis, Sepracor, Takeda, and Wyeth, is an advisor to King Pharmaceuticals and Sepracor, and is a speaker for GlaxoSmtihKline, Sepracor, and Wyeth.

Have you noticed two curious patterns in off-label prescribing? Psychiatrists avoid agents approved for treating insomnia but prescribe anticonvulsants for a variety of unapproved uses.

Most of us prescribe medications for therapeutic uses not found in FDA-approved labeling. Among 200 psychiatrists surveyed, 65% said they had prescribed off label in the previous month, and only 4% had ever received a patient complaint about the practice.^{Malpractice Verdicts).
Box}

Table 2

Why psychiatrists prescribe off-label

Therapeutic reasons
Patient has a disorder for which no drug is labeled
Patient falls outside of labeled age or demographic group, such as children, older patients, and pregnant women
Patient fails to respond to labeled products
Off-label product may potentiate response to a labeled agent or minimize its adverse effects
Preferences
Manufacturers and respected peers promote use of off-label products as first- or second-line agents18
Practitioner wishes to foster innovative treatments
Patients or families request an off-label drug instead of labeled alternatives
Practitioner avoids using a particular labeled drug or drug class

Informed consent. Failing to obtain informed consent can increase your risk of malpractice litigation if a patient is injured, although state laws generally do not require you to disclose that you are prescribing off label. In our experience, disclosure helps prevent patient confusion and anxiety when materials they receive at the pharmacy or find on the Internet do not list their diagnoses among prescribed medications’ approved indications.

Most state medical practice laws spell out the information required in the patient chart to demonstrate informed consent, defined variously as:

• what a reasonable provider would tell a patient
  
• what a reasonable patient would expect to hear from the provider
  
• what a patient would need to hear before deciding on a treatment course.
  

What the law says

Off-label prescribing is legal, common, necessary, and recognized in some states by statute and by U.S. Supreme Court review.

Court decisions. In a class action suit before the top court (Buckman Company vs. Plaintiff’s Legal Commission, 2001), 5,000 plaintiffs claimed damages from orthopedic screws and plates that were FDA-approved for use in long bones but not for use in the spine. A unanimous court held that such off-label use is an accepted and necessary offshoot of FDA regulatory function and does not interfere with the practice of medicine.

The courts also have determined that off-label use does not mean “experimental” and itself is not a risk. Off-label use may be consistent with the standard of care and does not categorically indicate negligence (though a practitioner who prescribes negligently—such as prescribing a drug to which a patient is known to be allergic—may be found liable).

Drug manufacturers’ risk. The courts recognize that patients receive prescription drugs from doctors, not directly from the manufacturers. The law thus provides some immunity to manufacturers if your patient is injured by a drug you prescribe off-label. The learned-intermediary rule says anufacturers must warn you adequately of a drug’s foreseeable risks, and you then assume the responsibility to warn the patient.

The courts recognize exceptions, though, and have required manufacturers to warn patients directly about vaccines given in mass immunizations, drugs withdrawn from the market, drugs advertised directly to consumers, and other risks.

Related resources

• BMJ Publishing Group. Clinical evidence. Summary of what is known—and not known—about more than 200 medical disorders and 2,000 treatments. www.clinicalevidence.com.
  
• Cochrane Library of evidence-based clinical reviews. www.cochrane.org.
  
• Agency for Health Care Research and Quality. Draft comparative effectiveness review of off-label use of atypical antipsychotic drugs. http://effectivehealthcare.ahrq.gov/synthesize/reports/draft.cfm.
  

Drug brand names

• Amitriptyline • Elavil, others
  
• Carbamazepine • Carbetrol; Epitol; Equetro; Tegretol
  
• Gabapentin • Gabarone; Neurontin
  
• Lamotrigine • Lamictal
  
• Trazodone • Desyrel; Trialodine
  
• Valproate • Depakote; Depakene
  

Disclosures

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

Dr. McCall receives research support from GlaxoSmithKline, Sanofi-Aventis, Sepracor, Takeda, and Wyeth, is an advisor to King Pharmaceuticals and Sepracor, and is a speaker for GlaxoSmtihKline, Sepracor, and Wyeth.

Chronic fatigue syndrome (CFS) continues to puzzle and provoke. Years of research have failed to find a biomedical cause or to answer fundamental questions, such as “What is it?” and “Does it exist?”

Up to two-thirds of CFS patients have psychiatric disorders,¹ but psychiatrists are not the first physicians CFS patients usually see. Primary care physicians may ask you to help confirm the diagnosis, manage patients’ anxiety and depression, differentiate CFS from somatoform disorders, or provide psychotherapy for patients and their families.

Knowing what transpires in the referring physician’s office is key to helping a patient function despite CFS. This article describes:

• CFS clinical features and possible causes
  
• psychiatric comorbidities and exclusions
  
• cognitive behavioral therapy (CBT) and graded exercise, the only two therapies shown to improve CFS patients’ daily function.
  

Case: Anxious, depressed, and tired

Mr. A, age 43, is referred to you with anxiety and depressed mood associated with CFS, diagnosed 2 years ago. Fatigue predated Mr. A’s depression and anxiety, which his primary care physician considers consequences of CFS.

Mr. A is married, has three children, and owns a successful accounting practice. CFS was diagnosed from the classic presentation: abrupt onset of fatigue despite good health and a promising career. Now, overwhelming fatigue reduces his productivity. He makes up for frequent rest breaks by working in snatches of time, even at 4 AM. He is spending little time with his wife and children.

Defining CFS

The Centers for Disease Control and Prevention (CDC) defined CFS in 1988 while investigating infectious causes of fatigue (Table 1).^2,3 Epstein-Barr virus was thought to be the cause of CFS.

Most patients who present to their primary care physicians with complaints of fatigue do not meet CDC criteria for CFS, however. These “non-CFS” patients are diagnosed as having “idiopathic chronic fatigue,” a term that is not particularly helpful because CFS remains an idiopathic disorder.

Clinical findings. As with Mr. A, many CFS patients’ fatigue begins suddenly, often with flu-like symptoms. Patients lose tolerance for exercise and alcohol and become unable to work or socialize at pre-illness levels.

Medical symptoms can overlap those of other conditions, such as fibromyalgia, chemical sensitivities, and irritable bowel disorder. These associations make the condition difficult to assess and contribute to some physicians’ difficulty in accepting CFS as a biomedical condition. Mistrust and a poor patient-physician relationship can result when the physician doubts the symptoms’ “medical” nature and the patient resents the implication that the suffering is “all in your head.”

What causes CFS? No consistent factor has been identified that explains the pathophysiology of CFS symptoms. Many possibilities have been examined, but the evidence is confusing and contradictory.

A few preliminary studies suggest possible familial (shared environmental) and genetic components, but data are sparse and no more than suggestive.⁴ Findings of CNS studies are inconsistent, and the search for a change in immune function or an infectious agent has been fruitless despite some patients’ infection-like symptoms. The early hypothesis that Epstein-Barr virus was responsible has been disproved.

Imaging studies, psychological testing, and neuroendocrine investigations have identified abnormalities in some patients with CFS. The most-promising findings point to abnormalities in the hypothalamic-pituitary-adrenal axis and in serotonergic neurotransmission,⁵ suggesting an abnormal stress response in some patients.

Table 1

CDC diagnostic criteria for chronic fatigue syndrome

At least 6 months of fatigue sufficient to “substantially reduce” patient’s level of activity
4 or more of 8 concurrent symptoms: Poor memory/concentration Sore throat Tender glands Myalgia Joint pain Recent-onset headache Unrefreshing sleep Excessive tiredness on exercise
No obvious medical or psychiatric causes, such as eating disorders, psychosis, bipolar disorder, melancholia, or substance abuse*
CDC: Centers for Disease Control and Prevention
* Many nonpsychotic psychiatric disorders (such as atypical depression) do not exclude a CFS diagnosis
Source: References 1 and 2

Case continued: Test results are normal

Mr. A has undergone extensive medical assessment (complete blood cell count; renal, hepatic, and thyroid function tests; calcium, phosphate, and glucose determinations; and urinalysis), which yielded normal results. Brain MRI findings were also normal; specifically, no evidence of multiple sclerosis.

Even so, he has had nonspecific symptoms of impaired concentration, sore throat, tender cervical nodes, muscle pain, and nonrefreshing sleep. Physical exertion can leave him drained for at least 1 or 2 days.

Psychiatric Disorders

As many as 66% of CFS patients may have one or more psychiatric comorbidities; the most common are generalized anxiety disorder, panic disorder, depression, and somatoform disorder.¹ Because CFS symptoms are regarded as being not fully explained by a known medical disorder, patients are often diagnosed as having an undifferentiated somatoform disorder. Either disorder could be diagnosed in some cases, but this differentiation sheds no new light on the condition.

 

CFS and depression. Could CFS and depression be one and the same? Proponents of that position point out the similarity of symptoms, loss of function, and—in at least some cases—favorable response to antidepressants. Opponents cite other factors such as:

• presence of sore throat, lymphadenopathy, and post-exercise fatigue
  
• differences in sleep patterns
  
• frequent absence of psychiatric illness before fatigue onset
  
• evidence of hypocortisolism (also seen in patients with melancholic depression) in some CFS patients.
  

Notably, other forms of depression (atypical depression) may also be associated with hypocortisolism, suggesting common pathophysiologic features.⁷ Another possibility is that the depression and anxiety experienced by CFS patients are a response to a chronic debilitating condition, as is seen in other chronic illnesses.⁸

Primary Care Workup

Complaints of long-lasting, debilitating fatigue should alert the primary care physician to CFS. Like somatization disorder, CFS requires a physical workup, though as few as 2% of CFS patients are found to have an undiagnosed medical illness that explains the symptoms.⁹ The evaluation’s goal is not so much to find out what’s causing the fatigue as to reassure the patient that all avenues are considered before the diagnosis is made. When this is accomplished well, the patient is likely to accept psychiatric referral or treatment, if needed.

Two-part initial evaluation. If the initial physical exam and laboratory work find no biomedical cause for the patient’s chronic fatigue symptoms, we recommend a two-part primary care evaluation. This includes a focused discussion with the patient about CFS (Table 2).¹⁰ Goals of the first session are to:

• establish a relationship that will survive difficult times
  
• teach the patient to think of complex medical problems as having psychological and social consequences, if not causes.
  

During the second encounter, the primary care physician may begin to consider whether he or she will need help managing the patient’s psychiatric/psychological problems. Some physicians enjoy work of a psychological nature, whereas others prefer to refer to mental health professionals. Primary care treatment or referral to a psychiatrist, psychologist, or other psychotherapist depends on both the physician and the individual patient.

Primary care physicians usually request a psychiatric consultation to confirm or rule out psychiatric conditions that exclude a CFS diagnosis (melancholic depression, bipolar disorder, schizophrenia, anorexia nervosa or bulimia, and recent substance abuse). They also may refer in cases of other common disorders with poorly explained symptoms such as fibromyalgia and chemical sensitivity disorder.

Table 2

Two-part initial primary care evaluation of chronic fatigue

First session Focus on initial history Introduce concept of a biopsychosocial approach to problem Help patient understand that the disorder has no clear-cut cause, but its effects can be anticipated and addressed Ask patient to bring a relative or friend to next appointment and to keep notes on symptoms and functional difficulties to discuss at the second session Second session Refine the history Note recent events Establish more-complete picture of patient’s everyday life with help of relative’s or friend’s observations Focus on identifying comorbid psychiatric conditions and helping patient cope with chronic illness Consider referring patient to a mental health professional

Case continued: High anxiety

Mr. A describes how fatigue is affecting his work and home life. He is especially worried that he will not be attentive enough to catch accounting errors by his employees.

Interestingly, his anxiety remits but fatigue continues when he goes on vacation. He has no history of melancholic depression, bipolar disorder, psychosis, or substance abuse.

Psychiatric Assessment

The referring physician should provide a full account of the medical workup. This:

• assures you that possible medical causes of fatigue have been excluded
  
• provides information on psychiatric history and previous treatments
  
• delineates information on initial treatment efforts.
  

