Current Psychiatry

Mr. C, age 31, who has a 7-year history of schizophrenia and is currently on perphenazine, 24 mg twice a day, presents for psychiatric admission after experiencing paranoid delusions. Notable symptoms include delusions of reference and persecution, along with affective flattening and intermittent suicidal ideation. Perphenazine is tapered, and he is started on quetiapine, titrated to 600 mg/d.

Past antipsychotic trials include aripiprazole, olanzapine, paliperidone, haloperidol,

and ziprasidone. Because of his refractory symptoms and tolerability issues with other antipsychotics, Mr. C is switched to clozapine, 400 mg/d. His symptoms improve, but he experiences dose-limiting sialorrhea. Risperidone, 1 mg/d, is added to clozapine, which helps his psychosis and improves his functional status. Additionally, Mr. C develops enough insight to recognize his delusions and use skills learned in psychotherapy to cope with them.

Antipsychotic polypharmacy (APP), the concurrent use of ≥2 antipsychotics, is a topic of debate among mental health care providers. Studies indicate the prevalence of APP can reach upwards of 40%, with 1 systematic review citing more recent median APP prevalence in North America as 17%, an increase from a median of 12.7% in the 1980s.¹ Other studies cite more recent figures as around 20%.^2,3

The literature lists several reasons for use of long-term APP, including:

• incomplete cross-titration
• accidental continuation of APP that was intended to be temporary
• monotherapy failure
• mitigation or enhancement of effects of other antipsychotics (Table 1).^1,4

Other factors include direct-to-consumer advertising, external pressures to decrease hospital stays, and low doctor-to-patient ratios.⁵ Although it can take as long as 16 weeks to see clinically significant improvement with an antipsychotic, prescribers might expect results after 4 weeks of treatment.⁶ Therefore, treatments could be labeled ineffective because trials did not last long enough, leading to premature use of polypharmacy. Combinations of a first- and second-generation antipsychotic (SGA) or 2 SGAs are most common.^2,7,8

Treatment guidelines (Table 2)^9-17 suggest APP could be considered after several failures of monotherapy, including clozapine monotherapy, although some guidelines do not address the issue or recommend against APP because of lack of efficacy and safety data. Additionally, APP poses safety concerns (Table 3).^18-22 Recommendations for APP with combinations that do not include clozapine generally are not provided, because high-level evidence to support this strategy is lacking. Data on safety and efficacy of APP are mixed, with much of the literature dominated by case reports and uncontrolled studies.¹⁹

What to initiate
Clozapine. Higher-level evidence is available for clozapine APP. The combination of clozapine and risperidone is one of the most thoroughly studied and, therefore, is a reasonable first choice. Randomized controlled trials (RCTs) examining clozapine plus risperidone^23-29 have yielded mixed results and have not provided conclusive information regarding benefit for positive vs negative symptoms.^24-28

One RCT reported a significant change in Brief Psychiatric Rating Scale (BPRS) total and positive symptom scores.²⁷ Other RCTs have shown a non-significant trend toward greater change in total, positive, and negative symptom scores with the clozapine-risperidone combination compared with clozapine monotherapy.^25,28 In terms of cognition, this combination provided no additional benefit.²³ Response, defined as ≥20% reduction in total BPRS or Positive and Negative Syndrome Scale (PANSS) scores, for clozapine plus risperidone range from 13% to 83%, compared with 8% to 29% for clozapine plus placebo.^24,25,27,29

Data from 1 study²⁷ suggest a number needed to treat of 4 to achieve at least a 20% improvement in BPRS scores with clozapine plus risperidone vs clozapine monotherapy. Across these studies, the average risperidone dosage was 4 mg/d, although using the lowest effective dosage is encouraged. A small number of RCTs and articles examining other APP combinations (Table 4)^30-33 have yielded mixed results.

Overall, APP appears to be well-tolerated, although it is associated with an increased risk of adverse effects, including sedation, extrapyramidal symptoms, hyperprolactinemia, sexual dysfunction, cognitive impairment, anticholinergic effects, hyperlipidemia, and diabetes.^23,24,34-36 Surprisingly, 1 literature review³⁶ found no association between APP and increased risk of orthostasis. Increased occurrence of sedation, hyperprolactinemia, and an elevated fasting blood glucose level have been found for clozapine plus risperidone compared with clozapine monotherapy.^24-26,28

Aripiprazole. Adjunctive aripiprazole, a dopamine partial agonist, could reduce elevated prolactin levels caused by other antipsychotics.³² In a study³⁷ of 56 patients taking haloperidol who had hyperprolactinemia, prolactin levels normalized in 88.5% of patients taking adjunctive aripiprazole, 30 mg/d, compared with 3.6% of those with added placebo. Furthermore, results from 2 RCTs^38,39 of patients taking clozapine or olanzapine suggest adjunctive aripiprazole could improve weight and metabolic profile. Therefore, adding aripiprazole to existing antipsychotic regimens is reasonable for patients with drug-induced symptomatic hyperprolactinemia or metabolic effects and who cannot be easily switched to another antipsychotic.

When to initiate
Most treatment guidelines^9-17 recommend clozapine only after monotherapy with at least 2 other antipsychotics fails. It is reasonable to add an antipsychotic to clozapine in patients who have shown a partial response to clozapine after a minimum of 3 months. Non-clozapine APP should be considered when:

• a patient derives no benefit from clozapine
• refuses clozapine
• clozapine is contraindicated
• APP is initiated to mitigate side effects from another antipsychotic.

Antipsychotics could take up to 16 weeks to achieve full efficacy,⁶ therefore, an adequate trial period within the target dosage range is advised for all antipsychotics (Table 5).^13,40

Why initiate
Based on available data, partial response to maximum recommended dosages of antipsychotic monotherapy, including clozapine, or inability to tolerate higher dosages, provides a reason for initiating APP. Non-clozapine APP generally should be considered only in patients who refuse, cannot tolerate, or do not respond to clozapine. Consider using validated rating scales to track treatment outcomes (ideally, a ≥20% symptomatic reduction on the BPRS or PANSS), although there is no formal guidance regarding their use or benefit in APP.

Summing up
APP is a fairly common prescribing practice, even though safety and efficacy data are mixed. The issue of APP has become prevalent enough that regulatory bodies are involved in its monitoring and documentation.⁴¹

Clozapine APP, especially with risperidone, has the most substantial evidence to support it. Although APP generally is well tolerated, the overall dearth of conclusive safety and efficacy data indicates that this practice should be reserved for patients who have not responded adequately to monotherapy, including clozapine. Adjunctive aripiprazole could be considered for addressing symptomatic hyperprolactinemia or other metabolic effects caused by other antipsychotics.

An adequate trial as long as 16 weeks is advised before assessing the efficacy of any antipsychotic regimen. If APP provides inadequate response, or if there is no clear indication for APP, consider switching the patient back to monotherapy.^42-44

Mr. C, age 31, who has a 7-year history of schizophrenia and is currently on perphenazine, 24 mg twice a day, presents for psychiatric admission after experiencing paranoid delusions. Notable symptoms include delusions of reference and persecution, along with affective flattening and intermittent suicidal ideation. Perphenazine is tapered, and he is started on quetiapine, titrated to 600 mg/d.

Past antipsychotic trials include aripiprazole, olanzapine, paliperidone, haloperidol,

and ziprasidone. Because of his refractory symptoms and tolerability issues with other antipsychotics, Mr. C is switched to clozapine, 400 mg/d. His symptoms improve, but he experiences dose-limiting sialorrhea. Risperidone, 1 mg/d, is added to clozapine, which helps his psychosis and improves his functional status. Additionally, Mr. C develops enough insight to recognize his delusions and use skills learned in psychotherapy to cope with them.

Antipsychotic polypharmacy (APP), the concurrent use of ≥2 antipsychotics, is a topic of debate among mental health care providers. Studies indicate the prevalence of APP can reach upwards of 40%, with 1 systematic review citing more recent median APP prevalence in North America as 17%, an increase from a median of 12.7% in the 1980s.¹ Other studies cite more recent figures as around 20%.^2,3

The literature lists several reasons for use of long-term APP, including:

• incomplete cross-titration
• accidental continuation of APP that was intended to be temporary
• monotherapy failure
• mitigation or enhancement of effects of other antipsychotics (Table 1).^1,4

Other factors include direct-to-consumer advertising, external pressures to decrease hospital stays, and low doctor-to-patient ratios.⁵ Although it can take as long as 16 weeks to see clinically significant improvement with an antipsychotic, prescribers might expect results after 4 weeks of treatment.⁶ Therefore, treatments could be labeled ineffective because trials did not last long enough, leading to premature use of polypharmacy. Combinations of a first- and second-generation antipsychotic (SGA) or 2 SGAs are most common.^2,7,8

Treatment guidelines (Table 2)^9-17 suggest APP could be considered after several failures of monotherapy, including clozapine monotherapy, although some guidelines do not address the issue or recommend against APP because of lack of efficacy and safety data. Additionally, APP poses safety concerns (Table 3).^18-22 Recommendations for APP with combinations that do not include clozapine generally are not provided, because high-level evidence to support this strategy is lacking. Data on safety and efficacy of APP are mixed, with much of the literature dominated by case reports and uncontrolled studies.¹⁹

What to initiate
Clozapine. Higher-level evidence is available for clozapine APP. The combination of clozapine and risperidone is one of the most thoroughly studied and, therefore, is a reasonable first choice. Randomized controlled trials (RCTs) examining clozapine plus risperidone^23-29 have yielded mixed results and have not provided conclusive information regarding benefit for positive vs negative symptoms.^24-28

One RCT reported a significant change in Brief Psychiatric Rating Scale (BPRS) total and positive symptom scores.²⁷ Other RCTs have shown a non-significant trend toward greater change in total, positive, and negative symptom scores with the clozapine-risperidone combination compared with clozapine monotherapy.^25,28 In terms of cognition, this combination provided no additional benefit.²³ Response, defined as ≥20% reduction in total BPRS or Positive and Negative Syndrome Scale (PANSS) scores, for clozapine plus risperidone range from 13% to 83%, compared with 8% to 29% for clozapine plus placebo.^24,25,27,29

Data from 1 study²⁷ suggest a number needed to treat of 4 to achieve at least a 20% improvement in BPRS scores with clozapine plus risperidone vs clozapine monotherapy. Across these studies, the average risperidone dosage was 4 mg/d, although using the lowest effective dosage is encouraged. A small number of RCTs and articles examining other APP combinations (Table 4)^30-33 have yielded mixed results.

Overall, APP appears to be well-tolerated, although it is associated with an increased risk of adverse effects, including sedation, extrapyramidal symptoms, hyperprolactinemia, sexual dysfunction, cognitive impairment, anticholinergic effects, hyperlipidemia, and diabetes.^23,24,34-36 Surprisingly, 1 literature review³⁶ found no association between APP and increased risk of orthostasis. Increased occurrence of sedation, hyperprolactinemia, and an elevated fasting blood glucose level have been found for clozapine plus risperidone compared with clozapine monotherapy.^24-26,28

Aripiprazole. Adjunctive aripiprazole, a dopamine partial agonist, could reduce elevated prolactin levels caused by other antipsychotics.³² In a study³⁷ of 56 patients taking haloperidol who had hyperprolactinemia, prolactin levels normalized in 88.5% of patients taking adjunctive aripiprazole, 30 mg/d, compared with 3.6% of those with added placebo. Furthermore, results from 2 RCTs^38,39 of patients taking clozapine or olanzapine suggest adjunctive aripiprazole could improve weight and metabolic profile. Therefore, adding aripiprazole to existing antipsychotic regimens is reasonable for patients with drug-induced symptomatic hyperprolactinemia or metabolic effects and who cannot be easily switched to another antipsychotic.

When to initiate
Most treatment guidelines^9-17 recommend clozapine only after monotherapy with at least 2 other antipsychotics fails. It is reasonable to add an antipsychotic to clozapine in patients who have shown a partial response to clozapine after a minimum of 3 months. Non-clozapine APP should be considered when:

• a patient derives no benefit from clozapine
• refuses clozapine
• clozapine is contraindicated
• APP is initiated to mitigate side effects from another antipsychotic.

Antipsychotics could take up to 16 weeks to achieve full efficacy,⁶ therefore, an adequate trial period within the target dosage range is advised for all antipsychotics (Table 5).^13,40

Why initiate
Based on available data, partial response to maximum recommended dosages of antipsychotic monotherapy, including clozapine, or inability to tolerate higher dosages, provides a reason for initiating APP. Non-clozapine APP generally should be considered only in patients who refuse, cannot tolerate, or do not respond to clozapine. Consider using validated rating scales to track treatment outcomes (ideally, a ≥20% symptomatic reduction on the BPRS or PANSS), although there is no formal guidance regarding their use or benefit in APP.

Summing up
APP is a fairly common prescribing practice, even though safety and efficacy data are mixed. The issue of APP has become prevalent enough that regulatory bodies are involved in its monitoring and documentation.⁴¹

Clozapine APP, especially with risperidone, has the most substantial evidence to support it. Although APP generally is well tolerated, the overall dearth of conclusive safety and efficacy data indicates that this practice should be reserved for patients who have not responded adequately to monotherapy, including clozapine. Adjunctive aripiprazole could be considered for addressing symptomatic hyperprolactinemia or other metabolic effects caused by other antipsychotics.

An adequate trial as long as 16 weeks is advised before assessing the efficacy of any antipsychotic regimen. If APP provides inadequate response, or if there is no clear indication for APP, consider switching the patient back to monotherapy.^42-44

Mr. C, age 31, who has a 7-year history of schizophrenia and is currently on perphenazine, 24 mg twice a day, presents for psychiatric admission after experiencing paranoid delusions. Notable symptoms include delusions of reference and persecution, along with affective flattening and intermittent suicidal ideation. Perphenazine is tapered, and he is started on quetiapine, titrated to 600 mg/d.

Past antipsychotic trials include aripiprazole, olanzapine, paliperidone, haloperidol,

and ziprasidone. Because of his refractory symptoms and tolerability issues with other antipsychotics, Mr. C is switched to clozapine, 400 mg/d. His symptoms improve, but he experiences dose-limiting sialorrhea. Risperidone, 1 mg/d, is added to clozapine, which helps his psychosis and improves his functional status. Additionally, Mr. C develops enough insight to recognize his delusions and use skills learned in psychotherapy to cope with them.

Antipsychotic polypharmacy (APP), the concurrent use of ≥2 antipsychotics, is a topic of debate among mental health care providers. Studies indicate the prevalence of APP can reach upwards of 40%, with 1 systematic review citing more recent median APP prevalence in North America as 17%, an increase from a median of 12.7% in the 1980s.¹ Other studies cite more recent figures as around 20%.^2,3

The literature lists several reasons for use of long-term APP, including:

• incomplete cross-titration
• accidental continuation of APP that was intended to be temporary
• monotherapy failure
• mitigation or enhancement of effects of other antipsychotics (Table 1).^1,4

Other factors include direct-to-consumer advertising, external pressures to decrease hospital stays, and low doctor-to-patient ratios.⁵ Although it can take as long as 16 weeks to see clinically significant improvement with an antipsychotic, prescribers might expect results after 4 weeks of treatment.⁶ Therefore, treatments could be labeled ineffective because trials did not last long enough, leading to premature use of polypharmacy. Combinations of a first- and second-generation antipsychotic (SGA) or 2 SGAs are most common.^2,7,8

Treatment guidelines (Table 2)^9-17 suggest APP could be considered after several failures of monotherapy, including clozapine monotherapy, although some guidelines do not address the issue or recommend against APP because of lack of efficacy and safety data. Additionally, APP poses safety concerns (Table 3).^18-22 Recommendations for APP with combinations that do not include clozapine generally are not provided, because high-level evidence to support this strategy is lacking. Data on safety and efficacy of APP are mixed, with much of the literature dominated by case reports and uncontrolled studies.¹⁹

What to initiate
Clozapine. Higher-level evidence is available for clozapine APP. The combination of clozapine and risperidone is one of the most thoroughly studied and, therefore, is a reasonable first choice. Randomized controlled trials (RCTs) examining clozapine plus risperidone^23-29 have yielded mixed results and have not provided conclusive information regarding benefit for positive vs negative symptoms.^24-28

One RCT reported a significant change in Brief Psychiatric Rating Scale (BPRS) total and positive symptom scores.²⁷ Other RCTs have shown a non-significant trend toward greater change in total, positive, and negative symptom scores with the clozapine-risperidone combination compared with clozapine monotherapy.^25,28 In terms of cognition, this combination provided no additional benefit.²³ Response, defined as ≥20% reduction in total BPRS or Positive and Negative Syndrome Scale (PANSS) scores, for clozapine plus risperidone range from 13% to 83%, compared with 8% to 29% for clozapine plus placebo.^24,25,27,29

Data from 1 study²⁷ suggest a number needed to treat of 4 to achieve at least a 20% improvement in BPRS scores with clozapine plus risperidone vs clozapine monotherapy. Across these studies, the average risperidone dosage was 4 mg/d, although using the lowest effective dosage is encouraged. A small number of RCTs and articles examining other APP combinations (Table 4)^30-33 have yielded mixed results.

Overall, APP appears to be well-tolerated, although it is associated with an increased risk of adverse effects, including sedation, extrapyramidal symptoms, hyperprolactinemia, sexual dysfunction, cognitive impairment, anticholinergic effects, hyperlipidemia, and diabetes.^23,24,34-36 Surprisingly, 1 literature review³⁶ found no association between APP and increased risk of orthostasis. Increased occurrence of sedation, hyperprolactinemia, and an elevated fasting blood glucose level have been found for clozapine plus risperidone compared with clozapine monotherapy.^24-26,28

Aripiprazole. Adjunctive aripiprazole, a dopamine partial agonist, could reduce elevated prolactin levels caused by other antipsychotics.³² In a study³⁷ of 56 patients taking haloperidol who had hyperprolactinemia, prolactin levels normalized in 88.5% of patients taking adjunctive aripiprazole, 30 mg/d, compared with 3.6% of those with added placebo. Furthermore, results from 2 RCTs^38,39 of patients taking clozapine or olanzapine suggest adjunctive aripiprazole could improve weight and metabolic profile. Therefore, adding aripiprazole to existing antipsychotic regimens is reasonable for patients with drug-induced symptomatic hyperprolactinemia or metabolic effects and who cannot be easily switched to another antipsychotic.

When to initiate
Most treatment guidelines^9-17 recommend clozapine only after monotherapy with at least 2 other antipsychotics fails. It is reasonable to add an antipsychotic to clozapine in patients who have shown a partial response to clozapine after a minimum of 3 months. Non-clozapine APP should be considered when:

• a patient derives no benefit from clozapine
• refuses clozapine
• clozapine is contraindicated
• APP is initiated to mitigate side effects from another antipsychotic.

Antipsychotics could take up to 16 weeks to achieve full efficacy,⁶ therefore, an adequate trial period within the target dosage range is advised for all antipsychotics (Table 5).^13,40

Why initiate
Based on available data, partial response to maximum recommended dosages of antipsychotic monotherapy, including clozapine, or inability to tolerate higher dosages, provides a reason for initiating APP. Non-clozapine APP generally should be considered only in patients who refuse, cannot tolerate, or do not respond to clozapine. Consider using validated rating scales to track treatment outcomes (ideally, a ≥20% symptomatic reduction on the BPRS or PANSS), although there is no formal guidance regarding their use or benefit in APP.

Summing up
APP is a fairly common prescribing practice, even though safety and efficacy data are mixed. The issue of APP has become prevalent enough that regulatory bodies are involved in its monitoring and documentation.⁴¹

Clozapine APP, especially with risperidone, has the most substantial evidence to support it. Although APP generally is well tolerated, the overall dearth of conclusive safety and efficacy data indicates that this practice should be reserved for patients who have not responded adequately to monotherapy, including clozapine. Adjunctive aripiprazole could be considered for addressing symptomatic hyperprolactinemia or other metabolic effects caused by other antipsychotics.

An adequate trial as long as 16 weeks is advised before assessing the efficacy of any antipsychotic regimen. If APP provides inadequate response, or if there is no clear indication for APP, consider switching the patient back to monotherapy.^42-44

Picking your practice’s legal structure is far less exciting than choosing which couch to furnish your office with, but the impact of your choice will last far longer than any office furniture. With effects on your liability, finances, and time, choosing the right arrangement is one of the most important business decisions you will make.

Choose a business structure
Solo practice? If you are in solo private practice, you should establish sole proprietorship to, at the least, reduce identity theft. Because insurance companies and government agencies will need your taxpayer identification number (TIN) for you to do business (and unless you fancy giving out your Social Security number freely), forming a sole proprietorship will grant you a business-unique TIN that you can give out. Establishing sole proprietorship is easy on the Internal Revenue Service Web site.

It also is advisable for you to open a business bank account just for your practice, for bookkeeping and auditing purposes.

