Murali Rao, MD

CASE Posing a threat to his family

Mr. C, age 23, who was diagnosed with schizophrenia with daily auditory hallucinations 4 years earlier, is transferred from an outside psychiatric hospital to our emergency department (ED) after developing fever, tachycardia, headache, and nasal congestion for the past day. He had been admitted to the psychiatric hospital 3 weeks ago due to concerns he was experiencing increased hallucinations and delusions and posed a threat to his sister and her children, with whom he had been living.

Mr. C tells us that while at the psychiatric hospital, he had been started on clozapine, 250 mg/d. He said that prior to clozapine, he had been taking risperidone. We are unable to confirm past treatment information with the psychiatric hospital, including exactly when the clozapine had been started or how fast it had been titrated. We also were not able to obtain information on his prior medication regimen.

In the ED, Mr. C is febrile (39.4°C; 102.9°F), tachycardic (160 beats per minute; reference range 60 to 100), and tachypneic (24 breaths per minute; reference range 12 to 20). His blood pressure is 130/68 mm Hg, and his lactate level is 2.3 mmol/L (reference range <1.9 mmol/L). After he receives 3 liters of fluid, Mr. C’s heart rate decreases to 117 and his lactate level to 1.1 mmol/L. His white blood cell count is 10.6 × 10³/mm³ (reference range 4.0 to 10.0 × 10³/mm³); a differential can be found in the Table. His electrocardiogram (ECG) demonstrates sinus tachycardia and a QTc of 510 ms (reference range <430 ms), but is otherwise unremarkable. His creatinine kinase (CK) level is within normal limits at 76 U/L (reference range 52 to 336 U/L). A C-reactive protein (CRP) level was not drawn at this time. Other than marijuana and cocaine use, Mr. C’s medical history is unremarkable.

Mr. C is admitted to the hospital and is started on treatment for sepsis. On the evening of Day 1, Mr. C experiences worsening tachycardia (140 beats per minute) and tachypnea (≥40 breaths per minute). His temperature increases to 103.3°F, and his blood pressure drops to 97/55 mm Hg. His troponin level is 19.0 ng/mL (reference range <0.01 ng/mL) and CK level is 491 U/L.

As Mr. C continues to deteriorate, a rapid response is called and he is placed on non-rebreather oxygen and transferred to the medical intensive care unit (MICU).

[polldaddy:10226034]

The authors’ observations

With Mr. C’s presenting symptoms, multiple conditions were included in the differential diagnosis. The initial concern was for sepsis. Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.¹ Organ dysfunction is defined by a quick Sepsis-Related Organ Failure Assessment (qSOFA) score ≥2 and is associated with an increased probability of mortality (>10%). Although no infection had been identified in Mr. C, the combination of fever, altered vital signs, and elevated lactate level in the setting of a qSOFA score of 2 (for respiratory rate and blood pressure) raised suspicion enough to start empiric treatment.

With Mr. C’s subsequent deterioration on the evening of Day 1, we considered cardiopulmonary etiologies. His symptoms of dyspnea, hypotension, tachycardia, tachypnea, and fever were nonspecific and thus required consideration of multiple life-threatening etiologies. Thygesen et al² published an expert consensus of the definition of myocardial infarction, which was of concern given our patient’s elevated troponin level. Because there was already concern for sepsis, the addition of cardiac symptoms required us to consider infectious endocarditis.³ Sudden onset of dyspnea and a drop in blood pressure were concerning for pulmonary embolism, although our patient did not have the usual risk factors (cancer, immobilization, recent surgery, etc.).⁴ Additionally, in light of Mr. C’s psychiatric history and recent stressors of being moved from his sister’s house and admitted to a psychiatric hospital, coupled with dyspnea and hypotension, we included Takotsubo cardiomyopathy in the differential.^5,6 This disease often occurs in response to an emotional or physical stressor and is characterized by transient systolic dysfunction in the setting of ventricular wall-motion abnormalities reaching beyond the distribution of a single coronary artery. Acute ECG and biomarker findings mimic those of myocardial infarction.⁶

Continue to: Finally, we needed to consider...

Finally, we needed to consider the potential adverse effects of clozapine. Clozapine is a second-generation antipsychotic (SGA) used to treat patients with schizophrenia for whom other antipsychotic medications are ineffective. Clozapine has been shown to be more effective than first-generation antipsycho­tics (FGA) in reducing symptoms of schizophrenia.⁷ It has also been shown to be more effective than several SGAs, including quetiapine, risperidone, and olanzapine.⁷ In fact, in patients with an insufficient therapeutic response to an SGA, clozapine proves to be more effective than switching to a different SGA. As a result of more than 20 years of research, clozapine is the gold-standard for treatment-resistant schizophrenia.⁷ Yet despite this strong evidence supporting its use in patients with treatment-resistant schizophrenia, the medication continues to be underutilized, especially in patients at risk for suicide.⁷

It appears that clozapine remains a third-choice medication in the treatment of schizophrenia largely due to its serious adverse effect profile.⁷ The medication includes several black-box warnings, including severe neutropenia, orthostatic hypotension, bradycardia, syncope, seizures, myocarditis, cardiomyopathy, and mitral valve incompetence.⁸ Tachycardia, bradycardia, and orthostatic hypotension are all clozapine-related adverse effects associated with autonomic dysfunction, which can result in serious long-term cardiac complications.⁹ With regards to the drug’s neutropenia risk, the establishment of the Clozapine Risk Evaluation and Mitigation Strategy (REMS) program has allowed for safer use of clozapine and reduced deaths due to clozapine-induced agranulocytosis. Clinicians and pharmacists must be certified in order to prescribe clozapine, and patients must be registered and undergo frequent absolute neutrophil count (ANC) monitoring.

Clozapine-induced myocarditis, a condition observed in up to 3% of patients started on the medication,⁹ is more likely to develop early on during treatment, with a median time of detection of 16 days following drug initiation.¹⁰ Myocarditis often presents with nonspecific signs and symptoms that include chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, and/or hypotension.

[polldaddy:10226036]

The authors’ observations

Initial workup in the MICU for Mr. C included an ABG analysis, ECG, and cardiology consult. The ABG analysis demonstrated metabolic alkalosis; his ECG demonstrated sinus tachycardia and nonspecific ST elevation in the lateral leads (Figure). The cardiology consult team started Mr. C on treatment for a non-ST-elevation myocardial infarction (NSTEMI), which it believed to be most likely due to myocarditis with secondary demand ischemia, and less likely acute coronary syndrome. The cardiology consult team also recommended performing a workup for pulmonary emboli and infectious endocarditis if Mr. C’s symptoms persist or the infectious source could not be identified.

EVALUATION Gradual improvement

Mr. C demonstrates gradual improvement as his workup continues, and clozapine is held on the recommendation of the cardiac consult team. By Day 2, he stops complaining of auditory hallucinations, and does not report their return during the rest of his stay. His troponin level decreases to 8.6 ng/mL and lactate level to 1.4 mmol/L; trending is stopped for both. The erythrocyte sedimentation rate (ESR) is elevated at 59 mm/hr (reference range 0 to 22 mm/hr), along with a CRP level of 21 mg/L (reference range <8.0 mg/L). An echocardiogram demonstrates a 40% ejection fraction (reference range 55% to 75%) and moderate global hypokinesis. The cardiology consult team is concerned for Takotsubo cardiomyopathy with sepsis as a source of adrenergic surge vs myopericarditis of viral etiology. The cardiology team also suggests continued stoppage of clozapine, because the medication can cause hypotension and tachycardia.

Continue to: On Day 3...

On Day 3, Mr. C’s ST elevation resolves on ECG, and his CK level decreases to 70 U/L, at which point trending is stopped. On Day 5, Mr. C undergoes MRI, which demonstrates an ejection fraction of 55% and confirms myocarditis. No infectious source is identified.

By Day 6, with all other sources ruled out, clozapine is confirmed as the source of myocarditis for Mr. C.

The authors’ observations

Close cardiovascular monitoring should occur during the first 4 weeks after starting clozapine because 80% of cases of clozapine-induced myocarditis occur within 4 weeks of clozapine initiation.¹⁰ Baseline CRP, troponin I/T, and vital signs should be obtained before starting clozapine.¹¹ Vital signs must be monitored to assess for fever, tachycardia, and deviations from baseline blood pressures.¹¹ Although eosinophil counts and percentages can also be considered in addition to a baseline CRP value, they have not proven to be sensitive or specific for clozapine-induced myocarditis.¹² A baseline echocardiogram can also be obtained, but is not necessary, especially given that it may not be readily available in all clinics, and could therefore delay initiation of clozapine and limit its use. C-reactive protein and troponin levels should be assessed weekly during the first 6 weeks of clozapine therapy.¹¹ For symptomatic patients presenting with concern for clozapine-induced myocarditis, a CRP level >100 mg/L has 100% sensitivity in detecting clozapine-induced myocarditis.¹³ Clozapine should also be stopped if troponins levels reach twice the upper limit of normal. More mild elevations of CRP and troponins in the setting of persistent tachycardia or signs of an infectious process should be followed by daily CRP and troponins levels until these features resolve.¹¹

Mr. C’s case highlights clinical features that clinicians should consider when screening for myocarditis. The development of myocarditis is associated with quick titrations of clozapine during Days 1 to 9. In this case, Mr. C had recently been titrated at an outside hospital, and the time frame during which this titration occurred was unknown. Given this lack of information, the potential for a rapid titration should alert the clinician to the risk of developing myocarditis. Increased age is also associated with an increased risk of myocarditis, with a 31% increase for each decade. Further, the concomitant use of valproate sodium during the titration period also increases the risk of myocarditis 2.5-fold.¹⁴

When evaluating a patient such as Mr. C, an important clinical sign that must not be overlooked is that an elevation of body temperature of 1°C is expected to give rise to a 10-beats-per-minute increase in heart rate when the fever is the result of an infection.¹⁵ During Day 1 of his hospitalization, Mr. C was tachycardic to 160 beats per minute, with a fever of 39.4°C. Thus, his heart rate was elevated well beyond what would be expected from a fever secondary to an infectious process. This further illustrates the need to consider adverse effects caused by medication, such as clozapine-induced tachycardia.

Continue to: While clozapine had already been stopped...

While clozapine had already been stopped in Mr. C, it is conceivable that other patients would potentially continue receiving it because of the medication’s demonstrated efficacy in reducing hallucinations; however, this would result in worsening and potentially serious cardiac symptoms.

[polldaddy:10226037]

The authors’ observations

A diagnosis of clozapine-induced myocarditis should be followed by a prompt discontinuation of clozapine. Discontinuation of the drug should lead to spontaneous resolution of the myocarditis, with significantly improved left ventricular function observed within 5 days.¹³ Historically, rechallenging a patient with clozapine was not recommended, due to fear of recurrence of myocarditis. However, recent case studies indicate that myocarditis need not be an absolute contraindication to restarting clozapine.¹⁶ Rather, the risks must be balanced against demonstrated efficacy in patients who had a limited response to other antipsychotics, as was the case with Mr. C. For these patients, the decision to rechallenge should be made with the patient’s informed consent and involve slow dose titration and increased monitoring.¹⁷ Should this rechallenge fail, another antipsychotic plus augmentation with a mood stabilizer or ECT may be more efficacious than an antipsychotic alone.^18,19

OUTCOME Return to the psychiatric hospital

On Day 8, Mr. C is medically cleared; he had not reported auditory hallucinations since Day 2. He is discharged back to the psychiatric hospital for additional medication management of his schizophrenia.

Bottom Line

Clozapine-induced myocarditis should be included in the differential diagnosis for patients who present with nonspecific complaints and have an incomplete history pertaining to clozapine use. After discontinuing clozapine, and after myocarditis symptoms resolve, consider restarting clozapine in patients who have limited response to other treatments. If rechallenging fails, another antipsychotic plus augmentation with a mood stabilizer or electroconvulsive therapy may be more efficacious than an antipsychotic alone.

Related Resources

• Clozapine Risk Evaluation and Mitigation Strategy [REMS] Program. What is the Clozapine REMS Program? https://www.clozapinerems.com.
• Keating D, McWilliams S, Schneider I, et al. Pharmacological guidelines for schizophrenia: a systematic review and comparison of recommendations for the first episode. BMJ Open. 2017;7(1):e013881.
• Curto M, Girardi N, Lionetto L, et al. Systematic review of clozapine cardiotoxicity. Curr Psychiatry Rep. 2016;18(7):68.

Drug Brand Names

Clozapine • Clozaril
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Valproate • Depacon

CASE Posing a threat to his family

Mr. C, age 23, who was diagnosed with schizophrenia with daily auditory hallucinations 4 years earlier, is transferred from an outside psychiatric hospital to our emergency department (ED) after developing fever, tachycardia, headache, and nasal congestion for the past day. He had been admitted to the psychiatric hospital 3 weeks ago due to concerns he was experiencing increased hallucinations and delusions and posed a threat to his sister and her children, with whom he had been living.

Mr. C tells us that while at the psychiatric hospital, he had been started on clozapine, 250 mg/d. He said that prior to clozapine, he had been taking risperidone. We are unable to confirm past treatment information with the psychiatric hospital, including exactly when the clozapine had been started or how fast it had been titrated. We also were not able to obtain information on his prior medication regimen.

In the ED, Mr. C is febrile (39.4°C; 102.9°F), tachycardic (160 beats per minute; reference range 60 to 100), and tachypneic (24 breaths per minute; reference range 12 to 20). His blood pressure is 130/68 mm Hg, and his lactate level is 2.3 mmol/L (reference range <1.9 mmol/L). After he receives 3 liters of fluid, Mr. C’s heart rate decreases to 117 and his lactate level to 1.1 mmol/L. His white blood cell count is 10.6 × 10³/mm³ (reference range 4.0 to 10.0 × 10³/mm³); a differential can be found in the Table. His electrocardiogram (ECG) demonstrates sinus tachycardia and a QTc of 510 ms (reference range <430 ms), but is otherwise unremarkable. His creatinine kinase (CK) level is within normal limits at 76 U/L (reference range 52 to 336 U/L). A C-reactive protein (CRP) level was not drawn at this time. Other than marijuana and cocaine use, Mr. C’s medical history is unremarkable.

Mr. C is admitted to the hospital and is started on treatment for sepsis. On the evening of Day 1, Mr. C experiences worsening tachycardia (140 beats per minute) and tachypnea (≥40 breaths per minute). His temperature increases to 103.3°F, and his blood pressure drops to 97/55 mm Hg. His troponin level is 19.0 ng/mL (reference range <0.01 ng/mL) and CK level is 491 U/L.

As Mr. C continues to deteriorate, a rapid response is called and he is placed on non-rebreather oxygen and transferred to the medical intensive care unit (MICU).

[polldaddy:10226034]

The authors’ observations

With Mr. C’s presenting symptoms, multiple conditions were included in the differential diagnosis. The initial concern was for sepsis. Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.¹ Organ dysfunction is defined by a quick Sepsis-Related Organ Failure Assessment (qSOFA) score ≥2 and is associated with an increased probability of mortality (>10%). Although no infection had been identified in Mr. C, the combination of fever, altered vital signs, and elevated lactate level in the setting of a qSOFA score of 2 (for respiratory rate and blood pressure) raised suspicion enough to start empiric treatment.

With Mr. C’s subsequent deterioration on the evening of Day 1, we considered cardiopulmonary etiologies. His symptoms of dyspnea, hypotension, tachycardia, tachypnea, and fever were nonspecific and thus required consideration of multiple life-threatening etiologies. Thygesen et al² published an expert consensus of the definition of myocardial infarction, which was of concern given our patient’s elevated troponin level. Because there was already concern for sepsis, the addition of cardiac symptoms required us to consider infectious endocarditis.³ Sudden onset of dyspnea and a drop in blood pressure were concerning for pulmonary embolism, although our patient did not have the usual risk factors (cancer, immobilization, recent surgery, etc.).⁴ Additionally, in light of Mr. C’s psychiatric history and recent stressors of being moved from his sister’s house and admitted to a psychiatric hospital, coupled with dyspnea and hypotension, we included Takotsubo cardiomyopathy in the differential.^5,6 This disease often occurs in response to an emotional or physical stressor and is characterized by transient systolic dysfunction in the setting of ventricular wall-motion abnormalities reaching beyond the distribution of a single coronary artery. Acute ECG and biomarker findings mimic those of myocardial infarction.⁶

Continue to: Finally, we needed to consider...

Finally, we needed to consider the potential adverse effects of clozapine. Clozapine is a second-generation antipsychotic (SGA) used to treat patients with schizophrenia for whom other antipsychotic medications are ineffective. Clozapine has been shown to be more effective than first-generation antipsycho­tics (FGA) in reducing symptoms of schizophrenia.⁷ It has also been shown to be more effective than several SGAs, including quetiapine, risperidone, and olanzapine.⁷ In fact, in patients with an insufficient therapeutic response to an SGA, clozapine proves to be more effective than switching to a different SGA. As a result of more than 20 years of research, clozapine is the gold-standard for treatment-resistant schizophrenia.⁷ Yet despite this strong evidence supporting its use in patients with treatment-resistant schizophrenia, the medication continues to be underutilized, especially in patients at risk for suicide.⁷

It appears that clozapine remains a third-choice medication in the treatment of schizophrenia largely due to its serious adverse effect profile.⁷ The medication includes several black-box warnings, including severe neutropenia, orthostatic hypotension, bradycardia, syncope, seizures, myocarditis, cardiomyopathy, and mitral valve incompetence.⁸ Tachycardia, bradycardia, and orthostatic hypotension are all clozapine-related adverse effects associated with autonomic dysfunction, which can result in serious long-term cardiac complications.⁹ With regards to the drug’s neutropenia risk, the establishment of the Clozapine Risk Evaluation and Mitigation Strategy (REMS) program has allowed for safer use of clozapine and reduced deaths due to clozapine-induced agranulocytosis. Clinicians and pharmacists must be certified in order to prescribe clozapine, and patients must be registered and undergo frequent absolute neutrophil count (ANC) monitoring.

Clozapine-induced myocarditis, a condition observed in up to 3% of patients started on the medication,⁹ is more likely to develop early on during treatment, with a median time of detection of 16 days following drug initiation.¹⁰ Myocarditis often presents with nonspecific signs and symptoms that include chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, and/or hypotension.

[polldaddy:10226036]

The authors’ observations

Initial workup in the MICU for Mr. C included an ABG analysis, ECG, and cardiology consult. The ABG analysis demonstrated metabolic alkalosis; his ECG demonstrated sinus tachycardia and nonspecific ST elevation in the lateral leads (Figure). The cardiology consult team started Mr. C on treatment for a non-ST-elevation myocardial infarction (NSTEMI), which it believed to be most likely due to myocarditis with secondary demand ischemia, and less likely acute coronary syndrome. The cardiology consult team also recommended performing a workup for pulmonary emboli and infectious endocarditis if Mr. C’s symptoms persist or the infectious source could not be identified.

EVALUATION Gradual improvement

Mr. C demonstrates gradual improvement as his workup continues, and clozapine is held on the recommendation of the cardiac consult team. By Day 2, he stops complaining of auditory hallucinations, and does not report their return during the rest of his stay. His troponin level decreases to 8.6 ng/mL and lactate level to 1.4 mmol/L; trending is stopped for both. The erythrocyte sedimentation rate (ESR) is elevated at 59 mm/hr (reference range 0 to 22 mm/hr), along with a CRP level of 21 mg/L (reference range <8.0 mg/L). An echocardiogram demonstrates a 40% ejection fraction (reference range 55% to 75%) and moderate global hypokinesis. The cardiology consult team is concerned for Takotsubo cardiomyopathy with sepsis as a source of adrenergic surge vs myopericarditis of viral etiology. The cardiology team also suggests continued stoppage of clozapine, because the medication can cause hypotension and tachycardia.

Continue to: On Day 3...

On Day 3, Mr. C’s ST elevation resolves on ECG, and his CK level decreases to 70 U/L, at which point trending is stopped. On Day 5, Mr. C undergoes MRI, which demonstrates an ejection fraction of 55% and confirms myocarditis. No infectious source is identified.

By Day 6, with all other sources ruled out, clozapine is confirmed as the source of myocarditis for Mr. C.

