Current Psychiatry

Psychiatric providers often encounter older adult patients who report dif­ficulty with memory and express the fear they are “developing dementia.” Often, after a thorough evaluation of the reported deficits and history, we find that a serious or progressive neurocognitive disorder is unlikely. However, such occasions are an opportunity to discuss lifestyle changes that may help prevent, or at least slow, development of later-life cognitive decline.

Although I inform my patients that the body of evidence supporting many of these preventive measures still is evolving, I suggest the following approach that may provide a DEFENSE against future cogni­tive disability.

Diet options that are “heart healthy” seem to be “brain healthy” as well. This may be due, in part, to the antioxidant and anti-inflammatory effects of particular foods.¹ Therefore, I suggest patients try to implement a Mediterranean-type diet that emphasizes fish (especially those rich in omega-3 fats, such as salmon and tuna), poultry, fresh fruit, and vegetables, as well as legumes.

ETOH has been shown, in a moderate amount (eg, 1 drink a day for women and 1 to 2 drinks for men), to be brain protec­tive because of the antioxidants found in the alcohol or the direct relaxation effects that are produced—or both. Although red wine often is recommended, recent stud­ies have shown that those who enjoyed an active life into their 70s and 80s had consumed a moderate amount of alcohol over their lifetime regardless of the type of spirit (eg, 12 oz of beer, 4 oz of wine, 1 oz of hard liquor).²

Friends contribute to an active, stimulating, and emotionally supported life. Having a strong social network, an antidote to lone­liness and depression, has been shown to reduce the risk of “turning on” specific genes that stimulate an inflammatory process that can lead to brain cell death and neural damage.³

Exercise might be the most important ingre­dient for a longer, healthier, and more cogni­tively intact life. Moderate exercise, several times a week, increases blood flow to the brain and, subsequently, stimulates neuronal synapses and the hippocampus.⁴ The forms of exercise include walking, biking, swimming, resistance training, and even gardening.

No tobacco! It is known that smoking leads to accelerated aging for the heart and brain, so it is our responsibility to remain vigilant in promoting smoking cessation strategies.

Sleep has received increased attention, with recent studies providing evidence that the brain uses that time to “flush out” neurotoxic by-products of cognitive activity that have accumulated throughout the day.⁵ As evi­dence continues to be examined on this pro­cess, it is reasonable to recommend adequate sleep and a consistent sleep pattern as pos­sible defenses against brain cell insult.

Engagement in tasks that are cognitively stimulating has been promoted as potential “brain exercises” to stave off future memory loss. For example, computer games that are mentally challenging; lively and frequent conversations; and learning a language all appear to increase neural activation and communication throughout the brain.⁶

As brain research continues to expand, providers will become more knowledgeable and aware of the steps our patients can take when they discuss concerns about their risk of progressive cognitive disability and mem­ory loss. For now, however, it is important to describe what we do know based on cur­rent research and help our patients develop the best defense they can against age-related cognitive decline.

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

Psychiatric providers often encounter older adult patients who report dif­ficulty with memory and express the fear they are “developing dementia.” Often, after a thorough evaluation of the reported deficits and history, we find that a serious or progressive neurocognitive disorder is unlikely. However, such occasions are an opportunity to discuss lifestyle changes that may help prevent, or at least slow, development of later-life cognitive decline.

Although I inform my patients that the body of evidence supporting many of these preventive measures still is evolving, I suggest the following approach that may provide a DEFENSE against future cogni­tive disability.

Diet options that are “heart healthy” seem to be “brain healthy” as well. This may be due, in part, to the antioxidant and anti-inflammatory effects of particular foods.¹ Therefore, I suggest patients try to implement a Mediterranean-type diet that emphasizes fish (especially those rich in omega-3 fats, such as salmon and tuna), poultry, fresh fruit, and vegetables, as well as legumes.

ETOH has been shown, in a moderate amount (eg, 1 drink a day for women and 1 to 2 drinks for men), to be brain protec­tive because of the antioxidants found in the alcohol or the direct relaxation effects that are produced—or both. Although red wine often is recommended, recent stud­ies have shown that those who enjoyed an active life into their 70s and 80s had consumed a moderate amount of alcohol over their lifetime regardless of the type of spirit (eg, 12 oz of beer, 4 oz of wine, 1 oz of hard liquor).²

Friends contribute to an active, stimulating, and emotionally supported life. Having a strong social network, an antidote to lone­liness and depression, has been shown to reduce the risk of “turning on” specific genes that stimulate an inflammatory process that can lead to brain cell death and neural damage.³

Exercise might be the most important ingre­dient for a longer, healthier, and more cogni­tively intact life. Moderate exercise, several times a week, increases blood flow to the brain and, subsequently, stimulates neuronal synapses and the hippocampus.⁴ The forms of exercise include walking, biking, swimming, resistance training, and even gardening.

No tobacco! It is known that smoking leads to accelerated aging for the heart and brain, so it is our responsibility to remain vigilant in promoting smoking cessation strategies.

Sleep has received increased attention, with recent studies providing evidence that the brain uses that time to “flush out” neurotoxic by-products of cognitive activity that have accumulated throughout the day.⁵ As evi­dence continues to be examined on this pro­cess, it is reasonable to recommend adequate sleep and a consistent sleep pattern as pos­sible defenses against brain cell insult.

Engagement in tasks that are cognitively stimulating has been promoted as potential “brain exercises” to stave off future memory loss. For example, computer games that are mentally challenging; lively and frequent conversations; and learning a language all appear to increase neural activation and communication throughout the brain.⁶

As brain research continues to expand, providers will become more knowledgeable and aware of the steps our patients can take when they discuss concerns about their risk of progressive cognitive disability and mem­ory loss. For now, however, it is important to describe what we do know based on cur­rent research and help our patients develop the best defense they can against age-related cognitive decline.

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

Psychiatric providers often encounter older adult patients who report dif­ficulty with memory and express the fear they are “developing dementia.” Often, after a thorough evaluation of the reported deficits and history, we find that a serious or progressive neurocognitive disorder is unlikely. However, such occasions are an opportunity to discuss lifestyle changes that may help prevent, or at least slow, development of later-life cognitive decline.

Although I inform my patients that the body of evidence supporting many of these preventive measures still is evolving, I suggest the following approach that may provide a DEFENSE against future cogni­tive disability.

Diet options that are “heart healthy” seem to be “brain healthy” as well. This may be due, in part, to the antioxidant and anti-inflammatory effects of particular foods.¹ Therefore, I suggest patients try to implement a Mediterranean-type diet that emphasizes fish (especially those rich in omega-3 fats, such as salmon and tuna), poultry, fresh fruit, and vegetables, as well as legumes.

ETOH has been shown, in a moderate amount (eg, 1 drink a day for women and 1 to 2 drinks for men), to be brain protec­tive because of the antioxidants found in the alcohol or the direct relaxation effects that are produced—or both. Although red wine often is recommended, recent stud­ies have shown that those who enjoyed an active life into their 70s and 80s had consumed a moderate amount of alcohol over their lifetime regardless of the type of spirit (eg, 12 oz of beer, 4 oz of wine, 1 oz of hard liquor).²

Friends contribute to an active, stimulating, and emotionally supported life. Having a strong social network, an antidote to lone­liness and depression, has been shown to reduce the risk of “turning on” specific genes that stimulate an inflammatory process that can lead to brain cell death and neural damage.³

Exercise might be the most important ingre­dient for a longer, healthier, and more cogni­tively intact life. Moderate exercise, several times a week, increases blood flow to the brain and, subsequently, stimulates neuronal synapses and the hippocampus.⁴ The forms of exercise include walking, biking, swimming, resistance training, and even gardening.

No tobacco! It is known that smoking leads to accelerated aging for the heart and brain, so it is our responsibility to remain vigilant in promoting smoking cessation strategies.

Sleep has received increased attention, with recent studies providing evidence that the brain uses that time to “flush out” neurotoxic by-products of cognitive activity that have accumulated throughout the day.⁵ As evi­dence continues to be examined on this pro­cess, it is reasonable to recommend adequate sleep and a consistent sleep pattern as pos­sible defenses against brain cell insult.

Engagement in tasks that are cognitively stimulating has been promoted as potential “brain exercises” to stave off future memory loss. For example, computer games that are mentally challenging; lively and frequent conversations; and learning a language all appear to increase neural activation and communication throughout the brain.⁶

As brain research continues to expand, providers will become more knowledgeable and aware of the steps our patients can take when they discuss concerns about their risk of progressive cognitive disability and mem­ory loss. For now, however, it is important to describe what we do know based on cur­rent research and help our patients develop the best defense they can against age-related cognitive decline.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

First-episode psychosis (FEP) in schizophrenia is char­acterized by high response rates to antipsychotic therapy, followed by frequent antipsychotic discon­tinuation and elevated relapse rates soon after mainte­nance treatment begins.^1,2 With subsequent episodes, time to response progressively increases and likelihood of response decreases.^3,4

To address these issues, this article—the second of 2 parts⁵—describes the rationale and evidence for using non­standard first-line antipsychotic therapies to manage FEP. Specifically, we discuss when clinicians might consider mono­therapy exceeding FDA-approved maximum dosages, combi­nation therapy, long-acting injectable antipsychotics (LAIA), or clozapine.

Monotherapy beyond FDA-approved dosages
Treatment guidelines for FEP recommend oral antipsy­chotic dosages in the lower half of the treatment range and lower than those that are required for multi-episode schizo­phrenia.^6-16 Ultimately, clinicians prescribe individualized dosages for their patients based on symptom improvement and tolerability. The optimal dosage at which to achieve a favorable D2 receptor occupancy likely will vary from patient to patient.¹⁷

To control symptoms, higher dosages may be needed than those used in FEP clinical tri­als, recommended by guidelines for FEP or multi-episode patients, or approved by the FDA. Patients seen in everyday practice may be more complicated (eg, have a comorbid condition or history of nonresponse) than study populations. Higher dosages also may be reasonable to overcome drug−drug interactions (eg, cigarette smoking-mediated cytochrome P450 1A2 induction, resulting in increased olanzapine metabolism),¹⁸ or to establish antipsychotic failure if adequate trials at lower dosages have resulted in a suboptimal response and the patient is not experiencing tolerability or safety concerns.

In a study of low-, full-, and high-dosage antipsychotic therapy in FEP, an additional 15% of patients responded to higher dos­ages of olanzapine and risperidone after failing to respond to a standard dosage.¹⁹ A study of data from the Recovery After an Initial Schizophrenia Episode Project’s Early Treatment Program (RAISE-ETP) found that, of participants identified who may benefit from therapy modification, 8.8% were pre­scribed an antipsychotic (often, olanzapine, risperidone, and haloperidol) at a higher-than-recommended dosage.²⁰ Of note, only olanzapine was prescribed at higher than FDA-approved dosages.

Antipsychotic combination therapy
Prescribing combinations of antipsychot­ics—antipsychotic polypharmacy (APP)— has a negative connotation because of limited efficacy and safety data,²¹ and limited endorsement in schizophrenia treatment guidelines.^9,13 Caution with APP is war­ranted; a complex medication regimen may increase the potential for adverse effects, poorer adherence, and adverse drug-drug interactions.⁹ APP has been shown to inde­pendently predict both shorter treatment duration and discontinuation before 1 year.²²

Nonetheless, the clinician and patient may share the decision to implement APP and observe whether benefits outweigh risks in situations such as:
   • to optimize neuroreceptor occupancy and targets (eg, attempting to achieve ade­quate D2 receptor blockade while minimiz­ing side effects secondary to binding other receptors)
   • to manage co-existing symptom domains (eg, mood changes, aggression, negative symptoms, disorganization, and cognitive deficits)
   • to mitigate antipsychotic-induced side effects (eg, initiating aripiprazole to treat hyperprolactinemia induced by another anti­psychotic to which the patient has achieved a favorable response).²³

Clinicians report using APP to treat as many as 50% of patients with a history of multiple psychotic episodes.²³ For FEP patients, 23% of participants in the RAISE-ETP trial who were identified as possibly benefiting from therapy modification were prescribed APP.²⁰ Regrettably, research­ers have not found evidence to support a reported rationale for using APP—that lower dosages of individual antipsychotics when used in combination may avoid high-dosage prescriptions.²⁴

Before implementing APP, thoroughly explore and manage reasons for a patient’s suboptimal response to monotherapy.25 An adequate trial with any antipsychotic should be at the highest tolerated dosage for 12 to 16 weeks. Be mindful that response to an APP trial may be the result of additional time on the original antipsychotic.