Also, consider incorporating. You don’t have to have employees or partners to incorporate, and there are substantial benefits to doing so that should be considered.

Group practice? For a group practice, a fundamental rule is to not form a general partnership, because it exposes each member of the group to the liability and debts of the others. Instead, consider picking a limited liability structure or incorporating.

Incorporating. Every state recognizes corporations, although many require physicians to form “professional corporations” (PCs). There are 2 main types of corporations: “C” and “S.” A practice might elect to become an S corporation because it requires less paperwork—but it also means fewer tax benefits and profit or losses are passed through to your individual tax return. C corporations are taxed at corporate tax rates, but employees—including you, as owner—are eligible for more benefits, such as pre-tax commuter and parking reimbursement, flexible spending accounts for dependent care and health care, and pre-tax insurance premiums, to name a few.

Limited liability structure. State laws vary on which kind of limited liability structures are allowed but, typically, the options include forming a Limited Liability Company (LLC), Professional Limited Liability Company (PLLC), or Limited Liability Partnership (LLP). In general, they provide similar liability protection as corporations, and their tax treatment is similar to either a “C” or “S” corporation, depending on state law or what tax structure its members elect. However, they may offer less paperwork and compliance requirements than corporations.

To incorporate or not?
The pros. Decide if it’s worth the time and effort to become a PC:

• Being a PC will not reduce your tax rate (that went away years ago) and cannot protect you from professional malpractice (referred to as “piercing the corporate veil”), but it will protect personal assets from risk of seizure if you incur a non-professional liability, such as for a patient slipping on a banana peel in the waiting room, or an employee lawsuit.
• If you operate more than 1 type of business, a PC may be useful to protect one business from the liability of the other. Or, if you are in a group practice comprising solo practitioners—not employees of a clinic—being a PC could shield you from the liability of your group or any of its members.
• If you have full-time employees (whether they are a family member or not), then you are all eligible for group health insurance, which is typically more affordable than if you have to procure your own policy.

The cons. Consider the downsides to being a corporation:

• It takes paperwork to set up a corporation, for which you typically need to engage a lawyer to complete and file.
• Your corporation might be required to pay a minimum state fee (in California, for example, the fee is $800 annually), and additional tax if you don’t “zero out” your profit and loss by the end of the year (ie, completely distribute all profits through payroll costs or business expenses).
• A corporation must keep corporate documents, although there are templates that one can follow, such as for board resolutions or keeping minutes of meetings.
• Your accountant will charge you more annually for any additional tax paperwork.

Crunch the numbers
Choosing to establish sole proprietorship or a “deeper” legal structure must be thought through wisely. Calculate the cost and benefit to your practice, and consider your risk tolerance for liability.

Once you make a decision, go get that couch!

Picking your practice’s legal structure is far less exciting than choosing which couch to furnish your office with, but the impact of your choice will last far longer than any office furniture. With effects on your liability, finances, and time, choosing the right arrangement is one of the most important business decisions you will make.

Choose a business structure
Solo practice? If you are in solo private practice, you should establish sole proprietorship to, at the least, reduce identity theft. Because insurance companies and government agencies will need your taxpayer identification number (TIN) for you to do business (and unless you fancy giving out your Social Security number freely), forming a sole proprietorship will grant you a business-unique TIN that you can give out. Establishing sole proprietorship is easy on the Internal Revenue Service Web site.

It also is advisable for you to open a business bank account just for your practice, for bookkeeping and auditing purposes.

Also, consider incorporating. You don’t have to have employees or partners to incorporate, and there are substantial benefits to doing so that should be considered.

Group practice? For a group practice, a fundamental rule is to not form a general partnership, because it exposes each member of the group to the liability and debts of the others. Instead, consider picking a limited liability structure or incorporating.

Incorporating. Every state recognizes corporations, although many require physicians to form “professional corporations” (PCs). There are 2 main types of corporations: “C” and “S.” A practice might elect to become an S corporation because it requires less paperwork—but it also means fewer tax benefits and profit or losses are passed through to your individual tax return. C corporations are taxed at corporate tax rates, but employees—including you, as owner—are eligible for more benefits, such as pre-tax commuter and parking reimbursement, flexible spending accounts for dependent care and health care, and pre-tax insurance premiums, to name a few.

Limited liability structure. State laws vary on which kind of limited liability structures are allowed but, typically, the options include forming a Limited Liability Company (LLC), Professional Limited Liability Company (PLLC), or Limited Liability Partnership (LLP). In general, they provide similar liability protection as corporations, and their tax treatment is similar to either a “C” or “S” corporation, depending on state law or what tax structure its members elect. However, they may offer less paperwork and compliance requirements than corporations.

To incorporate or not?
The pros. Decide if it’s worth the time and effort to become a PC:

• Being a PC will not reduce your tax rate (that went away years ago) and cannot protect you from professional malpractice (referred to as “piercing the corporate veil”), but it will protect personal assets from risk of seizure if you incur a non-professional liability, such as for a patient slipping on a banana peel in the waiting room, or an employee lawsuit.
• If you operate more than 1 type of business, a PC may be useful to protect one business from the liability of the other. Or, if you are in a group practice comprising solo practitioners—not employees of a clinic—being a PC could shield you from the liability of your group or any of its members.
• If you have full-time employees (whether they are a family member or not), then you are all eligible for group health insurance, which is typically more affordable than if you have to procure your own policy.

The cons. Consider the downsides to being a corporation:

• It takes paperwork to set up a corporation, for which you typically need to engage a lawyer to complete and file.
• Your corporation might be required to pay a minimum state fee (in California, for example, the fee is $800 annually), and additional tax if you don’t “zero out” your profit and loss by the end of the year (ie, completely distribute all profits through payroll costs or business expenses).
• A corporation must keep corporate documents, although there are templates that one can follow, such as for board resolutions or keeping minutes of meetings.
• Your accountant will charge you more annually for any additional tax paperwork.

Crunch the numbers
Choosing to establish sole proprietorship or a “deeper” legal structure must be thought through wisely. Calculate the cost and benefit to your practice, and consider your risk tolerance for liability.

Once you make a decision, go get that couch!

Picking your practice’s legal structure is far less exciting than choosing which couch to furnish your office with, but the impact of your choice will last far longer than any office furniture. With effects on your liability, finances, and time, choosing the right arrangement is one of the most important business decisions you will make.

Choose a business structure
Solo practice? If you are in solo private practice, you should establish sole proprietorship to, at the least, reduce identity theft. Because insurance companies and government agencies will need your taxpayer identification number (TIN) for you to do business (and unless you fancy giving out your Social Security number freely), forming a sole proprietorship will grant you a business-unique TIN that you can give out. Establishing sole proprietorship is easy on the Internal Revenue Service Web site.

It also is advisable for you to open a business bank account just for your practice, for bookkeeping and auditing purposes.

Also, consider incorporating. You don’t have to have employees or partners to incorporate, and there are substantial benefits to doing so that should be considered.

Group practice? For a group practice, a fundamental rule is to not form a general partnership, because it exposes each member of the group to the liability and debts of the others. Instead, consider picking a limited liability structure or incorporating.

Incorporating. Every state recognizes corporations, although many require physicians to form “professional corporations” (PCs). There are 2 main types of corporations: “C” and “S.” A practice might elect to become an S corporation because it requires less paperwork—but it also means fewer tax benefits and profit or losses are passed through to your individual tax return. C corporations are taxed at corporate tax rates, but employees—including you, as owner—are eligible for more benefits, such as pre-tax commuter and parking reimbursement, flexible spending accounts for dependent care and health care, and pre-tax insurance premiums, to name a few.

Limited liability structure. State laws vary on which kind of limited liability structures are allowed but, typically, the options include forming a Limited Liability Company (LLC), Professional Limited Liability Company (PLLC), or Limited Liability Partnership (LLP). In general, they provide similar liability protection as corporations, and their tax treatment is similar to either a “C” or “S” corporation, depending on state law or what tax structure its members elect. However, they may offer less paperwork and compliance requirements than corporations.

To incorporate or not?
The pros. Decide if it’s worth the time and effort to become a PC:

• Being a PC will not reduce your tax rate (that went away years ago) and cannot protect you from professional malpractice (referred to as “piercing the corporate veil”), but it will protect personal assets from risk of seizure if you incur a non-professional liability, such as for a patient slipping on a banana peel in the waiting room, or an employee lawsuit.
• If you operate more than 1 type of business, a PC may be useful to protect one business from the liability of the other. Or, if you are in a group practice comprising solo practitioners—not employees of a clinic—being a PC could shield you from the liability of your group or any of its members.
• If you have full-time employees (whether they are a family member or not), then you are all eligible for group health insurance, which is typically more affordable than if you have to procure your own policy.

The cons. Consider the downsides to being a corporation:

• It takes paperwork to set up a corporation, for which you typically need to engage a lawyer to complete and file.
• Your corporation might be required to pay a minimum state fee (in California, for example, the fee is $800 annually), and additional tax if you don’t “zero out” your profit and loss by the end of the year (ie, completely distribute all profits through payroll costs or business expenses).
• A corporation must keep corporate documents, although there are templates that one can follow, such as for board resolutions or keeping minutes of meetings.
• Your accountant will charge you more annually for any additional tax paperwork.

Crunch the numbers
Choosing to establish sole proprietorship or a “deeper” legal structure must be thought through wisely. Calculate the cost and benefit to your practice, and consider your risk tolerance for liability.

Once you make a decision, go get that couch!

Cognitive impairment seen in severely mentally ill people is well documented, and has been shown to affect as many as 98% of patients with schizophrenia.¹ At this time, there are no FDA-approved medications for treating this cognitive impairment.²

Rusk State Hospital in Rusk, Texas, decided to put greater emphasis on improving cognitive impairment because of an increase in patients with a forensic commitment, either because of (1) not guilty by reason of insanity and (2) restoration of competency to stand trial, which typically require longer lengths of stay. Some of these patients experienced psychotic breaks while earning a college education, and one patient was a member of MENSA (an organization for people with a high IQ) before he became ill. Established programs were not adequate to address cognitive impairment.

How we developed and launched our program
Cognitive remediation is a new focus of psychiatry and is in its infancy; programs include cognitive remediation training (CRT) and cognitive enhancement therapy (CET) (Box^3-9). CRT focuses more on practice and rote learning and CET is more inclusive, including aspects such as social skills training. These terms are interchangeable for programs designed to improve cognition. Because there is no standardized model, programs differ in content, length, use of computers vs manuals, social skills training, mentoring, and other modalities.

We could not find a program that could be adapted to our setting because of lack of funding and insufficient patient access to computers. Therefore, we developed our own program to address cognitive impairment in a population of individuals with severe mental illness in a state hospital setting.¹⁰ Our CRT program was designed for inpatient psychiatric patients, both on civil and forensic commitments.

The program includes >500 exercises and addresses several cognitive domains. Adding a facilitator or teacher in a group setting introduces an additional dimension to learning. Criteria to participate in the program included:

• behavior stable enough to participate
• ability to read and write English
• no traumatic brain injury that caused cognitive impairment
• the patient had to want to participate in the training program.

We tested each participant at the beginning and end of the 12-week training program, which consisted of 2 one-hour classes a week, with a target group size of 6 to 10 participants. As a rating tool, we used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), which has been shown to be an efficient approach to screening for cognitive impairment across several domains.¹¹

We offered 2 levels of training: basic and advanced. Referral was based on the patient’s level of education and current cognitive function. Materials for the advanced group were at a high school or college level; the basic group used materials that were elementary school or mid-high school in scope. Assignment to the basic or advanced training was based on the recovery team’s or psychologist’s recommendation. The training was ongoing, meaning that a participant could begin at any time and continue until he (she) had completed the 12-week training program.

The weekly sessions in the CRT program were based on 12 categories (Table).¹⁰

1. Picture Puzzles: Part 1, Odd Man Out. Participants receive a series of 4 pictures and are asked to select the 1 that does not share a common link with the other 3 items. Targeted skills include pattern recognition, visual learning, reasoning, and creativity (looking for non-obvious answers). This plays a role in global cognition and everyday activities that are sight-related.

2. Word Problems. Participants receive math exercises with significant background information presented as text. Targeted skills include calculation, concentration, and reasoning. This helps with making change, figuring out the tip on a bill, balancing a checkbook, and assisting children with homework.

3. Picture Puzzles: Part 2, Matching.Participants view an illustration followed by a series of 4 other pictures, where ≥1 of which will have a close relationship to the example. The participant selects the item with the strongest link. Targeted skills include determining patterns, concentration, visual perception, and reasoning.

4. Verbal Challenge. Participants are provided a variety of word-based problems that involve word usage, definitions, games, and puzzles. Targeted skills include vocabulary, reading comprehension, reasoning, concentration, and global cognition.

5. Picture Puzzles: Part 3, Series Completion. Participants receive a sequence of 3 pictures followed by 4 possible solutions. The participant selects the item that completes the series or shares a common bond. Targeted skills include visual perception, picking up on patterns, creativity, reasoning, and concentration.

6. Mental Arithmetic: Part 1, Coin Counting. Participants are presented math problems related to money that can be solved by simple mental or quick paper calculation. Targeted skills include basic math, speed, concentration, and counting money. This helps with making change and balancing a checkbook.

7. Picture Puzzles: Part 4, Ratio. Participants receive presented analogy questions where the participant has to determine the ratio or proportional relation of the items. Targeted skills include memory, creativity, and decision-making.

8. Mental Arithmetic: Part 2, Potpourri. Participants receive a hodgepodge of math problems, including number sequences and word problems. Targeted skills include reasoning and computation.

9. Visual/spatial. Participants are presented exercises that require them to think in 3 dimensions and see “hidden” areas behind folds or on the other sides of figures. Targeted skills include spatial perception, reasoning, and decision-making.

10. Reasoning. Participants receive problems that involve taking in information, processing the data, analyzing the options based on previous experiences, and coming up with a decision that is factual and rational. Targeted skills include reasoning and decision-making.

11. Memory Exercise, Listening. Parti­ci­pants are provided a reading selection. After the reading, there is 20-minute waiting period during which the participant is engaged in other exercises before returning to answer questions about the reading. Targeted skills include listening, retention, and memory.

12. Speed Training. Participants receive exercises that provide practice in gathering and processing information and making decisions based on the given information. Targeted skills include decision-making, speed, and concentration.

Preliminary results, optimism about good outcomes
In the past 12 months, 28 participants have completed the CRT program: 11 in the basic training class and 17 in the advanced class. Of those, 7 in the basic program and 11 in the advanced program showed significant improvement as measured by the pre- and post-training RBANS; 64% of the participants improved. The average pre-test score in the basic group was 63 and post-test score was 72 (t₁₀ = 3.148, P < .05). The average advanced pre-test score in the advanced class was 75 and post-test score was 80 (t₁₆ = 2.476, P < .05) (Figure 1).

Because this program was developed as a treatment intervention for psychiatric inpatients, not a research study, we did not establish a control group.

In addition to the overall increase in cognitive functioning, individual successes have been noted. One participant who experienced a psychotic break while pursuing a college degree in literature scored 73 on his initial RBANS, indicating moderate impairment. After completing the 12-week program, his RBANS score increased to 95 (Figure 2). One year after completing the CRT program without additional cognitive training, the participant achieved an RBANS score of 104. Since then, the patient has been observed reading the classics in Latin and Greek, as he did before his psychotic break, and has been noted to be making more eye contact and engaging in conversations.

Success also has been noted for participants who did not see an increase in their RBANS scores. One participant historically had shown little interest in any programming or classes, but attended every CRT class, participated, and asked for additional worksheets to take back to the unit. Based on this feedback, each session now includes a worksheet that participants can take back with them.

Further findings of success
Cognitive impairment can be a significant disability in patients with severe mental illness. Longer lengths of stay present an opportunity to provide a CRT program over 12 weeks. However, some increase in cognitive functioning, as measured by the RBANS, was seen with participants who would not or could not complete all 24 classes. In addition to increased cognitive functioning, clinicians have noted improvements in patients’ participation in treatment and self-esteem.

The program engaged patients who previously were uninvolved in activities, and provided a sense of purpose and hope for them. One participant stated that he felt better about himself and had a more optimistic outlook for the future.

This program offers the possibility for participants to clear the mental fog caused by their illness or medication. The exercises stimulate cognitive activity when the goal is not to get the correct answer, but to think about and talk about possible solutions.

CRT, we have found, can greatly increase the quality of life of people with severe mental illness.

Cognitive impairment seen in severely mentally ill people is well documented, and has been shown to affect as many as 98% of patients with schizophrenia.¹ At this time, there are no FDA-approved medications for treating this cognitive impairment.²

Rusk State Hospital in Rusk, Texas, decided to put greater emphasis on improving cognitive impairment because of an increase in patients with a forensic commitment, either because of (1) not guilty by reason of insanity and (2) restoration of competency to stand trial, which typically require longer lengths of stay. Some of these patients experienced psychotic breaks while earning a college education, and one patient was a member of MENSA (an organization for people with a high IQ) before he became ill. Established programs were not adequate to address cognitive impairment.

How we developed and launched our program
Cognitive remediation is a new focus of psychiatry and is in its infancy; programs include cognitive remediation training (CRT) and cognitive enhancement therapy (CET) (Box^3-9). CRT focuses more on practice and rote learning and CET is more inclusive, including aspects such as social skills training. These terms are interchangeable for programs designed to improve cognition. Because there is no standardized model, programs differ in content, length, use of computers vs manuals, social skills training, mentoring, and other modalities.

We could not find a program that could be adapted to our setting because of lack of funding and insufficient patient access to computers. Therefore, we developed our own program to address cognitive impairment in a population of individuals with severe mental illness in a state hospital setting.¹⁰ Our CRT program was designed for inpatient psychiatric patients, both on civil and forensic commitments.

The program includes >500 exercises and addresses several cognitive domains. Adding a facilitator or teacher in a group setting introduces an additional dimension to learning. Criteria to participate in the program included:

• behavior stable enough to participate
• ability to read and write English
• no traumatic brain injury that caused cognitive impairment
• the patient had to want to participate in the training program.

We tested each participant at the beginning and end of the 12-week training program, which consisted of 2 one-hour classes a week, with a target group size of 6 to 10 participants. As a rating tool, we used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), which has been shown to be an efficient approach to screening for cognitive impairment across several domains.¹¹

We offered 2 levels of training: basic and advanced. Referral was based on the patient’s level of education and current cognitive function. Materials for the advanced group were at a high school or college level; the basic group used materials that were elementary school or mid-high school in scope. Assignment to the basic or advanced training was based on the recovery team’s or psychologist’s recommendation. The training was ongoing, meaning that a participant could begin at any time and continue until he (she) had completed the 12-week training program.

The weekly sessions in the CRT program were based on 12 categories (Table).¹⁰

1. Picture Puzzles: Part 1, Odd Man Out. Participants receive a series of 4 pictures and are asked to select the 1 that does not share a common link with the other 3 items. Targeted skills include pattern recognition, visual learning, reasoning, and creativity (looking for non-obvious answers). This plays a role in global cognition and everyday activities that are sight-related.

2. Word Problems. Participants receive math exercises with significant background information presented as text. Targeted skills include calculation, concentration, and reasoning. This helps with making change, figuring out the tip on a bill, balancing a checkbook, and assisting children with homework.

3. Picture Puzzles: Part 2, Matching.Participants view an illustration followed by a series of 4 other pictures, where ≥1 of which will have a close relationship to the example. The participant selects the item with the strongest link. Targeted skills include determining patterns, concentration, visual perception, and reasoning.

4. Verbal Challenge. Participants are provided a variety of word-based problems that involve word usage, definitions, games, and puzzles. Targeted skills include vocabulary, reading comprehension, reasoning, concentration, and global cognition.

5. Picture Puzzles: Part 3, Series Completion. Participants receive a sequence of 3 pictures followed by 4 possible solutions. The participant selects the item that completes the series or shares a common bond. Targeted skills include visual perception, picking up on patterns, creativity, reasoning, and concentration.

6. Mental Arithmetic: Part 1, Coin Counting. Participants are presented math problems related to money that can be solved by simple mental or quick paper calculation. Targeted skills include basic math, speed, concentration, and counting money. This helps with making change and balancing a checkbook.

7. Picture Puzzles: Part 4, Ratio. Participants receive presented analogy questions where the participant has to determine the ratio or proportional relation of the items. Targeted skills include memory, creativity, and decision-making.

8. Mental Arithmetic: Part 2, Potpourri. Participants receive a hodgepodge of math problems, including number sequences and word problems. Targeted skills include reasoning and computation.

9. Visual/spatial. Participants are presented exercises that require them to think in 3 dimensions and see “hidden” areas behind folds or on the other sides of figures. Targeted skills include spatial perception, reasoning, and decision-making.