The authors’ observations

Close cardiovascular monitoring should occur during the first 4 weeks after starting clozapine because 80% of cases of clozapine-induced myocarditis occur within 4 weeks of clozapine initiation.¹⁰ Baseline CRP, troponin I/T, and vital signs should be obtained before starting clozapine.¹¹ Vital signs must be monitored to assess for fever, tachycardia, and deviations from baseline blood pressures.¹¹ Although eosinophil counts and percentages can also be considered in addition to a baseline CRP value, they have not proven to be sensitive or specific for clozapine-induced myocarditis.¹² A baseline echocardiogram can also be obtained, but is not necessary, especially given that it may not be readily available in all clinics, and could therefore delay initiation of clozapine and limit its use. C-reactive protein and troponin levels should be assessed weekly during the first 6 weeks of clozapine therapy.¹¹ For symptomatic patients presenting with concern for clozapine-induced myocarditis, a CRP level >100 mg/L has 100% sensitivity in detecting clozapine-induced myocarditis.¹³ Clozapine should also be stopped if troponins levels reach twice the upper limit of normal. More mild elevations of CRP and troponins in the setting of persistent tachycardia or signs of an infectious process should be followed by daily CRP and troponins levels until these features resolve.¹¹

Mr. C’s case highlights clinical features that clinicians should consider when screening for myocarditis. The development of myocarditis is associated with quick titrations of clozapine during Days 1 to 9. In this case, Mr. C had recently been titrated at an outside hospital, and the time frame during which this titration occurred was unknown. Given this lack of information, the potential for a rapid titration should alert the clinician to the risk of developing myocarditis. Increased age is also associated with an increased risk of myocarditis, with a 31% increase for each decade. Further, the concomitant use of valproate sodium during the titration period also increases the risk of myocarditis 2.5-fold.¹⁴

When evaluating a patient such as Mr. C, an important clinical sign that must not be overlooked is that an elevation of body temperature of 1°C is expected to give rise to a 10-beats-per-minute increase in heart rate when the fever is the result of an infection.¹⁵ During Day 1 of his hospitalization, Mr. C was tachycardic to 160 beats per minute, with a fever of 39.4°C. Thus, his heart rate was elevated well beyond what would be expected from a fever secondary to an infectious process. This further illustrates the need to consider adverse effects caused by medication, such as clozapine-induced tachycardia.

Continue to: While clozapine had already been stopped...

While clozapine had already been stopped in Mr. C, it is conceivable that other patients would potentially continue receiving it because of the medication’s demonstrated efficacy in reducing hallucinations; however, this would result in worsening and potentially serious cardiac symptoms.

[polldaddy:10226037]

The authors’ observations

A diagnosis of clozapine-induced myocarditis should be followed by a prompt discontinuation of clozapine. Discontinuation of the drug should lead to spontaneous resolution of the myocarditis, with significantly improved left ventricular function observed within 5 days.¹³ Historically, rechallenging a patient with clozapine was not recommended, due to fear of recurrence of myocarditis. However, recent case studies indicate that myocarditis need not be an absolute contraindication to restarting clozapine.¹⁶ Rather, the risks must be balanced against demonstrated efficacy in patients who had a limited response to other antipsychotics, as was the case with Mr. C. For these patients, the decision to rechallenge should be made with the patient’s informed consent and involve slow dose titration and increased monitoring.¹⁷ Should this rechallenge fail, another antipsychotic plus augmentation with a mood stabilizer or ECT may be more efficacious than an antipsychotic alone.^18,19

OUTCOME Return to the psychiatric hospital

On Day 8, Mr. C is medically cleared; he had not reported auditory hallucinations since Day 2. He is discharged back to the psychiatric hospital for additional medication management of his schizophrenia.

Bottom Line

Clozapine-induced myocarditis should be included in the differential diagnosis for patients who present with nonspecific complaints and have an incomplete history pertaining to clozapine use. After discontinuing clozapine, and after myocarditis symptoms resolve, consider restarting clozapine in patients who have limited response to other treatments. If rechallenging fails, another antipsychotic plus augmentation with a mood stabilizer or electroconvulsive therapy may be more efficacious than an antipsychotic alone.

Related Resources

• Clozapine Risk Evaluation and Mitigation Strategy [REMS] Program. What is the Clozapine REMS Program? https://www.clozapinerems.com.
• Keating D, McWilliams S, Schneider I, et al. Pharmacological guidelines for schizophrenia: a systematic review and comparison of recommendations for the first episode. BMJ Open. 2017;7(1):e013881.
• Curto M, Girardi N, Lionetto L, et al. Systematic review of clozapine cardiotoxicity. Curr Psychiatry Rep. 2016;18(7):68.

Drug Brand Names

Clozapine • Clozaril
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Valproate • Depacon

CASE Posing a threat to his family

Mr. C, age 23, who was diagnosed with schizophrenia with daily auditory hallucinations 4 years earlier, is transferred from an outside psychiatric hospital to our emergency department (ED) after developing fever, tachycardia, headache, and nasal congestion for the past day. He had been admitted to the psychiatric hospital 3 weeks ago due to concerns he was experiencing increased hallucinations and delusions and posed a threat to his sister and her children, with whom he had been living.

Mr. C tells us that while at the psychiatric hospital, he had been started on clozapine, 250 mg/d. He said that prior to clozapine, he had been taking risperidone. We are unable to confirm past treatment information with the psychiatric hospital, including exactly when the clozapine had been started or how fast it had been titrated. We also were not able to obtain information on his prior medication regimen.

In the ED, Mr. C is febrile (39.4°C; 102.9°F), tachycardic (160 beats per minute; reference range 60 to 100), and tachypneic (24 breaths per minute; reference range 12 to 20). His blood pressure is 130/68 mm Hg, and his lactate level is 2.3 mmol/L (reference range <1.9 mmol/L). After he receives 3 liters of fluid, Mr. C’s heart rate decreases to 117 and his lactate level to 1.1 mmol/L. His white blood cell count is 10.6 × 10³/mm³ (reference range 4.0 to 10.0 × 10³/mm³); a differential can be found in the Table. His electrocardiogram (ECG) demonstrates sinus tachycardia and a QTc of 510 ms (reference range <430 ms), but is otherwise unremarkable. His creatinine kinase (CK) level is within normal limits at 76 U/L (reference range 52 to 336 U/L). A C-reactive protein (CRP) level was not drawn at this time. Other than marijuana and cocaine use, Mr. C’s medical history is unremarkable.

Mr. C is admitted to the hospital and is started on treatment for sepsis. On the evening of Day 1, Mr. C experiences worsening tachycardia (140 beats per minute) and tachypnea (≥40 breaths per minute). His temperature increases to 103.3°F, and his blood pressure drops to 97/55 mm Hg. His troponin level is 19.0 ng/mL (reference range <0.01 ng/mL) and CK level is 491 U/L.

As Mr. C continues to deteriorate, a rapid response is called and he is placed on non-rebreather oxygen and transferred to the medical intensive care unit (MICU).

[polldaddy:10226034]

The authors’ observations

With Mr. C’s presenting symptoms, multiple conditions were included in the differential diagnosis. The initial concern was for sepsis. Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.¹ Organ dysfunction is defined by a quick Sepsis-Related Organ Failure Assessment (qSOFA) score ≥2 and is associated with an increased probability of mortality (>10%). Although no infection had been identified in Mr. C, the combination of fever, altered vital signs, and elevated lactate level in the setting of a qSOFA score of 2 (for respiratory rate and blood pressure) raised suspicion enough to start empiric treatment.

With Mr. C’s subsequent deterioration on the evening of Day 1, we considered cardiopulmonary etiologies. His symptoms of dyspnea, hypotension, tachycardia, tachypnea, and fever were nonspecific and thus required consideration of multiple life-threatening etiologies. Thygesen et al² published an expert consensus of the definition of myocardial infarction, which was of concern given our patient’s elevated troponin level. Because there was already concern for sepsis, the addition of cardiac symptoms required us to consider infectious endocarditis.³ Sudden onset of dyspnea and a drop in blood pressure were concerning for pulmonary embolism, although our patient did not have the usual risk factors (cancer, immobilization, recent surgery, etc.).⁴ Additionally, in light of Mr. C’s psychiatric history and recent stressors of being moved from his sister’s house and admitted to a psychiatric hospital, coupled with dyspnea and hypotension, we included Takotsubo cardiomyopathy in the differential.^5,6 This disease often occurs in response to an emotional or physical stressor and is characterized by transient systolic dysfunction in the setting of ventricular wall-motion abnormalities reaching beyond the distribution of a single coronary artery. Acute ECG and biomarker findings mimic those of myocardial infarction.⁶

Continue to: Finally, we needed to consider...

Finally, we needed to consider the potential adverse effects of clozapine. Clozapine is a second-generation antipsychotic (SGA) used to treat patients with schizophrenia for whom other antipsychotic medications are ineffective. Clozapine has been shown to be more effective than first-generation antipsycho­tics (FGA) in reducing symptoms of schizophrenia.⁷ It has also been shown to be more effective than several SGAs, including quetiapine, risperidone, and olanzapine.⁷ In fact, in patients with an insufficient therapeutic response to an SGA, clozapine proves to be more effective than switching to a different SGA. As a result of more than 20 years of research, clozapine is the gold-standard for treatment-resistant schizophrenia.⁷ Yet despite this strong evidence supporting its use in patients with treatment-resistant schizophrenia, the medication continues to be underutilized, especially in patients at risk for suicide.⁷

It appears that clozapine remains a third-choice medication in the treatment of schizophrenia largely due to its serious adverse effect profile.⁷ The medication includes several black-box warnings, including severe neutropenia, orthostatic hypotension, bradycardia, syncope, seizures, myocarditis, cardiomyopathy, and mitral valve incompetence.⁸ Tachycardia, bradycardia, and orthostatic hypotension are all clozapine-related adverse effects associated with autonomic dysfunction, which can result in serious long-term cardiac complications.⁹ With regards to the drug’s neutropenia risk, the establishment of the Clozapine Risk Evaluation and Mitigation Strategy (REMS) program has allowed for safer use of clozapine and reduced deaths due to clozapine-induced agranulocytosis. Clinicians and pharmacists must be certified in order to prescribe clozapine, and patients must be registered and undergo frequent absolute neutrophil count (ANC) monitoring.

Clozapine-induced myocarditis, a condition observed in up to 3% of patients started on the medication,⁹ is more likely to develop early on during treatment, with a median time of detection of 16 days following drug initiation.¹⁰ Myocarditis often presents with nonspecific signs and symptoms that include chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, and/or hypotension.

[polldaddy:10226036]

The authors’ observations

Initial workup in the MICU for Mr. C included an ABG analysis, ECG, and cardiology consult. The ABG analysis demonstrated metabolic alkalosis; his ECG demonstrated sinus tachycardia and nonspecific ST elevation in the lateral leads (Figure). The cardiology consult team started Mr. C on treatment for a non-ST-elevation myocardial infarction (NSTEMI), which it believed to be most likely due to myocarditis with secondary demand ischemia, and less likely acute coronary syndrome. The cardiology consult team also recommended performing a workup for pulmonary emboli and infectious endocarditis if Mr. C’s symptoms persist or the infectious source could not be identified.

EVALUATION Gradual improvement

Mr. C demonstrates gradual improvement as his workup continues, and clozapine is held on the recommendation of the cardiac consult team. By Day 2, he stops complaining of auditory hallucinations, and does not report their return during the rest of his stay. His troponin level decreases to 8.6 ng/mL and lactate level to 1.4 mmol/L; trending is stopped for both. The erythrocyte sedimentation rate (ESR) is elevated at 59 mm/hr (reference range 0 to 22 mm/hr), along with a CRP level of 21 mg/L (reference range <8.0 mg/L). An echocardiogram demonstrates a 40% ejection fraction (reference range 55% to 75%) and moderate global hypokinesis. The cardiology consult team is concerned for Takotsubo cardiomyopathy with sepsis as a source of adrenergic surge vs myopericarditis of viral etiology. The cardiology team also suggests continued stoppage of clozapine, because the medication can cause hypotension and tachycardia.

Continue to: On Day 3...

On Day 3, Mr. C’s ST elevation resolves on ECG, and his CK level decreases to 70 U/L, at which point trending is stopped. On Day 5, Mr. C undergoes MRI, which demonstrates an ejection fraction of 55% and confirms myocarditis. No infectious source is identified.

By Day 6, with all other sources ruled out, clozapine is confirmed as the source of myocarditis for Mr. C.

The authors’ observations

Close cardiovascular monitoring should occur during the first 4 weeks after starting clozapine because 80% of cases of clozapine-induced myocarditis occur within 4 weeks of clozapine initiation.¹⁰ Baseline CRP, troponin I/T, and vital signs should be obtained before starting clozapine.¹¹ Vital signs must be monitored to assess for fever, tachycardia, and deviations from baseline blood pressures.¹¹ Although eosinophil counts and percentages can also be considered in addition to a baseline CRP value, they have not proven to be sensitive or specific for clozapine-induced myocarditis.¹² A baseline echocardiogram can also be obtained, but is not necessary, especially given that it may not be readily available in all clinics, and could therefore delay initiation of clozapine and limit its use. C-reactive protein and troponin levels should be assessed weekly during the first 6 weeks of clozapine therapy.¹¹ For symptomatic patients presenting with concern for clozapine-induced myocarditis, a CRP level >100 mg/L has 100% sensitivity in detecting clozapine-induced myocarditis.¹³ Clozapine should also be stopped if troponins levels reach twice the upper limit of normal. More mild elevations of CRP and troponins in the setting of persistent tachycardia or signs of an infectious process should be followed by daily CRP and troponins levels until these features resolve.¹¹

Mr. C’s case highlights clinical features that clinicians should consider when screening for myocarditis. The development of myocarditis is associated with quick titrations of clozapine during Days 1 to 9. In this case, Mr. C had recently been titrated at an outside hospital, and the time frame during which this titration occurred was unknown. Given this lack of information, the potential for a rapid titration should alert the clinician to the risk of developing myocarditis. Increased age is also associated with an increased risk of myocarditis, with a 31% increase for each decade. Further, the concomitant use of valproate sodium during the titration period also increases the risk of myocarditis 2.5-fold.¹⁴

When evaluating a patient such as Mr. C, an important clinical sign that must not be overlooked is that an elevation of body temperature of 1°C is expected to give rise to a 10-beats-per-minute increase in heart rate when the fever is the result of an infection.¹⁵ During Day 1 of his hospitalization, Mr. C was tachycardic to 160 beats per minute, with a fever of 39.4°C. Thus, his heart rate was elevated well beyond what would be expected from a fever secondary to an infectious process. This further illustrates the need to consider adverse effects caused by medication, such as clozapine-induced tachycardia.

Continue to: While clozapine had already been stopped...

While clozapine had already been stopped in Mr. C, it is conceivable that other patients would potentially continue receiving it because of the medication’s demonstrated efficacy in reducing hallucinations; however, this would result in worsening and potentially serious cardiac symptoms.

[polldaddy:10226037]

The authors’ observations

A diagnosis of clozapine-induced myocarditis should be followed by a prompt discontinuation of clozapine. Discontinuation of the drug should lead to spontaneous resolution of the myocarditis, with significantly improved left ventricular function observed within 5 days.¹³ Historically, rechallenging a patient with clozapine was not recommended, due to fear of recurrence of myocarditis. However, recent case studies indicate that myocarditis need not be an absolute contraindication to restarting clozapine.¹⁶ Rather, the risks must be balanced against demonstrated efficacy in patients who had a limited response to other antipsychotics, as was the case with Mr. C. For these patients, the decision to rechallenge should be made with the patient’s informed consent and involve slow dose titration and increased monitoring.¹⁷ Should this rechallenge fail, another antipsychotic plus augmentation with a mood stabilizer or ECT may be more efficacious than an antipsychotic alone.^18,19

OUTCOME Return to the psychiatric hospital

On Day 8, Mr. C is medically cleared; he had not reported auditory hallucinations since Day 2. He is discharged back to the psychiatric hospital for additional medication management of his schizophrenia.

Bottom Line

Clozapine-induced myocarditis should be included in the differential diagnosis for patients who present with nonspecific complaints and have an incomplete history pertaining to clozapine use. After discontinuing clozapine, and after myocarditis symptoms resolve, consider restarting clozapine in patients who have limited response to other treatments. If rechallenging fails, another antipsychotic plus augmentation with a mood stabilizer or electroconvulsive therapy may be more efficacious than an antipsychotic alone.

Related Resources

• Clozapine Risk Evaluation and Mitigation Strategy [REMS] Program. What is the Clozapine REMS Program? https://www.clozapinerems.com.
• Keating D, McWilliams S, Schneider I, et al. Pharmacological guidelines for schizophrenia: a systematic review and comparison of recommendations for the first episode. BMJ Open. 2017;7(1):e013881.
• Curto M, Girardi N, Lionetto L, et al. Systematic review of clozapine cardiotoxicity. Curr Psychiatry Rep. 2016;18(7):68.

Drug Brand Names

Clozapine • Clozaril
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Valproate • Depacon

CASE Rapid decline
Mr. X, age 67, is a businessman who had a diagnosis of bipolar depression 8 years ago, and who is being evaluated now for new-onset cognitive impairment, gait disturbance that resembles child-like steps, dyskinesia, and urinary incontinence of approximately 2 months’ duration. He has been treated for bipolar depression with valproic acid, 1,000 mg/d, and venlafaxine, 150 mg/d, without complaint until now, since the diagnosis was made 8 years ago. The serum valproic acid level, tested every month, is within the therapeutic range; liver function tests, ordered every 6 months, also are within the normal range.

Mr. X has become confined to his bedroom and needs assistance to walk. He has to be lifted to a standing position by 2 attendants, who bear his weight and instruct him to take one step at a time. He wears a diaper and needs assistance shaving, showering, and getting dressed. When the treatment team asks him about his condition, Mr. X turns to his wife to respond on his behalf. He is slow to speak and struggles to remember the details about his condition or the duration of his disability.

Mr. X is referred to a neurologist, based on cognitive impairment and gait disturbance, who orders an MRI scan of the brain that shows enlarged ventricles and some cortical atrophy (Figure 1). A neurosurgeon removes approximately 25 mL of CSF as a diagnostic and therapeutic intervention.

Videography of his ambulation, recorded before and after the CSF tap, shows slight improvement in gait. Mr. X is seen by a neurosurgery team, who recommends that he receive a ventriculoperitoneal shunt for hydrocephalus.

While awaiting surgical treatment, Mr. X’s psychotropic medications are withheld, and he is closely monitored for reemergence of psychiatric symptoms. Mr. X shows gradual but significant improvement in his gait within 8 to 10 weeks. His dyskinesia improves significantly, as does his cognitive function.

What additional testing is recommended beyond MRI?
   a) complete blood count with differential
   b) blood ammonia level
   c) neuropsychological evaluation
   d) APOE-e4 genetic testing
   e) all the above

The authors’ observations
Normal pressure hydrocephalus (NPH) is characterized by gait disturbance, dementia, or urinary incontinence that is associated with dilation of the brain’s ventricular system with normal opening CSF pressure (Table 1). Several studies have reported that patients with NPH might exhibit neuropsychiatric symptoms,^1-4 possibly related to alterations in central neurotransmitter activity.⁵ NPH patients could present with symptoms reflecting frontal dominance (Table 2,^6-9). In a study of 35 patients with idiopathic NPH in a tertiary hospital in Brazil,¹⁰ psychiatric symptoms were established by formal psychiatric evaluation in 71%, notably anxiety, depression, and psychotic syndromes.

Mechanism responsible for gait disturbance
Gait disturbance typically is the first and most prominent symptom of the NPH triad. Gait disturbance in NPH can be progressive because of expansion of the ventricular system, mainly the lateral ventricles, leading to pressure on the corticospinal motor fibers descending to the lumbosacral spinal cord. Although there is no one type of gait disturbance indicative of NPH, it often is described as shuffling, magnetic, and wide-based.¹¹ Slowness of gait and gait imbalance or disequilibrium are common and more likely to respond to shunting.¹²

Drug-induced gait disturbance is likely to result in parkinsonian symptoms.¹³ A possible mechanism involves inhibition of neurite outgrowth. Qian et al¹⁴ found that therapeutic plasma levels of valproic acid reduced cell proliferation and neurite outgrowth, using SY5Y neuroblastoma cells as a neuronal model. Researchers also reported that valproic acid reduced mRNA and protein levels of neurofilament 160; a possible mechanistic explanation involves inhibition of neurite outgrowth that leads to gait disturbance. These effects reversed 2 days after stopping valproic acid.