Long-acting injectable antipsychotics in FEP
Guideline recommendations. Most older guidelines for schizophrenia treat­ment suggest LAIA after multiple relapses related to medication nonadherence or when a patient prefers injected medica­tion (Table 1).^6-13 Expert consensus guide­lines also recommend considering LAIA in patients who lack insight into their illness. The Texas Medication Algorithm Project (TMAP) guidelines⁷ state LAIA can be con­sidered for inadequate adherence at any stage, whereas the 2010 British Association for Psychopharmacology (BAP) guide­lines⁹ express uncertainty about their use in FEP, because of limited evidence. Both the BAP and National Institute for Health and Care Excellence guidelines¹³ urge cli­nicians to consider LAIA when avoiding nonadherence is a treatment priority.

Barriers to LAIA use include:
   • slow dosage titration and increased time to reach steady state drug level
   • oral supplementation for some (eg, risperidone microspheres and aripiprazole long-acting injectable)
   • logistical challenges for some (eg, 3-hour post-injection monitoring for delir­ium sedation syndrome with olanzapine pamoate)
   • additional planning to coordinate care for scheduled injections
   • higher expenses up front
   • local injection site reactions
   • dosage adjustment difficulties if adverse effects occur.^28,29

Adoption rates of LAIA are low, especially for FEP.³⁰ Most surveys indicate that (1) physi­cians believe LAIA treatment is ineffective for FEP31 and (2) patients do not prefer injectable to oral antipsychotics,³² despite evidence to the contrary.^33,34 A survey of 198 psychiatrists identified 3 factors that influenced their deci­sions against using LAIA patients with FEP:
   • limited availability of SGA depot formu­lations (4, to date, in the United States)
   • frequent rejection by the patient when LAIA is offered without adequate expla­nation or encouragement
   • skepticism of FEP patients (and their family) who lack experience with relapse.³⁵

In reality, when SGA depots were intro­duced in the United Kingdom, prescribing rates of LAIA did not increase. As for patient rejection being a major reason for not pre­scribing LAIA, few patients (5% to 36%) are offered depot injections, particularly in FEP.²⁹ Most patients using LAIA are chronic, multi-episode, violent people who are receiving medications involuntarily.²⁹ Interestingly, this survey did not find 2 factors to be influential in psychiatrists’ decision not to use LAIA in FEP:
   • guidelines do not explicitly recommend depot treatment in FEP
   • treatment in FEP may be limited to 1 year, therefore depot administration is not worthwhile.³⁵

Preliminary evidence. At least a dozen stud­ies have explored LAIA treatment for FEP, with the use of fluphenazine decanoate,³⁶ per­phenazine enanthate³⁷ (discontinued), and risperidone microspheres.^37-48 The research demonstrates the efficacy and safety of LAIA in FEP as measured by these endpoints:
   • improved symptom control^{38,40-43,46,48}
   • adherence^43,44,48
   • reduced relapse rates^37,43 and rehospitalizations^37,47
   • lesser reductions in white matter brain volume⁴⁵
   • no differences in extrapyramidal side effects or prolactin-associated adverse effects.⁴⁸

A few small studies demonstrate signifi­cant differences in outcomes between ris­peridone LAIA and oral comparator groups (Table 3).^43-45 Ongoing studies of LAIA use in FEP are comparing paliperidone palmitate with risperidone microspheres and other oral antipsychotics.^49-51 No stud­ies are examining olanzapine pamoate in FEP, likely because several guidelines do not recommended its use. No studies have been published regarding aripiprazole long-acting injectable in FEP. This LAIA formulation was approved in February 2013, and robust studies of the oral formulation in FEP are limited.⁵²

Relapses begin within a few months of illness stabilization after FEP, and >50% of patients relapse within 1 or 2 years²—the recommended minimum treatment dura­tion for FEP.^8,9,13 The use of LAIA is advis­able in any patient with schizophrenia for whom long-term antipsychotic therapy is indicated.⁵⁶ LAIA administration require­ments objectively track medication adher­ence, which allows clinicians to be proactive in relapse prevention. Not using an inter­vention in FEP that improves adherence and decreases relapse rates contradicts our goal of instituting early, effective treatment to improve long-term functional outcomes (Figure 2).²⁹

Considering clozapine in FEP
Guideline recommendations. Schizo-phrenia treatment guidelines and FDA labeling⁵⁷ reserve clozapine for third-line treatment of refractory schizophrenia after 2 adequate antipsychotic trials have failed despite optimal dosing (Table 1).^6-13 Some guidelines specify 1 of the 2 failed anti­psychotic trials must include an SGA.^{6,7,10,11,13-16} Most say clozapine may be considered in patients with chronic aggression or hostility,^7-9,14,16 or suicidal thoughts and behav­iors.^6-8,14,16 TMAP guidelines recommend a clozapine trial with concomitant substance abuse, persistent positive symptoms during 2 years of consistent medication treatment, and after 5 years of inadequate response (“treatment resistance”), regardless of the number of antipsychotic trials.⁷ ­

Rationale and concerns. Clozapine is a superior choice for treatment-refractory delusions or hallucinations of schizophrenia, because it markedly enhances the response rate to antipsychotic therapy.⁵⁸ Researchers therefore have investigated whether clozap­ine, compared with other antipsychotics, would yield more favorable initial and long-term outcomes when used first-line in FEP.

Preliminary evidence. Five studies have explored the use of clozapine as first-line therapy in FEP (Table 4).^59-63 Interpreting the results is difficult because clozapine trials may be brief (mostly, 12 to 52 weeks); lack a comparator arm; suffer from a high attrition rate; enroll few patients; and lack potentially important outcome measures such as nega­tive symptoms, suicidality, and functional assessment.

At present, clozapine has not been shown superior to other antipsychotics as a first-line treatment for FEP. Research does underscore the importance of a clozapine trial as third-line treatment for FEP patients who have not responded well to 2 SGA trials.⁶³ Many of these nonresponders (77%) have demon­strated a favorable response when promptly switched to clozapine.⁶⁴

Discussion and recommendations. The limited evidence argues against using clo­zapine earlier than as third-line treatment in FEP. Perhaps the high treatment response that characterizes FEP creates a ceiling effect that obscures differences in antipsychotic efficacy at this stage.⁶⁵ Clozapine use as first-line treatment should be re-evaluated with more robust methodology. One approach could be to assess its benefit in FEP by the duration of untreated psychosis.

The odds of achieving remission have been shown to decrease by 15% for each year that psychosis has not been treated.⁵⁹ Studies exploring the use of clozapine as a second-line agent for FEP also are warranted, as anti­psychotic response during subsequent trials is substantially reduced. In fact, the Scottish Intercollegiate Guidelines Network guide­lines recommend this as an area for future research.¹¹

For now, clozapine should continue to be reserved as second- or third-line treatment in a patient with FEP. The risks of clozap­ine’s potentially serious adverse effects (eg, agranulocytosis, seizures, obesity, diabe­tes, dyslipidemia, myocarditis, pancreatitis, hypotension, sialorrhea, severe sedation, ileus) can be justified only in the treatment of severe and persistent psychotic symptoms.⁵⁷

Bottom Line
Nonstandard use of antipsychotic monotherapy dosages beyond the approved FDA limit and combination antipsychotic therapy may be reasonable for select first-episode psychosis (FEP) patients. Strongly consider long-acting injectable antipsychotics in FEP to proactively combat the high relapse rate and more easily identify antipsychotic failure. Continue to use clozapine as second- or third-line therapy in FEP: Studies have not found that it is more efficacious than other antipsychotics for first-line use.

Related Resource
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.

Drug Brand Names
Aripiprazole • Abilify, Abilify Maintena      
Chlorpromazine • Thorazine                     
Clozapine • Clozaril                              
Fluphenazine decanoate • Prolixin-D      
Haloperidol • Haldol                                      
Haloperidol decanoate • Haldol-D       
Olanzapine • Zyprexa
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Risperidone microspheres • Risperdal Consta

Disclosures
Dr. Gardner reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products. Dr. Nasrallah is a consultant to Acadia, Alkermes, Lundbeck, Janssen, Merck, Otsuka, and Sunovion, and is a speaker for Alkermes, Lundbeck, Janssen, Otsuka, and Sunovion.

First-episode psychosis (FEP) in schizophrenia is char­acterized by high response rates to antipsychotic therapy, followed by frequent antipsychotic discon­tinuation and elevated relapse rates soon after mainte­nance treatment begins.^1,2 With subsequent episodes, time to response progressively increases and likelihood of response decreases.^3,4

To address these issues, this article—the second of 2 parts⁵—describes the rationale and evidence for using non­standard first-line antipsychotic therapies to manage FEP. Specifically, we discuss when clinicians might consider mono­therapy exceeding FDA-approved maximum dosages, combi­nation therapy, long-acting injectable antipsychotics (LAIA), or clozapine.

Monotherapy beyond FDA-approved dosages
Treatment guidelines for FEP recommend oral antipsy­chotic dosages in the lower half of the treatment range and lower than those that are required for multi-episode schizo­phrenia.^6-16 Ultimately, clinicians prescribe individualized dosages for their patients based on symptom improvement and tolerability. The optimal dosage at which to achieve a favorable D2 receptor occupancy likely will vary from patient to patient.¹⁷

To control symptoms, higher dosages may be needed than those used in FEP clinical tri­als, recommended by guidelines for FEP or multi-episode patients, or approved by the FDA. Patients seen in everyday practice may be more complicated (eg, have a comorbid condition or history of nonresponse) than study populations. Higher dosages also may be reasonable to overcome drug−drug interactions (eg, cigarette smoking-mediated cytochrome P450 1A2 induction, resulting in increased olanzapine metabolism),¹⁸ or to establish antipsychotic failure if adequate trials at lower dosages have resulted in a suboptimal response and the patient is not experiencing tolerability or safety concerns.

In a study of low-, full-, and high-dosage antipsychotic therapy in FEP, an additional 15% of patients responded to higher dos­ages of olanzapine and risperidone after failing to respond to a standard dosage.¹⁹ A study of data from the Recovery After an Initial Schizophrenia Episode Project’s Early Treatment Program (RAISE-ETP) found that, of participants identified who may benefit from therapy modification, 8.8% were pre­scribed an antipsychotic (often, olanzapine, risperidone, and haloperidol) at a higher-than-recommended dosage.²⁰ Of note, only olanzapine was prescribed at higher than FDA-approved dosages.

Antipsychotic combination therapy
Prescribing combinations of antipsychot­ics—antipsychotic polypharmacy (APP)— has a negative connotation because of limited efficacy and safety data,²¹ and limited endorsement in schizophrenia treatment guidelines.^9,13 Caution with APP is war­ranted; a complex medication regimen may increase the potential for adverse effects, poorer adherence, and adverse drug-drug interactions.⁹ APP has been shown to inde­pendently predict both shorter treatment duration and discontinuation before 1 year.²²

Nonetheless, the clinician and patient may share the decision to implement APP and observe whether benefits outweigh risks in situations such as:
   • to optimize neuroreceptor occupancy and targets (eg, attempting to achieve ade­quate D2 receptor blockade while minimiz­ing side effects secondary to binding other receptors)
   • to manage co-existing symptom domains (eg, mood changes, aggression, negative symptoms, disorganization, and cognitive deficits)
   • to mitigate antipsychotic-induced side effects (eg, initiating aripiprazole to treat hyperprolactinemia induced by another anti­psychotic to which the patient has achieved a favorable response).²³

Clinicians report using APP to treat as many as 50% of patients with a history of multiple psychotic episodes.²³ For FEP patients, 23% of participants in the RAISE-ETP trial who were identified as possibly benefiting from therapy modification were prescribed APP.²⁰ Regrettably, research­ers have not found evidence to support a reported rationale for using APP—that lower dosages of individual antipsychotics when used in combination may avoid high-dosage prescriptions.²⁴

Before implementing APP, thoroughly explore and manage reasons for a patient’s suboptimal response to monotherapy.25 An adequate trial with any antipsychotic should be at the highest tolerated dosage for 12 to 16 weeks. Be mindful that response to an APP trial may be the result of additional time on the original antipsychotic.

