Current Psychiatry

Schizophrenia is characterized by psychotic symptoms that typically follow a prodromal period of premonitory signs and symptoms that appear before the manifestation of the full-blown syndrome. Signs and symptoms during the prodromal phase are subsyndromal, which implies a lower degree of intensity, duration, or frequency than observed when the patient meets the full criteria for the syndrome. Early detection of prodromal symptoms can improve prognosis, but these subtle symptoms may go unrecognized.

In schizophrenia, a patient may exhibit prodromal signs and symptoms before the appearance of pathognomonic symptoms, such as delusions, hallucinations, and disorganization. The schizophrenia prodrome can be conceptualized as a period of prepsychotic disturbances depicting an alteration in the individual’s behavior and perception. Prodromal symptoms can last from weeks to years before the psychotic illness clinically manifests.¹ The prodromal symptom cluster typically becomes evident during adolescence and young adulthood.²

In the mid-1990s, investigators tried to identify a “putative prodrome” for psychosis. The term “at-risk mental state” (ARMS) for psychosis is based on retrospective reports of prodromal symptoms in first-episode psychosis. Over the next 2 decades, scales such as the Comprehensive Assessment of ARMS (CAARMS)³ and the Structured Interview for Prodromal Syndrome⁴ were designed to enhance the objectivity and diagnostic accuracy of the ARMS. These scales have reasonable interrater reliability.⁵

Researchers also have attempted to stage the severity of ARMS.⁶ Key symptom group predictors were studied to determine which individual symptoms or cluster of symptoms are most associated with poor outcomes and progression to psychosis. Raballo et al⁷ found the severity of the CAARMS disorganization dimension was the strongest predictor of transition to frank psychosis. Other research suggests that approximately one-third of ARMS patients transition to psychosis within 3 years, another one-third have persistent attenuated psychotic symptoms, and the remaining one-third experience symptom remission.^8,9

Despite multiple studies and meta-analyses, current scales and clinical predictors continue to be imperfect.⁸ Efforts to identify specific biological markers and predictors of transition to clinical psychosis have not been successful for ARMS.^10,11 The Table^8,9,12,13 summarizes diagnostic criteria that have been developed to more clearly identify which ARMS patients face the highest imminent risk for transition to psychosis; these have been referred to as ultra high-risk (UHR) criteria.¹⁴ These UHR criteria depict 3 categories of clinical presentation believed to confer risk of transition to psychosis: attenuated psychotic symptoms, transient psychotic symptoms, and genetic predisposition. Subsequent research found that certain additional symptom variables, as well as combinations of specific symptom clusters, conferred increased risk and improved the positive predictive sensitivity to as high as 83%.¹⁵ In addition to the UHR criteria, the Table^8,9,12,13 also lists these additional variables shown to confer a high positive predictive value (PPV) of transition, alone or in combination with the UHR criterion. Thompson et al¹⁶ provide more detailed information on these later variables and their relative PPV.

What about treatment?

While discussion of the optimal treatment options for patients with prodromal symptoms of schizophrenia is beyond the scope of this article, early interventions can focus on preventing the biological, psychological, and social disruption that results from such symptoms. Establishing a therapeutic alliance with the patient while they retain insight and engaging supportive family members is a key starting point. Case management, cognitive-behavioral or supportive therapy, and treatment of comorbid mood, anxiety, or substance use disorders are helpful. There is no clear consensus on the utility of pharmacotherapy in the prodromal stage of psychosis. While scales and structured interviews can guide assessment, clinical judgment is the key driver of the appropriateness of initiating pharmacologic treatment to address symptoms. Because up to two-thirds of patients who satisfy UHR criteria do not go on to develop schizophrenia,¹⁶ clinicians should be thoughtful about the risks and benefits of antipsychotics.

Schizophrenia is characterized by psychotic symptoms that typically follow a prodromal period of premonitory signs and symptoms that appear before the manifestation of the full-blown syndrome. Signs and symptoms during the prodromal phase are subsyndromal, which implies a lower degree of intensity, duration, or frequency than observed when the patient meets the full criteria for the syndrome. Early detection of prodromal symptoms can improve prognosis, but these subtle symptoms may go unrecognized.

In schizophrenia, a patient may exhibit prodromal signs and symptoms before the appearance of pathognomonic symptoms, such as delusions, hallucinations, and disorganization. The schizophrenia prodrome can be conceptualized as a period of prepsychotic disturbances depicting an alteration in the individual’s behavior and perception. Prodromal symptoms can last from weeks to years before the psychotic illness clinically manifests.¹ The prodromal symptom cluster typically becomes evident during adolescence and young adulthood.²

In the mid-1990s, investigators tried to identify a “putative prodrome” for psychosis. The term “at-risk mental state” (ARMS) for psychosis is based on retrospective reports of prodromal symptoms in first-episode psychosis. Over the next 2 decades, scales such as the Comprehensive Assessment of ARMS (CAARMS)³ and the Structured Interview for Prodromal Syndrome⁴ were designed to enhance the objectivity and diagnostic accuracy of the ARMS. These scales have reasonable interrater reliability.⁵

Researchers also have attempted to stage the severity of ARMS.⁶ Key symptom group predictors were studied to determine which individual symptoms or cluster of symptoms are most associated with poor outcomes and progression to psychosis. Raballo et al⁷ found the severity of the CAARMS disorganization dimension was the strongest predictor of transition to frank psychosis. Other research suggests that approximately one-third of ARMS patients transition to psychosis within 3 years, another one-third have persistent attenuated psychotic symptoms, and the remaining one-third experience symptom remission.^8,9

Despite multiple studies and meta-analyses, current scales and clinical predictors continue to be imperfect.⁸ Efforts to identify specific biological markers and predictors of transition to clinical psychosis have not been successful for ARMS.^10,11 The Table^8,9,12,13 summarizes diagnostic criteria that have been developed to more clearly identify which ARMS patients face the highest imminent risk for transition to psychosis; these have been referred to as ultra high-risk (UHR) criteria.¹⁴ These UHR criteria depict 3 categories of clinical presentation believed to confer risk of transition to psychosis: attenuated psychotic symptoms, transient psychotic symptoms, and genetic predisposition. Subsequent research found that certain additional symptom variables, as well as combinations of specific symptom clusters, conferred increased risk and improved the positive predictive sensitivity to as high as 83%.¹⁵ In addition to the UHR criteria, the Table^8,9,12,13 also lists these additional variables shown to confer a high positive predictive value (PPV) of transition, alone or in combination with the UHR criterion. Thompson et al¹⁶ provide more detailed information on these later variables and their relative PPV.

What about treatment?

While discussion of the optimal treatment options for patients with prodromal symptoms of schizophrenia is beyond the scope of this article, early interventions can focus on preventing the biological, psychological, and social disruption that results from such symptoms. Establishing a therapeutic alliance with the patient while they retain insight and engaging supportive family members is a key starting point. Case management, cognitive-behavioral or supportive therapy, and treatment of comorbid mood, anxiety, or substance use disorders are helpful. There is no clear consensus on the utility of pharmacotherapy in the prodromal stage of psychosis. While scales and structured interviews can guide assessment, clinical judgment is the key driver of the appropriateness of initiating pharmacologic treatment to address symptoms. Because up to two-thirds of patients who satisfy UHR criteria do not go on to develop schizophrenia,¹⁶ clinicians should be thoughtful about the risks and benefits of antipsychotics.

Schizophrenia is characterized by psychotic symptoms that typically follow a prodromal period of premonitory signs and symptoms that appear before the manifestation of the full-blown syndrome. Signs and symptoms during the prodromal phase are subsyndromal, which implies a lower degree of intensity, duration, or frequency than observed when the patient meets the full criteria for the syndrome. Early detection of prodromal symptoms can improve prognosis, but these subtle symptoms may go unrecognized.

In schizophrenia, a patient may exhibit prodromal signs and symptoms before the appearance of pathognomonic symptoms, such as delusions, hallucinations, and disorganization. The schizophrenia prodrome can be conceptualized as a period of prepsychotic disturbances depicting an alteration in the individual’s behavior and perception. Prodromal symptoms can last from weeks to years before the psychotic illness clinically manifests.¹ The prodromal symptom cluster typically becomes evident during adolescence and young adulthood.²

In the mid-1990s, investigators tried to identify a “putative prodrome” for psychosis. The term “at-risk mental state” (ARMS) for psychosis is based on retrospective reports of prodromal symptoms in first-episode psychosis. Over the next 2 decades, scales such as the Comprehensive Assessment of ARMS (CAARMS)³ and the Structured Interview for Prodromal Syndrome⁴ were designed to enhance the objectivity and diagnostic accuracy of the ARMS. These scales have reasonable interrater reliability.⁵

Researchers also have attempted to stage the severity of ARMS.⁶ Key symptom group predictors were studied to determine which individual symptoms or cluster of symptoms are most associated with poor outcomes and progression to psychosis. Raballo et al⁷ found the severity of the CAARMS disorganization dimension was the strongest predictor of transition to frank psychosis. Other research suggests that approximately one-third of ARMS patients transition to psychosis within 3 years, another one-third have persistent attenuated psychotic symptoms, and the remaining one-third experience symptom remission.^8,9

Despite multiple studies and meta-analyses, current scales and clinical predictors continue to be imperfect.⁸ Efforts to identify specific biological markers and predictors of transition to clinical psychosis have not been successful for ARMS.^10,11 The Table^8,9,12,13 summarizes diagnostic criteria that have been developed to more clearly identify which ARMS patients face the highest imminent risk for transition to psychosis; these have been referred to as ultra high-risk (UHR) criteria.¹⁴ These UHR criteria depict 3 categories of clinical presentation believed to confer risk of transition to psychosis: attenuated psychotic symptoms, transient psychotic symptoms, and genetic predisposition. Subsequent research found that certain additional symptom variables, as well as combinations of specific symptom clusters, conferred increased risk and improved the positive predictive sensitivity to as high as 83%.¹⁵ In addition to the UHR criteria, the Table^8,9,12,13 also lists these additional variables shown to confer a high positive predictive value (PPV) of transition, alone or in combination with the UHR criterion. Thompson et al¹⁶ provide more detailed information on these later variables and their relative PPV.

What about treatment?

While discussion of the optimal treatment options for patients with prodromal symptoms of schizophrenia is beyond the scope of this article, early interventions can focus on preventing the biological, psychological, and social disruption that results from such symptoms. Establishing a therapeutic alliance with the patient while they retain insight and engaging supportive family members is a key starting point. Case management, cognitive-behavioral or supportive therapy, and treatment of comorbid mood, anxiety, or substance use disorders are helpful. There is no clear consensus on the utility of pharmacotherapy in the prodromal stage of psychosis. While scales and structured interviews can guide assessment, clinical judgment is the key driver of the appropriateness of initiating pharmacologic treatment to address symptoms. Because up to two-thirds of patients who satisfy UHR criteria do not go on to develop schizophrenia,¹⁶ clinicians should be thoughtful about the risks and benefits of antipsychotics.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact letters@currentpsychiatry.com.

I (MZP) just completed my first semester of medical school. An important lesson imparted in my coursework so far has been to remain a staunch advocate for patients. Yet compared to the rigors of medical school, over the past year it has been far more difficult to help patients locate generic Adderall. Physicians were already overburdened with administrative responsibilities stretching into burnout territory well before the shortage, and now this! Unlike paper prescriptions of old, which patients could take to any pharmacy, e-prescribing apps require selection of a specific pharmacy, and controlled substances such as stimulants require 2-factor authentication. But if the designated pharmacy does not have the medication in stock, the entire process must be repeated with an alternative pharmacy, long after the visit has concluded.

To add insult to injury, the generic stimulant shortage has grown even worse. As of February 2023, generic Adderall remained hard to find and generic Concerta was also in short supply. How did this happen? In 1985, Bulow et al¹ coined the game theory concept of “strategic substitutes,” where (for example) as beef becomes less readily accessible, consumers may switch to eating chicken as their protein. Unable to locate generic Adderall, many patients have turned to generic Concerta as a substitute psychostimulant to continue management of their attention-deficit/hyperactivity disorder.

In addition to the increase in demand, compounding the shortage is that one of the manufacturers of generic Concerta has discontinued production.² Branded methylphenidates and amphetamines, which are much more expensive than their generic counterparts, have remained in ample supply, but many insurers require trials of generics before considering coverage for more expensive brands.

Our approach to this situation

Each morning we call our local and chain pharmacies to take a census of their supply of generic stimulants. Some pharmacies refuse to release this information. Despite these census reports, we have found cases where patients have been turned away from pharmacies when they are not “regular customers,” while patients whom the pharmacies know retain access as “members.” Hence, a patient is unlikely to obtain these medications if their regular pharmacy is out of stock.

We want to share a workaround that has been effective. After unsuccessfully searching for generic stimulants at the patient’s regular pharmacy, I (RLP) write “dispense as written” for the closest branded version and file a prior authorization with the patient’s insurance company, noting “patient unable to trial any generic amphetamines or methylphenidates due to current nationwide shortage.” Even with the most difficult insurers, the response has been “a temporary 3-month authorization has been granted,” which is at least a small victory for our desperate patients and busy prescribers who are both struggling to negotiate a fragmented health care system.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact letters@currentpsychiatry.com.

I (MZP) just completed my first semester of medical school. An important lesson imparted in my coursework so far has been to remain a staunch advocate for patients. Yet compared to the rigors of medical school, over the past year it has been far more difficult to help patients locate generic Adderall. Physicians were already overburdened with administrative responsibilities stretching into burnout territory well before the shortage, and now this! Unlike paper prescriptions of old, which patients could take to any pharmacy, e-prescribing apps require selection of a specific pharmacy, and controlled substances such as stimulants require 2-factor authentication. But if the designated pharmacy does not have the medication in stock, the entire process must be repeated with an alternative pharmacy, long after the visit has concluded.

To add insult to injury, the generic stimulant shortage has grown even worse. As of February 2023, generic Adderall remained hard to find and generic Concerta was also in short supply. How did this happen? In 1985, Bulow et al¹ coined the game theory concept of “strategic substitutes,” where (for example) as beef becomes less readily accessible, consumers may switch to eating chicken as their protein. Unable to locate generic Adderall, many patients have turned to generic Concerta as a substitute psychostimulant to continue management of their attention-deficit/hyperactivity disorder.

In addition to the increase in demand, compounding the shortage is that one of the manufacturers of generic Concerta has discontinued production.² Branded methylphenidates and amphetamines, which are much more expensive than their generic counterparts, have remained in ample supply, but many insurers require trials of generics before considering coverage for more expensive brands.

Our approach to this situation

Each morning we call our local and chain pharmacies to take a census of their supply of generic stimulants. Some pharmacies refuse to release this information. Despite these census reports, we have found cases where patients have been turned away from pharmacies when they are not “regular customers,” while patients whom the pharmacies know retain access as “members.” Hence, a patient is unlikely to obtain these medications if their regular pharmacy is out of stock.

We want to share a workaround that has been effective. After unsuccessfully searching for generic stimulants at the patient’s regular pharmacy, I (RLP) write “dispense as written” for the closest branded version and file a prior authorization with the patient’s insurance company, noting “patient unable to trial any generic amphetamines or methylphenidates due to current nationwide shortage.” Even with the most difficult insurers, the response has been “a temporary 3-month authorization has been granted,” which is at least a small victory for our desperate patients and busy prescribers who are both struggling to negotiate a fragmented health care system.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact letters@currentpsychiatry.com.

I (MZP) just completed my first semester of medical school. An important lesson imparted in my coursework so far has been to remain a staunch advocate for patients. Yet compared to the rigors of medical school, over the past year it has been far more difficult to help patients locate generic Adderall. Physicians were already overburdened with administrative responsibilities stretching into burnout territory well before the shortage, and now this! Unlike paper prescriptions of old, which patients could take to any pharmacy, e-prescribing apps require selection of a specific pharmacy, and controlled substances such as stimulants require 2-factor authentication. But if the designated pharmacy does not have the medication in stock, the entire process must be repeated with an alternative pharmacy, long after the visit has concluded.

To add insult to injury, the generic stimulant shortage has grown even worse. As of February 2023, generic Adderall remained hard to find and generic Concerta was also in short supply. How did this happen? In 1985, Bulow et al¹ coined the game theory concept of “strategic substitutes,” where (for example) as beef becomes less readily accessible, consumers may switch to eating chicken as their protein. Unable to locate generic Adderall, many patients have turned to generic Concerta as a substitute psychostimulant to continue management of their attention-deficit/hyperactivity disorder.

In addition to the increase in demand, compounding the shortage is that one of the manufacturers of generic Concerta has discontinued production.² Branded methylphenidates and amphetamines, which are much more expensive than their generic counterparts, have remained in ample supply, but many insurers require trials of generics before considering coverage for more expensive brands.

Our approach to this situation

Each morning we call our local and chain pharmacies to take a census of their supply of generic stimulants. Some pharmacies refuse to release this information. Despite these census reports, we have found cases where patients have been turned away from pharmacies when they are not “regular customers,” while patients whom the pharmacies know retain access as “members.” Hence, a patient is unlikely to obtain these medications if their regular pharmacy is out of stock.

We want to share a workaround that has been effective. After unsuccessfully searching for generic stimulants at the patient’s regular pharmacy, I (RLP) write “dispense as written” for the closest branded version and file a prior authorization with the patient’s insurance company, noting “patient unable to trial any generic amphetamines or methylphenidates due to current nationwide shortage.” Even with the most difficult insurers, the response has been “a temporary 3-month authorization has been granted,” which is at least a small victory for our desperate patients and busy prescribers who are both struggling to negotiate a fragmented health care system.

More on ‘intellectual constipation’

Regarding your editorial, “From debate to stalemate and hate: An epidemic of intellectual constipation” (Current Psychiatry, January 2023, p. 3-4, doi:10.12788/cp.0321): fantastic and so very well put. As you (we) get older, we get more forceful in presenting our ideas. Your presentation is perfect for the times, and I hope your editorial is read by many. I have started a group of doctors (Psychiatrists of the Realm) that will be available to teach physicians and nonphysicians at no charge. It is our responsibility as the elder statesmen of medicine to make sure what wisdom we have acquired can be shared with others.

Robert W. Pollack, MD, ABPN, DLFAPA
Fort Myers, Florida

Disclosures
The author reports no financial relationships with any companies whose products are mentioned in this letter, or with manufacturers of competing products.

More on SWOT analysis of psychiatry

I loved your recent analysis of psychiatry (“Contemporary psychiatry: A SWOT analysis,” Current Psychiatry, January 2023, p. 16-19,27, doi:10.12788/cp.0320). What a great idea! It looks very complete to me. It occurs to me to consider adding a very simple but I think profound strength: the fact that one’s mental health affects every decision a person makes for their entire life. Taking this stance opens many doors and makes our input and expertise as a profession relevant to all aspects of society. Mental health is personal and matters deeply to all of us.

Paul R. Crosby, MD, MBA
President and CEO of the Frances and Craig Lindner Center of HOPE
Associate Professor and Vice Chair
Department of Psychiatry and Behavioral Neuroscience
University of Cincinnati College of Medicine
Cincinnati, Ohio

Disclosures
The author reports no financial relationships with any companies whose products are mentioned in this letter, or with manufacturers of competing products.

More on evolution’s triumphs and blunders

I enjoyed your editorial, “Is evolution’s greatest triumph its worst blunder?” (Current Psychiatry, November 2022, p. 5,10-11, doi:10.12788cp.0301). I commend you for the bravery and freshness of the view you suggest we reconsider. It is interesting that observation of humans' propensity for violence didn't cause Darwin to wonder how that fit into his survival paradigm since we were not likely to have been under threat of extinction while the human neocortex was undergoing its novel evolutionary design. Being born in 1809 would have given him enough time to have his doubts about undesired human evolutionary trajectories with potential extinction outcomes. I’m no expert, but I’ve never heard he considered that human potential could lean in that direction. You may have seen the article by Kirsch¹ about people who are advocating that humans voluntarily move toward extinction and let the planet live. I would be interested in a follow-up article on the type of comments and ideas inspired by your editorial. Kudos to you for your creativity.

Michele A. Packard, PhD
Boulder, Colorado

Disclosures
The author reports no financial relationships with any companies whose products are mentioned in this letter, or with manufacturers of competing products.

More on ‘intellectual constipation’

Regarding your editorial, “From debate to stalemate and hate: An epidemic of intellectual constipation” (Current Psychiatry, January 2023, p. 3-4, doi:10.12788/cp.0321): fantastic and so very well put. As you (we) get older, we get more forceful in presenting our ideas. Your presentation is perfect for the times, and I hope your editorial is read by many. I have started a group of doctors (Psychiatrists of the Realm) that will be available to teach physicians and nonphysicians at no charge. It is our responsibility as the elder statesmen of medicine to make sure what wisdom we have acquired can be shared with others.

Robert W. Pollack, MD, ABPN, DLFAPA
Fort Myers, Florida

Disclosures
The author reports no financial relationships with any companies whose products are mentioned in this letter, or with manufacturers of competing products.

More on SWOT analysis of psychiatry

I loved your recent analysis of psychiatry (“Contemporary psychiatry: A SWOT analysis,” Current Psychiatry, January 2023, p. 16-19,27, doi:10.12788/cp.0320). What a great idea! It looks very complete to me. It occurs to me to consider adding a very simple but I think profound strength: the fact that one’s mental health affects every decision a person makes for their entire life. Taking this stance opens many doors and makes our input and expertise as a profession relevant to all aspects of society. Mental health is personal and matters deeply to all of us.

Paul R. Crosby, MD, MBA
President and CEO of the Frances and Craig Lindner Center of HOPE
Associate Professor and Vice Chair
Department of Psychiatry and Behavioral Neuroscience
University of Cincinnati College of Medicine
Cincinnati, Ohio

Disclosures
The author reports no financial relationships with any companies whose products are mentioned in this letter, or with manufacturers of competing products.

More on evolution’s triumphs and blunders

I enjoyed your editorial, “Is evolution’s greatest triumph its worst blunder?” (Current Psychiatry, November 2022, p. 5,10-11, doi:10.12788cp.0301). I commend you for the bravery and freshness of the view you suggest we reconsider. It is interesting that observation of humans' propensity for violence didn't cause Darwin to wonder how that fit into his survival paradigm since we were not likely to have been under threat of extinction while the human neocortex was undergoing its novel evolutionary design. Being born in 1809 would have given him enough time to have his doubts about undesired human evolutionary trajectories with potential extinction outcomes. I’m no expert, but I’ve never heard he considered that human potential could lean in that direction. You may have seen the article by Kirsch¹ about people who are advocating that humans voluntarily move toward extinction and let the planet live. I would be interested in a follow-up article on the type of comments and ideas inspired by your editorial. Kudos to you for your creativity.

Michele A. Packard, PhD
Boulder, Colorado

Disclosures
The author reports no financial relationships with any companies whose products are mentioned in this letter, or with manufacturers of competing products.

More on ‘intellectual constipation’

Regarding your editorial, “From debate to stalemate and hate: An epidemic of intellectual constipation” (Current Psychiatry, January 2023, p. 3-4, doi:10.12788/cp.0321): fantastic and so very well put. As you (we) get older, we get more forceful in presenting our ideas. Your presentation is perfect for the times, and I hope your editorial is read by many. I have started a group of doctors (Psychiatrists of the Realm) that will be available to teach physicians and nonphysicians at no charge. It is our responsibility as the elder statesmen of medicine to make sure what wisdom we have acquired can be shared with others.

Robert W. Pollack, MD, ABPN, DLFAPA
Fort Myers, Florida

Disclosures
The author reports no financial relationships with any companies whose products are mentioned in this letter, or with manufacturers of competing products.

More on SWOT analysis of psychiatry

I loved your recent analysis of psychiatry (“Contemporary psychiatry: A SWOT analysis,” Current Psychiatry, January 2023, p. 16-19,27, doi:10.12788/cp.0320). What a great idea! It looks very complete to me. It occurs to me to consider adding a very simple but I think profound strength: the fact that one’s mental health affects every decision a person makes for their entire life. Taking this stance opens many doors and makes our input and expertise as a profession relevant to all aspects of society. Mental health is personal and matters deeply to all of us.

Paul R. Crosby, MD, MBA
President and CEO of the Frances and Craig Lindner Center of HOPE
Associate Professor and Vice Chair
Department of Psychiatry and Behavioral Neuroscience
University of Cincinnati College of Medicine
Cincinnati, Ohio

Disclosures
The author reports no financial relationships with any companies whose products are mentioned in this letter, or with manufacturers of competing products.

More on evolution’s triumphs and blunders

I enjoyed your editorial, “Is evolution’s greatest triumph its worst blunder?” (Current Psychiatry, November 2022, p. 5,10-11, doi:10.12788cp.0301). I commend you for the bravery and freshness of the view you suggest we reconsider. It is interesting that observation of humans' propensity for violence didn't cause Darwin to wonder how that fit into his survival paradigm since we were not likely to have been under threat of extinction while the human neocortex was undergoing its novel evolutionary design. Being born in 1809 would have given him enough time to have his doubts about undesired human evolutionary trajectories with potential extinction outcomes. I’m no expert, but I’ve never heard he considered that human potential could lean in that direction. You may have seen the article by Kirsch¹ about people who are advocating that humans voluntarily move toward extinction and let the planet live. I would be interested in a follow-up article on the type of comments and ideas inspired by your editorial. Kudos to you for your creativity.

Michele A. Packard, PhD
Boulder, Colorado

Disclosures
The author reports no financial relationships with any companies whose products are mentioned in this letter, or with manufacturers of competing products.

When left untreated, opioid use disorder (OUD) is a debilitating and potentially lethal illness. Despite the availability of safe and effective medications for OUD, the prevalence of opioid use and overdose deaths has been increasing every year.¹ An additional challenge in OUD treatment is the high prevalence of comorbid alcohol use disorder (AUD).^2-6 A Clinical Trials Network survey from the National Institute on Drug Abuse found 38% of persons seeking treatment for OUD also had AUD.⁷ Other analyses have found alcohol was involved in approximately one-fifth of opioid-related deaths.⁸ Research also reveals that comorbid OUD and AUD contributes to poor treatment outcomes, more medical comorbidities, and a high risk of death (including overdose death).^4,9 There is no standard of care for this particular patient population.³ This article reviews the evidence and summarizes practical considerations regarding the clinical management of patients with comorbid OUD and AUD.