Another possible mechanism is related to γ-aminobutyric acid (GABA) pathway disturbance leading to dopamine inhibition. This postulates that valproic acid or a metabolite of valproic acid, such as Δ-2-valproate, which may be a more potent inhibitor of the GABA-degrading enzyme than valproic acid, could cause a transient inhibitory effect on dopaminergic pathways.¹⁵

Mechanism of mood stabilizer action
Valproic acid is incorporated into neuronal membranes in a saturable manner and appears to displace naturally occurring branched-chain phospholipids.¹⁶ Chronic valproic acid use reduces protein kinase C (PKC) activity in patients with mania.¹⁷ Elevated PKC activity has been observed in patients with mania and in animal models of mania.¹⁸ Valproic acid has antioxidant effects and has reversed early DNA damage caused by amphetamine in an animal model of mania.¹⁹ Valproic acid and lithium both reduce inositol biosynthesis; the mechanism of action for valproic acid is unique, however, resulting from decreased myo-inositol-1-phosphate synthase inhibition.²⁰

There is not a strong correlation between serum valproic acid levels and antimanic effects, but levels in the range of 50 to 150 μg/mL generally are required for therapeutic effect.

Neuropsychiatric adverse effects of valproic acid
With most antiepileptic drugs, adverse effects mainly are dose-related and include sedation, drowsiness, incoordination, nausea, and fatigue. Careful dose titration can reduce the risk of these adverse effects. Research on mothers with epilepsy has shown an association between valproic acid exposure in utero and lower IQ and a higher prevalence of autism spectrum disorder in children.²¹

Adverse effects on cognitive functioning are infrequent; valproic acid improves cognition in select patients.²² In a 20-week randomized, observer-blinded, parallel-group trial, adding valproic acid to carbamazepine resulted in improvement in short-term verbal memory.²³ In a group of geriatric patients (mean age 77 years), no adverse cognitive effects were observed with valproic acid use.²⁴

Masmoudi et al²⁵ evaluated dementia and extrapyramidal symptoms associated with long-term valproic acid use. Among the side effects attributed to valproic acid, parkinsonian syndromes and cognitive impairment were not commonly reported. In a prospective study, Armon et al²⁶ found several abnormal symptoms and signs related to motor and cognitive function impairment in patients on long-term valproic acid therapy. These side effects might be related to a disturbance in the GABAergic pathways in the basal ganglia system. Note that Δ2-valproic acid, a metabolite of valproic acid, preferentially accumulates in select areas of the brain: the substantia nigra, superior and inferior colliculus, hippocampus, and medulla.

What is the next best step in management?
   a) surgically implant a shunt
   b) adjust the dosage of valproic acid
   c) switch to monotherapy
   d) switch to an alternative psychotropic medication
   e) provide observation and follow-up

The authors’ observations
Unusual appearances of NPH symptoms could hinder early diagnosis and proper treatment. Mr. X was taking valproic acid and venlafaxine for bipolar depression, without any complaints, and was asymptomatic for 8 years—until he developed symptoms of NPH.

In patients who have what can be considered classic symptoms of NPH and are taking valproic acid, consider discontinuing the drug on a trial basis before resorting to a more invasive procedure. This strategy could significantly reduce the cost of health care and contribute to the overall well-being of the patient.

NPH associated with chronic valproic acid use is rare, supported by only 1 case report¹³ in our literature review. Based on the severity of symptoms and chance for misdiagnosis, it is essential to identify such cases and differentiate them from others with underlying neuropathology or a secondary cause, such as age-related dementia or Parkinson’s disease, to avoid the burden of unnecessary diagnostic testing on the patient and physician.

Family history also is important in cases presenting with sensorineural hearing loss,¹³ which follows a pattern of maternal inheritance. Consider genetic testing in such cases.

Earlier diagnosis of valproic acid-induced NPH enables specific interventions and treatment. Treatment of NPH includes one of several forms of shunting and appropriate neuroleptic therapy for behavioral symptoms. Although there is a significant risk (40% to 50%) of psychiatric and behavioral symptoms as a shunt-related complication, as many as 60% of operated patients showed objective improvement. This makes the diagnosis of NPH, and referral for appropriate surgical treatment of NPH, an important challenge to the psychiatrist.²⁷

OUTCOME No reemergence
Findings on a repeat MRI 2.5 months after the CSF tap remain unchanged. Surgery is cancelled and medications are discontinued. Mr. X is advised to continue outpatient follow-up for monitoring of re-emerging symptoms of bipolar depression.

At a follow-up visit, Mr. X’s condition has returned to baseline. He ambulates spontaneously and responds to questions without evidence of cognitive deficit. He no longer is incontinent.

Follow-up MRI is performed and indicated normal results.

Neuropsychological testing is deemed unnecessary because Mr. X has fully recovered from cognitive clouding (and there would be no baseline results against which to compare current findings). Based on the medication history, the team concludes that prolonged use of valproic acid may have led to development of signs and symptoms of an NPH-like syndrome.

The authors’ observations
Awareness of an association of NPH with neuropsychiatric changes is important for clinical psychiatrists because early assessment and appropriate intervention can prevent associated long-term complications. Valproic acid is considered a relatively safe medication with few neurologic side effects, but the association of an NPH-like syndrome with chronic valproic acid use, documented in this case report, emphasizes the importance of studying long-term consequences of using valproic acid in geriatric patients. More such case reports need to be evaluated to study the association of neuropsychiatric complications with chronic valproic use in the geriatric population.

Mr. X apparently had cerebral atrophy with enlarged ventricles that was consistently evident for 10 years (Figure 2), although he has been maintained on valproic acid for 8 years. What is intriguing in this case is that discontinuing valproic acid relieved the triad of incontinence, imbalance, and memory deficits indicative of NPH. Mr. X remains free of these symptoms.

CASE Rapid decline
Mr. X, age 67, is a businessman who had a diagnosis of bipolar depression 8 years ago, and who is being evaluated now for new-onset cognitive impairment, gait disturbance that resembles child-like steps, dyskinesia, and urinary incontinence of approximately 2 months’ duration. He has been treated for bipolar depression with valproic acid, 1,000 mg/d, and venlafaxine, 150 mg/d, without complaint until now, since the diagnosis was made 8 years ago. The serum valproic acid level, tested every month, is within the therapeutic range; liver function tests, ordered every 6 months, also are within the normal range.

Mr. X has become confined to his bedroom and needs assistance to walk. He has to be lifted to a standing position by 2 attendants, who bear his weight and instruct him to take one step at a time. He wears a diaper and needs assistance shaving, showering, and getting dressed. When the treatment team asks him about his condition, Mr. X turns to his wife to respond on his behalf. He is slow to speak and struggles to remember the details about his condition or the duration of his disability.

Mr. X is referred to a neurologist, based on cognitive impairment and gait disturbance, who orders an MRI scan of the brain that shows enlarged ventricles and some cortical atrophy (Figure 1). A neurosurgeon removes approximately 25 mL of CSF as a diagnostic and therapeutic intervention.

Videography of his ambulation, recorded before and after the CSF tap, shows slight improvement in gait. Mr. X is seen by a neurosurgery team, who recommends that he receive a ventriculoperitoneal shunt for hydrocephalus.

While awaiting surgical treatment, Mr. X’s psychotropic medications are withheld, and he is closely monitored for reemergence of psychiatric symptoms. Mr. X shows gradual but significant improvement in his gait within 8 to 10 weeks. His dyskinesia improves significantly, as does his cognitive function.

What additional testing is recommended beyond MRI?
   a) complete blood count with differential
   b) blood ammonia level
   c) neuropsychological evaluation
   d) APOE-e4 genetic testing
   e) all the above

The authors’ observations
Normal pressure hydrocephalus (NPH) is characterized by gait disturbance, dementia, or urinary incontinence that is associated with dilation of the brain’s ventricular system with normal opening CSF pressure (Table 1). Several studies have reported that patients with NPH might exhibit neuropsychiatric symptoms,^1-4 possibly related to alterations in central neurotransmitter activity.⁵ NPH patients could present with symptoms reflecting frontal dominance (Table 2,^6-9). In a study of 35 patients with idiopathic NPH in a tertiary hospital in Brazil,¹⁰ psychiatric symptoms were established by formal psychiatric evaluation in 71%, notably anxiety, depression, and psychotic syndromes.

Mechanism responsible for gait disturbance
Gait disturbance typically is the first and most prominent symptom of the NPH triad. Gait disturbance in NPH can be progressive because of expansion of the ventricular system, mainly the lateral ventricles, leading to pressure on the corticospinal motor fibers descending to the lumbosacral spinal cord. Although there is no one type of gait disturbance indicative of NPH, it often is described as shuffling, magnetic, and wide-based.¹¹ Slowness of gait and gait imbalance or disequilibrium are common and more likely to respond to shunting.¹²

Drug-induced gait disturbance is likely to result in parkinsonian symptoms.¹³ A possible mechanism involves inhibition of neurite outgrowth. Qian et al¹⁴ found that therapeutic plasma levels of valproic acid reduced cell proliferation and neurite outgrowth, using SY5Y neuroblastoma cells as a neuronal model. Researchers also reported that valproic acid reduced mRNA and protein levels of neurofilament 160; a possible mechanistic explanation involves inhibition of neurite outgrowth that leads to gait disturbance. These effects reversed 2 days after stopping valproic acid.

Another possible mechanism is related to γ-aminobutyric acid (GABA) pathway disturbance leading to dopamine inhibition. This postulates that valproic acid or a metabolite of valproic acid, such as Δ-2-valproate, which may be a more potent inhibitor of the GABA-degrading enzyme than valproic acid, could cause a transient inhibitory effect on dopaminergic pathways.¹⁵

Mechanism of mood stabilizer action
Valproic acid is incorporated into neuronal membranes in a saturable manner and appears to displace naturally occurring branched-chain phospholipids.¹⁶ Chronic valproic acid use reduces protein kinase C (PKC) activity in patients with mania.¹⁷ Elevated PKC activity has been observed in patients with mania and in animal models of mania.¹⁸ Valproic acid has antioxidant effects and has reversed early DNA damage caused by amphetamine in an animal model of mania.¹⁹ Valproic acid and lithium both reduce inositol biosynthesis; the mechanism of action for valproic acid is unique, however, resulting from decreased myo-inositol-1-phosphate synthase inhibition.²⁰

There is not a strong correlation between serum valproic acid levels and antimanic effects, but levels in the range of 50 to 150 μg/mL generally are required for therapeutic effect.

Neuropsychiatric adverse effects of valproic acid
With most antiepileptic drugs, adverse effects mainly are dose-related and include sedation, drowsiness, incoordination, nausea, and fatigue. Careful dose titration can reduce the risk of these adverse effects. Research on mothers with epilepsy has shown an association between valproic acid exposure in utero and lower IQ and a higher prevalence of autism spectrum disorder in children.²¹

Adverse effects on cognitive functioning are infrequent; valproic acid improves cognition in select patients.²² In a 20-week randomized, observer-blinded, parallel-group trial, adding valproic acid to carbamazepine resulted in improvement in short-term verbal memory.²³ In a group of geriatric patients (mean age 77 years), no adverse cognitive effects were observed with valproic acid use.²⁴

Masmoudi et al²⁵ evaluated dementia and extrapyramidal symptoms associated with long-term valproic acid use. Among the side effects attributed to valproic acid, parkinsonian syndromes and cognitive impairment were not commonly reported. In a prospective study, Armon et al²⁶ found several abnormal symptoms and signs related to motor and cognitive function impairment in patients on long-term valproic acid therapy. These side effects might be related to a disturbance in the GABAergic pathways in the basal ganglia system. Note that Δ2-valproic acid, a metabolite of valproic acid, preferentially accumulates in select areas of the brain: the substantia nigra, superior and inferior colliculus, hippocampus, and medulla.

What is the next best step in management?
   a) surgically implant a shunt
   b) adjust the dosage of valproic acid
   c) switch to monotherapy
   d) switch to an alternative psychotropic medication
   e) provide observation and follow-up

The authors’ observations
Unusual appearances of NPH symptoms could hinder early diagnosis and proper treatment. Mr. X was taking valproic acid and venlafaxine for bipolar depression, without any complaints, and was asymptomatic for 8 years—until he developed symptoms of NPH.

In patients who have what can be considered classic symptoms of NPH and are taking valproic acid, consider discontinuing the drug on a trial basis before resorting to a more invasive procedure. This strategy could significantly reduce the cost of health care and contribute to the overall well-being of the patient.

NPH associated with chronic valproic acid use is rare, supported by only 1 case report¹³ in our literature review. Based on the severity of symptoms and chance for misdiagnosis, it is essential to identify such cases and differentiate them from others with underlying neuropathology or a secondary cause, such as age-related dementia or Parkinson’s disease, to avoid the burden of unnecessary diagnostic testing on the patient and physician.

Family history also is important in cases presenting with sensorineural hearing loss,¹³ which follows a pattern of maternal inheritance. Consider genetic testing in such cases.

Earlier diagnosis of valproic acid-induced NPH enables specific interventions and treatment. Treatment of NPH includes one of several forms of shunting and appropriate neuroleptic therapy for behavioral symptoms. Although there is a significant risk (40% to 50%) of psychiatric and behavioral symptoms as a shunt-related complication, as many as 60% of operated patients showed objective improvement. This makes the diagnosis of NPH, and referral for appropriate surgical treatment of NPH, an important challenge to the psychiatrist.²⁷

OUTCOME No reemergence
Findings on a repeat MRI 2.5 months after the CSF tap remain unchanged. Surgery is cancelled and medications are discontinued. Mr. X is advised to continue outpatient follow-up for monitoring of re-emerging symptoms of bipolar depression.

At a follow-up visit, Mr. X’s condition has returned to baseline. He ambulates spontaneously and responds to questions without evidence of cognitive deficit. He no longer is incontinent.

Follow-up MRI is performed and indicated normal results.

Neuropsychological testing is deemed unnecessary because Mr. X has fully recovered from cognitive clouding (and there would be no baseline results against which to compare current findings). Based on the medication history, the team concludes that prolonged use of valproic acid may have led to development of signs and symptoms of an NPH-like syndrome.

The authors’ observations
Awareness of an association of NPH with neuropsychiatric changes is important for clinical psychiatrists because early assessment and appropriate intervention can prevent associated long-term complications. Valproic acid is considered a relatively safe medication with few neurologic side effects, but the association of an NPH-like syndrome with chronic valproic acid use, documented in this case report, emphasizes the importance of studying long-term consequences of using valproic acid in geriatric patients. More such case reports need to be evaluated to study the association of neuropsychiatric complications with chronic valproic use in the geriatric population.

Mr. X apparently had cerebral atrophy with enlarged ventricles that was consistently evident for 10 years (Figure 2), although he has been maintained on valproic acid for 8 years. What is intriguing in this case is that discontinuing valproic acid relieved the triad of incontinence, imbalance, and memory deficits indicative of NPH. Mr. X remains free of these symptoms.

CASE Rapid decline
Mr. X, age 67, is a businessman who had a diagnosis of bipolar depression 8 years ago, and who is being evaluated now for new-onset cognitive impairment, gait disturbance that resembles child-like steps, dyskinesia, and urinary incontinence of approximately 2 months’ duration. He has been treated for bipolar depression with valproic acid, 1,000 mg/d, and venlafaxine, 150 mg/d, without complaint until now, since the diagnosis was made 8 years ago. The serum valproic acid level, tested every month, is within the therapeutic range; liver function tests, ordered every 6 months, also are within the normal range.

Mr. X has become confined to his bedroom and needs assistance to walk. He has to be lifted to a standing position by 2 attendants, who bear his weight and instruct him to take one step at a time. He wears a diaper and needs assistance shaving, showering, and getting dressed. When the treatment team asks him about his condition, Mr. X turns to his wife to respond on his behalf. He is slow to speak and struggles to remember the details about his condition or the duration of his disability.

Mr. X is referred to a neurologist, based on cognitive impairment and gait disturbance, who orders an MRI scan of the brain that shows enlarged ventricles and some cortical atrophy (Figure 1). A neurosurgeon removes approximately 25 mL of CSF as a diagnostic and therapeutic intervention.

Videography of his ambulation, recorded before and after the CSF tap, shows slight improvement in gait. Mr. X is seen by a neurosurgery team, who recommends that he receive a ventriculoperitoneal shunt for hydrocephalus.

While awaiting surgical treatment, Mr. X’s psychotropic medications are withheld, and he is closely monitored for reemergence of psychiatric symptoms. Mr. X shows gradual but significant improvement in his gait within 8 to 10 weeks. His dyskinesia improves significantly, as does his cognitive function.

What additional testing is recommended beyond MRI?
   a) complete blood count with differential
   b) blood ammonia level
   c) neuropsychological evaluation
   d) APOE-e4 genetic testing
   e) all the above

The authors’ observations
Normal pressure hydrocephalus (NPH) is characterized by gait disturbance, dementia, or urinary incontinence that is associated with dilation of the brain’s ventricular system with normal opening CSF pressure (Table 1). Several studies have reported that patients with NPH might exhibit neuropsychiatric symptoms,^1-4 possibly related to alterations in central neurotransmitter activity.⁵ NPH patients could present with symptoms reflecting frontal dominance (Table 2,^6-9). In a study of 35 patients with idiopathic NPH in a tertiary hospital in Brazil,¹⁰ psychiatric symptoms were established by formal psychiatric evaluation in 71%, notably anxiety, depression, and psychotic syndromes.

Mechanism responsible for gait disturbance
Gait disturbance typically is the first and most prominent symptom of the NPH triad. Gait disturbance in NPH can be progressive because of expansion of the ventricular system, mainly the lateral ventricles, leading to pressure on the corticospinal motor fibers descending to the lumbosacral spinal cord. Although there is no one type of gait disturbance indicative of NPH, it often is described as shuffling, magnetic, and wide-based.¹¹ Slowness of gait and gait imbalance or disequilibrium are common and more likely to respond to shunting.¹²

Drug-induced gait disturbance is likely to result in parkinsonian symptoms.¹³ A possible mechanism involves inhibition of neurite outgrowth. Qian et al¹⁴ found that therapeutic plasma levels of valproic acid reduced cell proliferation and neurite outgrowth, using SY5Y neuroblastoma cells as a neuronal model. Researchers also reported that valproic acid reduced mRNA and protein levels of neurofilament 160; a possible mechanistic explanation involves inhibition of neurite outgrowth that leads to gait disturbance. These effects reversed 2 days after stopping valproic acid.

Another possible mechanism is related to γ-aminobutyric acid (GABA) pathway disturbance leading to dopamine inhibition. This postulates that valproic acid or a metabolite of valproic acid, such as Δ-2-valproate, which may be a more potent inhibitor of the GABA-degrading enzyme than valproic acid, could cause a transient inhibitory effect on dopaminergic pathways.¹⁵

Mechanism of mood stabilizer action
Valproic acid is incorporated into neuronal membranes in a saturable manner and appears to displace naturally occurring branched-chain phospholipids.¹⁶ Chronic valproic acid use reduces protein kinase C (PKC) activity in patients with mania.¹⁷ Elevated PKC activity has been observed in patients with mania and in animal models of mania.¹⁸ Valproic acid has antioxidant effects and has reversed early DNA damage caused by amphetamine in an animal model of mania.¹⁹ Valproic acid and lithium both reduce inositol biosynthesis; the mechanism of action for valproic acid is unique, however, resulting from decreased myo-inositol-1-phosphate synthase inhibition.²⁰

There is not a strong correlation between serum valproic acid levels and antimanic effects, but levels in the range of 50 to 150 μg/mL generally are required for therapeutic effect.

Neuropsychiatric adverse effects of valproic acid
With most antiepileptic drugs, adverse effects mainly are dose-related and include sedation, drowsiness, incoordination, nausea, and fatigue. Careful dose titration can reduce the risk of these adverse effects. Research on mothers with epilepsy has shown an association between valproic acid exposure in utero and lower IQ and a higher prevalence of autism spectrum disorder in children.²¹

Adverse effects on cognitive functioning are infrequent; valproic acid improves cognition in select patients.²² In a 20-week randomized, observer-blinded, parallel-group trial, adding valproic acid to carbamazepine resulted in improvement in short-term verbal memory.²³ In a group of geriatric patients (mean age 77 years), no adverse cognitive effects were observed with valproic acid use.²⁴

Masmoudi et al²⁵ evaluated dementia and extrapyramidal symptoms associated with long-term valproic acid use. Among the side effects attributed to valproic acid, parkinsonian syndromes and cognitive impairment were not commonly reported. In a prospective study, Armon et al²⁶ found several abnormal symptoms and signs related to motor and cognitive function impairment in patients on long-term valproic acid therapy. These side effects might be related to a disturbance in the GABAergic pathways in the basal ganglia system. Note that Δ2-valproic acid, a metabolite of valproic acid, preferentially accumulates in select areas of the brain: the substantia nigra, superior and inferior colliculus, hippocampus, and medulla.