Like the primary care workup, your assessment is more for gathering relevant data than for its interpretation. You will follow well-defined diagnostic criteria in making sense of the information, but the quality of your data depends on the patient’s willingness to describe his or her symptoms.

Realize how defensive a patient may feel about being given a vague and disputed diagnosis such as CFS. Because the diagnosis depends somewhat on examining his or her volitional contribution to the symptoms,⁶ your listening skills are key to building the patient-physician relationship. Taking the patient’s suffering seriously is essential and may provide great relief.

When you confirm a CFS diagnosis, the next step is to identify any frequently occurring psychiatric comorbidities, such as nonmelancholic depression, anxiety, and somatoform disorders.

Psychiatric Treatment

CBT and exercise. Only CBT and graded exercise therapy yielded “promising results” in a systematic review of all CFS treatments studied in 44 controlled treatment trials.¹¹ By comparison, evidence is inconclusive or insufficient to support the use of:

 

• immunoglobulins or hydrocortisone
  
• most psychotropics—including all classes of antidepressants.
  

CBT and graded exercise protocols have been used successfully in adult^12,13 and adolescent¹⁴ CFS patients. Treatment is done in two steps:

• Patients learn about their illness, develop a realistic assessment of their limitations, and come to understand that physical activity will not harm them.
  
• Patients begin graded exercises designed to slowly extend their exercise tolerance and widen their range of daily activities.
  

Compared with controls, adult and adolescent CFS patients’ fatigue and overall functioning improved significantly, and the adolescents’ school attendance improved.

Trained psychologists usually do this work, and your role is to be aware of the key part this approach plays in managing CFS patients and to set up appropriate referrals.

Case continued: Relief and acceptance

Mr. A continues to see you and a therapist for treatment of mild depression and severe anxiety. His behavioral therapy focuses on helping him cope with how his illness limits his relationship to work and family. His therapist also explores with him the personal meanings of his new situation, his feelings about issues such as dependence, and limitations imposed on his life goals.

You start a trial of fluoxetine (up to 40 mg/d for several months) with minimal benefit. You then try nortriptyline, 25 mg nightly, and clonazepam, 0.5 mg bid. Although these drugs can be sedating, Mr. A reports feeling no more fatigued than he was before taking them. He improves slightly after 7 months but not enough that he wants to continue the medication.

Medications. Neither psychiatric nor other medication classes have shown efficacy in treating CFS core symptoms.¹⁵ One recent study¹⁶ found citalopram helped reduce chronic fatigue, but the study was small and uncontrolled. Although the subjects had chronic fatigue, not all met the formal definition of CFS for study inclusion.

Medication does play an important role in treating comorbid anxiety and depression. Usual psychopharmacologic strategies are appropriate. As in Mr. A’s case, most psychiatrists use SSRIs as first-line medications, but side effects are probably the most useful guide to medication choice.

Case continued: Additional treatment

Because medication has had little effect on Mr. A’s anxiety and depressed mood, you suggest adding a graded exercise program to his treatment plan. He improves steadily over time and says he is pleased. Although progress is slow, he finds it reassuring to be accomplishing realistic goals. He realizes that you and the therapist do not have the answer to his illness, but he trusts you and is comforted that you accept his condition and are willing to listen and help.

Related resources

• Afari N, Buchwald D. Chronic fatigue syndrome: a review. Am J Psychiatry 2003;160:221-36.
  
• Reid S, Chalder T, Cleare A, et al. Chronic fatigue syndrome. Clin Evid 2004;12:1578-93.
  
• Centers for Disease Control and Prevention. Chronic fatigue syndrome. http://www.cdc.gov/ncidod/diseases/cfs/.
  
• International Association for Chronic Fatigue Syndrome. http://www.aacfs.org.
  

Drug brand names

• Citalopram • Celexa, others
  
• Clonazepam • Lorazepam, others
  
• Fluoxetine • Prozac
  
• Nortriptyline • Aventyl, others
  

Disclosure

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

Chronic fatigue syndrome (CFS) continues to puzzle and provoke. Years of research have failed to find a biomedical cause or to answer fundamental questions, such as “What is it?” and “Does it exist?”

Up to two-thirds of CFS patients have psychiatric disorders,¹ but psychiatrists are not the first physicians CFS patients usually see. Primary care physicians may ask you to help confirm the diagnosis, manage patients’ anxiety and depression, differentiate CFS from somatoform disorders, or provide psychotherapy for patients and their families.

Knowing what transpires in the referring physician’s office is key to helping a patient function despite CFS. This article describes:

• CFS clinical features and possible causes
  
• psychiatric comorbidities and exclusions
  
• cognitive behavioral therapy (CBT) and graded exercise, the only two therapies shown to improve CFS patients’ daily function.
  

Case: Anxious, depressed, and tired

Mr. A, age 43, is referred to you with anxiety and depressed mood associated with CFS, diagnosed 2 years ago. Fatigue predated Mr. A’s depression and anxiety, which his primary care physician considers consequences of CFS.

Mr. A is married, has three children, and owns a successful accounting practice. CFS was diagnosed from the classic presentation: abrupt onset of fatigue despite good health and a promising career. Now, overwhelming fatigue reduces his productivity. He makes up for frequent rest breaks by working in snatches of time, even at 4 AM. He is spending little time with his wife and children.

Defining CFS

The Centers for Disease Control and Prevention (CDC) defined CFS in 1988 while investigating infectious causes of fatigue (Table 1).^2,3 Epstein-Barr virus was thought to be the cause of CFS.

Most patients who present to their primary care physicians with complaints of fatigue do not meet CDC criteria for CFS, however. These “non-CFS” patients are diagnosed as having “idiopathic chronic fatigue,” a term that is not particularly helpful because CFS remains an idiopathic disorder.

Clinical findings. As with Mr. A, many CFS patients’ fatigue begins suddenly, often with flu-like symptoms. Patients lose tolerance for exercise and alcohol and become unable to work or socialize at pre-illness levels.

Medical symptoms can overlap those of other conditions, such as fibromyalgia, chemical sensitivities, and irritable bowel disorder. These associations make the condition difficult to assess and contribute to some physicians’ difficulty in accepting CFS as a biomedical condition. Mistrust and a poor patient-physician relationship can result when the physician doubts the symptoms’ “medical” nature and the patient resents the implication that the suffering is “all in your head.”

What causes CFS? No consistent factor has been identified that explains the pathophysiology of CFS symptoms. Many possibilities have been examined, but the evidence is confusing and contradictory.

A few preliminary studies suggest possible familial (shared environmental) and genetic components, but data are sparse and no more than suggestive.⁴ Findings of CNS studies are inconsistent, and the search for a change in immune function or an infectious agent has been fruitless despite some patients’ infection-like symptoms. The early hypothesis that Epstein-Barr virus was responsible has been disproved.

Imaging studies, psychological testing, and neuroendocrine investigations have identified abnormalities in some patients with CFS. The most-promising findings point to abnormalities in the hypothalamic-pituitary-adrenal axis and in serotonergic neurotransmission,⁵ suggesting an abnormal stress response in some patients.

Table 1

CDC diagnostic criteria for chronic fatigue syndrome

At least 6 months of fatigue sufficient to “substantially reduce” patient’s level of activity
4 or more of 8 concurrent symptoms: Poor memory/concentration Sore throat Tender glands Myalgia Joint pain Recent-onset headache Unrefreshing sleep Excessive tiredness on exercise
No obvious medical or psychiatric causes, such as eating disorders, psychosis, bipolar disorder, melancholia, or substance abuse*
CDC: Centers for Disease Control and Prevention
* Many nonpsychotic psychiatric disorders (such as atypical depression) do not exclude a CFS diagnosis
Source: References 1 and 2

Case continued: Test results are normal

Mr. A has undergone extensive medical assessment (complete blood cell count; renal, hepatic, and thyroid function tests; calcium, phosphate, and glucose determinations; and urinalysis), which yielded normal results. Brain MRI findings were also normal; specifically, no evidence of multiple sclerosis.

Even so, he has had nonspecific symptoms of impaired concentration, sore throat, tender cervical nodes, muscle pain, and nonrefreshing sleep. Physical exertion can leave him drained for at least 1 or 2 days.

Psychiatric Disorders

As many as 66% of CFS patients may have one or more psychiatric comorbidities; the most common are generalized anxiety disorder, panic disorder, depression, and somatoform disorder.¹ Because CFS symptoms are regarded as being not fully explained by a known medical disorder, patients are often diagnosed as having an undifferentiated somatoform disorder. Either disorder could be diagnosed in some cases, but this differentiation sheds no new light on the condition.

 

CFS and depression. Could CFS and depression be one and the same? Proponents of that position point out the similarity of symptoms, loss of function, and—in at least some cases—favorable response to antidepressants. Opponents cite other factors such as:

• presence of sore throat, lymphadenopathy, and post-exercise fatigue
  
• differences in sleep patterns
  
• frequent absence of psychiatric illness before fatigue onset
  
• evidence of hypocortisolism (also seen in patients with melancholic depression) in some CFS patients.
  

Notably, other forms of depression (atypical depression) may also be associated with hypocortisolism, suggesting common pathophysiologic features.⁷ Another possibility is that the depression and anxiety experienced by CFS patients are a response to a chronic debilitating condition, as is seen in other chronic illnesses.⁸

Primary Care Workup

Complaints of long-lasting, debilitating fatigue should alert the primary care physician to CFS. Like somatization disorder, CFS requires a physical workup, though as few as 2% of CFS patients are found to have an undiagnosed medical illness that explains the symptoms.⁹ The evaluation’s goal is not so much to find out what’s causing the fatigue as to reassure the patient that all avenues are considered before the diagnosis is made. When this is accomplished well, the patient is likely to accept psychiatric referral or treatment, if needed.

Two-part initial evaluation. If the initial physical exam and laboratory work find no biomedical cause for the patient’s chronic fatigue symptoms, we recommend a two-part primary care evaluation. This includes a focused discussion with the patient about CFS (Table 2).¹⁰ Goals of the first session are to:

• establish a relationship that will survive difficult times
  
• teach the patient to think of complex medical problems as having psychological and social consequences, if not causes.
  

During the second encounter, the primary care physician may begin to consider whether he or she will need help managing the patient’s psychiatric/psychological problems. Some physicians enjoy work of a psychological nature, whereas others prefer to refer to mental health professionals. Primary care treatment or referral to a psychiatrist, psychologist, or other psychotherapist depends on both the physician and the individual patient.

Primary care physicians usually request a psychiatric consultation to confirm or rule out psychiatric conditions that exclude a CFS diagnosis (melancholic depression, bipolar disorder, schizophrenia, anorexia nervosa or bulimia, and recent substance abuse). They also may refer in cases of other common disorders with poorly explained symptoms such as fibromyalgia and chemical sensitivity disorder.

Table 2

Two-part initial primary care evaluation of chronic fatigue

First session Focus on initial history Introduce concept of a biopsychosocial approach to problem Help patient understand that the disorder has no clear-cut cause, but its effects can be anticipated and addressed Ask patient to bring a relative or friend to next appointment and to keep notes on symptoms and functional difficulties to discuss at the second session Second session Refine the history Note recent events Establish more-complete picture of patient’s everyday life with help of relative’s or friend’s observations Focus on identifying comorbid psychiatric conditions and helping patient cope with chronic illness Consider referring patient to a mental health professional

Case continued: High anxiety

Mr. A describes how fatigue is affecting his work and home life. He is especially worried that he will not be attentive enough to catch accounting errors by his employees.

Interestingly, his anxiety remits but fatigue continues when he goes on vacation. He has no history of melancholic depression, bipolar disorder, psychosis, or substance abuse.

Psychiatric Assessment

The referring physician should provide a full account of the medical workup. This:

• assures you that possible medical causes of fatigue have been excluded
  
• provides information on psychiatric history and previous treatments
  
• delineates information on initial treatment efforts.
  

Like the primary care workup, your assessment is more for gathering relevant data than for its interpretation. You will follow well-defined diagnostic criteria in making sense of the information, but the quality of your data depends on the patient’s willingness to describe his or her symptoms.

