Current Psychiatry

“Mr. Smith seems somewhat confused today” is one of the most serious and concerning pre-visit reports you can receive from your staff or the patient’s family. Such a descriptor can be confusing—pardon the pun—not only for the patient, but to even seasoned mental health providers.

The term confusion can be code for diagnoses ranging from delirium^a to a progressive neurocognitive disorder (NCD) such as major NCD due to Alzheimer’s disease (AD), or even a more challenging prob­lem such as beclouded dementia (delirium superimposed on demen­tia/NCD). It is essential for all mental health professionals to have an evidence-based approach when encountering signs or symptoms of confusion.

^aICD-10 code R41.0 encompasses Confusion, Other Specified Delirium, or Unspecified Delirium.

CASE REPORT
Ms. T, age 62, has hypothyroidism and bipolar I disorder, most recently depressed, with comorbid generalized anxiety disorder. She has been tak­ing lithium, 600 mg/d, to control her mood symptoms. Her daughter-in-law reports that Ms. T has been exhibiting increasing signs of confusion. During the office evaluation, Ms. T minimizes her symptoms, only describ­ing mild issues with forgetfulness while cooking and concern over increas­ing anxiety. Her daughter-in-law plays a voicemail message from earlier in the week, in which Ms. T’s speech is halting, disorganized, and in a word, confused. I decide to use the mnemonic decision chart MR. MIND (Table 1) to get to the bottom of her recent confusion.

Measure cognition
It is nice to receive advanced warning about a cognitive change or a change in activities of daily living; however, many patients present with subtle, sub-acute changes that are more difficult to assess. When encountering a broad symptom such as “confusion”—which has an equally broad differential diagnosis—systematic assess­ment of the current cognitive state com­pared with the patient’s baseline becomes the first order of business. However, this requires that the patient has had a baseline cognitive assessment.

In my practice, I often administer one of the validated neurocognitive screening instruments when a patient first begins care—even a brief test such as the Mini- Cog (3-item recall plus clock drawing test), which is comparable to longer screening tests at least for NCD/dementia.¹ During a presentation for confusion, a more detailed neurocognitive assessment instrument would be recommended, allowing one to marry the clinical impression with a validated, objective measure. Formal neu­ropsychological testing by a clinical neuro­psychologist is the gold standard, but such testing is time-consuming and expensive and often not readily available. The screen­ing instrument I use for a more thorough evaluation depends on the clinical scenario.

The Six-Item Screener is used in some emergency settings because it is short but boasts a higher sensitivity than the Mini- Cog (94% vs 75%) with similar specificity when screening for cognitive impairment.² The Mini-Mental State Examination (MMSE) is a valuable instrument, although, recently, the Saint Louis University Mental Status Examination has been thought to be better at detecting mild NCD than the MMSE; more data are needed to substan­tiate this claim.³ The Montreal Cognitive Assessment is another validated screening tool that has been shown to be superior to the MMSE in terms of screening for mild cognitive impairment.⁴ The best delirium-specific assessment tool is the Confusion Assessment Method (Table 2).⁵

Review medications
A review of the medication list is not just a Joint Commission mandate (medication reconciliation during each encounter) but is important whenever confusion is noted. Polypharmacy can be a concern, but is not as concerning as the class of medication prescribed, particularly anticholinergic and sedative medications in patients age >65. The Drug Burden Index can be helpful in assessing this risk.⁶ Medications such as the benzodiazepine-receptor agonists, tri­cyclic antidepressants, and antipsychotics should be discontinued if possible, keeping in mind that the addition or subtraction of medications must be done prudently and only after reviewing the evidence and in consultation with the patient. A detailed medication review is as important for confused outpatients as it is for an inpatient case (steps 2 and 3 of the inpatient algo­rithm outlined in Table 3).⁷

In Ms. T’s case, the primary concern on her medication list was that her medical team was prescribing levothyroxine, 112 mcg/d, and desiccated thyroid (combination thy­roxine and triiodothyronine in the form of 20 mg Armour Thyroid), despite a lack of data for such combination therapy. Earlier, I had discontinued lorazepam, leaving lithium, 600 mg/d, quetiapine, 400 mg/d, and escitalopram, 10 mg/d, as her remain­ing psychotropics. Her other medications included atorvastatin, 40 mg/d, for hyper-lipidemia and metformin, 750 mg/d, for type 2 diabetes mellitus.

Medical illness
An organic basis must rank high in the dif­ferential diagnosis if medications are not the culprit. There are myriad medical disorders that can lead to confusion (Table 4).⁸ In an outpatient psychiatric setting, labo­ratory and radiology testing might not be readily available. It then becomes impor­tant to collaborate with a patient’s medical team if any of the following are met:
   •there is high suspicion of a medical cause
   •there could be delays in performing a medical workup
   •a physical examination is needed.

Other laboratory testing could be valu­able depending on the clinical scenario. These include tests such as:
   •drug level monitoring (lithium, val­proic acid, etc.) to assess for toxicity
   •HIV and rapid plasma reagin for sus­pected sexually transmitted infections
   •vitamin levels in patients with poor nutrition or post bariatric surgery
   •erythrocyte sedimentation rate or C-reactive protein, or both, if there are signs of inflammation
   •bacterial culture if blood or tissue infec­tion is a concern.

Esoteric tests include ceruloplasmin (Wilson’s disease), heavy metals screen, and even tests such as anti-gliadin anti­bodies because the prevalence of gluten sensitivity and celiac disease appear to be on the rise and have been associated with neuropsychiatric problems including encephalopathy.¹⁰

Brain imaging is an important consider­ation when a medical differential diagnosis for confusion is formulated. Unfortunately, there is little evidence-based guidance as to when brain imaging should be performed, often leading to overuse of tests such as CT, especially in emergency settings when con­fusion is noted. From a clinical standpoint, a head CT scan often is best ordered for patients who demonstrate an acute change in mental status, are age >70, are receiving anticoagulation, or have sustained trauma to the head. The key concern would be intracranial hemorrhage. However, some data suggest that the best use of head CT is for patients who have an impaired level of consciousness or a new focal neurologic deficit.¹¹

Apart from more acute changes, a brain MRI study is more helpful than a head CT when evaluating the brain parenchyma for more sub-acute diagnoses such as multiple sclerosis or a brain tumor. T2-weighted hyperintensities seen on an MRI are thought to predict an increased risk of stroke, dementia, and death.

Their discov­ery should prompt a detailed evaluation for risk factors of stroke and dementia/NCD.¹²

In Ms. T’s case, she was taking lithium, so it was logical to obtain a trough lith­ium level 12 hours after the last dose and to check kidney function (serum creati­nine to estimate the glomerular filtration rate), which were in the therapeutic/nor­mal range. Her serum lithium level was 0.7 mEq/L. Brain imaging was not ordered, but several other labs (CMP, CBC, hemoglo­bin A1c [HgbA1c], and TSH) were drawn. These labs were notable for HgbA1c of 5.1% (normal <5.7%) and TSH of 0.5 mIU/L (normal level, 1.5 mIU/L), which is low for someone taking thyroid replacement.

I requested that Ms. T stop Armour Thyroid to address the suppressed TSH. I also requested that she stop metfor­min because, although hypoglycemia from metformin monotherapy is uncom­mon, it can happen in older patients. Hypoglycemia associated with metformin also can occur in situations when caloric intake is deficient or when metformin is used in combination with other drugs such as sulfonylureas (ie, glipizide), beta-adrenergic blocking drugs, angiotensin-converting enzyme inhibitors, or even nonsteroidal anti-inflammatory drugs.¹³

Identifying overlapping psychiatric (or psychological) illness
Symptoms of depression, anxiety, psycho­sis, and even dissociation can present as con­fusion. The term pseudodementia describes patients who exhibit cognitive symptoms consistent with NCD but could improve once the underlying mood, thought, anxi­ety, or personality disorder is treated.

For example, a patient with depression typically exhibits neurovegetative symp­toms—such as poor sleep or appetite— amotivation, and low energy. All of these can lead to abrupt-onset cognitive changes, which are a hallmark of pseudodementia rather than the more insidious pattern of mild NCD. In cases of pseudodementia, neurocognitive testing will show impair­ment that often rapidly improves after the primary psychiatric (or psychological) issue is rectified. Making a diagnosis of pseu­dodementia at the initial presentation is difficult because neurocognitive tests such as the MMSE often fail to separate depres­sion from true cognitive changes.¹⁴ Such a diagnosis typically requires hindsight. Yet, one must also keep in mind that pseudode­mentia may be part of a NCD prodrome.¹⁵

Conversion disorder as well as the disso­ciative disorders and substance-related dis­orders are notorious for causing confusion. In Ms. T’s case, pseudodementia stemming from her underlying bipolar disorder and anxiety figured prominently in the differ­ential diagnosis, but she did not have any other overt psychopathology, personality disorder, or signs of malingering to further complicate her picture.

Notebook. I recommend that my patients keep a small notebook to record medical data ranging from blood pressure and gly­cemic measurements to details about sleep and dietary intake. Such data comprise the necessary metrics to properly assess target conditions and then track changes once treatment is initiated. This exercise not only yields much-needed detail about the patient’s condition for the clinician; the act of journaling also can be therapeutic for the writer through a process known as experi­mental disclosure, in which writing down one’s thoughts and observations has a posi­tive impact on the writer’s physical health and psychology.¹⁶

Diagnosis. The first rule in medicine (perhaps the second, behind primum non nocere) is to determine what you are treat­ing before beginning treatment (decernite quid tractemus, prius cura ministrandi, for Latin buffs). This means trying to fash­ion the best diagnostic label, even if it is merely a place-holder, while assessment of the confused state continues. DSM-5 has attempted to remove stigma from several neuropsychiatric disorders. On the cog­nition front, the new name for dementia is “neurocognitive disorder (NCD),” the umbrella term that focuses on the decline from a previous level of cognitive func­tioning. NCD has been divided into mild or major cognitive impairment headings either “with” or “without behavioral dis­turbance” subspecifiers.¹⁷

Aside from NCD, there are several other diagnoses in the differential for confusion. Delirium remains the most prominent and focuses on disturbances in attention and orientation that develops over a short period of time, with a change seen in an additional cognitive domain, such as memory, but not in the context of a severely reduced level of arousal such as coma. Subjective cognitive impairment (SCI) is when subjective complaints of cog­nitive impairment are hallmark compared with objective findings—with evidence suggesting that the presence of SCI could predict a 4.5 times higher rate of develop­ing mild cognitive impairment (MCI) over 7 years.¹⁸ MCI was originally used to describe the early prodrome of AD, minus functional decline.


Treatment
After even a provisional diagnosis comes the final, all-important challenge: treating the neuropsychiatric symptoms (NPS) of the confused patient. NPS are nearly universal in NCD/delirium throughout the course of illness. There are no FDA-approved treat­ments for the NPS associated with these conditions. In terms of treating delirium, the best approach is to treat the underlying medical condition. For control of behavior, which can range from agitated to psychotic to hypoactive, nonpharmacotherapeutic interventions are paramount; they include making sure that the patient is at the appro­priate level of care, which, for the confused outpatient, could mean hospitalization. Ensuring proper nutrition, hydration, sen­sory care (hearing aids, glasses, etc.), and stability in ambulation must be done before considering pharmacotherapy.

Antipsychotic use has been the mainstay of drug treatment of behavioral dyscontrol. Haloperidol has been the traditional go-to medication because there is no evidence that low-dose haloperidol (<3 mg/d) has any different efficacy compared with the atypical antipsychotics or has a greater fre­quency of adverse drug effects. However, high-dose haloperidol (>4.5 mg/d) was associated with a greater incidence of adverse effects, mainly parkinsonism, than atypical antipsychotics.¹⁹ Neither the typi­cal nor atypical antipsychotics have shown mortality benefit—the real outcome mea­sure of interest.

In terms of treating major (or minor) NCD, there are only 2 FDA-approved medication classes: cholinesterase inhibi­tors (donepezil, galantamine, rivastig­mine, etc.) and memantine. However, these medication classes—even when combined together—have only shown marginal benefit in terms of improving cognition. Worse, even when given early in the course of illness they do not reduce the rate of NCD. For pseudodementia, selec­tive serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors tend to form the mainstay of treating underlying depression or anxiety leading to cognitive changes. Preliminary data suggest that some SSRIs might improve cognition in terms of process­ing speed, verbal learning, and memory.²⁰ More studies are needed before definitive conclusions can be drawn.

For the confused patient, a personalized therapeutic program, in which multiple interventions are considered at once (tar­geting all areas of the patient’s life) is gain­ing research traction. For example, a novel, comprehensive program involving mul­tiple modalities designed to achieve meta­bolic enhancement for neurodegeneration (MEND) recently has shown robust benefit for patients with AD, MCI, and SCI.²¹ Using an individual approach to improve diet, activity, sleep, metabolic status including body mass index, and several other mark­ers that affect neural plasticity, researchers demonstrated symptom improvement in 9 of 10 study patients.

Yet, some of the interventions, such as the use of statins for hyperlipidemia, remain controversial, with some studies suggesting that they help cognition,^22,23 and others showing no association.²⁴ The researchers caution that further research is warranted before costly dementia pre­vention trials with statins are undertaken. It does not appear that there are current MEND-type research projects in delirium but it’s to be hoped that we will see these in the future.

In the case of Ms. T, the cause of delir­ium vs mild NCD was thought to be mul­tifactorial. Discontinuing Armour Thyroid and metformin—symptoms of hypoglyce­mia emerged as a leading concern—were simple adjustments that led to resolution of the most concerning elements of her confusion. She continued her other psy­chotropics, although there might be mild residual cognitive issues that warrant close observation.

Related Resources
• Lin JS, O’Connor E, Rossum RC, et al. Screening for cognitive impairment in older adults: an evidence update for the U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality (US); 2013.
• Grover S, Kate N. Assessment scales for delirium: a review. World J Psychiatry. 2012;2(4):58-70.

Drug Brand Names
Atorvastatin • Lipitor                           Lithium • Eskalith, Lithobid
Donepezil • Aricept                              Lorazepam • Ativan
Escitalopram • Lexapro                        Memantine • Namenda
Flumazenil • Romazicon                       Metformin • Glucophage
Galantamine • Razadyne                      Naloxone • Narcan
Glipizide • Glucotrol                             Physostigmine • Antilirium
Haloperidol • Haldol                             Quetiapine • Seroquel
Levothyroxine • Levoxyl, Synthroid       Rivastigmine • Exelon
Lithium • Eskalith, Lithobid                   Valproic acid • Depakene

Disclosure
Dr. Raj is a speaker for Actavis Pharmaceuticals, AstraZeneca, and Merck.

“Mr. Smith seems somewhat confused today” is one of the most serious and concerning pre-visit reports you can receive from your staff or the patient’s family. Such a descriptor can be confusing—pardon the pun—not only for the patient, but to even seasoned mental health providers.

The term confusion can be code for diagnoses ranging from delirium^a to a progressive neurocognitive disorder (NCD) such as major NCD due to Alzheimer’s disease (AD), or even a more challenging prob­lem such as beclouded dementia (delirium superimposed on demen­tia/NCD). It is essential for all mental health professionals to have an evidence-based approach when encountering signs or symptoms of confusion.

^aICD-10 code R41.0 encompasses Confusion, Other Specified Delirium, or Unspecified Delirium.

CASE REPORT
Ms. T, age 62, has hypothyroidism and bipolar I disorder, most recently depressed, with comorbid generalized anxiety disorder. She has been tak­ing lithium, 600 mg/d, to control her mood symptoms. Her daughter-in-law reports that Ms. T has been exhibiting increasing signs of confusion. During the office evaluation, Ms. T minimizes her symptoms, only describ­ing mild issues with forgetfulness while cooking and concern over increas­ing anxiety. Her daughter-in-law plays a voicemail message from earlier in the week, in which Ms. T’s speech is halting, disorganized, and in a word, confused. I decide to use the mnemonic decision chart MR. MIND (Table 1) to get to the bottom of her recent confusion.

Measure cognition
It is nice to receive advanced warning about a cognitive change or a change in activities of daily living; however, many patients present with subtle, sub-acute changes that are more difficult to assess. When encountering a broad symptom such as “confusion”—which has an equally broad differential diagnosis—systematic assess­ment of the current cognitive state com­pared with the patient’s baseline becomes the first order of business. However, this requires that the patient has had a baseline cognitive assessment.

In my practice, I often administer one of the validated neurocognitive screening instruments when a patient first begins care—even a brief test such as the Mini- Cog (3-item recall plus clock drawing test), which is comparable to longer screening tests at least for NCD/dementia.¹ During a presentation for confusion, a more detailed neurocognitive assessment instrument would be recommended, allowing one to marry the clinical impression with a validated, objective measure. Formal neu­ropsychological testing by a clinical neuro­psychologist is the gold standard, but such testing is time-consuming and expensive and often not readily available. The screen­ing instrument I use for a more thorough evaluation depends on the clinical scenario.

The Six-Item Screener is used in some emergency settings because it is short but boasts a higher sensitivity than the Mini- Cog (94% vs 75%) with similar specificity when screening for cognitive impairment.² The Mini-Mental State Examination (MMSE) is a valuable instrument, although, recently, the Saint Louis University Mental Status Examination has been thought to be better at detecting mild NCD than the MMSE; more data are needed to substan­tiate this claim.³ The Montreal Cognitive Assessment is another validated screening tool that has been shown to be superior to the MMSE in terms of screening for mild cognitive impairment.⁴ The best delirium-specific assessment tool is the Confusion Assessment Method (Table 2).⁵

Review medications
A review of the medication list is not just a Joint Commission mandate (medication reconciliation during each encounter) but is important whenever confusion is noted. Polypharmacy can be a concern, but is not as concerning as the class of medication prescribed, particularly anticholinergic and sedative medications in patients age >65. The Drug Burden Index can be helpful in assessing this risk.⁶ Medications such as the benzodiazepine-receptor agonists, tri­cyclic antidepressants, and antipsychotics should be discontinued if possible, keeping in mind that the addition or subtraction of medications must be done prudently and only after reviewing the evidence and in consultation with the patient. A detailed medication review is as important for confused outpatients as it is for an inpatient case (steps 2 and 3 of the inpatient algo­rithm outlined in Table 3).⁷

In Ms. T’s case, the primary concern on her medication list was that her medical team was prescribing levothyroxine, 112 mcg/d, and desiccated thyroid (combination thy­roxine and triiodothyronine in the form of 20 mg Armour Thyroid), despite a lack of data for such combination therapy. Earlier, I had discontinued lorazepam, leaving lithium, 600 mg/d, quetiapine, 400 mg/d, and escitalopram, 10 mg/d, as her remain­ing psychotropics. Her other medications included atorvastatin, 40 mg/d, for hyper-lipidemia and metformin, 750 mg/d, for type 2 diabetes mellitus.

Medical illness
An organic basis must rank high in the dif­ferential diagnosis if medications are not the culprit. There are myriad medical disorders that can lead to confusion (Table 4).⁸ In an outpatient psychiatric setting, labo­ratory and radiology testing might not be readily available. It then becomes impor­tant to collaborate with a patient’s medical team if any of the following are met:
   •there is high suspicion of a medical cause
   •there could be delays in performing a medical workup
   •a physical examination is needed.

Other laboratory testing could be valu­able depending on the clinical scenario. These include tests such as:
   •drug level monitoring (lithium, val­proic acid, etc.) to assess for toxicity
   •HIV and rapid plasma reagin for sus­pected sexually transmitted infections
   •vitamin levels in patients with poor nutrition or post bariatric surgery
   •erythrocyte sedimentation rate or C-reactive protein, or both, if there are signs of inflammation
   •bacterial culture if blood or tissue infec­tion is a concern.

