Cases That Test Your Skills

CASE: Sad and suicidal

Mr. G, age 44, has chronic depression with suicidality. At presentation he says he has felt sad and suicidal for 2 weeks. He also has no appetite and trouble sleeping at night.

Mr. G’s depression has left him unable to work and has led to 4 hospitalizations over 10 years. He first attempted suicide in 1984 after his ex-wife took their child and left him. He endorses no suicide plan and has been sober for 7 years after 12-plus years of alcohol abuse, but says he has been tempted lately to resume drinking.

The patient was taking an antidepressant but stopped while at a homeless shelter, where he had been staying for several weeks. For more than 20 years, he also has been taking phenytoin, 300 mg/d, and phenobarbital, 30 mg bid, for a seizure disorder.

Mr. G is admitted with a working diagnosis of recurrent major depressive disorder. White blood cell count (WBC) at admission is 5.12×10⁹/L and neutrophils are 3.6×10⁹/L—both low-normal readings. Other laboratory results are normal.

We continue phenytoin and phenobarbital at the same dosages and start the selective serotonin reuptake inhibitor (SSRI) citalopram, 20 mg/d, which interacts minimally with both anticonvulsants.

After 2 weeks, Mr. G’s seizures are well controlled and he is tolerating citalopram, but his depressive symptoms have not improved. We cross-taper citalopram to prevent SSRI-induced discontinuation syndrome and start the dopamine and norepinephrine reuptake inhibitor bupropion, 75 mg bid. We titrate bupropion over 2 weeks to 150 mg each morning and 300 mg at bedtime, and watch Mr. G closely for seizures. Although his seizure history contraindicates bupropion use, we think he can tolerate the medication because his seizure disorder is well controlled.

Mr. G’s affect, appetite, and energy are improving with bupropion, but a routine complete blood count (CBC) 5 days after the medication is started reveals leukopenia (WBC 3.04×10⁹/L) without neutropenia (neutrophils 1.9×10⁹/L). Repeat blood tests 18 and 32 days after the first blood draw show continued low WBC. The gastrointestinal medicine team tests Mr. G’s liver function but finds no abnormalities.

The author’s observations

Mr. G’s low WBC and neutrophil counts coincided with bupropion use, suggesting medication-induced leukopenia. Phenytoin can cause neutropenia and other adverse hematologic effects,¹ but the patient had been using phenytoin and phenobarbital for years with no adverse reactions.

A medical cause also is unlikely. Mr. G’s liver function is normal, and he shows no other signs or symptoms of a medical problem. Bone marrow biopsy and immunologic workup could rule out cancer, but the timing of Mr. G’s abnormal blood readings strongly suggests bupropion intolerance.

TREATMENT: Other medications

We immediately stop bupropion, start the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine at 37.5 mg bid, and titrate it over 5 days to 225 mg/d. Blood draws 3 and 5 days after bupropion discontinuation show slight increases in WBC.

Eleven days after venlafaxine is started, Mr. G’s WBC and neutrophils are normal. However, he has become increasingly irritable and volatile, often arguing with a staff nurse and other patients. We cross-taper venlafaxine over 5 days, start the SSRI sertraline at 50 mg/d, and titrate sertraline over 1 week to 150 mg/d. Mr. G’s irritability and depressive symptoms improve at the latter dosage.

Because Mr. G developed neutropenia while taking a medication not associated with this adverse effect, we start watching his WBC counts more closely than usual. WBC is 4.58×10⁹/L 8 days after sertraline is started but falls to 3.4×10⁹/L after another 8 days, with neutrophils at 1.5×10⁹/L for both readings (Table).

We add lithium, 300 mg bid, to increase Mr. G’s neutrophils and augment sertraline’s antidepressant effects. Four days later, WBC is 5.8×10⁹/L with neutrophils at 4.2×10⁹/L.

We stop lithium briefly to see if WBC remains normal. After 3 days, WBC drops to 3.25×10⁹/L with neutrophils at 1.5×10⁹/L. We restart lithium, 300 mg/d, and Mr. G’s WBC increases to 4.18×109/L 4 days later, with neutrophils at 2.1×10⁹/L.

Table

Mr G’s white blood cell (WBC) and neutrophil counts (NC)*
while taking bupropion and sertraline

Antidepressant	When measurements were taken	WBC	NC
None for several weeks	Baseline, first hospital admission	5.12×109/L	3.6×109/L
Bupropion, 75 mg bid	5 days after starting bupropion	3.04×109/L	1.9×109/L
Bupropion, 450 mg/d total	23 days after starting bupropion	3.14×109/L	1.6×109/L
Bupropion, 450 mg/d total	2 weeks after previous test	2.73×109/L	1.6×109/L
Sertraline, 150 mg/d	8 days after starting sertraline (titration period)	4.58×109/L	1.5×109/L
Sertraline, 150 mg/d	16 days after starting sertraline	3.4×109/L	1.5×109/L
Sertraline, 150 mg/d, and lithium, 300 mg bid	4 days after lithium augmentation	5.8×109/L	4.2×109/L
None for 3 months	Baseline, second hospital admission	3.7×109/L	2.1×109/L
Sertraline, 150 mg/d	12 days after restarting sertraline	2.83×109/L	Not available
* Normal WBC values: 4.5 to 11×109/L; normal neutrophil values: 1.5 to 8×109/L

 

The authors’ observations

For Mr. G, both bupropion and sertraline appear to have caused neutropenia on separate occasions.

To our knowledge, bupropion-induced leukopenia or neutropenia have not been reported in the literature. Neutropenia—a rare adverse effect of antidepressants²—and leukopenia were seen during bupropion’s pre-marketing trials but were not definitely attributed to the drug.¹ According to pre- and post-marketing data, leukopenia was “infrequently” reported among 5,100 subjects who received bupropion.³

To our knowledge, sertraline-induced neutropenia has not been reported in nongeriatric patients, although sertraline-induced neutropenia⁴ and agranulocytosis⁵ have been reported in patients age >65. The Committee on Safety of Medicine in the United Kingdom has received 2 other reports of neutropenia and 1 report of leukopenia with sertraline.⁵

In one clinical trial, 2 of 1,304 patients taking unknown dosages of sertraline had low neutrophils (

Medication is the second most common cause of acquired neutropenia, with infection being most common.⁶ By definition, drug-induced neutropenia occurs within 4 weeks after starting the drug and usually resolves within 30 days after stopping it.

Neutropenia is an idiosyncratic reaction unrelated to pharmacologic action. Although overall neutropenia incidence is unknown, reported incidence of the rare, more severe agranulocytosis ranges from approximately 1 to 10 cases per million people annually, and medications have been implicated in 70% of these cases.⁶ Conversely, only 2 of 97 incidental neutropenia cases studied by Lima et al⁷ were medication-induced.

Drug-induced neutropenia can result from immune-mediated destruction of neutrophils by circulating antibodies or from direct toxic effects upon marrow granulocyte precursors. Whereas immune-mediated onset is acute and explosive, toxic effect is insidious (months to years) and asymptomatic.⁸ Clozapine is thought to deliver a direct toxic effect, whereas the thyroid-regulating drug propylthiouracil generates anti-neutrophil antibodies.⁹

Mr. G’s acute onset (within 5 to 16 days of starting bupropion or sertraline) and prompt return of neutropenia after stopping lithium suggest acute immune-mediated circulating neutrophil destruction.

Treating leukopenia

After 4 failed or intolerable antidepressant trials, lithium augmentation seemed reasonable and ultimately improved Mr. G’s neutrophil count and his mood.

Lithium has helped resolve clozapine-induced neutropenia in case reports.^10-12 Well-controlled studies, however, have followed only patients with antineoplastic, drug-induced neutropenia.¹

By acting on cyclic nucleotides, lithium prompts colony-stimulating factor production, which in turn stimulates neutrophil production by pluripotent stem cells. As with Mr. G, patients reach neutrophilia 3 to 7 days after starting lithium.

If the patient cannot tolerate lithium, try switching antidepressants or using growth factors to increase neutrophils.

Switching antidepressants.The SSRIs escitalopram or paroxetine, or the SNRI duloxetine are effective and do not necessarily cause neutropenia. Start at below-normal dosages to gauge tolerability, then titrate to normal dosages. Avoid tricyclics, which pose a higher risk of neutropenia than other antidepressant classes.

Case reports^13,14 associate fluoxetine and mirtazapine with neutropenia. The patient who received mirtazapine, 30 mg/d, later responded well to sertraline, 50 mg/d.¹³

If the new antidepressant is ineffective, consider adding the mood-stabilizing anticonvulsant lamotrigine, 12.5 mg/d. Increase lamotrigine to 25 mg/d after 1 week, then titrate by 25 mg weekly to 100 to 400 mg/d depending on efficacy and tolerability.

Although lamotrigine has been associated with neutropenia in case reports,¹ it is safer than other anticonvulsants. Carbamazepine, oxcarbazepine, and valproic acid can cause blood dyscrasias, which can lead to serious infection, abnormal bleeding, or other complications.

Using growth factors.Although their efficacy is not proven, growth factors are minimally toxic and might have helped Mr. G. Granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor resolved neutropenia in uncontrolled studies, but results of one randomized controlled trial were equivocal.⁸

TESTING: CT findings

Approximately 2 months after admission—shortly after a blood draw shows normal WBC and neutrophils—Mr. G complains of dizziness. He says he accidentally hit his head against a side table.

We order a full neurologic workup to check for traumatic brain injury or brain damage caused by long-term alcohol abuse:

• Head CT shows evidence of previous cerebrovascular infarcts in the bilateral frontal and cerebellar lobes and basal ganglia.
  
• MRI shows atrophied mammillary bodies, fornix, and corpus callosum.
  
• Magnetic resonance angiography reveals small cerebral vessel disease.
  

These findings and subsequent neuropsychiatric test results suggest an organic cause of depression, likely secondary to 12 years of alcohol abuse. In light of this new information, we change Mr. G’s diagnosis to mood disorder with depressive features secondary to a general medical condition.

FOLLOW-UP: Awaiting discharge

After 3 months of continuous hospitalization, Mr. G has become euthymic and nonsuicidal, though at times oversensitive and combative. We transfer him to an assisted-living center and continue sertraline, 150 mg/d; phenytoin, 300 mg/d; phenobarbital, 30 mg bid; lithium, 300 mg/d; and trazodone, 50 mg at night as needed for insomnia.

 

We also place Mr. G in a day treatment program for mentally ill chemical abusers. A psychiatrist sees him every 2 weeks, and staff supervise him daily.

The authors’ observations

Mr. G’s extended hospital stay allowed us to closely observe him and offered ready access to laboratory facilities while we cross-tapered medications. In outpatient treatment, however, a serious and life-threatening medication-induced complication could easily be missed.

If economically feasible, take CBCs for all patients before prescribing any medication that could cause neutropenia, such as an antidepressant or mood stabilizer. Make sure geriatric or medically ill patients have had a CBC ≤3 months before presentation and are seeing a primary care physician as needed. Order follow-up CBC for these patients 1 month after presentation, then every 6 months if CBC is normal.

For medically healthy outpatients, be sure CBC has been checked ≤6 months before presentation. Monitor CBC and urge the patient to see a primary care doctor if infection symptoms emerge. Watch for gingivitis, tooth abscess, and other oral cavity infections—which often are overlooked—and sore throat or fever.

Also check electrolytes and screen for SSRI-induced hyponatremia at baseline for all at-risk patients.

Stop the offending drug when WBC reaches 9/L or with absolute neutrophil count (ANC) 9/L, then take a peripheral smear to confirm neutropenia. If the patient is asymptomatic, check ANC 2 to 3 times weekly, particularly if he or she recently had an infection or started a medication that can cause neutropenia. Neutropenia should resolve within 6 to 8 weeks of stopping the offending drug.

If neutropenia persists, order bone marrow biopsy in collaboration with an internist or hematologist to test for cancer. If the biopsy is negative, test for:

• HIV infection
  
• antinuclear antibodies to check for collagen vascular disease
  
• antineutrophil antibody to rule out immune neutropenia
  
• serum folate and B₁₂ deficiency secondary to low WBC.
  

Also perform an immunoglobulins/immune evaluation to check for defects in cellular or humoral immunity, and bone marrow culture to test for infection.⁸

FOLLOW-UP: Stressor and relapse

Seven months later, Mr. G is readmitted for depression. Three months earlier, he had stopped all medications and resumed drinking after a family member died. WBC at admission is 3.70×10⁹/L

We restart sertraline, 150 mg/d. WBC falls to 2.83×10⁹/L 12 days later, so we add lithium, 300 mg/d. Two days later, WBC returns to normal and he is discharged. His depression has been stable throughout this second admission, and he is euthymic at discharge.

We refer Mr. G to an outpatient psychiatrist, who sees him monthly. Several months later, the psychiatrist reports a WBC of 4.58×10⁹/L.

Nearly 1 year later, Mr. G still lives at the assisted-living facility. He has not been rehospitalized for depression, is functioning well, and has a girlfriend.

The authors’ observations

Mr. G’s abnormal blood counts after sertraline rechallenge confirms that the SSRI probably was causing leukopenia. If we had restarted bupropion and neutropenia recurred during that regimen, we could have more certainly established a bupropion-leukopenia connection.

Related resources

• Neutropenia Support Association. www.neutropenia.ca.
  
• Baehner RL. Overview of neutropenia.UpToDate Online (version 15.1); March 30, 2006. www.uptodate.com.
  

Drug brand names

• Bupropion • Wellbutrin
  
• Carbamazepine • Tegretol, others
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Lamotrigine • Lamictal
  
• Lithium • various
  
• Mirtazapine • Remeron
  
• Oxcarbazepine • Trileptal
  
• Paroxetine • Paxil
  
• Phenobarbital • various
  
• Phenytoin • Dilantin
  
• Propylthiouracil • various
  
• Sertraline • Zoloft
  
• Trazodone • Desyrel
  
• Valproic acid • Depakene
  
• Venlafaxine • Effexor
  

Disclosure

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

CASE: Sad and suicidal

Mr. G, age 44, has chronic depression with suicidality. At presentation he says he has felt sad and suicidal for 2 weeks. He also has no appetite and trouble sleeping at night.

Mr. G’s depression has left him unable to work and has led to 4 hospitalizations over 10 years. He first attempted suicide in 1984 after his ex-wife took their child and left him. He endorses no suicide plan and has been sober for 7 years after 12-plus years of alcohol abuse, but says he has been tempted lately to resume drinking.

The patient was taking an antidepressant but stopped while at a homeless shelter, where he had been staying for several weeks. For more than 20 years, he also has been taking phenytoin, 300 mg/d, and phenobarbital, 30 mg bid, for a seizure disorder.

Mr. G is admitted with a working diagnosis of recurrent major depressive disorder. White blood cell count (WBC) at admission is 5.12×10⁹/L and neutrophils are 3.6×10⁹/L—both low-normal readings. Other laboratory results are normal.

We continue phenytoin and phenobarbital at the same dosages and start the selective serotonin reuptake inhibitor (SSRI) citalopram, 20 mg/d, which interacts minimally with both anticonvulsants.

After 2 weeks, Mr. G’s seizures are well controlled and he is tolerating citalopram, but his depressive symptoms have not improved. We cross-taper citalopram to prevent SSRI-induced discontinuation syndrome and start the dopamine and norepinephrine reuptake inhibitor bupropion, 75 mg bid. We titrate bupropion over 2 weeks to 150 mg each morning and 300 mg at bedtime, and watch Mr. G closely for seizures. Although his seizure history contraindicates bupropion use, we think he can tolerate the medication because his seizure disorder is well controlled.

Mr. G’s affect, appetite, and energy are improving with bupropion, but a routine complete blood count (CBC) 5 days after the medication is started reveals leukopenia (WBC 3.04×10⁹/L) without neutropenia (neutrophils 1.9×10⁹/L). Repeat blood tests 18 and 32 days after the first blood draw show continued low WBC. The gastrointestinal medicine team tests Mr. G’s liver function but finds no abnormalities.

The author’s observations

Mr. G’s low WBC and neutrophil counts coincided with bupropion use, suggesting medication-induced leukopenia. Phenytoin can cause neutropenia and other adverse hematologic effects,¹ but the patient had been using phenytoin and phenobarbital for years with no adverse reactions.

A medical cause also is unlikely. Mr. G’s liver function is normal, and he shows no other signs or symptoms of a medical problem. Bone marrow biopsy and immunologic workup could rule out cancer, but the timing of Mr. G’s abnormal blood readings strongly suggests bupropion intolerance.

TREATMENT: Other medications

We immediately stop bupropion, start the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine at 37.5 mg bid, and titrate it over 5 days to 225 mg/d. Blood draws 3 and 5 days after bupropion discontinuation show slight increases in WBC.

Eleven days after venlafaxine is started, Mr. G’s WBC and neutrophils are normal. However, he has become increasingly irritable and volatile, often arguing with a staff nurse and other patients. We cross-taper venlafaxine over 5 days, start the SSRI sertraline at 50 mg/d, and titrate sertraline over 1 week to 150 mg/d. Mr. G’s irritability and depressive symptoms improve at the latter dosage.

Because Mr. G developed neutropenia while taking a medication not associated with this adverse effect, we start watching his WBC counts more closely than usual. WBC is 4.58×10⁹/L 8 days after sertraline is started but falls to 3.4×10⁹/L after another 8 days, with neutrophils at 1.5×10⁹/L for both readings (Table).

We add lithium, 300 mg bid, to increase Mr. G’s neutrophils and augment sertraline’s antidepressant effects. Four days later, WBC is 5.8×10⁹/L with neutrophils at 4.2×10⁹/L.

We stop lithium briefly to see if WBC remains normal. After 3 days, WBC drops to 3.25×10⁹/L with neutrophils at 1.5×10⁹/L. We restart lithium, 300 mg/d, and Mr. G’s WBC increases to 4.18×109/L 4 days later, with neutrophils at 2.1×10⁹/L.

Table

Mr G’s white blood cell (WBC) and neutrophil counts (NC)*
while taking bupropion and sertraline

Antidepressant	When measurements were taken	WBC	NC
None for several weeks	Baseline, first hospital admission	5.12×109/L	3.6×109/L
Bupropion, 75 mg bid	5 days after starting bupropion	3.04×109/L	1.9×109/L
Bupropion, 450 mg/d total	23 days after starting bupropion	3.14×109/L	1.6×109/L
Bupropion, 450 mg/d total	2 weeks after previous test	2.73×109/L	1.6×109/L
Sertraline, 150 mg/d	8 days after starting sertraline (titration period)	4.58×109/L	1.5×109/L
Sertraline, 150 mg/d	16 days after starting sertraline	3.4×109/L	1.5×109/L
Sertraline, 150 mg/d, and lithium, 300 mg bid	4 days after lithium augmentation	5.8×109/L	4.2×109/L
None for 3 months	Baseline, second hospital admission	3.7×109/L	2.1×109/L
Sertraline, 150 mg/d	12 days after restarting sertraline	2.83×109/L	Not available
* Normal WBC values: 4.5 to 11×109/L; normal neutrophil values: 1.5 to 8×109/L

 

The authors’ observations

For Mr. G, both bupropion and sertraline appear to have caused neutropenia on separate occasions.

To our knowledge, bupropion-induced leukopenia or neutropenia have not been reported in the literature. Neutropenia—a rare adverse effect of antidepressants²—and leukopenia were seen during bupropion’s pre-marketing trials but were not definitely attributed to the drug.¹ According to pre- and post-marketing data, leukopenia was “infrequently” reported among 5,100 subjects who received bupropion.³

To our knowledge, sertraline-induced neutropenia has not been reported in nongeriatric patients, although sertraline-induced neutropenia⁴ and agranulocytosis⁵ have been reported in patients age >65. The Committee on Safety of Medicine in the United Kingdom has received 2 other reports of neutropenia and 1 report of leukopenia with sertraline.⁵

In one clinical trial, 2 of 1,304 patients taking unknown dosages of sertraline had low neutrophils (

Medication is the second most common cause of acquired neutropenia, with infection being most common.⁶ By definition, drug-induced neutropenia occurs within 4 weeks after starting the drug and usually resolves within 30 days after stopping it.

Neutropenia is an idiosyncratic reaction unrelated to pharmacologic action. Although overall neutropenia incidence is unknown, reported incidence of the rare, more severe agranulocytosis ranges from approximately 1 to 10 cases per million people annually, and medications have been implicated in 70% of these cases.⁶ Conversely, only 2 of 97 incidental neutropenia cases studied by Lima et al⁷ were medication-induced.

Drug-induced neutropenia can result from immune-mediated destruction of neutrophils by circulating antibodies or from direct toxic effects upon marrow granulocyte precursors. Whereas immune-mediated onset is acute and explosive, toxic effect is insidious (months to years) and asymptomatic.⁸ Clozapine is thought to deliver a direct toxic effect, whereas the thyroid-regulating drug propylthiouracil generates anti-neutrophil antibodies.⁹

Mr. G’s acute onset (within 5 to 16 days of starting bupropion or sertraline) and prompt return of neutropenia after stopping lithium suggest acute immune-mediated circulating neutrophil destruction.

Treating leukopenia

After 4 failed or intolerable antidepressant trials, lithium augmentation seemed reasonable and ultimately improved Mr. G’s neutrophil count and his mood.

Lithium has helped resolve clozapine-induced neutropenia in case reports.^10-12 Well-controlled studies, however, have followed only patients with antineoplastic, drug-induced neutropenia.¹

By acting on cyclic nucleotides, lithium prompts colony-stimulating factor production, which in turn stimulates neutrophil production by pluripotent stem cells. As with Mr. G, patients reach neutrophilia 3 to 7 days after starting lithium.

If the patient cannot tolerate lithium, try switching antidepressants or using growth factors to increase neutrophils.

Switching antidepressants.The SSRIs escitalopram or paroxetine, or the SNRI duloxetine are effective and do not necessarily cause neutropenia. Start at below-normal dosages to gauge tolerability, then titrate to normal dosages. Avoid tricyclics, which pose a higher risk of neutropenia than other antidepressant classes.

Case reports^13,14 associate fluoxetine and mirtazapine with neutropenia. The patient who received mirtazapine, 30 mg/d, later responded well to sertraline, 50 mg/d.¹³

If the new antidepressant is ineffective, consider adding the mood-stabilizing anticonvulsant lamotrigine, 12.5 mg/d. Increase lamotrigine to 25 mg/d after 1 week, then titrate by 25 mg weekly to 100 to 400 mg/d depending on efficacy and tolerability.

Although lamotrigine has been associated with neutropenia in case reports,¹ it is safer than other anticonvulsants. Carbamazepine, oxcarbazepine, and valproic acid can cause blood dyscrasias, which can lead to serious infection, abnormal bleeding, or other complications.

Using growth factors.Although their efficacy is not proven, growth factors are minimally toxic and might have helped Mr. G. Granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor resolved neutropenia in uncontrolled studies, but results of one randomized controlled trial were equivocal.⁸

TESTING: CT findings

Approximately 2 months after admission—shortly after a blood draw shows normal WBC and neutrophils—Mr. G complains of dizziness. He says he accidentally hit his head against a side table.

We order a full neurologic workup to check for traumatic brain injury or brain damage caused by long-term alcohol abuse:

• Head CT shows evidence of previous cerebrovascular infarcts in the bilateral frontal and cerebellar lobes and basal ganglia.
  
• MRI shows atrophied mammillary bodies, fornix, and corpus callosum.
  
• Magnetic resonance angiography reveals small cerebral vessel disease.
  

These findings and subsequent neuropsychiatric test results suggest an organic cause of depression, likely secondary to 12 years of alcohol abuse. In light of this new information, we change Mr. G’s diagnosis to mood disorder with depressive features secondary to a general medical condition.

FOLLOW-UP: Awaiting discharge

After 3 months of continuous hospitalization, Mr. G has become euthymic and nonsuicidal, though at times oversensitive and combative. We transfer him to an assisted-living center and continue sertraline, 150 mg/d; phenytoin, 300 mg/d; phenobarbital, 30 mg bid; lithium, 300 mg/d; and trazodone, 50 mg at night as needed for insomnia.

 

We also place Mr. G in a day treatment program for mentally ill chemical abusers. A psychiatrist sees him every 2 weeks, and staff supervise him daily.

The authors’ observations

Mr. G’s extended hospital stay allowed us to closely observe him and offered ready access to laboratory facilities while we cross-tapered medications. In outpatient treatment, however, a serious and life-threatening medication-induced complication could easily be missed.

If economically feasible, take CBCs for all patients before prescribing any medication that could cause neutropenia, such as an antidepressant or mood stabilizer. Make sure geriatric or medically ill patients have had a CBC ≤3 months before presentation and are seeing a primary care physician as needed. Order follow-up CBC for these patients 1 month after presentation, then every 6 months if CBC is normal.

For medically healthy outpatients, be sure CBC has been checked ≤6 months before presentation. Monitor CBC and urge the patient to see a primary care doctor if infection symptoms emerge. Watch for gingivitis, tooth abscess, and other oral cavity infections—which often are overlooked—and sore throat or fever.

Also check electrolytes and screen for SSRI-induced hyponatremia at baseline for all at-risk patients.

Stop the offending drug when WBC reaches 9/L or with absolute neutrophil count (ANC) 9/L, then take a peripheral smear to confirm neutropenia. If the patient is asymptomatic, check ANC 2 to 3 times weekly, particularly if he or she recently had an infection or started a medication that can cause neutropenia. Neutropenia should resolve within 6 to 8 weeks of stopping the offending drug.