Long-acting injectable antipsychotics in FEP
Guideline recommendations. Most older guidelines for schizophrenia treat­ment suggest LAIA after multiple relapses related to medication nonadherence or when a patient prefers injected medica­tion (Table 1).^6-13 Expert consensus guide­lines also recommend considering LAIA in patients who lack insight into their illness. The Texas Medication Algorithm Project (TMAP) guidelines⁷ state LAIA can be con­sidered for inadequate adherence at any stage, whereas the 2010 British Association for Psychopharmacology (BAP) guide­lines⁹ express uncertainty about their use in FEP, because of limited evidence. Both the BAP and National Institute for Health and Care Excellence guidelines¹³ urge cli­nicians to consider LAIA when avoiding nonadherence is a treatment priority.

Barriers to LAIA use include:
   • slow dosage titration and increased time to reach steady state drug level
   • oral supplementation for some (eg, risperidone microspheres and aripiprazole long-acting injectable)
   • logistical challenges for some (eg, 3-hour post-injection monitoring for delir­ium sedation syndrome with olanzapine pamoate)
   • additional planning to coordinate care for scheduled injections
   • higher expenses up front
   • local injection site reactions
   • dosage adjustment difficulties if adverse effects occur.^28,29

Adoption rates of LAIA are low, especially for FEP.³⁰ Most surveys indicate that (1) physi­cians believe LAIA treatment is ineffective for FEP31 and (2) patients do not prefer injectable to oral antipsychotics,³² despite evidence to the contrary.^33,34 A survey of 198 psychiatrists identified 3 factors that influenced their deci­sions against using LAIA patients with FEP:
   • limited availability of SGA depot formu­lations (4, to date, in the United States)
   • frequent rejection by the patient when LAIA is offered without adequate expla­nation or encouragement
   • skepticism of FEP patients (and their family) who lack experience with relapse.³⁵

In reality, when SGA depots were intro­duced in the United Kingdom, prescribing rates of LAIA did not increase. As for patient rejection being a major reason for not pre­scribing LAIA, few patients (5% to 36%) are offered depot injections, particularly in FEP.²⁹ Most patients using LAIA are chronic, multi-episode, violent people who are receiving medications involuntarily.²⁹ Interestingly, this survey did not find 2 factors to be influential in psychiatrists’ decision not to use LAIA in FEP:
   • guidelines do not explicitly recommend depot treatment in FEP
   • treatment in FEP may be limited to 1 year, therefore depot administration is not worthwhile.³⁵

Preliminary evidence. At least a dozen stud­ies have explored LAIA treatment for FEP, with the use of fluphenazine decanoate,³⁶ per­phenazine enanthate³⁷ (discontinued), and risperidone microspheres.^37-48 The research demonstrates the efficacy and safety of LAIA in FEP as measured by these endpoints:
   • improved symptom control^{38,40-43,46,48}
   • adherence^43,44,48
   • reduced relapse rates^37,43 and rehospitalizations^37,47
   • lesser reductions in white matter brain volume⁴⁵
   • no differences in extrapyramidal side effects or prolactin-associated adverse effects.⁴⁸

A few small studies demonstrate signifi­cant differences in outcomes between ris­peridone LAIA and oral comparator groups (Table 3).^43-45 Ongoing studies of LAIA use in FEP are comparing paliperidone palmitate with risperidone microspheres and other oral antipsychotics.^49-51 No stud­ies are examining olanzapine pamoate in FEP, likely because several guidelines do not recommended its use. No studies have been published regarding aripiprazole long-acting injectable in FEP. This LAIA formulation was approved in February 2013, and robust studies of the oral formulation in FEP are limited.⁵²

Relapses begin within a few months of illness stabilization after FEP, and >50% of patients relapse within 1 or 2 years²—the recommended minimum treatment dura­tion for FEP.^8,9,13 The use of LAIA is advis­able in any patient with schizophrenia for whom long-term antipsychotic therapy is indicated.⁵⁶ LAIA administration require­ments objectively track medication adher­ence, which allows clinicians to be proactive in relapse prevention. Not using an inter­vention in FEP that improves adherence and decreases relapse rates contradicts our goal of instituting early, effective treatment to improve long-term functional outcomes (Figure 2).²⁹

Considering clozapine in FEP
Guideline recommendations. Schizo-phrenia treatment guidelines and FDA labeling⁵⁷ reserve clozapine for third-line treatment of refractory schizophrenia after 2 adequate antipsychotic trials have failed despite optimal dosing (Table 1).^6-13 Some guidelines specify 1 of the 2 failed anti­psychotic trials must include an SGA.^{6,7,10,11,13-16} Most say clozapine may be considered in patients with chronic aggression or hostility,^7-9,14,16 or suicidal thoughts and behav­iors.^6-8,14,16 TMAP guidelines recommend a clozapine trial with concomitant substance abuse, persistent positive symptoms during 2 years of consistent medication treatment, and after 5 years of inadequate response (“treatment resistance”), regardless of the number of antipsychotic trials.⁷ ­

Rationale and concerns. Clozapine is a superior choice for treatment-refractory delusions or hallucinations of schizophrenia, because it markedly enhances the response rate to antipsychotic therapy.⁵⁸ Researchers therefore have investigated whether clozap­ine, compared with other antipsychotics, would yield more favorable initial and long-term outcomes when used first-line in FEP.

Preliminary evidence. Five studies have explored the use of clozapine as first-line therapy in FEP (Table 4).^59-63 Interpreting the results is difficult because clozapine trials may be brief (mostly, 12 to 52 weeks); lack a comparator arm; suffer from a high attrition rate; enroll few patients; and lack potentially important outcome measures such as nega­tive symptoms, suicidality, and functional assessment.

At present, clozapine has not been shown superior to other antipsychotics as a first-line treatment for FEP. Research does underscore the importance of a clozapine trial as third-line treatment for FEP patients who have not responded well to 2 SGA trials.⁶³ Many of these nonresponders (77%) have demon­strated a favorable response when promptly switched to clozapine.⁶⁴

Discussion and recommendations. The limited evidence argues against using clo­zapine earlier than as third-line treatment in FEP. Perhaps the high treatment response that characterizes FEP creates a ceiling effect that obscures differences in antipsychotic efficacy at this stage.⁶⁵ Clozapine use as first-line treatment should be re-evaluated with more robust methodology. One approach could be to assess its benefit in FEP by the duration of untreated psychosis.

The odds of achieving remission have been shown to decrease by 15% for each year that psychosis has not been treated.⁵⁹ Studies exploring the use of clozapine as a second-line agent for FEP also are warranted, as anti­psychotic response during subsequent trials is substantially reduced. In fact, the Scottish Intercollegiate Guidelines Network guide­lines recommend this as an area for future research.¹¹

For now, clozapine should continue to be reserved as second- or third-line treatment in a patient with FEP. The risks of clozap­ine’s potentially serious adverse effects (eg, agranulocytosis, seizures, obesity, diabe­tes, dyslipidemia, myocarditis, pancreatitis, hypotension, sialorrhea, severe sedation, ileus) can be justified only in the treatment of severe and persistent psychotic symptoms.⁵⁷

Bottom Line
Nonstandard use of antipsychotic monotherapy dosages beyond the approved FDA limit and combination antipsychotic therapy may be reasonable for select first-episode psychosis (FEP) patients. Strongly consider long-acting injectable antipsychotics in FEP to proactively combat the high relapse rate and more easily identify antipsychotic failure. Continue to use clozapine as second- or third-line therapy in FEP: Studies have not found that it is more efficacious than other antipsychotics for first-line use.

Related Resource
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.

Drug Brand Names
Aripiprazole • Abilify, Abilify Maintena      
Chlorpromazine • Thorazine                     
Clozapine • Clozaril                              
Fluphenazine decanoate • Prolixin-D      
Haloperidol • Haldol                                      
Haloperidol decanoate • Haldol-D       
Olanzapine • Zyprexa
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Risperidone microspheres • Risperdal Consta

Disclosures
Dr. Gardner reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products. Dr. Nasrallah is a consultant to Acadia, Alkermes, Lundbeck, Janssen, Merck, Otsuka, and Sunovion, and is a speaker for Alkermes, Lundbeck, Janssen, Otsuka, and Sunovion.

First-episode psychosis (FEP) in schizophrenia is char­acterized by high response rates to antipsychotic therapy, followed by frequent antipsychotic discon­tinuation and elevated relapse rates soon after mainte­nance treatment begins.^1,2 With subsequent episodes, time to response progressively increases and likelihood of response decreases.^3,4

To address these issues, this article—the second of 2 parts⁵—describes the rationale and evidence for using non­standard first-line antipsychotic therapies to manage FEP. Specifically, we discuss when clinicians might consider mono­therapy exceeding FDA-approved maximum dosages, combi­nation therapy, long-acting injectable antipsychotics (LAIA), or clozapine.

Monotherapy beyond FDA-approved dosages
Treatment guidelines for FEP recommend oral antipsy­chotic dosages in the lower half of the treatment range and lower than those that are required for multi-episode schizo­phrenia.^6-16 Ultimately, clinicians prescribe individualized dosages for their patients based on symptom improvement and tolerability. The optimal dosage at which to achieve a favorable D2 receptor occupancy likely will vary from patient to patient.¹⁷

To control symptoms, higher dosages may be needed than those used in FEP clinical tri­als, recommended by guidelines for FEP or multi-episode patients, or approved by the FDA. Patients seen in everyday practice may be more complicated (eg, have a comorbid condition or history of nonresponse) than study populations. Higher dosages also may be reasonable to overcome drug−drug interactions (eg, cigarette smoking-mediated cytochrome P450 1A2 induction, resulting in increased olanzapine metabolism),¹⁸ or to establish antipsychotic failure if adequate trials at lower dosages have resulted in a suboptimal response and the patient is not experiencing tolerability or safety concerns.

In a study of low-, full-, and high-dosage antipsychotic therapy in FEP, an additional 15% of patients responded to higher dos­ages of olanzapine and risperidone after failing to respond to a standard dosage.¹⁹ A study of data from the Recovery After an Initial Schizophrenia Episode Project’s Early Treatment Program (RAISE-ETP) found that, of participants identified who may benefit from therapy modification, 8.8% were pre­scribed an antipsychotic (often, olanzapine, risperidone, and haloperidol) at a higher-than-recommended dosage.²⁰ Of note, only olanzapine was prescribed at higher than FDA-approved dosages.

Antipsychotic combination therapy
Prescribing combinations of antipsychot­ics—antipsychotic polypharmacy (APP)— has a negative connotation because of limited efficacy and safety data,²¹ and limited endorsement in schizophrenia treatment guidelines.^9,13 Caution with APP is war­ranted; a complex medication regimen may increase the potential for adverse effects, poorer adherence, and adverse drug-drug interactions.⁹ APP has been shown to inde­pendently predict both shorter treatment duration and discontinuation before 1 year.²²

Nonetheless, the clinician and patient may share the decision to implement APP and observe whether benefits outweigh risks in situations such as:
   • to optimize neuroreceptor occupancy and targets (eg, attempting to achieve ade­quate D2 receptor blockade while minimiz­ing side effects secondary to binding other receptors)
   • to manage co-existing symptom domains (eg, mood changes, aggression, negative symptoms, disorganization, and cognitive deficits)
   • to mitigate antipsychotic-induced side effects (eg, initiating aripiprazole to treat hyperprolactinemia induced by another anti­psychotic to which the patient has achieved a favorable response).²³

Clinicians report using APP to treat as many as 50% of patients with a history of multiple psychotic episodes.²³ For FEP patients, 23% of participants in the RAISE-ETP trial who were identified as possibly benefiting from therapy modification were prescribed APP.²⁰ Regrettably, research­ers have not found evidence to support a reported rationale for using APP—that lower dosages of individual antipsychotics when used in combination may avoid high-dosage prescriptions.²⁴

Before implementing APP, thoroughly explore and manage reasons for a patient’s suboptimal response to monotherapy.25 An adequate trial with any antipsychotic should be at the highest tolerated dosage for 12 to 16 weeks. Be mindful that response to an APP trial may be the result of additional time on the original antipsychotic.