Esoteric tests include ceruloplasmin (Wilson’s disease), heavy metals screen, and even tests such as anti-gliadin anti­bodies because the prevalence of gluten sensitivity and celiac disease appear to be on the rise and have been associated with neuropsychiatric problems including encephalopathy.¹⁰

Brain imaging is an important consider­ation when a medical differential diagnosis for confusion is formulated. Unfortunately, there is little evidence-based guidance as to when brain imaging should be performed, often leading to overuse of tests such as CT, especially in emergency settings when con­fusion is noted. From a clinical standpoint, a head CT scan often is best ordered for patients who demonstrate an acute change in mental status, are age >70, are receiving anticoagulation, or have sustained trauma to the head. The key concern would be intracranial hemorrhage. However, some data suggest that the best use of head CT is for patients who have an impaired level of consciousness or a new focal neurologic deficit.¹¹

Apart from more acute changes, a brain MRI study is more helpful than a head CT when evaluating the brain parenchyma for more sub-acute diagnoses such as multiple sclerosis or a brain tumor. T2-weighted hyperintensities seen on an MRI are thought to predict an increased risk of stroke, dementia, and death.

Their discov­ery should prompt a detailed evaluation for risk factors of stroke and dementia/NCD.¹²

In Ms. T’s case, she was taking lithium, so it was logical to obtain a trough lith­ium level 12 hours after the last dose and to check kidney function (serum creati­nine to estimate the glomerular filtration rate), which were in the therapeutic/nor­mal range. Her serum lithium level was 0.7 mEq/L. Brain imaging was not ordered, but several other labs (CMP, CBC, hemoglo­bin A1c [HgbA1c], and TSH) were drawn. These labs were notable for HgbA1c of 5.1% (normal <5.7%) and TSH of 0.5 mIU/L (normal level, 1.5 mIU/L), which is low for someone taking thyroid replacement.

I requested that Ms. T stop Armour Thyroid to address the suppressed TSH. I also requested that she stop metfor­min because, although hypoglycemia from metformin monotherapy is uncom­mon, it can happen in older patients. Hypoglycemia associated with metformin also can occur in situations when caloric intake is deficient or when metformin is used in combination with other drugs such as sulfonylureas (ie, glipizide), beta-adrenergic blocking drugs, angiotensin-converting enzyme inhibitors, or even nonsteroidal anti-inflammatory drugs.¹³

Identifying overlapping psychiatric (or psychological) illness
Symptoms of depression, anxiety, psycho­sis, and even dissociation can present as con­fusion. The term pseudodementia describes patients who exhibit cognitive symptoms consistent with NCD but could improve once the underlying mood, thought, anxi­ety, or personality disorder is treated.

For example, a patient with depression typically exhibits neurovegetative symp­toms—such as poor sleep or appetite— amotivation, and low energy. All of these can lead to abrupt-onset cognitive changes, which are a hallmark of pseudodementia rather than the more insidious pattern of mild NCD. In cases of pseudodementia, neurocognitive testing will show impair­ment that often rapidly improves after the primary psychiatric (or psychological) issue is rectified. Making a diagnosis of pseu­dodementia at the initial presentation is difficult because neurocognitive tests such as the MMSE often fail to separate depres­sion from true cognitive changes.¹⁴ Such a diagnosis typically requires hindsight. Yet, one must also keep in mind that pseudode­mentia may be part of a NCD prodrome.¹⁵

Conversion disorder as well as the disso­ciative disorders and substance-related dis­orders are notorious for causing confusion. In Ms. T’s case, pseudodementia stemming from her underlying bipolar disorder and anxiety figured prominently in the differ­ential diagnosis, but she did not have any other overt psychopathology, personality disorder, or signs of malingering to further complicate her picture.

Notebook. I recommend that my patients keep a small notebook to record medical data ranging from blood pressure and gly­cemic measurements to details about sleep and dietary intake. Such data comprise the necessary metrics to properly assess target conditions and then track changes once treatment is initiated. This exercise not only yields much-needed detail about the patient’s condition for the clinician; the act of journaling also can be therapeutic for the writer through a process known as experi­mental disclosure, in which writing down one’s thoughts and observations has a posi­tive impact on the writer’s physical health and psychology.¹⁶

Diagnosis. The first rule in medicine (perhaps the second, behind primum non nocere) is to determine what you are treat­ing before beginning treatment (decernite quid tractemus, prius cura ministrandi, for Latin buffs). This means trying to fash­ion the best diagnostic label, even if it is merely a place-holder, while assessment of the confused state continues. DSM-5 has attempted to remove stigma from several neuropsychiatric disorders. On the cog­nition front, the new name for dementia is “neurocognitive disorder (NCD),” the umbrella term that focuses on the decline from a previous level of cognitive func­tioning. NCD has been divided into mild or major cognitive impairment headings either “with” or “without behavioral dis­turbance” subspecifiers.¹⁷

Aside from NCD, there are several other diagnoses in the differential for confusion. Delirium remains the most prominent and focuses on disturbances in attention and orientation that develops over a short period of time, with a change seen in an additional cognitive domain, such as memory, but not in the context of a severely reduced level of arousal such as coma. Subjective cognitive impairment (SCI) is when subjective complaints of cog­nitive impairment are hallmark compared with objective findings—with evidence suggesting that the presence of SCI could predict a 4.5 times higher rate of develop­ing mild cognitive impairment (MCI) over 7 years.¹⁸ MCI was originally used to describe the early prodrome of AD, minus functional decline.


Treatment
After even a provisional diagnosis comes the final, all-important challenge: treating the neuropsychiatric symptoms (NPS) of the confused patient. NPS are nearly universal in NCD/delirium throughout the course of illness. There are no FDA-approved treat­ments for the NPS associated with these conditions. In terms of treating delirium, the best approach is to treat the underlying medical condition. For control of behavior, which can range from agitated to psychotic to hypoactive, nonpharmacotherapeutic interventions are paramount; they include making sure that the patient is at the appro­priate level of care, which, for the confused outpatient, could mean hospitalization. Ensuring proper nutrition, hydration, sen­sory care (hearing aids, glasses, etc.), and stability in ambulation must be done before considering pharmacotherapy.

Antipsychotic use has been the mainstay of drug treatment of behavioral dyscontrol. Haloperidol has been the traditional go-to medication because there is no evidence that low-dose haloperidol (<3 mg/d) has any different efficacy compared with the atypical antipsychotics or has a greater fre­quency of adverse drug effects. However, high-dose haloperidol (>4.5 mg/d) was associated with a greater incidence of adverse effects, mainly parkinsonism, than atypical antipsychotics.¹⁹ Neither the typi­cal nor atypical antipsychotics have shown mortality benefit—the real outcome mea­sure of interest.

In terms of treating major (or minor) NCD, there are only 2 FDA-approved medication classes: cholinesterase inhibi­tors (donepezil, galantamine, rivastig­mine, etc.) and memantine. However, these medication classes—even when combined together—have only shown marginal benefit in terms of improving cognition. Worse, even when given early in the course of illness they do not reduce the rate of NCD. For pseudodementia, selec­tive serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors tend to form the mainstay of treating underlying depression or anxiety leading to cognitive changes. Preliminary data suggest that some SSRIs might improve cognition in terms of process­ing speed, verbal learning, and memory.²⁰ More studies are needed before definitive conclusions can be drawn.

For the confused patient, a personalized therapeutic program, in which multiple interventions are considered at once (tar­geting all areas of the patient’s life) is gain­ing research traction. For example, a novel, comprehensive program involving mul­tiple modalities designed to achieve meta­bolic enhancement for neurodegeneration (MEND) recently has shown robust benefit for patients with AD, MCI, and SCI.²¹ Using an individual approach to improve diet, activity, sleep, metabolic status including body mass index, and several other mark­ers that affect neural plasticity, researchers demonstrated symptom improvement in 9 of 10 study patients.

Yet, some of the interventions, such as the use of statins for hyperlipidemia, remain controversial, with some studies suggesting that they help cognition,^22,23 and others showing no association.²⁴ The researchers caution that further research is warranted before costly dementia pre­vention trials with statins are undertaken. It does not appear that there are current MEND-type research projects in delirium but it’s to be hoped that we will see these in the future.

In the case of Ms. T, the cause of delir­ium vs mild NCD was thought to be mul­tifactorial. Discontinuing Armour Thyroid and metformin—symptoms of hypoglyce­mia emerged as a leading concern—were simple adjustments that led to resolution of the most concerning elements of her confusion. She continued her other psy­chotropics, although there might be mild residual cognitive issues that warrant close observation.

Related Resources
• Lin JS, O’Connor E, Rossum RC, et al. Screening for cognitive impairment in older adults: an evidence update for the U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality (US); 2013.
• Grover S, Kate N. Assessment scales for delirium: a review. World J Psychiatry. 2012;2(4):58-70.

Drug Brand Names
Atorvastatin • Lipitor                           Lithium • Eskalith, Lithobid
Donepezil • Aricept                              Lorazepam • Ativan
Escitalopram • Lexapro                        Memantine • Namenda
Flumazenil • Romazicon                       Metformin • Glucophage
Galantamine • Razadyne                      Naloxone • Narcan
Glipizide • Glucotrol                             Physostigmine • Antilirium
Haloperidol • Haldol                             Quetiapine • Seroquel
Levothyroxine • Levoxyl, Synthroid       Rivastigmine • Exelon
Lithium • Eskalith, Lithobid                   Valproic acid • Depakene

Disclosure
Dr. Raj is a speaker for Actavis Pharmaceuticals, AstraZeneca, and Merck.

“Mr. Smith seems somewhat confused today” is one of the most serious and concerning pre-visit reports you can receive from your staff or the patient’s family. Such a descriptor can be confusing—pardon the pun—not only for the patient, but to even seasoned mental health providers.

The term confusion can be code for diagnoses ranging from delirium^a to a progressive neurocognitive disorder (NCD) such as major NCD due to Alzheimer’s disease (AD), or even a more challenging prob­lem such as beclouded dementia (delirium superimposed on demen­tia/NCD). It is essential for all mental health professionals to have an evidence-based approach when encountering signs or symptoms of confusion.

^aICD-10 code R41.0 encompasses Confusion, Other Specified Delirium, or Unspecified Delirium.

CASE REPORT
Ms. T, age 62, has hypothyroidism and bipolar I disorder, most recently depressed, with comorbid generalized anxiety disorder. She has been tak­ing lithium, 600 mg/d, to control her mood symptoms. Her daughter-in-law reports that Ms. T has been exhibiting increasing signs of confusion. During the office evaluation, Ms. T minimizes her symptoms, only describ­ing mild issues with forgetfulness while cooking and concern over increas­ing anxiety. Her daughter-in-law plays a voicemail message from earlier in the week, in which Ms. T’s speech is halting, disorganized, and in a word, confused. I decide to use the mnemonic decision chart MR. MIND (Table 1) to get to the bottom of her recent confusion.

Measure cognition
It is nice to receive advanced warning about a cognitive change or a change in activities of daily living; however, many patients present with subtle, sub-acute changes that are more difficult to assess. When encountering a broad symptom such as “confusion”—which has an equally broad differential diagnosis—systematic assess­ment of the current cognitive state com­pared with the patient’s baseline becomes the first order of business. However, this requires that the patient has had a baseline cognitive assessment.

In my practice, I often administer one of the validated neurocognitive screening instruments when a patient first begins care—even a brief test such as the Mini- Cog (3-item recall plus clock drawing test), which is comparable to longer screening tests at least for NCD/dementia.¹ During a presentation for confusion, a more detailed neurocognitive assessment instrument would be recommended, allowing one to marry the clinical impression with a validated, objective measure. Formal neu­ropsychological testing by a clinical neuro­psychologist is the gold standard, but such testing is time-consuming and expensive and often not readily available. The screen­ing instrument I use for a more thorough evaluation depends on the clinical scenario.

The Six-Item Screener is used in some emergency settings because it is short but boasts a higher sensitivity than the Mini- Cog (94% vs 75%) with similar specificity when screening for cognitive impairment.² The Mini-Mental State Examination (MMSE) is a valuable instrument, although, recently, the Saint Louis University Mental Status Examination has been thought to be better at detecting mild NCD than the MMSE; more data are needed to substan­tiate this claim.³ The Montreal Cognitive Assessment is another validated screening tool that has been shown to be superior to the MMSE in terms of screening for mild cognitive impairment.⁴ The best delirium-specific assessment tool is the Confusion Assessment Method (Table 2).⁵

Review medications
A review of the medication list is not just a Joint Commission mandate (medication reconciliation during each encounter) but is important whenever confusion is noted. Polypharmacy can be a concern, but is not as concerning as the class of medication prescribed, particularly anticholinergic and sedative medications in patients age >65. The Drug Burden Index can be helpful in assessing this risk.⁶ Medications such as the benzodiazepine-receptor agonists, tri­cyclic antidepressants, and antipsychotics should be discontinued if possible, keeping in mind that the addition or subtraction of medications must be done prudently and only after reviewing the evidence and in consultation with the patient. A detailed medication review is as important for confused outpatients as it is for an inpatient case (steps 2 and 3 of the inpatient algo­rithm outlined in Table 3).⁷

In Ms. T’s case, the primary concern on her medication list was that her medical team was prescribing levothyroxine, 112 mcg/d, and desiccated thyroid (combination thy­roxine and triiodothyronine in the form of 20 mg Armour Thyroid), despite a lack of data for such combination therapy. Earlier, I had discontinued lorazepam, leaving lithium, 600 mg/d, quetiapine, 400 mg/d, and escitalopram, 10 mg/d, as her remain­ing psychotropics. Her other medications included atorvastatin, 40 mg/d, for hyper-lipidemia and metformin, 750 mg/d, for type 2 diabetes mellitus.

Medical illness
An organic basis must rank high in the dif­ferential diagnosis if medications are not the culprit. There are myriad medical disorders that can lead to confusion (Table 4).⁸ In an outpatient psychiatric setting, labo­ratory and radiology testing might not be readily available. It then becomes impor­tant to collaborate with a patient’s medical team if any of the following are met:
   •there is high suspicion of a medical cause
   •there could be delays in performing a medical workup
   •a physical examination is needed.

Other laboratory testing could be valu­able depending on the clinical scenario. These include tests such as:
   •drug level monitoring (lithium, val­proic acid, etc.) to assess for toxicity
   •HIV and rapid plasma reagin for sus­pected sexually transmitted infections
   •vitamin levels in patients with poor nutrition or post bariatric surgery
   •erythrocyte sedimentation rate or C-reactive protein, or both, if there are signs of inflammation
   •bacterial culture if blood or tissue infec­tion is a concern.

Esoteric tests include ceruloplasmin (Wilson’s disease), heavy metals screen, and even tests such as anti-gliadin anti­bodies because the prevalence of gluten sensitivity and celiac disease appear to be on the rise and have been associated with neuropsychiatric problems including encephalopathy.¹⁰

Brain imaging is an important consider­ation when a medical differential diagnosis for confusion is formulated. Unfortunately, there is little evidence-based guidance as to when brain imaging should be performed, often leading to overuse of tests such as CT, especially in emergency settings when con­fusion is noted. From a clinical standpoint, a head CT scan often is best ordered for patients who demonstrate an acute change in mental status, are age >70, are receiving anticoagulation, or have sustained trauma to the head. The key concern would be intracranial hemorrhage. However, some data suggest that the best use of head CT is for patients who have an impaired level of consciousness or a new focal neurologic deficit.¹¹

Apart from more acute changes, a brain MRI study is more helpful than a head CT when evaluating the brain parenchyma for more sub-acute diagnoses such as multiple sclerosis or a brain tumor. T2-weighted hyperintensities seen on an MRI are thought to predict an increased risk of stroke, dementia, and death.

Their discov­ery should prompt a detailed evaluation for risk factors of stroke and dementia/NCD.¹²

In Ms. T’s case, she was taking lithium, so it was logical to obtain a trough lith­ium level 12 hours after the last dose and to check kidney function (serum creati­nine to estimate the glomerular filtration rate), which were in the therapeutic/nor­mal range. Her serum lithium level was 0.7 mEq/L. Brain imaging was not ordered, but several other labs (CMP, CBC, hemoglo­bin A1c [HgbA1c], and TSH) were drawn. These labs were notable for HgbA1c of 5.1% (normal <5.7%) and TSH of 0.5 mIU/L (normal level, 1.5 mIU/L), which is low for someone taking thyroid replacement.

I requested that Ms. T stop Armour Thyroid to address the suppressed TSH. I also requested that she stop metfor­min because, although hypoglycemia from metformin monotherapy is uncom­mon, it can happen in older patients. Hypoglycemia associated with metformin also can occur in situations when caloric intake is deficient or when metformin is used in combination with other drugs such as sulfonylureas (ie, glipizide), beta-adrenergic blocking drugs, angiotensin-converting enzyme inhibitors, or even nonsteroidal anti-inflammatory drugs.¹³

Identifying overlapping psychiatric (or psychological) illness
Symptoms of depression, anxiety, psycho­sis, and even dissociation can present as con­fusion. The term pseudodementia describes patients who exhibit cognitive symptoms consistent with NCD but could improve once the underlying mood, thought, anxi­ety, or personality disorder is treated.

For example, a patient with depression typically exhibits neurovegetative symp­toms—such as poor sleep or appetite— amotivation, and low energy. All of these can lead to abrupt-onset cognitive changes, which are a hallmark of pseudodementia rather than the more insidious pattern of mild NCD. In cases of pseudodementia, neurocognitive testing will show impair­ment that often rapidly improves after the primary psychiatric (or psychological) issue is rectified. Making a diagnosis of pseu­dodementia at the initial presentation is difficult because neurocognitive tests such as the MMSE often fail to separate depres­sion from true cognitive changes.¹⁴ Such a diagnosis typically requires hindsight. Yet, one must also keep in mind that pseudode­mentia may be part of a NCD prodrome.¹⁵

Conversion disorder as well as the disso­ciative disorders and substance-related dis­orders are notorious for causing confusion. In Ms. T’s case, pseudodementia stemming from her underlying bipolar disorder and anxiety figured prominently in the differ­ential diagnosis, but she did not have any other overt psychopathology, personality disorder, or signs of malingering to further complicate her picture.

Notebook. I recommend that my patients keep a small notebook to record medical data ranging from blood pressure and gly­cemic measurements to details about sleep and dietary intake. Such data comprise the necessary metrics to properly assess target conditions and then track changes once treatment is initiated. This exercise not only yields much-needed detail about the patient’s condition for the clinician; the act of journaling also can be therapeutic for the writer through a process known as experi­mental disclosure, in which writing down one’s thoughts and observations has a posi­tive impact on the writer’s physical health and psychology.¹⁶

Diagnosis. The first rule in medicine (perhaps the second, behind primum non nocere) is to determine what you are treat­ing before beginning treatment (decernite quid tractemus, prius cura ministrandi, for Latin buffs). This means trying to fash­ion the best diagnostic label, even if it is merely a place-holder, while assessment of the confused state continues. DSM-5 has attempted to remove stigma from several neuropsychiatric disorders. On the cog­nition front, the new name for dementia is “neurocognitive disorder (NCD),” the umbrella term that focuses on the decline from a previous level of cognitive func­tioning. NCD has been divided into mild or major cognitive impairment headings either “with” or “without behavioral dis­turbance” subspecifiers.¹⁷

Aside from NCD, there are several other diagnoses in the differential for confusion. Delirium remains the most prominent and focuses on disturbances in attention and orientation that develops over a short period of time, with a change seen in an additional cognitive domain, such as memory, but not in the context of a severely reduced level of arousal such as coma. Subjective cognitive impairment (SCI) is when subjective complaints of cog­nitive impairment are hallmark compared with objective findings—with evidence suggesting that the presence of SCI could predict a 4.5 times higher rate of develop­ing mild cognitive impairment (MCI) over 7 years.¹⁸ MCI was originally used to describe the early prodrome of AD, minus functional decline.