Realize how defensive a patient may feel about being given a vague and disputed diagnosis such as CFS. Because the diagnosis depends somewhat on examining his or her volitional contribution to the symptoms,⁶ your listening skills are key to building the patient-physician relationship. Taking the patient’s suffering seriously is essential and may provide great relief.

When you confirm a CFS diagnosis, the next step is to identify any frequently occurring psychiatric comorbidities, such as nonmelancholic depression, anxiety, and somatoform disorders.

Psychiatric Treatment

CBT and exercise. Only CBT and graded exercise therapy yielded “promising results” in a systematic review of all CFS treatments studied in 44 controlled treatment trials.¹¹ By comparison, evidence is inconclusive or insufficient to support the use of:

 

• immunoglobulins or hydrocortisone
  
• most psychotropics—including all classes of antidepressants.
  

CBT and graded exercise protocols have been used successfully in adult^12,13 and adolescent¹⁴ CFS patients. Treatment is done in two steps:

• Patients learn about their illness, develop a realistic assessment of their limitations, and come to understand that physical activity will not harm them.
  
• Patients begin graded exercises designed to slowly extend their exercise tolerance and widen their range of daily activities.
  

Compared with controls, adult and adolescent CFS patients’ fatigue and overall functioning improved significantly, and the adolescents’ school attendance improved.

Trained psychologists usually do this work, and your role is to be aware of the key part this approach plays in managing CFS patients and to set up appropriate referrals.

Case continued: Relief and acceptance

Mr. A continues to see you and a therapist for treatment of mild depression and severe anxiety. His behavioral therapy focuses on helping him cope with how his illness limits his relationship to work and family. His therapist also explores with him the personal meanings of his new situation, his feelings about issues such as dependence, and limitations imposed on his life goals.

You start a trial of fluoxetine (up to 40 mg/d for several months) with minimal benefit. You then try nortriptyline, 25 mg nightly, and clonazepam, 0.5 mg bid. Although these drugs can be sedating, Mr. A reports feeling no more fatigued than he was before taking them. He improves slightly after 7 months but not enough that he wants to continue the medication.

Medications. Neither psychiatric nor other medication classes have shown efficacy in treating CFS core symptoms.¹⁵ One recent study¹⁶ found citalopram helped reduce chronic fatigue, but the study was small and uncontrolled. Although the subjects had chronic fatigue, not all met the formal definition of CFS for study inclusion.

Medication does play an important role in treating comorbid anxiety and depression. Usual psychopharmacologic strategies are appropriate. As in Mr. A’s case, most psychiatrists use SSRIs as first-line medications, but side effects are probably the most useful guide to medication choice.

Case continued: Additional treatment

Because medication has had little effect on Mr. A’s anxiety and depressed mood, you suggest adding a graded exercise program to his treatment plan. He improves steadily over time and says he is pleased. Although progress is slow, he finds it reassuring to be accomplishing realistic goals. He realizes that you and the therapist do not have the answer to his illness, but he trusts you and is comforted that you accept his condition and are willing to listen and help.

Related resources

• Afari N, Buchwald D. Chronic fatigue syndrome: a review. Am J Psychiatry 2003;160:221-36.
  
• Reid S, Chalder T, Cleare A, et al. Chronic fatigue syndrome. Clin Evid 2004;12:1578-93.
  
• Centers for Disease Control and Prevention. Chronic fatigue syndrome. http://www.cdc.gov/ncidod/diseases/cfs/.
  
• International Association for Chronic Fatigue Syndrome. http://www.aacfs.org.
  

Drug brand names

• Citalopram • Celexa, others
  
• Clonazepam • Lorazepam, others
  
• Fluoxetine • Prozac
  
• Nortriptyline • Aventyl, others
  

Disclosure

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

Chronic fatigue syndrome (CFS) continues to puzzle and provoke. Years of research have failed to find a biomedical cause or to answer fundamental questions, such as “What is it?” and “Does it exist?”

Up to two-thirds of CFS patients have psychiatric disorders,¹ but psychiatrists are not the first physicians CFS patients usually see. Primary care physicians may ask you to help confirm the diagnosis, manage patients’ anxiety and depression, differentiate CFS from somatoform disorders, or provide psychotherapy for patients and their families.

Knowing what transpires in the referring physician’s office is key to helping a patient function despite CFS. This article describes:

• CFS clinical features and possible causes
  
• psychiatric comorbidities and exclusions
  
• cognitive behavioral therapy (CBT) and graded exercise, the only two therapies shown to improve CFS patients’ daily function.
  

Case: Anxious, depressed, and tired

Mr. A, age 43, is referred to you with anxiety and depressed mood associated with CFS, diagnosed 2 years ago. Fatigue predated Mr. A’s depression and anxiety, which his primary care physician considers consequences of CFS.

Mr. A is married, has three children, and owns a successful accounting practice. CFS was diagnosed from the classic presentation: abrupt onset of fatigue despite good health and a promising career. Now, overwhelming fatigue reduces his productivity. He makes up for frequent rest breaks by working in snatches of time, even at 4 AM. He is spending little time with his wife and children.

Defining CFS

The Centers for Disease Control and Prevention (CDC) defined CFS in 1988 while investigating infectious causes of fatigue (Table 1).^2,3 Epstein-Barr virus was thought to be the cause of CFS.

Most patients who present to their primary care physicians with complaints of fatigue do not meet CDC criteria for CFS, however. These “non-CFS” patients are diagnosed as having “idiopathic chronic fatigue,” a term that is not particularly helpful because CFS remains an idiopathic disorder.

Clinical findings. As with Mr. A, many CFS patients’ fatigue begins suddenly, often with flu-like symptoms. Patients lose tolerance for exercise and alcohol and become unable to work or socialize at pre-illness levels.

Medical symptoms can overlap those of other conditions, such as fibromyalgia, chemical sensitivities, and irritable bowel disorder. These associations make the condition difficult to assess and contribute to some physicians’ difficulty in accepting CFS as a biomedical condition. Mistrust and a poor patient-physician relationship can result when the physician doubts the symptoms’ “medical” nature and the patient resents the implication that the suffering is “all in your head.”

What causes CFS? No consistent factor has been identified that explains the pathophysiology of CFS symptoms. Many possibilities have been examined, but the evidence is confusing and contradictory.

A few preliminary studies suggest possible familial (shared environmental) and genetic components, but data are sparse and no more than suggestive.⁴ Findings of CNS studies are inconsistent, and the search for a change in immune function or an infectious agent has been fruitless despite some patients’ infection-like symptoms. The early hypothesis that Epstein-Barr virus was responsible has been disproved.

Imaging studies, psychological testing, and neuroendocrine investigations have identified abnormalities in some patients with CFS. The most-promising findings point to abnormalities in the hypothalamic-pituitary-adrenal axis and in serotonergic neurotransmission,⁵ suggesting an abnormal stress response in some patients.

Table 1

CDC diagnostic criteria for chronic fatigue syndrome

At least 6 months of fatigue sufficient to “substantially reduce” patient’s level of activity
4 or more of 8 concurrent symptoms: Poor memory/concentration Sore throat Tender glands Myalgia Joint pain Recent-onset headache Unrefreshing sleep Excessive tiredness on exercise
No obvious medical or psychiatric causes, such as eating disorders, psychosis, bipolar disorder, melancholia, or substance abuse*
CDC: Centers for Disease Control and Prevention
* Many nonpsychotic psychiatric disorders (such as atypical depression) do not exclude a CFS diagnosis
Source: References 1 and 2

Case continued: Test results are normal

Mr. A has undergone extensive medical assessment (complete blood cell count; renal, hepatic, and thyroid function tests; calcium, phosphate, and glucose determinations; and urinalysis), which yielded normal results. Brain MRI findings were also normal; specifically, no evidence of multiple sclerosis.

Even so, he has had nonspecific symptoms of impaired concentration, sore throat, tender cervical nodes, muscle pain, and nonrefreshing sleep. Physical exertion can leave him drained for at least 1 or 2 days.

Psychiatric Disorders

As many as 66% of CFS patients may have one or more psychiatric comorbidities; the most common are generalized anxiety disorder, panic disorder, depression, and somatoform disorder.¹ Because CFS symptoms are regarded as being not fully explained by a known medical disorder, patients are often diagnosed as having an undifferentiated somatoform disorder. Either disorder could be diagnosed in some cases, but this differentiation sheds no new light on the condition.

 

CFS and depression. Could CFS and depression be one and the same? Proponents of that position point out the similarity of symptoms, loss of function, and—in at least some cases—favorable response to antidepressants. Opponents cite other factors such as:

• presence of sore throat, lymphadenopathy, and post-exercise fatigue
  
• differences in sleep patterns
  
• frequent absence of psychiatric illness before fatigue onset
  
• evidence of hypocortisolism (also seen in patients with melancholic depression) in some CFS patients.
  

Notably, other forms of depression (atypical depression) may also be associated with hypocortisolism, suggesting common pathophysiologic features.⁷ Another possibility is that the depression and anxiety experienced by CFS patients are a response to a chronic debilitating condition, as is seen in other chronic illnesses.⁸

Primary Care Workup

Complaints of long-lasting, debilitating fatigue should alert the primary care physician to CFS. Like somatization disorder, CFS requires a physical workup, though as few as 2% of CFS patients are found to have an undiagnosed medical illness that explains the symptoms.⁹ The evaluation’s goal is not so much to find out what’s causing the fatigue as to reassure the patient that all avenues are considered before the diagnosis is made. When this is accomplished well, the patient is likely to accept psychiatric referral or treatment, if needed.

Two-part initial evaluation. If the initial physical exam and laboratory work find no biomedical cause for the patient’s chronic fatigue symptoms, we recommend a two-part primary care evaluation. This includes a focused discussion with the patient about CFS (Table 2).¹⁰ Goals of the first session are to:

• establish a relationship that will survive difficult times
  
• teach the patient to think of complex medical problems as having psychological and social consequences, if not causes.
  

During the second encounter, the primary care physician may begin to consider whether he or she will need help managing the patient’s psychiatric/psychological problems. Some physicians enjoy work of a psychological nature, whereas others prefer to refer to mental health professionals. Primary care treatment or referral to a psychiatrist, psychologist, or other psychotherapist depends on both the physician and the individual patient.

Primary care physicians usually request a psychiatric consultation to confirm or rule out psychiatric conditions that exclude a CFS diagnosis (melancholic depression, bipolar disorder, schizophrenia, anorexia nervosa or bulimia, and recent substance abuse). They also may refer in cases of other common disorders with poorly explained symptoms such as fibromyalgia and chemical sensitivity disorder.

Table 2

Two-part initial primary care evaluation of chronic fatigue

First session Focus on initial history Introduce concept of a biopsychosocial approach to problem Help patient understand that the disorder has no clear-cut cause, but its effects can be anticipated and addressed Ask patient to bring a relative or friend to next appointment and to keep notes on symptoms and functional difficulties to discuss at the second session Second session Refine the history Note recent events Establish more-complete picture of patient’s everyday life with help of relative’s or friend’s observations Focus on identifying comorbid psychiatric conditions and helping patient cope with chronic illness Consider referring patient to a mental health professional

Case continued: High anxiety

Mr. A describes how fatigue is affecting his work and home life. He is especially worried that he will not be attentive enough to catch accounting errors by his employees.

Interestingly, his anxiety remits but fatigue continues when he goes on vacation. He has no history of melancholic depression, bipolar disorder, psychosis, or substance abuse.

Psychiatric Assessment

The referring physician should provide a full account of the medical workup. This:

• assures you that possible medical causes of fatigue have been excluded
  
• provides information on psychiatric history and previous treatments
  
• delineates information on initial treatment efforts.
  

Like the primary care workup, your assessment is more for gathering relevant data than for its interpretation. You will follow well-defined diagnostic criteria in making sense of the information, but the quality of your data depends on the patient’s willingness to describe his or her symptoms.

Realize how defensive a patient may feel about being given a vague and disputed diagnosis such as CFS. Because the diagnosis depends somewhat on examining his or her volitional contribution to the symptoms,⁶ your listening skills are key to building the patient-physician relationship. Taking the patient’s suffering seriously is essential and may provide great relief.