10. Reasoning. Participants receive problems that involve taking in information, processing the data, analyzing the options based on previous experiences, and coming up with a decision that is factual and rational. Targeted skills include reasoning and decision-making.

11. Memory Exercise, Listening. Parti­ci­pants are provided a reading selection. After the reading, there is 20-minute waiting period during which the participant is engaged in other exercises before returning to answer questions about the reading. Targeted skills include listening, retention, and memory.

12. Speed Training. Participants receive exercises that provide practice in gathering and processing information and making decisions based on the given information. Targeted skills include decision-making, speed, and concentration.

Preliminary results, optimism about good outcomes
In the past 12 months, 28 participants have completed the CRT program: 11 in the basic training class and 17 in the advanced class. Of those, 7 in the basic program and 11 in the advanced program showed significant improvement as measured by the pre- and post-training RBANS; 64% of the participants improved. The average pre-test score in the basic group was 63 and post-test score was 72 (t₁₀ = 3.148, P < .05). The average advanced pre-test score in the advanced class was 75 and post-test score was 80 (t₁₆ = 2.476, P < .05) (Figure 1).

Because this program was developed as a treatment intervention for psychiatric inpatients, not a research study, we did not establish a control group.

In addition to the overall increase in cognitive functioning, individual successes have been noted. One participant who experienced a psychotic break while pursuing a college degree in literature scored 73 on his initial RBANS, indicating moderate impairment. After completing the 12-week program, his RBANS score increased to 95 (Figure 2). One year after completing the CRT program without additional cognitive training, the participant achieved an RBANS score of 104. Since then, the patient has been observed reading the classics in Latin and Greek, as he did before his psychotic break, and has been noted to be making more eye contact and engaging in conversations.

Success also has been noted for participants who did not see an increase in their RBANS scores. One participant historically had shown little interest in any programming or classes, but attended every CRT class, participated, and asked for additional worksheets to take back to the unit. Based on this feedback, each session now includes a worksheet that participants can take back with them.

Further findings of success
Cognitive impairment can be a significant disability in patients with severe mental illness. Longer lengths of stay present an opportunity to provide a CRT program over 12 weeks. However, some increase in cognitive functioning, as measured by the RBANS, was seen with participants who would not or could not complete all 24 classes. In addition to increased cognitive functioning, clinicians have noted improvements in patients’ participation in treatment and self-esteem.

The program engaged patients who previously were uninvolved in activities, and provided a sense of purpose and hope for them. One participant stated that he felt better about himself and had a more optimistic outlook for the future.

This program offers the possibility for participants to clear the mental fog caused by their illness or medication. The exercises stimulate cognitive activity when the goal is not to get the correct answer, but to think about and talk about possible solutions.

CRT, we have found, can greatly increase the quality of life of people with severe mental illness.

Cognitive impairment seen in severely mentally ill people is well documented, and has been shown to affect as many as 98% of patients with schizophrenia.¹ At this time, there are no FDA-approved medications for treating this cognitive impairment.²

Rusk State Hospital in Rusk, Texas, decided to put greater emphasis on improving cognitive impairment because of an increase in patients with a forensic commitment, either because of (1) not guilty by reason of insanity and (2) restoration of competency to stand trial, which typically require longer lengths of stay. Some of these patients experienced psychotic breaks while earning a college education, and one patient was a member of MENSA (an organization for people with a high IQ) before he became ill. Established programs were not adequate to address cognitive impairment.

How we developed and launched our program
Cognitive remediation is a new focus of psychiatry and is in its infancy; programs include cognitive remediation training (CRT) and cognitive enhancement therapy (CET) (Box^3-9). CRT focuses more on practice and rote learning and CET is more inclusive, including aspects such as social skills training. These terms are interchangeable for programs designed to improve cognition. Because there is no standardized model, programs differ in content, length, use of computers vs manuals, social skills training, mentoring, and other modalities.

We could not find a program that could be adapted to our setting because of lack of funding and insufficient patient access to computers. Therefore, we developed our own program to address cognitive impairment in a population of individuals with severe mental illness in a state hospital setting.¹⁰ Our CRT program was designed for inpatient psychiatric patients, both on civil and forensic commitments.

The program includes >500 exercises and addresses several cognitive domains. Adding a facilitator or teacher in a group setting introduces an additional dimension to learning. Criteria to participate in the program included:

• behavior stable enough to participate
• ability to read and write English
• no traumatic brain injury that caused cognitive impairment
• the patient had to want to participate in the training program.

We tested each participant at the beginning and end of the 12-week training program, which consisted of 2 one-hour classes a week, with a target group size of 6 to 10 participants. As a rating tool, we used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), which has been shown to be an efficient approach to screening for cognitive impairment across several domains.¹¹

We offered 2 levels of training: basic and advanced. Referral was based on the patient’s level of education and current cognitive function. Materials for the advanced group were at a high school or college level; the basic group used materials that were elementary school or mid-high school in scope. Assignment to the basic or advanced training was based on the recovery team’s or psychologist’s recommendation. The training was ongoing, meaning that a participant could begin at any time and continue until he (she) had completed the 12-week training program.

The weekly sessions in the CRT program were based on 12 categories (Table).¹⁰

1. Picture Puzzles: Part 1, Odd Man Out. Participants receive a series of 4 pictures and are asked to select the 1 that does not share a common link with the other 3 items. Targeted skills include pattern recognition, visual learning, reasoning, and creativity (looking for non-obvious answers). This plays a role in global cognition and everyday activities that are sight-related.

2. Word Problems. Participants receive math exercises with significant background information presented as text. Targeted skills include calculation, concentration, and reasoning. This helps with making change, figuring out the tip on a bill, balancing a checkbook, and assisting children with homework.

3. Picture Puzzles: Part 2, Matching.Participants view an illustration followed by a series of 4 other pictures, where ≥1 of which will have a close relationship to the example. The participant selects the item with the strongest link. Targeted skills include determining patterns, concentration, visual perception, and reasoning.

4. Verbal Challenge. Participants are provided a variety of word-based problems that involve word usage, definitions, games, and puzzles. Targeted skills include vocabulary, reading comprehension, reasoning, concentration, and global cognition.

5. Picture Puzzles: Part 3, Series Completion. Participants receive a sequence of 3 pictures followed by 4 possible solutions. The participant selects the item that completes the series or shares a common bond. Targeted skills include visual perception, picking up on patterns, creativity, reasoning, and concentration.

6. Mental Arithmetic: Part 1, Coin Counting. Participants are presented math problems related to money that can be solved by simple mental or quick paper calculation. Targeted skills include basic math, speed, concentration, and counting money. This helps with making change and balancing a checkbook.

7. Picture Puzzles: Part 4, Ratio. Participants receive presented analogy questions where the participant has to determine the ratio or proportional relation of the items. Targeted skills include memory, creativity, and decision-making.

8. Mental Arithmetic: Part 2, Potpourri. Participants receive a hodgepodge of math problems, including number sequences and word problems. Targeted skills include reasoning and computation.

9. Visual/spatial. Participants are presented exercises that require them to think in 3 dimensions and see “hidden” areas behind folds or on the other sides of figures. Targeted skills include spatial perception, reasoning, and decision-making.

10. Reasoning. Participants receive problems that involve taking in information, processing the data, analyzing the options based on previous experiences, and coming up with a decision that is factual and rational. Targeted skills include reasoning and decision-making.

11. Memory Exercise, Listening. Parti­ci­pants are provided a reading selection. After the reading, there is 20-minute waiting period during which the participant is engaged in other exercises before returning to answer questions about the reading. Targeted skills include listening, retention, and memory.

12. Speed Training. Participants receive exercises that provide practice in gathering and processing information and making decisions based on the given information. Targeted skills include decision-making, speed, and concentration.

Preliminary results, optimism about good outcomes
In the past 12 months, 28 participants have completed the CRT program: 11 in the basic training class and 17 in the advanced class. Of those, 7 in the basic program and 11 in the advanced program showed significant improvement as measured by the pre- and post-training RBANS; 64% of the participants improved. The average pre-test score in the basic group was 63 and post-test score was 72 (t₁₀ = 3.148, P < .05). The average advanced pre-test score in the advanced class was 75 and post-test score was 80 (t₁₆ = 2.476, P < .05) (Figure 1).

Because this program was developed as a treatment intervention for psychiatric inpatients, not a research study, we did not establish a control group.

In addition to the overall increase in cognitive functioning, individual successes have been noted. One participant who experienced a psychotic break while pursuing a college degree in literature scored 73 on his initial RBANS, indicating moderate impairment. After completing the 12-week program, his RBANS score increased to 95 (Figure 2). One year after completing the CRT program without additional cognitive training, the participant achieved an RBANS score of 104. Since then, the patient has been observed reading the classics in Latin and Greek, as he did before his psychotic break, and has been noted to be making more eye contact and engaging in conversations.

Success also has been noted for participants who did not see an increase in their RBANS scores. One participant historically had shown little interest in any programming or classes, but attended every CRT class, participated, and asked for additional worksheets to take back to the unit. Based on this feedback, each session now includes a worksheet that participants can take back with them.

Further findings of success
Cognitive impairment can be a significant disability in patients with severe mental illness. Longer lengths of stay present an opportunity to provide a CRT program over 12 weeks. However, some increase in cognitive functioning, as measured by the RBANS, was seen with participants who would not or could not complete all 24 classes. In addition to increased cognitive functioning, clinicians have noted improvements in patients’ participation in treatment and self-esteem.

The program engaged patients who previously were uninvolved in activities, and provided a sense of purpose and hope for them. One participant stated that he felt better about himself and had a more optimistic outlook for the future.

This program offers the possibility for participants to clear the mental fog caused by their illness or medication. The exercises stimulate cognitive activity when the goal is not to get the correct answer, but to think about and talk about possible solutions.

CRT, we have found, can greatly increase the quality of life of people with severe mental illness.

What has been the history of the development of laboratory tests in the field of psychiatry?

During my almost-40-year academic medical career, I have been interested in the development and incorporation of laboratory tests into psychiatry.¹ This interest initially focused on therapeutic drug monitoring (TDM) and the genetics of drug responsiveness, with an emphasis on drug metabolism. In addition to TDM—which I have long believed is vastly underutilized in psychiatry—there have been many failed attempts to develop diagnostic tests, including tests to distinguish between what were postulated to be serotonergic and noradrenergic forms of major depression in the 1970s^2,3 and the dexamethasone suppression test for melancholia in the 1980s.⁴ Recently, a 51-analyte immunoassay test was marketed by Rules-Based Medicine, Inc. (RBM), as an aid in the diagnosis of schizophrenia, but the test was found to suffer a high false-positive rate and was withdrawn from the market.⁵ Given this track record, caution is warranted when examining claims for new tests.

What types of tests are being developed?
Most tests in development are pharmacogenomic (PG)-based or immunoassay (IA)-based.

PG tests examine single nucleotide polymorphisms (SNP) in genes that code for pharmacokinetic mechanisms, primarily cytochrome P450 (CYP) enzymes responsible for drug metabolism and P-glycoprotein, responsible for drug transportation. The next most common type of test examines pharmacodynamic mechanisms, such as SNPs of specific receptor genes, including serotonin (or 5-hydroxytryptophan [5-HT] transporter [SET or 5-HTT]) or the 5-HT2A receptor.

The fact that CYP enzymes lead the list is not surprising: These enzymes and their role in the metabolism of specific drugs have been extensively studied since the late 1980s. Considerable data has been accumulated regarding variants of CYP enzymes, which convey clinically meaningful differences among individuals in terms of their ability to metabolize drug via these pathways. Individuals are commonly divided into 4 phenotypic categories: ultra-rapid, extensive (or normal), intermediate, and poor metabolizers. Based on these phenotypes, clinical consequences can be quantitated in terms of changes in drug concentration, concentration-dependent beneficial or adverse effects, and associated/recommended changes in dosing.

Research into the role of pharmacodynamic variants, however, is still in infancy and more difficult to measure in terms of assessing endpoints, with related limitations in clinical utility.

IA assays generally measure a variety of proteins, particularly those reflecting inflammatory processes (eg, various cytokines, such as interleukin-6).⁶ As with pharmacodynamic measures, research into the role of inflammatory biomarkers is in early stages. The clinical utility of associated tests is, therefore, less certain; witness the recent study⁵ I noted that revealed a high false-positive rate for the RBM schizophrenia panel in healthy controls. Nevertheless, considerable research is being conducted in all of these areas so that new developments might lend themselves to greater clinical utility.

(Note that PG biomarkers are trait measures, whereas IA biomarkers are state measures, so that complementary use of both types of tests might prove useful in diagnosis and clinical management. Although such integrative use of these 2 different types of tests generally is not done today.)

What does it take to market these tests?
At a minimum, offering these tests for sale requires that the laboratory be certified by the Centers for Medicare & Medicaid Services, according to the Clinical Laboratory Improvement Amendments (CLIA) standards (www.fda.gov/medicaldevices/deviceregulationandguidance/ivdregulatoryassistance/ucm124105.htm). CLIA-certified laboratories are required to demonstrate the analytical validity of tests that they offer—ie, the accuracy and reliability of the test in measuring a parameter of interest—but not the clinical validity or utility of those tests. The fact that a test in fact measures what it claims to be measuring in and of itself does not mean it has clinical validity or utility (see the discussion below).

Must the FDA approve laboratory tests?
No, but that situation might be changing.

Currently, only tests used in a setting considered high risk—eg, a test intended to detect or diagnose a malignancy or guide its treatment—requires formal FDA approval. The approval of such a test requires submission to the FDA of clinical data supporting its clinical validity and utility, in addition to evidence of analytic validity.

Even in such cases, the degree and quality of the clinical data required are generally not as high as would be required for approval of a drug. That distinction is understandable, given the type and quantity of data necessary for drug approval and the many years and billions of dollars it takes to accumulate such data. For most laboratory tests, providing the same level of data required to have a drug approved would be neither necessary nor feasible given the business model underlying most laboratories providing laboratory tests.

What do ‘clinical validity’ and ‘clinical utility’ mean?
These are higher evidence thresholds than is needed for analytic validity, although the latter is a necessary first step on the path to achieving these higher thresholds.

Clinical validity is the ability of a test to detect:

• a clinically meaningful measure, such as clinical response
• an adverse effect
• a biologically meaningful measure (eg, a drug level or a change in the electrocardiographic pattern).

Above the threshold of clinical validity is clinical utility, which is proof that the test can reliably be used to guide clinical management and thus meaningfully improve outcomes, such as guiding drug or dosage selection.

Is the use of PG testing recommended? If so, in what instances?
Specific types of PG testing is recommended by the FDA recommended. The FDA has been incorporating PG information into the labels of specific medications for several years; the agency has a Web site (www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm) that continuously updates this information. The involved drugs are in all therapeutic classes—from oncology to psychiatry.

More than 30 psychotropic drugs have PG information in their label; some of those drugs’ labels contain specific recommendations, such as obtaining PG information before selecting or starting a drug in a specific patient. An example is carbamazepine, for which the recommendation is to obtain HLA testing before starting the drug in patients of Han Chinese ancestry, because members of this large ethnic group are at greater risk of serious dermatologic adverse effects, including Stevens-Johnson syndrome.

In other instances, the recommendation is to do the testing before increasing beyond a specific dose. Examples of psychiatric drugs whose labels contain such PG information include pimozide and iloperidone as well as citalopram. In the FDA-approved label, guidance is provided that these drugs can be started without testing if prescribed at a reduced recommended starting dosage range, rather than the full starting dosage range. The guidance on these drugs further recommends testing for genetic CYP2D6 poor metabolizer (PM) status before dosing above that initial recommended, limited, starting dosage range.

The rationale for this guidance is to reduce the risk that (1) patients in question will achieve an excessively high plasma drug level that can cause significant prolongation of intracardiac conduction (eg, QTc prolongation) and thus (2) develop the potentially fatal arrhythmia torsades de pointes. Guidance is based on thorough QTc studies that were performed on each drug,^7,8 which makes them examples of instances in which the test has clinical validity and utility as well as analytical validity.

To find PG labeling in the package insert for these drugs, visit: www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

What about data for other tests that are marketed and promoted by developers?
Sometimes, there are—literally—no data on available tests beyond the analytical validity of the test; other times, the amount and quality of clinical data are quite variable, ranging from results of ≥1 small retrospective studies without controls to results of prospective, randomized, controlled studies. Even among the latter, the developer may conduct and analyze their studies without oversight by an independent agency, such as the FDA.

This situation (1) raises concern that study results are not independent of the developer’s business interests and, as one might expect, (2) leads to controversy about whether the data are compelling—or not.^9-12

What is a critical difference between PG test results and results of most laboratory tests?
PG tests are, as noted, trait rather than state characteristics. That means that the results do not change except for a phenomenon known as phenocoversion, discussed below. (Of course, advances in gene therapy might make it possible someday to change a person’s genetic makeup and for mitochondrial genes that is already possible.) 

For this reason, PG test results should not get buried in the medical record, as might happen with, say, a patient’s serum potassium level at a given point in time. Instead, PG test results need to be carried forward continuously. Results also should be given to the patient as part of his (her) personal health record and to all other health care providers that the patient is seeing or will see in the future. Each health care provider who obtains PG test results should consider sending them to all current clinicians providing care for the patient at the same time as they are.

Is your functional status at a given moment the same as your genetic status?
No. There is a phenomenon known as phenoconversion in which a person’s current functional status may be different from what would be expected based on their genetic status.

CYP2D6 functional status is susceptible to phenoconversion as follows: Administering fluoxetine and paroxetine, for example, at 20 or 40 mg/d converts 66% and 95%, respectively, of patients who are CYP2D6 extensive (ie, normal) metabolizers into phenocopies of people who, genetically, lack the ability to metabolize drugs via CYP2D6 (ie, genotypic CYP2D6 PM). Based on a recent study of 900 participants in routine clinical care who were taking an antidepressant, 4% of the general U.S. population are genetically CYP2D6 PM; an additional 24% are phenotypically CYP2D6 PM because of concomitant administration of a CYP2D6 substantial inhibitor, such as bupropion, fluoxetine, paroxetine, or terbenafine.¹³

That is the reason a provider needs to know what drugs a patient is taking concomitantly—to consider the possibility of phenoconversion and, when necessary, to dose accordingly.

What does the future hold?
Development of tests for use in psychiatric practice is likely to grow substantially, for at least 2 reasons:

• There is a huge unmet need for clinically meaningful tests to aid in the provision of optimal patient care and, therefore, a tremendous business opportunity
• Knowledge in the biological basis of psychiatric disorders is growing exponentially; with that knowledge comes the ability to develop new tests.

A recent example comes from a research group that devised a test that could predict suicidality.¹⁴ Time will tell whether this test or a derivative of it enters practice. Nevertheless, it is a harbinger of the likely dramatic changes in the landscape of clinical medicine particularly as it applies to psychiatry.

Given these developments, the syndromic diagnoses in DSM-5 will in the future likely be replaced by a new diagnostic schema that breaks down existing heterogenous syndromic diagnoses into pathophysiologically and etiologically meaningful entities using insights gained from genetic and biomarker data as well as functional brain imaging. Theoretically, those insights will lead to new modalities of treatment, including somatic treatments that target novel mechanisms of action, coupled to more effective psychosocial therapies—with both therapies guided by diagnostic tests to monitor response to specific treatment interventions.

During this transition from the past to the future, answers to the questions I’ve posed here about laboratory testing in psychiatry will, I hope, help the practitioner understand, evaluate, and incorporate these changes readily into practice.

What has been the history of the development of laboratory tests in the field of psychiatry?

During my almost-40-year academic medical career, I have been interested in the development and incorporation of laboratory tests into psychiatry.¹ This interest initially focused on therapeutic drug monitoring (TDM) and the genetics of drug responsiveness, with an emphasis on drug metabolism. In addition to TDM—which I have long believed is vastly underutilized in psychiatry—there have been many failed attempts to develop diagnostic tests, including tests to distinguish between what were postulated to be serotonergic and noradrenergic forms of major depression in the 1970s^2,3 and the dexamethasone suppression test for melancholia in the 1980s.⁴ Recently, a 51-analyte immunoassay test was marketed by Rules-Based Medicine, Inc. (RBM), as an aid in the diagnosis of schizophrenia, but the test was found to suffer a high false-positive rate and was withdrawn from the market.⁵ Given this track record, caution is warranted when examining claims for new tests.

What types of tests are being developed?
Most tests in development are pharmacogenomic (PG)-based or immunoassay (IA)-based.

PG tests examine single nucleotide polymorphisms (SNP) in genes that code for pharmacokinetic mechanisms, primarily cytochrome P450 (CYP) enzymes responsible for drug metabolism and P-glycoprotein, responsible for drug transportation. The next most common type of test examines pharmacodynamic mechanisms, such as SNPs of specific receptor genes, including serotonin (or 5-hydroxytryptophan [5-HT] transporter [SET or 5-HTT]) or the 5-HT2A receptor.