Long-acting injectable antipsychotics in FEP
Guideline recommendations. Most older guidelines for schizophrenia treat­ment suggest LAIA after multiple relapses related to medication nonadherence or when a patient prefers injected medica­tion (Table 1).^6-13 Expert consensus guide­lines also recommend considering LAIA in patients who lack insight into their illness. The Texas Medication Algorithm Project (TMAP) guidelines⁷ state LAIA can be con­sidered for inadequate adherence at any stage, whereas the 2010 British Association for Psychopharmacology (BAP) guide­lines⁹ express uncertainty about their use in FEP, because of limited evidence. Both the BAP and National Institute for Health and Care Excellence guidelines¹³ urge cli­nicians to consider LAIA when avoiding nonadherence is a treatment priority.

Barriers to LAIA use include:
   • slow dosage titration and increased time to reach steady state drug level
   • oral supplementation for some (eg, risperidone microspheres and aripiprazole long-acting injectable)
   • logistical challenges for some (eg, 3-hour post-injection monitoring for delir­ium sedation syndrome with olanzapine pamoate)
   • additional planning to coordinate care for scheduled injections
   • higher expenses up front
   • local injection site reactions
   • dosage adjustment difficulties if adverse effects occur.^28,29

Adoption rates of LAIA are low, especially for FEP.³⁰ Most surveys indicate that (1) physi­cians believe LAIA treatment is ineffective for FEP31 and (2) patients do not prefer injectable to oral antipsychotics,³² despite evidence to the contrary.^33,34 A survey of 198 psychiatrists identified 3 factors that influenced their deci­sions against using LAIA patients with FEP:
   • limited availability of SGA depot formu­lations (4, to date, in the United States)
   • frequent rejection by the patient when LAIA is offered without adequate expla­nation or encouragement
   • skepticism of FEP patients (and their family) who lack experience with relapse.³⁵

In reality, when SGA depots were intro­duced in the United Kingdom, prescribing rates of LAIA did not increase. As for patient rejection being a major reason for not pre­scribing LAIA, few patients (5% to 36%) are offered depot injections, particularly in FEP.²⁹ Most patients using LAIA are chronic, multi-episode, violent people who are receiving medications involuntarily.²⁹ Interestingly, this survey did not find 2 factors to be influential in psychiatrists’ decision not to use LAIA in FEP:
   • guidelines do not explicitly recommend depot treatment in FEP
   • treatment in FEP may be limited to 1 year, therefore depot administration is not worthwhile.³⁵

Preliminary evidence. At least a dozen stud­ies have explored LAIA treatment for FEP, with the use of fluphenazine decanoate,³⁶ per­phenazine enanthate³⁷ (discontinued), and risperidone microspheres.^37-48 The research demonstrates the efficacy and safety of LAIA in FEP as measured by these endpoints:
   • improved symptom control^{38,40-43,46,48}
   • adherence^43,44,48
   • reduced relapse rates^37,43 and rehospitalizations^37,47
   • lesser reductions in white matter brain volume⁴⁵
   • no differences in extrapyramidal side effects or prolactin-associated adverse effects.⁴⁸

A few small studies demonstrate signifi­cant differences in outcomes between ris­peridone LAIA and oral comparator groups (Table 3).^43-45 Ongoing studies of LAIA use in FEP are comparing paliperidone palmitate with risperidone microspheres and other oral antipsychotics.^49-51 No stud­ies are examining olanzapine pamoate in FEP, likely because several guidelines do not recommended its use. No studies have been published regarding aripiprazole long-acting injectable in FEP. This LAIA formulation was approved in February 2013, and robust studies of the oral formulation in FEP are limited.⁵²

Relapses begin within a few months of illness stabilization after FEP, and >50% of patients relapse within 1 or 2 years²—the recommended minimum treatment dura­tion for FEP.^8,9,13 The use of LAIA is advis­able in any patient with schizophrenia for whom long-term antipsychotic therapy is indicated.⁵⁶ LAIA administration require­ments objectively track medication adher­ence, which allows clinicians to be proactive in relapse prevention. Not using an inter­vention in FEP that improves adherence and decreases relapse rates contradicts our goal of instituting early, effective treatment to improve long-term functional outcomes (Figure 2).²⁹

Considering clozapine in FEP
Guideline recommendations. Schizo-phrenia treatment guidelines and FDA labeling⁵⁷ reserve clozapine for third-line treatment of refractory schizophrenia after 2 adequate antipsychotic trials have failed despite optimal dosing (Table 1).^6-13 Some guidelines specify 1 of the 2 failed anti­psychotic trials must include an SGA.^{6,7,10,11,13-16} Most say clozapine may be considered in patients with chronic aggression or hostility,^7-9,14,16 or suicidal thoughts and behav­iors.^6-8,14,16 TMAP guidelines recommend a clozapine trial with concomitant substance abuse, persistent positive symptoms during 2 years of consistent medication treatment, and after 5 years of inadequate response (“treatment resistance”), regardless of the number of antipsychotic trials.⁷ ­

Rationale and concerns. Clozapine is a superior choice for treatment-refractory delusions or hallucinations of schizophrenia, because it markedly enhances the response rate to antipsychotic therapy.⁵⁸ Researchers therefore have investigated whether clozap­ine, compared with other antipsychotics, would yield more favorable initial and long-term outcomes when used first-line in FEP.

Preliminary evidence. Five studies have explored the use of clozapine as first-line therapy in FEP (Table 4).^59-63 Interpreting the results is difficult because clozapine trials may be brief (mostly, 12 to 52 weeks); lack a comparator arm; suffer from a high attrition rate; enroll few patients; and lack potentially important outcome measures such as nega­tive symptoms, suicidality, and functional assessment.

At present, clozapine has not been shown superior to other antipsychotics as a first-line treatment for FEP. Research does underscore the importance of a clozapine trial as third-line treatment for FEP patients who have not responded well to 2 SGA trials.⁶³ Many of these nonresponders (77%) have demon­strated a favorable response when promptly switched to clozapine.⁶⁴

Discussion and recommendations. The limited evidence argues against using clo­zapine earlier than as third-line treatment in FEP. Perhaps the high treatment response that characterizes FEP creates a ceiling effect that obscures differences in antipsychotic efficacy at this stage.⁶⁵ Clozapine use as first-line treatment should be re-evaluated with more robust methodology. One approach could be to assess its benefit in FEP by the duration of untreated psychosis.

The odds of achieving remission have been shown to decrease by 15% for each year that psychosis has not been treated.⁵⁹ Studies exploring the use of clozapine as a second-line agent for FEP also are warranted, as anti­psychotic response during subsequent trials is substantially reduced. In fact, the Scottish Intercollegiate Guidelines Network guide­lines recommend this as an area for future research.¹¹

For now, clozapine should continue to be reserved as second- or third-line treatment in a patient with FEP. The risks of clozap­ine’s potentially serious adverse effects (eg, agranulocytosis, seizures, obesity, diabe­tes, dyslipidemia, myocarditis, pancreatitis, hypotension, sialorrhea, severe sedation, ileus) can be justified only in the treatment of severe and persistent psychotic symptoms.⁵⁷

Bottom Line
Nonstandard use of antipsychotic monotherapy dosages beyond the approved FDA limit and combination antipsychotic therapy may be reasonable for select first-episode psychosis (FEP) patients. Strongly consider long-acting injectable antipsychotics in FEP to proactively combat the high relapse rate and more easily identify antipsychotic failure. Continue to use clozapine as second- or third-line therapy in FEP: Studies have not found that it is more efficacious than other antipsychotics for first-line use.

Related Resource
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.

Drug Brand Names
Aripiprazole • Abilify, Abilify Maintena      
Chlorpromazine • Thorazine                     
Clozapine • Clozaril                              
Fluphenazine decanoate • Prolixin-D      
Haloperidol • Haldol                                      
Haloperidol decanoate • Haldol-D       
Olanzapine • Zyprexa
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Risperidone microspheres • Risperdal Consta

Disclosures
Dr. Gardner reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products. Dr. Nasrallah is a consultant to Acadia, Alkermes, Lundbeck, Janssen, Merck, Otsuka, and Sunovion, and is a speaker for Alkermes, Lundbeck, Janssen, Otsuka, and Sunovion.

Mr. T,  age 23, was given a diagnosis of bipolar disorder 1 year ago. After he experienced inadequate symp­tom relief with valproate, you switched him to extended-release lithium, 1,200 mg/d. Mr. T reported improved mood and stability with this medication adjustment. These posi­tive changes led him to resume activities he enjoyed before onset of bipolar disorder, such as running, reading, and going out to dinner with friends.

Now, Mr. T’s mother calls your office to express concern about her son’s slight

hand tremor, which appeared after 2 days of gas­trointestinal distress. She tells you that Mr. T sprained his ankle while running 1 week ago and has been taking over-the-counter ibu­profen for pain relief, which he did often in the past.

You suspect that Mr. T is experiencing lith­ium toxicity as a result of ibuprofen use.

Although mental health providers can eas­ily recognize the drug−drug interaction between lithium and nonsteroidal anti-inflammatory drugs (NSAIDs) that Mr. T experienced, interpreting the safety of a medication regimen with respect to drug− drug interactions before prescribing often is more daunting. This article reviews the basics of drug−drug interactions, while briefly highlighting common examples in psychiatric medicine (Table 1^1-5). We also provide an outline of additional points to consider when reviewing your patients’ medication regimens and encoun­tering unfamiliar drug−drug interactions.

Types of drug−drug interactions
Drug−drug interactions fall into 2 catego­ries: pharmacodynamic (PD) and pharmaco­kinetic (PK):
   • PD interactions are a result of the com­bined impact of medications on the body when there is no direct effect on absorp­tion, distribution, metabolism, or excretion characteristics, such as 2 medications that act at the same receptor or lead to similar or opposing pharmacologic effects.
   • PK interactions occur when a drug affects the absorption, distribution, metabo­lism, or excretion characteristics of another drug.

Although it is possible that drug−drug interactions will have no clinical effect, when the impact of a PD or PK drug−drug interaction is evident, it likely is the result of additive, synergistic, or antago­nistic consequences on the medications’ intended impact or side-effect profile.

Pharmacodynamic interactions
Serotonin syndrome. The potential for serotonin syndrome occurs when medica­tions that increase synaptic serotonin con­centration are used concomitantly.¹ This can occur through several mechanisms, including increased serotonin release, decreased reuptake, or decreased sero­tonin metabolism. A high serotonin con­centration in the CNS and in the periphery overstimulates serotonin receptors, lead­ing to signs and symptoms that can include diarrhea, fever, delirium, coma, and poten­tially death.

QT prolongation and anticholinergic toxicity are further examples of additive PD drug−drug interactions. Anticholinergic toxicity is possible when multiple medica­tions contribute to inhibition of the neuro-transmitter acetylcholine at muscarinic receptors. This leads to adverse effects such as dry mouth, constipation, confusion, and urinary retention.

QT prolongation, which can lead to arrhythmia, occurs when a patient is taking several medications that can increase the QT interval. Consider close monitoring and using alternative agents with less poten­tial to increase the QT interval in patients at risk of arrhythmias (geriatric patients, those with an increased QT interval at base­line, etc.).

Decreased seizure threshold. The increased risk of seizures with bupropion and other medications that lower the sei­zure threshold is another example of an additive PD drug interaction. Bupropion can increase the risk of seizures in a dose-dependent manner, which increases when bupropion is taken with other drugs that lower the seizure threshold.6 Seizure risk associated with alcohol or benzodiazepine withdrawal also may increase the risk for this interaction.

Of note, the increased risk of seizures with the combination of bupropion and alcohol in the absence of withdrawal is not well studied in humans, but positive corre­lation has been seen in an animal study.⁶

Decreased platelet function. Another example of a PD drug−drug interaction is increased risk of bleeding when a selec­tive serotonin reuptake inhibitor is used with a NSAID or oral anticoagulant. The proposed mechanism for this interaction is that blocking serotonin reuptake on platelets leads to decreased platelet func­tion and an increased risk for prolonged bleeding.7 This is somewhat controversial because, first, it has been noted that drugs with the highest degree of serotonin reup­take inhibition do not always cause the highest risk of bleeding and, second, most of the evidence for this interaction is from observational studies.⁷

This potential interaction could be most important for patients who need an anti­depressant, are on chronic NSAID or anti­coagulant therapy, and are at high risk of bleeding.