If neutropenia persists, order bone marrow biopsy in collaboration with an internist or hematologist to test for cancer. If the biopsy is negative, test for:

• HIV infection
  
• antinuclear antibodies to check for collagen vascular disease
  
• antineutrophil antibody to rule out immune neutropenia
  
• serum folate and B₁₂ deficiency secondary to low WBC.
  

Also perform an immunoglobulins/immune evaluation to check for defects in cellular or humoral immunity, and bone marrow culture to test for infection.⁸

FOLLOW-UP: Stressor and relapse

Seven months later, Mr. G is readmitted for depression. Three months earlier, he had stopped all medications and resumed drinking after a family member died. WBC at admission is 3.70×10⁹/L

We restart sertraline, 150 mg/d. WBC falls to 2.83×10⁹/L 12 days later, so we add lithium, 300 mg/d. Two days later, WBC returns to normal and he is discharged. His depression has been stable throughout this second admission, and he is euthymic at discharge.

We refer Mr. G to an outpatient psychiatrist, who sees him monthly. Several months later, the psychiatrist reports a WBC of 4.58×10⁹/L.

Nearly 1 year later, Mr. G still lives at the assisted-living facility. He has not been rehospitalized for depression, is functioning well, and has a girlfriend.

The authors’ observations

Mr. G’s abnormal blood counts after sertraline rechallenge confirms that the SSRI probably was causing leukopenia. If we had restarted bupropion and neutropenia recurred during that regimen, we could have more certainly established a bupropion-leukopenia connection.

Related resources

• Neutropenia Support Association. www.neutropenia.ca.
  
• Baehner RL. Overview of neutropenia.UpToDate Online (version 15.1); March 30, 2006. www.uptodate.com.
  

Drug brand names

• Bupropion • Wellbutrin
  
• Carbamazepine • Tegretol, others
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Lamotrigine • Lamictal
  
• Lithium • various
  
• Mirtazapine • Remeron
  
• Oxcarbazepine • Trileptal
  
• Paroxetine • Paxil
  
• Phenobarbital • various
  
• Phenytoin • Dilantin
  
• Propylthiouracil • various
  
• Sertraline • Zoloft
  
• Trazodone • Desyrel
  
• Valproic acid • Depakene
  
• Venlafaxine • Effexor
  

Disclosure

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

CASE: Sad and suicidal

Mr. G, age 44, has chronic depression with suicidality. At presentation he says he has felt sad and suicidal for 2 weeks. He also has no appetite and trouble sleeping at night.

Mr. G’s depression has left him unable to work and has led to 4 hospitalizations over 10 years. He first attempted suicide in 1984 after his ex-wife took their child and left him. He endorses no suicide plan and has been sober for 7 years after 12-plus years of alcohol abuse, but says he has been tempted lately to resume drinking.

The patient was taking an antidepressant but stopped while at a homeless shelter, where he had been staying for several weeks. For more than 20 years, he also has been taking phenytoin, 300 mg/d, and phenobarbital, 30 mg bid, for a seizure disorder.

Mr. G is admitted with a working diagnosis of recurrent major depressive disorder. White blood cell count (WBC) at admission is 5.12×10⁹/L and neutrophils are 3.6×10⁹/L—both low-normal readings. Other laboratory results are normal.

We continue phenytoin and phenobarbital at the same dosages and start the selective serotonin reuptake inhibitor (SSRI) citalopram, 20 mg/d, which interacts minimally with both anticonvulsants.

After 2 weeks, Mr. G’s seizures are well controlled and he is tolerating citalopram, but his depressive symptoms have not improved. We cross-taper citalopram to prevent SSRI-induced discontinuation syndrome and start the dopamine and norepinephrine reuptake inhibitor bupropion, 75 mg bid. We titrate bupropion over 2 weeks to 150 mg each morning and 300 mg at bedtime, and watch Mr. G closely for seizures. Although his seizure history contraindicates bupropion use, we think he can tolerate the medication because his seizure disorder is well controlled.

Mr. G’s affect, appetite, and energy are improving with bupropion, but a routine complete blood count (CBC) 5 days after the medication is started reveals leukopenia (WBC 3.04×10⁹/L) without neutropenia (neutrophils 1.9×10⁹/L). Repeat blood tests 18 and 32 days after the first blood draw show continued low WBC. The gastrointestinal medicine team tests Mr. G’s liver function but finds no abnormalities.

The author’s observations

Mr. G’s low WBC and neutrophil counts coincided with bupropion use, suggesting medication-induced leukopenia. Phenytoin can cause neutropenia and other adverse hematologic effects,¹ but the patient had been using phenytoin and phenobarbital for years with no adverse reactions.

A medical cause also is unlikely. Mr. G’s liver function is normal, and he shows no other signs or symptoms of a medical problem. Bone marrow biopsy and immunologic workup could rule out cancer, but the timing of Mr. G’s abnormal blood readings strongly suggests bupropion intolerance.

TREATMENT: Other medications

We immediately stop bupropion, start the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine at 37.5 mg bid, and titrate it over 5 days to 225 mg/d. Blood draws 3 and 5 days after bupropion discontinuation show slight increases in WBC.

Eleven days after venlafaxine is started, Mr. G’s WBC and neutrophils are normal. However, he has become increasingly irritable and volatile, often arguing with a staff nurse and other patients. We cross-taper venlafaxine over 5 days, start the SSRI sertraline at 50 mg/d, and titrate sertraline over 1 week to 150 mg/d. Mr. G’s irritability and depressive symptoms improve at the latter dosage.

Because Mr. G developed neutropenia while taking a medication not associated with this adverse effect, we start watching his WBC counts more closely than usual. WBC is 4.58×10⁹/L 8 days after sertraline is started but falls to 3.4×10⁹/L after another 8 days, with neutrophils at 1.5×10⁹/L for both readings (Table).

We add lithium, 300 mg bid, to increase Mr. G’s neutrophils and augment sertraline’s antidepressant effects. Four days later, WBC is 5.8×10⁹/L with neutrophils at 4.2×10⁹/L.

We stop lithium briefly to see if WBC remains normal. After 3 days, WBC drops to 3.25×10⁹/L with neutrophils at 1.5×10⁹/L. We restart lithium, 300 mg/d, and Mr. G’s WBC increases to 4.18×109/L 4 days later, with neutrophils at 2.1×10⁹/L.

Table

Mr G’s white blood cell (WBC) and neutrophil counts (NC)*
while taking bupropion and sertraline

Antidepressant	When measurements were taken	WBC	NC
None for several weeks	Baseline, first hospital admission	5.12×109/L	3.6×109/L
Bupropion, 75 mg bid	5 days after starting bupropion	3.04×109/L	1.9×109/L
Bupropion, 450 mg/d total	23 days after starting bupropion	3.14×109/L	1.6×109/L
Bupropion, 450 mg/d total	2 weeks after previous test	2.73×109/L	1.6×109/L
Sertraline, 150 mg/d	8 days after starting sertraline (titration period)	4.58×109/L	1.5×109/L
Sertraline, 150 mg/d	16 days after starting sertraline	3.4×109/L	1.5×109/L
Sertraline, 150 mg/d, and lithium, 300 mg bid	4 days after lithium augmentation	5.8×109/L	4.2×109/L
None for 3 months	Baseline, second hospital admission	3.7×109/L	2.1×109/L
Sertraline, 150 mg/d	12 days after restarting sertraline	2.83×109/L	Not available
* Normal WBC values: 4.5 to 11×109/L; normal neutrophil values: 1.5 to 8×109/L

 

The authors’ observations

For Mr. G, both bupropion and sertraline appear to have caused neutropenia on separate occasions.

To our knowledge, bupropion-induced leukopenia or neutropenia have not been reported in the literature. Neutropenia—a rare adverse effect of antidepressants²—and leukopenia were seen during bupropion’s pre-marketing trials but were not definitely attributed to the drug.¹ According to pre- and post-marketing data, leukopenia was “infrequently” reported among 5,100 subjects who received bupropion.³

To our knowledge, sertraline-induced neutropenia has not been reported in nongeriatric patients, although sertraline-induced neutropenia⁴ and agranulocytosis⁵ have been reported in patients age >65. The Committee on Safety of Medicine in the United Kingdom has received 2 other reports of neutropenia and 1 report of leukopenia with sertraline.⁵

In one clinical trial, 2 of 1,304 patients taking unknown dosages of sertraline had low neutrophils (

Medication is the second most common cause of acquired neutropenia, with infection being most common.⁶ By definition, drug-induced neutropenia occurs within 4 weeks after starting the drug and usually resolves within 30 days after stopping it.

Neutropenia is an idiosyncratic reaction unrelated to pharmacologic action. Although overall neutropenia incidence is unknown, reported incidence of the rare, more severe agranulocytosis ranges from approximately 1 to 10 cases per million people annually, and medications have been implicated in 70% of these cases.⁶ Conversely, only 2 of 97 incidental neutropenia cases studied by Lima et al⁷ were medication-induced.

Drug-induced neutropenia can result from immune-mediated destruction of neutrophils by circulating antibodies or from direct toxic effects upon marrow granulocyte precursors. Whereas immune-mediated onset is acute and explosive, toxic effect is insidious (months to years) and asymptomatic.⁸ Clozapine is thought to deliver a direct toxic effect, whereas the thyroid-regulating drug propylthiouracil generates anti-neutrophil antibodies.⁹

Mr. G’s acute onset (within 5 to 16 days of starting bupropion or sertraline) and prompt return of neutropenia after stopping lithium suggest acute immune-mediated circulating neutrophil destruction.

Treating leukopenia

After 4 failed or intolerable antidepressant trials, lithium augmentation seemed reasonable and ultimately improved Mr. G’s neutrophil count and his mood.

Lithium has helped resolve clozapine-induced neutropenia in case reports.^10-12 Well-controlled studies, however, have followed only patients with antineoplastic, drug-induced neutropenia.¹

By acting on cyclic nucleotides, lithium prompts colony-stimulating factor production, which in turn stimulates neutrophil production by pluripotent stem cells. As with Mr. G, patients reach neutrophilia 3 to 7 days after starting lithium.

If the patient cannot tolerate lithium, try switching antidepressants or using growth factors to increase neutrophils.

Switching antidepressants.The SSRIs escitalopram or paroxetine, or the SNRI duloxetine are effective and do not necessarily cause neutropenia. Start at below-normal dosages to gauge tolerability, then titrate to normal dosages. Avoid tricyclics, which pose a higher risk of neutropenia than other antidepressant classes.

Case reports^13,14 associate fluoxetine and mirtazapine with neutropenia. The patient who received mirtazapine, 30 mg/d, later responded well to sertraline, 50 mg/d.¹³

If the new antidepressant is ineffective, consider adding the mood-stabilizing anticonvulsant lamotrigine, 12.5 mg/d. Increase lamotrigine to 25 mg/d after 1 week, then titrate by 25 mg weekly to 100 to 400 mg/d depending on efficacy and tolerability.

Although lamotrigine has been associated with neutropenia in case reports,¹ it is safer than other anticonvulsants. Carbamazepine, oxcarbazepine, and valproic acid can cause blood dyscrasias, which can lead to serious infection, abnormal bleeding, or other complications.

Using growth factors.Although their efficacy is not proven, growth factors are minimally toxic and might have helped Mr. G. Granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor resolved neutropenia in uncontrolled studies, but results of one randomized controlled trial were equivocal.⁸

TESTING: CT findings

Approximately 2 months after admission—shortly after a blood draw shows normal WBC and neutrophils—Mr. G complains of dizziness. He says he accidentally hit his head against a side table.

We order a full neurologic workup to check for traumatic brain injury or brain damage caused by long-term alcohol abuse:

• Head CT shows evidence of previous cerebrovascular infarcts in the bilateral frontal and cerebellar lobes and basal ganglia.
  
• MRI shows atrophied mammillary bodies, fornix, and corpus callosum.
  
• Magnetic resonance angiography reveals small cerebral vessel disease.
  

These findings and subsequent neuropsychiatric test results suggest an organic cause of depression, likely secondary to 12 years of alcohol abuse. In light of this new information, we change Mr. G’s diagnosis to mood disorder with depressive features secondary to a general medical condition.

FOLLOW-UP: Awaiting discharge

After 3 months of continuous hospitalization, Mr. G has become euthymic and nonsuicidal, though at times oversensitive and combative. We transfer him to an assisted-living center and continue sertraline, 150 mg/d; phenytoin, 300 mg/d; phenobarbital, 30 mg bid; lithium, 300 mg/d; and trazodone, 50 mg at night as needed for insomnia.

 

We also place Mr. G in a day treatment program for mentally ill chemical abusers. A psychiatrist sees him every 2 weeks, and staff supervise him daily.

The authors’ observations

Mr. G’s extended hospital stay allowed us to closely observe him and offered ready access to laboratory facilities while we cross-tapered medications. In outpatient treatment, however, a serious and life-threatening medication-induced complication could easily be missed.

If economically feasible, take CBCs for all patients before prescribing any medication that could cause neutropenia, such as an antidepressant or mood stabilizer. Make sure geriatric or medically ill patients have had a CBC ≤3 months before presentation and are seeing a primary care physician as needed. Order follow-up CBC for these patients 1 month after presentation, then every 6 months if CBC is normal.

For medically healthy outpatients, be sure CBC has been checked ≤6 months before presentation. Monitor CBC and urge the patient to see a primary care doctor if infection symptoms emerge. Watch for gingivitis, tooth abscess, and other oral cavity infections—which often are overlooked—and sore throat or fever.

Also check electrolytes and screen for SSRI-induced hyponatremia at baseline for all at-risk patients.

Stop the offending drug when WBC reaches 9/L or with absolute neutrophil count (ANC) 9/L, then take a peripheral smear to confirm neutropenia. If the patient is asymptomatic, check ANC 2 to 3 times weekly, particularly if he or she recently had an infection or started a medication that can cause neutropenia. Neutropenia should resolve within 6 to 8 weeks of stopping the offending drug.

If neutropenia persists, order bone marrow biopsy in collaboration with an internist or hematologist to test for cancer. If the biopsy is negative, test for:

• HIV infection
  
• antinuclear antibodies to check for collagen vascular disease
  
• antineutrophil antibody to rule out immune neutropenia
  
• serum folate and B₁₂ deficiency secondary to low WBC.
  

Also perform an immunoglobulins/immune evaluation to check for defects in cellular or humoral immunity, and bone marrow culture to test for infection.⁸

FOLLOW-UP: Stressor and relapse

Seven months later, Mr. G is readmitted for depression. Three months earlier, he had stopped all medications and resumed drinking after a family member died. WBC at admission is 3.70×10⁹/L

We restart sertraline, 150 mg/d. WBC falls to 2.83×10⁹/L 12 days later, so we add lithium, 300 mg/d. Two days later, WBC returns to normal and he is discharged. His depression has been stable throughout this second admission, and he is euthymic at discharge.

We refer Mr. G to an outpatient psychiatrist, who sees him monthly. Several months later, the psychiatrist reports a WBC of 4.58×10⁹/L.

Nearly 1 year later, Mr. G still lives at the assisted-living facility. He has not been rehospitalized for depression, is functioning well, and has a girlfriend.

The authors’ observations

Mr. G’s abnormal blood counts after sertraline rechallenge confirms that the SSRI probably was causing leukopenia. If we had restarted bupropion and neutropenia recurred during that regimen, we could have more certainly established a bupropion-leukopenia connection.

Related resources

• Neutropenia Support Association. www.neutropenia.ca.
  
• Baehner RL. Overview of neutropenia.UpToDate Online (version 15.1); March 30, 2006. www.uptodate.com.
  

Drug brand names

• Bupropion • Wellbutrin
  
• Carbamazepine • Tegretol, others
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Lamotrigine • Lamictal
  
• Lithium • various
  
• Mirtazapine • Remeron
  
• Oxcarbazepine • Trileptal
  
• Paroxetine • Paxil
  
• Phenobarbital • various
  
• Phenytoin • Dilantin
  
• Propylthiouracil • various
  
• Sertraline • Zoloft
  
• Trazodone • Desyrel
  
• Valproic acid • Depakene
  
• Venlafaxine • Effexor
  

Disclosure

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

History: ‘They want to kill me’

Police and security agents arrest Ms. A, age 64, at a metropolitan airport. She is extremely agitated and behaving bizarrely, yelling that “the Mafia” is trying to kill her. She has spent 3 days hiding in area hotels, fleeing her “assailants.”

Police arrange Ms. A’s return home; under court order, she is hospitalized in a psychiatric facility. She is diagnosed with paranoid schizophrenia and receives IM haloperidol, 2 mg bid, but shows minimal improvement after 2½ weeks. Her psychotic symptoms improve slightly after the psychiatrist switches her to risperidone, 2 mg bid, but she still cannot function normally. Three weeks after admission, she is transferred to a nursing home for long-term care. She continues risperidone but remains paranoid and delusional.

Three months later, Ms. A is rehospitalized. She is anxious, delusional, confused, and hallucinating at admission. The patient is verbally and physically combative, fearful that medical staff will harm her. She is too violent to be examined, but staff notice that her skin appears thickened, her eyes puffy, and her hair coarse. Her voice sounds low and raspy.

I speak with Ms. A’s son, who reports that before his mother’s arrest he found her in the kitchen wielding a knife, exclaiming she wanted to kill herself. He says she heard a “whoosh” or “ringing” in her right ear while a male voice in her left ear told her, “End it, end it.”

Ms. A is severely obese (weight 325 lbs, body mass index 49 kg/m²). Blood pressure is 140/90 mm Hg, and she is taking captopril, 50 mg bid, for hypertension. Pulse rate and temperature are normal.

Dr. Lachover’s observations

Ms. A’s hallucinatory experiences are atypical, and her psychotic symptoms show little response after 2 months of aggressive inpatient treatment. Three months after discharge, she is rehospitalized in a florid paranoid psychotic state.

The patient’s weight poses an additional obstacle. I avoided second-generation antipsychotics (SGAs) that can cause weight gain, such as clozapine or olanzapine. I tried the SGA risperidone after IM haloperidol, a first-generation antipsychotic, produced minimal response.

Ms. A’s physical symptoms (thickened skin, coarse hair, puffiness under her eyes, and vocal raspiness) suggest an underlying organic process that might be causing her psychosis.

TESTING: Telling results

I order laboratory and other tests to check for an underlying organic disorder:

• Brain MRI is normal, as are CBC, renal and liver function, and serum copper, ceruloplasmin, vitamin B12, and heavy metal levels.
  
• Slit lamp eye exam reveals no Kayser-Fleischer ring, which would have indicated Wilson’s disease.
  
• EEG shows a diffuse, nonspecific, abnormal pattern of slowing and decreased amplitude, suggesting diffuse cerebral dysfunction.
  
• ECG shows sinus bradycardia and a significantly prolonged corrected QT (QTc) interval, indicating delayed ventricular repolarization.
  
• Thyroid panel is abnormal with markedly elevated thyrotropin (31.07 mIU/L).
  

I consult an internist, who diagnoses hypothyroidism based on Ms. A’s thyroid panel (Table 1). An endocrinologist also is consulted. Ms. A is started on levothyroxine, 0.025 mg/d, and continues risperidone, 2 mg bid, to address her paranoia and delusions.

Across 3 weeks, Ms. A’s delusional perceptions and hallucination intensity decrease, and her reality testing and socialization skills improve. She is discharged, after which the internist and I see her weekly to monitor thyroid function and psychiatric symptoms, respectively. Thyroid function gradually returns to normal over 4 to 6 months, and she is maintained on levothyroxine, 0.025 mg/d. Her weight gradually decreases over 12 months to 229 lbs.

Six months after discharge, Ms. A is notably more adept at activities of daily living. Mental status exam shows progressively improved reality testing and decreased paranoia. She is more active, and her mood and affect have brightened. Risperidone is stopped 10 months after discharge, and she has not been rehospitalized for psychiatric problems.

Table 1

Ms. A’s thyroid panel values

Component	Ms. A’s readings	Normal values
Serum cholesterol	310 mg/dL	100 to 199 mg/dL
TSH (thyrotropin)	31.07 mIU/L	0.25 to 4.30 mIU/L
Free T4	0.34 ng/dL	0.80 to 1.80 ng/dL
Total T4 (serum thyroxine)	1.5 µg/dL	4.6 to 12 µg/dL
Total T3 (serum triiodothyronine)	67 ng/dL	70 to 180 ng/dL

Dr. Lachover’s observations

Erroneously diagnosed with paranoid schizophrenia, Ms. A endured 2 extended hospitalizations. Her psychosis and mental state—both of which improved with thyroid replacement therapy—appear to have been a psychiatric manifestation of severe hypothyroidism, or “myxedema madness” (Box).^1-3

Myxedema prevalence in the general public has been reported at 0.5% to 18%. It is roughly 10 times more common in women than in men,⁴ and 5% to 15% of patients with myxedema might develop signs of psychosis.⁴ Myxedema-induced psychosis usually occurs during middle age but has been reported between ages 18 and 73. Prevalence increases with age.⁴

 

Recognizing ‘myxedema madness’

Detecting and treating myxedema in patients with treatment-resistant psychosis can resolve psychiatric and medical symptoms and restore quality of life. Left untreated, it can impair cognitive function and cause lethargy, dysarthria, myopathy, neuropathy, status epilepticus, and coma.^5-7

Psychiatric manifestationsof severe hypothyroidism vary greatly, and a pre-existing psychotic disorder can worsen the presentation. Confusion, disorientation, persecutory delusions, hallucinations, and violent episodes are common symptoms.⁸ The patient may resist medical examination, fearing her life is in danger or the physician is conspiring to harm her.

Myxedema can impair perception and intellectual functioning,⁹ and acute mania has been reported in some cases.¹⁰ Increasing delirium reduces integration of perceptual input, leading to misidentification and disorientation. Cognitive functioning may be impaired, and abnormal thyroid hormone levels might delay event-related brain potential.¹¹

Physical signs also can be telling. The patient might show general psychomotor retardation and slowed speech. The tongue might be swollen, the voice hoarse and croaking. Hair is often coarse and brittle, with hair loss along the sides of the eyebrows. Body temperature often dips below normal.⁴

Patients with hypothyroidism usually gain weight, leading to subcutaneous depositions of fat that frequently appear as a “buffalo-hump” or periorbital edema known as “myxedema facies.”¹² Because myxedema increases risk of heart disease, elevated cholesterol, and hypertension, immediate treatment is mandatory for severely obese patients such as Ms. A.

Dr. Lachover’s observations

Detecting Ms. A’s hypothyroidism early could have prevented needless hospitalizations and failed treatment. Order a baseline thyroid panel for every patient who presents with psychotic symptoms or depression, which is the primary affective disturbance seen in myxedema.

Box

Serum cholesterol >200 mg/dL, anemia and hypertension, basal metabolic rate≤20% of normal levels, triiodothyronine (T3) 4.5 mIU/L suggest myxedema (Table 2).

Diffuse slowing of background activity is the most common EEG change found in myxedema.¹³ ECG might show slow, regular sinus rhythm or bradycardia, low voltage, prolonged QTc interval, and flattened T waves.¹⁴ Prolonged QRS complexes on ECG indicate delayed ventricular repolarization.^11,15 Torsades de pointes, the potentially fatal ventricular tachycardia, can result from a prolonged QTc interval in rare myxedema cases.¹⁶

Table 2

Is it myxedema? Check the lab findings

Component	Values that suggest myxedema
Serum cholesterol	>200 mg/dL
Free T4
Total T4 (serum thyroxine)
Total T3 (serum triiodothyronine)
TSH (thyrotropin)	>4.5 mIU/L
EEG	Diffuse slowing
EKG	Prolonged QTc interval

Treating 2 sets of symptoms

Prescribe concomitant dessicated thyroid and low-dose antipsychotics over 4 to 6 months to treat both the thyroid dysfunction and psychosis. Because weight gain is common in myxedema, choose an antipsychotic that carries a relatively low risk of weight gain, such as risperidone, 2 mg bid, or aripiprazole, 5 to 10 mg/d.

Many patients reach euthyroidism and their psychosis improves gradually but notably over weeks or months after starting thyroid hormone replacement. Psychosis could recur if desiccated thyroid is stopped; restarting it will improve the patient’s mental state.¹⁷ Recovery takes about 3 months on average.⁴

Continue the SGA until delusion perception is gone and reality testing improves, then taper the medication until all psychotic symptoms have abated. Monitor thyroid function monthly.

For patients with myxedema-induced depression, supplement thyroid hormone replacement with a selective serotonin reuptake inhibitor such as sertraline at regular starting dosages.

Dr. Lachover’s observations

Consider contributing medical illness in any patient with psychosis, particularly with psychotic symptom onset after age 40 and lack of response to weeks of adequate antipsychotic therapy.

A meticulous search to rule out medical disorders in all patients with psychosis and/or depression is essential to planning treatment. Testing is especially urgent for elderly patients, as multiple medical comorbidities or medication side effects can mask hypothyroidism’s signs and symptoms and delay diagnosis.¹⁸

 

Check complete blood count, electrolytes, thyroid panel, urinalysis, urine drug screen, blood urea nitrogen, and creatinine to rule out an underlying metabolic or endocrinologic cause for psychosis. Watch for signs of anticholinergic syndrome during physical examination.