The fact that CYP enzymes lead the list is not surprising: These enzymes and their role in the metabolism of specific drugs have been extensively studied since the late 1980s. Considerable data has been accumulated regarding variants of CYP enzymes, which convey clinically meaningful differences among individuals in terms of their ability to metabolize drug via these pathways. Individuals are commonly divided into 4 phenotypic categories: ultra-rapid, extensive (or normal), intermediate, and poor metabolizers. Based on these phenotypes, clinical consequences can be quantitated in terms of changes in drug concentration, concentration-dependent beneficial or adverse effects, and associated/recommended changes in dosing.

Research into the role of pharmacodynamic variants, however, is still in infancy and more difficult to measure in terms of assessing endpoints, with related limitations in clinical utility.

IA assays generally measure a variety of proteins, particularly those reflecting inflammatory processes (eg, various cytokines, such as interleukin-6).⁶ As with pharmacodynamic measures, research into the role of inflammatory biomarkers is in early stages. The clinical utility of associated tests is, therefore, less certain; witness the recent study⁵ I noted that revealed a high false-positive rate for the RBM schizophrenia panel in healthy controls. Nevertheless, considerable research is being conducted in all of these areas so that new developments might lend themselves to greater clinical utility.

(Note that PG biomarkers are trait measures, whereas IA biomarkers are state measures, so that complementary use of both types of tests might prove useful in diagnosis and clinical management. Although such integrative use of these 2 different types of tests generally is not done today.)

What does it take to market these tests?
At a minimum, offering these tests for sale requires that the laboratory be certified by the Centers for Medicare & Medicaid Services, according to the Clinical Laboratory Improvement Amendments (CLIA) standards (www.fda.gov/medicaldevices/deviceregulationandguidance/ivdregulatoryassistance/ucm124105.htm). CLIA-certified laboratories are required to demonstrate the analytical validity of tests that they offer—ie, the accuracy and reliability of the test in measuring a parameter of interest—but not the clinical validity or utility of those tests. The fact that a test in fact measures what it claims to be measuring in and of itself does not mean it has clinical validity or utility (see the discussion below).

Must the FDA approve laboratory tests?
No, but that situation might be changing.

Currently, only tests used in a setting considered high risk—eg, a test intended to detect or diagnose a malignancy or guide its treatment—requires formal FDA approval. The approval of such a test requires submission to the FDA of clinical data supporting its clinical validity and utility, in addition to evidence of analytic validity.

Even in such cases, the degree and quality of the clinical data required are generally not as high as would be required for approval of a drug. That distinction is understandable, given the type and quantity of data necessary for drug approval and the many years and billions of dollars it takes to accumulate such data. For most laboratory tests, providing the same level of data required to have a drug approved would be neither necessary nor feasible given the business model underlying most laboratories providing laboratory tests.

What do ‘clinical validity’ and ‘clinical utility’ mean?
These are higher evidence thresholds than is needed for analytic validity, although the latter is a necessary first step on the path to achieving these higher thresholds.

Clinical validity is the ability of a test to detect:

• a clinically meaningful measure, such as clinical response
• an adverse effect
• a biologically meaningful measure (eg, a drug level or a change in the electrocardiographic pattern).

Above the threshold of clinical validity is clinical utility, which is proof that the test can reliably be used to guide clinical management and thus meaningfully improve outcomes, such as guiding drug or dosage selection.

Is the use of PG testing recommended? If so, in what instances?
Specific types of PG testing is recommended by the FDA recommended. The FDA has been incorporating PG information into the labels of specific medications for several years; the agency has a Web site (www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm) that continuously updates this information. The involved drugs are in all therapeutic classes—from oncology to psychiatry.

More than 30 psychotropic drugs have PG information in their label; some of those drugs’ labels contain specific recommendations, such as obtaining PG information before selecting or starting a drug in a specific patient. An example is carbamazepine, for which the recommendation is to obtain HLA testing before starting the drug in patients of Han Chinese ancestry, because members of this large ethnic group are at greater risk of serious dermatologic adverse effects, including Stevens-Johnson syndrome.

In other instances, the recommendation is to do the testing before increasing beyond a specific dose. Examples of psychiatric drugs whose labels contain such PG information include pimozide and iloperidone as well as citalopram. In the FDA-approved label, guidance is provided that these drugs can be started without testing if prescribed at a reduced recommended starting dosage range, rather than the full starting dosage range. The guidance on these drugs further recommends testing for genetic CYP2D6 poor metabolizer (PM) status before dosing above that initial recommended, limited, starting dosage range.

The rationale for this guidance is to reduce the risk that (1) patients in question will achieve an excessively high plasma drug level that can cause significant prolongation of intracardiac conduction (eg, QTc prolongation) and thus (2) develop the potentially fatal arrhythmia torsades de pointes. Guidance is based on thorough QTc studies that were performed on each drug,^7,8 which makes them examples of instances in which the test has clinical validity and utility as well as analytical validity.

To find PG labeling in the package insert for these drugs, visit: www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

What about data for other tests that are marketed and promoted by developers?
Sometimes, there are—literally—no data on available tests beyond the analytical validity of the test; other times, the amount and quality of clinical data are quite variable, ranging from results of ≥1 small retrospective studies without controls to results of prospective, randomized, controlled studies. Even among the latter, the developer may conduct and analyze their studies without oversight by an independent agency, such as the FDA.

This situation (1) raises concern that study results are not independent of the developer’s business interests and, as one might expect, (2) leads to controversy about whether the data are compelling—or not.^9-12

What is a critical difference between PG test results and results of most laboratory tests?
PG tests are, as noted, trait rather than state characteristics. That means that the results do not change except for a phenomenon known as phenocoversion, discussed below. (Of course, advances in gene therapy might make it possible someday to change a person’s genetic makeup and for mitochondrial genes that is already possible.) 

For this reason, PG test results should not get buried in the medical record, as might happen with, say, a patient’s serum potassium level at a given point in time. Instead, PG test results need to be carried forward continuously. Results also should be given to the patient as part of his (her) personal health record and to all other health care providers that the patient is seeing or will see in the future. Each health care provider who obtains PG test results should consider sending them to all current clinicians providing care for the patient at the same time as they are.

Is your functional status at a given moment the same as your genetic status?
No. There is a phenomenon known as phenoconversion in which a person’s current functional status may be different from what would be expected based on their genetic status.

CYP2D6 functional status is susceptible to phenoconversion as follows: Administering fluoxetine and paroxetine, for example, at 20 or 40 mg/d converts 66% and 95%, respectively, of patients who are CYP2D6 extensive (ie, normal) metabolizers into phenocopies of people who, genetically, lack the ability to metabolize drugs via CYP2D6 (ie, genotypic CYP2D6 PM). Based on a recent study of 900 participants in routine clinical care who were taking an antidepressant, 4% of the general U.S. population are genetically CYP2D6 PM; an additional 24% are phenotypically CYP2D6 PM because of concomitant administration of a CYP2D6 substantial inhibitor, such as bupropion, fluoxetine, paroxetine, or terbenafine.¹³

That is the reason a provider needs to know what drugs a patient is taking concomitantly—to consider the possibility of phenoconversion and, when necessary, to dose accordingly.

What does the future hold?
Development of tests for use in psychiatric practice is likely to grow substantially, for at least 2 reasons:

• There is a huge unmet need for clinically meaningful tests to aid in the provision of optimal patient care and, therefore, a tremendous business opportunity
• Knowledge in the biological basis of psychiatric disorders is growing exponentially; with that knowledge comes the ability to develop new tests.

A recent example comes from a research group that devised a test that could predict suicidality.¹⁴ Time will tell whether this test or a derivative of it enters practice. Nevertheless, it is a harbinger of the likely dramatic changes in the landscape of clinical medicine particularly as it applies to psychiatry.

Given these developments, the syndromic diagnoses in DSM-5 will in the future likely be replaced by a new diagnostic schema that breaks down existing heterogenous syndromic diagnoses into pathophysiologically and etiologically meaningful entities using insights gained from genetic and biomarker data as well as functional brain imaging. Theoretically, those insights will lead to new modalities of treatment, including somatic treatments that target novel mechanisms of action, coupled to more effective psychosocial therapies—with both therapies guided by diagnostic tests to monitor response to specific treatment interventions.

During this transition from the past to the future, answers to the questions I’ve posed here about laboratory testing in psychiatry will, I hope, help the practitioner understand, evaluate, and incorporate these changes readily into practice.

What has been the history of the development of laboratory tests in the field of psychiatry?

During my almost-40-year academic medical career, I have been interested in the development and incorporation of laboratory tests into psychiatry.¹ This interest initially focused on therapeutic drug monitoring (TDM) and the genetics of drug responsiveness, with an emphasis on drug metabolism. In addition to TDM—which I have long believed is vastly underutilized in psychiatry—there have been many failed attempts to develop diagnostic tests, including tests to distinguish between what were postulated to be serotonergic and noradrenergic forms of major depression in the 1970s^2,3 and the dexamethasone suppression test for melancholia in the 1980s.⁴ Recently, a 51-analyte immunoassay test was marketed by Rules-Based Medicine, Inc. (RBM), as an aid in the diagnosis of schizophrenia, but the test was found to suffer a high false-positive rate and was withdrawn from the market.⁵ Given this track record, caution is warranted when examining claims for new tests.

What types of tests are being developed?
Most tests in development are pharmacogenomic (PG)-based or immunoassay (IA)-based.

PG tests examine single nucleotide polymorphisms (SNP) in genes that code for pharmacokinetic mechanisms, primarily cytochrome P450 (CYP) enzymes responsible for drug metabolism and P-glycoprotein, responsible for drug transportation. The next most common type of test examines pharmacodynamic mechanisms, such as SNPs of specific receptor genes, including serotonin (or 5-hydroxytryptophan [5-HT] transporter [SET or 5-HTT]) or the 5-HT2A receptor.

The fact that CYP enzymes lead the list is not surprising: These enzymes and their role in the metabolism of specific drugs have been extensively studied since the late 1980s. Considerable data has been accumulated regarding variants of CYP enzymes, which convey clinically meaningful differences among individuals in terms of their ability to metabolize drug via these pathways. Individuals are commonly divided into 4 phenotypic categories: ultra-rapid, extensive (or normal), intermediate, and poor metabolizers. Based on these phenotypes, clinical consequences can be quantitated in terms of changes in drug concentration, concentration-dependent beneficial or adverse effects, and associated/recommended changes in dosing.

Research into the role of pharmacodynamic variants, however, is still in infancy and more difficult to measure in terms of assessing endpoints, with related limitations in clinical utility.

IA assays generally measure a variety of proteins, particularly those reflecting inflammatory processes (eg, various cytokines, such as interleukin-6).⁶ As with pharmacodynamic measures, research into the role of inflammatory biomarkers is in early stages. The clinical utility of associated tests is, therefore, less certain; witness the recent study⁵ I noted that revealed a high false-positive rate for the RBM schizophrenia panel in healthy controls. Nevertheless, considerable research is being conducted in all of these areas so that new developments might lend themselves to greater clinical utility.

(Note that PG biomarkers are trait measures, whereas IA biomarkers are state measures, so that complementary use of both types of tests might prove useful in diagnosis and clinical management. Although such integrative use of these 2 different types of tests generally is not done today.)

What does it take to market these tests?
At a minimum, offering these tests for sale requires that the laboratory be certified by the Centers for Medicare & Medicaid Services, according to the Clinical Laboratory Improvement Amendments (CLIA) standards (www.fda.gov/medicaldevices/deviceregulationandguidance/ivdregulatoryassistance/ucm124105.htm). CLIA-certified laboratories are required to demonstrate the analytical validity of tests that they offer—ie, the accuracy and reliability of the test in measuring a parameter of interest—but not the clinical validity or utility of those tests. The fact that a test in fact measures what it claims to be measuring in and of itself does not mean it has clinical validity or utility (see the discussion below).

Must the FDA approve laboratory tests?
No, but that situation might be changing.

Currently, only tests used in a setting considered high risk—eg, a test intended to detect or diagnose a malignancy or guide its treatment—requires formal FDA approval. The approval of such a test requires submission to the FDA of clinical data supporting its clinical validity and utility, in addition to evidence of analytic validity.

Even in such cases, the degree and quality of the clinical data required are generally not as high as would be required for approval of a drug. That distinction is understandable, given the type and quantity of data necessary for drug approval and the many years and billions of dollars it takes to accumulate such data. For most laboratory tests, providing the same level of data required to have a drug approved would be neither necessary nor feasible given the business model underlying most laboratories providing laboratory tests.

What do ‘clinical validity’ and ‘clinical utility’ mean?
These are higher evidence thresholds than is needed for analytic validity, although the latter is a necessary first step on the path to achieving these higher thresholds.

Clinical validity is the ability of a test to detect:

• a clinically meaningful measure, such as clinical response
• an adverse effect
• a biologically meaningful measure (eg, a drug level or a change in the electrocardiographic pattern).

Above the threshold of clinical validity is clinical utility, which is proof that the test can reliably be used to guide clinical management and thus meaningfully improve outcomes, such as guiding drug or dosage selection.

Is the use of PG testing recommended? If so, in what instances?
Specific types of PG testing is recommended by the FDA recommended. The FDA has been incorporating PG information into the labels of specific medications for several years; the agency has a Web site (www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm) that continuously updates this information. The involved drugs are in all therapeutic classes—from oncology to psychiatry.

More than 30 psychotropic drugs have PG information in their label; some of those drugs’ labels contain specific recommendations, such as obtaining PG information before selecting or starting a drug in a specific patient. An example is carbamazepine, for which the recommendation is to obtain HLA testing before starting the drug in patients of Han Chinese ancestry, because members of this large ethnic group are at greater risk of serious dermatologic adverse effects, including Stevens-Johnson syndrome.

In other instances, the recommendation is to do the testing before increasing beyond a specific dose. Examples of psychiatric drugs whose labels contain such PG information include pimozide and iloperidone as well as citalopram. In the FDA-approved label, guidance is provided that these drugs can be started without testing if prescribed at a reduced recommended starting dosage range, rather than the full starting dosage range. The guidance on these drugs further recommends testing for genetic CYP2D6 poor metabolizer (PM) status before dosing above that initial recommended, limited, starting dosage range.

The rationale for this guidance is to reduce the risk that (1) patients in question will achieve an excessively high plasma drug level that can cause significant prolongation of intracardiac conduction (eg, QTc prolongation) and thus (2) develop the potentially fatal arrhythmia torsades de pointes. Guidance is based on thorough QTc studies that were performed on each drug,^7,8 which makes them examples of instances in which the test has clinical validity and utility as well as analytical validity.

To find PG labeling in the package insert for these drugs, visit: www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

What about data for other tests that are marketed and promoted by developers?
Sometimes, there are—literally—no data on available tests beyond the analytical validity of the test; other times, the amount and quality of clinical data are quite variable, ranging from results of ≥1 small retrospective studies without controls to results of prospective, randomized, controlled studies. Even among the latter, the developer may conduct and analyze their studies without oversight by an independent agency, such as the FDA.

This situation (1) raises concern that study results are not independent of the developer’s business interests and, as one might expect, (2) leads to controversy about whether the data are compelling—or not.^9-12

What is a critical difference between PG test results and results of most laboratory tests?
PG tests are, as noted, trait rather than state characteristics. That means that the results do not change except for a phenomenon known as phenocoversion, discussed below. (Of course, advances in gene therapy might make it possible someday to change a person’s genetic makeup and for mitochondrial genes that is already possible.) 

For this reason, PG test results should not get buried in the medical record, as might happen with, say, a patient’s serum potassium level at a given point in time. Instead, PG test results need to be carried forward continuously. Results also should be given to the patient as part of his (her) personal health record and to all other health care providers that the patient is seeing or will see in the future. Each health care provider who obtains PG test results should consider sending them to all current clinicians providing care for the patient at the same time as they are.

Is your functional status at a given moment the same as your genetic status?
No. There is a phenomenon known as phenoconversion in which a person’s current functional status may be different from what would be expected based on their genetic status.

CYP2D6 functional status is susceptible to phenoconversion as follows: Administering fluoxetine and paroxetine, for example, at 20 or 40 mg/d converts 66% and 95%, respectively, of patients who are CYP2D6 extensive (ie, normal) metabolizers into phenocopies of people who, genetically, lack the ability to metabolize drugs via CYP2D6 (ie, genotypic CYP2D6 PM). Based on a recent study of 900 participants in routine clinical care who were taking an antidepressant, 4% of the general U.S. population are genetically CYP2D6 PM; an additional 24% are phenotypically CYP2D6 PM because of concomitant administration of a CYP2D6 substantial inhibitor, such as bupropion, fluoxetine, paroxetine, or terbenafine.¹³

That is the reason a provider needs to know what drugs a patient is taking concomitantly—to consider the possibility of phenoconversion and, when necessary, to dose accordingly.

What does the future hold?
Development of tests for use in psychiatric practice is likely to grow substantially, for at least 2 reasons:

• There is a huge unmet need for clinically meaningful tests to aid in the provision of optimal patient care and, therefore, a tremendous business opportunity
• Knowledge in the biological basis of psychiatric disorders is growing exponentially; with that knowledge comes the ability to develop new tests.

A recent example comes from a research group that devised a test that could predict suicidality.¹⁴ Time will tell whether this test or a derivative of it enters practice. Nevertheless, it is a harbinger of the likely dramatic changes in the landscape of clinical medicine particularly as it applies to psychiatry.

Given these developments, the syndromic diagnoses in DSM-5 will in the future likely be replaced by a new diagnostic schema that breaks down existing heterogenous syndromic diagnoses into pathophysiologically and etiologically meaningful entities using insights gained from genetic and biomarker data as well as functional brain imaging. Theoretically, those insights will lead to new modalities of treatment, including somatic treatments that target novel mechanisms of action, coupled to more effective psychosocial therapies—with both therapies guided by diagnostic tests to monitor response to specific treatment interventions.

During this transition from the past to the future, answers to the questions I’ve posed here about laboratory testing in psychiatry will, I hope, help the practitioner understand, evaluate, and incorporate these changes readily into practice.

View summaries from the event on the following pages.

Thursday, March 10, 2016

Make Way for Possibilities of an Adjunctive Treatment for Major Depressive Disorder
Roueen Rafeyan, MD, Feinberg School of Medicine at Northwestern University

Successful Aging
George T. Grossberg, MD, Saint Louis University 

Psychopharmacology and Pregnancy: The New Labeling Changes and Implications for Clinical Practice
Marlene P. Freeman, MD, Massachusetts General Hospital

Anxiety Disorders in Women Across the Lifecycle
Marlene P. Freeman, MD, Massachusetts General Hospital

Mild Cognitive Impairment: “Senior Moments” and DSM-5
George T. Grossberg, MD, Saint Louis University

Assessing major depressive disorder and an option for treatment
Jay D. Fawver, MD, Indiana University School of Medicine

Innovative Treatments of Anxiety, Part 1 (Use of Benzodiazepines)
Mark H. Pollack, MD, Rush University Medical Center

Innovative Treatments of Anxiety, Part 2 (Other Standard and Novel Therapeutic Approaches)
Mark H. Pollack, MD, Rush University Medical Center

Treatment of Chronic Depression
Andrew A. Nierenberg, MD, Massachusetts General Hospital

Friday, March 11, 2016

Subtypes of Depression
Andrew A. Nierenberg, MD, Massachusetts General Hospital, Alexian Brothers Behavioral Health Hospital for Violence Prevention Clinic/Program and ADHD Clinic

Managing ADHD: What Matters Most When Selecting a Treatment Option
Michael Feld, MD, Alexian Brothers Behavioral Health Hospital for Violence Prevention Clinic/Program and ADHD Clinic

Dr. Feld discussed the utility of the brand-name extended-release (ER) methylphenidate HCl (Aptensio) for its value in children—specifically, its ability to “extend the day” without additional dosing of a short-action medication. The design of Aptensio—a multilayered beaded delivery system in which every bead is both an immediate- and an extended-release vehicle—allows an early peak serum drug level and later peak level (at 8 hours). Aptensio is administered by sprinkling the contents of a capsule on applesauce; it is is safe practice, Dr. Feld explained, to augment the ER drug delivery with an immediate-release agent when deemed necessary, by observing how difficult it is for the patient to make it through the day at home, school, or work.