Pharmacokinetic interactions
PK interactions in psychiatry often are caused by interference of drug metabo­lizing enzymes. The cytochrome P450 (CYP450) family of metabolizing enzymes in particular is important to the break­down of medications in the body. Many drug−drug interactions involve medica­tions that can inhibit or induce metabolism of other drugs through their effect on the CYP450 system.

Inhibition interactions. When a drug’s metabolism is inhibited, the result is usu­ally increased serum concentration of that medication (because of less break­down) and a more potent impact on the primary mechanism of action or adverse effects. Sometimes, inhibiting metabo­lism can lead to decreased clinical effect. Tamoxifen (an oral agent used to treat breast cancer) and certain analgesics when used in combination with moderate or strong inhibitors of the CYP2D6 subfam­ily of CYP450 metabolizing enzymes are 2 examples of metabolism inhibition lead­ing to decreased efficacy.⁸ Both tamoxi­fen and the analgesics listed in Table 1^1-5 are prodrugs; that is, they must be metabolized to be active. When the enzymes that metabolize these drugs into their active form are inhibited, the concen­tration of active drug decreases.

Induction interactions. Alternatively, there is an increased rate of drug break­down and resulting decrease in effect when drugs that induce the activity of metabolizing enzymes are used with med­ications that are substrates of the same enzyme. Carbamazepine is commonly involved in this type of drug interaction because it is a strong inducer of CYP 1A2, 2B6, 2C19, 2C9, and 3A4, and the p-glyco­protein drug efflux pump.⁹ As a result of this rampant induction, carbamazepine can decrease the serum concentration of oral contraceptives below a reliably effec­tive level. Therefore, it is recommended that women of childbearing potential use other contraceptive methods, such as a progestin implant or an intrauterine device.¹⁰

In addition, the polycyclic aromatic hydrocarbons found in cigarettes induce activity of CYP1A2. Patients who smoke and use medications metabolized by this enzyme, such as clozapine and olanzap­ine, may need a higher dosage.

Drug elimination interactions
The last drug−drug interaction discussed here returns the discussion to Mr. T and involves drug elimination.² The NSAIDs Mr. T was using for pain likely caused decreased renal excretion of lithium. Because lithium is primarily excreted through the kidneys, Mr. T’s NSAID use, possibly in com­bination with dehydration caused by gastro­intestinal distress, resulted in lithium toxicity. This class of analgesics should be avoided or used cautiously in patients taking lithium.

Clinical applications
The relatively common drug−drug interac­tions discussed here are just a fraction of the potential interactions mental health practi­tioners see on a daily basis. Understanding the basics of PD and PK interactions in the setting of patient-specific factors can help to clarify the information found in drug−drug interaction databases, such as Micromedex, Lexicomp, Facts and Comparisons, and Epocrates. Table 2 lists additional insights into drug interactions.

Related Resources
• CredibleMeds. Online resource on QT prolonging drugs. http://crediblemeds.org.
• Madhusoodanan S, Velama U, Parmar J, et al. A current review of cytochrome P450 interactions of psychotropic drugs. Ann Clin Psychiatry. 2014;26(2):120-138.

Drug Brand Names
Benztropine • Cogentin                            Olanzapine • Zyprexa
Bupropion • Wellbutrin                             Oxycodone • Oxycontin
Carbamazepine • Tegretol                        Paroxetine • Paxil
Clozapine • Clozaril                                  Quetiapine • Seroquel
Diphenhydramine • Benadryl                     Sertraline • Zoloft
 Duloxetine • Cymbalta                             Tamoxifen • Soltamox
Fluoxetine • Prozac                                   Trazodone • Desyrel
Lithium • Eskalith, Lithobid                        Valproate • Divalproex
Haloperidol • Haldol                                  Ziprasidone • Geodon
Hydrocodone • Vicodin

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

Mr. T,  age 23, was given a diagnosis of bipolar disorder 1 year ago. After he experienced inadequate symp­tom relief with valproate, you switched him to extended-release lithium, 1,200 mg/d. Mr. T reported improved mood and stability with this medication adjustment. These posi­tive changes led him to resume activities he enjoyed before onset of bipolar disorder, such as running, reading, and going out to dinner with friends.

Now, Mr. T’s mother calls your office to express concern about her son’s slight

hand tremor, which appeared after 2 days of gas­trointestinal distress. She tells you that Mr. T sprained his ankle while running 1 week ago and has been taking over-the-counter ibu­profen for pain relief, which he did often in the past.

You suspect that Mr. T is experiencing lith­ium toxicity as a result of ibuprofen use.

Although mental health providers can eas­ily recognize the drug−drug interaction between lithium and nonsteroidal anti-inflammatory drugs (NSAIDs) that Mr. T experienced, interpreting the safety of a medication regimen with respect to drug− drug interactions before prescribing often is more daunting. This article reviews the basics of drug−drug interactions, while briefly highlighting common examples in psychiatric medicine (Table 1^1-5). We also provide an outline of additional points to consider when reviewing your patients’ medication regimens and encoun­tering unfamiliar drug−drug interactions.

Types of drug−drug interactions
Drug−drug interactions fall into 2 catego­ries: pharmacodynamic (PD) and pharmaco­kinetic (PK):
   • PD interactions are a result of the com­bined impact of medications on the body when there is no direct effect on absorp­tion, distribution, metabolism, or excretion characteristics, such as 2 medications that act at the same receptor or lead to similar or opposing pharmacologic effects.
   • PK interactions occur when a drug affects the absorption, distribution, metabo­lism, or excretion characteristics of another drug.

Although it is possible that drug−drug interactions will have no clinical effect, when the impact of a PD or PK drug−drug interaction is evident, it likely is the result of additive, synergistic, or antago­nistic consequences on the medications’ intended impact or side-effect profile.

Pharmacodynamic interactions
Serotonin syndrome. The potential for serotonin syndrome occurs when medica­tions that increase synaptic serotonin con­centration are used concomitantly.¹ This can occur through several mechanisms, including increased serotonin release, decreased reuptake, or decreased sero­tonin metabolism. A high serotonin con­centration in the CNS and in the periphery overstimulates serotonin receptors, lead­ing to signs and symptoms that can include diarrhea, fever, delirium, coma, and poten­tially death.

QT prolongation and anticholinergic toxicity are further examples of additive PD drug−drug interactions. Anticholinergic toxicity is possible when multiple medica­tions contribute to inhibition of the neuro-transmitter acetylcholine at muscarinic receptors. This leads to adverse effects such as dry mouth, constipation, confusion, and urinary retention.

QT prolongation, which can lead to arrhythmia, occurs when a patient is taking several medications that can increase the QT interval. Consider close monitoring and using alternative agents with less poten­tial to increase the QT interval in patients at risk of arrhythmias (geriatric patients, those with an increased QT interval at base­line, etc.).

Decreased seizure threshold. The increased risk of seizures with bupropion and other medications that lower the sei­zure threshold is another example of an additive PD drug interaction. Bupropion can increase the risk of seizures in a dose-dependent manner, which increases when bupropion is taken with other drugs that lower the seizure threshold.6 Seizure risk associated with alcohol or benzodiazepine withdrawal also may increase the risk for this interaction.

Of note, the increased risk of seizures with the combination of bupropion and alcohol in the absence of withdrawal is not well studied in humans, but positive corre­lation has been seen in an animal study.⁶

Decreased platelet function. Another example of a PD drug−drug interaction is increased risk of bleeding when a selec­tive serotonin reuptake inhibitor is used with a NSAID or oral anticoagulant. The proposed mechanism for this interaction is that blocking serotonin reuptake on platelets leads to decreased platelet func­tion and an increased risk for prolonged bleeding.7 This is somewhat controversial because, first, it has been noted that drugs with the highest degree of serotonin reup­take inhibition do not always cause the highest risk of bleeding and, second, most of the evidence for this interaction is from observational studies.⁷

This potential interaction could be most important for patients who need an anti­depressant, are on chronic NSAID or anti­coagulant therapy, and are at high risk of bleeding.

Pharmacokinetic interactions
PK interactions in psychiatry often are caused by interference of drug metabo­lizing enzymes. The cytochrome P450 (CYP450) family of metabolizing enzymes in particular is important to the break­down of medications in the body. Many drug−drug interactions involve medica­tions that can inhibit or induce metabolism of other drugs through their effect on the CYP450 system.

Inhibition interactions. When a drug’s metabolism is inhibited, the result is usu­ally increased serum concentration of that medication (because of less break­down) and a more potent impact on the primary mechanism of action or adverse effects. Sometimes, inhibiting metabo­lism can lead to decreased clinical effect. Tamoxifen (an oral agent used to treat breast cancer) and certain analgesics when used in combination with moderate or strong inhibitors of the CYP2D6 subfam­ily of CYP450 metabolizing enzymes are 2 examples of metabolism inhibition lead­ing to decreased efficacy.⁸ Both tamoxi­fen and the analgesics listed in Table 1^1-5 are prodrugs; that is, they must be metabolized to be active. When the enzymes that metabolize these drugs into their active form are inhibited, the concen­tration of active drug decreases.

Induction interactions. Alternatively, there is an increased rate of drug break­down and resulting decrease in effect when drugs that induce the activity of metabolizing enzymes are used with med­ications that are substrates of the same enzyme. Carbamazepine is commonly involved in this type of drug interaction because it is a strong inducer of CYP 1A2, 2B6, 2C19, 2C9, and 3A4, and the p-glyco­protein drug efflux pump.⁹ As a result of this rampant induction, carbamazepine can decrease the serum concentration of oral contraceptives below a reliably effec­tive level. Therefore, it is recommended that women of childbearing potential use other contraceptive methods, such as a progestin implant or an intrauterine device.¹⁰

In addition, the polycyclic aromatic hydrocarbons found in cigarettes induce activity of CYP1A2. Patients who smoke and use medications metabolized by this enzyme, such as clozapine and olanzap­ine, may need a higher dosage.

Drug elimination interactions
The last drug−drug interaction discussed here returns the discussion to Mr. T and involves drug elimination.² The NSAIDs Mr. T was using for pain likely caused decreased renal excretion of lithium. Because lithium is primarily excreted through the kidneys, Mr. T’s NSAID use, possibly in com­bination with dehydration caused by gastro­intestinal distress, resulted in lithium toxicity. This class of analgesics should be avoided or used cautiously in patients taking lithium.

Clinical applications
The relatively common drug−drug interac­tions discussed here are just a fraction of the potential interactions mental health practi­tioners see on a daily basis. Understanding the basics of PD and PK interactions in the setting of patient-specific factors can help to clarify the information found in drug−drug interaction databases, such as Micromedex, Lexicomp, Facts and Comparisons, and Epocrates. Table 2 lists additional insights into drug interactions.

Related Resources
• CredibleMeds. Online resource on QT prolonging drugs. http://crediblemeds.org.
• Madhusoodanan S, Velama U, Parmar J, et al. A current review of cytochrome P450 interactions of psychotropic drugs. Ann Clin Psychiatry. 2014;26(2):120-138.

Drug Brand Names
Benztropine • Cogentin                            Olanzapine • Zyprexa
Bupropion • Wellbutrin                             Oxycodone • Oxycontin
Carbamazepine • Tegretol                        Paroxetine • Paxil
Clozapine • Clozaril                                  Quetiapine • Seroquel
Diphenhydramine • Benadryl                     Sertraline • Zoloft
 Duloxetine • Cymbalta                             Tamoxifen • Soltamox
Fluoxetine • Prozac                                   Trazodone • Desyrel
Lithium • Eskalith, Lithobid                        Valproate • Divalproex
Haloperidol • Haldol                                  Ziprasidone • Geodon
Hydrocodone • Vicodin

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

Mr. T,  age 23, was given a diagnosis of bipolar disorder 1 year ago. After he experienced inadequate symp­tom relief with valproate, you switched him to extended-release lithium, 1,200 mg/d. Mr. T reported improved mood and stability with this medication adjustment. These posi­tive changes led him to resume activities he enjoyed before onset of bipolar disorder, such as running, reading, and going out to dinner with friends.