If any of the above results suggest a medical problem, test for the following as clinical suspicion warrants:

• serum copper/ceruloplasmin and liver function to rule out Wilson’s disease, a genetic disorder that causes copper to accumulate in the liver and brain
  
• systemic lupus erythematosus
  
• lead, magnesium, mercury, or manganese to rule out metal poisoning.
  

Order additional blood testing to check for vitamin B₁₂ deficiency, brain MRI to rule out Alzheimer’s or subcortical dementia, EEG to check for an infectious or malignant disorder or for cerebral dysfunction, or ECG to rule out a metabolic or degenerative disorder or electrolyte imbalance.

Related resources

• Cronin AJ. The Citadel. Boston: Little, Brown & Co.;1937:399.
  
• Asher R. Myxoedamatous madness. BMJ 1949;2:555-62.
  

Drug brand names

• Aripiprazole • Abilify
  
• Captopril • Capoten
  
• Clozapine • Clozaril
  
• Haloperidol • Haldol
  
• Levothyroxine • Synthroid
  
• Olanzapine • Zyprexa
  
• Risperidone • Risperdal
  

Disclosures

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

History: ‘They want to kill me’

Police and security agents arrest Ms. A, age 64, at a metropolitan airport. She is extremely agitated and behaving bizarrely, yelling that “the Mafia” is trying to kill her. She has spent 3 days hiding in area hotels, fleeing her “assailants.”

Police arrange Ms. A’s return home; under court order, she is hospitalized in a psychiatric facility. She is diagnosed with paranoid schizophrenia and receives IM haloperidol, 2 mg bid, but shows minimal improvement after 2½ weeks. Her psychotic symptoms improve slightly after the psychiatrist switches her to risperidone, 2 mg bid, but she still cannot function normally. Three weeks after admission, she is transferred to a nursing home for long-term care. She continues risperidone but remains paranoid and delusional.

Three months later, Ms. A is rehospitalized. She is anxious, delusional, confused, and hallucinating at admission. The patient is verbally and physically combative, fearful that medical staff will harm her. She is too violent to be examined, but staff notice that her skin appears thickened, her eyes puffy, and her hair coarse. Her voice sounds low and raspy.

I speak with Ms. A’s son, who reports that before his mother’s arrest he found her in the kitchen wielding a knife, exclaiming she wanted to kill herself. He says she heard a “whoosh” or “ringing” in her right ear while a male voice in her left ear told her, “End it, end it.”

Ms. A is severely obese (weight 325 lbs, body mass index 49 kg/m²). Blood pressure is 140/90 mm Hg, and she is taking captopril, 50 mg bid, for hypertension. Pulse rate and temperature are normal.

Dr. Lachover’s observations

Ms. A’s hallucinatory experiences are atypical, and her psychotic symptoms show little response after 2 months of aggressive inpatient treatment. Three months after discharge, she is rehospitalized in a florid paranoid psychotic state.

The patient’s weight poses an additional obstacle. I avoided second-generation antipsychotics (SGAs) that can cause weight gain, such as clozapine or olanzapine. I tried the SGA risperidone after IM haloperidol, a first-generation antipsychotic, produced minimal response.

Ms. A’s physical symptoms (thickened skin, coarse hair, puffiness under her eyes, and vocal raspiness) suggest an underlying organic process that might be causing her psychosis.

TESTING: Telling results

I order laboratory and other tests to check for an underlying organic disorder:

• Brain MRI is normal, as are CBC, renal and liver function, and serum copper, ceruloplasmin, vitamin B12, and heavy metal levels.
  
• Slit lamp eye exam reveals no Kayser-Fleischer ring, which would have indicated Wilson’s disease.
  
• EEG shows a diffuse, nonspecific, abnormal pattern of slowing and decreased amplitude, suggesting diffuse cerebral dysfunction.
  
• ECG shows sinus bradycardia and a significantly prolonged corrected QT (QTc) interval, indicating delayed ventricular repolarization.
  
• Thyroid panel is abnormal with markedly elevated thyrotropin (31.07 mIU/L).
  

I consult an internist, who diagnoses hypothyroidism based on Ms. A’s thyroid panel (Table 1). An endocrinologist also is consulted. Ms. A is started on levothyroxine, 0.025 mg/d, and continues risperidone, 2 mg bid, to address her paranoia and delusions.

Across 3 weeks, Ms. A’s delusional perceptions and hallucination intensity decrease, and her reality testing and socialization skills improve. She is discharged, after which the internist and I see her weekly to monitor thyroid function and psychiatric symptoms, respectively. Thyroid function gradually returns to normal over 4 to 6 months, and she is maintained on levothyroxine, 0.025 mg/d. Her weight gradually decreases over 12 months to 229 lbs.

Six months after discharge, Ms. A is notably more adept at activities of daily living. Mental status exam shows progressively improved reality testing and decreased paranoia. She is more active, and her mood and affect have brightened. Risperidone is stopped 10 months after discharge, and she has not been rehospitalized for psychiatric problems.

Table 1

Ms. A’s thyroid panel values

Component	Ms. A’s readings	Normal values
Serum cholesterol	310 mg/dL	100 to 199 mg/dL
TSH (thyrotropin)	31.07 mIU/L	0.25 to 4.30 mIU/L
Free T4	0.34 ng/dL	0.80 to 1.80 ng/dL
Total T4 (serum thyroxine)	1.5 µg/dL	4.6 to 12 µg/dL
Total T3 (serum triiodothyronine)	67 ng/dL	70 to 180 ng/dL

Dr. Lachover’s observations

Erroneously diagnosed with paranoid schizophrenia, Ms. A endured 2 extended hospitalizations. Her psychosis and mental state—both of which improved with thyroid replacement therapy—appear to have been a psychiatric manifestation of severe hypothyroidism, or “myxedema madness” (Box).^1-3

Myxedema prevalence in the general public has been reported at 0.5% to 18%. It is roughly 10 times more common in women than in men,⁴ and 5% to 15% of patients with myxedema might develop signs of psychosis.⁴ Myxedema-induced psychosis usually occurs during middle age but has been reported between ages 18 and 73. Prevalence increases with age.⁴

 

Recognizing ‘myxedema madness’

Detecting and treating myxedema in patients with treatment-resistant psychosis can resolve psychiatric and medical symptoms and restore quality of life. Left untreated, it can impair cognitive function and cause lethargy, dysarthria, myopathy, neuropathy, status epilepticus, and coma.^5-7

Psychiatric manifestationsof severe hypothyroidism vary greatly, and a pre-existing psychotic disorder can worsen the presentation. Confusion, disorientation, persecutory delusions, hallucinations, and violent episodes are common symptoms.⁸ The patient may resist medical examination, fearing her life is in danger or the physician is conspiring to harm her.

Myxedema can impair perception and intellectual functioning,⁹ and acute mania has been reported in some cases.¹⁰ Increasing delirium reduces integration of perceptual input, leading to misidentification and disorientation. Cognitive functioning may be impaired, and abnormal thyroid hormone levels might delay event-related brain potential.¹¹

Physical signs also can be telling. The patient might show general psychomotor retardation and slowed speech. The tongue might be swollen, the voice hoarse and croaking. Hair is often coarse and brittle, with hair loss along the sides of the eyebrows. Body temperature often dips below normal.⁴

Patients with hypothyroidism usually gain weight, leading to subcutaneous depositions of fat that frequently appear as a “buffalo-hump” or periorbital edema known as “myxedema facies.”¹² Because myxedema increases risk of heart disease, elevated cholesterol, and hypertension, immediate treatment is mandatory for severely obese patients such as Ms. A.

Dr. Lachover’s observations

Detecting Ms. A’s hypothyroidism early could have prevented needless hospitalizations and failed treatment. Order a baseline thyroid panel for every patient who presents with psychotic symptoms or depression, which is the primary affective disturbance seen in myxedema.

Box

Serum cholesterol >200 mg/dL, anemia and hypertension, basal metabolic rate≤20% of normal levels, triiodothyronine (T3) 4.5 mIU/L suggest myxedema (Table 2).

Diffuse slowing of background activity is the most common EEG change found in myxedema.¹³ ECG might show slow, regular sinus rhythm or bradycardia, low voltage, prolonged QTc interval, and flattened T waves.¹⁴ Prolonged QRS complexes on ECG indicate delayed ventricular repolarization.^11,15 Torsades de pointes, the potentially fatal ventricular tachycardia, can result from a prolonged QTc interval in rare myxedema cases.¹⁶

Table 2

Is it myxedema? Check the lab findings

Component	Values that suggest myxedema
Serum cholesterol	>200 mg/dL
Free T4
Total T4 (serum thyroxine)
Total T3 (serum triiodothyronine)
TSH (thyrotropin)	>4.5 mIU/L
EEG	Diffuse slowing
EKG	Prolonged QTc interval

Treating 2 sets of symptoms

Prescribe concomitant dessicated thyroid and low-dose antipsychotics over 4 to 6 months to treat both the thyroid dysfunction and psychosis. Because weight gain is common in myxedema, choose an antipsychotic that carries a relatively low risk of weight gain, such as risperidone, 2 mg bid, or aripiprazole, 5 to 10 mg/d.

Many patients reach euthyroidism and their psychosis improves gradually but notably over weeks or months after starting thyroid hormone replacement. Psychosis could recur if desiccated thyroid is stopped; restarting it will improve the patient’s mental state.¹⁷ Recovery takes about 3 months on average.⁴

Continue the SGA until delusion perception is gone and reality testing improves, then taper the medication until all psychotic symptoms have abated. Monitor thyroid function monthly.

For patients with myxedema-induced depression, supplement thyroid hormone replacement with a selective serotonin reuptake inhibitor such as sertraline at regular starting dosages.

Dr. Lachover’s observations

Consider contributing medical illness in any patient with psychosis, particularly with psychotic symptom onset after age 40 and lack of response to weeks of adequate antipsychotic therapy.

A meticulous search to rule out medical disorders in all patients with psychosis and/or depression is essential to planning treatment. Testing is especially urgent for elderly patients, as multiple medical comorbidities or medication side effects can mask hypothyroidism’s signs and symptoms and delay diagnosis.¹⁸

 

Check complete blood count, electrolytes, thyroid panel, urinalysis, urine drug screen, blood urea nitrogen, and creatinine to rule out an underlying metabolic or endocrinologic cause for psychosis. Watch for signs of anticholinergic syndrome during physical examination.

If any of the above results suggest a medical problem, test for the following as clinical suspicion warrants:

• serum copper/ceruloplasmin and liver function to rule out Wilson’s disease, a genetic disorder that causes copper to accumulate in the liver and brain
  
• systemic lupus erythematosus
  
• lead, magnesium, mercury, or manganese to rule out metal poisoning.
  

Order additional blood testing to check for vitamin B₁₂ deficiency, brain MRI to rule out Alzheimer’s or subcortical dementia, EEG to check for an infectious or malignant disorder or for cerebral dysfunction, or ECG to rule out a metabolic or degenerative disorder or electrolyte imbalance.

Related resources

• Cronin AJ. The Citadel. Boston: Little, Brown & Co.;1937:399.
  
• Asher R. Myxoedamatous madness. BMJ 1949;2:555-62.
  

Drug brand names

• Aripiprazole • Abilify
  
• Captopril • Capoten
  
• Clozapine • Clozaril
  
• Haloperidol • Haldol
  
• Levothyroxine • Synthroid
  
• Olanzapine • Zyprexa
  
• Risperidone • Risperdal
  

Disclosures

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

History: ‘They want to kill me’

Police and security agents arrest Ms. A, age 64, at a metropolitan airport. She is extremely agitated and behaving bizarrely, yelling that “the Mafia” is trying to kill her. She has spent 3 days hiding in area hotels, fleeing her “assailants.”

Police arrange Ms. A’s return home; under court order, she is hospitalized in a psychiatric facility. She is diagnosed with paranoid schizophrenia and receives IM haloperidol, 2 mg bid, but shows minimal improvement after 2½ weeks. Her psychotic symptoms improve slightly after the psychiatrist switches her to risperidone, 2 mg bid, but she still cannot function normally. Three weeks after admission, she is transferred to a nursing home for long-term care. She continues risperidone but remains paranoid and delusional.

Three months later, Ms. A is rehospitalized. She is anxious, delusional, confused, and hallucinating at admission. The patient is verbally and physically combative, fearful that medical staff will harm her. She is too violent to be examined, but staff notice that her skin appears thickened, her eyes puffy, and her hair coarse. Her voice sounds low and raspy.

I speak with Ms. A’s son, who reports that before his mother’s arrest he found her in the kitchen wielding a knife, exclaiming she wanted to kill herself. He says she heard a “whoosh” or “ringing” in her right ear while a male voice in her left ear told her, “End it, end it.”

Ms. A is severely obese (weight 325 lbs, body mass index 49 kg/m²). Blood pressure is 140/90 mm Hg, and she is taking captopril, 50 mg bid, for hypertension. Pulse rate and temperature are normal.

Dr. Lachover’s observations

Ms. A’s hallucinatory experiences are atypical, and her psychotic symptoms show little response after 2 months of aggressive inpatient treatment. Three months after discharge, she is rehospitalized in a florid paranoid psychotic state.

The patient’s weight poses an additional obstacle. I avoided second-generation antipsychotics (SGAs) that can cause weight gain, such as clozapine or olanzapine. I tried the SGA risperidone after IM haloperidol, a first-generation antipsychotic, produced minimal response.

Ms. A’s physical symptoms (thickened skin, coarse hair, puffiness under her eyes, and vocal raspiness) suggest an underlying organic process that might be causing her psychosis.

TESTING: Telling results

I order laboratory and other tests to check for an underlying organic disorder:

• Brain MRI is normal, as are CBC, renal and liver function, and serum copper, ceruloplasmin, vitamin B12, and heavy metal levels.
  
• Slit lamp eye exam reveals no Kayser-Fleischer ring, which would have indicated Wilson’s disease.
  
• EEG shows a diffuse, nonspecific, abnormal pattern of slowing and decreased amplitude, suggesting diffuse cerebral dysfunction.
  
• ECG shows sinus bradycardia and a significantly prolonged corrected QT (QTc) interval, indicating delayed ventricular repolarization.
  
• Thyroid panel is abnormal with markedly elevated thyrotropin (31.07 mIU/L).
  

I consult an internist, who diagnoses hypothyroidism based on Ms. A’s thyroid panel (Table 1). An endocrinologist also is consulted. Ms. A is started on levothyroxine, 0.025 mg/d, and continues risperidone, 2 mg bid, to address her paranoia and delusions.

Across 3 weeks, Ms. A’s delusional perceptions and hallucination intensity decrease, and her reality testing and socialization skills improve. She is discharged, after which the internist and I see her weekly to monitor thyroid function and psychiatric symptoms, respectively. Thyroid function gradually returns to normal over 4 to 6 months, and she is maintained on levothyroxine, 0.025 mg/d. Her weight gradually decreases over 12 months to 229 lbs.

Six months after discharge, Ms. A is notably more adept at activities of daily living. Mental status exam shows progressively improved reality testing and decreased paranoia. She is more active, and her mood and affect have brightened. Risperidone is stopped 10 months after discharge, and she has not been rehospitalized for psychiatric problems.

Table 1

Ms. A’s thyroid panel values

Component	Ms. A’s readings	Normal values
Serum cholesterol	310 mg/dL	100 to 199 mg/dL
TSH (thyrotropin)	31.07 mIU/L	0.25 to 4.30 mIU/L
Free T4	0.34 ng/dL	0.80 to 1.80 ng/dL
Total T4 (serum thyroxine)	1.5 µg/dL	4.6 to 12 µg/dL
Total T3 (serum triiodothyronine)	67 ng/dL	70 to 180 ng/dL

Dr. Lachover’s observations

Erroneously diagnosed with paranoid schizophrenia, Ms. A endured 2 extended hospitalizations. Her psychosis and mental state—both of which improved with thyroid replacement therapy—appear to have been a psychiatric manifestation of severe hypothyroidism, or “myxedema madness” (Box).^1-3

Myxedema prevalence in the general public has been reported at 0.5% to 18%. It is roughly 10 times more common in women than in men,⁴ and 5% to 15% of patients with myxedema might develop signs of psychosis.⁴ Myxedema-induced psychosis usually occurs during middle age but has been reported between ages 18 and 73. Prevalence increases with age.⁴

 

Recognizing ‘myxedema madness’

Detecting and treating myxedema in patients with treatment-resistant psychosis can resolve psychiatric and medical symptoms and restore quality of life. Left untreated, it can impair cognitive function and cause lethargy, dysarthria, myopathy, neuropathy, status epilepticus, and coma.^5-7

Psychiatric manifestationsof severe hypothyroidism vary greatly, and a pre-existing psychotic disorder can worsen the presentation. Confusion, disorientation, persecutory delusions, hallucinations, and violent episodes are common symptoms.⁸ The patient may resist medical examination, fearing her life is in danger or the physician is conspiring to harm her.

Myxedema can impair perception and intellectual functioning,⁹ and acute mania has been reported in some cases.¹⁰ Increasing delirium reduces integration of perceptual input, leading to misidentification and disorientation. Cognitive functioning may be impaired, and abnormal thyroid hormone levels might delay event-related brain potential.¹¹

Physical signs also can be telling. The patient might show general psychomotor retardation and slowed speech. The tongue might be swollen, the voice hoarse and croaking. Hair is often coarse and brittle, with hair loss along the sides of the eyebrows. Body temperature often dips below normal.⁴

Patients with hypothyroidism usually gain weight, leading to subcutaneous depositions of fat that frequently appear as a “buffalo-hump” or periorbital edema known as “myxedema facies.”¹² Because myxedema increases risk of heart disease, elevated cholesterol, and hypertension, immediate treatment is mandatory for severely obese patients such as Ms. A.

Dr. Lachover’s observations

Detecting Ms. A’s hypothyroidism early could have prevented needless hospitalizations and failed treatment. Order a baseline thyroid panel for every patient who presents with psychotic symptoms or depression, which is the primary affective disturbance seen in myxedema.

Box

Serum cholesterol >200 mg/dL, anemia and hypertension, basal metabolic rate≤20% of normal levels, triiodothyronine (T3) 4.5 mIU/L suggest myxedema (Table 2).

Diffuse slowing of background activity is the most common EEG change found in myxedema.¹³ ECG might show slow, regular sinus rhythm or bradycardia, low voltage, prolonged QTc interval, and flattened T waves.¹⁴ Prolonged QRS complexes on ECG indicate delayed ventricular repolarization.^11,15 Torsades de pointes, the potentially fatal ventricular tachycardia, can result from a prolonged QTc interval in rare myxedema cases.¹⁶

Table 2

Is it myxedema? Check the lab findings

Component	Values that suggest myxedema
Serum cholesterol	>200 mg/dL
Free T4
Total T4 (serum thyroxine)
Total T3 (serum triiodothyronine)
TSH (thyrotropin)	>4.5 mIU/L
EEG	Diffuse slowing
EKG	Prolonged QTc interval

Treating 2 sets of symptoms

Prescribe concomitant dessicated thyroid and low-dose antipsychotics over 4 to 6 months to treat both the thyroid dysfunction and psychosis. Because weight gain is common in myxedema, choose an antipsychotic that carries a relatively low risk of weight gain, such as risperidone, 2 mg bid, or aripiprazole, 5 to 10 mg/d.

Many patients reach euthyroidism and their psychosis improves gradually but notably over weeks or months after starting thyroid hormone replacement. Psychosis could recur if desiccated thyroid is stopped; restarting it will improve the patient’s mental state.¹⁷ Recovery takes about 3 months on average.⁴

Continue the SGA until delusion perception is gone and reality testing improves, then taper the medication until all psychotic symptoms have abated. Monitor thyroid function monthly.

For patients with myxedema-induced depression, supplement thyroid hormone replacement with a selective serotonin reuptake inhibitor such as sertraline at regular starting dosages.

Dr. Lachover’s observations

Consider contributing medical illness in any patient with psychosis, particularly with psychotic symptom onset after age 40 and lack of response to weeks of adequate antipsychotic therapy.

A meticulous search to rule out medical disorders in all patients with psychosis and/or depression is essential to planning treatment. Testing is especially urgent for elderly patients, as multiple medical comorbidities or medication side effects can mask hypothyroidism’s signs and symptoms and delay diagnosis.¹⁸

 

Check complete blood count, electrolytes, thyroid panel, urinalysis, urine drug screen, blood urea nitrogen, and creatinine to rule out an underlying metabolic or endocrinologic cause for psychosis. Watch for signs of anticholinergic syndrome during physical examination.

If any of the above results suggest a medical problem, test for the following as clinical suspicion warrants:

• serum copper/ceruloplasmin and liver function to rule out Wilson’s disease, a genetic disorder that causes copper to accumulate in the liver and brain
  
• systemic lupus erythematosus
  
• lead, magnesium, mercury, or manganese to rule out metal poisoning.
  

Order additional blood testing to check for vitamin B₁₂ deficiency, brain MRI to rule out Alzheimer’s or subcortical dementia, EEG to check for an infectious or malignant disorder or for cerebral dysfunction, or ECG to rule out a metabolic or degenerative disorder or electrolyte imbalance.

Related resources

• Cronin AJ. The Citadel. Boston: Little, Brown & Co.;1937:399.
  
• Asher R. Myxoedamatous madness. BMJ 1949;2:555-62.
  

Drug brand names

• Aripiprazole • Abilify
  
• Captopril • Capoten
  
• Clozapine • Clozaril
  
• Haloperidol • Haldol
  
• Levothyroxine • Synthroid
  
• Olanzapine • Zyprexa
  
• Risperidone • Risperdal
  

Disclosures

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

History: bipolar for 30 years

Mr. B, age 66, was diagnosed 30 years ago with type I bipolar disorder and has type 2 diabetes, hypertension, alcohol abuse disorder, and cardiac disease. After repeated suicide attempts and hospitalizations in the past, he has been stable for 20 years on lithium, 600 mg bid, and nortriptyline, 50 mg at bedtime. He has had intermittent mania with little evidence of depression.

Two years ago, Mr. B called a local clinic to report that an intruder had him “holed up.” His speech was pressured and garbled, and his thoughts were tangential, irrational, and markedly paranoid. A clinic psychiatrist called Mr. B’s son, who said his father “built a bomb shelter” because “trolls and little people” were out to kill him. A family member called police, and Mr. B was brought to the ER and admitted for treatment.

A hospital psychiatrist stopped lithium in light of Mr. B’s history of cardiac problems and because the psychiatrist considered the medication ineffective, even though serum lithium was only 0.03 mEq/L. The psychiatrist then started:

• divalproex at 500 mg bid, titrated over 1 week to 500 mg each morning and 1,000 mg at bed-time to reach serum valproate of 80 mEq/L
  
• quetiapine at 200 mg at bedtime, titrated over 1 week to 400 mg at bedtime.
  

Mr. B was still manic, paranoid, and hallucinating 1 week later, yet was discharged after he convinced the county hearing officer that he had recovered.

Two weeks later, Mr. B is brought to another psychiatric hospital, where a psychiatrist restarts unknown dosages of lithium, risperidone, and nortriptyline. From there, he is transferred to our in-patient unit. At presentation, he claims he has been drinking and that members of a drug cartel have recruited him. He says he has been skipping medications because he is “unclear which drugs to take.”

We stop lithium and restart divalproex, 500 mg each morning and 1,500 mg at bedtime, to try to treat his mania without causing cognitive problems.

We stop risperidone because of his hypotension and nortriptyline because it was not working, and restart quetiapine, 600 mg at bedtime, for his paranoia. He remains paranoid 1 week later but his mania improves, so we discharge him on the above regimen. We urge him to take his medications and follow up with his outpatient psychiatrist 1 week later.

Divorced, Mr. B lives alone with no family nearby. His son comes in from out of town to help him resettle after discharge, then leaves the next day.

Several months later, Mr. B’s paranoia returns. He is not taking his medications because “the doctors took away my lithium and these new drugs don’t work.” He tells staff he is a martial arts expert and has purchased 7 cars in recent weeks. We restart lithium at 600 mg bid; serum lithium reaches 1.1 mEq/L, but his mania persists. After 5 days, we add aripiprazole, 15 mg/d.

Nearly 2 weeks after admission, a county hearing officer recommends discharging Mr. B despite his severe mania and paranoia. We release him on the above regimen, arrange appointments with his outpatient psychiatrist and primary care physician, and urge medication adherence. We schedule a blood test 3 days after discharge to check serum lithium, but Mr. B does not keep the appointment.

The authors’ observations

Suspect delirium after rapid onset of mania or paranoia in any patient. Also consider dementia and cognitive deficits in older adults, although Mr. B’s symptoms resembled those of previous manic episodes. Although Mr. B’s psychosis was more severe than before, his case underscores the importance of a thorough patient history.

Late-life bipolar disorder. Little is known about diagnosing and treating bipolar disorder (BPD) in older patients. Gaps in empiric knowledge can confound diagnosis, treatment, and outcome. Also, patients age ≥65 with BPD often have severe medical illness and are difficult to treat.¹

Keys to detecting late-life BPD include:

• recognizing clinical features of BPD unique to older persons
  
• differentiating the disorder from late-life schizophrenia (Table).^1,2
  

Older patients’ symptoms usually match DSM-IV-TR criteria for BPD; their response to treatment mirrors that of younger adults.³

Secondary cause. When an older patient’s mania has atypical features or doesn’t respond to conventional treatment, look for a nonpsychiatric process such as a general medical condition or substance abuse (see possible medical causes with this article at www.currentpsychiatry.com). Order laboratory and other tests as clinical suspicion warrants.