Overview of Autism Spectrum Disorder
Robert L. Hendren, DO, University of California, San Francisco

Comorbidity of Schizophrenia and Substance Abuse
Henry A. Nasrallah, MD, Saint Louis University

Overview of PTSD
Carol S. North, MD, MPE, DFAPA, University of Texas Southwestern Medical Center

Bipolar Depression: Presentation, Diagnosis, and Treatment in the Outpatient Psychiatry Practice Setting
Peter J. Weiden, MD, University of Illinois at Chicago

Neuroinflammation and Oxidative Stress in Schizophrenia and Mood Disorders: Biomarkers and Therapeutic Targets
Henry A. Nasrallah, MD, Saint Louis University

Clinical Management of Autism Spectrum Disorders: What Happens Over Time/Borderline Intellectual Functioning
Robert L. Hendren, DO, University of California, San Francisco

Management of PTSD
Carol S. North, MD, MPE, DFAPA, University of Texas Southwestern Medical Center

Saturday, March 12, 2015

Managing the Difficult Child
Anthony L. Rostain, MD, MA, University of Pennsylvania

Major Depression With Subsyndromal Mania/Hypomania: Implications for Diagnosis and Management
Trisha Suppes, MD, PhD, Stanford University School of Medicine, Roger S. McIntyre, MD, FRCPC, University of Toronto, and J. Craig Nelson, MD, University of California, San Francisco

General Overview of Sleep Disorders
Thomas Roth, PhD, Henry Ford Hospital

Comorbid ADHD with Substance Abuse 
Anthony L. Rostain, MD, MA, University of Pennsylvania

How to Treat Patients with Insomnia
Thomas Roth, PhD, Henry Ford Hospital

View summaries from the event on the following pages.

Thursday, March 10, 2016

Make Way for Possibilities of an Adjunctive Treatment for Major Depressive Disorder
Roueen Rafeyan, MD, Feinberg School of Medicine at Northwestern University

Successful Aging
George T. Grossberg, MD, Saint Louis University 

Psychopharmacology and Pregnancy: The New Labeling Changes and Implications for Clinical Practice
Marlene P. Freeman, MD, Massachusetts General Hospital

Anxiety Disorders in Women Across the Lifecycle
Marlene P. Freeman, MD, Massachusetts General Hospital

Mild Cognitive Impairment: “Senior Moments” and DSM-5
George T. Grossberg, MD, Saint Louis University

Assessing major depressive disorder and an option for treatment
Jay D. Fawver, MD, Indiana University School of Medicine

Innovative Treatments of Anxiety, Part 1 (Use of Benzodiazepines)
Mark H. Pollack, MD, Rush University Medical Center

Innovative Treatments of Anxiety, Part 2 (Other Standard and Novel Therapeutic Approaches)
Mark H. Pollack, MD, Rush University Medical Center

Treatment of Chronic Depression
Andrew A. Nierenberg, MD, Massachusetts General Hospital

Friday, March 11, 2016

Subtypes of Depression
Andrew A. Nierenberg, MD, Massachusetts General Hospital, Alexian Brothers Behavioral Health Hospital for Violence Prevention Clinic/Program and ADHD Clinic

Managing ADHD: What Matters Most When Selecting a Treatment Option
Michael Feld, MD, Alexian Brothers Behavioral Health Hospital for Violence Prevention Clinic/Program and ADHD Clinic

Dr. Feld discussed the utility of the brand-name extended-release (ER) methylphenidate HCl (Aptensio) for its value in children—specifically, its ability to “extend the day” without additional dosing of a short-action medication. The design of Aptensio—a multilayered beaded delivery system in which every bead is both an immediate- and an extended-release vehicle—allows an early peak serum drug level and later peak level (at 8 hours). Aptensio is administered by sprinkling the contents of a capsule on applesauce; it is is safe practice, Dr. Feld explained, to augment the ER drug delivery with an immediate-release agent when deemed necessary, by observing how difficult it is for the patient to make it through the day at home, school, or work.

Overview of Autism Spectrum Disorder
Robert L. Hendren, DO, University of California, San Francisco

Comorbidity of Schizophrenia and Substance Abuse
Henry A. Nasrallah, MD, Saint Louis University

Overview of PTSD
Carol S. North, MD, MPE, DFAPA, University of Texas Southwestern Medical Center

Bipolar Depression: Presentation, Diagnosis, and Treatment in the Outpatient Psychiatry Practice Setting
Peter J. Weiden, MD, University of Illinois at Chicago

Neuroinflammation and Oxidative Stress in Schizophrenia and Mood Disorders: Biomarkers and Therapeutic Targets
Henry A. Nasrallah, MD, Saint Louis University

Clinical Management of Autism Spectrum Disorders: What Happens Over Time/Borderline Intellectual Functioning
Robert L. Hendren, DO, University of California, San Francisco

Management of PTSD
Carol S. North, MD, MPE, DFAPA, University of Texas Southwestern Medical Center

Saturday, March 12, 2015

Managing the Difficult Child
Anthony L. Rostain, MD, MA, University of Pennsylvania

Major Depression With Subsyndromal Mania/Hypomania: Implications for Diagnosis and Management
Trisha Suppes, MD, PhD, Stanford University School of Medicine, Roger S. McIntyre, MD, FRCPC, University of Toronto, and J. Craig Nelson, MD, University of California, San Francisco

General Overview of Sleep Disorders
Thomas Roth, PhD, Henry Ford Hospital

Comorbid ADHD with Substance Abuse 
Anthony L. Rostain, MD, MA, University of Pennsylvania

How to Treat Patients with Insomnia
Thomas Roth, PhD, Henry Ford Hospital

View summaries from the event on the following pages.

Thursday, March 10, 2016

Make Way for Possibilities of an Adjunctive Treatment for Major Depressive Disorder
Roueen Rafeyan, MD, Feinberg School of Medicine at Northwestern University

Successful Aging
George T. Grossberg, MD, Saint Louis University 

Psychopharmacology and Pregnancy: The New Labeling Changes and Implications for Clinical Practice
Marlene P. Freeman, MD, Massachusetts General Hospital

Anxiety Disorders in Women Across the Lifecycle
Marlene P. Freeman, MD, Massachusetts General Hospital

Mild Cognitive Impairment: “Senior Moments” and DSM-5
George T. Grossberg, MD, Saint Louis University

Assessing major depressive disorder and an option for treatment
Jay D. Fawver, MD, Indiana University School of Medicine

Innovative Treatments of Anxiety, Part 1 (Use of Benzodiazepines)
Mark H. Pollack, MD, Rush University Medical Center

Innovative Treatments of Anxiety, Part 2 (Other Standard and Novel Therapeutic Approaches)
Mark H. Pollack, MD, Rush University Medical Center

Treatment of Chronic Depression
Andrew A. Nierenberg, MD, Massachusetts General Hospital

Friday, March 11, 2016

Subtypes of Depression
Andrew A. Nierenberg, MD, Massachusetts General Hospital, Alexian Brothers Behavioral Health Hospital for Violence Prevention Clinic/Program and ADHD Clinic

Managing ADHD: What Matters Most When Selecting a Treatment Option
Michael Feld, MD, Alexian Brothers Behavioral Health Hospital for Violence Prevention Clinic/Program and ADHD Clinic

Dr. Feld discussed the utility of the brand-name extended-release (ER) methylphenidate HCl (Aptensio) for its value in children—specifically, its ability to “extend the day” without additional dosing of a short-action medication. The design of Aptensio—a multilayered beaded delivery system in which every bead is both an immediate- and an extended-release vehicle—allows an early peak serum drug level and later peak level (at 8 hours). Aptensio is administered by sprinkling the contents of a capsule on applesauce; it is is safe practice, Dr. Feld explained, to augment the ER drug delivery with an immediate-release agent when deemed necessary, by observing how difficult it is for the patient to make it through the day at home, school, or work.

Overview of Autism Spectrum Disorder
Robert L. Hendren, DO, University of California, San Francisco

Comorbidity of Schizophrenia and Substance Abuse
Henry A. Nasrallah, MD, Saint Louis University

Overview of PTSD
Carol S. North, MD, MPE, DFAPA, University of Texas Southwestern Medical Center

Bipolar Depression: Presentation, Diagnosis, and Treatment in the Outpatient Psychiatry Practice Setting
Peter J. Weiden, MD, University of Illinois at Chicago

Neuroinflammation and Oxidative Stress in Schizophrenia and Mood Disorders: Biomarkers and Therapeutic Targets
Henry A. Nasrallah, MD, Saint Louis University

Clinical Management of Autism Spectrum Disorders: What Happens Over Time/Borderline Intellectual Functioning
Robert L. Hendren, DO, University of California, San Francisco

Management of PTSD
Carol S. North, MD, MPE, DFAPA, University of Texas Southwestern Medical Center

Saturday, March 12, 2015

Managing the Difficult Child
Anthony L. Rostain, MD, MA, University of Pennsylvania

Major Depression With Subsyndromal Mania/Hypomania: Implications for Diagnosis and Management
Trisha Suppes, MD, PhD, Stanford University School of Medicine, Roger S. McIntyre, MD, FRCPC, University of Toronto, and J. Craig Nelson, MD, University of California, San Francisco

General Overview of Sleep Disorders
Thomas Roth, PhD, Henry Ford Hospital

Comorbid ADHD with Substance Abuse 
Anthony L. Rostain, MD, MA, University of Pennsylvania

How to Treat Patients with Insomnia
Thomas Roth, PhD, Henry Ford Hospital

CASE REPORT Evaluation for renal transplant

Mr. B, age 21, who has a diagnosis of autism spectrum disorder and an IQ comparable to that of a 4-year-old, is referred for evaluation of his candidacy for renal transplant.

A few months earlier, Mr. B pulled out his temporary dialysis catheter. Now, he receives hemodialysis through an arteriovenous fistula in the arm, but requires constant supervision during dialysis.

At evaluation, Mr. B is accompanied by his parents and his older sister, who have been providing day-to-day care for him. They appear fully committed to his well-being.

Mr. B does not have a living donor.

Needed: Assessment of adaptive functioning
DSM-5 defines intellectual disability as a disorder with onset during the developmental period. It includes deficits of intellectual and adaptive functioning in conceptual, social, and practical domains.

Regrettably, many authors focus exclusively on intellectual functioning and IQ, classifying patients as having intellectual disability based on intelligence tests alone.^1,2 Adaptive capabilities are insufficiently taken into consideration; there is an urgent need to supplement IQ testing with neuropsychological testing of a patient’s cognitive and adaptive functioning.

Landmark case
In 1995, Sandra Jensen, age 34, with trisomy 21 (Down syndrome) was denied a heart and lung transplant at 2 prominent academic institutions. The denial created a national debate; Jensen’s advocates persuaded one of the hospitals to reconsider.^3,4 

In 1996, Jensen received the transplant, but she died 18 months later from complications of immunosuppressive therapy. Her surgery was a landmark event; previously, no patient with trisomy 21 or intellectual disability had undergone organ transplantation.

Although attitudes and practices have changed in the past 2 decades, intellectual disability is still considered a relative contraindication to certain organ transplants.⁵

Why is intellectual disability still a contraindication?
Allocation of transplant organs is based primarily on the ethical principle of utilitarianism: ie, a morally good action is one that helps the greatest number of people. “Benefit” might take the form of the number of lives saved or the number of years added to a patient’s life.

There is little consensus on the definition of quality of life, with its debatable ideological standpoint that stands, at times, in contrast to distributive justice. Studies have shown that the long-term outcome for patients with intellectual disability who received a kidney transplant is comparable to the outcome after renal transplant for patients who are not intellectually disabled. In other studies, patients with intellectual disability and their caregivers report improvement in quality of life after transplant.

The goal of successful transplantation is improvement in quality of life and an increase in longevity. Compliance with all aspects of post-transplant treatment is essential—which is why intellectual disability remains a relative contraindication to heart transplantation in the guidelines of the International Society for Heart and Lung Transplantation. The society’s position is based on a theoretical rationale: ie, “concerns about compliance.”

Only 7 cases of successful long-term outcome after cardiac transplantation have been reported in patients with intellectual disability, and these were marked by the presence of the social and cognitive support necessary for post-transplant compliance with treatment.⁵ One of these 7 patients had a lengthy hospitalization 4 years after transplantation because of poor adherence to his medication regimen, following the functional decline of his primary caregiver.

Two-pronged evaluation is needed. Most patients undergoing organ transplantation receive a psychosocial assessment that varies from institution to institution. Intellectual disability can add complexity to the task of assessing candidacy for transplantation, however. In these patients, the availability and adequacy of caregivers is as important a part of decision-making as assessment of the patients themselves—yet studies of the assessment of caregivers are limited. The patient’s caregivers should be present during evaluation so that their knowledge, ability, and willingness to take on post-transplant responsibilities can be assessed. More research is needed on long-term outcomes of successful transplantation in patients with intellectual disability.

CASE CONTINUED Placement on hold
The transplant committee decides to postpone placing Mr. B on the transplant waiting list. Consensus is to revisit the question of placing him on the list at a later date.

What led to this decision?
The committee had several concerns about approving Mr. B for a transplant:

• His history of pulling out the catheter meant that he would require closer postoperative monitoring, because he would likely have drains and a urinary catheter inserted.
• Maintaining adequate oral hydration with a new kidney could be a challenge because Mr. B would not be able to comprehend how dehydration can destroy a new kidney.
• His parents believed that, after transplant, Mr. B would not be dependent on them; they failed to understand that he requires lifelong supervision to ensure compliance with immunosuppressive medications and return for follow-up.

The committee’s decision was aided by the rationale that dialysis is readily available and is a sustainable alternative to transplantation.

Mr. B’s case raises an ethical question
We speculate what the team’s decision about transplantation would have been if Mr. B (1) had a living donor or (2) was being considered for a heart, lung, or liver transplant—for which there is no analogous procedure to dialysis to sustain the patient.

CASE REPORT Evaluation for renal transplant

Mr. B, age 21, who has a diagnosis of autism spectrum disorder and an IQ comparable to that of a 4-year-old, is referred for evaluation of his candidacy for renal transplant.

A few months earlier, Mr. B pulled out his temporary dialysis catheter. Now, he receives hemodialysis through an arteriovenous fistula in the arm, but requires constant supervision during dialysis.

At evaluation, Mr. B is accompanied by his parents and his older sister, who have been providing day-to-day care for him. They appear fully committed to his well-being.

Mr. B does not have a living donor.

Needed: Assessment of adaptive functioning
DSM-5 defines intellectual disability as a disorder with onset during the developmental period. It includes deficits of intellectual and adaptive functioning in conceptual, social, and practical domains.

Regrettably, many authors focus exclusively on intellectual functioning and IQ, classifying patients as having intellectual disability based on intelligence tests alone.^1,2 Adaptive capabilities are insufficiently taken into consideration; there is an urgent need to supplement IQ testing with neuropsychological testing of a patient’s cognitive and adaptive functioning.

Landmark case
In 1995, Sandra Jensen, age 34, with trisomy 21 (Down syndrome) was denied a heart and lung transplant at 2 prominent academic institutions. The denial created a national debate; Jensen’s advocates persuaded one of the hospitals to reconsider.^3,4 

In 1996, Jensen received the transplant, but she died 18 months later from complications of immunosuppressive therapy. Her surgery was a landmark event; previously, no patient with trisomy 21 or intellectual disability had undergone organ transplantation.

Although attitudes and practices have changed in the past 2 decades, intellectual disability is still considered a relative contraindication to certain organ transplants.⁵

Why is intellectual disability still a contraindication?
Allocation of transplant organs is based primarily on the ethical principle of utilitarianism: ie, a morally good action is one that helps the greatest number of people. “Benefit” might take the form of the number of lives saved or the number of years added to a patient’s life.

There is little consensus on the definition of quality of life, with its debatable ideological standpoint that stands, at times, in contrast to distributive justice. Studies have shown that the long-term outcome for patients with intellectual disability who received a kidney transplant is comparable to the outcome after renal transplant for patients who are not intellectually disabled. In other studies, patients with intellectual disability and their caregivers report improvement in quality of life after transplant.

The goal of successful transplantation is improvement in quality of life and an increase in longevity. Compliance with all aspects of post-transplant treatment is essential—which is why intellectual disability remains a relative contraindication to heart transplantation in the guidelines of the International Society for Heart and Lung Transplantation. The society’s position is based on a theoretical rationale: ie, “concerns about compliance.”

Only 7 cases of successful long-term outcome after cardiac transplantation have been reported in patients with intellectual disability, and these were marked by the presence of the social and cognitive support necessary for post-transplant compliance with treatment.⁵ One of these 7 patients had a lengthy hospitalization 4 years after transplantation because of poor adherence to his medication regimen, following the functional decline of his primary caregiver.

Two-pronged evaluation is needed. Most patients undergoing organ transplantation receive a psychosocial assessment that varies from institution to institution. Intellectual disability can add complexity to the task of assessing candidacy for transplantation, however. In these patients, the availability and adequacy of caregivers is as important a part of decision-making as assessment of the patients themselves—yet studies of the assessment of caregivers are limited. The patient’s caregivers should be present during evaluation so that their knowledge, ability, and willingness to take on post-transplant responsibilities can be assessed. More research is needed on long-term outcomes of successful transplantation in patients with intellectual disability.

CASE CONTINUED Placement on hold
The transplant committee decides to postpone placing Mr. B on the transplant waiting list. Consensus is to revisit the question of placing him on the list at a later date.

What led to this decision?
The committee had several concerns about approving Mr. B for a transplant:

• His history of pulling out the catheter meant that he would require closer postoperative monitoring, because he would likely have drains and a urinary catheter inserted.
• Maintaining adequate oral hydration with a new kidney could be a challenge because Mr. B would not be able to comprehend how dehydration can destroy a new kidney.
• His parents believed that, after transplant, Mr. B would not be dependent on them; they failed to understand that he requires lifelong supervision to ensure compliance with immunosuppressive medications and return for follow-up.

The committee’s decision was aided by the rationale that dialysis is readily available and is a sustainable alternative to transplantation.

Mr. B’s case raises an ethical question
We speculate what the team’s decision about transplantation would have been if Mr. B (1) had a living donor or (2) was being considered for a heart, lung, or liver transplant—for which there is no analogous procedure to dialysis to sustain the patient.

CASE REPORT Evaluation for renal transplant

Mr. B, age 21, who has a diagnosis of autism spectrum disorder and an IQ comparable to that of a 4-year-old, is referred for evaluation of his candidacy for renal transplant.

A few months earlier, Mr. B pulled out his temporary dialysis catheter. Now, he receives hemodialysis through an arteriovenous fistula in the arm, but requires constant supervision during dialysis.

At evaluation, Mr. B is accompanied by his parents and his older sister, who have been providing day-to-day care for him. They appear fully committed to his well-being.

Mr. B does not have a living donor.

Needed: Assessment of adaptive functioning
DSM-5 defines intellectual disability as a disorder with onset during the developmental period. It includes deficits of intellectual and adaptive functioning in conceptual, social, and practical domains.

Regrettably, many authors focus exclusively on intellectual functioning and IQ, classifying patients as having intellectual disability based on intelligence tests alone.^1,2 Adaptive capabilities are insufficiently taken into consideration; there is an urgent need to supplement IQ testing with neuropsychological testing of a patient’s cognitive and adaptive functioning.

Landmark case
In 1995, Sandra Jensen, age 34, with trisomy 21 (Down syndrome) was denied a heart and lung transplant at 2 prominent academic institutions. The denial created a national debate; Jensen’s advocates persuaded one of the hospitals to reconsider.^3,4 

In 1996, Jensen received the transplant, but she died 18 months later from complications of immunosuppressive therapy. Her surgery was a landmark event; previously, no patient with trisomy 21 or intellectual disability had undergone organ transplantation.

Although attitudes and practices have changed in the past 2 decades, intellectual disability is still considered a relative contraindication to certain organ transplants.⁵

Why is intellectual disability still a contraindication?
Allocation of transplant organs is based primarily on the ethical principle of utilitarianism: ie, a morally good action is one that helps the greatest number of people. “Benefit” might take the form of the number of lives saved or the number of years added to a patient’s life.

There is little consensus on the definition of quality of life, with its debatable ideological standpoint that stands, at times, in contrast to distributive justice. Studies have shown that the long-term outcome for patients with intellectual disability who received a kidney transplant is comparable to the outcome after renal transplant for patients who are not intellectually disabled. In other studies, patients with intellectual disability and their caregivers report improvement in quality of life after transplant.

The goal of successful transplantation is improvement in quality of life and an increase in longevity. Compliance with all aspects of post-transplant treatment is essential—which is why intellectual disability remains a relative contraindication to heart transplantation in the guidelines of the International Society for Heart and Lung Transplantation. The society’s position is based on a theoretical rationale: ie, “concerns about compliance.”

Only 7 cases of successful long-term outcome after cardiac transplantation have been reported in patients with intellectual disability, and these were marked by the presence of the social and cognitive support necessary for post-transplant compliance with treatment.⁵ One of these 7 patients had a lengthy hospitalization 4 years after transplantation because of poor adherence to his medication regimen, following the functional decline of his primary caregiver.