Treatment
After even a provisional diagnosis comes the final, all-important challenge: treating the neuropsychiatric symptoms (NPS) of the confused patient. NPS are nearly universal in NCD/delirium throughout the course of illness. There are no FDA-approved treat­ments for the NPS associated with these conditions. In terms of treating delirium, the best approach is to treat the underlying medical condition. For control of behavior, which can range from agitated to psychotic to hypoactive, nonpharmacotherapeutic interventions are paramount; they include making sure that the patient is at the appro­priate level of care, which, for the confused outpatient, could mean hospitalization. Ensuring proper nutrition, hydration, sen­sory care (hearing aids, glasses, etc.), and stability in ambulation must be done before considering pharmacotherapy.

Antipsychotic use has been the mainstay of drug treatment of behavioral dyscontrol. Haloperidol has been the traditional go-to medication because there is no evidence that low-dose haloperidol (<3 mg/d) has any different efficacy compared with the atypical antipsychotics or has a greater fre­quency of adverse drug effects. However, high-dose haloperidol (>4.5 mg/d) was associated with a greater incidence of adverse effects, mainly parkinsonism, than atypical antipsychotics.¹⁹ Neither the typi­cal nor atypical antipsychotics have shown mortality benefit—the real outcome mea­sure of interest.

In terms of treating major (or minor) NCD, there are only 2 FDA-approved medication classes: cholinesterase inhibi­tors (donepezil, galantamine, rivastig­mine, etc.) and memantine. However, these medication classes—even when combined together—have only shown marginal benefit in terms of improving cognition. Worse, even when given early in the course of illness they do not reduce the rate of NCD. For pseudodementia, selec­tive serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors tend to form the mainstay of treating underlying depression or anxiety leading to cognitive changes. Preliminary data suggest that some SSRIs might improve cognition in terms of process­ing speed, verbal learning, and memory.²⁰ More studies are needed before definitive conclusions can be drawn.

For the confused patient, a personalized therapeutic program, in which multiple interventions are considered at once (tar­geting all areas of the patient’s life) is gain­ing research traction. For example, a novel, comprehensive program involving mul­tiple modalities designed to achieve meta­bolic enhancement for neurodegeneration (MEND) recently has shown robust benefit for patients with AD, MCI, and SCI.²¹ Using an individual approach to improve diet, activity, sleep, metabolic status including body mass index, and several other mark­ers that affect neural plasticity, researchers demonstrated symptom improvement in 9 of 10 study patients.

Yet, some of the interventions, such as the use of statins for hyperlipidemia, remain controversial, with some studies suggesting that they help cognition,^22,23 and others showing no association.²⁴ The researchers caution that further research is warranted before costly dementia pre­vention trials with statins are undertaken. It does not appear that there are current MEND-type research projects in delirium but it’s to be hoped that we will see these in the future.

In the case of Ms. T, the cause of delir­ium vs mild NCD was thought to be mul­tifactorial. Discontinuing Armour Thyroid and metformin—symptoms of hypoglyce­mia emerged as a leading concern—were simple adjustments that led to resolution of the most concerning elements of her confusion. She continued her other psy­chotropics, although there might be mild residual cognitive issues that warrant close observation.

Related Resources
• Lin JS, O’Connor E, Rossum RC, et al. Screening for cognitive impairment in older adults: an evidence update for the U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality (US); 2013.
• Grover S, Kate N. Assessment scales for delirium: a review. World J Psychiatry. 2012;2(4):58-70.

Drug Brand Names
Atorvastatin • Lipitor                           Lithium • Eskalith, Lithobid
Donepezil • Aricept                              Lorazepam • Ativan
Escitalopram • Lexapro                        Memantine • Namenda
Flumazenil • Romazicon                       Metformin • Glucophage
Galantamine • Razadyne                      Naloxone • Narcan
Glipizide • Glucotrol                             Physostigmine • Antilirium
Haloperidol • Haldol                             Quetiapine • Seroquel
Levothyroxine • Levoxyl, Synthroid       Rivastigmine • Exelon
Lithium • Eskalith, Lithobid                   Valproic acid • Depakene

Disclosure
Dr. Raj is a speaker for Actavis Pharmaceuticals, AstraZeneca, and Merck.

Suicide is the tenth leading cause of death among Americans and the third leading cause among those age 15 to 24.¹ As many as 36% of suicide victims leave a sui­cide note.² Researchers have analyzed such notes with the aim of identifying specific content and patterns that might aid in creating more effective strategies for preventing suicide.^3-5

One study found that the presence of a suicide note is an indi­cator of serious intent; that is, when the initial attempt fails, those who had left a suicide note were found to be at increased risk of subsequent completed suicide.4 Researchers also found that 75% of suicide notes contained the theme “apology/shame,” suggesting that many suicide victims might have welcomed an alternative to suicide to solve their personal predicament. Tragically, however, most suicide notes are not discovered until suicide has been attempted or completed.⁴

That’s where social media comes in. As platforms for self-expression, social networking sites such as Facebook, Twitter, and Tumblr are sources of real-time information that could aid in suicide prevention.⁶ With that in mind, we:
   • present 2 cases in which a patient announced her sui­cidal ideation on Facebook
   • consider the opportunities that social media present for early intervention
   • propose high-tech monitoring methods for high-risk patients.

CASE 1 Major depressive disorder (MDD) and nonadherence
Ms. S, age 24, has a 4-year history of MDD and treatment non­adherence. She had no history of suicide attempt or inpatient treatment, but she had briefly engaged in psychotherapy before discontinuing visits. Physically healthy and employed as a security officer, Ms. S recently broke up with her boy­friend who had abused her physically—and against whom she had an order of protection.

On the day in question, Ms. S posted several status updates on Facebook expressing hope­lessness, which, over the course of the day, esca­lated to expression of frank suicidal ideation:
   • “I am ugly, no man would ever want to live with me.”
   • “I have made no effect on the world and I’m just a waste of space.”
   • “It’s sad that I want to die but such is life. We all die one day.”
   • “I’m going to kill myself. It was nice knowing you world. Goodbye everyone.”

CASE 2 Substance abuse and previous suicide attempt
Ms. B, age 21, had a remote (approximately age 16) history of a suicide attempt and was actively abusing 3,4-methylenedioxymeth­amphetamine (MDMA [“Ecstasy,” “Molly”]) and Cannabis. She was not receiving outpatient care. One afternoon, Ms. B walked into the emergency department (ED) and said she had just taken 17 ibuprofen pills with the intent of killing herself.

On initial evaluation, Ms. B was irritable and uncooperative, denying all psychiatric symptoms and refusing to divulge details of her recent behavior. Her mother, who had not accompanied her daughter to the ED, reported that Ms. B had engaged in excessive risk-taking—speeding, driving while intoxi­cated, having multiple sex partners—for the past 5 years, resulting in several arrests for minor offenses, and she had been depressed and was sleeping and eating poorly in the 2 weeks leading up to the suicide attempt.

Two days ago, her mother added, Ms. B had posted disturbing notes on Facebook: ”Life is useless,” she declared in one post; “I’d be better off dead,” in another.

Suicidal content online
Worldwide, Facebook has 1.35 billion active users each month.⁷ Thus far, a limited num­ber of posts indicating suicidal intent have been reported in the lay press,⁸ but evidence suggests that the use of social media for this purpose is an emerging trend.⁹

A search of the literature yielded only 3 case reports.^8,10,11 In one case, a delayed response to a suicide note resulted in a fail­ure to prevent the suicide.⁸ In another, a cli­nician’s discovery of a patient’s explicitly suicidal Facebook post led to what the team leader described as a more meaningful thera­peutic relationship.¹⁰ The clinician’s discov­ery might have been pivotal in preventing the patient from committing suicide.

The authors of these case reports explored the idea of using Facebook for suicide pre­vention, raising a number of practical and ethical issues. Among them are the poten­tial for immediate intervention by other Facebook users and the extent to which sui­cidal posts on social media sites induce copy­cat suicides.⁸

Issues associated with clinicians’ use of social media to follow or monitor patients include the ethical concepts of beneficence and nonmaleficence, privacy and confi­dentiality, clinical judgment, and informed consent,8,10 including potential benefit and harm and the difference between actual and perceived privacy violations. Bennett et al11 recommend developing guidelines for the use of social media to enhance medical care and provide appropriate protections to both patients and providers.

Reporting suicidal content. Although the primary purpose of Facebook is to give users the opportunity to share life events and thoughts with friends and family, the com­pany does address the question of suicidal content in its Help Center (Box 1).¹² As our 2 cases illustrate, however, intervention can be significantly delayed.

CASE 1 CONTINUED Call to 911
Fortunately for Ms. S, a friend who read her Facebook posts called 911; even then, however, 16 hours passed between the initial postings and the patient’s arrival at the ED. When emer­gency medical services brought Ms. S to the Comprehensive Psychiatry Emergency Program, she acknowledged suicidal ideation with­out an active plan. Other symptoms included depressed mood, a sense of hopelessness, feel­ings of worthlessness lasting >2 months, low self-esteem, dissatisfaction with body image, and a recent verbal altercation with a friend.

Ms. S was admitted to the inpatient unit for further observation and stabilization.

CASE 2 CONTINUED No one answered her calls
Ms. B, who did not arrive at the ED until 2 days after her suicidal posts, corroborated the history given by her mother. She also reported that she had attempted to reach out to her friends for support, but no one had answered her phone calls. She felt hurt because of this, Ms. B said, and impulsively ingested the pills.

Ms. B said she regretted the suicide attempt. Nevertheless, in light of her recent attempt and persistent distress, she was admitted to the inpa­tient unit for observation and stabilization.

Can artificial intelligence help?
There is no effective means of tracking high-risk patients after their first contact with the mental health system, despite the fact that (1) those who attempt suicide are at high risk of subsequent suicide attempts³ and (2) we have the potential to prevent future attempts based on self-expressed online cues. We pro­pose machine learning algorithms—a branch of artificial intelligence—to capture and process suicide notes on Facebook in real time.

Machine learning can be broadly defined as computational methods using experience to improve performance or make accurate pre­dictions. In this context, “experience” refers to past information, typically in the form of electronic data collected and analyzed to design accurate and efficient predictive algorithms. Machine learning, which incor­porates fundamental concepts in computer science, as well as statistics, probability, and optimization, already has been established in a variety of applications, such as detecting e-mail spam, natural language processing, and computational biology.¹³

Affective computing, known as emotion-oriented computing, is a branch of artifi­cial intelligence that involves the design of systems and devices that can recognize, interpret, and process human moods and emotions (Box 2).¹⁴

Prediction models, developed by Poulin et al¹⁵ to estimate the risk of suicide (based on keywords and multiword phrases from unstructured clinical notes from a national sample of U.S. Veterans Administration medical records), resulted in an inference accuracy of ≥65%. Pestian et al¹⁶ created and annotated a collection of suicide notes—a vital resource for scientists to use for machine learning and data mining. Machine learning algorithms based on such notes and clini­cal data might be used to capture alarming social media posts by high-risk patients and activate crisis management, with potentially life-saving results.

But limitations remain
It is not easy to identify or analyze people’s emotions based on social media posts; emo­tions can be implicit, based on specific events or situations. To distinguish among different emotions purely on the basis of keywords is to deal in great subtlety. Framing algorithms to include multiple parameters—the dura­tion of suicidal content and the number of suicidal posts, for example—would help mitigate the risk of false alarms.

Another problem is that not all Facebook profiles are public. In fact, only 28% of users share all or most of their posts with anyone other than their friends.¹⁷ This limitation could be addressed by urging patients iden­tified as being at high risk of suicide during an initial clinical encounter with a mental health provider to “friend” a generic Web page created by the hospital or clinic to pro­tect patients’ privacy.

As Levahot et al¹⁰ wrote in their report of the patient whose clinician discovered a patient’s explicitly suicidal Facebook post, the incident “did not hinder the therapeu­tic alliance.” Instead, the team leader said, the discovery deepened the therapeutic relationship and helped the patient “better understand his mental illness and need for increased support.”

Bottom Line
Machine learning algorithms offer the possibility of analyzing status updates from patients who express suicidal ideation on social media and alerting clinicians to the need for early intervention. There are steps clinicians can take now, however, to take advantage of Facebook, in particular, to monitor and potentially prevent suicide attempts by those at high risk.

Related Resource
• Ahuja AK, Biesaga K, Sudak DM, et al. Suicide on Facebook. J Psychiatr Pract. 2014;20(2):141-146.

Acknowledgement
Zafar Sharif MD, Associate Clinical Professor of Psychiatry, Columbia University College of Physicians and Surgeons, and Director of Psychiatry, Harlem Hospital Center, New York, New York, and Michael Yogman MD, Assistant Clinical Professor of Pediatrics, Harvard Medical School, Boston Children’s Hospital, Boston, Massachusetts, provided insight into the topic and useful feedback on the manuscript of this article.

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

Suicide is the tenth leading cause of death among Americans and the third leading cause among those age 15 to 24.¹ As many as 36% of suicide victims leave a sui­cide note.² Researchers have analyzed such notes with the aim of identifying specific content and patterns that might aid in creating more effective strategies for preventing suicide.^3-5

One study found that the presence of a suicide note is an indi­cator of serious intent; that is, when the initial attempt fails, those who had left a suicide note were found to be at increased risk of subsequent completed suicide.4 Researchers also found that 75% of suicide notes contained the theme “apology/shame,” suggesting that many suicide victims might have welcomed an alternative to suicide to solve their personal predicament. Tragically, however, most suicide notes are not discovered until suicide has been attempted or completed.⁴

That’s where social media comes in. As platforms for self-expression, social networking sites such as Facebook, Twitter, and Tumblr are sources of real-time information that could aid in suicide prevention.⁶ With that in mind, we:
   • present 2 cases in which a patient announced her sui­cidal ideation on Facebook
   • consider the opportunities that social media present for early intervention
   • propose high-tech monitoring methods for high-risk patients.

CASE 1 Major depressive disorder (MDD) and nonadherence
Ms. S, age 24, has a 4-year history of MDD and treatment non­adherence. She had no history of suicide attempt or inpatient treatment, but she had briefly engaged in psychotherapy before discontinuing visits. Physically healthy and employed as a security officer, Ms. S recently broke up with her boy­friend who had abused her physically—and against whom she had an order of protection.

On the day in question, Ms. S posted several status updates on Facebook expressing hope­lessness, which, over the course of the day, esca­lated to expression of frank suicidal ideation:
   • “I am ugly, no man would ever want to live with me.”
   • “I have made no effect on the world and I’m just a waste of space.”
   • “It’s sad that I want to die but such is life. We all die one day.”
   • “I’m going to kill myself. It was nice knowing you world. Goodbye everyone.”

CASE 2 Substance abuse and previous suicide attempt
Ms. B, age 21, had a remote (approximately age 16) history of a suicide attempt and was actively abusing 3,4-methylenedioxymeth­amphetamine (MDMA [“Ecstasy,” “Molly”]) and Cannabis. She was not receiving outpatient care. One afternoon, Ms. B walked into the emergency department (ED) and said she had just taken 17 ibuprofen pills with the intent of killing herself.

On initial evaluation, Ms. B was irritable and uncooperative, denying all psychiatric symptoms and refusing to divulge details of her recent behavior. Her mother, who had not accompanied her daughter to the ED, reported that Ms. B had engaged in excessive risk-taking—speeding, driving while intoxi­cated, having multiple sex partners—for the past 5 years, resulting in several arrests for minor offenses, and she had been depressed and was sleeping and eating poorly in the 2 weeks leading up to the suicide attempt.

Two days ago, her mother added, Ms. B had posted disturbing notes on Facebook: ”Life is useless,” she declared in one post; “I’d be better off dead,” in another.

Suicidal content online
Worldwide, Facebook has 1.35 billion active users each month.⁷ Thus far, a limited num­ber of posts indicating suicidal intent have been reported in the lay press,⁸ but evidence suggests that the use of social media for this purpose is an emerging trend.⁹

A search of the literature yielded only 3 case reports.^8,10,11 In one case, a delayed response to a suicide note resulted in a fail­ure to prevent the suicide.⁸ In another, a cli­nician’s discovery of a patient’s explicitly suicidal Facebook post led to what the team leader described as a more meaningful thera­peutic relationship.¹⁰ The clinician’s discov­ery might have been pivotal in preventing the patient from committing suicide.

The authors of these case reports explored the idea of using Facebook for suicide pre­vention, raising a number of practical and ethical issues. Among them are the poten­tial for immediate intervention by other Facebook users and the extent to which sui­cidal posts on social media sites induce copy­cat suicides.⁸

Issues associated with clinicians’ use of social media to follow or monitor patients include the ethical concepts of beneficence and nonmaleficence, privacy and confi­dentiality, clinical judgment, and informed consent,8,10 including potential benefit and harm and the difference between actual and perceived privacy violations. Bennett et al11 recommend developing guidelines for the use of social media to enhance medical care and provide appropriate protections to both patients and providers.

Reporting suicidal content. Although the primary purpose of Facebook is to give users the opportunity to share life events and thoughts with friends and family, the com­pany does address the question of suicidal content in its Help Center (Box 1).¹² As our 2 cases illustrate, however, intervention can be significantly delayed.

CASE 1 CONTINUED Call to 911
Fortunately for Ms. S, a friend who read her Facebook posts called 911; even then, however, 16 hours passed between the initial postings and the patient’s arrival at the ED. When emer­gency medical services brought Ms. S to the Comprehensive Psychiatry Emergency Program, she acknowledged suicidal ideation with­out an active plan. Other symptoms included depressed mood, a sense of hopelessness, feel­ings of worthlessness lasting >2 months, low self-esteem, dissatisfaction with body image, and a recent verbal altercation with a friend.

Ms. S was admitted to the inpatient unit for further observation and stabilization.

CASE 2 CONTINUED No one answered her calls
Ms. B, who did not arrive at the ED until 2 days after her suicidal posts, corroborated the history given by her mother. She also reported that she had attempted to reach out to her friends for support, but no one had answered her phone calls. She felt hurt because of this, Ms. B said, and impulsively ingested the pills.

Ms. B said she regretted the suicide attempt. Nevertheless, in light of her recent attempt and persistent distress, she was admitted to the inpa­tient unit for observation and stabilization.

Can artificial intelligence help?
There is no effective means of tracking high-risk patients after their first contact with the mental health system, despite the fact that (1) those who attempt suicide are at high risk of subsequent suicide attempts³ and (2) we have the potential to prevent future attempts based on self-expressed online cues. We pro­pose machine learning algorithms—a branch of artificial intelligence—to capture and process suicide notes on Facebook in real time.

