Current Psychiatry

CASE: Agitated and paranoid

Police bring Mr. L, age 85, to the emergency department (ED) because he threatened his wife, claiming she is having an affair. Two days earlier, he was discharged from a different hospital, where he was treated for progressive and fluctuating irritability, depressed mood, confusion, disorientation, inattention, and delusional thinking that had started 4 to 5 months earlier. He has no other psychiatric history.

Mr. L has a history of atrial fibrillation, hypertension, benign prostatic hypertrophy, and noninsulin-dependent diabetes mellitus. Several months ago, he had hip surgery, which was complicated by a surgical wound infection. Medications include digoxin, 0.125 mg/d; atenolol, 100 mg/d; warfarin, 1 mg/d on Monday, Wednesday, Friday, Saturday, and Sunday and 0.5 mg/d Tuesday and Thursday; lisinopril, 40 mg/d; tamsulosin, 0.4 mg/d; and glyburide, 1.25 mg/d. During the previous hospitalization, physicians discovered he had myasthenia gravis, which they treated with prednisone and pyridostigmine. Mr. L also was diagnosed with hyperaldosteronism. An adrenal mass was found in an abdominal CT. At that time, he also was diagnosed with major depressive disorder (MDD) with psychotic features and started on aripiprazole, 10 mg/d, mirtazapine, 30 mg/d, and trazodone, 50 mg/d for sleep.

The authors’ observations

When evaluating mental status changes in older patients, consider the time course and characteristics of the changes, especially if the patient’s cognitive function changes. Acute mental status changes that occur over hours to days often represent delirium caused by a medical condition such as a coronary event or infection. Changes that develop over weeks to months often signal a primary psychiatric disorder such as depression, mania, or dementia. Mr. L’s mood and psychotic symptoms developed over 4 to 5 months and were thought to be a result of MDD with psychotic features. However, his fluctuating cognitive symptoms, confusion, and lack of psychiatric history suggest that the differential diagnosis should include a cognitive disorder such as delirium or dementia. The hypoactive form of delirium often is unrecognized or misdiagnosed as sedation or depression, particularly in older patients.¹

Multiple medical conditions and polypharmacy are important factors to consider when evaluating mental status changes in geriatric patients. In Mr. L’s case, atrial fibrillation, hypertension, and diabetes increase his risk of an acute cardiovascular or cerebrovascular event and chronic cerebrovascular disease. Hyperaldosteronism can lead to electrolyte abnormalities that may produce mental status changes. Treatment with an oral hypoglycemic raises the possibility that hypoglycemia is contributing to his mental status changes. Prednisone can cause psychosis, anxiety, and mania. Digoxin toxicity is associated with psychosis and irritability. Pyridostigmine also has been reported to cause psychosis. Use of an antidepressant, such as mirtazapine, could have exacerbated an underlying undiagnosed bipolar disorder. Antipsychotics, such as aripiprazole, may cause akathisia or activation. Substance intoxication or withdrawal should not be excluded solely because a patient is older. In older patients, medications with anti-cholinergic effects are common culprits for cognitive impairment (Table 1).^2,3

Table 1

Medications that could contribute to mental status changes

ASSESSMENT: More problems

At admission to the medical unit, Mr. L’s temperature is 36.7°C (98°F), with a heart rate of 77 beats per minute, respiratory rate of 24 breaths per minute, and blood pressure of 164/84 mm Hg with oxygen saturation of 96% at room air. Physical exam is notable for 2+ pitting edema in the lower extremities. Mr. L is oriented to person, place, and time and is psychomotorically activated. Neurologic examination is within normal limits.

Laboratory data reveal a potassium level of 2.5 mEq/L. Other results, including complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone, urinalysis, urine toxicology screen, B12, folate, venereal disease research laboratory, and ammonia are unremarkable. Chest radiography reveals an enlarged cardiomediastinum. A CT scan of the brain without contrast shows cortical volume loss and periventricular white matter disease without evidence of acute intracranial abnormality. ECG shows atrial fibrillation with a rate of 67 beats per minute.

Mr. L’s hypokalemia is corrected with potassium chloride and his hyperaldosteronism is treated with spironolactone, 25 mg/d. Physicians on the medical unit discontinue digoxin because Mr. L’s heart rate is controlled with atenolol and he is anticoagulated with warfarin.

Mr. L continues to be depressed and irritable with delusional jealousy. Mirtazapine is continued at 30 mg/d at bedtime. Aripiprazole and trazodone are discontinued and Mr. L is started on olanzapine, 10 mg/d, and haloperidol, 1 mg 4 times a day as needed for agitation. He requires multiple “as needed” haloperidol doses because of intermittent episodes of agitation. Mr. L is then transferred to the inpatient psychiatric unit for continued evaluation and treatment.

The authors’ observations

The fact that Mr. L is alert and oriented is encouraging; however, it does not rule out delirium because this condition is characterized by fluctuating levels of consciousness. Therefore, it is important to reassess him over time and perform a more thorough evaluation of cognitive function, especially attention and concentration, in addition to alertness and orientation. Psychomotor activation could suggest agitated depression, anxiety, mania, psychosis, substance intoxication, akathisia from antipsychotics, or delirium (Table 2).⁴ Initial evaluation— especially in older patients—should include a thorough history (including collateral sources) and be guided by the clinical presentation and physical examination, taking into consideration life-threatening conditions and common causes of mental status change such as infections, hypoxia, substance or medication effects, acute coronary syndromes, acute neurologic events, and metabolic conditions.

Table 2

DSM-IV-TR criteria for delirium caused by a medical condition

Reconsider the diagnosis

Even after being treated for hyperaldosteronism and discontinuing unnecessary medications, Mr. L continued to be treated for MDD with psychotic features despite intermittent confusion and agitation. At this point, it might have been useful to reconsider whether MDD with psychotic features was the most appropriate diagnosis to explain his mental status changes.

Mental status changes caused by medical disorders or medications do not immediately clear after the medical disorder is corrected or the medication is discontinued; it could take days or weeks for a patient to return to baseline. In Mr. L’s case it may be useful to simplify his medication regimen because polypharmacy contributes to delirium. Finally, olanzapine could worsen his condition because of its anticholinergic effects.⁵

EVALUATION: Poor cognitive status

Mental status examination upon admission to the psychiatric unit reveals a poorly cooperative patient with irritable mood and affect with slowed psychomotor activity. Mr. L’s thought process is organized with normal associations and thought content does not reveal suicidality or homicidality. However, he verbalizes delusions about his wife having an affair with a neighbor. He is partially oriented to time but believes he is in Germany. His insight is limited and he demonstrates impaired attention and concentration. We cannot complete a Mini-Mental State Exam (MMSE) because Mr. L does not cooperate.

After admission, Mr. L is intermittently confused, agitated, and disoriented. Between these episodes he is pleasant, cooperative, and oriented. Jealous delusions regarding his wife continue. Olanzapine and mirtazapine are tapered and discontinued. Haloperidol dose is changed to 1 mg 3 times a day, then to 1.5 mg in the morning and 3 mg in the evening. Prednisone is tapered and discontinued.

The authors’ observations

Cognitive testing is essential for the diagnosis and treatment of patients with mental status changes and for evaluating their response to treatment. Although the MMSE is widely used, other scales—including the Confusion Assessment Method, the Organic Brain Syndrome Scale, the Memorial Delirium Assessment Scale, and the delirium severity index⁶—may be more sensitive for detecting delirium. All of these scales can be difficult to complete when evaluating confused and combative patients. Quick screening instruments for inattention, such as the digit span test and listing days of the week backwards, could be used as well.

HISTORY: Surgical complications

Further questioning of Mr. L’s family reveals that his behavior started to change 7 months ago; this was 1 month after undergoing hip replacement surgery, which was complicated by a surgical wound infection and worsened his medical illnesses. Within a month, Mr. L became withdrawn and appeared depressed. He was confused and intermittently disoriented to place and time. He became irritable and started reporting concerns about his wife having an affair. During this time different medications were introduced, including steroids and several antibiotics.

The authors’ observations

A thorough history from the patient and caregivers, including the time course of mental status changes, new medication use, and history of medical and psychiatric disorders—especially depression and dementia—are important to obtain, especially early in the evaluation.

Although Mr. L’s irritability, delusions, and psychomotor slowing could be signs of psychotic depression, his fluctuating mental status, disorientation, poor attention, and impaired concentration suggest delirium (Table 3).^4,7 This diagnosis is supported by the fact that Mr. L’s symptoms emerged after orthopedic surgery. Delirium after orthopedic surgery is common among older patients.⁸ Contributing and perpetuating factors in Mr. L’s case may have included postoperative complications, hypokalemia (hyperaldosteronism), medications (prednisone, digoxin, and olanzapine), and environmental unfamiliarity during hospitalization. A delirium diagnosis should be based on a high index of suspicion and a careful clinical assessment rather than diagnostic tests.

Table 3

Deconstructing delirium

OUTCOME: Return home

Mr. L’s confusion and delusional jealousy decrease over time, as do his disorientation and inattention, as evidenced by improvement on MMSE scores. His last MMSE score is 27/30, failing mostly in attention and recall.

After sustained improvement in cognition and behavior, Mr. L is discharged home on haloperidol and the remainder of his nonpsychiatric medications with outpatient medical and psychiatric follow-up. Over several months, he continues to show improvement and haloperidol is discontinued.

The authors’ observations

Delirium treatment should focus on prompt identification and management of precipitating and contributing factors.⁷ Antipsychotics are considered first-line treatment for patients with delirium, agitation, or psychosis who pose a risk to themselves or others. Benzodiazepines should be avoided in older patients unless symptoms are secondary to CNS-depressant withdrawal (ie, alcohol, benzodiazepines).⁹

Although there are no-FDA approved medications for delirium, haloperidol has been widely studied and used for treatment of agitation and psychosis in delirium. There is no evidence that low-dose haloperidol is any less effective than olanzapine or risperidone, or is more likely to cause adverse drug effects such as extrapyramidal syndrome.¹⁰ Antipsychotic use in a confused or agitated dementia patient increases risk of mortality compared with dementia patients who do not receive antipsychotics.¹¹ The use of typical or atypical antipsychotics for delirium should be guided by the patient’s characteristics, such as cardiovascular status and presence or absence of underlying dementia. Atypical antipsychotics should be used carefully because—as in Mr. L’s case—anticholinergic side effects of medications such as olanzapine could worsen delirium.⁵ Once delirium has resolved, antipsychotics should be tapered and discontinued.

Other components of delirium treatment and prevention include:

• reorientation (verbally, with clocks, calendars, etc.)
• safe ambulation
• adequate sleep, food, and fluid intake
• adaptive equipment for vision and hearing impairment
• adequate management of pain and other comorbidities.¹²

Related Resources

• Khan RA, Kahn D, Bourgeois JA. Delirium: sifting through the confusion. Curr Psychiatry Rep. 2009;11(3):226-234.
• Maldonado JR. Delirium in the acute care setting: characteristics, diagnosis, and treatment. Crit Care Clin. 2008;24:657-722.
• Young J, Inouye SK. Delirium in older people. BMJ. 2007;334(7598):842-846.

Drug Brand Names

• Amantadine • Symmetrel
• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Atenolol • Tenormin
• Atropine • AtroPen
• Benztropine • Cogentin
• Cimetidine • Tagamet
• Clozapine • Clozaril
• Digoxin • Lanoxicaps, Lanoxin
• Glyburide • DiaBeta, Micronase
• Haloperidol • Haldol
• Levodopa/carbidopa • Parcopa, Sinemet
• Lisinopril • Prinivil, Zestril
• Lorazepam • Ativan
• Meperidine • Demerol
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Oxybutynin • Ditropan
• Pergolide • Permax
• Phenytoin • Dilantin, Phenytek
• Prednisolone • Orapred, Prelone, others
• Prednisone • Deltasone, Meticorten
• Pyridostigmine • Mestinon
• Ranitidine • Zantac
• Risperidone • Risperdal
• Selegiline • Eldepryl, Zelapar
• Spironolactone • Aldactone
• Tamsulosin • Flomax
• Thioridazine • Mellaril
• Trazodone • Desyrel
• Warfarin • Coumadin

Disclosure

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

CASE: Agitated and paranoid

Police bring Mr. L, age 85, to the emergency department (ED) because he threatened his wife, claiming she is having an affair. Two days earlier, he was discharged from a different hospital, where he was treated for progressive and fluctuating irritability, depressed mood, confusion, disorientation, inattention, and delusional thinking that had started 4 to 5 months earlier. He has no other psychiatric history.

Mr. L has a history of atrial fibrillation, hypertension, benign prostatic hypertrophy, and noninsulin-dependent diabetes mellitus. Several months ago, he had hip surgery, which was complicated by a surgical wound infection. Medications include digoxin, 0.125 mg/d; atenolol, 100 mg/d; warfarin, 1 mg/d on Monday, Wednesday, Friday, Saturday, and Sunday and 0.5 mg/d Tuesday and Thursday; lisinopril, 40 mg/d; tamsulosin, 0.4 mg/d; and glyburide, 1.25 mg/d. During the previous hospitalization, physicians discovered he had myasthenia gravis, which they treated with prednisone and pyridostigmine. Mr. L also was diagnosed with hyperaldosteronism. An adrenal mass was found in an abdominal CT. At that time, he also was diagnosed with major depressive disorder (MDD) with psychotic features and started on aripiprazole, 10 mg/d, mirtazapine, 30 mg/d, and trazodone, 50 mg/d for sleep.

The authors’ observations

When evaluating mental status changes in older patients, consider the time course and characteristics of the changes, especially if the patient’s cognitive function changes. Acute mental status changes that occur over hours to days often represent delirium caused by a medical condition such as a coronary event or infection. Changes that develop over weeks to months often signal a primary psychiatric disorder such as depression, mania, or dementia. Mr. L’s mood and psychotic symptoms developed over 4 to 5 months and were thought to be a result of MDD with psychotic features. However, his fluctuating cognitive symptoms, confusion, and lack of psychiatric history suggest that the differential diagnosis should include a cognitive disorder such as delirium or dementia. The hypoactive form of delirium often is unrecognized or misdiagnosed as sedation or depression, particularly in older patients.¹

Multiple medical conditions and polypharmacy are important factors to consider when evaluating mental status changes in geriatric patients. In Mr. L’s case, atrial fibrillation, hypertension, and diabetes increase his risk of an acute cardiovascular or cerebrovascular event and chronic cerebrovascular disease. Hyperaldosteronism can lead to electrolyte abnormalities that may produce mental status changes. Treatment with an oral hypoglycemic raises the possibility that hypoglycemia is contributing to his mental status changes. Prednisone can cause psychosis, anxiety, and mania. Digoxin toxicity is associated with psychosis and irritability. Pyridostigmine also has been reported to cause psychosis. Use of an antidepressant, such as mirtazapine, could have exacerbated an underlying undiagnosed bipolar disorder. Antipsychotics, such as aripiprazole, may cause akathisia or activation. Substance intoxication or withdrawal should not be excluded solely because a patient is older. In older patients, medications with anti-cholinergic effects are common culprits for cognitive impairment (Table 1).^2,3

Table 1

Medications that could contribute to mental status changes

ASSESSMENT: More problems

At admission to the medical unit, Mr. L’s temperature is 36.7°C (98°F), with a heart rate of 77 beats per minute, respiratory rate of 24 breaths per minute, and blood pressure of 164/84 mm Hg with oxygen saturation of 96% at room air. Physical exam is notable for 2+ pitting edema in the lower extremities. Mr. L is oriented to person, place, and time and is psychomotorically activated. Neurologic examination is within normal limits.

Laboratory data reveal a potassium level of 2.5 mEq/L. Other results, including complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone, urinalysis, urine toxicology screen, B12, folate, venereal disease research laboratory, and ammonia are unremarkable. Chest radiography reveals an enlarged cardiomediastinum. A CT scan of the brain without contrast shows cortical volume loss and periventricular white matter disease without evidence of acute intracranial abnormality. ECG shows atrial fibrillation with a rate of 67 beats per minute.

Mr. L’s hypokalemia is corrected with potassium chloride and his hyperaldosteronism is treated with spironolactone, 25 mg/d. Physicians on the medical unit discontinue digoxin because Mr. L’s heart rate is controlled with atenolol and he is anticoagulated with warfarin.