Two-pronged evaluation is needed. Most patients undergoing organ transplantation receive a psychosocial assessment that varies from institution to institution. Intellectual disability can add complexity to the task of assessing candidacy for transplantation, however. In these patients, the availability and adequacy of caregivers is as important a part of decision-making as assessment of the patients themselves—yet studies of the assessment of caregivers are limited. The patient’s caregivers should be present during evaluation so that their knowledge, ability, and willingness to take on post-transplant responsibilities can be assessed. More research is needed on long-term outcomes of successful transplantation in patients with intellectual disability.

CASE CONTINUED Placement on hold
The transplant committee decides to postpone placing Mr. B on the transplant waiting list. Consensus is to revisit the question of placing him on the list at a later date.

What led to this decision?
The committee had several concerns about approving Mr. B for a transplant:

• His history of pulling out the catheter meant that he would require closer postoperative monitoring, because he would likely have drains and a urinary catheter inserted.
• Maintaining adequate oral hydration with a new kidney could be a challenge because Mr. B would not be able to comprehend how dehydration can destroy a new kidney.
• His parents believed that, after transplant, Mr. B would not be dependent on them; they failed to understand that he requires lifelong supervision to ensure compliance with immunosuppressive medications and return for follow-up.

The committee’s decision was aided by the rationale that dialysis is readily available and is a sustainable alternative to transplantation.

Mr. B’s case raises an ethical question
We speculate what the team’s decision about transplantation would have been if Mr. B (1) had a living donor or (2) was being considered for a heart, lung, or liver transplant—for which there is no analogous procedure to dialysis to sustain the patient.

Initiation has been a part of the tradition of many sororities, fraternities, sports teams, and other organizations to screen and evaluate potential members. Initiation activities can range from humorous, such as pulling pranks on others, to more serious, such as being able to recite the organization’s rules and creed. It is used in the hopes of increasing a new member’s commitment to the group, with the goal of creating group cohesion.

Hazing is not initiation

Hazing is the use of ritualized physical, sexual, and psychological abuse in the guise of initiation. Hazing activities do not help identify the qualities that a person needs for group membership, and can lead to severe physical and psychological harm. Many hazing rituals are done behind closed doors, some with a vow of secrecy.

Studies indicate that 47% of students have been hazed before college, and that 3 of every 5 college students have been subjected to hazing.¹ Military and sports teams also have a high rate of hazing; 40% of athletes report that a coach or advisor knew about the hazing.²

Dangers of hazing

Victims of hazing might be brought to the emergency room with severe injury, including broken bones, burns, alcohol intoxication–related injury, chest trauma, multi-organ system failure, sexual trauma, and other medical emergencies, or could die from injuries sustained during hazing activities.

In the 44 states where hazing is illegal, hazing participants could be held be civilly and criminally liable for their actions. Hazing victims may be required to commit crimes, ranging from destruction of property to kidnapping. One-half of all hazing activities involve the use of alcohol,² and 82% of hazing-related deaths involve alcohol.¹

What is your role in treating hazing victims?

You might be called on to treat the psychological symptoms of hazing, including:

• depression
• anxiety
• acute stress syndrome
• alcohol- and drug-related delirium
• posttraumatic stress syndrome.

In addition, you might find yourself needing to:

Arrange for medical care immediately if the patient has a medical problem or an injury.

Contact a victim advocacy programif the victim has made allegations about, or there is evidence of, sexual assault, rape, other sexual injury, or physical or psychological violence.

Notify appropriate law enforcement personnel.

Notify the leadership of the organization (eg, team, school, club) within which the hazing occurred.

Perform a psychiatric assessment and provide treatment for the victim. Some symptoms seen in victims of hazing include sleep disturbance and insomnia, poor grades, eating disorders, depression, anxiety, feelings of low self-esteem and self-worth, trust issues, and symptoms commonly seen in patients with posttraumatic stress syndrome. Symptoms sometimes appear immediately after a hazing event; other times, they develop weeks later. Supportive counseling, stabilization, and advocacy are the immediate goals.

Provide education and treatment for the perpetrator. Unlike bullying, most hazing is not instituted to harm the victim but is seen as a tradition and ritual to increase commitment and bonding. The perpetrator might feel surprise and guilt as to the harm that was done to the victim. Observers of hazing rituals might be traumatized by viewing participants humiliated or abused, and both observers and perpetrators as participants may face legal consequences. Counseling and group debriefing provide education and help them cope with these issues.

Act as a consultant to schools, teams, and other organizations to ensure that group cohesion and team building is obtained in a way that benefits the group and does not harm a member or the organization.

Psychiatrists can provide literature and information especially to adolescent and young adult patients who are at highest risk of hazing. Handouts, informational brochures and posters and be placed in the waiting areas for patient to view. These can be found online (such as www.doe.in.gov/sites/default/files/safety/and-hazing.pdf) or obtained from local colleges and school systems.

Initiation has been a part of the tradition of many sororities, fraternities, sports teams, and other organizations to screen and evaluate potential members. Initiation activities can range from humorous, such as pulling pranks on others, to more serious, such as being able to recite the organization’s rules and creed. It is used in the hopes of increasing a new member’s commitment to the group, with the goal of creating group cohesion.

Hazing is not initiation

Hazing is the use of ritualized physical, sexual, and psychological abuse in the guise of initiation. Hazing activities do not help identify the qualities that a person needs for group membership, and can lead to severe physical and psychological harm. Many hazing rituals are done behind closed doors, some with a vow of secrecy.

Studies indicate that 47% of students have been hazed before college, and that 3 of every 5 college students have been subjected to hazing.¹ Military and sports teams also have a high rate of hazing; 40% of athletes report that a coach or advisor knew about the hazing.²

Dangers of hazing

Victims of hazing might be brought to the emergency room with severe injury, including broken bones, burns, alcohol intoxication–related injury, chest trauma, multi-organ system failure, sexual trauma, and other medical emergencies, or could die from injuries sustained during hazing activities.

In the 44 states where hazing is illegal, hazing participants could be held be civilly and criminally liable for their actions. Hazing victims may be required to commit crimes, ranging from destruction of property to kidnapping. One-half of all hazing activities involve the use of alcohol,² and 82% of hazing-related deaths involve alcohol.¹

What is your role in treating hazing victims?

You might be called on to treat the psychological symptoms of hazing, including:

• depression
• anxiety
• acute stress syndrome
• alcohol- and drug-related delirium
• posttraumatic stress syndrome.

In addition, you might find yourself needing to:

Arrange for medical care immediately if the patient has a medical problem or an injury.

Contact a victim advocacy programif the victim has made allegations about, or there is evidence of, sexual assault, rape, other sexual injury, or physical or psychological violence.

Notify appropriate law enforcement personnel.

Notify the leadership of the organization (eg, team, school, club) within which the hazing occurred.

Perform a psychiatric assessment and provide treatment for the victim. Some symptoms seen in victims of hazing include sleep disturbance and insomnia, poor grades, eating disorders, depression, anxiety, feelings of low self-esteem and self-worth, trust issues, and symptoms commonly seen in patients with posttraumatic stress syndrome. Symptoms sometimes appear immediately after a hazing event; other times, they develop weeks later. Supportive counseling, stabilization, and advocacy are the immediate goals.

Provide education and treatment for the perpetrator. Unlike bullying, most hazing is not instituted to harm the victim but is seen as a tradition and ritual to increase commitment and bonding. The perpetrator might feel surprise and guilt as to the harm that was done to the victim. Observers of hazing rituals might be traumatized by viewing participants humiliated or abused, and both observers and perpetrators as participants may face legal consequences. Counseling and group debriefing provide education and help them cope with these issues.

Act as a consultant to schools, teams, and other organizations to ensure that group cohesion and team building is obtained in a way that benefits the group and does not harm a member or the organization.

Psychiatrists can provide literature and information especially to adolescent and young adult patients who are at highest risk of hazing. Handouts, informational brochures and posters and be placed in the waiting areas for patient to view. These can be found online (such as www.doe.in.gov/sites/default/files/safety/and-hazing.pdf) or obtained from local colleges and school systems.

Initiation has been a part of the tradition of many sororities, fraternities, sports teams, and other organizations to screen and evaluate potential members. Initiation activities can range from humorous, such as pulling pranks on others, to more serious, such as being able to recite the organization’s rules and creed. It is used in the hopes of increasing a new member’s commitment to the group, with the goal of creating group cohesion.

Hazing is not initiation

Hazing is the use of ritualized physical, sexual, and psychological abuse in the guise of initiation. Hazing activities do not help identify the qualities that a person needs for group membership, and can lead to severe physical and psychological harm. Many hazing rituals are done behind closed doors, some with a vow of secrecy.

Studies indicate that 47% of students have been hazed before college, and that 3 of every 5 college students have been subjected to hazing.¹ Military and sports teams also have a high rate of hazing; 40% of athletes report that a coach or advisor knew about the hazing.²

Dangers of hazing

Victims of hazing might be brought to the emergency room with severe injury, including broken bones, burns, alcohol intoxication–related injury, chest trauma, multi-organ system failure, sexual trauma, and other medical emergencies, or could die from injuries sustained during hazing activities.

In the 44 states where hazing is illegal, hazing participants could be held be civilly and criminally liable for their actions. Hazing victims may be required to commit crimes, ranging from destruction of property to kidnapping. One-half of all hazing activities involve the use of alcohol,² and 82% of hazing-related deaths involve alcohol.¹

What is your role in treating hazing victims?

You might be called on to treat the psychological symptoms of hazing, including:

• depression
• anxiety
• acute stress syndrome
• alcohol- and drug-related delirium
• posttraumatic stress syndrome.

In addition, you might find yourself needing to:

Arrange for medical care immediately if the patient has a medical problem or an injury.

Contact a victim advocacy programif the victim has made allegations about, or there is evidence of, sexual assault, rape, other sexual injury, or physical or psychological violence.

Notify appropriate law enforcement personnel.

Notify the leadership of the organization (eg, team, school, club) within which the hazing occurred.

Perform a psychiatric assessment and provide treatment for the victim. Some symptoms seen in victims of hazing include sleep disturbance and insomnia, poor grades, eating disorders, depression, anxiety, feelings of low self-esteem and self-worth, trust issues, and symptoms commonly seen in patients with posttraumatic stress syndrome. Symptoms sometimes appear immediately after a hazing event; other times, they develop weeks later. Supportive counseling, stabilization, and advocacy are the immediate goals.

Provide education and treatment for the perpetrator. Unlike bullying, most hazing is not instituted to harm the victim but is seen as a tradition and ritual to increase commitment and bonding. The perpetrator might feel surprise and guilt as to the harm that was done to the victim. Observers of hazing rituals might be traumatized by viewing participants humiliated or abused, and both observers and perpetrators as participants may face legal consequences. Counseling and group debriefing provide education and help them cope with these issues.

Act as a consultant to schools, teams, and other organizations to ensure that group cohesion and team building is obtained in a way that benefits the group and does not harm a member or the organization.

Psychiatrists can provide literature and information especially to adolescent and young adult patients who are at highest risk of hazing. Handouts, informational brochures and posters and be placed in the waiting areas for patient to view. These can be found online (such as www.doe.in.gov/sites/default/files/safety/and-hazing.pdf) or obtained from local colleges and school systems.

Life expectancy for both males and females has been increasing over the past several decades to an average of 76 years. However, the life expectancy among individuals with schizophrenia in the United States is 61 years—a 20% reduction.¹ Patients with schizophrenia are known to be at increased risk of several comorbid medical conditions, such as type 2 diabetes mellitus (T2DM), coronary artery disease, and digestive and liver disorders, compared with healthy people (Figure, page 32).^2-5 This risk may be heightened by several factors, including sedentary lifestyle, a high rate of cigarette use, poor self-management skills, homelessness, and poor diet. 

Although substantial attention is paid to the psychiatric and behavioral management of schizophrenia, many barriers impede the detection and treatment of patients’ medical conditions, which have been implicated in excess unforeseen deaths. Patients with schizophrenia might experience delays in diagnosis, leading to more acute comorbidity at time of diagnosis and premature mortality

Cardiovascular disease is the leading cause of death among psychiatric patients.⁶ Key risk factors for cardiovascular disease include smoking, obesity, hypertension, dyslipidemia, diabetes, and lack of physical activity, all of which are more prevalent among patients with schizophrenia.⁷ In addition, antipsychotics are associated with adverse metabolic effects.⁸ In general, smoking and obesity are the most modifiable and preventable risk factors for many medical conditions, such as cardiovascular disease, hyperlipidemia, diabetes, and many forms of cancer (Table 1).

In this article, we discuss how to manage common medical comorbidities in patients with schizophrenia. Comprehensive management for all these medical conditions in this population is beyond the scope of this article; we limit ourselves to discussing (1) how common these conditions are in patients with schizophrenia compared with the general population and (2) what can be done in psychiatric practice to manage these medical comorbidities (Box).

Obesity
Obesity—defined as body mass index (BMI) of >30—is common among patients with schizophrenia. The condition leads to poor self-image, decreased treatment adherence, and an increased risk of many chronic medical conditions (Table 1). Being overweight or obese can increase stigma and social discrimination, which will undermine self-esteem and, in turn, affect adherence with medications, leading to relapse.

The prevalence of obesity among patients with schizophrenia is almost double that of the general population⁹ (Figure^2-5). Several factors predispose these patients to overweight or obese, including sedentary lifestyle, lack of exercise, a high-fat diet, medications side effects, and genetic factors. Recent studies report the incidence of weight gain among patients treated with antipsychotics is as high as 80%¹⁰ (Table 2).

Mechanisms involved in antipsychotic-induced weight gain are not completely understood, but antagonism of serotonergic (5-HT2C, 5-HT1A), histamine (H1), dopamine (D2), muscarinic, and other receptors are involved in modulation of food intake. Decreased energy expenditure also has been blamed for antipsychotic-induced weight gain.¹⁰

Pharmacotherapy and bariatric surgery can be as effective among patients with schizophrenia as they are among the general population. Maintaining a BMI of <25 kg/m² lowers the risk of cardiovascular disease by 35% to 55%.⁶ Metformin has modest potential for offsetting weight gain and providing some metabolic control in overweight outpatients with schizophrenia,¹¹ and should be considered early when treating at-risk patients.

Managing obesity. Clinicians can apply several measures to manage obesity in a patient with schizophrenia:

• Educate the patient, and the family, about the risks of being overweight or obese.
• Monitor weight and BMI at each visit.
• Advise smoking cessation.
• When clinically appropriate, switch to an antipsychotic with a lower risk of weight gain—eg, from olanzapine or high-dose quetiapine to a high- or medium-potency typical antipsychotic (eg, haloperidol, perphenazine), ziprasidone, aripiprazole, iloperidone, and lurasidone (Table 2, page 36).
• Consider prophylactic use of metformin with an antipsychotic; the drug has modest potential for offsetting weight gain and providing better metabolic control in an overweight patient with schizophrenia.¹¹
• Encourage the patient to engage in modest physical activity; for example, a 20-minute walk, every day, reduces the risk of cardiovascular disease by 35% to 55%.⁶
• Recommend a formal lifestyle modification program, such as behavioral group-based treatment for weight reduction.¹²
• Refer the patient and family to a dietitian.

Type 2 diabetes mellitus
There is strong association between T2DM and schizophrenia that is related to abnormal glucose regulation independent of any adverse medication effect.¹³ Ryan et al¹⁴ reported that first-episode, drug-naïve patients with schizophrenia had a higher level of intra-abdominal fat than age- and BMI-matched healthy controls, suggesting that schizophrenia could be associated with changes in adiposity that might increase the risk of insulin resistance, hyperlipidemia, and dyslipidemia. Mechanisms that increase the risk of T2DM in schizophrenia include genetic and environmental factors, such as family history, lack of physical activity, and poor diet.

Diagnosis. All patients with schizophrenia should be evaluated for undiagnosed diabetes. The diagnosis of T2DM is made by documenting:

• a fasting plasma glucose reading of ≥126 mg/dL
• symptoms of T2DM, along with a random plasma glucose reading of ≥200 mg/dL
• 2-hour reading of a plasma glucose level >200 mg/dL on an oral glucose tolerance test.

Recent guidelines also suggest using a hemoglobin A_1c value cutoff of ≥6.5% to diagnose T2DM.

In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, 38% of patients with schizophrenia and diabetes were not receiving any treatment for T2DM.¹⁵

Risk factors for T2DM are:

• BMI >25
• a first-degree relative with diabetes
• lack of physical activity
• being a member of a high-risk ethnic group (African American, Hispanic American, Native American, Asian American, or Pacific Islander)
• having delivered a baby >9 lb or having had gestational diabetes
• hypertension
• high-density lipoprotein (HDL) cholesterol level of ≤35 mg/dL
• triglyceride level of ≥250 mg/dL
• history of an abnormal glucose tolerance test
• history of abnormal findings on a fasting plasma glucose test
• history of vascular disease.

Early detection and management.

• Educate the patient and family about signs and symptoms of T2DM, such as polyuria, nocturia, polydipsia, fatigue, visual disturbances, and (in women) vulvitis. Also, psychiatrists should be aware of, and inquire about, symptoms of diabetic ketoacidosis.
• At the start of therapy with any antipsychotic, particularly a second-generation antipsychotic (SGA), ask patients about a family history of diabetes and measure the hemoglobin A_1c value.
• Monitor the hemoglobin A_1c level 4 months after starting an antipsychotic, then annually, in a patient with significant risk factors for diabetes.
• Monitor blood glucose every 6 months in patients with no change from initial results and more frequently in those with significant risk factors for diabetes and those who gain weight.
• Order a lipid panel and measure the serum glucose level to rule out dyslipidemia and diabetes, because a patient with high lipid levels and diabetes is at higher risk of developing cardiovascular conditions.
• Advocate for smoking cessation.
• Switch to an antipsychotic with a lower risk of diabetes when clinically appropriate, such as switching a patient from olanzapine or high-dose quetiapine to a high- or medium-potency typical antipsychotic (such as haloperidol or perphenazine), ziprasidone, aripiprazole, iloperidone, and lurasidone (Table 2).
• Consider prophylactic use of metformin along with antipsychotics. Metformin has been used to improve insulin sensitivity and can lead to weight loss in diabetic and non-diabetic patients. The drug has modest potential for offsetting weight gain and providing better metabolic control in overweight outpatients with schizophrenia.¹¹ Metformin is simple to use, does not lead to hypoglycemia, does not require serum glucose monitoring, and has a favorable safety profile.¹¹
• Educate the patient about modest physical activity. For example, a 20-minute walk every day reduces the risk of cardiovascular disease by 35% to 55%.⁶
• Refer the patient to a dietitian to develop an appropriate diet plan.
• When diabetes is diagnosed, ensure appropriate follow-up and initiation or continuation of therapy with a general practitioner or an endocrinologist.
• Reinforce the need for ongoing follow-up and compliance with therapy for diabetes.

Hyperlipidemia and dyslipidemia
Elevated cholesterol and triglyceride levels are associated with cardiovascular diseases, such as ischemic heart disease and myocardial infarction. A 10% increase in cholesterol levels is associated with a 20% to 30% increase in the risk of coronary artery disease; lowering cholesterol by 10% decreases the risk by 20% to 30%.¹⁶ Triglyceride levels ≥250 mg/dL are associated with 2-fold higher risk of cardiovascular disease.¹⁶

The incidence of dyslipidemia is not as well studied as diabetes in patients with schizophrenia. There is increased prevalence of dyslipidemia in patients with schizophrenia compared with the general population because of obesity, lack of physical activity, and poor dietary habits.¹⁶

Data regarding the effects of first-generation antipsychotics (FGAs) on lipid levels are limited, but high-potency drugs, such as haloperidol, seem to carry a lower risk of hyperlipidemia than low-potency drugs, such as chlorpromazine and thioridazine.¹⁷ A comprehensive review on the effects of SGAs on plasma lipid levels suggested that clozapine, olanzapine, and quetiapine are associated with a higher risk of dyslipidemia¹⁷ (Table 2).

In the CATIE study, olanzapine and clozapine were associated with a greater increase in the serum level of cholesterol and triglycerides compared with other antipsychotics, even after adjusting for treatment duration. Furthermore, a retrospective chart review of patients who switched to aripiprazole from other SGAs showed a decrease in levels of total cholesterol and low-density lipoprotein cholesterol¹⁵ (Table 2).

Patients with schizophrenia are more likely to have dyslipidemia go undiagnosed, and therefore are less likely to be treated for the disorder. In the CATIE study, 88% of patients with dyslipidemia were not receiving any treatment.¹⁵

Management for dyslipidemia.