Machine learning can be broadly defined as computational methods using experience to improve performance or make accurate pre­dictions. In this context, “experience” refers to past information, typically in the form of electronic data collected and analyzed to design accurate and efficient predictive algorithms. Machine learning, which incor­porates fundamental concepts in computer science, as well as statistics, probability, and optimization, already has been established in a variety of applications, such as detecting e-mail spam, natural language processing, and computational biology.¹³

Affective computing, known as emotion-oriented computing, is a branch of artifi­cial intelligence that involves the design of systems and devices that can recognize, interpret, and process human moods and emotions (Box 2).¹⁴

Prediction models, developed by Poulin et al¹⁵ to estimate the risk of suicide (based on keywords and multiword phrases from unstructured clinical notes from a national sample of U.S. Veterans Administration medical records), resulted in an inference accuracy of ≥65%. Pestian et al¹⁶ created and annotated a collection of suicide notes—a vital resource for scientists to use for machine learning and data mining. Machine learning algorithms based on such notes and clini­cal data might be used to capture alarming social media posts by high-risk patients and activate crisis management, with potentially life-saving results.

But limitations remain
It is not easy to identify or analyze people’s emotions based on social media posts; emo­tions can be implicit, based on specific events or situations. To distinguish among different emotions purely on the basis of keywords is to deal in great subtlety. Framing algorithms to include multiple parameters—the dura­tion of suicidal content and the number of suicidal posts, for example—would help mitigate the risk of false alarms.

Another problem is that not all Facebook profiles are public. In fact, only 28% of users share all or most of their posts with anyone other than their friends.¹⁷ This limitation could be addressed by urging patients iden­tified as being at high risk of suicide during an initial clinical encounter with a mental health provider to “friend” a generic Web page created by the hospital or clinic to pro­tect patients’ privacy.

As Levahot et al¹⁰ wrote in their report of the patient whose clinician discovered a patient’s explicitly suicidal Facebook post, the incident “did not hinder the therapeu­tic alliance.” Instead, the team leader said, the discovery deepened the therapeutic relationship and helped the patient “better understand his mental illness and need for increased support.”

Bottom Line
Machine learning algorithms offer the possibility of analyzing status updates from patients who express suicidal ideation on social media and alerting clinicians to the need for early intervention. There are steps clinicians can take now, however, to take advantage of Facebook, in particular, to monitor and potentially prevent suicide attempts by those at high risk.

Related Resource
• Ahuja AK, Biesaga K, Sudak DM, et al. Suicide on Facebook. J Psychiatr Pract. 2014;20(2):141-146.

Acknowledgement
Zafar Sharif MD, Associate Clinical Professor of Psychiatry, Columbia University College of Physicians and Surgeons, and Director of Psychiatry, Harlem Hospital Center, New York, New York, and Michael Yogman MD, Assistant Clinical Professor of Pediatrics, Harvard Medical School, Boston Children’s Hospital, Boston, Massachusetts, provided insight into the topic and useful feedback on the manuscript of this article.

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

Suicide is the tenth leading cause of death among Americans and the third leading cause among those age 15 to 24.¹ As many as 36% of suicide victims leave a sui­cide note.² Researchers have analyzed such notes with the aim of identifying specific content and patterns that might aid in creating more effective strategies for preventing suicide.^3-5

One study found that the presence of a suicide note is an indi­cator of serious intent; that is, when the initial attempt fails, those who had left a suicide note were found to be at increased risk of subsequent completed suicide.4 Researchers also found that 75% of suicide notes contained the theme “apology/shame,” suggesting that many suicide victims might have welcomed an alternative to suicide to solve their personal predicament. Tragically, however, most suicide notes are not discovered until suicide has been attempted or completed.⁴

That’s where social media comes in. As platforms for self-expression, social networking sites such as Facebook, Twitter, and Tumblr are sources of real-time information that could aid in suicide prevention.⁶ With that in mind, we:
   • present 2 cases in which a patient announced her sui­cidal ideation on Facebook
   • consider the opportunities that social media present for early intervention
   • propose high-tech monitoring methods for high-risk patients.

CASE 1 Major depressive disorder (MDD) and nonadherence
Ms. S, age 24, has a 4-year history of MDD and treatment non­adherence. She had no history of suicide attempt or inpatient treatment, but she had briefly engaged in psychotherapy before discontinuing visits. Physically healthy and employed as a security officer, Ms. S recently broke up with her boy­friend who had abused her physically—and against whom she had an order of protection.

On the day in question, Ms. S posted several status updates on Facebook expressing hope­lessness, which, over the course of the day, esca­lated to expression of frank suicidal ideation:
   • “I am ugly, no man would ever want to live with me.”
   • “I have made no effect on the world and I’m just a waste of space.”
   • “It’s sad that I want to die but such is life. We all die one day.”
   • “I’m going to kill myself. It was nice knowing you world. Goodbye everyone.”

CASE 2 Substance abuse and previous suicide attempt
Ms. B, age 21, had a remote (approximately age 16) history of a suicide attempt and was actively abusing 3,4-methylenedioxymeth­amphetamine (MDMA [“Ecstasy,” “Molly”]) and Cannabis. She was not receiving outpatient care. One afternoon, Ms. B walked into the emergency department (ED) and said she had just taken 17 ibuprofen pills with the intent of killing herself.

On initial evaluation, Ms. B was irritable and uncooperative, denying all psychiatric symptoms and refusing to divulge details of her recent behavior. Her mother, who had not accompanied her daughter to the ED, reported that Ms. B had engaged in excessive risk-taking—speeding, driving while intoxi­cated, having multiple sex partners—for the past 5 years, resulting in several arrests for minor offenses, and she had been depressed and was sleeping and eating poorly in the 2 weeks leading up to the suicide attempt.

Two days ago, her mother added, Ms. B had posted disturbing notes on Facebook: ”Life is useless,” she declared in one post; “I’d be better off dead,” in another.

Suicidal content online
Worldwide, Facebook has 1.35 billion active users each month.⁷ Thus far, a limited num­ber of posts indicating suicidal intent have been reported in the lay press,⁸ but evidence suggests that the use of social media for this purpose is an emerging trend.⁹

A search of the literature yielded only 3 case reports.^8,10,11 In one case, a delayed response to a suicide note resulted in a fail­ure to prevent the suicide.⁸ In another, a cli­nician’s discovery of a patient’s explicitly suicidal Facebook post led to what the team leader described as a more meaningful thera­peutic relationship.¹⁰ The clinician’s discov­ery might have been pivotal in preventing the patient from committing suicide.

The authors of these case reports explored the idea of using Facebook for suicide pre­vention, raising a number of practical and ethical issues. Among them are the poten­tial for immediate intervention by other Facebook users and the extent to which sui­cidal posts on social media sites induce copy­cat suicides.⁸

Issues associated with clinicians’ use of social media to follow or monitor patients include the ethical concepts of beneficence and nonmaleficence, privacy and confi­dentiality, clinical judgment, and informed consent,8,10 including potential benefit and harm and the difference between actual and perceived privacy violations. Bennett et al11 recommend developing guidelines for the use of social media to enhance medical care and provide appropriate protections to both patients and providers.

Reporting suicidal content. Although the primary purpose of Facebook is to give users the opportunity to share life events and thoughts with friends and family, the com­pany does address the question of suicidal content in its Help Center (Box 1).¹² As our 2 cases illustrate, however, intervention can be significantly delayed.

CASE 1 CONTINUED Call to 911
Fortunately for Ms. S, a friend who read her Facebook posts called 911; even then, however, 16 hours passed between the initial postings and the patient’s arrival at the ED. When emer­gency medical services brought Ms. S to the Comprehensive Psychiatry Emergency Program, she acknowledged suicidal ideation with­out an active plan. Other symptoms included depressed mood, a sense of hopelessness, feel­ings of worthlessness lasting >2 months, low self-esteem, dissatisfaction with body image, and a recent verbal altercation with a friend.

Ms. S was admitted to the inpatient unit for further observation and stabilization.

CASE 2 CONTINUED No one answered her calls
Ms. B, who did not arrive at the ED until 2 days after her suicidal posts, corroborated the history given by her mother. She also reported that she had attempted to reach out to her friends for support, but no one had answered her phone calls. She felt hurt because of this, Ms. B said, and impulsively ingested the pills.

Ms. B said she regretted the suicide attempt. Nevertheless, in light of her recent attempt and persistent distress, she was admitted to the inpa­tient unit for observation and stabilization.

Can artificial intelligence help?
There is no effective means of tracking high-risk patients after their first contact with the mental health system, despite the fact that (1) those who attempt suicide are at high risk of subsequent suicide attempts³ and (2) we have the potential to prevent future attempts based on self-expressed online cues. We pro­pose machine learning algorithms—a branch of artificial intelligence—to capture and process suicide notes on Facebook in real time.

Machine learning can be broadly defined as computational methods using experience to improve performance or make accurate pre­dictions. In this context, “experience” refers to past information, typically in the form of electronic data collected and analyzed to design accurate and efficient predictive algorithms. Machine learning, which incor­porates fundamental concepts in computer science, as well as statistics, probability, and optimization, already has been established in a variety of applications, such as detecting e-mail spam, natural language processing, and computational biology.¹³

Affective computing, known as emotion-oriented computing, is a branch of artifi­cial intelligence that involves the design of systems and devices that can recognize, interpret, and process human moods and emotions (Box 2).¹⁴

Prediction models, developed by Poulin et al¹⁵ to estimate the risk of suicide (based on keywords and multiword phrases from unstructured clinical notes from a national sample of U.S. Veterans Administration medical records), resulted in an inference accuracy of ≥65%. Pestian et al¹⁶ created and annotated a collection of suicide notes—a vital resource for scientists to use for machine learning and data mining. Machine learning algorithms based on such notes and clini­cal data might be used to capture alarming social media posts by high-risk patients and activate crisis management, with potentially life-saving results.

But limitations remain
It is not easy to identify or analyze people’s emotions based on social media posts; emo­tions can be implicit, based on specific events or situations. To distinguish among different emotions purely on the basis of keywords is to deal in great subtlety. Framing algorithms to include multiple parameters—the dura­tion of suicidal content and the number of suicidal posts, for example—would help mitigate the risk of false alarms.

Another problem is that not all Facebook profiles are public. In fact, only 28% of users share all or most of their posts with anyone other than their friends.¹⁷ This limitation could be addressed by urging patients iden­tified as being at high risk of suicide during an initial clinical encounter with a mental health provider to “friend” a generic Web page created by the hospital or clinic to pro­tect patients’ privacy.

As Levahot et al¹⁰ wrote in their report of the patient whose clinician discovered a patient’s explicitly suicidal Facebook post, the incident “did not hinder the therapeu­tic alliance.” Instead, the team leader said, the discovery deepened the therapeutic relationship and helped the patient “better understand his mental illness and need for increased support.”

Bottom Line
Machine learning algorithms offer the possibility of analyzing status updates from patients who express suicidal ideation on social media and alerting clinicians to the need for early intervention. There are steps clinicians can take now, however, to take advantage of Facebook, in particular, to monitor and potentially prevent suicide attempts by those at high risk.

Related Resource
• Ahuja AK, Biesaga K, Sudak DM, et al. Suicide on Facebook. J Psychiatr Pract. 2014;20(2):141-146.

Acknowledgement
Zafar Sharif MD, Associate Clinical Professor of Psychiatry, Columbia University College of Physicians and Surgeons, and Director of Psychiatry, Harlem Hospital Center, New York, New York, and Michael Yogman MD, Assistant Clinical Professor of Pediatrics, Harvard Medical School, Boston Children’s Hospital, Boston, Massachusetts, provided insight into the topic and useful feedback on the manuscript of this article.

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

With a prevalence >17%, depression is one of the most common mental disorders in the United States and the second leading cause of disability worldwide.^1,2 For decades, primary care and mental health providers have used selective serotonin reuptake inhibitors (SSRIs) as first-line treatment for depression—yet the remission rate after the first trial of an antidepressant is <30%, and continues to decline after a first antidepressant failure.³

That is why clinicians continue to seek effective treatments for depres­sion—ones that will provide quick and sustainable remission—and why scientists and pharmaceutical manufacturers have been competing to develop more effective antidepressant medications.

In the past 4 years, the FDA has approved 3 antidepressants—vilazodone, levomilnacipran, and vortioxetine—with the hope of increasing options for patients who suffer from major depression. These 3 antidepressants differ in their mechanisms of action from other available antidepressants, and all have been shown to have acceptable safety and tolerability profiles.

In this article, we review these novel antidepressants and present some clinical pearls for their use. We also present our observations that each agent appears to show particular advantage in a certain subpopulation of depressed patients who often do not respond, or who do not adequately respond, to other antidepressants.

Vilazodone
Vilazodone was approved by the FDA in 2011 (Table 1). The drug increases serotonin bioavailability in synapses through a strong dual action:
   • blocking serotonin reuptake through the serotonin transporter
   • partial agonism of the 5-HT1A presyn­aptic receptor.

Vilazodone also has a moderate effect on the 5-HT4 receptor and on dopamine and norepinephrine uptake inhibition.

The unique presynaptic 5-HT1A partial agonism of vilazodone is similar to that of buspirone, in which both drugs initially inhibit serotonin synthesis and neuronal firing.⁴ Researchers therefore expected that vilazodone would be more suitable for patients who have depression and a comor­bid anxiety disorder; current FDA approval, however, is for depression only.

Adverse effects. The 5-HT4 receptor on which vilazodone acts is present in the gas­trointestinal (GI) tract, and contributes to regulating symptoms in patients with irri­table bowel syndrome (IBS)⁵; not surpris­ingly, the most frequent adverse effects of vilazodone are GI in nature (diarrhea, nau­sea, vomiting).

Headache is the most common non- GI side effect of vilazodone. Depressed patients who took vilazodone had no sig­nificant weight gain and did not report adverse sexual effects, compared with sub­jects given placebo.⁶

The following case—a patient with depression, significant anxiety, and IBS— exemplifies the type of patient for whom we find vilazodone most useful.

CASE Ms. A, age 19, is a college student with a history of major depressive disorder, social anxiety, and panic attacks for 2 years and IBS for 3 years. She was taking lubiprostone for IBS, with incomplete relief of GI symptoms. Because the family history included depres­sion in Ms. A’s mother and sister, and both were doing well on escitalopram, we began a trial of that drug, 10 mg/d, that was quickly titrated to 20 mg/d.

Ms. A did not respond to 20 mg of escitalo­pram combined with psychotherapy.

We then started vilazodone, 10 mg/d after breakfast, for the first week, and reduced escital­opram to 10 mg/d. During Week 2, escitalopram was discontinued and vilazodone was increased to 20 mg/d. During Week 3, vilazodone was titrated to 40 mg/d.

Ms. A tolerated vilazodone well. Her depressive symptoms improved at the end of Week 2.

Unlike her experience with escitalopram, Ms. A’s anxiety symptoms—tenseness, racing thoughts, and panic attacks—all diminished when she switched to vilazodone. Notably, her IBS symptoms also were relieved, and she dis­continued lubiprostone.

Ms. A’s depression remained in remission for 2 years, except for a brief period one sum­mer, when she thought she “could do without any medication.” She tapered the vilazodone, week by week, to 10 mg/d, but her anxiety and bowel symptoms resurfaced to a degree that she resumed the 40-mg/d dosage.

Levomilnacipran
This drug is a 2013 addition to the small serotonin–norepinephrine reuptake inhibi­tor (SNRI) family of venlafaxine, des­venlafaxine, and duloxetine⁷ (Table 2). Levomilnacipran is the enantiomer of mil­nacipran, approved in Europe for depres­sion but only for fibromyalgia pain and peripheral neuropathy in the United States.⁸ (Levomilnacipran is not FDA-approved for treating fibromyalgia pain.)

Continue to: The benefits of levomilnacipran

The following case illustrates the benefits of levomilnacipran in a depressed patient who suffers from chronic pain and impaired social function.

CASE Mrs. C, age 44, was referred by her outpatient psychologist and her primary care provider for management of refractory depression. She did not respond to an SSRI, an SNRI, or augmentation with bupropion and aripiprazole.

Mrs. C was on disability leave from work because of depression and cervical spine pain that might have been related to repeti­tive movement as a telephone customer service representative. She complained of loss of motivation, fatigue, and high anxiety about returning to work because of the many unhappy customers she felt she had to soothe.

Levomilnacipran was started at 20 mg/d for 2 days, then titrated to 40 mg/d for 5 days, 80 mg/d for 1 week, and 120 mg/d thereafter. Her previous antidepressants, fluoxetine and bupropion, were discontinued while levomil­nacipran was titrated.

Mrs. C continued to receive weekly psy­chotherapy and physical therapy and to take tizanidine, a muscle relaxant, and over-the-counter medications for pain. Her Patient Health Questionnaire (PHQ-9) score declined from 13 when levomilnacipran was started to 5 at the next visit, 6 weeks later.

Within 4 months of initiating levomilnacipran, Mrs. C returned to work with a series of cue cards to use when speaking with irate or unhappy customers. At that point, her cervical spine pain was barely noticeable and no longer interfered with function.

Vortioxetine
This agent has a novel multimodal mecha­nism of action (Table 3). It is an SSRI as well as a 5-HT1A full agonist and 5-HT3 receptor antagonist. Vortioxetine also has an inhibitory effect on 5-HT7 and 5-HT1D receptors and partial agonism of 5-HT1B receptors.

Vortioxetine is the only antidepressant among the 3 discussed in this article that was studied over a long period to ensure that short-term benefits continue beyond the 6- to 8-week acute Phase-III studies. A high remission rate (61%) was observed in patients who were treated on an open-label basis with vortioxetine, 10 mg/d, then ran­domized to maintenance with vortioxetine or placebo.¹²

Older patients. Vortioxetine is unique among these 3 antidepressants in that it is the only one studied separately in geri­atric patients: In an 8-week Phase-III trial, 452 geriatric patients age 64 to 88 were ran­domized to 5 mg/d of vortioxetine or pla­cebo.¹³ Vortioxetine was significantly more effective than placebo at Week 6.

Vortioxetine also is the only antidepres­sant investigated for an effect on cognitive deficits: In a Phase-III double-blind, placebo-controlled study of 602 patients with major depressive disorder, using duloxetine as active reference, vortioxetine was found to have a significant effect on Digit Symbol Substitution Test scores, compared with pla­cebo, independent of its antidepressant effect (ie, patients who did not show any anti­depressant benefit still showed an improve­ment in attention, speed processing, memory, and executive function).¹⁴

We have found, therefore, that vortiox­etine is helpful for depressed patients who have cognitive deficits, especially geriatric patients.

CASE Mrs. B, age 84, married, has a 4-year history of depression. She has taken several antidepressants with little consistent relief.

A brief psychiatric hospitalization 2 years ago temporarily reduced the severity of Mrs. B’s depression; gradually, she relapsed. She felt hopeless and resisted another psychiatric evalu­ation. Mrs. B’s family includes several clinicians, who wondered if she was developing cognitive deficits that were interfering with her recovery.

At initial evaluation, Mrs. B failed to recall 2 of 3 objects but performed the clock drawing test perfectly—qualifying her for a diagnosis of mild cognitive impairment in addition to major depression. Her PHQ-9 score at baseline was 22.

On the assumption that the severity of her depression was contributing to cognitive defi­cits, vortioxetine, 5 mg/d, was initiated for 2 weeks and then titrated to 10 mg/d.

At 4 weeks’ follow-up, Mrs. B passed the Mini-Cog test; her PHQ-9 score fell to 8. She has remained asymptomatic for 6 months at the 10-mg/d dosage; her lowest PHQ-9 score was 5.

Adverse effects. The most common adverse effects are mild or moderate GI in nature. Weight gain and adverse sexual effects were not significantly different among patients receiving vortioxetine than among patients given placebo.

A note about the safety of these agents
All 3 of these antidepressants carry the stan­dard black-box warning about the elevated risk of suicide in patients taking an antide­pressant. None of them are approved for patients age <18.