Cognitive deficits secondary to BPD can occur at any age and be persistent or progressive,⁴ although Depp et al¹ found more-severe impairment in older patients. Cognitive impairment can endure after successful BPD treatment, although acute treatment might improve cognition in older patients.⁵

 

Lithium can cause dull affect, cognitive slowing, and depersonalization. Titrating to the lowest effective dosage might minimize these effects.

Dementia. Cognitive deficits that accompany mania in older adults could suggest dementia, which usually develops over years and is preceded by cognitive changes without manic-type symptoms. By contrast, bipolar mania emerges more abruptly and is accompanied by affective symptoms. Agitation and psychosis—both symptoms of late-stage dementia—can be early signs of geriatric BPD.²

Delirium. Restlessness, irritability, aggression, and changes in affect can accompany delirium, especially the hyperactive or hyperalert types. Symptoms of anxiety, depression, fear, and loose or tangential thinking also are common.

Mania shares some of these features but typically presents with an abnormally and persistently elevated or irritable mood lasting ≥1 week, usually without prominent cognitive impairment.⁶ Mania can also include:

• grandiosity
  
• decreased need for sleep
  
• flight of ideas
  
• distractibility
  
• pressured or increased rate of speech
  
• psychomotor agitation
  
• potentially harmful activities
  
• increased goal-directed activities.⁶
  

By contrast, delirium is marked by waxing and waning consciousness and changes in cognition, such as disorientation and confusion.⁶

Frontal lobe lesions. Decreased prefrontal executive control could underlie mania’s cognitive and emotional symptoms. Decreased right rostral and orbital prefrontal cortex activation has been associated with impaired planning, judgment, and insight, as well as inappropriate conduct.⁷

Table

Clinical features of geriatric bipolar disorder (BPD)

Psychotic features (delusions, hallucinations)
Mean prevalence of 64% (range 20% to 85%) is similar to that of mixed-age groups; paranoia might be more prevalent
Family history
High rates of psychiatric disorders (“affective disorder” in most studies) reported in 10 studies
Compared with younger adults with BPD, older patients:
show longer latency from first depression to mania onset might be more likely to relapse into depression after mania might have less-intense mania are hospitalized longer, possibly because of greater medical comorbidity have less comorbid substance abuse and more-prominent age-associated morphologic abnormalities on neuroimaging2
Compared with late-life schizophrenia, late-life BPD patients show:
more depressive symptoms fewer positive and negative symptoms greater community living and relationship skills, with similar activities of daily living
Source: References 1,2

Continued treatment: depression emerges

Several months later, Mr. B presents with severe depression and continued medication nonadherence. He complains of hypersomnia, poor appetite, anhedonia, amotivation, and a leaden-like paresis in his hands and feet.

We readmit Mr. B to the psychiatric unit. He avoids contact with others, has lost 18 lbs over 6 weeks, and suffers hypotension caused by poor hydration before admission. Three weeks later, he complains that ants are crawling around his room and into his mouth.

Noncontrast brain CT shows no abnormalities. Laboratory tests performed at admission show a subtherapeutic lithium level (0.03 mEq/L), unremarkable thyroid panel, and normal B12 and folate, so we begin to rule out a medical cause for his psychiatric symptoms.

The authors’ observations

Check for these and other possible causes of depressive symptoms in older patients with a history of BPD. Mr. B’s depression likely resulted from multiple causes, including medical disease, functional impairment, loss of social and family contacts, and substance abuse—all late-life predictors of depression. BPD also predisposed him to depression.

Bipolar depression. Despite its profound morbidity and mortality, bipolar depression remains a mystery, especially in the elderly. Mr. B’s depression emerged after he was free of depressive symptoms for more than 20 years.

Some researchers believe that compared with other depressions, bipolar depression has a more acute onset, marked psychomotor retardation, and lessened response to antidepressants.^6,8 Kraepelin associated bipolar depression with lethargy, mental slowing, and hypersomnia, whereas agitation and insomnia signal unipolar depression.⁹

To differentiate bipolar from unipolar or secondary depression in older patients, watch for:

• suicide risk, which is heightened during BPD’s depressive phase⁹
  
• secondary manias, for which underlying causes must be determined and treated if possible.
  

Medication-induced depression. Medications can cause depressive symptoms (see Related resources), but identifying an offending agent without an obvious chronologic relationship can be difficult, especially in older patients who are taking numerous medications.⁹

Depression caused by medication might be limited to somatic complaints such as fatigue or tiredness,⁹ and often lacks features seen with mood disorders such as depressed mood, anhedonia, guilt, and diminished interest in activities. Mr. B’s anhedonia and amotivation suggest his depression was not medication-induced.¹⁰

Disease-induced depression. Medical comorbidities are common among older persons with mood disorders and can complicate treatment response and outcome. Physical disease can cause or worsen depression:¹¹

• Endocrine and immunologic diseases might cause depression or mania.
  
• Cardiovascular and cerebrovascular diseases; CNS disorders such as dementia, Parkinson’s disease, and multiple sclerosis; cancer; and connective tissue disease increase risk for comorbid depression.
  

Mr. B’s hypertension, diabetes, or coronary artery disease could have contributed to his depression or complicated the course.

 

¹¹

Vascular depression. Comorbid depressive symptoms and vascular disease—or “vascular depression”—can cause ischemic brain lesions, cognitive impairment, increased apathy and retardation, and impaired fluency and naming.¹²

What defines vascular depression has been debated. Watch for clinical or laboratory evidence of vascular disease, depression, and neuropsychological impairment.¹³

Treatment: searching for evidence

Two days after admission, Mr. B is transferred to the ICU after suffering severe hypoglycemia and showing signs of medically induced delirium. Elevated creatinine (1.7 mg/dL) indicates acute renal failure, which could be related to his elevated serum lithium (1.7 mEq/L). Acting on the internist’s advice, the consulting psychiatrist stops lithium and restarts valproate, 500 mg bid.

Mr. B becomes medically stable after 3 days, mostly through acute IV hydration and by withholding oral diabetes medications, which normalizes his blood sugar. He is transferred back to the psychiatry unit. We try lithium again at 300 mg bid, but creatinine and serum lithium quickly rise.

Mr. B remains hospitalized for 3 months with severe, treatment-resistant depression. Trials of nearly every second-generation antipsychotic (SGA) cause symptomatic orthostatic hypotension, leading to several falls. He does not respond to divalproex, up to 2,000 mg/d; citalopram, 60 mg/d; mirtazapine, 30 mg at bedtime; venlafaxine, 100 mg tid; or bupropion, 100 mg tid.

We suggest electroconvulsive therapy (ECT) but Mr. B declines, saying this treatment caused his mother to decompensate. We try lamotrigine, 25 mg/d, and titrate it over 6 weeks to 200 mg bid. After we add haloperidol, 5 mg at bedtime, and bupropion, 300 mg/d, Mr. B becomes mentally stable.

The authors’ observations

Numerous clinical challenges—such as managing complicated/refractory BPD, medical comorbidity, and medication adherence (Box)^14,15—complicate treatment of late-life BPD.¹⁶ Regular communication with providers and integrating health care services can minimize complication risk.¹⁶

Pharmacotherapy, a core element of BPD treatment, is challenging in older patients because of their:

• heightened threat of complications and sensitivity to side effects because of age-related pharmacokinetic changes
  
• increased risk of drug-drug interactions
  
• increased potential for age-related psychosocial problems (increased social isolation, financial difficulties, demoralization, increased stress, inability to work).
  

Box

Initial clinical and laboratory evaluations can rule out aggravating or causative factors and identify conditions that can cause drug intolerability.⁵ Check orthostatic vital signs and perform a detailed medical and psychosocial history, neurologic examination, ECG, and cognitive evaluation.

Consider side effects, medical and neurologic comorbidities, and treatment history before prescribing a mood stabilizer, antipsychotic, or antidepressant to an older patient. Avoid unwarranted discontinuation of a previously effective agent, such as when drug concentrations are elevated or inadequate—as happened with Mr. B.⁵ Also investigate the patient’s side-effect history before stopping a medication.⁵

Medications. Mr. B’s inability to tolerate lithium posed a treatment challenge. Adjusting lithium dosages to compensate for age-related pharmacokinetic, pharmacodynamic, and renal clearance changes can prevent toxicity.⁵ Avoid stopping lithium abruptly, as this can trigger recurrence of manic or depressive episodes.¹⁷

Lamotrigine, indicated for BPD maintenance therapy, appears to prevent depressive/mood relapse. Compared with other anticonvulsants, lamotrigine might cause fewer negative effects on cognition and less induction of hepatic enzymes. It is well tolerated by older patients but has not been studied adequately in this age group.¹⁶

Antipsychotics are widely used in BPD,¹⁶ especially when psychosis is present with mania or depression or the patient is agitated. Most studies of antipsychotics in BPD have followed younger adults, however, and most studies in older patients have followed those with dementia or schizophrenia.

Use of first-generation antipsychotics such as haloperidol is especially challenging in the elderly because these drugs increase risk of cardiovascular effects, extrapyramidal symptoms, and tardive dyskinesia and can cause depression in BPD.¹⁶ By comparison, SGAs carry a lower risk of involuntary motion¹⁸ but can increase risk of obesity, diabetes, and dyslipidemia. However:

• The need to manage psychosis usually overrides concerns about metabolic sequelae.
  
• Older patients might be less susceptible to metabolic effects,¹⁶ though this has not been confirmed.
  

 

SGAs can be used safely in patients with a history of diabetes. Start at lower-than-normal dosages and titrate slowly. Perform baseline and regular checks—including weight, blood glucose, lipid levels, and blood pressure—following American Psychiatric Association and American Diabetes Association consensus guidelines.¹⁹ Also check glycosylated hemoglobin every 3 to 6 months in patients with diabetes, and follow up with other providers to ensure proper diabetes management.

As with most aspects of late-life BPD, scant evidence guides SGA use. Avoid low-potency neuroleptics such as chlorpromazine, which can cause severe sedation and orthostatic hypotension. For Mr. B, a more-tolerable SGA such as aripiprazole or ziprasidone might be prudent, given his propensity for orthostatic hypotension and history of diabetes. Olanzapine or clozapine can cause anticholinergic effects and—in Mr. B’s case—lead to weight gain and worsen diabetes.

Antidepressant use in BPD usually is reserved for depressive symptoms that impair occupational or social functioning and exceed DSM-IV-TR diagnostic criteria.^8,9 Consider later-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs), because tricyclics pose a greater risk of triggering a switch into hypomania or mania and can cause sedation and orthostatic, cardiac, anticholinergic, and anti-alpha 1 effects.

Among SSRIs, consider citalopram, escitalopram, or sertraline for older patients taking one or more other medications, as these antidepressants have less potential for drug-drug interactions than fluoxetine and paroxetine.¹¹ In a recent comparison of newer antidepressants,²⁰ venlafaxine showed the highest relative risk of mood polarity switching and bupropion the lowest.

Consider ECT for older patients with refractory mania or depression or who show evidence of suicidality or inadequate nutrition.⁵

Follow-up: ongoing issues

Three months after his admission, we discharge Mr. B to a board-and-care facility because family members will not take him in. Several weeks later, he again ignores his prescriptions and decompensates with worsening depression.

Family members have Mr. B admitted to an inpatient psychiatric facility closer to their home. He remains depressed, stays at the facility on and off for almost 1 year, and is eventually conserved by the county. Adverse side effects—mostly constipation and orthostatic hypotension—continue to complicate treatment.

Before Mr. B’s most recent discharge, another psychiatrist restarts lithium, 300 mg bid, and nortriptyline, 100 mg at bedtime—the combination that kept Mr. B relatively stable for more than 2 decades.

Related resources

• National Institute of Mental Health—depression information. www.nimh.nih.gov/healthinformation/depressionmenu.cfm.
  
• Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). www.stepbd.org.
  
• Medicinenet.com. Medicines that cause depression. www.medicinenet.com/depression/index.htm. Click on “Medicines that cause depression.”
  

Drug brand name

• Aripiprazole • Abilify
  
• Bupropion • Wellbutrin
  
• Chlorpromazine • Thorazine
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Divalproex • Depakote
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Haloperidol • Haldol
  
• Lamotrigine • Lamictal
  
• Lithium • Various
  
• Mirtazapine • Remeron
  
• Nortriptyline • Pamelor
  
• Olanzapine • Zyprexa
  
• Paroxetine • Paxil
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Sertraline • Zoloft
  
• Venlafaxine • Effexor
  
• Ziprasidone • Geodon
  

Disclosures

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

History: bipolar for 30 years

Mr. B, age 66, was diagnosed 30 years ago with type I bipolar disorder and has type 2 diabetes, hypertension, alcohol abuse disorder, and cardiac disease. After repeated suicide attempts and hospitalizations in the past, he has been stable for 20 years on lithium, 600 mg bid, and nortriptyline, 50 mg at bedtime. He has had intermittent mania with little evidence of depression.

Two years ago, Mr. B called a local clinic to report that an intruder had him “holed up.” His speech was pressured and garbled, and his thoughts were tangential, irrational, and markedly paranoid. A clinic psychiatrist called Mr. B’s son, who said his father “built a bomb shelter” because “trolls and little people” were out to kill him. A family member called police, and Mr. B was brought to the ER and admitted for treatment.

A hospital psychiatrist stopped lithium in light of Mr. B’s history of cardiac problems and because the psychiatrist considered the medication ineffective, even though serum lithium was only 0.03 mEq/L. The psychiatrist then started:

• divalproex at 500 mg bid, titrated over 1 week to 500 mg each morning and 1,000 mg at bed-time to reach serum valproate of 80 mEq/L
  
• quetiapine at 200 mg at bedtime, titrated over 1 week to 400 mg at bedtime.
  

Mr. B was still manic, paranoid, and hallucinating 1 week later, yet was discharged after he convinced the county hearing officer that he had recovered.

Two weeks later, Mr. B is brought to another psychiatric hospital, where a psychiatrist restarts unknown dosages of lithium, risperidone, and nortriptyline. From there, he is transferred to our in-patient unit. At presentation, he claims he has been drinking and that members of a drug cartel have recruited him. He says he has been skipping medications because he is “unclear which drugs to take.”

We stop lithium and restart divalproex, 500 mg each morning and 1,500 mg at bedtime, to try to treat his mania without causing cognitive problems.

We stop risperidone because of his hypotension and nortriptyline because it was not working, and restart quetiapine, 600 mg at bedtime, for his paranoia. He remains paranoid 1 week later but his mania improves, so we discharge him on the above regimen. We urge him to take his medications and follow up with his outpatient psychiatrist 1 week later.

Divorced, Mr. B lives alone with no family nearby. His son comes in from out of town to help him resettle after discharge, then leaves the next day.

Several months later, Mr. B’s paranoia returns. He is not taking his medications because “the doctors took away my lithium and these new drugs don’t work.” He tells staff he is a martial arts expert and has purchased 7 cars in recent weeks. We restart lithium at 600 mg bid; serum lithium reaches 1.1 mEq/L, but his mania persists. After 5 days, we add aripiprazole, 15 mg/d.

Nearly 2 weeks after admission, a county hearing officer recommends discharging Mr. B despite his severe mania and paranoia. We release him on the above regimen, arrange appointments with his outpatient psychiatrist and primary care physician, and urge medication adherence. We schedule a blood test 3 days after discharge to check serum lithium, but Mr. B does not keep the appointment.

The authors’ observations

Suspect delirium after rapid onset of mania or paranoia in any patient. Also consider dementia and cognitive deficits in older adults, although Mr. B’s symptoms resembled those of previous manic episodes. Although Mr. B’s psychosis was more severe than before, his case underscores the importance of a thorough patient history.

Late-life bipolar disorder. Little is known about diagnosing and treating bipolar disorder (BPD) in older patients. Gaps in empiric knowledge can confound diagnosis, treatment, and outcome. Also, patients age ≥65 with BPD often have severe medical illness and are difficult to treat.¹

Keys to detecting late-life BPD include:

• recognizing clinical features of BPD unique to older persons
  
• differentiating the disorder from late-life schizophrenia (Table).^1,2
  

Older patients’ symptoms usually match DSM-IV-TR criteria for BPD; their response to treatment mirrors that of younger adults.³

Secondary cause. When an older patient’s mania has atypical features or doesn’t respond to conventional treatment, look for a nonpsychiatric process such as a general medical condition or substance abuse (see possible medical causes with this article at www.currentpsychiatry.com). Order laboratory and other tests as clinical suspicion warrants.

Cognitive deficits secondary to BPD can occur at any age and be persistent or progressive,⁴ although Depp et al¹ found more-severe impairment in older patients. Cognitive impairment can endure after successful BPD treatment, although acute treatment might improve cognition in older patients.⁵

 

Lithium can cause dull affect, cognitive slowing, and depersonalization. Titrating to the lowest effective dosage might minimize these effects.

Dementia. Cognitive deficits that accompany mania in older adults could suggest dementia, which usually develops over years and is preceded by cognitive changes without manic-type symptoms. By contrast, bipolar mania emerges more abruptly and is accompanied by affective symptoms. Agitation and psychosis—both symptoms of late-stage dementia—can be early signs of geriatric BPD.²

Delirium. Restlessness, irritability, aggression, and changes in affect can accompany delirium, especially the hyperactive or hyperalert types. Symptoms of anxiety, depression, fear, and loose or tangential thinking also are common.

Mania shares some of these features but typically presents with an abnormally and persistently elevated or irritable mood lasting ≥1 week, usually without prominent cognitive impairment.⁶ Mania can also include:

• grandiosity
  
• decreased need for sleep
  
• flight of ideas
  
• distractibility
  
• pressured or increased rate of speech
  
• psychomotor agitation
  
• potentially harmful activities
  
• increased goal-directed activities.⁶
  

By contrast, delirium is marked by waxing and waning consciousness and changes in cognition, such as disorientation and confusion.⁶

Frontal lobe lesions. Decreased prefrontal executive control could underlie mania’s cognitive and emotional symptoms. Decreased right rostral and orbital prefrontal cortex activation has been associated with impaired planning, judgment, and insight, as well as inappropriate conduct.⁷

Table

Clinical features of geriatric bipolar disorder (BPD)

Psychotic features (delusions, hallucinations)
Mean prevalence of 64% (range 20% to 85%) is similar to that of mixed-age groups; paranoia might be more prevalent
Family history
High rates of psychiatric disorders (“affective disorder” in most studies) reported in 10 studies
Compared with younger adults with BPD, older patients:
show longer latency from first depression to mania onset might be more likely to relapse into depression after mania might have less-intense mania are hospitalized longer, possibly because of greater medical comorbidity have less comorbid substance abuse and more-prominent age-associated morphologic abnormalities on neuroimaging2
Compared with late-life schizophrenia, late-life BPD patients show:
more depressive symptoms fewer positive and negative symptoms greater community living and relationship skills, with similar activities of daily living
Source: References 1,2

Continued treatment: depression emerges

Several months later, Mr. B presents with severe depression and continued medication nonadherence. He complains of hypersomnia, poor appetite, anhedonia, amotivation, and a leaden-like paresis in his hands and feet.

We readmit Mr. B to the psychiatric unit. He avoids contact with others, has lost 18 lbs over 6 weeks, and suffers hypotension caused by poor hydration before admission. Three weeks later, he complains that ants are crawling around his room and into his mouth.

Noncontrast brain CT shows no abnormalities. Laboratory tests performed at admission show a subtherapeutic lithium level (0.03 mEq/L), unremarkable thyroid panel, and normal B12 and folate, so we begin to rule out a medical cause for his psychiatric symptoms.

The authors’ observations

Check for these and other possible causes of depressive symptoms in older patients with a history of BPD. Mr. B’s depression likely resulted from multiple causes, including medical disease, functional impairment, loss of social and family contacts, and substance abuse—all late-life predictors of depression. BPD also predisposed him to depression.

Bipolar depression. Despite its profound morbidity and mortality, bipolar depression remains a mystery, especially in the elderly. Mr. B’s depression emerged after he was free of depressive symptoms for more than 20 years.

Some researchers believe that compared with other depressions, bipolar depression has a more acute onset, marked psychomotor retardation, and lessened response to antidepressants.^6,8 Kraepelin associated bipolar depression with lethargy, mental slowing, and hypersomnia, whereas agitation and insomnia signal unipolar depression.⁹

To differentiate bipolar from unipolar or secondary depression in older patients, watch for:

• suicide risk, which is heightened during BPD’s depressive phase⁹
  
• secondary manias, for which underlying causes must be determined and treated if possible.
  

Medication-induced depression. Medications can cause depressive symptoms (see Related resources), but identifying an offending agent without an obvious chronologic relationship can be difficult, especially in older patients who are taking numerous medications.⁹

Depression caused by medication might be limited to somatic complaints such as fatigue or tiredness,⁹ and often lacks features seen with mood disorders such as depressed mood, anhedonia, guilt, and diminished interest in activities. Mr. B’s anhedonia and amotivation suggest his depression was not medication-induced.¹⁰

Disease-induced depression. Medical comorbidities are common among older persons with mood disorders and can complicate treatment response and outcome. Physical disease can cause or worsen depression:¹¹

• Endocrine and immunologic diseases might cause depression or mania.
  
• Cardiovascular and cerebrovascular diseases; CNS disorders such as dementia, Parkinson’s disease, and multiple sclerosis; cancer; and connective tissue disease increase risk for comorbid depression.
  

Mr. B’s hypertension, diabetes, or coronary artery disease could have contributed to his depression or complicated the course.

 

¹¹

Vascular depression. Comorbid depressive symptoms and vascular disease—or “vascular depression”—can cause ischemic brain lesions, cognitive impairment, increased apathy and retardation, and impaired fluency and naming.¹²

What defines vascular depression has been debated. Watch for clinical or laboratory evidence of vascular disease, depression, and neuropsychological impairment.¹³

Treatment: searching for evidence

Two days after admission, Mr. B is transferred to the ICU after suffering severe hypoglycemia and showing signs of medically induced delirium. Elevated creatinine (1.7 mg/dL) indicates acute renal failure, which could be related to his elevated serum lithium (1.7 mEq/L). Acting on the internist’s advice, the consulting psychiatrist stops lithium and restarts valproate, 500 mg bid.

Mr. B becomes medically stable after 3 days, mostly through acute IV hydration and by withholding oral diabetes medications, which normalizes his blood sugar. He is transferred back to the psychiatry unit. We try lithium again at 300 mg bid, but creatinine and serum lithium quickly rise.

Mr. B remains hospitalized for 3 months with severe, treatment-resistant depression. Trials of nearly every second-generation antipsychotic (SGA) cause symptomatic orthostatic hypotension, leading to several falls. He does not respond to divalproex, up to 2,000 mg/d; citalopram, 60 mg/d; mirtazapine, 30 mg at bedtime; venlafaxine, 100 mg tid; or bupropion, 100 mg tid.

We suggest electroconvulsive therapy (ECT) but Mr. B declines, saying this treatment caused his mother to decompensate. We try lamotrigine, 25 mg/d, and titrate it over 6 weeks to 200 mg bid. After we add haloperidol, 5 mg at bedtime, and bupropion, 300 mg/d, Mr. B becomes mentally stable.

The authors’ observations

Numerous clinical challenges—such as managing complicated/refractory BPD, medical comorbidity, and medication adherence (Box)^14,15—complicate treatment of late-life BPD.¹⁶ Regular communication with providers and integrating health care services can minimize complication risk.¹⁶

Pharmacotherapy, a core element of BPD treatment, is challenging in older patients because of their:

• heightened threat of complications and sensitivity to side effects because of age-related pharmacokinetic changes
  
• increased risk of drug-drug interactions
  
• increased potential for age-related psychosocial problems (increased social isolation, financial difficulties, demoralization, increased stress, inability to work).
  

Box

Initial clinical and laboratory evaluations can rule out aggravating or causative factors and identify conditions that can cause drug intolerability.⁵ Check orthostatic vital signs and perform a detailed medical and psychosocial history, neurologic examination, ECG, and cognitive evaluation.

Consider side effects, medical and neurologic comorbidities, and treatment history before prescribing a mood stabilizer, antipsychotic, or antidepressant to an older patient. Avoid unwarranted discontinuation of a previously effective agent, such as when drug concentrations are elevated or inadequate—as happened with Mr. B.⁵ Also investigate the patient’s side-effect history before stopping a medication.⁵

Medications. Mr. B’s inability to tolerate lithium posed a treatment challenge. Adjusting lithium dosages to compensate for age-related pharmacokinetic, pharmacodynamic, and renal clearance changes can prevent toxicity.⁵ Avoid stopping lithium abruptly, as this can trigger recurrence of manic or depressive episodes.¹⁷

Lamotrigine, indicated for BPD maintenance therapy, appears to prevent depressive/mood relapse. Compared with other anticonvulsants, lamotrigine might cause fewer negative effects on cognition and less induction of hepatic enzymes. It is well tolerated by older patients but has not been studied adequately in this age group.¹⁶

Antipsychotics are widely used in BPD,¹⁶ especially when psychosis is present with mania or depression or the patient is agitated. Most studies of antipsychotics in BPD have followed younger adults, however, and most studies in older patients have followed those with dementia or schizophrenia.

Use of first-generation antipsychotics such as haloperidol is especially challenging in the elderly because these drugs increase risk of cardiovascular effects, extrapyramidal symptoms, and tardive dyskinesia and can cause depression in BPD.¹⁶ By comparison, SGAs carry a lower risk of involuntary motion¹⁸ but can increase risk of obesity, diabetes, and dyslipidemia. However:

• The need to manage psychosis usually overrides concerns about metabolic sequelae.
  