To illustrate the various decision points, we will follow 2 hypothetical patients through various stages of treatment (Figure), from their presentation in the emergency department (ED) or outpatient clinic, through their hospital admission (if needed), and into their outpatient follow-up treatment.

CASE REPORTS

Ms. A and Ms. B present to the ED for evaluation of nausea, vomiting, sweating, anxiety, and tremor. Both patients describe their most recent use of both alcohol and opioids approximately 12 hours ago, and each has been attempting to stop using both substances at home.

Decision-making in the emergency setting

In the ED, a few important decisions need to be made regarding treatment:

• Are the presenting symptoms primarily due to alcohol withdrawal syndrome (AWS), opioid withdrawal syndrome (OWS), or both?
• Does the patient require inpatient medical withdrawal management (detoxification) based on the history and severity of the withdrawal symptoms?
• What are the patient’s treatment goals for their AUD and OUD?
• Is maintenance medication for OUD indicated? If so, which medication is most appropriate?

In the ED, the presentation of individuals affected by both OUD and AUD can be challenging because OWS shares overlapping features with AWS, including nausea, vomiting, diarrhea, sweating, anxiety, and tremor. However, although acute OWS is typically very uncomfortable, it is rarely lethal. On the other hand, severe AWS may result in delirium, seizures, and death,¹⁰ which makes it essential to recognize and treat appropriately.

Both Ms. A and Ms. B should be medically evaluated and treated by an emergency medicine physician in conjunction with psychiatric (or addiction medicine) consultation. The ED assessment of a patient presenting with both AUD and OUD should include vital signs monitoring; physical examination; blood work including comprehensive metabolic panel, serum magnesium, and phosphorus; complete blood count; pregnancy test for women of reproductive age; urine drug screen (UDS); urinalysis; and serum ethanol level. Of note, sympathetic hyperactivity is found in both alcohol and opioid withdrawal, and patients with alcohol withdrawal may also have hypokalemia, a condition associated with an increased risk of arrhythmia. Furthermore, a prolonged QTc would affect clinical decision-making about medications for OUD (ie, methadone) and withdrawal management (ie, ondansetron, trazodone, and hydroxyzine). Therefore, an electrocardiogram should be conducted, where appropriate.

Initial treatment of AWS includes vitamin supplementation (thiamine, folic acid, and multivitamins) and benzodiazepine administration (symptom-triggered and/or scheduled taper). It may also include IV fluid resuscitation, analgesics for pain, ondansetron for nausea and vomiting, and other electrolyte repletion as indicated by the laboratory results.¹¹ Additional measures for patients in opioid withdrawal should include alpha-2 agonists such as clonidine or lofexidine for adrenergic symptoms, antiemetics, antidiarrheals, muscle relaxants, anxiolytics such as hydroxyzine, and sleep medications such as trazodone.¹²

Continue to: The next decision...

The next decision is whether the patient needs to be admitted for inpatient treatment. This decision is based primarily on the risk assessment and severity of AWS, including a compelling history of complicated AWS such as seizures or delirium tremens as well as consideration of the complexity and severity of any comorbid medical or psychiatric conditions. Other indications for medical withdrawal management include a history of unsuccessful ambulatory withdrawal management and pregnancy. For severe AWS, a scheduled benzodiazepine taper in addition to the symptom-triggered protocol should be considered.^13-15 A psychiatric evaluation may be obtained in the ED, as long as the patient is sober enough to meaningfully participate in the psychiatric interview. Wherever possible, psychiatric interviews should be supplemented by collateral information.

CASE REPORTS CONTINUED

Ms. A admits to a 5-year history of alcohol and opioid use that meets the criteria for severe AUD and severe OUD. She has previously required inpatient treatment for seizures related to AWS. Laboratory results are notable for a serum ethanol level of 380 mg/dL, UDS positive for opioids, and a negative pregnancy test.

Disposition of patients in alcohol and opioid withdrawal

Given Ms. A’s history of seizures while withdrawing from alcohol, she is appropriate for hospital admission for medically managed withdrawal observation. As previously mentioned, there is clinical overlap between AWS and OWS, and differentiating between the 2 syndromes is essential and may be lifesaving. Whereas anxiety, agitation, diaphoresis, tachycardia, hypertension, and insomnia can be seen in both opioid and alcohol withdrawal, OWS-specific symptoms include mydriasis, lacrimation, rhinorrhea, bone or joint aches, yawning, and piloerection. AWS may present with visual or tactile hallucinations, delirium, and grand mal seizures.¹⁵

The details of inpatient management are beyond the scope of this article; however, both patients should be started on thiamine, folic acid, and a multivitamin. For patients in alcohol withdrawal with a history of poor diet who appear malnourished or have a history of malabsorption (such as gastric bypass surgery), thiamine 100 mg/d IV should be given for 3 to 5 days to prevent Wernicke encephalopathy.¹⁶ Where there is any concern the patient may be exhibiting signs of Wernicke-Korsakoff Syndrome (impaired cognition, evident malnourishment, ataxia, or eye movement abnormalities), high-dose thiamine IV should be given presumptively as follows: 500 mg IV 3 times a day for 3 days, 250 mg/d IV for 5 days, and then oral supplementation 100 mg/d for at least 30 days.¹⁷

In summary, on presentation to the ED, both patients should be medically stabilized and started on benzodiazepines for alcohol withdrawal. The risk assessment and the severity of the AWS often determines the level of care.

CASE REPORTS CONTINUED

On hospital Day 2, Ms. A tells the consulting psychiatrist she would like to start medications to treat her substance use disorders. She has a long history of failed attempts to achieve abstinence from opioids, so she and the psychiatrist agree to initiate a trial of buprenorphine/naloxone for her OUD, 4 mg/1 mg to 8 mg/2 mg for Day 1. Although buprenorphine/naloxone seems to help her alcohol cravings somewhat, she requests additional help. She experiences migraine headaches, which is in part why she began using opioid medications. Via joint decision making with her psychiatrist, she agrees to a trial of topiramate, with a slow titration schedule starting at 25 mg/d.

Continue to: Management decisions

The next issue is to determine the appropriate treatment for the patient’s OUD. Although treating OWS is important in improving the patient’s health, decreasing their discomfort, and facilitating their participation in a psychosocial treatment program,¹⁸ current evidence suggests that opioid withdrawal management alone without medication for OUD rarely leads to long-term recovery.^19,20 Some research suggests that the risk of accidental opioid overdose immediately following acute withdrawal management may actually be increased due to decreased tolerance in these patients.^12,21,22

Three medications have the most evidence for OUD treatment: buprenorphine, methadone, and naltrexone.¹⁵ The decision to use buprenorphine, methadone, or naltrexone depends on a variety of factors, including the severity of the OUD, patient history of prior treatment successes and failures, comorbid medical and psychiatric conditions, and patient preference.⁴ Treatment with buprenorphine or methadone is preferred over naltrexone for patients who do not want to or cannot tolerate the physical and emotional discomfort of the opioid withdrawal process, who experience moderate to severe OUD, who have a history of failed abstinence-based treatment, or who have more severe physiological tolerance/dependence.¹² Buprenorphine is a mu opioid receptor partial agonist that has been shown to reduce opioid cravings,²³ provide moderate pain relief,²⁴ and ameliorate OWS.¹² It does not typically result in significant respiratory depression, which is the biggest safety concern for opioid use.¹² Buprenorphine may also treat comorbid AUD at higher doses; however, the data are inconclusive.^25,26 Buprenorphine should be prescribed with caution to patients with comorbid, uncontrolled AUD, due to the risk of respiratory depression when combined with alcohol. Patients who continue to drink alcohol but are able to abstain from opioids may consider starting an AUD-specific medication. Pharmacologic options are discussed in more detail in the next section.

For patients who have higher physiological dependence or more severe OUD, methadone may be a reasonable alternative to buprenorphine. Methadone, a mu-opioid receptor agonist, ameliorates OWS, reduces opioid cravings, and reduces the euphoric effects of opioid ingestion if the patient relapses. However, methadone can only be dispensed for the treatment of OUD by a federally-certified treatment program governed by restrictive and federally mandated guidelines. Compared to buprenorphine, methadone is more dangerous in overdose, has more drug interactions, and is more commonly diverted for recreational use.²⁷ Furthermore, methadone should be prescribed with caution to patients with comorbid, uncontrolled AUD, because both alcohol and methadone can result in respiratory depression.

By contrast, the first-line treatment for individuals experiencing moderateto severe AUD is typically naltrexone.²⁸ Naltrexone is contraindicated in Ms. A because she has a severe OUD and is unlikely to tolerate the opioid withdrawal process. Research suggests that the use of naltrexone for OUD should be limited to patients who have a mild disorder or who show low physiological dependence.²⁹ Alternatively, acamprosate, disulfiram, topiramate, or gabapentin should be considered for Ms. A.^4,28,30 Because each of these medications have specific strengths and weaknesses, medication selection should be based on individual patient factors such as comorbid psychiatric and medical conditions and/or patient preference.²⁸

Management decisions: AUD augmentation strategies

Naltrexone is contraindicated for patients who are receiving opioids, including opioid agonist therapy for OUD. Therefore, clinicians need to consider other options for these individuals. There are several medications with good evidence, including acamprosate, disulfiram, topiramate, and gabapentin. Acamprosate and disulfiram are FDA-approved for AUD; the latter 2 have been used off-label.

Continue to: Acamprosate is a glutamate receptor modulator...

Acamprosate is a glutamate receptor modulator that reduces alcohol cravings and is recommended for patients who have achieved and wish to maintain abstinence. It can be used in patients with liver disease, because it is not hepatically metabolized.³⁰ Topiramate is also used to reduce alcohol cravings. It antagonizes glutamate at alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and kainite receptors, facilitates gamma-aminobutyric acid (GABA) function, and reduces the extracellular release of dopamine in the mesocorticolimbic regions of the brain.³⁰ Topiramate is a reasonable option for patients with a seizure disorder, a history of migraine headaches,³⁰ or who are overweight or obese and wish to lose weight.³¹ In a nonrandomized study, topiramate reduced alcohol intake and cravings more than naltrexone.³²

Disulfiram is another second-line therapy for AUD. It is best used under close supervision because it does not reduce alcohol cravings but makes ingesting alcohol extremely aversive by preventing the breakdown of the alcohol metabolite acetaldehyde, and in doing so causes a cluster of unpleasant symptoms, including sweating, palpitations, flushing, nausea/vomiting, and increased sympathetic tone.²⁸ Disulfiram only works if it is taken daily, and it requires a high degree of motivation and/or daily supervision at home or in the clinic.³³ It is not recommended to be used as a first-line treatment based on its potential toxicity, adverse effects, and mixed findings on its efficacy. In addition, it should not be given to medically vulnerable/fragile individuals.

Lastly, gabapentin, a voltage-gated calcium channel modulator, may also be used as a second-line agent for AUD. Patients who have started alcohol withdrawal management with gabapentin may wish to continue treatment to assist with craving suppression.³⁰ It is also a good choice for patients who have comorbid diabetic neuropathy or other neuro­pathic pain conditions, anxiety, or insomnia.^30,34 Of note, there have been reports of gabapentin misuse.

CASE REPORTS CONTINUED

Ms. B presents to the ED with a 5-year history of moderate AUD and a 2-year history of mild OUD. She denies a history of severe or complicated AWS. Her laboratory results are significant for a serum ethanol level of 250 mg/dL, UDS positive for opioids, and a negative pregnancy test.

Management decisions: Naltrexone for OUD

In contrast to Ms. A, Ms. B is likely able to complete the opioid withdrawal management process. It is reasonable to treat her uncomplicated, moderate alcohol withdrawal as an outpatient with gabapentin or a benzodiazepine taper. Had her AUD been as severe as Ms. A’s, or if she were unsuccessful with ambulatory withdrawal treatment attempts, Ms. B would also be a candidate for inpatient medical treatment for alcohol withdrawal regardless of the severity of her OUD. Ongoing pharmacotherapy for her AUD after withdrawal management is the same as previously outlined. After Ms. B completes the taper (typically 1 week after the ED visit), she should follow up for initiation of pharmacotherapy for AUD. Ms. B is an ideal candidate for naltrexone, which targets both AUD and OUD.

Continue to: Naltrexone is a semi-synthetic...

Naltrexone is a semi-synthetic competitive antagonist at mu-opioid receptors and a partial agonist at kappa receptors; it has little to no activity at delta receptors. Naltrexone has been shown to reduce alcohol cravings and diminish the euphoric effects of alcohol by reducing endogenous opioid release and receptor activation.³⁵ Thus, even when patients do use alcohol while taking naltrexone, the amount of alcohol they use is typically substantially reduced.³⁶ In fact, at a standard dose of 50 mg/d, 95% of mu-opioid receptors are occupied and are shown to yield approximately 40% alcohol abstinence rates at 1 year.³⁶

Once Ms. B has completed withdrawal management from both alcohol and opioids, she should have a trial period of oral naltrexone to prove tolerability, and then transition to the long-acting injectable (LAI) formulation. Patients able to complete withdrawal management from opioids and transition to LAI naltrexone have been shown to have equivalent rates of successful abstinence from opioids compared to buprenorphine.³⁷ Though Ms. B could opt to try buprenorphine to treat her mild OUD, naltrexone would be the preferred option because it has 3 advantages:

• it blocks the mu-opioid receptor, which prevents euphoria if an illicit substance is used
• it does not cause physiologic dependence or withdrawal syndrome if/when stopped
• if it is not effective, it is easy to switch to buprenorphine.

Lastly, all patients with OUD should be prescribed a rescue naloxone kit, in accordance with harm-reduction guidelines. Naloxone, a potent opioid receptor antagonist, is used to prevent or reverse respiratory depression in opioid overdose. Naloxone rescue kits include intranasal naloxone, which makes it easy for nonclinician bystanders to administer while waiting for emergency transport.³⁸ Most states allow naloxone kits to be prescribed to individuals who have a concern for overdose among friends, family, or others in the community. The wide distribution and easy availability of naloxone rescue kits have been essential in decreasing overdose deaths among patients who misuse opioids.³⁹

Take-home points

Patients with both OUD and AUD are relatively common and often pose significant management challenges when they present to the clinic or the ED in withdrawal. Because severe AWS can be life-threatening, hospitalization should be considered. OWS is often accompanied by intense cravings that can lead to relapse and the risk of accidental opioid overdose/death. As soon as patients are able to engage in a discussion about their treatment options, clinicians need to clarify the patient’s goals and priorities. In medications for OUD, the decision of whether to use buprenorphine, naltrexone, or methadone is guided by the severity of the OUD, the patient’s past treatment experience (illicit as well as prescribed), and patient preference. If the OUD is mild or if the patient prefers to avoid opioid agonist medications and can tolerate the opioid withdrawal process, both the AUD and OUD can be treated with naltrexone, preferably with the LAI formulation. Other AUD medications and outpatient psychotherapy may be used to augment treatment outcomes. For patients with a moderate to severe OUD, buprenorphine (preferably with immediate initiation) or methadone therapy should be offered. Patients with comorbid OUD and AUD who are treated with opioid agonists should be offered medication for AUD other than naltrexone, as outlined above. All patients with substance use disorders would benefit from psychosocial interventions, including group and individual therapy as well as community sober support groups.

Bottom Line

Patients with comorbid opioid use disorder (OUD) and alcohol use disorder (AUD) often pose significant management challenges when they present in withdrawal. This article reviews the evidence and summarizes practical considerations regarding the clinical management of patients with comorbid OUD and AUD.

Related Resources

• Chaney L, Mathia C, Cole T. Transitioning patients with opioid use disorder from methadone to buprenorphine. Current Psychiatry. 2022;21(12):23-24,28. doi:10.12788/ cp.0305
• Eatmon CV, Trent K. Pharmacotherapy for alcohol use disorder in patients with hepatic impairment. Current Psychiatry. 2021;20(12):25-28. doi:10.12788/cp.0068

Drug Brand Names

Acamprosate • Campral
Buprenorphine/naloxone • Suboxone, Zubsolv
Clonidine • Catapres
Disulfiram • Antabuse
Gabapentin • Neurontin
Hydroxyzine • Vistaril
Lofexidine • Lucemyra
Methadone • Methadose, Dolophine
Naloxone • Narcan
Naltrexone • ReVia, Vivitrol
Ondansetron • Zofran
Topiramate • Topamax
Trazodone • Desyrel, Oleptro

When left untreated, opioid use disorder (OUD) is a debilitating and potentially lethal illness. Despite the availability of safe and effective medications for OUD, the prevalence of opioid use and overdose deaths has been increasing every year.¹ An additional challenge in OUD treatment is the high prevalence of comorbid alcohol use disorder (AUD).^2-6 A Clinical Trials Network survey from the National Institute on Drug Abuse found 38% of persons seeking treatment for OUD also had AUD.⁷ Other analyses have found alcohol was involved in approximately one-fifth of opioid-related deaths.⁸ Research also reveals that comorbid OUD and AUD contributes to poor treatment outcomes, more medical comorbidities, and a high risk of death (including overdose death).^4,9 There is no standard of care for this particular patient population.³ This article reviews the evidence and summarizes practical considerations regarding the clinical management of patients with comorbid OUD and AUD.

To illustrate the various decision points, we will follow 2 hypothetical patients through various stages of treatment (Figure), from their presentation in the emergency department (ED) or outpatient clinic, through their hospital admission (if needed), and into their outpatient follow-up treatment.

CASE REPORTS

Ms. A and Ms. B present to the ED for evaluation of nausea, vomiting, sweating, anxiety, and tremor. Both patients describe their most recent use of both alcohol and opioids approximately 12 hours ago, and each has been attempting to stop using both substances at home.

Decision-making in the emergency setting

In the ED, a few important decisions need to be made regarding treatment:

• Are the presenting symptoms primarily due to alcohol withdrawal syndrome (AWS), opioid withdrawal syndrome (OWS), or both?
• Does the patient require inpatient medical withdrawal management (detoxification) based on the history and severity of the withdrawal symptoms?
• What are the patient’s treatment goals for their AUD and OUD?
• Is maintenance medication for OUD indicated? If so, which medication is most appropriate?

In the ED, the presentation of individuals affected by both OUD and AUD can be challenging because OWS shares overlapping features with AWS, including nausea, vomiting, diarrhea, sweating, anxiety, and tremor. However, although acute OWS is typically very uncomfortable, it is rarely lethal. On the other hand, severe AWS may result in delirium, seizures, and death,¹⁰ which makes it essential to recognize and treat appropriately.

Both Ms. A and Ms. B should be medically evaluated and treated by an emergency medicine physician in conjunction with psychiatric (or addiction medicine) consultation. The ED assessment of a patient presenting with both AUD and OUD should include vital signs monitoring; physical examination; blood work including comprehensive metabolic panel, serum magnesium, and phosphorus; complete blood count; pregnancy test for women of reproductive age; urine drug screen (UDS); urinalysis; and serum ethanol level. Of note, sympathetic hyperactivity is found in both alcohol and opioid withdrawal, and patients with alcohol withdrawal may also have hypokalemia, a condition associated with an increased risk of arrhythmia. Furthermore, a prolonged QTc would affect clinical decision-making about medications for OUD (ie, methadone) and withdrawal management (ie, ondansetron, trazodone, and hydroxyzine). Therefore, an electrocardiogram should be conducted, where appropriate.

Initial treatment of AWS includes vitamin supplementation (thiamine, folic acid, and multivitamins) and benzodiazepine administration (symptom-triggered and/or scheduled taper). It may also include IV fluid resuscitation, analgesics for pain, ondansetron for nausea and vomiting, and other electrolyte repletion as indicated by the laboratory results.¹¹ Additional measures for patients in opioid withdrawal should include alpha-2 agonists such as clonidine or lofexidine for adrenergic symptoms, antiemetics, antidiarrheals, muscle relaxants, anxiolytics such as hydroxyzine, and sleep medications such as trazodone.¹²

Continue to: The next decision...

The next decision is whether the patient needs to be admitted for inpatient treatment. This decision is based primarily on the risk assessment and severity of AWS, including a compelling history of complicated AWS such as seizures or delirium tremens as well as consideration of the complexity and severity of any comorbid medical or psychiatric conditions. Other indications for medical withdrawal management include a history of unsuccessful ambulatory withdrawal management and pregnancy. For severe AWS, a scheduled benzodiazepine taper in addition to the symptom-triggered protocol should be considered.^13-15 A psychiatric evaluation may be obtained in the ED, as long as the patient is sober enough to meaningfully participate in the psychiatric interview. Wherever possible, psychiatric interviews should be supplemented by collateral information.

CASE REPORTS CONTINUED

Ms. A admits to a 5-year history of alcohol and opioid use that meets the criteria for severe AUD and severe OUD. She has previously required inpatient treatment for seizures related to AWS. Laboratory results are notable for a serum ethanol level of 380 mg/dL, UDS positive for opioids, and a negative pregnancy test.

Disposition of patients in alcohol and opioid withdrawal

Given Ms. A’s history of seizures while withdrawing from alcohol, she is appropriate for hospital admission for medically managed withdrawal observation. As previously mentioned, there is clinical overlap between AWS and OWS, and differentiating between the 2 syndromes is essential and may be lifesaving. Whereas anxiety, agitation, diaphoresis, tachycardia, hypertension, and insomnia can be seen in both opioid and alcohol withdrawal, OWS-specific symptoms include mydriasis, lacrimation, rhinorrhea, bone or joint aches, yawning, and piloerection. AWS may present with visual or tactile hallucinations, delirium, and grand mal seizures.¹⁵

The details of inpatient management are beyond the scope of this article; however, both patients should be started on thiamine, folic acid, and a multivitamin. For patients in alcohol withdrawal with a history of poor diet who appear malnourished or have a history of malabsorption (such as gastric bypass surgery), thiamine 100 mg/d IV should be given for 3 to 5 days to prevent Wernicke encephalopathy.¹⁶ Where there is any concern the patient may be exhibiting signs of Wernicke-Korsakoff Syndrome (impaired cognition, evident malnourishment, ataxia, or eye movement abnormalities), high-dose thiamine IV should be given presumptively as follows: 500 mg IV 3 times a day for 3 days, 250 mg/d IV for 5 days, and then oral supplementation 100 mg/d for at least 30 days.¹⁷

In summary, on presentation to the ED, both patients should be medically stabilized and started on benzodiazepines for alcohol withdrawal. The risk assessment and the severity of the AWS often determines the level of care.

CASE REPORTS CONTINUED

On hospital Day 2, Ms. A tells the consulting psychiatrist she would like to start medications to treat her substance use disorders. She has a long history of failed attempts to achieve abstinence from opioids, so she and the psychiatrist agree to initiate a trial of buprenorphine/naloxone for her OUD, 4 mg/1 mg to 8 mg/2 mg for Day 1. Although buprenorphine/naloxone seems to help her alcohol cravings somewhat, she requests additional help. She experiences migraine headaches, which is in part why she began using opioid medications. Via joint decision making with her psychiatrist, she agrees to a trial of topiramate, with a slow titration schedule starting at 25 mg/d.

Continue to: Management decisions

The next issue is to determine the appropriate treatment for the patient’s OUD. Although treating OWS is important in improving the patient’s health, decreasing their discomfort, and facilitating their participation in a psychosocial treatment program,¹⁸ current evidence suggests that opioid withdrawal management alone without medication for OUD rarely leads to long-term recovery.^19,20 Some research suggests that the risk of accidental opioid overdose immediately following acute withdrawal management may actually be increased due to decreased tolerance in these patients.^12,21,22

Three medications have the most evidence for OUD treatment: buprenorphine, methadone, and naltrexone.¹⁵ The decision to use buprenorphine, methadone, or naltrexone depends on a variety of factors, including the severity of the OUD, patient history of prior treatment successes and failures, comorbid medical and psychiatric conditions, and patient preference.⁴ Treatment with buprenorphine or methadone is preferred over naltrexone for patients who do not want to or cannot tolerate the physical and emotional discomfort of the opioid withdrawal process, who experience moderate to severe OUD, who have a history of failed abstinence-based treatment, or who have more severe physiological tolerance/dependence.¹² Buprenorphine is a mu opioid receptor partial agonist that has been shown to reduce opioid cravings,²³ provide moderate pain relief,²⁴ and ameliorate OWS.¹² It does not typically result in significant respiratory depression, which is the biggest safety concern for opioid use.¹² Buprenorphine may also treat comorbid AUD at higher doses; however, the data are inconclusive.^25,26 Buprenorphine should be prescribed with caution to patients with comorbid, uncontrolled AUD, due to the risk of respiratory depression when combined with alcohol. Patients who continue to drink alcohol but are able to abstain from opioids may consider starting an AUD-specific medication. Pharmacologic options are discussed in more detail in the next section.

For patients who have higher physiological dependence or more severe OUD, methadone may be a reasonable alternative to buprenorphine. Methadone, a mu-opioid receptor agonist, ameliorates OWS, reduces opioid cravings, and reduces the euphoric effects of opioid ingestion if the patient relapses. However, methadone can only be dispensed for the treatment of OUD by a federally-certified treatment program governed by restrictive and federally mandated guidelines. Compared to buprenorphine, methadone is more dangerous in overdose, has more drug interactions, and is more commonly diverted for recreational use.²⁷ Furthermore, methadone should be prescribed with caution to patients with comorbid, uncontrolled AUD, because both alcohol and methadone can result in respiratory depression.

By contrast, the first-line treatment for individuals experiencing moderateto severe AUD is typically naltrexone.²⁸ Naltrexone is contraindicated in Ms. A because she has a severe OUD and is unlikely to tolerate the opioid withdrawal process. Research suggests that the use of naltrexone for OUD should be limited to patients who have a mild disorder or who show low physiological dependence.²⁹ Alternatively, acamprosate, disulfiram, topiramate, or gabapentin should be considered for Ms. A.^4,28,30 Because each of these medications have specific strengths and weaknesses, medication selection should be based on individual patient factors such as comorbid psychiatric and medical conditions and/or patient preference.²⁸

Management decisions: AUD augmentation strategies

Naltrexone is contraindicated for patients who are receiving opioids, including opioid agonist therapy for OUD. Therefore, clinicians need to consider other options for these individuals. There are several medications with good evidence, including acamprosate, disulfiram, topiramate, and gabapentin. Acamprosate and disulfiram are FDA-approved for AUD; the latter 2 have been used off-label.

Continue to: Acamprosate is a glutamate receptor modulator...

