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Approach to managing increased risk for cardiovascular disease in patients with severe mental illness - UpToDate

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Approach to managing increased risk for

cardiovascular disease in patients with severe mental
illness
Authors: Stephen Marder, MD, L Fredrik Jarskog, MD, Benjamin Druss, MD, MPH
Section Editor: Murray B Stein, MD, MPH
Deputy Editor: Michael Friedman, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Sep 2022. | This topic last updated: Apr 06, 2022.

INTRODUCTION

Lifespans in people with severe mental illness (SMI) are reduced by 15 to 25 years compared
with the general population [1-3]. Cardiovascular disease (CVD) represents the most
common natural cause of this excess mortality [1,4,5]. People with schizophrenia, for
example, are twice as likely to die from CVD [6-8].

The elevated risk of CVD among patients with SMI is caused in part by the increased
prevalence of CVD risk factors in this population – obesity, diabetes mellitus, hypertension,
and dyslipidemia – compared with the general population. Other factors contributing to
increased CVD in patients with SMI include a possible genetic predisposition, as well as
behaviors such as smoking, lack of physical exercise, and poor diet leading to excess body
weight.

Multiple, concurrent risk factors for CVD are described, collectively, as metabolic syndrome,
which is more common in patients with SMI compared with the general population.
Metabolic syndrome is also a common side effect of antipsychotic medications. Metabolic
abnormalities, however, often go undiagnosed and untreated or undertreated in patients
with SMI.

This topic reviews our approach to selecting treatments for CVD risk factors in patients with
SMI ( algorithm 1). The epidemiology, pathogenesis, and clinical implications of metabolic
syndrome in patients with SMI are reviewed separately. The epidemiology, administration of
treatments, treatment efficacy of CVD risk factors in patients with SMI and lifestyle

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interventions for obesity and overweight patients with SMI are also reviewed separately. (See
"Metabolic syndrome in patients with severe mental illness: Epidemiology, contributing
factors, pathogenesis, and clinical implications" and "Modifiable risk factors for
cardiovascular disease in patients with severe mental illness" and "Lifestyle interventions for
obesity and overweight patients with severe mental illness".)

OVERVIEW

Patients with severe mental illness (SMI) are at risk for cardiovascular disease (CVD) and
should be routinely monitored for metabolic abnormalities and receive aggressive treatment
when present. A recommended monitoring schedule is summarized in a table ( table 1)
and reviewed separately. (See "Modifiable risk factors for cardiovascular disease in patients
with severe mental illness", section on 'Monitoring'.)

The overall goal of treating metabolic abnormalities is to prevent the development of type 2
diabetes and CVD. All patients with SMI, regardless of whether they are taking an
antipsychotic drug, should receive education about nutrition and weight management and
encouragement to increase physical activity.

The selection of a treatment strategy for one or more metabolic abnormalities depends on
multiple factors including the patient’s history of responsiveness to different antipsychotics,
the severity of the metabolic disturbance, and the willingness of the patient to make lifestyle
changes. Since there are often multiple contributors to CVD, treatment will often include
both medical and lifestyle interventions.

Treatment for metabolic risk in patients with SMI is similar whether or not the patient takes
an antipsychotic drug:

● For patients who acquire CVD risk factors as side effects of an antipsychotic
medication, the choice and dose of antipsychotic should be reevaluated. (See 'Patients
taking an antipsychotic drug' below.)

● All overweight patients with SMI should receive education on weight management and
encouragement to increase physical activity, preferably through a lifestyle intervention
tailored to the needs of the individual patient. (See 'Obesity and overweight patients'
below.)

● Other metabolic abnormalities and risk factors should be treated individually if they
persist despite antipsychotic and lifestyle changes. (See 'Other metabolic abnormalities'
below.)

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PATIENTS TAKING AN ANTIPSYCHOTIC DRUG

For patients with antipsychotic-induced weight gain, we suggest reviewing the antipsychotic
regimen for the feasibility of the options below (see "Schizophrenia in adults: Maintenance
therapy and side effect management", section on 'Implementation of medication changes'):

Antipsychotic dose reduction — The patient’s medication history, clinical status, and

current antipsychotic should be reviewed for opportunities to reduce the dose. Dose
reduction should be done gradually and under close monitoring for the possibility of
symptom exacerbation.