Now, Mr. T’s mother calls your office to express concern about her son’s slight

hand tremor, which appeared after 2 days of gas­trointestinal distress. She tells you that Mr. T sprained his ankle while running 1 week ago and has been taking over-the-counter ibu­profen for pain relief, which he did often in the past.

You suspect that Mr. T is experiencing lith­ium toxicity as a result of ibuprofen use.

Although mental health providers can eas­ily recognize the drug−drug interaction between lithium and nonsteroidal anti-inflammatory drugs (NSAIDs) that Mr. T experienced, interpreting the safety of a medication regimen with respect to drug− drug interactions before prescribing often is more daunting. This article reviews the basics of drug−drug interactions, while briefly highlighting common examples in psychiatric medicine (Table 1^1-5). We also provide an outline of additional points to consider when reviewing your patients’ medication regimens and encoun­tering unfamiliar drug−drug interactions.

Types of drug−drug interactions
Drug−drug interactions fall into 2 catego­ries: pharmacodynamic (PD) and pharmaco­kinetic (PK):
   • PD interactions are a result of the com­bined impact of medications on the body when there is no direct effect on absorp­tion, distribution, metabolism, or excretion characteristics, such as 2 medications that act at the same receptor or lead to similar or opposing pharmacologic effects.
   • PK interactions occur when a drug affects the absorption, distribution, metabo­lism, or excretion characteristics of another drug.

Although it is possible that drug−drug interactions will have no clinical effect, when the impact of a PD or PK drug−drug interaction is evident, it likely is the result of additive, synergistic, or antago­nistic consequences on the medications’ intended impact or side-effect profile.

Pharmacodynamic interactions
Serotonin syndrome. The potential for serotonin syndrome occurs when medica­tions that increase synaptic serotonin con­centration are used concomitantly.¹ This can occur through several mechanisms, including increased serotonin release, decreased reuptake, or decreased sero­tonin metabolism. A high serotonin con­centration in the CNS and in the periphery overstimulates serotonin receptors, lead­ing to signs and symptoms that can include diarrhea, fever, delirium, coma, and poten­tially death.

QT prolongation and anticholinergic toxicity are further examples of additive PD drug−drug interactions. Anticholinergic toxicity is possible when multiple medica­tions contribute to inhibition of the neuro-transmitter acetylcholine at muscarinic receptors. This leads to adverse effects such as dry mouth, constipation, confusion, and urinary retention.

QT prolongation, which can lead to arrhythmia, occurs when a patient is taking several medications that can increase the QT interval. Consider close monitoring and using alternative agents with less poten­tial to increase the QT interval in patients at risk of arrhythmias (geriatric patients, those with an increased QT interval at base­line, etc.).

Decreased seizure threshold. The increased risk of seizures with bupropion and other medications that lower the sei­zure threshold is another example of an additive PD drug interaction. Bupropion can increase the risk of seizures in a dose-dependent manner, which increases when bupropion is taken with other drugs that lower the seizure threshold.6 Seizure risk associated with alcohol or benzodiazepine withdrawal also may increase the risk for this interaction.

Of note, the increased risk of seizures with the combination of bupropion and alcohol in the absence of withdrawal is not well studied in humans, but positive corre­lation has been seen in an animal study.⁶

Decreased platelet function. Another example of a PD drug−drug interaction is increased risk of bleeding when a selec­tive serotonin reuptake inhibitor is used with a NSAID or oral anticoagulant. The proposed mechanism for this interaction is that blocking serotonin reuptake on platelets leads to decreased platelet func­tion and an increased risk for prolonged bleeding.7 This is somewhat controversial because, first, it has been noted that drugs with the highest degree of serotonin reup­take inhibition do not always cause the highest risk of bleeding and, second, most of the evidence for this interaction is from observational studies.⁷

This potential interaction could be most important for patients who need an anti­depressant, are on chronic NSAID or anti­coagulant therapy, and are at high risk of bleeding.

Pharmacokinetic interactions
PK interactions in psychiatry often are caused by interference of drug metabo­lizing enzymes. The cytochrome P450 (CYP450) family of metabolizing enzymes in particular is important to the break­down of medications in the body. Many drug−drug interactions involve medica­tions that can inhibit or induce metabolism of other drugs through their effect on the CYP450 system.

Inhibition interactions. When a drug’s metabolism is inhibited, the result is usu­ally increased serum concentration of that medication (because of less break­down) and a more potent impact on the primary mechanism of action or adverse effects. Sometimes, inhibiting metabo­lism can lead to decreased clinical effect. Tamoxifen (an oral agent used to treat breast cancer) and certain analgesics when used in combination with moderate or strong inhibitors of the CYP2D6 subfam­ily of CYP450 metabolizing enzymes are 2 examples of metabolism inhibition lead­ing to decreased efficacy.⁸ Both tamoxi­fen and the analgesics listed in Table 1^1-5 are prodrugs; that is, they must be metabolized to be active. When the enzymes that metabolize these drugs into their active form are inhibited, the concen­tration of active drug decreases.

Induction interactions. Alternatively, there is an increased rate of drug break­down and resulting decrease in effect when drugs that induce the activity of metabolizing enzymes are used with med­ications that are substrates of the same enzyme. Carbamazepine is commonly involved in this type of drug interaction because it is a strong inducer of CYP 1A2, 2B6, 2C19, 2C9, and 3A4, and the p-glyco­protein drug efflux pump.⁹ As a result of this rampant induction, carbamazepine can decrease the serum concentration of oral contraceptives below a reliably effec­tive level. Therefore, it is recommended that women of childbearing potential use other contraceptive methods, such as a progestin implant or an intrauterine device.¹⁰

In addition, the polycyclic aromatic hydrocarbons found in cigarettes induce activity of CYP1A2. Patients who smoke and use medications metabolized by this enzyme, such as clozapine and olanzap­ine, may need a higher dosage.

Drug elimination interactions
The last drug−drug interaction discussed here returns the discussion to Mr. T and involves drug elimination.² The NSAIDs Mr. T was using for pain likely caused decreased renal excretion of lithium. Because lithium is primarily excreted through the kidneys, Mr. T’s NSAID use, possibly in com­bination with dehydration caused by gastro­intestinal distress, resulted in lithium toxicity. This class of analgesics should be avoided or used cautiously in patients taking lithium.

Clinical applications
The relatively common drug−drug interac­tions discussed here are just a fraction of the potential interactions mental health practi­tioners see on a daily basis. Understanding the basics of PD and PK interactions in the setting of patient-specific factors can help to clarify the information found in drug−drug interaction databases, such as Micromedex, Lexicomp, Facts and Comparisons, and Epocrates. Table 2 lists additional insights into drug interactions.

Related Resources
• CredibleMeds. Online resource on QT prolonging drugs. http://crediblemeds.org.
• Madhusoodanan S, Velama U, Parmar J, et al. A current review of cytochrome P450 interactions of psychotropic drugs. Ann Clin Psychiatry. 2014;26(2):120-138.

Drug Brand Names
Benztropine • Cogentin                            Olanzapine • Zyprexa
Bupropion • Wellbutrin                             Oxycodone • Oxycontin
Carbamazepine • Tegretol                        Paroxetine • Paxil
Clozapine • Clozaril                                  Quetiapine • Seroquel
Diphenhydramine • Benadryl                     Sertraline • Zoloft
 Duloxetine • Cymbalta                             Tamoxifen • Soltamox
Fluoxetine • Prozac                                   Trazodone • Desyrel
Lithium • Eskalith, Lithobid                        Valproate • Divalproex
Haloperidol • Haldol                                  Ziprasidone • Geodon
Hydrocodone • Vicodin

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

People with serious mental illness (SMI) have a life expectancy that is 25 years less than the general population, according to the Centers for Disease Control and Prevention.¹ This disparity is partially a consequence of the lack of primary and preventive medical care for those with psychiatric illness. Decades of research have shown that people with SMI experience higher medical morbidity and mortality in addition to facing the stigma of mental illness.

This article aims to advance the idea that longitudinal “cross educa­tion” between primary care providers (PCPs) and behavioral health providers (BHPs) is essential in addressing this problem. BHPs include psychiatry clinics, which often are part of a university or large health sys­tems; county-based community mental health programs; and indepen­dent mental health clinics that contract with public and private health plans to provide mental health services.

Although suicide and injury account for 40% of the excess mortality in schizophrenia, 60% can be attributed to cardiovascular disease, diabetes, respiratory diseases, and infection.² Patients with SMI have 2 to 3 times the risk of diabetes, dyslipidemia, hypertension, and obesity.^3,4 Furthermore, those with SMI consume more than one-third of tobacco products,⁵ and 50% to 80% of people with SMI smoke tobacco, an important reversible risk factor for cardiovascular disease.

Figure 1 shows that people with SMI are at higher risk of dying from a chronic medical condition, such as cardiovascular disease, diabetes, chronic obstructive pulmonary disease, and hepatitis C^6-8—many of which can be managed by primary and preventive medical interven­tions. These and other conditions often are not diagnosed or effectively managed in patients with SMI.

The high prevalence of metabolic syn­drome and tobacco dependence among people with SMI accelerates development of cardiovascular disease, as shown by several studies. Bobes et al⁹ found that the preva­lence of metabolic syndrome and cardiovas­cular risk among patients with SMI is similar to what is found in the general population at 10 to 15 years of greater age. Osborn et al¹⁰ demonstrated that people with SMI age 18 to 49 had a higher relative risk of death from coronary heart disease, stroke, and lung can­cer than age-matched controls (Figure 2).

Iatrogenic causes of morbidity
Many psychiatric medications, especially second-generation antipsychotics (SGAs), could exacerbate cardiovascular and meta­bolic conditions by increasing the risk of weight gain, insulin resistance, and dyslip­idemia. Antipsychotics that generally are considered to be more effective for refrac­tory psychotic illness (eg, clozapine and olanzapine) are associated with the highest risk of metabolic syndrome. Simon et al¹¹ found a dose-response relationship between olanzapine and clozapine serum concentra­tions and worsening metabolic outcomes. Valproic acid also can cause significant weight gain and could require monitor­ing similar to what is done with to SGAs, although there has been less clinical and research attention to this mood stabilizer.

The American Diabetes Association et al¹² have published guidelines on monitoring antipsychotic-induced obesity and diabetes, but adoption of these guidelines has been slow. Mackin et al¹³ found that providers are slow to recognize the elevated rate of obesity and dyslipidemia among psychiat­ric patients, possibly because of “an alarm­ingly poor rate of monitoring of metabolic parameters.”

Treating adverse metabolic outcomes also seems to lag behind. The same study13 found that physical health parameters among psy­chiatric patients continue to become worse even when appropriate health care profes­sionals were notified. Rates of nontreatment for diabetes, dyslipidemia, and hyperten­sion were 30%, 60%, and 88% respectively, according to Nasrallah et al.¹⁴

Randomized controlled studies have shown that obesity and metabolic syndrome can be effectively managed using lifestyle and pharmacotherapeutic approaches,^15,16 but more research is needed to test long-term outcomes and how to best incorporate these interventions. Newcomer et al¹⁷ found that gradually switching an antipsychotic with high risk of metabolic adverse effects to one with lower risk could reduce adverse meta­bolic outcomes; however, some patients returned to their prior antipsychotic because other medications did not effectively treat their schizophrenia symptoms. Therefore, physicians must pay careful attention to the trade-off between benefits and risks of anti­psychotics and make treatment decisions on an individual basis.

Barriers to medical care
Research has demonstrated that patients with SMI receive less screening and fewer preventive medical services, especially blood pressure monitoring, vaccina­tions, mammography, lipid monitoring, and osteoporosis screening, compared with the general population (Table).¹⁸ Some barriers to preventive services could exist because of demographic fac­tors and medical insurance coverage¹⁹ or medical providers’ discomfort with symp­toms of SMI,²⁰ although Mitchell et al²¹ found that disparities in mammography screening could not be explained by the presence of emotional distress in women with SMI.

Therefore, not only are patients with SMI less likely to receive preventive care, they are also less likely to receive poten­tially lifesaving treatments for SMI. Because those with SMI might not be able to advocate for themselves in these mat­ters, psychiatric clinicians can improve their patients’ lives by advocating for appropriate medical care despite multiple barriers.