Acamprosate is a glutamate receptor modulator that reduces alcohol cravings and is recommended for patients who have achieved and wish to maintain abstinence. It can be used in patients with liver disease, because it is not hepatically metabolized.³⁰ Topiramate is also used to reduce alcohol cravings. It antagonizes glutamate at alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and kainite receptors, facilitates gamma-aminobutyric acid (GABA) function, and reduces the extracellular release of dopamine in the mesocorticolimbic regions of the brain.³⁰ Topiramate is a reasonable option for patients with a seizure disorder, a history of migraine headaches,³⁰ or who are overweight or obese and wish to lose weight.³¹ In a nonrandomized study, topiramate reduced alcohol intake and cravings more than naltrexone.³²

Disulfiram is another second-line therapy for AUD. It is best used under close supervision because it does not reduce alcohol cravings but makes ingesting alcohol extremely aversive by preventing the breakdown of the alcohol metabolite acetaldehyde, and in doing so causes a cluster of unpleasant symptoms, including sweating, palpitations, flushing, nausea/vomiting, and increased sympathetic tone.²⁸ Disulfiram only works if it is taken daily, and it requires a high degree of motivation and/or daily supervision at home or in the clinic.³³ It is not recommended to be used as a first-line treatment based on its potential toxicity, adverse effects, and mixed findings on its efficacy. In addition, it should not be given to medically vulnerable/fragile individuals.

Lastly, gabapentin, a voltage-gated calcium channel modulator, may also be used as a second-line agent for AUD. Patients who have started alcohol withdrawal management with gabapentin may wish to continue treatment to assist with craving suppression.³⁰ It is also a good choice for patients who have comorbid diabetic neuropathy or other neuro­pathic pain conditions, anxiety, or insomnia.^30,34 Of note, there have been reports of gabapentin misuse.

CASE REPORTS CONTINUED

Ms. B presents to the ED with a 5-year history of moderate AUD and a 2-year history of mild OUD. She denies a history of severe or complicated AWS. Her laboratory results are significant for a serum ethanol level of 250 mg/dL, UDS positive for opioids, and a negative pregnancy test.

Management decisions: Naltrexone for OUD

In contrast to Ms. A, Ms. B is likely able to complete the opioid withdrawal management process. It is reasonable to treat her uncomplicated, moderate alcohol withdrawal as an outpatient with gabapentin or a benzodiazepine taper. Had her AUD been as severe as Ms. A’s, or if she were unsuccessful with ambulatory withdrawal treatment attempts, Ms. B would also be a candidate for inpatient medical treatment for alcohol withdrawal regardless of the severity of her OUD. Ongoing pharmacotherapy for her AUD after withdrawal management is the same as previously outlined. After Ms. B completes the taper (typically 1 week after the ED visit), she should follow up for initiation of pharmacotherapy for AUD. Ms. B is an ideal candidate for naltrexone, which targets both AUD and OUD.

Continue to: Naltrexone is a semi-synthetic...

Naltrexone is a semi-synthetic competitive antagonist at mu-opioid receptors and a partial agonist at kappa receptors; it has little to no activity at delta receptors. Naltrexone has been shown to reduce alcohol cravings and diminish the euphoric effects of alcohol by reducing endogenous opioid release and receptor activation.³⁵ Thus, even when patients do use alcohol while taking naltrexone, the amount of alcohol they use is typically substantially reduced.³⁶ In fact, at a standard dose of 50 mg/d, 95% of mu-opioid receptors are occupied and are shown to yield approximately 40% alcohol abstinence rates at 1 year.³⁶

Once Ms. B has completed withdrawal management from both alcohol and opioids, she should have a trial period of oral naltrexone to prove tolerability, and then transition to the long-acting injectable (LAI) formulation. Patients able to complete withdrawal management from opioids and transition to LAI naltrexone have been shown to have equivalent rates of successful abstinence from opioids compared to buprenorphine.³⁷ Though Ms. B could opt to try buprenorphine to treat her mild OUD, naltrexone would be the preferred option because it has 3 advantages:

• it blocks the mu-opioid receptor, which prevents euphoria if an illicit substance is used
• it does not cause physiologic dependence or withdrawal syndrome if/when stopped
• if it is not effective, it is easy to switch to buprenorphine.

Lastly, all patients with OUD should be prescribed a rescue naloxone kit, in accordance with harm-reduction guidelines. Naloxone, a potent opioid receptor antagonist, is used to prevent or reverse respiratory depression in opioid overdose. Naloxone rescue kits include intranasal naloxone, which makes it easy for nonclinician bystanders to administer while waiting for emergency transport.³⁸ Most states allow naloxone kits to be prescribed to individuals who have a concern for overdose among friends, family, or others in the community. The wide distribution and easy availability of naloxone rescue kits have been essential in decreasing overdose deaths among patients who misuse opioids.³⁹

Take-home points

Patients with both OUD and AUD are relatively common and often pose significant management challenges when they present to the clinic or the ED in withdrawal. Because severe AWS can be life-threatening, hospitalization should be considered. OWS is often accompanied by intense cravings that can lead to relapse and the risk of accidental opioid overdose/death. As soon as patients are able to engage in a discussion about their treatment options, clinicians need to clarify the patient’s goals and priorities. In medications for OUD, the decision of whether to use buprenorphine, naltrexone, or methadone is guided by the severity of the OUD, the patient’s past treatment experience (illicit as well as prescribed), and patient preference. If the OUD is mild or if the patient prefers to avoid opioid agonist medications and can tolerate the opioid withdrawal process, both the AUD and OUD can be treated with naltrexone, preferably with the LAI formulation. Other AUD medications and outpatient psychotherapy may be used to augment treatment outcomes. For patients with a moderate to severe OUD, buprenorphine (preferably with immediate initiation) or methadone therapy should be offered. Patients with comorbid OUD and AUD who are treated with opioid agonists should be offered medication for AUD other than naltrexone, as outlined above. All patients with substance use disorders would benefit from psychosocial interventions, including group and individual therapy as well as community sober support groups.

Bottom Line

Patients with comorbid opioid use disorder (OUD) and alcohol use disorder (AUD) often pose significant management challenges when they present in withdrawal. This article reviews the evidence and summarizes practical considerations regarding the clinical management of patients with comorbid OUD and AUD.

Related Resources

• Chaney L, Mathia C, Cole T. Transitioning patients with opioid use disorder from methadone to buprenorphine. Current Psychiatry. 2022;21(12):23-24,28. doi:10.12788/ cp.0305
• Eatmon CV, Trent K. Pharmacotherapy for alcohol use disorder in patients with hepatic impairment. Current Psychiatry. 2021;20(12):25-28. doi:10.12788/cp.0068

Drug Brand Names

Acamprosate • Campral
Buprenorphine/naloxone • Suboxone, Zubsolv
Clonidine • Catapres
Disulfiram • Antabuse
Gabapentin • Neurontin
Hydroxyzine • Vistaril
Lofexidine • Lucemyra
Methadone • Methadose, Dolophine
Naloxone • Narcan
Naltrexone • ReVia, Vivitrol
Ondansetron • Zofran
Topiramate • Topamax
Trazodone • Desyrel, Oleptro

When left untreated, opioid use disorder (OUD) is a debilitating and potentially lethal illness. Despite the availability of safe and effective medications for OUD, the prevalence of opioid use and overdose deaths has been increasing every year.¹ An additional challenge in OUD treatment is the high prevalence of comorbid alcohol use disorder (AUD).^2-6 A Clinical Trials Network survey from the National Institute on Drug Abuse found 38% of persons seeking treatment for OUD also had AUD.⁷ Other analyses have found alcohol was involved in approximately one-fifth of opioid-related deaths.⁸ Research also reveals that comorbid OUD and AUD contributes to poor treatment outcomes, more medical comorbidities, and a high risk of death (including overdose death).^4,9 There is no standard of care for this particular patient population.³ This article reviews the evidence and summarizes practical considerations regarding the clinical management of patients with comorbid OUD and AUD.

To illustrate the various decision points, we will follow 2 hypothetical patients through various stages of treatment (Figure), from their presentation in the emergency department (ED) or outpatient clinic, through their hospital admission (if needed), and into their outpatient follow-up treatment.

CASE REPORTS

Ms. A and Ms. B present to the ED for evaluation of nausea, vomiting, sweating, anxiety, and tremor. Both patients describe their most recent use of both alcohol and opioids approximately 12 hours ago, and each has been attempting to stop using both substances at home.

Decision-making in the emergency setting

In the ED, a few important decisions need to be made regarding treatment:

• Are the presenting symptoms primarily due to alcohol withdrawal syndrome (AWS), opioid withdrawal syndrome (OWS), or both?
• Does the patient require inpatient medical withdrawal management (detoxification) based on the history and severity of the withdrawal symptoms?
• What are the patient’s treatment goals for their AUD and OUD?
• Is maintenance medication for OUD indicated? If so, which medication is most appropriate?

In the ED, the presentation of individuals affected by both OUD and AUD can be challenging because OWS shares overlapping features with AWS, including nausea, vomiting, diarrhea, sweating, anxiety, and tremor. However, although acute OWS is typically very uncomfortable, it is rarely lethal. On the other hand, severe AWS may result in delirium, seizures, and death,¹⁰ which makes it essential to recognize and treat appropriately.

Both Ms. A and Ms. B should be medically evaluated and treated by an emergency medicine physician in conjunction with psychiatric (or addiction medicine) consultation. The ED assessment of a patient presenting with both AUD and OUD should include vital signs monitoring; physical examination; blood work including comprehensive metabolic panel, serum magnesium, and phosphorus; complete blood count; pregnancy test for women of reproductive age; urine drug screen (UDS); urinalysis; and serum ethanol level. Of note, sympathetic hyperactivity is found in both alcohol and opioid withdrawal, and patients with alcohol withdrawal may also have hypokalemia, a condition associated with an increased risk of arrhythmia. Furthermore, a prolonged QTc would affect clinical decision-making about medications for OUD (ie, methadone) and withdrawal management (ie, ondansetron, trazodone, and hydroxyzine). Therefore, an electrocardiogram should be conducted, where appropriate.

Initial treatment of AWS includes vitamin supplementation (thiamine, folic acid, and multivitamins) and benzodiazepine administration (symptom-triggered and/or scheduled taper). It may also include IV fluid resuscitation, analgesics for pain, ondansetron for nausea and vomiting, and other electrolyte repletion as indicated by the laboratory results.¹¹ Additional measures for patients in opioid withdrawal should include alpha-2 agonists such as clonidine or lofexidine for adrenergic symptoms, antiemetics, antidiarrheals, muscle relaxants, anxiolytics such as hydroxyzine, and sleep medications such as trazodone.¹²

Continue to: The next decision...

The next decision is whether the patient needs to be admitted for inpatient treatment. This decision is based primarily on the risk assessment and severity of AWS, including a compelling history of complicated AWS such as seizures or delirium tremens as well as consideration of the complexity and severity of any comorbid medical or psychiatric conditions. Other indications for medical withdrawal management include a history of unsuccessful ambulatory withdrawal management and pregnancy. For severe AWS, a scheduled benzodiazepine taper in addition to the symptom-triggered protocol should be considered.^13-15 A psychiatric evaluation may be obtained in the ED, as long as the patient is sober enough to meaningfully participate in the psychiatric interview. Wherever possible, psychiatric interviews should be supplemented by collateral information.

CASE REPORTS CONTINUED

Ms. A admits to a 5-year history of alcohol and opioid use that meets the criteria for severe AUD and severe OUD. She has previously required inpatient treatment for seizures related to AWS. Laboratory results are notable for a serum ethanol level of 380 mg/dL, UDS positive for opioids, and a negative pregnancy test.

Disposition of patients in alcohol and opioid withdrawal

Given Ms. A’s history of seizures while withdrawing from alcohol, she is appropriate for hospital admission for medically managed withdrawal observation. As previously mentioned, there is clinical overlap between AWS and OWS, and differentiating between the 2 syndromes is essential and may be lifesaving. Whereas anxiety, agitation, diaphoresis, tachycardia, hypertension, and insomnia can be seen in both opioid and alcohol withdrawal, OWS-specific symptoms include mydriasis, lacrimation, rhinorrhea, bone or joint aches, yawning, and piloerection. AWS may present with visual or tactile hallucinations, delirium, and grand mal seizures.¹⁵

The details of inpatient management are beyond the scope of this article; however, both patients should be started on thiamine, folic acid, and a multivitamin. For patients in alcohol withdrawal with a history of poor diet who appear malnourished or have a history of malabsorption (such as gastric bypass surgery), thiamine 100 mg/d IV should be given for 3 to 5 days to prevent Wernicke encephalopathy.¹⁶ Where there is any concern the patient may be exhibiting signs of Wernicke-Korsakoff Syndrome (impaired cognition, evident malnourishment, ataxia, or eye movement abnormalities), high-dose thiamine IV should be given presumptively as follows: 500 mg IV 3 times a day for 3 days, 250 mg/d IV for 5 days, and then oral supplementation 100 mg/d for at least 30 days.¹⁷

In summary, on presentation to the ED, both patients should be medically stabilized and started on benzodiazepines for alcohol withdrawal. The risk assessment and the severity of the AWS often determines the level of care.

CASE REPORTS CONTINUED

On hospital Day 2, Ms. A tells the consulting psychiatrist she would like to start medications to treat her substance use disorders. She has a long history of failed attempts to achieve abstinence from opioids, so she and the psychiatrist agree to initiate a trial of buprenorphine/naloxone for her OUD, 4 mg/1 mg to 8 mg/2 mg for Day 1. Although buprenorphine/naloxone seems to help her alcohol cravings somewhat, she requests additional help. She experiences migraine headaches, which is in part why she began using opioid medications. Via joint decision making with her psychiatrist, she agrees to a trial of topiramate, with a slow titration schedule starting at 25 mg/d.

Continue to: Management decisions

The next issue is to determine the appropriate treatment for the patient’s OUD. Although treating OWS is important in improving the patient’s health, decreasing their discomfort, and facilitating their participation in a psychosocial treatment program,¹⁸ current evidence suggests that opioid withdrawal management alone without medication for OUD rarely leads to long-term recovery.^19,20 Some research suggests that the risk of accidental opioid overdose immediately following acute withdrawal management may actually be increased due to decreased tolerance in these patients.^12,21,22

Three medications have the most evidence for OUD treatment: buprenorphine, methadone, and naltrexone.¹⁵ The decision to use buprenorphine, methadone, or naltrexone depends on a variety of factors, including the severity of the OUD, patient history of prior treatment successes and failures, comorbid medical and psychiatric conditions, and patient preference.⁴ Treatment with buprenorphine or methadone is preferred over naltrexone for patients who do not want to or cannot tolerate the physical and emotional discomfort of the opioid withdrawal process, who experience moderate to severe OUD, who have a history of failed abstinence-based treatment, or who have more severe physiological tolerance/dependence.¹² Buprenorphine is a mu opioid receptor partial agonist that has been shown to reduce opioid cravings,²³ provide moderate pain relief,²⁴ and ameliorate OWS.¹² It does not typically result in significant respiratory depression, which is the biggest safety concern for opioid use.¹² Buprenorphine may also treat comorbid AUD at higher doses; however, the data are inconclusive.^25,26 Buprenorphine should be prescribed with caution to patients with comorbid, uncontrolled AUD, due to the risk of respiratory depression when combined with alcohol. Patients who continue to drink alcohol but are able to abstain from opioids may consider starting an AUD-specific medication. Pharmacologic options are discussed in more detail in the next section.

For patients who have higher physiological dependence or more severe OUD, methadone may be a reasonable alternative to buprenorphine. Methadone, a mu-opioid receptor agonist, ameliorates OWS, reduces opioid cravings, and reduces the euphoric effects of opioid ingestion if the patient relapses. However, methadone can only be dispensed for the treatment of OUD by a federally-certified treatment program governed by restrictive and federally mandated guidelines. Compared to buprenorphine, methadone is more dangerous in overdose, has more drug interactions, and is more commonly diverted for recreational use.²⁷ Furthermore, methadone should be prescribed with caution to patients with comorbid, uncontrolled AUD, because both alcohol and methadone can result in respiratory depression.

By contrast, the first-line treatment for individuals experiencing moderateto severe AUD is typically naltrexone.²⁸ Naltrexone is contraindicated in Ms. A because she has a severe OUD and is unlikely to tolerate the opioid withdrawal process. Research suggests that the use of naltrexone for OUD should be limited to patients who have a mild disorder or who show low physiological dependence.²⁹ Alternatively, acamprosate, disulfiram, topiramate, or gabapentin should be considered for Ms. A.^4,28,30 Because each of these medications have specific strengths and weaknesses, medication selection should be based on individual patient factors such as comorbid psychiatric and medical conditions and/or patient preference.²⁸

Management decisions: AUD augmentation strategies

Naltrexone is contraindicated for patients who are receiving opioids, including opioid agonist therapy for OUD. Therefore, clinicians need to consider other options for these individuals. There are several medications with good evidence, including acamprosate, disulfiram, topiramate, and gabapentin. Acamprosate and disulfiram are FDA-approved for AUD; the latter 2 have been used off-label.

Continue to: Acamprosate is a glutamate receptor modulator...

Acamprosate is a glutamate receptor modulator that reduces alcohol cravings and is recommended for patients who have achieved and wish to maintain abstinence. It can be used in patients with liver disease, because it is not hepatically metabolized.³⁰ Topiramate is also used to reduce alcohol cravings. It antagonizes glutamate at alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and kainite receptors, facilitates gamma-aminobutyric acid (GABA) function, and reduces the extracellular release of dopamine in the mesocorticolimbic regions of the brain.³⁰ Topiramate is a reasonable option for patients with a seizure disorder, a history of migraine headaches,³⁰ or who are overweight or obese and wish to lose weight.³¹ In a nonrandomized study, topiramate reduced alcohol intake and cravings more than naltrexone.³²

Disulfiram is another second-line therapy for AUD. It is best used under close supervision because it does not reduce alcohol cravings but makes ingesting alcohol extremely aversive by preventing the breakdown of the alcohol metabolite acetaldehyde, and in doing so causes a cluster of unpleasant symptoms, including sweating, palpitations, flushing, nausea/vomiting, and increased sympathetic tone.²⁸ Disulfiram only works if it is taken daily, and it requires a high degree of motivation and/or daily supervision at home or in the clinic.³³ It is not recommended to be used as a first-line treatment based on its potential toxicity, adverse effects, and mixed findings on its efficacy. In addition, it should not be given to medically vulnerable/fragile individuals.

Lastly, gabapentin, a voltage-gated calcium channel modulator, may also be used as a second-line agent for AUD. Patients who have started alcohol withdrawal management with gabapentin may wish to continue treatment to assist with craving suppression.³⁰ It is also a good choice for patients who have comorbid diabetic neuropathy or other neuro­pathic pain conditions, anxiety, or insomnia.^30,34 Of note, there have been reports of gabapentin misuse.

CASE REPORTS CONTINUED

Ms. B presents to the ED with a 5-year history of moderate AUD and a 2-year history of mild OUD. She denies a history of severe or complicated AWS. Her laboratory results are significant for a serum ethanol level of 250 mg/dL, UDS positive for opioids, and a negative pregnancy test.

Management decisions: Naltrexone for OUD

In contrast to Ms. A, Ms. B is likely able to complete the opioid withdrawal management process. It is reasonable to treat her uncomplicated, moderate alcohol withdrawal as an outpatient with gabapentin or a benzodiazepine taper. Had her AUD been as severe as Ms. A’s, or if she were unsuccessful with ambulatory withdrawal treatment attempts, Ms. B would also be a candidate for inpatient medical treatment for alcohol withdrawal regardless of the severity of her OUD. Ongoing pharmacotherapy for her AUD after withdrawal management is the same as previously outlined. After Ms. B completes the taper (typically 1 week after the ED visit), she should follow up for initiation of pharmacotherapy for AUD. Ms. B is an ideal candidate for naltrexone, which targets both AUD and OUD.

Continue to: Naltrexone is a semi-synthetic...

Naltrexone is a semi-synthetic competitive antagonist at mu-opioid receptors and a partial agonist at kappa receptors; it has little to no activity at delta receptors. Naltrexone has been shown to reduce alcohol cravings and diminish the euphoric effects of alcohol by reducing endogenous opioid release and receptor activation.³⁵ Thus, even when patients do use alcohol while taking naltrexone, the amount of alcohol they use is typically substantially reduced.³⁶ In fact, at a standard dose of 50 mg/d, 95% of mu-opioid receptors are occupied and are shown to yield approximately 40% alcohol abstinence rates at 1 year.³⁶

Once Ms. B has completed withdrawal management from both alcohol and opioids, she should have a trial period of oral naltrexone to prove tolerability, and then transition to the long-acting injectable (LAI) formulation. Patients able to complete withdrawal management from opioids and transition to LAI naltrexone have been shown to have equivalent rates of successful abstinence from opioids compared to buprenorphine.³⁷ Though Ms. B could opt to try buprenorphine to treat her mild OUD, naltrexone would be the preferred option because it has 3 advantages:

• it blocks the mu-opioid receptor, which prevents euphoria if an illicit substance is used
• it does not cause physiologic dependence or withdrawal syndrome if/when stopped
• if it is not effective, it is easy to switch to buprenorphine.

Lastly, all patients with OUD should be prescribed a rescue naloxone kit, in accordance with harm-reduction guidelines. Naloxone, a potent opioid receptor antagonist, is used to prevent or reverse respiratory depression in opioid overdose. Naloxone rescue kits include intranasal naloxone, which makes it easy for nonclinician bystanders to administer while waiting for emergency transport.³⁸ Most states allow naloxone kits to be prescribed to individuals who have a concern for overdose among friends, family, or others in the community. The wide distribution and easy availability of naloxone rescue kits have been essential in decreasing overdose deaths among patients who misuse opioids.³⁹

Take-home points

Patients with both OUD and AUD are relatively common and often pose significant management challenges when they present to the clinic or the ED in withdrawal. Because severe AWS can be life-threatening, hospitalization should be considered. OWS is often accompanied by intense cravings that can lead to relapse and the risk of accidental opioid overdose/death. As soon as patients are able to engage in a discussion about their treatment options, clinicians need to clarify the patient’s goals and priorities. In medications for OUD, the decision of whether to use buprenorphine, naltrexone, or methadone is guided by the severity of the OUD, the patient’s past treatment experience (illicit as well as prescribed), and patient preference. If the OUD is mild or if the patient prefers to avoid opioid agonist medications and can tolerate the opioid withdrawal process, both the AUD and OUD can be treated with naltrexone, preferably with the LAI formulation. Other AUD medications and outpatient psychotherapy may be used to augment treatment outcomes. For patients with a moderate to severe OUD, buprenorphine (preferably with immediate initiation) or methadone therapy should be offered. Patients with comorbid OUD and AUD who are treated with opioid agonists should be offered medication for AUD other than naltrexone, as outlined above. All patients with substance use disorders would benefit from psychosocial interventions, including group and individual therapy as well as community sober support groups.

Bottom Line

Patients with comorbid opioid use disorder (OUD) and alcohol use disorder (AUD) often pose significant management challenges when they present in withdrawal. This article reviews the evidence and summarizes practical considerations regarding the clinical management of patients with comorbid OUD and AUD.

Related Resources

• Chaney L, Mathia C, Cole T. Transitioning patients with opioid use disorder from methadone to buprenorphine. Current Psychiatry. 2022;21(12):23-24,28. doi:10.12788/ cp.0305
• Eatmon CV, Trent K. Pharmacotherapy for alcohol use disorder in patients with hepatic impairment. Current Psychiatry. 2021;20(12):25-28. doi:10.12788/cp.0068

Drug Brand Names

Acamprosate • Campral
Buprenorphine/naloxone • Suboxone, Zubsolv
Clonidine • Catapres
Disulfiram • Antabuse
Gabapentin • Neurontin
Hydroxyzine • Vistaril
Lofexidine • Lucemyra
Methadone • Methadose, Dolophine
Naloxone • Narcan
Naltrexone • ReVia, Vivitrol
Ondansetron • Zofran
Topiramate • Topamax
Trazodone • Desyrel, Oleptro

In 2021, suicide was the 11th leading cause of death in the United States.¹ Suicide resulted in 49,000 US deaths during 2021; it was the second most common cause of death in individuals age 10 to 34, and the fifth leading cause among children.^1,2 Women are 3 to 4 times more likely than men to attempt suicide, but men are 4 times more likely to die by suicide.²

The evaluation of patients with suicidal ideation who have not made an attempt generally involves assessing 4 factors: the specific plan, access to lethal means, any recent social stressors, and the presence of a psychiatric disorder.³ The clinician should also assess which potential deterrents, such as religious beliefs or dependent children, might be present.

Mental health clinicians are often called upon to evaluate a patient after a suicide attempt to assess intent for continued self-harm and to determine appropriate disposition. Such an evaluation must consider multiple factors, including the method used, premeditation, consequences of the attempt, the presence of severe depression and/or psychosis, and the role of substance use. Assessment after a suicide attempt differs from the examination of individuals who harbor suicidal thoughts but have not made an attempt; the latter group may be more likely to respond to interventions such as intensive outpatient care, mobilization of family support, and religious proscriptions against suicide. However, for patients who make an attempt to end their life, whatever potential safeguards or deterrents to suicide that were in place obviously did not prevent the self-harm act. The consequences of the attempt, such as disabling injuries or medical complications, and possible involuntary commitment, need to be considered. Assessment of the patient’s feelings about having survived the attempt is important because the psychological impact of the attempt on family members may serve to intensify the patient’s depression and make a subsequent attempt more likely.

Many individuals who think of suicide have communicated self-harm thoughts or intentions, but such comments are often minimized or ignored. There is a common but erroneous belief that if patients are encouraged to discuss thoughts of self-harm, they will be more likely to act upon them. Because the opposite is true,⁴ clinicians should ask vulnerable patients about suicidal ideation or intent. Importantly, noncompliance with life-saving medical care, risk-taking behaviors, and substance use may also signal a desire for self-harm. Passive thoughts of death, typified by comments such as “I don’t care whether I wake up or not,” should also be elicited. Many patients who think of suicide speak of being in a “bad place” where reason and logic give way to an intense desire to end their misery.

The evaluation of a patient who has attempted suicide is an important component of providing psychiatric care. This article reflects our 45 years of evaluating such patients. As such, it reflects our clinical experience and is not evidence-based. We offer a checklist of 14 questions that we have found helpful when determining if it would be best for a patient to receive inpatient psychiatric hospitalization or a discharge referral for outpatient care (Table). Questions 1 through 6 are specific for patients who have made a suicide attempt, while questions 7 through 14 are helpful for assessing global risk factors for suicide.