When you confirm a CFS diagnosis, the next step is to identify any frequently occurring psychiatric comorbidities, such as nonmelancholic depression, anxiety, and somatoform disorders.

Psychiatric Treatment

CBT and exercise. Only CBT and graded exercise therapy yielded “promising results” in a systematic review of all CFS treatments studied in 44 controlled treatment trials.¹¹ By comparison, evidence is inconclusive or insufficient to support the use of:

 

• immunoglobulins or hydrocortisone
  
• most psychotropics—including all classes of antidepressants.
  

CBT and graded exercise protocols have been used successfully in adult^12,13 and adolescent¹⁴ CFS patients. Treatment is done in two steps:

• Patients learn about their illness, develop a realistic assessment of their limitations, and come to understand that physical activity will not harm them.
  
• Patients begin graded exercises designed to slowly extend their exercise tolerance and widen their range of daily activities.
  

Compared with controls, adult and adolescent CFS patients’ fatigue and overall functioning improved significantly, and the adolescents’ school attendance improved.

Trained psychologists usually do this work, and your role is to be aware of the key part this approach plays in managing CFS patients and to set up appropriate referrals.

Case continued: Relief and acceptance

Mr. A continues to see you and a therapist for treatment of mild depression and severe anxiety. His behavioral therapy focuses on helping him cope with how his illness limits his relationship to work and family. His therapist also explores with him the personal meanings of his new situation, his feelings about issues such as dependence, and limitations imposed on his life goals.

You start a trial of fluoxetine (up to 40 mg/d for several months) with minimal benefit. You then try nortriptyline, 25 mg nightly, and clonazepam, 0.5 mg bid. Although these drugs can be sedating, Mr. A reports feeling no more fatigued than he was before taking them. He improves slightly after 7 months but not enough that he wants to continue the medication.

Medications. Neither psychiatric nor other medication classes have shown efficacy in treating CFS core symptoms.¹⁵ One recent study¹⁶ found citalopram helped reduce chronic fatigue, but the study was small and uncontrolled. Although the subjects had chronic fatigue, not all met the formal definition of CFS for study inclusion.

Medication does play an important role in treating comorbid anxiety and depression. Usual psychopharmacologic strategies are appropriate. As in Mr. A’s case, most psychiatrists use SSRIs as first-line medications, but side effects are probably the most useful guide to medication choice.

Case continued: Additional treatment

Because medication has had little effect on Mr. A’s anxiety and depressed mood, you suggest adding a graded exercise program to his treatment plan. He improves steadily over time and says he is pleased. Although progress is slow, he finds it reassuring to be accomplishing realistic goals. He realizes that you and the therapist do not have the answer to his illness, but he trusts you and is comforted that you accept his condition and are willing to listen and help.

Related resources

• Afari N, Buchwald D. Chronic fatigue syndrome: a review. Am J Psychiatry 2003;160:221-36.
  
• Reid S, Chalder T, Cleare A, et al. Chronic fatigue syndrome. Clin Evid 2004;12:1578-93.
  
• Centers for Disease Control and Prevention. Chronic fatigue syndrome. http://www.cdc.gov/ncidod/diseases/cfs/.
  
• International Association for Chronic Fatigue Syndrome. http://www.aacfs.org.
  

Drug brand names

• Citalopram • Celexa, others
  
• Clonazepam • Lorazepam, others
  
• Fluoxetine • Prozac
  
• Nortriptyline • Aventyl, others
  

Disclosure

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

When a patient presents with psychotic symptoms, you might not recognize or pursue hints of bipolarity if you assume psychosis means schizophrenia. Yet psychotic bipolar disorder can explain every sign, symptom, course, and other characteristic traditionally assumed to indicate schizophrenia (Table 1). The literature, including recent genetic data,^1-6 marshals a persuasive argument that patients diagnosed with schizophrenia usually suffer from a psychotic bipolar disorder.

Consider here how a cascade of changing signs and symptoms, initially unrecognized, caused five sequential re-evaluations of one psychotic patient’s primary Axis I diagnosis. His case highlights why the correct initial diagnosis of the disease causing psychosis is essential to effective treatment.^4,7-9

Table 1

DSM-IV-TR criteria for schizophrenia vs. psychotic mood disorder

Schizophrenia diagnosis6	Seen in psychotic mood disorders
Criterion A
Hallucinations and delusions	50% to 80% explained by mood16,21
Paranoia	Hides grandiosity4
Catatonia	75% explained by mood7,8
Disorganized speech and behavior	All patients with moderate to severe mania1-5
Negative symptoms	All patients with moderate to severe depression4
Criterion B
Social and job dysfunction	All patients with moderate to severe bipolar disorder5,13
Criterion C
Chronic continuous symptoms	Patients can have psychotic symptoms continuously for 2 years to life5,6,13

Case: Carved in stone

Police officers carry Mr. C, age 30, into the emergency department. He is mentally disorganized and arrives in a rigid, catatonic posture. According to a neighbor, Mr. C was kneeling motionless on his mother’s front lawn, alternating between mutism and inappropriately loud, disorganized religious preaching. When his arm is lifted, it remains as placed. He is admitted to the acute care inpatient unit.

Mr. C’s most striking symptoms are catatonia and psychosis. Postural rigidity, waxy flexibility, and automatic obedience are characteristics of catatonia.^6-8 An organic cause is first considered, such as hyperthyroidism, cerebrovascular accident, cerebral neoplasm, head trauma, seizure disorder, dementia, neuroleptic malignant syndrome, pheochromocytoma, or—especially—intoxication from illegal drugs.⁷

While awaiting results from physical, mental status, and lab exams and imaging studies, staff assign him two admitting diagnoses: catatonic disorder due to a general medical condition and psychotic disorder not otherwise specified.⁶

Case: Inconclusive workup

Mr. C denies using illegal substances or alcohol, which his mother confirms. He has no history of seizures or other medical conditions. His distractibility prevents him from focusing on a formal mental status exam. Physical exam, urine drug screen, lab results, and imaging studies are unremarkable except for an admitting blood pressure of 145/95 mm Hg and pulse of 115 beats per minute. These readings normalize within 1 hour. IM haloperidol and lorazepam are given as needed for agitation, but physicians withhold scheduled medications to allow staff to observe his symptoms.

Organic causes of catatonia now seem less likely, though past use of drugs such as phencyclidine that can cause chronic psychosis cannot be ruled out. Schizophrenia is considered likely because catatonia is one of schizophrenia’s five core diagnostic symptoms.⁶ Catatonia can also be a symptom of bipolar disorder.^6-9 Staff make a preliminary diagnosis of schizophrenia, catatonic type.

Case: ‘Hit men are after me’

Staff observe Mr. C responding to threatening auditory hallucinations. His affect is “fearful to terrified.” He says he hears the voice of God warning him of danger and continuing a running commentary on his actions. He fears for his life because “hit men have been sent to kill me” and have “infiltrated” the inpatient ward. He does not eat, saying his food is poisoned. He says these beliefs have escalated over the past year.

Mr. C’s catatonic symptoms resolve overnight, but obtaining additional history is difficult because of his paranoia. He denies any history of bizarre behavior or past contact with mental health services. He claims not to be especially religious. He is unmarried and lives with his mother, is college-educated, but has held only menial jobs.

Inpatient staff shifts its diagnostic focus to functional disorders associated with auditory hallucinations, paranoid delusions, and gross disorganization. According to Schneider and the DSM-IV-TR,^6,10 hearing a voice “keeping up a running commentary on one’s behavior” is especially diagnostic of schizophrenia.

Because of the rapid resolution of his “catatonic” symptoms and prominence of paranoia, they change his diagnosis on day 2 to schizophrenia, paranoid type. Mr. C meets all diagnostic criteria for schizophrenia except one: the staff has overlooked and has not adequately excluded a psychotic mood disorder.

Case: A turn for the worse

That night, nursing staff find Mr. C naked and cowering in the fetal position in a corner of his room. He has smeared his feces on his face and in his hair and mouth. While being cleaned up, he suddenly begins quoting scripture in a loud, disorganized voice. His expressed thoughts are incomprehensible. He is given haloperidol and lorazepam immediately; oral haloperidol is continued at 10 mg bid.

 

Both Bleuler and Kraepelin concluded “coprophilia and coprophagia are unique to children and patients with schizophrenia.”^11,12 The DSM casebook cites Kraepelin’s description of a catatonic patient who “smeared feces about” as a “classic, textbook case” of schizophrenia.¹¹ The casebook goes on to say: “In the absence of any known general medical condition, the combination of coprophilia, disorganized speech, and catatonic behavior clearly indicates the diagnosis of schizophrenia.”

Mr. C shows each of these. Staff changes his diagnosis again—to schizophrenia, disorganized type, which carries a poor prognosis.^11,12

Case: Banking and ray guns

By day 5, Mr. C’s mental status is normalizing and his psychosis improving. He volunteers for a weekly student case conference. There, he reveals additional information that staff could have discovered at admission with more-focused questions.

He reports that 2 years earlier he suffered severe suicidal depression. Six months later, during a hypomanic episode, he began “toying with the idea” that he might become part owner of his local bank. He believes “the Secret Service decided to transfer ownership to me.”

His plans upon acquiring the bank include buying three houses and six cars valued at several million dollars and running for state governor. For weeks before admission, he did not need sleep, experienced an increase in energy and activities, and his mind was racing. His job seemed so “trivial” that he quit. Immediately before his hospital admission, his delusions intensified to include an “evil conspiracy” to murder him for ownership of the bank and he feared his execution was imminent.

He explains his catatonic behavior on the lawn by his belief that “hit men” hiding across the street aimed a “motion-detecting, heat-seeking ray gun” at him so that if he had “moved an inch,” he would die. He says the “feces incident” was an effort to get himself transferred to the state hospital, where he thought he would be safer because his present caretakers were “infiltrated.” He also says his mother received electroconvulsive therapy in her 20s.

These symptoms—especially the striking grandiosity, lack of need for sleep, racing thoughts, hallucinations and delusions—define a manic episode with psychotic features. Only one manic episode as described here is diagnostic of bipolar disorder, type I.^2,6,13 Staff changes his diagnosis to schizoaffective disorder, a compromise used to include patients with bipolar and psychotic (schizophrenic) features. Some authors contend schizoaffective disorder is psychotic bipolar disorder and not a separate disease.^3,4,9

Case: From SSRI to lithium

After 2 weeks, Mr. C is discharged on haloperidol, 5 mg bid, but no mood stabilizer. He receives follow-up care at a community mental health center. When he develops severe depressive symptoms 6 months after discharge, the attending psychiatrist starts him on a selective serotonin reuptake inhibitor (SSRI). Within 2 weeks, Mr. C switches from depression to a mixed, dysphoric mania. After the SSRI is discontinued and lithium is added to his haloperidol, his mood gradually stabilizes to moderate depression. He develops rigidity, masked faces, and a fine tremor in his hands.

About 10% of bipolar depressed patients given an antidepressant—especially without a mood stabilizer—switch to mania, and their cycle frequency increases.^2,13-15 A correct initial diagnosis and treatment with a mood stabilizer might have avoided Mr. C’s switch.

Mixed bipolar disorder with overlapping depressive and manic symptoms is often resistant to monotherapy, requiring two or more mood stabilizers such as lithium and an anticonvulsant.¹⁴ Without a mood-stabilizing combination, the mixed, rapid-cycling type of bipolar disorder is likely to progress, with more-rapid and more-severe episodes.^2,13-15 Adding lamotrigine, a mood stabilizer with antidepressant effects, can help.^2,14

Stopping the SSRI is correct, despite Mr. C’s severe depression, to avoid increasing the cycle frequency.^13-15 Some authors recommend tapering the antipsychotic, using it only as needed for psychotic features after psychosis has resolved.^14-17 Continuing antipsychotic drugs after psychosis has remitted increases rates of cycling to depression, depressive and extrapyramidal symptoms, and medication discontinuation.¹⁷ Lithium may have aggravated Mr. C’s antipsychotic-induced parkinsonism, but discontinuing haloperidol may have been the most therapeutic decision.

The community mental health staff changes his diagnosis again, this time to bipolar disorder, type I, mixed, severe with psychotic features. We concur that this is correct.