Continue to: Suicidal ideation was reported

Suicidal ideation was reported in 11.2% of patients taking vortioxetine, compared with 12.5% of those given placebo15; 24% of patients taking levomilnacipran reported suicidal ideation, compared with 22% of those who took placebo.¹⁶ In a long-term study of 599 patients taking vilazodone, 4 given placebo exhibited suicidal behavior, compared with 2 who took vilazodone.¹⁷

Drug-drug interactions are an important consideration when vilazodone, levomil­nacipran, and vortioxetine are prescribed in combination with other medications. See the following discussion.

Vilazodone should be taken with food because it has 72% bioavailability after a meal.¹⁸ The drug is metabolized primarily by cytochrome P (CYP) 3A4 and CYP3A5; it does not affect CYP substrates or, it’s likely, produce significant changes to other medica­tions metabolized by the CYP pathway.

Conversely, the dosage of vilazodone should be reduced to 20 mg/d if it is co- administered with a strong CYP3A4 inhibi­tor (eg, ketoconazole). The dosage should be increased as much as 2-fold when vilazo­done is used concomitantly used with a strong CYP3A4 inducer (eg, carbamazepine) for >14 days. The maximum daily dosage should not exceed 80 mg/d.

Levomilnacipran. Unlike vilazodone and vortioxetine, levomilnacipran is affected by renal function.¹⁹ Concomitant medications, however, including those that influence CYP renal transporters (particularly CYP3A4, which metabolizes levomilnacipran), do not show an impact on the blood level of levomilnacipran.

No dosage adjustment is needed for patients who have mild renal impairment, but the maintenance dosage of levomil­nacipran for patients who have moderate or severe renal impairment should not exceed 80 mg/d in 1 dose, and 60 mg/d in 1 dose, respectively.²⁰

Vortioxetine. Seventy percent of a dose of vortioxetine is absorbed independent of food; the drug has a half-life of 66 hours. Vortioxetine is metabolized primarily by the CYP450 enzyme system, including 2D6, and, to a lesser extent, by CYP3A4, CYP3A5, CYP2C9, and CYP2C19.²¹

Vortioxetine has minimal effect on P450 substrates in in vitro studies, which was confirmed in 4 other in vivo studies.^21-23 In studies of hormonal contraception, bupro­pion, and omeprazole, vortioxetine did not produce significant changes in the blood level of the other medications. The blood level of vortioxetine increased by 128% when taken with the CYP2D6 inhibitor bupropion,²⁴ but the blood level did not markedly change with other inhibitors because the drug utilizes uses several CYP pathways. Use caution, therefore, when adding bupropion to vortioxetine because the combination elevates the risk of nausea, diarrhea, and headache.

With each agent, specific benefit
Vilazodone, levomilnacipran, and vor­tioxetine each add distinct benefit to the clinician’s toolbox of treatments for major depressive disorder. Although all antidepres­sants to some extent alleviate anxiety and pain and reverse cognitive decline associated with depression, our experience suggests using vilazodone for anxious depressed patients; levomilnacipran for depressed patients who experience pain; and vortiox­etine for depressed patients who suffer cog­nitive decline and for geriatric patients.

Bottom Line
The FDA has approved 3 antidepressants in the past 4 years: vilazodone, levomilnacipran, and vortioxetine. The hope is that these agents will bolster treatment options for major depression—perhaps especially so, as we have seen, in the anxious depressed (vilazodone), the depressed in pain (levomilnacipran), and the depressed with cognitive decline, or geriatric patients (vortioxetine).

Related Resources
• Kalia R, Mittal M, Preskorn S. Vilazodone for major depres­sive disorder. Current Psychiatry. 2011;10(4):84-86,88.
• Lincoln J, Wehler C. Vortioxetine for major depressive disor­der. Current Psychiatry. 2014;13(2):67-70.
• Macaluso M, Kazanchi H, Malhotra V. Levomilnacipran for the treatment of major depressive disorder. Current Psychiatry. 2013;12(12):50-52,54,55.
• McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557-1567.
• Thase ME, Chen D, Edwards J, et al. Efficacy of vilazodone on anxiety symptoms in patients with major depressive disor­der. Int Clin Psychopharmacol. 2014;29(6):351-356.

Drug Brand Names
Aripiprazole • Abilify                                    Levomilnacipran • Fetzima
Bupropion • Wellbutrin, Zyban                      Lubiprostone • Amitiza
Buspirone • BuSpar                                     Milnacipran • Savella
Carbamazepine • Tegretol, Equetro               Omeprazole • Prilosec
Desvenlafaxine • Pristiq                               Tizanidine • Zanaflex
Duloxetine • Cymbalta                                 Venlafaxine • Effexor
Escitalopram • Lexapro                                Vilazodone • Viibryd
Fluoxetine • Prozac                                     Vortioxetine • Brintellix
Ketoconazole • Nizoral

With a prevalence >17%, depression is one of the most common mental disorders in the United States and the second leading cause of disability worldwide.^1,2 For decades, primary care and mental health providers have used selective serotonin reuptake inhibitors (SSRIs) as first-line treatment for depression—yet the remission rate after the first trial of an antidepressant is <30%, and continues to decline after a first antidepressant failure.³

That is why clinicians continue to seek effective treatments for depres­sion—ones that will provide quick and sustainable remission—and why scientists and pharmaceutical manufacturers have been competing to develop more effective antidepressant medications.

In the past 4 years, the FDA has approved 3 antidepressants—vilazodone, levomilnacipran, and vortioxetine—with the hope of increasing options for patients who suffer from major depression. These 3 antidepressants differ in their mechanisms of action from other available antidepressants, and all have been shown to have acceptable safety and tolerability profiles.

In this article, we review these novel antidepressants and present some clinical pearls for their use. We also present our observations that each agent appears to show particular advantage in a certain subpopulation of depressed patients who often do not respond, or who do not adequately respond, to other antidepressants.

Vilazodone
Vilazodone was approved by the FDA in 2011 (Table 1). The drug increases serotonin bioavailability in synapses through a strong dual action:
   • blocking serotonin reuptake through the serotonin transporter
   • partial agonism of the 5-HT1A presyn­aptic receptor.

Vilazodone also has a moderate effect on the 5-HT4 receptor and on dopamine and norepinephrine uptake inhibition.

The unique presynaptic 5-HT1A partial agonism of vilazodone is similar to that of buspirone, in which both drugs initially inhibit serotonin synthesis and neuronal firing.⁴ Researchers therefore expected that vilazodone would be more suitable for patients who have depression and a comor­bid anxiety disorder; current FDA approval, however, is for depression only.

Adverse effects. The 5-HT4 receptor on which vilazodone acts is present in the gas­trointestinal (GI) tract, and contributes to regulating symptoms in patients with irri­table bowel syndrome (IBS)⁵; not surpris­ingly, the most frequent adverse effects of vilazodone are GI in nature (diarrhea, nau­sea, vomiting).

Headache is the most common non- GI side effect of vilazodone. Depressed patients who took vilazodone had no sig­nificant weight gain and did not report adverse sexual effects, compared with sub­jects given placebo.⁶

The following case—a patient with depression, significant anxiety, and IBS— exemplifies the type of patient for whom we find vilazodone most useful.

CASE Ms. A, age 19, is a college student with a history of major depressive disorder, social anxiety, and panic attacks for 2 years and IBS for 3 years. She was taking lubiprostone for IBS, with incomplete relief of GI symptoms. Because the family history included depres­sion in Ms. A’s mother and sister, and both were doing well on escitalopram, we began a trial of that drug, 10 mg/d, that was quickly titrated to 20 mg/d.

Ms. A did not respond to 20 mg of escitalo­pram combined with psychotherapy.

We then started vilazodone, 10 mg/d after breakfast, for the first week, and reduced escital­opram to 10 mg/d. During Week 2, escitalopram was discontinued and vilazodone was increased to 20 mg/d. During Week 3, vilazodone was titrated to 40 mg/d.

Ms. A tolerated vilazodone well. Her depressive symptoms improved at the end of Week 2.

Unlike her experience with escitalopram, Ms. A’s anxiety symptoms—tenseness, racing thoughts, and panic attacks—all diminished when she switched to vilazodone. Notably, her IBS symptoms also were relieved, and she dis­continued lubiprostone.

Ms. A’s depression remained in remission for 2 years, except for a brief period one sum­mer, when she thought she “could do without any medication.” She tapered the vilazodone, week by week, to 10 mg/d, but her anxiety and bowel symptoms resurfaced to a degree that she resumed the 40-mg/d dosage.

Levomilnacipran
This drug is a 2013 addition to the small serotonin–norepinephrine reuptake inhibi­tor (SNRI) family of venlafaxine, des­venlafaxine, and duloxetine⁷ (Table 2). Levomilnacipran is the enantiomer of mil­nacipran, approved in Europe for depres­sion but only for fibromyalgia pain and peripheral neuropathy in the United States.⁸ (Levomilnacipran is not FDA-approved for treating fibromyalgia pain.)

Continue to: The benefits of levomilnacipran

The following case illustrates the benefits of levomilnacipran in a depressed patient who suffers from chronic pain and impaired social function.

CASE Mrs. C, age 44, was referred by her outpatient psychologist and her primary care provider for management of refractory depression. She did not respond to an SSRI, an SNRI, or augmentation with bupropion and aripiprazole.

Mrs. C was on disability leave from work because of depression and cervical spine pain that might have been related to repeti­tive movement as a telephone customer service representative. She complained of loss of motivation, fatigue, and high anxiety about returning to work because of the many unhappy customers she felt she had to soothe.

Levomilnacipran was started at 20 mg/d for 2 days, then titrated to 40 mg/d for 5 days, 80 mg/d for 1 week, and 120 mg/d thereafter. Her previous antidepressants, fluoxetine and bupropion, were discontinued while levomil­nacipran was titrated.

Mrs. C continued to receive weekly psy­chotherapy and physical therapy and to take tizanidine, a muscle relaxant, and over-the-counter medications for pain. Her Patient Health Questionnaire (PHQ-9) score declined from 13 when levomilnacipran was started to 5 at the next visit, 6 weeks later.

Within 4 months of initiating levomilnacipran, Mrs. C returned to work with a series of cue cards to use when speaking with irate or unhappy customers. At that point, her cervical spine pain was barely noticeable and no longer interfered with function.

Vortioxetine
This agent has a novel multimodal mecha­nism of action (Table 3). It is an SSRI as well as a 5-HT1A full agonist and 5-HT3 receptor antagonist. Vortioxetine also has an inhibitory effect on 5-HT7 and 5-HT1D receptors and partial agonism of 5-HT1B receptors.

Vortioxetine is the only antidepressant among the 3 discussed in this article that was studied over a long period to ensure that short-term benefits continue beyond the 6- to 8-week acute Phase-III studies. A high remission rate (61%) was observed in patients who were treated on an open-label basis with vortioxetine, 10 mg/d, then ran­domized to maintenance with vortioxetine or placebo.¹²

Older patients. Vortioxetine is unique among these 3 antidepressants in that it is the only one studied separately in geri­atric patients: In an 8-week Phase-III trial, 452 geriatric patients age 64 to 88 were ran­domized to 5 mg/d of vortioxetine or pla­cebo.¹³ Vortioxetine was significantly more effective than placebo at Week 6.

Vortioxetine also is the only antidepres­sant investigated for an effect on cognitive deficits: In a Phase-III double-blind, placebo-controlled study of 602 patients with major depressive disorder, using duloxetine as active reference, vortioxetine was found to have a significant effect on Digit Symbol Substitution Test scores, compared with pla­cebo, independent of its antidepressant effect (ie, patients who did not show any anti­depressant benefit still showed an improve­ment in attention, speed processing, memory, and executive function).¹⁴

We have found, therefore, that vortiox­etine is helpful for depressed patients who have cognitive deficits, especially geriatric patients.

CASE Mrs. B, age 84, married, has a 4-year history of depression. She has taken several antidepressants with little consistent relief.

A brief psychiatric hospitalization 2 years ago temporarily reduced the severity of Mrs. B’s depression; gradually, she relapsed. She felt hopeless and resisted another psychiatric evalu­ation. Mrs. B’s family includes several clinicians, who wondered if she was developing cognitive deficits that were interfering with her recovery.

At initial evaluation, Mrs. B failed to recall 2 of 3 objects but performed the clock drawing test perfectly—qualifying her for a diagnosis of mild cognitive impairment in addition to major depression. Her PHQ-9 score at baseline was 22.

On the assumption that the severity of her depression was contributing to cognitive defi­cits, vortioxetine, 5 mg/d, was initiated for 2 weeks and then titrated to 10 mg/d.

At 4 weeks’ follow-up, Mrs. B passed the Mini-Cog test; her PHQ-9 score fell to 8. She has remained asymptomatic for 6 months at the 10-mg/d dosage; her lowest PHQ-9 score was 5.

Adverse effects. The most common adverse effects are mild or moderate GI in nature. Weight gain and adverse sexual effects were not significantly different among patients receiving vortioxetine than among patients given placebo.

A note about the safety of these agents
All 3 of these antidepressants carry the stan­dard black-box warning about the elevated risk of suicide in patients taking an antide­pressant. None of them are approved for patients age <18.

Continue to: Suicidal ideation was reported

Suicidal ideation was reported in 11.2% of patients taking vortioxetine, compared with 12.5% of those given placebo15; 24% of patients taking levomilnacipran reported suicidal ideation, compared with 22% of those who took placebo.¹⁶ In a long-term study of 599 patients taking vilazodone, 4 given placebo exhibited suicidal behavior, compared with 2 who took vilazodone.¹⁷

Drug-drug interactions are an important consideration when vilazodone, levomil­nacipran, and vortioxetine are prescribed in combination with other medications. See the following discussion.

Vilazodone should be taken with food because it has 72% bioavailability after a meal.¹⁸ The drug is metabolized primarily by cytochrome P (CYP) 3A4 and CYP3A5; it does not affect CYP substrates or, it’s likely, produce significant changes to other medica­tions metabolized by the CYP pathway.

Conversely, the dosage of vilazodone should be reduced to 20 mg/d if it is co- administered with a strong CYP3A4 inhibi­tor (eg, ketoconazole). The dosage should be increased as much as 2-fold when vilazo­done is used concomitantly used with a strong CYP3A4 inducer (eg, carbamazepine) for >14 days. The maximum daily dosage should not exceed 80 mg/d.

Levomilnacipran. Unlike vilazodone and vortioxetine, levomilnacipran is affected by renal function.¹⁹ Concomitant medications, however, including those that influence CYP renal transporters (particularly CYP3A4, which metabolizes levomilnacipran), do not show an impact on the blood level of levomilnacipran.

No dosage adjustment is needed for patients who have mild renal impairment, but the maintenance dosage of levomil­nacipran for patients who have moderate or severe renal impairment should not exceed 80 mg/d in 1 dose, and 60 mg/d in 1 dose, respectively.²⁰

Vortioxetine. Seventy percent of a dose of vortioxetine is absorbed independent of food; the drug has a half-life of 66 hours. Vortioxetine is metabolized primarily by the CYP450 enzyme system, including 2D6, and, to a lesser extent, by CYP3A4, CYP3A5, CYP2C9, and CYP2C19.²¹

Vortioxetine has minimal effect on P450 substrates in in vitro studies, which was confirmed in 4 other in vivo studies.^21-23 In studies of hormonal contraception, bupro­pion, and omeprazole, vortioxetine did not produce significant changes in the blood level of the other medications. The blood level of vortioxetine increased by 128% when taken with the CYP2D6 inhibitor bupropion,²⁴ but the blood level did not markedly change with other inhibitors because the drug utilizes uses several CYP pathways. Use caution, therefore, when adding bupropion to vortioxetine because the combination elevates the risk of nausea, diarrhea, and headache.

With each agent, specific benefit
Vilazodone, levomilnacipran, and vor­tioxetine each add distinct benefit to the clinician’s toolbox of treatments for major depressive disorder. Although all antidepres­sants to some extent alleviate anxiety and pain and reverse cognitive decline associated with depression, our experience suggests using vilazodone for anxious depressed patients; levomilnacipran for depressed patients who experience pain; and vortiox­etine for depressed patients who suffer cog­nitive decline and for geriatric patients.

Bottom Line
The FDA has approved 3 antidepressants in the past 4 years: vilazodone, levomilnacipran, and vortioxetine. The hope is that these agents will bolster treatment options for major depression—perhaps especially so, as we have seen, in the anxious depressed (vilazodone), the depressed in pain (levomilnacipran), and the depressed with cognitive decline, or geriatric patients (vortioxetine).

Related Resources
• Kalia R, Mittal M, Preskorn S. Vilazodone for major depres­sive disorder. Current Psychiatry. 2011;10(4):84-86,88.
• Lincoln J, Wehler C. Vortioxetine for major depressive disor­der. Current Psychiatry. 2014;13(2):67-70.
• Macaluso M, Kazanchi H, Malhotra V. Levomilnacipran for the treatment of major depressive disorder. Current Psychiatry. 2013;12(12):50-52,54,55.
• McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557-1567.
• Thase ME, Chen D, Edwards J, et al. Efficacy of vilazodone on anxiety symptoms in patients with major depressive disor­der. Int Clin Psychopharmacol. 2014;29(6):351-356.

Drug Brand Names
Aripiprazole • Abilify                                    Levomilnacipran • Fetzima
Bupropion • Wellbutrin, Zyban                      Lubiprostone • Amitiza
Buspirone • BuSpar                                     Milnacipran • Savella
Carbamazepine • Tegretol, Equetro               Omeprazole • Prilosec
Desvenlafaxine • Pristiq                               Tizanidine • Zanaflex
Duloxetine • Cymbalta                                 Venlafaxine • Effexor
Escitalopram • Lexapro                                Vilazodone • Viibryd
Fluoxetine • Prozac                                     Vortioxetine • Brintellix
Ketoconazole • Nizoral

With a prevalence >17%, depression is one of the most common mental disorders in the United States and the second leading cause of disability worldwide.^1,2 For decades, primary care and mental health providers have used selective serotonin reuptake inhibitors (SSRIs) as first-line treatment for depression—yet the remission rate after the first trial of an antidepressant is <30%, and continues to decline after a first antidepressant failure.³

That is why clinicians continue to seek effective treatments for depres­sion—ones that will provide quick and sustainable remission—and why scientists and pharmaceutical manufacturers have been competing to develop more effective antidepressant medications.

In the past 4 years, the FDA has approved 3 antidepressants—vilazodone, levomilnacipran, and vortioxetine—with the hope of increasing options for patients who suffer from major depression. These 3 antidepressants differ in their mechanisms of action from other available antidepressants, and all have been shown to have acceptable safety and tolerability profiles.

In this article, we review these novel antidepressants and present some clinical pearls for their use. We also present our observations that each agent appears to show particular advantage in a certain subpopulation of depressed patients who often do not respond, or who do not adequately respond, to other antidepressants.

Vilazodone
Vilazodone was approved by the FDA in 2011 (Table 1). The drug increases serotonin bioavailability in synapses through a strong dual action:
   • blocking serotonin reuptake through the serotonin transporter
   • partial agonism of the 5-HT1A presyn­aptic receptor.

Vilazodone also has a moderate effect on the 5-HT4 receptor and on dopamine and norepinephrine uptake inhibition.

The unique presynaptic 5-HT1A partial agonism of vilazodone is similar to that of buspirone, in which both drugs initially inhibit serotonin synthesis and neuronal firing.⁴ Researchers therefore expected that vilazodone would be more suitable for patients who have depression and a comor­bid anxiety disorder; current FDA approval, however, is for depression only.