1. Was the attempt premeditated?

Determining premeditation vs impulsivity is an essential element of the assessment following a suicide attempt. Many such acts may occur without forethought in response to an unexpected stressor, such as an altercation between partners or family conflicts. Impulsive attempts can occur when an individual is involved in a distressing event and/or while intoxicated. Conversely, premeditation involves forethought and planning, which may increase the risk of suicide in the near future.

Examples of premeditated behavior include:

• Contemplating the attempt days or weeks beforehand
• Researching the effects of a medication or combination of medications in terms of potential lethality
• Engaging in behavior that would decrease the likelihood of their body being discovered after the attempt
• Obtaining weapons and/or stockpiling pills
• Canvassing potential sites such as bridges or tall buildings
• Engaging in a suicide attempt “practice run”
• Leaving a suicide note or message on social media
• Making funeral arrangements, such as choosing burial clothing
• Writing a will and arranging for the custody of dependent children
• Purchasing life insurance that does not deny payment of benefits in cases of death by suicide.

Continue to: Patients with a premeditated...

Patients with a premeditated suicide attempt generally do not expect to survive and are often surprised or upset that the act was not fatal. The presence of indicators that the attempt was premeditated should direct the disposition more toward hospitalization than discharge. In assessing the impact of premeditation, it is important to gauge not just the examples listed above, but also the patient’s perception of these issues (such as potential loss of child custody). Consider how much the patient is emotionally affected by such thinking.

2. What were the consequences of the attempt?

Assessing the reason for the attempt (if any) and determining whether the inciting circumstance has changed due to the suicide attempt are an important part of the evaluation. A suicide attempt may result in reconciliation with and/or renewed support from family members or partners, who might not have been aware of the patient’s emotional distress. Such unexpected support often results in the patient exhibiting improved mood and affect, and possibly temporary resolution of suicidal thoughts. This “flight into health” may be short-lived, but it also may be enough to engage the patient in a therapeutic alliance. That may permit a discharge with safe disposition to the outpatient clinic while in the custody of a family member, partner, or close friend.

Alternatively, some people experience a troubling worsening of precipitants following a suicide attempt. Preexisting medical conditions and financial, occupational, and/or social woes may be exacerbated. Child custody determinations may be affected, assuming the patient understands the possibility of this adverse consequence. Violent methods may result in disfigurement and body image issues. Individuals from small, close-knit communities may experience stigmatization and unwanted notoriety because of their suicide attempt. Such negative consequences may render some patients more likely to make another attempt to die by suicide. It is crucial to consider how a suicide attempt may have changed the original stress that led to the attempt.

3. Which method was used?

Most fatal suicides in the US are by firearms, and many individuals who survive such attempts do so because of unfamiliarity with the weapon, gun malfunction, faulty aim, or alcohol use.^5-7 Some survivors report intending to shoot themselves in the heart, but instead suffered shoulder injuries. Unfortunately, for a patient who survives self-inflicted gunshot wounds, the sequelae of chronic pain, multiple surgical procedures, disability, and disfigurement may serve as constant negative reminders of the event. Some individuals with suicidal intent eschew the idea of using firearms because they hope to avoid having a family member be the first to discover them. Witnessing the aftermath of a fatal suicide by gunshot can induce symptoms of posttraumatic stress disorder in family members and/or partners.⁸

For a patient with self-inflicted gunshot wounds, always determine whether the weapon has been secured or if the patient still has access to it. Asking about weapon availability is essential during the evaluation of any patient with depression, major life crises, or other factors that may yield a desire to die; this is especially true for individuals with substance use disorders (SUDs). Whenever readily available to such individuals, weapons need to be safely removed.

Continue to: Other self-harm methods...

Other self-harm methods with a high degree of lethality include jumping from bridges or buildings, poisonings, self-immolation, cutting, and hangings. Individuals who choose these approaches generally do not intend to survive. Many of these methods also entail premeditation, as in the case of individuals who canvass bridges and note time when traffic is light so they are less likely to be interrupted. Between 1937 and 2012, there were >1,600 deaths by suicide from San Francisco’s Golden Gate Bridge.⁹ Patients who choose highly lethal methods are often irritated during the postattempt evaluation because their plans were not fatal. Usually, patients who choose such potentially lethal methods are hospitalized initially on medical and surgical floors, and receive most of their psychiatric care from consultation psychiatrists. Following discharge, these patients may be at high risk for subsequent suicide attempts.

In the US, the most common method of attempting suicide is by overdose.⁴ Lethality is determined by the agent or combination of substances ingested, the amount taken, the person’s health status, and the length of time before they are discovered. Many patients mistakenly assume that readily available agents such as acetaminophen and aspirin are less likely to be fatal than prescription medications. Evaluators may want to assess for suicidality in individuals with erratic, risk-taking behaviors, who are at especially high risk for death. Learning about the method the patient used can help the clinician determine the imminent risk of another suicide attempt. The more potentially fatal the patient’s method, the more serious their suicide intent, and the higher the risk they will make another suicide attempt, possibly using an even more lethal method.

4. What was the intent?

“What did you want to happen when you made this attempt?” Many patients will respond that they wanted to die, sleep, not wake up, or did not care what happened. Others say it was a gesture to evoke a certain response from another person. If this is the case, it is important to know whether the desired outcome was achieved. These so-called gestures often involve making sure the intended person is aware of the attempt, often by writing a letter, sending a text, or posting on social media. Such behaviors may be exhibited by patients with personality disorders. While such attempts often are impulsive, if the attempt fails to generate the anticipated effect, the patient may try to gain more attention by escalating their suicide actions.

Conversely, if a spouse or partner reconciles with the patient solely because of a suicide attempt, this may set a pattern for future self-harm events in which the patient hopes to achieve the same outcome. Nevertheless, it is better to err for safety because some of these patients will make another attempt, just to prove that they should have been taken more seriously. An exploration of such intent can help the evaluation because even supposed “gestures” can have dangerous consequences. Acts that do not result in the desired outcome should precipitate hospitalization rather than discharge.

5. What facilitated the patient’s rescue?

“Why is this patient still alive?” Determine if the patient did anything to save themself, such as calling an ambulance, inducing emesis, telling someone what they did, or coming to the hospital on their own. If yes, asking them what changed their mind may provide information about what exists in their lives to potentially prevent future attempts, or about wishes to stay alive. These issues can be used to guide outpatient therapy.

Continue to: How does the patient feel about having survived?

When a patient is asked how they feel about having survived a suicide attempt, some will label their act “stupid” and profess embarrassment. Others exhibit future-oriented thought, which is a very good prognostic sign. More ominous is subsequent dysphoria or lamenting that “I could not even do this right.” Patients often express anger toward anyone who rescued them, especially those whose attempts were carefully planned or were discovered by accident. Some patients might also express ambivalence about having survived.

The patient’s response to this question may be shaped by their desire to avoid hospitalization, so beyond their verbal answers, be attentive to clinical cues that may suggest the patient is not being fully transparent. Anger or ambivalence about having survived, a lack of future-oriented thought, and a restricted affect despite verbalizing joy about still being alive are features that suggest psychiatric hospitalization may be warranted.

7. Has the patient made previous suicide attempts?

Compared to individuals with no previous suicide attempts, patients with a history of suicide attempts are 30 to 40 times more likely to die by suicide.² Many patients who present after a suicide attempt have tried to kill themselves multiple times. Exploring the number of past attempts, how recent the attempts were, and what dispositions were made can be of benefit. Reviewing the potential lethality of past attempts (eg, was hospitalization required, was the patient placed in an intensive care unit, and/or was intubation needed) is recommended. If outpatient care was suggested or medication prescribed, was the patient adherent? Consider asking about passive suicidal behavior, such as not seeking care for medical issues, discontinuing life-saving medication, or engaging in reckless behavior. While such behaviors may not have been classified as a suicide attempt, it might indicate a feeling of indifference toward staying alive. A patient with a past attempt, especially if recent, merits consideration for inpatient care. Once again, referring previously nonadherent patients to outpatient treatment is less likely to be effective.

8. Does the patient have a support network?

Before discharging a patient who has made a suicide attempt, consider the quality of their support network. Gauging the response of the family and friends to the patient’s attempt can be beneficial. Indifference or resentment on the part of loved ones is a bad sign. Some patients have access to support networks they either did not know were available or chose not to utilize. In other instances, after realizing how depressed the patient has been, the family might provide a new safety net. Strong religious affiliations can also be valuable because devout spirituality can be a deterrent to suicide behaviors.¹⁰ For an individual whose attempt was motivated by loneliness or feeling unloved or underappreciated, a newly realized support network can be an additional protective deterrent.

9. Does the patient have a family history of suicide?

There may be a familial component to suicide. Knowing about any suicide history in the family contributes to future therapeutic planning. The clinician may want to explore the patient’s family suicide history in detail because such information can have substantial impact on the patient’s motivation for attempting suicide. The evaluator may want to determine if the anniversary of a family suicide is coming. Triggers for a suicide attempt could include the anniversary of a death, birthdays, family-oriented holidays, and similar events. It is productive to understand how the patient feels about family members who have died by suicide. Some will empathize with the deceased, commenting that they did the “right thing.” Others, upon realizing how their own attempt affected others, will be remorseful and determined not to inflict more pain on their family. Such patients may need to be reminded of the misery associated with their family being left without them. These understandings are helpful at setting a safe disposition. However, a history of death by suicide in the family should always be thoroughly evaluated, regardless of the patient’s attitude about that death.

Continue to: Was the attempt the result of depression?

For a patient experiencing depressive symptoms, the prognosis is less positive; they are more likely to harbor serious intent, premeditation, hopelessness, and social isolation, and less likely to express future-oriented thought. They often exhibit a temporary “flight into health.” Such progress is often transitory and may not represent recovery. Because mood disorders may still be present despite a temporary improvement, inpatient and pharmacologic treatment may be needed. If a patient’s suicide attempt occurred as a result of severe depression, it is possible they will make another suicide attempt unless their depression is addressed in a safe and secure setting, such as inpatient hospitalization, or through close family observation while the patient is receiving intensive outpatient treatment.

11. Does the patient have a psychotic disorder?

Many patients with a psychotic illness die following their first attempt without ever having contact with a mental health professional.¹¹ Features of psychosis might include malevolent auditory hallucinations that suggest self-destruction.¹¹ Such “voices” can be intense and self-deprecating; many patients with this type of hallucination report having made a suicide attempt “just to make the voices stop.”

Symptoms of paranoia can make it less likely for individuals with psychosis to confide in family members, friends, or medical personnel. Religious elements are often of a delusional nature and can be dangerous. Psychosis is more difficult to hide than depression and the presence of psychoses concurrent with major depressive disorder (MDD) increases the probability of suicidality.¹¹ Psychosis secondary to substance use may diminish inhibitions and heighten impulsivity, thereby exacerbating the likelihood of self-harm. Usually, the presence of psychotic features precipitating or following a suicide attempt leads to psychiatric hospitalization.

12. Is the patient in a high-risk demographic group?

When evaluating a patient who has attempted suicide, it helps to consider not just what they did, but who they are. Specifically, does the individual belong to a demographic group that traditionally has a high rate of suicide? For example, patients who are Native American or Alaska Natives warrant extra caution.² Older White males, especially those who are divorced, widowed, retired, and/or have chronic health problems, are also at greater risk. Compared to the general population, individuals age >80 have a massively elevated chance for self-induced death.¹² Some of the reasons include:

• medical comorbidities make surviving an attempt less likely
• access to large amounts of medications
• more irreversible issues, such as chronic pain, disability, or widowhood
• living alone, which may delay discovery.

Patients who are members of any of these demographic groups may deserve serious consideration for inpatient psychiatric admission, regardless of other factors.

Continue to: Were drugs or alcohol involved?

This factor is unique in that it is both a chronic risk factor (SUDs) and a warning sign for imminent suicide, as in the case of an individual who gets intoxicated to disinhibit their fear of death so they can attempt suicide. Alcohol use disorders are associated with depression and suicide. Overdoses by fentanyl and other opiates have become more frequent.¹³ In many cases, fatalities are unintentional because users overestimate their tolerance or ingest contaminated substances.¹⁴ Disinhibition by alcohol and/or other drugs is a risk factor for attempting suicide and can intensify the depth of MDD. Some patients will ingest substances before an attempt just to give them the courage to act; many think of suicide only when intoxicated. Toxicology screens are indicated as part of the evaluation after a suicide attempt.

Depressive and suicidal thoughts often occur in people “coming down” from cocaine or other stimulants. These circumstances require determining whether to refer the patient for treatment for an SUD or psychiatric hospitalization.

In summary, getting intoxicated solely to diminish anxiety about suicide is a dangerous feature, whereas attempting suicide due to intoxication is less concerning. The latter patient may not consider suicide unless they become intoxicated again. When available, dual diagnosis treatment facilities can be an appropriate referral for such patients. Emergency department holding beds can allow these individuals to detoxify prior to the evaluation.

14. Does the patient have future-oriented thoughts?

When evaluating a patient who has attempted suicide, the presence of future planning and anticipation can be reassuring, but these features should be carefully assessed.^14-16

After-the-fact comments may be more reliable when a patient offers them spontaneously, as opposed to in response to direct questioning.^15-17 An inability to produce future-oriented thoughts is linked to long-term suicide risks.^15-17 Patients may fabricate future plans as a way to avoid psychiatric hospitalization, so be wary of plans that are generalized, less detailed, and only mentioned when an inpatient disposition is proposed. A patient may in fact have been dreading events they now profess to be eagerly awaiting. Corroboration from family members can be helpful in determining how involved the patient has been in preparing for future events. More concerning are patients without future plans or who exhibit anhedonia regarding upcoming events that previously were of interest. When assessing for future-oriented thoughts, consider:

• the specificity of the future plans
• corroboration from the family and others about the patient’s previous investment in the upcoming event
• whether the patient mentions such plans spontaneously or only in response to direct questioning
• the patient’s emotional expression or affect when discussing their future
• whether such plans are reasonable, grandiose, and/or unrealistic.

Bottom Line

When assessing a patient after a suicide attempt, both the patient’s presentation and history and the clinician’s instincts are important. Careful consideration of the method, stated intent, premeditation vs impulsivity, feelings about having survived, presence of psychiatric illness, high-risk demographic, postattempt demeanor and affect, quality of support, presence of self-rescue behaviors, future-oriented thoughts, and other factors can help in making the appropriate disposition.

Related Resources

• Kim H, Kim Y, Shin MH, et al. Early psychiatric referral after attempted suicide helps prevent suicide reattempts: a longitudinal national cohort study in South Korea. Front Psychiatry. 2022;13:607892. doi:10.3389/fpsyt.2022.607892
• Michaud L, Berva S, Ostertag L, et al. When to discharge and when to voluntary or compulsory hospitalize? Factors associated with treatment decision after self-harm. Psychiatry Res. 2022;317:114810. doi:10.1016/j.psychres.2022.114810

In 2021, suicide was the 11th leading cause of death in the United States.¹ Suicide resulted in 49,000 US deaths during 2021; it was the second most common cause of death in individuals age 10 to 34, and the fifth leading cause among children.^1,2 Women are 3 to 4 times more likely than men to attempt suicide, but men are 4 times more likely to die by suicide.²

The evaluation of patients with suicidal ideation who have not made an attempt generally involves assessing 4 factors: the specific plan, access to lethal means, any recent social stressors, and the presence of a psychiatric disorder.³ The clinician should also assess which potential deterrents, such as religious beliefs or dependent children, might be present.

Mental health clinicians are often called upon to evaluate a patient after a suicide attempt to assess intent for continued self-harm and to determine appropriate disposition. Such an evaluation must consider multiple factors, including the method used, premeditation, consequences of the attempt, the presence of severe depression and/or psychosis, and the role of substance use. Assessment after a suicide attempt differs from the examination of individuals who harbor suicidal thoughts but have not made an attempt; the latter group may be more likely to respond to interventions such as intensive outpatient care, mobilization of family support, and religious proscriptions against suicide. However, for patients who make an attempt to end their life, whatever potential safeguards or deterrents to suicide that were in place obviously did not prevent the self-harm act. The consequences of the attempt, such as disabling injuries or medical complications, and possible involuntary commitment, need to be considered. Assessment of the patient’s feelings about having survived the attempt is important because the psychological impact of the attempt on family members may serve to intensify the patient’s depression and make a subsequent attempt more likely.

Many individuals who think of suicide have communicated self-harm thoughts or intentions, but such comments are often minimized or ignored. There is a common but erroneous belief that if patients are encouraged to discuss thoughts of self-harm, they will be more likely to act upon them. Because the opposite is true,⁴ clinicians should ask vulnerable patients about suicidal ideation or intent. Importantly, noncompliance with life-saving medical care, risk-taking behaviors, and substance use may also signal a desire for self-harm. Passive thoughts of death, typified by comments such as “I don’t care whether I wake up or not,” should also be elicited. Many patients who think of suicide speak of being in a “bad place” where reason and logic give way to an intense desire to end their misery.

The evaluation of a patient who has attempted suicide is an important component of providing psychiatric care. This article reflects our 45 years of evaluating such patients. As such, it reflects our clinical experience and is not evidence-based. We offer a checklist of 14 questions that we have found helpful when determining if it would be best for a patient to receive inpatient psychiatric hospitalization or a discharge referral for outpatient care (Table). Questions 1 through 6 are specific for patients who have made a suicide attempt, while questions 7 through 14 are helpful for assessing global risk factors for suicide.

1. Was the attempt premeditated?

Determining premeditation vs impulsivity is an essential element of the assessment following a suicide attempt. Many such acts may occur without forethought in response to an unexpected stressor, such as an altercation between partners or family conflicts. Impulsive attempts can occur when an individual is involved in a distressing event and/or while intoxicated. Conversely, premeditation involves forethought and planning, which may increase the risk of suicide in the near future.

Examples of premeditated behavior include:

• Contemplating the attempt days or weeks beforehand
• Researching the effects of a medication or combination of medications in terms of potential lethality
• Engaging in behavior that would decrease the likelihood of their body being discovered after the attempt
• Obtaining weapons and/or stockpiling pills
• Canvassing potential sites such as bridges or tall buildings
• Engaging in a suicide attempt “practice run”
• Leaving a suicide note or message on social media
• Making funeral arrangements, such as choosing burial clothing
• Writing a will and arranging for the custody of dependent children
• Purchasing life insurance that does not deny payment of benefits in cases of death by suicide.

Continue to: Patients with a premeditated...

Patients with a premeditated suicide attempt generally do not expect to survive and are often surprised or upset that the act was not fatal. The presence of indicators that the attempt was premeditated should direct the disposition more toward hospitalization than discharge. In assessing the impact of premeditation, it is important to gauge not just the examples listed above, but also the patient’s perception of these issues (such as potential loss of child custody). Consider how much the patient is emotionally affected by such thinking.

2. What were the consequences of the attempt?

Assessing the reason for the attempt (if any) and determining whether the inciting circumstance has changed due to the suicide attempt are an important part of the evaluation. A suicide attempt may result in reconciliation with and/or renewed support from family members or partners, who might not have been aware of the patient’s emotional distress. Such unexpected support often results in the patient exhibiting improved mood and affect, and possibly temporary resolution of suicidal thoughts. This “flight into health” may be short-lived, but it also may be enough to engage the patient in a therapeutic alliance. That may permit a discharge with safe disposition to the outpatient clinic while in the custody of a family member, partner, or close friend.

Alternatively, some people experience a troubling worsening of precipitants following a suicide attempt. Preexisting medical conditions and financial, occupational, and/or social woes may be exacerbated. Child custody determinations may be affected, assuming the patient understands the possibility of this adverse consequence. Violent methods may result in disfigurement and body image issues. Individuals from small, close-knit communities may experience stigmatization and unwanted notoriety because of their suicide attempt. Such negative consequences may render some patients more likely to make another attempt to die by suicide. It is crucial to consider how a suicide attempt may have changed the original stress that led to the attempt.

3. Which method was used?

Most fatal suicides in the US are by firearms, and many individuals who survive such attempts do so because of unfamiliarity with the weapon, gun malfunction, faulty aim, or alcohol use.^5-7 Some survivors report intending to shoot themselves in the heart, but instead suffered shoulder injuries. Unfortunately, for a patient who survives self-inflicted gunshot wounds, the sequelae of chronic pain, multiple surgical procedures, disability, and disfigurement may serve as constant negative reminders of the event. Some individuals with suicidal intent eschew the idea of using firearms because they hope to avoid having a family member be the first to discover them. Witnessing the aftermath of a fatal suicide by gunshot can induce symptoms of posttraumatic stress disorder in family members and/or partners.⁸

For a patient with self-inflicted gunshot wounds, always determine whether the weapon has been secured or if the patient still has access to it. Asking about weapon availability is essential during the evaluation of any patient with depression, major life crises, or other factors that may yield a desire to die; this is especially true for individuals with substance use disorders (SUDs). Whenever readily available to such individuals, weapons need to be safely removed.

Continue to: Other self-harm methods...

Other self-harm methods with a high degree of lethality include jumping from bridges or buildings, poisonings, self-immolation, cutting, and hangings. Individuals who choose these approaches generally do not intend to survive. Many of these methods also entail premeditation, as in the case of individuals who canvass bridges and note time when traffic is light so they are less likely to be interrupted. Between 1937 and 2012, there were >1,600 deaths by suicide from San Francisco’s Golden Gate Bridge.⁹ Patients who choose highly lethal methods are often irritated during the postattempt evaluation because their plans were not fatal. Usually, patients who choose such potentially lethal methods are hospitalized initially on medical and surgical floors, and receive most of their psychiatric care from consultation psychiatrists. Following discharge, these patients may be at high risk for subsequent suicide attempts.

In the US, the most common method of attempting suicide is by overdose.⁴ Lethality is determined by the agent or combination of substances ingested, the amount taken, the person’s health status, and the length of time before they are discovered. Many patients mistakenly assume that readily available agents such as acetaminophen and aspirin are less likely to be fatal than prescription medications. Evaluators may want to assess for suicidality in individuals with erratic, risk-taking behaviors, who are at especially high risk for death. Learning about the method the patient used can help the clinician determine the imminent risk of another suicide attempt. The more potentially fatal the patient’s method, the more serious their suicide intent, and the higher the risk they will make another suicide attempt, possibly using an even more lethal method.

4. What was the intent?

“What did you want to happen when you made this attempt?” Many patients will respond that they wanted to die, sleep, not wake up, or did not care what happened. Others say it was a gesture to evoke a certain response from another person. If this is the case, it is important to know whether the desired outcome was achieved. These so-called gestures often involve making sure the intended person is aware of the attempt, often by writing a letter, sending a text, or posting on social media. Such behaviors may be exhibited by patients with personality disorders. While such attempts often are impulsive, if the attempt fails to generate the anticipated effect, the patient may try to gain more attention by escalating their suicide actions.

Conversely, if a spouse or partner reconciles with the patient solely because of a suicide attempt, this may set a pattern for future self-harm events in which the patient hopes to achieve the same outcome. Nevertheless, it is better to err for safety because some of these patients will make another attempt, just to prove that they should have been taken more seriously. An exploration of such intent can help the evaluation because even supposed “gestures” can have dangerous consequences. Acts that do not result in the desired outcome should precipitate hospitalization rather than discharge.

5. What facilitated the patient’s rescue?

“Why is this patient still alive?” Determine if the patient did anything to save themself, such as calling an ambulance, inducing emesis, telling someone what they did, or coming to the hospital on their own. If yes, asking them what changed their mind may provide information about what exists in their lives to potentially prevent future attempts, or about wishes to stay alive. These issues can be used to guide outpatient therapy.

Continue to: How does the patient feel about having survived?

When a patient is asked how they feel about having survived a suicide attempt, some will label their act “stupid” and profess embarrassment. Others exhibit future-oriented thought, which is a very good prognostic sign. More ominous is subsequent dysphoria or lamenting that “I could not even do this right.” Patients often express anger toward anyone who rescued them, especially those whose attempts were carefully planned or were discovered by accident. Some patients might also express ambivalence about having survived.

The patient’s response to this question may be shaped by their desire to avoid hospitalization, so beyond their verbal answers, be attentive to clinical cues that may suggest the patient is not being fully transparent. Anger or ambivalence about having survived, a lack of future-oriented thought, and a restricted affect despite verbalizing joy about still being alive are features that suggest psychiatric hospitalization may be warranted.

7. Has the patient made previous suicide attempts?

Compared to individuals with no previous suicide attempts, patients with a history of suicide attempts are 30 to 40 times more likely to die by suicide.² Many patients who present after a suicide attempt have tried to kill themselves multiple times. Exploring the number of past attempts, how recent the attempts were, and what dispositions were made can be of benefit. Reviewing the potential lethality of past attempts (eg, was hospitalization required, was the patient placed in an intensive care unit, and/or was intubation needed) is recommended. If outpatient care was suggested or medication prescribed, was the patient adherent? Consider asking about passive suicidal behavior, such as not seeking care for medical issues, discontinuing life-saving medication, or engaging in reckless behavior. While such behaviors may not have been classified as a suicide attempt, it might indicate a feeling of indifference toward staying alive. A patient with a past attempt, especially if recent, merits consideration for inpatient care. Once again, referring previously nonadherent patients to outpatient treatment is less likely to be effective.

8. Does the patient have a support network?

Before discharging a patient who has made a suicide attempt, consider the quality of their support network. Gauging the response of the family and friends to the patient’s attempt can be beneficial. Indifference or resentment on the part of loved ones is a bad sign. Some patients have access to support networks they either did not know were available or chose not to utilize. In other instances, after realizing how depressed the patient has been, the family might provide a new safety net. Strong religious affiliations can also be valuable because devout spirituality can be a deterrent to suicide behaviors.¹⁰ For an individual whose attempt was motivated by loneliness or feeling unloved or underappreciated, a newly realized support network can be an additional protective deterrent.