Case: A diagnostic step back

Two years later, Mr. C is working and continues to take lithium and haloperidol prescribed at the mental health center. His intermittent depressive episodes persist, but—apparently because he has not had another manic episode—the staff switches his diagnosis back to schizoaffective disorder.

We disagree with this change. A diagnosis of schizoaffective disorder precludes ideal pharmacotherapy for Mr. C’s rapid-cycling bipolar disorder and increases the risk of adverse drug effects and stigma. Persuasive evidence shows that schizoaffective disorder is psychotic bipolar disorder; there is no schizoaffective disorder (Box).^3,4,16-18

 

Box

Misdiagnosis of psychosis

Bipolar disorder can be missed when patients present with psychotic symptoms, but clinicians could have initially recognized Mr. C’s bipolar disorder. His diagnostic trail illustrates important points about psychotic presentations:

• Predominant psychotic symptoms can obscure mood disturbances.
  
• Mistakenly believing that psychosis means schizophrenia can jeopardize patient care.
  
• When paranoia and fear hide grandiosity, then mania—not schizophrenia—is likely.
  
• Psychotic mood disorders—not schizophrenia—cause functional psychosis; there is no schizophrenia (Box).
  
• Pursuing mood symptoms in psychotic presentations is critical in an initial diagnostic interview.
  

Questioning the concept that hallucinations, delusions, catatonia, and disorganization are specific to and diagnostic of schizophrenia is not new. In 1978, Pope and Lipinski compared symptoms, course, outcome, family history, and responses to lithium in bipolar disorder and schizophrenia.³ They and others find no symptom, group of symptoms, or course that differentiates schizophrenia from psychotic bipolar disorder.^{3-5,8,9,16,18,19} They conclude that most cases diagnosed as schizophrenia or schizoaffective disorder are misdiagnosed cases of bipolar illness, whereas others question the validity of schizophrenia.²⁰

Bipolar disorder has a broad spectrum of severity and course; it frequently reaches psychotic levels that can become chronic.^2,5,21 Psychotic symptoms of rigorously diagnosed bipolar patients can deteriorate until their overwhelming psychosis obscures bipolar symptoms.^5,6,13,21 Like most, if not all, acutely psychotic bipolar patients, Mr. C shows all diagnostic criteria for schizophrenia.^1-6,21

Patients with severe, psychotic bipolar disorder can stop responding to medication and suffer chronic deterioration without remission.^5,21 They can lose their jobs, families, friends, and health until they are homeless, hungry, sick, and psychotic. A deteriorating course such as this has typically defined the schizophrenic process, but this concept has been reassessed.^1-6,13,15

Most, but not all, bipolar type I patients experience psychosis. Mr. C’s bipolar symptoms were not initially obvious because of predominant psychosis and were revealed only with specific, focused questions. Without the student case conference, his diagnosis might have remained schizophrenia. His treatment would have remained substandard because of the conventional belief that schizophrenia requires lifelong antipsychotics, usually without mood stabilizers.

Our patient satisfied all DSM-IV-TR criteria for both schizophrenia and psychotic bipolar. Bleuler and Schneider would have diagnosed him as having schizophrenia because they thought all psychotic disorders were schizophrenic.^10,12 They were incorrect, as psychotic symptoms are common in patients with severe bipolar disorder.^1-6,13,22

Cinical implications

Our observations about this case suggest four important clinical questions:

• Do data justify diagnosing patients such as Mr. C with bipolar disorder and not schizophrenia?
  
• Do data substantiate either diagnosis as valid?
  
• Does the diagnosis matter?
  
• What is standard-of-care treatment for these patients?
  

Which diagnosis? No psychiatric disorder can be validated as rigorously as Koch’s postulates did for infectious diseases. To be considered scientifically grounded, a psychiatric illness must show one or more symptoms not found in any other disorder. Bipolar disorder meets this criterion; schizophrenia does not because the psychotic symptoms and chronic course used to diagnose it are not disease-specific. Psychotic symptoms are not diagnostic of bipolar disorder but define its severity.⁶

Evidence for validity? Bipolar disorder’s two extremes in mood and behavior are so different from those in persons without bipolar disorder or with any other condition that homogeneous bipolar populations can be identified and studied with confidence.^2,5,13,21 DSM-IV-TR diagnostic symptoms for bipolar disorder are unique (Table 2).

For a psychiatric disorder to be considered valid, patients must share other characteristics. Bipolar disorder has been validated as a specific disease by consistent genetic,^1,13,23,24 pharmacologic,^2,14,15 and epidemiologic¹ data accumulated across 30 years. The concordance for bipolar disorder in monozygotic twins is approximately 75%, and susceptibility loci for bipolar disorder are established.^23,24

Table 2

Characteristics indicating a mood disorder, not schizophrenia*

History	Past diagnosis or symptoms of a mood disorder; family history of mood disorder or alcoholism
Past medications	Lithium, valproic acid, or other mood stabilizers
Periods of uncharacteristic and excessive goal-directed activities	Political, religious, legal, sexual, business, criminal, medical, physical, spending, calling, writing, preaching, cleaning, planning, exercise
Presence of uncharacteristic emotions or conflict	Irritability, anger, violence, conflict with law enforcement, elation, grandiosity (paranoia), sadness, hopelessness, crying, suicidal ideation
Periods of appropriate affect	Smiles, laughs, cries, irritable, angry
Mood-congruent delusions and/or hallucinations	Consider grandiosity when there is paranoia and fear
Episodes of relatively normal function/remission; premorbid personality positive	Friends, dating, team sports, group activities, election to an office/title, club or gang memberships
Current social interactions	Enjoys a friendship, active interactions with spouse and own children, regular interactions with others
*Absence of any or all does not rule out mood disorder.

 

Does the diagnosis matter? Failing to make an accurate initial diagnosis can worsen the course of patients who present with psychosis (Table 3):

• Bipolar illness not treated with mood stabilizers progresses, with episodes becoming more frequent and severe.^2,14,15
  
• Antipsychotics are given longer and in higher dosages for schizophrenia than for psychotic bipolar disorder and tend to have more common, chronic, and disabling adverse effects than do antidepressants and mood stabilizers.^14,16
  
• Mr. C was given an antidepressant without mood stabilization, which is contraindicated in bipolar I disorder (especially mixed type) because the cycling rate increases.^2,14,15
  

Paranoia and fear often hide grandiosity that is diagnostic of bipolar disorder, but patients such as Mr. C focus on perceived threats to their lives, not their grandiose delusions. Admitting physicians listening to their paranoid complaints may overlook the grandiose source and the possibility of psychotic bipolar disorder. Mr. C’s manic grandiosity explains the motivation for each of his psychotic behaviors: paranoid delusions, catatonia, and coprophilia.

Several initial signs could have raised suspicion that Mr. C had psychotic bipolar disorder (Table 4). Standard-of-care treatment in psychotic patients is predicated on early and correct diagnosis. On the basis of the evidence and our experience, we recommend that you look for bipolar symptoms when a patient:

• presents for the first time with psychosis, and you rule out an organic cause
  
• is readmitted for treatment of psychotic symptoms after having been diagnosed with schizophrenia.
  

Table 3

Consequences of misdiagnosing psychotic mood disorder as schizophrenia

For patient Less likely to receive a mood stabilizer or antidepressant Without a mood stabilizer, cycles increase and occur more rapidly; symptoms worsen More likely to receive neuroleptics for life, increasing risk for severe and permanent side effects Greater stigma with schizophrenia Less likely to be employed More likely to receive disability for life More likely to “give up”
For clinician Increased risk of liability if patient given long-term neuroleptics instead of mood stabilizers develops tardive dyskinesia or commits suicide

Table 4

Mr. C’s symptoms that indicated bipolar disorder

Religiosity	Loud preaching and no past special interest in religion
Catatonia	Most frequently associated with bipolar disorder
Paranoia; fear	Usually hides grandiosity, which is diagnostic of mania
Distractibility	Could not stay focused in the diagnostic interview; showed ‘flight of ideas’
Pressured speech	Rapid, disorganized thoughts
Disorganization	Hallmark of mania; present in all patients with severe mania
Functional psychosis	If an organic cause is ruled out, a psychotic mood disorder is the most likely diagnosis
Trouble with the law	Police found patient disturbing neighborhood and escorted him to hospital
Patient history	Severe depression
Family history	Mother was treated for depression with ECT
ECT: electroconvulsive therapy

What is standard of care? Patients with psychotic mania warrant polypharmacy:

• an antipsychotic, with or without a benzodiazepine for sedation, to enhance ward safety and treat acute psychotic symptoms
  
• and a first-line mood stabilizer such as valproate, carbamazepine, lithium, or lamotrigine, followed by atypical antipsychotics.
  

Antidepressants appear to be contraindicated, even in psychotic bipolar depressed patients.^14,15 We suggest that you taper and discontinue the initial antipsychotic when psychotic symptoms resolve. Some data indicate that continuing antipsychotics in psychotic bipolar patients is detrimental after the psychosis has resolved.¹⁷ Medication-resistant cases may require two or three mood stabilizers and possibly an atypical antipsychotic.

The idea that “symptoms should be treated, not the diagnosis” is inaccurate and provides substandard care. When psychotic symptoms overwhelm and obscure bipolar symptoms, giving only antipsychotics is beyond standard of care.

Related resources

• Berrettini WH. Molecular linkage studies of bipolar disorders. Bipolar Disord 2001;3:276-83.
  
• Lake CR, Hurwitz N. Schizoaffective disorders are psychotic mood disorders; there are no schizoaffective disorders. Psychiatry Res 2006 (in press).
  
• Pope HG, Lipinski JF. Diagnosis in schizophrenia and manic-depressive illness, a reassessment of the specificity of “schizophrenic” symptoms in the light of current research. Arch Gen Psychiatry 1978;35:811-28.
  
• Post RM. Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry 1992;149:999-1010.
  

Drug brand names

• Haloperidol • Haldol
  
• Lamotrigine • Lamictal
  
• Lithium • Lithobid
  
• Lorazepam • Ativan
  
• Carbamazepine • Tegretol
  
• Valproate • Depakote
  

Disclosures

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

Acknowledgements

The patient described in this case report gave informed, written consent to interviews and to the anonymous publication of his treatment.

The authors thank Anita Swisher for technical assistance.

When a patient presents with psychotic symptoms, you might not recognize or pursue hints of bipolarity if you assume psychosis means schizophrenia. Yet psychotic bipolar disorder can explain every sign, symptom, course, and other characteristic traditionally assumed to indicate schizophrenia (Table 1). The literature, including recent genetic data,^1-6 marshals a persuasive argument that patients diagnosed with schizophrenia usually suffer from a psychotic bipolar disorder.

Consider here how a cascade of changing signs and symptoms, initially unrecognized, caused five sequential re-evaluations of one psychotic patient’s primary Axis I diagnosis. His case highlights why the correct initial diagnosis of the disease causing psychosis is essential to effective treatment.^4,7-9

Table 1

DSM-IV-TR criteria for schizophrenia vs. psychotic mood disorder

Schizophrenia diagnosis6	Seen in psychotic mood disorders
Criterion A
Hallucinations and delusions	50% to 80% explained by mood16,21
Paranoia	Hides grandiosity4
Catatonia	75% explained by mood7,8
Disorganized speech and behavior	All patients with moderate to severe mania1-5
Negative symptoms	All patients with moderate to severe depression4
Criterion B
Social and job dysfunction	All patients with moderate to severe bipolar disorder5,13
Criterion C
Chronic continuous symptoms	Patients can have psychotic symptoms continuously for 2 years to life5,6,13

Case: Carved in stone

Police officers carry Mr. C, age 30, into the emergency department. He is mentally disorganized and arrives in a rigid, catatonic posture. According to a neighbor, Mr. C was kneeling motionless on his mother’s front lawn, alternating between mutism and inappropriately loud, disorganized religious preaching. When his arm is lifted, it remains as placed. He is admitted to the acute care inpatient unit.