What is the next best step in management?
   a) surgically implant a shunt
   b) adjust the dosage of valproic acid
   c) switch to monotherapy
   d) switch to an alternative psychotropic medication
   e) provide observation and follow-up

The authors’ observations
Unusual appearances of NPH symptoms could hinder early diagnosis and proper treatment. Mr. X was taking valproic acid and venlafaxine for bipolar depression, without any complaints, and was asymptomatic for 8 years—until he developed symptoms of NPH.

In patients who have what can be considered classic symptoms of NPH and are taking valproic acid, consider discontinuing the drug on a trial basis before resorting to a more invasive procedure. This strategy could significantly reduce the cost of health care and contribute to the overall well-being of the patient.

NPH associated with chronic valproic acid use is rare, supported by only 1 case report¹³ in our literature review. Based on the severity of symptoms and chance for misdiagnosis, it is essential to identify such cases and differentiate them from others with underlying neuropathology or a secondary cause, such as age-related dementia or Parkinson’s disease, to avoid the burden of unnecessary diagnostic testing on the patient and physician.

Family history also is important in cases presenting with sensorineural hearing loss,¹³ which follows a pattern of maternal inheritance. Consider genetic testing in such cases.

Earlier diagnosis of valproic acid-induced NPH enables specific interventions and treatment. Treatment of NPH includes one of several forms of shunting and appropriate neuroleptic therapy for behavioral symptoms. Although there is a significant risk (40% to 50%) of psychiatric and behavioral symptoms as a shunt-related complication, as many as 60% of operated patients showed objective improvement. This makes the diagnosis of NPH, and referral for appropriate surgical treatment of NPH, an important challenge to the psychiatrist.²⁷

OUTCOME No reemergence
Findings on a repeat MRI 2.5 months after the CSF tap remain unchanged. Surgery is cancelled and medications are discontinued. Mr. X is advised to continue outpatient follow-up for monitoring of re-emerging symptoms of bipolar depression.

At a follow-up visit, Mr. X’s condition has returned to baseline. He ambulates spontaneously and responds to questions without evidence of cognitive deficit. He no longer is incontinent.

Follow-up MRI is performed and indicated normal results.

Neuropsychological testing is deemed unnecessary because Mr. X has fully recovered from cognitive clouding (and there would be no baseline results against which to compare current findings). Based on the medication history, the team concludes that prolonged use of valproic acid may have led to development of signs and symptoms of an NPH-like syndrome.

The authors’ observations
Awareness of an association of NPH with neuropsychiatric changes is important for clinical psychiatrists because early assessment and appropriate intervention can prevent associated long-term complications. Valproic acid is considered a relatively safe medication with few neurologic side effects, but the association of an NPH-like syndrome with chronic valproic acid use, documented in this case report, emphasizes the importance of studying long-term consequences of using valproic acid in geriatric patients. More such case reports need to be evaluated to study the association of neuropsychiatric complications with chronic valproic use in the geriatric population.

Mr. X apparently had cerebral atrophy with enlarged ventricles that was consistently evident for 10 years (Figure 2), although he has been maintained on valproic acid for 8 years. What is intriguing in this case is that discontinuing valproic acid relieved the triad of incontinence, imbalance, and memory deficits indicative of NPH. Mr. X remains free of these symptoms.

CASE Light-headed
Mr. M, age 73, is a retired project manager who feels light-headed while walking his dog, causing him to go to the emergency depart­ment. His history is significant for hyperten­sion, coronary artery disease (CAD), 3-vessel coronary artery bypass graft surgery (CABG), hyperlipidemia, erectile dysfunction, open-angle glaucoma, hemiretinal vein occlusion, symptoms suggesting rapid eye-movement behavior disorder (RBD), and major depressive disorder (MDD).

The psychiatry consultation-liaison service is asked to help manage Mr. M’s psychiat­ric medications in the context of orthostatic hypotension and cognitive deficits.

What could be causing Mr. M’s symptoms?
   a) drug adverse effect
   b) progressive cardiovascular disease
   c) MDD
   d) all of the above

HISTORY Depression, heart disease
15 years ago. Mr. M experienced his first major depressive episode. His primary care physician (PCP) commented on a history of falling asleep while driving and 1 episode of sleepwalking. His depression was treated to remission with fluoxetine and methylphenidate (dosages were not recorded), the latter also addressed his falling asleep while driving.

5 years ago. Mr. M had another depres­sive episode characterized by anxiety, difficulty sleeping, and irritability. He also described chest pain; a cardiac work-up revealed extensive CAD, which led to 3-vessel CABG later that year. He also reported dizziness upon standing, which was treated with compression stockings and an increase in sodium intake.

Mr. M continued to express feelings of depression. His cardiologist started him on par­oxetine, 10 mg/d, which he took for 2 months and decided to stop because he felt better. He declined psychiatric referral.

4 years ago. Mr. M’s PCP referred him to a psychiatrist for depressed mood, anhedonia, decreased appetite, decreased energy, and dif­ficulty concentrating. Immediate and delayed recall were found to be intact. The psychiatrist diagnosed MDD and Mr. M started escitalopram, 5 mg/d, titrated to 15 mg/d, and trazodone, 50 mg/d.

After starting treatment, Mr. M reported decreased libido. Sustained-release bupropion, 150 mg/d, was added to boost the effects of escitalopram and counteract sexual side effects.

At follow-up, Mr. M reported that his depres­sive symptoms and libido had improved, but that he had been experiencing unsteady gait when getting out of his car, which he had been noticing “for a while”—before he began trazo­done. Mr. M was referred to his PCP, who attrib­uted his symptoms to orthostasis. No treatment was indicated at the time because Mr. M’s light­headedness had resolved.

3 years ago. Mr. M reported a syncopal attack and continued “dizziness.” His PCP pre­scribed fludrocortisone, 0.1 mg/d, later to be dosed 0.2 mg/d, and symptoms improved.

Although Mr. M had a history of orthostatic hypotension, he was later noted to have supine hypertension. Mr. M’s PCP was concerned that fludrocortisone could be causing the supine hypertension but that decreasing the dosage would cause his orthostatic hypotension to return.

The PCP also was concerned that the psy­chiatric medications (escitalopram, trazodone, and bupropion) could be causing orthostasis. There was discussion among Mr. M, his PCP, and his psychiatrist of stopping the psycho­tropics to see if the symptoms would remit; however, because of concerns about Mr. M’s depression, the medications were continued. Mr. M monitored his blood pressure at home and was referred to a neurologist for work-up of potential autonomic dysfunction.

Shortly afterward, Mr. M reported intermit­tent difficulty keeping track of his thoughts and finishing sentences. His psychiatrist ordered an MRI, which showed chronic small vessel ischemic changes, and started him on donepezil, 5 mg/d.

Neuropsychological testing revealed decreased processing speed and poor rec­ognition memory; otherwise, results showed above-average intellectual ability and average or above-average performance in measures of language, attention, visuospatial/construc­tional functions, and executive functions—a pattern typically attributable to psychogenic factors, such as depression.

Mr. M reported to his neurologist that he for­gets directions while driving but can focus bet­ter if he makes a conscious effort. Physical exam was significant hypotension; flat affect; deficits in concentration and short-term recall; mild impairment of Luria motor sequence (com­posed of a go/no-go and a reciprocal motor task); and vertical and horizontal saccades.¹

Mr. M consulted with an ophthalmologist for anterior iridocyclitis and ocular hypertension, which was controlled with travoprost. He con­tinued to experience trouble with his vision and was given a diagnosis of right inferior hemireti­nal vein occlusion, macular edema, and sus­pected glaucoma. Subsequent notes recorded a history of Posner-Schlossman syndrome (a disease characterized by recurrent attacks of increased intraocular pressure in 1 eye with concomitant anterior chamber inflammation). His vision deteriorated until he was diagnosed with ocular hypertension, open-angle glau­coma, and dermatochalasis.

The authors’ observations
Involvement of multiple specialties in a patient’s care brings to question one’s philosophy on medical diagnosis. Interdisciplinary communication would seem to promote the principle of diagnostic parsimony, or Occam’s razor, which sug­gests a unifying diagnosis to explain all of the patient’s symptoms. Lack of communi­cation might favor Hickam’s dictum, which states that “patients can have as many dis­eases as they damn well please.”

HISTORY Low energy, forgetfulness
2 years ago. Mr. M noticed low energy and motivation. He continued to work full-time but thought that it was taking him longer to get work done. He was tapered off escitalo­pram and started on desvenlafaxine, 50 mg/d; donepezil was increased to 10 mg/d.

The syncopal episodes resolved but blood pressure measured at home averaged 150/70 mm Hg. Mr. M was advised to decrease fludrocortisone from 0.2 mg/d to 0.1 mg/d. He tolerated the change and blood pressure measured at home dropped on average to 120 to 130/70 mm Hg.

1 year ago. Mr. M reported that his mem­ory loss had become worse. He perceived hav­ing more stress because of forgetfulness and visual difficulties, which had led him to stop driving at night.

At a follow-up appointment with his psy­chiatrist, Mr. M reported that, first, he had not tapered escitalopram as discussed and, second, he forgot to increase the dosage of desvenlafaxine. A home blood pressure log revealed consistent hypotension; the psychia­trist was concerned that hypotension could be the cause of concentration difficulties and malaise. The psychiatrist advised Mr. M to fol­low-up with his PCP and neurologist.

Current admission. Shortly after the visit to the psychiatrist, Mr. M presented to the emergency department for increased synco­pal events. Work-up was negative for a car­diac cause. A cosyntropin stimulation test was negative, showing that adrenal insufficiency did not cause his orthostatic hypotension. Chart review showed he had been having blood pressure problems for many years, inde­pendent of antidepressants. Physical exam revealed lower extremity ataxia and a bilateral extensor plantar reflex.

What diagnosis explains Mr. M’s symptoms?
   a) Parkinson’s disease
   b) multiple system atrophy (MSA)
   c) depression due to a general medical condition
  d) dementia

The authors’ observations
MSA, previously referred to as Shy-Drager syndrome, is a rare, rapidly progressive neurodegenerative disorder with an esti­mated prevalence of 3.7 cases for every 100,000 people worldwide.² MSA primarily affects middle-aged patients; because it has no cure, most patients die in 7 to 10 years.³

MSA has 2 clinical variants^4,5:
   • parkinsonian type (MSA-P), charac­terized by striatonigral degeneration and increased spasticity
   • cerebellar type (MSA-C), character­ized by more autonomic dysfunction.

MSA has a range of symptoms, mak­ing it a challenging diagnosis (Table).⁶ Although psychiatric symptoms are not part of the diagnostic criteria, they can aid in its diagnosis. In Mr. M’s case, depres­sion, anxiety, orthostatic hypotension, and ataxia support a diagnosis of MSA.

Gilman et al⁶ delineated 3 diagnostic categories for MSA: definite MSA, prob­able MSA, and possible MSA. Clinical cri­teria shared by the 3 diagnostic categories are sporadic and progressive onset after age 30.

Definite MSA requires “neuropathological findings of widespread and abundant CNS alpha-synuclein-positive glial cytoplasmic inclusions,” along with “neurodegenera­tive changes in striatonigral or olivoponto­cerebellar structures” at autopsy.⁶

Probable MSA. Without autopsy findings required for definite MSA, the next most specific diagnostic category is probable MSA. Probable MSA also specifies that the patient show either autonomic fail­ure involving urinary incontinence—this includes erectile dysfunction in men—or, if autonomic failure is absent, orthostatic hypotension within 3 minutes of standing by at least 30 mm Hg systolic pressure or 15 mm Hg diastolic pressure.

Possible MSA has less stringent crite­ria for orthostatic hypotension. The cat­egory includes patients who have only 1 symptom that suggests autonomic failure. Criteria for possible MSA include parkin­sonism or a cerebellar syndrome in addition to symptoms of MSA listed in the Table, whereas probable MSA has specific crite­ria of either a poorly levodopa-responsive parkinsonism (MSA-P) or a cerebellar syn­drome (MSA-C). In addition to having par­kinsonism or a cerebellar syndrome, and 1 sign of autonomic failure or orthostatic hypotension, patients also must have ≥1 additional feature to be assigned a diagno­sis of possible MSA, including:
   • rapidly progressive parkinsonism
   • poor response to levodopa
   • postural instability within 3 years of motor onset
   • gait ataxia, cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction
   • dysphagia within 5 years of motor onset
   • atrophy on MRI of putamen, mid­dle cerebellar peduncle, pons, or cerebellum
   • hypometabolism on fluorodeoxyglucose- PET in putamen, brainstem, or cerebellum.⁶

Diagnosing MSA can be challenging because its features are similar to those of many other disorders. Nonetheless, Gilman et al6 lists specific criteria for prob­able MSA, including autonomic dysfunc­tion, orthostatic hypotension, and either parkinsonism or cerebellar syndrome symptoms. Although a definite MSA diag­nosis only can be made by postmortem brain specimen analysis, Osaki et al⁷ found that a probable MSA diagnosis has a posi­tive predictive value of 92% with a sensi­tivity of 22% for definite MSA.

Mr. M’s symptoms were consistent with a diagnosis of probable MSA, cerebellar type (Figure).

Psychiatric manifestations of MSA
There are a few case reports of depression identified early in patients who were later given a diagnosis of MSA.⁸

Depression. In a study by Benrud-Larson et al⁹ (N = 99), 49% of patients who had MSA reported moderate or severe depres­sion, as indicated by a score of ≥17 on the Beck Depression Inventory (BDI); 80% reported at least mild depression (BDI ≥10, mean 17.0, standard deviation, 8.7).

In a similar study, by Balas et al,¹⁰ depres­sion was reported as a common symptom and was statistically significant in MSA-P patients compared with controls (P = .013).

Anxiety, another symptom that was reported by Mr. M, is another psychiat­ric manifestation described by Balas et al¹⁰ and Chang et al.¹¹ Balas et al¹⁰ noted that MSA-C and MSA-P patients had sig­nificantly more state anxiety (P = .009 and P = .022, respectively) compared with con­trols, although Chang et al¹¹ noted higher anxiety scores in MSA-C patients com­pared with controls and MSA-P patients (P < .01).

Balas et al¹⁰ hypothesized that anxiety and depression contribute to cognitive decline; their study showed that MSA-C patients had difficulty learning new ver­bal information (P < .022) and controlling attention (P < .023). Mr. M exhibited some of these cognitive difficulties in his reports of losing track of conversations, forgetting the topic of a conversation when speaking, trouble focusing, and difficulty concentrat­ing when driving.

Mr. M had depression and anxiety well before onset of autonomic dysfunction (orthostatic hypotension and erectile dys­function), which eventually led to an MSA diagnosis. Psychiatrists should under­stand additional manifestations of MSA so that they can use psychiatric symptoms to identify these conditions in their patients. One of the most well-known and early manifestations of MSA is autonomic dys­function; among men, another early sign is erectile dysfunction.⁶ Our patient also exhibited other less well-known symptoms linked to MSA and autonomic dysregula­tion, including RBD and ocular symptoms (iridocyclitis, glaucoma, decreased visual acuity).

Rapid eye-movement behavior disorder. Psychiatrists should consider screen­ing for RBD during assessment of sleep problems. Identifying RBD is important because early studies have shown a strong association between RBD and develop­ment of a neurodegenerative disorder. Mr. M’s clinicians did not consider RBD, although his symptoms of sleepwalking and falling asleep while driving suggest a possible diagnosis. Also, considering this diagnosis would aid in diagnosing a synu­cleinopathy disorder because a higher incidence of RBD was noted in patients who developed synucleinopathy disor­ders (eg, Parkinson’s disease [PD] and dementia with Lewy bodies [DLB]) com­pared with patients who developed non-synucleinopathies (eg, frontotemporal dementia, corticobasal degeneration, pro­gressive supranuclear palsy, mild cogni­tive impairment, primary progressive aphasia, and posterior cortical atrophy) or tauopathies (eg, Alzheimer’s disease).¹²

Zanigni et al¹³ reported similar findings in a later study that classified patients with RBD as having idiopathic RBD (IRBD) or RBD sec­ondary to an underlying neurodegenerative disorder, particularly an α-synucleinopathy: PD, MSA, and DLB. Most IRBD patients developed 1 of the above mentioned neuro­degenerative disorders as long as 10 years after a diagnosis of RBD.

In a study by Iranzo et al,¹⁴ patients with MSA were noted to have more severe RBD compared with PD patients. Severity is illus­trated by greater periodic leg movements during sleep (P = .001), less total sleep time (P = .023), longer sleep onset latency (P = .023), and a higher percentage of REM sleep without atonia (RSWA, P = .001). McCarter et al¹⁵ also noted a higher inci­dence of RSWA in patients with MSA.

Patients with MSA might therefore be more likely to exhibit difficulty initiating and maintaining sleep and as having RSWA years before the MSA diagnosis.

Several psychotropics (eg, first-generation antipsychotics, tricyclic anti­depressants, lithium, benzodiazepines, carbamazepine, topiramate, and selective serotonin reuptake inhibitors) can cause adverse ocular effects, such as closed-angle glaucoma in predisposed persons and retinopathy.¹⁶ Therefore, it is important for psychiatrists to ask about ocular symptoms because they might be an early sign of auto­nomic dysfunction.

Posner and Schlossman¹⁷ theorized a causal relationship between autonomic dys­function and ocular diseases after studying a group of patients who had intermittent unilateral attacks of iridocyclitis and glau­coma (now known as Posner-Schlossman syndrome). They hypothesized that a cen­tral cause in the hypothalamus, combined with underlying autonomic dysregulation, could cause the intermittent attacks.

Gherghel et al¹⁸ noted a significant differ­ence in ocular blood flow and blood pres­sure in patients with primary open-angle glaucoma (POAG) compared with con­trols. Patients with POAG did not show an increase in blood pressure or ocular blood flow when challenged by cold water, which should have increased their sympathetic activity. Gherghel et al¹⁸ concluded that this indicated possible systemic autonomic dys­function in patients with POAG. In a study by Fischer et al,¹⁹ MSA patients also were noted to have significant loss of nasal reti­nal nerve fiber layer thickness vs controls (P < .05), leading to decreased peripheral vision sensitivity.

Bottom Line
Although psychiatric symptoms are not part of the diagnostic criteria for multiple system atrophy (MSA), they may serve as a clue to consider when they occur with other MSA symptoms. Evaluate the importance of psychiatric symptoms in terms of the whole picture of the patient. Although the diagnosis might not alter the patient’s course, it can allow family members to understand the patient’s condition and prepare for complications that will arise.

Related Resources
• The MSA Coalition. www.multiplesystematrophy.org.
• National Institute of Neurological Disorders and Stroke. Multiple system atrophy fact sheet. www.ninds.nih.gov/disorders/msa/detailmsa.htm.
• Wenning GK, Fanciulli A, eds. Multiple system atrophy. Vienna, Austria: Springer-Verlag Wien; 2014.

Drug Brand Names
Bupropion • Wellbutrin                Lithium • Eskalith, Lithobid
Carbamazepine • Tegretol           Methylphenidate • Ritalin
Desvenlafaxine • Pristiq              Paroxetine • Paxil
Donepezil • Aricept                     Travoprost • Travatan
Escitalopram • Lexapro               Trazodone • Desyrel, Oleptro
Fludrocortisone • Florinef            Topiramate • Topamax
Fluoxetine • Prozac

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

CASE Light-headed
Mr. M, age 73, is a retired project manager who feels light-headed while walking his dog, causing him to go to the emergency depart­ment. His history is significant for hyperten­sion, coronary artery disease (CAD), 3-vessel coronary artery bypass graft surgery (CABG), hyperlipidemia, erectile dysfunction, open-angle glaucoma, hemiretinal vein occlusion, symptoms suggesting rapid eye-movement behavior disorder (RBD), and major depressive disorder (MDD).

The psychiatry consultation-liaison service is asked to help manage Mr. M’s psychiat­ric medications in the context of orthostatic hypotension and cognitive deficits.

What could be causing Mr. M’s symptoms?
   a) drug adverse effect
   b) progressive cardiovascular disease
   c) MDD
   d) all of the above

HISTORY Depression, heart disease
15 years ago. Mr. M experienced his first major depressive episode. His primary care physician (PCP) commented on a history of falling asleep while driving and 1 episode of sleepwalking. His depression was treated to remission with fluoxetine and methylphenidate (dosages were not recorded), the latter also addressed his falling asleep while driving.