Switching antipsychotic drugs — Studies have shown that switching from an antipsychotic

with a relatively high risk of weight gain and dyslipidemia (eg, olanzapine, quetiapine,
risperidone) to an antipsychotic with lower risks (eg, aripiprazole or ziprasidone) is often (but
not always) effective in promoting weight loss and improving lipid profiles ( table 2) [9-11].

Careful monitoring of clinical status is recommended when attempting such a switch. A

gradual cross titration from the current to the newer drug over one to three weeks will
usually protect patients against an exacerbation of psychosis. For some patients, however,
the risks of exacerbation with switching may be unacceptably high, such as those stabilized
on clozapine, or on an antipsychotic from which they have previously decompensated
following an attempted switch to another drug.

Weight loss may not occur immediately; patients should be observed for at least two to
three months to assess the effectiveness of the change.

OBESITY AND OVERWEIGHT PATIENTS

Patients with serious mental illness (SMI) are at increased risk for obesity compared with the
general population. For patients with SMI who are overweight (body mass index between 25
and ≤30), we suggest first-line treatment with either a comprehensive lifestyle intervention
or medication, with the choice based on the intervention’s availability as well as the patient’s
preferences, motivation, and capabilities.

Compared with the general population, patients with SMI are more likely to have lifestyles
placing them at increased risk of obesity, with less physical activity and unhealthier diets [12-
14]. Lifestyle interventions developed to help overweight patients from the general
population to lose weight can present challenges to patients with SMI. (See "Obesity in
adults: Overview of management", section on 'Comprehensive lifestyle intervention' and
"Lifestyle interventions for obesity and overweight patients with severe mental illness",
section on 'Addressing challenges with SMI'.)
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For patients with the willingness and capability to participate, a lifestyle intervention should
generally be recommended first, proceeding to medication if the intervention is ineffective.
Data on weight gain among patients who have recently started taking an antipsychotic [15]
support more aggressive management (ie, an earlier introduction of medication treatment).

Preference for lifestyle intervention — In our clinical experience, lifestyle interventions

customized to challenges faced by patients with SMI can help them to lose weight and
improve other metabolic abnormalities. Clinical trials of the interventions versus inactive
controls (which are reviewed separately) have shown mixed results [16]. Their efficacy has
not been compared with that of medication for weight loss, nor has the combination of
lifestyle interventions and medication been compared with either as monotherapy. (See
"Lifestyle interventions for obesity and overweight patients with severe mental illness",
section on 'Efficacy'.)

The availability of lifestyle interventions customized for SMI patients is limited, varying
widely even in countries where they have been disseminated. (See "Lifestyle interventions
for obesity and overweight patients with severe mental illness", section on 'Key
components'.)

Based on data from intervention trials, we favor the use of interventions with characteristics
associated with better outcomes:

● In SMI patients [17]:

• Longer duration (three or more months)

• Manualized, structured approach
• Focus on both health education and physical activity
• Active monitoring such as weigh-ins and food diaries
• Active monitoring of physical activity and fitness levels

● In patients from the general population:

• Use of multiple components (eg, diet, exercise, and behavioral therapy)

• Personalization
• More frequent contact
• Training for treatment providers

Preference for medication — For most patients with SMI who are overweight and who seek
treatment with medication to lose weight, we suggest first-line treatment with metformin
rather than other agents. Topiramate or, in the case of patients treated with clozapine,
augmentation with aripiprazole are reasonable alternatives, as well as liraglutide if other
options are not effective. An option for people who are gaining weight on olanzapine or are
about to start olanzapine and wish to limit potential weight gain is the fixed-dose
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combination treatment olanzapine/samidorphan. Each of these medications have

demonstrated efficacy in this population in randomized controlled trials [18-21]. Clinical
trials have not compared their efficacy among each other, but in our clinical experience,
metformin is best tolerated and most effective. Topiramate and liraglutide may be more
effective than aripiprazole but also more likely to cause side effects. The efficacy, side effects,
dosing, and contraindications of these medications are reviewed separately. (See "Modifiable
risk factors for cardiovascular disease in patients with severe mental illness", section on
'Adjunctive medications'.)