Mr. C’s most striking symptoms are catatonia and psychosis. Postural rigidity, waxy flexibility, and automatic obedience are characteristics of catatonia.^6-8 An organic cause is first considered, such as hyperthyroidism, cerebrovascular accident, cerebral neoplasm, head trauma, seizure disorder, dementia, neuroleptic malignant syndrome, pheochromocytoma, or—especially—intoxication from illegal drugs.⁷

While awaiting results from physical, mental status, and lab exams and imaging studies, staff assign him two admitting diagnoses: catatonic disorder due to a general medical condition and psychotic disorder not otherwise specified.⁶

Case: Inconclusive workup

Mr. C denies using illegal substances or alcohol, which his mother confirms. He has no history of seizures or other medical conditions. His distractibility prevents him from focusing on a formal mental status exam. Physical exam, urine drug screen, lab results, and imaging studies are unremarkable except for an admitting blood pressure of 145/95 mm Hg and pulse of 115 beats per minute. These readings normalize within 1 hour. IM haloperidol and lorazepam are given as needed for agitation, but physicians withhold scheduled medications to allow staff to observe his symptoms.

Organic causes of catatonia now seem less likely, though past use of drugs such as phencyclidine that can cause chronic psychosis cannot be ruled out. Schizophrenia is considered likely because catatonia is one of schizophrenia’s five core diagnostic symptoms.⁶ Catatonia can also be a symptom of bipolar disorder.^6-9 Staff make a preliminary diagnosis of schizophrenia, catatonic type.

Case: ‘Hit men are after me’

Staff observe Mr. C responding to threatening auditory hallucinations. His affect is “fearful to terrified.” He says he hears the voice of God warning him of danger and continuing a running commentary on his actions. He fears for his life because “hit men have been sent to kill me” and have “infiltrated” the inpatient ward. He does not eat, saying his food is poisoned. He says these beliefs have escalated over the past year.

Mr. C’s catatonic symptoms resolve overnight, but obtaining additional history is difficult because of his paranoia. He denies any history of bizarre behavior or past contact with mental health services. He claims not to be especially religious. He is unmarried and lives with his mother, is college-educated, but has held only menial jobs.

Inpatient staff shifts its diagnostic focus to functional disorders associated with auditory hallucinations, paranoid delusions, and gross disorganization. According to Schneider and the DSM-IV-TR,^6,10 hearing a voice “keeping up a running commentary on one’s behavior” is especially diagnostic of schizophrenia.

Because of the rapid resolution of his “catatonic” symptoms and prominence of paranoia, they change his diagnosis on day 2 to schizophrenia, paranoid type. Mr. C meets all diagnostic criteria for schizophrenia except one: the staff has overlooked and has not adequately excluded a psychotic mood disorder.

Case: A turn for the worse

That night, nursing staff find Mr. C naked and cowering in the fetal position in a corner of his room. He has smeared his feces on his face and in his hair and mouth. While being cleaned up, he suddenly begins quoting scripture in a loud, disorganized voice. His expressed thoughts are incomprehensible. He is given haloperidol and lorazepam immediately; oral haloperidol is continued at 10 mg bid.

 

Both Bleuler and Kraepelin concluded “coprophilia and coprophagia are unique to children and patients with schizophrenia.”^11,12 The DSM casebook cites Kraepelin’s description of a catatonic patient who “smeared feces about” as a “classic, textbook case” of schizophrenia.¹¹ The casebook goes on to say: “In the absence of any known general medical condition, the combination of coprophilia, disorganized speech, and catatonic behavior clearly indicates the diagnosis of schizophrenia.”

Mr. C shows each of these. Staff changes his diagnosis again—to schizophrenia, disorganized type, which carries a poor prognosis.^11,12

Case: Banking and ray guns

By day 5, Mr. C’s mental status is normalizing and his psychosis improving. He volunteers for a weekly student case conference. There, he reveals additional information that staff could have discovered at admission with more-focused questions.

He reports that 2 years earlier he suffered severe suicidal depression. Six months later, during a hypomanic episode, he began “toying with the idea” that he might become part owner of his local bank. He believes “the Secret Service decided to transfer ownership to me.”

His plans upon acquiring the bank include buying three houses and six cars valued at several million dollars and running for state governor. For weeks before admission, he did not need sleep, experienced an increase in energy and activities, and his mind was racing. His job seemed so “trivial” that he quit. Immediately before his hospital admission, his delusions intensified to include an “evil conspiracy” to murder him for ownership of the bank and he feared his execution was imminent.

He explains his catatonic behavior on the lawn by his belief that “hit men” hiding across the street aimed a “motion-detecting, heat-seeking ray gun” at him so that if he had “moved an inch,” he would die. He says the “feces incident” was an effort to get himself transferred to the state hospital, where he thought he would be safer because his present caretakers were “infiltrated.” He also says his mother received electroconvulsive therapy in her 20s.

These symptoms—especially the striking grandiosity, lack of need for sleep, racing thoughts, hallucinations and delusions—define a manic episode with psychotic features. Only one manic episode as described here is diagnostic of bipolar disorder, type I.^2,6,13 Staff changes his diagnosis to schizoaffective disorder, a compromise used to include patients with bipolar and psychotic (schizophrenic) features. Some authors contend schizoaffective disorder is psychotic bipolar disorder and not a separate disease.^3,4,9

Case: From SSRI to lithium

After 2 weeks, Mr. C is discharged on haloperidol, 5 mg bid, but no mood stabilizer. He receives follow-up care at a community mental health center. When he develops severe depressive symptoms 6 months after discharge, the attending psychiatrist starts him on a selective serotonin reuptake inhibitor (SSRI). Within 2 weeks, Mr. C switches from depression to a mixed, dysphoric mania. After the SSRI is discontinued and lithium is added to his haloperidol, his mood gradually stabilizes to moderate depression. He develops rigidity, masked faces, and a fine tremor in his hands.

About 10% of bipolar depressed patients given an antidepressant—especially without a mood stabilizer—switch to mania, and their cycle frequency increases.^2,13-15 A correct initial diagnosis and treatment with a mood stabilizer might have avoided Mr. C’s switch.

Mixed bipolar disorder with overlapping depressive and manic symptoms is often resistant to monotherapy, requiring two or more mood stabilizers such as lithium and an anticonvulsant.¹⁴ Without a mood-stabilizing combination, the mixed, rapid-cycling type of bipolar disorder is likely to progress, with more-rapid and more-severe episodes.^2,13-15 Adding lamotrigine, a mood stabilizer with antidepressant effects, can help.^2,14

Stopping the SSRI is correct, despite Mr. C’s severe depression, to avoid increasing the cycle frequency.^13-15 Some authors recommend tapering the antipsychotic, using it only as needed for psychotic features after psychosis has resolved.^14-17 Continuing antipsychotic drugs after psychosis has remitted increases rates of cycling to depression, depressive and extrapyramidal symptoms, and medication discontinuation.¹⁷ Lithium may have aggravated Mr. C’s antipsychotic-induced parkinsonism, but discontinuing haloperidol may have been the most therapeutic decision.

The community mental health staff changes his diagnosis again, this time to bipolar disorder, type I, mixed, severe with psychotic features. We concur that this is correct.

Case: A diagnostic step back

Two years later, Mr. C is working and continues to take lithium and haloperidol prescribed at the mental health center. His intermittent depressive episodes persist, but—apparently because he has not had another manic episode—the staff switches his diagnosis back to schizoaffective disorder.

We disagree with this change. A diagnosis of schizoaffective disorder precludes ideal pharmacotherapy for Mr. C’s rapid-cycling bipolar disorder and increases the risk of adverse drug effects and stigma. Persuasive evidence shows that schizoaffective disorder is psychotic bipolar disorder; there is no schizoaffective disorder (Box).^3,4,16-18

 

Box

Misdiagnosis of psychosis

Bipolar disorder can be missed when patients present with psychotic symptoms, but clinicians could have initially recognized Mr. C’s bipolar disorder. His diagnostic trail illustrates important points about psychotic presentations:

• Predominant psychotic symptoms can obscure mood disturbances.
  
• Mistakenly believing that psychosis means schizophrenia can jeopardize patient care.
  
• When paranoia and fear hide grandiosity, then mania—not schizophrenia—is likely.
  
• Psychotic mood disorders—not schizophrenia—cause functional psychosis; there is no schizophrenia (Box).
  
• Pursuing mood symptoms in psychotic presentations is critical in an initial diagnostic interview.
  

Questioning the concept that hallucinations, delusions, catatonia, and disorganization are specific to and diagnostic of schizophrenia is not new. In 1978, Pope and Lipinski compared symptoms, course, outcome, family history, and responses to lithium in bipolar disorder and schizophrenia.³ They and others find no symptom, group of symptoms, or course that differentiates schizophrenia from psychotic bipolar disorder.^{3-5,8,9,16,18,19} They conclude that most cases diagnosed as schizophrenia or schizoaffective disorder are misdiagnosed cases of bipolar illness, whereas others question the validity of schizophrenia.²⁰

Bipolar disorder has a broad spectrum of severity and course; it frequently reaches psychotic levels that can become chronic.^2,5,21 Psychotic symptoms of rigorously diagnosed bipolar patients can deteriorate until their overwhelming psychosis obscures bipolar symptoms.^5,6,13,21 Like most, if not all, acutely psychotic bipolar patients, Mr. C shows all diagnostic criteria for schizophrenia.^1-6,21

Patients with severe, psychotic bipolar disorder can stop responding to medication and suffer chronic deterioration without remission.^5,21 They can lose their jobs, families, friends, and health until they are homeless, hungry, sick, and psychotic. A deteriorating course such as this has typically defined the schizophrenic process, but this concept has been reassessed.^1-6,13,15

Most, but not all, bipolar type I patients experience psychosis. Mr. C’s bipolar symptoms were not initially obvious because of predominant psychosis and were revealed only with specific, focused questions. Without the student case conference, his diagnosis might have remained schizophrenia. His treatment would have remained substandard because of the conventional belief that schizophrenia requires lifelong antipsychotics, usually without mood stabilizers.

Our patient satisfied all DSM-IV-TR criteria for both schizophrenia and psychotic bipolar. Bleuler and Schneider would have diagnosed him as having schizophrenia because they thought all psychotic disorders were schizophrenic.^10,12 They were incorrect, as psychotic symptoms are common in patients with severe bipolar disorder.^1-6,13,22

Cinical implications

Our observations about this case suggest four important clinical questions:

• Do data justify diagnosing patients such as Mr. C with bipolar disorder and not schizophrenia?
  
• Do data substantiate either diagnosis as valid?
  
• Does the diagnosis matter?
  
• What is standard-of-care treatment for these patients?
  

Which diagnosis? No psychiatric disorder can be validated as rigorously as Koch’s postulates did for infectious diseases. To be considered scientifically grounded, a psychiatric illness must show one or more symptoms not found in any other disorder. Bipolar disorder meets this criterion; schizophrenia does not because the psychotic symptoms and chronic course used to diagnose it are not disease-specific. Psychotic symptoms are not diagnostic of bipolar disorder but define its severity.⁶

Evidence for validity? Bipolar disorder’s two extremes in mood and behavior are so different from those in persons without bipolar disorder or with any other condition that homogeneous bipolar populations can be identified and studied with confidence.^2,5,13,21 DSM-IV-TR diagnostic symptoms for bipolar disorder are unique (Table 2).

For a psychiatric disorder to be considered valid, patients must share other characteristics. Bipolar disorder has been validated as a specific disease by consistent genetic,^1,13,23,24 pharmacologic,^2,14,15 and epidemiologic¹ data accumulated across 30 years. The concordance for bipolar disorder in monozygotic twins is approximately 75%, and susceptibility loci for bipolar disorder are established.^23,24

Table 2

Characteristics indicating a mood disorder, not schizophrenia*

History	Past diagnosis or symptoms of a mood disorder; family history of mood disorder or alcoholism
Past medications	Lithium, valproic acid, or other mood stabilizers
Periods of uncharacteristic and excessive goal-directed activities	Political, religious, legal, sexual, business, criminal, medical, physical, spending, calling, writing, preaching, cleaning, planning, exercise
Presence of uncharacteristic emotions or conflict	Irritability, anger, violence, conflict with law enforcement, elation, grandiosity (paranoia), sadness, hopelessness, crying, suicidal ideation
Periods of appropriate affect	Smiles, laughs, cries, irritable, angry
Mood-congruent delusions and/or hallucinations	Consider grandiosity when there is paranoia and fear
Episodes of relatively normal function/remission; premorbid personality positive	Friends, dating, team sports, group activities, election to an office/title, club or gang memberships
Current social interactions	Enjoys a friendship, active interactions with spouse and own children, regular interactions with others
*Absence of any or all does not rule out mood disorder.