Mr. L continues to be depressed and irritable with delusional jealousy. Mirtazapine is continued at 30 mg/d at bedtime. Aripiprazole and trazodone are discontinued and Mr. L is started on olanzapine, 10 mg/d, and haloperidol, 1 mg 4 times a day as needed for agitation. He requires multiple “as needed” haloperidol doses because of intermittent episodes of agitation. Mr. L is then transferred to the inpatient psychiatric unit for continued evaluation and treatment.

The authors’ observations

The fact that Mr. L is alert and oriented is encouraging; however, it does not rule out delirium because this condition is characterized by fluctuating levels of consciousness. Therefore, it is important to reassess him over time and perform a more thorough evaluation of cognitive function, especially attention and concentration, in addition to alertness and orientation. Psychomotor activation could suggest agitated depression, anxiety, mania, psychosis, substance intoxication, akathisia from antipsychotics, or delirium (Table 2).⁴ Initial evaluation— especially in older patients—should include a thorough history (including collateral sources) and be guided by the clinical presentation and physical examination, taking into consideration life-threatening conditions and common causes of mental status change such as infections, hypoxia, substance or medication effects, acute coronary syndromes, acute neurologic events, and metabolic conditions.

Table 2

DSM-IV-TR criteria for delirium caused by a medical condition

Reconsider the diagnosis

Even after being treated for hyperaldosteronism and discontinuing unnecessary medications, Mr. L continued to be treated for MDD with psychotic features despite intermittent confusion and agitation. At this point, it might have been useful to reconsider whether MDD with psychotic features was the most appropriate diagnosis to explain his mental status changes.

Mental status changes caused by medical disorders or medications do not immediately clear after the medical disorder is corrected or the medication is discontinued; it could take days or weeks for a patient to return to baseline. In Mr. L’s case it may be useful to simplify his medication regimen because polypharmacy contributes to delirium. Finally, olanzapine could worsen his condition because of its anticholinergic effects.⁵

EVALUATION: Poor cognitive status

Mental status examination upon admission to the psychiatric unit reveals a poorly cooperative patient with irritable mood and affect with slowed psychomotor activity. Mr. L’s thought process is organized with normal associations and thought content does not reveal suicidality or homicidality. However, he verbalizes delusions about his wife having an affair with a neighbor. He is partially oriented to time but believes he is in Germany. His insight is limited and he demonstrates impaired attention and concentration. We cannot complete a Mini-Mental State Exam (MMSE) because Mr. L does not cooperate.

After admission, Mr. L is intermittently confused, agitated, and disoriented. Between these episodes he is pleasant, cooperative, and oriented. Jealous delusions regarding his wife continue. Olanzapine and mirtazapine are tapered and discontinued. Haloperidol dose is changed to 1 mg 3 times a day, then to 1.5 mg in the morning and 3 mg in the evening. Prednisone is tapered and discontinued.

The authors’ observations

Cognitive testing is essential for the diagnosis and treatment of patients with mental status changes and for evaluating their response to treatment. Although the MMSE is widely used, other scales—including the Confusion Assessment Method, the Organic Brain Syndrome Scale, the Memorial Delirium Assessment Scale, and the delirium severity index⁶—may be more sensitive for detecting delirium. All of these scales can be difficult to complete when evaluating confused and combative patients. Quick screening instruments for inattention, such as the digit span test and listing days of the week backwards, could be used as well.

HISTORY: Surgical complications

Further questioning of Mr. L’s family reveals that his behavior started to change 7 months ago; this was 1 month after undergoing hip replacement surgery, which was complicated by a surgical wound infection and worsened his medical illnesses. Within a month, Mr. L became withdrawn and appeared depressed. He was confused and intermittently disoriented to place and time. He became irritable and started reporting concerns about his wife having an affair. During this time different medications were introduced, including steroids and several antibiotics.

The authors’ observations

A thorough history from the patient and caregivers, including the time course of mental status changes, new medication use, and history of medical and psychiatric disorders—especially depression and dementia—are important to obtain, especially early in the evaluation.

Although Mr. L’s irritability, delusions, and psychomotor slowing could be signs of psychotic depression, his fluctuating mental status, disorientation, poor attention, and impaired concentration suggest delirium (Table 3).^4,7 This diagnosis is supported by the fact that Mr. L’s symptoms emerged after orthopedic surgery. Delirium after orthopedic surgery is common among older patients.⁸ Contributing and perpetuating factors in Mr. L’s case may have included postoperative complications, hypokalemia (hyperaldosteronism), medications (prednisone, digoxin, and olanzapine), and environmental unfamiliarity during hospitalization. A delirium diagnosis should be based on a high index of suspicion and a careful clinical assessment rather than diagnostic tests.

Table 3

Deconstructing delirium

OUTCOME: Return home

Mr. L’s confusion and delusional jealousy decrease over time, as do his disorientation and inattention, as evidenced by improvement on MMSE scores. His last MMSE score is 27/30, failing mostly in attention and recall.

After sustained improvement in cognition and behavior, Mr. L is discharged home on haloperidol and the remainder of his nonpsychiatric medications with outpatient medical and psychiatric follow-up. Over several months, he continues to show improvement and haloperidol is discontinued.

The authors’ observations

Delirium treatment should focus on prompt identification and management of precipitating and contributing factors.⁷ Antipsychotics are considered first-line treatment for patients with delirium, agitation, or psychosis who pose a risk to themselves or others. Benzodiazepines should be avoided in older patients unless symptoms are secondary to CNS-depressant withdrawal (ie, alcohol, benzodiazepines).⁹

Although there are no-FDA approved medications for delirium, haloperidol has been widely studied and used for treatment of agitation and psychosis in delirium. There is no evidence that low-dose haloperidol is any less effective than olanzapine or risperidone, or is more likely to cause adverse drug effects such as extrapyramidal syndrome.¹⁰ Antipsychotic use in a confused or agitated dementia patient increases risk of mortality compared with dementia patients who do not receive antipsychotics.¹¹ The use of typical or atypical antipsychotics for delirium should be guided by the patient’s characteristics, such as cardiovascular status and presence or absence of underlying dementia. Atypical antipsychotics should be used carefully because—as in Mr. L’s case—anticholinergic side effects of medications such as olanzapine could worsen delirium.⁵ Once delirium has resolved, antipsychotics should be tapered and discontinued.

Other components of delirium treatment and prevention include:

• reorientation (verbally, with clocks, calendars, etc.)
• safe ambulation
• adequate sleep, food, and fluid intake
• adaptive equipment for vision and hearing impairment
• adequate management of pain and other comorbidities.¹²

Related Resources

• Khan RA, Kahn D, Bourgeois JA. Delirium: sifting through the confusion. Curr Psychiatry Rep. 2009;11(3):226-234.
• Maldonado JR. Delirium in the acute care setting: characteristics, diagnosis, and treatment. Crit Care Clin. 2008;24:657-722.
• Young J, Inouye SK. Delirium in older people. BMJ. 2007;334(7598):842-846.

Drug Brand Names

• Amantadine • Symmetrel
• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Atenolol • Tenormin
• Atropine • AtroPen
• Benztropine • Cogentin
• Cimetidine • Tagamet
• Clozapine • Clozaril
• Digoxin • Lanoxicaps, Lanoxin
• Glyburide • DiaBeta, Micronase
• Haloperidol • Haldol
• Levodopa/carbidopa • Parcopa, Sinemet
• Lisinopril • Prinivil, Zestril
• Lorazepam • Ativan
• Meperidine • Demerol
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Oxybutynin • Ditropan
• Pergolide • Permax
• Phenytoin • Dilantin, Phenytek
• Prednisolone • Orapred, Prelone, others
• Prednisone • Deltasone, Meticorten
• Pyridostigmine • Mestinon
• Ranitidine • Zantac
• Risperidone • Risperdal
• Selegiline • Eldepryl, Zelapar
• Spironolactone • Aldactone
• Tamsulosin • Flomax
• Thioridazine • Mellaril
• Trazodone • Desyrel
• Warfarin • Coumadin

Disclosure

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

CASE: Agitated and paranoid

Police bring Mr. L, age 85, to the emergency department (ED) because he threatened his wife, claiming she is having an affair. Two days earlier, he was discharged from a different hospital, where he was treated for progressive and fluctuating irritability, depressed mood, confusion, disorientation, inattention, and delusional thinking that had started 4 to 5 months earlier. He has no other psychiatric history.

Mr. L has a history of atrial fibrillation, hypertension, benign prostatic hypertrophy, and noninsulin-dependent diabetes mellitus. Several months ago, he had hip surgery, which was complicated by a surgical wound infection. Medications include digoxin, 0.125 mg/d; atenolol, 100 mg/d; warfarin, 1 mg/d on Monday, Wednesday, Friday, Saturday, and Sunday and 0.5 mg/d Tuesday and Thursday; lisinopril, 40 mg/d; tamsulosin, 0.4 mg/d; and glyburide, 1.25 mg/d. During the previous hospitalization, physicians discovered he had myasthenia gravis, which they treated with prednisone and pyridostigmine. Mr. L also was diagnosed with hyperaldosteronism. An adrenal mass was found in an abdominal CT. At that time, he also was diagnosed with major depressive disorder (MDD) with psychotic features and started on aripiprazole, 10 mg/d, mirtazapine, 30 mg/d, and trazodone, 50 mg/d for sleep.

The authors’ observations

When evaluating mental status changes in older patients, consider the time course and characteristics of the changes, especially if the patient’s cognitive function changes. Acute mental status changes that occur over hours to days often represent delirium caused by a medical condition such as a coronary event or infection. Changes that develop over weeks to months often signal a primary psychiatric disorder such as depression, mania, or dementia. Mr. L’s mood and psychotic symptoms developed over 4 to 5 months and were thought to be a result of MDD with psychotic features. However, his fluctuating cognitive symptoms, confusion, and lack of psychiatric history suggest that the differential diagnosis should include a cognitive disorder such as delirium or dementia. The hypoactive form of delirium often is unrecognized or misdiagnosed as sedation or depression, particularly in older patients.¹

Multiple medical conditions and polypharmacy are important factors to consider when evaluating mental status changes in geriatric patients. In Mr. L’s case, atrial fibrillation, hypertension, and diabetes increase his risk of an acute cardiovascular or cerebrovascular event and chronic cerebrovascular disease. Hyperaldosteronism can lead to electrolyte abnormalities that may produce mental status changes. Treatment with an oral hypoglycemic raises the possibility that hypoglycemia is contributing to his mental status changes. Prednisone can cause psychosis, anxiety, and mania. Digoxin toxicity is associated with psychosis and irritability. Pyridostigmine also has been reported to cause psychosis. Use of an antidepressant, such as mirtazapine, could have exacerbated an underlying undiagnosed bipolar disorder. Antipsychotics, such as aripiprazole, may cause akathisia or activation. Substance intoxication or withdrawal should not be excluded solely because a patient is older. In older patients, medications with anti-cholinergic effects are common culprits for cognitive impairment (Table 1).^2,3

Table 1

Medications that could contribute to mental status changes

ASSESSMENT: More problems

At admission to the medical unit, Mr. L’s temperature is 36.7°C (98°F), with a heart rate of 77 beats per minute, respiratory rate of 24 breaths per minute, and blood pressure of 164/84 mm Hg with oxygen saturation of 96% at room air. Physical exam is notable for 2+ pitting edema in the lower extremities. Mr. L is oriented to person, place, and time and is psychomotorically activated. Neurologic examination is within normal limits.

Laboratory data reveal a potassium level of 2.5 mEq/L. Other results, including complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone, urinalysis, urine toxicology screen, B12, folate, venereal disease research laboratory, and ammonia are unremarkable. Chest radiography reveals an enlarged cardiomediastinum. A CT scan of the brain without contrast shows cortical volume loss and periventricular white matter disease without evidence of acute intracranial abnormality. ECG shows atrial fibrillation with a rate of 67 beats per minute.

Mr. L’s hypokalemia is corrected with potassium chloride and his hyperaldosteronism is treated with spironolactone, 25 mg/d. Physicians on the medical unit discontinue digoxin because Mr. L’s heart rate is controlled with atenolol and he is anticoagulated with warfarin.

Mr. L continues to be depressed and irritable with delusional jealousy. Mirtazapine is continued at 30 mg/d at bedtime. Aripiprazole and trazodone are discontinued and Mr. L is started on olanzapine, 10 mg/d, and haloperidol, 1 mg 4 times a day as needed for agitation. He requires multiple “as needed” haloperidol doses because of intermittent episodes of agitation. Mr. L is then transferred to the inpatient psychiatric unit for continued evaluation and treatment.

The authors’ observations

The fact that Mr. L is alert and oriented is encouraging; however, it does not rule out delirium because this condition is characterized by fluctuating levels of consciousness. Therefore, it is important to reassess him over time and perform a more thorough evaluation of cognitive function, especially attention and concentration, in addition to alertness and orientation. Psychomotor activation could suggest agitated depression, anxiety, mania, psychosis, substance intoxication, akathisia from antipsychotics, or delirium (Table 2).⁴ Initial evaluation— especially in older patients—should include a thorough history (including collateral sources) and be guided by the clinical presentation and physical examination, taking into consideration life-threatening conditions and common causes of mental status change such as infections, hypoxia, substance or medication effects, acute coronary syndromes, acute neurologic events, and metabolic conditions.

Table 2

DSM-IV-TR criteria for delirium caused by a medical condition

Reconsider the diagnosis

Even after being treated for hyperaldosteronism and discontinuing unnecessary medications, Mr. L continued to be treated for MDD with psychotic features despite intermittent confusion and agitation. At this point, it might have been useful to reconsider whether MDD with psychotic features was the most appropriate diagnosis to explain his mental status changes.

Mental status changes caused by medical disorders or medications do not immediately clear after the medical disorder is corrected or the medication is discontinued; it could take days or weeks for a patient to return to baseline. In Mr. L’s case it may be useful to simplify his medication regimen because polypharmacy contributes to delirium. Finally, olanzapine could worsen his condition because of its anticholinergic effects.⁵

EVALUATION: Poor cognitive status

Mental status examination upon admission to the psychiatric unit reveals a poorly cooperative patient with irritable mood and affect with slowed psychomotor activity. Mr. L’s thought process is organized with normal associations and thought content does not reveal suicidality or homicidality. However, he verbalizes delusions about his wife having an affair with a neighbor. He is partially oriented to time but believes he is in Germany. His insight is limited and he demonstrates impaired attention and concentration. We cannot complete a Mini-Mental State Exam (MMSE) because Mr. L does not cooperate.

After admission, Mr. L is intermittently confused, agitated, and disoriented. Between these episodes he is pleasant, cooperative, and oriented. Jealous delusions regarding his wife continue. Olanzapine and mirtazapine are tapered and discontinued. Haloperidol dose is changed to 1 mg 3 times a day, then to 1.5 mg in the morning and 3 mg in the evening. Prednisone is tapered and discontinued.

The authors’ observations

Cognitive testing is essential for the diagnosis and treatment of patients with mental status changes and for evaluating their response to treatment. Although the MMSE is widely used, other scales—including the Confusion Assessment Method, the Organic Brain Syndrome Scale, the Memorial Delirium Assessment Scale, and the delirium severity index⁶—may be more sensitive for detecting delirium. All of these scales can be difficult to complete when evaluating confused and combative patients. Quick screening instruments for inattention, such as the digit span test and listing days of the week backwards, could be used as well.

HISTORY: Surgical complications

Further questioning of Mr. L’s family reveals that his behavior started to change 7 months ago; this was 1 month after undergoing hip replacement surgery, which was complicated by a surgical wound infection and worsened his medical illnesses. Within a month, Mr. L became withdrawn and appeared depressed. He was confused and intermittently disoriented to place and time. He became irritable and started reporting concerns about his wife having an affair. During this time different medications were introduced, including steroids and several antibiotics.

The authors’ observations

A thorough history from the patient and caregivers, including the time course of mental status changes, new medication use, and history of medical and psychiatric disorders—especially depression and dementia—are important to obtain, especially early in the evaluation.

Although Mr. L’s irritability, delusions, and psychomotor slowing could be signs of psychotic depression, his fluctuating mental status, disorientation, poor attention, and impaired concentration suggest delirium (Table 3).^4,7 This diagnosis is supported by the fact that Mr. L’s symptoms emerged after orthopedic surgery. Delirium after orthopedic surgery is common among older patients.⁸ Contributing and perpetuating factors in Mr. L’s case may have included postoperative complications, hypokalemia (hyperaldosteronism), medications (prednisone, digoxin, and olanzapine), and environmental unfamiliarity during hospitalization. A delirium diagnosis should be based on a high index of suspicion and a careful clinical assessment rather than diagnostic tests.