Bridging the gap: Managing mental health in primary care
Research from the 1970s and 1980s demon­strated that most persons who sought help for depression or anxiety received treatment from their PCP, many of whom felt limited by their lack of behavioral health training. Moreover, many patients failed to receive a psychiatric diagnosis or adequate treatment, despite efforts to educate primary care phy­sicians on appropriate diagnosis and treat­ment of mental illness.

Katon et al²⁵ at the University of Washington developed the collaborative care model in the early 1990s to help improve treatment of depression in primary care set­tings. This model involved:
   • case load review by psychiatrists
   • use of nurses and other support staff to help monitor patients’ adherence and treatment response
   • use of standardized tools such as the Patient Health Questionnaire to moni­tor symptoms
   • enhancement of patient education with pamphlets or classes.

Studies evaluating the success of collab­orative care models found overall improved outcomes, making it the only evidence-based model for integration of behavioral health and primary care.²⁶ As a result, the collaborative care model has been imple­mented across the United States in primary care clinics and specialty care settings, such as obstetrics and gynecology.²⁷

Regrettably, access to primary care has been hampered by:  
   • population growth  
   • a shortage of PCPs  
   • enrollment of a flood of new patients into the health care marketplace as a result of mandates of the Affordable Care Act (ACA).

In many settings, a psychiatrist might be the patient’s only consistent care provider, and could be thought of as a “primary care psychiatrist.”

To resolve this predicament, mental health professionals need to recognize the unique medical conditions faced by people with SMI, and also might need to provide treatment of common medical conditions, either directly or through collaborative arrangements. Psychiatrists who are capa­ble of managing core medical issues likely will witness improved psychiatric and overall health outcomes in their patients. Consequently, psychiatrists and mental health professionals are increasingly called on to be advocates to improve access to medical services in patients with SMI and to participate in health systems reform.

Managing medical conditions in mental health settings
Although traditional collaborative care involves mental health providers working at primary care sites, other models have emerged that manage chronic disease in behavioral health settings. Federally funded grants for primary behavioral health care integration have allowed community men­tal health centers to partner with federally qualified health centers to provide on-site primary care services.²⁸

In these models, care managers in mental health clinics:
   • link patients to primary care services
   • encourage lifestyle changes to improve their overall health
   • identify and overcome barriers to receiving care
   • track clinical outcomes in a registry format.

Currently, 126 mental health sites in the United States have received these grants and are working toward greater integration of primary care.

In addition, the ACA provided funding for “health homes” in non-primary care settings, which includes SMI. These health homes cannot provide direct primary care, but can deliver comprehensive care man­agement, care coordination, health pro­motion, comprehensive transitional care services between facilities, individual and family support, and referral to commu­nity social support services. In these health homes, a PCP can act as a consultant to help establish priorities for disease management and improving health status.²⁹ The PCP consultant also can support psychiatric staff and collaborate with providers who want to provide some direct care of medical conditions.³⁰

Last, some behavioral health sites are choosing to apply for Federally Qualified Health Clinic status or add primary care services to their clinics, with the hope that sustainable funding will become available. Without additional funding to cover the limited reimbursement provided by pub­lic payers, such as Medicaid and Medicare, these models might be unsustainable. Current innovations in health care fund­ing reform hopefully will offer solutions for sites to provide medical care in the natural “medical home” of the SMI population.

Bottom Line
Psychiatric providers are in a favorable position to develop and oversee a partnership with primary care physicians with the goal of addressing significant and often lethal health disparities among those with mental illness. Psychiatric providers must use evidence-based practices that include assessment and prevention of cardiopulmonary, metabolic, infectious, and oncologic disorders. True primary care–behavioral health integration must include longitudinal “cross education” and changes in health care policy, with an emphasis on decreasing morbidity and mortality in psychiatric patients.

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

People with serious mental illness (SMI) have a life expectancy that is 25 years less than the general population, according to the Centers for Disease Control and Prevention.¹ This disparity is partially a consequence of the lack of primary and preventive medical care for those with psychiatric illness. Decades of research have shown that people with SMI experience higher medical morbidity and mortality in addition to facing the stigma of mental illness.

This article aims to advance the idea that longitudinal “cross educa­tion” between primary care providers (PCPs) and behavioral health providers (BHPs) is essential in addressing this problem. BHPs include psychiatry clinics, which often are part of a university or large health sys­tems; county-based community mental health programs; and indepen­dent mental health clinics that contract with public and private health plans to provide mental health services.

Although suicide and injury account for 40% of the excess mortality in schizophrenia, 60% can be attributed to cardiovascular disease, diabetes, respiratory diseases, and infection.² Patients with SMI have 2 to 3 times the risk of diabetes, dyslipidemia, hypertension, and obesity.^3,4 Furthermore, those with SMI consume more than one-third of tobacco products,⁵ and 50% to 80% of people with SMI smoke tobacco, an important reversible risk factor for cardiovascular disease.

Figure 1 shows that people with SMI are at higher risk of dying from a chronic medical condition, such as cardiovascular disease, diabetes, chronic obstructive pulmonary disease, and hepatitis C^6-8—many of which can be managed by primary and preventive medical interven­tions. These and other conditions often are not diagnosed or effectively managed in patients with SMI.

The high prevalence of metabolic syn­drome and tobacco dependence among people with SMI accelerates development of cardiovascular disease, as shown by several studies. Bobes et al⁹ found that the preva­lence of metabolic syndrome and cardiovas­cular risk among patients with SMI is similar to what is found in the general population at 10 to 15 years of greater age. Osborn et al¹⁰ demonstrated that people with SMI age 18 to 49 had a higher relative risk of death from coronary heart disease, stroke, and lung can­cer than age-matched controls (Figure 2).

Iatrogenic causes of morbidity
Many psychiatric medications, especially second-generation antipsychotics (SGAs), could exacerbate cardiovascular and meta­bolic conditions by increasing the risk of weight gain, insulin resistance, and dyslip­idemia. Antipsychotics that generally are considered to be more effective for refrac­tory psychotic illness (eg, clozapine and olanzapine) are associated with the highest risk of metabolic syndrome. Simon et al¹¹ found a dose-response relationship between olanzapine and clozapine serum concentra­tions and worsening metabolic outcomes. Valproic acid also can cause significant weight gain and could require monitor­ing similar to what is done with to SGAs, although there has been less clinical and research attention to this mood stabilizer.

The American Diabetes Association et al¹² have published guidelines on monitoring antipsychotic-induced obesity and diabetes, but adoption of these guidelines has been slow. Mackin et al¹³ found that providers are slow to recognize the elevated rate of obesity and dyslipidemia among psychiat­ric patients, possibly because of “an alarm­ingly poor rate of monitoring of metabolic parameters.”

Treating adverse metabolic outcomes also seems to lag behind. The same study13 found that physical health parameters among psy­chiatric patients continue to become worse even when appropriate health care profes­sionals were notified. Rates of nontreatment for diabetes, dyslipidemia, and hyperten­sion were 30%, 60%, and 88% respectively, according to Nasrallah et al.¹⁴

Randomized controlled studies have shown that obesity and metabolic syndrome can be effectively managed using lifestyle and pharmacotherapeutic approaches,^15,16 but more research is needed to test long-term outcomes and how to best incorporate these interventions. Newcomer et al¹⁷ found that gradually switching an antipsychotic with high risk of metabolic adverse effects to one with lower risk could reduce adverse meta­bolic outcomes; however, some patients returned to their prior antipsychotic because other medications did not effectively treat their schizophrenia symptoms. Therefore, physicians must pay careful attention to the trade-off between benefits and risks of anti­psychotics and make treatment decisions on an individual basis.

Barriers to medical care
Research has demonstrated that patients with SMI receive less screening and fewer preventive medical services, especially blood pressure monitoring, vaccina­tions, mammography, lipid monitoring, and osteoporosis screening, compared with the general population (Table).¹⁸ Some barriers to preventive services could exist because of demographic fac­tors and medical insurance coverage¹⁹ or medical providers’ discomfort with symp­toms of SMI,²⁰ although Mitchell et al²¹ found that disparities in mammography screening could not be explained by the presence of emotional distress in women with SMI.

Therefore, not only are patients with SMI less likely to receive preventive care, they are also less likely to receive poten­tially lifesaving treatments for SMI. Because those with SMI might not be able to advocate for themselves in these mat­ters, psychiatric clinicians can improve their patients’ lives by advocating for appropriate medical care despite multiple barriers.

Bridging the gap: Managing mental health in primary care
Research from the 1970s and 1980s demon­strated that most persons who sought help for depression or anxiety received treatment from their PCP, many of whom felt limited by their lack of behavioral health training. Moreover, many patients failed to receive a psychiatric diagnosis or adequate treatment, despite efforts to educate primary care phy­sicians on appropriate diagnosis and treat­ment of mental illness.

Katon et al²⁵ at the University of Washington developed the collaborative care model in the early 1990s to help improve treatment of depression in primary care set­tings. This model involved:
   • case load review by psychiatrists
   • use of nurses and other support staff to help monitor patients’ adherence and treatment response
   • use of standardized tools such as the Patient Health Questionnaire to moni­tor symptoms
   • enhancement of patient education with pamphlets or classes.

Studies evaluating the success of collab­orative care models found overall improved outcomes, making it the only evidence-based model for integration of behavioral health and primary care.²⁶ As a result, the collaborative care model has been imple­mented across the United States in primary care clinics and specialty care settings, such as obstetrics and gynecology.²⁷

Regrettably, access to primary care has been hampered by:  
   • population growth  
   • a shortage of PCPs  
   • enrollment of a flood of new patients into the health care marketplace as a result of mandates of the Affordable Care Act (ACA).

In many settings, a psychiatrist might be the patient’s only consistent care provider, and could be thought of as a “primary care psychiatrist.”

To resolve this predicament, mental health professionals need to recognize the unique medical conditions faced by people with SMI, and also might need to provide treatment of common medical conditions, either directly or through collaborative arrangements. Psychiatrists who are capa­ble of managing core medical issues likely will witness improved psychiatric and overall health outcomes in their patients. Consequently, psychiatrists and mental health professionals are increasingly called on to be advocates to improve access to medical services in patients with SMI and to participate in health systems reform.

Managing medical conditions in mental health settings
Although traditional collaborative care involves mental health providers working at primary care sites, other models have emerged that manage chronic disease in behavioral health settings. Federally funded grants for primary behavioral health care integration have allowed community men­tal health centers to partner with federally qualified health centers to provide on-site primary care services.²⁸

In these models, care managers in mental health clinics:
   • link patients to primary care services
   • encourage lifestyle changes to improve their overall health
   • identify and overcome barriers to receiving care
   • track clinical outcomes in a registry format.

Currently, 126 mental health sites in the United States have received these grants and are working toward greater integration of primary care.

In addition, the ACA provided funding for “health homes” in non-primary care settings, which includes SMI. These health homes cannot provide direct primary care, but can deliver comprehensive care man­agement, care coordination, health pro­motion, comprehensive transitional care services between facilities, individual and family support, and referral to commu­nity social support services. In these health homes, a PCP can act as a consultant to help establish priorities for disease management and improving health status.²⁹ The PCP consultant also can support psychiatric staff and collaborate with providers who want to provide some direct care of medical conditions.³⁰

Last, some behavioral health sites are choosing to apply for Federally Qualified Health Clinic status or add primary care services to their clinics, with the hope that sustainable funding will become available. Without additional funding to cover the limited reimbursement provided by pub­lic payers, such as Medicaid and Medicare, these models might be unsustainable. Current innovations in health care fund­ing reform hopefully will offer solutions for sites to provide medical care in the natural “medical home” of the SMI population.

Bottom Line
Psychiatric providers are in a favorable position to develop and oversee a partnership with primary care physicians with the goal of addressing significant and often lethal health disparities among those with mental illness. Psychiatric providers must use evidence-based practices that include assessment and prevention of cardiopulmonary, metabolic, infectious, and oncologic disorders. True primary care–behavioral health integration must include longitudinal “cross education” and changes in health care policy, with an emphasis on decreasing morbidity and mortality in psychiatric patients.

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

People with serious mental illness (SMI) have a life expectancy that is 25 years less than the general population, according to the Centers for Disease Control and Prevention.¹ This disparity is partially a consequence of the lack of primary and preventive medical care for those with psychiatric illness. Decades of research have shown that people with SMI experience higher medical morbidity and mortality in addition to facing the stigma of mental illness.