 

Does the diagnosis matter? Failing to make an accurate initial diagnosis can worsen the course of patients who present with psychosis (Table 3):

• Bipolar illness not treated with mood stabilizers progresses, with episodes becoming more frequent and severe.^2,14,15
  
• Antipsychotics are given longer and in higher dosages for schizophrenia than for psychotic bipolar disorder and tend to have more common, chronic, and disabling adverse effects than do antidepressants and mood stabilizers.^14,16
  
• Mr. C was given an antidepressant without mood stabilization, which is contraindicated in bipolar I disorder (especially mixed type) because the cycling rate increases.^2,14,15
  

Paranoia and fear often hide grandiosity that is diagnostic of bipolar disorder, but patients such as Mr. C focus on perceived threats to their lives, not their grandiose delusions. Admitting physicians listening to their paranoid complaints may overlook the grandiose source and the possibility of psychotic bipolar disorder. Mr. C’s manic grandiosity explains the motivation for each of his psychotic behaviors: paranoid delusions, catatonia, and coprophilia.

Several initial signs could have raised suspicion that Mr. C had psychotic bipolar disorder (Table 4). Standard-of-care treatment in psychotic patients is predicated on early and correct diagnosis. On the basis of the evidence and our experience, we recommend that you look for bipolar symptoms when a patient:

• presents for the first time with psychosis, and you rule out an organic cause
  
• is readmitted for treatment of psychotic symptoms after having been diagnosed with schizophrenia.
  

Table 3

Consequences of misdiagnosing psychotic mood disorder as schizophrenia

For patient Less likely to receive a mood stabilizer or antidepressant Without a mood stabilizer, cycles increase and occur more rapidly; symptoms worsen More likely to receive neuroleptics for life, increasing risk for severe and permanent side effects Greater stigma with schizophrenia Less likely to be employed More likely to receive disability for life More likely to “give up”
For clinician Increased risk of liability if patient given long-term neuroleptics instead of mood stabilizers develops tardive dyskinesia or commits suicide

Table 4

Mr. C’s symptoms that indicated bipolar disorder

Religiosity	Loud preaching and no past special interest in religion
Catatonia	Most frequently associated with bipolar disorder
Paranoia; fear	Usually hides grandiosity, which is diagnostic of mania
Distractibility	Could not stay focused in the diagnostic interview; showed ‘flight of ideas’
Pressured speech	Rapid, disorganized thoughts
Disorganization	Hallmark of mania; present in all patients with severe mania
Functional psychosis	If an organic cause is ruled out, a psychotic mood disorder is the most likely diagnosis
Trouble with the law	Police found patient disturbing neighborhood and escorted him to hospital
Patient history	Severe depression
Family history	Mother was treated for depression with ECT
ECT: electroconvulsive therapy

What is standard of care? Patients with psychotic mania warrant polypharmacy:

• an antipsychotic, with or without a benzodiazepine for sedation, to enhance ward safety and treat acute psychotic symptoms
  
• and a first-line mood stabilizer such as valproate, carbamazepine, lithium, or lamotrigine, followed by atypical antipsychotics.
  

Antidepressants appear to be contraindicated, even in psychotic bipolar depressed patients.^14,15 We suggest that you taper and discontinue the initial antipsychotic when psychotic symptoms resolve. Some data indicate that continuing antipsychotics in psychotic bipolar patients is detrimental after the psychosis has resolved.¹⁷ Medication-resistant cases may require two or three mood stabilizers and possibly an atypical antipsychotic.

The idea that “symptoms should be treated, not the diagnosis” is inaccurate and provides substandard care. When psychotic symptoms overwhelm and obscure bipolar symptoms, giving only antipsychotics is beyond standard of care.

Related resources

• Berrettini WH. Molecular linkage studies of bipolar disorders. Bipolar Disord 2001;3:276-83.
  
• Lake CR, Hurwitz N. Schizoaffective disorders are psychotic mood disorders; there are no schizoaffective disorders. Psychiatry Res 2006 (in press).
  
• Pope HG, Lipinski JF. Diagnosis in schizophrenia and manic-depressive illness, a reassessment of the specificity of “schizophrenic” symptoms in the light of current research. Arch Gen Psychiatry 1978;35:811-28.
  
• Post RM. Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry 1992;149:999-1010.
  

Drug brand names

• Haloperidol • Haldol
  
• Lamotrigine • Lamictal
  
• Lithium • Lithobid
  
• Lorazepam • Ativan
  
• Carbamazepine • Tegretol
  
• Valproate • Depakote
  

Disclosures

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

Acknowledgements

The patient described in this case report gave informed, written consent to interviews and to the anonymous publication of his treatment.

The authors thank Anita Swisher for technical assistance.

When a patient presents with psychotic symptoms, you might not recognize or pursue hints of bipolarity if you assume psychosis means schizophrenia. Yet psychotic bipolar disorder can explain every sign, symptom, course, and other characteristic traditionally assumed to indicate schizophrenia (Table 1). The literature, including recent genetic data,^1-6 marshals a persuasive argument that patients diagnosed with schizophrenia usually suffer from a psychotic bipolar disorder.

Consider here how a cascade of changing signs and symptoms, initially unrecognized, caused five sequential re-evaluations of one psychotic patient’s primary Axis I diagnosis. His case highlights why the correct initial diagnosis of the disease causing psychosis is essential to effective treatment.^4,7-9

Table 1

DSM-IV-TR criteria for schizophrenia vs. psychotic mood disorder

Schizophrenia diagnosis6	Seen in psychotic mood disorders
Criterion A
Hallucinations and delusions	50% to 80% explained by mood16,21
Paranoia	Hides grandiosity4
Catatonia	75% explained by mood7,8
Disorganized speech and behavior	All patients with moderate to severe mania1-5
Negative symptoms	All patients with moderate to severe depression4
Criterion B
Social and job dysfunction	All patients with moderate to severe bipolar disorder5,13
Criterion C
Chronic continuous symptoms	Patients can have psychotic symptoms continuously for 2 years to life5,6,13

Case: Carved in stone

Police officers carry Mr. C, age 30, into the emergency department. He is mentally disorganized and arrives in a rigid, catatonic posture. According to a neighbor, Mr. C was kneeling motionless on his mother’s front lawn, alternating between mutism and inappropriately loud, disorganized religious preaching. When his arm is lifted, it remains as placed. He is admitted to the acute care inpatient unit.

Mr. C’s most striking symptoms are catatonia and psychosis. Postural rigidity, waxy flexibility, and automatic obedience are characteristics of catatonia.^6-8 An organic cause is first considered, such as hyperthyroidism, cerebrovascular accident, cerebral neoplasm, head trauma, seizure disorder, dementia, neuroleptic malignant syndrome, pheochromocytoma, or—especially—intoxication from illegal drugs.⁷

While awaiting results from physical, mental status, and lab exams and imaging studies, staff assign him two admitting diagnoses: catatonic disorder due to a general medical condition and psychotic disorder not otherwise specified.⁶

Case: Inconclusive workup

Mr. C denies using illegal substances or alcohol, which his mother confirms. He has no history of seizures or other medical conditions. His distractibility prevents him from focusing on a formal mental status exam. Physical exam, urine drug screen, lab results, and imaging studies are unremarkable except for an admitting blood pressure of 145/95 mm Hg and pulse of 115 beats per minute. These readings normalize within 1 hour. IM haloperidol and lorazepam are given as needed for agitation, but physicians withhold scheduled medications to allow staff to observe his symptoms.

Organic causes of catatonia now seem less likely, though past use of drugs such as phencyclidine that can cause chronic psychosis cannot be ruled out. Schizophrenia is considered likely because catatonia is one of schizophrenia’s five core diagnostic symptoms.⁶ Catatonia can also be a symptom of bipolar disorder.^6-9 Staff make a preliminary diagnosis of schizophrenia, catatonic type.

Case: ‘Hit men are after me’

Staff observe Mr. C responding to threatening auditory hallucinations. His affect is “fearful to terrified.” He says he hears the voice of God warning him of danger and continuing a running commentary on his actions. He fears for his life because “hit men have been sent to kill me” and have “infiltrated” the inpatient ward. He does not eat, saying his food is poisoned. He says these beliefs have escalated over the past year.

Mr. C’s catatonic symptoms resolve overnight, but obtaining additional history is difficult because of his paranoia. He denies any history of bizarre behavior or past contact with mental health services. He claims not to be especially religious. He is unmarried and lives with his mother, is college-educated, but has held only menial jobs.

Inpatient staff shifts its diagnostic focus to functional disorders associated with auditory hallucinations, paranoid delusions, and gross disorganization. According to Schneider and the DSM-IV-TR,^6,10 hearing a voice “keeping up a running commentary on one’s behavior” is especially diagnostic of schizophrenia.

Because of the rapid resolution of his “catatonic” symptoms and prominence of paranoia, they change his diagnosis on day 2 to schizophrenia, paranoid type. Mr. C meets all diagnostic criteria for schizophrenia except one: the staff has overlooked and has not adequately excluded a psychotic mood disorder.

Case: A turn for the worse

That night, nursing staff find Mr. C naked and cowering in the fetal position in a corner of his room. He has smeared his feces on his face and in his hair and mouth. While being cleaned up, he suddenly begins quoting scripture in a loud, disorganized voice. His expressed thoughts are incomprehensible. He is given haloperidol and lorazepam immediately; oral haloperidol is continued at 10 mg bid.

 

Both Bleuler and Kraepelin concluded “coprophilia and coprophagia are unique to children and patients with schizophrenia.”^11,12 The DSM casebook cites Kraepelin’s description of a catatonic patient who “smeared feces about” as a “classic, textbook case” of schizophrenia.¹¹ The casebook goes on to say: “In the absence of any known general medical condition, the combination of coprophilia, disorganized speech, and catatonic behavior clearly indicates the diagnosis of schizophrenia.”

Mr. C shows each of these. Staff changes his diagnosis again—to schizophrenia, disorganized type, which carries a poor prognosis.^11,12

Case: Banking and ray guns

By day 5, Mr. C’s mental status is normalizing and his psychosis improving. He volunteers for a weekly student case conference. There, he reveals additional information that staff could have discovered at admission with more-focused questions.

He reports that 2 years earlier he suffered severe suicidal depression. Six months later, during a hypomanic episode, he began “toying with the idea” that he might become part owner of his local bank. He believes “the Secret Service decided to transfer ownership to me.”

His plans upon acquiring the bank include buying three houses and six cars valued at several million dollars and running for state governor. For weeks before admission, he did not need sleep, experienced an increase in energy and activities, and his mind was racing. His job seemed so “trivial” that he quit. Immediately before his hospital admission, his delusions intensified to include an “evil conspiracy” to murder him for ownership of the bank and he feared his execution was imminent.

He explains his catatonic behavior on the lawn by his belief that “hit men” hiding across the street aimed a “motion-detecting, heat-seeking ray gun” at him so that if he had “moved an inch,” he would die. He says the “feces incident” was an effort to get himself transferred to the state hospital, where he thought he would be safer because his present caretakers were “infiltrated.” He also says his mother received electroconvulsive therapy in her 20s.