Table 3

Deconstructing delirium

OUTCOME: Return home

Mr. L’s confusion and delusional jealousy decrease over time, as do his disorientation and inattention, as evidenced by improvement on MMSE scores. His last MMSE score is 27/30, failing mostly in attention and recall.

After sustained improvement in cognition and behavior, Mr. L is discharged home on haloperidol and the remainder of his nonpsychiatric medications with outpatient medical and psychiatric follow-up. Over several months, he continues to show improvement and haloperidol is discontinued.

The authors’ observations

Delirium treatment should focus on prompt identification and management of precipitating and contributing factors.⁷ Antipsychotics are considered first-line treatment for patients with delirium, agitation, or psychosis who pose a risk to themselves or others. Benzodiazepines should be avoided in older patients unless symptoms are secondary to CNS-depressant withdrawal (ie, alcohol, benzodiazepines).⁹

Although there are no-FDA approved medications for delirium, haloperidol has been widely studied and used for treatment of agitation and psychosis in delirium. There is no evidence that low-dose haloperidol is any less effective than olanzapine or risperidone, or is more likely to cause adverse drug effects such as extrapyramidal syndrome.¹⁰ Antipsychotic use in a confused or agitated dementia patient increases risk of mortality compared with dementia patients who do not receive antipsychotics.¹¹ The use of typical or atypical antipsychotics for delirium should be guided by the patient’s characteristics, such as cardiovascular status and presence or absence of underlying dementia. Atypical antipsychotics should be used carefully because—as in Mr. L’s case—anticholinergic side effects of medications such as olanzapine could worsen delirium.⁵ Once delirium has resolved, antipsychotics should be tapered and discontinued.

Other components of delirium treatment and prevention include:

• reorientation (verbally, with clocks, calendars, etc.)
• safe ambulation
• adequate sleep, food, and fluid intake
• adaptive equipment for vision and hearing impairment
• adequate management of pain and other comorbidities.¹²

Related Resources

• Khan RA, Kahn D, Bourgeois JA. Delirium: sifting through the confusion. Curr Psychiatry Rep. 2009;11(3):226-234.
• Maldonado JR. Delirium in the acute care setting: characteristics, diagnosis, and treatment. Crit Care Clin. 2008;24:657-722.
• Young J, Inouye SK. Delirium in older people. BMJ. 2007;334(7598):842-846.

Drug Brand Names

• Amantadine • Symmetrel
• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Atenolol • Tenormin
• Atropine • AtroPen
• Benztropine • Cogentin
• Cimetidine • Tagamet
• Clozapine • Clozaril
• Digoxin • Lanoxicaps, Lanoxin
• Glyburide • DiaBeta, Micronase
• Haloperidol • Haldol
• Levodopa/carbidopa • Parcopa, Sinemet
• Lisinopril • Prinivil, Zestril
• Lorazepam • Ativan
• Meperidine • Demerol
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Oxybutynin • Ditropan
• Pergolide • Permax
• Phenytoin • Dilantin, Phenytek
• Prednisolone • Orapred, Prelone, others
• Prednisone • Deltasone, Meticorten
• Pyridostigmine • Mestinon
• Ranitidine • Zantac
• Risperidone • Risperdal
• Selegiline • Eldepryl, Zelapar
• Spironolactone • Aldactone
• Tamsulosin • Flomax
• Thioridazine • Mellaril
• Trazodone • Desyrel
• Warfarin • Coumadin

Disclosure

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

The authors of the “The mysterious foreign accent” (Cases that Test Your Skills, Current Psychiatry, March 2011, p. 57-63) left us hanging by tantalizing us with an axis III diagnosis of asymptomatic hyperammonemia. They most likely did more work to come to that diagnostic conclusion but it’s not evident in the article. I’m left with the feeling that a young person with delusions, psychosis, and average intelligence might have a metabolic source for those symptoms—particularly because she seems to have a high-achieving father, yet is a high school dropout. The discussion of foreign accent syndrome mentions structural cerebral lesions as a major source for the disorder. A quick Internet search failed to turn up an association with hyperammonemia but that would not necessarily rule out a connection in this case because both are rare disorders.

I also would think the presence of hyperammonemia would preclude use of valproate or certainly would need to be addressed during treatment. The response to risperidone and valproate would be in keeping with the standard response of a mild delirium to antipsychotic treatment. The history of physical and emotional abuse would be in keeping with the exploitation that mentally disordered people often are subjected to as Dr. Henry A. Nasrallah mentions in the Comments and Controversies section (Current Psychiatry, March 2011, p. 5,64).

Kenneth Lipman, MD
Chief of Psychiatry
Kaiser Permanente
Vacaville, CA

The authors respond

Hyperammonemia was an incidental finding. As a part of standard check-up, blood work was done. In the workup for the basic metabolic panel, ammonia level was found to be elevated above the normal range. But this lab finding was not correlated with other clinical findings. The liver panel was normal. The patient did not have any features of encephalopathy, nor did she have any clinical signs or symptoms. There have been reports of hyperammonemia associated with the use of valproate but unless the patient is clinically symptomatic, dose adjustment for valproate is not warranted. Periodic monitoring for ammonia level may be needed for high-risk patients on valproate if they have clinical signs and symptoms.

Panchajanya Paul, MD
Second-Year Resident
Department of Psychiatry
The University of Toledo
Toledo, OH

Barry Beckman, PsyD
Psychologist
Northwest Ohio Psychiatric Hospital
Toledo, OH

David Bellian, MD
Psychiatrist
Northwest Ohio Psychiatric Hospital
Clinical Assistant Professor of Psychiatry
The University of Toledo
Toledo, OH

Thomas Osinowo, MD
Psychiatrist
Northwest Ohio Psychiatric Hospital
Clinical Assistant Professor of Psychiatry
The University of Toledo
Toledo, OH

The authors of the “The mysterious foreign accent” (Cases that Test Your Skills, Current Psychiatry, March 2011, p. 57-63) left us hanging by tantalizing us with an axis III diagnosis of asymptomatic hyperammonemia. They most likely did more work to come to that diagnostic conclusion but it’s not evident in the article. I’m left with the feeling that a young person with delusions, psychosis, and average intelligence might have a metabolic source for those symptoms—particularly because she seems to have a high-achieving father, yet is a high school dropout. The discussion of foreign accent syndrome mentions structural cerebral lesions as a major source for the disorder. A quick Internet search failed to turn up an association with hyperammonemia but that would not necessarily rule out a connection in this case because both are rare disorders.

I also would think the presence of hyperammonemia would preclude use of valproate or certainly would need to be addressed during treatment. The response to risperidone and valproate would be in keeping with the standard response of a mild delirium to antipsychotic treatment. The history of physical and emotional abuse would be in keeping with the exploitation that mentally disordered people often are subjected to as Dr. Henry A. Nasrallah mentions in the Comments and Controversies section (Current Psychiatry, March 2011, p. 5,64).

Kenneth Lipman, MD
Chief of Psychiatry
Kaiser Permanente
Vacaville, CA

The authors respond

Hyperammonemia was an incidental finding. As a part of standard check-up, blood work was done. In the workup for the basic metabolic panel, ammonia level was found to be elevated above the normal range. But this lab finding was not correlated with other clinical findings. The liver panel was normal. The patient did not have any features of encephalopathy, nor did she have any clinical signs or symptoms. There have been reports of hyperammonemia associated with the use of valproate but unless the patient is clinically symptomatic, dose adjustment for valproate is not warranted. Periodic monitoring for ammonia level may be needed for high-risk patients on valproate if they have clinical signs and symptoms.

Panchajanya Paul, MD
Second-Year Resident
Department of Psychiatry
The University of Toledo
Toledo, OH

Barry Beckman, PsyD
Psychologist
Northwest Ohio Psychiatric Hospital
Toledo, OH

David Bellian, MD
Psychiatrist
Northwest Ohio Psychiatric Hospital
Clinical Assistant Professor of Psychiatry
The University of Toledo
Toledo, OH

Thomas Osinowo, MD
Psychiatrist
Northwest Ohio Psychiatric Hospital
Clinical Assistant Professor of Psychiatry
The University of Toledo
Toledo, OH

The authors of the “The mysterious foreign accent” (Cases that Test Your Skills, Current Psychiatry, March 2011, p. 57-63) left us hanging by tantalizing us with an axis III diagnosis of asymptomatic hyperammonemia. They most likely did more work to come to that diagnostic conclusion but it’s not evident in the article. I’m left with the feeling that a young person with delusions, psychosis, and average intelligence might have a metabolic source for those symptoms—particularly because she seems to have a high-achieving father, yet is a high school dropout. The discussion of foreign accent syndrome mentions structural cerebral lesions as a major source for the disorder. A quick Internet search failed to turn up an association with hyperammonemia but that would not necessarily rule out a connection in this case because both are rare disorders.

I also would think the presence of hyperammonemia would preclude use of valproate or certainly would need to be addressed during treatment. The response to risperidone and valproate would be in keeping with the standard response of a mild delirium to antipsychotic treatment. The history of physical and emotional abuse would be in keeping with the exploitation that mentally disordered people often are subjected to as Dr. Henry A. Nasrallah mentions in the Comments and Controversies section (Current Psychiatry, March 2011, p. 5,64).

Kenneth Lipman, MD
Chief of Psychiatry
Kaiser Permanente
Vacaville, CA

The authors respond

Hyperammonemia was an incidental finding. As a part of standard check-up, blood work was done. In the workup for the basic metabolic panel, ammonia level was found to be elevated above the normal range. But this lab finding was not correlated with other clinical findings. The liver panel was normal. The patient did not have any features of encephalopathy, nor did she have any clinical signs or symptoms. There have been reports of hyperammonemia associated with the use of valproate but unless the patient is clinically symptomatic, dose adjustment for valproate is not warranted. Periodic monitoring for ammonia level may be needed for high-risk patients on valproate if they have clinical signs and symptoms.

Panchajanya Paul, MD
Second-Year Resident
Department of Psychiatry
The University of Toledo
Toledo, OH

Barry Beckman, PsyD
Psychologist
Northwest Ohio Psychiatric Hospital
Toledo, OH

David Bellian, MD
Psychiatrist
Northwest Ohio Psychiatric Hospital
Clinical Assistant Professor of Psychiatry
The University of Toledo
Toledo, OH

Thomas Osinowo, MD
Psychiatrist
Northwest Ohio Psychiatric Hospital
Clinical Assistant Professor of Psychiatry
The University of Toledo
Toledo, OH

The article “Dextromethorphan/quinidine for pseudobulbar affect” (Out of the Pipeline, Current Psychiatry, February 2011, p. 60-67) was of great interest. For the past 5 years I have led the clinical development of Nuedexta^TM (dextromethorphan hydrobromide and quinidine sulfate; DMQ) and I found the review extraordinarily comprehensive and applaud the authors for their exhaustive research. I would, however, like to take the opportunity to provide some additional insight into a few areas covered by the article.

The authors, in describing the control groups in an earlier phase III study of DMQ for the treatment of patients with pseudobulbar affect (PBA), state, “However, the control conditions may not have been adequate. Quinidine alone would not be expected to have an effect on PBA, and the DM dose, which was the same in combination and monotherapy, may have been too low to be effective by itself. In support of this hypothesis, the DM plasma level was 18 times higher in patients taking DMQ 30-30 than those taking DM monotherapy.” Although their observations regarding the effectiveness of higher doses may be true, the study was designed to meet the FDA standards for combination products—that a combination product’s efficacy needs to exceed that which is appreciated by either of the components administered alone. As the authors correctly pointed out, even high doses of DM, when administered alone, are rapidly metabolized and cannot reach substantial bioavailability in order to exert a therapeutic effect.

Having been involved in clinical drug development for nearly 20 years, I cannot agree with the authors conclusions that: “Although DMQ is convenient, its advantage over starting with DM alone and adding a small dose of a nonserotonergic 2D6 inhibitor if DM is not effective remains to be demonstrated.” The statement implies that a reasonable approach is to consider testing DM combined with a series of arbitrary CYP2D6 inhibitors. These combinations have not been tested and there is no evidence on which to base the efficacy or safety of this approach. As clinical researchers, we have an obligation to make recommendations that are based on available data and that ensure patient safety. In our own exhaustive research, we believe there is no other CYP2D6 inhibitor, other than low-dose quinidine, 10 mg/d (1% to 3% of a typical antiarrhythmic dose), that can provide a safe and predictable pharmacologic profile when used in combination with DM. Lastly, I am disappointed with the assertion that “it would seem prudent to consider using an SSRI (selective serotonin reuptake inhibitor) or a TCA (tricyclic antidepressant) first.” These drugs have not been extensively studied for the treatment of PBA, and have their own (not benign) risks. Moreover, these antidepressants have not met the standard of substantial clinical evidence required by the FDA and thus, are not approved for treating patients with PBA.

Randall E. Kaye, MD, MPH
Chief Medical Officer
Avanir Pharmaceuticals
Aliso Viejo, CA

The authors respond

We appreciate Dr. Kaye’s letter, but would like to point out that registration trials designed to get FDA approval are designed to demonstrate superiority of the product to placebo and not to answer the question “under what circumstances and compared with what alternatives is this product more likely to be effective and safe?” We would not necessarily agree that this particular product is superior because it was approved by the FDA in placebo-controlled research designed to maximize the apparent benefit of the combination, when only clinical experience supports the use of alternatives. Perhaps the manufacturer would care to design head-to-head comparisons to support Dr. Kaye’s contention that his product should be the first choice in the treatment of PBA, which has been done with cancer and human immunodeficiency virus products, among others. Such comparison trials should include patients with complex and comorbid disorders to reflect real-life clinical practice rather than efficacy in patients selected for their likelihood to respond to the product. In the meantime, clinicians have the task of evaluating marketing of products and ideas, which is inherent in many clinical recommendations, not only those for which the only controlled data come from industry-sponsored trials.

Alfonso Tan III, MD
Assistant Professor of Psychiatry
University at Buffalo
Buffalo, NY

Steven L. Dubovsky, MD
Professor and Chair
Department of Psychiatry
University at Buffalo
Buffalo, NY
Adjoint Professor of Psychiatry
and Medicine
University of Colorado
Denver, CO

The article “Dextromethorphan/quinidine for pseudobulbar affect” (Out of the Pipeline, Current Psychiatry, February 2011, p. 60-67) was of great interest. For the past 5 years I have led the clinical development of Nuedexta^TM (dextromethorphan hydrobromide and quinidine sulfate; DMQ) and I found the review extraordinarily comprehensive and applaud the authors for their exhaustive research. I would, however, like to take the opportunity to provide some additional insight into a few areas covered by the article.

The authors, in describing the control groups in an earlier phase III study of DMQ for the treatment of patients with pseudobulbar affect (PBA), state, “However, the control conditions may not have been adequate. Quinidine alone would not be expected to have an effect on PBA, and the DM dose, which was the same in combination and monotherapy, may have been too low to be effective by itself. In support of this hypothesis, the DM plasma level was 18 times higher in patients taking DMQ 30-30 than those taking DM monotherapy.” Although their observations regarding the effectiveness of higher doses may be true, the study was designed to meet the FDA standards for combination products—that a combination product’s efficacy needs to exceed that which is appreciated by either of the components administered alone. As the authors correctly pointed out, even high doses of DM, when administered alone, are rapidly metabolized and cannot reach substantial bioavailability in order to exert a therapeutic effect.

Having been involved in clinical drug development for nearly 20 years, I cannot agree with the authors conclusions that: “Although DMQ is convenient, its advantage over starting with DM alone and adding a small dose of a nonserotonergic 2D6 inhibitor if DM is not effective remains to be demonstrated.” The statement implies that a reasonable approach is to consider testing DM combined with a series of arbitrary CYP2D6 inhibitors. These combinations have not been tested and there is no evidence on which to base the efficacy or safety of this approach. As clinical researchers, we have an obligation to make recommendations that are based on available data and that ensure patient safety. In our own exhaustive research, we believe there is no other CYP2D6 inhibitor, other than low-dose quinidine, 10 mg/d (1% to 3% of a typical antiarrhythmic dose), that can provide a safe and predictable pharmacologic profile when used in combination with DM. Lastly, I am disappointed with the assertion that “it would seem prudent to consider using an SSRI (selective serotonin reuptake inhibitor) or a TCA (tricyclic antidepressant) first.” These drugs have not been extensively studied for the treatment of PBA, and have their own (not benign) risks. Moreover, these antidepressants have not met the standard of substantial clinical evidence required by the FDA and thus, are not approved for treating patients with PBA.