• Educate the patient and family about risks involved with dyslipidemia.
• Monitor weight and BMI at each visit.
• Monitor lipids to rule out dyslipidemia. Obtain a pretreatment fasting or random lipid profile for any patient receiving an antipsychotic; repeat at least every 6 months after starting the antipsychotic.
• Counsel the patient to quit smoking.
• Switch to an antipsychotic with lower risk of weight gain and dyslipidemia, such as switching from olanzapine or high-dose quetiapine to high- or medium-potency typical antipsychotics (such as, haloperidol or perphenazine), ziprasidone, aripiprazole, iloperidone, and lurasidone (Table 2).
• Educate and encourage the patient about modest physical activity. For example, a 20-minute walk everyday will reduce cardiovascular disease risk by 35% to 55%.⁶
• Refer to a dietitian if indicated.
• Ensure follow-up and initiation of treatment with a general practitioner.
• Educate and encourage the patient about modest physical activity. For example, a 20-minute walk everyday will reduce cardiovascular disease risk by 35% to 55%.

Metabolic syndrome
Metabolic syndrome is cluster of cardiovascular risk factors, including central adiposity, hyperglycemia, dyslipidemia, and hypertension. The National Cholesterol Education Program’s Adult Treatment Panel III report defines metabolic syndrome as the presence of 3 of 5 of the following factors:

• abdominal obesity (waist circumference of >40 inches in men, or >35 inches in women)
• triglyceride level, >150 mg/dL
• HDL cholesterol, <40 mg/dL in men and <50 mg/dL in women
• blood pressure, >130/85 mm Hg
• fasting plasma glucose level, >110 mg/dL.

The presence of metabolic syndrome in the general population is a strong predictor of cardiovascular diseases and diabetes.¹⁸ The adverse effects of metabolic syndrome are thought to relate to atherogenic dyslipidemia, higher blood pressure, insulin resistance with or without glucose intolerance, a proinflammatory state, and a prothrombotic state.

The prevalence of metabolic syndrome in patients with schizophrenia is 2- to 3-fold higher than the general population.¹⁹ In the CATIE study, approximately one-third of patients met criteria for metabolic syndrome at baseline.¹⁵ In a prospective study, De Hert et al²⁰ reported that patients who were started on a SGA had more than twice the rate of developing metabolic syndrome compared with those treated with a FGA (Table 2). Other possible causes of metabolic syndrome are visceral adiposity and insulin resistance.¹⁶Management of the metabolic syndrome involves addressing the individual components that have been described in the preceding sections on T2DM and dyslipidemia.

Hepatitis C
Hepatitis C virus (HCV) infection is thought to be the most common blood-borne illness, with an estimated prevalence of 1% of the U.S. population. Some studies suggest that as many as 16% of people with schizophrenia have HCV infection.⁴ Risk factors for HCV infection include unsafe sexual practices, prostitution, homosexuality, homelessness, and IV drug use.

HCV treatments typically have involved regimens with interferon alfa, which is associated with significant neuropsychiatric side effects, including depression and suicide. There is a dearth of research on treatment of HCV in patients with schizophrenia; however, at least 1 study suggests that there was no increase in psychiatric symptoms in patients treated with interferon-containing regimens.²¹ There is even less evidence to guide the use of newer, non-interferon–based HCV treatment regimens that are better tolerated and have a higher response rate in the general population; there is reason, however, to be hopeful about their potential in patients with schizophrenia and HCV infection.

Managing HCV infection.

• Educate the patients and family about risk factors associated with contracting HCV.
• Screen for HCV infection in patients with schizophrenia because there is higher prevalence of HCV in these patients compared with the general population.
• When HCV infection is diagnosed, educate the patients and family about available treatments.
• Facilitate referral to an HCV specialist for appropriate treatment.

HIV/AIDS
HIV infection is highly prevalent among people suffering from severe mental illness such as schizophrenia. The incidence of HIV/AIDS in patients with schizophrenia is estimated to be 4% to 23%, compared with 0.6% in the general population.²² Risk factors associated with a higher incidence of HIV/AIDS in patients with schizophrenia are lack of knowledge about contracting HIV, unsafe sexual practices, prostitution, homosexuality, homelessness, and IV drug use.²²

Managing HIV/AIDS.

• Educate the patient and family about risk factors associated with contracting HIV/AIDS.
• Educate patients about safe sex practices.
• All patients with schizophrenia should be screened for HIV because there is 10-fold higher HIV prevalence in schizophrenia compared with the general population.
• When HIV infection is diagnosed, facilitate referral to a HIV or infectious disease specialist for treatment.
• Educate the patient in whom HIV/AIDS has been diagnosed about the importance of (1) adherence to his (her) HIV medication regimen and (2) follow-up visits with an infectious disease practitioner and appropriate laboratory tests.
• Educate the patient’s family and significant other about the illness.
• Screen for and treat substance use.
• At each visit, inquire about the patient’s adherence to HIV medical therapy, viral load, and CD4 cell count.

Chronic obstructive pulmonary disease
Patients with schizophrenia are more likely to suffer from respiratory disease, such as chronic obstructive pulmonary disease (COPD) and asthma, compared with the general population.²³ Smoking is a major risk factor for COPD. In a study by Dickerson et al,²⁴ 64% of people with schizophrenia were current smokers, compared with 19% of those without mental illness.

A high rate of smoking rate among people with schizophrenia suggests a “self-medication” hypothesis: That is, stimulation of CNS nicotinic cholinergic receptors treats the negative symptoms of schizophrenia and overcomes the dopamine blocking effects of antipsychotics.²⁵ Among SGAs, only clozapine has a substantial body of evidence to support its association with decreased smoking behavior.

Managing COPD.

• Educate the patient and family about risk factors associated with COPD and smoking.
• Screen for tobacco use at each visit; try to increase motivation to quit smoking.
• Educate the patients and family about the value and availability of smoking cessation programs.
• Prescribe medication to help with smoking cessation when needed. Bupropion and varenicline have been shown to be effective in patients with schizophrenia; nicotine replacement therapies are safe and can be helpful.
• When treating a patient who is in the process of quitting, encourage and help him to maintain his commitment and enlist support from his family.
• Refer to an appropriate medical provider (primary care provider or pulmonologist) for a patient with an established or suspected diagnosis of COPD.

Cancer
Since 1909, when the Board of Control of the Commissioners in Lunacy for England and Wales noted the possibility of a decreased incidence in cancer among psychiatric patients, this connection has been a matter of controversy.²⁶ Subsequent research has been equivocal; the prevalence of cancer has been reported to be either increased, similar, or decreased compared with the general population.^26-28 Risk factors for cancer, including smoking, obesity, poor diet, sedentary lifestyle, and hyperprolactinemia, are more common among patients with schizophrenia.

Genetic factors and a possible protective effect from antipsychotics have been cited as potential causes of decreased prevalence. Clozapine is associated with an increased risk of leukemia. No conclusion can be drawn about the overall prevalence of cancer in schizophrenia.

Managing cancer in a patient with schizophrenia, however, poses a significant challenge²⁹; he might lack capacity to make decisions about cancer treatment. The patient—or his surrogate decision-makers—need to carefully weigh current quality of life against potential benefits of treatment and risks of side effects. Adherence to complex, often toxic, therapies can be challenging for the patient with psychosis. Successful cancer treatment often requires close collaboration between the cancer treatment team and the patient’s support system, including the treating psychiatrist and case management teams.

Bottom Line
Patients with schizophrenia are at higher risk of developing comorbid medical
conditions because of the illness itself, lifestyle behaviors, genetics, and adverse
effects of medications. Because mental health clinicians focus attention on the
psychiatric and behavioral aspect of treatment, often there is delay in screening,
detecting, and treating medical comorbidities. This screening can be done in any
psychiatric practice, which can lead to timely management for those conditions
and preventing premature mortality in patients with schizophrenia.

Life expectancy for both males and females has been increasing over the past several decades to an average of 76 years. However, the life expectancy among individuals with schizophrenia in the United States is 61 years—a 20% reduction.¹ Patients with schizophrenia are known to be at increased risk of several comorbid medical conditions, such as type 2 diabetes mellitus (T2DM), coronary artery disease, and digestive and liver disorders, compared with healthy people (Figure, page 32).^2-5 This risk may be heightened by several factors, including sedentary lifestyle, a high rate of cigarette use, poor self-management skills, homelessness, and poor diet. 

Although substantial attention is paid to the psychiatric and behavioral management of schizophrenia, many barriers impede the detection and treatment of patients’ medical conditions, which have been implicated in excess unforeseen deaths. Patients with schizophrenia might experience delays in diagnosis, leading to more acute comorbidity at time of diagnosis and premature mortality

Cardiovascular disease is the leading cause of death among psychiatric patients.⁶ Key risk factors for cardiovascular disease include smoking, obesity, hypertension, dyslipidemia, diabetes, and lack of physical activity, all of which are more prevalent among patients with schizophrenia.⁷ In addition, antipsychotics are associated with adverse metabolic effects.⁸ In general, smoking and obesity are the most modifiable and preventable risk factors for many medical conditions, such as cardiovascular disease, hyperlipidemia, diabetes, and many forms of cancer (Table 1).

In this article, we discuss how to manage common medical comorbidities in patients with schizophrenia. Comprehensive management for all these medical conditions in this population is beyond the scope of this article; we limit ourselves to discussing (1) how common these conditions are in patients with schizophrenia compared with the general population and (2) what can be done in psychiatric practice to manage these medical comorbidities (Box).

Obesity
Obesity—defined as body mass index (BMI) of >30—is common among patients with schizophrenia. The condition leads to poor self-image, decreased treatment adherence, and an increased risk of many chronic medical conditions (Table 1). Being overweight or obese can increase stigma and social discrimination, which will undermine self-esteem and, in turn, affect adherence with medications, leading to relapse.

The prevalence of obesity among patients with schizophrenia is almost double that of the general population⁹ (Figure^2-5). Several factors predispose these patients to overweight or obese, including sedentary lifestyle, lack of exercise, a high-fat diet, medications side effects, and genetic factors. Recent studies report the incidence of weight gain among patients treated with antipsychotics is as high as 80%¹⁰ (Table 2).

Mechanisms involved in antipsychotic-induced weight gain are not completely understood, but antagonism of serotonergic (5-HT2C, 5-HT1A), histamine (H1), dopamine (D2), muscarinic, and other receptors are involved in modulation of food intake. Decreased energy expenditure also has been blamed for antipsychotic-induced weight gain.¹⁰

Pharmacotherapy and bariatric surgery can be as effective among patients with schizophrenia as they are among the general population. Maintaining a BMI of <25 kg/m² lowers the risk of cardiovascular disease by 35% to 55%.⁶ Metformin has modest potential for offsetting weight gain and providing some metabolic control in overweight outpatients with schizophrenia,¹¹ and should be considered early when treating at-risk patients.

Managing obesity. Clinicians can apply several measures to manage obesity in a patient with schizophrenia:

• Educate the patient, and the family, about the risks of being overweight or obese.
• Monitor weight and BMI at each visit.
• Advise smoking cessation.
• When clinically appropriate, switch to an antipsychotic with a lower risk of weight gain—eg, from olanzapine or high-dose quetiapine to a high- or medium-potency typical antipsychotic (eg, haloperidol, perphenazine), ziprasidone, aripiprazole, iloperidone, and lurasidone (Table 2, page 36).
• Consider prophylactic use of metformin with an antipsychotic; the drug has modest potential for offsetting weight gain and providing better metabolic control in an overweight patient with schizophrenia.¹¹
• Encourage the patient to engage in modest physical activity; for example, a 20-minute walk, every day, reduces the risk of cardiovascular disease by 35% to 55%.⁶
• Recommend a formal lifestyle modification program, such as behavioral group-based treatment for weight reduction.¹²
• Refer the patient and family to a dietitian.

Type 2 diabetes mellitus
There is strong association between T2DM and schizophrenia that is related to abnormal glucose regulation independent of any adverse medication effect.¹³ Ryan et al¹⁴ reported that first-episode, drug-naïve patients with schizophrenia had a higher level of intra-abdominal fat than age- and BMI-matched healthy controls, suggesting that schizophrenia could be associated with changes in adiposity that might increase the risk of insulin resistance, hyperlipidemia, and dyslipidemia. Mechanisms that increase the risk of T2DM in schizophrenia include genetic and environmental factors, such as family history, lack of physical activity, and poor diet.

Diagnosis. All patients with schizophrenia should be evaluated for undiagnosed diabetes. The diagnosis of T2DM is made by documenting:

• a fasting plasma glucose reading of ≥126 mg/dL
• symptoms of T2DM, along with a random plasma glucose reading of ≥200 mg/dL
• 2-hour reading of a plasma glucose level >200 mg/dL on an oral glucose tolerance test.

Recent guidelines also suggest using a hemoglobin A_1c value cutoff of ≥6.5% to diagnose T2DM.

In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, 38% of patients with schizophrenia and diabetes were not receiving any treatment for T2DM.¹⁵

Risk factors for T2DM are:

• BMI >25
• a first-degree relative with diabetes
• lack of physical activity
• being a member of a high-risk ethnic group (African American, Hispanic American, Native American, Asian American, or Pacific Islander)
• having delivered a baby >9 lb or having had gestational diabetes
• hypertension
• high-density lipoprotein (HDL) cholesterol level of ≤35 mg/dL
• triglyceride level of ≥250 mg/dL
• history of an abnormal glucose tolerance test
• history of abnormal findings on a fasting plasma glucose test
• history of vascular disease.

Early detection and management.

• Educate the patient and family about signs and symptoms of T2DM, such as polyuria, nocturia, polydipsia, fatigue, visual disturbances, and (in women) vulvitis. Also, psychiatrists should be aware of, and inquire about, symptoms of diabetic ketoacidosis.
• At the start of therapy with any antipsychotic, particularly a second-generation antipsychotic (SGA), ask patients about a family history of diabetes and measure the hemoglobin A_1c value.
• Monitor the hemoglobin A_1c level 4 months after starting an antipsychotic, then annually, in a patient with significant risk factors for diabetes.
• Monitor blood glucose every 6 months in patients with no change from initial results and more frequently in those with significant risk factors for diabetes and those who gain weight.
• Order a lipid panel and measure the serum glucose level to rule out dyslipidemia and diabetes, because a patient with high lipid levels and diabetes is at higher risk of developing cardiovascular conditions.
• Advocate for smoking cessation.
• Switch to an antipsychotic with a lower risk of diabetes when clinically appropriate, such as switching a patient from olanzapine or high-dose quetiapine to a high- or medium-potency typical antipsychotic (such as haloperidol or perphenazine), ziprasidone, aripiprazole, iloperidone, and lurasidone (Table 2).
• Consider prophylactic use of metformin along with antipsychotics. Metformin has been used to improve insulin sensitivity and can lead to weight loss in diabetic and non-diabetic patients. The drug has modest potential for offsetting weight gain and providing better metabolic control in overweight outpatients with schizophrenia.¹¹ Metformin is simple to use, does not lead to hypoglycemia, does not require serum glucose monitoring, and has a favorable safety profile.¹¹
• Educate the patient about modest physical activity. For example, a 20-minute walk every day reduces the risk of cardiovascular disease by 35% to 55%.⁶
• Refer the patient to a dietitian to develop an appropriate diet plan.
• When diabetes is diagnosed, ensure appropriate follow-up and initiation or continuation of therapy with a general practitioner or an endocrinologist.
• Reinforce the need for ongoing follow-up and compliance with therapy for diabetes.

Hyperlipidemia and dyslipidemia
Elevated cholesterol and triglyceride levels are associated with cardiovascular diseases, such as ischemic heart disease and myocardial infarction. A 10% increase in cholesterol levels is associated with a 20% to 30% increase in the risk of coronary artery disease; lowering cholesterol by 10% decreases the risk by 20% to 30%.¹⁶ Triglyceride levels ≥250 mg/dL are associated with 2-fold higher risk of cardiovascular disease.¹⁶

The incidence of dyslipidemia is not as well studied as diabetes in patients with schizophrenia. There is increased prevalence of dyslipidemia in patients with schizophrenia compared with the general population because of obesity, lack of physical activity, and poor dietary habits.¹⁶

Data regarding the effects of first-generation antipsychotics (FGAs) on lipid levels are limited, but high-potency drugs, such as haloperidol, seem to carry a lower risk of hyperlipidemia than low-potency drugs, such as chlorpromazine and thioridazine.¹⁷ A comprehensive review on the effects of SGAs on plasma lipid levels suggested that clozapine, olanzapine, and quetiapine are associated with a higher risk of dyslipidemia¹⁷ (Table 2).

In the CATIE study, olanzapine and clozapine were associated with a greater increase in the serum level of cholesterol and triglycerides compared with other antipsychotics, even after adjusting for treatment duration. Furthermore, a retrospective chart review of patients who switched to aripiprazole from other SGAs showed a decrease in levels of total cholesterol and low-density lipoprotein cholesterol¹⁵ (Table 2).

Patients with schizophrenia are more likely to have dyslipidemia go undiagnosed, and therefore are less likely to be treated for the disorder. In the CATIE study, 88% of patients with dyslipidemia were not receiving any treatment.¹⁵

Management for dyslipidemia.

• Educate the patient and family about risks involved with dyslipidemia.
• Monitor weight and BMI at each visit.
• Monitor lipids to rule out dyslipidemia. Obtain a pretreatment fasting or random lipid profile for any patient receiving an antipsychotic; repeat at least every 6 months after starting the antipsychotic.
• Counsel the patient to quit smoking.
• Switch to an antipsychotic with lower risk of weight gain and dyslipidemia, such as switching from olanzapine or high-dose quetiapine to high- or medium-potency typical antipsychotics (such as, haloperidol or perphenazine), ziprasidone, aripiprazole, iloperidone, and lurasidone (Table 2).
• Educate and encourage the patient about modest physical activity. For example, a 20-minute walk everyday will reduce cardiovascular disease risk by 35% to 55%.⁶
• Refer to a dietitian if indicated.
• Ensure follow-up and initiation of treatment with a general practitioner.
• Educate and encourage the patient about modest physical activity. For example, a 20-minute walk everyday will reduce cardiovascular disease risk by 35% to 55%.

Metabolic syndrome
Metabolic syndrome is cluster of cardiovascular risk factors, including central adiposity, hyperglycemia, dyslipidemia, and hypertension. The National Cholesterol Education Program’s Adult Treatment Panel III report defines metabolic syndrome as the presence of 3 of 5 of the following factors:

• abdominal obesity (waist circumference of >40 inches in men, or >35 inches in women)
• triglyceride level, >150 mg/dL
• HDL cholesterol, <40 mg/dL in men and <50 mg/dL in women
• blood pressure, >130/85 mm Hg
• fasting plasma glucose level, >110 mg/dL.

The presence of metabolic syndrome in the general population is a strong predictor of cardiovascular diseases and diabetes.¹⁸ The adverse effects of metabolic syndrome are thought to relate to atherogenic dyslipidemia, higher blood pressure, insulin resistance with or without glucose intolerance, a proinflammatory state, and a prothrombotic state.

The prevalence of metabolic syndrome in patients with schizophrenia is 2- to 3-fold higher than the general population.¹⁹ In the CATIE study, approximately one-third of patients met criteria for metabolic syndrome at baseline.¹⁵ In a prospective study, De Hert et al²⁰ reported that patients who were started on a SGA had more than twice the rate of developing metabolic syndrome compared with those treated with a FGA (Table 2). Other possible causes of metabolic syndrome are visceral adiposity and insulin resistance.¹⁶Management of the metabolic syndrome involves addressing the individual components that have been described in the preceding sections on T2DM and dyslipidemia.

Hepatitis C
Hepatitis C virus (HCV) infection is thought to be the most common blood-borne illness, with an estimated prevalence of 1% of the U.S. population. Some studies suggest that as many as 16% of people with schizophrenia have HCV infection.⁴ Risk factors for HCV infection include unsafe sexual practices, prostitution, homosexuality, homelessness, and IV drug use.

HCV treatments typically have involved regimens with interferon alfa, which is associated with significant neuropsychiatric side effects, including depression and suicide. There is a dearth of research on treatment of HCV in patients with schizophrenia; however, at least 1 study suggests that there was no increase in psychiatric symptoms in patients treated with interferon-containing regimens.²¹ There is even less evidence to guide the use of newer, non-interferon–based HCV treatment regimens that are better tolerated and have a higher response rate in the general population; there is reason, however, to be hopeful about their potential in patients with schizophrenia and HCV infection.

Managing HCV infection.

• Educate the patients and family about risk factors associated with contracting HCV.
• Screen for HCV infection in patients with schizophrenia because there is higher prevalence of HCV in these patients compared with the general population.
• When HCV infection is diagnosed, educate the patients and family about available treatments.
• Facilitate referral to an HCV specialist for appropriate treatment.

HIV/AIDS
HIV infection is highly prevalent among people suffering from severe mental illness such as schizophrenia. The incidence of HIV/AIDS in patients with schizophrenia is estimated to be 4% to 23%, compared with 0.6% in the general population.²² Risk factors associated with a higher incidence of HIV/AIDS in patients with schizophrenia are lack of knowledge about contracting HIV, unsafe sexual practices, prostitution, homosexuality, homelessness, and IV drug use.²²

Managing HIV/AIDS.