5 years ago. Mr. M had another depres­sive episode characterized by anxiety, difficulty sleeping, and irritability. He also described chest pain; a cardiac work-up revealed extensive CAD, which led to 3-vessel CABG later that year. He also reported dizziness upon standing, which was treated with compression stockings and an increase in sodium intake.

Mr. M continued to express feelings of depression. His cardiologist started him on par­oxetine, 10 mg/d, which he took for 2 months and decided to stop because he felt better. He declined psychiatric referral.

4 years ago. Mr. M’s PCP referred him to a psychiatrist for depressed mood, anhedonia, decreased appetite, decreased energy, and dif­ficulty concentrating. Immediate and delayed recall were found to be intact. The psychiatrist diagnosed MDD and Mr. M started escitalopram, 5 mg/d, titrated to 15 mg/d, and trazodone, 50 mg/d.

After starting treatment, Mr. M reported decreased libido. Sustained-release bupropion, 150 mg/d, was added to boost the effects of escitalopram and counteract sexual side effects.

At follow-up, Mr. M reported that his depres­sive symptoms and libido had improved, but that he had been experiencing unsteady gait when getting out of his car, which he had been noticing “for a while”—before he began trazo­done. Mr. M was referred to his PCP, who attrib­uted his symptoms to orthostasis. No treatment was indicated at the time because Mr. M’s light­headedness had resolved.

3 years ago. Mr. M reported a syncopal attack and continued “dizziness.” His PCP pre­scribed fludrocortisone, 0.1 mg/d, later to be dosed 0.2 mg/d, and symptoms improved.

Although Mr. M had a history of orthostatic hypotension, he was later noted to have supine hypertension. Mr. M’s PCP was concerned that fludrocortisone could be causing the supine hypertension but that decreasing the dosage would cause his orthostatic hypotension to return.

The PCP also was concerned that the psy­chiatric medications (escitalopram, trazodone, and bupropion) could be causing orthostasis. There was discussion among Mr. M, his PCP, and his psychiatrist of stopping the psycho­tropics to see if the symptoms would remit; however, because of concerns about Mr. M’s depression, the medications were continued. Mr. M monitored his blood pressure at home and was referred to a neurologist for work-up of potential autonomic dysfunction.

Shortly afterward, Mr. M reported intermit­tent difficulty keeping track of his thoughts and finishing sentences. His psychiatrist ordered an MRI, which showed chronic small vessel ischemic changes, and started him on donepezil, 5 mg/d.

Neuropsychological testing revealed decreased processing speed and poor rec­ognition memory; otherwise, results showed above-average intellectual ability and average or above-average performance in measures of language, attention, visuospatial/construc­tional functions, and executive functions—a pattern typically attributable to psychogenic factors, such as depression.

Mr. M reported to his neurologist that he for­gets directions while driving but can focus bet­ter if he makes a conscious effort. Physical exam was significant hypotension; flat affect; deficits in concentration and short-term recall; mild impairment of Luria motor sequence (com­posed of a go/no-go and a reciprocal motor task); and vertical and horizontal saccades.¹

Mr. M consulted with an ophthalmologist for anterior iridocyclitis and ocular hypertension, which was controlled with travoprost. He con­tinued to experience trouble with his vision and was given a diagnosis of right inferior hemireti­nal vein occlusion, macular edema, and sus­pected glaucoma. Subsequent notes recorded a history of Posner-Schlossman syndrome (a disease characterized by recurrent attacks of increased intraocular pressure in 1 eye with concomitant anterior chamber inflammation). His vision deteriorated until he was diagnosed with ocular hypertension, open-angle glau­coma, and dermatochalasis.

The authors’ observations
Involvement of multiple specialties in a patient’s care brings to question one’s philosophy on medical diagnosis. Interdisciplinary communication would seem to promote the principle of diagnostic parsimony, or Occam’s razor, which sug­gests a unifying diagnosis to explain all of the patient’s symptoms. Lack of communi­cation might favor Hickam’s dictum, which states that “patients can have as many dis­eases as they damn well please.”

HISTORY Low energy, forgetfulness
2 years ago. Mr. M noticed low energy and motivation. He continued to work full-time but thought that it was taking him longer to get work done. He was tapered off escitalo­pram and started on desvenlafaxine, 50 mg/d; donepezil was increased to 10 mg/d.

The syncopal episodes resolved but blood pressure measured at home averaged 150/70 mm Hg. Mr. M was advised to decrease fludrocortisone from 0.2 mg/d to 0.1 mg/d. He tolerated the change and blood pressure measured at home dropped on average to 120 to 130/70 mm Hg.

1 year ago. Mr. M reported that his mem­ory loss had become worse. He perceived hav­ing more stress because of forgetfulness and visual difficulties, which had led him to stop driving at night.

At a follow-up appointment with his psy­chiatrist, Mr. M reported that, first, he had not tapered escitalopram as discussed and, second, he forgot to increase the dosage of desvenlafaxine. A home blood pressure log revealed consistent hypotension; the psychia­trist was concerned that hypotension could be the cause of concentration difficulties and malaise. The psychiatrist advised Mr. M to fol­low-up with his PCP and neurologist.

Current admission. Shortly after the visit to the psychiatrist, Mr. M presented to the emergency department for increased synco­pal events. Work-up was negative for a car­diac cause. A cosyntropin stimulation test was negative, showing that adrenal insufficiency did not cause his orthostatic hypotension. Chart review showed he had been having blood pressure problems for many years, inde­pendent of antidepressants. Physical exam revealed lower extremity ataxia and a bilateral extensor plantar reflex.

What diagnosis explains Mr. M’s symptoms?
   a) Parkinson’s disease
   b) multiple system atrophy (MSA)
   c) depression due to a general medical condition
  d) dementia

The authors’ observations
MSA, previously referred to as Shy-Drager syndrome, is a rare, rapidly progressive neurodegenerative disorder with an esti­mated prevalence of 3.7 cases for every 100,000 people worldwide.² MSA primarily affects middle-aged patients; because it has no cure, most patients die in 7 to 10 years.³

MSA has 2 clinical variants^4,5:
   • parkinsonian type (MSA-P), charac­terized by striatonigral degeneration and increased spasticity
   • cerebellar type (MSA-C), character­ized by more autonomic dysfunction.

MSA has a range of symptoms, mak­ing it a challenging diagnosis (Table).⁶ Although psychiatric symptoms are not part of the diagnostic criteria, they can aid in its diagnosis. In Mr. M’s case, depres­sion, anxiety, orthostatic hypotension, and ataxia support a diagnosis of MSA.

Gilman et al⁶ delineated 3 diagnostic categories for MSA: definite MSA, prob­able MSA, and possible MSA. Clinical cri­teria shared by the 3 diagnostic categories are sporadic and progressive onset after age 30.

Definite MSA requires “neuropathological findings of widespread and abundant CNS alpha-synuclein-positive glial cytoplasmic inclusions,” along with “neurodegenera­tive changes in striatonigral or olivoponto­cerebellar structures” at autopsy.⁶

Probable MSA. Without autopsy findings required for definite MSA, the next most specific diagnostic category is probable MSA. Probable MSA also specifies that the patient show either autonomic fail­ure involving urinary incontinence—this includes erectile dysfunction in men—or, if autonomic failure is absent, orthostatic hypotension within 3 minutes of standing by at least 30 mm Hg systolic pressure or 15 mm Hg diastolic pressure.

Possible MSA has less stringent crite­ria for orthostatic hypotension. The cat­egory includes patients who have only 1 symptom that suggests autonomic failure. Criteria for possible MSA include parkin­sonism or a cerebellar syndrome in addition to symptoms of MSA listed in the Table, whereas probable MSA has specific crite­ria of either a poorly levodopa-responsive parkinsonism (MSA-P) or a cerebellar syn­drome (MSA-C). In addition to having par­kinsonism or a cerebellar syndrome, and 1 sign of autonomic failure or orthostatic hypotension, patients also must have ≥1 additional feature to be assigned a diagno­sis of possible MSA, including:
   • rapidly progressive parkinsonism
   • poor response to levodopa
   • postural instability within 3 years of motor onset
   • gait ataxia, cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction
   • dysphagia within 5 years of motor onset
   • atrophy on MRI of putamen, mid­dle cerebellar peduncle, pons, or cerebellum
   • hypometabolism on fluorodeoxyglucose- PET in putamen, brainstem, or cerebellum.⁶

Diagnosing MSA can be challenging because its features are similar to those of many other disorders. Nonetheless, Gilman et al6 lists specific criteria for prob­able MSA, including autonomic dysfunc­tion, orthostatic hypotension, and either parkinsonism or cerebellar syndrome symptoms. Although a definite MSA diag­nosis only can be made by postmortem brain specimen analysis, Osaki et al⁷ found that a probable MSA diagnosis has a posi­tive predictive value of 92% with a sensi­tivity of 22% for definite MSA.

Mr. M’s symptoms were consistent with a diagnosis of probable MSA, cerebellar type (Figure).

Psychiatric manifestations of MSA
There are a few case reports of depression identified early in patients who were later given a diagnosis of MSA.⁸

Depression. In a study by Benrud-Larson et al⁹ (N = 99), 49% of patients who had MSA reported moderate or severe depres­sion, as indicated by a score of ≥17 on the Beck Depression Inventory (BDI); 80% reported at least mild depression (BDI ≥10, mean 17.0, standard deviation, 8.7).

In a similar study, by Balas et al,¹⁰ depres­sion was reported as a common symptom and was statistically significant in MSA-P patients compared with controls (P = .013).

Anxiety, another symptom that was reported by Mr. M, is another psychiat­ric manifestation described by Balas et al¹⁰ and Chang et al.¹¹ Balas et al¹⁰ noted that MSA-C and MSA-P patients had sig­nificantly more state anxiety (P = .009 and P = .022, respectively) compared with con­trols, although Chang et al¹¹ noted higher anxiety scores in MSA-C patients com­pared with controls and MSA-P patients (P < .01).

Balas et al¹⁰ hypothesized that anxiety and depression contribute to cognitive decline; their study showed that MSA-C patients had difficulty learning new ver­bal information (P < .022) and controlling attention (P < .023). Mr. M exhibited some of these cognitive difficulties in his reports of losing track of conversations, forgetting the topic of a conversation when speaking, trouble focusing, and difficulty concentrat­ing when driving.

Mr. M had depression and anxiety well before onset of autonomic dysfunction (orthostatic hypotension and erectile dys­function), which eventually led to an MSA diagnosis. Psychiatrists should under­stand additional manifestations of MSA so that they can use psychiatric symptoms to identify these conditions in their patients. One of the most well-known and early manifestations of MSA is autonomic dys­function; among men, another early sign is erectile dysfunction.⁶ Our patient also exhibited other less well-known symptoms linked to MSA and autonomic dysregula­tion, including RBD and ocular symptoms (iridocyclitis, glaucoma, decreased visual acuity).

Rapid eye-movement behavior disorder. Psychiatrists should consider screen­ing for RBD during assessment of sleep problems. Identifying RBD is important because early studies have shown a strong association between RBD and develop­ment of a neurodegenerative disorder. Mr. M’s clinicians did not consider RBD, although his symptoms of sleepwalking and falling asleep while driving suggest a possible diagnosis. Also, considering this diagnosis would aid in diagnosing a synu­cleinopathy disorder because a higher incidence of RBD was noted in patients who developed synucleinopathy disor­ders (eg, Parkinson’s disease [PD] and dementia with Lewy bodies [DLB]) com­pared with patients who developed non-synucleinopathies (eg, frontotemporal dementia, corticobasal degeneration, pro­gressive supranuclear palsy, mild cogni­tive impairment, primary progressive aphasia, and posterior cortical atrophy) or tauopathies (eg, Alzheimer’s disease).¹²

Zanigni et al¹³ reported similar findings in a later study that classified patients with RBD as having idiopathic RBD (IRBD) or RBD sec­ondary to an underlying neurodegenerative disorder, particularly an α-synucleinopathy: PD, MSA, and DLB. Most IRBD patients developed 1 of the above mentioned neuro­degenerative disorders as long as 10 years after a diagnosis of RBD.

In a study by Iranzo et al,¹⁴ patients with MSA were noted to have more severe RBD compared with PD patients. Severity is illus­trated by greater periodic leg movements during sleep (P = .001), less total sleep time (P = .023), longer sleep onset latency (P = .023), and a higher percentage of REM sleep without atonia (RSWA, P = .001). McCarter et al¹⁵ also noted a higher inci­dence of RSWA in patients with MSA.

Patients with MSA might therefore be more likely to exhibit difficulty initiating and maintaining sleep and as having RSWA years before the MSA diagnosis.

Several psychotropics (eg, first-generation antipsychotics, tricyclic anti­depressants, lithium, benzodiazepines, carbamazepine, topiramate, and selective serotonin reuptake inhibitors) can cause adverse ocular effects, such as closed-angle glaucoma in predisposed persons and retinopathy.¹⁶ Therefore, it is important for psychiatrists to ask about ocular symptoms because they might be an early sign of auto­nomic dysfunction.

Posner and Schlossman¹⁷ theorized a causal relationship between autonomic dys­function and ocular diseases after studying a group of patients who had intermittent unilateral attacks of iridocyclitis and glau­coma (now known as Posner-Schlossman syndrome). They hypothesized that a cen­tral cause in the hypothalamus, combined with underlying autonomic dysregulation, could cause the intermittent attacks.

Gherghel et al¹⁸ noted a significant differ­ence in ocular blood flow and blood pres­sure in patients with primary open-angle glaucoma (POAG) compared with con­trols. Patients with POAG did not show an increase in blood pressure or ocular blood flow when challenged by cold water, which should have increased their sympathetic activity. Gherghel et al¹⁸ concluded that this indicated possible systemic autonomic dys­function in patients with POAG. In a study by Fischer et al,¹⁹ MSA patients also were noted to have significant loss of nasal reti­nal nerve fiber layer thickness vs controls (P < .05), leading to decreased peripheral vision sensitivity.

Bottom Line
Although psychiatric symptoms are not part of the diagnostic criteria for multiple system atrophy (MSA), they may serve as a clue to consider when they occur with other MSA symptoms. Evaluate the importance of psychiatric symptoms in terms of the whole picture of the patient. Although the diagnosis might not alter the patient’s course, it can allow family members to understand the patient’s condition and prepare for complications that will arise.

Related Resources
• The MSA Coalition. www.multiplesystematrophy.org.
• National Institute of Neurological Disorders and Stroke. Multiple system atrophy fact sheet. www.ninds.nih.gov/disorders/msa/detailmsa.htm.
• Wenning GK, Fanciulli A, eds. Multiple system atrophy. Vienna, Austria: Springer-Verlag Wien; 2014.

Drug Brand Names
Bupropion • Wellbutrin                Lithium • Eskalith, Lithobid
Carbamazepine • Tegretol           Methylphenidate • Ritalin
Desvenlafaxine • Pristiq              Paroxetine • Paxil
Donepezil • Aricept                     Travoprost • Travatan
Escitalopram • Lexapro               Trazodone • Desyrel, Oleptro
Fludrocortisone • Florinef            Topiramate • Topamax
Fluoxetine • Prozac

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

CASE Light-headed
Mr. M, age 73, is a retired project manager who feels light-headed while walking his dog, causing him to go to the emergency depart­ment. His history is significant for hyperten­sion, coronary artery disease (CAD), 3-vessel coronary artery bypass graft surgery (CABG), hyperlipidemia, erectile dysfunction, open-angle glaucoma, hemiretinal vein occlusion, symptoms suggesting rapid eye-movement behavior disorder (RBD), and major depressive disorder (MDD).

The psychiatry consultation-liaison service is asked to help manage Mr. M’s psychiat­ric medications in the context of orthostatic hypotension and cognitive deficits.

What could be causing Mr. M’s symptoms?
   a) drug adverse effect
   b) progressive cardiovascular disease
   c) MDD
   d) all of the above

HISTORY Depression, heart disease
15 years ago. Mr. M experienced his first major depressive episode. His primary care physician (PCP) commented on a history of falling asleep while driving and 1 episode of sleepwalking. His depression was treated to remission with fluoxetine and methylphenidate (dosages were not recorded), the latter also addressed his falling asleep while driving.

5 years ago. Mr. M had another depres­sive episode characterized by anxiety, difficulty sleeping, and irritability. He also described chest pain; a cardiac work-up revealed extensive CAD, which led to 3-vessel CABG later that year. He also reported dizziness upon standing, which was treated with compression stockings and an increase in sodium intake.

Mr. M continued to express feelings of depression. His cardiologist started him on par­oxetine, 10 mg/d, which he took for 2 months and decided to stop because he felt better. He declined psychiatric referral.

4 years ago. Mr. M’s PCP referred him to a psychiatrist for depressed mood, anhedonia, decreased appetite, decreased energy, and dif­ficulty concentrating. Immediate and delayed recall were found to be intact. The psychiatrist diagnosed MDD and Mr. M started escitalopram, 5 mg/d, titrated to 15 mg/d, and trazodone, 50 mg/d.

After starting treatment, Mr. M reported decreased libido. Sustained-release bupropion, 150 mg/d, was added to boost the effects of escitalopram and counteract sexual side effects.

At follow-up, Mr. M reported that his depres­sive symptoms and libido had improved, but that he had been experiencing unsteady gait when getting out of his car, which he had been noticing “for a while”—before he began trazo­done. Mr. M was referred to his PCP, who attrib­uted his symptoms to orthostasis. No treatment was indicated at the time because Mr. M’s light­headedness had resolved.

3 years ago. Mr. M reported a syncopal attack and continued “dizziness.” His PCP pre­scribed fludrocortisone, 0.1 mg/d, later to be dosed 0.2 mg/d, and symptoms improved.

Although Mr. M had a history of orthostatic hypotension, he was later noted to have supine hypertension. Mr. M’s PCP was concerned that fludrocortisone could be causing the supine hypertension but that decreasing the dosage would cause his orthostatic hypotension to return.

The PCP also was concerned that the psy­chiatric medications (escitalopram, trazodone, and bupropion) could be causing orthostasis. There was discussion among Mr. M, his PCP, and his psychiatrist of stopping the psycho­tropics to see if the symptoms would remit; however, because of concerns about Mr. M’s depression, the medications were continued. Mr. M monitored his blood pressure at home and was referred to a neurologist for work-up of potential autonomic dysfunction.

Shortly afterward, Mr. M reported intermit­tent difficulty keeping track of his thoughts and finishing sentences. His psychiatrist ordered an MRI, which showed chronic small vessel ischemic changes, and started him on donepezil, 5 mg/d.

Neuropsychological testing revealed decreased processing speed and poor rec­ognition memory; otherwise, results showed above-average intellectual ability and average or above-average performance in measures of language, attention, visuospatial/construc­tional functions, and executive functions—a pattern typically attributable to psychogenic factors, such as depression.

Mr. M reported to his neurologist that he for­gets directions while driving but can focus bet­ter if he makes a conscious effort. Physical exam was significant hypotension; flat affect; deficits in concentration and short-term recall; mild impairment of Luria motor sequence (com­posed of a go/no-go and a reciprocal motor task); and vertical and horizontal saccades.¹

Mr. M consulted with an ophthalmologist for anterior iridocyclitis and ocular hypertension, which was controlled with travoprost. He con­tinued to experience trouble with his vision and was given a diagnosis of right inferior hemireti­nal vein occlusion, macular edema, and sus­pected glaucoma. Subsequent notes recorded a history of Posner-Schlossman syndrome (a disease characterized by recurrent attacks of increased intraocular pressure in 1 eye with concomitant anterior chamber inflammation). His vision deteriorated until he was diagnosed with ocular hypertension, open-angle glau­coma, and dermatochalasis.

The authors’ observations
Involvement of multiple specialties in a patient’s care brings to question one’s philosophy on medical diagnosis. Interdisciplinary communication would seem to promote the principle of diagnostic parsimony, or Occam’s razor, which sug­gests a unifying diagnosis to explain all of the patient’s symptoms. Lack of communi­cation might favor Hickam’s dictum, which states that “patients can have as many dis­eases as they damn well please.”

HISTORY Low energy, forgetfulness
2 years ago. Mr. M noticed low energy and motivation. He continued to work full-time but thought that it was taking him longer to get work done. He was tapered off escitalo­pram and started on desvenlafaxine, 50 mg/d; donepezil was increased to 10 mg/d.