9. Does the patient have a family history of suicide?

There may be a familial component to suicide. Knowing about any suicide history in the family contributes to future therapeutic planning. The clinician may want to explore the patient’s family suicide history in detail because such information can have substantial impact on the patient’s motivation for attempting suicide. The evaluator may want to determine if the anniversary of a family suicide is coming. Triggers for a suicide attempt could include the anniversary of a death, birthdays, family-oriented holidays, and similar events. It is productive to understand how the patient feels about family members who have died by suicide. Some will empathize with the deceased, commenting that they did the “right thing.” Others, upon realizing how their own attempt affected others, will be remorseful and determined not to inflict more pain on their family. Such patients may need to be reminded of the misery associated with their family being left without them. These understandings are helpful at setting a safe disposition. However, a history of death by suicide in the family should always be thoroughly evaluated, regardless of the patient’s attitude about that death.

Continue to: Was the attempt the result of depression?

For a patient experiencing depressive symptoms, the prognosis is less positive; they are more likely to harbor serious intent, premeditation, hopelessness, and social isolation, and less likely to express future-oriented thought. They often exhibit a temporary “flight into health.” Such progress is often transitory and may not represent recovery. Because mood disorders may still be present despite a temporary improvement, inpatient and pharmacologic treatment may be needed. If a patient’s suicide attempt occurred as a result of severe depression, it is possible they will make another suicide attempt unless their depression is addressed in a safe and secure setting, such as inpatient hospitalization, or through close family observation while the patient is receiving intensive outpatient treatment.

11. Does the patient have a psychotic disorder?

Many patients with a psychotic illness die following their first attempt without ever having contact with a mental health professional.¹¹ Features of psychosis might include malevolent auditory hallucinations that suggest self-destruction.¹¹ Such “voices” can be intense and self-deprecating; many patients with this type of hallucination report having made a suicide attempt “just to make the voices stop.”

Symptoms of paranoia can make it less likely for individuals with psychosis to confide in family members, friends, or medical personnel. Religious elements are often of a delusional nature and can be dangerous. Psychosis is more difficult to hide than depression and the presence of psychoses concurrent with major depressive disorder (MDD) increases the probability of suicidality.¹¹ Psychosis secondary to substance use may diminish inhibitions and heighten impulsivity, thereby exacerbating the likelihood of self-harm. Usually, the presence of psychotic features precipitating or following a suicide attempt leads to psychiatric hospitalization.

12. Is the patient in a high-risk demographic group?

When evaluating a patient who has attempted suicide, it helps to consider not just what they did, but who they are. Specifically, does the individual belong to a demographic group that traditionally has a high rate of suicide? For example, patients who are Native American or Alaska Natives warrant extra caution.² Older White males, especially those who are divorced, widowed, retired, and/or have chronic health problems, are also at greater risk. Compared to the general population, individuals age >80 have a massively elevated chance for self-induced death.¹² Some of the reasons include:

• medical comorbidities make surviving an attempt less likely
• access to large amounts of medications
• more irreversible issues, such as chronic pain, disability, or widowhood
• living alone, which may delay discovery.

Patients who are members of any of these demographic groups may deserve serious consideration for inpatient psychiatric admission, regardless of other factors.

Continue to: Were drugs or alcohol involved?

This factor is unique in that it is both a chronic risk factor (SUDs) and a warning sign for imminent suicide, as in the case of an individual who gets intoxicated to disinhibit their fear of death so they can attempt suicide. Alcohol use disorders are associated with depression and suicide. Overdoses by fentanyl and other opiates have become more frequent.¹³ In many cases, fatalities are unintentional because users overestimate their tolerance or ingest contaminated substances.¹⁴ Disinhibition by alcohol and/or other drugs is a risk factor for attempting suicide and can intensify the depth of MDD. Some patients will ingest substances before an attempt just to give them the courage to act; many think of suicide only when intoxicated. Toxicology screens are indicated as part of the evaluation after a suicide attempt.

Depressive and suicidal thoughts often occur in people “coming down” from cocaine or other stimulants. These circumstances require determining whether to refer the patient for treatment for an SUD or psychiatric hospitalization.

In summary, getting intoxicated solely to diminish anxiety about suicide is a dangerous feature, whereas attempting suicide due to intoxication is less concerning. The latter patient may not consider suicide unless they become intoxicated again. When available, dual diagnosis treatment facilities can be an appropriate referral for such patients. Emergency department holding beds can allow these individuals to detoxify prior to the evaluation.

14. Does the patient have future-oriented thoughts?

When evaluating a patient who has attempted suicide, the presence of future planning and anticipation can be reassuring, but these features should be carefully assessed.^14-16

After-the-fact comments may be more reliable when a patient offers them spontaneously, as opposed to in response to direct questioning.^15-17 An inability to produce future-oriented thoughts is linked to long-term suicide risks.^15-17 Patients may fabricate future plans as a way to avoid psychiatric hospitalization, so be wary of plans that are generalized, less detailed, and only mentioned when an inpatient disposition is proposed. A patient may in fact have been dreading events they now profess to be eagerly awaiting. Corroboration from family members can be helpful in determining how involved the patient has been in preparing for future events. More concerning are patients without future plans or who exhibit anhedonia regarding upcoming events that previously were of interest. When assessing for future-oriented thoughts, consider:

• the specificity of the future plans
• corroboration from the family and others about the patient’s previous investment in the upcoming event
• whether the patient mentions such plans spontaneously or only in response to direct questioning
• the patient’s emotional expression or affect when discussing their future
• whether such plans are reasonable, grandiose, and/or unrealistic.

Bottom Line

When assessing a patient after a suicide attempt, both the patient’s presentation and history and the clinician’s instincts are important. Careful consideration of the method, stated intent, premeditation vs impulsivity, feelings about having survived, presence of psychiatric illness, high-risk demographic, postattempt demeanor and affect, quality of support, presence of self-rescue behaviors, future-oriented thoughts, and other factors can help in making the appropriate disposition.

Related Resources

• Kim H, Kim Y, Shin MH, et al. Early psychiatric referral after attempted suicide helps prevent suicide reattempts: a longitudinal national cohort study in South Korea. Front Psychiatry. 2022;13:607892. doi:10.3389/fpsyt.2022.607892
• Michaud L, Berva S, Ostertag L, et al. When to discharge and when to voluntary or compulsory hospitalize? Factors associated with treatment decision after self-harm. Psychiatry Res. 2022;317:114810. doi:10.1016/j.psychres.2022.114810

In 2021, suicide was the 11th leading cause of death in the United States.¹ Suicide resulted in 49,000 US deaths during 2021; it was the second most common cause of death in individuals age 10 to 34, and the fifth leading cause among children.^1,2 Women are 3 to 4 times more likely than men to attempt suicide, but men are 4 times more likely to die by suicide.²

The evaluation of patients with suicidal ideation who have not made an attempt generally involves assessing 4 factors: the specific plan, access to lethal means, any recent social stressors, and the presence of a psychiatric disorder.³ The clinician should also assess which potential deterrents, such as religious beliefs or dependent children, might be present.

Mental health clinicians are often called upon to evaluate a patient after a suicide attempt to assess intent for continued self-harm and to determine appropriate disposition. Such an evaluation must consider multiple factors, including the method used, premeditation, consequences of the attempt, the presence of severe depression and/or psychosis, and the role of substance use. Assessment after a suicide attempt differs from the examination of individuals who harbor suicidal thoughts but have not made an attempt; the latter group may be more likely to respond to interventions such as intensive outpatient care, mobilization of family support, and religious proscriptions against suicide. However, for patients who make an attempt to end their life, whatever potential safeguards or deterrents to suicide that were in place obviously did not prevent the self-harm act. The consequences of the attempt, such as disabling injuries or medical complications, and possible involuntary commitment, need to be considered. Assessment of the patient’s feelings about having survived the attempt is important because the psychological impact of the attempt on family members may serve to intensify the patient’s depression and make a subsequent attempt more likely.

Many individuals who think of suicide have communicated self-harm thoughts or intentions, but such comments are often minimized or ignored. There is a common but erroneous belief that if patients are encouraged to discuss thoughts of self-harm, they will be more likely to act upon them. Because the opposite is true,⁴ clinicians should ask vulnerable patients about suicidal ideation or intent. Importantly, noncompliance with life-saving medical care, risk-taking behaviors, and substance use may also signal a desire for self-harm. Passive thoughts of death, typified by comments such as “I don’t care whether I wake up or not,” should also be elicited. Many patients who think of suicide speak of being in a “bad place” where reason and logic give way to an intense desire to end their misery.

The evaluation of a patient who has attempted suicide is an important component of providing psychiatric care. This article reflects our 45 years of evaluating such patients. As such, it reflects our clinical experience and is not evidence-based. We offer a checklist of 14 questions that we have found helpful when determining if it would be best for a patient to receive inpatient psychiatric hospitalization or a discharge referral for outpatient care (Table). Questions 1 through 6 are specific for patients who have made a suicide attempt, while questions 7 through 14 are helpful for assessing global risk factors for suicide.

1. Was the attempt premeditated?

Determining premeditation vs impulsivity is an essential element of the assessment following a suicide attempt. Many such acts may occur without forethought in response to an unexpected stressor, such as an altercation between partners or family conflicts. Impulsive attempts can occur when an individual is involved in a distressing event and/or while intoxicated. Conversely, premeditation involves forethought and planning, which may increase the risk of suicide in the near future.

Examples of premeditated behavior include:

• Contemplating the attempt days or weeks beforehand
• Researching the effects of a medication or combination of medications in terms of potential lethality
• Engaging in behavior that would decrease the likelihood of their body being discovered after the attempt
• Obtaining weapons and/or stockpiling pills
• Canvassing potential sites such as bridges or tall buildings
• Engaging in a suicide attempt “practice run”
• Leaving a suicide note or message on social media
• Making funeral arrangements, such as choosing burial clothing
• Writing a will and arranging for the custody of dependent children
• Purchasing life insurance that does not deny payment of benefits in cases of death by suicide.

Continue to: Patients with a premeditated...

Patients with a premeditated suicide attempt generally do not expect to survive and are often surprised or upset that the act was not fatal. The presence of indicators that the attempt was premeditated should direct the disposition more toward hospitalization than discharge. In assessing the impact of premeditation, it is important to gauge not just the examples listed above, but also the patient’s perception of these issues (such as potential loss of child custody). Consider how much the patient is emotionally affected by such thinking.

2. What were the consequences of the attempt?

Assessing the reason for the attempt (if any) and determining whether the inciting circumstance has changed due to the suicide attempt are an important part of the evaluation. A suicide attempt may result in reconciliation with and/or renewed support from family members or partners, who might not have been aware of the patient’s emotional distress. Such unexpected support often results in the patient exhibiting improved mood and affect, and possibly temporary resolution of suicidal thoughts. This “flight into health” may be short-lived, but it also may be enough to engage the patient in a therapeutic alliance. That may permit a discharge with safe disposition to the outpatient clinic while in the custody of a family member, partner, or close friend.

Alternatively, some people experience a troubling worsening of precipitants following a suicide attempt. Preexisting medical conditions and financial, occupational, and/or social woes may be exacerbated. Child custody determinations may be affected, assuming the patient understands the possibility of this adverse consequence. Violent methods may result in disfigurement and body image issues. Individuals from small, close-knit communities may experience stigmatization and unwanted notoriety because of their suicide attempt. Such negative consequences may render some patients more likely to make another attempt to die by suicide. It is crucial to consider how a suicide attempt may have changed the original stress that led to the attempt.

3. Which method was used?

Most fatal suicides in the US are by firearms, and many individuals who survive such attempts do so because of unfamiliarity with the weapon, gun malfunction, faulty aim, or alcohol use.^5-7 Some survivors report intending to shoot themselves in the heart, but instead suffered shoulder injuries. Unfortunately, for a patient who survives self-inflicted gunshot wounds, the sequelae of chronic pain, multiple surgical procedures, disability, and disfigurement may serve as constant negative reminders of the event. Some individuals with suicidal intent eschew the idea of using firearms because they hope to avoid having a family member be the first to discover them. Witnessing the aftermath of a fatal suicide by gunshot can induce symptoms of posttraumatic stress disorder in family members and/or partners.⁸

For a patient with self-inflicted gunshot wounds, always determine whether the weapon has been secured or if the patient still has access to it. Asking about weapon availability is essential during the evaluation of any patient with depression, major life crises, or other factors that may yield a desire to die; this is especially true for individuals with substance use disorders (SUDs). Whenever readily available to such individuals, weapons need to be safely removed.

Continue to: Other self-harm methods...

Other self-harm methods with a high degree of lethality include jumping from bridges or buildings, poisonings, self-immolation, cutting, and hangings. Individuals who choose these approaches generally do not intend to survive. Many of these methods also entail premeditation, as in the case of individuals who canvass bridges and note time when traffic is light so they are less likely to be interrupted. Between 1937 and 2012, there were >1,600 deaths by suicide from San Francisco’s Golden Gate Bridge.⁹ Patients who choose highly lethal methods are often irritated during the postattempt evaluation because their plans were not fatal. Usually, patients who choose such potentially lethal methods are hospitalized initially on medical and surgical floors, and receive most of their psychiatric care from consultation psychiatrists. Following discharge, these patients may be at high risk for subsequent suicide attempts.

In the US, the most common method of attempting suicide is by overdose.⁴ Lethality is determined by the agent or combination of substances ingested, the amount taken, the person’s health status, and the length of time before they are discovered. Many patients mistakenly assume that readily available agents such as acetaminophen and aspirin are less likely to be fatal than prescription medications. Evaluators may want to assess for suicidality in individuals with erratic, risk-taking behaviors, who are at especially high risk for death. Learning about the method the patient used can help the clinician determine the imminent risk of another suicide attempt. The more potentially fatal the patient’s method, the more serious their suicide intent, and the higher the risk they will make another suicide attempt, possibly using an even more lethal method.

4. What was the intent?

“What did you want to happen when you made this attempt?” Many patients will respond that they wanted to die, sleep, not wake up, or did not care what happened. Others say it was a gesture to evoke a certain response from another person. If this is the case, it is important to know whether the desired outcome was achieved. These so-called gestures often involve making sure the intended person is aware of the attempt, often by writing a letter, sending a text, or posting on social media. Such behaviors may be exhibited by patients with personality disorders. While such attempts often are impulsive, if the attempt fails to generate the anticipated effect, the patient may try to gain more attention by escalating their suicide actions.

Conversely, if a spouse or partner reconciles with the patient solely because of a suicide attempt, this may set a pattern for future self-harm events in which the patient hopes to achieve the same outcome. Nevertheless, it is better to err for safety because some of these patients will make another attempt, just to prove that they should have been taken more seriously. An exploration of such intent can help the evaluation because even supposed “gestures” can have dangerous consequences. Acts that do not result in the desired outcome should precipitate hospitalization rather than discharge.

5. What facilitated the patient’s rescue?

“Why is this patient still alive?” Determine if the patient did anything to save themself, such as calling an ambulance, inducing emesis, telling someone what they did, or coming to the hospital on their own. If yes, asking them what changed their mind may provide information about what exists in their lives to potentially prevent future attempts, or about wishes to stay alive. These issues can be used to guide outpatient therapy.

Continue to: How does the patient feel about having survived?

When a patient is asked how they feel about having survived a suicide attempt, some will label their act “stupid” and profess embarrassment. Others exhibit future-oriented thought, which is a very good prognostic sign. More ominous is subsequent dysphoria or lamenting that “I could not even do this right.” Patients often express anger toward anyone who rescued them, especially those whose attempts were carefully planned or were discovered by accident. Some patients might also express ambivalence about having survived.

The patient’s response to this question may be shaped by their desire to avoid hospitalization, so beyond their verbal answers, be attentive to clinical cues that may suggest the patient is not being fully transparent. Anger or ambivalence about having survived, a lack of future-oriented thought, and a restricted affect despite verbalizing joy about still being alive are features that suggest psychiatric hospitalization may be warranted.

7. Has the patient made previous suicide attempts?

Compared to individuals with no previous suicide attempts, patients with a history of suicide attempts are 30 to 40 times more likely to die by suicide.² Many patients who present after a suicide attempt have tried to kill themselves multiple times. Exploring the number of past attempts, how recent the attempts were, and what dispositions were made can be of benefit. Reviewing the potential lethality of past attempts (eg, was hospitalization required, was the patient placed in an intensive care unit, and/or was intubation needed) is recommended. If outpatient care was suggested or medication prescribed, was the patient adherent? Consider asking about passive suicidal behavior, such as not seeking care for medical issues, discontinuing life-saving medication, or engaging in reckless behavior. While such behaviors may not have been classified as a suicide attempt, it might indicate a feeling of indifference toward staying alive. A patient with a past attempt, especially if recent, merits consideration for inpatient care. Once again, referring previously nonadherent patients to outpatient treatment is less likely to be effective.

8. Does the patient have a support network?

Before discharging a patient who has made a suicide attempt, consider the quality of their support network. Gauging the response of the family and friends to the patient’s attempt can be beneficial. Indifference or resentment on the part of loved ones is a bad sign. Some patients have access to support networks they either did not know were available or chose not to utilize. In other instances, after realizing how depressed the patient has been, the family might provide a new safety net. Strong religious affiliations can also be valuable because devout spirituality can be a deterrent to suicide behaviors.¹⁰ For an individual whose attempt was motivated by loneliness or feeling unloved or underappreciated, a newly realized support network can be an additional protective deterrent.

9. Does the patient have a family history of suicide?

There may be a familial component to suicide. Knowing about any suicide history in the family contributes to future therapeutic planning. The clinician may want to explore the patient’s family suicide history in detail because such information can have substantial impact on the patient’s motivation for attempting suicide. The evaluator may want to determine if the anniversary of a family suicide is coming. Triggers for a suicide attempt could include the anniversary of a death, birthdays, family-oriented holidays, and similar events. It is productive to understand how the patient feels about family members who have died by suicide. Some will empathize with the deceased, commenting that they did the “right thing.” Others, upon realizing how their own attempt affected others, will be remorseful and determined not to inflict more pain on their family. Such patients may need to be reminded of the misery associated with their family being left without them. These understandings are helpful at setting a safe disposition. However, a history of death by suicide in the family should always be thoroughly evaluated, regardless of the patient’s attitude about that death.

Continue to: Was the attempt the result of depression?

For a patient experiencing depressive symptoms, the prognosis is less positive; they are more likely to harbor serious intent, premeditation, hopelessness, and social isolation, and less likely to express future-oriented thought. They often exhibit a temporary “flight into health.” Such progress is often transitory and may not represent recovery. Because mood disorders may still be present despite a temporary improvement, inpatient and pharmacologic treatment may be needed. If a patient’s suicide attempt occurred as a result of severe depression, it is possible they will make another suicide attempt unless their depression is addressed in a safe and secure setting, such as inpatient hospitalization, or through close family observation while the patient is receiving intensive outpatient treatment.

11. Does the patient have a psychotic disorder?

Many patients with a psychotic illness die following their first attempt without ever having contact with a mental health professional.¹¹ Features of psychosis might include malevolent auditory hallucinations that suggest self-destruction.¹¹ Such “voices” can be intense and self-deprecating; many patients with this type of hallucination report having made a suicide attempt “just to make the voices stop.”

Symptoms of paranoia can make it less likely for individuals with psychosis to confide in family members, friends, or medical personnel. Religious elements are often of a delusional nature and can be dangerous. Psychosis is more difficult to hide than depression and the presence of psychoses concurrent with major depressive disorder (MDD) increases the probability of suicidality.¹¹ Psychosis secondary to substance use may diminish inhibitions and heighten impulsivity, thereby exacerbating the likelihood of self-harm. Usually, the presence of psychotic features precipitating or following a suicide attempt leads to psychiatric hospitalization.

12. Is the patient in a high-risk demographic group?

When evaluating a patient who has attempted suicide, it helps to consider not just what they did, but who they are. Specifically, does the individual belong to a demographic group that traditionally has a high rate of suicide? For example, patients who are Native American or Alaska Natives warrant extra caution.² Older White males, especially those who are divorced, widowed, retired, and/or have chronic health problems, are also at greater risk. Compared to the general population, individuals age >80 have a massively elevated chance for self-induced death.¹² Some of the reasons include:

• medical comorbidities make surviving an attempt less likely
• access to large amounts of medications
• more irreversible issues, such as chronic pain, disability, or widowhood
• living alone, which may delay discovery.

Patients who are members of any of these demographic groups may deserve serious consideration for inpatient psychiatric admission, regardless of other factors.

Continue to: Were drugs or alcohol involved?

This factor is unique in that it is both a chronic risk factor (SUDs) and a warning sign for imminent suicide, as in the case of an individual who gets intoxicated to disinhibit their fear of death so they can attempt suicide. Alcohol use disorders are associated with depression and suicide. Overdoses by fentanyl and other opiates have become more frequent.¹³ In many cases, fatalities are unintentional because users overestimate their tolerance or ingest contaminated substances.¹⁴ Disinhibition by alcohol and/or other drugs is a risk factor for attempting suicide and can intensify the depth of MDD. Some patients will ingest substances before an attempt just to give them the courage to act; many think of suicide only when intoxicated. Toxicology screens are indicated as part of the evaluation after a suicide attempt.

Depressive and suicidal thoughts often occur in people “coming down” from cocaine or other stimulants. These circumstances require determining whether to refer the patient for treatment for an SUD or psychiatric hospitalization.

In summary, getting intoxicated solely to diminish anxiety about suicide is a dangerous feature, whereas attempting suicide due to intoxication is less concerning. The latter patient may not consider suicide unless they become intoxicated again. When available, dual diagnosis treatment facilities can be an appropriate referral for such patients. Emergency department holding beds can allow these individuals to detoxify prior to the evaluation.

14. Does the patient have future-oriented thoughts?

When evaluating a patient who has attempted suicide, the presence of future planning and anticipation can be reassuring, but these features should be carefully assessed.^14-16

After-the-fact comments may be more reliable when a patient offers them spontaneously, as opposed to in response to direct questioning.^15-17 An inability to produce future-oriented thoughts is linked to long-term suicide risks.^15-17 Patients may fabricate future plans as a way to avoid psychiatric hospitalization, so be wary of plans that are generalized, less detailed, and only mentioned when an inpatient disposition is proposed. A patient may in fact have been dreading events they now profess to be eagerly awaiting. Corroboration from family members can be helpful in determining how involved the patient has been in preparing for future events. More concerning are patients without future plans or who exhibit anhedonia regarding upcoming events that previously were of interest. When assessing for future-oriented thoughts, consider:

• the specificity of the future plans
• corroboration from the family and others about the patient’s previous investment in the upcoming event
• whether the patient mentions such plans spontaneously or only in response to direct questioning
• the patient’s emotional expression or affect when discussing their future
• whether such plans are reasonable, grandiose, and/or unrealistic.

Bottom Line

When assessing a patient after a suicide attempt, both the patient’s presentation and history and the clinician’s instincts are important. Careful consideration of the method, stated intent, premeditation vs impulsivity, feelings about having survived, presence of psychiatric illness, high-risk demographic, postattempt demeanor and affect, quality of support, presence of self-rescue behaviors, future-oriented thoughts, and other factors can help in making the appropriate disposition.

Related Resources

• Kim H, Kim Y, Shin MH, et al. Early psychiatric referral after attempted suicide helps prevent suicide reattempts: a longitudinal national cohort study in South Korea. Front Psychiatry. 2022;13:607892. doi:10.3389/fpsyt.2022.607892
• Michaud L, Berva S, Ostertag L, et al. When to discharge and when to voluntary or compulsory hospitalize? Factors associated with treatment decision after self-harm. Psychiatry Res. 2022;317:114810. doi:10.1016/j.psychres.2022.114810

The human microbiota refers to the collection of bacteria, archaea, eukarya, and viruses that reside within the human body. The term gut microbiome indicates the composition of these microbes and genetic codes in the intestine.¹ Harkening back to the ancient Greek physician Galen, who treated gastrointestinal (GI) symptoms to relieve mental disturbances such as psychosis, the gut has been a therapeutic target in schizophrenia long before antipsychotics and the DSM.² In recent years, research into the gut microbiome has drastically increased, with genetic sequencing affording a more precise look into the specific bacteria that call the human intestines their home. This has led to the recognition that the gut microbiome may be severely disrupted in schizophrenia, a condition known as dysbiosis. Preliminary research suggests that gut bacteria are more helpful than many human genes in distinguishing individuals with schizophrenia from their healthy counterparts.^3,4 In this article, we discuss the potential role of the gut microbiome in schizophrenia, including new research correlating clinical symptoms of psychosis with dysbiosis. We also provide recommendations for promoting a healthy gut microbiome.

The enteric brain across life

The composition of our bodies is far more microbiota than human. Strikingly, microbiota cells in the gut outnumber human cells, and the distal gut alone hosts bacteria with 100 times the genetic content of the entire genome.⁵ The intricate meshwork of nerves in the gut is often called the enteric brain because the gut consists of 100 million neurons and synthesizes many neuroactive chemicals implicated in mood disorders and psychosis, including serotonin, dopamine, gamma-aminobutyric acid (GABA), and acetylcholine.⁶ The variety of neuro­immunologic, hormonal, and metabolic paths by which the gutmicrobiome and the brain interact are collectively known as the gut-microbiota-brainaxis.⁷

How do we acquire our gut microbiome, and how does it come to influence ourbrain and behavior? On the first day of life, as babies pass through the birth canal, they are bathed in their mother’s vaginal microbiota. In the following weeks, the microbiome expands and colonizes the gut as bacteria are introduced from environmental sources such as skin-to-skin contact and breastmilk.⁸ The microbiome continues to evolve throughout early life. As children expand their diets and navigate new aspects of the physical world, additional bacteria join the unseen ecosystem growing inside.⁹ The development of the microbiome coincides with the development of the brain. From preclinical studies, we know the gut microbiome mediates important aspects of neurodevelopment such as the formation of the blood-brain barrier (BBB), synaptic pruning, glial activation, and myelination.¹⁰ Interestingly, many of the risk factors for schizophrenia are associated with gut dysbiosis, including obstetric complications, infections treated with antibiotics, and urbanization.^11-15

Throughout human life, the gut and brain remain in close communication. The gut microbiota continue to produce monoamines, along with other metabolites that are able to cross the BBB.⁶ The HPA axis, stimulation of the immune system, and the vagus nerve all provide highways of communication between the gut and the brain.⁷ The relationship between the enteric brain and cephalic brain continues through life, even up to a person’s final hour. One autopsy study that is often cited (but soberingly, cannot be found online) allegedly revealed that 92% of schizophrenia patients had developed colitis by the time of death.^16,17

First-episode psychosis and antipsychotic treatment

For patients with schizophrenia, first-episode psychosis (FEP) represents a cocktail of mounting genetic and environmental factors. Typically, by the time a patient receives psychiatric care, they present with characteristic psychotic symptoms—hallucinations, delusions, bizarre behavior, and unusual thought process—along with a unique gut microbiome profile.