• Older patients might be less susceptible to metabolic effects,¹⁶ though this has not been confirmed.
  

 

SGAs can be used safely in patients with a history of diabetes. Start at lower-than-normal dosages and titrate slowly. Perform baseline and regular checks—including weight, blood glucose, lipid levels, and blood pressure—following American Psychiatric Association and American Diabetes Association consensus guidelines.¹⁹ Also check glycosylated hemoglobin every 3 to 6 months in patients with diabetes, and follow up with other providers to ensure proper diabetes management.

As with most aspects of late-life BPD, scant evidence guides SGA use. Avoid low-potency neuroleptics such as chlorpromazine, which can cause severe sedation and orthostatic hypotension. For Mr. B, a more-tolerable SGA such as aripiprazole or ziprasidone might be prudent, given his propensity for orthostatic hypotension and history of diabetes. Olanzapine or clozapine can cause anticholinergic effects and—in Mr. B’s case—lead to weight gain and worsen diabetes.

Antidepressant use in BPD usually is reserved for depressive symptoms that impair occupational or social functioning and exceed DSM-IV-TR diagnostic criteria.^8,9 Consider later-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs), because tricyclics pose a greater risk of triggering a switch into hypomania or mania and can cause sedation and orthostatic, cardiac, anticholinergic, and anti-alpha 1 effects.

Among SSRIs, consider citalopram, escitalopram, or sertraline for older patients taking one or more other medications, as these antidepressants have less potential for drug-drug interactions than fluoxetine and paroxetine.¹¹ In a recent comparison of newer antidepressants,²⁰ venlafaxine showed the highest relative risk of mood polarity switching and bupropion the lowest.

Consider ECT for older patients with refractory mania or depression or who show evidence of suicidality or inadequate nutrition.⁵

Follow-up: ongoing issues

Three months after his admission, we discharge Mr. B to a board-and-care facility because family members will not take him in. Several weeks later, he again ignores his prescriptions and decompensates with worsening depression.

Family members have Mr. B admitted to an inpatient psychiatric facility closer to their home. He remains depressed, stays at the facility on and off for almost 1 year, and is eventually conserved by the county. Adverse side effects—mostly constipation and orthostatic hypotension—continue to complicate treatment.

Before Mr. B’s most recent discharge, another psychiatrist restarts lithium, 300 mg bid, and nortriptyline, 100 mg at bedtime—the combination that kept Mr. B relatively stable for more than 2 decades.

Related resources

• National Institute of Mental Health—depression information. www.nimh.nih.gov/healthinformation/depressionmenu.cfm.
  
• Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). www.stepbd.org.
  
• Medicinenet.com. Medicines that cause depression. www.medicinenet.com/depression/index.htm. Click on “Medicines that cause depression.”
  

Drug brand name

• Aripiprazole • Abilify
  
• Bupropion • Wellbutrin
  
• Chlorpromazine • Thorazine
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Divalproex • Depakote
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Haloperidol • Haldol
  
• Lamotrigine • Lamictal
  
• Lithium • Various
  
• Mirtazapine • Remeron
  
• Nortriptyline • Pamelor
  
• Olanzapine • Zyprexa
  
• Paroxetine • Paxil
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Sertraline • Zoloft
  
• Venlafaxine • Effexor
  
• Ziprasidone • Geodon
  

Disclosures

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

History: bipolar for 30 years

Mr. B, age 66, was diagnosed 30 years ago with type I bipolar disorder and has type 2 diabetes, hypertension, alcohol abuse disorder, and cardiac disease. After repeated suicide attempts and hospitalizations in the past, he has been stable for 20 years on lithium, 600 mg bid, and nortriptyline, 50 mg at bedtime. He has had intermittent mania with little evidence of depression.

Two years ago, Mr. B called a local clinic to report that an intruder had him “holed up.” His speech was pressured and garbled, and his thoughts were tangential, irrational, and markedly paranoid. A clinic psychiatrist called Mr. B’s son, who said his father “built a bomb shelter” because “trolls and little people” were out to kill him. A family member called police, and Mr. B was brought to the ER and admitted for treatment.

A hospital psychiatrist stopped lithium in light of Mr. B’s history of cardiac problems and because the psychiatrist considered the medication ineffective, even though serum lithium was only 0.03 mEq/L. The psychiatrist then started:

• divalproex at 500 mg bid, titrated over 1 week to 500 mg each morning and 1,000 mg at bed-time to reach serum valproate of 80 mEq/L
  
• quetiapine at 200 mg at bedtime, titrated over 1 week to 400 mg at bedtime.
  

Mr. B was still manic, paranoid, and hallucinating 1 week later, yet was discharged after he convinced the county hearing officer that he had recovered.

Two weeks later, Mr. B is brought to another psychiatric hospital, where a psychiatrist restarts unknown dosages of lithium, risperidone, and nortriptyline. From there, he is transferred to our in-patient unit. At presentation, he claims he has been drinking and that members of a drug cartel have recruited him. He says he has been skipping medications because he is “unclear which drugs to take.”

We stop lithium and restart divalproex, 500 mg each morning and 1,500 mg at bedtime, to try to treat his mania without causing cognitive problems.

We stop risperidone because of his hypotension and nortriptyline because it was not working, and restart quetiapine, 600 mg at bedtime, for his paranoia. He remains paranoid 1 week later but his mania improves, so we discharge him on the above regimen. We urge him to take his medications and follow up with his outpatient psychiatrist 1 week later.

Divorced, Mr. B lives alone with no family nearby. His son comes in from out of town to help him resettle after discharge, then leaves the next day.

Several months later, Mr. B’s paranoia returns. He is not taking his medications because “the doctors took away my lithium and these new drugs don’t work.” He tells staff he is a martial arts expert and has purchased 7 cars in recent weeks. We restart lithium at 600 mg bid; serum lithium reaches 1.1 mEq/L, but his mania persists. After 5 days, we add aripiprazole, 15 mg/d.

Nearly 2 weeks after admission, a county hearing officer recommends discharging Mr. B despite his severe mania and paranoia. We release him on the above regimen, arrange appointments with his outpatient psychiatrist and primary care physician, and urge medication adherence. We schedule a blood test 3 days after discharge to check serum lithium, but Mr. B does not keep the appointment.

The authors’ observations

Suspect delirium after rapid onset of mania or paranoia in any patient. Also consider dementia and cognitive deficits in older adults, although Mr. B’s symptoms resembled those of previous manic episodes. Although Mr. B’s psychosis was more severe than before, his case underscores the importance of a thorough patient history.

Late-life bipolar disorder. Little is known about diagnosing and treating bipolar disorder (BPD) in older patients. Gaps in empiric knowledge can confound diagnosis, treatment, and outcome. Also, patients age ≥65 with BPD often have severe medical illness and are difficult to treat.¹

Keys to detecting late-life BPD include:

• recognizing clinical features of BPD unique to older persons
  
• differentiating the disorder from late-life schizophrenia (Table).^1,2
  

Older patients’ symptoms usually match DSM-IV-TR criteria for BPD; their response to treatment mirrors that of younger adults.³

Secondary cause. When an older patient’s mania has atypical features or doesn’t respond to conventional treatment, look for a nonpsychiatric process such as a general medical condition or substance abuse (see possible medical causes with this article at www.currentpsychiatry.com). Order laboratory and other tests as clinical suspicion warrants.

Cognitive deficits secondary to BPD can occur at any age and be persistent or progressive,⁴ although Depp et al¹ found more-severe impairment in older patients. Cognitive impairment can endure after successful BPD treatment, although acute treatment might improve cognition in older patients.⁵

 

Lithium can cause dull affect, cognitive slowing, and depersonalization. Titrating to the lowest effective dosage might minimize these effects.

Dementia. Cognitive deficits that accompany mania in older adults could suggest dementia, which usually develops over years and is preceded by cognitive changes without manic-type symptoms. By contrast, bipolar mania emerges more abruptly and is accompanied by affective symptoms. Agitation and psychosis—both symptoms of late-stage dementia—can be early signs of geriatric BPD.²

Delirium. Restlessness, irritability, aggression, and changes in affect can accompany delirium, especially the hyperactive or hyperalert types. Symptoms of anxiety, depression, fear, and loose or tangential thinking also are common.

Mania shares some of these features but typically presents with an abnormally and persistently elevated or irritable mood lasting ≥1 week, usually without prominent cognitive impairment.⁶ Mania can also include:

• grandiosity
  
• decreased need for sleep
  
• flight of ideas
  
• distractibility
  
• pressured or increased rate of speech
  
• psychomotor agitation
  
• potentially harmful activities
  
• increased goal-directed activities.⁶
  

By contrast, delirium is marked by waxing and waning consciousness and changes in cognition, such as disorientation and confusion.⁶

Frontal lobe lesions. Decreased prefrontal executive control could underlie mania’s cognitive and emotional symptoms. Decreased right rostral and orbital prefrontal cortex activation has been associated with impaired planning, judgment, and insight, as well as inappropriate conduct.⁷

Table

Clinical features of geriatric bipolar disorder (BPD)

Psychotic features (delusions, hallucinations)
Mean prevalence of 64% (range 20% to 85%) is similar to that of mixed-age groups; paranoia might be more prevalent
Family history
High rates of psychiatric disorders (“affective disorder” in most studies) reported in 10 studies
Compared with younger adults with BPD, older patients:
show longer latency from first depression to mania onset might be more likely to relapse into depression after mania might have less-intense mania are hospitalized longer, possibly because of greater medical comorbidity have less comorbid substance abuse and more-prominent age-associated morphologic abnormalities on neuroimaging2
Compared with late-life schizophrenia, late-life BPD patients show:
more depressive symptoms fewer positive and negative symptoms greater community living and relationship skills, with similar activities of daily living
Source: References 1,2

Continued treatment: depression emerges

Several months later, Mr. B presents with severe depression and continued medication nonadherence. He complains of hypersomnia, poor appetite, anhedonia, amotivation, and a leaden-like paresis in his hands and feet.

We readmit Mr. B to the psychiatric unit. He avoids contact with others, has lost 18 lbs over 6 weeks, and suffers hypotension caused by poor hydration before admission. Three weeks later, he complains that ants are crawling around his room and into his mouth.

Noncontrast brain CT shows no abnormalities. Laboratory tests performed at admission show a subtherapeutic lithium level (0.03 mEq/L), unremarkable thyroid panel, and normal B12 and folate, so we begin to rule out a medical cause for his psychiatric symptoms.

The authors’ observations

Check for these and other possible causes of depressive symptoms in older patients with a history of BPD. Mr. B’s depression likely resulted from multiple causes, including medical disease, functional impairment, loss of social and family contacts, and substance abuse—all late-life predictors of depression. BPD also predisposed him to depression.

Bipolar depression. Despite its profound morbidity and mortality, bipolar depression remains a mystery, especially in the elderly. Mr. B’s depression emerged after he was free of depressive symptoms for more than 20 years.

Some researchers believe that compared with other depressions, bipolar depression has a more acute onset, marked psychomotor retardation, and lessened response to antidepressants.^6,8 Kraepelin associated bipolar depression with lethargy, mental slowing, and hypersomnia, whereas agitation and insomnia signal unipolar depression.⁹

To differentiate bipolar from unipolar or secondary depression in older patients, watch for:

• suicide risk, which is heightened during BPD’s depressive phase⁹
  
• secondary manias, for which underlying causes must be determined and treated if possible.
  

Medication-induced depression. Medications can cause depressive symptoms (see Related resources), but identifying an offending agent without an obvious chronologic relationship can be difficult, especially in older patients who are taking numerous medications.⁹

Depression caused by medication might be limited to somatic complaints such as fatigue or tiredness,⁹ and often lacks features seen with mood disorders such as depressed mood, anhedonia, guilt, and diminished interest in activities. Mr. B’s anhedonia and amotivation suggest his depression was not medication-induced.¹⁰

Disease-induced depression. Medical comorbidities are common among older persons with mood disorders and can complicate treatment response and outcome. Physical disease can cause or worsen depression:¹¹

• Endocrine and immunologic diseases might cause depression or mania.
  
• Cardiovascular and cerebrovascular diseases; CNS disorders such as dementia, Parkinson’s disease, and multiple sclerosis; cancer; and connective tissue disease increase risk for comorbid depression.
  

Mr. B’s hypertension, diabetes, or coronary artery disease could have contributed to his depression or complicated the course.

 

¹¹

Vascular depression. Comorbid depressive symptoms and vascular disease—or “vascular depression”—can cause ischemic brain lesions, cognitive impairment, increased apathy and retardation, and impaired fluency and naming.¹²

What defines vascular depression has been debated. Watch for clinical or laboratory evidence of vascular disease, depression, and neuropsychological impairment.¹³

Treatment: searching for evidence

Two days after admission, Mr. B is transferred to the ICU after suffering severe hypoglycemia and showing signs of medically induced delirium. Elevated creatinine (1.7 mg/dL) indicates acute renal failure, which could be related to his elevated serum lithium (1.7 mEq/L). Acting on the internist’s advice, the consulting psychiatrist stops lithium and restarts valproate, 500 mg bid.

Mr. B becomes medically stable after 3 days, mostly through acute IV hydration and by withholding oral diabetes medications, which normalizes his blood sugar. He is transferred back to the psychiatry unit. We try lithium again at 300 mg bid, but creatinine and serum lithium quickly rise.

Mr. B remains hospitalized for 3 months with severe, treatment-resistant depression. Trials of nearly every second-generation antipsychotic (SGA) cause symptomatic orthostatic hypotension, leading to several falls. He does not respond to divalproex, up to 2,000 mg/d; citalopram, 60 mg/d; mirtazapine, 30 mg at bedtime; venlafaxine, 100 mg tid; or bupropion, 100 mg tid.

We suggest electroconvulsive therapy (ECT) but Mr. B declines, saying this treatment caused his mother to decompensate. We try lamotrigine, 25 mg/d, and titrate it over 6 weeks to 200 mg bid. After we add haloperidol, 5 mg at bedtime, and bupropion, 300 mg/d, Mr. B becomes mentally stable.

The authors’ observations

Numerous clinical challenges—such as managing complicated/refractory BPD, medical comorbidity, and medication adherence (Box)^14,15—complicate treatment of late-life BPD.¹⁶ Regular communication with providers and integrating health care services can minimize complication risk.¹⁶

Pharmacotherapy, a core element of BPD treatment, is challenging in older patients because of their:

• heightened threat of complications and sensitivity to side effects because of age-related pharmacokinetic changes
  
• increased risk of drug-drug interactions
  
• increased potential for age-related psychosocial problems (increased social isolation, financial difficulties, demoralization, increased stress, inability to work).
  

Box

Initial clinical and laboratory evaluations can rule out aggravating or causative factors and identify conditions that can cause drug intolerability.⁵ Check orthostatic vital signs and perform a detailed medical and psychosocial history, neurologic examination, ECG, and cognitive evaluation.

Consider side effects, medical and neurologic comorbidities, and treatment history before prescribing a mood stabilizer, antipsychotic, or antidepressant to an older patient. Avoid unwarranted discontinuation of a previously effective agent, such as when drug concentrations are elevated or inadequate—as happened with Mr. B.⁵ Also investigate the patient’s side-effect history before stopping a medication.⁵

Medications. Mr. B’s inability to tolerate lithium posed a treatment challenge. Adjusting lithium dosages to compensate for age-related pharmacokinetic, pharmacodynamic, and renal clearance changes can prevent toxicity.⁵ Avoid stopping lithium abruptly, as this can trigger recurrence of manic or depressive episodes.¹⁷

Lamotrigine, indicated for BPD maintenance therapy, appears to prevent depressive/mood relapse. Compared with other anticonvulsants, lamotrigine might cause fewer negative effects on cognition and less induction of hepatic enzymes. It is well tolerated by older patients but has not been studied adequately in this age group.¹⁶

Antipsychotics are widely used in BPD,¹⁶ especially when psychosis is present with mania or depression or the patient is agitated. Most studies of antipsychotics in BPD have followed younger adults, however, and most studies in older patients have followed those with dementia or schizophrenia.

Use of first-generation antipsychotics such as haloperidol is especially challenging in the elderly because these drugs increase risk of cardiovascular effects, extrapyramidal symptoms, and tardive dyskinesia and can cause depression in BPD.¹⁶ By comparison, SGAs carry a lower risk of involuntary motion¹⁸ but can increase risk of obesity, diabetes, and dyslipidemia. However:

• The need to manage psychosis usually overrides concerns about metabolic sequelae.
  
• Older patients might be less susceptible to metabolic effects,¹⁶ though this has not been confirmed.
  

 

SGAs can be used safely in patients with a history of diabetes. Start at lower-than-normal dosages and titrate slowly. Perform baseline and regular checks—including weight, blood glucose, lipid levels, and blood pressure—following American Psychiatric Association and American Diabetes Association consensus guidelines.¹⁹ Also check glycosylated hemoglobin every 3 to 6 months in patients with diabetes, and follow up with other providers to ensure proper diabetes management.

As with most aspects of late-life BPD, scant evidence guides SGA use. Avoid low-potency neuroleptics such as chlorpromazine, which can cause severe sedation and orthostatic hypotension. For Mr. B, a more-tolerable SGA such as aripiprazole or ziprasidone might be prudent, given his propensity for orthostatic hypotension and history of diabetes. Olanzapine or clozapine can cause anticholinergic effects and—in Mr. B’s case—lead to weight gain and worsen diabetes.

Antidepressant use in BPD usually is reserved for depressive symptoms that impair occupational or social functioning and exceed DSM-IV-TR diagnostic criteria.^8,9 Consider later-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs), because tricyclics pose a greater risk of triggering a switch into hypomania or mania and can cause sedation and orthostatic, cardiac, anticholinergic, and anti-alpha 1 effects.

Among SSRIs, consider citalopram, escitalopram, or sertraline for older patients taking one or more other medications, as these antidepressants have less potential for drug-drug interactions than fluoxetine and paroxetine.¹¹ In a recent comparison of newer antidepressants,²⁰ venlafaxine showed the highest relative risk of mood polarity switching and bupropion the lowest.

Consider ECT for older patients with refractory mania or depression or who show evidence of suicidality or inadequate nutrition.⁵

Follow-up: ongoing issues

Three months after his admission, we discharge Mr. B to a board-and-care facility because family members will not take him in. Several weeks later, he again ignores his prescriptions and decompensates with worsening depression.

Family members have Mr. B admitted to an inpatient psychiatric facility closer to their home. He remains depressed, stays at the facility on and off for almost 1 year, and is eventually conserved by the county. Adverse side effects—mostly constipation and orthostatic hypotension—continue to complicate treatment.

Before Mr. B’s most recent discharge, another psychiatrist restarts lithium, 300 mg bid, and nortriptyline, 100 mg at bedtime—the combination that kept Mr. B relatively stable for more than 2 decades.

Related resources

• National Institute of Mental Health—depression information. www.nimh.nih.gov/healthinformation/depressionmenu.cfm.
  
• Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). www.stepbd.org.
  
• Medicinenet.com. Medicines that cause depression. www.medicinenet.com/depression/index.htm. Click on “Medicines that cause depression.”
  

Drug brand name

• Aripiprazole • Abilify
  
• Bupropion • Wellbutrin
  
• Chlorpromazine • Thorazine
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Divalproex • Depakote
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Haloperidol • Haldol
  
• Lamotrigine • Lamictal
  
• Lithium • Various
  
• Mirtazapine • Remeron
  
• Nortriptyline • Pamelor
  
• Olanzapine • Zyprexa
  
• Paroxetine • Paxil
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Sertraline • Zoloft
  
• Venlafaxine • Effexor
  
• Ziprasidone • Geodon
  

Disclosures

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

Presentation: unconscious on the street

Emergency medical personnel bring Mr. M, age 66, to the ER after passers-by find him supine on the sidewalk. On arrival, he is comatose as confirmed by a Glasgow Coma Scale score of 8 (eye opening 3, verbal response 2, motor response 3). Systolic blood pressure is 108 mm Hg on palpation, pulse is 135 beats per minute, and temperature is 105 °F. Minor abrasions cover his face and arms, and his hands and feet are rigid.

Mr. M has lived at a board-and-care facility for 30 years. The facility’s operator tells us that Mr. M has had schizophrenia for 40 years and has been taking:

• olanzapine, 7.5 mg each morning and 10 mg at bedtime
  
• chlorpromazine, 50 mg nightly
  
• lithium carbonate, 300 mg tid
  
• and benztropine, 2 mg bid.
  

For years, Mr. M had taken chlorpromazine, 600 mg/d, without suffering adverse effects. Six weeks before the patient presented to us, his outpatient psychiatrist added standard-release bupropion, 150 mg each morning, to help him quit smoking and improve his mood. Mr. M’s boarding facility caregivers say that earlier today, he had seen the psychiatrist for a routine visit. The psychiatrist did not change his medication.

Three weeks ago, Mr. M was hospitalized for 6 days with pneumonia. In 3 months, he will undergo surgery for prostate cancer. He is taking no medication for the prostate cancer.

Creatine phosphokinase (CPK) is 2,939 IU/L, indicating neuroleptic malignant syndrome (NMS). Other laboratory test results suggest diabetes or renal failure (Table 1). Lumbar puncture shows protein at 91 mg/dL, glucose at 74 mg/dL, and red- and white-blood-cell counts at 0 and 1, respectively. CSF Gram’s stain and brain CT are unremarkable. ECG is normal except for sinus tachycardia. Serum lithium is normal (1.1 mmol/L).

Mr. M undergoes tracheal intubation and receives ceftazidime, dose unknown, because chest radiograph shows lower lung opacities, suggesting aspiration. He receives morphine, 2 to 4 mg hourly as needed, to calm him during intubation. He is then transferred to the intensive care unit.

Table 1

Diabetes, renal failure, or NMS? The story behind Mr. M’s laboratory values

Mr. M’s reading	Normal range	Might suggest
CPK	2,939 IU/L	8-150 IU/L	NMS
Serum creatinine	1.9 mg/dL	0.6-1.5 mg/dL	Renal failure, a complication from elevated CPK
Serum glucose	143 mg/dL	66-99 mg/dL	Diabetes mellitus
NMS: Neuroleptic malignant syndrome
CPK: Creatine phosphokinase

The authors’ observations

NMS, a potentially fatal side effect of antipsychotics, is characterized by rigidity, hyperthermia, and autonomic instability¹—as seen with Mr. M.

The patient’s rigidity, elevated creatine kinase, and face and arm abrasions could suggest a seizure. Mr. M’s EEG is negative, however, and he has no history of seizures or head trauma, so seizure is ruled out.

Researchers have associated bupropion with a small risk of developing seizures. Richmond and Zwar² reported a 0.1% risk with bupropion, ≥300 mg/d, but Mr. M was taking 150 mg/d. Dunner et al³ estimated the risk of developing seizure while taking standard-release bupropion—the form Mr. M used—at 0.06%, but patients in this study who developed seizures typically had a past seizure disorder or head trauma.

The combination of hyperthermia, tachycardia, altered mental status, and positive chest X-ray suggest pneumonia, which was addressed with antibiotics. Pneumonia, however, does not solely account for Mr. M’s fever, rigidity, and profoundly increased CPK. These findings suggest NMS.

The Glasgow Coma Scale (GCS) is used to quantitatively rate degree of responsiveness in critically ill or injured patients (Table 2). Total scores range from 3 to 15 based on the patient’s best eye, motor, and verbal responses. Total score ≤8 indicates a probable coma. Serial GCS scores can measure clinical course in comatose patients.

Table 2

Using Glasgow Coma Scale to determine level of consciousness

Component	Response	Score
Best eye response	No eye opening	1
	Eye opening to pain	2
	Eye opening to verbal command	3
	Eyes open spontaneously	4
Best verbal response	No verbal response	1
	Incomprehensible sounds	2
	Inappropriate words	3
	Confused	4
	Oriented	5
Best motor response	No motor response	1
	Extension to pain	2
	Flexion to pain	3
	Withdrawal from pain	4
	Localizing pain	5
	Obeys commands	6
Total score ≤8 is severe, and 90% of patients with scores ≤8 are in a coma). Coma is defined as not opening eyes, not obeying commands, and not saying understandable words. Composite scores listing eye, verbal, and motor responses (such as E3V3M5) are clinically more useful than totals.
Source: Reprinted from Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;304(7872):81-4, with permission from Elsevier.

Treatment: slow progress

In the ICU, we diagnose NMS and stop all psychotropics, fearing that interactions between any of them might be causing NMS. We give midazolam, 1 to 2 mg hourly as needed for agitation, and continue morphine, 2 to 4 mg hourly as needed for pain. We stop ceftazidime after ruling out aspiration risk.

 

On day 2 of hospitalization, we call the neurology and consultation-liaison (C-L) psychiatry services. The C-L psychiatrist attempts a mental status examination, but Mr. M is too frail and sedated to communicate. Neurologic exam shows increased foot rigidity, and follow-up studies show negative EEG, normal head and neck MRIs and MRAs, a peak in CPK at 5,487 IU/L, and normal chest films.

We taper and discontinue midazolam and morphine, and Mr. M’s consciousness improves as the dosages decrease. We add lorazepam, 1 mg tid, to address Mr. M’s agitation. He also starts physical therapy to address potential movement problems caused by laying static for 3 days. By day 7, he is extubated and transferred to the general medical unit.