OTHER METABOLIC ABNORMALITIES

Other metabolic abnormalities should be treated individually if they persist despite

antipsychotic and lifestyle changes:

Hyperglycemia/diabetes — Mental health practitioners should feel confident in recognizing

signs of hyperglycemia:

● Thirst
● Polyuria
● Weight loss
● Blurry vision

A recommended schedule for routine monitoring for hyperglycemia/diabetes in patients

with severe mental illness (SMI) is shown in a table ( table 1) and reviewed separately. (See
"Modifiable risk factors for cardiovascular disease in patients with severe mental illness",
section on 'Monitoring'.)

Patients with new-onset diabetes (hemoglobin A1C >6.5 percent, fasting blood glucose ≥126
mg/dL or random glucose ≥200 mg/dL) should be referred to a primary care clinician or
endocrinologist for evaluation and treatment, but diabetes treatment may be possible in the
mental health setting with primary care/internist consultation if there are no other options.
(See 'Site of treatment' below.)

Initial management of type 2 diabetes is reviewed separately. (See "Initial management of

hyperglycemia in adults with type 2 diabetes mellitus".)

The patient should also be referred to a lifestyle intervention developed for patients with
SMI with diabetes, if available. If SMI-specific resources are not available, community-based
resources that serve all patients with diabetes include diabetes self-management classes,
nutrition, and physical activity programs. To enhance adherence to diabetes-care
recommendations, we engage the patient's social supports and use motivational
interviewing to set and monitor goals. We also involve peer support when available. Lifestyle
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interventions for patients with SMI with diabetes are reviewed separately, as is motivational
interviewing (as applied to substance use disorders). (See "Modifiable risk factors for
cardiovascular disease in patients with severe mental illness", section on 'Diabetes' and
"Motivational interviewing for substance use disorders".)

Hypertension — A recommended schedule for routine monitoring of blood pressure in

patients with SMI is shown in a table ( table 1) and reviewed separately. Diagnosis of
hypertension as well as selection and initiation of an antihypertensive agent are reviewed
separately. (See "Modifiable risk factors for cardiovascular disease in patients with severe
mental illness", section on 'Monitoring' and "Overview of hypertension in adults".)

Dyslipidemia — A recommended schedule for routine monitoring for dyslipidemia in

patients with SMI is shown in a table ( table 1) and reviewed separately. (See "Modifiable
risk factors for cardiovascular disease in patients with severe mental illness", section on
'Monitoring'.)

Management of dyslipidemia is reviewed separately. (See "Management of low density

lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

TOBACCO SMOKING

For patients with severe mental illness (SMI) attempting to stop smoking, we suggest first-
line treatment with varenicline and nicotine replacement therapy (NRT) accompanied by
smoking cessation education or a support group rather than other medication or
psychosocial treatment. Bupropion is a reasonable alternative to varenicline if the latter is
poorly tolerated or the patient continues to smoke after three months of treatment.

There is limited evidence comparing the efficacy of smoking cessation medications, but
varenicline appears to be more effective for smoking cessation compared with either NRT or
bupropion in patients with SMI. A clinical trial in 4116 SMI patients found that varenicline
achieved greater abstinence compared with NRT (1.51, 95% CI 1.19-1.93), and compared with
bupropion (1.41, 95% CI 1.11-1.79) over 24 weeks [22].

In patients with bipolar disorder and depression (or mood disorders), as well as
schizophrenia (or other psychotic disorders), clinical trials have found varenicline [23-27],
bupropion [23,24,28,29], and NRT [23,30] to be similarly efficacious as compared with
placebo. An exception is that NRT has not been found to be efficacious in patients with
schizophrenia/psychotic disorders [29], although this finding is confounded by a relatively
small sample size. Earlier, smaller trials found inconsistent results for NRT, and for
bupropion in bipolar disorder or depression (or mood disorders), but a large trial provided
more robust evidence of efficacy [29].

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The efficacy of smoking cessation medications in patients with SMI is reviewed in greater
detail separately. (See "Modifiable risk factors for cardiovascular disease in patients with
severe mental illness", section on 'Tobacco smoking'.)

In the general population, varenicline [31], bupropion sustained release [32], and NRT
[23,33,34] are all efficacious for smoking cessation compared with placebo. The efficacy of
smoking cessation medications in the general population is reviewed in greater detail
separately. (See "Pharmacotherapy for smoking cessation in adults".)