This disrupted microbiome coincides with a marked state of inflammation in the intestines. Inflammation triggers increased endothelial barrier permeability, similar to the way immune signals increase capillary permeability to allow immune cells into the periphery of the blood. Specific gut bacteria play specific roles in maintaining the gut barrier.^18,19 Disruptions in the bacteria that maintain the gut barrier, combined with inflammation, contribute to a leaky gut. A leaky gut barrier allows bacterial and immune products to more easily enter the bloodstream and then the brain, which is a potential source of neuroinflammation in schizophrenia.²⁰ This increase in gut permeability (leaky gut syndrome) is likely one of several reasons low-grade inflammation is common in schizophrenia—numerous studies show higher serum levels of proinflammatory cytokines along with antibacterial immunoglobulins in patients with FEP.^21,22

Fortunately, antipsychotics, especially the second-generation agents, help restore a healthy gut microbiome and have substantial anti-inflammatory properties.^23,24 These medications interact heavily with the gut microbiome: they have been found to have antibiotic properties, even in doses lower than would normally reach the gut microbiome.²⁵ In humans, a randomized controlled trial of probiotic supplementation for schizophrenia patients taking antipsychotics showed a reduction in GI symptoms but no significant improvement in psychotic symptoms.²⁶

Dysbiosis in schizophrenia: cause or effect?

There is no consensus on what constitutes a healthy gut microbiome because the gut microbiome is highly variable, even among healthy individuals, and can change quickly. Those who adopt new diets, for example, see drastic shifts in the gut microbiome within a few days.²⁷ Despite this variation, the main separation between a healthy and dysbiotic gut comes from the diversity of bacteria present in the gut—a healthy gut microbiome is associated with increased diversity. Numerous disease states have been associated with decreased bacterial diversity, including Clostridium difficile infection, Parkinson disease, depression, Crohn disease, and schizophrenia spectrum disorders.^28,29

Although there are ethical limitations to studying causality in humans directly, animal models have provided a great deal of insight into the gut microbiome’s role in the development of schizophrenia. A recent study used fecal transplant to provide the gut microbiome from patients with schizophrenia to a group of germ-free mice and compared these animals to a group of mice that received a fecal transplant from individuals with a healthy gut microbiome. The mice receiving the schizophrenia microbiome showed an increased startle response and hyperactivity.³ This was consistent with mouse models of schizophrenia, although with obvious limitations.³⁰ In addition, the brains of these animals showed changes in glutamate, glutamine, and GABA in the hippocampus; these chemicals play a role in the neurophysiology of schizophrenia.^3,31 This study has not yet been replicated, and considerable variation remains within the schizophrenia biosignature.

Continue to: Clinical symptoms of psychosis and the gut microbiome

Previous literature has grouped patients with schizophrenia spectrum disorders as 1 unified study group. But as is the case with many psychiatric conditions, there is a great deal of heterogeneity in neurobiology, genetics, and microbiome composition among individuals with schizophrenia.³²

Researchers have begun to investigate ways in which the gut microbiome varies regarding the clinical symptoms of psychosis.³³ The Table^3,34-39 provides an overview of 7 human studies of gut microbiome changes relating to clinical features of schizophrenia. In these studies, researchers have found correlations between the gut microbiome and a tendency toward violence,³⁷ cognitive deficits,^34-36,39 depressive symptoms,^35,39 and numerous other clinical features of psychosis. Most of these correlations have not yet been replicated by further studies. But among studies with similar clinical questions, 3 reported changes in gut microbiome correlated with overall symptom severity, and 4 studies correlated changes with negative symptom severity. In 2 studies,^3,34Lachnospiraceae was correlated with worsened symptom severity. However, this may have been the result of poor control for antipsychotic use, as 1 study in bipolar patients found that Lachnospiraceae was increased in those taking antipsychotics compared to those who were not treated with antipsychotics.⁴⁰ The specific shifts in bacteria seen for overall symptom and negative symptom severity were not consistent across studies. This is not surprising because the gut microbiome varies with diet and geographic region,⁴¹ and patients in these studies were from a variety of regions. Multiple studies demonstrated gut microbiome alterations for patients with more severe negative symptoms. This is particularly interesting because negative symptoms are often difficult to treat and do not respond to antipsychotics.⁴² This research suggests the gut microbiome may be helpful in developing future treatments for patients with negative symptoms that do not respond to existing treatments.

Research of probiotic supplementation for ameliorating symptoms of schizophrenia has yielded mixed results.⁴³ It is possible that studies of probiotic supplementation have failed to consider the variations in the gut microbiome among individuals with schizophrenia. A better understanding of the variations in gut microbiome may allow for the development of more personalized interventions.

Recommendations for a healthy gut microbiome

In addition to antipsychotics, many other evidence-based interventions can be used to help restore a healthy gut microbiome in patients with schizophrenia. To improve the gut microbiome, we suggest discussing the following changes with patients:

• Quitting smoking. Smoking is common among patients with schizophrenia but decreases gut microbiome diversity.⁴⁴
• Avoiding excessive alcohol use. Excessive alcohol use contributes to dysbiosis and increased intestinal permeability.⁴⁵ Moderate alcohol consumption does not appear to have the same harmful effects on the microbiome.⁴⁶
• Avoiding the use of recreational drugs, including marijuana, which impact the gut microbiome.⁴⁷
• Consuming a diet rich in fiber.⁴⁸ Presently, there is not enough evidence to recommend probiotic supplementation to reduce symptoms of schizophrenia.⁴¹ Similar to probiotics, fermented foods contain Lactobacillus, a bacterial species that produces lactic acid.⁴⁹Lactobacillus is enriched in the gut microbiome in some neurodegenerative diseases, and lactic acid can be neurotoxic at high levels.^50-52 Therefore, clinicians should not explicitly recommend fermented foods under the assumption of improved brain health. A diet rich in soluble fiber has been consistently shown to promote anti-inflammatory bacteria and is much more likely to be beneficial.^53,54 Soluble fiber is found in foods such as fruits, vegetables, beans, and oats.
• Exercising can increase microbiome diversity and provide anti-inflammatory effects in the gut.^55,56 A recent review found that steady-state aerobic and high-intensity exercise interventions have positive effects on mood, cognition, and other negative symptoms in patients with schizophrenia.⁵⁵
• Minimizing stress. Psychological stress and physiological stress from untreated medical conditions are toxic to healthy gut bacteria and weaken the gut barrier.⁵⁷
• Mitigating exposure to pollution. Environmental pollution, including exposures to air pollution, heavy metals, and pesticides, disrupts the gut microbiome.⁵⁸

The American Heart Association publishes lifestyle recommendations for individuals with heart disease and the National Institutes of Health publishes lifestyle recommendations for patients with chronic kidney disease. This leads us to question why the American Psychiatric Association has not published lifestyle recommendations for those with severe mental illness. The effects of lifestyle on both the gut microbiome and symptom mitigation is critical. With increasingly shortened appointments, standardized guidelines would benefit psychiatrists and patients alike.

Bottom Line

The gut microbiome is connected to the clinical symptoms of psychosis via a variety of hormonal, neuroimmune, and metabolic mechanisms active across the lifespan. Despite advances in research, there is still much to be understood regarding this relationship. Clinicians should discuss with patients ways to promote a healthy gut microbiome, including consuming a diet rich in fiber, avoiding use of recreational drugs, and exercising regularly.

Related Resources

• Nocera A, Nasrallah HA. The association of the gut microbiota with clinical features in schizophrenia. Behav Sci. 2022;12(4):89.
• Nasrallah HA. It takes guts to be mentally ill: microbiota and psychopathology. Current Psychiatry. 2018;17(9):4-6.

The human microbiota refers to the collection of bacteria, archaea, eukarya, and viruses that reside within the human body. The term gut microbiome indicates the composition of these microbes and genetic codes in the intestine.¹ Harkening back to the ancient Greek physician Galen, who treated gastrointestinal (GI) symptoms to relieve mental disturbances such as psychosis, the gut has been a therapeutic target in schizophrenia long before antipsychotics and the DSM.² In recent years, research into the gut microbiome has drastically increased, with genetic sequencing affording a more precise look into the specific bacteria that call the human intestines their home. This has led to the recognition that the gut microbiome may be severely disrupted in schizophrenia, a condition known as dysbiosis. Preliminary research suggests that gut bacteria are more helpful than many human genes in distinguishing individuals with schizophrenia from their healthy counterparts.^3,4 In this article, we discuss the potential role of the gut microbiome in schizophrenia, including new research correlating clinical symptoms of psychosis with dysbiosis. We also provide recommendations for promoting a healthy gut microbiome.

The enteric brain across life

The composition of our bodies is far more microbiota than human. Strikingly, microbiota cells in the gut outnumber human cells, and the distal gut alone hosts bacteria with 100 times the genetic content of the entire genome.⁵ The intricate meshwork of nerves in the gut is often called the enteric brain because the gut consists of 100 million neurons and synthesizes many neuroactive chemicals implicated in mood disorders and psychosis, including serotonin, dopamine, gamma-aminobutyric acid (GABA), and acetylcholine.⁶ The variety of neuro­immunologic, hormonal, and metabolic paths by which the gutmicrobiome and the brain interact are collectively known as the gut-microbiota-brainaxis.⁷

How do we acquire our gut microbiome, and how does it come to influence ourbrain and behavior? On the first day of life, as babies pass through the birth canal, they are bathed in their mother’s vaginal microbiota. In the following weeks, the microbiome expands and colonizes the gut as bacteria are introduced from environmental sources such as skin-to-skin contact and breastmilk.⁸ The microbiome continues to evolve throughout early life. As children expand their diets and navigate new aspects of the physical world, additional bacteria join the unseen ecosystem growing inside.⁹ The development of the microbiome coincides with the development of the brain. From preclinical studies, we know the gut microbiome mediates important aspects of neurodevelopment such as the formation of the blood-brain barrier (BBB), synaptic pruning, glial activation, and myelination.¹⁰ Interestingly, many of the risk factors for schizophrenia are associated with gut dysbiosis, including obstetric complications, infections treated with antibiotics, and urbanization.^11-15

Throughout human life, the gut and brain remain in close communication. The gut microbiota continue to produce monoamines, along with other metabolites that are able to cross the BBB.⁶ The HPA axis, stimulation of the immune system, and the vagus nerve all provide highways of communication between the gut and the brain.⁷ The relationship between the enteric brain and cephalic brain continues through life, even up to a person’s final hour. One autopsy study that is often cited (but soberingly, cannot be found online) allegedly revealed that 92% of schizophrenia patients had developed colitis by the time of death.^16,17

First-episode psychosis and antipsychotic treatment

For patients with schizophrenia, first-episode psychosis (FEP) represents a cocktail of mounting genetic and environmental factors. Typically, by the time a patient receives psychiatric care, they present with characteristic psychotic symptoms—hallucinations, delusions, bizarre behavior, and unusual thought process—along with a unique gut microbiome profile.

This disrupted microbiome coincides with a marked state of inflammation in the intestines. Inflammation triggers increased endothelial barrier permeability, similar to the way immune signals increase capillary permeability to allow immune cells into the periphery of the blood. Specific gut bacteria play specific roles in maintaining the gut barrier.^18,19 Disruptions in the bacteria that maintain the gut barrier, combined with inflammation, contribute to a leaky gut. A leaky gut barrier allows bacterial and immune products to more easily enter the bloodstream and then the brain, which is a potential source of neuroinflammation in schizophrenia.²⁰ This increase in gut permeability (leaky gut syndrome) is likely one of several reasons low-grade inflammation is common in schizophrenia—numerous studies show higher serum levels of proinflammatory cytokines along with antibacterial immunoglobulins in patients with FEP.^21,22

Fortunately, antipsychotics, especially the second-generation agents, help restore a healthy gut microbiome and have substantial anti-inflammatory properties.^23,24 These medications interact heavily with the gut microbiome: they have been found to have antibiotic properties, even in doses lower than would normally reach the gut microbiome.²⁵ In humans, a randomized controlled trial of probiotic supplementation for schizophrenia patients taking antipsychotics showed a reduction in GI symptoms but no significant improvement in psychotic symptoms.²⁶

Dysbiosis in schizophrenia: cause or effect?

There is no consensus on what constitutes a healthy gut microbiome because the gut microbiome is highly variable, even among healthy individuals, and can change quickly. Those who adopt new diets, for example, see drastic shifts in the gut microbiome within a few days.²⁷ Despite this variation, the main separation between a healthy and dysbiotic gut comes from the diversity of bacteria present in the gut—a healthy gut microbiome is associated with increased diversity. Numerous disease states have been associated with decreased bacterial diversity, including Clostridium difficile infection, Parkinson disease, depression, Crohn disease, and schizophrenia spectrum disorders.^28,29

Although there are ethical limitations to studying causality in humans directly, animal models have provided a great deal of insight into the gut microbiome’s role in the development of schizophrenia. A recent study used fecal transplant to provide the gut microbiome from patients with schizophrenia to a group of germ-free mice and compared these animals to a group of mice that received a fecal transplant from individuals with a healthy gut microbiome. The mice receiving the schizophrenia microbiome showed an increased startle response and hyperactivity.³ This was consistent with mouse models of schizophrenia, although with obvious limitations.³⁰ In addition, the brains of these animals showed changes in glutamate, glutamine, and GABA in the hippocampus; these chemicals play a role in the neurophysiology of schizophrenia.^3,31 This study has not yet been replicated, and considerable variation remains within the schizophrenia biosignature.

Continue to: Clinical symptoms of psychosis and the gut microbiome

Previous literature has grouped patients with schizophrenia spectrum disorders as 1 unified study group. But as is the case with many psychiatric conditions, there is a great deal of heterogeneity in neurobiology, genetics, and microbiome composition among individuals with schizophrenia.³²

Researchers have begun to investigate ways in which the gut microbiome varies regarding the clinical symptoms of psychosis.³³ The Table^3,34-39 provides an overview of 7 human studies of gut microbiome changes relating to clinical features of schizophrenia. In these studies, researchers have found correlations between the gut microbiome and a tendency toward violence,³⁷ cognitive deficits,^34-36,39 depressive symptoms,^35,39 and numerous other clinical features of psychosis. Most of these correlations have not yet been replicated by further studies. But among studies with similar clinical questions, 3 reported changes in gut microbiome correlated with overall symptom severity, and 4 studies correlated changes with negative symptom severity. In 2 studies,^3,34Lachnospiraceae was correlated with worsened symptom severity. However, this may have been the result of poor control for antipsychotic use, as 1 study in bipolar patients found that Lachnospiraceae was increased in those taking antipsychotics compared to those who were not treated with antipsychotics.⁴⁰ The specific shifts in bacteria seen for overall symptom and negative symptom severity were not consistent across studies. This is not surprising because the gut microbiome varies with diet and geographic region,⁴¹ and patients in these studies were from a variety of regions. Multiple studies demonstrated gut microbiome alterations for patients with more severe negative symptoms. This is particularly interesting because negative symptoms are often difficult to treat and do not respond to antipsychotics.⁴² This research suggests the gut microbiome may be helpful in developing future treatments for patients with negative symptoms that do not respond to existing treatments.

Research of probiotic supplementation for ameliorating symptoms of schizophrenia has yielded mixed results.⁴³ It is possible that studies of probiotic supplementation have failed to consider the variations in the gut microbiome among individuals with schizophrenia. A better understanding of the variations in gut microbiome may allow for the development of more personalized interventions.

Recommendations for a healthy gut microbiome

In addition to antipsychotics, many other evidence-based interventions can be used to help restore a healthy gut microbiome in patients with schizophrenia. To improve the gut microbiome, we suggest discussing the following changes with patients:

• Quitting smoking. Smoking is common among patients with schizophrenia but decreases gut microbiome diversity.⁴⁴
• Avoiding excessive alcohol use. Excessive alcohol use contributes to dysbiosis and increased intestinal permeability.⁴⁵ Moderate alcohol consumption does not appear to have the same harmful effects on the microbiome.⁴⁶
• Avoiding the use of recreational drugs, including marijuana, which impact the gut microbiome.⁴⁷
• Consuming a diet rich in fiber.⁴⁸ Presently, there is not enough evidence to recommend probiotic supplementation to reduce symptoms of schizophrenia.⁴¹ Similar to probiotics, fermented foods contain Lactobacillus, a bacterial species that produces lactic acid.⁴⁹Lactobacillus is enriched in the gut microbiome in some neurodegenerative diseases, and lactic acid can be neurotoxic at high levels.^50-52 Therefore, clinicians should not explicitly recommend fermented foods under the assumption of improved brain health. A diet rich in soluble fiber has been consistently shown to promote anti-inflammatory bacteria and is much more likely to be beneficial.^53,54 Soluble fiber is found in foods such as fruits, vegetables, beans, and oats.
• Exercising can increase microbiome diversity and provide anti-inflammatory effects in the gut.^55,56 A recent review found that steady-state aerobic and high-intensity exercise interventions have positive effects on mood, cognition, and other negative symptoms in patients with schizophrenia.⁵⁵
• Minimizing stress. Psychological stress and physiological stress from untreated medical conditions are toxic to healthy gut bacteria and weaken the gut barrier.⁵⁷
• Mitigating exposure to pollution. Environmental pollution, including exposures to air pollution, heavy metals, and pesticides, disrupts the gut microbiome.⁵⁸

The American Heart Association publishes lifestyle recommendations for individuals with heart disease and the National Institutes of Health publishes lifestyle recommendations for patients with chronic kidney disease. This leads us to question why the American Psychiatric Association has not published lifestyle recommendations for those with severe mental illness. The effects of lifestyle on both the gut microbiome and symptom mitigation is critical. With increasingly shortened appointments, standardized guidelines would benefit psychiatrists and patients alike.

Bottom Line

The gut microbiome is connected to the clinical symptoms of psychosis via a variety of hormonal, neuroimmune, and metabolic mechanisms active across the lifespan. Despite advances in research, there is still much to be understood regarding this relationship. Clinicians should discuss with patients ways to promote a healthy gut microbiome, including consuming a diet rich in fiber, avoiding use of recreational drugs, and exercising regularly.

Related Resources

• Nocera A, Nasrallah HA. The association of the gut microbiota with clinical features in schizophrenia. Behav Sci. 2022;12(4):89.
• Nasrallah HA. It takes guts to be mentally ill: microbiota and psychopathology. Current Psychiatry. 2018;17(9):4-6.

The human microbiota refers to the collection of bacteria, archaea, eukarya, and viruses that reside within the human body. The term gut microbiome indicates the composition of these microbes and genetic codes in the intestine.¹ Harkening back to the ancient Greek physician Galen, who treated gastrointestinal (GI) symptoms to relieve mental disturbances such as psychosis, the gut has been a therapeutic target in schizophrenia long before antipsychotics and the DSM.² In recent years, research into the gut microbiome has drastically increased, with genetic sequencing affording a more precise look into the specific bacteria that call the human intestines their home. This has led to the recognition that the gut microbiome may be severely disrupted in schizophrenia, a condition known as dysbiosis. Preliminary research suggests that gut bacteria are more helpful than many human genes in distinguishing individuals with schizophrenia from their healthy counterparts.^3,4 In this article, we discuss the potential role of the gut microbiome in schizophrenia, including new research correlating clinical symptoms of psychosis with dysbiosis. We also provide recommendations for promoting a healthy gut microbiome.

The enteric brain across life

The composition of our bodies is far more microbiota than human. Strikingly, microbiota cells in the gut outnumber human cells, and the distal gut alone hosts bacteria with 100 times the genetic content of the entire genome.⁵ The intricate meshwork of nerves in the gut is often called the enteric brain because the gut consists of 100 million neurons and synthesizes many neuroactive chemicals implicated in mood disorders and psychosis, including serotonin, dopamine, gamma-aminobutyric acid (GABA), and acetylcholine.⁶ The variety of neuro­immunologic, hormonal, and metabolic paths by which the gutmicrobiome and the brain interact are collectively known as the gut-microbiota-brainaxis.⁷

How do we acquire our gut microbiome, and how does it come to influence ourbrain and behavior? On the first day of life, as babies pass through the birth canal, they are bathed in their mother’s vaginal microbiota. In the following weeks, the microbiome expands and colonizes the gut as bacteria are introduced from environmental sources such as skin-to-skin contact and breastmilk.⁸ The microbiome continues to evolve throughout early life. As children expand their diets and navigate new aspects of the physical world, additional bacteria join the unseen ecosystem growing inside.⁹ The development of the microbiome coincides with the development of the brain. From preclinical studies, we know the gut microbiome mediates important aspects of neurodevelopment such as the formation of the blood-brain barrier (BBB), synaptic pruning, glial activation, and myelination.¹⁰ Interestingly, many of the risk factors for schizophrenia are associated with gut dysbiosis, including obstetric complications, infections treated with antibiotics, and urbanization.^11-15

Throughout human life, the gut and brain remain in close communication. The gut microbiota continue to produce monoamines, along with other metabolites that are able to cross the BBB.⁶ The HPA axis, stimulation of the immune system, and the vagus nerve all provide highways of communication between the gut and the brain.⁷ The relationship between the enteric brain and cephalic brain continues through life, even up to a person’s final hour. One autopsy study that is often cited (but soberingly, cannot be found online) allegedly revealed that 92% of schizophrenia patients had developed colitis by the time of death.^16,17

First-episode psychosis and antipsychotic treatment

For patients with schizophrenia, first-episode psychosis (FEP) represents a cocktail of mounting genetic and environmental factors. Typically, by the time a patient receives psychiatric care, they present with characteristic psychotic symptoms—hallucinations, delusions, bizarre behavior, and unusual thought process—along with a unique gut microbiome profile.

This disrupted microbiome coincides with a marked state of inflammation in the intestines. Inflammation triggers increased endothelial barrier permeability, similar to the way immune signals increase capillary permeability to allow immune cells into the periphery of the blood. Specific gut bacteria play specific roles in maintaining the gut barrier.^18,19 Disruptions in the bacteria that maintain the gut barrier, combined with inflammation, contribute to a leaky gut. A leaky gut barrier allows bacterial and immune products to more easily enter the bloodstream and then the brain, which is a potential source of neuroinflammation in schizophrenia.²⁰ This increase in gut permeability (leaky gut syndrome) is likely one of several reasons low-grade inflammation is common in schizophrenia—numerous studies show higher serum levels of proinflammatory cytokines along with antibacterial immunoglobulins in patients with FEP.^21,22

Fortunately, antipsychotics, especially the second-generation agents, help restore a healthy gut microbiome and have substantial anti-inflammatory properties.^23,24 These medications interact heavily with the gut microbiome: they have been found to have antibiotic properties, even in doses lower than would normally reach the gut microbiome.²⁵ In humans, a randomized controlled trial of probiotic supplementation for schizophrenia patients taking antipsychotics showed a reduction in GI symptoms but no significant improvement in psychotic symptoms.²⁶

Dysbiosis in schizophrenia: cause or effect?

There is no consensus on what constitutes a healthy gut microbiome because the gut microbiome is highly variable, even among healthy individuals, and can change quickly. Those who adopt new diets, for example, see drastic shifts in the gut microbiome within a few days.²⁷ Despite this variation, the main separation between a healthy and dysbiotic gut comes from the diversity of bacteria present in the gut—a healthy gut microbiome is associated with increased diversity. Numerous disease states have been associated with decreased bacterial diversity, including Clostridium difficile infection, Parkinson disease, depression, Crohn disease, and schizophrenia spectrum disorders.^28,29

Although there are ethical limitations to studying causality in humans directly, animal models have provided a great deal of insight into the gut microbiome’s role in the development of schizophrenia. A recent study used fecal transplant to provide the gut microbiome from patients with schizophrenia to a group of germ-free mice and compared these animals to a group of mice that received a fecal transplant from individuals with a healthy gut microbiome. The mice receiving the schizophrenia microbiome showed an increased startle response and hyperactivity.³ This was consistent with mouse models of schizophrenia, although with obvious limitations.³⁰ In addition, the brains of these animals showed changes in glutamate, glutamine, and GABA in the hippocampus; these chemicals play a role in the neurophysiology of schizophrenia.^3,31 This study has not yet been replicated, and considerable variation remains within the schizophrenia biosignature.

Continue to: Clinical symptoms of psychosis and the gut microbiome

Previous literature has grouped patients with schizophrenia spectrum disorders as 1 unified study group. But as is the case with many psychiatric conditions, there is a great deal of heterogeneity in neurobiology, genetics, and microbiome composition among individuals with schizophrenia.³²

Researchers have begun to investigate ways in which the gut microbiome varies regarding the clinical symptoms of psychosis.³³ The Table^3,34-39 provides an overview of 7 human studies of gut microbiome changes relating to clinical features of schizophrenia. In these studies, researchers have found correlations between the gut microbiome and a tendency toward violence,³⁷ cognitive deficits,^34-36,39 depressive symptoms,^35,39 and numerous other clinical features of psychosis. Most of these correlations have not yet been replicated by further studies. But among studies with similar clinical questions, 3 reported changes in gut microbiome correlated with overall symptom severity, and 4 studies correlated changes with negative symptom severity. In 2 studies,^3,34Lachnospiraceae was correlated with worsened symptom severity. However, this may have been the result of poor control for antipsychotic use, as 1 study in bipolar patients found that Lachnospiraceae was increased in those taking antipsychotics compared to those who were not treated with antipsychotics.⁴⁰ The specific shifts in bacteria seen for overall symptom and negative symptom severity were not consistent across studies. This is not surprising because the gut microbiome varies with diet and geographic region,⁴¹ and patients in these studies were from a variety of regions. Multiple studies demonstrated gut microbiome alterations for patients with more severe negative symptoms. This is particularly interesting because negative symptoms are often difficult to treat and do not respond to antipsychotics.⁴² This research suggests the gut microbiome may be helpful in developing future treatments for patients with negative symptoms that do not respond to existing treatments.

Research of probiotic supplementation for ameliorating symptoms of schizophrenia has yielded mixed results.⁴³ It is possible that studies of probiotic supplementation have failed to consider the variations in the gut microbiome among individuals with schizophrenia. A better understanding of the variations in gut microbiome may allow for the development of more personalized interventions.