Randall E. Kaye, MD, MPH
Chief Medical Officer
Avanir Pharmaceuticals
Aliso Viejo, CA

The authors respond

We appreciate Dr. Kaye’s letter, but would like to point out that registration trials designed to get FDA approval are designed to demonstrate superiority of the product to placebo and not to answer the question “under what circumstances and compared with what alternatives is this product more likely to be effective and safe?” We would not necessarily agree that this particular product is superior because it was approved by the FDA in placebo-controlled research designed to maximize the apparent benefit of the combination, when only clinical experience supports the use of alternatives. Perhaps the manufacturer would care to design head-to-head comparisons to support Dr. Kaye’s contention that his product should be the first choice in the treatment of PBA, which has been done with cancer and human immunodeficiency virus products, among others. Such comparison trials should include patients with complex and comorbid disorders to reflect real-life clinical practice rather than efficacy in patients selected for their likelihood to respond to the product. In the meantime, clinicians have the task of evaluating marketing of products and ideas, which is inherent in many clinical recommendations, not only those for which the only controlled data come from industry-sponsored trials.

Alfonso Tan III, MD
Assistant Professor of Psychiatry
University at Buffalo
Buffalo, NY

Steven L. Dubovsky, MD
Professor and Chair
Department of Psychiatry
University at Buffalo
Buffalo, NY
Adjoint Professor of Psychiatry
and Medicine
University of Colorado
Denver, CO

The article “Dextromethorphan/quinidine for pseudobulbar affect” (Out of the Pipeline, Current Psychiatry, February 2011, p. 60-67) was of great interest. For the past 5 years I have led the clinical development of Nuedexta^TM (dextromethorphan hydrobromide and quinidine sulfate; DMQ) and I found the review extraordinarily comprehensive and applaud the authors for their exhaustive research. I would, however, like to take the opportunity to provide some additional insight into a few areas covered by the article.

The authors, in describing the control groups in an earlier phase III study of DMQ for the treatment of patients with pseudobulbar affect (PBA), state, “However, the control conditions may not have been adequate. Quinidine alone would not be expected to have an effect on PBA, and the DM dose, which was the same in combination and monotherapy, may have been too low to be effective by itself. In support of this hypothesis, the DM plasma level was 18 times higher in patients taking DMQ 30-30 than those taking DM monotherapy.” Although their observations regarding the effectiveness of higher doses may be true, the study was designed to meet the FDA standards for combination products—that a combination product’s efficacy needs to exceed that which is appreciated by either of the components administered alone. As the authors correctly pointed out, even high doses of DM, when administered alone, are rapidly metabolized and cannot reach substantial bioavailability in order to exert a therapeutic effect.

Having been involved in clinical drug development for nearly 20 years, I cannot agree with the authors conclusions that: “Although DMQ is convenient, its advantage over starting with DM alone and adding a small dose of a nonserotonergic 2D6 inhibitor if DM is not effective remains to be demonstrated.” The statement implies that a reasonable approach is to consider testing DM combined with a series of arbitrary CYP2D6 inhibitors. These combinations have not been tested and there is no evidence on which to base the efficacy or safety of this approach. As clinical researchers, we have an obligation to make recommendations that are based on available data and that ensure patient safety. In our own exhaustive research, we believe there is no other CYP2D6 inhibitor, other than low-dose quinidine, 10 mg/d (1% to 3% of a typical antiarrhythmic dose), that can provide a safe and predictable pharmacologic profile when used in combination with DM. Lastly, I am disappointed with the assertion that “it would seem prudent to consider using an SSRI (selective serotonin reuptake inhibitor) or a TCA (tricyclic antidepressant) first.” These drugs have not been extensively studied for the treatment of PBA, and have their own (not benign) risks. Moreover, these antidepressants have not met the standard of substantial clinical evidence required by the FDA and thus, are not approved for treating patients with PBA.

Randall E. Kaye, MD, MPH
Chief Medical Officer
Avanir Pharmaceuticals
Aliso Viejo, CA

The authors respond

We appreciate Dr. Kaye’s letter, but would like to point out that registration trials designed to get FDA approval are designed to demonstrate superiority of the product to placebo and not to answer the question “under what circumstances and compared with what alternatives is this product more likely to be effective and safe?” We would not necessarily agree that this particular product is superior because it was approved by the FDA in placebo-controlled research designed to maximize the apparent benefit of the combination, when only clinical experience supports the use of alternatives. Perhaps the manufacturer would care to design head-to-head comparisons to support Dr. Kaye’s contention that his product should be the first choice in the treatment of PBA, which has been done with cancer and human immunodeficiency virus products, among others. Such comparison trials should include patients with complex and comorbid disorders to reflect real-life clinical practice rather than efficacy in patients selected for their likelihood to respond to the product. In the meantime, clinicians have the task of evaluating marketing of products and ideas, which is inherent in many clinical recommendations, not only those for which the only controlled data come from industry-sponsored trials.

Alfonso Tan III, MD
Assistant Professor of Psychiatry
University at Buffalo
Buffalo, NY

Steven L. Dubovsky, MD
Professor and Chair
Department of Psychiatry
University at Buffalo
Buffalo, NY
Adjoint Professor of Psychiatry
and Medicine
University of Colorado
Denver, CO

Mr. Z, age 27, seeks treatment for substance abuse at a mental health clinic. He has a 7-year substance use history and his last urine drug screen 1 month ago was positive for marijuana, opiates, and benzodiazepines. Mr. Z reveals that he purchases prescription drugs on the street, including hydrocodone, diazepam, and quetiapine. He states that when he takes a 100-mg dose of quetiapine, he feels happy, relaxed, and “drunk without the mind-numbing effects that you get with alcohol.” Mr. Z often takes quetiapine while smoking marijuana. He sleeps well with this and does not experience a hangover effect.

Although clinicians always are vigilant about patients’ misuse of psychoactive substances, recent case reports have described abuse of antipsychotics, particularly second-generation antipsychotics (SGAs). A PubMed and PsycINFO literature search revealed several case reports of quetiapine abuse (Table)^1-6 and 2 case reports of olanzapine misuse.

Table

Case reports of quetiapine abuse

Quetiapine

Methods of quetiapine misuse include ingesting pills, inhaling crushed tablets, and injecting a solution of dissolved tablets.^1-7 In case studies, patients report abusing quetiapine for its sedative, anxiolytic, and calming effects.^1,2,4-7 One patient reported snorting crushed quetiapine tablets combined with cocaine for “hallucinogenic” effects.³ Street names for quetiapine include “quell,” “Susie-Q,” and “baby heroin,” and “Q-ball” refers to a combination of cocaine and quetiapine.⁸ Quetiapine tablets have a street value of $3 to $8 for doses ranging from 25 mg to 100 mg.⁹ Although outpatient misuse of quetiapine is common, abuse in correctional settings also is becoming more frequent.¹⁰ Residents of jails and prisons misuse quetiapine for reasons similar to those cited by outpatients: sedation, relief of anxiety, and hallucinogenic effects or “getting high.”^1,2,10 Clinicians must differentiate inmates who have legitimate psychiatric symptoms that require antipsychotic treatment from those who are malingering to obtain the drug. Efforts to treat inmates for substance use disorders may be thwarted by the easy availability of drugs in correctional settings.¹⁰

Other SGAs

The incidence of misuse of olanzapine and other SGAs is more difficult to ascertain. Only 2 case reports describe olanzapine abuse, both in outpatient settings. One describes a patient treated for depression with psychosis who was using increasingly higher doses of olanzapine to obtain euphoric effects.¹¹ Switching to aripiprazole effectively treated her illness and addressed her olanzapine misuse.

In the other case, a patient with bipolar disorder was able to obtain olanzapine, 40 mg/d, by complaining of worsened manic symptoms.¹² He described the experience of misusing olanzapine as getting a “buzz,” feeling “very relaxed,” and blunting the negative jitteriness he felt when he used cocaine.¹² This patient stated that he had observed others abusing olanzapine, both orally and intravenously.

Although the literature lacks reports on the risks of antipsychotic abuse, numerous Web sites purport to sell these drugs without a prescription and some describe the experience of illicit use of drugs such as haloperidol, risperidone, quetiapine, and olanzapine and ways to “enhance” the experience by combining drugs.¹³ Reported experiences with risperidone tend to be negative, citing extrapyramidal side effects and feeling “numb,” whereas olanzapine and quetiapine users describe feeling “drunk without the bad effects of alcohol” and “really happy, calm.” These sites also describe hallucinogenic effects of these agents.¹³

Mechanism of action

The neuropharmacologic reasons for antipsychotics’ abuse potential are difficult to quantify. Quetiapine and olanzapine have been used to treat cocaine and alcohol abuse, and work perhaps by decreasing the dopamine reward system response to substance use.^14,15 Quetiapine’s rapid dissociation from the dopamine receptor has been theorized to contribute to the drug’s abuse potential, possibly through relatively lower potency and decreased residence time at the dopamine receptor.^14-16 This mechanism also contributes to quetiapine’s lower risk of extrapyramidal side effects, which make the drug easier to tolerate.

Although dopamine is a factor in substance abuse and treatment of psychotic disorders, other neuropharmacologic mechanisms must be considered. SGAs are theorized to cause dopamine release in the frontal cortex through effects as 5-HT1A agonists and 5-HT2A antagonists.¹⁶ Antagonism of α-adrenergic and histaminic receptors may account for these agents’ anxiolytic and sedative properties.⁸

Misuse of anticholinergic agents has been reported for >50 years.¹⁷ Psychiatric patients have been reported to increase use of anticholinergics for their movement side effects as well as hallucinogenic effects.¹⁸

Treatment

Regardless of the substance that patients abuse, the treatment goals are the same: to reduce use and achieve recovery. If a patient with psychosis is abusing an SGA, consider switching to an antipsychotic with less abuse potential. Another option is to limit the supply of the abused drug by prescribing smaller quantities or increase the frequency of follow-up visits to ensure compliant use.

Related Resources

• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.
• Galanter M, Kelber HD. The American Psychiatric Publishing textbook of substance abuse treatment. Arlington, VA: American Psychiatric Publishing, Inc; 2008.

Drug Brand Names

• Aripiprazole • Abilify
• Diazepam • Valium
• Haloperidol • Haldol
• Hydrocodone/acetaminophen • Vicodin
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal

Disclosure

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

Mr. Z, age 27, seeks treatment for substance abuse at a mental health clinic. He has a 7-year substance use history and his last urine drug screen 1 month ago was positive for marijuana, opiates, and benzodiazepines. Mr. Z reveals that he purchases prescription drugs on the street, including hydrocodone, diazepam, and quetiapine. He states that when he takes a 100-mg dose of quetiapine, he feels happy, relaxed, and “drunk without the mind-numbing effects that you get with alcohol.” Mr. Z often takes quetiapine while smoking marijuana. He sleeps well with this and does not experience a hangover effect.

Although clinicians always are vigilant about patients’ misuse of psychoactive substances, recent case reports have described abuse of antipsychotics, particularly second-generation antipsychotics (SGAs). A PubMed and PsycINFO literature search revealed several case reports of quetiapine abuse (Table)^1-6 and 2 case reports of olanzapine misuse.

Table

Case reports of quetiapine abuse

Quetiapine

Methods of quetiapine misuse include ingesting pills, inhaling crushed tablets, and injecting a solution of dissolved tablets.^1-7 In case studies, patients report abusing quetiapine for its sedative, anxiolytic, and calming effects.^1,2,4-7 One patient reported snorting crushed quetiapine tablets combined with cocaine for “hallucinogenic” effects.³ Street names for quetiapine include “quell,” “Susie-Q,” and “baby heroin,” and “Q-ball” refers to a combination of cocaine and quetiapine.⁸ Quetiapine tablets have a street value of $3 to $8 for doses ranging from 25 mg to 100 mg.⁹ Although outpatient misuse of quetiapine is common, abuse in correctional settings also is becoming more frequent.¹⁰ Residents of jails and prisons misuse quetiapine for reasons similar to those cited by outpatients: sedation, relief of anxiety, and hallucinogenic effects or “getting high.”^1,2,10 Clinicians must differentiate inmates who have legitimate psychiatric symptoms that require antipsychotic treatment from those who are malingering to obtain the drug. Efforts to treat inmates for substance use disorders may be thwarted by the easy availability of drugs in correctional settings.¹⁰

Other SGAs

The incidence of misuse of olanzapine and other SGAs is more difficult to ascertain. Only 2 case reports describe olanzapine abuse, both in outpatient settings. One describes a patient treated for depression with psychosis who was using increasingly higher doses of olanzapine to obtain euphoric effects.¹¹ Switching to aripiprazole effectively treated her illness and addressed her olanzapine misuse.

In the other case, a patient with bipolar disorder was able to obtain olanzapine, 40 mg/d, by complaining of worsened manic symptoms.¹² He described the experience of misusing olanzapine as getting a “buzz,” feeling “very relaxed,” and blunting the negative jitteriness he felt when he used cocaine.¹² This patient stated that he had observed others abusing olanzapine, both orally and intravenously.

Although the literature lacks reports on the risks of antipsychotic abuse, numerous Web sites purport to sell these drugs without a prescription and some describe the experience of illicit use of drugs such as haloperidol, risperidone, quetiapine, and olanzapine and ways to “enhance” the experience by combining drugs.¹³ Reported experiences with risperidone tend to be negative, citing extrapyramidal side effects and feeling “numb,” whereas olanzapine and quetiapine users describe feeling “drunk without the bad effects of alcohol” and “really happy, calm.” These sites also describe hallucinogenic effects of these agents.¹³

Mechanism of action

The neuropharmacologic reasons for antipsychotics’ abuse potential are difficult to quantify. Quetiapine and olanzapine have been used to treat cocaine and alcohol abuse, and work perhaps by decreasing the dopamine reward system response to substance use.^14,15 Quetiapine’s rapid dissociation from the dopamine receptor has been theorized to contribute to the drug’s abuse potential, possibly through relatively lower potency and decreased residence time at the dopamine receptor.^14-16 This mechanism also contributes to quetiapine’s lower risk of extrapyramidal side effects, which make the drug easier to tolerate.

Although dopamine is a factor in substance abuse and treatment of psychotic disorders, other neuropharmacologic mechanisms must be considered. SGAs are theorized to cause dopamine release in the frontal cortex through effects as 5-HT1A agonists and 5-HT2A antagonists.¹⁶ Antagonism of α-adrenergic and histaminic receptors may account for these agents’ anxiolytic and sedative properties.⁸

Misuse of anticholinergic agents has been reported for >50 years.¹⁷ Psychiatric patients have been reported to increase use of anticholinergics for their movement side effects as well as hallucinogenic effects.¹⁸

Treatment

Regardless of the substance that patients abuse, the treatment goals are the same: to reduce use and achieve recovery. If a patient with psychosis is abusing an SGA, consider switching to an antipsychotic with less abuse potential. Another option is to limit the supply of the abused drug by prescribing smaller quantities or increase the frequency of follow-up visits to ensure compliant use.

Related Resources

• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.
• Galanter M, Kelber HD. The American Psychiatric Publishing textbook of substance abuse treatment. Arlington, VA: American Psychiatric Publishing, Inc; 2008.

Drug Brand Names

• Aripiprazole • Abilify
• Diazepam • Valium
• Haloperidol • Haldol
• Hydrocodone/acetaminophen • Vicodin
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal

Disclosure

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

Mr. Z, age 27, seeks treatment for substance abuse at a mental health clinic. He has a 7-year substance use history and his last urine drug screen 1 month ago was positive for marijuana, opiates, and benzodiazepines. Mr. Z reveals that he purchases prescription drugs on the street, including hydrocodone, diazepam, and quetiapine. He states that when he takes a 100-mg dose of quetiapine, he feels happy, relaxed, and “drunk without the mind-numbing effects that you get with alcohol.” Mr. Z often takes quetiapine while smoking marijuana. He sleeps well with this and does not experience a hangover effect.