These symptoms—especially the striking grandiosity, lack of need for sleep, racing thoughts, hallucinations and delusions—define a manic episode with psychotic features. Only one manic episode as described here is diagnostic of bipolar disorder, type I.^2,6,13 Staff changes his diagnosis to schizoaffective disorder, a compromise used to include patients with bipolar and psychotic (schizophrenic) features. Some authors contend schizoaffective disorder is psychotic bipolar disorder and not a separate disease.^3,4,9

Case: From SSRI to lithium

After 2 weeks, Mr. C is discharged on haloperidol, 5 mg bid, but no mood stabilizer. He receives follow-up care at a community mental health center. When he develops severe depressive symptoms 6 months after discharge, the attending psychiatrist starts him on a selective serotonin reuptake inhibitor (SSRI). Within 2 weeks, Mr. C switches from depression to a mixed, dysphoric mania. After the SSRI is discontinued and lithium is added to his haloperidol, his mood gradually stabilizes to moderate depression. He develops rigidity, masked faces, and a fine tremor in his hands.

About 10% of bipolar depressed patients given an antidepressant—especially without a mood stabilizer—switch to mania, and their cycle frequency increases.^2,13-15 A correct initial diagnosis and treatment with a mood stabilizer might have avoided Mr. C’s switch.

Mixed bipolar disorder with overlapping depressive and manic symptoms is often resistant to monotherapy, requiring two or more mood stabilizers such as lithium and an anticonvulsant.¹⁴ Without a mood-stabilizing combination, the mixed, rapid-cycling type of bipolar disorder is likely to progress, with more-rapid and more-severe episodes.^2,13-15 Adding lamotrigine, a mood stabilizer with antidepressant effects, can help.^2,14

Stopping the SSRI is correct, despite Mr. C’s severe depression, to avoid increasing the cycle frequency.^13-15 Some authors recommend tapering the antipsychotic, using it only as needed for psychotic features after psychosis has resolved.^14-17 Continuing antipsychotic drugs after psychosis has remitted increases rates of cycling to depression, depressive and extrapyramidal symptoms, and medication discontinuation.¹⁷ Lithium may have aggravated Mr. C’s antipsychotic-induced parkinsonism, but discontinuing haloperidol may have been the most therapeutic decision.

The community mental health staff changes his diagnosis again, this time to bipolar disorder, type I, mixed, severe with psychotic features. We concur that this is correct.

Case: A diagnostic step back

Two years later, Mr. C is working and continues to take lithium and haloperidol prescribed at the mental health center. His intermittent depressive episodes persist, but—apparently because he has not had another manic episode—the staff switches his diagnosis back to schizoaffective disorder.

We disagree with this change. A diagnosis of schizoaffective disorder precludes ideal pharmacotherapy for Mr. C’s rapid-cycling bipolar disorder and increases the risk of adverse drug effects and stigma. Persuasive evidence shows that schizoaffective disorder is psychotic bipolar disorder; there is no schizoaffective disorder (Box).^3,4,16-18

 

Box

Misdiagnosis of psychosis

Bipolar disorder can be missed when patients present with psychotic symptoms, but clinicians could have initially recognized Mr. C’s bipolar disorder. His diagnostic trail illustrates important points about psychotic presentations:

• Predominant psychotic symptoms can obscure mood disturbances.
  
• Mistakenly believing that psychosis means schizophrenia can jeopardize patient care.
  
• When paranoia and fear hide grandiosity, then mania—not schizophrenia—is likely.
  
• Psychotic mood disorders—not schizophrenia—cause functional psychosis; there is no schizophrenia (Box).
  
• Pursuing mood symptoms in psychotic presentations is critical in an initial diagnostic interview.
  

Questioning the concept that hallucinations, delusions, catatonia, and disorganization are specific to and diagnostic of schizophrenia is not new. In 1978, Pope and Lipinski compared symptoms, course, outcome, family history, and responses to lithium in bipolar disorder and schizophrenia.³ They and others find no symptom, group of symptoms, or course that differentiates schizophrenia from psychotic bipolar disorder.^{3-5,8,9,16,18,19} They conclude that most cases diagnosed as schizophrenia or schizoaffective disorder are misdiagnosed cases of bipolar illness, whereas others question the validity of schizophrenia.²⁰

Bipolar disorder has a broad spectrum of severity and course; it frequently reaches psychotic levels that can become chronic.^2,5,21 Psychotic symptoms of rigorously diagnosed bipolar patients can deteriorate until their overwhelming psychosis obscures bipolar symptoms.^5,6,13,21 Like most, if not all, acutely psychotic bipolar patients, Mr. C shows all diagnostic criteria for schizophrenia.^1-6,21

Patients with severe, psychotic bipolar disorder can stop responding to medication and suffer chronic deterioration without remission.^5,21 They can lose their jobs, families, friends, and health until they are homeless, hungry, sick, and psychotic. A deteriorating course such as this has typically defined the schizophrenic process, but this concept has been reassessed.^1-6,13,15

Most, but not all, bipolar type I patients experience psychosis. Mr. C’s bipolar symptoms were not initially obvious because of predominant psychosis and were revealed only with specific, focused questions. Without the student case conference, his diagnosis might have remained schizophrenia. His treatment would have remained substandard because of the conventional belief that schizophrenia requires lifelong antipsychotics, usually without mood stabilizers.

Our patient satisfied all DSM-IV-TR criteria for both schizophrenia and psychotic bipolar. Bleuler and Schneider would have diagnosed him as having schizophrenia because they thought all psychotic disorders were schizophrenic.^10,12 They were incorrect, as psychotic symptoms are common in patients with severe bipolar disorder.^1-6,13,22

Cinical implications

Our observations about this case suggest four important clinical questions:

• Do data justify diagnosing patients such as Mr. C with bipolar disorder and not schizophrenia?
  
• Do data substantiate either diagnosis as valid?
  
• Does the diagnosis matter?
  
• What is standard-of-care treatment for these patients?
  

Which diagnosis? No psychiatric disorder can be validated as rigorously as Koch’s postulates did for infectious diseases. To be considered scientifically grounded, a psychiatric illness must show one or more symptoms not found in any other disorder. Bipolar disorder meets this criterion; schizophrenia does not because the psychotic symptoms and chronic course used to diagnose it are not disease-specific. Psychotic symptoms are not diagnostic of bipolar disorder but define its severity.⁶

Evidence for validity? Bipolar disorder’s two extremes in mood and behavior are so different from those in persons without bipolar disorder or with any other condition that homogeneous bipolar populations can be identified and studied with confidence.^2,5,13,21 DSM-IV-TR diagnostic symptoms for bipolar disorder are unique (Table 2).

For a psychiatric disorder to be considered valid, patients must share other characteristics. Bipolar disorder has been validated as a specific disease by consistent genetic,^1,13,23,24 pharmacologic,^2,14,15 and epidemiologic¹ data accumulated across 30 years. The concordance for bipolar disorder in monozygotic twins is approximately 75%, and susceptibility loci for bipolar disorder are established.^23,24

Table 2

Characteristics indicating a mood disorder, not schizophrenia*

History	Past diagnosis or symptoms of a mood disorder; family history of mood disorder or alcoholism
Past medications	Lithium, valproic acid, or other mood stabilizers
Periods of uncharacteristic and excessive goal-directed activities	Political, religious, legal, sexual, business, criminal, medical, physical, spending, calling, writing, preaching, cleaning, planning, exercise
Presence of uncharacteristic emotions or conflict	Irritability, anger, violence, conflict with law enforcement, elation, grandiosity (paranoia), sadness, hopelessness, crying, suicidal ideation
Periods of appropriate affect	Smiles, laughs, cries, irritable, angry
Mood-congruent delusions and/or hallucinations	Consider grandiosity when there is paranoia and fear
Episodes of relatively normal function/remission; premorbid personality positive	Friends, dating, team sports, group activities, election to an office/title, club or gang memberships
Current social interactions	Enjoys a friendship, active interactions with spouse and own children, regular interactions with others
*Absence of any or all does not rule out mood disorder.

 

Does the diagnosis matter? Failing to make an accurate initial diagnosis can worsen the course of patients who present with psychosis (Table 3):

• Bipolar illness not treated with mood stabilizers progresses, with episodes becoming more frequent and severe.^2,14,15
  
• Antipsychotics are given longer and in higher dosages for schizophrenia than for psychotic bipolar disorder and tend to have more common, chronic, and disabling adverse effects than do antidepressants and mood stabilizers.^14,16
  
• Mr. C was given an antidepressant without mood stabilization, which is contraindicated in bipolar I disorder (especially mixed type) because the cycling rate increases.^2,14,15
  

Paranoia and fear often hide grandiosity that is diagnostic of bipolar disorder, but patients such as Mr. C focus on perceived threats to their lives, not their grandiose delusions. Admitting physicians listening to their paranoid complaints may overlook the grandiose source and the possibility of psychotic bipolar disorder. Mr. C’s manic grandiosity explains the motivation for each of his psychotic behaviors: paranoid delusions, catatonia, and coprophilia.

Several initial signs could have raised suspicion that Mr. C had psychotic bipolar disorder (Table 4). Standard-of-care treatment in psychotic patients is predicated on early and correct diagnosis. On the basis of the evidence and our experience, we recommend that you look for bipolar symptoms when a patient:

• presents for the first time with psychosis, and you rule out an organic cause
  
• is readmitted for treatment of psychotic symptoms after having been diagnosed with schizophrenia.
  

Table 3

Consequences of misdiagnosing psychotic mood disorder as schizophrenia

For patient Less likely to receive a mood stabilizer or antidepressant Without a mood stabilizer, cycles increase and occur more rapidly; symptoms worsen More likely to receive neuroleptics for life, increasing risk for severe and permanent side effects Greater stigma with schizophrenia Less likely to be employed More likely to receive disability for life More likely to “give up”
For clinician Increased risk of liability if patient given long-term neuroleptics instead of mood stabilizers develops tardive dyskinesia or commits suicide

Table 4

Mr. C’s symptoms that indicated bipolar disorder

Religiosity	Loud preaching and no past special interest in religion
Catatonia	Most frequently associated with bipolar disorder
Paranoia; fear	Usually hides grandiosity, which is diagnostic of mania
Distractibility	Could not stay focused in the diagnostic interview; showed ‘flight of ideas’
Pressured speech	Rapid, disorganized thoughts
Disorganization	Hallmark of mania; present in all patients with severe mania
Functional psychosis	If an organic cause is ruled out, a psychotic mood disorder is the most likely diagnosis
Trouble with the law	Police found patient disturbing neighborhood and escorted him to hospital
Patient history	Severe depression
Family history	Mother was treated for depression with ECT
ECT: electroconvulsive therapy

What is standard of care? Patients with psychotic mania warrant polypharmacy:

• an antipsychotic, with or without a benzodiazepine for sedation, to enhance ward safety and treat acute psychotic symptoms
  
• and a first-line mood stabilizer such as valproate, carbamazepine, lithium, or lamotrigine, followed by atypical antipsychotics.
  

Antidepressants appear to be contraindicated, even in psychotic bipolar depressed patients.^14,15 We suggest that you taper and discontinue the initial antipsychotic when psychotic symptoms resolve. Some data indicate that continuing antipsychotics in psychotic bipolar patients is detrimental after the psychosis has resolved.¹⁷ Medication-resistant cases may require two or three mood stabilizers and possibly an atypical antipsychotic.

The idea that “symptoms should be treated, not the diagnosis” is inaccurate and provides substandard care. When psychotic symptoms overwhelm and obscure bipolar symptoms, giving only antipsychotics is beyond standard of care.

Related resources

• Berrettini WH. Molecular linkage studies of bipolar disorders. Bipolar Disord 2001;3:276-83.
  
• Lake CR, Hurwitz N. Schizoaffective disorders are psychotic mood disorders; there are no schizoaffective disorders. Psychiatry Res 2006 (in press).
  
• Pope HG, Lipinski JF. Diagnosis in schizophrenia and manic-depressive illness, a reassessment of the specificity of “schizophrenic” symptoms in the light of current research. Arch Gen Psychiatry 1978;35:811-28.
  
• Post RM. Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry 1992;149:999-1010.
  

Drug brand names

• Haloperidol • Haldol
  
• Lamotrigine • Lamictal
  
• Lithium • Lithobid
  
• Lorazepam • Ativan
  
• Carbamazepine • Tegretol
  
• Valproate • Depakote
  

Disclosures

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

Acknowledgements

The patient described in this case report gave informed, written consent to interviews and to the anonymous publication of his treatment.

The authors thank Anita Swisher for technical assistance.