Adverse effects. The 5-HT4 receptor on which vilazodone acts is present in the gas­trointestinal (GI) tract, and contributes to regulating symptoms in patients with irri­table bowel syndrome (IBS)⁵; not surpris­ingly, the most frequent adverse effects of vilazodone are GI in nature (diarrhea, nau­sea, vomiting).

Headache is the most common non- GI side effect of vilazodone. Depressed patients who took vilazodone had no sig­nificant weight gain and did not report adverse sexual effects, compared with sub­jects given placebo.⁶

The following case—a patient with depression, significant anxiety, and IBS— exemplifies the type of patient for whom we find vilazodone most useful.

CASE Ms. A, age 19, is a college student with a history of major depressive disorder, social anxiety, and panic attacks for 2 years and IBS for 3 years. She was taking lubiprostone for IBS, with incomplete relief of GI symptoms. Because the family history included depres­sion in Ms. A’s mother and sister, and both were doing well on escitalopram, we began a trial of that drug, 10 mg/d, that was quickly titrated to 20 mg/d.

Ms. A did not respond to 20 mg of escitalo­pram combined with psychotherapy.

We then started vilazodone, 10 mg/d after breakfast, for the first week, and reduced escital­opram to 10 mg/d. During Week 2, escitalopram was discontinued and vilazodone was increased to 20 mg/d. During Week 3, vilazodone was titrated to 40 mg/d.

Ms. A tolerated vilazodone well. Her depressive symptoms improved at the end of Week 2.

Unlike her experience with escitalopram, Ms. A’s anxiety symptoms—tenseness, racing thoughts, and panic attacks—all diminished when she switched to vilazodone. Notably, her IBS symptoms also were relieved, and she dis­continued lubiprostone.

Ms. A’s depression remained in remission for 2 years, except for a brief period one sum­mer, when she thought she “could do without any medication.” She tapered the vilazodone, week by week, to 10 mg/d, but her anxiety and bowel symptoms resurfaced to a degree that she resumed the 40-mg/d dosage.

Levomilnacipran
This drug is a 2013 addition to the small serotonin–norepinephrine reuptake inhibi­tor (SNRI) family of venlafaxine, des­venlafaxine, and duloxetine⁷ (Table 2). Levomilnacipran is the enantiomer of mil­nacipran, approved in Europe for depres­sion but only for fibromyalgia pain and peripheral neuropathy in the United States.⁸ (Levomilnacipran is not FDA-approved for treating fibromyalgia pain.)

Continue to: The benefits of levomilnacipran

The following case illustrates the benefits of levomilnacipran in a depressed patient who suffers from chronic pain and impaired social function.

CASE Mrs. C, age 44, was referred by her outpatient psychologist and her primary care provider for management of refractory depression. She did not respond to an SSRI, an SNRI, or augmentation with bupropion and aripiprazole.

Mrs. C was on disability leave from work because of depression and cervical spine pain that might have been related to repeti­tive movement as a telephone customer service representative. She complained of loss of motivation, fatigue, and high anxiety about returning to work because of the many unhappy customers she felt she had to soothe.

Levomilnacipran was started at 20 mg/d for 2 days, then titrated to 40 mg/d for 5 days, 80 mg/d for 1 week, and 120 mg/d thereafter. Her previous antidepressants, fluoxetine and bupropion, were discontinued while levomil­nacipran was titrated.

Mrs. C continued to receive weekly psy­chotherapy and physical therapy and to take tizanidine, a muscle relaxant, and over-the-counter medications for pain. Her Patient Health Questionnaire (PHQ-9) score declined from 13 when levomilnacipran was started to 5 at the next visit, 6 weeks later.

Within 4 months of initiating levomilnacipran, Mrs. C returned to work with a series of cue cards to use when speaking with irate or unhappy customers. At that point, her cervical spine pain was barely noticeable and no longer interfered with function.

Vortioxetine
This agent has a novel multimodal mecha­nism of action (Table 3). It is an SSRI as well as a 5-HT1A full agonist and 5-HT3 receptor antagonist. Vortioxetine also has an inhibitory effect on 5-HT7 and 5-HT1D receptors and partial agonism of 5-HT1B receptors.

Vortioxetine is the only antidepressant among the 3 discussed in this article that was studied over a long period to ensure that short-term benefits continue beyond the 6- to 8-week acute Phase-III studies. A high remission rate (61%) was observed in patients who were treated on an open-label basis with vortioxetine, 10 mg/d, then ran­domized to maintenance with vortioxetine or placebo.¹²

Older patients. Vortioxetine is unique among these 3 antidepressants in that it is the only one studied separately in geri­atric patients: In an 8-week Phase-III trial, 452 geriatric patients age 64 to 88 were ran­domized to 5 mg/d of vortioxetine or pla­cebo.¹³ Vortioxetine was significantly more effective than placebo at Week 6.

Vortioxetine also is the only antidepres­sant investigated for an effect on cognitive deficits: In a Phase-III double-blind, placebo-controlled study of 602 patients with major depressive disorder, using duloxetine as active reference, vortioxetine was found to have a significant effect on Digit Symbol Substitution Test scores, compared with pla­cebo, independent of its antidepressant effect (ie, patients who did not show any anti­depressant benefit still showed an improve­ment in attention, speed processing, memory, and executive function).¹⁴

We have found, therefore, that vortiox­etine is helpful for depressed patients who have cognitive deficits, especially geriatric patients.

CASE Mrs. B, age 84, married, has a 4-year history of depression. She has taken several antidepressants with little consistent relief.

A brief psychiatric hospitalization 2 years ago temporarily reduced the severity of Mrs. B’s depression; gradually, she relapsed. She felt hopeless and resisted another psychiatric evalu­ation. Mrs. B’s family includes several clinicians, who wondered if she was developing cognitive deficits that were interfering with her recovery.

At initial evaluation, Mrs. B failed to recall 2 of 3 objects but performed the clock drawing test perfectly—qualifying her for a diagnosis of mild cognitive impairment in addition to major depression. Her PHQ-9 score at baseline was 22.

On the assumption that the severity of her depression was contributing to cognitive defi­cits, vortioxetine, 5 mg/d, was initiated for 2 weeks and then titrated to 10 mg/d.

At 4 weeks’ follow-up, Mrs. B passed the Mini-Cog test; her PHQ-9 score fell to 8. She has remained asymptomatic for 6 months at the 10-mg/d dosage; her lowest PHQ-9 score was 5.

Adverse effects. The most common adverse effects are mild or moderate GI in nature. Weight gain and adverse sexual effects were not significantly different among patients receiving vortioxetine than among patients given placebo.

A note about the safety of these agents
All 3 of these antidepressants carry the stan­dard black-box warning about the elevated risk of suicide in patients taking an antide­pressant. None of them are approved for patients age <18.

Continue to: Suicidal ideation was reported

Suicidal ideation was reported in 11.2% of patients taking vortioxetine, compared with 12.5% of those given placebo15; 24% of patients taking levomilnacipran reported suicidal ideation, compared with 22% of those who took placebo.¹⁶ In a long-term study of 599 patients taking vilazodone, 4 given placebo exhibited suicidal behavior, compared with 2 who took vilazodone.¹⁷

Drug-drug interactions are an important consideration when vilazodone, levomil­nacipran, and vortioxetine are prescribed in combination with other medications. See the following discussion.

Vilazodone should be taken with food because it has 72% bioavailability after a meal.¹⁸ The drug is metabolized primarily by cytochrome P (CYP) 3A4 and CYP3A5; it does not affect CYP substrates or, it’s likely, produce significant changes to other medica­tions metabolized by the CYP pathway.

Conversely, the dosage of vilazodone should be reduced to 20 mg/d if it is co- administered with a strong CYP3A4 inhibi­tor (eg, ketoconazole). The dosage should be increased as much as 2-fold when vilazo­done is used concomitantly used with a strong CYP3A4 inducer (eg, carbamazepine) for >14 days. The maximum daily dosage should not exceed 80 mg/d.

Levomilnacipran. Unlike vilazodone and vortioxetine, levomilnacipran is affected by renal function.¹⁹ Concomitant medications, however, including those that influence CYP renal transporters (particularly CYP3A4, which metabolizes levomilnacipran), do not show an impact on the blood level of levomilnacipran.

No dosage adjustment is needed for patients who have mild renal impairment, but the maintenance dosage of levomil­nacipran for patients who have moderate or severe renal impairment should not exceed 80 mg/d in 1 dose, and 60 mg/d in 1 dose, respectively.²⁰

Vortioxetine. Seventy percent of a dose of vortioxetine is absorbed independent of food; the drug has a half-life of 66 hours. Vortioxetine is metabolized primarily by the CYP450 enzyme system, including 2D6, and, to a lesser extent, by CYP3A4, CYP3A5, CYP2C9, and CYP2C19.²¹

Vortioxetine has minimal effect on P450 substrates in in vitro studies, which was confirmed in 4 other in vivo studies.^21-23 In studies of hormonal contraception, bupro­pion, and omeprazole, vortioxetine did not produce significant changes in the blood level of the other medications. The blood level of vortioxetine increased by 128% when taken with the CYP2D6 inhibitor bupropion,²⁴ but the blood level did not markedly change with other inhibitors because the drug utilizes uses several CYP pathways. Use caution, therefore, when adding bupropion to vortioxetine because the combination elevates the risk of nausea, diarrhea, and headache.

With each agent, specific benefit
Vilazodone, levomilnacipran, and vor­tioxetine each add distinct benefit to the clinician’s toolbox of treatments for major depressive disorder. Although all antidepres­sants to some extent alleviate anxiety and pain and reverse cognitive decline associated with depression, our experience suggests using vilazodone for anxious depressed patients; levomilnacipran for depressed patients who experience pain; and vortiox­etine for depressed patients who suffer cog­nitive decline and for geriatric patients.

Bottom Line
The FDA has approved 3 antidepressants in the past 4 years: vilazodone, levomilnacipran, and vortioxetine. The hope is that these agents will bolster treatment options for major depression—perhaps especially so, as we have seen, in the anxious depressed (vilazodone), the depressed in pain (levomilnacipran), and the depressed with cognitive decline, or geriatric patients (vortioxetine).

Related Resources
• Kalia R, Mittal M, Preskorn S. Vilazodone for major depres­sive disorder. Current Psychiatry. 2011;10(4):84-86,88.
• Lincoln J, Wehler C. Vortioxetine for major depressive disor­der. Current Psychiatry. 2014;13(2):67-70.
• Macaluso M, Kazanchi H, Malhotra V. Levomilnacipran for the treatment of major depressive disorder. Current Psychiatry. 2013;12(12):50-52,54,55.
• McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557-1567.
• Thase ME, Chen D, Edwards J, et al. Efficacy of vilazodone on anxiety symptoms in patients with major depressive disor­der. Int Clin Psychopharmacol. 2014;29(6):351-356.

Drug Brand Names
Aripiprazole • Abilify                                    Levomilnacipran • Fetzima
Bupropion • Wellbutrin, Zyban                      Lubiprostone • Amitiza
Buspirone • BuSpar                                     Milnacipran • Savella
Carbamazepine • Tegretol, Equetro               Omeprazole • Prilosec
Desvenlafaxine • Pristiq                               Tizanidine • Zanaflex
Duloxetine • Cymbalta                                 Venlafaxine • Effexor
Escitalopram • Lexapro                                Vilazodone • Viibryd
Fluoxetine • Prozac                                     Vortioxetine • Brintellix
Ketoconazole • Nizoral

CASE Delusional and aggressive
Mr. P, age 78, of Filipino heritage, is brought to the psychiatric hospital because he has been verbally aggressive toward his wife for sev­eral weeks. He has no history of a psychiatric diagnosis or inpatient psychiatric hospitaliza­tion, and no history of taking any psychotropic medications.

According to his wife, Mr. P has been rumi­nating about his father, who died in World War II, saying that “the Japanese never gave his body back” to him. Also, his wife describes 3 weeks of physically aggressive behavior, such as throwing punches; the last episode was 2 days before admission.

Mr. P is not bathing, eating, taking his medi­cations, and attending to his activities of daily living. He sleeps for only 1 to 2 hours a night; is irritable and easily distractible; and experi­ences flight of ideas. Mr. P has been buying lottery tickets, telling his daughter that he will become a millionaire and then buy a house in the Philippines.

Mr. P reports depressed mood, but no other depressive symptoms are present. He reports no suicidal or homicidal ideations, auditory or visual hallucinations, or anxiety symptoms. He has no history of substance abuse.

What diagnosis would you give Mr. P?
   a) late-onset bipolar disorder
   b) Alzheimer’s disease
   c) major depressive disorder
   d) frontotemporal dementia

The authors’ observations
Bipolar disorder in later life is a complex and confounding neuropsychiatric syn­drome with diagnostic and therapeutic challenges. The disorder can affect people of all ages and is not uncommon among geriatric patients, with a 1-year prevalence in United States of 0.4%.¹ In one study, 10% of new bipolar disorder cases were found to occur after age 50.² As the American population grows older, the number of bipolar disorder cases among seniors is expected to increase.³

It was once thought that symptoms of bipolar disorder disappear with age; newer research has disproved this theory, and proposes that untreated bipolar dis­order worsens over time.⁴ Persons who are given the diagnosis later in life could have had bipolar disorder for decades, but symptoms became more noticeable and problematic with age.⁵

Common symptoms in geriatric patients can differ from what we might expect in younger patients: agitation, hyperactivity, irritability, confusion, and psychosis.⁶ When the disorder presents in patients age >60, it can be severe, with significant changes in cognitive function, including difficulties with memory, perception, judgment, and problem-solving.^7,8

HISTORY Medical comorbidities
Mr. P emigrated from the Philippines 20 years ago, is married, and lives with his wife. He has 3 brothers; his parents were divorced, and his mother remarried. Mr. P completed high school.

Mr. P has an extensive medical history: diabetes mellitus, hypertension, dyslipid­emia, and recent double coronary artery bypass grafting. He is taking several medi­cations: sitagliptin, 25 mg/d; pantoprazole, 5 mg/d; metformin, 1,000 mg/d; rivaroxaban, 20 mg/d; amiodarone, 200 mg/d; metoprolol, 12.5 mg/d; olmesartan medoxomil, 40 mg/d; aspirin, 81 mg/d; simvastatin, 10 mg/d; eszopi­clone, 3 mg at bedtime; and amlodipine, 5 mg at bedtime.

Mr. P was following up with his primary care physician for his medical conditions and was adherent with treatment until 1 week before he was admitted to our facility.

The authors’ observations
Always rule out medical causes in a case of new-onset mania, which is particu­larly important in geriatric patients. Older patients with new-onset mania are more than twice as likely to have a comorbid neurologic disorder.⁹ Neurologic causes of late-onset mania include:
   • stroke
   • tumor
   • epilepsy
   • Huntington’s disease and other movement disorders
   • multiple sclerosis and other white-matter diseases
   • head trauma
   • infection (such as neurosyphilis)
   • Creutzfeldt-Jakob disease
   • frontotemporal dementia.¹⁰

Mr. P’s presentation of psychomotor agitation, impaired functioning, decreased need for sleep, increased energy, hyperver­bal speech, and complex paranoid delu­sions meets DSM-5 criteria for bipolar disorder, manic phase. In addition, older manic patients frequently present with confusion, disorientation, and distract­ibility. Younger patients with mania often present with euphoric moods and gran­diosity; in contrast, geriatric patients are more likely to show a mixture of depressed affect and manic symptoms (pressured speech and a decreased need for sleep).^11-15

We considered an emerging neurode­generative process, because dementia can present early with disinhibition, lability, and other behavioral disturbances, includ­ing classic manic syndromes.¹⁶ Although we could not fully rule out a neurode­generative process in the initial phase of treatment, Mr. P’s longitudinal course demonstrated no change in baseline cog­nitive function and no evidence of subse­quent decline, making dementia unlikely.¹⁷

Patients with frontotemporal demen­tia are more likely to present initially to a psychiatrist than to a neurologist.¹⁸

Frontotemporal dementia is a progressive neurodegenerative disease that affects the frontal and temporal cortices; it is a com­mon cause of dementia in patients age <65.¹⁹ Frontotemporal dementia is char­acterized by insidious behavioral and personality changes; often, the initial pre­sentation lacks any clear neurologic signs or symptoms. Key features include apa­thy, disinhibition, loss of sympathy and empathy, repetitive motor behaviors, and overeating.²⁰

Mr. P’s symptoms stabilized with dival­proex sprinkles and risperidone. There was no evidence of decline in memory, social interaction, or behavior.

EVALUATION Paranoia
On mental status exam, Mr. P has an appropri­ate appearance; he is clean and shaven, with good eye contact. Muscular tone and gait are within normal limits. Level of activity is increased; he exhibits psychomotor agitation. Speech is rapid, over-productive, and loud; thought process shows flight of ideas, and thought associations are circumstantial.

Mr. P has paranoid delusions about the staff trying to hurt him. His judgment is poor, evidenced by an inability to take care of him­self. Insight is minimal, as seen by noncompli­ance with treatment. Mr. P is oriented only to person and place. His mood is anxious; affect is labile.

Complete blood count, comprehensive met­abolic profile, blood alcohol level, urine analy­sis, urine toxicology, electrocardiogram, and CT scan of the head are within normal limits.

Mr. P is given a diagnosis of mood disorder due to general medical condition, psychotic disorder due to general medical condition. The team rules out acute delirium, bipolar I disor­der, and neurodegenerative disorders such as frontotemporal dementia.

Mr. P is maintained on pre-admission medi­cations for his medical conditions. A mood sta­bilizer, divalproex sprinkles, 250 mg/d, is added.

Once on the unit, Mr. P is re-evaluated. Divalproex is increased to 500 mg/d; risperi­done, 0.5 mg/d, is added to address paranoia. Mr. P also receives group and individual psy­chotherapy. He does not participate in neuro­psychological testing, and no single-photon emission CT analysis is done. Mr. P remains in the hospital for 2 weeks. After a family meeting, his daughter says she feels comfortable taking Mr. P home. He follows up in the outpatient clinic and is doing well.

The authors’ observations
Treating geriatric patients with bipolar disorder requires attention to several fac­tors (Table). Older patients might tolerate or metabolize medications differently than younger adults, and therefore may need a different dosage. Older patients are more likely to have comorbid medical conditions and to be taking medications for those ail­ments. Treatment is much more compli­cated for this age group because physicians need to account for possible drug-drug interactions.²¹

Psychotherapy can be a valuable addition to pharmacotherapy in older adults. Some psychotherapy programs are specifically geared to older bipolar disorder patients.^22,23

Use of divalproex sodium in older patients
First, perform baseline laboratory tests: complete blood count, liver function, and electrocardiogram. Initiate divalproex sodium, 250 mg at bedtime, increasing the dosage every 3 to 5 days by 250 mg, with a target dose of 500 to 2,000 mg/d (divided into 2 or 3 doses). Monitor serum levels; levels of 29 to 100 μg/mL are effective and well tolerated. Common side effects include excess sedation, ataxia, tremor, nausea, and, rarely, hepatotoxicity, leuko­penia, and thrombocytopenia.²⁴

Use of lithium in geriatric patients
First, perform baseline laboratory tests: electrolytes, creatinine, blood urea nitro­gen, urine, thyroid stimulating hormone, and electrocardiogram. Starting dosage is 300 mg at bedtime (150 mg for frail cachec­tic patients). Monitor serum levels 12 hours after last dose, adjusting dosage every 5 days until a target serum level of 0.5 to 0.8 mEq/L is reached. Common dosages for geriatric patients are 300 to 600 mg/d, which often can be given as a single bed­time dose. Cautions: When using lithium with a thiazide diuretic or nonsteroidal anti-inflammatory drug, watch for dehy­dration, vomiting, and diarrhea, which will elevate the serum lithium level. Side effects include ataxia, tremor, urinary frequency, thirst, nausea, diarrhea, hypothyroidism, and exacerbation of psoriasis. Once sta­bilized, monitor the serum lithium level, thyroid-stimulating hormone, and kidney function every 3 to 6 months.²⁴

Bottom Line
In geriatric patients, bipolar disorder can present with agitation, irritability, confusion, and psychosis, rather than euphoric mood and grandiosity. When you suspect bipolar disorder in an older patient, first rule out medical causes of symptoms. When selecting treatment, consider comorbid medical conditions and possible drug-drug interactions.