Earlier concerns that varenicline and bupropion might exacerbate symptoms of SMI were
not borne out in subsequent, larger analyses [35]. (See "Modifiable risk factors for
cardiovascular disease in patients with severe mental illness", section on 'Safety'.)

Some data suggest that antidepressants can lead to improvement in negative symptoms of
schizophrenia [36]. Antidepressants, including bupropion, can precipitate mania and must
be used with caution in patients with bipolar disorder who are not also treated with a mood
stabilizer. (See "Overview of smoking cessation management in adults", section on 'Nicotine
withdrawal'.)

In addition to medication, we suggest adjunctive treatment with a cessation education or

support group rather than a specific psychosocial intervention. In contrast to the general
population, in which a number of psychosocial interventions have shown efficacy for
smoking cessation, these treatments have not been shown to be efficacious in patients with
SMI. (See "Behavioral approaches to smoking cessation".)

Among patients with SMI treated for smoking cessation, closer monitoring is warranted for
those with more severe illness, suicidality, and/or unstable symptoms. Referral to or
coordination with the patient's psychiatrist or other mental health provider is recommended.

SITE OF TREATMENT

For some patients with severe mental illness (SMI), the mental health care setting is their
only site of clinical care. Some patients are unable or unwilling to follow through on a
referral to primary care or attend regular visits for a chronic condition.

Given the risks of cardiovascular and other disease in patients with SMI and their impact on
mortality, we often treat metabolic abnormalities (eg, by prescribing medications to treat
hyperglycemia, hyperlipidemia, and/or hypertension). The provider’s level of comfort in
doing so may be influenced by the presence of organizational support, or the availability of a
primary care clinician or specialist for consultation [37].

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In complex cases we consult a provider with expertise in treating metabolic abnormalities

(eg, internal medicine, endocrinology). In many cases treatment is facilitated by a care
manager or other allied health professional. Such personnel can also facilitate collaboration
among clinicians, as well as patient navigation of often complex health care systems.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Smoking cessation,
e-cigarettes, and tobacco control".)

SUMMARY AND RECOMMENDATIONS

● Our approach to managing increased risk for cardiovascular disease in patients with
severe mental illness (SMI) is summarized in an algorithm ( algorithm 1).

● All overweight patients with SMI should receive education about nutrition and weight
management and encouragement to increase physical activity. (See 'Overview' above.)

● For patients with antipsychotic-induced weight gain, the antipsychotic regimen should
be reviewed for opportunities to reduce the dose and/or switch the antipsychotic from
one with a higher risk of weight gain (eg, olanzapine, quetiapine, risperidone) to one
with a lower risk (eg, aripiprazole or ziprasidone). Changes should be made slowly with
careful monitoring to avoid an exacerbation of psychosis. (See 'Patients taking an
antipsychotic drug' above.)

● For patients with SMI with obesity or who are overweight, we favor first-line treatment
for weight reduction with either a comprehensive lifestyle intervention or medication.
The choice between them is based on their availability, as well as the patient’s
preferences, motivation, and capabilities. (See 'Obesity and overweight patients'
above.)

● Lifestyle interventions have been customized to address challenges faced by

individuals with SMI. Other characteristics of lifestyle interventions associated with
better outcomes are those with a longer duration, a manualized, structured approach,
both health education and physical activity, and active monitoring. (See 'Preference for
lifestyle intervention' above.)

● For most patients with SMI with metabolic syndrome treated with medication to lose
weight, we suggest first-line treatment with metformin rather than other medications
(Grade 2C). Topiramate, liraglutide, or, in the case of patients treated with clozapine,

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augmentation with aripiprazole are reasonable alternatives. For patients starting

olanzapine or gaining weight on olanzapine, the combination treatment
olanzapine/samidorphan can limit continued weight gain. (See 'Preference for
medication' above.)

● For patients with SMI attempting to stop smoking, we suggest first-line treatment with
varenicline and nicotine replacement therapy (NRT) rather than bupropion and NRT
(Grade 2B). Bupropion is a reasonable alternative if the latter is poorly tolerated or if
patient continues to smoke after three months’ treatment. (See 'Tobacco smoking'
above.)