• Educate the patient and family about risk factors associated with contracting HIV/AIDS.
• Educate patients about safe sex practices.
• All patients with schizophrenia should be screened for HIV because there is 10-fold higher HIV prevalence in schizophrenia compared with the general population.
• When HIV infection is diagnosed, facilitate referral to a HIV or infectious disease specialist for treatment.
• Educate the patient in whom HIV/AIDS has been diagnosed about the importance of (1) adherence to his (her) HIV medication regimen and (2) follow-up visits with an infectious disease practitioner and appropriate laboratory tests.
• Educate the patient’s family and significant other about the illness.
• Screen for and treat substance use.
• At each visit, inquire about the patient’s adherence to HIV medical therapy, viral load, and CD4 cell count.

Chronic obstructive pulmonary disease
Patients with schizophrenia are more likely to suffer from respiratory disease, such as chronic obstructive pulmonary disease (COPD) and asthma, compared with the general population.²³ Smoking is a major risk factor for COPD. In a study by Dickerson et al,²⁴ 64% of people with schizophrenia were current smokers, compared with 19% of those without mental illness.

A high rate of smoking rate among people with schizophrenia suggests a “self-medication” hypothesis: That is, stimulation of CNS nicotinic cholinergic receptors treats the negative symptoms of schizophrenia and overcomes the dopamine blocking effects of antipsychotics.²⁵ Among SGAs, only clozapine has a substantial body of evidence to support its association with decreased smoking behavior.

Managing COPD.

• Educate the patient and family about risk factors associated with COPD and smoking.
• Screen for tobacco use at each visit; try to increase motivation to quit smoking.
• Educate the patients and family about the value and availability of smoking cessation programs.
• Prescribe medication to help with smoking cessation when needed. Bupropion and varenicline have been shown to be effective in patients with schizophrenia; nicotine replacement therapies are safe and can be helpful.
• When treating a patient who is in the process of quitting, encourage and help him to maintain his commitment and enlist support from his family.
• Refer to an appropriate medical provider (primary care provider or pulmonologist) for a patient with an established or suspected diagnosis of COPD.

Cancer
Since 1909, when the Board of Control of the Commissioners in Lunacy for England and Wales noted the possibility of a decreased incidence in cancer among psychiatric patients, this connection has been a matter of controversy.²⁶ Subsequent research has been equivocal; the prevalence of cancer has been reported to be either increased, similar, or decreased compared with the general population.^26-28 Risk factors for cancer, including smoking, obesity, poor diet, sedentary lifestyle, and hyperprolactinemia, are more common among patients with schizophrenia.

Genetic factors and a possible protective effect from antipsychotics have been cited as potential causes of decreased prevalence. Clozapine is associated with an increased risk of leukemia. No conclusion can be drawn about the overall prevalence of cancer in schizophrenia.

Managing cancer in a patient with schizophrenia, however, poses a significant challenge²⁹; he might lack capacity to make decisions about cancer treatment. The patient—or his surrogate decision-makers—need to carefully weigh current quality of life against potential benefits of treatment and risks of side effects. Adherence to complex, often toxic, therapies can be challenging for the patient with psychosis. Successful cancer treatment often requires close collaboration between the cancer treatment team and the patient’s support system, including the treating psychiatrist and case management teams.

Bottom Line
Patients with schizophrenia are at higher risk of developing comorbid medical
conditions because of the illness itself, lifestyle behaviors, genetics, and adverse
effects of medications. Because mental health clinicians focus attention on the
psychiatric and behavioral aspect of treatment, often there is delay in screening,
detecting, and treating medical comorbidities. This screening can be done in any
psychiatric practice, which can lead to timely management for those conditions
and preventing premature mortality in patients with schizophrenia.

Life expectancy for both males and females has been increasing over the past several decades to an average of 76 years. However, the life expectancy among individuals with schizophrenia in the United States is 61 years—a 20% reduction.¹ Patients with schizophrenia are known to be at increased risk of several comorbid medical conditions, such as type 2 diabetes mellitus (T2DM), coronary artery disease, and digestive and liver disorders, compared with healthy people (Figure, page 32).^2-5 This risk may be heightened by several factors, including sedentary lifestyle, a high rate of cigarette use, poor self-management skills, homelessness, and poor diet. 

Although substantial attention is paid to the psychiatric and behavioral management of schizophrenia, many barriers impede the detection and treatment of patients’ medical conditions, which have been implicated in excess unforeseen deaths. Patients with schizophrenia might experience delays in diagnosis, leading to more acute comorbidity at time of diagnosis and premature mortality

Cardiovascular disease is the leading cause of death among psychiatric patients.⁶ Key risk factors for cardiovascular disease include smoking, obesity, hypertension, dyslipidemia, diabetes, and lack of physical activity, all of which are more prevalent among patients with schizophrenia.⁷ In addition, antipsychotics are associated with adverse metabolic effects.⁸ In general, smoking and obesity are the most modifiable and preventable risk factors for many medical conditions, such as cardiovascular disease, hyperlipidemia, diabetes, and many forms of cancer (Table 1).

In this article, we discuss how to manage common medical comorbidities in patients with schizophrenia. Comprehensive management for all these medical conditions in this population is beyond the scope of this article; we limit ourselves to discussing (1) how common these conditions are in patients with schizophrenia compared with the general population and (2) what can be done in psychiatric practice to manage these medical comorbidities (Box).

Obesity
Obesity—defined as body mass index (BMI) of >30—is common among patients with schizophrenia. The condition leads to poor self-image, decreased treatment adherence, and an increased risk of many chronic medical conditions (Table 1). Being overweight or obese can increase stigma and social discrimination, which will undermine self-esteem and, in turn, affect adherence with medications, leading to relapse.

The prevalence of obesity among patients with schizophrenia is almost double that of the general population⁹ (Figure^2-5). Several factors predispose these patients to overweight or obese, including sedentary lifestyle, lack of exercise, a high-fat diet, medications side effects, and genetic factors. Recent studies report the incidence of weight gain among patients treated with antipsychotics is as high as 80%¹⁰ (Table 2).

Mechanisms involved in antipsychotic-induced weight gain are not completely understood, but antagonism of serotonergic (5-HT2C, 5-HT1A), histamine (H1), dopamine (D2), muscarinic, and other receptors are involved in modulation of food intake. Decreased energy expenditure also has been blamed for antipsychotic-induced weight gain.¹⁰

Pharmacotherapy and bariatric surgery can be as effective among patients with schizophrenia as they are among the general population. Maintaining a BMI of <25 kg/m² lowers the risk of cardiovascular disease by 35% to 55%.⁶ Metformin has modest potential for offsetting weight gain and providing some metabolic control in overweight outpatients with schizophrenia,¹¹ and should be considered early when treating at-risk patients.

Managing obesity. Clinicians can apply several measures to manage obesity in a patient with schizophrenia:

• Educate the patient, and the family, about the risks of being overweight or obese.
• Monitor weight and BMI at each visit.
• Advise smoking cessation.
• When clinically appropriate, switch to an antipsychotic with a lower risk of weight gain—eg, from olanzapine or high-dose quetiapine to a high- or medium-potency typical antipsychotic (eg, haloperidol, perphenazine), ziprasidone, aripiprazole, iloperidone, and lurasidone (Table 2, page 36).
• Consider prophylactic use of metformin with an antipsychotic; the drug has modest potential for offsetting weight gain and providing better metabolic control in an overweight patient with schizophrenia.¹¹
• Encourage the patient to engage in modest physical activity; for example, a 20-minute walk, every day, reduces the risk of cardiovascular disease by 35% to 55%.⁶
• Recommend a formal lifestyle modification program, such as behavioral group-based treatment for weight reduction.¹²
• Refer the patient and family to a dietitian.

Type 2 diabetes mellitus
There is strong association between T2DM and schizophrenia that is related to abnormal glucose regulation independent of any adverse medication effect.¹³ Ryan et al¹⁴ reported that first-episode, drug-naïve patients with schizophrenia had a higher level of intra-abdominal fat than age- and BMI-matched healthy controls, suggesting that schizophrenia could be associated with changes in adiposity that might increase the risk of insulin resistance, hyperlipidemia, and dyslipidemia. Mechanisms that increase the risk of T2DM in schizophrenia include genetic and environmental factors, such as family history, lack of physical activity, and poor diet.

Diagnosis. All patients with schizophrenia should be evaluated for undiagnosed diabetes. The diagnosis of T2DM is made by documenting:

• a fasting plasma glucose reading of ≥126 mg/dL
• symptoms of T2DM, along with a random plasma glucose reading of ≥200 mg/dL
• 2-hour reading of a plasma glucose level >200 mg/dL on an oral glucose tolerance test.

Recent guidelines also suggest using a hemoglobin A_1c value cutoff of ≥6.5% to diagnose T2DM.

In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, 38% of patients with schizophrenia and diabetes were not receiving any treatment for T2DM.¹⁵

Risk factors for T2DM are:

• BMI >25
• a first-degree relative with diabetes
• lack of physical activity
• being a member of a high-risk ethnic group (African American, Hispanic American, Native American, Asian American, or Pacific Islander)
• having delivered a baby >9 lb or having had gestational diabetes
• hypertension
• high-density lipoprotein (HDL) cholesterol level of ≤35 mg/dL
• triglyceride level of ≥250 mg/dL
• history of an abnormal glucose tolerance test
• history of abnormal findings on a fasting plasma glucose test
• history of vascular disease.

Early detection and management.

• Educate the patient and family about signs and symptoms of T2DM, such as polyuria, nocturia, polydipsia, fatigue, visual disturbances, and (in women) vulvitis. Also, psychiatrists should be aware of, and inquire about, symptoms of diabetic ketoacidosis.
• At the start of therapy with any antipsychotic, particularly a second-generation antipsychotic (SGA), ask patients about a family history of diabetes and measure the hemoglobin A_1c value.
• Monitor the hemoglobin A_1c level 4 months after starting an antipsychotic, then annually, in a patient with significant risk factors for diabetes.
• Monitor blood glucose every 6 months in patients with no change from initial results and more frequently in those with significant risk factors for diabetes and those who gain weight.
• Order a lipid panel and measure the serum glucose level to rule out dyslipidemia and diabetes, because a patient with high lipid levels and diabetes is at higher risk of developing cardiovascular conditions.
• Advocate for smoking cessation.
• Switch to an antipsychotic with a lower risk of diabetes when clinically appropriate, such as switching a patient from olanzapine or high-dose quetiapine to a high- or medium-potency typical antipsychotic (such as haloperidol or perphenazine), ziprasidone, aripiprazole, iloperidone, and lurasidone (Table 2).
• Consider prophylactic use of metformin along with antipsychotics. Metformin has been used to improve insulin sensitivity and can lead to weight loss in diabetic and non-diabetic patients. The drug has modest potential for offsetting weight gain and providing better metabolic control in overweight outpatients with schizophrenia.¹¹ Metformin is simple to use, does not lead to hypoglycemia, does not require serum glucose monitoring, and has a favorable safety profile.¹¹
• Educate the patient about modest physical activity. For example, a 20-minute walk every day reduces the risk of cardiovascular disease by 35% to 55%.⁶
• Refer the patient to a dietitian to develop an appropriate diet plan.
• When diabetes is diagnosed, ensure appropriate follow-up and initiation or continuation of therapy with a general practitioner or an endocrinologist.
• Reinforce the need for ongoing follow-up and compliance with therapy for diabetes.

Hyperlipidemia and dyslipidemia
Elevated cholesterol and triglyceride levels are associated with cardiovascular diseases, such as ischemic heart disease and myocardial infarction. A 10% increase in cholesterol levels is associated with a 20% to 30% increase in the risk of coronary artery disease; lowering cholesterol by 10% decreases the risk by 20% to 30%.¹⁶ Triglyceride levels ≥250 mg/dL are associated with 2-fold higher risk of cardiovascular disease.¹⁶

The incidence of dyslipidemia is not as well studied as diabetes in patients with schizophrenia. There is increased prevalence of dyslipidemia in patients with schizophrenia compared with the general population because of obesity, lack of physical activity, and poor dietary habits.¹⁶

Data regarding the effects of first-generation antipsychotics (FGAs) on lipid levels are limited, but high-potency drugs, such as haloperidol, seem to carry a lower risk of hyperlipidemia than low-potency drugs, such as chlorpromazine and thioridazine.¹⁷ A comprehensive review on the effects of SGAs on plasma lipid levels suggested that clozapine, olanzapine, and quetiapine are associated with a higher risk of dyslipidemia¹⁷ (Table 2).

In the CATIE study, olanzapine and clozapine were associated with a greater increase in the serum level of cholesterol and triglycerides compared with other antipsychotics, even after adjusting for treatment duration. Furthermore, a retrospective chart review of patients who switched to aripiprazole from other SGAs showed a decrease in levels of total cholesterol and low-density lipoprotein cholesterol¹⁵ (Table 2).

Patients with schizophrenia are more likely to have dyslipidemia go undiagnosed, and therefore are less likely to be treated for the disorder. In the CATIE study, 88% of patients with dyslipidemia were not receiving any treatment.¹⁵

Management for dyslipidemia.

• Educate the patient and family about risks involved with dyslipidemia.
• Monitor weight and BMI at each visit.
• Monitor lipids to rule out dyslipidemia. Obtain a pretreatment fasting or random lipid profile for any patient receiving an antipsychotic; repeat at least every 6 months after starting the antipsychotic.
• Counsel the patient to quit smoking.
• Switch to an antipsychotic with lower risk of weight gain and dyslipidemia, such as switching from olanzapine or high-dose quetiapine to high- or medium-potency typical antipsychotics (such as, haloperidol or perphenazine), ziprasidone, aripiprazole, iloperidone, and lurasidone (Table 2).
• Educate and encourage the patient about modest physical activity. For example, a 20-minute walk everyday will reduce cardiovascular disease risk by 35% to 55%.⁶
• Refer to a dietitian if indicated.
• Ensure follow-up and initiation of treatment with a general practitioner.
• Educate and encourage the patient about modest physical activity. For example, a 20-minute walk everyday will reduce cardiovascular disease risk by 35% to 55%.

Metabolic syndrome
Metabolic syndrome is cluster of cardiovascular risk factors, including central adiposity, hyperglycemia, dyslipidemia, and hypertension. The National Cholesterol Education Program’s Adult Treatment Panel III report defines metabolic syndrome as the presence of 3 of 5 of the following factors:

• abdominal obesity (waist circumference of >40 inches in men, or >35 inches in women)
• triglyceride level, >150 mg/dL
• HDL cholesterol, <40 mg/dL in men and <50 mg/dL in women
• blood pressure, >130/85 mm Hg
• fasting plasma glucose level, >110 mg/dL.

The presence of metabolic syndrome in the general population is a strong predictor of cardiovascular diseases and diabetes.¹⁸ The adverse effects of metabolic syndrome are thought to relate to atherogenic dyslipidemia, higher blood pressure, insulin resistance with or without glucose intolerance, a proinflammatory state, and a prothrombotic state.

The prevalence of metabolic syndrome in patients with schizophrenia is 2- to 3-fold higher than the general population.¹⁹ In the CATIE study, approximately one-third of patients met criteria for metabolic syndrome at baseline.¹⁵ In a prospective study, De Hert et al²⁰ reported that patients who were started on a SGA had more than twice the rate of developing metabolic syndrome compared with those treated with a FGA (Table 2). Other possible causes of metabolic syndrome are visceral adiposity and insulin resistance.¹⁶Management of the metabolic syndrome involves addressing the individual components that have been described in the preceding sections on T2DM and dyslipidemia.

Hepatitis C
Hepatitis C virus (HCV) infection is thought to be the most common blood-borne illness, with an estimated prevalence of 1% of the U.S. population. Some studies suggest that as many as 16% of people with schizophrenia have HCV infection.⁴ Risk factors for HCV infection include unsafe sexual practices, prostitution, homosexuality, homelessness, and IV drug use.

HCV treatments typically have involved regimens with interferon alfa, which is associated with significant neuropsychiatric side effects, including depression and suicide. There is a dearth of research on treatment of HCV in patients with schizophrenia; however, at least 1 study suggests that there was no increase in psychiatric symptoms in patients treated with interferon-containing regimens.²¹ There is even less evidence to guide the use of newer, non-interferon–based HCV treatment regimens that are better tolerated and have a higher response rate in the general population; there is reason, however, to be hopeful about their potential in patients with schizophrenia and HCV infection.

Managing HCV infection.

• Educate the patients and family about risk factors associated with contracting HCV.
• Screen for HCV infection in patients with schizophrenia because there is higher prevalence of HCV in these patients compared with the general population.
• When HCV infection is diagnosed, educate the patients and family about available treatments.
• Facilitate referral to an HCV specialist for appropriate treatment.

HIV/AIDS
HIV infection is highly prevalent among people suffering from severe mental illness such as schizophrenia. The incidence of HIV/AIDS in patients with schizophrenia is estimated to be 4% to 23%, compared with 0.6% in the general population.²² Risk factors associated with a higher incidence of HIV/AIDS in patients with schizophrenia are lack of knowledge about contracting HIV, unsafe sexual practices, prostitution, homosexuality, homelessness, and IV drug use.²²

Managing HIV/AIDS.

• Educate the patient and family about risk factors associated with contracting HIV/AIDS.
• Educate patients about safe sex practices.
• All patients with schizophrenia should be screened for HIV because there is 10-fold higher HIV prevalence in schizophrenia compared with the general population.
• When HIV infection is diagnosed, facilitate referral to a HIV or infectious disease specialist for treatment.
• Educate the patient in whom HIV/AIDS has been diagnosed about the importance of (1) adherence to his (her) HIV medication regimen and (2) follow-up visits with an infectious disease practitioner and appropriate laboratory tests.
• Educate the patient’s family and significant other about the illness.
• Screen for and treat substance use.
• At each visit, inquire about the patient’s adherence to HIV medical therapy, viral load, and CD4 cell count.

Chronic obstructive pulmonary disease
Patients with schizophrenia are more likely to suffer from respiratory disease, such as chronic obstructive pulmonary disease (COPD) and asthma, compared with the general population.²³ Smoking is a major risk factor for COPD. In a study by Dickerson et al,²⁴ 64% of people with schizophrenia were current smokers, compared with 19% of those without mental illness.

A high rate of smoking rate among people with schizophrenia suggests a “self-medication” hypothesis: That is, stimulation of CNS nicotinic cholinergic receptors treats the negative symptoms of schizophrenia and overcomes the dopamine blocking effects of antipsychotics.²⁵ Among SGAs, only clozapine has a substantial body of evidence to support its association with decreased smoking behavior.

Managing COPD.

• Educate the patient and family about risk factors associated with COPD and smoking.
• Screen for tobacco use at each visit; try to increase motivation to quit smoking.
• Educate the patients and family about the value and availability of smoking cessation programs.
• Prescribe medication to help with smoking cessation when needed. Bupropion and varenicline have been shown to be effective in patients with schizophrenia; nicotine replacement therapies are safe and can be helpful.
• When treating a patient who is in the process of quitting, encourage and help him to maintain his commitment and enlist support from his family.
• Refer to an appropriate medical provider (primary care provider or pulmonologist) for a patient with an established or suspected diagnosis of COPD.

Cancer
Since 1909, when the Board of Control of the Commissioners in Lunacy for England and Wales noted the possibility of a decreased incidence in cancer among psychiatric patients, this connection has been a matter of controversy.²⁶ Subsequent research has been equivocal; the prevalence of cancer has been reported to be either increased, similar, or decreased compared with the general population.^26-28 Risk factors for cancer, including smoking, obesity, poor diet, sedentary lifestyle, and hyperprolactinemia, are more common among patients with schizophrenia.

Genetic factors and a possible protective effect from antipsychotics have been cited as potential causes of decreased prevalence. Clozapine is associated with an increased risk of leukemia. No conclusion can be drawn about the overall prevalence of cancer in schizophrenia.

Managing cancer in a patient with schizophrenia, however, poses a significant challenge²⁹; he might lack capacity to make decisions about cancer treatment. The patient—or his surrogate decision-makers—need to carefully weigh current quality of life against potential benefits of treatment and risks of side effects. Adherence to complex, often toxic, therapies can be challenging for the patient with psychosis. Successful cancer treatment often requires close collaboration between the cancer treatment team and the patient’s support system, including the treating psychiatrist and case management teams.

Bottom Line
Patients with schizophrenia are at higher risk of developing comorbid medical
conditions because of the illness itself, lifestyle behaviors, genetics, and adverse
effects of medications. Because mental health clinicians focus attention on the
psychiatric and behavioral aspect of treatment, often there is delay in screening,
detecting, and treating medical comorbidities. This screening can be done in any
psychiatric practice, which can lead to timely management for those conditions
and preventing premature mortality in patients with schizophrenia.