The syncopal episodes resolved but blood pressure measured at home averaged 150/70 mm Hg. Mr. M was advised to decrease fludrocortisone from 0.2 mg/d to 0.1 mg/d. He tolerated the change and blood pressure measured at home dropped on average to 120 to 130/70 mm Hg.

1 year ago. Mr. M reported that his mem­ory loss had become worse. He perceived hav­ing more stress because of forgetfulness and visual difficulties, which had led him to stop driving at night.

At a follow-up appointment with his psy­chiatrist, Mr. M reported that, first, he had not tapered escitalopram as discussed and, second, he forgot to increase the dosage of desvenlafaxine. A home blood pressure log revealed consistent hypotension; the psychia­trist was concerned that hypotension could be the cause of concentration difficulties and malaise. The psychiatrist advised Mr. M to fol­low-up with his PCP and neurologist.

Current admission. Shortly after the visit to the psychiatrist, Mr. M presented to the emergency department for increased synco­pal events. Work-up was negative for a car­diac cause. A cosyntropin stimulation test was negative, showing that adrenal insufficiency did not cause his orthostatic hypotension. Chart review showed he had been having blood pressure problems for many years, inde­pendent of antidepressants. Physical exam revealed lower extremity ataxia and a bilateral extensor plantar reflex.

What diagnosis explains Mr. M’s symptoms?
   a) Parkinson’s disease
   b) multiple system atrophy (MSA)
   c) depression due to a general medical condition
  d) dementia

The authors’ observations
MSA, previously referred to as Shy-Drager syndrome, is a rare, rapidly progressive neurodegenerative disorder with an esti­mated prevalence of 3.7 cases for every 100,000 people worldwide.² MSA primarily affects middle-aged patients; because it has no cure, most patients die in 7 to 10 years.³

MSA has 2 clinical variants^4,5:
   • parkinsonian type (MSA-P), charac­terized by striatonigral degeneration and increased spasticity
   • cerebellar type (MSA-C), character­ized by more autonomic dysfunction.

MSA has a range of symptoms, mak­ing it a challenging diagnosis (Table).⁶ Although psychiatric symptoms are not part of the diagnostic criteria, they can aid in its diagnosis. In Mr. M’s case, depres­sion, anxiety, orthostatic hypotension, and ataxia support a diagnosis of MSA.

Gilman et al⁶ delineated 3 diagnostic categories for MSA: definite MSA, prob­able MSA, and possible MSA. Clinical cri­teria shared by the 3 diagnostic categories are sporadic and progressive onset after age 30.

Definite MSA requires “neuropathological findings of widespread and abundant CNS alpha-synuclein-positive glial cytoplasmic inclusions,” along with “neurodegenera­tive changes in striatonigral or olivoponto­cerebellar structures” at autopsy.⁶

Probable MSA. Without autopsy findings required for definite MSA, the next most specific diagnostic category is probable MSA. Probable MSA also specifies that the patient show either autonomic fail­ure involving urinary incontinence—this includes erectile dysfunction in men—or, if autonomic failure is absent, orthostatic hypotension within 3 minutes of standing by at least 30 mm Hg systolic pressure or 15 mm Hg diastolic pressure.

Possible MSA has less stringent crite­ria for orthostatic hypotension. The cat­egory includes patients who have only 1 symptom that suggests autonomic failure. Criteria for possible MSA include parkin­sonism or a cerebellar syndrome in addition to symptoms of MSA listed in the Table, whereas probable MSA has specific crite­ria of either a poorly levodopa-responsive parkinsonism (MSA-P) or a cerebellar syn­drome (MSA-C). In addition to having par­kinsonism or a cerebellar syndrome, and 1 sign of autonomic failure or orthostatic hypotension, patients also must have ≥1 additional feature to be assigned a diagno­sis of possible MSA, including:
   • rapidly progressive parkinsonism
   • poor response to levodopa
   • postural instability within 3 years of motor onset
   • gait ataxia, cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction
   • dysphagia within 5 years of motor onset
   • atrophy on MRI of putamen, mid­dle cerebellar peduncle, pons, or cerebellum
   • hypometabolism on fluorodeoxyglucose- PET in putamen, brainstem, or cerebellum.⁶

Diagnosing MSA can be challenging because its features are similar to those of many other disorders. Nonetheless, Gilman et al6 lists specific criteria for prob­able MSA, including autonomic dysfunc­tion, orthostatic hypotension, and either parkinsonism or cerebellar syndrome symptoms. Although a definite MSA diag­nosis only can be made by postmortem brain specimen analysis, Osaki et al⁷ found that a probable MSA diagnosis has a posi­tive predictive value of 92% with a sensi­tivity of 22% for definite MSA.

Mr. M’s symptoms were consistent with a diagnosis of probable MSA, cerebellar type (Figure).

Psychiatric manifestations of MSA
There are a few case reports of depression identified early in patients who were later given a diagnosis of MSA.⁸

Depression. In a study by Benrud-Larson et al⁹ (N = 99), 49% of patients who had MSA reported moderate or severe depres­sion, as indicated by a score of ≥17 on the Beck Depression Inventory (BDI); 80% reported at least mild depression (BDI ≥10, mean 17.0, standard deviation, 8.7).

In a similar study, by Balas et al,¹⁰ depres­sion was reported as a common symptom and was statistically significant in MSA-P patients compared with controls (P = .013).

Anxiety, another symptom that was reported by Mr. M, is another psychiat­ric manifestation described by Balas et al¹⁰ and Chang et al.¹¹ Balas et al¹⁰ noted that MSA-C and MSA-P patients had sig­nificantly more state anxiety (P = .009 and P = .022, respectively) compared with con­trols, although Chang et al¹¹ noted higher anxiety scores in MSA-C patients com­pared with controls and MSA-P patients (P < .01).

Balas et al¹⁰ hypothesized that anxiety and depression contribute to cognitive decline; their study showed that MSA-C patients had difficulty learning new ver­bal information (P < .022) and controlling attention (P < .023). Mr. M exhibited some of these cognitive difficulties in his reports of losing track of conversations, forgetting the topic of a conversation when speaking, trouble focusing, and difficulty concentrat­ing when driving.

Mr. M had depression and anxiety well before onset of autonomic dysfunction (orthostatic hypotension and erectile dys­function), which eventually led to an MSA diagnosis. Psychiatrists should under­stand additional manifestations of MSA so that they can use psychiatric symptoms to identify these conditions in their patients. One of the most well-known and early manifestations of MSA is autonomic dys­function; among men, another early sign is erectile dysfunction.⁶ Our patient also exhibited other less well-known symptoms linked to MSA and autonomic dysregula­tion, including RBD and ocular symptoms (iridocyclitis, glaucoma, decreased visual acuity).

Rapid eye-movement behavior disorder. Psychiatrists should consider screen­ing for RBD during assessment of sleep problems. Identifying RBD is important because early studies have shown a strong association between RBD and develop­ment of a neurodegenerative disorder. Mr. M’s clinicians did not consider RBD, although his symptoms of sleepwalking and falling asleep while driving suggest a possible diagnosis. Also, considering this diagnosis would aid in diagnosing a synu­cleinopathy disorder because a higher incidence of RBD was noted in patients who developed synucleinopathy disor­ders (eg, Parkinson’s disease [PD] and dementia with Lewy bodies [DLB]) com­pared with patients who developed non-synucleinopathies (eg, frontotemporal dementia, corticobasal degeneration, pro­gressive supranuclear palsy, mild cogni­tive impairment, primary progressive aphasia, and posterior cortical atrophy) or tauopathies (eg, Alzheimer’s disease).¹²

Zanigni et al¹³ reported similar findings in a later study that classified patients with RBD as having idiopathic RBD (IRBD) or RBD sec­ondary to an underlying neurodegenerative disorder, particularly an α-synucleinopathy: PD, MSA, and DLB. Most IRBD patients developed 1 of the above mentioned neuro­degenerative disorders as long as 10 years after a diagnosis of RBD.

In a study by Iranzo et al,¹⁴ patients with MSA were noted to have more severe RBD compared with PD patients. Severity is illus­trated by greater periodic leg movements during sleep (P = .001), less total sleep time (P = .023), longer sleep onset latency (P = .023), and a higher percentage of REM sleep without atonia (RSWA, P = .001). McCarter et al¹⁵ also noted a higher inci­dence of RSWA in patients with MSA.

Patients with MSA might therefore be more likely to exhibit difficulty initiating and maintaining sleep and as having RSWA years before the MSA diagnosis.

Several psychotropics (eg, first-generation antipsychotics, tricyclic anti­depressants, lithium, benzodiazepines, carbamazepine, topiramate, and selective serotonin reuptake inhibitors) can cause adverse ocular effects, such as closed-angle glaucoma in predisposed persons and retinopathy.¹⁶ Therefore, it is important for psychiatrists to ask about ocular symptoms because they might be an early sign of auto­nomic dysfunction.

Posner and Schlossman¹⁷ theorized a causal relationship between autonomic dys­function and ocular diseases after studying a group of patients who had intermittent unilateral attacks of iridocyclitis and glau­coma (now known as Posner-Schlossman syndrome). They hypothesized that a cen­tral cause in the hypothalamus, combined with underlying autonomic dysregulation, could cause the intermittent attacks.

Gherghel et al¹⁸ noted a significant differ­ence in ocular blood flow and blood pres­sure in patients with primary open-angle glaucoma (POAG) compared with con­trols. Patients with POAG did not show an increase in blood pressure or ocular blood flow when challenged by cold water, which should have increased their sympathetic activity. Gherghel et al¹⁸ concluded that this indicated possible systemic autonomic dys­function in patients with POAG. In a study by Fischer et al,¹⁹ MSA patients also were noted to have significant loss of nasal reti­nal nerve fiber layer thickness vs controls (P < .05), leading to decreased peripheral vision sensitivity.

Bottom Line
Although psychiatric symptoms are not part of the diagnostic criteria for multiple system atrophy (MSA), they may serve as a clue to consider when they occur with other MSA symptoms. Evaluate the importance of psychiatric symptoms in terms of the whole picture of the patient. Although the diagnosis might not alter the patient’s course, it can allow family members to understand the patient’s condition and prepare for complications that will arise.

Related Resources
• The MSA Coalition. www.multiplesystematrophy.org.
• National Institute of Neurological Disorders and Stroke. Multiple system atrophy fact sheet. www.ninds.nih.gov/disorders/msa/detailmsa.htm.
• Wenning GK, Fanciulli A, eds. Multiple system atrophy. Vienna, Austria: Springer-Verlag Wien; 2014.

Drug Brand Names
Bupropion • Wellbutrin                Lithium • Eskalith, Lithobid
Carbamazepine • Tegretol           Methylphenidate • Ritalin
Desvenlafaxine • Pristiq              Paroxetine • Paxil
Donepezil • Aricept                     Travoprost • Travatan
Escitalopram • Lexapro               Trazodone • Desyrel, Oleptro
Fludrocortisone • Florinef            Topiramate • Topamax
Fluoxetine • Prozac

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

For more than 50 years, depression has been studied, and understood, as a deficiency of specific neurotransmitters in the brain—namely dopamine, norepinephrine, and serotonin. Treatments for depression have been engineered to increase the release, or block the degradation, of these neurotransmitters within the synaptic cleft. Although a large body of evidence supports involvement of dopamine, norepinephrine, and serotonin in the pathophysiology of depression, the observation that pharmacotherapy is able to induce remission only in <50% of patients¹ has prompted researchers to look beyond neurotransmitters for an understanding of depressive disorders (Table 1).

Today, theories of depression focus more on differences in neuron density in various regions of the brain; the effect of stress on neurogenesis and neuronal cell apoptosis; alterations in feedback pathways connecting the pre-frontal cortex to the limbic system; and the role of proinflammatory mediators evoked during the stress response (Box,^2,3). These theories should not be viewed as separate entities because they are highly interconnected. Integrating them provides for a more expansive understanding of the pathophysiology of depression and biomarkers that are involved (Table 2).

In this article, we:

• integrate the large body of evidence supporting the contribution of the above variables to the onset and persistence of depression

• propose a possible risk stratification model

• explore possibilities for treatment.

The stress response: How does it affect the brain?

Stress initiates a cascade of events in the brain and peripheral systems that enable an organism to cope with, and adapt to, new and challenging situations. That is why physiologic and behavioral responses to stress generally are considered beneficial to survival.

When stress is maintained for a long period, both brain and body are harmed because target cells undergo prolonged exposure to physiologic stress mediators. For example, Woolley and Gould⁴ exposed rats to varying durations of glucocorticoids and observed that treating animals with corticosterone injection for 21 days induced neuronal atrophy in the hippocampus and prefrontal cortex and increased release of proinflammatory cytokines from astrocytes within the limbic system. Stressful experiences are believed to be closely associated with development of psychological alterations and, thus, neuropsychiatric disorders.⁵ To go further: Chronic stress is believed to be the leading cause of depression.

When the brain perceives an external threat, the stress response is called into action. The amygdala, part of the primitive limbic system, is the primary area of the brain responsible for triggering the stress response,⁶ signaling the hypothalamus to release corticotropin-releasing hormone (CRH) to the anterior pituitary gland, which, in turn releases adrenocorticotropic hormone to the adrenal glands (Figure 1).⁷ The adrenal glands are responsible for releasing glucocorticoids, which, because of their lipophilic nature, can cross the blood-brain barrier and are found in higher levels in the cerebrospinal fluid (CSF) of depressed persons.⁷

Once in the brain, glucocorticoids can be irreversibly degraded in the cytosol by the enzyme 11-β hydroxysteroid dehydrogenase type 2, a potential target for treating depression, or can bind to the glucocorticoid receptor (GR). Results of a research study of the role of cortisol in suppression of proinflammatory cytokine signaling activity in rainbow trout hepatocytes suggest a negative feedback loop for GR gene regulation during stress.⁸

Because this auto-regulation is a crucial step in the physiological stress response, the idea of the GR as an important biomarker in depression has gained popularity. In humans, when the GR binds to glucocorticoids that are released from the adrenal cortex during the stress response, the activated GR-cortisol complex represses expression of proinflammatory proteins in astrocytes and microglial cells and in all cells in the periphery before they are transcribed into proteins.⁹ The GR also has been shown to modulate neurogenesis.⁸ Repeated stress that persists over a long period leads to GR resistance, thereby reducing inhibition of production of proinflammatory cytokines.

Exposure to stress for >21 days leads to overactivity of the HPA axis and GR resistance,¹⁰ which decreases suppression of proinflammatory cytokines. There is evidence that proinflammatory cytokines, tumor necrosis factor-α, and interleukin-6 further induce GR receptor resistance by preventing the cortisol-GR receptor complex from entering cell nuclei and decreasing binding to DNA within the nuclei.¹¹ Dexamethasone, a GR agonist, has been implicated in research studies for potential re-regulation of the HPA axis in depressed persons.¹²

Nerve cell death in the hippocampus

Studies showing reduced hippocampal volume in unipolar depression and a correlation between the number of episodes and a consequence of untreated depression and studies suggesting that treatment can stop or reduce shrinkage,¹³ and recent findings of rapid neurogenesis in hippocampi in response to ketamine, brings our focus to hippocampus in depression.

The greatest density of GRs is found in the hippocampus, which is closely associated with the limbic system.⁷ Therefore, the hippocampus is sensitive to increases in glucocorticoids in the brain and plays a crucial role in regulation of the HPA axis.

Evidence shows that in chronic stress exposure (≥21 days), nerve cells in the hippocampus begin to atrophy and can no longer provide negative feedback inhibition to the hypothalamus, causing HPA axis dysregulation and uncontrolled release of glucocorticoids into the bloodstream and CSF.² In patients with Cushing syndrome, who produce abnormally high levels of glucocorticoid, the incidence of depression is as high as 50%.¹⁴ Similarly, patients treated with glucocorticoids such as prednisone often experience psychiatric symptoms, the most common being depression. Gould found that partial adrenalectomy increased hippocampal neurogenesis in rat brains, indicating the beneficial effect of stress hormone antagonism.⁴ CRH antagonists are being looked at as a promising and less invasive treatment option for depression.

Focus has been diverted to the role of the hippocampus in depression because of its ability to regenerate throughout adulthood, leading potentially to a re-regulation of the HPA axis and subsiding of the stress response, which is universally believed to be the primary precipitating factor in depression onset. Rats require 10 to 21 days of rest to recover from the effects of chronic (21 days) administration of glucocorticoids.¹⁵ If this proves to be a directly proportional relationship, then rats would need an estimated 120 days to recover from 6 months of constant glucocorticoid exposure. Considering that the same is true for humans, current depression treatment programs, which average 6 weeks, are not long enough for adequate recovery.

Antidepressants such as selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclics stimulate neurogenesis in the hippocampus via increases in brain-derived neurotrophic factor (BDNF), suggesting that these neurotransmitters play an important role depression.¹⁶

Repetitive transcranial magnetic stimulation (rTMS), a noninvasive neuromodulation therapy approved to treat major depression, delivers brief magnetic pulses to the limbic structures. Treatment facilitates focal stimulation, rapidly applying electrical charges to the cortical neurons. TMS targets prefrontal circuits of the brain that are underactive during depressive episodes. Recent animal studies have suggested that bromodeoxyuridine (BrdU)-positive cells (newborn cells) are increased significantly in the dentate gyrus, in turn suggesting that hippocampal neurogenesis might be involved in the antidepressant effects of chronic rTMS.¹⁷ Although the underlying therapeutic mechanisms of rTMS treatment of depression remain unclear, it appears that hippocampal neurogenesis might be required to produce the effects of antidepressant treatments, including drugs and electroconvulsive therapy.¹⁷

Selective ‘shunting’ of energy occurs during the stress response

Hormones released from the adrenal glands during stress divert glucose to exercising muscles and the brain’s limbic system, which are involved in the fight-or-flight response.¹⁸ However, metabolic functions and areas of the brain that are not involved in the stress response, such as the cerebral cortex and hippocampus, are deprived of energy as a consequence of this innate selective shunting (Figure 2).¹⁹

Positron-emission tomography (PET) scanning of the resting brain shows that components of the cerebral cortex (prefrontal cortex, hippocampus, striatum) and areas connecting the cerebral cortex to the limbic system exhibit the most energy consumption in the brain during rest (Figure 3).²⁰ PET studies also show that neuronal connections within these energy-demanding areas atrophy more rapidly than in any other area of the brain when their energy supply is reduced or cut off.⁶

When the supply of oxygen and glucose to certain areas of the brain is reduced—such as in traumatic brain injury or stroke—the excitatory neurotransmitter glutamate accumulates in extracellular fluid and causes nerve-cell death.²¹ When a conditioned stimulus is presented during fear acquisition, functional magnetic resonance imaging (fMRI) studies of fear-conditioning have consistently reported, in the prefrontal cortex:

• a decrease in the blood oxygen level-dependent signal, below resting baseline
• a reduction in blood flow (Figure 4).²²

This discovery adds to evidence that demonstrates a decrease in gray-matter density in the frontal lobes as a result of glutaminergic toxicity (Figure 5).

Activation of L-glutamate, believed to play a significant role in depression and other neuropsychiatric disorders, triggers calcium-dependent intracellular responses that “excite cells to death,” so to speak—thereby causing nerve-cell apoptosis and a reduction in synaptic connections between different areas of the brain responsible for learning and memory.²³ Malfunction of these synaptic connections is thought to be partially responsible for depression and other psychiatric disorders.

Excessive activation of N-methyl-d-asparate (NMDA) receptors is thought to be the underlying mechanism that leads to neuronal cell death in glutaminergic toxicity. Therefore, NMDA receptor proteins have become a target in treating neurodegenerative psychiatric illnesses. There is more than one type of NMDA receptor; some of them are excitatory, others are inhibitory. Four compounds have presented as therapeutic candidates for inhibition of NMDA receptor functioning and treatment of depression: those that inhibit glutamate binding, those that block the ion channel, and those that inhibit receptor binding to the terminal regulatory domain.²⁴

Regrettably, these chemical compounds are not receptor-selective, but small structural modifications of these NMDA receptors have been found and lead to significant changes in potency and selectivity. This should serve as a unique starting point for developing highly specific NMDA receptor modulator agents for a variety of neuropsychiatric and neurological conditions. GLYX-13, a derivative of ketamine (an NMDA receptor antagonist), has been implicated for use in treating depression. It has been tested on 2 large phase-II study groups.²⁵

Neuronal circuitry of depression is altered by prolonged stress

Symptoms of depression can be explained by the anatomical circuit shown in Figure 6.^15,20 Impaired concentration, diminished ability to process new information, and decline in memory function are associated with decreased nerve density in the hippocampus, which plays a key role in learning, memory, and encoding of emotionally relevant data into memory.²⁶ The hippocampus interacts with the amygdala to provide input about the context in which stimuli occur.