● Earlier concerns that varenicline and bupropion might exacerbate symptoms of SMI
have not borne out in subsequent, more robust analyses. (See 'Tobacco smoking' above
and "Modifiable risk factors for cardiovascular disease in patients with severe mental
illness", section on 'Safety'.)

● For patients with SMI attempting to stop smoking, we suggest adjunctive treatment
with a smoking cessation education or support group rather than a particular
psychosocial intervention (Grade 2C). (See 'Tobacco smoking' above and "Behavioral
approaches to smoking cessation".)

● For patients who continue to smoke after taking varenicline/NRT for three months, we
favor switching to bupropion and NRT rather than other medications. (See 'Tobacco
smoking' above.)

● For patients with SMI with hyperglycemia, hyperlipidemia, and/or hypertension who
are unwilling or unable to follow through on a referral to primary care, the psychiatrist
should consider treating the conditions. Their ability to do so may be influenced by a
level of comfort, the presence of organizational support, or the availability of a primary
care clinician or specialist for consultation. (See 'Site of treatment' above.)

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GRAPHICS

Approach to managing increased risk for cardiovascular disease in patients

with severe mental illness

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* Assess patient's ability/willingness to follow through on referral to primary care or medical

specialist. If patient's health care is limited to mental health setting, psychiatrist should consider
treating cardiovascular risk factors with primary care or specialist consultation.

¶ Olanzapine, quetiapine, and risperidone have a higher risk of causing weight gain and
dyslipidemia; aripiprazole and ziprasidone have a lower risk.

Δ For patients with the willingness and capability to participate, a lifestyle intervention is generally
recommended first, with medication to follow if the intervention is not effective. Data on
antipsychotic-induced weight gain, however, support an earlier introduction of medication
treatment.

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Recommendations for metabolic risk factor monitoring in patients with

severe mental illness or on antipsychotic medication

Timing of assessment

Risk factor First year of antipsychotic Ongoing monitoring*

3 12
Baseline 6 weeks Quarterly¶ Annually¶
months months

Personal and family X         X

history of diabetes,
hypertension, or
cardiovascular disease

Smoking status, X X X   X  
physical activity, dietΔ

Weight, body mass X X X   X  

indexΔ

Blood pressureΔ X X X   X  

Fasting glucose or X X§ X X   X
HbA1c◊

Lipid profile (fasting or X   X X   X

nonfasting)

* In subsequent years of antipsychotic and in patients with severe mental illness.

¶ Ongoing quarterly and annual monitoring is appropriate when health indicators are within the
normal range. More frequent monitoring is indicated when health indicators are out of range.

Δ Assess regularly as part of general health maintenance.

◊ HbA1c is usually more practical to obtain than fasting glucose but either can be used.

§ Fasting glucose at 6 weeks is only recommended by European guidelines, but given evidence
for rapid-onset hyperglycemia in some individuals starting antipsychotics, this represents
prudent monitoring, especially for clozapine and olanzapine.

Adapted from: De Hert M, Detraux J, van Winkel R, et al. Metabolic and cardiovascular adverse effects associated with
antipsychotic drugs. Nature Rev Endocrinol 2011; 8:114.

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Selected adverse effects of antipsychotic medications for

schizophrenia[1,2]

Weight Glucose
  Hyperlipidemia Akathisia Parkinson
gain abnormalities

Second-generation agents

Aripiprazole + + + ++ +

Asenapine ++ ++ ++ ++ +

Brexpiprazole¶ + + ++ ++ +

Cariprazine¶ ++ + + ++ +

ClozapineΔ +++ +++ +++ + +

Iloperidone ++ ++ + + +

Lumateperone¶ + + + + +

Lurasidone + ++ ++ ++ ++

Olanzapine +++ +++ +++ ++ ++

Paliperidone ++ + ++ ++ ++

Pimavanserin – + + + +

Quetiapine ++ ++ +++ + +

Risperidone ++ ++ + ++ ++

Ziprasidone + + + ++ +

First-generation agents

Chlorpromazine ++ ++ + ++ ++

Fluphenazine ++ + + +++ +++

Haloperidol ++ + + +++ +++

Loxapine + + + ++ ++

Molindone + + + ++ ++

Perphenazine ++ + + ++ ++

Pimozide + + + +++ +++

Thioridazine§ ++ + + + +

Thiothixene + + + +++ +++

Trifluoperazine ++ + + ++ ++

Adverse effect rankings, with the exception of the QTc classifications, are consistent with
American Psychiatric Association practice guidelines for the treatment of schizophrenia.[1] The
QTc classifications are determined by Lexicomp according to US Food & Drug Administration

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guidance.[2,3] Other sources may use different classification systems resulting in some agents
being classified differently.