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

CASE Delusional and aggressive
Mr. P, age 78, of Filipino heritage, is brought to the psychiatric hospital because he has been verbally aggressive toward his wife for sev­eral weeks. He has no history of a psychiatric diagnosis or inpatient psychiatric hospitaliza­tion, and no history of taking any psychotropic medications.

According to his wife, Mr. P has been rumi­nating about his father, who died in World War II, saying that “the Japanese never gave his body back” to him. Also, his wife describes 3 weeks of physically aggressive behavior, such as throwing punches; the last episode was 2 days before admission.

Mr. P is not bathing, eating, taking his medi­cations, and attending to his activities of daily living. He sleeps for only 1 to 2 hours a night; is irritable and easily distractible; and experi­ences flight of ideas. Mr. P has been buying lottery tickets, telling his daughter that he will become a millionaire and then buy a house in the Philippines.

Mr. P reports depressed mood, but no other depressive symptoms are present. He reports no suicidal or homicidal ideations, auditory or visual hallucinations, or anxiety symptoms. He has no history of substance abuse.

What diagnosis would you give Mr. P?
   a) late-onset bipolar disorder
   b) Alzheimer’s disease
   c) major depressive disorder
   d) frontotemporal dementia

The authors’ observations
Bipolar disorder in later life is a complex and confounding neuropsychiatric syn­drome with diagnostic and therapeutic challenges. The disorder can affect people of all ages and is not uncommon among geriatric patients, with a 1-year prevalence in United States of 0.4%.¹ In one study, 10% of new bipolar disorder cases were found to occur after age 50.² As the American population grows older, the number of bipolar disorder cases among seniors is expected to increase.³

It was once thought that symptoms of bipolar disorder disappear with age; newer research has disproved this theory, and proposes that untreated bipolar dis­order worsens over time.⁴ Persons who are given the diagnosis later in life could have had bipolar disorder for decades, but symptoms became more noticeable and problematic with age.⁵

Common symptoms in geriatric patients can differ from what we might expect in younger patients: agitation, hyperactivity, irritability, confusion, and psychosis.⁶ When the disorder presents in patients age >60, it can be severe, with significant changes in cognitive function, including difficulties with memory, perception, judgment, and problem-solving.^7,8

HISTORY Medical comorbidities
Mr. P emigrated from the Philippines 20 years ago, is married, and lives with his wife. He has 3 brothers; his parents were divorced, and his mother remarried. Mr. P completed high school.

Mr. P has an extensive medical history: diabetes mellitus, hypertension, dyslipid­emia, and recent double coronary artery bypass grafting. He is taking several medi­cations: sitagliptin, 25 mg/d; pantoprazole, 5 mg/d; metformin, 1,000 mg/d; rivaroxaban, 20 mg/d; amiodarone, 200 mg/d; metoprolol, 12.5 mg/d; olmesartan medoxomil, 40 mg/d; aspirin, 81 mg/d; simvastatin, 10 mg/d; eszopi­clone, 3 mg at bedtime; and amlodipine, 5 mg at bedtime.

Mr. P was following up with his primary care physician for his medical conditions and was adherent with treatment until 1 week before he was admitted to our facility.

The authors’ observations
Always rule out medical causes in a case of new-onset mania, which is particu­larly important in geriatric patients. Older patients with new-onset mania are more than twice as likely to have a comorbid neurologic disorder.⁹ Neurologic causes of late-onset mania include:
   • stroke
   • tumor
   • epilepsy
   • Huntington’s disease and other movement disorders
   • multiple sclerosis and other white-matter diseases
   • head trauma
   • infection (such as neurosyphilis)
   • Creutzfeldt-Jakob disease
   • frontotemporal dementia.¹⁰

Mr. P’s presentation of psychomotor agitation, impaired functioning, decreased need for sleep, increased energy, hyperver­bal speech, and complex paranoid delu­sions meets DSM-5 criteria for bipolar disorder, manic phase. In addition, older manic patients frequently present with confusion, disorientation, and distract­ibility. Younger patients with mania often present with euphoric moods and gran­diosity; in contrast, geriatric patients are more likely to show a mixture of depressed affect and manic symptoms (pressured speech and a decreased need for sleep).^11-15

We considered an emerging neurode­generative process, because dementia can present early with disinhibition, lability, and other behavioral disturbances, includ­ing classic manic syndromes.¹⁶ Although we could not fully rule out a neurode­generative process in the initial phase of treatment, Mr. P’s longitudinal course demonstrated no change in baseline cog­nitive function and no evidence of subse­quent decline, making dementia unlikely.¹⁷

Patients with frontotemporal demen­tia are more likely to present initially to a psychiatrist than to a neurologist.¹⁸

Frontotemporal dementia is a progressive neurodegenerative disease that affects the frontal and temporal cortices; it is a com­mon cause of dementia in patients age <65.¹⁹ Frontotemporal dementia is char­acterized by insidious behavioral and personality changes; often, the initial pre­sentation lacks any clear neurologic signs or symptoms. Key features include apa­thy, disinhibition, loss of sympathy and empathy, repetitive motor behaviors, and overeating.²⁰

Mr. P’s symptoms stabilized with dival­proex sprinkles and risperidone. There was no evidence of decline in memory, social interaction, or behavior.

EVALUATION Paranoia
On mental status exam, Mr. P has an appropri­ate appearance; he is clean and shaven, with good eye contact. Muscular tone and gait are within normal limits. Level of activity is increased; he exhibits psychomotor agitation. Speech is rapid, over-productive, and loud; thought process shows flight of ideas, and thought associations are circumstantial.

Mr. P has paranoid delusions about the staff trying to hurt him. His judgment is poor, evidenced by an inability to take care of him­self. Insight is minimal, as seen by noncompli­ance with treatment. Mr. P is oriented only to person and place. His mood is anxious; affect is labile.

Complete blood count, comprehensive met­abolic profile, blood alcohol level, urine analy­sis, urine toxicology, electrocardiogram, and CT scan of the head are within normal limits.

Mr. P is given a diagnosis of mood disorder due to general medical condition, psychotic disorder due to general medical condition. The team rules out acute delirium, bipolar I disor­der, and neurodegenerative disorders such as frontotemporal dementia.

Mr. P is maintained on pre-admission medi­cations for his medical conditions. A mood sta­bilizer, divalproex sprinkles, 250 mg/d, is added.

Once on the unit, Mr. P is re-evaluated. Divalproex is increased to 500 mg/d; risperi­done, 0.5 mg/d, is added to address paranoia. Mr. P also receives group and individual psy­chotherapy. He does not participate in neuro­psychological testing, and no single-photon emission CT analysis is done. Mr. P remains in the hospital for 2 weeks. After a family meeting, his daughter says she feels comfortable taking Mr. P home. He follows up in the outpatient clinic and is doing well.

The authors’ observations
Treating geriatric patients with bipolar disorder requires attention to several fac­tors (Table). Older patients might tolerate or metabolize medications differently than younger adults, and therefore may need a different dosage. Older patients are more likely to have comorbid medical conditions and to be taking medications for those ail­ments. Treatment is much more compli­cated for this age group because physicians need to account for possible drug-drug interactions.²¹

Psychotherapy can be a valuable addition to pharmacotherapy in older adults. Some psychotherapy programs are specifically geared to older bipolar disorder patients.^22,23

Use of divalproex sodium in older patients
First, perform baseline laboratory tests: complete blood count, liver function, and electrocardiogram. Initiate divalproex sodium, 250 mg at bedtime, increasing the dosage every 3 to 5 days by 250 mg, with a target dose of 500 to 2,000 mg/d (divided into 2 or 3 doses). Monitor serum levels; levels of 29 to 100 μg/mL are effective and well tolerated. Common side effects include excess sedation, ataxia, tremor, nausea, and, rarely, hepatotoxicity, leuko­penia, and thrombocytopenia.²⁴

Use of lithium in geriatric patients
First, perform baseline laboratory tests: electrolytes, creatinine, blood urea nitro­gen, urine, thyroid stimulating hormone, and electrocardiogram. Starting dosage is 300 mg at bedtime (150 mg for frail cachec­tic patients). Monitor serum levels 12 hours after last dose, adjusting dosage every 5 days until a target serum level of 0.5 to 0.8 mEq/L is reached. Common dosages for geriatric patients are 300 to 600 mg/d, which often can be given as a single bed­time dose. Cautions: When using lithium with a thiazide diuretic or nonsteroidal anti-inflammatory drug, watch for dehy­dration, vomiting, and diarrhea, which will elevate the serum lithium level. Side effects include ataxia, tremor, urinary frequency, thirst, nausea, diarrhea, hypothyroidism, and exacerbation of psoriasis. Once sta­bilized, monitor the serum lithium level, thyroid-stimulating hormone, and kidney function every 3 to 6 months.²⁴

Bottom Line
In geriatric patients, bipolar disorder can present with agitation, irritability, confusion, and psychosis, rather than euphoric mood and grandiosity. When you suspect bipolar disorder in an older patient, first rule out medical causes of symptoms. When selecting treatment, consider comorbid medical conditions and possible drug-drug interactions.

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

CASE Delusional and aggressive
Mr. P, age 78, of Filipino heritage, is brought to the psychiatric hospital because he has been verbally aggressive toward his wife for sev­eral weeks. He has no history of a psychiatric diagnosis or inpatient psychiatric hospitaliza­tion, and no history of taking any psychotropic medications.

According to his wife, Mr. P has been rumi­nating about his father, who died in World War II, saying that “the Japanese never gave his body back” to him. Also, his wife describes 3 weeks of physically aggressive behavior, such as throwing punches; the last episode was 2 days before admission.

Mr. P is not bathing, eating, taking his medi­cations, and attending to his activities of daily living. He sleeps for only 1 to 2 hours a night; is irritable and easily distractible; and experi­ences flight of ideas. Mr. P has been buying lottery tickets, telling his daughter that he will become a millionaire and then buy a house in the Philippines.

Mr. P reports depressed mood, but no other depressive symptoms are present. He reports no suicidal or homicidal ideations, auditory or visual hallucinations, or anxiety symptoms. He has no history of substance abuse.

What diagnosis would you give Mr. P?
   a) late-onset bipolar disorder
   b) Alzheimer’s disease
   c) major depressive disorder
   d) frontotemporal dementia

The authors’ observations
Bipolar disorder in later life is a complex and confounding neuropsychiatric syn­drome with diagnostic and therapeutic challenges. The disorder can affect people of all ages and is not uncommon among geriatric patients, with a 1-year prevalence in United States of 0.4%.¹ In one study, 10% of new bipolar disorder cases were found to occur after age 50.² As the American population grows older, the number of bipolar disorder cases among seniors is expected to increase.³

It was once thought that symptoms of bipolar disorder disappear with age; newer research has disproved this theory, and proposes that untreated bipolar dis­order worsens over time.⁴ Persons who are given the diagnosis later in life could have had bipolar disorder for decades, but symptoms became more noticeable and problematic with age.⁵

Common symptoms in geriatric patients can differ from what we might expect in younger patients: agitation, hyperactivity, irritability, confusion, and psychosis.⁶ When the disorder presents in patients age >60, it can be severe, with significant changes in cognitive function, including difficulties with memory, perception, judgment, and problem-solving.^7,8

HISTORY Medical comorbidities
Mr. P emigrated from the Philippines 20 years ago, is married, and lives with his wife. He has 3 brothers; his parents were divorced, and his mother remarried. Mr. P completed high school.

Mr. P has an extensive medical history: diabetes mellitus, hypertension, dyslipid­emia, and recent double coronary artery bypass grafting. He is taking several medi­cations: sitagliptin, 25 mg/d; pantoprazole, 5 mg/d; metformin, 1,000 mg/d; rivaroxaban, 20 mg/d; amiodarone, 200 mg/d; metoprolol, 12.5 mg/d; olmesartan medoxomil, 40 mg/d; aspirin, 81 mg/d; simvastatin, 10 mg/d; eszopi­clone, 3 mg at bedtime; and amlodipine, 5 mg at bedtime.

Mr. P was following up with his primary care physician for his medical conditions and was adherent with treatment until 1 week before he was admitted to our facility.

The authors’ observations
Always rule out medical causes in a case of new-onset mania, which is particu­larly important in geriatric patients. Older patients with new-onset mania are more than twice as likely to have a comorbid neurologic disorder.⁹ Neurologic causes of late-onset mania include:
   • stroke
   • tumor
   • epilepsy
   • Huntington’s disease and other movement disorders
   • multiple sclerosis and other white-matter diseases
   • head trauma
   • infection (such as neurosyphilis)
   • Creutzfeldt-Jakob disease
   • frontotemporal dementia.¹⁰

Mr. P’s presentation of psychomotor agitation, impaired functioning, decreased need for sleep, increased energy, hyperver­bal speech, and complex paranoid delu­sions meets DSM-5 criteria for bipolar disorder, manic phase. In addition, older manic patients frequently present with confusion, disorientation, and distract­ibility. Younger patients with mania often present with euphoric moods and gran­diosity; in contrast, geriatric patients are more likely to show a mixture of depressed affect and manic symptoms (pressured speech and a decreased need for sleep).^11-15

We considered an emerging neurode­generative process, because dementia can present early with disinhibition, lability, and other behavioral disturbances, includ­ing classic manic syndromes.¹⁶ Although we could not fully rule out a neurode­generative process in the initial phase of treatment, Mr. P’s longitudinal course demonstrated no change in baseline cog­nitive function and no evidence of subse­quent decline, making dementia unlikely.¹⁷

Patients with frontotemporal demen­tia are more likely to present initially to a psychiatrist than to a neurologist.¹⁸

Frontotemporal dementia is a progressive neurodegenerative disease that affects the frontal and temporal cortices; it is a com­mon cause of dementia in patients age <65.¹⁹ Frontotemporal dementia is char­acterized by insidious behavioral and personality changes; often, the initial pre­sentation lacks any clear neurologic signs or symptoms. Key features include apa­thy, disinhibition, loss of sympathy and empathy, repetitive motor behaviors, and overeating.²⁰

Mr. P’s symptoms stabilized with dival­proex sprinkles and risperidone. There was no evidence of decline in memory, social interaction, or behavior.

EVALUATION Paranoia
On mental status exam, Mr. P has an appropri­ate appearance; he is clean and shaven, with good eye contact. Muscular tone and gait are within normal limits. Level of activity is increased; he exhibits psychomotor agitation. Speech is rapid, over-productive, and loud; thought process shows flight of ideas, and thought associations are circumstantial.

Mr. P has paranoid delusions about the staff trying to hurt him. His judgment is poor, evidenced by an inability to take care of him­self. Insight is minimal, as seen by noncompli­ance with treatment. Mr. P is oriented only to person and place. His mood is anxious; affect is labile.

Complete blood count, comprehensive met­abolic profile, blood alcohol level, urine analy­sis, urine toxicology, electrocardiogram, and CT scan of the head are within normal limits.

Mr. P is given a diagnosis of mood disorder due to general medical condition, psychotic disorder due to general medical condition. The team rules out acute delirium, bipolar I disor­der, and neurodegenerative disorders such as frontotemporal dementia.

Mr. P is maintained on pre-admission medi­cations for his medical conditions. A mood sta­bilizer, divalproex sprinkles, 250 mg/d, is added.

Once on the unit, Mr. P is re-evaluated. Divalproex is increased to 500 mg/d; risperi­done, 0.5 mg/d, is added to address paranoia. Mr. P also receives group and individual psy­chotherapy. He does not participate in neuro­psychological testing, and no single-photon emission CT analysis is done. Mr. P remains in the hospital for 2 weeks. After a family meeting, his daughter says she feels comfortable taking Mr. P home. He follows up in the outpatient clinic and is doing well.

The authors’ observations
Treating geriatric patients with bipolar disorder requires attention to several fac­tors (Table). Older patients might tolerate or metabolize medications differently than younger adults, and therefore may need a different dosage. Older patients are more likely to have comorbid medical conditions and to be taking medications for those ail­ments. Treatment is much more compli­cated for this age group because physicians need to account for possible drug-drug interactions.²¹

Psychotherapy can be a valuable addition to pharmacotherapy in older adults. Some psychotherapy programs are specifically geared to older bipolar disorder patients.^22,23

Use of divalproex sodium in older patients
First, perform baseline laboratory tests: complete blood count, liver function, and electrocardiogram. Initiate divalproex sodium, 250 mg at bedtime, increasing the dosage every 3 to 5 days by 250 mg, with a target dose of 500 to 2,000 mg/d (divided into 2 or 3 doses). Monitor serum levels; levels of 29 to 100 μg/mL are effective and well tolerated. Common side effects include excess sedation, ataxia, tremor, nausea, and, rarely, hepatotoxicity, leuko­penia, and thrombocytopenia.²⁴

Use of lithium in geriatric patients
First, perform baseline laboratory tests: electrolytes, creatinine, blood urea nitro­gen, urine, thyroid stimulating hormone, and electrocardiogram. Starting dosage is 300 mg at bedtime (150 mg for frail cachec­tic patients). Monitor serum levels 12 hours after last dose, adjusting dosage every 5 days until a target serum level of 0.5 to 0.8 mEq/L is reached. Common dosages for geriatric patients are 300 to 600 mg/d, which often can be given as a single bed­time dose. Cautions: When using lithium with a thiazide diuretic or nonsteroidal anti-inflammatory drug, watch for dehy­dration, vomiting, and diarrhea, which will elevate the serum lithium level. Side effects include ataxia, tremor, urinary frequency, thirst, nausea, diarrhea, hypothyroidism, and exacerbation of psoriasis. Once sta­bilized, monitor the serum lithium level, thyroid-stimulating hormone, and kidney function every 3 to 6 months.²⁴

Bottom Line
In geriatric patients, bipolar disorder can present with agitation, irritability, confusion, and psychosis, rather than euphoric mood and grandiosity. When you suspect bipolar disorder in an older patient, first rule out medical causes of symptoms. When selecting treatment, consider comorbid medical conditions and possible drug-drug interactions.

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

Mrs. S, age 46, has been struggling to manage depression for 7 years. She completed adequate trials of several selective serotonin reuptake inhibitors and bupropion. Currently, she is taking dulox­etine, 60 mg/d, and aripiprazole, 5 mg/d.

At her most recent clinic visit, Mrs. S reports that she is doing “OK,” but that she still feels sad and disengaged most days of the week. She wants to know more about ketamine for treating depression after read­ing about it on the Internet and hearing it mentioned in a support group she attends. She asks if you think it would work for her, and gives you with a copy of an article about its use in patients with treatment-resistant depression. Mrs. S has no other health condi­tions and takes a daily vitamin D and calcium supplement.