Although clinicians always are vigilant about patients’ misuse of psychoactive substances, recent case reports have described abuse of antipsychotics, particularly second-generation antipsychotics (SGAs). A PubMed and PsycINFO literature search revealed several case reports of quetiapine abuse (Table)^1-6 and 2 case reports of olanzapine misuse.

Table

Case reports of quetiapine abuse

Quetiapine

Methods of quetiapine misuse include ingesting pills, inhaling crushed tablets, and injecting a solution of dissolved tablets.^1-7 In case studies, patients report abusing quetiapine for its sedative, anxiolytic, and calming effects.^1,2,4-7 One patient reported snorting crushed quetiapine tablets combined with cocaine for “hallucinogenic” effects.³ Street names for quetiapine include “quell,” “Susie-Q,” and “baby heroin,” and “Q-ball” refers to a combination of cocaine and quetiapine.⁸ Quetiapine tablets have a street value of $3 to $8 for doses ranging from 25 mg to 100 mg.⁹ Although outpatient misuse of quetiapine is common, abuse in correctional settings also is becoming more frequent.¹⁰ Residents of jails and prisons misuse quetiapine for reasons similar to those cited by outpatients: sedation, relief of anxiety, and hallucinogenic effects or “getting high.”^1,2,10 Clinicians must differentiate inmates who have legitimate psychiatric symptoms that require antipsychotic treatment from those who are malingering to obtain the drug. Efforts to treat inmates for substance use disorders may be thwarted by the easy availability of drugs in correctional settings.¹⁰

Other SGAs

The incidence of misuse of olanzapine and other SGAs is more difficult to ascertain. Only 2 case reports describe olanzapine abuse, both in outpatient settings. One describes a patient treated for depression with psychosis who was using increasingly higher doses of olanzapine to obtain euphoric effects.¹¹ Switching to aripiprazole effectively treated her illness and addressed her olanzapine misuse.

In the other case, a patient with bipolar disorder was able to obtain olanzapine, 40 mg/d, by complaining of worsened manic symptoms.¹² He described the experience of misusing olanzapine as getting a “buzz,” feeling “very relaxed,” and blunting the negative jitteriness he felt when he used cocaine.¹² This patient stated that he had observed others abusing olanzapine, both orally and intravenously.

Although the literature lacks reports on the risks of antipsychotic abuse, numerous Web sites purport to sell these drugs without a prescription and some describe the experience of illicit use of drugs such as haloperidol, risperidone, quetiapine, and olanzapine and ways to “enhance” the experience by combining drugs.¹³ Reported experiences with risperidone tend to be negative, citing extrapyramidal side effects and feeling “numb,” whereas olanzapine and quetiapine users describe feeling “drunk without the bad effects of alcohol” and “really happy, calm.” These sites also describe hallucinogenic effects of these agents.¹³

Mechanism of action

The neuropharmacologic reasons for antipsychotics’ abuse potential are difficult to quantify. Quetiapine and olanzapine have been used to treat cocaine and alcohol abuse, and work perhaps by decreasing the dopamine reward system response to substance use.^14,15 Quetiapine’s rapid dissociation from the dopamine receptor has been theorized to contribute to the drug’s abuse potential, possibly through relatively lower potency and decreased residence time at the dopamine receptor.^14-16 This mechanism also contributes to quetiapine’s lower risk of extrapyramidal side effects, which make the drug easier to tolerate.

Although dopamine is a factor in substance abuse and treatment of psychotic disorders, other neuropharmacologic mechanisms must be considered. SGAs are theorized to cause dopamine release in the frontal cortex through effects as 5-HT1A agonists and 5-HT2A antagonists.¹⁶ Antagonism of α-adrenergic and histaminic receptors may account for these agents’ anxiolytic and sedative properties.⁸

Misuse of anticholinergic agents has been reported for >50 years.¹⁷ Psychiatric patients have been reported to increase use of anticholinergics for their movement side effects as well as hallucinogenic effects.¹⁸

Treatment

Regardless of the substance that patients abuse, the treatment goals are the same: to reduce use and achieve recovery. If a patient with psychosis is abusing an SGA, consider switching to an antipsychotic with less abuse potential. Another option is to limit the supply of the abused drug by prescribing smaller quantities or increase the frequency of follow-up visits to ensure compliant use.

Related Resources

• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.
• Galanter M, Kelber HD. The American Psychiatric Publishing textbook of substance abuse treatment. Arlington, VA: American Psychiatric Publishing, Inc; 2008.

Drug Brand Names

• Aripiprazole • Abilify
• Diazepam • Valium
• Haloperidol • Haldol
• Hydrocodone/acetaminophen • Vicodin
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal

Disclosure

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

The least effective, most costly method of reducing patient violence is to attempt to contain it after it has occurred. If containment includes using restraints, staff and patients are at additional risk for injury.

Our facility, a 315-bed, medium-security forensic program and a 75-bed civil program, is in its 16th year of violence and restraint reduction.¹ We have reduced restraint usage by >95%, and our hospital is one of the safest in our state. In March 2010, we were 1 of 10 institutions recognized by the Substance Abuse and Mental Health Services Administration for our efforts in reducing and preventing use of seclusion and restraints. If your facility is interested in such efforts, we recommend becoming familiar with the Six Core Strategies Planning Tool.²

Leadership toward organizational change. Any restraint reduction program is likely to encounter resistance. Active and visible presence of hospital leadership is essential to success. According to LeBel, ³ “Advancing seclusion and restraint standards is in the hands of administrators. The knowledge… is available, but it takes leadership, courage, and effort.”

Using data to inform practice. Leadership’s most effective tool is data. When we began our efforts in 1995 by doing nothing more than telling staff we would be tracking restraint usage, usage decreased by 36%. Next, leadership reduced the maximum time for a restraint order from 4 to 2 hours. Eventually, we reduced the maximum time to 1 hour. Restraint orders seldom required renewal.

One of the most useful pieces of data we developed established that on average, our well-trained staff incurred injuries severe enough to require medical treatment in 1 of every 4 instances of applying mechanical restraints. All staff could appreciate that as restraint usage was reduced, the number of associated staff injuries also would fall.

Workforce development. Leadership’s most valuable resource is its workforce. Experience showed that a substantial number of restraint episodes started with rigid enforcement of unit rules. We provide staff with the tools necessary to make clinically based decisions, rather than relying on strict adherence to rules. Staff should never get the impression that patients are being empowered but staff are not.

Initially, we relied on a “champion” or “train the trainer” model. This proved nonproductive because our message often was distorted by the time it reached direct care staff. We developed a half-day training program in which our hospital administrator and medical directors participated. In 16 sessions over 9 months we trained 590 clinical staff, security officers, and other support personnel. Training included interactive education in the public health prevention model, principles of recovery, trauma informed care, and conflict resolution. Recovery specialists and patients were among the presenters. We acted out and analyzed conflict scenarios based on actual experiences on the units with varying approaches. We learned that a number of our direct care staff had informally developed various techniques for successfully resolving problematic situations in a noncoercive manner. We celebrated these staff members and incorporated their ideas into our training sessions.

Ongoing efforts include sessions for direct care staff on subjects such as relaxation techniques, verbal de-escalation, and fundamentals of a mental status evaluation. These are conducted primarily by staff psychologists or incorporated into required annual staff training.

Use of seclusion and restraint reduction tools. Our psychiatric evaluation, which included a thorough assessment for violence risk, was revised to include assessment of risk factors for restraint use. Nursing assessments were revised to include history of restraint or seclusion use, options for early intervention, and patient preferences for anger management and interventions. Intake areas and common rooms were repainted and amenities added to create a more pleasant, less institutional atmosphere. For a description of comfort rooms, visit www.power2u.org/downloads/ComfortRooms4-23-09.pdf Where there wasn’t space for a comfort room, we created comfort kits, which include items such as stress balls, word games, and soothing pictures. These kits are for patients’ benefit and patients should have a role in designing them. Use is voluntary. Comfort kits are not a substitute for therapeutic involvement or necessary seclusion or restraint to prevent imminent injury.

Consumer roles in inpatient settings. Patients are an often-overlooked resource. They too have a vested interest in hospital safety. We involved patients in staff training sessions. Consumer councils were consulted on relevant hospital policy changes and participated in revising the hospital’s Patient/ Family Handbooks. Patient/staff work-groups were asked to replace ad hoc unit rules with expectations for civil behavior that apply to patients and staff. Patients were trained to co-lead groups dealing with accepting responsibility for their own recovery.

Debriefing techniques. The patient and staff are debriefed after every restraint and seclusion episode. A nurse and psychologist debrief the patient, focusing on what the staff and patient could have done to avoid the incident. A recovery specialist and a medical administrator attend each debriefing. The focus initially was to justify restraint and seclusion use, but quickly broadened to include exploring early signs that if recognized and addressed could prevent a repeat incidence.

Different hospitals may place different emphasis on each core strategy. In our experience, the 2 strategies most important to positive results were:

• active, unwavering, and visible commitment of hospital leadership to reducing violence and restraints, and
• timely analysis of relevant data, and the determination to address the results of such analysis in a coherent and collegial manner.

Disclosure

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

The least effective, most costly method of reducing patient violence is to attempt to contain it after it has occurred. If containment includes using restraints, staff and patients are at additional risk for injury.

Our facility, a 315-bed, medium-security forensic program and a 75-bed civil program, is in its 16th year of violence and restraint reduction.¹ We have reduced restraint usage by >95%, and our hospital is one of the safest in our state. In March 2010, we were 1 of 10 institutions recognized by the Substance Abuse and Mental Health Services Administration for our efforts in reducing and preventing use of seclusion and restraints. If your facility is interested in such efforts, we recommend becoming familiar with the Six Core Strategies Planning Tool.²

Leadership toward organizational change. Any restraint reduction program is likely to encounter resistance. Active and visible presence of hospital leadership is essential to success. According to LeBel, ³ “Advancing seclusion and restraint standards is in the hands of administrators. The knowledge… is available, but it takes leadership, courage, and effort.”

Using data to inform practice. Leadership’s most effective tool is data. When we began our efforts in 1995 by doing nothing more than telling staff we would be tracking restraint usage, usage decreased by 36%. Next, leadership reduced the maximum time for a restraint order from 4 to 2 hours. Eventually, we reduced the maximum time to 1 hour. Restraint orders seldom required renewal.

One of the most useful pieces of data we developed established that on average, our well-trained staff incurred injuries severe enough to require medical treatment in 1 of every 4 instances of applying mechanical restraints. All staff could appreciate that as restraint usage was reduced, the number of associated staff injuries also would fall.

Workforce development. Leadership’s most valuable resource is its workforce. Experience showed that a substantial number of restraint episodes started with rigid enforcement of unit rules. We provide staff with the tools necessary to make clinically based decisions, rather than relying on strict adherence to rules. Staff should never get the impression that patients are being empowered but staff are not.

Initially, we relied on a “champion” or “train the trainer” model. This proved nonproductive because our message often was distorted by the time it reached direct care staff. We developed a half-day training program in which our hospital administrator and medical directors participated. In 16 sessions over 9 months we trained 590 clinical staff, security officers, and other support personnel. Training included interactive education in the public health prevention model, principles of recovery, trauma informed care, and conflict resolution. Recovery specialists and patients were among the presenters. We acted out and analyzed conflict scenarios based on actual experiences on the units with varying approaches. We learned that a number of our direct care staff had informally developed various techniques for successfully resolving problematic situations in a noncoercive manner. We celebrated these staff members and incorporated their ideas into our training sessions.

Ongoing efforts include sessions for direct care staff on subjects such as relaxation techniques, verbal de-escalation, and fundamentals of a mental status evaluation. These are conducted primarily by staff psychologists or incorporated into required annual staff training.

Use of seclusion and restraint reduction tools. Our psychiatric evaluation, which included a thorough assessment for violence risk, was revised to include assessment of risk factors for restraint use. Nursing assessments were revised to include history of restraint or seclusion use, options for early intervention, and patient preferences for anger management and interventions. Intake areas and common rooms were repainted and amenities added to create a more pleasant, less institutional atmosphere. For a description of comfort rooms, visit www.power2u.org/downloads/ComfortRooms4-23-09.pdf Where there wasn’t space for a comfort room, we created comfort kits, which include items such as stress balls, word games, and soothing pictures. These kits are for patients’ benefit and patients should have a role in designing them. Use is voluntary. Comfort kits are not a substitute for therapeutic involvement or necessary seclusion or restraint to prevent imminent injury.

Consumer roles in inpatient settings. Patients are an often-overlooked resource. They too have a vested interest in hospital safety. We involved patients in staff training sessions. Consumer councils were consulted on relevant hospital policy changes and participated in revising the hospital’s Patient/ Family Handbooks. Patient/staff work-groups were asked to replace ad hoc unit rules with expectations for civil behavior that apply to patients and staff. Patients were trained to co-lead groups dealing with accepting responsibility for their own recovery.

Debriefing techniques. The patient and staff are debriefed after every restraint and seclusion episode. A nurse and psychologist debrief the patient, focusing on what the staff and patient could have done to avoid the incident. A recovery specialist and a medical administrator attend each debriefing. The focus initially was to justify restraint and seclusion use, but quickly broadened to include exploring early signs that if recognized and addressed could prevent a repeat incidence.

Different hospitals may place different emphasis on each core strategy. In our experience, the 2 strategies most important to positive results were:

• active, unwavering, and visible commitment of hospital leadership to reducing violence and restraints, and
• timely analysis of relevant data, and the determination to address the results of such analysis in a coherent and collegial manner.

Disclosure

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

The least effective, most costly method of reducing patient violence is to attempt to contain it after it has occurred. If containment includes using restraints, staff and patients are at additional risk for injury.

Our facility, a 315-bed, medium-security forensic program and a 75-bed civil program, is in its 16th year of violence and restraint reduction.¹ We have reduced restraint usage by >95%, and our hospital is one of the safest in our state. In March 2010, we were 1 of 10 institutions recognized by the Substance Abuse and Mental Health Services Administration for our efforts in reducing and preventing use of seclusion and restraints. If your facility is interested in such efforts, we recommend becoming familiar with the Six Core Strategies Planning Tool.²

Leadership toward organizational change. Any restraint reduction program is likely to encounter resistance. Active and visible presence of hospital leadership is essential to success. According to LeBel, ³ “Advancing seclusion and restraint standards is in the hands of administrators. The knowledge… is available, but it takes leadership, courage, and effort.”

Using data to inform practice. Leadership’s most effective tool is data. When we began our efforts in 1995 by doing nothing more than telling staff we would be tracking restraint usage, usage decreased by 36%. Next, leadership reduced the maximum time for a restraint order from 4 to 2 hours. Eventually, we reduced the maximum time to 1 hour. Restraint orders seldom required renewal.

One of the most useful pieces of data we developed established that on average, our well-trained staff incurred injuries severe enough to require medical treatment in 1 of every 4 instances of applying mechanical restraints. All staff could appreciate that as restraint usage was reduced, the number of associated staff injuries also would fall.

Workforce development. Leadership’s most valuable resource is its workforce. Experience showed that a substantial number of restraint episodes started with rigid enforcement of unit rules. We provide staff with the tools necessary to make clinically based decisions, rather than relying on strict adherence to rules. Staff should never get the impression that patients are being empowered but staff are not.

Initially, we relied on a “champion” or “train the trainer” model. This proved nonproductive because our message often was distorted by the time it reached direct care staff. We developed a half-day training program in which our hospital administrator and medical directors participated. In 16 sessions over 9 months we trained 590 clinical staff, security officers, and other support personnel. Training included interactive education in the public health prevention model, principles of recovery, trauma informed care, and conflict resolution. Recovery specialists and patients were among the presenters. We acted out and analyzed conflict scenarios based on actual experiences on the units with varying approaches. We learned that a number of our direct care staff had informally developed various techniques for successfully resolving problematic situations in a noncoercive manner. We celebrated these staff members and incorporated their ideas into our training sessions.

Ongoing efforts include sessions for direct care staff on subjects such as relaxation techniques, verbal de-escalation, and fundamentals of a mental status evaluation. These are conducted primarily by staff psychologists or incorporated into required annual staff training.