IV: intravenous.

* Clinically significant QTc prolongation was not detected in preliminary studies or reported in
the manufacturer's labeling.

¶ Based upon limited experience.

Δ Clozapine also causes granulocytopenia or agranulocytosis in approximately 1% of patients

requiring regular blood cell count monitoring. Clozapine has been associated with excess risk of
myocarditis and venous thromboembolic events including fatal pulmonary embolism. These
issues are addressed in the UpToDate topic review of guidelines for prescribing clozapine section
on adverse effects.

◊ Although the available evidence concerning the average QTc prolonging effect of pimozide is
consistent with a classification of moderate significance (ie, ++), label warnings have
characterized the QTc effect and cardiovascular risks as severe and sudden deaths in patients on
pimozide have been reported.

§ Thioridazine is also associated with dose-dependent retinitis pigmentosa. Refer to UpToDate

text.

References:
1. Keepers GA, Fochtmann LJ, Anzia JM, et al. The American Psychiatric Association practice guideline for the
treatment of patients with schizophrenia. American Psychiatric Association 2020. Available at:
https://www.psychiatry.org/psychiatrists/practice/clinical-practice-guidelines (Accessed on March 24, 2020).
2. Lexicomp Online. Copyright © 1978-2022 Lexicomp, Inc. All Rights Reserved.
3. Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs –
Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2). Available
at:
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073161.pdf.

Graphic 82533 Version 40.0

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Contributor Disclosures
Stephen Marder, MD Grant/Research/Clinical Trial Support: Boeringer-Ingleheim
[Psychosis/schizophrenia].
Consultant/Advisory Boards: Bioexcel [Psychosis/schizophrenia]; Biogen
[Psychosis/schizophrenia]; Boeringer-Ingleheim [Psychosis/schizophrenia]; Merck [Psychosis]; Otsuka
[Psychosis/schizophrenia]; Sunovion [Psychosis/schizophrenia].
All of the relevant financial
relationships listed have been mitigated. L Fredrik Jarskog, MD Grant/Research/Clinical Trial Support:
Boehringer Ingelheim [Cognitive impairment associated with schizophrenia]; Corcept [Antipsychotic-
associated weight gain]; Otsuka [Schizophrenia, substance use disorders].
Consultant/Advisory Boards:
Signant Health [Psychosis rating scales].
All of the relevant financial relationships listed have been
mitigated. Benjamin Druss, MD, MPH No relevant financial relationship(s) with ineligible companies
to disclose. Murray B Stein, MD, MPH Equity Ownership/Stock Options: EpiVario [Substance use
disorders and PTSD]; Oxeia Biopharmaceuticals [Traumatic brain injury].
Consultant/Advisory Boards:
Acadia Pharmaceuticals [Anxiety and traumatic stress-related disorders]; Aptinyx [Anxiety and
traumatic stress-related disorders]; atai Life Sciences [Anxiety and traumatic stress-related disorders];
Bionomics [Anxiety and traumatic stress-related disorders]; BioXcel Therapeutics [Anxiety and
traumatic stress-related disorders]; Boehringer-Ingelheim [Anxiety and traumatic stress-related
disorders]; Clexio [Anxiety and traumatic stress-related disorders]; Eisai [Anxiety and traumatic stress-
related disorders]; EmpowerPharm [Anxiety and traumatic stress-related disorders]; Engrail
Therapeutics [Anxiety and traumatic stress-related disorders]; GABA Therapeutics [Anxiety and
traumatic stress-related disorders]; Jazz Pharmaceuticals [Anxiety and traumatic stress-related
disorders]; Oxeia Biopharmaceuticals [Traumatic brain injury]; Roche/Genentech [Anxiety and
traumatic stress-related disorders].
Other Financial Interest: Biological Psychiatry [Deputy Editor];
Depression and Anxiety [Editor-in-chief].
All of the relevant financial relationships listed have been
mitigated. Michael Friedman, MD No relevant financial relationship(s) with ineligible companies to
disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

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