The monoamine hypothesis of depres­sion postulates that symptoms originate from underactivity of monoamines, such as serotonin, norepinephrine, and dopa­mine, in the brain. This hypothesis was formulated in the 1960s after researchers observed that monoamine oxidase inhibi­tors and tricyclic antidepressants relieved depressive symptoms; both were known to increase monoamine concentrations in the synaptic cleft.¹

Regrettably, these medications do not adequately relieve depressive symptoms for many people. In fact, symptom remis­sion occurs in only one-third of treated patients.² This low remission rate reflects a lack of understanding of the patho­physiology of depression, and the need for drugs with unique mechanisms of action.

One of the newest drug targets shown to be relevant in psychiatric illness is the

glutamatergic system. Glutamate is the predominant excitatory neurotransmit­ter in the CNS, and it is responsible for many key functions, including synaptic plasticity, learning, memory, and locomo­tion.³ Normally, the glutamatergic system tightly regulates the amount of glutamate in the neuronal synapse via receptors on presynaptic and postsynaptic neurons, as well as on glial cells (Figure). When this equilibrium is disrupted in stressful situ­ations, such as ischemia, trauma, or sei­zures, excess glutamate is released into the synapse. The resulting glutamatergic hyperactivity can lead to neurotoxicity and cell death when neuronal receptors are activated for an extended period.

A key component of the glutamater­gic system that is responsible for remov­ing excess glutamate from the synapse is membrane-bound transporters, which are similar to serotonin and norepineph­rine transporters. These excitatory amino acid transporters (EAATs) are impor­tant because glutamate metabolism does not occur within the synapse and EAATS are responsible for removing most of the glutamate from the synapse into glial cells.³

The network of receptors within the synapse that are activated by glutamate is extensive and complex. There are at least 11 glutamate-responsive receptors: 3 are ionotropic action channels, and the remaining 8 are metabotropic G protein-coupled receptors. Previous studies have shown regional changes in glutamate receptors, as well as elevated levels of glu­tamate, in the brains of patients with major depressive disorder (MDD).⁴

Ketamine. The ionotropic receptor N-methyl-d-aspartate (NMDA) is one of the most studied glutamate receptors. Pharmacologically, ketamine is a noncom­petitive NMDA receptor antagonist that also activates the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) recep­tor, which is another subtype of ionotropic glutamate receptors. In open-label clinical trials, ketamine has demonstrated rapid antidepressant action in patients with treat­ment-resistant MDD.^4,5

Recently, Murrough et al6 performed the first randomized, psychoactive con­trolled trial using a single IV infusion of ketamine dosed below anesthesia ranges (0.5 mg/kg), or midazolam (0.045 mg/kg), in patients with treatment-resistant depres­sion who had been antidepressant-free for at least 4 weeks. They found that 24 hours after medication administration, the likelihood of response to ketamine was significantly higher than the response to midazolam (OR: 2.18; 95% CI: 1.21 to 4.14), with a response rate of 64% in the ketamine group and 28% in the midazolam group.⁶

Psychotropic side effects, such as hal­lucinations, are a major concern with ketamine tolerability and abuse poten­tial. This is largely because of ketamine’s antagonism of the NMDA receptor, which is a property shared with other abused drugs such as phencyclidine (PCP) and dextromethorphan. In the Murrough et al⁶ study, there were no reported cases of paranoia or hallucinations, but dissocia­tive symptoms were relatively common (17%).

Although the results in this trial appear encouraging, there are several limitations to using ketamine to treat MDD, especially in an ambulatory setting. Concerns include ketamine’s IV administration, potential for abuse, long-term efficacy, and side-effect profile—particularly psychotic symptoms and hemodynamic changes. An ideal com­pound would have the rapid efficacy of ket­amine, but with a safer side-effect profile, easier administration, and less potential for abuse.

Riluzole also acts on the glutamatergic sys­tem, but has not shown antidepressant effi­cacy as consistently as ketamine. Riluzole is FDA-approved for treating amyotrophic lateral sclerosis.⁵ Pharmacologically, rilu­zole is a glutamatergic modulator that increases glutamate reuptake into glial cells, decreases glutamate release, and increases AMPA trafficking. In open-label studies riluzole has shown efficacy in reducing depressive symptoms.^4,5 However, when compared with placebo as a means of sustaining treatment response after a 1-time dose of ketamine, riluzole showed was no significant improvement in time to depres­sive relapse.⁷

Acamprosate, often used for treating alco­hol abuse, is another a drug with gluta­matergic activity that has been studied for possible use as an antidepressant.⁵

A review by Lapidus et al⁵ has a more extensive listing of current medications and investigational compounds that modulate glutamate transmission, and are of inter­est for their possible antidepressant activ­ity. Given the relatively new “glutamatergic hypothesis” of depression, it is exciting that so many current and novel glutamatergic drug therapies are being evaluated.

Future of ketamine treatment
Glutamate has been shown to play an important part in the pathophysiology of depression. The rapid antidepressant efficacy of ketamine provides evidence that future medications with glutamate-modulating activity could be useful for patients who struggle to achieve symp­tom relief using available antidepressants. Several limitations exist regarding ket­amine use, and more work in this important therapeutic area needs to be done. This last point is important to remember when speak­ing with patients such as Mrs. S. Although it is understandable for her to be excited about novel treatment options such as ket­amine, stress to her that treating depression with ketamine at this time is strictly inves­tigational, and that the drug needs to be thoroughly evaluated for safety and efficacy before it can be prescribed for this indication.

CASE CONTINUED
Mrs. S realizes that ketamine may not be the best next step for her, and she agrees to explore other approaches to treat her residual depressive symptoms.

Related Resources
• Machado-Vieira R, Ibrahim L, Henter ID, et al. Novel gluta­matergic agents for major depressive disorder and bipolar disorder. Pharmacol Biochem Behav. 2012;100(4):678-687.
• Mathews DC, Henter ID, Zarate CA. Targeting the glutama­tergic system to treat major depressive disorder: rationale and progress to date. Drugs. 2012;72(10):1313-1333.

Drug Brand Names
Acamprosate • Campral               Duloxetine • Cymbalta
Aripiprazole • Abilify                    Ketamine • Ketalar
Bupropion • Wellbutrin, Zyban     Riluzole • Rilutek

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

Mrs. S, age 46, has been struggling to manage depression for 7 years. She completed adequate trials of several selective serotonin reuptake inhibitors and bupropion. Currently, she is taking dulox­etine, 60 mg/d, and aripiprazole, 5 mg/d.

At her most recent clinic visit, Mrs. S reports that she is doing “OK,” but that she still feels sad and disengaged most days of the week. She wants to know more about ketamine for treating depression after read­ing about it on the Internet and hearing it mentioned in a support group she attends. She asks if you think it would work for her, and gives you with a copy of an article about its use in patients with treatment-resistant depression. Mrs. S has no other health condi­tions and takes a daily vitamin D and calcium supplement.

The monoamine hypothesis of depres­sion postulates that symptoms originate from underactivity of monoamines, such as serotonin, norepinephrine, and dopa­mine, in the brain. This hypothesis was formulated in the 1960s after researchers observed that monoamine oxidase inhibi­tors and tricyclic antidepressants relieved depressive symptoms; both were known to increase monoamine concentrations in the synaptic cleft.¹

Regrettably, these medications do not adequately relieve depressive symptoms for many people. In fact, symptom remis­sion occurs in only one-third of treated patients.² This low remission rate reflects a lack of understanding of the patho­physiology of depression, and the need for drugs with unique mechanisms of action.

One of the newest drug targets shown to be relevant in psychiatric illness is the

glutamatergic system. Glutamate is the predominant excitatory neurotransmit­ter in the CNS, and it is responsible for many key functions, including synaptic plasticity, learning, memory, and locomo­tion.³ Normally, the glutamatergic system tightly regulates the amount of glutamate in the neuronal synapse via receptors on presynaptic and postsynaptic neurons, as well as on glial cells (Figure). When this equilibrium is disrupted in stressful situ­ations, such as ischemia, trauma, or sei­zures, excess glutamate is released into the synapse. The resulting glutamatergic hyperactivity can lead to neurotoxicity and cell death when neuronal receptors are activated for an extended period.

A key component of the glutamater­gic system that is responsible for remov­ing excess glutamate from the synapse is membrane-bound transporters, which are similar to serotonin and norepineph­rine transporters. These excitatory amino acid transporters (EAATs) are impor­tant because glutamate metabolism does not occur within the synapse and EAATS are responsible for removing most of the glutamate from the synapse into glial cells.³

The network of receptors within the synapse that are activated by glutamate is extensive and complex. There are at least 11 glutamate-responsive receptors: 3 are ionotropic action channels, and the remaining 8 are metabotropic G protein-coupled receptors. Previous studies have shown regional changes in glutamate receptors, as well as elevated levels of glu­tamate, in the brains of patients with major depressive disorder (MDD).⁴

Ketamine. The ionotropic receptor N-methyl-d-aspartate (NMDA) is one of the most studied glutamate receptors. Pharmacologically, ketamine is a noncom­petitive NMDA receptor antagonist that also activates the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) recep­tor, which is another subtype of ionotropic glutamate receptors. In open-label clinical trials, ketamine has demonstrated rapid antidepressant action in patients with treat­ment-resistant MDD.^4,5

Recently, Murrough et al6 performed the first randomized, psychoactive con­trolled trial using a single IV infusion of ketamine dosed below anesthesia ranges (0.5 mg/kg), or midazolam (0.045 mg/kg), in patients with treatment-resistant depres­sion who had been antidepressant-free for at least 4 weeks. They found that 24 hours after medication administration, the likelihood of response to ketamine was significantly higher than the response to midazolam (OR: 2.18; 95% CI: 1.21 to 4.14), with a response rate of 64% in the ketamine group and 28% in the midazolam group.⁶

Psychotropic side effects, such as hal­lucinations, are a major concern with ketamine tolerability and abuse poten­tial. This is largely because of ketamine’s antagonism of the NMDA receptor, which is a property shared with other abused drugs such as phencyclidine (PCP) and dextromethorphan. In the Murrough et al⁶ study, there were no reported cases of paranoia or hallucinations, but dissocia­tive symptoms were relatively common (17%).

Although the results in this trial appear encouraging, there are several limitations to using ketamine to treat MDD, especially in an ambulatory setting. Concerns include ketamine’s IV administration, potential for abuse, long-term efficacy, and side-effect profile—particularly psychotic symptoms and hemodynamic changes. An ideal com­pound would have the rapid efficacy of ket­amine, but with a safer side-effect profile, easier administration, and less potential for abuse.

Riluzole also acts on the glutamatergic sys­tem, but has not shown antidepressant effi­cacy as consistently as ketamine. Riluzole is FDA-approved for treating amyotrophic lateral sclerosis.⁵ Pharmacologically, rilu­zole is a glutamatergic modulator that increases glutamate reuptake into glial cells, decreases glutamate release, and increases AMPA trafficking. In open-label studies riluzole has shown efficacy in reducing depressive symptoms.^4,5 However, when compared with placebo as a means of sustaining treatment response after a 1-time dose of ketamine, riluzole showed was no significant improvement in time to depres­sive relapse.⁷

Acamprosate, often used for treating alco­hol abuse, is another a drug with gluta­matergic activity that has been studied for possible use as an antidepressant.⁵

A review by Lapidus et al⁵ has a more extensive listing of current medications and investigational compounds that modulate glutamate transmission, and are of inter­est for their possible antidepressant activ­ity. Given the relatively new “glutamatergic hypothesis” of depression, it is exciting that so many current and novel glutamatergic drug therapies are being evaluated.

Future of ketamine treatment
Glutamate has been shown to play an important part in the pathophysiology of depression. The rapid antidepressant efficacy of ketamine provides evidence that future medications with glutamate-modulating activity could be useful for patients who struggle to achieve symp­tom relief using available antidepressants. Several limitations exist regarding ket­amine use, and more work in this important therapeutic area needs to be done. This last point is important to remember when speak­ing with patients such as Mrs. S. Although it is understandable for her to be excited about novel treatment options such as ket­amine, stress to her that treating depression with ketamine at this time is strictly inves­tigational, and that the drug needs to be thoroughly evaluated for safety and efficacy before it can be prescribed for this indication.

CASE CONTINUED
Mrs. S realizes that ketamine may not be the best next step for her, and she agrees to explore other approaches to treat her residual depressive symptoms.

Related Resources
• Machado-Vieira R, Ibrahim L, Henter ID, et al. Novel gluta­matergic agents for major depressive disorder and bipolar disorder. Pharmacol Biochem Behav. 2012;100(4):678-687.
• Mathews DC, Henter ID, Zarate CA. Targeting the glutama­tergic system to treat major depressive disorder: rationale and progress to date. Drugs. 2012;72(10):1313-1333.

Drug Brand Names
Acamprosate • Campral               Duloxetine • Cymbalta
Aripiprazole • Abilify                    Ketamine • Ketalar
Bupropion • Wellbutrin, Zyban     Riluzole • Rilutek

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

Mrs. S, age 46, has been struggling to manage depression for 7 years. She completed adequate trials of several selective serotonin reuptake inhibitors and bupropion. Currently, she is taking dulox­etine, 60 mg/d, and aripiprazole, 5 mg/d.

At her most recent clinic visit, Mrs. S reports that she is doing “OK,” but that she still feels sad and disengaged most days of the week. She wants to know more about ketamine for treating depression after read­ing about it on the Internet and hearing it mentioned in a support group she attends. She asks if you think it would work for her, and gives you with a copy of an article about its use in patients with treatment-resistant depression. Mrs. S has no other health condi­tions and takes a daily vitamin D and calcium supplement.

The monoamine hypothesis of depres­sion postulates that symptoms originate from underactivity of monoamines, such as serotonin, norepinephrine, and dopa­mine, in the brain. This hypothesis was formulated in the 1960s after researchers observed that monoamine oxidase inhibi­tors and tricyclic antidepressants relieved depressive symptoms; both were known to increase monoamine concentrations in the synaptic cleft.¹

Regrettably, these medications do not adequately relieve depressive symptoms for many people. In fact, symptom remis­sion occurs in only one-third of treated patients.² This low remission rate reflects a lack of understanding of the patho­physiology of depression, and the need for drugs with unique mechanisms of action.

One of the newest drug targets shown to be relevant in psychiatric illness is the

glutamatergic system. Glutamate is the predominant excitatory neurotransmit­ter in the CNS, and it is responsible for many key functions, including synaptic plasticity, learning, memory, and locomo­tion.³ Normally, the glutamatergic system tightly regulates the amount of glutamate in the neuronal synapse via receptors on presynaptic and postsynaptic neurons, as well as on glial cells (Figure). When this equilibrium is disrupted in stressful situ­ations, such as ischemia, trauma, or sei­zures, excess glutamate is released into the synapse. The resulting glutamatergic hyperactivity can lead to neurotoxicity and cell death when neuronal receptors are activated for an extended period.

A key component of the glutamater­gic system that is responsible for remov­ing excess glutamate from the synapse is membrane-bound transporters, which are similar to serotonin and norepineph­rine transporters. These excitatory amino acid transporters (EAATs) are impor­tant because glutamate metabolism does not occur within the synapse and EAATS are responsible for removing most of the glutamate from the synapse into glial cells.³

The network of receptors within the synapse that are activated by glutamate is extensive and complex. There are at least 11 glutamate-responsive receptors: 3 are ionotropic action channels, and the remaining 8 are metabotropic G protein-coupled receptors. Previous studies have shown regional changes in glutamate receptors, as well as elevated levels of glu­tamate, in the brains of patients with major depressive disorder (MDD).⁴

Ketamine. The ionotropic receptor N-methyl-d-aspartate (NMDA) is one of the most studied glutamate receptors. Pharmacologically, ketamine is a noncom­petitive NMDA receptor antagonist that also activates the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) recep­tor, which is another subtype of ionotropic glutamate receptors. In open-label clinical trials, ketamine has demonstrated rapid antidepressant action in patients with treat­ment-resistant MDD.^4,5

Recently, Murrough et al6 performed the first randomized, psychoactive con­trolled trial using a single IV infusion of ketamine dosed below anesthesia ranges (0.5 mg/kg), or midazolam (0.045 mg/kg), in patients with treatment-resistant depres­sion who had been antidepressant-free for at least 4 weeks. They found that 24 hours after medication administration, the likelihood of response to ketamine was significantly higher than the response to midazolam (OR: 2.18; 95% CI: 1.21 to 4.14), with a response rate of 64% in the ketamine group and 28% in the midazolam group.⁶

Psychotropic side effects, such as hal­lucinations, are a major concern with ketamine tolerability and abuse poten­tial. This is largely because of ketamine’s antagonism of the NMDA receptor, which is a property shared with other abused drugs such as phencyclidine (PCP) and dextromethorphan. In the Murrough et al⁶ study, there were no reported cases of paranoia or hallucinations, but dissocia­tive symptoms were relatively common (17%).

Although the results in this trial appear encouraging, there are several limitations to using ketamine to treat MDD, especially in an ambulatory setting. Concerns include ketamine’s IV administration, potential for abuse, long-term efficacy, and side-effect profile—particularly psychotic symptoms and hemodynamic changes. An ideal com­pound would have the rapid efficacy of ket­amine, but with a safer side-effect profile, easier administration, and less potential for abuse.

Riluzole also acts on the glutamatergic sys­tem, but has not shown antidepressant effi­cacy as consistently as ketamine. Riluzole is FDA-approved for treating amyotrophic lateral sclerosis.⁵ Pharmacologically, rilu­zole is a glutamatergic modulator that increases glutamate reuptake into glial cells, decreases glutamate release, and increases AMPA trafficking. In open-label studies riluzole has shown efficacy in reducing depressive symptoms.^4,5 However, when compared with placebo as a means of sustaining treatment response after a 1-time dose of ketamine, riluzole showed was no significant improvement in time to depres­sive relapse.⁷

Acamprosate, often used for treating alco­hol abuse, is another a drug with gluta­matergic activity that has been studied for possible use as an antidepressant.⁵

A review by Lapidus et al⁵ has a more extensive listing of current medications and investigational compounds that modulate glutamate transmission, and are of inter­est for their possible antidepressant activ­ity. Given the relatively new “glutamatergic hypothesis” of depression, it is exciting that so many current and novel glutamatergic drug therapies are being evaluated.

Future of ketamine treatment
Glutamate has been shown to play an important part in the pathophysiology of depression. The rapid antidepressant efficacy of ketamine provides evidence that future medications with glutamate-modulating activity could be useful for patients who struggle to achieve symp­tom relief using available antidepressants. Several limitations exist regarding ket­amine use, and more work in this important therapeutic area needs to be done. This last point is important to remember when speak­ing with patients such as Mrs. S. Although it is understandable for her to be excited about novel treatment options such as ket­amine, stress to her that treating depression with ketamine at this time is strictly inves­tigational, and that the drug needs to be thoroughly evaluated for safety and efficacy before it can be prescribed for this indication.

CASE CONTINUED
Mrs. S realizes that ketamine may not be the best next step for her, and she agrees to explore other approaches to treat her residual depressive symptoms.

Related Resources
• Machado-Vieira R, Ibrahim L, Henter ID, et al. Novel gluta­matergic agents for major depressive disorder and bipolar disorder. Pharmacol Biochem Behav. 2012;100(4):678-687.
• Mathews DC, Henter ID, Zarate CA. Targeting the glutama­tergic system to treat major depressive disorder: rationale and progress to date. Drugs. 2012;72(10):1313-1333.

Drug Brand Names
Acamprosate • Campral               Duloxetine • Cymbalta
Aripiprazole • Abilify                    Ketamine • Ketalar
Bupropion • Wellbutrin, Zyban     Riluzole • Rilutek

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