Recommendations for a healthy gut microbiome

In addition to antipsychotics, many other evidence-based interventions can be used to help restore a healthy gut microbiome in patients with schizophrenia. To improve the gut microbiome, we suggest discussing the following changes with patients:

• Quitting smoking. Smoking is common among patients with schizophrenia but decreases gut microbiome diversity.⁴⁴
• Avoiding excessive alcohol use. Excessive alcohol use contributes to dysbiosis and increased intestinal permeability.⁴⁵ Moderate alcohol consumption does not appear to have the same harmful effects on the microbiome.⁴⁶
• Avoiding the use of recreational drugs, including marijuana, which impact the gut microbiome.⁴⁷
• Consuming a diet rich in fiber.⁴⁸ Presently, there is not enough evidence to recommend probiotic supplementation to reduce symptoms of schizophrenia.⁴¹ Similar to probiotics, fermented foods contain Lactobacillus, a bacterial species that produces lactic acid.⁴⁹Lactobacillus is enriched in the gut microbiome in some neurodegenerative diseases, and lactic acid can be neurotoxic at high levels.^50-52 Therefore, clinicians should not explicitly recommend fermented foods under the assumption of improved brain health. A diet rich in soluble fiber has been consistently shown to promote anti-inflammatory bacteria and is much more likely to be beneficial.^53,54 Soluble fiber is found in foods such as fruits, vegetables, beans, and oats.
• Exercising can increase microbiome diversity and provide anti-inflammatory effects in the gut.^55,56 A recent review found that steady-state aerobic and high-intensity exercise interventions have positive effects on mood, cognition, and other negative symptoms in patients with schizophrenia.⁵⁵
• Minimizing stress. Psychological stress and physiological stress from untreated medical conditions are toxic to healthy gut bacteria and weaken the gut barrier.⁵⁷
• Mitigating exposure to pollution. Environmental pollution, including exposures to air pollution, heavy metals, and pesticides, disrupts the gut microbiome.⁵⁸

The American Heart Association publishes lifestyle recommendations for individuals with heart disease and the National Institutes of Health publishes lifestyle recommendations for patients with chronic kidney disease. This leads us to question why the American Psychiatric Association has not published lifestyle recommendations for those with severe mental illness. The effects of lifestyle on both the gut microbiome and symptom mitigation is critical. With increasingly shortened appointments, standardized guidelines would benefit psychiatrists and patients alike.

Bottom Line

The gut microbiome is connected to the clinical symptoms of psychosis via a variety of hormonal, neuroimmune, and metabolic mechanisms active across the lifespan. Despite advances in research, there is still much to be understood regarding this relationship. Clinicians should discuss with patients ways to promote a healthy gut microbiome, including consuming a diet rich in fiber, avoiding use of recreational drugs, and exercising regularly.

Related Resources

• Nocera A, Nasrallah HA. The association of the gut microbiota with clinical features in schizophrenia. Behav Sci. 2022;12(4):89.
• Nasrallah HA. It takes guts to be mentally ill: microbiota and psychopathology. Current Psychiatry. 2018;17(9):4-6.

Clinicians generally regard major depressive disorder (MDD) and schizophrenia as 2 separate and distinct psychiatric brain disorders. However, despite some differences, those 2 psychiatric syndromes have numerous similarities across clinical features and neurobiologic parameters.

Biological similarities

Both disorders share the following variables:

• Highly genetic in etiology but with environmental influences and epigenetics
• Associated with childhood maltreatment, abuse, or neglect
• Disrupted neuroplasticity, especially shrinkage in hippocampal volume
• Significant drop in brain-derived neurotrophic factor resulting in decreased neurogenesis
• Extensive white matter pathology across interhemispheric and intrahemispheric bundles
• Increased levels of serum cortisol, a stress hormone and inflammatory biomarker
• Hypofrontal cerebral blood flow during acute episodes of both MDD and schizophrenia
• Reduced dendritic spines (in number and size) and impaired experiential neuroplasticity
• Neuroinflammation (eg, cytokines, tumor necrosis factor-alpha, C-reactive protein) during acute episodes
• Elevated oxidative stress biomarkers, indicating an increase in free radicals
• Overactive default mode network associated with ruminations in MDD and “daydreaming” in schizophrenia
• Decrease in gamma-aminobutyric acid (GABA) and its inhibitory activity, translating into dysregulation of glutamatergic pathways and other neurotransmitters
• Immune dysregulation and comorbid autoimmune disorders

Clinical similarities

• Psychotic symptoms, especially delusional thinking such as paranoia in schizophrenia and severe self-deprecation in MDD
• Significantly elevated lifetime suicide risk
• Cognitive impairment (more severe in schizophrenia across several cognitive functions)
• Similarity of depressive and negative symptoms (especially anhedonia, apathy, restricted facial expression, social withdrawal)
• Antidepressant medications im­-prove depressive and negative symptoms (though not completely in the case of negative symptoms of schizophrenia)
• Both have treatment-resistant subtypes that fail to respond to standard therapies
• Both are associated with comorbid generalized anxiety disorder
• Both are associated with comorbid obsessive-compulsive disorder
• Both are associated with serious alcohol and drug use
• Early mortality from general medical conditions, especially cardiovascular risks due to obesity, diabetes, hypertension, dyslipidemia
• Elevated risk of dementia with aging compared to the unaffected general population
• Opioids improve MDD and psychosis (buprenorphine in MDD and morphine in schizophrenia)
• Several second-generation antipsychotic medications are approved for both MDD and schizophrenia
• Electroconvulsive therapy is effective when pharmacotherapy fails in both MDD and schizophrenia

Biological differences

• Glutamate N-methyl-D-aspar­tate receptor antagonists (eg, ketamine) improve MDD but worsen schizophrenia
• Muscarinic agonists improve psychosis but worsen depression
• High pain threshold in schizophrenia (pain insensitivity) and low threshold in MDD (in which pain is a common comorbidity)
• Cortical thinning more severe in schizophrenia
• Hippocampal atrophy is reversible with successful treatment in MDD but not in schizophrenia
• Hypofrontality is reversible with remission in MDD but not in schizophrenia

Clinical differences

• Auditory and visual hallucinations are more common in schizophrenia than in MDD
• Anosognosia is common in schizophrenia but not in MDD
• Implausible delusions are more common in schizophrenia than in MDD
• Mood-congruent delusions are more common in MDD than in schizophrenia
• Sadness, crying, pessimism, and self-deprecation are common in MDD but not in schizophrenia
• Achieving full remission is more common in MDD than in schizophrenia
• Long-acting injectable medications are available for schizophrenia but not for MDD
• Evidence-based psychotherapy, without pharmacotherapy, is more likely to be effective in MDD than in schizophrenia

A transdiagnostic model of psychopathology

The significant overlap between MDD and schizophrenia should not be surprising. They are both generated by the same organ, the human brain, with disrupted neurochemical and physiological circuits in the brain.

The overlap is also consistent with the emerging transdiagnostic model of psychopathology.^1-9 This model proposes that there is a “core” genetic risk for psychopathology with different iterations. The transdiagnostic model is in stark contrast to the prevailing DSM-5, which categorizes psychiatric disorders in “silos,” as if they are completely independent from each other despite many shared features. This is highly debatable according to the substantial evidence that multiple psychiatric disorders share many genes that influence brain development in utero and predispose individuals to a variety of clinical symptoms in adolescence and young adulthood.

The origin of mental illness is being disentangled by emerging research, which is identifying the common links among the various disorders currently listed in DSM-5.¹⁰ However, the evolution of psychiatric diagnosis has come full circle from a single entity before DSM, to multiple entities with DSM, and now back to a unified transdiagnostic model that is rapidly emerging.¹¹ This has implications for the FDA’s persistent dogma that clinical trials for new drugs must be targeted for 1 of the DSM-5 categories, a flawed and narrow assumption. Given the accelerating body of evidence for a unified, transdiagnostic model, it makes much more sense for the FDA to approve medications that target a psychiatric symptom that is shared by multiple psychiatric conditions within a transdiagnostic clinical system. When medications are approved for a symptom regardless of a DSM diagnosis, the term “off-label” and its “stigma” will then fade into history, along with the malignant preauthorization racket that was invented by greedy insurance companies that exploit the off-label use of medications (even when an FDA-approved medication for the patient’s condition does not yet exist) simply to deny coverage, lower their expenses, and fatten their profits.

Clinicians generally regard major depressive disorder (MDD) and schizophrenia as 2 separate and distinct psychiatric brain disorders. However, despite some differences, those 2 psychiatric syndromes have numerous similarities across clinical features and neurobiologic parameters.

Biological similarities

Both disorders share the following variables:

• Highly genetic in etiology but with environmental influences and epigenetics
• Associated with childhood maltreatment, abuse, or neglect
• Disrupted neuroplasticity, especially shrinkage in hippocampal volume
• Significant drop in brain-derived neurotrophic factor resulting in decreased neurogenesis
• Extensive white matter pathology across interhemispheric and intrahemispheric bundles
• Increased levels of serum cortisol, a stress hormone and inflammatory biomarker
• Hypofrontal cerebral blood flow during acute episodes of both MDD and schizophrenia
• Reduced dendritic spines (in number and size) and impaired experiential neuroplasticity
• Neuroinflammation (eg, cytokines, tumor necrosis factor-alpha, C-reactive protein) during acute episodes
• Elevated oxidative stress biomarkers, indicating an increase in free radicals
• Overactive default mode network associated with ruminations in MDD and “daydreaming” in schizophrenia
• Decrease in gamma-aminobutyric acid (GABA) and its inhibitory activity, translating into dysregulation of glutamatergic pathways and other neurotransmitters
• Immune dysregulation and comorbid autoimmune disorders

Clinical similarities

• Psychotic symptoms, especially delusional thinking such as paranoia in schizophrenia and severe self-deprecation in MDD
• Significantly elevated lifetime suicide risk
• Cognitive impairment (more severe in schizophrenia across several cognitive functions)
• Similarity of depressive and negative symptoms (especially anhedonia, apathy, restricted facial expression, social withdrawal)
• Antidepressant medications im­-prove depressive and negative symptoms (though not completely in the case of negative symptoms of schizophrenia)
• Both have treatment-resistant subtypes that fail to respond to standard therapies
• Both are associated with comorbid generalized anxiety disorder
• Both are associated with comorbid obsessive-compulsive disorder
• Both are associated with serious alcohol and drug use
• Early mortality from general medical conditions, especially cardiovascular risks due to obesity, diabetes, hypertension, dyslipidemia
• Elevated risk of dementia with aging compared to the unaffected general population
• Opioids improve MDD and psychosis (buprenorphine in MDD and morphine in schizophrenia)
• Several second-generation antipsychotic medications are approved for both MDD and schizophrenia
• Electroconvulsive therapy is effective when pharmacotherapy fails in both MDD and schizophrenia

Biological differences

• Glutamate N-methyl-D-aspar­tate receptor antagonists (eg, ketamine) improve MDD but worsen schizophrenia
• Muscarinic agonists improve psychosis but worsen depression
• High pain threshold in schizophrenia (pain insensitivity) and low threshold in MDD (in which pain is a common comorbidity)
• Cortical thinning more severe in schizophrenia
• Hippocampal atrophy is reversible with successful treatment in MDD but not in schizophrenia
• Hypofrontality is reversible with remission in MDD but not in schizophrenia

Clinical differences

• Auditory and visual hallucinations are more common in schizophrenia than in MDD
• Anosognosia is common in schizophrenia but not in MDD
• Implausible delusions are more common in schizophrenia than in MDD
• Mood-congruent delusions are more common in MDD than in schizophrenia
• Sadness, crying, pessimism, and self-deprecation are common in MDD but not in schizophrenia
• Achieving full remission is more common in MDD than in schizophrenia
• Long-acting injectable medications are available for schizophrenia but not for MDD
• Evidence-based psychotherapy, without pharmacotherapy, is more likely to be effective in MDD than in schizophrenia

A transdiagnostic model of psychopathology

The significant overlap between MDD and schizophrenia should not be surprising. They are both generated by the same organ, the human brain, with disrupted neurochemical and physiological circuits in the brain.

The overlap is also consistent with the emerging transdiagnostic model of psychopathology.^1-9 This model proposes that there is a “core” genetic risk for psychopathology with different iterations. The transdiagnostic model is in stark contrast to the prevailing DSM-5, which categorizes psychiatric disorders in “silos,” as if they are completely independent from each other despite many shared features. This is highly debatable according to the substantial evidence that multiple psychiatric disorders share many genes that influence brain development in utero and predispose individuals to a variety of clinical symptoms in adolescence and young adulthood.

The origin of mental illness is being disentangled by emerging research, which is identifying the common links among the various disorders currently listed in DSM-5.¹⁰ However, the evolution of psychiatric diagnosis has come full circle from a single entity before DSM, to multiple entities with DSM, and now back to a unified transdiagnostic model that is rapidly emerging.¹¹ This has implications for the FDA’s persistent dogma that clinical trials for new drugs must be targeted for 1 of the DSM-5 categories, a flawed and narrow assumption. Given the accelerating body of evidence for a unified, transdiagnostic model, it makes much more sense for the FDA to approve medications that target a psychiatric symptom that is shared by multiple psychiatric conditions within a transdiagnostic clinical system. When medications are approved for a symptom regardless of a DSM diagnosis, the term “off-label” and its “stigma” will then fade into history, along with the malignant preauthorization racket that was invented by greedy insurance companies that exploit the off-label use of medications (even when an FDA-approved medication for the patient’s condition does not yet exist) simply to deny coverage, lower their expenses, and fatten their profits.

Clinicians generally regard major depressive disorder (MDD) and schizophrenia as 2 separate and distinct psychiatric brain disorders. However, despite some differences, those 2 psychiatric syndromes have numerous similarities across clinical features and neurobiologic parameters.

Biological similarities

Both disorders share the following variables:

• Highly genetic in etiology but with environmental influences and epigenetics
• Associated with childhood maltreatment, abuse, or neglect
• Disrupted neuroplasticity, especially shrinkage in hippocampal volume
• Significant drop in brain-derived neurotrophic factor resulting in decreased neurogenesis
• Extensive white matter pathology across interhemispheric and intrahemispheric bundles
• Increased levels of serum cortisol, a stress hormone and inflammatory biomarker
• Hypofrontal cerebral blood flow during acute episodes of both MDD and schizophrenia
• Reduced dendritic spines (in number and size) and impaired experiential neuroplasticity
• Neuroinflammation (eg, cytokines, tumor necrosis factor-alpha, C-reactive protein) during acute episodes
• Elevated oxidative stress biomarkers, indicating an increase in free radicals
• Overactive default mode network associated with ruminations in MDD and “daydreaming” in schizophrenia
• Decrease in gamma-aminobutyric acid (GABA) and its inhibitory activity, translating into dysregulation of glutamatergic pathways and other neurotransmitters
• Immune dysregulation and comorbid autoimmune disorders

Clinical similarities

• Psychotic symptoms, especially delusional thinking such as paranoia in schizophrenia and severe self-deprecation in MDD
• Significantly elevated lifetime suicide risk
• Cognitive impairment (more severe in schizophrenia across several cognitive functions)
• Similarity of depressive and negative symptoms (especially anhedonia, apathy, restricted facial expression, social withdrawal)
• Antidepressant medications im­-prove depressive and negative symptoms (though not completely in the case of negative symptoms of schizophrenia)
• Both have treatment-resistant subtypes that fail to respond to standard therapies
• Both are associated with comorbid generalized anxiety disorder
• Both are associated with comorbid obsessive-compulsive disorder
• Both are associated with serious alcohol and drug use
• Early mortality from general medical conditions, especially cardiovascular risks due to obesity, diabetes, hypertension, dyslipidemia
• Elevated risk of dementia with aging compared to the unaffected general population
• Opioids improve MDD and psychosis (buprenorphine in MDD and morphine in schizophrenia)
• Several second-generation antipsychotic medications are approved for both MDD and schizophrenia
• Electroconvulsive therapy is effective when pharmacotherapy fails in both MDD and schizophrenia

Biological differences

• Glutamate N-methyl-D-aspar­tate receptor antagonists (eg, ketamine) improve MDD but worsen schizophrenia
• Muscarinic agonists improve psychosis but worsen depression
• High pain threshold in schizophrenia (pain insensitivity) and low threshold in MDD (in which pain is a common comorbidity)
• Cortical thinning more severe in schizophrenia
• Hippocampal atrophy is reversible with successful treatment in MDD but not in schizophrenia
• Hypofrontality is reversible with remission in MDD but not in schizophrenia

Clinical differences

• Auditory and visual hallucinations are more common in schizophrenia than in MDD
• Anosognosia is common in schizophrenia but not in MDD
• Implausible delusions are more common in schizophrenia than in MDD
• Mood-congruent delusions are more common in MDD than in schizophrenia
• Sadness, crying, pessimism, and self-deprecation are common in MDD but not in schizophrenia
• Achieving full remission is more common in MDD than in schizophrenia
• Long-acting injectable medications are available for schizophrenia but not for MDD
• Evidence-based psychotherapy, without pharmacotherapy, is more likely to be effective in MDD than in schizophrenia

A transdiagnostic model of psychopathology

The significant overlap between MDD and schizophrenia should not be surprising. They are both generated by the same organ, the human brain, with disrupted neurochemical and physiological circuits in the brain.

The overlap is also consistent with the emerging transdiagnostic model of psychopathology.^1-9 This model proposes that there is a “core” genetic risk for psychopathology with different iterations. The transdiagnostic model is in stark contrast to the prevailing DSM-5, which categorizes psychiatric disorders in “silos,” as if they are completely independent from each other despite many shared features. This is highly debatable according to the substantial evidence that multiple psychiatric disorders share many genes that influence brain development in utero and predispose individuals to a variety of clinical symptoms in adolescence and young adulthood.

The origin of mental illness is being disentangled by emerging research, which is identifying the common links among the various disorders currently listed in DSM-5.¹⁰ However, the evolution of psychiatric diagnosis has come full circle from a single entity before DSM, to multiple entities with DSM, and now back to a unified transdiagnostic model that is rapidly emerging.¹¹ This has implications for the FDA’s persistent dogma that clinical trials for new drugs must be targeted for 1 of the DSM-5 categories, a flawed and narrow assumption. Given the accelerating body of evidence for a unified, transdiagnostic model, it makes much more sense for the FDA to approve medications that target a psychiatric symptom that is shared by multiple psychiatric conditions within a transdiagnostic clinical system. When medications are approved for a symptom regardless of a DSM diagnosis, the term “off-label” and its “stigma” will then fade into history, along with the malignant preauthorization racket that was invented by greedy insurance companies that exploit the off-label use of medications (even when an FDA-approved medication for the patient’s condition does not yet exist) simply to deny coverage, lower their expenses, and fatten their profits.

What does a doctor look like? Throughout history, this concept has shifted due to societal norms and increased access to medical education. Today, the idea of a physician has expanded to incorporate a myriad of people; however, stigma still exists in medicine regarding mental illness and disability. I would like to share my personal journey through high school, college, medical school, and now residency, and how my identity and struggles have shaped me into the physician I am today. There are few conversations around disability—especially disability and mental health—in medicine, and through my own advocacy, I have met many students with disability who feel that medical school is unattainable. Additionally, I have met many medical students, residents, and pre-health advisors who are happy for the experience to learn more about a marginalized group in medicine. My hope in sharing my story is to offer a space for conversation about intersectionality within medical communities and how physicians and physicians in training can facilitate that change, regardless of their position or specialty. Additionally, I hope to shed light on the unique mental health needs of patients with disabilities and how mental health clinicians can address those needs.

Perceived weaknesses turned into strengths

“Why do you walk like that?” “What is that brace on your leg?” The early years of my childhood were marked by these questions and others like them. I was the kid with the limp, the kid with a brace on his leg, and the kid who disappeared multiple times a week for doctor’s appointments or physical therapy. I learned to deflect these questions or give nebulous answers about an accident or injury. The reality is that I was born with cerebral palsy (CP). My CP manifested as hemiparesis on the left side of my body. I was in aggressive physical therapy throughout childhood, received Botox injections for muscle spasticity, and underwent corrective surgery on my left leg to straighten my foot. In childhood, the diagnosis meant nothing more than 2 words that sounded like they belonged to superheroes in comic books. Even with supportive parents and family, I kept my disability a secret, much like the powers and abilities of my favorite superheroes.

However, like all great origin stories, what I once thought were weaknesses turned out to be strengths that pushed me through college, medical school, and now psychiatry residency. Living with a disability has shaped how I see the world and relate to my patients. My experience has helped me connect to my patients in ways others might not. These properties are important in any physician but vital in psychiatry, where many patients feel neglected or stigmatized; this is another reason there should be more doctors with disabilities in medicine. Unfortunately, systemic barriers are still in place that disincentivize those with a disability from pursuing careers in medicine. Stories like mine are important to inspire a reexamination of what a physician should be and how medicine, patients, and communities benefit from this change.

My experience through medical school

My path to psychiatry and residency was shaped by my early experience with the medical field and treatment. From the early days of my diagnosis at age 4, I was told that my brain was “wired differently” and that, because of this disruption in circuitry, I would have difficulty with physical activity. I grew to appreciate the intricacies of the brain and pathology to understand my body. With greater understanding came the existential realization that I would live with a disability for the rest of my life. Rather than dream of a future where I would be “normal,” I focused on adapting my life to my normal. An unfortunate reality of this normal was that no doctor would be able to relate to me, and my health care would focus on limitations rather than possibilities.

I focused on school as a distraction and slowly warmed to the idea of pursuing medicine as a career. The seed was planted years prior by the numerous doctors’ visits and procedures, and was cultivated by a desire to understand pathologies and offer treatment to patients from the perspective of a patient. When I applied to medical school, I did not know how to address my CP. Living as a person with CP was a core reason for my decision to pursue medicine, but I was afraid that a disclosure of disability would preclude any admission to medical school. Research into programs offered little guidance because most institutions only listed vague “physical expectations” of each student. There were times I doubted if I would be accepted anywhere. Many programs I reached out to about my situation seemed unenthusiastic about the prospect of a student with CP, and when I brought up my CP in interviews, the reaction was often of surprise and an admission that they had forgotten about “that part” of my application. Fortunately, I was accepted to medical school, but still struggled with the fear that one day I would be found out and not allowed to continue. No one in my class or school was like me, and a meeting with an Americans with Disabilities Act coordinator who asked me to reexamine the physical competencies of the school before advancing to clinical clerkships only further reinforced this fear. I decided to fly under the radar and not say anything about my disability to my attendings. I slowly worked my way through clerkships by making do with adapted ways to perform procedures and exams with additional practice and maneuvering at home. I found myself drawn to psychiatry because of the similarities I saw in the patients and myself. I empathized with how the patients struggled with chronic conditions that left them feeling separated from society and how they felt that their diagnosis was something they needed to hide. When medical school ended and I decided to pursue psychiatry, I wanted to share my story to inspire others with a disability to consider medicine as a career given their unique experiences. My experience thus far has been uplifting as my journey has echoed so many others.

A need for greater representation

Disability representation in medicine is needed more than ever. According to the CDC, >60 million adults in the United States (1 in 4) live with a disability.¹ Although the physical health disparities are often discussed, there is less conversation surrounding mental health for individuals with disabilities. A 2018 study by Cree et al² found that approximately 17.4 million adults with disabilities experienced frequent mental distress, defined as reporting ≥14 mentally unhealthy days in the past 30 days. Furthermore, compared to individuals without a disability, those with a disability are statistically more likely to have suicidal ideation, suicidal planning, and suicide attempts.³ One way to address this disparity is to recruit medical students with disabilities to become physicians with disabilities. Evidence suggests that physicians who are members of groups that are underrepresented in medicine are more likely to deliver care to underrepresented patients.⁴ However, medical schools and institutions have been slow to address the disparity. A 2019 survey found an estimated 4.6% of medical students responded “yes” when asked if they had a disability, with most students reporting a psychological or attention/hyperactive disorder.⁵ Existing barriers include restrictive language surrounding technical standards influenced by long-standing vestiges of what a physician should be.⁶

An opportunity to connect with patients

I now do not see myself as having a secret identity to hide. Although my CP does not give me any superpowers, it has given me the opportunity to connect with my patients and serve as an example of why medical school recruitment and admissions should expand. Psychiatrists have been on the forefront of change in medicine and can shift the perception of a physician. In doing so, we not only enrich our field but also the lives of our patients who may need it most.

What does a doctor look like? Throughout history, this concept has shifted due to societal norms and increased access to medical education. Today, the idea of a physician has expanded to incorporate a myriad of people; however, stigma still exists in medicine regarding mental illness and disability. I would like to share my personal journey through high school, college, medical school, and now residency, and how my identity and struggles have shaped me into the physician I am today. There are few conversations around disability—especially disability and mental health—in medicine, and through my own advocacy, I have met many students with disability who feel that medical school is unattainable. Additionally, I have met many medical students, residents, and pre-health advisors who are happy for the experience to learn more about a marginalized group in medicine. My hope in sharing my story is to offer a space for conversation about intersectionality within medical communities and how physicians and physicians in training can facilitate that change, regardless of their position or specialty. Additionally, I hope to shed light on the unique mental health needs of patients with disabilities and how mental health clinicians can address those needs.

Perceived weaknesses turned into strengths

“Why do you walk like that?” “What is that brace on your leg?” The early years of my childhood were marked by these questions and others like them. I was the kid with the limp, the kid with a brace on his leg, and the kid who disappeared multiple times a week for doctor’s appointments or physical therapy. I learned to deflect these questions or give nebulous answers about an accident or injury. The reality is that I was born with cerebral palsy (CP). My CP manifested as hemiparesis on the left side of my body. I was in aggressive physical therapy throughout childhood, received Botox injections for muscle spasticity, and underwent corrective surgery on my left leg to straighten my foot. In childhood, the diagnosis meant nothing more than 2 words that sounded like they belonged to superheroes in comic books. Even with supportive parents and family, I kept my disability a secret, much like the powers and abilities of my favorite superheroes.

However, like all great origin stories, what I once thought were weaknesses turned out to be strengths that pushed me through college, medical school, and now psychiatry residency. Living with a disability has shaped how I see the world and relate to my patients. My experience has helped me connect to my patients in ways others might not. These properties are important in any physician but vital in psychiatry, where many patients feel neglected or stigmatized; this is another reason there should be more doctors with disabilities in medicine. Unfortunately, systemic barriers are still in place that disincentivize those with a disability from pursuing careers in medicine. Stories like mine are important to inspire a reexamination of what a physician should be and how medicine, patients, and communities benefit from this change.