This article aims to advance the idea that longitudinal “cross educa­tion” between primary care providers (PCPs) and behavioral health providers (BHPs) is essential in addressing this problem. BHPs include psychiatry clinics, which often are part of a university or large health sys­tems; county-based community mental health programs; and indepen­dent mental health clinics that contract with public and private health plans to provide mental health services.

Although suicide and injury account for 40% of the excess mortality in schizophrenia, 60% can be attributed to cardiovascular disease, diabetes, respiratory diseases, and infection.² Patients with SMI have 2 to 3 times the risk of diabetes, dyslipidemia, hypertension, and obesity.^3,4 Furthermore, those with SMI consume more than one-third of tobacco products,⁵ and 50% to 80% of people with SMI smoke tobacco, an important reversible risk factor for cardiovascular disease.

Figure 1 shows that people with SMI are at higher risk of dying from a chronic medical condition, such as cardiovascular disease, diabetes, chronic obstructive pulmonary disease, and hepatitis C^6-8—many of which can be managed by primary and preventive medical interven­tions. These and other conditions often are not diagnosed or effectively managed in patients with SMI.

The high prevalence of metabolic syn­drome and tobacco dependence among people with SMI accelerates development of cardiovascular disease, as shown by several studies. Bobes et al⁹ found that the preva­lence of metabolic syndrome and cardiovas­cular risk among patients with SMI is similar to what is found in the general population at 10 to 15 years of greater age. Osborn et al¹⁰ demonstrated that people with SMI age 18 to 49 had a higher relative risk of death from coronary heart disease, stroke, and lung can­cer than age-matched controls (Figure 2).

Iatrogenic causes of morbidity
Many psychiatric medications, especially second-generation antipsychotics (SGAs), could exacerbate cardiovascular and meta­bolic conditions by increasing the risk of weight gain, insulin resistance, and dyslip­idemia. Antipsychotics that generally are considered to be more effective for refrac­tory psychotic illness (eg, clozapine and olanzapine) are associated with the highest risk of metabolic syndrome. Simon et al¹¹ found a dose-response relationship between olanzapine and clozapine serum concentra­tions and worsening metabolic outcomes. Valproic acid also can cause significant weight gain and could require monitor­ing similar to what is done with to SGAs, although there has been less clinical and research attention to this mood stabilizer.

The American Diabetes Association et al¹² have published guidelines on monitoring antipsychotic-induced obesity and diabetes, but adoption of these guidelines has been slow. Mackin et al¹³ found that providers are slow to recognize the elevated rate of obesity and dyslipidemia among psychiat­ric patients, possibly because of “an alarm­ingly poor rate of monitoring of metabolic parameters.”

Treating adverse metabolic outcomes also seems to lag behind. The same study13 found that physical health parameters among psy­chiatric patients continue to become worse even when appropriate health care profes­sionals were notified. Rates of nontreatment for diabetes, dyslipidemia, and hyperten­sion were 30%, 60%, and 88% respectively, according to Nasrallah et al.¹⁴

Randomized controlled studies have shown that obesity and metabolic syndrome can be effectively managed using lifestyle and pharmacotherapeutic approaches,^15,16 but more research is needed to test long-term outcomes and how to best incorporate these interventions. Newcomer et al¹⁷ found that gradually switching an antipsychotic with high risk of metabolic adverse effects to one with lower risk could reduce adverse meta­bolic outcomes; however, some patients returned to their prior antipsychotic because other medications did not effectively treat their schizophrenia symptoms. Therefore, physicians must pay careful attention to the trade-off between benefits and risks of anti­psychotics and make treatment decisions on an individual basis.

Barriers to medical care
Research has demonstrated that patients with SMI receive less screening and fewer preventive medical services, especially blood pressure monitoring, vaccina­tions, mammography, lipid monitoring, and osteoporosis screening, compared with the general population (Table).¹⁸ Some barriers to preventive services could exist because of demographic fac­tors and medical insurance coverage¹⁹ or medical providers’ discomfort with symp­toms of SMI,²⁰ although Mitchell et al²¹ found that disparities in mammography screening could not be explained by the presence of emotional distress in women with SMI.

Therefore, not only are patients with SMI less likely to receive preventive care, they are also less likely to receive poten­tially lifesaving treatments for SMI. Because those with SMI might not be able to advocate for themselves in these mat­ters, psychiatric clinicians can improve their patients’ lives by advocating for appropriate medical care despite multiple barriers.

Bridging the gap: Managing mental health in primary care
Research from the 1970s and 1980s demon­strated that most persons who sought help for depression or anxiety received treatment from their PCP, many of whom felt limited by their lack of behavioral health training. Moreover, many patients failed to receive a psychiatric diagnosis or adequate treatment, despite efforts to educate primary care phy­sicians on appropriate diagnosis and treat­ment of mental illness.

Katon et al²⁵ at the University of Washington developed the collaborative care model in the early 1990s to help improve treatment of depression in primary care set­tings. This model involved:
   • case load review by psychiatrists
   • use of nurses and other support staff to help monitor patients’ adherence and treatment response
   • use of standardized tools such as the Patient Health Questionnaire to moni­tor symptoms
   • enhancement of patient education with pamphlets or classes.

Studies evaluating the success of collab­orative care models found overall improved outcomes, making it the only evidence-based model for integration of behavioral health and primary care.²⁶ As a result, the collaborative care model has been imple­mented across the United States in primary care clinics and specialty care settings, such as obstetrics and gynecology.²⁷

Regrettably, access to primary care has been hampered by:  
   • population growth  
   • a shortage of PCPs  
   • enrollment of a flood of new patients into the health care marketplace as a result of mandates of the Affordable Care Act (ACA).

In many settings, a psychiatrist might be the patient’s only consistent care provider, and could be thought of as a “primary care psychiatrist.”

To resolve this predicament, mental health professionals need to recognize the unique medical conditions faced by people with SMI, and also might need to provide treatment of common medical conditions, either directly or through collaborative arrangements. Psychiatrists who are capa­ble of managing core medical issues likely will witness improved psychiatric and overall health outcomes in their patients. Consequently, psychiatrists and mental health professionals are increasingly called on to be advocates to improve access to medical services in patients with SMI and to participate in health systems reform.

Managing medical conditions in mental health settings
Although traditional collaborative care involves mental health providers working at primary care sites, other models have emerged that manage chronic disease in behavioral health settings. Federally funded grants for primary behavioral health care integration have allowed community men­tal health centers to partner with federally qualified health centers to provide on-site primary care services.²⁸

In these models, care managers in mental health clinics:
   • link patients to primary care services
   • encourage lifestyle changes to improve their overall health
   • identify and overcome barriers to receiving care
   • track clinical outcomes in a registry format.

Currently, 126 mental health sites in the United States have received these grants and are working toward greater integration of primary care.

In addition, the ACA provided funding for “health homes” in non-primary care settings, which includes SMI. These health homes cannot provide direct primary care, but can deliver comprehensive care man­agement, care coordination, health pro­motion, comprehensive transitional care services between facilities, individual and family support, and referral to commu­nity social support services. In these health homes, a PCP can act as a consultant to help establish priorities for disease management and improving health status.²⁹ The PCP consultant also can support psychiatric staff and collaborate with providers who want to provide some direct care of medical conditions.³⁰

Last, some behavioral health sites are choosing to apply for Federally Qualified Health Clinic status or add primary care services to their clinics, with the hope that sustainable funding will become available. Without additional funding to cover the limited reimbursement provided by pub­lic payers, such as Medicaid and Medicare, these models might be unsustainable. Current innovations in health care fund­ing reform hopefully will offer solutions for sites to provide medical care in the natural “medical home” of the SMI population.

Bottom Line
Psychiatric providers are in a favorable position to develop and oversee a partnership with primary care physicians with the goal of addressing significant and often lethal health disparities among those with mental illness. Psychiatric providers must use evidence-based practices that include assessment and prevention of cardiopulmonary, metabolic, infectious, and oncologic disorders. True primary care–behavioral health integration must include longitudinal “cross education” and changes in health care policy, with an emphasis on decreasing morbidity and mortality in psychiatric patients.

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

"This patient had presented 2-weeks postpartum in a manic state with psycotic features. She was screened by Ob-Gyn who collaborated with her care while she was admitted to the psychiatric inpatient unit. Patient had been non-compliant with prescribed medications prior to admission and she was started on aripiprazole from day one and the dose was tapered up to 15 mg BID by day 5. Patient's manic symptoms improved slowly as the days progressed by day 8 psychotic symptoms started to subside. As delivery was imminent, patient was transferred to Ob-Gyn service. She delivered a healthy but premature child via csection on day 12. Child did not exhibit any gross or anatomic malformations. She was continued on aripiprazole 15 mg BID after discharge and was seen weeks later in outpatient psychiatry."

Read more from the Poster Abstracts from the 2015 APA Annual Meeting

"This patient had presented 2-weeks postpartum in a manic state with psycotic features. She was screened by Ob-Gyn who collaborated with her care while she was admitted to the psychiatric inpatient unit. Patient had been non-compliant with prescribed medications prior to admission and she was started on aripiprazole from day one and the dose was tapered up to 15 mg BID by day 5. Patient's manic symptoms improved slowly as the days progressed by day 8 psychotic symptoms started to subside. As delivery was imminent, patient was transferred to Ob-Gyn service. She delivered a healthy but premature child via csection on day 12. Child did not exhibit any gross or anatomic malformations. She was continued on aripiprazole 15 mg BID after discharge and was seen weeks later in outpatient psychiatry."

Read more from the Poster Abstracts from the 2015 APA Annual Meeting

"This patient had presented 2-weeks postpartum in a manic state with psycotic features. She was screened by Ob-Gyn who collaborated with her care while she was admitted to the psychiatric inpatient unit. Patient had been non-compliant with prescribed medications prior to admission and she was started on aripiprazole from day one and the dose was tapered up to 15 mg BID by day 5. Patient's manic symptoms improved slowly as the days progressed by day 8 psychotic symptoms started to subside. As delivery was imminent, patient was transferred to Ob-Gyn service. She delivered a healthy but premature child via csection on day 12. Child did not exhibit any gross or anatomic malformations. She was continued on aripiprazole 15 mg BID after discharge and was seen weeks later in outpatient psychiatry."

Read more from the Poster Abstracts from the 2015 APA Annual Meeting

Nyer et al examined whether fatigue was associated with greater symptomatic burden and functional impairment in 287 college students with depressive symptoms using data from the self-report Beck Depression Inventory (BDI). Students endorsing significant symptoms of depression (BDI score ≥13) were grouped into 3 levels: no fatigue, mild fatigue, or moderate/severe fatigue. Researchers compared the 3 levels of fatigue across a battery of psychiatric and functional outcome measures.

The study found that depressed college students with symptoms of fatigue demonstrated functional impairment and symptomatic burden that worsened with increasing levels of fatigue. The authors call for more attention to assessing and treating symptoms of fatigue within this population.

Nyer et al examined whether fatigue was associated with greater symptomatic burden and functional impairment in 287 college students with depressive symptoms using data from the self-report Beck Depression Inventory (BDI). Students endorsing significant symptoms of depression (BDI score ≥13) were grouped into 3 levels: no fatigue, mild fatigue, or moderate/severe fatigue. Researchers compared the 3 levels of fatigue across a battery of psychiatric and functional outcome measures.

The study found that depressed college students with symptoms of fatigue demonstrated functional impairment and symptomatic burden that worsened with increasing levels of fatigue. The authors call for more attention to assessing and treating symptoms of fatigue within this population.

Nyer et al examined whether fatigue was associated with greater symptomatic burden and functional impairment in 287 college students with depressive symptoms using data from the self-report Beck Depression Inventory (BDI). Students endorsing significant symptoms of depression (BDI score ≥13) were grouped into 3 levels: no fatigue, mild fatigue, or moderate/severe fatigue. Researchers compared the 3 levels of fatigue across a battery of psychiatric and functional outcome measures.

The study found that depressed college students with symptoms of fatigue demonstrated functional impairment and symptomatic burden that worsened with increasing levels of fatigue. The authors call for more attention to assessing and treating symptoms of fatigue within this population.