On day 9, Mr. M’s recall and concentration are diminished, and he cannot follow a 3-step command. His Mini-Mental State Examination (MMSE) score of 17 points to a cognitive impairment.

By day 12, residual psychosis is increasing Mr. M’s confusion, paranoia, and agitation. Despite this complication, he is able to work with his occupational and physical therapists.

By day 20, Mr. M becomes more paranoid, with tangential and loose associations. To address these symptoms, we stop lorazepam and start aripiprazole, 15 mg each morning. Because aripiprazole is a partial dopamine agonist and antagonist, it is less likely than other antipsychotics to cause recurrence of NMS symptoms.

Four days later, Mr. M is medically cleared for transfer to the county psychiatric hospital. Creatinine and CPK elevations, metabolic acidosis, and anemia have resolved.

Treatment: new facility, new drugs

On initial evaluation at the psychiatric hospital, Mr. M is cooperative and aware of person, place, and time. His thought processes range from tangential to disorganized, and his paranoia persists.

The attending psychiatrist stops aripiprazole and starts risperidone, 1 mg bid, possibly because he is less familiar with aripiprazole—a newer antipsychotic— than with risperidone. Laboratory results within 3 days of starting risperidone show normal serum levels, blood counts, liver enzymes, and CPK.

On day 2 at the psychiatric hospital, Mr. M’s behavior worsens; he frequently disrobes in front of others, yells at staff, and requires verbal redirection. His MMSE score has fallen to 15. The attending psychiatrist modifies risperidone to 2 mg nightly and adds donepezil, 10 mg each morning, to try to reverse his cognitive decline.

By day 8, Mr. M is more cooperative and his behavior improves. He is transferred back to his board-and-care facility on risperidone and donepezil at the above dosages.

The following month, Mr. M presents to his outpatient psychiatrist with improved cognitive function, but he is still delusional. The psychiatrist stops risperidone and donepezil and resumes olanzapine, 7.5 mg each morning and 10 mg nightly, and chlorpromazine, 50 mg nightly, to try to restore the patient’s pre-NMS function.

Mr. M undergoes successful prostate cancer surgery before his 3-month psychiatry follow-up, at which the psychiatrist adds lithium carbonate, 300 mg tid, for residual irritability. Serum lithium levels are normal; bupropion is not restarted.

One year after presentation, Mr. M is minimally delusional but functioning well. No symptoms suggesting NMS recurrence have been reported.

The authors’ observations

Though the precise mechanism is unknown, NMS has been linked with use of FGAs such as chlorpromazine, which can trigger excessive dopamine blockade.⁴ Studies increasingly associate SGAs such as olanzapine, risperidone, and aripiprazole with NMS onset.^4-6 Mood stabilizers such as lithium carbonate also have been implicated, especially when used with antipsychotics.^6-9 No association between antibiotics and NMS has been found.

For years, Mr. M has been taking FGAs and concomitant olanzapine and lithium carbonate without developing NMS symptoms until now. Since discharge, he has been free of NMS symptoms despite taking two SGAs (aripiprazole and risperidone) at different times and later resuming chlorpromazine, olanzapine, and lithium carbonate.

Of note, bupropion—the last psychotropic added before NMS onset—has not been restarted. The literature does not link bupropion to NMS, although one case report¹⁰ suggests an association between fluoxetine and NMS after the patient had taken several antipsychotic/antidepressant combinations.

As a dopamine agonist, bupropion should protect against NMS. Case reports,^11,12 however, have described patients who developed NMS after antipsychotics were discontinued, and stopping an antipsychotic essentially mimics bupropion’s action by eliminating the dopamine blockade. Additionally, bupropion’s norepinephrine modulation could have precipitated NMS by dysregulating the sympathetic nervous system.¹³

Mr. M’s board-and-care operator indicated that the patient’s tobacco consumption decreased—from about a pack to a half-pack of cigarettes daily—after bupropion was added. Alternatively, the effects of pneumonia could have curtailed Mr. M’s smoking. Because nicotine increases metabolism of neuroleptics,^14,15 decreased nicotine consumption might have increased dopamine blockade to the point of causing NMS.

 

Other possibilities. Mr. M’s pneumonia might have caused dehydration, which can also lead to NMS.

Bupropion also reportedly alters metabolism of chlorpromazine and other phenothiazine antipsychotics by inhibiting the cytochrome P-450 2D6 isoenzyme. This pharmacokinetic interaction could have precipitated Mr. M’s NMS episode independent of an antipsychotic dosage increase.¹⁶

Because this case is so complex, pinpointing a specific cause for Mr. M’s apparent NMS symptoms is difficult. Be aware that combining psychotropics can lead to NMS. Patients who present with mental status changes, hyperthermia, rigidity, and/or increased creatine kinase while taking psychotropics should be promptly evaluated and managed.

Treating NMS

A review of NMS treatment by Davis et al¹⁷ suggests that you:

• consider NMS in the differential diagnosis of an acutely delirious patient who has used antipsychotics, no matter how long he or she has been taking the medication(s) or how stable the dosage
  
• check for other signs of NMS—such as rigidity or autonomic instability—during the physical examination.
  
• consider NMS as a possible cause of dysarthria, diaphoresis, dysphagia, sialorrhea, and myoclonus, although these are less common signs of the disorder
  
• include CPK levels, chemistry panel, CBC, and liver enzyme assessment in the early evaluation of laboratory results. Consider performing a urine drug screen to check for illicit substance use. Head CT results might also help confirm NMS diagnosis.
  

If patient history, physical, and laboratory signs suggest NMS, immediately transfer the patient to a general hospital ICU. Withhold antipsychotics until the NMS episode is resolved, the patient receives aggressive hydration and fluid management, and other causes for delirium are investigated.

If sedation becomes necessary, use benzodiazepines cautiously. Serial CPKs and daily reassessment of clinical degree of rigidity are essential; continued rigidity may indicate use of dopamine agonists and dantrolene.¹⁷

Related resources

• Neuroleptic Malignant Syndrome Information Service. Archive of articles addressing NMS diagnosis and treatment, and listing of psychotropics associated with NMS. www.nmsis.org.
  

Drug brand name

• Aripiprazole • Abilify
  
• Benztropine • Cogentin
  
• Bupropion SR • Wellbutrin, Zyban
  
• Ceftazidime • various
  
• Chlorpromazine • Thorazine
  
• Dantrolene • Dantrium
  
• Donepezil • Aricept
  
• Lithium carbonate • various
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Risperidone • Risperdal
  

Disclosures

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

Presentation: unconscious on the street

Emergency medical personnel bring Mr. M, age 66, to the ER after passers-by find him supine on the sidewalk. On arrival, he is comatose as confirmed by a Glasgow Coma Scale score of 8 (eye opening 3, verbal response 2, motor response 3). Systolic blood pressure is 108 mm Hg on palpation, pulse is 135 beats per minute, and temperature is 105 °F. Minor abrasions cover his face and arms, and his hands and feet are rigid.

Mr. M has lived at a board-and-care facility for 30 years. The facility’s operator tells us that Mr. M has had schizophrenia for 40 years and has been taking:

• olanzapine, 7.5 mg each morning and 10 mg at bedtime
  
• chlorpromazine, 50 mg nightly
  
• lithium carbonate, 300 mg tid
  
• and benztropine, 2 mg bid.
  

For years, Mr. M had taken chlorpromazine, 600 mg/d, without suffering adverse effects. Six weeks before the patient presented to us, his outpatient psychiatrist added standard-release bupropion, 150 mg each morning, to help him quit smoking and improve his mood. Mr. M’s boarding facility caregivers say that earlier today, he had seen the psychiatrist for a routine visit. The psychiatrist did not change his medication.

Three weeks ago, Mr. M was hospitalized for 6 days with pneumonia. In 3 months, he will undergo surgery for prostate cancer. He is taking no medication for the prostate cancer.

Creatine phosphokinase (CPK) is 2,939 IU/L, indicating neuroleptic malignant syndrome (NMS). Other laboratory test results suggest diabetes or renal failure (Table 1). Lumbar puncture shows protein at 91 mg/dL, glucose at 74 mg/dL, and red- and white-blood-cell counts at 0 and 1, respectively. CSF Gram’s stain and brain CT are unremarkable. ECG is normal except for sinus tachycardia. Serum lithium is normal (1.1 mmol/L).

Mr. M undergoes tracheal intubation and receives ceftazidime, dose unknown, because chest radiograph shows lower lung opacities, suggesting aspiration. He receives morphine, 2 to 4 mg hourly as needed, to calm him during intubation. He is then transferred to the intensive care unit.

Table 1

Diabetes, renal failure, or NMS? The story behind Mr. M’s laboratory values

Mr. M’s reading	Normal range	Might suggest
CPK	2,939 IU/L	8-150 IU/L	NMS
Serum creatinine	1.9 mg/dL	0.6-1.5 mg/dL	Renal failure, a complication from elevated CPK
Serum glucose	143 mg/dL	66-99 mg/dL	Diabetes mellitus
NMS: Neuroleptic malignant syndrome
CPK: Creatine phosphokinase

The authors’ observations

NMS, a potentially fatal side effect of antipsychotics, is characterized by rigidity, hyperthermia, and autonomic instability¹—as seen with Mr. M.

The patient’s rigidity, elevated creatine kinase, and face and arm abrasions could suggest a seizure. Mr. M’s EEG is negative, however, and he has no history of seizures or head trauma, so seizure is ruled out.

Researchers have associated bupropion with a small risk of developing seizures. Richmond and Zwar² reported a 0.1% risk with bupropion, ≥300 mg/d, but Mr. M was taking 150 mg/d. Dunner et al³ estimated the risk of developing seizure while taking standard-release bupropion—the form Mr. M used—at 0.06%, but patients in this study who developed seizures typically had a past seizure disorder or head trauma.

The combination of hyperthermia, tachycardia, altered mental status, and positive chest X-ray suggest pneumonia, which was addressed with antibiotics. Pneumonia, however, does not solely account for Mr. M’s fever, rigidity, and profoundly increased CPK. These findings suggest NMS.

The Glasgow Coma Scale (GCS) is used to quantitatively rate degree of responsiveness in critically ill or injured patients (Table 2). Total scores range from 3 to 15 based on the patient’s best eye, motor, and verbal responses. Total score ≤8 indicates a probable coma. Serial GCS scores can measure clinical course in comatose patients.

Table 2

Using Glasgow Coma Scale to determine level of consciousness

Component	Response	Score
Best eye response	No eye opening	1
	Eye opening to pain	2
	Eye opening to verbal command	3
	Eyes open spontaneously	4
Best verbal response	No verbal response	1
	Incomprehensible sounds	2
	Inappropriate words	3
	Confused	4
	Oriented	5
Best motor response	No motor response	1
	Extension to pain	2
	Flexion to pain	3
	Withdrawal from pain	4
	Localizing pain	5
	Obeys commands	6
Total score ≤8 is severe, and 90% of patients with scores ≤8 are in a coma). Coma is defined as not opening eyes, not obeying commands, and not saying understandable words. Composite scores listing eye, verbal, and motor responses (such as E3V3M5) are clinically more useful than totals.
Source: Reprinted from Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;304(7872):81-4, with permission from Elsevier.

Treatment: slow progress

In the ICU, we diagnose NMS and stop all psychotropics, fearing that interactions between any of them might be causing NMS. We give midazolam, 1 to 2 mg hourly as needed for agitation, and continue morphine, 2 to 4 mg hourly as needed for pain. We stop ceftazidime after ruling out aspiration risk.

 

On day 2 of hospitalization, we call the neurology and consultation-liaison (C-L) psychiatry services. The C-L psychiatrist attempts a mental status examination, but Mr. M is too frail and sedated to communicate. Neurologic exam shows increased foot rigidity, and follow-up studies show negative EEG, normal head and neck MRIs and MRAs, a peak in CPK at 5,487 IU/L, and normal chest films.

We taper and discontinue midazolam and morphine, and Mr. M’s consciousness improves as the dosages decrease. We add lorazepam, 1 mg tid, to address Mr. M’s agitation. He also starts physical therapy to address potential movement problems caused by laying static for 3 days. By day 7, he is extubated and transferred to the general medical unit.

On day 9, Mr. M’s recall and concentration are diminished, and he cannot follow a 3-step command. His Mini-Mental State Examination (MMSE) score of 17 points to a cognitive impairment.

By day 12, residual psychosis is increasing Mr. M’s confusion, paranoia, and agitation. Despite this complication, he is able to work with his occupational and physical therapists.

By day 20, Mr. M becomes more paranoid, with tangential and loose associations. To address these symptoms, we stop lorazepam and start aripiprazole, 15 mg each morning. Because aripiprazole is a partial dopamine agonist and antagonist, it is less likely than other antipsychotics to cause recurrence of NMS symptoms.

Four days later, Mr. M is medically cleared for transfer to the county psychiatric hospital. Creatinine and CPK elevations, metabolic acidosis, and anemia have resolved.

Treatment: new facility, new drugs

On initial evaluation at the psychiatric hospital, Mr. M is cooperative and aware of person, place, and time. His thought processes range from tangential to disorganized, and his paranoia persists.

The attending psychiatrist stops aripiprazole and starts risperidone, 1 mg bid, possibly because he is less familiar with aripiprazole—a newer antipsychotic— than with risperidone. Laboratory results within 3 days of starting risperidone show normal serum levels, blood counts, liver enzymes, and CPK.

On day 2 at the psychiatric hospital, Mr. M’s behavior worsens; he frequently disrobes in front of others, yells at staff, and requires verbal redirection. His MMSE score has fallen to 15. The attending psychiatrist modifies risperidone to 2 mg nightly and adds donepezil, 10 mg each morning, to try to reverse his cognitive decline.

By day 8, Mr. M is more cooperative and his behavior improves. He is transferred back to his board-and-care facility on risperidone and donepezil at the above dosages.

The following month, Mr. M presents to his outpatient psychiatrist with improved cognitive function, but he is still delusional. The psychiatrist stops risperidone and donepezil and resumes olanzapine, 7.5 mg each morning and 10 mg nightly, and chlorpromazine, 50 mg nightly, to try to restore the patient’s pre-NMS function.

Mr. M undergoes successful prostate cancer surgery before his 3-month psychiatry follow-up, at which the psychiatrist adds lithium carbonate, 300 mg tid, for residual irritability. Serum lithium levels are normal; bupropion is not restarted.

One year after presentation, Mr. M is minimally delusional but functioning well. No symptoms suggesting NMS recurrence have been reported.

The authors’ observations

Though the precise mechanism is unknown, NMS has been linked with use of FGAs such as chlorpromazine, which can trigger excessive dopamine blockade.⁴ Studies increasingly associate SGAs such as olanzapine, risperidone, and aripiprazole with NMS onset.^4-6 Mood stabilizers such as lithium carbonate also have been implicated, especially when used with antipsychotics.^6-9 No association between antibiotics and NMS has been found.

For years, Mr. M has been taking FGAs and concomitant olanzapine and lithium carbonate without developing NMS symptoms until now. Since discharge, he has been free of NMS symptoms despite taking two SGAs (aripiprazole and risperidone) at different times and later resuming chlorpromazine, olanzapine, and lithium carbonate.

Of note, bupropion—the last psychotropic added before NMS onset—has not been restarted. The literature does not link bupropion to NMS, although one case report¹⁰ suggests an association between fluoxetine and NMS after the patient had taken several antipsychotic/antidepressant combinations.

As a dopamine agonist, bupropion should protect against NMS. Case reports,^11,12 however, have described patients who developed NMS after antipsychotics were discontinued, and stopping an antipsychotic essentially mimics bupropion’s action by eliminating the dopamine blockade. Additionally, bupropion’s norepinephrine modulation could have precipitated NMS by dysregulating the sympathetic nervous system.¹³

Mr. M’s board-and-care operator indicated that the patient’s tobacco consumption decreased—from about a pack to a half-pack of cigarettes daily—after bupropion was added. Alternatively, the effects of pneumonia could have curtailed Mr. M’s smoking. Because nicotine increases metabolism of neuroleptics,^14,15 decreased nicotine consumption might have increased dopamine blockade to the point of causing NMS.

 

Other possibilities. Mr. M’s pneumonia might have caused dehydration, which can also lead to NMS.

Bupropion also reportedly alters metabolism of chlorpromazine and other phenothiazine antipsychotics by inhibiting the cytochrome P-450 2D6 isoenzyme. This pharmacokinetic interaction could have precipitated Mr. M’s NMS episode independent of an antipsychotic dosage increase.¹⁶

Because this case is so complex, pinpointing a specific cause for Mr. M’s apparent NMS symptoms is difficult. Be aware that combining psychotropics can lead to NMS. Patients who present with mental status changes, hyperthermia, rigidity, and/or increased creatine kinase while taking psychotropics should be promptly evaluated and managed.

Treating NMS

A review of NMS treatment by Davis et al¹⁷ suggests that you:

• consider NMS in the differential diagnosis of an acutely delirious patient who has used antipsychotics, no matter how long he or she has been taking the medication(s) or how stable the dosage
  
• check for other signs of NMS—such as rigidity or autonomic instability—during the physical examination.
  
• consider NMS as a possible cause of dysarthria, diaphoresis, dysphagia, sialorrhea, and myoclonus, although these are less common signs of the disorder
  
• include CPK levels, chemistry panel, CBC, and liver enzyme assessment in the early evaluation of laboratory results. Consider performing a urine drug screen to check for illicit substance use. Head CT results might also help confirm NMS diagnosis.
  

If patient history, physical, and laboratory signs suggest NMS, immediately transfer the patient to a general hospital ICU. Withhold antipsychotics until the NMS episode is resolved, the patient receives aggressive hydration and fluid management, and other causes for delirium are investigated.

If sedation becomes necessary, use benzodiazepines cautiously. Serial CPKs and daily reassessment of clinical degree of rigidity are essential; continued rigidity may indicate use of dopamine agonists and dantrolene.¹⁷

Related resources

• Neuroleptic Malignant Syndrome Information Service. Archive of articles addressing NMS diagnosis and treatment, and listing of psychotropics associated with NMS. www.nmsis.org.
  

Drug brand name

• Aripiprazole • Abilify
  
• Benztropine • Cogentin
  
• Bupropion SR • Wellbutrin, Zyban
  
• Ceftazidime • various
  
• Chlorpromazine • Thorazine
  
• Dantrolene • Dantrium
  
• Donepezil • Aricept
  
• Lithium carbonate • various
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Risperidone • Risperdal
  

Disclosures

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

Presentation: unconscious on the street

Emergency medical personnel bring Mr. M, age 66, to the ER after passers-by find him supine on the sidewalk. On arrival, he is comatose as confirmed by a Glasgow Coma Scale score of 8 (eye opening 3, verbal response 2, motor response 3). Systolic blood pressure is 108 mm Hg on palpation, pulse is 135 beats per minute, and temperature is 105 °F. Minor abrasions cover his face and arms, and his hands and feet are rigid.

Mr. M has lived at a board-and-care facility for 30 years. The facility’s operator tells us that Mr. M has had schizophrenia for 40 years and has been taking:

• olanzapine, 7.5 mg each morning and 10 mg at bedtime
  
• chlorpromazine, 50 mg nightly
  
• lithium carbonate, 300 mg tid
  
• and benztropine, 2 mg bid.
  

For years, Mr. M had taken chlorpromazine, 600 mg/d, without suffering adverse effects. Six weeks before the patient presented to us, his outpatient psychiatrist added standard-release bupropion, 150 mg each morning, to help him quit smoking and improve his mood. Mr. M’s boarding facility caregivers say that earlier today, he had seen the psychiatrist for a routine visit. The psychiatrist did not change his medication.

Three weeks ago, Mr. M was hospitalized for 6 days with pneumonia. In 3 months, he will undergo surgery for prostate cancer. He is taking no medication for the prostate cancer.

Creatine phosphokinase (CPK) is 2,939 IU/L, indicating neuroleptic malignant syndrome (NMS). Other laboratory test results suggest diabetes or renal failure (Table 1). Lumbar puncture shows protein at 91 mg/dL, glucose at 74 mg/dL, and red- and white-blood-cell counts at 0 and 1, respectively. CSF Gram’s stain and brain CT are unremarkable. ECG is normal except for sinus tachycardia. Serum lithium is normal (1.1 mmol/L).

Mr. M undergoes tracheal intubation and receives ceftazidime, dose unknown, because chest radiograph shows lower lung opacities, suggesting aspiration. He receives morphine, 2 to 4 mg hourly as needed, to calm him during intubation. He is then transferred to the intensive care unit.

Table 1

Diabetes, renal failure, or NMS? The story behind Mr. M’s laboratory values

Mr. M’s reading	Normal range	Might suggest
CPK	2,939 IU/L	8-150 IU/L	NMS
Serum creatinine	1.9 mg/dL	0.6-1.5 mg/dL	Renal failure, a complication from elevated CPK
Serum glucose	143 mg/dL	66-99 mg/dL	Diabetes mellitus
NMS: Neuroleptic malignant syndrome
CPK: Creatine phosphokinase

The authors’ observations

NMS, a potentially fatal side effect of antipsychotics, is characterized by rigidity, hyperthermia, and autonomic instability¹—as seen with Mr. M.

The patient’s rigidity, elevated creatine kinase, and face and arm abrasions could suggest a seizure. Mr. M’s EEG is negative, however, and he has no history of seizures or head trauma, so seizure is ruled out.

Researchers have associated bupropion with a small risk of developing seizures. Richmond and Zwar² reported a 0.1% risk with bupropion, ≥300 mg/d, but Mr. M was taking 150 mg/d. Dunner et al³ estimated the risk of developing seizure while taking standard-release bupropion—the form Mr. M used—at 0.06%, but patients in this study who developed seizures typically had a past seizure disorder or head trauma.

The combination of hyperthermia, tachycardia, altered mental status, and positive chest X-ray suggest pneumonia, which was addressed with antibiotics. Pneumonia, however, does not solely account for Mr. M’s fever, rigidity, and profoundly increased CPK. These findings suggest NMS.

The Glasgow Coma Scale (GCS) is used to quantitatively rate degree of responsiveness in critically ill or injured patients (Table 2). Total scores range from 3 to 15 based on the patient’s best eye, motor, and verbal responses. Total score ≤8 indicates a probable coma. Serial GCS scores can measure clinical course in comatose patients.

Table 2

Using Glasgow Coma Scale to determine level of consciousness

Component	Response	Score
Best eye response	No eye opening	1
	Eye opening to pain	2
	Eye opening to verbal command	3
	Eyes open spontaneously	4
Best verbal response	No verbal response	1
	Incomprehensible sounds	2
	Inappropriate words	3
	Confused	4
	Oriented	5
Best motor response	No motor response	1
	Extension to pain	2
	Flexion to pain	3
	Withdrawal from pain	4
	Localizing pain	5
	Obeys commands	6
Total score ≤8 is severe, and 90% of patients with scores ≤8 are in a coma). Coma is defined as not opening eyes, not obeying commands, and not saying understandable words. Composite scores listing eye, verbal, and motor responses (such as E3V3M5) are clinically more useful than totals.
Source: Reprinted from Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;304(7872):81-4, with permission from Elsevier.

Treatment: slow progress

In the ICU, we diagnose NMS and stop all psychotropics, fearing that interactions between any of them might be causing NMS. We give midazolam, 1 to 2 mg hourly as needed for agitation, and continue morphine, 2 to 4 mg hourly as needed for pain. We stop ceftazidime after ruling out aspiration risk.

 

On day 2 of hospitalization, we call the neurology and consultation-liaison (C-L) psychiatry services. The C-L psychiatrist attempts a mental status examination, but Mr. M is too frail and sedated to communicate. Neurologic exam shows increased foot rigidity, and follow-up studies show negative EEG, normal head and neck MRIs and MRAs, a peak in CPK at 5,487 IU/L, and normal chest films.

We taper and discontinue midazolam and morphine, and Mr. M’s consciousness improves as the dosages decrease. We add lorazepam, 1 mg tid, to address Mr. M’s agitation. He also starts physical therapy to address potential movement problems caused by laying static for 3 days. By day 7, he is extubated and transferred to the general medical unit.

On day 9, Mr. M’s recall and concentration are diminished, and he cannot follow a 3-step command. His Mini-Mental State Examination (MMSE) score of 17 points to a cognitive impairment.

By day 12, residual psychosis is increasing Mr. M’s confusion, paranoia, and agitation. Despite this complication, he is able to work with his occupational and physical therapists.

By day 20, Mr. M becomes more paranoid, with tangential and loose associations. To address these symptoms, we stop lorazepam and start aripiprazole, 15 mg each morning. Because aripiprazole is a partial dopamine agonist and antagonist, it is less likely than other antipsychotics to cause recurrence of NMS symptoms.

Four days later, Mr. M is medically cleared for transfer to the county psychiatric hospital. Creatinine and CPK elevations, metabolic acidosis, and anemia have resolved.

Treatment: new facility, new drugs

On initial evaluation at the psychiatric hospital, Mr. M is cooperative and aware of person, place, and time. His thought processes range from tangential to disorganized, and his paranoia persists.

The attending psychiatrist stops aripiprazole and starts risperidone, 1 mg bid, possibly because he is less familiar with aripiprazole—a newer antipsychotic— than with risperidone. Laboratory results within 3 days of starting risperidone show normal serum levels, blood counts, liver enzymes, and CPK.