Depressed people often demonstrate impulsivity and have difficulty controlling expression of emotions—traits that are attributed to increased neuronal density in the amygdala and insula, which has been illustrated in PET scans and voxel-based morphometry in depressed patients.²⁷ These brain areas are implicated in subjective emotional experience, processing of emotional reactions, and impulsive decision-making. The amygdala is normally highly regulated by the prefrontal cortex, which uses rational judgment to interpret stimuli and regulate the expression of emotion.

A study involving a facial expression processing task demonstrated reduced connectivity between the amygdala and prefrontal cortex and increased functional connectivity among the amygdala, hippocampus, and caudate-putamen in depressed patients.²⁴ And in a study that measured white matter conduction in various brain areas in depressed patients, the greatest reduction was found in areas connecting the limbic system to the prefrontal cortex and hippocampus—believed to be caused by stress response-induced ischemic glutaminergic neuroapoptosis.²¹ Such neuroapoptosis might lead to irrational interpretation of stimuli, unchecked expression of emotion, and impulsive thoughts and behavior that are often present in depression and other mood disorders.

Deep brain stimulation (DBS), in which electrodes are implanted in the brain, has proved effective at increasing synaptic connections between the prefrontal cortex and the limbic system when electrodes are placed appropriately.²⁸ Patients with refractory depression who are treated with DBS show increased gray-matter density and functional activity in the prefrontal cortex, hippocampus, and fronto-limbic connections.²⁹ DBS also increases neurotransmission of dopamine, serotonin, and norepinephrine within the fronto-limbic circuitry.³⁰

Identifying risk factors for depression

Genetic risk factors. Forty percent of patients with depression have a first-degree relative with depression, suggesting a strong genetic component.¹⁰ Inherited differences in hippocampal volume, synaptic connections between the prefrontal cortex and amygdala, γ-aminobutyric acid (GABA)/glutamate balance, BDNF neurotransmitter receptors, and anatomic positioning of the limbic system in relation to other brain structures might account for the heritability of psychiatric disorders such as depression.

Evidence has been consistent that hippocampal volume is diminished in the brain of depressed persons. However, there is no prospective cohort study to determine whether people who have lower gray-matter hippocampal density or volume, or both, before depression onset develop symptoms later in life. There also is no study to determine the percentage of people who have lower-than-average hippocampal gray-matter density or volume and who have a first-degree relative with depression. Such studies would yield valuable information about anatomic variables that increase the risk of depression.

It has been proposed that low GABA function is an inherited biomarker for depression. Bjork and co-workers found a lower plasma level of GABA in depressed subjects and in their first-degree relatives, confirming that GABAergic tone might be under genetic control.¹¹ Genetic loci studies in mice have linked depressive-like behavior to GABAergic loci on chromosomes 8 and 11, encoding alpha 1, alpha 6, and gamma subunits of GABA_A receptors.²³

A recent study in humans showed that severe, treatment-resistant depression with anxiety was linked to a mutation in the B1 subunit of the GABA_A receptor. Positive genetic associations were found between polymorphism in human GABA_A receptor subunit genes.¹¹

GABA metabolizing enzymes also can be considered biological modifiers of depression. For example:

• GABA uptake and metabolism is controlled by the enzyme glutamic acid decarboxylase (GAD); depression has been found to be associated with a polymorphism in the GAD67 gene encoding an isoform of GAD.¹¹

• GABA transaminase (GABA-T) is another key enzyme in GABA turnover.³¹ It catabolizes GABA.

We can conclude that, to a high degree, depression depends on GABA production and metabolism.

A variant in the human BDNF gene, in which valine is substituted for methionine in position 66 of the pro-domain of the BDNF protein, is associated with

• a decrease in the production of BDNF

• increased susceptibility to neuropsychiatric disorders, including depression, anxiety disorder, and bipolar disorder (Figure 7).³²

People with the MM allele have been found to have a small hippocampal neuronal density and poor hippocampus-dependent memory function in neuroimaging studies.²³ They also displayed diminished ventromedial prefrontal cortex volume and presented with aversive memory extinction deficit (ie, “holding grudges”).

Another neurotrophic factor, vascular endothelial growth factor (VEGF), is a survival factor for endothelial cells and neurons and a modulator of synaptic transmission. Understanding the molecular and cellular specificity of antidepressant-induced VEGF will be critical to determine its potential as a therapeutic target in depression.³³ Delineating the relationship between VEGF and depression has, ultimately, the potential to shed light on the still elusive neural mechanisms that underlie the pathophysiology of depression and the mechanisms by which antidepressants exert their effects.³⁴

Genetic polymorphisms in monoamine receptors (5-HT2A), transporters (SERTPR, 5-HTTLPR, STin2, rs25531, SLC6A4), and regulatory enzymes should not be overlooked.³⁵ There is reproducible evidence that variability in these polymorphisms are associated with variability in:

• vulnerability to depression

• the response to treatment with existing antidepressant medications.¹

Most studies that look at changes in neuronal circuitry focus on the integrity of synaptic connections between the frontal cortex and limbic system; few of them have closely examined the importance of the anatomic proximity of the 2 regions. It might be that having an amygdala that is relatively closer to the frontal cortex and the hippocampus reduces a person’s risk of depression, and vice versa. This association needs to be investigated further with imaging studies.

Environmental risk factors. The brain is thought to be plastic until age 30.⁵ Plasticity diminishes with age after age 7—except for the hippocampus, which can regenerate throughout life.³⁶ Early life experiences play an important role in forming synaptic connections between the frontal cortex and the limbic system, through a process known as fear conditioning.

Children learn early in life which stimuli are to be perceived as threatening or aversive and how to respond to best preserves their safety and internal sense of well-being. Those who grow up in a hostile environment learn to perceive more stimuli as threatening than children who grow up in a nurturing environment.³² It is possible that the amygdala is larger in children who grow up in less-than-ideal circumstances because this region is constantly being recruited—at the expense of the more rational frontal cortex.

Evidence suggests that these conditions reduce hippocampal neurogenesis³⁷:

• increasing age

• substance abuse (opiates and methamphetamines)

• inadequate housing

• minimal physical activity

• little opportunity for social stimulation

• minimal learning experience.

Bottom Line

Depression has been understood as a neurotransmitter deficiency in the brain; treatments were engineered to increase release, or block degradation, of those neurotransmitters. Novel theories—all interconnected—of the neuroanatomical pathophysiology of depression focus more on differences in neuron density in the brain; effects of stress on neurogenesis and neuronal cell apoptosis; alterations in feedback pathways connecting the pre-frontal cortex to the limbic system; and the role of pro-inflammatory mediators evoked during the stress response.

Related Resources

• Fuchs E. Neurogenesis in the adult brain: is there an association with mental disorders? Eur Arch Psychiatry Clin Neurosci. 2007;257(5):247-249.

• Videbech P, Ravnkilde B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry. 2004; 161(11):1957-1966.

Disclosure

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

Acknowledgement

Anita Rao, second-year medical student, Stritch School of Medicine, Loyola University, Chicago, Illinois, assisted in the preparation of this manuscript.

For more than 50 years, depression has been studied, and understood, as a deficiency of specific neurotransmitters in the brain—namely dopamine, norepinephrine, and serotonin. Treatments for depression have been engineered to increase the release, or block the degradation, of these neurotransmitters within the synaptic cleft. Although a large body of evidence supports involvement of dopamine, norepinephrine, and serotonin in the pathophysiology of depression, the observation that pharmacotherapy is able to induce remission only in <50% of patients¹ has prompted researchers to look beyond neurotransmitters for an understanding of depressive disorders (Table 1).

Today, theories of depression focus more on differences in neuron density in various regions of the brain; the effect of stress on neurogenesis and neuronal cell apoptosis; alterations in feedback pathways connecting the pre-frontal cortex to the limbic system; and the role of proinflammatory mediators evoked during the stress response (Box,^2,3). These theories should not be viewed as separate entities because they are highly interconnected. Integrating them provides for a more expansive understanding of the pathophysiology of depression and biomarkers that are involved (Table 2).

In this article, we:

• integrate the large body of evidence supporting the contribution of the above variables to the onset and persistence of depression

• propose a possible risk stratification model

• explore possibilities for treatment.

The stress response: How does it affect the brain?

Stress initiates a cascade of events in the brain and peripheral systems that enable an organism to cope with, and adapt to, new and challenging situations. That is why physiologic and behavioral responses to stress generally are considered beneficial to survival.

When stress is maintained for a long period, both brain and body are harmed because target cells undergo prolonged exposure to physiologic stress mediators. For example, Woolley and Gould⁴ exposed rats to varying durations of glucocorticoids and observed that treating animals with corticosterone injection for 21 days induced neuronal atrophy in the hippocampus and prefrontal cortex and increased release of proinflammatory cytokines from astrocytes within the limbic system. Stressful experiences are believed to be closely associated with development of psychological alterations and, thus, neuropsychiatric disorders.⁵ To go further: Chronic stress is believed to be the leading cause of depression.

When the brain perceives an external threat, the stress response is called into action. The amygdala, part of the primitive limbic system, is the primary area of the brain responsible for triggering the stress response,⁶ signaling the hypothalamus to release corticotropin-releasing hormone (CRH) to the anterior pituitary gland, which, in turn releases adrenocorticotropic hormone to the adrenal glands (Figure 1).⁷ The adrenal glands are responsible for releasing glucocorticoids, which, because of their lipophilic nature, can cross the blood-brain barrier and are found in higher levels in the cerebrospinal fluid (CSF) of depressed persons.⁷

Once in the brain, glucocorticoids can be irreversibly degraded in the cytosol by the enzyme 11-β hydroxysteroid dehydrogenase type 2, a potential target for treating depression, or can bind to the glucocorticoid receptor (GR). Results of a research study of the role of cortisol in suppression of proinflammatory cytokine signaling activity in rainbow trout hepatocytes suggest a negative feedback loop for GR gene regulation during stress.⁸

Because this auto-regulation is a crucial step in the physiological stress response, the idea of the GR as an important biomarker in depression has gained popularity. In humans, when the GR binds to glucocorticoids that are released from the adrenal cortex during the stress response, the activated GR-cortisol complex represses expression of proinflammatory proteins in astrocytes and microglial cells and in all cells in the periphery before they are transcribed into proteins.⁹ The GR also has been shown to modulate neurogenesis.⁸ Repeated stress that persists over a long period leads to GR resistance, thereby reducing inhibition of production of proinflammatory cytokines.

Exposure to stress for >21 days leads to overactivity of the HPA axis and GR resistance,¹⁰ which decreases suppression of proinflammatory cytokines. There is evidence that proinflammatory cytokines, tumor necrosis factor-α, and interleukin-6 further induce GR receptor resistance by preventing the cortisol-GR receptor complex from entering cell nuclei and decreasing binding to DNA within the nuclei.¹¹ Dexamethasone, a GR agonist, has been implicated in research studies for potential re-regulation of the HPA axis in depressed persons.¹²

Nerve cell death in the hippocampus

Studies showing reduced hippocampal volume in unipolar depression and a correlation between the number of episodes and a consequence of untreated depression and studies suggesting that treatment can stop or reduce shrinkage,¹³ and recent findings of rapid neurogenesis in hippocampi in response to ketamine, brings our focus to hippocampus in depression.

The greatest density of GRs is found in the hippocampus, which is closely associated with the limbic system.⁷ Therefore, the hippocampus is sensitive to increases in glucocorticoids in the brain and plays a crucial role in regulation of the HPA axis.

Evidence shows that in chronic stress exposure (≥21 days), nerve cells in the hippocampus begin to atrophy and can no longer provide negative feedback inhibition to the hypothalamus, causing HPA axis dysregulation and uncontrolled release of glucocorticoids into the bloodstream and CSF.² In patients with Cushing syndrome, who produce abnormally high levels of glucocorticoid, the incidence of depression is as high as 50%.¹⁴ Similarly, patients treated with glucocorticoids such as prednisone often experience psychiatric symptoms, the most common being depression. Gould found that partial adrenalectomy increased hippocampal neurogenesis in rat brains, indicating the beneficial effect of stress hormone antagonism.⁴ CRH antagonists are being looked at as a promising and less invasive treatment option for depression.

Focus has been diverted to the role of the hippocampus in depression because of its ability to regenerate throughout adulthood, leading potentially to a re-regulation of the HPA axis and subsiding of the stress response, which is universally believed to be the primary precipitating factor in depression onset. Rats require 10 to 21 days of rest to recover from the effects of chronic (21 days) administration of glucocorticoids.¹⁵ If this proves to be a directly proportional relationship, then rats would need an estimated 120 days to recover from 6 months of constant glucocorticoid exposure. Considering that the same is true for humans, current depression treatment programs, which average 6 weeks, are not long enough for adequate recovery.

Antidepressants such as selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclics stimulate neurogenesis in the hippocampus via increases in brain-derived neurotrophic factor (BDNF), suggesting that these neurotransmitters play an important role depression.¹⁶

Repetitive transcranial magnetic stimulation (rTMS), a noninvasive neuromodulation therapy approved to treat major depression, delivers brief magnetic pulses to the limbic structures. Treatment facilitates focal stimulation, rapidly applying electrical charges to the cortical neurons. TMS targets prefrontal circuits of the brain that are underactive during depressive episodes. Recent animal studies have suggested that bromodeoxyuridine (BrdU)-positive cells (newborn cells) are increased significantly in the dentate gyrus, in turn suggesting that hippocampal neurogenesis might be involved in the antidepressant effects of chronic rTMS.¹⁷ Although the underlying therapeutic mechanisms of rTMS treatment of depression remain unclear, it appears that hippocampal neurogenesis might be required to produce the effects of antidepressant treatments, including drugs and electroconvulsive therapy.¹⁷

Selective ‘shunting’ of energy occurs during the stress response

Hormones released from the adrenal glands during stress divert glucose to exercising muscles and the brain’s limbic system, which are involved in the fight-or-flight response.¹⁸ However, metabolic functions and areas of the brain that are not involved in the stress response, such as the cerebral cortex and hippocampus, are deprived of energy as a consequence of this innate selective shunting (Figure 2).¹⁹

Positron-emission tomography (PET) scanning of the resting brain shows that components of the cerebral cortex (prefrontal cortex, hippocampus, striatum) and areas connecting the cerebral cortex to the limbic system exhibit the most energy consumption in the brain during rest (Figure 3).²⁰ PET studies also show that neuronal connections within these energy-demanding areas atrophy more rapidly than in any other area of the brain when their energy supply is reduced or cut off.⁶

When the supply of oxygen and glucose to certain areas of the brain is reduced—such as in traumatic brain injury or stroke—the excitatory neurotransmitter glutamate accumulates in extracellular fluid and causes nerve-cell death.²¹ When a conditioned stimulus is presented during fear acquisition, functional magnetic resonance imaging (fMRI) studies of fear-conditioning have consistently reported, in the prefrontal cortex:

• a decrease in the blood oxygen level-dependent signal, below resting baseline
• a reduction in blood flow (Figure 4).²²

This discovery adds to evidence that demonstrates a decrease in gray-matter density in the frontal lobes as a result of glutaminergic toxicity (Figure 5).

Activation of L-glutamate, believed to play a significant role in depression and other neuropsychiatric disorders, triggers calcium-dependent intracellular responses that “excite cells to death,” so to speak—thereby causing nerve-cell apoptosis and a reduction in synaptic connections between different areas of the brain responsible for learning and memory.²³ Malfunction of these synaptic connections is thought to be partially responsible for depression and other psychiatric disorders.

Excessive activation of N-methyl-d-asparate (NMDA) receptors is thought to be the underlying mechanism that leads to neuronal cell death in glutaminergic toxicity. Therefore, NMDA receptor proteins have become a target in treating neurodegenerative psychiatric illnesses. There is more than one type of NMDA receptor; some of them are excitatory, others are inhibitory. Four compounds have presented as therapeutic candidates for inhibition of NMDA receptor functioning and treatment of depression: those that inhibit glutamate binding, those that block the ion channel, and those that inhibit receptor binding to the terminal regulatory domain.²⁴

Regrettably, these chemical compounds are not receptor-selective, but small structural modifications of these NMDA receptors have been found and lead to significant changes in potency and selectivity. This should serve as a unique starting point for developing highly specific NMDA receptor modulator agents for a variety of neuropsychiatric and neurological conditions. GLYX-13, a derivative of ketamine (an NMDA receptor antagonist), has been implicated for use in treating depression. It has been tested on 2 large phase-II study groups.²⁵

Neuronal circuitry of depression is altered by prolonged stress

Symptoms of depression can be explained by the anatomical circuit shown in Figure 6.^15,20 Impaired concentration, diminished ability to process new information, and decline in memory function are associated with decreased nerve density in the hippocampus, which plays a key role in learning, memory, and encoding of emotionally relevant data into memory.²⁶ The hippocampus interacts with the amygdala to provide input about the context in which stimuli occur.

Depressed people often demonstrate impulsivity and have difficulty controlling expression of emotions—traits that are attributed to increased neuronal density in the amygdala and insula, which has been illustrated in PET scans and voxel-based morphometry in depressed patients.²⁷ These brain areas are implicated in subjective emotional experience, processing of emotional reactions, and impulsive decision-making. The amygdala is normally highly regulated by the prefrontal cortex, which uses rational judgment to interpret stimuli and regulate the expression of emotion.

A study involving a facial expression processing task demonstrated reduced connectivity between the amygdala and prefrontal cortex and increased functional connectivity among the amygdala, hippocampus, and caudate-putamen in depressed patients.²⁴ And in a study that measured white matter conduction in various brain areas in depressed patients, the greatest reduction was found in areas connecting the limbic system to the prefrontal cortex and hippocampus—believed to be caused by stress response-induced ischemic glutaminergic neuroapoptosis.²¹ Such neuroapoptosis might lead to irrational interpretation of stimuli, unchecked expression of emotion, and impulsive thoughts and behavior that are often present in depression and other mood disorders.

Deep brain stimulation (DBS), in which electrodes are implanted in the brain, has proved effective at increasing synaptic connections between the prefrontal cortex and the limbic system when electrodes are placed appropriately.²⁸ Patients with refractory depression who are treated with DBS show increased gray-matter density and functional activity in the prefrontal cortex, hippocampus, and fronto-limbic connections.²⁹ DBS also increases neurotransmission of dopamine, serotonin, and norepinephrine within the fronto-limbic circuitry.³⁰

Identifying risk factors for depression

Genetic risk factors. Forty percent of patients with depression have a first-degree relative with depression, suggesting a strong genetic component.¹⁰ Inherited differences in hippocampal volume, synaptic connections between the prefrontal cortex and amygdala, γ-aminobutyric acid (GABA)/glutamate balance, BDNF neurotransmitter receptors, and anatomic positioning of the limbic system in relation to other brain structures might account for the heritability of psychiatric disorders such as depression.

Evidence has been consistent that hippocampal volume is diminished in the brain of depressed persons. However, there is no prospective cohort study to determine whether people who have lower gray-matter hippocampal density or volume, or both, before depression onset develop symptoms later in life. There also is no study to determine the percentage of people who have lower-than-average hippocampal gray-matter density or volume and who have a first-degree relative with depression. Such studies would yield valuable information about anatomic variables that increase the risk of depression.

It has been proposed that low GABA function is an inherited biomarker for depression. Bjork and co-workers found a lower plasma level of GABA in depressed subjects and in their first-degree relatives, confirming that GABAergic tone might be under genetic control.¹¹ Genetic loci studies in mice have linked depressive-like behavior to GABAergic loci on chromosomes 8 and 11, encoding alpha 1, alpha 6, and gamma subunits of GABA_A receptors.²³

A recent study in humans showed that severe, treatment-resistant depression with anxiety was linked to a mutation in the B1 subunit of the GABA_A receptor. Positive genetic associations were found between polymorphism in human GABA_A receptor subunit genes.¹¹

GABA metabolizing enzymes also can be considered biological modifiers of depression. For example:

• GABA uptake and metabolism is controlled by the enzyme glutamic acid decarboxylase (GAD); depression has been found to be associated with a polymorphism in the GAD67 gene encoding an isoform of GAD.¹¹

• GABA transaminase (GABA-T) is another key enzyme in GABA turnover.³¹ It catabolizes GABA.