My experience through medical school

My path to psychiatry and residency was shaped by my early experience with the medical field and treatment. From the early days of my diagnosis at age 4, I was told that my brain was “wired differently” and that, because of this disruption in circuitry, I would have difficulty with physical activity. I grew to appreciate the intricacies of the brain and pathology to understand my body. With greater understanding came the existential realization that I would live with a disability for the rest of my life. Rather than dream of a future where I would be “normal,” I focused on adapting my life to my normal. An unfortunate reality of this normal was that no doctor would be able to relate to me, and my health care would focus on limitations rather than possibilities.

I focused on school as a distraction and slowly warmed to the idea of pursuing medicine as a career. The seed was planted years prior by the numerous doctors’ visits and procedures, and was cultivated by a desire to understand pathologies and offer treatment to patients from the perspective of a patient. When I applied to medical school, I did not know how to address my CP. Living as a person with CP was a core reason for my decision to pursue medicine, but I was afraid that a disclosure of disability would preclude any admission to medical school. Research into programs offered little guidance because most institutions only listed vague “physical expectations” of each student. There were times I doubted if I would be accepted anywhere. Many programs I reached out to about my situation seemed unenthusiastic about the prospect of a student with CP, and when I brought up my CP in interviews, the reaction was often of surprise and an admission that they had forgotten about “that part” of my application. Fortunately, I was accepted to medical school, but still struggled with the fear that one day I would be found out and not allowed to continue. No one in my class or school was like me, and a meeting with an Americans with Disabilities Act coordinator who asked me to reexamine the physical competencies of the school before advancing to clinical clerkships only further reinforced this fear. I decided to fly under the radar and not say anything about my disability to my attendings. I slowly worked my way through clerkships by making do with adapted ways to perform procedures and exams with additional practice and maneuvering at home. I found myself drawn to psychiatry because of the similarities I saw in the patients and myself. I empathized with how the patients struggled with chronic conditions that left them feeling separated from society and how they felt that their diagnosis was something they needed to hide. When medical school ended and I decided to pursue psychiatry, I wanted to share my story to inspire others with a disability to consider medicine as a career given their unique experiences. My experience thus far has been uplifting as my journey has echoed so many others.

A need for greater representation

Disability representation in medicine is needed more than ever. According to the CDC, >60 million adults in the United States (1 in 4) live with a disability.¹ Although the physical health disparities are often discussed, there is less conversation surrounding mental health for individuals with disabilities. A 2018 study by Cree et al² found that approximately 17.4 million adults with disabilities experienced frequent mental distress, defined as reporting ≥14 mentally unhealthy days in the past 30 days. Furthermore, compared to individuals without a disability, those with a disability are statistically more likely to have suicidal ideation, suicidal planning, and suicide attempts.³ One way to address this disparity is to recruit medical students with disabilities to become physicians with disabilities. Evidence suggests that physicians who are members of groups that are underrepresented in medicine are more likely to deliver care to underrepresented patients.⁴ However, medical schools and institutions have been slow to address the disparity. A 2019 survey found an estimated 4.6% of medical students responded “yes” when asked if they had a disability, with most students reporting a psychological or attention/hyperactive disorder.⁵ Existing barriers include restrictive language surrounding technical standards influenced by long-standing vestiges of what a physician should be.⁶

An opportunity to connect with patients

I now do not see myself as having a secret identity to hide. Although my CP does not give me any superpowers, it has given me the opportunity to connect with my patients and serve as an example of why medical school recruitment and admissions should expand. Psychiatrists have been on the forefront of change in medicine and can shift the perception of a physician. In doing so, we not only enrich our field but also the lives of our patients who may need it most.

What does a doctor look like? Throughout history, this concept has shifted due to societal norms and increased access to medical education. Today, the idea of a physician has expanded to incorporate a myriad of people; however, stigma still exists in medicine regarding mental illness and disability. I would like to share my personal journey through high school, college, medical school, and now residency, and how my identity and struggles have shaped me into the physician I am today. There are few conversations around disability—especially disability and mental health—in medicine, and through my own advocacy, I have met many students with disability who feel that medical school is unattainable. Additionally, I have met many medical students, residents, and pre-health advisors who are happy for the experience to learn more about a marginalized group in medicine. My hope in sharing my story is to offer a space for conversation about intersectionality within medical communities and how physicians and physicians in training can facilitate that change, regardless of their position or specialty. Additionally, I hope to shed light on the unique mental health needs of patients with disabilities and how mental health clinicians can address those needs.

Perceived weaknesses turned into strengths

“Why do you walk like that?” “What is that brace on your leg?” The early years of my childhood were marked by these questions and others like them. I was the kid with the limp, the kid with a brace on his leg, and the kid who disappeared multiple times a week for doctor’s appointments or physical therapy. I learned to deflect these questions or give nebulous answers about an accident or injury. The reality is that I was born with cerebral palsy (CP). My CP manifested as hemiparesis on the left side of my body. I was in aggressive physical therapy throughout childhood, received Botox injections for muscle spasticity, and underwent corrective surgery on my left leg to straighten my foot. In childhood, the diagnosis meant nothing more than 2 words that sounded like they belonged to superheroes in comic books. Even with supportive parents and family, I kept my disability a secret, much like the powers and abilities of my favorite superheroes.

However, like all great origin stories, what I once thought were weaknesses turned out to be strengths that pushed me through college, medical school, and now psychiatry residency. Living with a disability has shaped how I see the world and relate to my patients. My experience has helped me connect to my patients in ways others might not. These properties are important in any physician but vital in psychiatry, where many patients feel neglected or stigmatized; this is another reason there should be more doctors with disabilities in medicine. Unfortunately, systemic barriers are still in place that disincentivize those with a disability from pursuing careers in medicine. Stories like mine are important to inspire a reexamination of what a physician should be and how medicine, patients, and communities benefit from this change.

My experience through medical school

My path to psychiatry and residency was shaped by my early experience with the medical field and treatment. From the early days of my diagnosis at age 4, I was told that my brain was “wired differently” and that, because of this disruption in circuitry, I would have difficulty with physical activity. I grew to appreciate the intricacies of the brain and pathology to understand my body. With greater understanding came the existential realization that I would live with a disability for the rest of my life. Rather than dream of a future where I would be “normal,” I focused on adapting my life to my normal. An unfortunate reality of this normal was that no doctor would be able to relate to me, and my health care would focus on limitations rather than possibilities.

I focused on school as a distraction and slowly warmed to the idea of pursuing medicine as a career. The seed was planted years prior by the numerous doctors’ visits and procedures, and was cultivated by a desire to understand pathologies and offer treatment to patients from the perspective of a patient. When I applied to medical school, I did not know how to address my CP. Living as a person with CP was a core reason for my decision to pursue medicine, but I was afraid that a disclosure of disability would preclude any admission to medical school. Research into programs offered little guidance because most institutions only listed vague “physical expectations” of each student. There were times I doubted if I would be accepted anywhere. Many programs I reached out to about my situation seemed unenthusiastic about the prospect of a student with CP, and when I brought up my CP in interviews, the reaction was often of surprise and an admission that they had forgotten about “that part” of my application. Fortunately, I was accepted to medical school, but still struggled with the fear that one day I would be found out and not allowed to continue. No one in my class or school was like me, and a meeting with an Americans with Disabilities Act coordinator who asked me to reexamine the physical competencies of the school before advancing to clinical clerkships only further reinforced this fear. I decided to fly under the radar and not say anything about my disability to my attendings. I slowly worked my way through clerkships by making do with adapted ways to perform procedures and exams with additional practice and maneuvering at home. I found myself drawn to psychiatry because of the similarities I saw in the patients and myself. I empathized with how the patients struggled with chronic conditions that left them feeling separated from society and how they felt that their diagnosis was something they needed to hide. When medical school ended and I decided to pursue psychiatry, I wanted to share my story to inspire others with a disability to consider medicine as a career given their unique experiences. My experience thus far has been uplifting as my journey has echoed so many others.

A need for greater representation

Disability representation in medicine is needed more than ever. According to the CDC, >60 million adults in the United States (1 in 4) live with a disability.¹ Although the physical health disparities are often discussed, there is less conversation surrounding mental health for individuals with disabilities. A 2018 study by Cree et al² found that approximately 17.4 million adults with disabilities experienced frequent mental distress, defined as reporting ≥14 mentally unhealthy days in the past 30 days. Furthermore, compared to individuals without a disability, those with a disability are statistically more likely to have suicidal ideation, suicidal planning, and suicide attempts.³ One way to address this disparity is to recruit medical students with disabilities to become physicians with disabilities. Evidence suggests that physicians who are members of groups that are underrepresented in medicine are more likely to deliver care to underrepresented patients.⁴ However, medical schools and institutions have been slow to address the disparity. A 2019 survey found an estimated 4.6% of medical students responded “yes” when asked if they had a disability, with most students reporting a psychological or attention/hyperactive disorder.⁵ Existing barriers include restrictive language surrounding technical standards influenced by long-standing vestiges of what a physician should be.⁶

An opportunity to connect with patients

I now do not see myself as having a secret identity to hide. Although my CP does not give me any superpowers, it has given me the opportunity to connect with my patients and serve as an example of why medical school recruitment and admissions should expand. Psychiatrists have been on the forefront of change in medicine and can shift the perception of a physician. In doing so, we not only enrich our field but also the lives of our patients who may need it most.

Mr. R, age 29, was diagnosed with schizophrenia 6 years ago. To manage his disorder, he has been receiving paliperidone palmitate long-acting injectable (LAI) 156 mg once a month for 2 years. Prior to maintenance with paliperidone palmitate, Mr. R was stabilized on oral paliperidone 9 mg/d. Though he was originally initiated on paliperidone palmitate due to nonadherence concerns, Mr. R has been adherent with each injection for 1 year.

At a recent visit, Mr. R says he wants to discontinue the injection because he is not interested in receiving an ongoing injectable medication and is not able to continue monthly clinic visits. He wants to take a daily oral antipsychotic again, despite the availability of longer-acting products.

A paucity of evidence exists regarding the discontinuation of LAI antipsychotics and the next steps that follow in treatment. There is neither a consensus nor recognized guidelines advising how and when to discontinue an LAI and restart an oral antipsychotic. A recent systematic review and meta-analysis evaluated different maintenance treatment strategies; however, switching from an LAI antipsychotic to an oral medication was not a focus.¹ In this article, we outline a possible approach to discontinuing an LAI antipsychotic and restarting an oral formulation. Before discontinuing an LAI antipsychotic, clinicians should review with the patient the risks and benefits of switching medications, including the risk of decompensation and potential adverse effects.

Switching to an oral antipsychotic

The first step in the discontinuation process is to determine whether the patient will continue the same oral medication as the LAI antipsychotic or if a different oral antipsychotic will be initiated. Next, determining when to initiate the oral medication requires several pieces of information, including the oral dose equivalent of the patient’s current LAI, the half-life of the LAI, and the release mechanism of the LAI (Table 1).^2-5 To determine the appropriate time frame for restarting oral treatment, it is also vital to know the date of the last injection.

Based on the date of the next injection, the clinician will utilize the LAI’s half-life and its release mechanism to determine the appropriate time to start a new oral antipsychotic. Research demonstrates that in patients who have achieved steady state with a first-generation antipsychotic, plasma concentrations stay relatively consistent for 6 to 7 weeks after the last injection, which suggests oral medications may not need to be initiated until that time.^6-9

For many second-generation LAI antipsychotics, oral medications may be initiated at the date of the next injection. Initiation of an oral antipsychotic may require more time between the last injection dose and the date of administration for oral medication due to the pharmacokinetic profile of risperidone microspheres. Once a patient is at steady state with risperidone microspheres, trough levels are not observed until 3 to 4 weeks after discontinuation.¹⁰

Previous pharmacokinetic model–based stimulations of active moiety plasma concentrations of risperidone microspheres demonstrate that 2 weeks after an injection of risperidone microspheres, the concentration of active moiety continued to approximate the steady-state concentration for 3 to 5 weeks.¹¹ This is likely due to the product’s delay in release being 3 weeks from the time of injection to the last release phase. Of note, there was a rapid decline in the active moiety concentration; it reached nearly 0 by Week 5.¹¹ The same pharmacokinetic model–based stimulation demonstrated a steady and slow decline of the concentration of active moiety of paliperidone palmitate after discontinuation of the LAI.¹¹

Continue to: No guidance exists for...

No guidance exists for aripiprazole LAI medications; however, based on the pharmacokinetic data, administration of oral medications should be initiated at the date of next injection. Given the long half-life of aripiprazole, a cross-titration of the LAI with oral medication is reasonable.

Monitoring drug levels

In addition to utilizing the pharmacokinetic data from LAI antipsychotics, therapeutic drug levels can be instrumental in determining the dose of oral medication to use and when to begin titration (Table 2).^12-14 Obtaining a drug level on the date of the next injection can provide the clinician with data regarding the release of the medication specific to the patient. Based on the level and the current symptomatology, the clinician could choose to start the oral medication at a lower dose and titrate back to the LAI equivalent oral dose, or initiate the oral dose at the LAI equivalent oral dose. Continued therapeutic drug levels can aid in this determination.

No guidance exists on the appropriate discontinuation of LAI antipsychotics. Utilizing a medication’s half-life and release mechanism, as well as the patient’s previous medication history, date of last injection, and therapeutic drug levels, should be considered when determining the schedule for restarting an oral antipsychotic.

CASE CONTINUED

Based on the current dosing of paliperidone palmitate of 156 mg once a month, Mr. R likely requires 9 mg/d of oral paliperidone upon discontinuation of the LAI. On the date of the next injection, the clinician could decide to initiate a lower dose of paliperidone, such as to 3 mg/d or 6 mg/d, and increase the dose as tolerated over the next 10 to 14 days as the paliperidone palmitate is further metabolized. Additionally, the clinician may consider obtaining a therapeutic drug level to determine the current paliperidone level prior to initiating the oral medication. Each treatment option offers individual risks and benefits. The decision on when and how to initiate the oral medication will be based on the individual patient’s situation and history, as well as the comfort and discretion of the clinician. The clinician should arrange appropriate monitoring for potential increased symptomatology during the transition, and adverse effects should be assessed regularly until steady state is achieved with the targeted oral dose of medication.

Related Resources

• Parmentier BL. Second-generation long-acting injectable antipsychotics: a practical guide. Current Psychiatry. 2020;19(3):24-32.
• Thippaiah SM, Fargason RE, Birur B. Switching antipsychotics: a guide to dose equivalents. Current Psychiatry. 2021;20(4):13-14. doi:10.12788/cp.0103

Drug Brand Names

Aripiprazole lauroxil • Aristada
Aripiprazole monohydrate • Maintena
Haloperidol injection • Haldol decanoate
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone • Invega
Paliperidone palmitate once monthly • Invega Sustenna
Paliperidone palmitate every 3 months • Invega Trinza
Paliperidone palmitate every 6 months • Invega Hafyera
Risperidone microspheres • Risperdal Consta
Risperidone polymer • Perseris

Mr. R, age 29, was diagnosed with schizophrenia 6 years ago. To manage his disorder, he has been receiving paliperidone palmitate long-acting injectable (LAI) 156 mg once a month for 2 years. Prior to maintenance with paliperidone palmitate, Mr. R was stabilized on oral paliperidone 9 mg/d. Though he was originally initiated on paliperidone palmitate due to nonadherence concerns, Mr. R has been adherent with each injection for 1 year.

At a recent visit, Mr. R says he wants to discontinue the injection because he is not interested in receiving an ongoing injectable medication and is not able to continue monthly clinic visits. He wants to take a daily oral antipsychotic again, despite the availability of longer-acting products.

A paucity of evidence exists regarding the discontinuation of LAI antipsychotics and the next steps that follow in treatment. There is neither a consensus nor recognized guidelines advising how and when to discontinue an LAI and restart an oral antipsychotic. A recent systematic review and meta-analysis evaluated different maintenance treatment strategies; however, switching from an LAI antipsychotic to an oral medication was not a focus.¹ In this article, we outline a possible approach to discontinuing an LAI antipsychotic and restarting an oral formulation. Before discontinuing an LAI antipsychotic, clinicians should review with the patient the risks and benefits of switching medications, including the risk of decompensation and potential adverse effects.

Switching to an oral antipsychotic

The first step in the discontinuation process is to determine whether the patient will continue the same oral medication as the LAI antipsychotic or if a different oral antipsychotic will be initiated. Next, determining when to initiate the oral medication requires several pieces of information, including the oral dose equivalent of the patient’s current LAI, the half-life of the LAI, and the release mechanism of the LAI (Table 1).^2-5 To determine the appropriate time frame for restarting oral treatment, it is also vital to know the date of the last injection.

Based on the date of the next injection, the clinician will utilize the LAI’s half-life and its release mechanism to determine the appropriate time to start a new oral antipsychotic. Research demonstrates that in patients who have achieved steady state with a first-generation antipsychotic, plasma concentrations stay relatively consistent for 6 to 7 weeks after the last injection, which suggests oral medications may not need to be initiated until that time.^6-9

For many second-generation LAI antipsychotics, oral medications may be initiated at the date of the next injection. Initiation of an oral antipsychotic may require more time between the last injection dose and the date of administration for oral medication due to the pharmacokinetic profile of risperidone microspheres. Once a patient is at steady state with risperidone microspheres, trough levels are not observed until 3 to 4 weeks after discontinuation.¹⁰

Previous pharmacokinetic model–based stimulations of active moiety plasma concentrations of risperidone microspheres demonstrate that 2 weeks after an injection of risperidone microspheres, the concentration of active moiety continued to approximate the steady-state concentration for 3 to 5 weeks.¹¹ This is likely due to the product’s delay in release being 3 weeks from the time of injection to the last release phase. Of note, there was a rapid decline in the active moiety concentration; it reached nearly 0 by Week 5.¹¹ The same pharmacokinetic model–based stimulation demonstrated a steady and slow decline of the concentration of active moiety of paliperidone palmitate after discontinuation of the LAI.¹¹

Continue to: No guidance exists for...

No guidance exists for aripiprazole LAI medications; however, based on the pharmacokinetic data, administration of oral medications should be initiated at the date of next injection. Given the long half-life of aripiprazole, a cross-titration of the LAI with oral medication is reasonable.

Monitoring drug levels

In addition to utilizing the pharmacokinetic data from LAI antipsychotics, therapeutic drug levels can be instrumental in determining the dose of oral medication to use and when to begin titration (Table 2).^12-14 Obtaining a drug level on the date of the next injection can provide the clinician with data regarding the release of the medication specific to the patient. Based on the level and the current symptomatology, the clinician could choose to start the oral medication at a lower dose and titrate back to the LAI equivalent oral dose, or initiate the oral dose at the LAI equivalent oral dose. Continued therapeutic drug levels can aid in this determination.

No guidance exists on the appropriate discontinuation of LAI antipsychotics. Utilizing a medication’s half-life and release mechanism, as well as the patient’s previous medication history, date of last injection, and therapeutic drug levels, should be considered when determining the schedule for restarting an oral antipsychotic.

CASE CONTINUED

Based on the current dosing of paliperidone palmitate of 156 mg once a month, Mr. R likely requires 9 mg/d of oral paliperidone upon discontinuation of the LAI. On the date of the next injection, the clinician could decide to initiate a lower dose of paliperidone, such as to 3 mg/d or 6 mg/d, and increase the dose as tolerated over the next 10 to 14 days as the paliperidone palmitate is further metabolized. Additionally, the clinician may consider obtaining a therapeutic drug level to determine the current paliperidone level prior to initiating the oral medication. Each treatment option offers individual risks and benefits. The decision on when and how to initiate the oral medication will be based on the individual patient’s situation and history, as well as the comfort and discretion of the clinician. The clinician should arrange appropriate monitoring for potential increased symptomatology during the transition, and adverse effects should be assessed regularly until steady state is achieved with the targeted oral dose of medication.

Related Resources

• Parmentier BL. Second-generation long-acting injectable antipsychotics: a practical guide. Current Psychiatry. 2020;19(3):24-32.
• Thippaiah SM, Fargason RE, Birur B. Switching antipsychotics: a guide to dose equivalents. Current Psychiatry. 2021;20(4):13-14. doi:10.12788/cp.0103

Drug Brand Names

Aripiprazole lauroxil • Aristada
Aripiprazole monohydrate • Maintena
Haloperidol injection • Haldol decanoate
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone • Invega
Paliperidone palmitate once monthly • Invega Sustenna
Paliperidone palmitate every 3 months • Invega Trinza
Paliperidone palmitate every 6 months • Invega Hafyera
Risperidone microspheres • Risperdal Consta
Risperidone polymer • Perseris

Mr. R, age 29, was diagnosed with schizophrenia 6 years ago. To manage his disorder, he has been receiving paliperidone palmitate long-acting injectable (LAI) 156 mg once a month for 2 years. Prior to maintenance with paliperidone palmitate, Mr. R was stabilized on oral paliperidone 9 mg/d. Though he was originally initiated on paliperidone palmitate due to nonadherence concerns, Mr. R has been adherent with each injection for 1 year.

At a recent visit, Mr. R says he wants to discontinue the injection because he is not interested in receiving an ongoing injectable medication and is not able to continue monthly clinic visits. He wants to take a daily oral antipsychotic again, despite the availability of longer-acting products.

A paucity of evidence exists regarding the discontinuation of LAI antipsychotics and the next steps that follow in treatment. There is neither a consensus nor recognized guidelines advising how and when to discontinue an LAI and restart an oral antipsychotic. A recent systematic review and meta-analysis evaluated different maintenance treatment strategies; however, switching from an LAI antipsychotic to an oral medication was not a focus.¹ In this article, we outline a possible approach to discontinuing an LAI antipsychotic and restarting an oral formulation. Before discontinuing an LAI antipsychotic, clinicians should review with the patient the risks and benefits of switching medications, including the risk of decompensation and potential adverse effects.

Switching to an oral antipsychotic

The first step in the discontinuation process is to determine whether the patient will continue the same oral medication as the LAI antipsychotic or if a different oral antipsychotic will be initiated. Next, determining when to initiate the oral medication requires several pieces of information, including the oral dose equivalent of the patient’s current LAI, the half-life of the LAI, and the release mechanism of the LAI (Table 1).^2-5 To determine the appropriate time frame for restarting oral treatment, it is also vital to know the date of the last injection.

Based on the date of the next injection, the clinician will utilize the LAI’s half-life and its release mechanism to determine the appropriate time to start a new oral antipsychotic. Research demonstrates that in patients who have achieved steady state with a first-generation antipsychotic, plasma concentrations stay relatively consistent for 6 to 7 weeks after the last injection, which suggests oral medications may not need to be initiated until that time.^6-9

For many second-generation LAI antipsychotics, oral medications may be initiated at the date of the next injection. Initiation of an oral antipsychotic may require more time between the last injection dose and the date of administration for oral medication due to the pharmacokinetic profile of risperidone microspheres. Once a patient is at steady state with risperidone microspheres, trough levels are not observed until 3 to 4 weeks after discontinuation.¹⁰

Previous pharmacokinetic model–based stimulations of active moiety plasma concentrations of risperidone microspheres demonstrate that 2 weeks after an injection of risperidone microspheres, the concentration of active moiety continued to approximate the steady-state concentration for 3 to 5 weeks.¹¹ This is likely due to the product’s delay in release being 3 weeks from the time of injection to the last release phase. Of note, there was a rapid decline in the active moiety concentration; it reached nearly 0 by Week 5.¹¹ The same pharmacokinetic model–based stimulation demonstrated a steady and slow decline of the concentration of active moiety of paliperidone palmitate after discontinuation of the LAI.¹¹

Continue to: No guidance exists for...

No guidance exists for aripiprazole LAI medications; however, based on the pharmacokinetic data, administration of oral medications should be initiated at the date of next injection. Given the long half-life of aripiprazole, a cross-titration of the LAI with oral medication is reasonable.

Monitoring drug levels

In addition to utilizing the pharmacokinetic data from LAI antipsychotics, therapeutic drug levels can be instrumental in determining the dose of oral medication to use and when to begin titration (Table 2).^12-14 Obtaining a drug level on the date of the next injection can provide the clinician with data regarding the release of the medication specific to the patient. Based on the level and the current symptomatology, the clinician could choose to start the oral medication at a lower dose and titrate back to the LAI equivalent oral dose, or initiate the oral dose at the LAI equivalent oral dose. Continued therapeutic drug levels can aid in this determination.

No guidance exists on the appropriate discontinuation of LAI antipsychotics. Utilizing a medication’s half-life and release mechanism, as well as the patient’s previous medication history, date of last injection, and therapeutic drug levels, should be considered when determining the schedule for restarting an oral antipsychotic.

CASE CONTINUED

Based on the current dosing of paliperidone palmitate of 156 mg once a month, Mr. R likely requires 9 mg/d of oral paliperidone upon discontinuation of the LAI. On the date of the next injection, the clinician could decide to initiate a lower dose of paliperidone, such as to 3 mg/d or 6 mg/d, and increase the dose as tolerated over the next 10 to 14 days as the paliperidone palmitate is further metabolized. Additionally, the clinician may consider obtaining a therapeutic drug level to determine the current paliperidone level prior to initiating the oral medication. Each treatment option offers individual risks and benefits. The decision on when and how to initiate the oral medication will be based on the individual patient’s situation and history, as well as the comfort and discretion of the clinician. The clinician should arrange appropriate monitoring for potential increased symptomatology during the transition, and adverse effects should be assessed regularly until steady state is achieved with the targeted oral dose of medication.

Related Resources

• Parmentier BL. Second-generation long-acting injectable antipsychotics: a practical guide. Current Psychiatry. 2020;19(3):24-32.
• Thippaiah SM, Fargason RE, Birur B. Switching antipsychotics: a guide to dose equivalents. Current Psychiatry. 2021;20(4):13-14. doi:10.12788/cp.0103

Drug Brand Names

Aripiprazole lauroxil • Aristada
Aripiprazole monohydrate • Maintena
Haloperidol injection • Haldol decanoate
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone • Invega
Paliperidone palmitate once monthly • Invega Sustenna
Paliperidone palmitate every 3 months • Invega Trinza
Paliperidone palmitate every 6 months • Invega Hafyera
Risperidone microspheres • Risperdal Consta
Risperidone polymer • Perseris