Use of seclusion and restraint reduction tools. Our psychiatric evaluation, which included a thorough assessment for violence risk, was revised to include assessment of risk factors for restraint use. Nursing assessments were revised to include history of restraint or seclusion use, options for early intervention, and patient preferences for anger management and interventions. Intake areas and common rooms were repainted and amenities added to create a more pleasant, less institutional atmosphere. For a description of comfort rooms, visit www.power2u.org/downloads/ComfortRooms4-23-09.pdf Where there wasn’t space for a comfort room, we created comfort kits, which include items such as stress balls, word games, and soothing pictures. These kits are for patients’ benefit and patients should have a role in designing them. Use is voluntary. Comfort kits are not a substitute for therapeutic involvement or necessary seclusion or restraint to prevent imminent injury.

Consumer roles in inpatient settings. Patients are an often-overlooked resource. They too have a vested interest in hospital safety. We involved patients in staff training sessions. Consumer councils were consulted on relevant hospital policy changes and participated in revising the hospital’s Patient/ Family Handbooks. Patient/staff work-groups were asked to replace ad hoc unit rules with expectations for civil behavior that apply to patients and staff. Patients were trained to co-lead groups dealing with accepting responsibility for their own recovery.

Debriefing techniques. The patient and staff are debriefed after every restraint and seclusion episode. A nurse and psychologist debrief the patient, focusing on what the staff and patient could have done to avoid the incident. A recovery specialist and a medical administrator attend each debriefing. The focus initially was to justify restraint and seclusion use, but quickly broadened to include exploring early signs that if recognized and addressed could prevent a repeat incidence.

Different hospitals may place different emphasis on each core strategy. In our experience, the 2 strategies most important to positive results were:

• active, unwavering, and visible commitment of hospital leadership to reducing violence and restraints, and
• timely analysis of relevant data, and the determination to address the results of such analysis in a coherent and collegial manner.

Disclosure

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

A substantial proportion of psychiatric patients suffer from a somatic illness concomitantly with a mood, thought, or behavioral disorder. Some complicated patients may be afflicted by a combination of 4 or 5 different psychiatric or general medical disorders, requiring the use of multiple medications, which almost always increases the risk of adverse effects, pharmacokinetic interactions, and adherence gaps, and also escalates costs.

In addition, multiple medications may set off other iatrogenic consequences, such as exacerbation of psychiatric symptoms caused by a nonpsychotropic medication (such as an antihypertensive worsening depressive symptoms) or aggravation of a general medical condition by a psychotropic (such as prolongation of the QT interval or hyperglycemia secondary to an atypical antipsychotic).

Thus, it is quite pleasing when the use of a single medication can simultaneously relieve ≥2 unrelated medical disorders, preempting the need for multiple medications. This is the essence of parsimonious pharmacotherapy, a “2 birds with 1 stone” approach that evades polypharmacy and its side effect burden and added cost.

Consider the following examples of how a single psychotropic—by virtue of both its efficacy and what may be considered a side effect—can relieve 2 psychiatric disorders, or a psychiatric and a physical disorder, or even 2 physical disorders:

Depression with premature ejaculation. Delayed orgasm associated with selective serotonin reuptake inhibitors (SSRIs) administered for depression can simultaneously mitigate premature ejaculation as an added benefit.

Bipolar disorder with migraine. Valproate is a commonly used mood stabilizer that also is effective and indicated for migraines. Lithium, another widely used mood stabilizer, can relieve cluster headaches.

A mood or psychotic disorder with insomnia. Antidepressant medications with sedating properties can treat unipolar or bipolar depression and simultaneously allay the insomnia that often coexists with a mood disorder. Similarly, sedating antipsychotic medications administered at bedtime can relieve psychosis and its coexisting insomnia.

A mood or psychotic disorder with anxiety. Anxiety frequently accompanies unipolar or bipolar depression or schizophrenia. An SSRI can help both depression and anxiety, and some antipsychotics also can relieve both psychosis and anxiety.

Bipolar disorder or schizophrenia with obesity. Some metabolically neutral atypical agents (aripiprazole, lurasidone, ziprasidone) can control schizophrenia symptoms and/or bipolar mania while helping obese patients shed weight acquired during previous treatment with an obesogenic antipsychotic.

Depression and/or anxiety with thrombotic disease. SSRIs treat both depression and anxiety, and their anticoagulant side effect reduces the risk of thrombus formation in patients at risk for thrombotic disease.

Bipolar disorder with leukopenia. Lithium is a standard mood stabilizer that controls bipolar disorder, and its leukocytosis side effect helps increase white blood cell production and alleviate leukopenia.

Depression or anxiety with pain. This is a well-known parsimonious pharmacotherapy. Pain symptoms are a common feature or comorbidity of depression, and practically all antidepressants have analgesic effects.

Bipolar disorder with alcohol or cocaine addiction. The anticonvulsant/mood stabilizer valproate has been shown to significantly reduce both manic symptoms and comorbid heavy drinking in placebo- controlled studies. Another anticonvulsant/antimanic agent, carbamazepine, has been reported to reduce cocaine craving.

Migraine and obesity in a psychiatric patient. Topiramate is approved for migraines but its appetite-suppressing side effect can help decrease weight in patients with a high body mass index.

Posttraumatic stress disorder (PTSD) patients with depression, anxiety, obsessive-compulsive disorder, impulsivity, and insomnia. Here is a good example of how a sedating antidepressant agent—especially an SSRI—can help multiple symptom domains of PTSD.

Most psychiatric practitioners are aware of how to exploit side effects to help a coexisting medical disorder, or how to employ a multi-action drug to relieve a cluster of coexisting symptoms. Thus, psychiatric patients’ medical history can and should influence drug selection for the possible employment of parsimonious pharmacotherapy, which is gratifying for clinicians and a welcome antidote to polypharmacy in some patients with multiple medical disorders.

A substantial proportion of psychiatric patients suffer from a somatic illness concomitantly with a mood, thought, or behavioral disorder. Some complicated patients may be afflicted by a combination of 4 or 5 different psychiatric or general medical disorders, requiring the use of multiple medications, which almost always increases the risk of adverse effects, pharmacokinetic interactions, and adherence gaps, and also escalates costs.

In addition, multiple medications may set off other iatrogenic consequences, such as exacerbation of psychiatric symptoms caused by a nonpsychotropic medication (such as an antihypertensive worsening depressive symptoms) or aggravation of a general medical condition by a psychotropic (such as prolongation of the QT interval or hyperglycemia secondary to an atypical antipsychotic).

Thus, it is quite pleasing when the use of a single medication can simultaneously relieve ≥2 unrelated medical disorders, preempting the need for multiple medications. This is the essence of parsimonious pharmacotherapy, a “2 birds with 1 stone” approach that evades polypharmacy and its side effect burden and added cost.

Consider the following examples of how a single psychotropic—by virtue of both its efficacy and what may be considered a side effect—can relieve 2 psychiatric disorders, or a psychiatric and a physical disorder, or even 2 physical disorders:

Depression with premature ejaculation. Delayed orgasm associated with selective serotonin reuptake inhibitors (SSRIs) administered for depression can simultaneously mitigate premature ejaculation as an added benefit.

Bipolar disorder with migraine. Valproate is a commonly used mood stabilizer that also is effective and indicated for migraines. Lithium, another widely used mood stabilizer, can relieve cluster headaches.

A mood or psychotic disorder with insomnia. Antidepressant medications with sedating properties can treat unipolar or bipolar depression and simultaneously allay the insomnia that often coexists with a mood disorder. Similarly, sedating antipsychotic medications administered at bedtime can relieve psychosis and its coexisting insomnia.

A mood or psychotic disorder with anxiety. Anxiety frequently accompanies unipolar or bipolar depression or schizophrenia. An SSRI can help both depression and anxiety, and some antipsychotics also can relieve both psychosis and anxiety.

Bipolar disorder or schizophrenia with obesity. Some metabolically neutral atypical agents (aripiprazole, lurasidone, ziprasidone) can control schizophrenia symptoms and/or bipolar mania while helping obese patients shed weight acquired during previous treatment with an obesogenic antipsychotic.

Depression and/or anxiety with thrombotic disease. SSRIs treat both depression and anxiety, and their anticoagulant side effect reduces the risk of thrombus formation in patients at risk for thrombotic disease.

Bipolar disorder with leukopenia. Lithium is a standard mood stabilizer that controls bipolar disorder, and its leukocytosis side effect helps increase white blood cell production and alleviate leukopenia.

Depression or anxiety with pain. This is a well-known parsimonious pharmacotherapy. Pain symptoms are a common feature or comorbidity of depression, and practically all antidepressants have analgesic effects.

Bipolar disorder with alcohol or cocaine addiction. The anticonvulsant/mood stabilizer valproate has been shown to significantly reduce both manic symptoms and comorbid heavy drinking in placebo- controlled studies. Another anticonvulsant/antimanic agent, carbamazepine, has been reported to reduce cocaine craving.

Migraine and obesity in a psychiatric patient. Topiramate is approved for migraines but its appetite-suppressing side effect can help decrease weight in patients with a high body mass index.

Posttraumatic stress disorder (PTSD) patients with depression, anxiety, obsessive-compulsive disorder, impulsivity, and insomnia. Here is a good example of how a sedating antidepressant agent—especially an SSRI—can help multiple symptom domains of PTSD.

Most psychiatric practitioners are aware of how to exploit side effects to help a coexisting medical disorder, or how to employ a multi-action drug to relieve a cluster of coexisting symptoms. Thus, psychiatric patients’ medical history can and should influence drug selection for the possible employment of parsimonious pharmacotherapy, which is gratifying for clinicians and a welcome antidote to polypharmacy in some patients with multiple medical disorders.

A substantial proportion of psychiatric patients suffer from a somatic illness concomitantly with a mood, thought, or behavioral disorder. Some complicated patients may be afflicted by a combination of 4 or 5 different psychiatric or general medical disorders, requiring the use of multiple medications, which almost always increases the risk of adverse effects, pharmacokinetic interactions, and adherence gaps, and also escalates costs.

In addition, multiple medications may set off other iatrogenic consequences, such as exacerbation of psychiatric symptoms caused by a nonpsychotropic medication (such as an antihypertensive worsening depressive symptoms) or aggravation of a general medical condition by a psychotropic (such as prolongation of the QT interval or hyperglycemia secondary to an atypical antipsychotic).

Thus, it is quite pleasing when the use of a single medication can simultaneously relieve ≥2 unrelated medical disorders, preempting the need for multiple medications. This is the essence of parsimonious pharmacotherapy, a “2 birds with 1 stone” approach that evades polypharmacy and its side effect burden and added cost.

Consider the following examples of how a single psychotropic—by virtue of both its efficacy and what may be considered a side effect—can relieve 2 psychiatric disorders, or a psychiatric and a physical disorder, or even 2 physical disorders:

Depression with premature ejaculation. Delayed orgasm associated with selective serotonin reuptake inhibitors (SSRIs) administered for depression can simultaneously mitigate premature ejaculation as an added benefit.

Bipolar disorder with migraine. Valproate is a commonly used mood stabilizer that also is effective and indicated for migraines. Lithium, another widely used mood stabilizer, can relieve cluster headaches.

A mood or psychotic disorder with insomnia. Antidepressant medications with sedating properties can treat unipolar or bipolar depression and simultaneously allay the insomnia that often coexists with a mood disorder. Similarly, sedating antipsychotic medications administered at bedtime can relieve psychosis and its coexisting insomnia.

A mood or psychotic disorder with anxiety. Anxiety frequently accompanies unipolar or bipolar depression or schizophrenia. An SSRI can help both depression and anxiety, and some antipsychotics also can relieve both psychosis and anxiety.

Bipolar disorder or schizophrenia with obesity. Some metabolically neutral atypical agents (aripiprazole, lurasidone, ziprasidone) can control schizophrenia symptoms and/or bipolar mania while helping obese patients shed weight acquired during previous treatment with an obesogenic antipsychotic.

Depression and/or anxiety with thrombotic disease. SSRIs treat both depression and anxiety, and their anticoagulant side effect reduces the risk of thrombus formation in patients at risk for thrombotic disease.

Bipolar disorder with leukopenia. Lithium is a standard mood stabilizer that controls bipolar disorder, and its leukocytosis side effect helps increase white blood cell production and alleviate leukopenia.

Depression or anxiety with pain. This is a well-known parsimonious pharmacotherapy. Pain symptoms are a common feature or comorbidity of depression, and practically all antidepressants have analgesic effects.

Bipolar disorder with alcohol or cocaine addiction. The anticonvulsant/mood stabilizer valproate has been shown to significantly reduce both manic symptoms and comorbid heavy drinking in placebo- controlled studies. Another anticonvulsant/antimanic agent, carbamazepine, has been reported to reduce cocaine craving.

Migraine and obesity in a psychiatric patient. Topiramate is approved for migraines but its appetite-suppressing side effect can help decrease weight in patients with a high body mass index.

Posttraumatic stress disorder (PTSD) patients with depression, anxiety, obsessive-compulsive disorder, impulsivity, and insomnia. Here is a good example of how a sedating antidepressant agent—especially an SSRI—can help multiple symptom domains of PTSD.

Most psychiatric practitioners are aware of how to exploit side effects to help a coexisting medical disorder, or how to employ a multi-action drug to relieve a cluster of coexisting symptoms. Thus, psychiatric patients’ medical history can and should influence drug selection for the possible employment of parsimonious pharmacotherapy, which is gratifying for clinicians and a welcome antidote to polypharmacy in some patients with multiple medical disorders.

Discuss this article at www.facebook.com/CurrentPsychiatry

Patients who present with impairment in academic, cognitive, social, and vocational functioning might be struggling with an unrecognized learning disorder. Ten percent of the US population has some form of learning disability, and up to 40% of those with learning disorders may meet diagnostic criteria for a psychiatric disorder.^1,2 Some learning disorders affect a person’s ability to read, write, or do math, whereas less-recognized nonverbal learning disorder (NLD) impacts the social and emotional functioning of children, adolescents, and adults. Common features of NLD include:

• deficits in nonlinguistic information processing
• speech prosody deficits
• difficulty reading facial expressions
• associated impairment in interpersonal functioning.

The severity of these deficits varies among individuals with NLD. Patients may experience chronic low self-esteem, anxiety, and mood symptoms because of their limited ability to express their feelings within an appropriate social context. NLD may be first misdiagnosed as attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), or Asperger’s disorder.

In this article we review the underlying neurophysiology of NLD and present a clinical approach to these patients, including the differential diagnosis and factors that will allow clinicians to distinguish NLD from psychiatric conditions with symptomatic and syndromic overlap. We also describe treatment for patients with NLD.

The learning process

Learning is a cognitive process of acquiring and processing information and experiences from the environment that allows us to acquire knowledge, skills, and social abilities. When we learn how to relate to others, we undergo neurophysiologic changes that subsequently influence behavior and the way we understand our environment. Deficits in learning processes or the ability to acquire relational skills result in impaired affect regulation in regard to others and may lead to low self-esteem, depression, anxiety, interpersonal conflict, and anger toward others. Learning influences a person’s ability to navigate social relationships and perform academically and occupationally.

The impact of learning deficits may be magnified in adulthood after an individual has suffered years of in-securities and poor self-esteem. Adults with learning disabilities often seek psychiatric treatment as a result of their disappointment about difficulties in relationships and work. NLD may coexist with or mimic other neuropsychiatric disorders. For example, problematic behavior within a family or at the workplace is a common reason for referral to a psychiatrist. These behaviors may be influenced by a patient’s NLD symptoms, which can complicate diagnosis and treatment.

Persons with NLD are at increased risk for depression because of failures in coping, loss of self-esteem, internalized psychopathology, and other social and emotional strains. In addition, individuals with NLD may experience multiple psychosocial impairments, including difficulty maintaining employment, achieving goals, and maintaining relationships.³

A variable presentation

NLD has been associated with right hemispheric dysfunction.³ For a description of the neurophysiology of NLD, see this article at CurrentPsychiatry.com. In childhood, NLD may present as deficits in:

• processing nonlinguistic information
• expressing or comprehending nonverbal components of language such as pitch, volume, or rate of speech (aprosodia)
• reading facial expressions
• social or emotional functioning, such as difficulty understanding social situations, violations of personal space, or difficulty learning from past emotional experiences.⁴

The extent of these deficits varies among patients. As children, patients with NLD often show strengths in rote verbal memory, spoken language mechanics or form, and word reading. These children may be hyperverbal and use language at a level higher than expected for their age group, which may mask some learning difficulties and delay diagnosis.