We can conclude that, to a high degree, depression depends on GABA production and metabolism.

A variant in the human BDNF gene, in which valine is substituted for methionine in position 66 of the pro-domain of the BDNF protein, is associated with

• a decrease in the production of BDNF

• increased susceptibility to neuropsychiatric disorders, including depression, anxiety disorder, and bipolar disorder (Figure 7).³²

People with the MM allele have been found to have a small hippocampal neuronal density and poor hippocampus-dependent memory function in neuroimaging studies.²³ They also displayed diminished ventromedial prefrontal cortex volume and presented with aversive memory extinction deficit (ie, “holding grudges”).

Another neurotrophic factor, vascular endothelial growth factor (VEGF), is a survival factor for endothelial cells and neurons and a modulator of synaptic transmission. Understanding the molecular and cellular specificity of antidepressant-induced VEGF will be critical to determine its potential as a therapeutic target in depression.³³ Delineating the relationship between VEGF and depression has, ultimately, the potential to shed light on the still elusive neural mechanisms that underlie the pathophysiology of depression and the mechanisms by which antidepressants exert their effects.³⁴

Genetic polymorphisms in monoamine receptors (5-HT2A), transporters (SERTPR, 5-HTTLPR, STin2, rs25531, SLC6A4), and regulatory enzymes should not be overlooked.³⁵ There is reproducible evidence that variability in these polymorphisms are associated with variability in:

• vulnerability to depression

• the response to treatment with existing antidepressant medications.¹

Most studies that look at changes in neuronal circuitry focus on the integrity of synaptic connections between the frontal cortex and limbic system; few of them have closely examined the importance of the anatomic proximity of the 2 regions. It might be that having an amygdala that is relatively closer to the frontal cortex and the hippocampus reduces a person’s risk of depression, and vice versa. This association needs to be investigated further with imaging studies.

Environmental risk factors. The brain is thought to be plastic until age 30.⁵ Plasticity diminishes with age after age 7—except for the hippocampus, which can regenerate throughout life.³⁶ Early life experiences play an important role in forming synaptic connections between the frontal cortex and the limbic system, through a process known as fear conditioning.

Children learn early in life which stimuli are to be perceived as threatening or aversive and how to respond to best preserves their safety and internal sense of well-being. Those who grow up in a hostile environment learn to perceive more stimuli as threatening than children who grow up in a nurturing environment.³² It is possible that the amygdala is larger in children who grow up in less-than-ideal circumstances because this region is constantly being recruited—at the expense of the more rational frontal cortex.

Evidence suggests that these conditions reduce hippocampal neurogenesis³⁷:

• increasing age

• substance abuse (opiates and methamphetamines)

• inadequate housing

• minimal physical activity

• little opportunity for social stimulation

• minimal learning experience.

Bottom Line

Depression has been understood as a neurotransmitter deficiency in the brain; treatments were engineered to increase release, or block degradation, of those neurotransmitters. Novel theories—all interconnected—of the neuroanatomical pathophysiology of depression focus more on differences in neuron density in the brain; effects of stress on neurogenesis and neuronal cell apoptosis; alterations in feedback pathways connecting the pre-frontal cortex to the limbic system; and the role of pro-inflammatory mediators evoked during the stress response.

Related Resources

• Fuchs E. Neurogenesis in the adult brain: is there an association with mental disorders? Eur Arch Psychiatry Clin Neurosci. 2007;257(5):247-249.

• Videbech P, Ravnkilde B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry. 2004; 161(11):1957-1966.

Disclosure

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

Acknowledgement

Anita Rao, second-year medical student, Stritch School of Medicine, Loyola University, Chicago, Illinois, assisted in the preparation of this manuscript.

For more than 50 years, depression has been studied, and understood, as a deficiency of specific neurotransmitters in the brain—namely dopamine, norepinephrine, and serotonin. Treatments for depression have been engineered to increase the release, or block the degradation, of these neurotransmitters within the synaptic cleft. Although a large body of evidence supports involvement of dopamine, norepinephrine, and serotonin in the pathophysiology of depression, the observation that pharmacotherapy is able to induce remission only in <50% of patients¹ has prompted researchers to look beyond neurotransmitters for an understanding of depressive disorders (Table 1).

Today, theories of depression focus more on differences in neuron density in various regions of the brain; the effect of stress on neurogenesis and neuronal cell apoptosis; alterations in feedback pathways connecting the pre-frontal cortex to the limbic system; and the role of proinflammatory mediators evoked during the stress response (Box,^2,3). These theories should not be viewed as separate entities because they are highly interconnected. Integrating them provides for a more expansive understanding of the pathophysiology of depression and biomarkers that are involved (Table 2).

In this article, we:

• integrate the large body of evidence supporting the contribution of the above variables to the onset and persistence of depression

• propose a possible risk stratification model

• explore possibilities for treatment.

The stress response: How does it affect the brain?

Stress initiates a cascade of events in the brain and peripheral systems that enable an organism to cope with, and adapt to, new and challenging situations. That is why physiologic and behavioral responses to stress generally are considered beneficial to survival.

When stress is maintained for a long period, both brain and body are harmed because target cells undergo prolonged exposure to physiologic stress mediators. For example, Woolley and Gould⁴ exposed rats to varying durations of glucocorticoids and observed that treating animals with corticosterone injection for 21 days induced neuronal atrophy in the hippocampus and prefrontal cortex and increased release of proinflammatory cytokines from astrocytes within the limbic system. Stressful experiences are believed to be closely associated with development of psychological alterations and, thus, neuropsychiatric disorders.⁵ To go further: Chronic stress is believed to be the leading cause of depression.

When the brain perceives an external threat, the stress response is called into action. The amygdala, part of the primitive limbic system, is the primary area of the brain responsible for triggering the stress response,⁶ signaling the hypothalamus to release corticotropin-releasing hormone (CRH) to the anterior pituitary gland, which, in turn releases adrenocorticotropic hormone to the adrenal glands (Figure 1).⁷ The adrenal glands are responsible for releasing glucocorticoids, which, because of their lipophilic nature, can cross the blood-brain barrier and are found in higher levels in the cerebrospinal fluid (CSF) of depressed persons.⁷

Once in the brain, glucocorticoids can be irreversibly degraded in the cytosol by the enzyme 11-β hydroxysteroid dehydrogenase type 2, a potential target for treating depression, or can bind to the glucocorticoid receptor (GR). Results of a research study of the role of cortisol in suppression of proinflammatory cytokine signaling activity in rainbow trout hepatocytes suggest a negative feedback loop for GR gene regulation during stress.⁸

Because this auto-regulation is a crucial step in the physiological stress response, the idea of the GR as an important biomarker in depression has gained popularity. In humans, when the GR binds to glucocorticoids that are released from the adrenal cortex during the stress response, the activated GR-cortisol complex represses expression of proinflammatory proteins in astrocytes and microglial cells and in all cells in the periphery before they are transcribed into proteins.⁹ The GR also has been shown to modulate neurogenesis.⁸ Repeated stress that persists over a long period leads to GR resistance, thereby reducing inhibition of production of proinflammatory cytokines.

Exposure to stress for >21 days leads to overactivity of the HPA axis and GR resistance,¹⁰ which decreases suppression of proinflammatory cytokines. There is evidence that proinflammatory cytokines, tumor necrosis factor-α, and interleukin-6 further induce GR receptor resistance by preventing the cortisol-GR receptor complex from entering cell nuclei and decreasing binding to DNA within the nuclei.¹¹ Dexamethasone, a GR agonist, has been implicated in research studies for potential re-regulation of the HPA axis in depressed persons.¹²

Nerve cell death in the hippocampus

Studies showing reduced hippocampal volume in unipolar depression and a correlation between the number of episodes and a consequence of untreated depression and studies suggesting that treatment can stop or reduce shrinkage,¹³ and recent findings of rapid neurogenesis in hippocampi in response to ketamine, brings our focus to hippocampus in depression.

The greatest density of GRs is found in the hippocampus, which is closely associated with the limbic system.⁷ Therefore, the hippocampus is sensitive to increases in glucocorticoids in the brain and plays a crucial role in regulation of the HPA axis.

Evidence shows that in chronic stress exposure (≥21 days), nerve cells in the hippocampus begin to atrophy and can no longer provide negative feedback inhibition to the hypothalamus, causing HPA axis dysregulation and uncontrolled release of glucocorticoids into the bloodstream and CSF.² In patients with Cushing syndrome, who produce abnormally high levels of glucocorticoid, the incidence of depression is as high as 50%.¹⁴ Similarly, patients treated with glucocorticoids such as prednisone often experience psychiatric symptoms, the most common being depression. Gould found that partial adrenalectomy increased hippocampal neurogenesis in rat brains, indicating the beneficial effect of stress hormone antagonism.⁴ CRH antagonists are being looked at as a promising and less invasive treatment option for depression.

Focus has been diverted to the role of the hippocampus in depression because of its ability to regenerate throughout adulthood, leading potentially to a re-regulation of the HPA axis and subsiding of the stress response, which is universally believed to be the primary precipitating factor in depression onset. Rats require 10 to 21 days of rest to recover from the effects of chronic (21 days) administration of glucocorticoids.¹⁵ If this proves to be a directly proportional relationship, then rats would need an estimated 120 days to recover from 6 months of constant glucocorticoid exposure. Considering that the same is true for humans, current depression treatment programs, which average 6 weeks, are not long enough for adequate recovery.

Antidepressants such as selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclics stimulate neurogenesis in the hippocampus via increases in brain-derived neurotrophic factor (BDNF), suggesting that these neurotransmitters play an important role depression.¹⁶

Repetitive transcranial magnetic stimulation (rTMS), a noninvasive neuromodulation therapy approved to treat major depression, delivers brief magnetic pulses to the limbic structures. Treatment facilitates focal stimulation, rapidly applying electrical charges to the cortical neurons. TMS targets prefrontal circuits of the brain that are underactive during depressive episodes. Recent animal studies have suggested that bromodeoxyuridine (BrdU)-positive cells (newborn cells) are increased significantly in the dentate gyrus, in turn suggesting that hippocampal neurogenesis might be involved in the antidepressant effects of chronic rTMS.¹⁷ Although the underlying therapeutic mechanisms of rTMS treatment of depression remain unclear, it appears that hippocampal neurogenesis might be required to produce the effects of antidepressant treatments, including drugs and electroconvulsive therapy.¹⁷

Selective ‘shunting’ of energy occurs during the stress response

Hormones released from the adrenal glands during stress divert glucose to exercising muscles and the brain’s limbic system, which are involved in the fight-or-flight response.¹⁸ However, metabolic functions and areas of the brain that are not involved in the stress response, such as the cerebral cortex and hippocampus, are deprived of energy as a consequence of this innate selective shunting (Figure 2).¹⁹

Positron-emission tomography (PET) scanning of the resting brain shows that components of the cerebral cortex (prefrontal cortex, hippocampus, striatum) and areas connecting the cerebral cortex to the limbic system exhibit the most energy consumption in the brain during rest (Figure 3).²⁰ PET studies also show that neuronal connections within these energy-demanding areas atrophy more rapidly than in any other area of the brain when their energy supply is reduced or cut off.⁶

When the supply of oxygen and glucose to certain areas of the brain is reduced—such as in traumatic brain injury or stroke—the excitatory neurotransmitter glutamate accumulates in extracellular fluid and causes nerve-cell death.²¹ When a conditioned stimulus is presented during fear acquisition, functional magnetic resonance imaging (fMRI) studies of fear-conditioning have consistently reported, in the prefrontal cortex:

• a decrease in the blood oxygen level-dependent signal, below resting baseline
• a reduction in blood flow (Figure 4).²²

This discovery adds to evidence that demonstrates a decrease in gray-matter density in the frontal lobes as a result of glutaminergic toxicity (Figure 5).

Activation of L-glutamate, believed to play a significant role in depression and other neuropsychiatric disorders, triggers calcium-dependent intracellular responses that “excite cells to death,” so to speak—thereby causing nerve-cell apoptosis and a reduction in synaptic connections between different areas of the brain responsible for learning and memory.²³ Malfunction of these synaptic connections is thought to be partially responsible for depression and other psychiatric disorders.

Excessive activation of N-methyl-d-asparate (NMDA) receptors is thought to be the underlying mechanism that leads to neuronal cell death in glutaminergic toxicity. Therefore, NMDA receptor proteins have become a target in treating neurodegenerative psychiatric illnesses. There is more than one type of NMDA receptor; some of them are excitatory, others are inhibitory. Four compounds have presented as therapeutic candidates for inhibition of NMDA receptor functioning and treatment of depression: those that inhibit glutamate binding, those that block the ion channel, and those that inhibit receptor binding to the terminal regulatory domain.²⁴

Regrettably, these chemical compounds are not receptor-selective, but small structural modifications of these NMDA receptors have been found and lead to significant changes in potency and selectivity. This should serve as a unique starting point for developing highly specific NMDA receptor modulator agents for a variety of neuropsychiatric and neurological conditions. GLYX-13, a derivative of ketamine (an NMDA receptor antagonist), has been implicated for use in treating depression. It has been tested on 2 large phase-II study groups.²⁵

Neuronal circuitry of depression is altered by prolonged stress

Symptoms of depression can be explained by the anatomical circuit shown in Figure 6.^15,20 Impaired concentration, diminished ability to process new information, and decline in memory function are associated with decreased nerve density in the hippocampus, which plays a key role in learning, memory, and encoding of emotionally relevant data into memory.²⁶ The hippocampus interacts with the amygdala to provide input about the context in which stimuli occur.

Depressed people often demonstrate impulsivity and have difficulty controlling expression of emotions—traits that are attributed to increased neuronal density in the amygdala and insula, which has been illustrated in PET scans and voxel-based morphometry in depressed patients.²⁷ These brain areas are implicated in subjective emotional experience, processing of emotional reactions, and impulsive decision-making. The amygdala is normally highly regulated by the prefrontal cortex, which uses rational judgment to interpret stimuli and regulate the expression of emotion.

A study involving a facial expression processing task demonstrated reduced connectivity between the amygdala and prefrontal cortex and increased functional connectivity among the amygdala, hippocampus, and caudate-putamen in depressed patients.²⁴ And in a study that measured white matter conduction in various brain areas in depressed patients, the greatest reduction was found in areas connecting the limbic system to the prefrontal cortex and hippocampus—believed to be caused by stress response-induced ischemic glutaminergic neuroapoptosis.²¹ Such neuroapoptosis might lead to irrational interpretation of stimuli, unchecked expression of emotion, and impulsive thoughts and behavior that are often present in depression and other mood disorders.

Deep brain stimulation (DBS), in which electrodes are implanted in the brain, has proved effective at increasing synaptic connections between the prefrontal cortex and the limbic system when electrodes are placed appropriately.²⁸ Patients with refractory depression who are treated with DBS show increased gray-matter density and functional activity in the prefrontal cortex, hippocampus, and fronto-limbic connections.²⁹ DBS also increases neurotransmission of dopamine, serotonin, and norepinephrine within the fronto-limbic circuitry.³⁰

Identifying risk factors for depression

Genetic risk factors. Forty percent of patients with depression have a first-degree relative with depression, suggesting a strong genetic component.¹⁰ Inherited differences in hippocampal volume, synaptic connections between the prefrontal cortex and amygdala, γ-aminobutyric acid (GABA)/glutamate balance, BDNF neurotransmitter receptors, and anatomic positioning of the limbic system in relation to other brain structures might account for the heritability of psychiatric disorders such as depression.

Evidence has been consistent that hippocampal volume is diminished in the brain of depressed persons. However, there is no prospective cohort study to determine whether people who have lower gray-matter hippocampal density or volume, or both, before depression onset develop symptoms later in life. There also is no study to determine the percentage of people who have lower-than-average hippocampal gray-matter density or volume and who have a first-degree relative with depression. Such studies would yield valuable information about anatomic variables that increase the risk of depression.

It has been proposed that low GABA function is an inherited biomarker for depression. Bjork and co-workers found a lower plasma level of GABA in depressed subjects and in their first-degree relatives, confirming that GABAergic tone might be under genetic control.¹¹ Genetic loci studies in mice have linked depressive-like behavior to GABAergic loci on chromosomes 8 and 11, encoding alpha 1, alpha 6, and gamma subunits of GABA_A receptors.²³

A recent study in humans showed that severe, treatment-resistant depression with anxiety was linked to a mutation in the B1 subunit of the GABA_A receptor. Positive genetic associations were found between polymorphism in human GABA_A receptor subunit genes.¹¹

GABA metabolizing enzymes also can be considered biological modifiers of depression. For example:

• GABA uptake and metabolism is controlled by the enzyme glutamic acid decarboxylase (GAD); depression has been found to be associated with a polymorphism in the GAD67 gene encoding an isoform of GAD.¹¹

• GABA transaminase (GABA-T) is another key enzyme in GABA turnover.³¹ It catabolizes GABA.

We can conclude that, to a high degree, depression depends on GABA production and metabolism.

A variant in the human BDNF gene, in which valine is substituted for methionine in position 66 of the pro-domain of the BDNF protein, is associated with

• a decrease in the production of BDNF

• increased susceptibility to neuropsychiatric disorders, including depression, anxiety disorder, and bipolar disorder (Figure 7).³²

People with the MM allele have been found to have a small hippocampal neuronal density and poor hippocampus-dependent memory function in neuroimaging studies.²³ They also displayed diminished ventromedial prefrontal cortex volume and presented with aversive memory extinction deficit (ie, “holding grudges”).

Another neurotrophic factor, vascular endothelial growth factor (VEGF), is a survival factor for endothelial cells and neurons and a modulator of synaptic transmission. Understanding the molecular and cellular specificity of antidepressant-induced VEGF will be critical to determine its potential as a therapeutic target in depression.³³ Delineating the relationship between VEGF and depression has, ultimately, the potential to shed light on the still elusive neural mechanisms that underlie the pathophysiology of depression and the mechanisms by which antidepressants exert their effects.³⁴

Genetic polymorphisms in monoamine receptors (5-HT2A), transporters (SERTPR, 5-HTTLPR, STin2, rs25531, SLC6A4), and regulatory enzymes should not be overlooked.³⁵ There is reproducible evidence that variability in these polymorphisms are associated with variability in:

• vulnerability to depression

• the response to treatment with existing antidepressant medications.¹

Most studies that look at changes in neuronal circuitry focus on the integrity of synaptic connections between the frontal cortex and limbic system; few of them have closely examined the importance of the anatomic proximity of the 2 regions. It might be that having an amygdala that is relatively closer to the frontal cortex and the hippocampus reduces a person’s risk of depression, and vice versa. This association needs to be investigated further with imaging studies.

Environmental risk factors. The brain is thought to be plastic until age 30.⁵ Plasticity diminishes with age after age 7—except for the hippocampus, which can regenerate throughout life.³⁶ Early life experiences play an important role in forming synaptic connections between the frontal cortex and the limbic system, through a process known as fear conditioning.

Children learn early in life which stimuli are to be perceived as threatening or aversive and how to respond to best preserves their safety and internal sense of well-being. Those who grow up in a hostile environment learn to perceive more stimuli as threatening than children who grow up in a nurturing environment.³² It is possible that the amygdala is larger in children who grow up in less-than-ideal circumstances because this region is constantly being recruited—at the expense of the more rational frontal cortex.

Evidence suggests that these conditions reduce hippocampal neurogenesis³⁷:

• increasing age

• substance abuse (opiates and methamphetamines)

• inadequate housing

• minimal physical activity

• little opportunity for social stimulation

• minimal learning experience.

Bottom Line

Depression has been understood as a neurotransmitter deficiency in the brain; treatments were engineered to increase release, or block degradation, of those neurotransmitters. Novel theories—all interconnected—of the neuroanatomical pathophysiology of depression focus more on differences in neuron density in the brain; effects of stress on neurogenesis and neuronal cell apoptosis; alterations in feedback pathways connecting the pre-frontal cortex to the limbic system; and the role of pro-inflammatory mediators evoked during the stress response.

Related Resources

• Fuchs E. Neurogenesis in the adult brain: is there an association with mental disorders? Eur Arch Psychiatry Clin Neurosci. 2007;257(5):247-249.

• Videbech P, Ravnkilde B. Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatry. 2004; 161(11):1957-1966.

Disclosure

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

Acknowledgement

Anita Rao, second-year medical student, Stritch School of Medicine, Loyola University, Chicago, Illinois, assisted in the preparation of this manuscript.