On day 2 at the psychiatric hospital, Mr. M’s behavior worsens; he frequently disrobes in front of others, yells at staff, and requires verbal redirection. His MMSE score has fallen to 15. The attending psychiatrist modifies risperidone to 2 mg nightly and adds donepezil, 10 mg each morning, to try to reverse his cognitive decline.

By day 8, Mr. M is more cooperative and his behavior improves. He is transferred back to his board-and-care facility on risperidone and donepezil at the above dosages.

The following month, Mr. M presents to his outpatient psychiatrist with improved cognitive function, but he is still delusional. The psychiatrist stops risperidone and donepezil and resumes olanzapine, 7.5 mg each morning and 10 mg nightly, and chlorpromazine, 50 mg nightly, to try to restore the patient’s pre-NMS function.

Mr. M undergoes successful prostate cancer surgery before his 3-month psychiatry follow-up, at which the psychiatrist adds lithium carbonate, 300 mg tid, for residual irritability. Serum lithium levels are normal; bupropion is not restarted.

One year after presentation, Mr. M is minimally delusional but functioning well. No symptoms suggesting NMS recurrence have been reported.

The authors’ observations

Though the precise mechanism is unknown, NMS has been linked with use of FGAs such as chlorpromazine, which can trigger excessive dopamine blockade.⁴ Studies increasingly associate SGAs such as olanzapine, risperidone, and aripiprazole with NMS onset.^4-6 Mood stabilizers such as lithium carbonate also have been implicated, especially when used with antipsychotics.^6-9 No association between antibiotics and NMS has been found.

For years, Mr. M has been taking FGAs and concomitant olanzapine and lithium carbonate without developing NMS symptoms until now. Since discharge, he has been free of NMS symptoms despite taking two SGAs (aripiprazole and risperidone) at different times and later resuming chlorpromazine, olanzapine, and lithium carbonate.

Of note, bupropion—the last psychotropic added before NMS onset—has not been restarted. The literature does not link bupropion to NMS, although one case report¹⁰ suggests an association between fluoxetine and NMS after the patient had taken several antipsychotic/antidepressant combinations.

As a dopamine agonist, bupropion should protect against NMS. Case reports,^11,12 however, have described patients who developed NMS after antipsychotics were discontinued, and stopping an antipsychotic essentially mimics bupropion’s action by eliminating the dopamine blockade. Additionally, bupropion’s norepinephrine modulation could have precipitated NMS by dysregulating the sympathetic nervous system.¹³

Mr. M’s board-and-care operator indicated that the patient’s tobacco consumption decreased—from about a pack to a half-pack of cigarettes daily—after bupropion was added. Alternatively, the effects of pneumonia could have curtailed Mr. M’s smoking. Because nicotine increases metabolism of neuroleptics,^14,15 decreased nicotine consumption might have increased dopamine blockade to the point of causing NMS.

 

Other possibilities. Mr. M’s pneumonia might have caused dehydration, which can also lead to NMS.

Bupropion also reportedly alters metabolism of chlorpromazine and other phenothiazine antipsychotics by inhibiting the cytochrome P-450 2D6 isoenzyme. This pharmacokinetic interaction could have precipitated Mr. M’s NMS episode independent of an antipsychotic dosage increase.¹⁶

Because this case is so complex, pinpointing a specific cause for Mr. M’s apparent NMS symptoms is difficult. Be aware that combining psychotropics can lead to NMS. Patients who present with mental status changes, hyperthermia, rigidity, and/or increased creatine kinase while taking psychotropics should be promptly evaluated and managed.

Treating NMS

A review of NMS treatment by Davis et al¹⁷ suggests that you:

• consider NMS in the differential diagnosis of an acutely delirious patient who has used antipsychotics, no matter how long he or she has been taking the medication(s) or how stable the dosage
  
• check for other signs of NMS—such as rigidity or autonomic instability—during the physical examination.
  
• consider NMS as a possible cause of dysarthria, diaphoresis, dysphagia, sialorrhea, and myoclonus, although these are less common signs of the disorder
  
• include CPK levels, chemistry panel, CBC, and liver enzyme assessment in the early evaluation of laboratory results. Consider performing a urine drug screen to check for illicit substance use. Head CT results might also help confirm NMS diagnosis.
  

If patient history, physical, and laboratory signs suggest NMS, immediately transfer the patient to a general hospital ICU. Withhold antipsychotics until the NMS episode is resolved, the patient receives aggressive hydration and fluid management, and other causes for delirium are investigated.

If sedation becomes necessary, use benzodiazepines cautiously. Serial CPKs and daily reassessment of clinical degree of rigidity are essential; continued rigidity may indicate use of dopamine agonists and dantrolene.¹⁷

Related resources

• Neuroleptic Malignant Syndrome Information Service. Archive of articles addressing NMS diagnosis and treatment, and listing of psychotropics associated with NMS. www.nmsis.org.
  

Drug brand name

• Aripiprazole • Abilify
  
• Benztropine • Cogentin
  
• Bupropion SR • Wellbutrin, Zyban
  
• Ceftazidime • various
  
• Chlorpromazine • Thorazine
  
• Dantrolene • Dantrium
  
• Donepezil • Aricept
  
• Lithium carbonate • various
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Risperidone • Risperdal
  

Disclosures

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

History: shop talk

Ms. B, age 46, presents to the ER at her brother’s insistence. For about 6 months, she says, she has been “hearing voices”—including that of her boss—talking to each other about work.

Ms. B has no personal or family psychiatric history but notes that her sister died 6 months ago, and her father died the following month. At work, she is having trouble getting along with her boss. She adds that she has been skipping church lately because she believes her church is under investigation and the inquiry might be targeting her.

Ms. B has been a company manager for 20 years. She is divorced, has no children, and lives alone. She says she does not smoke or use illicit drugs and seldom drinks alcohol. She denies suicidal or homicidal thoughts, depressed mood, or visual hallucinations. She says she is sleeping only 3 to 4 hours nightly and feels fatigued in the afternoon. She denies loss of concentration or functioning.

Mental status. Ms. B is well groomed, maintains good eye contact, and is superficially cooperative but increasingly guarded with further questioning. She describes her mood as “OK,” but her affect is blunted. Thought process is logical but circumstantial at times, and her thoughts consist of auditory hallucinations, paranoid thinking, persecutory delusions, and ideas of reference. She has poor insight into her symptoms and does not want to be admitted.

Physical examination and laboratory tests are unremarkable. Negative ethanol and urine drug screens rule out substance abuse, and preliminary noncontrast head CT shows no acute changes.

The author’s observations

In women, schizophrenia typically emerges between ages 17 and 37;¹ onset after age 45 is unusual.² Ms. B’s age, family history, and lack of a formal thought disorder or negative symptoms make late-onset schizophrenia unlikely, though it cannot be ruled out.

Ms. B denies mood symptoms, but significant stressors—such as the recent deaths of her sister and father and difficulties at work—could precipitate a mood disorder. Of the possible diagnoses, major depressive disorder is most likely at this time.^1,3 Because Ms. B’s symptoms do not clearly match any diagnosis, we speak with her brother and sister-in-law to seek collateral information.

Collateral history: beware of spies

Ms. B’s brother says his sister began behaving strangely about 8 months ago and has worsened lately. He says she suspects that her boss hired spies to watch her house, car, and her parent’s house. After work, she often parks in paid garages rather than at home to avoid being “followed.” When visiting, he says, she leaves her keys outside because she fears they contain a tracking device. Family members say Ms. B sometimes drops by at night—as late as 5 AM—complaining that she cannot sleep because she is being “watched.”

Ms. B’s family hired a private investigator 3 or 4 months ago to examine her house and car. Although no tracking devices were found, her brother says, Ms. B remains convinced she is being followed. He says she often speaks in “code” and whispers to herself.

According to her brother, Ms. B often hears voices while trying to sleep, saying such things as “Why won’t she turn over?” She reportedly wears a towel while showering because the “spies” are watching. During a conference she attended last week, she told her brother that a group of government investigators followed her there and arrested her boss.

Ms. B’s sister-in-law says the patient’s functioning has declined sharply, and that she has been helping Ms. B complete routine work. Neither she nor Ms. B’s brother have noticed a change in the patient’s energy, productivity, or speech production or speed, thus ruling out bipolar disorder. Ms. B’s brother confirms that there is no family history of mental illness.

The author’s observations

Collateral information about Ms. B points to psychosis rather than a mood disorder with psychotic features, but she lacks the formal thought disorder and negative symptoms common in primary psychotic disorders.

Because Ms. B’s presentation is atypical, we order brain MRI to check for a general medical condition (Figure 1). If brain MRI suggests a medical problem, we will follow with EEG, lumbar puncture, or other tests.

Figure 1 Clinical steps to rule out medical causes of late-onset psychosis

treatment, testing: what mri suggests

We admit Ms. B to the locked inpatient psychiatric unit—where she remains paranoid and guarded—and prescribe risperidone, 1 mg/d, to address her paranoia. She refuses medication at first because she feels she does not need psychiatric care, but we give her lorazepam, 0.5 mg/d for her anxiety, along with psychoeducation and family support. After 3 days, we stop lorazepam and Ms. B agrees to take risperidone.

 

Within 4 days of starting risperidone, Ms. B’s auditory hallucinations and paranoia have lessened and her insight is improved. We recommend increasing the dosage to 2 mg/d because we feel that 1 mg/d will not sufficiently control her symptoms. She remains paranoid but is reluctant to increase the dosage for fear of adverse effects, though she has reported none so far.

Brain MRI taken the night Ms. B was admitted shows:

• multiple focal, well-defined hyperintense periventricular lesions on fluid-attenuated inversion recovery (FLAIR)- and T2-weighted images (Figure 2). Some lesions are flame-shaped.
• a 1.5-cm lesion adjacent to the right frontal horn showing a hyperintense signal on T2-weighted images and a hypointense signal on T1-weighted images without contrast enhancement. White-matter edema surrounds this lesion.
• no gadolinium-enhancing lesions.

Two radiologists confirm possible demyelination, suggesting multiple sclerosis (MS). Final report of initial brain CT shows lowdensity, periventricular white matter changes consistent with the MRI findings.

Results of subsequent laboratory tests are normal. Erythrocyte sedimentation rate is slightly elevated at 35 mm/hr, suggesting a possible autoimmune disorder. ECG shows sinus bradycardia, and chest x-ray and MR angiogram are unremarkable, as are EEG and visual evoked potential results.

Lumbar puncture and CSF studies show increased immunoglobulin G to albumin ratio. CSF fluid is clear, blood counts and protein are normal, Gram’s stain and culture are negative, and cytologic findings show a marked increase in mature lymphocytes. These results suggest inflammation, but follow-up neurologic exam is unremarkable.

Figure 2 FLAIR-weighted image after Ms. B’s brain MRI

Right 1.5-cm lesion adjacent to right frontal horn and multiple left hyperintense lesions on fluid-attenuated inversion recovery (FLAIR)-weighted image.

The authors’ observations

Determining disease dissemination in time and space is key to diagnosing MS. Clinical presentation or MRI can determine both criteria (Table 1). Ms. B’s lesions and CSF results suggest that MS has disseminated throughout her body, but neurologic examination shows no objective clinical evidence of lesions.

Neuropsychological testing might help evaluate Ms. B’s cognition and executive functioning, but these deficits do not specifically suggest MS. The cortex, particularly the prefrontal cortex, is believed to coordinate organization, planning, and socially appropriate behavior. MS typically involves white matter rather than the cortex, but researchers have suggested that MS-related demyelination might disrupt the axonal circuits that connect the cortex to other brain areas.¹⁸

Increased lesion load has been correlated with decreased cognitive function. Neuropsychological testing could indirectly point to a lesion load increase by recording decreased cognitive function, but this decline cannot be attributed to MS without an MRI.

Ms. B’s psychotic symptoms could be clinical evidence of MS, but we cannot solidify the diagnosis until we establish dissemination in time. To do that, we need a second MRI 3 months after the first one. Concurrent late-onset paraphrenia and MS is possible but rare.

Table 1

Findings needed to determine MS diagnosis based on clinical presentation

Clinical presentation	Findings needed for MS diagnosis
>2 clinical attacks* Objective clinical evidence of >2 lesions	None
>2 clinical attacks Objective clinical evidence of 1 lesion	Dissemination in space by MRI
	or
	>2 MRI-detected lesions consistent with MS plus positive CSF
	or
	Await further attack implicating a different site
1 clinical attack >2 objective clinical lesions	Dissemination in time by MRI
	or
	Second clinical attack
1 clinical attack 1 objective clinical lesion	Dissemination in space by MRI
	or
	>2 MRI-detected lesions consistent with MS plus positive CSF
	and
	Dissemination in time by MRI
	or
	Second clinical attack
* Clinical attack: neurologic disturbance defined by subjective report or objective observation lasting at least 24 hours.
Source: Reference 5

Follow-up: where is she?

Ms. B is discharged after 10 days. She denies hallucinations, and staff notices decreased paranoia, brighter affect, and improved insight. We tell her to continue taking risperidone, 1 mg/d.

Three weeks later, Ms. B sees an outpatient psychiatrist. She is paranoid, guarded, and has not been taking risperidone.

Because Ms. B’s previous MRI results are suspect, we ask the hospital’s neurology service to examine her. Findings are unremarkable, but the neurologist recommends a followup brain MRI in 3 months or sooner if symptoms emerge. More than 2 years later, she has not completed a second MRI or contacted her psychiatrist or neurologist.

The authors’ observations

Ms. B’s case highlights the importance of:

• recognizing an atypical presentation of a primary psychotic disorder
• checking for a medical cause of psychosis (Table 2)
• knowing which psychiatric symptoms are common in MS.

Despite absence of neurologic symptoms, Ms. B’s psychosis could have been the initial presentation of MS, which is more prevalent among psychiatric inpatients than in the general population.^6,7 In a prospective study,⁸ 95% of patients with MS had neuropsychiatric symptoms, and 79% had depressive symptoms. Hallucinations and delusions were reported in 10% and 7% of MS patients, respectively. These findings suggest that mood disturbances are considerably more common than psychosis among patients with MS.

 

Diagnosis of MSrelated psychosis has been addressed only in case reports or small studies, most of which have not clearly defined psychosis or adequately described the symptoms or confounding factors such as medications. Findings on prevalence of psychosis as the initial presentation in MS are more limited and confounded by instances in which neurologic symptoms might have been overlooked.^9,11

Few studies have investigated whether lesion location correlates with specific neuropsychiatric symptoms. In one study,⁸ brain MRI taken within 9 months of presenting symptoms showed that MS was not significantly more severe among patients with psychosis compared with nonpsychotic MS patients. These data support psychosis as a possible early finding in MS.

At least two studies^12,13 suggest a correlation between temporal lobe lesions and psychosis, but both study samples were small (8 and 10 patients) and used a combination of diagnoses. One case report also supports this correlation.¹⁴

Table 2

Medical conditions that can cause psychotic symptoms

Cerebral malignancy (primary and metastases)
Cerebral trauma
Cerebral vascular accident
Creutzfeldt-Jakob disease
Delirium
Dementia
Epilepsy
Huntington's disease
Infection
Multiple sclerosis
Parkinson's disease
Systemic lupus erythematosus
Source: Reference 4

Treating ms-related psychosis

MS-related psychosis should abate with MS treatment, but no systematized studies have verified this or determined which antipsychotics would be suitable. Single case reports suggest successful treatment with risperidone,¹³ haloperidol,¹⁵ clozapine,¹⁶ or ziprasidone.¹⁷ Ms. B showed initial improvement with risperidone, but because she was lost to follow-up we cannot say if this medication would work long-term.

Related resources

• Feinstein A. The clinical neuropsychiatry of multiple sclerosis. New York: Cambridge University Press; 1999.
• National Multiple Sclerosis Society. www.nationalmssociety.org.

Drug brand name

• Clozapine • Clozaril
• Risperidone • Risperdal
• Haloperidol • Haldol
• Ziprasidone • Geodon
• Lorazepam • Ativan

Disclosures

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

Dr. Rafeyan is a speaker for AstraZeneca, BristolMyers Squibb Co., Eli Lilly and Co., GlaxoSmithKline, Pfizer, and Wyeth. He is also an advisor to Abbott Laboratories and Forest Pharmaceuticals.

History: shop talk

Ms. B, age 46, presents to the ER at her brother’s insistence. For about 6 months, she says, she has been “hearing voices”—including that of her boss—talking to each other about work.

Ms. B has no personal or family psychiatric history but notes that her sister died 6 months ago, and her father died the following month. At work, she is having trouble getting along with her boss. She adds that she has been skipping church lately because she believes her church is under investigation and the inquiry might be targeting her.

Ms. B has been a company manager for 20 years. She is divorced, has no children, and lives alone. She says she does not smoke or use illicit drugs and seldom drinks alcohol. She denies suicidal or homicidal thoughts, depressed mood, or visual hallucinations. She says she is sleeping only 3 to 4 hours nightly and feels fatigued in the afternoon. She denies loss of concentration or functioning.

Mental status. Ms. B is well groomed, maintains good eye contact, and is superficially cooperative but increasingly guarded with further questioning. She describes her mood as “OK,” but her affect is blunted. Thought process is logical but circumstantial at times, and her thoughts consist of auditory hallucinations, paranoid thinking, persecutory delusions, and ideas of reference. She has poor insight into her symptoms and does not want to be admitted.

Physical examination and laboratory tests are unremarkable. Negative ethanol and urine drug screens rule out substance abuse, and preliminary noncontrast head CT shows no acute changes.

The author’s observations

In women, schizophrenia typically emerges between ages 17 and 37;¹ onset after age 45 is unusual.² Ms. B’s age, family history, and lack of a formal thought disorder or negative symptoms make late-onset schizophrenia unlikely, though it cannot be ruled out.

Ms. B denies mood symptoms, but significant stressors—such as the recent deaths of her sister and father and difficulties at work—could precipitate a mood disorder. Of the possible diagnoses, major depressive disorder is most likely at this time.^1,3 Because Ms. B’s symptoms do not clearly match any diagnosis, we speak with her brother and sister-in-law to seek collateral information.

Collateral history: beware of spies

Ms. B’s brother says his sister began behaving strangely about 8 months ago and has worsened lately. He says she suspects that her boss hired spies to watch her house, car, and her parent’s house. After work, she often parks in paid garages rather than at home to avoid being “followed.” When visiting, he says, she leaves her keys outside because she fears they contain a tracking device. Family members say Ms. B sometimes drops by at night—as late as 5 AM—complaining that she cannot sleep because she is being “watched.”

Ms. B’s family hired a private investigator 3 or 4 months ago to examine her house and car. Although no tracking devices were found, her brother says, Ms. B remains convinced she is being followed. He says she often speaks in “code” and whispers to herself.

According to her brother, Ms. B often hears voices while trying to sleep, saying such things as “Why won’t she turn over?” She reportedly wears a towel while showering because the “spies” are watching. During a conference she attended last week, she told her brother that a group of government investigators followed her there and arrested her boss.

Ms. B’s sister-in-law says the patient’s functioning has declined sharply, and that she has been helping Ms. B complete routine work. Neither she nor Ms. B’s brother have noticed a change in the patient’s energy, productivity, or speech production or speed, thus ruling out bipolar disorder. Ms. B’s brother confirms that there is no family history of mental illness.

The author’s observations

Collateral information about Ms. B points to psychosis rather than a mood disorder with psychotic features, but she lacks the formal thought disorder and negative symptoms common in primary psychotic disorders.

Because Ms. B’s presentation is atypical, we order brain MRI to check for a general medical condition (Figure 1). If brain MRI suggests a medical problem, we will follow with EEG, lumbar puncture, or other tests.

Figure 1 Clinical steps to rule out medical causes of late-onset psychosis

treatment, testing: what mri suggests

We admit Ms. B to the locked inpatient psychiatric unit—where she remains paranoid and guarded—and prescribe risperidone, 1 mg/d, to address her paranoia. She refuses medication at first because she feels she does not need psychiatric care, but we give her lorazepam, 0.5 mg/d for her anxiety, along with psychoeducation and family support. After 3 days, we stop lorazepam and Ms. B agrees to take risperidone.

 

Within 4 days of starting risperidone, Ms. B’s auditory hallucinations and paranoia have lessened and her insight is improved. We recommend increasing the dosage to 2 mg/d because we feel that 1 mg/d will not sufficiently control her symptoms. She remains paranoid but is reluctant to increase the dosage for fear of adverse effects, though she has reported none so far.

Brain MRI taken the night Ms. B was admitted shows:

• multiple focal, well-defined hyperintense periventricular lesions on fluid-attenuated inversion recovery (FLAIR)- and T2-weighted images (Figure 2). Some lesions are flame-shaped.
• a 1.5-cm lesion adjacent to the right frontal horn showing a hyperintense signal on T2-weighted images and a hypointense signal on T1-weighted images without contrast enhancement. White-matter edema surrounds this lesion.
• no gadolinium-enhancing lesions.

Two radiologists confirm possible demyelination, suggesting multiple sclerosis (MS). Final report of initial brain CT shows lowdensity, periventricular white matter changes consistent with the MRI findings.

Results of subsequent laboratory tests are normal. Erythrocyte sedimentation rate is slightly elevated at 35 mm/hr, suggesting a possible autoimmune disorder. ECG shows sinus bradycardia, and chest x-ray and MR angiogram are unremarkable, as are EEG and visual evoked potential results.

Lumbar puncture and CSF studies show increased immunoglobulin G to albumin ratio. CSF fluid is clear, blood counts and protein are normal, Gram’s stain and culture are negative, and cytologic findings show a marked increase in mature lymphocytes. These results suggest inflammation, but follow-up neurologic exam is unremarkable.

Figure 2 FLAIR-weighted image after Ms. B’s brain MRI

Right 1.5-cm lesion adjacent to right frontal horn and multiple left hyperintense lesions on fluid-attenuated inversion recovery (FLAIR)-weighted image.

The authors’ observations

Determining disease dissemination in time and space is key to diagnosing MS. Clinical presentation or MRI can determine both criteria (Table 1). Ms. B’s lesions and CSF results suggest that MS has disseminated throughout her body, but neurologic examination shows no objective clinical evidence of lesions.

Neuropsychological testing might help evaluate Ms. B’s cognition and executive functioning, but these deficits do not specifically suggest MS. The cortex, particularly the prefrontal cortex, is believed to coordinate organization, planning, and socially appropriate behavior. MS typically involves white matter rather than the cortex, but researchers have suggested that MS-related demyelination might disrupt the axonal circuits that connect the cortex to other brain areas.¹⁸

Increased lesion load has been correlated with decreased cognitive function. Neuropsychological testing could indirectly point to a lesion load increase by recording decreased cognitive function, but this decline cannot be attributed to MS without an MRI.

Ms. B’s psychotic symptoms could be clinical evidence of MS, but we cannot solidify the diagnosis until we establish dissemination in time. To do that, we need a second MRI 3 months after the first one. Concurrent late-onset paraphrenia and MS is possible but rare.

Table 1

Findings needed to determine MS diagnosis based on clinical presentation

Clinical presentation	Findings needed for MS diagnosis
>2 clinical attacks* Objective clinical evidence of >2 lesions	None
>2 clinical attacks Objective clinical evidence of 1 lesion	Dissemination in space by MRI
	or
	>2 MRI-detected lesions consistent with MS plus positive CSF
	or
	Await further attack implicating a different site
1 clinical attack >2 objective clinical lesions	Dissemination in time by MRI
	or
	Second clinical attack
1 clinical attack 1 objective clinical lesion	Dissemination in space by MRI
	or
	>2 MRI-detected lesions consistent with MS plus positive CSF
	and
	Dissemination in time by MRI
	or
	Second clinical attack
* Clinical attack: neurologic disturbance defined by subjective report or objective observation lasting at least 24 hours.
Source: Reference 5

Follow-up: where is she?

Ms. B is discharged after 10 days. She denies hallucinations, and staff notices decreased paranoia, brighter affect, and improved insight. We tell her to continue taking risperidone, 1 mg/d.

Three weeks later, Ms. B sees an outpatient psychiatrist. She is paranoid, guarded, and has not been taking risperidone.

Because Ms. B’s previous MRI results are suspect, we ask the hospital’s neurology service to examine her. Findings are unremarkable, but the neurologist recommends a followup brain MRI in 3 months or sooner if symptoms emerge. More than 2 years later, she has not completed a second MRI or contacted her psychiatrist or neurologist.

The authors’ observations

Ms. B’s case highlights the importance of:

• recognizing an atypical presentation of a primary psychotic disorder
• checking for a medical cause of psychosis (Table 2)
• knowing which psychiatric symptoms are common in MS.

Despite absence of neurologic symptoms, Ms. B’s psychosis could have been the initial presentation of MS, which is more prevalent among psychiatric inpatients than in the general population.^6,7 In a prospective study,⁸ 95% of patients with MS had neuropsychiatric symptoms, and 79% had depressive symptoms. Hallucinations and delusions were reported in 10% and 7% of MS patients, respectively. These findings suggest that mood disturbances are considerably more common than psychosis among patients with MS.

 

Diagnosis of MSrelated psychosis has been addressed only in case reports or small studies, most of which have not clearly defined psychosis or adequately described the symptoms or confounding factors such as medications. Findings on prevalence of psychosis as the initial presentation in MS are more limited and confounded by instances in which neurologic symptoms might have been overlooked.^9,11

Few studies have investigated whether lesion location correlates with specific neuropsychiatric symptoms. In one study,⁸ brain MRI taken within 9 months of presenting symptoms showed that MS was not significantly more severe among patients with psychosis compared with nonpsychotic MS patients. These data support psychosis as a possible early finding in MS.