Throughout life, NLD manifests as difficulty interacting with peers. Children with NLD may have difficulty playing with others and making friends and as result may feel socially isolated. Without the critical skills of social reciprocity or understanding social context, NLD patients often have many superficial friendships but lack deep relationships.^4,5

Patients with NLD may rely on their verbal skills for relating socially and relieving anxiety and tend to withdraw from social situations as they become aware of their deficits.

NLD can be characterized on the basis of primary, secondary, and tertiary deficits. Primary deficits in tactile and visual perception and complex psychomotor skills lead to secondary deficits in attention and exploratory behavior, which lead to tertiary deficits in memory and executive function.⁶

Given NLD’s variable presentation, clinicians must remain vigilant to this possible diagnosis in patients with a history of multiple pharmacotherapy or psychotherapy failures for axis I disorders. Using clues from symptoms described in Table 1⁷ may provide information necessary to refer for formal psychoeducational testing to diagnose NLD. Early diagnosis can help target NLD symptoms and tailor treatment of comorbid psychopathology.⁷ NLD is a chronic disability and—similar to other learning disabilities—early, targeted interventions initiated by parents, teachers, and clinicians can improve outcomes.

Neuropsychological/psychoeducational testing. Traditionally, clinicians suspected NLD if a patient had a ≥10 point difference between performance intelligence quotient (IQ) and verbal IQ on the Wechsler Intelligence Scale for Children (WISC-III).⁸ However, the most recent version—the WISC-IV⁹—incorporates changes based on new neurologic models of cognitive functioning, and performance IQ and verbal IQ are no longer calculated. Thus, interpreting this split in IQ type with regard to NLD is no longer straightforward. IQ tests, such as the Woodcock-Johnson¹⁰ battery, which assesses visual-spatial thinking and fluid reasoning, may be particularly important in characterizing NLD deficits—especially when used in conjunction with other neuropsychological batteries, which may directly assess discrete abilities related to visual and spatial processing.

A thorough social and educational history, IQ testing, neuropsychological batteries, and a psychoeducational assessment can help determine the extent of cognitive deficits that may require accommodations at school or work and characterize the complex interplay of specific deficits and functioning.

Table 1

Clinical manifestation of nonverbal learning disorder

Differential diagnosis

ADHD. Patients diagnosed with ADHD or NLD may have a history of attention difficulties and hyperactivity. These clinical similarities may include restlessness, distractibility, impulsivity, and poor attention (Table 2).^11,12 In adults, these features may attenuate and patients with NLD or ADHD could appear normoactive. Individuals with NLD demonstrate withdrawal, anxiety, and continued social skills deficits,¹³ whereas adult ADHD patients show persistent attention difficulties. Although both groups may have difficulty maintaining steady employment, NLD patients’ employment failures often are caused by cognitive and social difficulties as opposed to problems with attention.

The psychopathology of these 2 conditions differs in that ADHD is characterized primarily by prefrontal dysfunction.¹⁴ However, in a small study of children with NLD (N=20), all participants also met diagnostic criteria for ADHD; therefore, the true epidemiologic comorbidity is unknown.¹⁵

BD. Because patients with NLD may experience affective symptoms similar to those with BD, it is critical to clarify the temporal course of mood symptoms and understand the complex relationships between symptoms and external events (Table 2).^11,12 In BD, mood symptoms are cyclical, punctuated by discrete periods of euthymia. In NLD affective symptoms are clearly linked to learning difficulties and impaired information processing. Research shows cognitive deficits in individuals with BD often persist during euthymic periods.¹⁶ Literature suggests that cognitive deficits in adult BD commonly involve verbal memory, executive function, and attention, whereas patients with NLD often have strong verbal memory.^17,18

Individuals with BD may understand the intentions of others and—especially in periods of hypomania or mania—will engage others. In contrast, persons with NLD struggle to attract and engage friends, may be irritable when they misunderstand social cues, may be bullied or taken advantage of by others, and may struggle to communicate this problem to clinicians. NLD patients’ sense of frustration typically does not vary; a continuous depressed or anxious mood may improve briefly when they feel accepted in their environment. This pattern can be discerned from BD by strictly applying DSM-IV-TR criteria for variability in mood states.¹⁹ BD treatment may be complicated in patients with comorbid NLD. These patients may underreport adverse effects of medications, including metabolic effects and cognitive dulling, which results in a complicated and frustrating clinical course.²⁰

Asperger’s disorder. Patients with NLD—a neuropsychological disorder—may present with social interaction difficulties that seem similar to those of Asperger’s disorder—a behavioral disorder. Overlapping behaviors, similar cognitive processes, and coexisting conditions may challenge even experienced clinicians (Table 3).^21-23 However, impairments are more severe in Asperger’s disorder and will present as early as age 4. Patients with Asperger’s disorder show difficulty communicating characterized by unusual interactions, such as pedantic or 1-sided discussions of topics that are unusual for the patient’s age group and inattentiveness to social cues. By contrast, communication difficulties in children with NLD are not apparent until after they start school.

Both Asperger’s disorder and NLD patients will show noticeable variations in thought process that often are apparent in conversations. Individuals with Asperger’s disorder may have some concrete thinking, although they often express idiosyncratic thinking, whereas individuals with NLD often show concrete logic. An individual with NLD may be easily overwhelmed by peer group social interactions but remains emotionally aware of his or her shortcomings and may be able to handle 1-on-1 interactions. Individuals with Asperger’s disorder will demonstrate restrictive interests or repetitive behaviors, a characteristic typically not seen in individuals with NLD. Patients with Asperger’s disorder may have specific skills, such as expertise with directions and spatial reasoning, whereas individuals with NLD may get lost even when traveling to familiar places or may have difficulty relating directions. Both groups likely will have good reading skills but patients with NLD will have trouble comprehending and integrating the material, evident by difficulty with multiple choice questions or “story problems.” Individuals with either disorder may develop frustration and anger with their challenges.

In adults, many of these subtle differences in language and thought process may be masked by years of difficult and frustrating communication, making definitive diagnosis challenging. Semistructured interviews, such as the Autism Diagnostic Observation Schedule²⁴ or the Gilliam Asperger’s Disorder Scale,²⁵ may help in differentiating Asperger’s disorder from NLD. However, these 2 disorders may be comorbid, thus complicating the diagnostic process.²¹

Table 2

Differences among NLD, ADHD, and bipolar disorder

Table 3

Differences between NLD and Asperger’s disorder

Treatment implications

The day-to-day care of patients with NLD and a comorbid psychiatric disorder may include systems-level interventions, supportive psychotherapy, and psychopharmacologic treatments that are informed by the comorbid condition (Table 4).^7,26 Open, honest dialogue about strengths and challenges for individuals with NLD will help reframe expectations and frustrations. Early recognition of NLD may, in some cases, prevent internalized psychopathology and loss of self-esteem.^27,28

Children and adolescents with NLD require early intervention to help them function socially and academically. Involving family and school personnel is important to develop accommodations to improve functioning. Comprehension problems associated with NLD often become more noticeable as the student moves into upper elementary grades, where abstract thinking and the ability to manage novelty (eg, unfamiliar content or situations) are required. Many students with NLD can manage rote memorization and concrete facts, but have trouble with inference, integration, and reasoning. Academically appropriate classroom placement, limited writing, and use of voice recognition software may aid success. Parents can help by teaching and modeling social skills such as appropriate expression of emotions, which can be facilitated by watching movies or attending group activities together.

Adults. Patients with NLD may be late for appointments and often forget what is discussed. They may be at increased risk for noncompliance with pharmacotherapy for comorbid disorders and may require written instructions, frequent reminders, and reviews of treatment plan. In addition, interactions with clinicians may seem shallow and unsatisfying, despite the clinician’s best efforts to empathize. The pattern of feeling misunderstood likely exists in the patient’s other relationships, including significant others and employers. Although no systemic evaluations exist, mindfulness-based therapies might help alleviate this deficit.^29,30

Treatment plans may involve family-focused modalities where NLD patients learn to rely on family members to interpret others’ motives and intentions.³¹ Education of the patient and family and friends should emphasize the need for consistent daily schedules and frequent verbal feedback, such as taking turns in conversations. Academic accommodations in college are crucial for success. Education experts have advocated for increased use of technology for students with NLD, including voice recognition software, laptop computers, and audio recordings of class notes.³²

Table 4

Treating patients with NLD

Related Resources

• Rourke BP. Syndrome of nonverbal learning disabilities: Neurodevelopmental manifestations. New York, NY: Guilford Press; 1995.
• NLD Line. www.nldline.com.
• NLD on the Web. www.nldontheweb.org.
• Massachusetts General Hospital school psychiatry program and Mood and Anxiety Disorders Institute resource center. www2.massgeneral.org/schoolpsychiatry.

Disclosures

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

Dr. Strawn has received research support from the American Academy of Child and Adolescent Psychiatry and Eli Lilly and Company.

Acknowledgements

The authors acknowledge Drs. Michele Berg and Carleen Franz for their careful review of this manuscript and for their critiques, which have greatly improved this contribution.

Discuss this article at www.facebook.com/CurrentPsychiatry

Patients who present with impairment in academic, cognitive, social, and vocational functioning might be struggling with an unrecognized learning disorder. Ten percent of the US population has some form of learning disability, and up to 40% of those with learning disorders may meet diagnostic criteria for a psychiatric disorder.^1,2 Some learning disorders affect a person’s ability to read, write, or do math, whereas less-recognized nonverbal learning disorder (NLD) impacts the social and emotional functioning of children, adolescents, and adults. Common features of NLD include:

• deficits in nonlinguistic information processing
• speech prosody deficits
• difficulty reading facial expressions
• associated impairment in interpersonal functioning.

The severity of these deficits varies among individuals with NLD. Patients may experience chronic low self-esteem, anxiety, and mood symptoms because of their limited ability to express their feelings within an appropriate social context. NLD may be first misdiagnosed as attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), or Asperger’s disorder.

In this article we review the underlying neurophysiology of NLD and present a clinical approach to these patients, including the differential diagnosis and factors that will allow clinicians to distinguish NLD from psychiatric conditions with symptomatic and syndromic overlap. We also describe treatment for patients with NLD.

The learning process

Learning is a cognitive process of acquiring and processing information and experiences from the environment that allows us to acquire knowledge, skills, and social abilities. When we learn how to relate to others, we undergo neurophysiologic changes that subsequently influence behavior and the way we understand our environment. Deficits in learning processes or the ability to acquire relational skills result in impaired affect regulation in regard to others and may lead to low self-esteem, depression, anxiety, interpersonal conflict, and anger toward others. Learning influences a person’s ability to navigate social relationships and perform academically and occupationally.

The impact of learning deficits may be magnified in adulthood after an individual has suffered years of in-securities and poor self-esteem. Adults with learning disabilities often seek psychiatric treatment as a result of their disappointment about difficulties in relationships and work. NLD may coexist with or mimic other neuropsychiatric disorders. For example, problematic behavior within a family or at the workplace is a common reason for referral to a psychiatrist. These behaviors may be influenced by a patient’s NLD symptoms, which can complicate diagnosis and treatment.

Persons with NLD are at increased risk for depression because of failures in coping, loss of self-esteem, internalized psychopathology, and other social and emotional strains. In addition, individuals with NLD may experience multiple psychosocial impairments, including difficulty maintaining employment, achieving goals, and maintaining relationships.³

A variable presentation

NLD has been associated with right hemispheric dysfunction.³ For a description of the neurophysiology of NLD, see this article at CurrentPsychiatry.com. In childhood, NLD may present as deficits in:

• processing nonlinguistic information
• expressing or comprehending nonverbal components of language such as pitch, volume, or rate of speech (aprosodia)
• reading facial expressions
• social or emotional functioning, such as difficulty understanding social situations, violations of personal space, or difficulty learning from past emotional experiences.⁴

The extent of these deficits varies among patients. As children, patients with NLD often show strengths in rote verbal memory, spoken language mechanics or form, and word reading. These children may be hyperverbal and use language at a level higher than expected for their age group, which may mask some learning difficulties and delay diagnosis.

Throughout life, NLD manifests as difficulty interacting with peers. Children with NLD may have difficulty playing with others and making friends and as result may feel socially isolated. Without the critical skills of social reciprocity or understanding social context, NLD patients often have many superficial friendships but lack deep relationships.^4,5

Patients with NLD may rely on their verbal skills for relating socially and relieving anxiety and tend to withdraw from social situations as they become aware of their deficits.

NLD can be characterized on the basis of primary, secondary, and tertiary deficits. Primary deficits in tactile and visual perception and complex psychomotor skills lead to secondary deficits in attention and exploratory behavior, which lead to tertiary deficits in memory and executive function.⁶

Given NLD’s variable presentation, clinicians must remain vigilant to this possible diagnosis in patients with a history of multiple pharmacotherapy or psychotherapy failures for axis I disorders. Using clues from symptoms described in Table 1⁷ may provide information necessary to refer for formal psychoeducational testing to diagnose NLD. Early diagnosis can help target NLD symptoms and tailor treatment of comorbid psychopathology.⁷ NLD is a chronic disability and—similar to other learning disabilities—early, targeted interventions initiated by parents, teachers, and clinicians can improve outcomes.

Neuropsychological/psychoeducational testing. Traditionally, clinicians suspected NLD if a patient had a ≥10 point difference between performance intelligence quotient (IQ) and verbal IQ on the Wechsler Intelligence Scale for Children (WISC-III).⁸ However, the most recent version—the WISC-IV⁹—incorporates changes based on new neurologic models of cognitive functioning, and performance IQ and verbal IQ are no longer calculated. Thus, interpreting this split in IQ type with regard to NLD is no longer straightforward. IQ tests, such as the Woodcock-Johnson¹⁰ battery, which assesses visual-spatial thinking and fluid reasoning, may be particularly important in characterizing NLD deficits—especially when used in conjunction with other neuropsychological batteries, which may directly assess discrete abilities related to visual and spatial processing.

A thorough social and educational history, IQ testing, neuropsychological batteries, and a psychoeducational assessment can help determine the extent of cognitive deficits that may require accommodations at school or work and characterize the complex interplay of specific deficits and functioning.

Table 1

Clinical manifestation of nonverbal learning disorder

Differential diagnosis

ADHD. Patients diagnosed with ADHD or NLD may have a history of attention difficulties and hyperactivity. These clinical similarities may include restlessness, distractibility, impulsivity, and poor attention (Table 2).^11,12 In adults, these features may attenuate and patients with NLD or ADHD could appear normoactive. Individuals with NLD demonstrate withdrawal, anxiety, and continued social skills deficits,¹³ whereas adult ADHD patients show persistent attention difficulties. Although both groups may have difficulty maintaining steady employment, NLD patients’ employment failures often are caused by cognitive and social difficulties as opposed to problems with attention.

The psychopathology of these 2 conditions differs in that ADHD is characterized primarily by prefrontal dysfunction.¹⁴ However, in a small study of children with NLD (N=20), all participants also met diagnostic criteria for ADHD; therefore, the true epidemiologic comorbidity is unknown.¹⁵

BD. Because patients with NLD may experience affective symptoms similar to those with BD, it is critical to clarify the temporal course of mood symptoms and understand the complex relationships between symptoms and external events (Table 2).^11,12 In BD, mood symptoms are cyclical, punctuated by discrete periods of euthymia. In NLD affective symptoms are clearly linked to learning difficulties and impaired information processing. Research shows cognitive deficits in individuals with BD often persist during euthymic periods.¹⁶ Literature suggests that cognitive deficits in adult BD commonly involve verbal memory, executive function, and attention, whereas patients with NLD often have strong verbal memory.^17,18

Individuals with BD may understand the intentions of others and—especially in periods of hypomania or mania—will engage others. In contrast, persons with NLD struggle to attract and engage friends, may be irritable when they misunderstand social cues, may be bullied or taken advantage of by others, and may struggle to communicate this problem to clinicians. NLD patients’ sense of frustration typically does not vary; a continuous depressed or anxious mood may improve briefly when they feel accepted in their environment. This pattern can be discerned from BD by strictly applying DSM-IV-TR criteria for variability in mood states.¹⁹ BD treatment may be complicated in patients with comorbid NLD. These patients may underreport adverse effects of medications, including metabolic effects and cognitive dulling, which results in a complicated and frustrating clinical course.²⁰

Asperger’s disorder. Patients with NLD—a neuropsychological disorder—may present with social interaction difficulties that seem similar to those of Asperger’s disorder—a behavioral disorder. Overlapping behaviors, similar cognitive processes, and coexisting conditions may challenge even experienced clinicians (Table 3).^21-23 However, impairments are more severe in Asperger’s disorder and will present as early as age 4. Patients with Asperger’s disorder show difficulty communicating characterized by unusual interactions, such as pedantic or 1-sided discussions of topics that are unusual for the patient’s age group and inattentiveness to social cues. By contrast, communication difficulties in children with NLD are not apparent until after they start school.