At least two studies^12,13 suggest a correlation between temporal lobe lesions and psychosis, but both study samples were small (8 and 10 patients) and used a combination of diagnoses. One case report also supports this correlation.¹⁴

Table 2

Medical conditions that can cause psychotic symptoms

Cerebral malignancy (primary and metastases)
Cerebral trauma
Cerebral vascular accident
Creutzfeldt-Jakob disease
Delirium
Dementia
Epilepsy
Huntington's disease
Infection
Multiple sclerosis
Parkinson's disease
Systemic lupus erythematosus
Source: Reference 4

Treating ms-related psychosis

MS-related psychosis should abate with MS treatment, but no systematized studies have verified this or determined which antipsychotics would be suitable. Single case reports suggest successful treatment with risperidone,¹³ haloperidol,¹⁵ clozapine,¹⁶ or ziprasidone.¹⁷ Ms. B showed initial improvement with risperidone, but because she was lost to follow-up we cannot say if this medication would work long-term.

Related resources

• Feinstein A. The clinical neuropsychiatry of multiple sclerosis. New York: Cambridge University Press; 1999.
• National Multiple Sclerosis Society. www.nationalmssociety.org.

Drug brand name

• Clozapine • Clozaril
• Risperidone • Risperdal
• Haloperidol • Haldol
• Ziprasidone • Geodon
• Lorazepam • Ativan

Disclosures

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

Dr. Rafeyan is a speaker for AstraZeneca, BristolMyers Squibb Co., Eli Lilly and Co., GlaxoSmithKline, Pfizer, and Wyeth. He is also an advisor to Abbott Laboratories and Forest Pharmaceuticals.

History: shop talk

Ms. B, age 46, presents to the ER at her brother’s insistence. For about 6 months, she says, she has been “hearing voices”—including that of her boss—talking to each other about work.

Ms. B has no personal or family psychiatric history but notes that her sister died 6 months ago, and her father died the following month. At work, she is having trouble getting along with her boss. She adds that she has been skipping church lately because she believes her church is under investigation and the inquiry might be targeting her.

Ms. B has been a company manager for 20 years. She is divorced, has no children, and lives alone. She says she does not smoke or use illicit drugs and seldom drinks alcohol. She denies suicidal or homicidal thoughts, depressed mood, or visual hallucinations. She says she is sleeping only 3 to 4 hours nightly and feels fatigued in the afternoon. She denies loss of concentration or functioning.

Mental status. Ms. B is well groomed, maintains good eye contact, and is superficially cooperative but increasingly guarded with further questioning. She describes her mood as “OK,” but her affect is blunted. Thought process is logical but circumstantial at times, and her thoughts consist of auditory hallucinations, paranoid thinking, persecutory delusions, and ideas of reference. She has poor insight into her symptoms and does not want to be admitted.

Physical examination and laboratory tests are unremarkable. Negative ethanol and urine drug screens rule out substance abuse, and preliminary noncontrast head CT shows no acute changes.

The author’s observations

In women, schizophrenia typically emerges between ages 17 and 37;¹ onset after age 45 is unusual.² Ms. B’s age, family history, and lack of a formal thought disorder or negative symptoms make late-onset schizophrenia unlikely, though it cannot be ruled out.

Ms. B denies mood symptoms, but significant stressors—such as the recent deaths of her sister and father and difficulties at work—could precipitate a mood disorder. Of the possible diagnoses, major depressive disorder is most likely at this time.^1,3 Because Ms. B’s symptoms do not clearly match any diagnosis, we speak with her brother and sister-in-law to seek collateral information.

Collateral history: beware of spies

Ms. B’s brother says his sister began behaving strangely about 8 months ago and has worsened lately. He says she suspects that her boss hired spies to watch her house, car, and her parent’s house. After work, she often parks in paid garages rather than at home to avoid being “followed.” When visiting, he says, she leaves her keys outside because she fears they contain a tracking device. Family members say Ms. B sometimes drops by at night—as late as 5 AM—complaining that she cannot sleep because she is being “watched.”

Ms. B’s family hired a private investigator 3 or 4 months ago to examine her house and car. Although no tracking devices were found, her brother says, Ms. B remains convinced she is being followed. He says she often speaks in “code” and whispers to herself.

According to her brother, Ms. B often hears voices while trying to sleep, saying such things as “Why won’t she turn over?” She reportedly wears a towel while showering because the “spies” are watching. During a conference she attended last week, she told her brother that a group of government investigators followed her there and arrested her boss.

Ms. B’s sister-in-law says the patient’s functioning has declined sharply, and that she has been helping Ms. B complete routine work. Neither she nor Ms. B’s brother have noticed a change in the patient’s energy, productivity, or speech production or speed, thus ruling out bipolar disorder. Ms. B’s brother confirms that there is no family history of mental illness.

The author’s observations

Collateral information about Ms. B points to psychosis rather than a mood disorder with psychotic features, but she lacks the formal thought disorder and negative symptoms common in primary psychotic disorders.

Because Ms. B’s presentation is atypical, we order brain MRI to check for a general medical condition (Figure 1). If brain MRI suggests a medical problem, we will follow with EEG, lumbar puncture, or other tests.

Figure 1 Clinical steps to rule out medical causes of late-onset psychosis

treatment, testing: what mri suggests

We admit Ms. B to the locked inpatient psychiatric unit—where she remains paranoid and guarded—and prescribe risperidone, 1 mg/d, to address her paranoia. She refuses medication at first because she feels she does not need psychiatric care, but we give her lorazepam, 0.5 mg/d for her anxiety, along with psychoeducation and family support. After 3 days, we stop lorazepam and Ms. B agrees to take risperidone.

 

Within 4 days of starting risperidone, Ms. B’s auditory hallucinations and paranoia have lessened and her insight is improved. We recommend increasing the dosage to 2 mg/d because we feel that 1 mg/d will not sufficiently control her symptoms. She remains paranoid but is reluctant to increase the dosage for fear of adverse effects, though she has reported none so far.

Brain MRI taken the night Ms. B was admitted shows:

• multiple focal, well-defined hyperintense periventricular lesions on fluid-attenuated inversion recovery (FLAIR)- and T2-weighted images (Figure 2). Some lesions are flame-shaped.
• a 1.5-cm lesion adjacent to the right frontal horn showing a hyperintense signal on T2-weighted images and a hypointense signal on T1-weighted images without contrast enhancement. White-matter edema surrounds this lesion.
• no gadolinium-enhancing lesions.

Two radiologists confirm possible demyelination, suggesting multiple sclerosis (MS). Final report of initial brain CT shows lowdensity, periventricular white matter changes consistent with the MRI findings.

Results of subsequent laboratory tests are normal. Erythrocyte sedimentation rate is slightly elevated at 35 mm/hr, suggesting a possible autoimmune disorder. ECG shows sinus bradycardia, and chest x-ray and MR angiogram are unremarkable, as are EEG and visual evoked potential results.

Lumbar puncture and CSF studies show increased immunoglobulin G to albumin ratio. CSF fluid is clear, blood counts and protein are normal, Gram’s stain and culture are negative, and cytologic findings show a marked increase in mature lymphocytes. These results suggest inflammation, but follow-up neurologic exam is unremarkable.

Figure 2 FLAIR-weighted image after Ms. B’s brain MRI

Right 1.5-cm lesion adjacent to right frontal horn and multiple left hyperintense lesions on fluid-attenuated inversion recovery (FLAIR)-weighted image.

The authors’ observations

Determining disease dissemination in time and space is key to diagnosing MS. Clinical presentation or MRI can determine both criteria (Table 1). Ms. B’s lesions and CSF results suggest that MS has disseminated throughout her body, but neurologic examination shows no objective clinical evidence of lesions.

Neuropsychological testing might help evaluate Ms. B’s cognition and executive functioning, but these deficits do not specifically suggest MS. The cortex, particularly the prefrontal cortex, is believed to coordinate organization, planning, and socially appropriate behavior. MS typically involves white matter rather than the cortex, but researchers have suggested that MS-related demyelination might disrupt the axonal circuits that connect the cortex to other brain areas.¹⁸

Increased lesion load has been correlated with decreased cognitive function. Neuropsychological testing could indirectly point to a lesion load increase by recording decreased cognitive function, but this decline cannot be attributed to MS without an MRI.

Ms. B’s psychotic symptoms could be clinical evidence of MS, but we cannot solidify the diagnosis until we establish dissemination in time. To do that, we need a second MRI 3 months after the first one. Concurrent late-onset paraphrenia and MS is possible but rare.

Table 1

Findings needed to determine MS diagnosis based on clinical presentation

Clinical presentation	Findings needed for MS diagnosis
>2 clinical attacks* Objective clinical evidence of >2 lesions	None
>2 clinical attacks Objective clinical evidence of 1 lesion	Dissemination in space by MRI
	or
	>2 MRI-detected lesions consistent with MS plus positive CSF
	or
	Await further attack implicating a different site
1 clinical attack >2 objective clinical lesions	Dissemination in time by MRI
	or
	Second clinical attack
1 clinical attack 1 objective clinical lesion	Dissemination in space by MRI
	or
	>2 MRI-detected lesions consistent with MS plus positive CSF
	and
	Dissemination in time by MRI
	or
	Second clinical attack
* Clinical attack: neurologic disturbance defined by subjective report or objective observation lasting at least 24 hours.
Source: Reference 5

Follow-up: where is she?

Ms. B is discharged after 10 days. She denies hallucinations, and staff notices decreased paranoia, brighter affect, and improved insight. We tell her to continue taking risperidone, 1 mg/d.

Three weeks later, Ms. B sees an outpatient psychiatrist. She is paranoid, guarded, and has not been taking risperidone.

Because Ms. B’s previous MRI results are suspect, we ask the hospital’s neurology service to examine her. Findings are unremarkable, but the neurologist recommends a followup brain MRI in 3 months or sooner if symptoms emerge. More than 2 years later, she has not completed a second MRI or contacted her psychiatrist or neurologist.

The authors’ observations

Ms. B’s case highlights the importance of:

• recognizing an atypical presentation of a primary psychotic disorder
• checking for a medical cause of psychosis (Table 2)
• knowing which psychiatric symptoms are common in MS.

Despite absence of neurologic symptoms, Ms. B’s psychosis could have been the initial presentation of MS, which is more prevalent among psychiatric inpatients than in the general population.^6,7 In a prospective study,⁸ 95% of patients with MS had neuropsychiatric symptoms, and 79% had depressive symptoms. Hallucinations and delusions were reported in 10% and 7% of MS patients, respectively. These findings suggest that mood disturbances are considerably more common than psychosis among patients with MS.

 

Diagnosis of MSrelated psychosis has been addressed only in case reports or small studies, most of which have not clearly defined psychosis or adequately described the symptoms or confounding factors such as medications. Findings on prevalence of psychosis as the initial presentation in MS are more limited and confounded by instances in which neurologic symptoms might have been overlooked.^9,11

Few studies have investigated whether lesion location correlates with specific neuropsychiatric symptoms. In one study,⁸ brain MRI taken within 9 months of presenting symptoms showed that MS was not significantly more severe among patients with psychosis compared with nonpsychotic MS patients. These data support psychosis as a possible early finding in MS.

At least two studies^12,13 suggest a correlation between temporal lobe lesions and psychosis, but both study samples were small (8 and 10 patients) and used a combination of diagnoses. One case report also supports this correlation.¹⁴

Table 2

Medical conditions that can cause psychotic symptoms

Cerebral malignancy (primary and metastases)
Cerebral trauma
Cerebral vascular accident
Creutzfeldt-Jakob disease
Delirium
Dementia
Epilepsy
Huntington's disease
Infection
Multiple sclerosis
Parkinson's disease
Systemic lupus erythematosus
Source: Reference 4

Treating ms-related psychosis

MS-related psychosis should abate with MS treatment, but no systematized studies have verified this or determined which antipsychotics would be suitable. Single case reports suggest successful treatment with risperidone,¹³ haloperidol,¹⁵ clozapine,¹⁶ or ziprasidone.¹⁷ Ms. B showed initial improvement with risperidone, but because she was lost to follow-up we cannot say if this medication would work long-term.

Related resources

• Feinstein A. The clinical neuropsychiatry of multiple sclerosis. New York: Cambridge University Press; 1999.
• National Multiple Sclerosis Society. www.nationalmssociety.org.

Drug brand name

• Clozapine • Clozaril
• Risperidone • Risperdal
• Haloperidol • Haldol
• Ziprasidone • Geodon
• Lorazepam • Ativan

Disclosures

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

Dr. Rafeyan is a speaker for AstraZeneca, BristolMyers Squibb Co., Eli Lilly and Co., GlaxoSmithKline, Pfizer, and Wyeth. He is also an advisor to Abbott Laboratories and Forest Pharmaceuticals.

History: normal on paper

Mr. C, age 65, presents to an endocrinologist complaining of hot flashes and low libido. Initial testing shows low male testosterone, but a repeat test shows normal levels. No medical cause is found for his symptoms.

“My testosterone might be normal on paper,” Mr. C tells the endocrinologist, “but I’m not. I think I’m a woman.”

Mr. C requests referral to a female psychiatrist because he feels more comfortable discussing sexual issues with a woman. The endocrinologist refers him to me for evaluation.

Over 7 years, Mr. C’s other psychiatrist—a man—has been treating him for obsessive-compulsive disorder (OCD), anxiety disorder, and bipolar disorder type II. Mr. C takes paroxetine, 60 mg/d, for depressive symptoms and was taking divalproex, 1,500 mg/d, to stabilize his mood. He recently stopped divalproex because it was causing nausea and sedation.

During our initial visit, Mr. C says he’s “through pretending to be a man.” He says he first questioned his sexual identity in early childhood, when he sometimes dressed in his mother’s clothes for play. As an adult, he mostly cross-dresses in lingerie; he wears a woman’s tank top in public once or twice weekly underneath his polo dress shirt. Fifteen years ago, he suffered anorexia and bulimia while trying to look as svelte as a woman.

At 6 feet, 2 inches with good muscle tone and short, wavy black hair, Mr. C looks strikingly masculine. Now retired, he served in the Air Force and later worked as a commercial pilot and in construction. In private, however, he prefers gardening and cooking over sports and cars.

Mr. C is married but seldom has sexual intercourse with women. He gains sexual fulfillment by visualizing himself as a woman having sex with other women or with himself as a man. He denies interest in male-male sex.

The patient has been masturbating since age 5, mostly by rubbing his scrotum against a swing set pole he still keeps in his utility shed. He often tucks his penis to mimic female genitalia and makes believe his rectum is a vagina.

Box

Mr. C’s sexual identity and intimacy problems destroyed three marriages. His first two lasted 6 months and 2 years; the third ended after 10 years when his then-wife accused him of being gay. His fourth marriage has lasted 22 years and harbors much affection and foreplay but little intercourse.

Mr. C’s Mini-Mental State Examination score of 30 indicates no underlying dementia. He shows stable affect with no evidence of derailment, paranoia, thought blocking, or auditory hallucinations.

Medical examination results are normal. Negative urine toxicology screen rules out substance abuse, and negative rapid plasma reagin rules out syphilis. Testosterone is not rechecked because levels were normal 2 days before.

The author’s observations

I suspect gender dysphoria, which describes a heterogeneous group of persons who express varying degrees of distress with their anatomic sex and sometimes desire secondary opposite-gender sexual characteristics (Box).

Sexual identity in gender dysphoria is often fluid. Symptoms might suggest transvestism, then evolve to transsexualism. Recognizing this heterogeneity and fluidity is crucial to diagnosis and treatment.

Primary transsexualism. The term “transsexualism” describes persons who want to live and be accepted within the opposite sex.¹ The transsexual identity persists for ≥ 2 years and is not caused by another mental disorder or intersexed condition. Fetishism is classically absent and cross-dressing is not sexually gratifying. Most transsexuals want surgical and hormone treatment to make their bodies as congruent as possible with the preferred sex.

In 1994, DSM-IV recognized that some late-onset transsexuals showed features of comorbid transvestism and were sexually aroused by female dress and behaviors. Gender identity disorder (GID) replaced the term “transsexualism” and includes these individuals. A secondary diagnosis of transvestism is applied.

Secondary transsexualism. Case reports² describe psychosis-induced transsexual desires in patients with schizophrenia. Gender dysphoria improved as their schizophrenia symptoms lessened.

The relationship between transsexualism and schizophrenia has been debated. Hyde and Kenna³ view transsexualism as a schizophrenia spectrum disorder, whereas sexologists consider transsexualism and schizophrenia distinct syndromes that can occur simultaneously.

Affective disorders might also alter contentment with gender role, but the relationship is unclear. Case reports of patients with bipolar disorder suggest that gender dysphoria intensity fluctuates with affective excursions.⁴ O’Gorman,⁵ however, described a bipolar patient whose gender dysphoria was mitigated during manic episodes.

 

Paraphilias are sexual disorders with recurrent intense urges and fantasies that do not follow normative arousal patterns and can diminish capacity for sexual intimacy.⁶ Manifestations include exhibitionism, fetishism, frotteurism, pedophilia, masochism/sadism, voyeurism, and transvestic fetishism.

Dividing transsexualism and pure transvestism paraphilia into discrete categories is simplistic, as transvestites can develop secondary components of transsexualism. Hoenig and Kenna⁷ assert that transsexualism—though not an anomalous erotic preference—is almost always preceded by transvestism or accompanied by cross-gender fetishism.

Nonparaphilic sexual addiction—included in DSM-IV-TR as sexual disorder not otherwise specified—describes culturally acceptable sexual interests and behaviors that are frequent or intense enough to reduce capacity for sexual intimacy. Such behaviors include compulsive masturbation, repetitive promiscuity, and dependence on anonymous sexual encounters.

An addiction model conceptualizes paraphilia as a form of pleasure seeking that has become habitual and self-destructive. Treatment involves directing patients to 12-step groups patterned after Alcoholics Anonymous.

Other models place paraphilias and related disorders within the OCD spectrum.^8-13 Persons with OCD often are obsessed with sexual content and might grapple with religious and moral concerns about sexual issues. They typically consider their symptoms intrusive or senseless. Selective serotonin reuptake inhibitors—the standard medication for OCD—might alleviate paraphilia, but results are mixed.¹⁴

Mr. C’s symptoms. Mr. C shows features of GID and transvestism. His strong, persistent cross-gender identification and sense of inappropriateness with being a man indicate GID. His recurrent sexual urges and fantasies and impaired capacity for sexual intimacy suggest a paraphilia or transvestism.

The significance of Mr. C’s comorbid bipolar disorder and OCD is unclear. Both appeared controlled, but the potential for mania-induced hypersexuality cannot be ignored.

Diagnosing gender dysphoria

A thorough medical, psychiatric, and sexual history can reveal sexual identity symptoms’ source.

Consider a medical cause. Your medical workup may include a genital exam to check for irregularities such as hermaphrodism that can compound questions of sexual identity, and karyotyping to probe chromosomal anomalies, such as mosaicism or chimerism.

Consider schizophrenia or bipolar disorder, as mania or psychosis can cause aberrant sexual behavior. In gender-dysphoric patients with either disorder, treating the psychiatric comorbidity might alleviate the dysphoria. Watch for fluctuations in gender dysphoria intensity when you treat other psychopathologies.

Take a thorough sexual history. Being matter-of-fact while discussing unusual sexual acts will help the patient “open up” about his sexual problems. Ask him if he:

• showed gender-atypical behavior as a child, which can predict transsexualism or homosexuality has engaged in heterosexual, homosexual, or abnormal sexual acts; ask about frequency and preference
  
• is married or has a girlfriend. If so, are they getting along? How often do they have sex?
  
• cross-dresses. Does his partner cross-dress as well and, if so, do they cross-dress for sexual gratification or to identify with the opposite gender? Has this response changed over time? Where and how often do they cross-dress?
  
• is achieving sexual gratification. If so, how?
  
• has sexual fantasies involving breast-feeding, giving birth, or forced feminization through gender-changing surgeries or other means
  
• “tucks” his penis, urinates sitting down, or mimics other stereotypical feminine behavior.
  

Also find out how long these behaviors have persisted. Have they fluctuated? Have relationships, life stressors, or other factors influenced them?

The answers will uncover a motivation behind these behaviors, which is key to diagnosis. Sexual gratification as a motive suggests paraphilia, whereas a desire to live as a woman points to transsexualism. Because of the myriad presentations, multiple patient visits are necessary for a specific diagnosis.

Diagnosis: ‘i enjoy womanhood, but…’

I diagnose gender dysphoria, but because Mr. C’s mood is euthymic, I cannot discern how his mood instability might affect his dysphoria. His sexual fantasies are mood-congruent and evoke no shame.

Mr. C then states that he adamantly opposes living outwardly as a woman, and fears that an overt sex change would destroy his marriage and other relationships. Even so, he desires hormone therapy and surgical breast implants so he can more closely mimic physical womanhood and make masturbation more pleasurable. He says he would flatten his breasts with gauze while in public so he can continue to look like a man.

Though comfortable with his sexual fantasies, Mr. C laments that presenting himself as an “alpha male” drains his psychic energy.

The author’s observations

Mr. C meets criteria for GID and transvestism. Some transvestites also meet criteria for autogynephilia and report erotic arousal upon seeing oneself as a woman. Character pathology, specifically sexual fantasies associated with schizoid personality, might also contribute to unusual gender presentation. Sexologists also propose fluidity in gender identification across populations and over a person’s life span.

Autogynephilia—by which a man becomes sexually aroused by imagining or seeing himself as a woman¹⁵—usually is associated with transvestism. Autogynephiles often have sexual fantasies of possessing female anatomical structures, engaging in feminine behaviors, or performing female bodily functions such as lactation, menstruation, or childbirth.

 

Autogynephilia may be a misdirected heterosexuality and is more prevalent among male-to-female transsexuals who are attracted to women, both sexes, or neither sex than among those attracted only to men.¹⁶

Gender identity fluidity. Clinicians have recorded fluidity in gender identity (sense of masculinity or femininity) and sexual orientation (the sex to which one is attracted). Sexologists have tried to create scales that gauge these changes.

The Kinsey Heterosexual-Homosexual Rating Scale¹⁷ is based on Kinsey’s theory that men are not strictly heterosexual or homosexual. Scores between 0 and 6 indicate some degree of both (Table).

The Benjamin Gender Disorientation Scale, which measures gender identity variations, recognizes variability of gender dysphoria expression and underscores the difficulty of classifying patients who—like Mr. C—present with varied symptoms. The scale is available at www.wpath.org.

I did not administer the Kinsey or Benjamin scales to Mr. C. Although his case shows how innate sense of masculinity or femininity can vary among patients with gender dysphoria, his presentation has been stable, albeit unusual.

Mr. C’s symptoms. Mr. C shows autogynephilic features. He lacks the schizoid’s emotional inertness and his gender presentation is static, though dramatic. He appears to meet criteria for GID and transvestism, autogynephilic variant.

Schizoid and other personality disorders are associated with unusual sexual fantasies. Mr. C lacks primary schizoid features, such as flattened affectivity and indifference to close relationships.

Table

Kinsey Heterosexual-Homosexual Rating Scale

Score	Indicates…
0	Exclusively heterosexual
1	Predominantly heterosexual, incidentally homosexual
2	Predominantly heterosexual, more than incidentally homosexual
3	Equally heterosexual and homosexual
4	Predominantly homosexual, more than incidentally heterosexual
5	Predominantly homosexual, incidentally heterosexual
6	Exclusively homosexual
Source: Reference 17. Reprinted by permission of The Kinsey Institute for Research in Sex, Gender, and Reproduction, Inc., Indiana University, Bloomington.

The author’s observations

Mr. C is a poor candidate for hormone therapy or gender reassignment surgery because of his circumscribed desire to live as a woman at home. Also, sexual gratification is his primary motivation for wanting to develop breasts.

Treating gender dysphoria

Serotonergic agents such as fluoxetine have shown effectiveness for treating paraphilias and nonparaphilic sexual addiction in case reports.^18,19

Behavioral techniques, however, might have a more definite impact on gender dysphoria. Marks¹⁹ reported a 4-year remission of transsexualism in a patient after comorbid OCD improved with self-exposure therapy.

Psychotherapy will not resolve gender identity disorder but can promote a stable lifestyle and improve the patient’s chances for success in relationships, education, work, and gender identity expression.²⁰ Psychotherapy can also help determine patients’ readiness for sexual reassignment surgery.

Treatment: learning to accept

I refer Mr. C back to his primary psychiatrist, who adds aripiprazole, 5 mg/d, to address grandiosity and hypomania that emerged months after my initial evaluation.

I also refer Mr. C to a gender disorder specialist for psychotherapy directed at examining his history, understanding his dilemmas, and identifying unrealistic ideas and maladaptive behaviors. The therapist has been teaching Mr. C coping skills and educating him on gender disorders and normal gender variations in activities and interests. He has been attending weekly sessions for 4 months.

To address his resentment over trying to look manly, I assure him that he doesn’t need to assume additional “masculine” behaviors and attitudes, and that his height and features make him appear masculine.

Related resources

• World Professional Association for Transgender Health, formerly the Harry Benjamin International Gender Dysphoria Association (offers links to transgender resources, gender programs, and sexologists). www.hbigda.org.
  

Drug brand name

• Divalproex sodium • Depakote
  
• Fluoxetine • Prozac
  
• Paroxetine • Paxil
  

Disclosures

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