Both Asperger’s disorder and NLD patients will show noticeable variations in thought process that often are apparent in conversations. Individuals with Asperger’s disorder may have some concrete thinking, although they often express idiosyncratic thinking, whereas individuals with NLD often show concrete logic. An individual with NLD may be easily overwhelmed by peer group social interactions but remains emotionally aware of his or her shortcomings and may be able to handle 1-on-1 interactions. Individuals with Asperger’s disorder will demonstrate restrictive interests or repetitive behaviors, a characteristic typically not seen in individuals with NLD. Patients with Asperger’s disorder may have specific skills, such as expertise with directions and spatial reasoning, whereas individuals with NLD may get lost even when traveling to familiar places or may have difficulty relating directions. Both groups likely will have good reading skills but patients with NLD will have trouble comprehending and integrating the material, evident by difficulty with multiple choice questions or “story problems.” Individuals with either disorder may develop frustration and anger with their challenges.

In adults, many of these subtle differences in language and thought process may be masked by years of difficult and frustrating communication, making definitive diagnosis challenging. Semistructured interviews, such as the Autism Diagnostic Observation Schedule²⁴ or the Gilliam Asperger’s Disorder Scale,²⁵ may help in differentiating Asperger’s disorder from NLD. However, these 2 disorders may be comorbid, thus complicating the diagnostic process.²¹

Table 2

Differences among NLD, ADHD, and bipolar disorder

Table 3

Differences between NLD and Asperger’s disorder

Treatment implications

The day-to-day care of patients with NLD and a comorbid psychiatric disorder may include systems-level interventions, supportive psychotherapy, and psychopharmacologic treatments that are informed by the comorbid condition (Table 4).^7,26 Open, honest dialogue about strengths and challenges for individuals with NLD will help reframe expectations and frustrations. Early recognition of NLD may, in some cases, prevent internalized psychopathology and loss of self-esteem.^27,28

Children and adolescents with NLD require early intervention to help them function socially and academically. Involving family and school personnel is important to develop accommodations to improve functioning. Comprehension problems associated with NLD often become more noticeable as the student moves into upper elementary grades, where abstract thinking and the ability to manage novelty (eg, unfamiliar content or situations) are required. Many students with NLD can manage rote memorization and concrete facts, but have trouble with inference, integration, and reasoning. Academically appropriate classroom placement, limited writing, and use of voice recognition software may aid success. Parents can help by teaching and modeling social skills such as appropriate expression of emotions, which can be facilitated by watching movies or attending group activities together.

Adults. Patients with NLD may be late for appointments and often forget what is discussed. They may be at increased risk for noncompliance with pharmacotherapy for comorbid disorders and may require written instructions, frequent reminders, and reviews of treatment plan. In addition, interactions with clinicians may seem shallow and unsatisfying, despite the clinician’s best efforts to empathize. The pattern of feeling misunderstood likely exists in the patient’s other relationships, including significant others and employers. Although no systemic evaluations exist, mindfulness-based therapies might help alleviate this deficit.^29,30

Treatment plans may involve family-focused modalities where NLD patients learn to rely on family members to interpret others’ motives and intentions.³¹ Education of the patient and family and friends should emphasize the need for consistent daily schedules and frequent verbal feedback, such as taking turns in conversations. Academic accommodations in college are crucial for success. Education experts have advocated for increased use of technology for students with NLD, including voice recognition software, laptop computers, and audio recordings of class notes.³²

Table 4

Treating patients with NLD

Related Resources

• Rourke BP. Syndrome of nonverbal learning disabilities: Neurodevelopmental manifestations. New York, NY: Guilford Press; 1995.
• NLD Line. www.nldline.com.
• NLD on the Web. www.nldontheweb.org.
• Massachusetts General Hospital school psychiatry program and Mood and Anxiety Disorders Institute resource center. www2.massgeneral.org/schoolpsychiatry.

Disclosures

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

Dr. Strawn has received research support from the American Academy of Child and Adolescent Psychiatry and Eli Lilly and Company.

Acknowledgements

The authors acknowledge Drs. Michele Berg and Carleen Franz for their careful review of this manuscript and for their critiques, which have greatly improved this contribution.

Discuss this article at www.facebook.com/CurrentPsychiatry

Patients who present with impairment in academic, cognitive, social, and vocational functioning might be struggling with an unrecognized learning disorder. Ten percent of the US population has some form of learning disability, and up to 40% of those with learning disorders may meet diagnostic criteria for a psychiatric disorder.^1,2 Some learning disorders affect a person’s ability to read, write, or do math, whereas less-recognized nonverbal learning disorder (NLD) impacts the social and emotional functioning of children, adolescents, and adults. Common features of NLD include:

• deficits in nonlinguistic information processing
• speech prosody deficits
• difficulty reading facial expressions
• associated impairment in interpersonal functioning.

The severity of these deficits varies among individuals with NLD. Patients may experience chronic low self-esteem, anxiety, and mood symptoms because of their limited ability to express their feelings within an appropriate social context. NLD may be first misdiagnosed as attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), or Asperger’s disorder.

In this article we review the underlying neurophysiology of NLD and present a clinical approach to these patients, including the differential diagnosis and factors that will allow clinicians to distinguish NLD from psychiatric conditions with symptomatic and syndromic overlap. We also describe treatment for patients with NLD.

The learning process

Learning is a cognitive process of acquiring and processing information and experiences from the environment that allows us to acquire knowledge, skills, and social abilities. When we learn how to relate to others, we undergo neurophysiologic changes that subsequently influence behavior and the way we understand our environment. Deficits in learning processes or the ability to acquire relational skills result in impaired affect regulation in regard to others and may lead to low self-esteem, depression, anxiety, interpersonal conflict, and anger toward others. Learning influences a person’s ability to navigate social relationships and perform academically and occupationally.

The impact of learning deficits may be magnified in adulthood after an individual has suffered years of in-securities and poor self-esteem. Adults with learning disabilities often seek psychiatric treatment as a result of their disappointment about difficulties in relationships and work. NLD may coexist with or mimic other neuropsychiatric disorders. For example, problematic behavior within a family or at the workplace is a common reason for referral to a psychiatrist. These behaviors may be influenced by a patient’s NLD symptoms, which can complicate diagnosis and treatment.

Persons with NLD are at increased risk for depression because of failures in coping, loss of self-esteem, internalized psychopathology, and other social and emotional strains. In addition, individuals with NLD may experience multiple psychosocial impairments, including difficulty maintaining employment, achieving goals, and maintaining relationships.³

A variable presentation

NLD has been associated with right hemispheric dysfunction.³ For a description of the neurophysiology of NLD, see this article at CurrentPsychiatry.com. In childhood, NLD may present as deficits in:

• processing nonlinguistic information
• expressing or comprehending nonverbal components of language such as pitch, volume, or rate of speech (aprosodia)
• reading facial expressions
• social or emotional functioning, such as difficulty understanding social situations, violations of personal space, or difficulty learning from past emotional experiences.⁴

The extent of these deficits varies among patients. As children, patients with NLD often show strengths in rote verbal memory, spoken language mechanics or form, and word reading. These children may be hyperverbal and use language at a level higher than expected for their age group, which may mask some learning difficulties and delay diagnosis.

Throughout life, NLD manifests as difficulty interacting with peers. Children with NLD may have difficulty playing with others and making friends and as result may feel socially isolated. Without the critical skills of social reciprocity or understanding social context, NLD patients often have many superficial friendships but lack deep relationships.^4,5

Patients with NLD may rely on their verbal skills for relating socially and relieving anxiety and tend to withdraw from social situations as they become aware of their deficits.

NLD can be characterized on the basis of primary, secondary, and tertiary deficits. Primary deficits in tactile and visual perception and complex psychomotor skills lead to secondary deficits in attention and exploratory behavior, which lead to tertiary deficits in memory and executive function.⁶

Given NLD’s variable presentation, clinicians must remain vigilant to this possible diagnosis in patients with a history of multiple pharmacotherapy or psychotherapy failures for axis I disorders. Using clues from symptoms described in Table 1⁷ may provide information necessary to refer for formal psychoeducational testing to diagnose NLD. Early diagnosis can help target NLD symptoms and tailor treatment of comorbid psychopathology.⁷ NLD is a chronic disability and—similar to other learning disabilities—early, targeted interventions initiated by parents, teachers, and clinicians can improve outcomes.

Neuropsychological/psychoeducational testing. Traditionally, clinicians suspected NLD if a patient had a ≥10 point difference between performance intelligence quotient (IQ) and verbal IQ on the Wechsler Intelligence Scale for Children (WISC-III).⁸ However, the most recent version—the WISC-IV⁹—incorporates changes based on new neurologic models of cognitive functioning, and performance IQ and verbal IQ are no longer calculated. Thus, interpreting this split in IQ type with regard to NLD is no longer straightforward. IQ tests, such as the Woodcock-Johnson¹⁰ battery, which assesses visual-spatial thinking and fluid reasoning, may be particularly important in characterizing NLD deficits—especially when used in conjunction with other neuropsychological batteries, which may directly assess discrete abilities related to visual and spatial processing.

A thorough social and educational history, IQ testing, neuropsychological batteries, and a psychoeducational assessment can help determine the extent of cognitive deficits that may require accommodations at school or work and characterize the complex interplay of specific deficits and functioning.

Table 1

Clinical manifestation of nonverbal learning disorder

Differential diagnosis

ADHD. Patients diagnosed with ADHD or NLD may have a history of attention difficulties and hyperactivity. These clinical similarities may include restlessness, distractibility, impulsivity, and poor attention (Table 2).^11,12 In adults, these features may attenuate and patients with NLD or ADHD could appear normoactive. Individuals with NLD demonstrate withdrawal, anxiety, and continued social skills deficits,¹³ whereas adult ADHD patients show persistent attention difficulties. Although both groups may have difficulty maintaining steady employment, NLD patients’ employment failures often are caused by cognitive and social difficulties as opposed to problems with attention.

The psychopathology of these 2 conditions differs in that ADHD is characterized primarily by prefrontal dysfunction.¹⁴ However, in a small study of children with NLD (N=20), all participants also met diagnostic criteria for ADHD; therefore, the true epidemiologic comorbidity is unknown.¹⁵

BD. Because patients with NLD may experience affective symptoms similar to those with BD, it is critical to clarify the temporal course of mood symptoms and understand the complex relationships between symptoms and external events (Table 2).^11,12 In BD, mood symptoms are cyclical, punctuated by discrete periods of euthymia. In NLD affective symptoms are clearly linked to learning difficulties and impaired information processing. Research shows cognitive deficits in individuals with BD often persist during euthymic periods.¹⁶ Literature suggests that cognitive deficits in adult BD commonly involve verbal memory, executive function, and attention, whereas patients with NLD often have strong verbal memory.^17,18

Individuals with BD may understand the intentions of others and—especially in periods of hypomania or mania—will engage others. In contrast, persons with NLD struggle to attract and engage friends, may be irritable when they misunderstand social cues, may be bullied or taken advantage of by others, and may struggle to communicate this problem to clinicians. NLD patients’ sense of frustration typically does not vary; a continuous depressed or anxious mood may improve briefly when they feel accepted in their environment. This pattern can be discerned from BD by strictly applying DSM-IV-TR criteria for variability in mood states.¹⁹ BD treatment may be complicated in patients with comorbid NLD. These patients may underreport adverse effects of medications, including metabolic effects and cognitive dulling, which results in a complicated and frustrating clinical course.²⁰

Asperger’s disorder. Patients with NLD—a neuropsychological disorder—may present with social interaction difficulties that seem similar to those of Asperger’s disorder—a behavioral disorder. Overlapping behaviors, similar cognitive processes, and coexisting conditions may challenge even experienced clinicians (Table 3).^21-23 However, impairments are more severe in Asperger’s disorder and will present as early as age 4. Patients with Asperger’s disorder show difficulty communicating characterized by unusual interactions, such as pedantic or 1-sided discussions of topics that are unusual for the patient’s age group and inattentiveness to social cues. By contrast, communication difficulties in children with NLD are not apparent until after they start school.

Both Asperger’s disorder and NLD patients will show noticeable variations in thought process that often are apparent in conversations. Individuals with Asperger’s disorder may have some concrete thinking, although they often express idiosyncratic thinking, whereas individuals with NLD often show concrete logic. An individual with NLD may be easily overwhelmed by peer group social interactions but remains emotionally aware of his or her shortcomings and may be able to handle 1-on-1 interactions. Individuals with Asperger’s disorder will demonstrate restrictive interests or repetitive behaviors, a characteristic typically not seen in individuals with NLD. Patients with Asperger’s disorder may have specific skills, such as expertise with directions and spatial reasoning, whereas individuals with NLD may get lost even when traveling to familiar places or may have difficulty relating directions. Both groups likely will have good reading skills but patients with NLD will have trouble comprehending and integrating the material, evident by difficulty with multiple choice questions or “story problems.” Individuals with either disorder may develop frustration and anger with their challenges.

In adults, many of these subtle differences in language and thought process may be masked by years of difficult and frustrating communication, making definitive diagnosis challenging. Semistructured interviews, such as the Autism Diagnostic Observation Schedule²⁴ or the Gilliam Asperger’s Disorder Scale,²⁵ may help in differentiating Asperger’s disorder from NLD. However, these 2 disorders may be comorbid, thus complicating the diagnostic process.²¹

Table 2

Differences among NLD, ADHD, and bipolar disorder

Table 3

Differences between NLD and Asperger’s disorder

Treatment implications

The day-to-day care of patients with NLD and a comorbid psychiatric disorder may include systems-level interventions, supportive psychotherapy, and psychopharmacologic treatments that are informed by the comorbid condition (Table 4).^7,26 Open, honest dialogue about strengths and challenges for individuals with NLD will help reframe expectations and frustrations. Early recognition of NLD may, in some cases, prevent internalized psychopathology and loss of self-esteem.^27,28

Children and adolescents with NLD require early intervention to help them function socially and academically. Involving family and school personnel is important to develop accommodations to improve functioning. Comprehension problems associated with NLD often become more noticeable as the student moves into upper elementary grades, where abstract thinking and the ability to manage novelty (eg, unfamiliar content or situations) are required. Many students with NLD can manage rote memorization and concrete facts, but have trouble with inference, integration, and reasoning. Academically appropriate classroom placement, limited writing, and use of voice recognition software may aid success. Parents can help by teaching and modeling social skills such as appropriate expression of emotions, which can be facilitated by watching movies or attending group activities together.

Adults. Patients with NLD may be late for appointments and often forget what is discussed. They may be at increased risk for noncompliance with pharmacotherapy for comorbid disorders and may require written instructions, frequent reminders, and reviews of treatment plan. In addition, interactions with clinicians may seem shallow and unsatisfying, despite the clinician’s best efforts to empathize. The pattern of feeling misunderstood likely exists in the patient’s other relationships, including significant others and employers. Although no systemic evaluations exist, mindfulness-based therapies might help alleviate this deficit.^29,30

Treatment plans may involve family-focused modalities where NLD patients learn to rely on family members to interpret others’ motives and intentions.³¹ Education of the patient and family and friends should emphasize the need for consistent daily schedules and frequent verbal feedback, such as taking turns in conversations. Academic accommodations in college are crucial for success. Education experts have advocated for increased use of technology for students with NLD, including voice recognition software, laptop computers, and audio recordings of class notes.³²

Table 4

Treating patients with NLD

Related Resources

• Rourke BP. Syndrome of nonverbal learning disabilities: Neurodevelopmental manifestations. New York, NY: Guilford Press; 1995.
• NLD Line. www.nldline.com.
• NLD on the Web. www.nldontheweb.org.
• Massachusetts General Hospital school psychiatry program and Mood and Anxiety Disorders Institute resource center. www2.massgeneral.org/schoolpsychiatry.

Disclosures

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

Dr. Strawn has received research support from the American Academy of Child and Adolescent Psychiatry and Eli Lilly and Company.

Acknowledgements

The authors acknowledge Drs. Michele Berg and Carleen Franz for their careful review of this manuscript and for their critiques, which have greatly improved this contribution.